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Thông tư 35/2018/TT-BYT quy định về Thực hành tốt sản xuất thuốc nguyên liệu làm thuốc

Số hiệu: 35/2018/TT-BYT Loại văn bản: Thông tư
Nơi ban hành: Bộ Y tế Người ký: Trương Quốc Cường
Ngày ban hành: 22/11/2018 Ngày hiệu lực: Đã biết
Ngày công báo: Đã biết Số công báo: Đã biết
Tình trạng: Đã biết

BỘ Y TẾ
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CỘNG HÒA XÃ HỘI CHỦ NGHĨA VIỆT NAM
Độc lập - Tự do - Hạnh phúc
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Số: 35/2018/TT-BYT

Hà Nội, ngày 22 tháng 11 năm 2018

 

THÔNG TƯ

QUY ĐỊNH VỀ THỰC HÀNH TỐT SẢN XUẤT THUỐC, NGUYÊN LIỆU LÀM THUỐC

Căn cứ Luật số 105/2016/QH13 ngày 06 tháng 4 năm 2016 về dược;

Căn cứ Nghị định số 54/2017/NĐ-CP ngày 08 tháng 5 năm 2017 của Chính phủ quy định chi tiết một số điều và biện pháp thi hành Luật Dược;

Căn cứ Nghị định số 155/2018/NĐ-CP ngày 12 tháng 11 năm 2018 của Chính phủ sửa đổi, bổ sung một số quy định liên quan đến điều kiện đầu tư kinh doanh thuộc phạm vi quản lý nhà nước của Bộ Y tế;

Căn cứ Nghị định số 75/2017/NĐ-CP ngày 20 tháng 6 năm 2017 của Chính phủ quy định chức năng, nhiệm vụ, quyền hạn và cơ cấu tổ chức của Bộ Y tế;

Theo đề nghị của Cục trưởng Cục Quản lý Dược, Cục trưởng Cục Quản lý Y, Dược cổ truyền,

Bộ trưởng Bộ Y tế ban hành Thông tư quy định về Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc.

Chương I

QUY ĐỊNH CHUNG

Điều 1. Phạm vi điều chỉnh

Thông tư này quy định việc công bố áp dụng, ban hành và đánh giá việc đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc.

Điều 2. Giải thích từ ngữ

Trong Thông tư này, các từ ngữ dưới đây được hiểu như sau:

1. Thực hành tốt sản xuất thuốc là bộ nguyên tắc, tiêu chuẩn về sản xuất thuốc, nguyên liệu làm thuốc nhằm bảo đảm thuốc, nguyên liệu làm thuốc luôn được sản xuất và kiểm tra một cách nhất quán theo các tiêu chuẩn chất lượng phù hợp với mục đích sử dụng và yêu cầu của giấy đăng ký lưu hành thuốc, nguyên liệu làm thuốc.

2. Cơ sở sản xuất (bao gồm cơ sở sản xuất thuốc hóa dược, thuốc dược liệu, vắc xin, sinh phẩm, thuốc cổ truyền, vị thuốc cổ truyền, nguyên liệu làm thuốc) là cơ sở có hoạt động dược thuộc diện cấp hoặc không thuộc diện cấp Giấy chứng nhận đủ điều kiện kinh doanh dược có phạm vi thực hiện một, một số hoặc toàn bộ các công đoạn của quá trình sản xuất thuốc, nguyên liệu làm thuốc.

3. Tồn tại là sai lệch so với nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc (GMP) hoặc với quy định pháp luật hiện hành về quản lý dược.

4. GMP là chữ viết tắt của cụm từ tiếng Anh “Good Manufacturing Practices”, được dịch sang tiếng Việt là “Thực hành tốt sản xuất”.

5. WHO là chữ viết tắt của cụm từ tiếng Anh “World Health Organization”, được dịch sang tiếng Việt là “Tổ chức Y tế thế giới”.

6. WHO - GMP là chữ viết tắt của “Thực hành tốt sản xuất của Tổ chức Y tế thế gii”.

7. PIC/S là chữ viết tắt của cụm từ tiếng Anh “Pharmaceutical Inspection Co-operation Scheme”, được dịch sang tiếng Việt là “Hệ thống hợp tác thanh tra dược phẩm”.

8. PIC/S - GMP là chữ viết tắt của “Thực hành tốt sản xuất của Hệ thống hợp tác thanh tra dược phẩm”.

9. EU là chữ viết tắt của từ tiếng Anh “European Union”, được dịch sang tiếng Việt là “Liên minh Châu Âu”.

10. EU - GMP là chữ viết tắt của “Thực hành tốt sản xuất của Liên minh Châu Âu”.

11. USchữ viết tắt của từ tiếng Anh “United States”, được dịch sang tiếng Việt là “Hoa Kỳ”

12. SRA là chữ viết tắt của từ tiếng Anh “Stringent Regulatory Agency”, được dịch sang tiếng Việt là “Cơ quan quản lý dược nghiêm ngặt” theo định nghĩa của WHO.

Chương II

CÔNG BỐ ÁP DỤNG, BAN HÀNH THỰC HÀNH TỐT SẢN XUẤT THUỐC, NGUYÊN LIỆU LÀM THUỐC

Điều 3. Tài liệu về nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Công bố áp dụng các nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc sau đây:

a) Nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc của Tổ chức Y tế thế giới quy định tại Phụ lục I ban hành kèm theo Thông tư này và tài liệu cập nhật được quy định tại khoản 3 Điều này;

b) Nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc sinh học là dẫn xuất của máu và huyết tương người của Tổ chức Y tế thế giới quy định tại Phụ lục II ban hành kèm theo Thông tư này và tài liệu cập nhật được quy định tại khoản 3 Điều này;

c) Nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc của Hệ thống hợp tác thanh tra dược phẩm quy định tại Phụ lục III ban hành kèm theo Thông tư này và tài liệu cập nhật được quy định tại khoản 3 Điều này;

d) Nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc của Liên minh Châu Âu quy định tại Phụ lục IV ban hành kèm theo Thông tư này và tài liệu cập nhật được quy định tại khoản 3 Điều này.

2. Ban hành các nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc sau đây:

a) Nguyên tc, tiêu chuẩn Thực hành tốt sản xuất thuốc dược liệu quy định tại Phụ lục V ban hành kèm theo Thông tư này;

b) Nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc cổ truyền quy định tại Phụ lục VI ban hành kèm theo Thông tư này;

c) Nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất vị thuốc cổ truyền quy định tại Phụ lục VII ban hành kèm theo Thông tư này.

3. Ngoài các nguyên tắc, tiêu chuẩn GMP quy định tại khoản 1, khoản 2 Điều này, các nguyên tắc, tiêu chuẩn GMP khác tương đương với nguyên tắc, tiêu chuẩn EU - GMP do cơ quan quản lý dược các nước SRA ban hành được phép áp dụng. Cơ sở sản xuất thuốc, nguyên liệu làm thuốc triển khai áp dụng có trách nhiệm dịch, xác nhận bản dịch theo quy định của pháp luật về công chứng, chứng thực gửi Cục Quản lý Dược để đăng tải trên Cổng thông tin điện tử của Bộ Y tế và Trang thông tin điện tử của Cục Quản lý Dược.

4. Trường hợp Tổ chức Y tế thế giới, Hệ thống hợp tác thanh tra dược phẩm, Liên minh Châu Âu, cơ quan quản lý dược các nước SRA có sửa đổi, bổ sung nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc (sau đây gọi là tài liệu cập nhật) quy định tại khoản 1 Điều này, trong thời hạn 06 tháng, kể từ ngày các tài liệu cập nhật được công bố trên Cổng thông tin điện tử của các cơ quan này, Cục Quản lý Dược tổ chức dịch và công bố nội dung sửa đổi, bổ sung trên Cổng thông tin điện tử của Bộ Y tế và Trang thông tin điện tử của Cục Quản lý Dược, Cục Quản lý Y Dược cổ truyền để các đối tượng có liên quan tra cứu, cập nhật và áp dụng.

Điều 4. Áp dụng nguyên tắc, tiêu chuẩn Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Cơ sở sản xuất thuốc, nguyên liệu làm thuốc triển khai áp dụng GMP quy định tại Phụ lục I hoặc Phụ lục III hoặc Phụ lục IV ban hành kèm theo Thông tư này và tài liệu cập nhật theo quy định tại khoản 4 Điều 3 Thông tư này.

2. Cơ sở sản xuất thuốc sinh học là dẫn xuất của máu và huyết tương người triển khai áp dụng GMP quy định tại Phụ lục II ban hành kèm theo Thông tư này và tài liệu cập nhật theo quy định tại khoản 4 Điều 3 Thông tư này.

3. Cơ sở sản xuất thuốc dược liệu triển khai áp dụng GMP quy định tại Phụ lục V ban hành kèm theo Thông tư này.

4. Cơ sở sản xuất thuốc cổ truyền chỉ sản xuất thuốc cổ truyền có dạng bào chế cao, đơn, hoàn tán triển khai áp dụng GMP quy định tại Phần I - Phụ lục VI ban hành kèm theo Thông tư này.

5. Cơ sở sản xuất thuốc cổ truyền dưới dạng bào chế hiện đại (thuốc viên nang, viên nén, thuốc cốm, thuốc nước và các dạng bào chế hiện đại khác) không thuộc trường hợp quy định tại khoản 4 Điều này triển khai áp dụng GMP quy định tại Phần II - Phụ lục VI ban hành kèm theo Thông tư này.

6. Cơ sở sản xuất vị thuốc cổ truyền triển khai áp dụng GMP quy định tại Phụ lục VII ban hành kèm theo Thông tư này.

7. Cơ sở sản xuất thuốc, nguyên liệu làm thuốc được triển khai áp dụng nguyên tắc, tiêu chuẩn GMP khác, tương đương với nguyên tắc tiêu chuẩn EU - GMP, do Cơ quan quản lý dược các nước SRA ban hành và tài liệu cập nhật quy định tại khoản 4 Điều 3 Thông tư này.

8. Cơ sở sản xuất thuốc dược liệu, thuốc cổ truyền, vị thuốc cổ truyền được triển khai áp dụng nguyên tắc, tiêu chuẩn GMP quy định tại Phụ lục I hoặc Phụ lục III hoặc Phụ lục IV ban hành kèm theo Thông tư này và tài liệu cập nhật theo quy định tại khoản 4 Điều 3 Thông tư này.

9. Cơ sở sản xuất thuốc cổ truyền, vị thuốc cổ truyền được phép triển khai áp dụng nguyên tắc, tiêu chuẩn GMP quy định tại Phần II Phụ lục VI hoặc Phụ lục I hoặc Phụ lục III hoặc Phụ lục IV ban hành kèm theo Thông tư này và tài liệu cập nhật theo quy định tại khoản 4 Điều 3 Thông tư này.

10. Thuốc và nguyên liệu làm thuốc chứa kháng sinh nhóm betalactam (Penicillins, Cephalosporins, Penems và tương tự), thuốc độc tế bào/thuốc kìm tế bào, thuốc chứa hormone sinh dục thuộc nhóm có tác dụng tránh thai, vắc xin, sinh phẩm và các thuốc có yêu cầu sản xuất riêng biệt theo quy định tại nguyên tắc, tiêu chuẩn GMP, ngoài yêu cầu được sản xuất tại cơ sở sản xuất triển khai áp dụng GMP tương ứng quy định tại Điều này, phải bảo đảm được sản xuất tại nhà xưởng, trang thiết bị sản xuất riêng biệt và có biện pháp phòng tránh phát tán, gây nhiễm môi trường và sản phẩm thuốc khác sản xuất tại cùng khu vực.

11. Cơ sở sản xuất thuốc hóa dược dưới dạng bào chế thuốc viên nang mềm, thuốc nước uống, thuốc dùng ngoài (thuốc kem, thuốc gel, thuốc mỡ và thuốc nước dùng ngoài) được sản xuất thuốc dược liệu từ dịch chiết dược liệu, cao, cốm dược liệu đã được tiêu chuẩn hóa trên dây chuyền sản xuất có dạng bào chế tương ứng và phải triển khai áp dụng GMP quy định tại Phụ lục I hoặc Phụ lục III hoặc Phụ lục IV ban hành kèm theo Thông tư này và tài liệu cập nhật theo quy định tại khoản 4 Điều 3 Thông tư này

12. Cơ sở sản xuất thuốc dược liệu được sản xuất thuốc dược liệu có bổ sung thêm thành phần tinh khiết chiết xuất từ tinh dầu, tinh dầu, vitamin và khoáng chất và phải triển khai áp dụng GMP quy định tại Phụ lục V ban hành kèm theo Thông tư này.

13. Cơ sở sản xuất thuốc cổ truyền được sản xuất thuốc c truyền có bổ sung thêm thành phần tinh khiết chiết xuất từ tinh dầu, tinh dầu, vitamin và khoáng chất và phải triển khai áp dụng GMP quy định tại Phụ lục VI ban hành kèm theo Thông tư này.

14. Cơ sở sản xuất thực hiện một hoặc một số công đoạn của quá trình sản xuất thuốc, nguyên liệu làm thuốc triển khai áp dụng và đáp ứng GMP theo các nội dung yêu cầu tương ứng phù hợp với công đoạn sản xuất thuốc, nguyên liệu làm thuốc quy định tại các khoản 1, 2, 3, 4 và 5 Điều này.

15. Cơ sở sản xuất thuốc, nguyên liệu làm thuốc triển khai áp dụng tài liệu GMP cập nhật quy định tại khoản 3 Điều 3 Thông tư này trong thời hạn:

a) 12 tháng đối với trường hợp có yêu cầu thay đổi về nhà xưởng, thiết bị sản xuất, tính từ thời điểm tài liệu cập nhật được công bố trên Cổng thông tin điện tử của Bộ Y tế và Trang thông tin điện tử của Cục Quản lý Dược;

b) 06 tháng đối với các cập nhật không thuộc điểm a khoản này, tính từ thời điểm tài liệu cập nhật được công bố trên Cổng thông tin điện tử của Bộ Y tế và Trang thông tin điện tử của Cục Quản lý Dược.

Chương III

ĐÁNH GIÁ VIỆC ĐÁP ỨNG THỰC HÀNH TỐT SẢN XUẤT THUỐC, NGUYÊN LIỆU LÀM THUỐC

Điều 5. Hồ sơ làm căn cứ để đánh giá đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Hồ sơ làm căn cứ để đánh giá đáp ứng GMP đối với cơ sở kinh doanh dược là Hồ sơ đề nghị cấp Giấy chứng nhận đ điều kiện kinh doanh dược (được nộp khi đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược, cơ sở sản xuất không phải nộp thêm hồ sơ để đánh giá đáp ứng GMP) theo quy định tại Điều 38 của Luật dượcĐiều 32 Nghị định số 54/2017/NĐ-CP ngày 08 tháng 5 năm 2017 của Chính phủ quy định chi tiết một số điều và biện pháp thi hành Luật dược (sau đây được gọi tắt là Nghị định số 54/2017/NĐ-CP). Đối với cơ sở sản xuất thuốc phải kiểm soát đặc biệt, thực hiện theo quy định tại Điều 38 của Luật dượckhoản 31 Điều 5 Nghị định số 155/2018/NĐ-CP ngày 12 tháng 11 năm 2018 của Chính phủ sửa đổi, bổ sung một số quy định liên quan đến điều kiện đầu tư kinh doanh thuộc phạm vi quản lý nhà nước của Bộ Y tế (sau đây được gọi tắt là Nghị định số 155/2018/NĐ-CP).

Tài liệu kỹ thuật về cơ sở sản xuất phải được trình bày theo hướng dẫn về hồ sơ tổng thể của cơ sở sản xuất quy định tại Phụ lục VIII ban hành kèm theo Thông tư này hoặc hồ sơ tổng thể được cập nhật trong trường hợp bổ sung phạm vi hoạt động.

2. Trường hợp cơ sở sản xuất đề nghị cấp Giấy chứng nhận GMP cùng với Giấy chứng nhận đủ điều kiện kinh doanh dược, cơ sở sản xuất phải ghi rõ nội dung này và loại tài liệu nguyên tc, tiêu chuẩn GMP áp dụng tại cơ sở trong Đơn đề nghị cấp Giấy chứng nhận đ điều kiện kinh doanh dược.

3. Trường hợp cơ sở sản xuất đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược có bán thuốc, nguyên liệu làm thuốc do cơ sở sản xuất cho cơ sở bán buôn, bán lẻ, cơ sở khám bệnh, chữa bệnh nếu đề nghị cấp Giấy chứng nhận đáp ứng Thực hành tốt phân phối thuốc, nguyên liệu làm thuốc (GDP) cùng với Giấy chứng nhận đủ điều kiện kinh doanh dược trong Đơn đề nghị và nộp thêm tài liệu chuyên môn kỹ thuật và nhân sự theo quy định tại khoản 2 Điều 32 Nghị định số 54/2017/NĐ-CP, Cơ quan tiếp nhận thực hiện đánh giá đồng thời việc đáp ứng Thực hành tốt phân phối thuốc, nguyên liệu làm thuốc (GDP) khi đánh giá việc đáp ứng GMP của cơ sở theo các quy định của pháp luật có liên quan về Thực hành tốt phân phối thuốc, nguyên liệu làm thuốc.

Điều 6. Trình tự đánh giá việc đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Tiếp nhận hồ sơ:

Cơ sở sản xuất nộp 01 (một) bộ hồ sơ theo quy định tại Điều 5 Thông tư này kèm phí thẩm định theo quy định của Bộ trưởng Bộ Tài chính về phí thẩm định tiêu chuẩn và điều kiện sản xuất đến cơ quan tiếp nhận của Bộ Y tế như sau:

a) Cục Quản lý Y, Dược cổ truyền đối với cơ sở sản xuất đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược với phạm vi chỉ sản xuất dược liệu, thuốc cổ truyền, vị thuốc cổ truyền tại thời điểm nộp hồ sơ đề nghị;

b) Cục Quản lý Dược đối với cơ sở sản xuất đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược với phạm vi sản xuất nguyên liệu làm thuốc (không bao gồm dược liệu), thuốc hóa dược, thuốc dược liệu, vắc xin, sinh phẩm;

c) Cục Quản lý Dược đối với cơ sở sản xuất đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược với phạm vi đồng thời sản xuất một trong các thuốc, nguyên liệu làm thuốc quy định tại điểm a khoản này và một trong các thuốc, nguyên liệu làm thuốc được quy định tại điểm b khoản này tại thời điểm nộp hồ sơ đề nghị.

2. Trình tự tiếp nhận và thẩm định hồ sơ:

Thực hiện theo quy định tại khoản 2 và khoản 5 Điều 33 Nghị định số 54/2017/NĐ-CPkhoản 12 Điều 5 Nghị định số 155/2018/NĐ-CP.

3. Trong thời hạn 05 ngày, kể từ ngày nhận được hồ sơ hợp lệ, Cơ quan tiếp nhận thành lập Đoàn đánh giá và gửi cho cơ sở sản xuất quyết định thành lập Đoàn đánh giá trong đó có dự kiến thời gian đánh giá thực tế tại cơ sở sản xuất.

Trong thời hạn 15 ngày, kể từ ngày có quyết định thành lập, Đoàn đánh giá tiến hành đánh giá thực tế tại cơ sở sản xuất.

Điều 7. Quy trình đánh giá việc đáp ứng và phân loại đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Nguyên tắc sử dụng tài liệu GMP trong đánh giá việc đáp ứng GMP:

a) Tài liệu nguyên tắc, tiêu chuẩn GMP được cơ sở sản xuất công bố áp dụng và ghi trên Đơn đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược.

b) Tài liệu nguyên tắc, tiêu chuẩn EU - GMP hoặc PIC/S - GMP hoặc tài liệu GMP quy định tại khoản 3 Điều 3 Thông tư này đối với trường hợp cơ sở sản xuất đã được cơ quan quản lý dược SRA đánh giá, chứng nhận đáp ứng GMP và đề nghị công bố cơ sở đáp ứng tiêu chuẩn GMP này.

c) Tài liệu nguyên tắc, tiêu chuẩn WHO - GMP hoặc tài liệu GMP được quy định tại các khoản 2, 3, 4, 5, và 6 Điều 4 Thông tư này tương ứng với hoạt động sản xuất đối với trường hợp cơ sở sản xuất không ghi rõ nguyên tắc, tiêu chuẩn GMP áp dụng trong Đơn đề nghị cấp giấy chứng nhận đủ điều kiện kinh doanh dược.

2. Quy trình đánh giá:

a) Bước 1. Đoàn đánh giá công bố Quyết định thành lập Đoàn đánh giá, mục đích, nội dung và kế hoạch đánh giá tại cơ sở sản xuất;

b) Bước 2. Cơ sở sản xuất trình bày tóm tắt về tổ chức, nhân sự và hoạt động triển khai, áp dụng GMP hoặc nội dung cụ thể theo nội dung của đợt đánh giá;

c) Bước 3. Đoàn đánh giá tiến hành đánh giá thực tế việc triển khai áp dụng GMP tại cơ sở sản xuất theo từng nội dung cụ thể. Trường hợp cơ sở thực hiện một hoặc một số công đoạn của quá trình sản xuất thì nội dung đánh giá chỉ bao gồm các yêu cầu tương ứng với một hoặc một số công đoạn sản xuất mà cơ sở thực hiện;

d) Bước 4. Đoàn đánh giá họp với cơ sở sản xuất để thông báo về tồn tại phát hiện trong quá trình đánh giá (nếu có); đánh giá mức độ của từng tồn tại; thảo luận với cơ sở sản xuất trong trường hợp cơ sở sản xuất không thống nhất với đánh giá của Đoàn đánh giá đối với từng tồn tại hoặc về mức độ đáp ứng nguyên tắc, tiêu chuẩn GMP của cơ sở sản xuất;

đ) Bước 5. Lập và ký biên bản đánh giá:

Ngay sau khi hoàn thành việc đánh giá thực tế tại cơ sở sản xuất, Đoàn đánh giá lập biên bản đánh giá theo Mẫu số 03 quy định tại Phụ lục X ban hành kèm theo Thông tư này. Biên bản đánh giá phải thể hiện thành phần Đoàn đánh giá, thành phần của cơ sở sản xuất, địa điểm, thời gian, phạm vi đánh giá, vấn đề chưa thống nhất giữa Đoàn đánh giá và cơ sở sản xuất (nếu có). Lãnh đạo cơ sở sản xuất và Trưởng Đoàn đánh giá ký xác nhận vào biên bản đánh giá. Biên bản được làm thành 03 bản: 01 bản lưu tại cơ sở sản xuất, 02 bản lưu tại Cơ quan tiếp nhận.

e) Bước 6. Hoàn thiện Báo cáo đánh giá:

Đoàn đánh giá có trách nhiệm lập báo cáo đánh giá GMP theo Mẫu số 04 quy định tại Phụ lục X ban hành kèm theo Thông tư này, liệt kê và phân tích, phân loại mức độ tồn tại mà cơ sở sản xuất cần khắc phục, sửa chữa; tham chiếu điều khoản quy định tương ứng của văn bản pháp luật và nguyên tắc, tiêu chuẩn GMP, đánh giá mức độ tuân thủ GMP của cơ sở sản xuất. Việc phân loại mức độ tồn tại và đánh giá mức độ tuân thủ GMP của cơ sở sản xuất (cụ thể theo từng dây chuyền sản xuất) quy định tại Phụ lục IX ban hành kèm theo Thông tư này.

3. Mức độ tuân thủ GMP:

Mức độ tuân thủ GMP của cơ sở sản xuất quy định tại Phụ lục IX ban hành kèm theo Thông tư này, gồm các mức độ sau đây:

a) Cơ sở sản xuất tuân thủ GMP ở mức độ 1;

b) Cơ sở sản xuất tuân thủ GMP ở mức độ 2;

c) Cơ sở sản xuất tuân thủ GMP ở mức độ 3;

d) Cơ sở sản xuất tuân thủ GMP ở mức độ 4.

Điều 8. Xử lý kết quả đánh giá đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Trường hợp báo cáo đánh giá GMP kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 1 theo quy định tại điểm a khoản 3 Điều 7 Thông tư này:

Trong thời hạn 10 ngày làm việc, kể từ ngày ký biên bản đánh giá, Cơ quan tiếp nhận trình Bộ trưởng Bộ Y tế cấp Giấy chứng nhận đủ điều kiện kinh doanh dược và thực hiện cấp Giấy chứng nhận GMP theo Mẫu số 05 quy định tại Phụ lục X ban hành kèm theo Thông tư này nếu cơ sở sản xuất đã có đề nghị trong Đơn đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược.

2. Trường hợp báo cáo đánh giá GMP kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 2 theo quy định tại điểm b khoản 3 Điều 7 Thông tư này:

a) Trong thời hạn 05 ngày làm việc, kể từ ngày ký biên bản đánh giá, Cơ quan tiếp nhận gửi báo cáo đánh giá GMP cho cơ sở sản xuất theo quy định tại điểm b khoản 6 Điều 33 Nghị định số 54/2017/NĐ-CP.

b) Sau khi hoàn thành việc khắc phục, sửa chữa, cơ sở sản xuất phải có văn bản báo cáo khắc phục bao gồm kế hoạch và bằng chứng chứng minh (hồ sơ tài liệu, hình ảnh, video, giấy chứng nhận hoặc các tài liệu chứng minh khác) việc khắc phục, sửa chữa tồn tại được ghi trong báo cáo đánh giá GMP.

c) Trong thời hạn 20 ngày, kể từ ngày nhận được văn bản báo cáo khắc phục, Cơ quan tiếp nhận đánh giá kết quả khắc phục của cơ sở sản xuất và kết luận về tình trạng đáp ứng GMP của cơ sở sản xuất:

- Trường hợp việc khắc phục của cơ sở sản xuất đã đáp ứng yêu cầu: Cơ quan tiếp nhận trình Bộ trưởng Bộ Y tế cấp Giấy chứng nhận đủ điều kiện kinh doanh dược và thực hiện cấp Giấy chứng nhận GMP theo Mẫu số 05 quy định tại Phụ lục X ban hành kèm theo Thông tư này nếu cơ sở sản xuất đã có đề nghị trong Đơn đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược;

- Trường hợp việc khắc phục của cơ sở sản xuất chưa đáp ứng yêu cầu: Cơ quan tiếp nhận có văn bản thông báo cho cơ sở và nêu rõ lý do.

d) Trong thời hạn 06 tháng, kể từ ngày Cơ quan tiếp nhận gửi Báo cáo đánh giá có nội dung yêu cầu sửa đổi, bổ sung, cơ sở sản xuất phải nộp hồ sơ sửa đổi, bổ sung. Sau thời hạn trên, cơ sở sản xuất không sửa đổi, bổ sung hoặc sau 12 tháng kể từ ngày nộp hồ sơ đề nghị lần đầu mà hồ sơ sửa đổi, bổ sung không đáp ứng yêu cầu thì hồ sơ đề nghị đã nộp không còn giá trị.

3. Trường hợp báo cáo đánh giá GMP kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 3 theo quy định tại điểm c khoản 3 Điều 7 Thông tư này:

Trình tự, thời gian xử lý kết quả đánh giá đáp ứng GMP theo quy định tại khoản 2 Điều này.

Trong thời hạn 20 ngày, kể từ ngày nhận được văn bản báo cáo khắc phục, Cơ quan tiếp nhận tiến hành đánh giá thực tế việc khắc phục tại cơ sở sản xuất trước khi kết luận tình trạng đáp ứng GMP của cơ sở sản xuất theo quy định tại điểm c khoản 2 Điều này.

4. Trường hợp báo cáo đánh giá GMP kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 4 theo quy định tại điểm d khoản 3 Điều 7 Thông tư này:

Trong thời hạn 05 ngày làm việc, kể từ ngày ký biên bản đánh giá, Cơ quan tiếp nhận ban hành văn bản thông báo về việc không đáp ứng GMP kèm theo báo cáo đánh giá GMP cho cơ sở sản xuất và không cấp Giấy chứng nhận đủ điều kiện kinh doanh dược.

5. Trường hợp cơ sở sản xuất có ý kiến không thống nhất với tồn tại theo đánh giá của Đoàn đánh giá, trong thời hạn 30 ngày, kể từ ngày Đoàn đánh giá có báo cáo đánh giá GMP hoặc báo cáo đánh giá hành động khắc phục, cơ sở sản xuất có văn bản kiến nghị gửi Cơ quan tiếp nhận kèm theo bằng chứng (hồ sơ tài liệu, hình ảnh, video, giấy chứng nhận) chng minh liên quan đến tồn tại đó.

Trong thời hạn 10 ngày làm việc, kể từ ngày nhận được văn bản kiến nghị của cơ sở sản xuất, Cơ quan tiếp nhận tổ chức rà soát báo cáo đánh giá GMP, nội dung kiến nghị của cơ sở sản xuất, nếu cần thiết, lấy ý kiến tư vấn chuyên gia trong lĩnh vực có liên quan và có văn bản trả lời cơ sở sản xuất. Văn bản trả lời phải nêu rõ nội dung chấp thuận, không chấp thuận đối với nội dung kiến nghị của cơ sở sản xuất, lý do không chấp thuận. Thời gian này không tính vào thời hạn đánh giá.

6. Trong thời gian 05 ngày làm việc, kể từ ngày cấp Giấy chứng nhận đủ điều kiện kinh doanh dược, Cơ quan tiếp nhận công bố trên Cổng Thông tin điện tử của Bộ Y tế và Trang Thông tin điện tử của cơ quan tiếp nhận các thông tin sau đây:

a) Tên và địa chỉ cơ sở sản xuất;

b) Họ tên người chịu trách nhiệm chuyên môn về dược, người phụ trách về bảo đảm chất lượng và số Chứng chỉ hành nghề dược;

c) Số Giấy chứng nhận đủ điều kiện kinh doanh dược và số Giấy chứng nhận GMP (nếu có);

d) Thời hạn hết hiệu lực của việc đánh giá đáp ứng GMP;

đ) Phạm vi hoạt động ca cơ sở sản xuất.

e) Số Giấy chứng nhận EU - GMP, thời hạn hiệu lực và cơ quan cấp Giấy chứng nhận đối với cơ sở sản xuất đã được cơ quan quản lý dược SRA đánh giá đáp ứng EU - GMP hoặc tương đương.

Chương IV

ĐÁNH GIÁ VIỆC DUY TRÌ ĐÁP ỨNG THỰC HÀNH TỐT SẢN XUẤT THUỐC, NGUYÊN LIỆU LÀM THUỐC

Điều 9. Đánh giá định kỳ việc duy trì đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Thời gian định kỳ đánh giá việc duy trì đáp ứng GMP tại cơ sở sản xuất là 03 năm, kể từ ngày ký biên bản đánh giá lần đánh giá liền trước (không bao gồm các lần đánh giá đột xuất, thanh tra, kiểm tra của Bộ Y tế, Sở Y tế).

2. Tháng 11 hằng năm, Cơ quan tiếp nhận công bố trên Trang Thông tin điện tử của Cơ quan tiếp nhận về kế hoạch đánh giá định kỳ việc duy trì đáp ứng GMP của các cơ sở sản xuất trong năm kế tiếp và gửi bản kế hoạch này đến các cơ sở sản xuất có tên trong kế hoạch. Đối với trường hợp cơ sở sản xuất quy định tại điểm c khoản 1 Điều 6 Thông tư này, Cục Quản lý Dược công bố và thực hiện kế hoạch đánh giá định kỳ, trừ trường hợp cơ sở đề nghị đánh giá riêng biệt.

3. Tối thiểu 30 ngày trước thời điểm đánh giá định kỳ việc duy trì đáp ứng GMP theo kế hoạch đã được Cơ quan tiếp nhận công bố, cơ sở sản xuất phải gửi về Cơ quan tiếp nhận báo cáo về hoạt động sản xuất thuốc, nguyên liệu làm thuốc và việc duy trì đáp ứng tiêu chuẩn GMP (sau đây viết tắt là báo cáo hoạt động - duy trì đáp ứng GMP) của cơ sở theo Mẫu số 2 quy định tại Phụ lục X ban hành kèm theo Thông tư này, kèm theo tài liệu kỹ thuật cập nhật về điều kiện cơ sở vật chất, kỹ thuật và nhân sự của cơ sở sản xuất (nếu có thay đổi).

Ví dụ: Thời điểm dự kiến đánh giá định kỳ tại cơ sở sản xuất A là ngày 18 tháng 8 năm 2018 thì cơ sở sản xuất A phải nộp báo cáo hoạt động và việc duy trì đáp ứng GMP về Cơ quan tiếp nhận trước ngày 18 tháng 7 năm 2018.

4. Trường hợp cơ sở sản xuất không nộp báo cáo hoạt động - duy trì đáp ứng GMP theo thời hạn được quy định tại khoản 3 Điều này, trong thời gian 15 ngày kể từ ngày đến hạn nộp báo cáo, Cơ quan tiếp nhận có văn bản yêu cầu cơ sở sản xuất thực hiện việc báo cáo hoạt động - duy trì đáp ứng GMP theo quy định.

5. Trong thời hạn 45 ngày, kể từ ngày Cơ quan tiếp nhận có văn bản yêu cầu, cơ sở sản xuất phải nộp báo cáo hoạt động - duy trì đáp ứng GMP kèm theo giải trình về lý do chậm nộp báo cáo. Nếu sau thời hạn này, cơ sở sản xuất không nộp báo cáo, Cơ quan tiếp nhận tiến hành đánh giá đột xuất, thanh tra, kiểm tra việc duy trì đáp ứng GMP của cơ sở theo quy định tại Điều 12 Thông tư này.

6. Sau khi nộp báo cáo hoạt động - duy trì đáp ứng GMP theo thời gian quy định, cơ sở sản xuất được tiếp tục hoạt động sản xuất thuốc, nguyên liệu làm thuốc theo phạm vi quy định tại Giấy chứng nhận đủ điều kiện kinh doanh dược, cho đến khi có kết quả đánh giá định kỳ việc duy trì đáp ứng GMP và phải bảo đảm duy trì việc đáp ứng GMP.

7. Trình tự đánh giá, quy trình đánh giá, phân loại kết quả đánh giá đáp ứng GMP thực hiện theo quy định tại Điều 6 và Điều 7 Thông tư này.

Điều 10. Xử lý kết quả đánh giá định kỳ việc duy trì đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Trường hợp báo cáo đánh giá GMP kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 1 theo quy định tại điểm a khoản 3 Điều 7 Thông tư này:

Trong thời hạn 10 ngày làm việc, kể từ ngày ký biên bản đánh giá, Cơ quan tiếp nhận cập nhật thông tin về việc duy trì đáp ứng GMP của cơ sở trên Cổng Thông tin điện tử của Bộ Y tế và Trang Thông tin điện tử của cơ quan tiếp nhận theo quy định tại khoản 6 Điều 8 Thông tư này và thực hiện việc cấp Giấy chứng nhận GMP theo Mẫu số 05 quy định tại Phụ lục X ban hành kèm theo Thông tư này đối với cơ sở đề nghị cấp Giấy chứng nhận GMP.

2. Trường hợp báo cáo đánh giá GMP kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 2 theo quy định tại điểm b khoản 3 Điều 7 Thông tư này:

a) Trong thời hạn 05 ngày làm việc, kể từ ngày ký biên bản đánh giá, Cơ quan tiếp nhận gửi báo cáo đánh giá GMP cho cơ sở sản xuất để tiến hành khắc phục, sửa chữa tồn tại và gửi báo cáo khắc phục về Cơ quan tiếp nhận;

b) Trong thời hạn 45 ngày, kể từ ngày Cơ quan tiếp nhận gửi báo cáo đánh giá GMP, cơ sở sản xuất phải có văn bản báo cáo khắc phục bao gồm kế hoạch và bằng chứng chứng minh (hồ sơ tài liệu, hình ảnh, video, giấy chứng nhận hoặc các tài liệu chứng minh khác) việc khắc phục, sửa chữa tồn tại được ghi trong báo cáo đánh giá GMP;

c) Trong thời hạn 20 ngày, kể từ ngày nhận được văn bản báo cáo khắc phục, Cơ quan tiếp nhận đánh giá kết quả khắc phục của cơ sở sản xuất và kết luận về tình trạng đáp ứng GMP của cơ sở sản xuất:

- Trường hợp việc khắc phục của cơ sở sản xuất đã đáp ứng yêu cầu: Cơ quan tiếp nhận cập nhật thông tin về việc duy trì đáp ứng GMP của cơ sở trên Cổng Thông tin điện tử của Bộ Y tế và Trang Thông tin điện tử của cơ quan tiếp nhận theo quy định tại khoản 6 Điều 8 Thông tư này và thực hiện việc cấp Giấy chứng nhận GMP theo Mẫu số 05 quy định tại Phụ lục X ban hành kèm theo Thông tư này đối với cơ sở đề nghị cấp Giấy chứng nhận GMP;

- Trường hợp việc khắc phục của cơ sở sản xuất chưa đáp ứng yêu cầu: Cơ quan tiếp nhận có văn bản thông báo nội dung cần tiếp tục khắc phục, sửa chữa và nộp báo cáo bổ sung. Thời gian gia hạn để tiếp tục khắc phục, sửa chữa và báo cáo là 45 ngày, kể từ ngày có văn bản yêu cầu.

d) Trong thời hạn 90 ngày, kể từ ngày ký biên bản đánh giá mà cơ sở sản xuất không có báo cáo khắc phục hoặc sau khi khắc phục theo quy định tại điểm c Khoản này mà kết quả khắc phục vẫn tiếp tục không đạt yêu cầu, Cơ quan tiếp nhận ban hành văn bản thông báo về việc không đáp ứng GMP và tùy theo tính chất, mức độ vi phạm, Cơ quan tiếp nhận thực hiện một hoặc các biện pháp theo quy định tại điểm a và điểm b khoản 4 Điều này.

3. Trường hợp báo cáo đánh giá GMP kết luận cơ sở sản xuất tuân thủ GMP mức độ 3 theo quy định tại điểm c khoản 3 Điều 7 Thông tư này:

Trình tự, thời gian xử lý kết quả đánh giá đáp ứng GMP theo quy định tại khoản 2 Điều này.

Trong thời hạn 20 ngày, kể từ ngày nhận được văn bản báo cáo khắc phục, Cơ quan tiếp nhận tiến hành giám sát, đánh giá thực tế việc khắc phục tại cơ sở sản xuất trước khi kết luận tình trạng đáp ứng GMP của cơ sở sản xuất theo quy định tại điểm c khoản 2 Điều này.

4. Trường hợp báo cáo đánh giá GMP kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 4 theo quy định tại điểm d khoản 3 Điều 7 Thông tư này:

Trong thời hạn 05 ngày làm việc, kể từ ngày ký biên bản đánh giá, trên cơ sở đánh giá nguy cơ về tồn tại được phát hiện đối với chất lượng thuốc, nguyên liệu làm thuốc, an toàn của người sử dụng thuốc, Cơ quan tiếp nhận ban hành văn bản thông báo về việc không đáp ứng GMP kèm theo báo cáo đánh giá GMP. Tùy theo tính chất, mức độ vi phạm, Cơ quan tiếp nhận thực hiện một hoặc các biện pháp sau đây:

a) Xử phạt vi phạm hành chính theo quy định của pháp luật về xử lý vi phạm hành chính;

b) Trình Bộ trưởng Bộ Y tế ra quyết định thu hồi Giấy chứng nhận đủ điều kiện kinh doanh dược đã cấp theo quy định tại khoản 2 Điều 40 của Luật dược và thực hiện thu hồi Giấy chứng nhận GMP đã cấp (nếu có).

c) Trường hợp cơ sở sản xuất không đáp ứng một hoặc một số phạm vi kinh doanh trong Giấy chứng nhận đủ điều kiện kinh doanh dược đã cấp, Cơ quan tiếp nhận:

- Trình Bộ trưởng Bộ Y tế ra quyết định thu hồi Giấy chứng nhận đủ điều kiện kinh doanh dược đã cấp để loại bỏ phạm vi kinh doanh không đáp ứng theo quy định tại Điều 40 của Luật dược, đồng thời cấp Giấy chứng nhận đủ điều kiện kinh doanh dược phù hợp với phạm vi kinh doanh mà cơ sở sản xuất đáp ứng GMP;

- Thực hiện cấp Giấy chứng nhận GMP phù hợp với phạm vi mà cơ sở sản xuất đáp ứng nếu cơ sở có yêu cầu.

5. Trong thời hạn 05 ngày làm việc, kể từ ngày kết luận cơ sở sản xuất đáp ứng việc duy trì GMP hoặc từ ngày ban hành Quyết định thu hồi Giấy chứng nhận đủ điều kiện kinh doanh dược đã cấp do cơ sở sản xuất không duy trì đáp ứng GMP, Cơ quan tiếp nhận cập nhật tình trạng đáp ứng GMP trên Trang Thông tin điện tử của Cơ quan tiếp nhận theo nội dung quy định tại khoản 6 Điều 8 Thông tư này đối với cơ sở sản xuất đáp ứng GMP hoặc thông tin về việc thu hồi Giấy chứng nhận đủ điều kiện kinh doanh dược, Giấy chứng nhận GMP (nếu có) đã cấp đối với cơ sở sản xuất không duy trì đáp ứng GMP.

6. Trường hợp mẫu thuốc, nguyên liệu làm thuốc do Đoàn đánh giá lấy trong quá trình đánh giá bị kết luận vi phạm chất lượng, cơ quan tiếp nhận tiến hành xử lý thuốc, nguyên liệu làm thuốc vi phạm theo quy định hiện hành.

Điều 11. Kiểm soát thay đổi

1. Cơ sở sản xuất vắc xin trước khi tiến hành thay đổi thuộc một trong các trường hợp được quy định tại điểm a, b khoản này phải có văn bản thông báo kèm theo đánh giá về nguy cơ, ảnh hưởng của các thay đổi dự kiến thực hiện đến chất lượng, an toàn của sản phẩm:

a) Trường hợp quy định tại các điểm d, đ, e, và g khoản 2 Điều này;

b) Sản xuất, sản xuất thử vắc xin hoặc sản phẩm thuốc khác trên dây chuyền sản xuất vắc xin đã được cấp chứng nhận;

Trong thời hạn 15 ngày, Cục Quản lý Dược có ý kiến trả lời bằng văn bản trong trường hợp không đồng ý với đề xuất thay đổi của cơ sở sản xuất vắc xin.

2. Cơ sở sản xuất sau khi tiến hành thay đổi phải thực hiện thủ tục đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược hoặc báo cáo thay đổi theo Mẫu số 06 quy định tại Phụ lục X ban hành kèm theo Thông tư này nếu thuộc một trong các trường hợp sau đây:

a) Thay đổi thuộc một trong các trường hợp được quy định tại điểm b khoản 1 Điều 36 của Luật dược;

b) Thay đổi vị trí nhà máy sản xuất tại cùng địa điểm kinh doanh;

c) Bổ sung nhà máy sản xuất ở vị trí mới tại cùng địa điểm kinh doanh;

d) Mở rộng nhà máy sản xuất trên cơ sở cấu trúc nhà máy đã có;

đ) Sửa chữa, thay đổi lớn về cấu trúc, bố trí nhà xưởng, dây chuyền sản xuất làm thay đổi điều kiện môi trường sản xuất, quy trình sản xuất;

e) Thay đổi các thiết bị sản xuất chính, quan trọng gây ảnh hưởng tới quy trình sản xuất, chất lượng thuốc, nguyên liệu làm thuốc;

g) Thay đổi hệ thống phụ trợ hoặc thay đổi nguyên lý thiết kế, vận hành hệ thống tiện ích mà có ảnh hưởng tới môi trường sản xuất;

h) Cơ sở sản xuất thay đổi tiêu chuẩn GMP áp dụng, được cơ quan quản lý dược SRA đánh giá, chứng nhận đáp ứng EU - GMP hoặc tương đương (Japan - GMP, US - Current GMP, PIC/S -GMP) và đề nghị công bố việc đáp ứng này.

3. Trường hợp cơ sở sản xuất có thay đổi theo quy định tại điểm a khoản 2 Điều này, cơ sở sản xuất phải gửi hồ sơ đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược theo quy định tại khoản 2 và khoản 4 Điều 38 của Luật dược.

Trình tự đánh giá việc đáp ứng GMP, phân loại kết quả và xử lý kết quả đánh giá mức độ tuân thủ GMP được thực hiện theo quy định tại các điều 6, 7 và 8 Thông tư này.

4. Trường hợp cơ sở sản xuất có thay đổi thuộc một trong các trường hợp quy định tại các điểm b, c, d hoặc h khoản 2 Điều này hoặc trường hợp cơ sở sản xuất sản xuất thuốc, nguyên liệu làm thuốc vô trùng có thay đổi thuộc điểm đ khoản 2 Điều này, cơ sở sản xuất phải nộp báo cáo thay đổi kèm tài liệu kỹ thuật tương ứng với sự thay đổi về Cơ quan tiếp nhận.

a) Cơ quan tiếp nhận thực hiện đánh giá thực tế tại cơ sở sản xuất. Trường hợp cơ sở sản xuất đáp ứng yêu cầu, Cơ quan tiếp nhận có văn bản đồng ý với thay đổi của cơ sở sản xuất;

b) Trình tự đánh giá, phân loại kết quả và xử lý kết quả đánh giá đối với cơ sở sản xuất có thay đổi theo quy định tại điểm b khoản 2 Điều này được thực hiện theo quy định tại các điều 6, 7 và 10 Thông tư này;

c) Trình tự đánh giá, phân loại kết quả và xử lý kết quả đánh giá đối với cơ sở sản xuất có thay đổi theo quy định tại điểm c hoặc d khoản 2 Điều này hoặc cơ sở sản xuất sản xuất thuốc, nguyên liệu làm thuốc vô trùng có thay đổi thuộc điểm đ khoản 2 Điều này được thực hiện theo quy định tại các điều 6, 7 và 8 Thông tư này.

5. Trường hợp cơ sở sản xuất có thay đổi theo quy định tại điểm h khoản 2 Điều này, cơ sở sản xuất có văn bản thông báo thay đổi tiêu chuẩn GMP áp dụng và về việc kiểm tra, đánh giá do cơ quan quản lý dược SRA thực hiện tại cơ sở (tên cơ quan quản lý dược SRA, thời gian đánh giá, nội dung/phạm vi đánh giá, kết quả đánh giá) kèm tài liệu kỹ thuật tương ứng với sự thay đổi, giấy chứng nhận GMP/giấy xác nhận đáp ứng GMP hoặc báo cáo thanh tra GMP do cơ quan quản lý dược SRA cấp.

a) Cơ quan tiếp nhận thực hiện rà soát thông báo và các tài liệu kèm theo, bổ sung/cập nhật thông tin về việc đáp ứng EU - GMP hoặc tương đương của cơ sở sản xuất theo quy định tại khoản 6 Điều 8 Thông tư này.

b) Cơ quan tiếp nhận thực hiện đánh giá việc duy trì đáp ứng EU - GMP hoặc tương đương tại cơ sở sản xuất theo quy định tại Điều 12 Thông tư này.

6. Trường hợp cơ sở sản xuất có thay đổi thuộc một trong các trường hợp quy định tại điểm đ, e hoặc g khoản 2 Điều này (trừ trường hợp quy định tại khoản 4 và khoản 6 Điều này), cơ sở sản xuất phải nộp báo cáo thay đổi kèm tài liệu kỹ thuật tương ứng với sự thay đổi về Cơ quan tiếp nhận. Cơ quan tiếp nhận thực hiện đánh giá báo cáo thay đổi của cơ sở sản xuất.

a) Trong thời hạn 10 ngày làm việc, kể từ ngày nhận được văn bản thông báo của cơ sở sản xuất, Cơ quan tiếp nhận ban hành văn bản thông báo về việc đồng ý với nội dung thay đổi trong trường hợp việc thay đổi đáp ứng yêu cầu hoặc thông báo về nội dung cần khắc phục, sửa chữa trong trường hợp chưa đáp ứng yêu cầu;

b) Trong thời hạn 45 ngày, kể từ ngày Cơ quan tiếp nhận có văn bản thông báo, cơ sở sản xuất phải hoàn thành việc khắc phục, sửa chữa và có văn bản báo cáo kèm theo các bng chứng chứng minh (hồ sơ tài liệu, hình ảnh, video, giấy chứng nhận và các tài liệu khác) đã hoàn thành việc khắc phục, sửa chữa tồn tại được nêu trong văn bản thông báo;

c) Trong thời hạn 10 ngày, kể từ ngày nhận được báo cáo khắc phục của cơ sở sản xuất, kèm theo bằng chứng chứng minh (hồ sơ tài liệu, hình ảnh, video, giấy chứng nhận và các tài liệu khác), Cơ quan tiếp nhận đánh giá kết qu khắc phục của cơ sở sản xuất và kết luận về tình trạng đáp ứng GMP của cơ sở sản xuất:

- Trường hợp việc khắc phục đã đáp ứng yêu cầu: Cơ quan tiếp nhận hồ sơ ban hành văn bản thông báo về việc đồng ý với nội dung thay đổi;

- Trường hợp việc khắc phục chưa đáp ứng yêu cầu: Cơ quan tiếp nhận thực hiện việc đánh giá đột xuất, xử lý kết quả đánh giá theo quy định tại Điều 12 Thông tư này.

7. Trường hợp cơ sở sản xuất thuốc, nguyên liệu làm thuốc dùng ngoài không vô trùng có thay đổi thuộc một trong các trường hợp quy định tại các điểm đ, e và g khoản 2 Điều này, cơ sở sản xuất phải nộp báo cáo thay đổi kèm tài liệu kỹ thuật tương ứng với sự thay đổi về Cơ quan tiếp nhận. Cơ sở sản xuất phải tiếp tục đảm bảo duy trì các hoạt động sản xuất theo nguyên tắc, tiêu chuẩn GMP.

Điều 12. Đánh giá đột xuất, thanh tra, kiểm tra việc duy trì đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc

1. Công tác thanh tra, kiểm tra việc duy trì đáp ứng GMP của cơ sở sản xuất được thực hiện theo quy định của pháp luật.

2. Cơ quan tiếp nhận tiến hành đánh giá đột xuất việc duy trì đáp ứng GMP tại cơ sở sản xuất khi cơ sở sản xuất thuộc một trong các trường hợp sau đây:

a) Cơ sở sản xuất khắc phục chưa đáp ứng yêu cầu quy định tại tiết 2 điểm c khoản 6 Điều 11 Thông tư này;

b) Cơ sở sản xuất tuân thủ GMP ở mức 3 hoặc mức 4 quy định tại điểm c và d khoản 3 Điều 7 Thông tư này phải được đánh giá đột xuất ít nhất 01 lần trong thời hạn 03 (ba) năm kể từ ngày kết thúc đợt đánh giá kỳ trước;

c) Cơ sở sản xuất có từ 01 lô thuốc bị thu hồi do vi phạm ở mức độ 1;

d) Cơ sở sản xuất có thuốc được ghi nhận có chuỗi báo cáo phản ứng có hại của thuốc (ADR) trong đó có phản ứng có hại nghiêm trọng;

đ) Cơ sở sản xuất có kết quả thanh tra, kiểm tra của cơ quan chức năng kết luận có vi phạm nghiêm trọng nguyên tắc, tiêu chuẩn GMP;

e) Trường hợp có thông tin phản ánh, tố giác cơ sở vi phạm nghiêm trọng nguyên tắc, tiêu chuẩn GMP;

g) Cơ sở sản xuất không nộp báo cáo hoạt động - duy trì đáp ứng GMP theo quy định tại khoản 5 Điều 9 Thông tư này.

3. Thành phần Đoàn đánh giá do Thủ trưởng Cơ quan tiếp nhận quyết định theo quy định tại Điều 15 Thông tư này.

4. Trình tự đánh giá đột xuất tại cơ sở sản xuất thực hiện theo quy định tại Điều 7 Thông tư này.

5. Việc xử lý kết quả thanh tra, kiểm tra, đánh giá đột xuất tại cơ sở sản xuất thực hiện theo quy định của pháp luật.

Chương V

ĐÁNH GIÁ VIỆC ĐÁP ỨNG THỰC HÀNH TỐT SẢN XUẤT THUỐC, NGUYÊN LIỆU LÀM THUỐC CỦA CƠ SỞ SẢN XUẤT KHÔNG THUỘC DIỆN CẤP GIẤY CHỨNG NHẬN ĐỦ ĐIỀU KIỆN KINH DOANH DƯỢC VÀ CỦA CƠ SỞ SẢN XUẤT NƯỚC NGOÀI KHI ĐĂNG KÝ LƯU HÀNH THUỐC, NGUYÊN LIỆU LÀM THUỐC TẠI VIỆT NAM

Điều 13. Đánh giá việc đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc đối với cơ sở sản xuất không thuộc diện cấp Giấy chứng nhận đủ điều kiện kinh doanh dược

1. Cơ sở sản xuất không thuộc diện cấp Giấy chứng nhận đủ điều kiện kinh doanh dược (cơ sở có hoạt động dược nhưng không vì mục đích thương mại) phải tuân thủ GMP theo quy định tại Điểm a khoản 2 Điều 35 Luật Dược.

2. Cơ sở sản xuất không thuộc diện cấp Giấy chứng nhận đủ điều kiện kinh doanh dược (trừ bộ phận pha chế thuốc của cơ sở khám bệnh chữa bệnh) nộp văn bản đề nghị đánh giá đáp ứng GMP theo Mẫu số 1 quy định tại Phụ lục X ban hành kèm theo Thông tư này và tài liệu kỹ thuật về cơ sở sản xuất thuốc được trình bày theo hướng dẫn về hồ sơ tổng thể của cơ sở sản xuất quy định tại Phụ lục VIII ban hành kèm theo Thông tư này đối với trường hợp đánh giá lần đầu hoặc báo cáo hoạt động sản xuất - duy trì đáp ứng GMP của cơ sở, kèm theo tài liệu kỹ thuật cập nhật về cơ sở sản xuất (nếu có thay đổi) theo quy định tại khoản 3 Điều 9 đối với trường hợp đánh giá định kỳ.

3. Trình tự đánh giá, quy trình đánh giá, phân loại kết quả đánh giá, kiểm soát thay đổi và đánh giá đột xuất việc đáp ứng GMP đối với cơ sở sản xuất thuốc, nguyên liệu làm thuốc không thuộc diện cấp Giấy chứng nhận đủ điều kiện kinh doanh dược thực hiện theo quy định tương ứng tại các điều 6, 7, 9, 11 và 12 Thông tư này.

4. Xử lý kết quả đánh giá lần đầu việc đáp ứng GMP của cơ sở sản xuất thuốc, nguyên liệu làm thuốc không thuộc diện cấp Giấy chứng nhận đủ điều kiện kinh doanh dược:

a) Trình tự, thời gian xử lý kết quả đánh giá lần đầu việc đáp ứng GMP của cơ sở sản xuất được thực hiện theo quy định tại Điều 8 Thông tư này.

b) Cơ quan tiếp nhận có văn bản thông báo tình trạng đáp ứng GMP của cơ sở sản xuất và công bố trên Cổng Thông tin điện tử của Bộ Y tế và Trang Thông tin điện tử của cơ quan tiếp nhận theo quy định tại khoản 6 Điều này.

5. Xử lý kết quả đánh giá định kỳ, kiểm tra đánh giá đột xuất việc duy trì đáp ứng GMP của cơ sở sản xuất thuốc, nguyên liệu làm thuốc không thuộc diện cấp Giấy chứng nhận đủ điều kiện kinh doanh dược:

a) Trường hợp kết quả kiểm tra đánh giá kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 1 hoặc 2 hoặc 3 theo quy định tại điểm a, b và điểm c khoản 3 Điều 7 Thông tư này, cơ quan tiến hành kiểm tra, đánh giá xử lý theo quy định tại các khoản 1, 2 và 3 Điều 10 Thông tư này.

b) Trường hợp kết quả kiểm tra đánh giá kết luận cơ sở sản xuất tuân thủ GMP ở mức độ 4 theo quy định tại điểm d khoản 3 Điều 7 Thông tư này thì cơ quan tiến hành kiểm tra, đánh giá ban hành quyết định tạm ngừng toàn bộ hoạt động sản xuất hoặc phạm vi hoạt động sản xuất không đáp ứng cho đến khi cơ sở tiến hành khắc phục, sửa chữa tồn tại đạt yêu cầu.

c) Trường hợp mẫu thuốc, nguyên liệu làm thuốc do Đoàn kiểm tra đánh giá lấy trong quá trình kiểm tra đánh giá bị kết luận vi phạm chất lượng, cơ quan tiếp nhận tiến hành xử lý thuốc, nguyên liệu làm thuốc vi phạm theo quy định hiện hành về quản lý chất lượng thuốc, nguyên liệu làm thuốc. Người đứng đầu cơ sở sản xuất phải chịu trách nhiệm trước pháp luật về vi phạm này.

6. Trong thời gian 05 ngày làm việc, kể từ ngày kết luận việc đáp ứng/duy trì đáp ứng GMP của cơ sở sản xuất thuốc, nguyên liệu làm thuốc không thuộc diện cấp Giấy chứng nhận đủ điều kiện kinh doanh dược, Cơ quan tiếp nhận công bố, cập nhật trên Cổng Thông tin điện tử của Bộ Y tế và Trang Thông tin điện tử của cơ quan tiếp nhận các thông tin sau đây:

a) Tên và địa chỉ cơ sở sản xuất;

b) Họ tên người chịu trách nhiệm chuyên môn về dược, người phụ trách về bảo đảm chất lượng và số Chứng chỉ hành nghề dược;

c) Số Giấy chứng nhận GMP;

d) Thời hạn hết hiệu lực của việc đánh giá đáp ứng GMP;

đ) Phạm vi hoạt động của cơ sở sản xuất.

e) Số Giấy chứng nhận EU - GMP, thời hạn hiệu lực và cơ quan cấp Giấy chứng nhận đối với cơ sở sản xuất đã được cơ quan quản lý dược SRA đánh giá đáp ứng EU - GMP hoặc tương đương (nếu có).

Điều 14. Đánh giá việc đáp ứng Thực hành tốt sản xuất thuốc, nguyên liệu làm thuốc đối với cơ sở sản xuất nước ngoài có thuốc, nguyên liệu làm thuốc đăng ký lưu hành tại Việt Nam

1. Cơ sở sản xuất thuốc, nguyên liệu làm thuốc nước ngoài trước khi nộp hồ sơ đề nghị đánh giá đáp ứng GMP tại Bộ Y tế (Cơ quan tiếp nhận theo quy định tại khoản 1 Điều 6 Thông tư này) phải được cơ quan quản lý dược có thẩm quyền của nước sở tại đánh giá, chứng nhận đáp ứng GMP.

2. Hình thức đánh giá, nội dung đánh giá, hồ sơ đánh giá, trình tự thủ tục, thẩm quyền đánh giá việc đáp ứng GMP của cơ sở sản xuất nước ngoài được thực hiện theo quy định tại các điều 96, 97, 98 và 99 Nghị định 54/2017/NĐ-CP.

Trường hợp đánh giá đáp ứng GMP được thực hiện theo hình thức kiểm tra tại cơ sở sản xuất, quy trình đánh giá, phân loại và xử lý kết quả đánh giá, kiểm soát thay đổi được thực hiện theo quy định tại các điều 6, 7, 8, 9, 10, 11 và 12 Thông tư này.

3. Trong thời gian 10 ngày làm việc, kể từ ngày có kết quả đánh giá cơ sở đáp ứng GMP, Cơ quan tiếp nhận công bố trên Cổng thông tin điện tử Bộ Y tế và Trang Thông tin điện tử của cơ quan tiếp nhận các thông tin sau đây:

a) Tên và địa chỉ cơ sở sản xuất;

b) Số giấy chứng nhận GMP, tài liệu GMP áp dụng, thời hạn hiệu lực Giấy chứng nhận GMP và tên cơ quan quản lý dược nước ngoài có thẩm quyền đối với các trường hợp quy định tại điểm a và b khoản 5 Điều 54 của Luật dược hoặc ngày đánh giá đáp ứng GMP của Bộ Y tế Việt Nam, tài liệu GMP áp dụng, thời hạn hiệu lực kết quả đánh giá GMP đối với trường hợp quy định tại điểm c khoản 5 Điều 54 của Luật dược;

c) Phạm vi hoạt động của cơ sở sản xuất được đánh giá.

Chương VI

ĐOÀN ĐÁNH GIÁ VIỆC ĐÁP ỨNG THỰC HÀNH TỐT SẢN XUẤT THUỐC, NGUYÊN LIỆU LÀM THUỐC

Điều 15. Thành phần và tiêu chuẩn của thành viên Đoàn đánh giá

1. Thành phần Đoàn đánh giá bao gồm:

a) Trưởng Đoàn và 01 hoặc 02 thành viên thuộc Cơ quan tiếp nhận. Đối với cơ sở sản xuất quy định tại điểm c khoản 1 Điều 6 Thông tư này thì bổ sung 01 hoặc 02 thành viên thuộc Cục Quản lý Y Dược cổ truyền;

b) 01 thành viên là đại diện Viện Kiểm nghiệm thuốc Trung ương hoặc Viện Kiểm nghiệm thuốc Thành phố Hồ Chí Minh hoặc Viện Kiểm định vắc xin và sinh phẩm Quốc gia (đối với cơ sở sản xuất vắc xin, sinh phẩm);

c) 01 thành viên là đại diện Sở Y tế tnh, thành phố trực thuộc Trung ương (sau đây được gọi tắt là Sở Y tế) nơi đặt nhà máy sản xuất.

d) Thành viên của cơ quan liên quan trong trường hợp cần thiết.

2. Thành viên tham gia Đoàn đánh giá phải đáp ứng tiêu chuẩn sau đây:

a) Có trình độ đại học trở lên và được đào tạo các môn khoa học về y, dược, sinh học, quản lý chất lượng thuốc và công tác quản lý dược;

b) Đã được đào tạo, tập huấn về GMP, thanh tra, đánh giá GMP và nắm vững nguyên tắc, tiêu chuẩn GMP. Riêng thành viên tham gia Đoàn đánh giá cơ sở sản xuất thuốc cổ truyền, dược liệu thì phải được đào tạo, tập huấn về GMP thuốc cổ truyền, dược liệu.

c) Trung thực, khách quan và nghiêm chỉnh chấp hành các quy chế, quy định pháp luật trong quá trình đánh giá, không có xung đột lợi ích với cơ sở sản xuất được đánh giá theo quy định tại Khoản 3 Điều này;

d) Trưởng Đoàn đánh giá có kinh nghiệm trong công tác quản lý dược từ 03 (ba) năm trở lên.

3. Nguyên tắc đánh giá xung đột lợi ích: Thành viên Đoàn đánh giá được coi là có xung đột lợi ích với cơ sở sản xuất được đánh giá nếu thuộc một trong các trường hợp sau đây:

a) Đã từng làm việc hoặc tham gia hoạt động tư vấn trong thời gian 05 năm gần đây cho cơ sở sản xuất được đánh giá;

b) Đang có quyền lợi về tài chính với cơ sở sản xuất được đánh giá;

c) Có vợ hoặc chồng, con, bố hoặc mẹ, anh chị em ruột, bố hoặc mẹ của vợ, bố hoặc mẹ của chồng đang làm việc cho cơ sở sản xuất được đánh giá.

Điều 16. Trách nhiệm và quyền hạn của Đoàn đánh giá

1. Trách nhiệm của Đoàn đánh giá:

a) Đánh giá toàn bộ hoạt động của cơ sở sản xuất theo nguyên tắc, tiêu chuẩn GMP tương ứng quy định tại Điều 3 Thông tư này, phiên bản cập nhật nguyên tắc, tiêu chuẩn GMP và các văn bản quy phạm pháp luật, quy định chuyên môn có liên quan; ghi nhận cụ thể nội dung đánh giá, tồn tại phát hiện được, lập biên bản đánh giá và Báo cáo đánh giá GMP;

b) Báo cáo kết quả đánh giá hoặc giải trình về báo cáo kết quả đánh giá GMP trong trường hợp cơ sở sản xuất có ý kiến không thống nhất với nội dung Báo cáo đánh giá GMP;

c) Bảo mật toàn bộ thông tin liên quan về nội dung đánh giá và toàn bộ thông tin liên quan đến hoạt động sản xuất, kiểm tra chất lượng, bảo quản, phân phối thuốc (các quy trình sản xuất, kiểm nghiệm, vệ sinh, các bí mật công nghệ...), trừ trường hợp có sự đồng ý của cơ sở sản xuất hoặc theo yêu cầu của cơ quan Nhà nước có thẩm quyền để phục vụ công tác thanh tra, điều tra.

2. Quyền hạn của Đoàn đánh giá:

a) Kiểm tra toàn bộ khu vực, nhà xưởng thuộc cơ sở sản xuất, và có quyền đề nghị kiểm tra khu vực khác có liên quan đến hoạt động sản xuất, bảo quản, kiểm nghiệm thuốc và nguyên liệu làm thuốc. Riêng đối với sản xuất vị thuốc cổ truyền thì kiểm tra thêm các quy trình chế biến, sản xuất vị thuốc cổ truyền của cơ sở dự kiến sản xuất.

b) Yêu cầu cung cấp hồ sơ tài liệu liên quan đến hoạt động quản lý chất lượng, sản xuất, kiểm nghiệm, bảo quản thuốc, nguyên liệu làm thuốc;

c) Thực hiện việc thu thập hồ sơ tài liệu, bằng chứng chứng minh (sao chụp tài liệu, chụp ảnh, quay video...) về tồn tại phát hiện trong quá trình đánh giá;

d) Lấy mẫu thuốc, bán thành phẩm, dược liệu và nguyên liệu làm thuốc để gửi kiểm tra chất lượng theo quy định pháp luật;

đ) Lập biên bản, yêu cầu cơ sở sản xuất tạm dừng hoạt động một, một số hoặc toàn bộ hoạt động sản xuất liên quan đến vi phạm. Nếu trong quá trình đánh giá, Đoàn đánh giá phát hiện cơ sở sản xuất có vi phạm ảnh hưởng nghiêm trọng tới chất lượng một hoặc nhiều sản phẩm thuốc, nguyên liệu làm thuốc phải báo cáo người có thẩm quyền xử lý theo quy định của pháp luật.

Chương VII

ĐIỀU KHOẢN THI HÀNH

Điều 17. Hiệu lực thi hành

1. Thông tư này có hiệu lực thi hành kể từ ngày 10 tháng 01 năm 2019.

2. Các văn bản, quy định sau đây hết hiệu lực kể từ ngày Thông tư này có hiệu lực:

a) Quyết định số 3886/2004/QĐ-BYT ngày 03 tháng 11 năm 2004 của Bộ trưởng Bộ Y tế quy định về việc triển khai áp dụng nguyên tắc, tiêu chuẩn “Thực hành tốt sản xuất thuốc” theo khuyến cáo của Tổ chức Y tế Thế giới;

b) Các quy định về Thực hành tốt sản xuất thuốc trong Quyết định số 27/2007/QĐ-BYT ngày 19 tháng 04 năm 2007 của Bộ trưởng Bộ Y tế về việc ban hành lộ trình triển khai áp dụng nguyên tắc, tiêu chuẩn "Thực hành tốt sản xuất thuốc" và nguyên tắc "Thực hành tốt bảo quản thuốc";

c) Các quy định về Thực hành tốt sản xuất thuốc trong Thông tư số 45/2011/TT-BYT ngày 21 tháng 12 năm 2011 của Bộ trưởng Bộ Y tế sửa đổi, bổ sung một số điều của Quyết định số 1570/2000/QĐ-BYT ngày 22 tháng 5 năm 2000 của Bộ trưởng Bộ Y tế về việc triển khai áp dụng nguyên tắc "Thực hành tốt phòng kiểm nghiệm thuốc"; Quyết định số 2701/2001/QĐ-BYT ngày 29 tháng 6 năm 2001 của Bộ trưởng Bộ Y tế về việc triển khai áp dụng nguyên tắc "Thực hành tốt bảo quản thuốc"; Thông tư số 06/2004/TT-BYT ngày 28 tháng 5 năm 2004 hướng dẫn sản xuất gia công thuốc; Quyết định số 3886/2004/QĐ-BYT ngày 03 tháng 11 năm 2004 của Bộ Y tế về việc triển khai áp dụng nguyên tắc, tiêu chuẩn "Thực hành tốt sản xuất thuốc" theo khuyến cáo của Tổ chức Y tế thế giới; Thông tư số 13/2009/TT-BYT ngày 01 tháng 9 năm 2009 của Bộ Y tế hướng dẫn hoạt động thông tin quảng cáo thuốc; Thông tư số 22/2009/TT-BYT ngày 24 tháng 11 năm 2009 của Bộ Y tế quy định về đăng ký thuốc; Thông tư số 47/2010/TT-BYT ngày 29 tháng 12 năm 2010 hướng dẫn hoạt động xuất khẩu, nhập khẩu thuốc và bao bì tiếp xúc trực tiếp với thuốc.

d) Riêng các quy định về điều kiện chế biến dược liệu trong Thông tư số 03/2016/TT-BYT ngày 21 tháng 01 năm 2016 của Bộ trưởng Bộ Y tế quy định về hoạt động kinh doanh dược liệu được tiếp tục có hiệu lực đến hết ngày 31/12/2020 đối với các trường hợp theo quy định tại khoản 4 Điều 19 Thông tư này.

đ) Quy định: “Nếu cơ sở thử nghiệm không nộp hồ sơ đề nghị đánh giá định kỳ theo quy định thì Bộ Y tế thu hồi Giấy chứng nhận đủ điều kiện kinh doanh dược của cơ sở thử nghiệm theo quy định tại khoản 2 Điều 40 của Luật Dược” tại khoản 5 Điều 9 Thông tư 04/2018/TT-BYT của Bộ trưởng Bộ Y tế ngày 09 tháng 02 năm 2018 quy định về Thực hành tốt phòng thí nghim

Điều 18. Điều khoản tham chiếu

Trong trường hợp các văn bản quy phạm pháp luật và các quy định được viện dẫn trong Thông tư này có sự thay đổi, bổ sung hoặc được thay thế thì áp dụng theo văn bản quy phạm pháp luật mới.

Điều 19. Điều khoản chuyển tiếp

1. Đối với các cơ sở sản xuất thuốc, nguyên liệu làm thuốc đã được cấp Giấy chứng nhận đủ điều kiện kinh doanh dược có phạm vi sản xuất thuốc, nguyên liệu làm thuốc hoặc giấy chứng nhận GMP có thời hạn còn hiệu lực, cấp trước ngày Thông tư này có hiệu lực, cơ sở được phép sản xuất thuốc, nguyên liệu làm thuốc đến hết thời hạn ghi trên giấy chứng nhận.

Trường hợp Giấy chứng nhận đủ điều kiện kinh doanh dược hết thời hạn hiệu lực, cơ sở sản xuất phải tiến hành thủ tục đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược theo quy định của pháp luật.

Trường hợp Giấy chứng nhận GMP hết thời hạn trước, cơ sở sản xuất phải tiến hành thủ tục đề nghị đánh giá duy trì đáp ứng GMP theo quy định tại Chương IV Thông tư này để tiếp tục hoạt động theo quy định.

2. Đối với cơ sở sản xuất thuốc, nguyên liệu làm thuốc đã được cấp Giấy chứng nhận đủ điều kiện kinh doanh dược phạm vi sản xuất thuốc, nguyên liệu làm thuốc không thời hạn, khi hết thời hạn Giấy chứng nhận GMP, cơ sở phải thực hiện thủ tục để cơ quan tiếp nhận đánh giá việc duy trì đáp ứng GMP và thực hiện các thủ tục có liên quan theo quy định của pháp luật.

3. Đối với hồ sơ đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược hoặc hồ sơ đăng ký đánh giá định kỳ đáp ứng GMP đã được nộp về Cơ quan tiếp nhận trước ngày Thông tư này có hiệu lực, Cơ quan tiếp nhận tiếp tục tiến hành đánh giá cơ sở sản xuất theo tiêu chuẩn GMP được ban hành kèm theo Quyết định số 3886/2004/QĐ-BYT ngày 03 tháng 11 năm 2004 của Bộ trưởng Bộ Y tế quy định về việc triển khai áp dụng nguyên tắc, tiêu chuẩn “Thực hành tốt sản xuất thuốc” theo khuyến cáo của WHO hoặc theo quy định tại Thông tư này nếu cơ sở sản xuất đề nghị.

4. Đối với cơ sở kinh doanh dược liệu có hoạt động chế biến dược liệu đã được Cục Quản lý Y, Dược cổ truyền kiểm tra và công bố trên cổng thông tin điện tử theo quy định tại Thông tư số 03/2016/TT-BYT ngày 21 tháng 01 năm 2016 của Bộ trưởng Bộ Y tế quy định về hoạt động kinh doanh dược liệu thì được tiếp tục hoạt động đến hết ngày 31 tháng 12 năm 2020. Trước ngày 01/01/2021, cơ sở sản xuất chế biến dược liệu, vị thuốc cổ truyền nộp hồ sơ đề nghị cấp Giấy chứng nhận đủ điều kiện kinh doanh dược phạm vi chế biến dược liệu, sản xuất vị thuốc c truyền theo quy định tại Điều 5 Thông tư này và áp dụng điều kiện sản xuất theo quy định tại các điều 13, 14, 15, 16, 17, 18, 19 và 20 Thông tư số 03/2016/TT-BYT ngày 21 tháng 01 năm 2016 của Bộ trưởng Bộ Y tế quy định về hoạt động kinh doanh dược liệu. Hồ sơ, quy trình đánh giá, xử lý kết quả đánh giá thực hiện theo quy định tại các điều 5, 6, 7 và 8 Thông tư này.

Điều 20. Trách nhiệm thi hành

1. Cục Quản lý Dược có trách nhiệm:

a) Chủ trì, phối hợp với các đơn vị liên quan tổ chức tuyên truyền phổ biến Thông tư này. Đầu mối biên soạn danh mục đánh giá GMP phù hợp với từng loại hình sản xuất theo nguyên tắc minh bạch, rõ ràng và chính xác để đánh giá, trình Bộ Y tế ban hành, làm cơ sở cho việc triển khai áp dụng GMP tại cơ sở sản xuất thuốc, nguyên liệu làm thuốc và việc đánh giá của cơ quan quản lý dược.

b) Triển khai việc thực hiện Thông tư này cho Sở Y tế, Y tế ngành và cơ sở sản xuất thuốc, nguyên liệu làm thuốc thuộc phạm vi chức năng, nhiệm vụ được giao;

c) Tổng hợp và công bố trên Trang Thông tin điện tử của Cục Quản lý Dược danh sách cơ sở sản xuất trên toàn quốc đã được cấp Giấy chứng nhận đủ điều kiện kinh doanh dược và/hoặc Giấy chứng nhận GMP; cập nhật tình trạng Giấy chứng nhận đủ điều kiện kinh doanh dược và/hoặc Giấy chứng nhận GMP, tình trạng đáp ứng GMP và các thông tin khác theo quy định tại khoản 6 Điều 8 Thông tư này theo phạm vi chức năng, nhiệm vụ được giao;

d) Công bố tài liệu cập nhật GMP trên Cổng Thông tin điện tử của Bộ Y tế và Trang Thông tin điện tử của Cục Quản lý Dược;

đ) Đầu mối hoặc phối hợp với Thanh tra Bộ thực hiện kiểm tra, thanh tra việc tuân thủ đáp ứng GMP và xử lý vi phạm theo thẩm quyền.

2. Cục Quản lý Y, Dược cổ truyền có trách nhiệm:

a) Triển khai việc thực hiện Thông tư này cho Sở Y tế, Y tế ngành và cơ sở sản xuất thuốc, nguyên liệu làm thuốc thuộc phạm vi chức năng, nhiệm vụ được giao;

b) Tổng hợp và công bố trên Trang Thông tin điện tử của Cục Quản lý Y, Dược cổ truyền danh sách cơ sở sản xuất trên toàn quốc đã được cấp Giấy chứng nhận đủ điều kiện kinh doanh dược hoặc Giấy chứng nhận GMP, cập nhật tình trạng Giấy chứng nhận đủ điều kiện kinh doanh dược hoặc Giấy chứng nhận GMP, tình trạng đáp ứng GMP và các thông tin khác theo quy định tại khoản 6 Điều 8 Thông tư này theo phạm vi chức năng, nhiệm vụ được giao;

c) Đầu mối hoặc phối hợp với Thanh tra Bộ thực hiện kiểm tra, thanh tra việc tuân thủ đáp ứng GMP và xử lý vi phạm theo thẩm quyền.

3. Sở Y tế có trách nhiệm:

a) Phối hợp với các đơn vị liên quan tổ chức tuyên truyền phổ biến Thông tư này và hướng dẫn triển khai cho các đơn vị trên địa bàn;

b) Tham gia Đoàn kiểm tra, thanh tra, đánh giá đáp ứng GMP; giám sát và xử lý vi phạm theo thẩm quyền việc tuân thủ đối với các cơ sở sản xuất thuốc, nguyên liệu làm thuốc trên địa bàn.

4. Viện Kiểm nghiệm thuốc Trung ương, Viện Kiểm nghiệm thuốc Thành phố Hồ Chí Minh, Viện Kiểm định Quốc gia về vắc xin và sinh phẩm y tế có trách nhiệm tham gia Đoàn đánh giá đáp ứng GMP khi có văn bản đề nghị.

5. Cơ sở sản xuất thuốc, nguyên liệu làm thuốc có trách nhiệm:

a) Tổ chức triển khai thực hiện Thông tư này;

b) Bảo đảm luôn đáp ứng nguyên tắc, tiêu chuẩn GMP trong suốt quá trình hoạt động của cơ sở sản xuất;

c) Thực hiện các hoạt động sản xuất theo đúng phạm vi được đánh giá, cấp phép trên cơ sở tuân thủ các quy định của pháp luật.

Trong quá trình thực hiện nếu có khó khăn, vướng mắc, các cơ quan, tổ chức, cá nhân phản ánh về Bộ Y tế (Cục Quản lý Dược, Cục Quản lý Y, Dược cổ truyền) để xem xét, giải quyết./.

 


Nơi nhận:
- Ủy ban VCVĐXH, Ủy ban PL của Quốc hội;
- Văn phòng Chính phủ (Phòng công báo,
Cổng thông tin điện tử CP);
- Bộ trưởng, các Thứ trưởng Bộ Y tế;
- Bộ, cơ quan ngang Bộ, cơ quan thuộc Chính phủ;
- Bộ Tư pháp (Cục Kiểm tra VB);
- Các Vụ, Cục, Tổng cục,
VP Bộ, Thanh tra Bộ Y tế;
- UBND các tỉnh, thành phố trực thuộc TW;
- Sở Y tế các tỉnh, thành phố trực thuộc TW;
- Viện KN thuốc TW, Viện KN thuốc Tp. HCM,
Viện KĐQG vắc xin và sinh phẩm y tế;
- Hiệp hội SXKDDVN;
- Cổng thông tin điện tử Bộ Y tế;
- Lưu: VT, PC, YDCT, QLD (2 bản).

KT. BỘ TRƯỞNG
THỨ TRƯỞNG




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Independence - Freedom - Happiness
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No. 35/2018/TT-BYT

Hanoi, November 22, 2018

CIRCULAR

GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL PRODUCTS AND PHARMACEUTICAL STARTING MATERIALS

Pursuant to the Law on Pharmacy No. 105/2016/QH13 dated April 06, 2016;

Pursuant to the Government’s Decree No. 54/2017/ND-CP dated May 08, 2017 on guidelines for implementation of the Law on Pharmacy;

Pursuant to the Government’s Decree No. 155/2018/ND-CP dated November 12, 2018 on amendments to some Articles related to business conditions under state management of the Ministry of Health;

Pursuant to the Government’s Decree No. 75/2017/ND-CP dated June 20, 2017 defining functions, tasks, entitlements and organizational structure of the Ministry of Health;

At the request of the General Director of the Drug Administration of Vietnam and the General Director of the Traditional Medicine Administration of Vietnam,

The Minister of Health hereby promulgates a Circular on Good Manufacturing Practices for pharmaceutical products and pharmaceutical starting materials.

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GENERAL PROVISIONS

Article 1. Scope

This Circular provides for application and promulgation of Good Manufacturing Practices for pharmaceutical products and pharmaceutical starting materials (hereinafter referred to as “GMP”) and inspection of GMP compliance.

Article 2. Definitions

For the purposes of this Circular, the terms below shall be construed as follows:

1. “Good Manufacturing Practices” (GMP) means a set of principles and standards for manufacture of pharmaceutical products and pharmaceutical starting materials to ensure that pharmaceutical products and pharmaceutical starting materials are consistently manufactured and controlled to the quality standards appropriate to their intended use and as required by the certificate of pharmaceutical product and pharmaceutical starting material registration.

2. “manufacturer” (including manufacturers of chemical pharmaceutical products, herbal pharmaceutical products, vaccines, biologicals, traditional pharmaceutical products, traditional pharmaceutical products, prepared traditional pharmaceutical materials, pharmaceutical starting materials) means a pharmacy establishment that is required or not required to obtain Certificates of eligibility for pharmacy business and enters one, some or all stages of the process of manufacturing pharmaceutical products and pharmaceutical starting materials.

3. “deficiency” means a deviation from GMP principles or other applicable regulations on pharmacy management.

4. “GMP” stands for Good Manufacturing Practices.

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6. “WHO - GMP” means Good Manufacturing Practices of World Health Organization.

7. “PIC/S” stands for Pharmaceutical Inspection Co-operation Scheme.

8. “PIC/S - GMP” means Good Manufacturing Practices of Pharmaceutical Inspection Co-operation Scheme.

9. “EU” stands for European Union.

10. “EU - GMP” means Good Manufacturing Practices of European Union.

11. “US” stands for United States.

12. “SRA” stands for Stringent Regulatory Agency.

Chapter II

APPLICATION AND PROMULGATION OF GMP

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1. The following GMP principles shall be applied:

a) WHO GMP principles provided in the Appendix I hereof and updated documents specified in Clause 3 of this Article;

b) Principles of WHO - GMP for biological medicinal products derived from Human Blood or Plasma provided in the Appendix II hereof and updated documents specified in Clause 3 of this Article;

c) GMP principles of Pharmaceutical Inspection Co-operation Scheme provided in the Appendix I hereof and updated documents specified in Clause 3 of this Article;

d) EU - GMP principles provided in the Appendix IV hereof and updated documents specified in Clause 3 of this Article.

2. The following GMP principles shall be promulgated:

a) Principles of GMP for herbal pharmaceutical products provided in the Appendix V hereof;

b) Principles of GMP for traditional pharmaceutical products provided in the Appendix VI hereof;

c) Principles of GMP for prepared traditional medicinal materials provided in the Appendix VII hereof.

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4. In the cases where WHO, PICS, EU or pharmacy authorities of SRA countries make any revision to GMP principles (hereinafter referred to as “updated documents) specified in Clause 1 of this Article, within 06 months from the date on which updated documents are published on websites of such authorities, the Drug Administration of Vietnam shall translate and publish the revisions on the web portal of the Ministry of Health and websites of the Drug Administration of Vietnam and Traditional Medicine Administration of Vietnam.

Article 4. Application of GMP principles

1. Manufacturers of pharmaceutical products and pharmaceutical starting materials shall apply GMP principles specified in the Appendix I or Appendix III or Appendix IV hereof and updated documents specified in Clause 4 Article 3 hereof.

2. Manufacturers of biological medicinal products derived from human blood or plasma shall apply GMP principles specified in the Appendix II hereof and updated documents specified in Clause 4 Article 3 hereof.

3. Manufacturers of herbal pharmaceutical products shall apply GMP in accordance with regulations specified in Appendix V hereof.

4. Manufacturers of traditional pharmaceutical products in the form of extractions, pills, pellets or powder shall apply GMP principles specified in Part I - Appendix VI hereof.

5. Manufacturers of traditional pharmaceutical products in modern dosage forms (capsules, tablets, granules, liquid medicines and other modern dosage forms) other than those specified in Clause 4 of this Article shall apply GMP principles specified in Part II - Appendix VI hereof.

6. Manufacturers of prepared traditional medicinal materials shall apply GMP principles specified in Appendix VII hereof.

7. Manufacturers of pharmaceutical products and pharmaceutical starting materials are entitled to apply other GMP principles proved equivalent to EU - GMP principles promulgated by pharmacy authorities of SRA countries and updated documents specified in Clause 4 Article 3 hereof.

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9. Manufacturers of traditional pharmaceutical products and prepared traditional pharmaceutical materials are permitted to apply GMP principles specified in Part II Appendix VI or Appendix I or Appendix III or Appendix IV hereof and updated documents specified in Clause 4 Article 3 hereof.

10. In addition to being manufactured by the manufacturer applying corresponding GMP specified in this Article, pharmaceutical products and pharmaceutical starting materials containing beta-lactam antibiotics (Penicillins, Cephalosporins, Penems and equivalent), cytotoxics/cytostatics, contraceptive sex hormones, vaccines, biologicals and pharmaceutical products with special requirements specified in GMP must be manufacturered at separate facilities using separate equipment, and measures should be in place to prevent the release of such pharmaceutical products, which is likely to affect the environment and other pharmaceutical products manufactured in the same area.

11. Manufacturers of chemical pharmaceutical products in the form of soft capsules, oral liquids and external medicines (creams, gels, ointments and lotions) are entitled to manufacture herbal pharmaceutical products from herbal extract, glue and granule which have been standardized on production lines capable of producing the same dosage forms, and must apply GMP principles specified in the Appendix I or Appendix III or Appendix IV hereof and updated documents specified in Clause 4 Article 3 hereof.

12. Manufacturers of herbal pharmaceutical products are entitled to manufacture herbal pharmaceutical products with added pure ingredients extracted from essential oils, vitamins and minerals, and must apply GMP principles specified in the Appendix V hereof.

13. Manufacturers of traditional pharmaceutical products are entitled to manufacture traditional pharmaceutical products with added pure ingredients extracted from essential oils, vitamins and minerals, and must apply GMP principles specified in the Appendix VI hereof.

14. Manufacturers entering one or some stages of the process of manufacturing pharmaceutical products and pharmaceutical starting materials shall apply and comply with corresponding GMP principles mentioned in Clauses 1, 2, 3, 4 and 5 of this Article.

15. Manufacturers of pharmaceutical products and pharmaceutical starting materials shall apply updated documents specified in Clause 3 Article 3 hereof within:

a) 12 months in case of any change of premises or manufacturing equipment, from the date on which updated documents are published on the website of the Ministry of Health and web portal of the Drug Administration of Vietnam;

b) 06 months in case of updates other than those specified in Point a of this Clause, from the date on which updated documents are published on the website of the Ministry of Health and web portal of the Drug Administration of Vietnam.

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INSPECTION OF GMP COMPLIANCE

Article 5. Documents used as basis for inspection of GMP compliance

1. Documents used as basis for inspection of GMP compliance by a pharmacy business establishment are those included in its application for certificate of eligibility for pharmacy business (the establishment is not required to submit these documents because they have been submitted when it applies for the certificate of eligibility for pharmacy business) prescribed in Article 38 of the Law on Pharmacy and Article 32 of the Government’s Decree No. 54/2017/ND-CP dated May 08, 2017 on guidelines for the implementation of the Law on Pharmacy (hereinafter referred to as “the Decree No. 54/2017/ND-CP”). Manufacturers of special-controlled pharmaceutical products must have the documents prescribed in Article 38 of the Law on Pharmacy and Clause 31 Article 5 of the Government’s Decree No. 155/2018/ND-CP dated November 12, 2018 on amendments to some Articles related to business conditions under state management of the Ministry of Health (hereinafter referred to as “the Decree No.155/2018/ND-CP”).

Technical documents about a manufacturer shall be prepared in accordance with guidelines for the site master file provided in the Appendix VIII hereof or the site master file that is updated in the case of change of scope of operation.

2. If a manufacturer applies for both certificate of GMP compliance and certificate of eligibility for pharmacy business, this content and applied GMP principles must be clearly specified in its application form for certificate of eligibility for pharmacy business.

3. If the manufacturer applying for certificate of eligibility for pharmacy business sells pharmaceutical products and pharmaceutical starting materials to wholesalers, retailers or health facilities, documents about its technologies and personnel according to Clause 2 Article 32 of the Decree No. 54/2017/ND-CP are required when it applies for both certificate of GDP compliance and certificate of eligibility for pharmacy business. The receiving authority shall inspect its compliance with both GDP and GMP in accordance with regulations on GDP.

Article 6. Sequence of inspection of GMP compliance

1. Receipt of applications:

The manufacturer shall submit an application, which includes the documents specified in Article 5 herein, accompanied by the application fees in accordance with regulations of the Minister of Finance to:

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b) the Drug Administration of Vietnam if the manufacturer applies for the certificate for eligibility for pharmacy business that allows manufacture of pharmaceutical starting materials (excluding herbal materials), chemical pharmaceutical products, herbal pharmaceutical products, vaccines and biologicals;

c) the Drug Administration of Vietnam if the manufacturer applies for the certificate for eligibility for pharmacy business that allows manufacture of both one of the pharmaceutical products and pharmaceutical starting materials specified in Point a of this Clause and one of the pharmaceutical products and pharmaceutical starting materials specified in Point b of this Clause at the time of submission.

2. Sequence of receiving and processing applications is prescribed in Clauses 2 and 5 Article 33 of the Decree No. 54/2017/ND-CP and Clause 12 Article 5 of the Decree No. 155/2018/ND-CP .

3. Within 05 days from the receipt of the satisfactory application, the receiving authority shall establish an inspectorate and send the manufacturer the decision on inspectorate establishment specifying expected date of the site inspection.

Within 15 days from the date of issuing the decision, the inspectorate shall carry out a site inspection of the manufacturer.

Article 7. Procedures for inspection and classification of GMP compliance

1. Principles of using GMP documents for inspection of GMP compliance:

a) GMP documents are applied by the manufacturer and specified in the application form for certificate of eligibility for pharmacy business.

b) EU - GMP or PIC/S - GMP or GMP documents specified in Clause 3 Article 3 of this Article are applied if the manufacturer has undergone GMP inspection by SRA and been recommended by SRA to make the declaration of compliance with GMP.

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2. Inspection procedures:

a) Step 1. The inspectorate shall publish the decision on inspectorate establishment, purposes, contents and plan for the inspection at the manufacturer;

b) Step 2. The manufacturer shall make a brief introduction of its organizational structure, personnel and implementation or application of GMP, or specific contents in conformity with the inspected contents;

c) Step 3. The inspectorate shall carry out a site inspection of the application of GMP at the manufacturer. If the manufacturer enters one or some stages of the manufacturing process, only GMP applied to such stages is inspected.

d) Step 4. The inspectorate shall have a talk with the manufacturer about deficiencies found during the inspection (if any) and assess the level of each deficiency; discuss with the manufacturer in case the manufacturer does not agree with the inspectorate about the assessment of each deficiency or level of GMP compliance;

dd) Step 5. An inspection record is prepared and signed as follows:

After the site inspection, the inspectorate shall make an inspection record using the Form No. 03 in the Appendix X hereof. It shall clearly specify members of the inspectorate and the manufacturer, location, date and scope of the inspection and disagreements (if any) between the inspectorate and the manufacturer. It shall be signed by the head of the manufacturer and chief of the inspectorate. The record shall be made into 03 copies, among which one is kept by the manufacturer and the others are kept by the receiving authority.

e) Step 6. The inspection record is completed as follows:

The inspectorate shall make a GMP inspection report using the Form No. 04 in the Appendix X hereof, list, analyze and classify deficiencies that need to be rectified by the manufacturer, make a comparison of corresponding regulations specified in legal documents and GMP, and assess the level of GMP compliance. The deficiency classification and assessment of level of GMP compliance (applied to each production line) are prescribed in the Appendix IX hereof.

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The inspection of manufacturer's compliance with GMP specified in Appendix IX hereof shall be carried out according to the following 04 levels:

a) GMP level 1 manufacturer;

b) GMP level 2 manufacturer;

c) GMP level 3 manufacturer;

d) GMP level 4 manufacturer.

Article 8. Processing results of inspection of GMP compliance

1. If the GMP inspection report indicates that the manufacturer complies with GMP at level 1 as prescribed in Point a Clause 3 Article 7 of this Circular:

Within 10 working days from the date of signing the inspection record, the receiving authority shall request the Minister of Health to issue the certificate of eligibility for pharmacy business and issue the Certificate of GMP compliance according to Form No. 05 in the Appendix X hereof if the manufacturer applies for both certificate of GMP compliance and certificate of eligibility for pharmacy business.

2. If the GMP inspection report indicates that the manufacturer complies with GMP at level 2 as prescribed in Point b Clause 3 Article 7 of this Circular:

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b) Upon completion of deficiency rectification, the manufacturer shall submit a rectification report including a plan and evidences (such as documents, images, videos, certificates or other documentary evidences) for completion of rectification of deficiencies specified in the GMP inspection report;

c) Within 20 days from the receipt of the rectification report, the receiving authority shall assess result of deficiency rectification by the manufacturer and conclude the level of its GMP compliance. To be specific:

- If the result of deficiency rectification makes the manufacturer comply with GMP, the receiving authority shall request the Minister of Health to issue the certificate of eligibility for pharmacy business and the certificate of GMP compliance according to the Form No. 05 in the Appendix X hereof if the manufacturer applies for both certificate of GMP compliance and certificate of eligibility for pharmacy business;

- If the result of deficiency rectification shows that the manufacturer still fails to comply with GMP, the receiving authority shall respond and provide explanation in writing.

d) Within 06 months from the date on which additional documents are requested in writing by the receiving authority, the manufacturer shall submit them as requested. If the manufacturer fails to satisfy such request by the aforementioned deadline or the application is not satisfactory within 12 months from the first time it is submitted, the application will be rejected.

3. If the GMP inspection report indicates that the manufacturer complies with GMP at level 3 as prescribed in Point c Clause 3 Article 7 of this Circular:

Sequence and time of processing result of inspection of GMP compliance are specified in Clause 2 of this Article.

Within 20 days from the receipt of the rectification report, the receiving authority shall carry out a site inspection of deficiency rectification at the manufacturer before concluding the level of GMP compliance as prescribed in Point c Clause 2 of this Article.

4. If the GMP inspection report indicates that the manufacturer complies with GMP at level 4 as prescribed in Point d Clause 3 Article 7 of this Circular:

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5. In the cases where the manufacturer does not agree with the deficiency stated by the inspectorate, within 30 days from the date on which the inspectorate sends GMP inspection report or rectification report, the manufacturer shall submit a written recommendation enclosed with evidences (such as documents, images, videos and certificates) related to such deficiency to the receiving authority.

Within 10 working days from the receipt of the written recommendation, the receiving authority shall review GMP inspection report and written recommendation submitted by the manufacturer, if necessary, consult relevant exports and respond to the manufacturer in writing. The written response must clearly specify agreements and disagreements with the written recommendation submitted by the manufacturer and reasons for disagreements. The abovementioned length of time shall not add to the time limit for inspection.

6. Within 05 working days from the date of issuing the certificate of eligibility for pharmacy business, the receiving authority shall publish the following information on its website and web portal of the Ministry of Health:

a) Name and address of the manufacturer;

b) Full name of the person in charge of pharmacy, person in charge of quality assurance and number of his/her pharmacy practicing certificate;

c) Number of the certificate of eligibility for pharmacy business and Certificate of GMP compliance (if any);

d) Expiry date of inspection of GMP compliance;

dd) Scope of operation of the manufacturer;

e) EU - GMP certificate number, validity period and issuing authority if the manufacturer has its compliance with EU - GMP or equivalent inspected by SRA.

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INSPECTION OF GMP COMPLIANCE AND MAINTENANCE THEREOF

Article 9. Periodic inspection of GMP compliance

1. GMP compliance by a manufacturer shall be periodically inspected every 03 year from the date of signing the previous inspection record (except surprise inspections or audits by the Ministry of Health or the Provincial Department of Health).

2. In November, every receiving authority shall publish the plan for periodic inspection of GMP compliance by manufacturers in the succeeding year on its website and send it to manufacturers that are mentioned in the plan. Regarding the manufacturer specified in Point c Clause 1 Article 6 of this Circular, the Drug Administration of Vietnam shall publish and implement the periodic inspection plan, except in the cases where the manufacturer applies for a particular inspection.

3. At least 30 days prior to the date of carrying out periodic inspection of GMP compliance according to the published plan, the manufacturer shall submit a report on its manufacture of pharmaceutical products and pharmaceutical starting materials and GMP compliance (hereinafter referred to as “operation and GMP compliance report”) according to the Form No. 2 in the Appendix X hereof enclosed with updated technical documents about infrastructure, technologies and personnel of the manufacturer (in case any change is made) to the receiving authority.

E.g.: If the estimated date of periodic inspection of the manufacturer A is on August 18, 2018, the manufacturer A is required to submit an operation and GMP compliance report to the receiving authority by July 18, 2018.

4. If the manufacturer fails to submit the operation and GMP compliance report within the time limit prescribed in Clause 3 of this Article, within 15 days from the deadline for submission of the report, the receiving authority shall request the manufacturer in writing to submit the operation and GMP compliance report as prescribed.

5. Within 45 days from the date on which the operation and GMP compliance report is requested in writing by the receiving authority, the manufacturer shall submit the report enclosed with a written explanation for its delay in submission. By the aforementioned deadline, if the manufacturer fails to submit the report, the receiving authority shall carry out an surprise inspection or audit of GMP compliance by the manufacturer as prescribed in Article 12 of this Circular.

6. After submitting the operation and GMP compliance report within the prescribed time limit, the manufacturer is entitled to keep manufacturing pharmaceutical products and pharmaceutical starting materials within the scope specified in the certificate for eligibility for pharmacy business until the result of periodic inspection of GMP compliance is available and shall ensure its maintenance of GMP compliance.

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Article 10. Processing of results of periodic inspection of GMP compliance

1. If the GMP inspection report indicates that the manufacturer complies with GMP at level 1 as prescribed in Point a Clause 3 Article 7 of this Circular:

Within 10 working days from the date of signing the inspection record, the receiving authority shall update information about the maintenance of GMP compliance by the manufacturer on its website and web portal of the Ministry of Health as prescribed in Clause 6 Article 8 of this Circular and issue the Certificate of GMP compliance according to Form No. 05 in the Appendix X hereof if the manufacturer applies for the certificate of GMP compliance.

2. If the GMP inspection report indicates that the manufacturer complies with GMP at level 2 as prescribed in Point b Clause 3 Article 7 of this Circular:

a) Within 05 working days from the date of signing the inspection record, the receiving authority shall send the GMP inspection report to the manufacturer so that it can rectify deficiencies and send a rectification report to the receiving authority;

b) Within 45 days from the date on which the receiving authority sends the GMP inspection report, the manufacturer shall submit a rectification report including a plan and evidences (such as documents, images, videos, certificates or other documentary evidences) for completion of rectification of deficiencies specified in the GMP inspection report;

c) Within 20 days from the receipt of the rectification report, the receiving authority shall assess result of deficiency rectification by the manufacturer and conclude the level of its GMP compliance. To be specific:

- If the result of deficiency rectification makes the manufacturer comply with GMP, the receiving authority shall update information about the maintenance of GMP compliance by the manufacturer on its website and web portal of the Ministry of Health as prescribed in Clause 6 Article 8 of this Circular and issue the Certificate of GMP compliance according to Form No. 05 in the Appendix X hereof if the manufacturer applies for the certificate of GMP compliance;

- If the result of deficiency rectification shows that the manufacturer still fails to comply with GMP, the receiving authority shall request the manufacturer in writing to take more corrective actions against deficiencies and submit an additional report. The manufacturer shall have 45 days from the receipt of the written request to complete corrective actions and send report thereof as requested.

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3. If the GMP inspection report indicates that the manufacturer complies with GMP at level 3 as prescribed in Point c Clause 3 Article 7 of this Circular:

Sequence and time of processing result of inspection of GMP compliance are specified in Clause 2 of this Article.

Within 20 days from the receipt of the rectification report, the receiving authority shall carry out a site inspection and supervision of deficiency rectification at the manufacturer before concluding the level of GMP compliance as prescribed in Point c Clause 2 of this Article.

4. If the GMP inspection report indicates that the manufacturer complies with GMP at level 4 as prescribed in Point d Clause 3 Article 7 of this Circular:

Within 05 working days from the date of signing the inspection record, according to the assessment of risks of deficiencies in the quality of pharmaceutical products and pharmaceutical starting materials, and pharmaceutical product user safety, the receiving authority shall send a notification of failure to comply with GMP enclosed with a GMP inspection report. Depending on the nature and level of non-compliance with GMP, the receiving authority shall impose one or some of the following measures:

a) Impose penalties for administrative violations in accordance with regulations of the Law on penalties for administrative violations;

b) Request the Minister of Health to issue a decision on revocation of the certificate of eligibility for pharmacy business as prescribed in Clause 2 Article 40 of the Law on Pharmacy and revoke the certificate of GMP compliance (if any).

c) If the manufacturer is ineligible for one or several business activities specified in its certificate of eligibility for pharmacy business, the receiving authority shall:

- request the Minister of Health to issue a decision on revocation of the certificate of eligibility for pharmacy business to remove the business activity for which the manufacturer is ineligible and issue a new certificate of eligibility for pharmacy business which is conformable with the business activity for which the manufacturer is eligible;

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5. Within 05 working days from the date of concluding that the manufacturer maintains its compliance with GMP or issuing the decision on revocation of the issued certificate of eligibility for pharmacy business because of the manufacturer’s failure to maintain GMP compliance, the receiving authority shall update GMP compliance status on its website as prescribed in Clause 6 Article 8 of this Circular if the manufacturer complies with GMP or information about the revocation of the certificate of eligibility for pharmacy business or Certificate of GMP compliance (if any) if the manufacturer fails to maintain its GMP compliance.

6. If it is concluded that a sample of pharmaceutical product or pharmaceutical starting material collected by the inspectorate during the inspection violates quality regulations, the receiving authority shall handle it in accordance with applicable regulations.

Article 11. Control of changes

1. Before making one of the changes specified in Points a and b of this Clause, a vaccine manufacturer shall send a notification including the result of assessment of risks and effect of changes expected to be made on the product quality and safety:

a) Changes specified in Points d, dd, e and g Clause 2 of this Article;

b) Manufacture or trial manufacture of vaccines or other pharmaceutical products on the vaccine production line that has been certified;

Within 15 days, the Drug Administration of Vietnam shall respond in writing in case it does not agree with the changes proposed by the vaccine manufacturer.

2. After making any change, the manufacturer shall apply for the certificate of eligibility for pharmacy business or submit a report on its change using the Form No. 06 in the Appendix X hereof if:

a) making one of the changes specified in Point b Clause 1 Article 36 of the Law on Pharmacy; or

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c) opening a new factory at the same business location; or

d) expanding existing factory; or

dd) repairing or having significant changes in structure and floor plan of the premises and production line, which results in changes to environmental conditions and manufacturing process; or

e) changing important manufacturing equipment, thereby affecting manufacturing process and quality of pharmaceutical products and pharmaceutical starting materials; or

g) changing auxiliary system or principle of designing and operating utility systems, thereby affecting manufacturing environment; or

h) changing applied GMP and undergoing inspection of compliance with EU - GMP or equivalent (Japan - GMP, US - Current GMP, PIC/S -GMP) by an SRA and being recommended by an SRA to make the declaration of compliance with GMP.

3. In case of changes specified in Point a Clause 2 of this Article, the manufacturer shall submit an application for the certificate of eligibility for pharmacy business as prescribed in Clause 2 and Clause 4 Article 38 of the Law on Pharmacy.

Sequence of inspecting, classifying and processing the result of inspection of GMP compliance is specified in Articles 6, 7 and 8 of this Circular.

4. If the manufacturer has one of the changes prescribed in Points b, c, d or h Clause 2 of this Article or the manufacturer of sterile pharmaceutical products and pharmaceutical starting materials has the change specified in Point dd Clause 2 of this Article, the manufacturer is required to submit a report on its changes, accompanied by relevant technical documents, to the receiving authority.

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b) Sequence of inspecting, classifying and processing the result of inspection of GMP compliance in case of the change specified in Point b Clause 2 of this Article is prescribed in Articles 6, 7 and 10 of this Circular;

c) Sequence of inspecting, classifying and processing the result of inspection of GMP compliance by the manufacturer that makes the change specified in Point c or d Clause 2 of this Article or the manufacturer of sterile pharmaceutical products and pharmaceutical starting materials that makes the change specified in Point dd Clause 2 of this Article is prescribed in Articles 6, 7 and 8 of this Circular.

5. In case of the change specified in Point h Clause 2 of this Article, the manufacturer shall send a notification of change of applied GMP and inspection by SRA at the manufacturer (name of SRA, date of inspection, content/scope of inspection and inspection result) enclosed with relevant technical documents, certificate of GMP compliance or GMP inspection report issued by SRA.

a) The receiving authority shall review the notification and enclosed documents and add/update information about compliance with EU - GMP or equivalent by the manufacturer as prescribed in Clause 6 Article 8 of this Circular.

b) The receiving authority shall inspect compliance with EU - GMP or equivalent by the manufacturer as prescribed in Article 12 of this Circular.

6. In case of one of the changes prescribed in Point dd, e or g Clause 2 of this Article (except in the cases specified in Clauses 4 and 6 of this Article), the manufacturer shall submit a report on its change, accompanied by relevant technical documents, to the receiving authority. The receiving authority shall assess the manufacturer’s report on changes.

a) Within 10 working days from the receipt of the report on changes, the receiving authority shall notify the manufacturer in writing of approval for its changes if they meet requirements or issue a notification of deficiencies that need rectifying if its changes fail to meet with requirements;

b) Within 45 days from the receipt of the notification, the manufacturer shall complete deficiency rectification and send a rectification report enclosed with documentary evidences (such as documents, images, videos, certificates and other documentary evidences) for completion of rectification of deficiencies specified in the notification;

c) Within 10 days from the receipt of the rectification report enclosed with documentary evidences (such as documents, images, videos, certificates and other documentary evidences), the receiving authority shall assess result of deficiency rectification by the manufacturer and conclude the level of its GMP compliance. To be specific:

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- If the result of deficiency rectification shows the manufacturer still fails to comply with GMP, the receiving authority shall carry out an surprise inspection and process inspection result as prescribed in Article 12 of this Circular.

7. If the manufacturer of non-sterile pharmaceutical products and pharmaceutical starting materials for external use has one of the changes prescribed in Points dd, e and g Clause 2 of this Article, the manufacturer is required to submit a report on its change, accompanied by relevant technical documents, to the receiving authority. The manufacturer shall keep carrying out manufacturing operations in accordance with principles of GMP.

Article 12. Unexpected inspection of GMP compliance or audit of GMP compliance and maintenance thereof

1. Audit of GMP compliance and maintenance thereof by manufacturers shall be conducted as prescribed by law.

2. An surprise inspection of GMP compliance and maintenance thereof shall be carried out at the manufacturer in one of the following cases:

a) The result of deficiency rectification by the manufacturer shows it still fails to comply with GMP according to Sub-point 2 Point c Clause 6 Article 11 of this Circular;

b) The manufacturer that complies with GMP at level 3 or level 4 according to Points c and d Clause 3 Article 7 of this Circular shall undergo an surprise inspection at least once within 03 (three) years from the end of the previous inspection;

c) The manufacturer has at least 01 batch of pharmaceutical products which is recalled because of first-degree violations;

d) The manufacturer has a pharmaceutical product that is reported to have adverse effects, including serious ones;

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e) There is any complaint or denunciation that the manufacturer seriously violates GMP;

g) The manufacturer fails to submit the operation and GMP compliance report according to Clause 5 Article 9 of this Circular.

3. The head of the receiving authority shall decide on members of the inspectorate as prescribed in Article 15 of this Circular.

4. Sequence of conducting surprise inspections at a manufacturer is mentioned in Article 7 of this Circular.

5. Results of surprise inspections or audits conducted at a manufacturer shall be processed as prescribed by law.

Chapter V

INSPECTION OF GMP COMPLIANCE BY MANUFACTURERS NOT REQUIRED TO OBTAIN CERTIFICATES OF ELIGIBILITY FOR PHARMACY BUSINESS AND OVERSEAS MANUFACTURERS WHEN THEY APPLY FOR REGISTRATION OF PHARMACEUTICAL PRODUCTS AND PHARMACEUTICAL STARTING MATERIALS IN VIETNAM

Article 13. Inspection of GMP compliance by manufacturers not required to obtain certificates of eligibility for pharmacy business

1. A manufacturer not required to obtain the certificate of eligibility for pharmacy business (non-commercial pharmacy establishment) must comply with GMP as prescribed in Point a Clause 2 Article 35 of the Law on Pharmacy.

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3. Sequence of inspection and procedures for inspection and classification of results of inspection of GMP compliance, control of changes and surprise inspection of GMP compliance by manufacturers of pharmaceutical products and pharmaceutical starting materials not required to obtain certificates of eligibility for pharmacy business are mentioned in Articles 6, 7, 9, 11 and 12 of this Circular.

4. Results of first inspection of GMP compliance by a manufacturer of pharmaceutical products and pharmaceutical starting materials not required to obtain the certificate of eligibility for pharmacy business shall be processed as follows:

a) Sequence and time of processing result of first inspection of GMP compliance by the manufacturer are mentioned in Article 8 of this Circular.

b) The receiving authority shall send a notification of status of GMP compliance by the manufacturer and publish it on its website and web portal of the Ministry of Health as prescribed in Clause 6 of this Article.

5. Results of surprise and periodic inspections of GMP compliance by a manufacturer of pharmaceutical products and pharmaceutical starting materials not required to obtain the certificate of eligibility for pharmacy business shall be processed as follows:

a) If the inspection result shows that the manufacturer complies with GMP at level 1 or level 2 or level 3 as prescribed in Points a, b and c Clause 3 Article 7 of this Circular, the receiving authority shall carry out inspection as prescribed in Clauses 1, 2 and 3 Article 10 of this Circular.

b) If the inspection result shows that the manufacturer complies with GMP at level 4 as prescribed in Point d Clause 3 Article 7 of this Circular, the receiving authority shall carry out an inspection and issue a decision on suspension of all manufacturing operations or manufacturing operations that fail to comply with GMP until the result of deficiency rectification by the manufacturer rectifies is satisfactory.

c) If it is concluded that a sample of pharmaceutical product or pharmaceutical starting material collected by the inspectorate during the inspection violates quality regulations, the receiving authority shall handle it in accordance with applicable regulations on management of quality of pharmaceutical products and pharmaceutical starting materials. The head of the manufacturer shall be responsible to law for such violation.

6. Within 05 working days from the date of concluding that the GMP compliance or maintenance of GMP compliance by a manufacturer of pharmaceutical products and pharmaceutical starting materials not required to obtain the certificate of eligibility for pharmacy business, the receiving authority shall publish the following information on its website and web portal of the Ministry of Health:

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b) Full name of the person in charge of pharmacy, person in charge of quality assurance and number of his/her pharmacy practicing certificate;

c) Number of certificate of GMP compliance;

d) Expiry date of inspection of GMP compliance;

dd) Scope of operation of the manufacturer.

e) EU - GMP certificate number, validity period and issuing authority if the manufacturer has its compliance with EU - GMP or equivalent (if any) inspected by SRA.

Article 14. Inspection of GMP compliance by overseas manufacturers when they apply for registration of pharmaceutical products and pharmaceutical starting materials in Vietnam

1. Before submitting an application for inspection of GMP compliance to the Ministry of Health (the receiving authority specified in Clause 1 Article 6 of this Circular) shall have its GMP compliance inspected and certified by a competent pharmacy authority of the home country.

2. Methods, contents, documentation, sequence, procedures and power for inspection of GMP compliance by overseas manufacturers are mentioned in Articles 96, 97, 98 and 99 of the Decree No. 54/2017/ND-CP .

In the cases where the inspection of GMP compliance is conducted using the method for conducting a inspection at the manufacturer, procedures for inspecting, classifying and processing inspection results and controlling changes is prescribed in Articles 6, 7, 8, 9, 10, 11 and 12 of this Circular.

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a) Name and address of the manufacturer;

b) Number of certificate of GMP compliance, GMP documents applied, validity period of certificate of GMP compliance and name of the competent pharmacy authority in the cases specified in Points a and b Clause 5 Article 54 of the Law on Pharmacy or date of GMP compliance inspection by the Vietnam Ministry of Health, GMP documents applied and validity period of result of inspection of GMP compliance in the case specified in Point c Clause 5 Article 54 of the Law on Pharmacy;

c) Scope of operation of the inspected manufacturer.

Chapter VI

INSPECTORATE CONDUCTING INSPECTIONS OF GMP COMPLIANCE

Article 15. Members and standards to be satisfied by members of an inspectorate

1. An inspectorate includes:

a) the chief and 01 or 02 members of the receiving authority. 01 or 02 members of the Traditional Medicine Administration of Vietnam, regarding the manufacturer specified in Point c Clause 1 Article 6 of this Circular;

b) 01 member: the representative of the National Institute of Drug Quality Control or Institute of Drug Quality Control - Ho Chi Minh City or National Institute for Control of Vaccine and Biologicals (regarding the manufacturer of vaccines and biologicals);

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d) Members of relevant authorities where necessary.

2. A member of the inspectorate must satisfy the following standards:

a) He/she must obtain at least a bachelor’s degree and has been provided with training medicine, pharmacy, biology, pharmaceutical product quality management and pharmacy management;

b) He/she has been trained in GMP and inspection of GMP compliance, and has a thorough grasp of GPP principles. Members joining the inspectorate conducting inspections of manufacturers of traditional pharmaceutical products and herbal materials must be trained in GMP for traditional pharmaceutical products and herbal materials.

c) He/she must be honest, objective strictly comply with regulations during the inspection and must not create any conflict of interest with the inspected manufacturer as prescribed in Clause 3 of this Article;

d) The chief must have at least 03 (three) years’ experience in pharmacy management.

3. Rules for assessing the conflict of interest: A member of the inspectorate shall be deemed to involve a conflict of interest with the inspected manufacturer in one of the following cases:

a) He/she has worked or participated in providing consulting services for the inspected manufacturer in the past 05 years;

b) He/she is receiving financial benefits associated with the inspected manufacturer;

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Article 16. Rights and responsibilities of an inspectorate

1. The inspectorate has the responsibility to:

a) inspect all operations of a manufacture according to corresponding GMP prescribed in Article 3 of this Circular, updated versions of GMP principles and relevant legislative documents and regulations; clearly record inspection contents and deficiencies found, prepare GMP inspection records and reports;

b) report inspection results or provide explanation for the GMP inspection report if the manufacturer has any disagreements with the report;

c) maintain confidentiality of all information about the inspection and manufacturing operations, inspection of quality, storage and distribution of pharmaceutical products (manufacturing, testing and cleaning process, technological secrets, etc.) unless otherwise agreed upon by the manufacturer or requested by the competent authority.

2. The inspectorate has the right to:

a) inspect all areas and premises of the manufacturer and request inspection of other areas related to the manufacture, storage and testing of pharmaceutical products and pharmaceutical starting materials. Regarding manufacture of prepared traditional pharmaceutical materials, inspect the prepared traditional pharmaceutical material processing and manufacturing process.

b) request the manufacturer to provide documents concerning its quality management, manufacture, testing and storage of pharmaceutical products and pharmaceutical starting materials;

c) collect documentary evidences (by copying documents, taking pictures or recording videos) of deficiencies found during the inspection;

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dd) make inspection records and request the manufacturer to suspend one, some or all of its manufacturing operations related to violations. During the inspection, if the inspectorate finds that the manufacturer commits a violation which seriously affects quality of one or multiple pharmaceutical products and pharmaceutical starting materials, it is required to notify the competent person thereof.

Chapter VII

IMPLEMENTATION CLAUSE

Article 17. Effect

1. This Circular comes into force from January 10, 2019.

2. The following documents and regulations are null and void from the effective date of this Circular:

a) Decision No. 3886/2004/QD-BYT dated November 03, 2004 of the Minister of Health;

b) Regulations on GMP specified in the Decision No. 27/2007/QD-BYT dated April 19, 2007 of the Minister of Health;

c) Regulations on GMP specified in the Circular No. 45/2011/TT-BYT dated December 21, 2011 of the Minister of Health; Decision No. 2701/2001/QD-BYT dated June 29, 2001 of the Minister of Health; Circular No. 06/2004/TT-BYT dated May 28, 2004; Decision No. 3886/2004/QD-BYT dated November 03, 2004 of the Ministry of Health; Circular No. 13/2009/TT-BYT September 01, 2009 of the Ministry of Health; Circular No. 22/2009/TT-BYT dated November 24, 2009 of the Ministry of Health; Circular No. 2010/TT-BYT dated December 29, 2010.

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dd) Regulation: “If the test facility fails to submit the application as prescribed, the Ministry of Health shall revoke its certificate of eligibility for pharmacy business as prescribed in Clause 2 Article 40 of the Law on Pharmacy” specified in Clause 5 Article 9 of the Circular No. 04/2018/TT-BYT of the Minister of Health dated February 09, 2018.

Article 18. Reference clause

In the cases where any of the legislative documents and regulations referred to in this Circular is amended or replaced, the newest one shall apply.

Article 19. Transitional clauses

1. Any manufacturer of pharmaceutical products and pharmaceutical starting materials that has been issued with the certificate for eligibility for pharmacy business that allows manufacture of pharmaceutical products and pharmaceutical starting materials or certificate of GMP compliance before the effective date of this Circular is entitled to manufacture pharmaceutical products and pharmaceutical starting materials until the expiry date of such certificate.

If the certificate of eligibility for pharmacy business expires, the manufacturer shall apply for the certificate of eligibility for pharmacy business as prescribed by law.

If the certificate of GMP compliance expires before the expiry date of the certificate of eligibility for pharmacy business, the manufacturer shall apply for inspection of GMP compliance and maintenance thereof according to Chapter IV of this Circular in order to keep operating as prescribed.

2. Regarding the manufacturer of pharmaceutical products and pharmaceutical starting materials that has been issued with the indefinite term certificate for eligibility for pharmacy business that allows manufacture of pharmaceutical products and pharmaceutical starting materials, it shall, upon the expiry date of the certificate of GMP compliance, apply for inspection of GMP compliance and follow relevant procedures as prescribed by law.

3. Regarding applications for certificate of eligibility for pharmacy business or applications for periodic inspection of GMP compliance submitted to the receiving authority before the effective date of this Circular, the receiving authority shall keep inspecting the manufacturer according to GMP promulgated together with the Decision No. 3886/2004/QD-BYT dated November 03, 2004 of the Minister of Health or regulations of this Circular if the manufacturer so requests.

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Article 20. Responsibility for implementation

1. The Drug Administration of Vietnam shall:

a) take charge and cooperate with relevant units in organizing the dissemination of this Circular. Take charge of compiling a list of GMP criteria relevant to each type of manufacturing according to the principle of transparency, clarity and accuracy and request the Ministry of Health to promulgate it to form a basis for application of GMP to manufacturers of pharmaceutical products and pharmaceutical starting materials and inspection by pharmacy authorities.

b) within its jurisdiction, instruct Provincial Departments of Health, health authorities and manufacturers of pharmaceutical products and pharmaceutical starting materials to implement this Circular;

c) consolidate and publish the list of manufacturers that have been granted the certificate of eligibility for pharmacy business and/or Certificate of GMP compliance, status of such certificates, status of GMP compliance and other information on its website according to Clause 6 Article 8 of this Circular within its jurisdiction;

d) publish updated GMP documents on its website and the web portal of the Ministry of Health;

dd) take charge or cooperate with the Ministry Inspectorate in inspecting and auditing GMP compliance and take actions against violations within its power.

2. The Traditional Medicine Administration of Vietnam shall:

a) within its jurisdiction, instruct Provincial Departments of Health, health authorities and manufacturers of pharmaceutical products and pharmaceutical starting materials to implement this Circular;

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c) take charge or cooperate with the Ministry Inspectorate in inspecting and auditing GMP compliance and take actions against violations within its power.

3. Provincial Departments of Health shall:

a) cooperate with relevant units in organizing the dissemination of this Circular and instruct units within provinces to implement this Circular;

b) join the inspectorate conducting inspections of GMP compliance; within their power, supervise and takes actions against violations against regulations on GMP compliance by manufacturers of pharmaceutical products and pharmaceutical starting materials within provinces.

4. The National Institute of Drug Quality Control, Institute of Drug Quality Control - Ho Chi Minh City and National Institute for Control of Vaccine and Biologicals shall join the inspectorate conducting inspections of GMP compliance upon request.

5. Manufacturers of pharmaceutical products and pharmaceutical starting materials shall:

a) organize the implementation of this Circular;

b) ensure their compliance with GMP during their operation;

c) carry out manufacturing operations within the inspected and licensed scope according to regulations of law.

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PP. THE MINISTER
THE DEPUTY MINISTER




Truong Quoc Cuong

APPENDIX I

WHO GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL PRODUCTS: MAIN PRINCIPLES
(Enclosed with the Circular No.
35/2018/TT-BYT dated November 22, 2018 of the Minister of Health)

PART I. GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL PRODUCTS - MAIN PRINCIPLES

General considerations

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Quality management in the medicines industry: philosophy and essential elements

1. Pharmaceutical quality system

2. Good manufacturing practices for pharmaceutical products

3. Sanitation and hygiene

4. Qualification and validation

5. Complaints

6. Product recalls

7. Contract production, analysis and other activities

8. Self-inspection, quality audits and suppliers’ audits and approval

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10. Training

11. Personal hygiene

12. Premises

13. Equipment

14. Materials

15. Documentation

16. Good practices in production

17. Good practices in quality control

PART II. GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL STARTING MATERIALS

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2. Quality management

3. Personnel

4. Buildings and facilities

5. Process equipment

6. Documentation and records

7. Materials management

8. Production and in-process controls

9. Packaging and identification labeling of APIs and intermediates

10. Storage and distribution

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12. Validation

13. Change control

14. Rejection and re-use of materials

15. Complaints and recalls

16. Contract manufacturers (including laboratories)

17. Agents, brokers, traders, distributors, repackers, and relabellers

18. Specific guidance for APIs manufactured by cell culture/fermentation

19. APIs for use in clinical trials

20. Glossary

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1. Introduction

2. Scope

3. Terminology

4. Principles and general considerations

5. Pharmaceutical quality system and quality risk management

6. Personnel

7. Starting materials

8. Seed lots and cell banks

9. Premises and equipment

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11. Clean rooms

12. Production

13. Campaign production

14. Labelling

15. Validation

16. Quality control

17. Documentation (batch processing records)

18. Use of animals

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GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL PRODUCTS - MAIN PRINCIPLES

General considerations

Licensed pharmaceutical products (marketing authorization) should be manufactured only by licensed manufacturers (holders of a manufacturing authorization) whose activities are regularly inspected by competent national authorities. This guide to GMP shall be used as a standard to justify GMP status, which constitutes one of the elements of the WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce, through the assessment of applications for manufacturing authorizations and as a basis for the inspection of manufacturing facilities. It may also be used as training material for government medicines inspectors, as well as for production, QC and QA personnel in the industry.

The guide is applicable to operations for the manufacture of medicines in their finished dosage forms, including large-scale processes in hospitals and the preparation of supplies for use in clinical trials.

The good practices outlined below are to be considered general guides, and they may be adapted to meet individual needs. The equivalence of alternative approaches to QA, however, should be validated. The guide as a whole does not cover safety aspects for the personnel engaged in manufacture, or environmental protection: these are normally governed by national legislation. A new concept of hazard analysis related to the risks in production and personnel safety has also been recently recommended (WHO Technical Report Series, No. 961, Annex 7). The manufacturer should assure the safety of workers and take the necessary measures to prevent pollution of the external environment.

International Nonproprietary Names (INN) for pharmaceutical substances designated by WHO should be used when available, together with other designated names.

Glossary

The definitions given below apply to the terms used in this guide. They may have different meanings in other contexts.

active pharmaceutical ingredient (API)

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airlock

An enclosed space with two or more doors, which is interposed between two or more rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An airlock is designed for use either by people or for goods and/or equipment.

authorized person

The person recognized by the national regulatory authority as having the responsibility for ensuring that each batch of finished product has been manufactured, tested and approved for release in compliance with the laws and regulations in force in that country.

batch (or lot)

A defined quantity of starting material, packaging material, or product processed in a single process or series of processes so that it is expected to be homogeneous.  It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch. In the case of terminal sterilization, the batch size is determined by the capacity of the autoclave. In continuous manufacture, the batch must correspond to a defined fraction of the production, characterized by its intended homogeneity. The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time interval.

batch number

A distinctive combination of numbers and/or letters which uniquely identifies a batch on the labels, its batch records and corresponding certificates of analysis, etc.

batch records

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bulk product

Any product that has completed all processing stages up to, but not including, final packaging.

calibration

The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established.

clean area

An area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.

consignment (or delivery)

The quantity of a pharmaceutical or pharmaceuticals, made by one manufacturer and supplied at one time in response to a particular request or order. A consignment may comprise one or more packages or containers and may include material belonging to more than one batch.

contamination

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critical operation

An operation in the manufacturing process that may cause variation in the quality of the pharmaceutical product.

cross-contamination

Contamination of a starting material, intermediate product or finished product with another starting material or product during production.

finished product

A finished dosage form that has undergone all stages of manufacture, including packaging in its final container and labelling.

in-process control

Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of in-process control.

intermediate product

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large-volume parenterals

Sterile solutions intended for parenteral application with a volume of 100 ml or more in one container of the finished dosage form.

manufacture

All operations of purchase of materials and products, production, quality control (QC), release, storage and distribution of pharmaceutical products, and the related controls.

manufacturer

A company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals.

marketing authorization (product licence, registration certificate)

A legal document issued by the competent medicines regulatory authority that establishes the detailed composition and formulation of the product and the pharmacopoeial or other recognized specifications of its ingredients and of the final product itself, and includes details of packaging, labelling and shelf-life.

master formula

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master record

A document or set of documents that serve as a basis for the batch documentation (blank batch record).

packaging

All operations, including filling and labelling, that a bulk product has to undergo in order to become a finished product. Filling of a sterile product under aseptic conditions or a product intended to be terminally sterilized, would not normally be regarded as part of packaging.

packaging material

Any material, including printed material, employed in the packaging of a pharmaceutical, but excluding any outer packaging used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product.

pharmaceutical product

Any material or product intended for human or veterinary use presented in its finished dosage form, or as a starting material for use in such a dosage form, that is subject to control by pharmaceutical legislation in the exporting state and/or the importing state.

 production

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qualification

Action of proving that any premises, systems and items of equipment work correctly and actually lead to the expected results. The meaning of the word “validation” is sometimes extended to incorporate the concept of qualification.

quality assurance

See Part 1 (6).

quality unit(s)

An organizational unit independent of production which fulfils both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

quarantine

The status of starting or packaging materials, intermediates, or bulk or finished products isolated physically or by other effective means while a decision is awaited on their release, rejection or reprocessing.

reconciliation

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recovery

The introduction of all or part of previous batches (or of redistilled solvents and similar products) of the required quality into another batch at a defined stage of manufacture. It includes the removal of impurities from waste to obtain a pure substance or the recovery of used materials for a separate use.

reprocessing

Subjecting all or part of a batch or lot of an in-process medicine, bulk process intermediate (final biological bulk intermediate) or bulk product of a single batch or lot to a previous step in the validated manufacturing process due to failure to meet predetermined specifications. Reprocessing procedures are foreseen as occasionally necessary for biological medicines and, in such cases, are validated and pre-approved as part of the marketing authorization.

reworking

Subjecting all or part of a batch or lot of an in-process medicine, bulk process intermediate (final biological bulk intermediate) or bulk product of a single batch or lot to a previous step in the validated manufacturing process due to failure to meet predetermined specifications. Reworking is an unexpected occurrence and is not pre-approved as part of the marketing authorization.

self-contained area

Premises which provide complete and total separation of all aspects of an operation, including personnel and equipment movement, with well established procedures, controls and monitoring. This includes physical barriers as well as separate air-handling systems, but does not necessarily imply two distinct and separate buildings.

specification

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standard operating procedure (SOP)

An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.

starting material

Any substance of a defined quality used in the production of a pharmaceutical product, but excluding packaging materials.

validation

Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or system actually leads to the expected results.

Quality management in the medicines industry: philosophy and essential elements

In the medicines industry at large, quality management is usually defined as the aspect of the management function that determines and implements the “quality policy”, i.e. the overall intention and direction of an organization regarding quality, as formally expressed and authorized by top management.  The basic elements of quality management are:

- an appropriate infrastructure or “quality system”, encompassing the organizational structure, procedures, processes and resources;

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The totality of these actions is termed “QA”. Within an organization, QA serves as a management tool. In contractual situations, QA also serves to generate confidence in the supplier. The concepts of QA, GMP, QC and quality risk management (QRM) are interrelated aspects of quality management and should be the responsibility of all personnel. They are described here in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products.

1. Pharmaceutical quality system

1.1. Principle: The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of staff in many different departments and at all levels within the company, the company’s suppliers and the distributors. To achieve this quality objective reliably there must be a comprehensively designed and correctly implemented pharmaceutical quality system (PQS) incorporating GMP and QRM.

1.2. Senior management has the ultimate responsibility to ensure an effective PQS is in place, is adequately resourced, and that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organization. Senior management’s leadership and active participation in the PQS is essential. This leadership should ensure the support and commitment of staff at all levels and sites within the organization to the PQS.

1.3. Quality management is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality management, therefore, incorporates GMP and other factors, including those outside the scope of this guide, such as product design and development.

1.4. GMP applies to the life-cycle stages from the manufacture of investigational medicinal products, technology transfer, and commercial manufacturing, through to product discontinuation. The PQS can extend to the pharmaceutical development life-cycle stage and should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities. All parts of the PQS should be adequately resourced and maintained, including being provided with sufficient competent personnel, suitable premises, equipment and facilities.

1.5. The PQS appropriate to the manufacture of pharmaceutical products should ensure that:

a) product realization is achieved by designing, qualifying, planning, implementing, maintaining and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes;

b) product and process knowledge is managed throughout all lifecycle stages;

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d) production and control operations are clearly specified in a written form and GMP requirements are adopted;

e) managerial responsibilities are clearly specified in job descriptions;

f) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials, the selection and monitoring of suppliers and for verifying that each delivery is the correct material from the approved supply chain;

g) all necessary controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations and validations are carried out;

h) the finished product is correctly processed and checked, according to the defined procedures;

i) pharmaceutical products are not sold or supplied before the authorized persons (see also sections 9.11 and 9.12) have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of pharmaceutical products;

j) processes are in place to assure the management of outsourced activities;

k) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf-life;

l) there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the PQS;

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n) arrangements are in place for the prospective evaluation and approval of planned changes and their approval prior to implementation taking into account regulatory notification and approval where required. After implementation of any change, an evaluation is undertaken to confirm that the quality objectives were achieved and that there was no unintended adverse impact on product quality.

o) regular reviews of the quality of pharmaceutical products are conducted with the objective of verifying the consistency of the process and identifying where there is a need for improvement;

p) a state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality;

q) continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge;

r) there is a system for QRM;

s) deviations, suspected product defects and other problems are reported, investigated and recorded. An appropriate level of root cause analysis is applied during such investigations. The most likely root cause(s) should be identified and appropriate corrective actions and/or preventive actions (CAPAs) should be identified and taken. The effectiveness of CAPAs should be monitored.

1.6. There should be periodic management reviews, with the involvement of senior management, of the operation of the PQS to identify opportunities for continual improvement of products, processes and the system itself. Unless otherwise justified, such reviews should be conducted at least annually

1.7. The PQS should be defined and documented. A quality manual or equivalent documentation should be established and should contain a description of the quality management system including management responsibilities.

Quality risk management

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1.9. QRM should ensure that:

- the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient;

- the level of effort, formality and documentation of the QRM process is commensurate with the level of risk.

Product quality review

1.10. Regular, periodic or rolling quality reviews of all pharmaceutical products, including export-only products, should be conducted with the objective of verifying the consistency of the existing process and the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least:

a) review of starting materials and packaging materials used for the product, especially those from new sources and in particular the review of supply chain traceability of active substances;

b) a review of critical in-process controls, and finished product results;

c) a review of all batches that failed to meet established specification(s) and their investigation;

d) a review of all significant deviations or non-conformances, the related investigations and the effectiveness of resultant CAPAs taken;

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f) a review of dossier variations submitted, granted or refused;

g) a review of the results of the stability monitoring programme and any adverse trends;

h) a review of all quality-related returns, complaints and recalls and the investigations performed at the time;

i) a review of adequacy of any other previous corrective actions on product processes or equipment;

j) post-marketing commitments for new dossiers and variations to the dossiers;

k) the qualification status of relevant equipment and utilities, e.g. heating, ventilation and air-conditioning (HVAC), water or compressed gases and a review of the results of monitoring the output of such equipment and utilities;

l) a review of technical agreements to ensure that they are up to date.

The manufacturer and, where different, marketing authorization holder, should evaluate the results of the review and an assessment should be made as to whether CAPA or any revalidation should be undertaken, under the PQS. CAPAs should be completed in a timely and effective manner, according to documented procedures. There should be procedures for the ongoing management and review of these actions, and the effectiveness of these procedures should be verified during self-inspection. Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, or sterile products, where scientifically justified. Where the marketing authorization holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the quality review. The authorized person responsible for final batch certification, together with the marketing authorization holder, should ensure that the quality review is performed in a timely manner and is accurate.

2. Good manufacturing practices for pharmaceutical products

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a) all manufacturing processes are clearly defined, systematically reviewed for associated risks in the light of scientific knowledge and experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications;

b) qualification and validation are performed;

c) all necessary resources are provided, including:

(i) sufficient and appropriately qualified and trained personnel;

(ii) adequate premises and space;

(iii) suitable equipment and services;

(iv) appropriate materials, containers and labels;

(v) approved procedures and instructions;

(vi) suitable storage and transport; and

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d) instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided;

e) procedures are carried out correctly and personnel are trained to do so;

f) records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected. Any significant deviations are fully recorded and investigated with the objective of determining the root cause and appropriate corrective and preventive action is implemented;

g) records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

h) the proper storage and distribution of the products minimizes any risk to their quality and takes account of good distribution practices (GDP);

i) a system is available to recall any batch of product from sale or supply;

j) complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products to prevent recurrence.

3. Sanitation and hygiene

3.1. A high level of sanitation and hygiene should be practised in every aspect of the manufacture of medicines. The scope of sanitation and hygiene covers personnel, premises, equipment and apparatus, production materials and containers, products for cleaning and disinfection, and anything that could become a source of contamination to the product. Potential sources of contamination should be eliminated through an integrated comprehensive programme of sanitation and hygiene. (For Personal hygiene see section 11, and for sanitation see section 12, “Premises”.)

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4.1. In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled.

4.2. The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan.

4.3. Qualification and validation should establish and provide documentary evidence that:

a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification or DQ);

b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications (installation qualification or IQ);

c) the premises, supporting utilities and equipment operate in accordance with their design specifications (operational qualification or OQ);

d) a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation or PV, also called performance qualification or PQ).

4.4. Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated.

4.5. Qualification and validation should not be considered as one-off exercises. An ongoing programme should follow their first implementation and should be based on an annual review.

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4.7. The responsibility for performing validation should be clearly defined.

4.8. Validation studies are an essential part of GMP and should be conducted in accordance with predefined and approved protocols.

4.9. A written report summarizing the results recorded and the conclusions reached should be prepared and stored.

4.10. Processes and procedures should be established on the basis of the results of the validation performed.

4.11. Particular attention should be paid to the validation of analytical test methods, automated systems and cleaning procedures.

5. Complaints

5.1. Principle. All complaints and other information concerning potentially defective products should be carefully reviewed according to written procedures and the corrective action should be taken.

5.2. A person responsible for handling the complaints and deciding the measures to be taken should be designated, together with sufficient supporting staff to assist him or her. If this person is different from the authorized person, the latter should be made aware of any complaint, investigation or recall.

5.3. There should be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect.

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5.5. Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for QC should normally be involved in the review of such investigations.

5.6. If a product defect is discovered or suspected in a batch, consideration should be given to whether other batches should be checked in order to determine whether they are also affected. In particular, other batches that may contain reprocessed product from the defective batch should be investigated.

5.7. Where necessary, appropriate follow-up action, possibly including product recall, should be taken after investigation and evaluation of the complaint.

5.8. All decisions made and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records.

5.9. Complaints records should be regularly reviewed for any indication of specific or recurring problems that require attention and might justify the recall of marketed products.

5.10. The competent authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, a suspect product or any other serious quality problems with a product.

6. Product recalls

6.1. Principle. There should be a system to recall from the market, promptly and effectively, products known or suspected to be defective.

6.2. The authorized person should be responsible for the execution and coordination of recalls. He or she should have sufficient staff to handle all aspects of the recalls with the appropriate degree of urgency.

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6.4. An instruction should be included in the written procedures to store recalled products in a secure segregated area while their fate is decided.

6.5. All competent authorities of all countries to which a given product has been distributed should be promptly informed of any intention to recall the product because it is, or is suspected of being, defective.

6.6. The distribution records should be readily available to the authorized person, and they should contain sufficient information on wholesalers and directly supplied customers (including, for exported products, those who have received samples for clinical tests and medical samples) to permit an effective recall.

6.7. The progress of the recall process should be monitored and recorded. Records should include the disposition of the product. A final report should be issued, including a reconciliation between the delivered and recovered quantities of the products.

6.8. The effectiveness of the arrangements for recalls should be tested and evaluated from time to time.

7. Contract production, analysis and other activities

7.1. Principle. Contract production, analysis and any other activity covered by GMP must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product, or work or analysis, of unsatisfactory quality.

General

7.2. All arrangements for contract production and analysis, including technology transfer and any proposed changes in technical or other arrangements, should be in accordance with the marketing authorization for the product concerned.

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7.4. In the case of contract analysis, the final approval for release must be given by the authorized person in accordance with GMP and the marketing authorization as specified in the contract.

The contract giver

7.5. The PQS of the contract giver should include the control and review of any outsourced activities. The contract giver is responsible for assessing the legality, suitability and competence of the contract acceptor to successfully carry out the work or tests required, for approval for contract activities, and for ensuring by means of the contract that the principles of GMP incorporating QRM principles are followed.

7.6. The contract giver should provide the contract acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorization and any other legal requirements. The contract giver should ensure that the contract acceptor is fully aware of any hazards associated with the product, work or tests that might pose a risk to premises, equipment, personnel, other materials or other products.

7.7. The contract giver should review and assess the records and results related to the outsourced activities. The contract giver should ensure that all products and materials delivered by the contract acceptor have been processed in accordance with GMP and the marketing authorization; comply with their specifications and that the product has been released by the authorized person in accordance with GMP and the marketing authorization.

7.8. The contract giver should monitor and review the performance of the contract acceptor including the implementation of any needed improvements and their effectiveness.

7.9. The contract giver is responsible for ensuring that the contract acceptor understands that his or her activities may be subject to inspection by competent authorities.

The contract acceptor

7.10. The contract acceptor must have adequate premises, equipment, knowledge, experience and competent personnel to satisfactorily carry out the work ordered by the contract giver. Contract manufacture may be undertaken only by a manufacturer who holds a valid manufacturing authorization.

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7.12. The contract acceptor should refrain from any activity (including unauthorized changes outside the terms of the contract) that may adversely affect the quality of the product manufactured and/or analysed for the contract giver.

The contract

7.13. There must be a written contract between the contract giver and the contract acceptor which clearly establishes the responsibilities of each party, covering the outsourced activities, the products or operations to which they are related, communication processes relating to the outsourced activities and any technical arrangements made in connection with it.

7.14. The contract must clearly state the way in which the authorized person, in releasing each batch of product for sale or issuing the certificate of analysis, exercises his or her full responsibility and ensures that each batch has been manufactured in, and checked for, compliance with the requirements of the marketing authorization.

7.15. Technical aspects of the contract should be drawn up by competent persons with suitable knowledge of pharmaceutical technology, analysis and GMP.

7.16. All arrangements for production and analysis must be in accordance with the marketing authorization and agreed by both parties.

7.17. The contract should clearly describe who is responsible for contracted activities, e.g. knowledge management, technology transfer, supply chain, subcontracting, testing and releasing materials and undertaking production and QC, including in-process controls, and who has responsibility for sampling and analysis. In the case of contract analysis, the contract should state whether or not the contract acceptor should take samples at the premises of the manufacturer.

7.18. Manufacturing, analytical and distribution records, and reference samples, should be kept by, or be available to, the contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect, or to investigating in the case of a suspected falsified product or laboratory fraud, must be accessible and specified in the procedures of the contract giver.

7.19. The contract should describe the handling of starting materials, intermediate, bulk and finished products, if they are rejected. It should also describe the procedure to be followed if the contract analysis shows that the tested product must be rejected.

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8.1. Principle. The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and QC. The selfinspection programme should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections should be performed routinely, and may be, in addition, performed on special occasions, e.g. in the case of product recalls or repeated rejections, or when an inspection by the health authorities is announced. The team responsible for self-inspection should consist of personnel who can evaluate the implementation of GMP objectively. All recommendations for corrective action should be implemented. The procedure for self-inspection should be documented, and there should be an effective follow-up programme.

Items for self-inspection

8.2. Written instructions for self-inspection should be established to provide a minimum and uniform standard of requirements. These may include questionnaires on GMP requirements covering at least the following items:

a) Personnel;

b) premises including personnel facilities;

c) maintenance of buildings and equipment;

d) storage of starting materials and finished products;

e) equipment;

f) production and in-process controls;

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h) documentation;

i) sanitation and hygiene;

j) validation and revalidation programmes;

k) calibration of instruments or measurement systems;

l) recall procedures;

m) complaints management;

n) labels control;

o) results of previous self-inspections and any corrective steps taken.

Self-inspection team

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Frequency of self-inspection

8.4. The frequency with which self-inspections are conducted may depend on company requirements but should preferably be at least once a year. The frequency should be stated in the procedure.

Self-inspection report

8.5. A report should be made at the completion of a self-inspection. The report should include:

a) self-inspection results;

b) evaluation and conclusions;

c) recommended corrective actions.

Follow-up action

8.6. There should be an effective follow-up programme. The company management should evaluate both the self-inspection report and the corrective actions as necessary.

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8.7. It may be useful to supplement self-inspections with a quality audit. A quality audit consists of an examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits may also be extended to suppliers and contractors (see section 7, “Contract production and analysis”).

Suppliers’ audits and approval

8.8. The person responsible for QC should have responsibility, together with other relevant departments, for approving suppliers who can reliably supply starting and packaging materials that meet established specifications.

8.9. Before suppliers are approved and included in the approved suppliers’ list or specifications, they should be evaluated. The evaluation should take into account a supplier’s history and the nature of the materials to be supplied. If an audit is required, it should determine the supplier’s ability to conform with GMP standards.

9. Personnel

9.1. Principle. The establishment and maintenance of a satisfactory system of QA and the correct manufacture and control of pharmaceutical products and active ingredients rely upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks for which the manufacturer is responsible. Individual responsibilities should be clearly defined and understood by the persons concerned and recorded as written descriptions.

General

9.2. The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.

9.3. Responsible staff should have its specific duties recorded in written descriptions and adequate authority to carry out its responsibilities. Its duties may be delegated to designated deputies with a satisfactory level of qualifications. There should be no gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of GMP. The manufacturer should have an organization chart.

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9.5. Steps should be taken to prevent unauthorized people from entering production, storage and QC areas. Personnel who do not work in these areas should not use them as a passageway.

Key personnel

9.6. Key personnel include the heads of production, the head(s) of quality unit(s) and the authorized person. The quality unit(s) typically comprise the quality assurance and quality control functions. In some cases, these could be combined in one department. The authorized person may also be responsible for one or more of these quality unit(s). Normally, key posts should be occupied by full-time personnel. The heads of production and quality unit(s) should be independent of each other. In large organizations, it may be necessary to delegate some of the functions; however, the responsibility cannot be delegated.

9.7. Key personnel responsible for supervising the production and quality unit(s) for pharmaceutical products should possess the qualifications of a scientific education and practical experience required by national legislation. Their education should include the study of an appropriate combination of:

a) chemistry (analytical or organic) or biochemistry;       

b) chemical engineering;

c) microbiology;

d) pharmaceutical sciences and technology;

e) pharmacology and toxicology;

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g) other related sciences.

They should also have adequate practical experience in the manufacture and QA of pharmaceutical products. In order to gain such experience, a preparatory period may be required, during which they should perform their duties under professional guidance. The scientific education and practical experience of experts should be such as to enable them to exercise independent professional judgement, based on the application of scientific principles and understanding to the practical problems encountered in the manufacture and QC of pharmaceutical products.

9.8. The heads of the production and the quality unit(s) generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, depending on national regulations:

a) authorization of written procedures and other documents, including amendments;

b) monitoring and control of the manufacturing environment;

c) plant hygiene;

d) process validation and calibration of analytical apparatus;

e) training, including the application and principles of QA;

f) approval and monitoring of suppliers of materials;

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h) designation and monitoring of storage conditions for materials and products;

i) performance and evaluation of in-process controls;

j) retention of records;

k) monitoring of compliance with GMP requirements;

l) inspection, investigation and taking of samples in order to monitor factors that may affect product quality.

9.9. The head of production generally has the following responsibilities:

a) to ensure that products are produced and stored in accordance with the appropriate documentation in order to obtain the required quality;

b) to approve the instructions relating to production operations, including the in-process controls, and to ensure their strict implementation;

c) to ensure that the production records are evaluated and signed by a designated person;

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e) to ensure that the appropriate process validations and calibrations of control equipment are performed and recorded and the reports made available;

f) to ensure that the required initial and continuing training of production personnel is carried out and adapted according to need.

9.10. The head(s) of the quality unit(s) generally have the following responsibilities:

a) to approve or reject starting materials, packaging materials, and intermediate, bulk and finished products in relation to their specifications;

b) to evaluate batch records;

c) to ensure that all necessary testing is carried out;

d) to approve sampling instructions, specifications, test methods and other QC procedures;

e) to approve and monitor analyses carried out under contract;

f) to check the maintenance of the department, premises and equipment;

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h) to ensure that the required initial and continuing training of quality unit personnel is carried out and adapted according to need;

i) establishment, implementation and maintenance of the quality system;

j) supervision of the regular internal audits or self-inspections;

k) participation in external audit (vendor audit);

j) participation in validation programmes.

Other duties of QC are summarized in sections 17.3 and 17.4.

9.11. The authorized person is responsible for compliance with technical or regulatory requirements related to the quality of finished products and the approval of the release of the finished product for sale or supply.

9.12. Assessment of finished products should embrace all relevant factors, including the production conditions, the results of in-process testing, the manufacturing (including packaging) documentation, compliance with the specification for the finished product, and an examination of the finished pack.

9.13. No batch of product is to be released for sale or supply prior to certification by the authorized person(s). In certain countries, by law, the batch release is a task of the authorized person from production together with the authorized person from QC.

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a) the marketing authorization and the manufacturing authorization requirements for the product have been met for the batch concerned;

b) the principles and guidelines of GMP, as laid down in the guidelines published by WHO, have been followed;

c) the principal manufacturing and testing processes have been validated;

d) all the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records;

e) any planned changes or deviations in manufacturing or QC have been notified in accordance with a well-defined reporting system before any product is released. Such changes may need notification to, and approval by, the medicines regulatory authority;

f) any additional sampling, inspection, tests and checks have been carried out or initiated, as appropriate, to cover planned changes and deviations;

g) all necessary production and QC documentation has been completed and endorsed by supervisors trained in appropriate disciplines;

h) appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff;

i) approval has been given by the head of QC;

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9.15. The function of the approval of the release of a finished batch or a product can be delegated to a designated person with appropriate qualifications and experience who will release the product in accordance with an approved procedure. This is normally done by QA by means of batch review.

10. Training

10.1. The manufacturer should provide training in accordance with a written programme for all personnel whose duties take them into manufacturing areas or into control laboratories (including the technical, maintenance and cleaning personnel) and for other personnel as required.

10.2. Besides basic training on the theory and practice of GMP, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness periodically assessed. Approved training programmes should be available. Training records should be kept.

10.3. Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly active, toxic, infectious or sensitizing materials are handled, should be given specific training.

10.4. The concept of QA and all the measures which aid its understanding and implementation should be fully discussed during the training sessions.

10.5. Visitors or untrained personnel should preferably not be taken into the production and QC areas. If this is unavoidable, they should be given relevant information in advance (particularly about personal hygiene) and the prescribed protective clothing. They should be closely supervised.

10.6. Consultant and contract staff should be qualified for the services they provide. Evidence of this should be included in the training records.

11. Personal hygiene

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11.2. All personnel should be trained in the practices of personal hygiene. A high level of personal hygiene should be observed by all those concerned with manufacturing processes. In particular, personnel should be instructed to wash their hands before entering production areas. . Signs to this effect should be posted and instructions complied with.

11.3. Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials or medicines until the condition is no longer judged to be a risk.

11.4. All employees should be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment or personnel) that they consider may adversely affect the products.

11.5. Direct contact should be avoided between the operator’s hands and starting materials, primary packaging materials and intermediate or bulk product.

11.6. To ensure protection of the product from contamination, personnel should wear clean body coverings appropriate to the duties they perform, including appropriate hair covering.

Used clothes, if reusable, should be stored in separate closed containers until properly laundered and, if necessary, disinfected or sterilized.

11.7. Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines should not be permitted in production, laboratory and storage areas, or in any other areas where they might adversely influence product quality.

11.8. Personal hygiene procedures, including the wearing of protective clothing, should apply to all persons entering production areas, whether they are temporary or full-time employees or non-employees, e.g. contractors’ employees, visitors, senior managers and inspectors.

12. Premises

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General

12.2. The layout and design of premises must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid crosscontamination, build-up of dust or dirt, and in general, any adverse effect on the quality of products.

12.3. Where dust is generated (e.g. during sampling, weighing, mixing and processing operations, or packaging of powder), measures should be taken to avoid cross-contamination and facilitate cleaning.

12.4. Premises should be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimum risk of causing any contamination of materials or products.

12.5. Premises used for the manufacture of finished products should be suitably designed and constructed to facilitate good sanitation.

12.6. Premises should be carefully maintained, and it should be ensured that repair and maintenance operations do not present any hazard to the quality of products.

12.7. Premises should be cleaned and, where applicable, disinfected according to detailed written procedures. Records should be maintained.

12.8. Electrical supply, lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment.

12.9. Premises should be designed and equipped so as to afford maximum protection against the entry of insects, birds or other animals. There should be a procedure for rodent and pest control.

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Ancillary areas

12.11. Rest and refreshment rooms should be separate from manufacturing and control areas.

12.12. Facilities for changing and storing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not communicate directly with production or storage areas.

12.13. Maintenance workshops should if possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.

12.14. Animal houses should be well isolated from other areas, with separate entrance (animal access) and air-handling facilities.

Storage areas

12.15. Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products with proper separation and segregation: starting and packaging materials, intermediates, bulk and finished products, products in quarantine, and released, rejected, returned or recalled products.

12.16. Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean, dry, sufficiently lit and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity), these should be provided, controlled, monitored and recorded where appropriate.

12.17. Receiving and dispatch bays should be separated and should protect materials and products from the weather. Receiving areas should be designed and equipped to allow containers of incoming materials to be cleaned, if necessary, before storage.

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12.19. Segregation should be provided for the storage of rejected, recalled, or returned materials or products.

12.20. Highly active and radioactive materials, narcotics, other dangerous medicines, and substances presenting special risks of abuse, fire or explosion should be stored in safe and secure areas.

12.21. Printed packaging materials are considered critical to the conformity of the pharmaceutical product to its labelling and special attention should be paid to sampling and the safe and secure storage of these materials.

12.22. There should normally be a separate sampling area for starting materials. (If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.)

Weighing areas

12.23. The weighing of starting materials and the estimation of yield by weighing should be carried out in separate weighing areas designed for that use, for example, with provisions for dust control. Such areas may be part of either storage or production areas.

Production areas

12.24. In order to minimize the risk of a serious medical hazard due to crosscontamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. live microorganisms). The production of certain other highly active products, such as some antibiotics, hormones, cytotoxic substances and certain non-pharmaceutical products, should not be conducted in the same facilities. In exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations (including cleaning validation) are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of pharmaceutical products.

12.25. Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.

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12.27. Where starting and primary packaging materials and intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth and free from cracks and open joints, should not shed particulate matter, and should permit easy and effective cleaning and, if necessary, disinfection.

12.28. Pipework, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.

12.29. Drains should be of adequate size and designed and equipped to prevent back-flow. Open channels should be avoided where possible, but if they are necessary they should be shallow to facilitate cleaning and disinfection.

12.30. Production areas should be effectively ventilated, with air-control facilities (including filtration of air to a sufficient level to prevent contamination and cross-contamination, as well as control of temperature and, where necessary, humidity) appropriate to the products handled, to the operations undertaken and to the external environment. These areas should be regularly monitored during both production and non-production periods to ensure compliance with their design specifications.

12.31. Premises for the packaging of pharmaceutical products should be specifically designed and laid out so as to avoid mix ups, contamination or cross-contamination.

12.32. Production areas should be well lit, particularly where visual online controls are carried out.

Quality control areas

12.33. QC laboratories should be separated from production areas. Areas where biological, microbiological or radioisotope test methods are employed should be separated from each other.

12.34. QC laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix ups and crosscontamination. There should be adequate suitable storage space for samples, reference standards (if necessary, with cooling), solvents, reagents and records.

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12.36. A separate room may be needed for instruments to protect them against electrical interference, vibration, contact with excessive moisture and other external factors, or where it is necessary to isolate the instruments.

13. Equipment

13.1. Equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. The layout and design of equipment must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products.

13.2. Equipment should be installed in such a way as to minimize any risk of error or of contamination.

13.3. Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow.

13.4. All service pipework and devices should be adequately marked and special attention paid to the provision of non-interchangeable connections or adaptors for dangerous gases and liquids.13.5. Balances and other measuring equipment of an appropriate range and precision should be available for production and control operations and should be calibrated according to a fixed schedule.

13.6. Production equipment should be thoroughly cleaned according to a fixed schedule.

13.7. Laboratory equipment and instruments should be suited to the testing procedures undertaken.

13.8. Washing, cleaning and drying equipment should be chosen and used so as not to be a source of contamination.

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13.10. Defective equipment should be removed from production and QC areas. If this is not possible, it should be clearly labelled as defective to prevent use.

13.11. Closed equipment should be used whenever appropriate. Where open equipment is used or equipment is opened, precautions should be taken to minimize contamination.

13.12. Non-dedicated equipment should be cleaned according to validated cleaning procedures between being used for production of different pharmaceutical products to prevent cross-contamination.

13.13. Current drawings of critical equipment and support systems should be maintained.

14. Materials

14.1. Principle. The main objective of a pharmaceutical plant is to produce finished products for patients’ use from a combination of materials (starting and packaging).

14.2. Materials include starting materials, packaging materials, gases, solvents, process aids, reagents and labelling materials.

General

14.3. No materials used for operations such as cleaning, lubrication of equipment and pest control should come into direct contact with the product. Where possible, such materials should be of a suitable grade (e.g. food grade) to minimize health risks.

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14.5. All materials and products should be stored under the appropriate conditions established by the manufacturer, and in an orderly fashion, to permit batch segregation and stock rotation by a first-expire, first-out rule.

14.6. Water used in the manufacture of pharmaceutical products should be suitable for its intended use.

Starting material

14.7. The purchase of starting materials is an important operation that should involve staff who have a particular and thorough knowledge of the products and suppliers.

14.8. Starting materials should be purchased only from approved suppliers and, where possible, directly from the producer.  It is also recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is beneficial for all critical aspects of the production and control of the starting material in question, including handling, labelling and packaging requirements as well as complaints and rejection procedures, to be contractually agreed between the manufacturer and the supplier.

14.9. For each consignment, at a minimum, the containers should be checked at least for integrity of package and seal and for correspondence between the order, the delivery note, and the supplier’s labels.

14.10. All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labelled, if required, with the prescribed information. Where additional labels are attached to containers, the original information should not be lost.

14.11. Damage to containers and any other problem that might adversely affect the quality of a material should be recorded and reported to the QC department and investigated.

14.12. If one delivery of material is made up of different batches, each batch must be considered as separate for sampling, testing and release.

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a) the designated name of the product and the internal code reference where applicable;

b) the batch number given by the supplier and, on receipt, the control or batch number given by the manufacturer, if any, documented so as to ensure traceability;

c) the status of the contents (e.g. in quarantine, on test, released, rejected, returned, recalled);

d) where appropriate, an expiry date or a date beyond which retesting is necessary. When fully validated computerized storage systems are used, not all of the above information need be in a legible form on the label.

14.14. There should be appropriate procedures or measures to ensure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified.

14.15. Only starting materials released by the QC department and within their shelf-life should be used.

14.16. Starting materials should be dispensed only by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.

14.17. Each dispensed material and its weight or volume should be independently checked and the check recorded.

14.18. Materials dispensed for each batch of the final product should be kept together and conspicuously labelled as such.

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14.19. The purchase, handling and control of primary and printed packaging materials should be as for starting materials.

14.20. Particular attention should be paid to printed packaging materials. They should be stored in secure conditions so as to exclude the possibility of unauthorized access. Roll feed labels should be used wherever possible. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix ups. Packaging materials should be issued for use only by designated personnel following an approved and documented procedure.

14.21. Each delivery or batch of printed or primary packaging material should be given a specific reference number or identification mark.

14.22. Outdated or obsolete primary packaging material or printed packaging material should be destroyed and its disposal recorded.

14.23. All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity and conformity with the packaging instructions.

Intermediate and bulk products

14.24. Intermediate and bulk products should be kept under appropriate conditions.

14.25. Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials.

Finished products

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14.27. The evaluation of finished products and the documentation necessary for release of a product for sale are described in section 17, “Good practices in quality control”.

Rejected, recovered, reprocessed and reworked materials

14.28. Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed in a timely manner. Whatever action is taken should be approved by authorized personnel and recorded.

14.29. The reworking or recovery of rejected products should be exceptional. It is permitted only if the quality of the final product is not affected, if the specifications are met, and if it is done in accordance with a defined and authorized procedure after evaluation of the risks involved. A record should be kept of the reworking or recovery. A reworked batch should be given a new batch number.

14.30. The introduction of all or part of earlier batches, conforming to the required quality standards, into a batch of the same product at a defined stage of manufacture should be authorized beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf-life. The recovery should be recorded.

14.31. The need for additional testing of any finished product that has been reprocessed, reworked or into which a recovered product has been incorporated, should be considered by the QC department.

Recalled products

14.32. Recalled products should be identified and stored separately in a secure area until a decision is taken on their fate. This decision should be made as soon as possible.

Returned goods

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Reagents and culture media

14.34. There should be records for the receipt and preparation of reagents and culture media.

14.35. Reagents made up in the laboratory should be prepared according to written procedures and appropriately labelled. The label should indicate the concentration, standardization factor, shelf-life, the date when restandardization is due, and the storage conditions. The label should be signed and dated by the person preparing the reagent.

14.36. Both positive and negative controls should be applied to verify the suitability of culture media each time they are prepared and used. The size of the inoculum used in positive controls should be appropriate to the sensitivity required.

Reference standards

14.37. Whenever official reference standards exist, these should preferably be used.

14.38. Official reference standards should be used only for the purpose described in the appropriate monograph.

14.39. Reference standards prepared by the producer should be tested, released and stored in the same way as official standards. They should be kept under the responsibility of a designated person in a secure area.

14.40. Secondary or working standards may be established by the application of appropriate tests and checks at regular intervals to ensure standardization.

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a) name of the material;

b) batch or lot number and control number;

c) date of preparation;

d) shelf-life;

e) potency;

f) storage conditions.

14.42. All in-house reference standards should be standardized against an official reference standard, when available, initially and at regular intervals thereafter.

14.43. All reference standards should be stored and used in a manner that will not adversely affect their quality.

Waste materials

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14.45. Waste material should not be allowed to accumulate. It should be collected in suitable receptacles for removal to collection points outside the buildings and disposed of safely and in a sanitary manner at regular and frequent intervals.

Miscellaneous

14.46. Rodenticides, insecticides, fumigating agents and sanitizing materials should not be permitted to contaminate equipment, starting materials, packaging materials, in-process materials or finished products.

15. Documentation

15.1. Principle. Good documentation is an essential part of the quality assurance system and, as such, should exist for all aspects of GMP. Its aims are to define the specifications and procedures for all materials and methods of manufacture and control; to ensure that all personnel concerned with manufacture know what to do and when to do it; to ensure that authorized persons have all the information necessary to decide whether or not to release a batch of a medicine for sale; to ensure the existence of documented evidence, traceability, and to provide records and an audit trail that will permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis. The design and use of documents depend upon the manufacturer. In some cases some or all of the documents described below may be brought together, but they will usually be separate.

General

15.2. Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorizations.

15.3. Documents should be approved, signed and dated by the appropriate responsible persons. No document should be changed without authorization and approval.

15.4. Documents should have unambiguous contents: the title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.

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15.6. Where documents require the entry of data, these entries should be clear, legible and indelible. Sufficient space should be provided for such entries.

15.7. Any alteration made to a document should be signed and dated; the alteration should be done in such a way as to permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

15.8. Records should be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records should be retained for at least one year after the expiry date of the finished product.

15.9. Data (and records for storage) may be recorded by electronic dataprocessing systems or by photographic or other reliable means. Master formulae and detailed SOPs relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data-processing methods, only authorized persons should be able to enter or modify data in the computer system, and there should be a record of changes and deletions; access should be restricted by passwords or other means and the entry of critical data should be independently checked. Batch records stored electronically should be protected by back-up transfer on magnetic tape, microfilm, electronic discs, paper printouts or other means. It is particularly important that, during the period of retention, the data are readily available.

Documents required

Labels

15.10. Labels applied to containers, equipment or premises should be clear, unambiguous and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (e.g. quarantined, accepted, rejected, clean).

15.11. All finished medicines should be identified by labelling, as required by the national legislation, bearing at least the following information:

a) the name of the medicines;

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c) the batch number assigned by the manufacturer;

d) the expiry date in an uncoded form;

e) any special storage conditions or handling precautions that may be necessary;

f) directions for use, and warnings and precautions that may be necessary;

g) the name and address of the manufacturer or the company or the person responsible for placing the product on the market.

15.12. For reference standards, the label and/or accompanying document should indicate potency or concentration, date of manufacture, expiry date, date the closure is first opened, storage conditions and control number, as appropriate.

Specifications and testing procedures

15.13. Testing procedures described in documents should be validated in the context of available facilities and equipment before they are adopted for routine testing;

15.14. There should be appropriately authorized and dated specifications, including tests on identity, content, purity and quality, for starting and packaging materials and for finished products; where appropriate, they should also be available for intermediate or bulk products. Specifications for water, solvents and reagents (e.g. acids and bases) used in production should be included.

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15.16. Periodic revisions of the specifications may be necessary to comply with new editions of the national pharmacopoeia or other official compendia.

15.17. Pharmacopoeias, reference standards, reference spectra and other reference materials should be available in the QC laboratory.

Specifications for starting and packaging materials

15.18. Specifications for starting, primary and printed packaging materials should provide, if applicable, a description of the materials, including:

a) the designated name (if applicable, the INN) and internal code reference;

b) the reference, if any, to a pharmacopoeial monograph;

c) qualitative and quantitative requirements with acceptance limits.

Depending on the company’s practice other data may be added to the specification, such as:

a) the supplier and the original producer of the materials;

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c) directions for sampling and testing, or a reference to procedures;

d) storage conditions and precautions;

e) the maximum period of storage before reexamination.

Packaging material should conform to specifications, and should be compatible with the material and/or with the medicines it contains. The material should be examined for compliance with the specification, and for defects as well as for the correctness of identity markings.

15.19. Documents describing testing procedures should state the required frequency for re-assaying each starting material, as determined by its stability.

Specifications for intermediate and bulk products

15.20. Specifications for intermediate and bulk products should be available. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.

Specifications for finished products

15.21. Specifications for finished products should include:

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b) the designated name(s) of the active ingredient(s) (if applicable, with the INN(s));

c) the formula or a reference to the formula;

d) a description of the dosage form and package details;

e) directions for sampling and testing or a reference to procedures;

f) the qualitative and quantitative requirements, with acceptance limits;

g) the storage conditions and precautions, where applicable;

h) the shelf-life.

Master formulae

15.22. A formally authorized master formula should exist for each product and batch size to be manufactured.

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a) the name of the product, with a product reference code relating to its specification;

b) a description of the dosage form, strength of the product and batch size;

c) a list of all starting materials to be used (if applicable with the INNs), with the amount of each, described using the designated name and a reference that is unique to that material (mention should be made of any substance that may disappear in the course of processing);

d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable;

e) a statement of the processing location and the principal equipment to be used;

f) the methods, or reference to the methods, to be used for preparing and operating the critical equipment, e.g. cleaning (especially after a change in product), assembling, calibrating, sterilizing, use;

g) detailed step-wise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);

h) the instructions for any in-process controls with their limits;

i) where necessary, the requirements for storage of the products, including the container, the labelling, and any special storage conditions;

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Packaging instructions

15.24. Formally authorized packaging instructions should exist for each product, pack size and type. These should normally include, or make reference to:

a) the name of the product;

b) a description of its pharmaceutical form, strength and, where applicable, method of application;

c) the pack size expressed in terms of the number, weight or volume of the product in the final container;

d) a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types, with the code or reference number relating to the specifications for each packaging material;

e) where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked;

f) special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before and after packaging operations;

g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used;

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Batch processing records

15.25. A batch processing record should be kept for each batch processed. It should be based on the relevant parts of the currently approved specifications on the record. The method of preparation of such records should be designed to avoid errors. (Copying or validated computer programs are recommended. Transcribing from approved documents should be avoided.)

15.26. Before any processing begins a check should be made that the equipment and work station are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check should be recorded.

15.27. During processing, the following information should be recorded at the time each action is taken, and after completion the record should be dated and signed by the person responsible for the processing operations:

a) the name of the product;

b) the number of the batch being manufactured;

c) dates and times of commencement, of significant intermediate stages, and of completion of production;

d) the name of the person responsible for each stage of production;

e) the initials of the operator(s) of different significant steps of production and, where appropriate, of the person(s) who checked each of these operations (e.g. weighing);

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g) any relevant processing operation or event and the major equipment used;

h) the in-process controls performed, the initials of the person(s) carrying them out, and the results obtained;

i) the amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanations for significant deviations from the expected yield;

j) notes on special problems including details, with signed authorization for any deviation from the master formula.

Batch packaging records

15.28. A batch packaging record should be kept for each batch or part batch processed. It should be based on the relevant parts of the approved packaging instructions, and the method of preparing such records should be designed to avoid errors. (Copying or validated computer programs are recommended. Transcribing from approved documents should be avoided.)

These checks should be recorded.

15.30. The following information should be recorded at the time each action is taken, and the date and the person responsible should be clearly identified by signature or electronic password:

a) the name of the product, the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation;

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c) the name of the responsible person carrying out the packaging operation;

d) the initials of the operators of the different significant steps;

e) the checks made for identity and conformity with the packaging instructions, including the results of in-process controls;

f) details of the packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product if it is unpacked or a record of returning product that has not been packaged to the storage area;

g) whenever possible, samples of the printed packaging materials used, including specimens bearing the approval for the printing of and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting;

h) notes on any special problems, including details of any deviation from the packaging instructions, with written authorization by an appropriate person;

i) the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of product obtained to permit an adequate reconciliation.

Standard operating procedures and records

15.31. SOPs and associated records of actions taken or, where appropriate, conclusions reached should be available for:

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b) analytical apparatus and calibration;

c) maintenance, cleaning and sanitization;

d) personnel matters including qualification, training, clothing and hygiene;

e) environmental monitoring;

f) pest control;

g) complaints;

h) recalls;

i) returns.

15.32. There should be SOPs and records for the receipt of each delivery of starting material and primary and printed packaging material.

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a) the name of the material on the delivery note and the containers;

b) the “in-house” name and/or code of material if different from (a);

c) the date of receipt;

d) the supplier’s name and, if possible, manufacturer’s name;

e) the manufacturer’s batch or reference number;

f) the total quantity, and number of containers received;

g) the batch number assigned after receipt;

h) any relevant comment (e.g. state of the containers).

15.34. There should be SOPs for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.

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15.36. There should be SOPs for sampling, which specify the person(s) authorized to take samples.

15.37. The sampling instructions should include:

a) the method of sampling and the sampling plan;

b) the equipment to be used;

c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality;

d) the amount(s) of sample(s) to be taken;

e) instructions for any required subdivision of the sample;

f) the type of sample container(s) to be used, and whether they are for aseptic sampling or for normal sampling, and labelling;

g) any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material.

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15.39. The SOPs for batch numbering that are applied to the processing stage and to the respective packaging stage should be related to each other.

15.40. The SOP for batch numbering should ensure that the same batch numbers will not be used repeatedly; this applies also to reprocessing.

15.41. Batch-number allocation should be immediately recorded, e.g. in a logbook. The record should include at least the date of allocation, product identity and size of batch.

15.42. There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded.

15.43. Analysis records should include at least the following data:

a) the name of the material or product and, where applicable, dosage form;

b) the batch number and, where appropriate, the manufacturer and/ or supplier;

c) references to the relevant specifications and testing procedures;

d) test results, including observations and calculations, and reference to any specifications (limits);

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f) the initials of the persons who performed the testing;

g) the date and initials of the persons who verified the testing and the calculations, where appropriate;

h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person.

15.44. Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by an authorized person.

15.45. Records should be maintained of the distribution of each batch of a product in order, for example, to facilitate the recall of the batch if necessary.

15.46. Records should be kept for major and critical equipment, as appropriate, of any validations, calibrations, maintenance, cleaning or repair operations, including dates and the identity of the people who carried out these operations.

15.47. The use of major and critical equipment and the areas where products have been processed should be appropriately recorded in chronological order.

15.48. There should be written procedures assigning responsibility for cleaning and sanitation and describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used and facilities and equipment to be cleaned. Such written procedures should be followed.

16. Good practices in production

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General

16.2. All handling of materials and products, such as receipt and cleaning, quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded.

16.3. Deviation from instructions or procedures should be avoided as far as possible. If deviations occur, they should be in accordance with an approved procedure. The authorization of the deviation should be approved in writing by a designated person, with the involvement of the QC department, when appropriate.

16.4. Checks on yields and reconciliation of quantities should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.

16.5. Operations on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix up or cross-contamination.

16.6. At all times during processing, all materials, bulk containers, major items of equipment, and, where appropriate, the rooms and packaging lines being used, should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and the batch number. Where applicable, this indication should also mention the stage of production. In some cases it may be useful to also record the name of the previous product that has been processed.

16.7. Access to production premises should be restricted to authorized personnel.

16.8. Normally, non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products.

16.9. In-process controls are usually performed within the production area. The performance of such in-process controls should not have any negative effect on the quality of the product or another product (e.g. cross-contamination or mix up).

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16.10. When dry materials and products are used in production, special precautions should be taken to prevent the generation and dissemination of dust. Provision should be made for proper air control (e.g. supply and extraction of air of suitable quality).

16.11. Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, particles, vapours, sprays or organisms from materials and products in process, from residues on equipment, from intruding insects, and from operators’ clothing, skin, etc. The significance of this risk varies with the type of contaminant and of the product being contaminated. Among the most hazardous contaminants are highly sensitizing materials, biological preparations such as living organisms, certain hormones, cytotoxic substances, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection or applied to open wounds and those given in large doses and/or over a long time.

16.12. Cross-contamination should be avoided by taking appropriate technical or organizational measures, for example:

a) carrying out production in dedicated and self-contained areas (which may be required for products such as penicillins, live vaccines, live bacterial preparations and certain other biologicals);

b) conducting campaign production (separation in time) followed by appropriate cleaning in accordance with a validated cleaning procedure;

c) providing appropriately designed airlocks, pressure differentials, and air supply and extraction systems;

d) minimizing the risk of contamination caused by recirculation or reentry of untreated or insufficiently treated air;

e) wearing protective clothing where products or materials are handled;

f) using cleaning and decontamination procedures of known effectiveness;

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h) testing for residues;

i) using cleanliness status labels on equipment.

16.13. Measures to prevent cross-contamination and their effectiveness should be checked periodically according to SOPs.

16.14. Production areas where susceptible products are processed should undergo periodic environmental monitoring (e.g. for microbiological and particulate matter, where appropriate).

Processing operations

16.15. Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues, labels or documents not required for the current operation.

16.16. Any necessary in-process controls and environmental controls should be carried out and recorded.

 16.17. Means should be instituted of indicating failures of equipment or of services (e.g. water, gas) to equipment. Defective equipment should be withdrawn from use until the defect has been rectified. After use, production equipment should be cleaned without delay according to detailed written procedures and stored under clean and dry conditions in a separate area or in a manner that will prevent contamination.

16.18. Time limits for storage of equipment after cleaning and before use should be stated and based on relevant data.

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16.20. Any significant deviation from the expected yield should be recorded and investigated.

16.21. Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in the correct manner.

16.22. Pipes used for conveying distilled or deionized water and, where appropriate, other water pipes should be sanitized and stored according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

16.23. Measuring, weighing, recording, and control equipment and instruments should be serviced and calibrated at prespecified intervals and records maintained. To ensure satisfactory functioning, instruments should be checked daily or prior to use for performing analytical tests. The date of calibration and servicing and the date when recalibration is due should be clearly indicated on a label attached to the instrument.

16.24. Repair and maintenance operations should not present any hazard to the quality of the products.

Packaging operations

16.25. When the programme for packaging operations is being set up, particular attention should be given to minimizing the risk of cross-contamination, mix ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation or an alternative system that will provide equal assurance.

16.26. Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents used previously and which are not required for the current operation. The line clearance should be performed according to an appropriate procedure and checklist, and recorded.

16.27. The name and batch number of the product being handled should be displayed at each packaging station or line.

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16.29. The correct performance of any printing (e.g. of code numbers or expiry dates) done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand, which should be rechecked at regular intervals.

16.30. Special care should be taken when cut labels are used and when overprinting is carried out off-line, and in hand-packaging operations. Roll-feed labels are normally preferable to cut labels in helping to avoid mix ups. Online verification of all labels by automated electronic means can be helpful in preventing mix ups, but checks should be made to ensure that any electronic code readers, label counters, or similar devices are operating correctly. When labels are attached manually, in-process control checks should be performed more frequently.

16.31. Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing.

16.32. Regular online control of the product during packaging should include at a minimum checks on:

a) the general appearance of the packages;

b) whether the packages are complete;

c) whether the correct products and packaging materials are used;

d) whether any overprinting is correct;

e) the correct functioning of line monitors. Samples taken away from the packaging line should not be returned.

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16.34. Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced should be investigated, satisfactorily accounted for, and recorded before release.

16.35. Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure requiring checks to be performed before returning unused materials should be followed if uncoded printed materials are returned to stock.

16.36. Production records should be reviewed as part of the approval process of batch release before transfer to the authorized person. Any divergence or failure of a batch to meet production specifications should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. A written record of the investigation should be made and should include the conclusion and follow-up action.

17. Good practices in quality control

17.1. QC is the part of GMP concerned with sampling, specifications and testing, and with the organization and documentation which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be compliant with the requirements. QC is not confined to laboratory operations, but may be involved in many decisions concerning the quality of the product.

17.2. The independence of QC from production is considered fundamental.

17.3. Each manufacturer should have a QC function. The QC function should be independent of other departments and under the authority of a person with appropriate qualifications and experience. Adequate resources must be available to ensure that all the QC arrangements are effectively and reliably carried out. The basic requirements for QC are as follows:

a) adequate facilities, trained personnel and approved procedures must be available for sampling, inspecting, and testing starting materials, packaging materials, and intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes;

b) samples of starting materials, packaging materials, intermediate products, bulk products and finished products must be taken by methods and personnel approved by the QC department;

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d) records must be made (manually and/or by recording instruments) demonstrating that all the required sampling, inspecting and testing procedures have actually been carried out and that any deviations have been fully recorded and investigated;

e) the finished products must contain ingredients complying with the qualitative and quantitative composition of the product described in the marketing authorization; the ingredients must be of the required purity, in their proper container and correctly labelled;

f) records must be made of the results of inspecting and testing the materials and intermediate, bulk and finished products against specifications; product assessment must include a review and evaluation of the relevant production documentation and an assessment of deviations from specified procedures;

g) sufficient samples of starting materials and products must be retained to permit future examination of the product if necessary; the retained product must be kept for the appropriate time in its final pack unless the pack is exceptionally large, in which case one that is equivalent to the marketed packaging system may be used.17.4. Other QC responsibilities include:

a) establishing, validating and implementing all QC procedures;

b) evaluating, maintaining and storing reference standards for substances;

c) ensuring the correct labelling of containers of materials and products;

d) ensuring that the stability of the active pharmaceutical ingredients and products is monitored;

e) participating in the investigation of complaints related to the quality of the product;

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g) participation in QRM programmes.

These activities should be carried out in accordance with written procedures and, where necessary, recorded.

17.5. QC personnel must have access to production areas for sampling and investigation as appropriate.

Control of starting materials and intermediate, bulk and finished products

17.6. All tests should follow the instructions given in the relevant written test procedure for each material or product. The result should be checked by the supervisor before the material or product is released or rejected.

17.7. Samples should be representative of the batches of material from which they are taken in accordance with the approved written procedure.

17.8. Sampling should be carried out so as to avoid contamination or other adverse effects on quality. The containers that have been sampled should be marked accordingly and carefully resealed after sampling.

17.9. Care should be taken during sampling to guard against contamination or mix up of, or by, the material being sampled. All sampling equipment that comes into contact with the material should be clean. Some particularly hazardous or potent materials may require special precautions.

17.10. Sampling equipment should be cleaned and, if necessary, sterilized before and after each use and stored separately from other laboratory equipment.

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a) the name of the sampled material;

b) the batch or lot number;

c) the number of the container from which the sample has been taken;

d) the number of the sample;

e) the signature of the person who has taken the sample; and

f) the date of sampling.

17.12. Out-of-specification results obtained during testing of materials or products should be investigated in accordance with an approved procedure. Records should be maintained.

Test requirements

Starting and packaging materials

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17.14. An identity test should be conducted on a sample from each container of starting material (see also section 14.14). It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labelled. This validation should take account of at least the following aspects:

- the nature and status of the manufacturer and of the supplier and their understanding of the GMP requirements;

- the QA system of the manufacturer of the starting material;

- the manufacturing conditions under which the starting material is produced and controlled;

- the nature of the starting material and the medicinal products in which it will be used;

Under such a system it is possible that a validated procedure for exemption from the requirement for identity testing of each incoming container of starting material could be accepted for the following:

- starting materials coming from a single product manufacturer or plant; or

- starting materials coming directly from a manufacturer, or in the manufacturer’s sealed container where there is a history of reliability, and regular audits of the manufacturer’s QA system are conducted by the purchaser (the manufacturer of the medicinal product) or by an officially accredited body.

It is improbable that such a procedure could be satisfactorily validated for either:

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- starting materials for use in parenteral products;

17.15. Each batch (lot) of printed packaging materials must be examined following receipt.

17.16. In lieu of full testing by the manufacturer, a certificate of analysis may be accepted from the supplier, provided that the manufacturer establishes the reliability of the supplier’s analysis through appropriate periodic validation of the supplier’s test results (see sections 8.8 and 8.9) and through on-site audits of the supplier’s capabilities. (This does not affect section 17.15.) Certificates must be originals (not photocopies) or otherwise have their authenticity assured. Certificates must contain at least the following information (7):

a) identification (name and address) of the issuing supplier;

b) signature of the competent official, and statement of his or her qualifications;

c) the name of the material tested;

d) the batch number of the material tested;

e) the specifications and methods used;

f) the test results obtained;

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In-process control

17.17. In-process control records should be maintained and form a part of the batch records (see section 15.25).

Finished products

17.18. For each batch of medicines, there should be an appropriate laboratory determination of satisfactory conformity to its finished product specification prior to release.

17.19. Products failing to meet the established specifications or any other relevant quality criteria should be rejected.

Batch record review

17.20. QC records should be reviewed as part of the approval process of batch release before transfer to the authorized person. Any divergence or failure of a batch to meet its specifications should be thoroughly investigated. The investigation should, if necessary, extend to other batches of the same product and other products that may have been associated with the specific failure or discrepancy. A written record of the investigation should be made and should include the conclusion and follow-up action.

17.21. Retention samples from each batch of finished product should be kept for at least one year after the expiry date. Finished products should usually be kept in their final packaging and stored under the recommended conditions. If exceptionally large packages are produced, smaller samples might be stored in appropriate containers. Samples of active starting materials should be retained for at least one year beyond the expiry date of the corresponding finished product. Other starting materials (other than solvents, gases and water) should be retained for a minimum of two years if their stability allows. Retention samples of materials and products should be of a size sufficient to permit at least two full reexaminations.

Stability studies

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17.23. QC should establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions.

17.24. A written programme for ongoing stability determination should be developed and implemented to include elements such as:

a) a complete description of the medicine involved in the study;

b) the complete set of testing parameters and methods, describing all tests for potency, purity, and physical characteristics and documented evidence that these tests indicate stability;

c) provision for the inclusion of a sufficient number of batches;

d) the testing schedule for each medicine;

e) provision for special storage conditions;

f) provision for adequate sample retention;

g) a summary of all the data generated, including the evaluation and the conclusions of the study.

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PART II

GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL STARTING MATERIALS

1. Introduction

Objective

This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess.

In this guidance, the term manufacturing is defined to include all operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage and distribution of APIs and the related controls.

The guidance as a whole does not cover safety aspects for the personnel engaged in manufacturing, nor aspects related to protecting the environment. These controls are inherent responsibilities of the manufacturer and are governed by national laws.

This guidance is not intended to define registration and/or filing requirements or modify pharmacopoeial requirements. This guidance does not affect the ability of the responsible regulatory agency to establish specific registration/filing requirements regarding APIs within the context of marketing/manufacturing authorizations or drug applications. All commitments in registration/filing documents should be met.

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Within the world community, materials may vary as to their legal classification as an API. When a material is classified as an API in the region or country in which it is manufactured or used in a drug product, it should be manufactured according to this guidance.

1.3. Scope

This guidance applies to the manufacture of APIs for use in human drug (medicinal) products. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by this guidance, but should be performed in accordance with GMP guidances for drug (medicinal) products as defined by local authorities.

This guidance covers APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes.

Specific guidance for APIs manufactured by cell culture/fermentation is described in Section 18.

This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that are produced using blood or plasma as raw materials. Note that cell substrates (mammalian, plant, insect or microbial cells, tissue or animal sources including transgenic animals) and early process steps may be subject to GMP but are not covered by this guidance. In addition, the guidance does not apply to medical gases, bulk-packaged drug (medicinal) products (e.g., tablets or capsules in bulk containers), or radiopharmaceuticals.

Section 19 contains guidance that only applies to the manufacture of APIs used in the production of drug (medicinal) products specifically for clinical trials.

“An API starting material” is a raw material, an intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced inhouse.

API starting materials normally have defined chemical properties and structure. The company should designate and document the rationale for the point at which production of the API begins. For synthetic processes, this is known as the point at which API starting materials are entered into the process. For other processes (e.g., fermentation, extraction, purification), this rationale should be established on a case-by-case basis.

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The guidance in this document would normally be applied to the steps shown in gray in Table 1. However, all steps shown may not need to be completed. The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps, purification, and packaging. Physical processing of APIs, such as granulation, coating or physical manipulation of particle size (e.g., milling, micronizing) should be conducted according to this guidance.

This GMP guidance does not apply to steps prior to the introduction of the defined API starting material.

Table 1. a Application of this Guidance to API Manufacturing

Type of Manufacturing

Application of this guidance to steps (shown in gray) used in this type of manufacturing

Chemical Manufacturing

Production of the API starting material

Introduction of the API starting material into process

Production of Intermediate(s)

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Physical processing, and packaging

API derived from animal sources

Collection of organ, fluid, or tissue

Cutting, mixing, and/or initial processing

Introduction of the API starting material into process

Isolation and purification

Physical processing, and packaging

API extracted from plant sources

Collection of plant

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Introduction of the API starting material into process

Isolation and purification

Physical processing, and packaging

Herbal extracts used as API

Collection of plants

Cutting and initial extraction

Further extraction

Physical processing, and packaging

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Collection of plants and/or cultivation and harvesting

Cutting/ comminuting

Physical processing, and packaging

Biotechnology: fermentation/ cell culture

Establishment of master cell bank and working cell bank

Maintenance of working cell bank

Cell culture and/or fermentation

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Physical processing, and packaging

“Classical” Fermentation to produce an API

Establishment of cell bank

Maintenance of the cell bank

Introduction of the cells into fermentation

Isolation and purification

Physical processing, and packaging

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2. Quality management

2.1. Principles

2.10. Quality should be the responsibility of all persons involved in manufacturing.

2.11. Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.

2.12. The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality-related activities should be defined and documented.

2.13. There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

2.14. The persons authorized to release intermediates and APIs should be specified.

2.15. All quality-related activities should be recorded at the time they are performed.

2.16. Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.

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2.18. Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality-related complaints, recalls, and regulatory actions).

2.2. Responsibilities of the Quality Unit(s)

2.20. The quality unit(s) should be involved in all quality-related matters.

2.21. The quality unit(s) should review and approve all appropriate quality-related documents.

2.22. The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to the following:

1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company;

2. Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials;

3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution;

4. Making sure that critical deviations are investigated and resolved;

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6. Approving all procedures affecting the quality of intermediates or APIs;

7. Making sure that internal audits (self-inspections) are performed;

8. Approving intermediate and API contract manufacturers;

9. Approving changes that potentially affect intermediate or API quality;

10. Reviewing and approving validation protocols and reports;

11. Making sure that quality-related complaints are investigated and resolved;

12. Making sure that effective systems are used for maintaining and calibrating critical equipment;

13. Making sure that materials are appropriately tested and the results are reported;

14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates, where appropriate; and

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2.3. Responsibility for Production Activities

The responsibility for production activities should be described in writing and should include, but not necessarily be limited to:

1. Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or APIs according to written procedures;

2. Producing APIs and, when appropriate, intermediates according to pre-approved instructions;

3. Reviewing all production batch records and ensuring that these are completed and signed;

4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded;

5. Making sure that production facilities are clean and, when appropriate, disinfected;

6. Making sure that the necessary calibrations are performed and records kept.

7. Making sure that the premises and equipment are maintained and records kept;

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9. Evaluating proposed changes in product, process or equipment

10. Making sure that new and, when appropriate, modified facilities and equipment are qualified.

2.4. Internal Audits (Self Inspection)

2.40. To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.

2.41. Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner.

2.5. Product Quality Review

2.50. Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least the following:

- A review of critical in-process control and critical API test results;

- A review of all batches that failed to meet established specification(s);

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- A review of any changes carried out to the processes or analytical methods;

- A review of results of the stability monitoring program;

- A review of all quality-related returns, complaints and recalls;

- A review of adequacy of corrective actions.

2.51. The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner.

3. Personnel

3.1. Personnel Qualifications

3.10. There should be an adequate number of personnel qualified by appropriate education, training, and/or experience to perform and supervise the manufacture of intermediates and APIs.

3.11. The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.

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3.2. Personnel Hygiene

3.20. Personnel should practice good sanitation and health habits.

3.21. Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed, when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn, when necessary, to protect intermediates and APIs from contamination.

3.22. Personnel should avoid direct contact with intermediates or APIs.

3.23. Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas.

3.24. Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs.

3.3. Consultants

3.30. Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.

3.31. Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.

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4.1. Design and Construction

4.10. Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants, as appropriate.

4.11. Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination.

4.12. Where the equipment itself (e.g., closed or contained systems) provides adequate protection of the material, such equipment can be located outdoors.

4.13. The flow of materials and personnel through the building or facilities should be designed to prevent mix-ups or contamination.

4.14. There should be defined areas or other control systems for the following activities:

► Receipt, identification, sampling, and quarantine of incoming materials, pending release or rejection;

► Quarantine before release or rejection of intermediates and APIs;

► Sampling of intermediates and APIs;

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► Storage of released materials;

► Production operations;

► Packaging and labeling operations; and

► Laboratory operations.

4.15. Adequate and clean washing and toilet facilities should be provided for personnel. These facilities should be equipped with hot and cold water, as appropriate, soap or detergent, air dryers, or single service towels. The washing and toilet facilities should be separate from, but easily accessible to, manufacturing areas. Adequate facilities for showering and/or changing clothes should be provided, when appropriate.

4.16. Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, in particular those used for in-process controls, can be located in production areas, provided the operations of the production process do not adversely affect the accuracy of the laboratory measurements, and the laboratory and its operations do not adversely affect the production process, intermediate, or API.

4.2. Utilities

4.20. All utilities that could affect product quality (e.g., steam, gas, compressed air, heating, ventilation, and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available.

4.21. Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimize risks of contamination and crosscontamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be given to areas where APIs are exposed to the environment.

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4.23. Permanently installed pipework should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control systems, or alternative means. Pipework should be located to avoid risks of contamination of the intermediate or API.

4.24. Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when appropriate.

4.3. Water

4.30. Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use.

4.31. Unless otherwise justified, process water should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (potable) water quality.

4.32. If drinking (potable) water is insufficient to ensure API quality and tighter chemical and/or microbiological water quality specifications are called for, appropriate specifications for physical/chemical attributes, total microbial counts, objectionable organisms, and/or endotoxins should be established.

4.33. Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.

4.34. Where the manufacturer of a nonsterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug (medicinal) product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.

4.4. Containment

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4.41. The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.

4.42. Appropriate measures should be established and implemented to prevent cross-contamination from personnel and materials moving from one dedicated area to another.

4.43. Any production activities (including weighing, milling, or packaging) of highly toxic nonpharmaceutical materials, such as herbicides and pesticides, should not be conducted using the buildings and/or equipment being used for the production of APIs. Handling and storage of these highly toxic nonpharmaceutical materials should be separate from APIs.

4.5. Lighting

4.50. Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.

4.6. Sewage and Refuse

4.60. Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in and from buildings and the immediate surrounding area should be disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified.

4.7. Sanitation and Maintenance

4.70. Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.

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4.72. When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labeling materials, intermediates, and APIs.

5. Process equipment

5.1. Design and Construction

5.10. Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitation (where appropriate), and maintenance.

5.11. Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications.

5.12. Production equipment should only be used within its qualified operating range.

5.13. Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified.

5.14. Any substances associated with the operation of equipment, such as lubricants, heating fluids or coolants, should not contact intermediates or APIs so as to alter the quality of APIs or intermediates beyond the official or other established specifications. Any deviations from this practice should be evaluated to ensure that there are no detrimental effects on the material's fitness for use. Wherever possible, food grade lubricants and oils should be used.

5.15. Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.

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5.2. Equipment Maintenance and Cleaning

5.20. Schedules and procedures (including assignment of responsibility) should be established for the preventative maintenance of equipment.

5.21. Written procedures should be established for cleaning equipment and its subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include the following:

► Assignment of responsibility for cleaning of equipment;

► Cleaning schedules, including, where appropriate, sanitizing schedules;

► A complete description of the methods and materials, including dilution of cleaning agents used to clean equipment;

 When appropriate, instructions for disassembling and reassembling each article of equipment to ensure proper cleaning;

► Instructions for the removal or obliteration of previous batch identification;

► Instructions for the protection of clean equipment from contamination prior to use;

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► Establishing the maximum time that may elapse between the completion of processing and equipment cleaning, when appropriate.

5.22. Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.

5.23. Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g., degradants or objectionable levels of microorganisms).

5.24. Nondedicated equipment should be cleaned between production of different materials to prevent cross-contamination.

5.25. Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.

5.26. Equipment should be identified as to its contents and its cleanliness status by appropriate means.

5.3. Calibration

5.30. Control, weighing, measuring, monitoring, and testing equipment critical for ensuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule.

5.31. Equipment calibrations should be performed using standards traceable to certified standards, if they exist.

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5.33. The current calibration status of critical equipment should be known and verifiable.

5.34. Instruments that do not meet calibration criteria should not be used.

5.35. Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an effect on the quality of the intermediate(s) or API(s) manufactured using this equipment since the last successful calibration.

5.4. Computerized Systems

5.40. GMP-related computerized systems should be validated. The depth and scope of validation depends on the diversity, complexity, and criticality of the computerized application.

5.41. Appropriate installation and operational qualifications should demonstrate the suitability of computer hardware and software to perform assigned tasks.

5.42. Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at time of installation, a retrospective validation could be conducted if appropriate documentation is available.

5.43. Computerized systems should have sufficient controls to prevent unauthorized access or changes to data. There should be controls to prevent omissions in data (e.g., system turned off and data not captured). There should be a record of any data change made, the previous entry, who made the change, and when the change was made.

5.44. Written procedures should be available for the operation and maintenance of computerized systems.

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5.46. Incidents related to computerized systems that could affect the quality of intermediates or APIs or the reliability of records or test results should be recorded and investigated.

5.47. Changes to computerized systems should be made according to a change procedure and should be formally authorized, documented, and tested. Records should be kept of all changes, including modifications and enhancements made to the hardware, software, and any other critical component of the system. These records should demonstrate that the system is maintained in a validated state.

5.48. If system breakdowns or failures would result in the permanent loss of records, a back-up system should be provided. A means of ensuring data protection should be established for all computerized systems.

5.49. Data can be recorded by a second means in addition to the computer system.

6. Documentation and records

6.1. Documentation System and Specifications

6.10. All documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved, and distributed according to written procedures. Such documents can be in paper or electronic form.

6.11. The issuance, revision, superseding, and withdrawal of all documents should be controlled by maintaining revision histories.

6.12. A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-up reports, technical transfer reports, process validation reports, training records, production records, control records, and distribution records). The retention periods for these documents should be specified.

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6.14. When entries are made in records, these should be made indelibly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry. Corrections to entries should be dated and signed and leave the original entry still legible.

6.15. During the retention period, originals or copies of records should be readily available at the establishment where the activities described in such records occurred. Records that can be promptly retrieved from another location by electronic or other means are acceptable.

6.16. Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are used, suitable retrieval equipment and a means to produce a hard copy should be readily available.

6.17. Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labeling and packaging materials. In addition, specifications may be appropriate for certain other materials, such as process aids, gaskets, or other materials used during the production of intermediates or APIs that could critically affect quality. Acceptance criteria should be established and documented for in-process controls.

6.18. If electronic signatures are used on documents, they should be authenticated and secure.

6.2. Equipment Cleaning and Use Record

6.20. Records of major equipment use, cleaning, sanitation, and/or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment and the person who performed the cleaning and maintenance.

6.21. If equipment is dedicated to manufacturing one intermediate or API, individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.

6.3. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials

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► The name of the manufacturer, identity, and quantity of each shipment of each batch of raw materials, intermediates, or labeling and packaging materials for API's; the name of the supplier; the supplier's control number(s), if known, or other identification number; the number allocated on receipt; and the date of receipt;

► The results of any test or examination performed and the conclusions derived from this;

► Records tracing the use of materials;

► Documentation of the examination and review of API labeling and packaging materials for conformity with established specifications; and

► The final decision regarding rejected raw materials, intermediates, or API labeling and packaging materials.

6.31. Master (approved) labels should be maintained for comparison to issued labels.

6.4. Master Production Instructions (Master Production and Control Records)

6.40. To ensure uniformity from batch to batch, master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit(s).

6.41. Master production instructions should include the following:

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► A complete list of raw materials and intermediates designated by names or codes sufficiently specific to identify any special quality characteristics;

► An accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure. Where the quantity is not fixed, the calculation for each batch size or rate of production should be included. Variations to quantities should be included where they are justified;

► The production location and major production equipment to be used;

► Detailed production instructions, including the:

- sequences to be followed,

- ranges of process parameters to be used,

- - sampling instructions and in-process controls with their acceptance criteria, where appropriate,

- time limits for completion of individual processing steps and/or the total process, where appropriate, and

- expected yield ranges at appropriate phases of processing or time;

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► The instructions for storage of the intermediate or API to ensure its suitability for use, including the labelling and packaging materials and special storage conditions with time limits, where appropriate.

6.5. Batch Production Records (Batch Production and Control Records)

6.50. Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to ensure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. If the batch production record is produced from a separate part of the master document, that document should include a reference to the current master production instruction being used.

6.51. These records should be numbered with a unique batch or identification number, dated and signed when issued. In continuous production, the product code together with the date and time can serve as the unique identifier until the final number is allocated.

6.52. Documentation of completion of each significant step in the batch production records (batch production and control records) should include the following:

► Dates and, when appropriate, times;

► Identity of major equipment (e.g., reactors, driers, mills, etc.) used;

► Specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing;

► Actual results recorded for critical process parameters;

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► Signatures of the persons performing and directly supervising or checking each critical step in the operation;

► In-process and laboratory test results;

► Actual yield at appropriate phases or times;

► Description of packaging and label for intermediate or API;

► Representative label of API or intermediate if made commercially available;

► Any deviation noted, its evaluation, investigation conducted (if appropriate) or reference to that investigation if stored separately; and

► Results of release testing.

6.53. Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.

6.6. Laboratory Control Records

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► A description of samples received for testing, including the material name or source, batch number or other distinctive code, date sample was taken, and, where appropriate, the quantity and date the sample was received for testing;

► • A statement of or reference to each test method used;

► A statement of the weight or measure of sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions;

► A complete record of all raw data generated during each test, in addition to graphs, charts and spectra from laboratory instrumentation, properly identified to show the specific material and batch tested;

► A record of all calculations performed in connection with the test, including, for example, units of measure, conversion factors, and equivalency factors;

► A statement of the test results and how they compare with established acceptance criteria;

► The signature of the person who performed each test and the date(s) the tests were performed; and

► The date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

6.61. Complete records should also be maintained for the following:

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► Periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;

► All stability testing performed on APIs; and

► Out-of-specification (OOS) investigations.

6.7. Batch Production Record Review

6.70. Written procedures should be established and followed for the review and approval of batch production and laboratory control records, including packaging and labeling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed.

6.71. Batch production and laboratory control records of critical process steps should be reviewed and approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory control records of noncritical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s).

6.72. All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.

6.73. The quality unit(s) can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company.

7. Materials management

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7.10. There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

7.11. Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials.

7.12. Materials should be purchased against an agreed specification, from a supplier, or suppliers, approved by the quality unit(s).

7.13. If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.

7.14. Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control.

7.2. Receipt and Quarantine

7.20. Upon receipt and before acceptance, each container or grouping of containers of materials should be examined visually for correct labeling (including correlation between the name used by the supplier and the in-house name, if these are different), container damage, broken seals and evidence of tampering or contamination. Materials should be held under quarantine until they have been sampled, examined, or tested, as appropriate, and released for use.

7.21. Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in silos), they should be identified as correct, tested, if appropriate, and released. Procedures should be available to prevent discharging incoming materials wrongly into the existing stock.

7.22. If bulk deliveries are made in nondedicated tankers, there should be assurance of no crosscontamination from the tanker. Means of providing this assurance could include one or more of the following:

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► testing for trace impurities

► audit of the supplier

7.23. Large storage containers and their attendant manifolds, filling, and discharge lines should be appropriately identified.

7.24. Each container or grouping of containers (batches) of materials should be assigned and identified with a distinctive code, batch, or receipt number. This number should be used in recording the disposition of each batch. A system should be in place to identify the status of each batch.

7.3. Sampling and Testing of Incoming Production Materials

7.30. At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described in 7.32 below. A supplier's certificate of analysis can be used in place of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers.

7.31. Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Complete analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a complete analysis should be performed at appropriate intervals and compared with the certificates of analysis. Reliability of certificates of analysis should be checked at regular intervals.

7.32. Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company’s control do not need to be tested if the manufacturer’s certificate of analysis is obtained, showing that these raw materials conform to established specifications. Visual examination of containers, labels, and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented.

7.33. Samples should be representative of the batch of material from which they are taken. Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based on a sampling plan that takes into consideration the criticality of the material, material variability, past quality history of the supplier, and the quantity needed for analysis.

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7.35. Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. They should be marked to indicate that a sample has been taken.

7.4. Storage

7.40. Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination.

7.41. Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.

7.42. Materials should be stored under conditions and for a period that have no adverse effect on their quality, and should normally be controlled so that the oldest stock is used first.

7.43. Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.

7.44. Materials should be re-evaluated, as appropriate, to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity).

7.5. Re-evaluation

7.50. Materials should be re-evaluated, as appropriate, to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity).

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8.1. Production Operations

8.10. Raw materials for intermediate and API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use. Weighing and measuring devices should be of suitable accuracy for the intended use.

8.11. If a material is subdivided for later use in production operations, the container receiving the material should be suitable and should be so identified that the following information is available:

► Material name and/or item code;

► Receiving or control number;

► Weight or measure of material in the new container; and

► Re-evaluation or retest date if appropriate.

8.12. Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Prior to use, production personnel should verify that the materials are those specified in the batch record for the intended intermediate or API.

8.13. Other critical activities should be witnessed or subjected to an equivalent control.

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8.15. Any deviation should be documented and explained. Any critical deviation should be investigated.

8.16. The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.

8.17. Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.

8.2. Time Limits

8.20. If time limits are specified in the master production instruction (see 6.14), these time limits should be met to ensure the quality of intermediates and APIs. Deviations should be documented and evaluated. Time limits may be inappropriate when processing to a target value (e.g., pH adjustment, hydrogenation, drying to predetermined specification) because completion of reactions or processing steps are determined by in-process sampling and testing.

8.21. Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use.

8.3. In-process Sampling and Controls

8.30. Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the developmental stage or from historical data.

8.31. The acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product’s quality. Less stringent inprocess controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps).

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8.33. In-process controls can be performed by qualified production department personnel and the process adjusted without prior quality unit(s) approval if the adjustments are made within preestablished limits approved by the quality unit(s). All tests and results should be fully documented as part of the batch record.

8.34. Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on scientifically sound sampling practices.

8.35. In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other intermediates or APIs. Procedures should be established to ensure the integrity of samples after collection.

8.36. Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.

8.4. Blending Batches of Intermediates or APIs

8.40. For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending.

8.41. Out-of-specification batches should not be blended with other batches for the purpose of meeting specifications. Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.

8.42. Acceptable blending operations include, but are not limited to:

► Blending of small batches to increase batch size;’

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8.43. Blending processes should be adequately controlled and documented, and the blended batch should be tested for conformance to established specifications, where appropriate.

8.44. The batch record of the blending process should allow traceability back to the individual batches that make up the blend.

8.45. Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms or suspensions), blending operations should be validated to show homogeneity of the combined batch. Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and tap density) that may be affected by the blending process.

8.46. If the blending could adversely affect stability, stability testing of the final blended batches should be performed.

8.47. The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend.

8.5. Contamination Control

8.50. Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.

8.51. Production operations should be conducted in a manner that prevents contamination of intermediates or APIs by other materials.

8.52. Precautions to avoid contamination should be taken when APIs are handled after purification.

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9.1. General

9.10. There should be written procedures describing the receipt, identification, quarantine, sampling, examination, and/or testing, release, and handling of packaging and labeling materials.

9.11. Packaging and labeling materials should conform to established specifications. Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable.

9.12. Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.

9.2. Packaging materials

9.20. Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and recommended storage.

9.21. Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the specified limits.

9.22. If containers are reused, they should be cleaned in accordance with documented procedures, and all previous labels should be removed or defaced.

9.3. Label Issuance and Control

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9.31. Procedures should be established to reconcile the quantities of labels issued, used, and returned and to evaluate discrepancies found between the number of containers labeled and the number of labels issued. Such discrepancies should be investigated, and the investigation should be approved by the quality unit(s).

9.32. All excess labels bearing batch numbers or other batch-related printing should be destroyed. Returned labels should be maintained and stored in a manner that prevents mix-ups and provides proper identification.

9.33. Obsolete and out-dated labels should be destroyed.

9.34. Printing devices used to print labels for packaging operations should be controlled to ensure that all imprinting conforms to the print specified in the batch production record.

9.35. Printed labels issued for a batch should be carefully examined for proper identity and conformity to specifications in the master production record. The results of this examination should be documented.

9.36. A printed label representative of those used should be included in the batch production record.

9.4. Packaging and Labeling Operations

9.40. There should be documented procedures designed to ensure that correct packaging materials and labels are used.

9.41. Labeling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs.

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9.43. If the intermediate or API is intended to be transferred outside the control of the manufacturer’s material management system, the name and address of the manufacturer, quantity of contents, special transport conditions, and any special legal requirements should also be included on the label. For intermediates or APIs with an expiry date, the expiry date should be indicated on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.

9.44. Packaging and labeling facilities should be inspected immediately before use to ensure that all materials not needed for the next packaging operation have been removed. This examination should be documented in the batch production records, the facility log, or other documentation system.

9.45. Packaged and labeled intermediates or APIs should be examined to ensure that containers and packages in the batch have the correct label. This examination should be part of the packaging operation. Results of these examinations should be recorded in the batch production or control records.

9.46. Intermediate or API containers that are transported outside of the manufacturer's control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered.

10. Storage and distribution

10.1. Warehousing Procedures

10.10. Facilities should be available for the storage of all materials under appropriate conditions (e.g., controlled temperature and humidity when necessary). Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.

10.11. Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision as to their future use has been made.

10.2. Distribution Procedures

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10.21. APIs and intermediates should be transported in a manner that does not adversely affect their quality.

10.22. Special transport or storage conditions for an API or intermediate should be stated on the label.

10.23. The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.

10.A system should be in place by which the distribution of each batch of intermediate and/or API can be readily determined to permit its recall.

11. Laboratory controls

11.1. General Controls

11.10. The independent quality unit(s) should have at its disposal adequate laboratory facilities.

11.11. There should be documented procedures describing sampling, testing, approval, or rejection of materials and recording and storage of laboratory data. Laboratory records should be maintained in accordance with Section 6.6.

11.12. All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).

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11.14. Laboratory controls should be followed and documented at the time of performance. Any departures from the above-described procedures should be documented and explained.

11.15. Any out-of-specification (OOS) result obtained should be investigated and documented according to a procedure. This procedure should include analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any resampling and/or retesting after OOS results should be performed according to a documented procedure.

11.16. Reagents and standard solutions should be prepared and labeled following written procedures. “Use by dates” should be applied, as appropriate, for analytical reagents or standard solutions.

11.17. Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.

11.18. Where a primary reference standard is not available from an officially recognized source, an inhouse primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.

11.19. Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.

11.2. Testing of Intermediates and APIs

11.20. For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.

11.21. An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent). The impurity profile is normally dependent upon the production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH guidance Q6B.

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11.23. Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.

11.3. Validation of Analytical Procedures - See Section 12.

11.4. Certificates of Analysis

11.40. Authentic certificates of analysis should be issued for each batch of intermediate or API on request..

11.41. Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis. For intermediates or APIs with an expiry date, the expiry date should be provided on the label and certificate of analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or certificate of analysis.

11.42. The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).

11.43. Certificates should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. Where the analysis has been carried out by a repacker or reprocessor, the certificate of analysis should show the name, address, and telephone number of the repacker/reprocessor and reference the name of the original manufacturer.

11.44. If new certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these certificates should show the name, address and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which should be attached.

11.5. Stability Monitoring of APIs

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11.51. The test procedures used in stability testing should be validated and be stability indicating.

11.52. Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums.

11.53. Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected to remain stable for at least 2 years, fewer than three batches can be used.

11.54. Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.

11.55. For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first 3 months, and at 3-month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g., 9-month testing) can be considered.

11.56. Where appropriate, the stability storage conditions should be consistent with the ICH guidances on stability.

11.6. Expiry and Retest Dating

11.60. When an intermediate is intended to be transferred outside the control of the manufacturer’s material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g., published data, test results).

11.61. An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date.

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11.63. A representative sample should be taken for the purpose of performing a retest.

11.7. Reserve/Retention Samples

11.70. The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.

11.71. Appropriately identified reserve samples of each API batch should be retained for 1 year after the expiry date of the batch assigned by the manufacturer, or for 3 years after distribution of the batch, whichever is longer. For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer.

11.72. The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.

12. Validation Policy

12.1. Validation Policy

12.10. The company's overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented.

12.11. The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include the following:

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► Identifying process parameters that could affect the critical quality attributes of the API;

► Determining the range for each critical process parameter expected to be used during routine manufacturing and process control.

12.12. Validation should extend to those operations determined to be critical to the quality and purity of the API.

12.2. Validation Documentation

12.20. A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units.

12.21. The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g., retrospective, prospective, concurrent) and the number of process runs.

12.22. A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.

12.23. Any variations from the validation protocol should be documented with appropriate justification.

12.3. Qualification

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► Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose;

► Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements;

► Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges.

► Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications.

12.4. Approaches to Process Validation

12.40. Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.

12.41. There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here.

12.42. Prospective validation should normally be performed for all API processes as defined in 12.12. Prospective validation of an API process should be completed before the commercial distribution of the final drug product manufactured from that API.

12.43. Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.

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1) Critical quality attributes and critical process parameters have been identified;

2) Appropriate in-process acceptance criteria and controls have been established;

3) There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability; and

4) Impurity profiles have been established for the existing API.

11.45. Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.

12.5. Process Validation Program

12.50. The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process (e.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.

12.51. Critical process parameters should be controlled and monitored during process validation studies.

12.52. Process validation should confirm that the impurity profile for each API is within the limits specified.

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12.60. Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.

12.7. Cleaning Validation

12.70. Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps.

12.71. Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.

12.72. The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labeled.

12.73. Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).

12.74. Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. The method’s attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue. Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component.

12.75. Equipment cleaning/sanitation studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).

12.76. Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.

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12.80. Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented.

12.81. Methods should be validated to include consideration of characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

12.82. Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods.

12.83. Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.

13. Change control

13.10. A formal change control system should be established to evaluate all changes that could affect the production and control of the intermediate or API.

13.11. Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labeling and packaging materials, and computer software.

13.12. Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality unit(s).

13.13. The potential impact of the proposed change on the quality of the intermediate or API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g., as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgment should determine what additional testing and validation studies are appropriate to justify a change in a validated process.

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13.15. After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.

13.16. The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.

13.17. Current dosage form manufacturers should be notified of changes from established production and process control procedures that can affect the quality of the API.

14. Rejection and re-use of materials

14.1. Rejection

14.10. Intermediates and APIs failing to meet established specifications should be identified as such and quarantined. These intermediates or APIs can be reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.

14.2. Reprocessing

14.20. Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.

14.21. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing.

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14.3. Reworking

14.30. Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for nonconformance should be performed.

14.31. Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is often the appropriate validation approach for rework procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, a report can be written and the batch released once it is found to be acceptable.

14.32. Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.

14.4. Recovery of Materials and Solvents

14.40. Recovery (e.g., from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.

14.41. Solvents can be recovered and reused in the same processes or in different processes, provided that the recovery procedures are controlled and monitored to ensure that solvents meet appropriate standards before reuse or commingling with other approved materials.

14.42. Fresh and recovered solvents and reagents can be combined if adequate testing has shown their suitability for all manufacturing processes in which they may be used.

14.43. The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.

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14.50. Returned intermediates or APIs should be identified as such and quarantined.

14.51. If the conditions under which returned intermediates or APIs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned intermediates or APIs should be reprocessed, reworked, or destroyed, as appropriate.

14.52. Records of returned intermediates or APIs should be maintained. For each return, documentation should include the following:

► Name and address of the consignee

► Intermediate or API, batch number, and quantity returned

► Reason for return

► Use or disposal of the returned intermediate or API

15. Complaints and recalls

15.10. All quality-related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.

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► Name and address of complainant;

► Name (and, where appropriate, title) and phone number of person submitting the complaint;

► Complaint nature (including name and batch number of the API);

► Date complaint is received;

► Action initially taken (including dates and identity of person taking the action);

► Any follow-up action taken;

► Response provided to the originator of complaint (including date response sent); and

► Final decision on intermediate or API batch or lot.

15.12. Records of complaints should be retained to evaluate trends, product-related frequencies, and severity with a view to taking additional, and if appropriate, immediate corrective action.

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15.14. The recall procedure should designate who should be involved in evaluating the information, how a recall should be initiated, who should be informed about the recall, and how the recalled material should be treated.

15.15. In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.

16. Contract manufacturers (including laboratories)

16.10. All contract manufacturers (including laboratories) should comply with the GMP defined in this guidance. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.

16.11. Companies should evaluate any contractors (including laboratories) to ensure GMP compliance of the specific operations occurring at the contractor sites.

16.12. There should be a written and approved contract or formal agreement between a company and its contractors that defines in detail the GMP responsibilities, including the quality measures, of each party.

16.13. A contract should permit a company to audit its contractor's facilities for compliance with GMP.

16.14. Where subcontracting is allowed, a contractor should not pass to a third party any of the work entrusted to it under the contract without the company's prior evaluation and approval of the arrangements.

16.15. Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.

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17. Agents, brokers, traders, distributors, repackers, and relabellers

17.1. Applicability

17.10. This section applies to any party other than the original manufacturer who may trade and/or take possession, repack, relabel, manipulate, distribute, or store an API or intermediate.

17.11. All agents, brokers, traders, distributors, repackers, and relabelers should comply with GMP as defined in this guidance.

17.2. Traceability of Distributed APIs and Intermediates

17.20. Agents, brokers, traders, distributors, repackers, or relabelers should maintain complete traceability of APIs and intermediates that they distribute. Documents that should be retained and available include the following:

► Identity of original manufacturer

► Address of original manufacturer

► Purchase orders

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► Receipt documents

► Name or designation of API or intermediate

► Manufacturer’s batch number

► Transportation and distribution records

► All authentic Certificates of Analysis, including those of the original manufacturer

► Retest or expiry date

17.3. Quality management

Agents, brokers, traders, distributors, repackers, or relabelers should establish, document and implement an effective system of managing quality, as specified in Section 2.

17.4. Repackaging, Relabeling, and Holding of APIs and Intermediates

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17.41. Repackaging should be conducted under appropriate environmental conditions to avoid contamination and cross-contamination.

17.5. Stability

17.50. Stability studies to justify assigned expiration or retest dates should be conducted if the API or intermediate is repackaged in a different type of container than that used by the API or intermediate manufacturer.

17.6. Transfer of Information

17.60. Agents, brokers, distributors, repackers, or relabelers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.

17.61. The agent, broker, trader, distributor, repacker, or relabeler who supplies the API or intermediate to the customer should provide the name of the original API or intermediate manufacturer and the batch number(s) supplied.

17.62. The agent should also provide the identity of the original API or intermediate manufacturer to regulatory authorities upon request. The original manufacturer can respond to the regulatory authority directly or through its authorized agents, depending on the legal relationship between the authorized agents and the original API or intermediate manufacturer. (In this context authorized refers to authorized by the manufacturer.)

17.63. The specific guidance for certificate of analysis included in Section 11.4 should be met.

17.7. Handling of Complaints and Recalls

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17.71. If the situation warrants, the agents, brokers, traders, distributors, repackers, or relabelers should review the complaint with the original API or intermediate manufacturer to determine whether any further action, either with other customers who may have received this API or intermediate or with the regulatory authority, or both, should be initiated. The investigation into the cause for the complaint or recall should be conducted and documented by the appropriate party.

17.72. Where a complaint is referred to the original API or intermediate manufacturer, the record maintained by the agents, brokers, traders, distributors, repackers, or relabelers should include any response received from the original API or intermediate manufacturer (including date and information provided).

17.8. Handling of Returns

17.80. Returns should be handled as specified in Section 14.5. The agents, brokers, traders, distributors, repackers, or relabelers should maintain documentation of returned APIs and intermediates.

18. Specific guidance for APIs manufactured by cell culture/fermentation

18.1. General

18.10. Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms and that have not been covered adequately in the previous sections. It is not intended to be a stand-alone section. In general, the GMP principles in the other sections of this document apply. Note that the principles of fermentation for classical processes for production of small molecules and for processes using recombinant and nonrecombinant organisms for production of proteins and/or polypeptides are the same, although the degree of control will differ. Where practical, this section will address these differences. In general, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.

18.11. The term “biotechnological process” (biotech) refers to the use of cells or organisms that have been generated or modified by recombinant DNA, hybridoma, or other technology to produce APIs. The APIs produced by biotechnological processes normally consist of high molecular weight substances, such as proteins and polypeptides, for which specific guidance is given in this Section. Certain APIs of low molecular weight, such as antibiotics, amino acids, vitamins, and carbohydrates, can also be produced by recombinant DNA technology. The level of control for these types of APIs is similar to that employed for classical fermentation.

18.12. The term classical fermentation refers to processes that use microorganisms existing in nature and/or modified by conventional methods (e.g., irradiation or chemical mutagenesis) to produce APIs. APIs produced by classical fermentation are normally low molecular weight products such as antibiotics, amino acids, vitamins, and carbohydrates.

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18.14. Appropriate controls should be established at all stages of manufacturing to ensure intermediate and/or API quality. While this guidance starts at the cell culture/fermentation step, prior steps (e.g., cell banking) should be performed under appropriate process controls. This guidance covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use in manufacturing.

18.15. Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for determining environmental quality and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems).         

18.16. In general, process controls should take into account the following:

► Maintenance of the working cell bank (where appropriate);

► Proper inoculation and expansion of the culture;

► Control of the critical operating parameters during fermentation/cell culture;

► Monitoring of the process for cell growth, viability (for most cell culture processes) and productivity, where appropriate;

► Harvest and purification procedures that remove cells, cellular debris and media components while protecting the intermediate or API from contamination (particularly of a microbiological nature) and from loss of quality.

► Monitoring of bioburden and, where needed, endotoxin levels at appropriate stages of production; and

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18.17. Where appropriate, the removal of media components, host cell proteins, other process-related impurities, product-related impurities and contaminants should be demonstrated.

18.2. Cell Bank Maintenance and Record Keeping

18.20. Access to cell banks should be limited to authorized personnel.

18.21. Cell banks should be maintained under storage conditions designed to maintain viability and prevent contamination.

18.22. Records of the use of the vials from the cell banks and storage conditions should be maintained.

18.23. Where appropriate, cell banks should be periodically monitored to determine suitability for use.

18.24. See ICH guidance Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion of cell banking.

18.3. Cell Culture/Fermentation

18.30. Where cell substrates, media, buffers, and gases are to be added under aseptic conditions, closed or contained systems should be used where possible. If the inoculation of the initial vessel or subsequent transfers or additions (media, buffers) are performed in open vessels, there should be controls and procedures in place to minimize the risk of contamination.

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18.32. Personnel should be appropriately gowned and take special precautions handling the cultures.

18.33. Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) should be monitored to ensure consistency with the established process. Cell growth, viability (for most cell culture processes), and, where appropriate, productivity should also be monitored. Critical parameters will vary from one process to another, and for classical fermentation, certain parameters (cell viability, for example) may not need to be monitored.

18.34. Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, sanitized, or sterilized.

18.35. Culture media should be sterilized before use, when necessary, to protect the quality of the API.

18.36. Appropriate procedures should be in place to detect contamination and determine the course of action to be taken. Procedures should be available to determine the impact of the contamination on the product and to decontaminate the equipment and return it to a condition to be used in subsequent batches. Foreign organisms observed during fermentation processes should be identified, as appropriate, and the effect of their presence on product quality should be assessed, if necessary. The results of such assessments should be taken into consideration in the disposition of the material produced.

18.37. Records of contamination events should be maintained.

18.38. Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.

18.4. Harvesting, Isolation and Purification

18.40. Harvesting steps, either to remove cells or cellular components or to collect cellular components after disruption should be performed in equipment and areas designed to minimize the risk of contamination.

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18.42. All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.

18.43. If open systems are used, purification should be performed under environmental conditions appropriate for the preservation of product quality.

18.44. Additional controls, such as the use of dedicated chromatography resins or additional testing, may be appropriate if equipment is to be used for multiple products.

18.5. Viral Removal/Inactivation steps

18.50. See ICH guidance Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin for more specific information.

18.51. Viral removal and viral inactivation steps are critical processing steps for some processes and should be performed within their validated parameters.

18.52. Appropriate precautions should be taken to prevent potential viral contamination from previral to postviral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.

18.53. The same equipment is not normally used for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g., through equipment or environment) from previous steps.

19. APIs for use in clinical trials

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19.10. Not all the controls in the previous sections of this guidance are appropriate for the manufacture of a new API for investigational use during its development. Section XIX (19) provides specific guidance unique to these circumstances.

19.11. The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.

19.2. Quality

19.20. Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a suitable mechanism for approval of each batch.

19.21. A quality unit(s) independent from production should be established for the approval or rejection of each batch of API for use in clinical trials.

19.22. Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.

19.23. Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.

19.24. Process and quality problems should be evaluated.

19.25. Labeling for APIs intended for use in clinical trials should be appropriately controlled and should identify the material as being for investigational use.

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19.30. During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean, and suitable for its intended use.

19.31. Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.

19.4. Control of Raw Materials

19.40. Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier’s analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.

19.41. In some instances, the suitability of a raw material can be determined before use based on acceptability in small-scale reactions (i.e., use testing) rather than on analytical testing alone.

19.5. Production

19.50. The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.

19.51. Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.

19.6. Validation

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19.61. Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.

19.7. Changes

19.70. Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded.

19.8. Laboratory Controls

19.80. While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound.

19.81. A system for retaining reserve samples of all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application.

19.82. Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.

19.9. Documentation

19.90. A system should be in place to ensure that information gained during the development and the manufacture of APIs for use in clinical trials is documented and available.

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19.92. A system for retaining production and control records and documents should be used. This system should ensure that records and documents are retained for an appropriate length of time after the approval, termination, or discontinuation of an application.

20. Glossary

Acceptance Criteria

Numerical limits, ranges, or other suitable measures for acceptance of test results.

Active Pharmaceutical Ingredient (API) (or Drug Substance)

Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

API Starting Material

A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials are normally of defined chemical properties and structure.

batch (or lot)

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Batch Number (or Lot Number)

A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.

Bioburden

The level and type (e.g., objectionable or not) of microorganisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected.

Calibration

The demonstration that a particular instrument or device produces results within specified limits by comparison with results produced by a reference or traceable standard over an appropriate range of measurements.

Computer System

A group of hardware components and associated software designed and assembled to perform a specific function or group of functions.

Computerized System

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Contamination

The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging, or repackaging, storage or transport.

Contract Manufacturer

A manufacturer who performs some aspect of manufacturing on behalf of the original manufacturer.

Critical

Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.

Cross-contamination

Contamination of a material or product with another material or product.

Deviation

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Drug (Medicinal) Product

The dosage form in the final immediate packaging intended for marketing. (Reference Q1A).

Drug Substance

See Active Pharmaceutical Ingredient.

Expiry Date (or Expiration Date)

The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf life specifications if stored under defined conditions and after which it should not be used.

Impurity

Any component present in the intermediate or API that is not the desired entity.

Impurity Profile

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In-Process Control (or Process Control)

Checks performed during production to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API conforms to its specifications.

intermediate product

A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. (Note: this guidance only addresses those intermediates produced after the point that a company has defined as the point at which the production of the API begins.)

Lot

See Batch.

Bacth number

See Batch Number.

Manufacture

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Material

A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, APIs, and packaging and labeling materials.

Mother Liquor

The residual liquid that remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the API, and/or impurities. It can be used for further processing.

Packaging material

Any material intended to protect an intermediate or API during storage and transport.

Procedure

A documented description of the operations to be performed, the precautions to be taken, and measures to be applied directly or indirectly related to the manufacture of an intermediate or API.

Process Aids

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Process Control

See In-Process Control.

Production

All operations involved in the preparation of an API from receipt of materials through processing and packaging of the API.

Qualification

Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.

Quality Assurance

The sum total of the organized arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.

Quality Control

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Quality Unit(s)

An organizational unit independent of production that fulfills both quality assurance and quality control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

Quarantine

The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.

Raw Material

A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.

Reference Standard, Primary

A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be: (1) obtained from an officially recognized source, (2) prepared by independent synthesis, (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material.

Reference Standard, Secondary

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Reprocessing

Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete, is considered to be part of the normal process, and is not reprocessing.

Retest Date

The date when a material should be re-examined to ensure that it is still suitable for use.

Reworking

Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent).

Signed (signature)

See definition for signed.

Signed (signature)

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Solvent

An inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacture of an intermediate or API.

Specification

A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. Conformance to specification means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

Validation

A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria.

Validation Protocol

A written plan starting how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters and/or operating ranges, product characteristrics, sampling, test data to be collected, number of validation runs, and accpetable test results.

Yield, expected

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Yield, theoretical

The quantity that would be produced at any approproate phase of production based upon the quantity of material to be used, in the absence of any loss or error in actual production.

PART III

GOOD MANUFACTURING PRACTICES FOR BIOLOGICAL PRODUCTS

Abbreviations

AEFI     adverse event following immunization

ATMP   advanced therapy medicinal product

BCG     bacille Calmette–Guérin

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HEPA   high-efficiency particulate air

HVAC   heating, ventilation and air conditioning

IgE       immunoglobulin E

mAb     monoclonal antibody

MCB     master cell bank

MSL     master seed lot

MVS master virus seed

NRA     national regulatory authority

PDL      population doubling level

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PQS     pharmaceutical quality system

QRM     quality risk management

rDNA    recombinant DNA

SPF      specific pathogen free

TSE      transmissible spongiform encephalopathy

ƯCB     working cell bank

WSL     working seed lot

WVS     working virus seed

1. Introduction

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This document is intended to serve as a basis for establishing national guidelines for GMP for biological products.

2. Scope

This guidance provided in this document applies to the manufacture, control and testing of biological products for human use - from starting materials and preparations (including seed lots, cell banks and intermediates) to the finished product.

Manufacturing procedures within the scope of this document include:

- Growth of strains of microorganisms and eukaryotic and cells;

- extraction of substances from biological tissues, including human, animal and plant tissues, and fungi;

- recombinant DNA (rDNA) techniques;

- hybridoma techniques;

- propagation of microorganisms in embryos or animals.

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For human whole blood, blood components and plasma-derived products for therapeutic use separate comprehensive WHO guidance is available and should be followed.

In some countries certain small-molecule medicinal products (for example, antibiotics) are not defined as biological products.

The preparation of investigational medicinal products for use in clinical trials should follow the basic principles of GMP set out in these and other WHO GMP guidelines as appropriate. However, certain other requirements (such as process and analytical method validations) could be completed before marketing authorization.

The current document does not provide detailed recommendations for specific classes of biological products (for example, vaccines). Attention is therefore directed to other relevant WHO documents, and in particular to WHO recommendations to assure the quality, safety and efficacy of specific products.

Table 1 illustrates the typical risk-based application of the current document.

Table 1. Scope of the current document (illustrative)

Type and source of material

Example products

Application of this document to steps in manufacture

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Heparins, insulin, enzymes, proteins, allergen extract, ATMPs, animal immune sera

Collection of plant, organ, tissue or fluid

Cutting, mixing and/or initial processing

Isolation and purification

Formulation and filling

2. Virus or bacteria/ fermentation/cell culture

Viral or bacterial vaccines, enzymes, proteins

Establishment and maintenance of MCB, WCB, MSL/ MVS, WSL/WVS

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Inactivation when applicable, isolation and purification

Formulation and filling

3. Biotechnology fermentation/cell culture

Recombinant products, mAbs, allergens, vaccines, gene therapy (viral and non-viral vectors, plasmids)

Establishment and maintenance of MCB, WCB, MSL, WSL

Cell culture and/or fermentation

Isolation, purification and modification

Formulation and filling

4. Animal sources: transgenic

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Master and working transgenic bank

Collection, cutting, mixing and/or initial processing

Isolation, purification and modification

Formulation and filling

5. Plant sources: transgenic

Recombinant proteins, vaccines, allergens

Master and working transgenic bank

Growing and/or harvesting

Initial extraction, isolation, purification and modification

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Table 1. Scope of the current document (illustrative)

Type and source of material

Example products

Application of this document to steps in manufacture

6. Human sources

Urine-derived enzymes, hormones

Collection of fluid

Mixing and/or initial processing

Isolation and purification

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7. Human and/or animal sources

Gene therapy:

genetically modified cells

Donation, procurement and testing of starting tissue/cells *

Vector manufacture and cell purification and processing

Ex vivo genetic modification of cells, establish MCB, WCB or cell stock.

Formulation and filling.

Somatic cell therapy

Donation, procurement and testing of starting tissue/cells *

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Cell isolation, culture purification and combination with non-cellular components.

Formulation, combination and filling.

Tissue-engineered products

Donation, procurement and testing of starting tissue/cells *

Initial processing, isolation and purification, establishing and maintaining MCB, WCB, primary cell stock.

Cell isolation, culture purification and combination with non-cellular components.

Formulation, combination and filling.

* GMP guidelines, as described in this document, are not applied to this step. Other national regulations, requirements, recommendations and/or guidelines may apply as deemed necessary by the NRA.

MCB = master cell bank; MSL = master seed lot; MVS = master virus seed; WCB = working cell bank; WSL = working seed lot; WVS = working virus seed.

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In addition to the terms defined in WHO good manufacturing practices for pharmaceutical products: main principles and WHO good manufacturing practices for sterile pharmaceutical products, the definitions given below apply to the terms as used in the current document. These terms may have different meanings in other contexts.

Adventitious agents: contaminating microorganisms of the cell culture or source materials, including bacteria, fungi, mycoplasmas/spiroplasmas, mycobacteria, rickettsia, protozoa, parasites, transmissible spongiform encephalopathy (TSE) agents and viruses that have been unintentionally introduced into the manufacturing process of a biological product.. The source of these contaminants may be the legacy of the cell line, or the raw materials used in the culture medium to propagate the cells (in banking, in production or in their legacy), the environment, personnel, equipment or elsewhere.

Allergen: a molecule capable of inducing an immunoglobulin E (IgE) response and/or a Type I allergic reaction.

Antibodies: proteins produced naturally by the B-lymphocytes that bind to specific antigens. Using rDNA technology antibodies are also produced in other (continuous) cell lines. Antibodies may be divided into two main types – monoclonal and polyclonal antibodies – based on key differences in their methods of manufacture. Also called immunoglobulins.

Antigens: substances (for example, toxins, foreign proteins, bacteria, tissue cells and venoms) capable of inducing specific immune responses.

Axenic: a single organism in culture which is not contaminated with any other organism.

Bioburden: the level and type (objectionable or not) of microorganisms present in raw materials, media, biological substances, intermediates or finished products. Regarded as contamination when the level and/or type exceed specifications.

Biohazard: any biological material considered to be hazardous to people and/or the environment.

Biological starting materials: starting materials derived from a biological source that mark the beginning of the manufacturing process of a drug, as described in a marketing authorization or licence application, and from which the active ingredient is derived either directly (for example, plasma derivatives, ascitic fluid and bovine lung) or indirectly (for example, cell substrates, host/ vector production cells, eggs and viral strains).

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Campaign manufacture: the manufacture of an uninterrupted sequence of batches of the same product or intermediate in a given time period, followed by strict adherence to accepted control measures before switching to another product or different serotype. The different products are not run at the same time but may be run on the same equipment.

Cell bank: a collection of appropriate containers whose contents are of uniform composition and stored under defined conditions. Each container represents an aliquot of a single pool of cells.

Cell culture: the process by which cells that are no longer organized into tissues are grown in vitro under defined and controlled conditions. Cell cultures are operated and processed under axenic conditions to ensure a pure culture absent of microbial contamination.

Cell stock: primary cells expanded to a given number of cells to be aliquoted and used as starting material for production of a limited number of lots of a cell-based medicinal product.

Containment: the concept of using a process, equipment, personnel, utilities, system and/or facility to contain product, dust or contaminants in one zone, preventing them from entering into another zone and/or escaping.

Continuous culture: a process by which the growth of cells is maintained by periodically replacing a portion of the cells and the medium so that there is no lag or saturation phase.

Control strategy: a planned set of controls derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to active substance and finished product materials and components; facility and equipment operating conditions; in-process controls; finished product specifications; and the associated methods and frequency of monitoring and control.

Cross-contamination: contamination of a starting material, intermediate product or finished product with another starting material or product during production. In multi-product facilities, cross-contamination can occur throughout the manufacturing process, from generation of the master cell bank (MCB) and working cell bank (WCB) to finished product.

Dedicated: facility, personnel, equipment or piece of equipment used only in the manufacture of a particular product or group of specified products of similar risk.

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Feeder cells: cells used in co-culture to maintain pluripotent stem cells. For human embryonic stem cell culture, typical feeder layers include mouse embryonic fibroblasts or human embryonic fibroblasts that have been treated to prevent them from dividing.

Finished product: a finished dosage form that has undergone all stages of manufacture, including packaging in its final container and labelling. Also referred to as “finished dosage form”, “drug product” or “final product” in other documents.

Fermentation: maintenance or propagation of microbial cells in vitro (fermenter). Fermentation is operated and progressed under axenic conditions to ensure a pure culture absent of contaminating microorganisms.

Harvesting: the procedure by which the cells, inclusion bodies or crude supernatants containing the unpurified active ingredient are recovered.

Hybridoma: an immortalized cell line that secretes desired (monoclonal) antibodies and which is typically derived by fusing B-lymphocytes with tumour cells.

Inactivation: removal or reduction to an acceptable limit of infectivity of microorganisms or detoxification of toxins by chemical or physical modification.

Master cell bank (MCB): a quantity of well-characterized cells of animal or other origin, derived from a cell seed at a specific population doubling level (PDL) or passage level, dispensed into multiple containers and stored under defined conditions. The MCB is prepared from a single homogeneously mixed pool of cells. In some cases, such as genetically engineered cells, the MCB may be prepared from a selected cell clone established under defined conditions. However, the MCB may not be clonal. The MCB is used to derive a working cell bank (WCB).

Monoclonal antibodies (mAbs): homogenous antibody population obtained from a single clone of lymphocytes or by recombinant technology and which bind to a single epitope.

Pharmaceutical quality system (PQS): management system used by a pharmaceutical company to direct and control its activities with regard to quality.

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Primary containment: a system of containment that prevents the escape of a biological agent into the immediate working environment. It involves the use of closed containers or biological safety cabinets along with secure operating procedures.Quality risk management (QRM): a systematic process for the assessment, control, communication and review of risks to the quality of pharmaceutical products across the product life-cycle.

Reference sample: a sample of a batch of starting material, packaging material, intermediate or finished product which is stored for the purpose of being analysed should the need arise during the shelf-life of the batch concerned.

Retention sample: a sample of a fully packaged unit from a batch of finished product. It is stored for identification purposes (for example, of presentation, packaging, labelling, patient information leaflet, batch number and expiry date) should the need arise during the shelf-life of the batch concerned.

Seed lot: a quantity of live cells or viruses which has been derived from a single culture (though not necessarily clonal), has a uniform composition and is aliquoted into appropriate storage containers from which all future products will be derived, either directly or via a seed lot system. The following derived terms are used in this document – master seed lot (MSL): a lot or bank of cells or viruses from which all future vaccine production will be derived. The MSL represents a well-characterized collection of cells or viruses or bacteria of uniform composition. Also referred to as “master virus seed” (MVS) for virus seeds, “master seed bank”, “master seed antigen” or “master transgenic bank” in other documents; and working seed lot (WSL): a cell or viral or bacterial seed lot derived by propagation from the MSL under defined conditions and used to initiate production of vaccines on a lot-by-lot basis. Also referred to as “working virus seed” (WVS) for virus seeds, “working seed bank”, “working seed antigen” or “working transgenic bank” in other documents.

Specific pathogen free (SPF): denoting animals or animal materials (such as chickens, embryos, eggs or cell cultures) derived from groups of animals (for example, flocks or herds) free from specified pathogens, and used for the production or quality control of biological products. Such flocks or herds are defined as animals sharing a common environment and having their own caretakers who have no contact with non-SPF groups.

Starting materials: any substances of a defined quality used in the production of a pharmaceutical product, but excluding packaging materials. In the context of biological products manufacturing, examples of starting materials may include cryo-protectants, feeder cells, reagents, growth media, buffers, serum, enzymes, cytokines, growth factors and amino acids.

Transgenic: denoting an organism that contains a foreign gene in its normal genetic component for the expression of biological pharmaceutical materials.

Vaccine: a preparation containing antigens capable of inducing an active immune response for the prevention, amelioration or treatment of infectious diseases.

Working cell bank (WCB): a quantity of well-characterized cells of animal or other origin, derived from an MCB at a specific PDL or passage level, dispensed into multiple containers and stored under defined conditions. The WCB is prepared from a single homogeneously mixed pool of cells (often, this is the MCB). One or more of the WCB containers is used for each production culture.

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The manufacture of biological products should be undertaken in accordance with the basic principles of GMP. The points covered by the current document should, therefore, be considered as complementary to the general recommendations set out in the current WHO good manufacturing practices for pharmaceutical products: main principles and associated specialized guidelines and recommendations as well as other WHO documents related specifically to the production and control of biological products established by the WHO Expert Committee on Biological Standardization.

The manufacture, control and administration of biological active substances and finished products require certain specific considerations and precautions arising from the nature of these products and their processes. Unlike conventional pharmaceutical products which are manufactured using chemical and physical techniques capable of a high degree of consistency, the manufacture of biological active substances and finished products involves biological processes and materials, such as cultivation of cells or extraction from living organisms. As these biological processes may display inherent variability, the range and nature of by-products may also be variable. As a result, quality risk management (QRM) principles are particularly important for this class of materials and should be used to develop the control strategy across all stages of manufacture so as to minimize variability and reduce the opportunity for contamination and cross-contamination.

Materials and processing conditions used in cultivation processes are designed to provide conditions for the growth of target cells and microorganisms – therefore, extraneous microbial contaminants have the opportunity to grow. Furthermore, many biological products have limited ability to withstand certain purification techniques, particularly those designed to inactivate or remove adventitious viral contaminants. The design of the processes, equipment, facilities, utilities, the conditions of preparation and addition of buffers and reagents, sampling, and training of the operators are key considerations in minimizing such contamination events. Specifications outlined in WHO guidelines and recommendations will determine whether and to what stage of production substances and materials can have a defined level of bioburden or need to be sterile. Similarly, manufacturing should be consistent with other specifications set out in the product summary files, marketing authorization or clinical trial approvals (for example, number of generations (expressed as doublings or passages) between the seed lot or cell bank and the finished product).

Many biological materials (such as live-attenuated bacteria and viruses) cannot be terminally sterilized by heat, gas or radiation. In addition, some products, such as certain live and adjuvanted vaccines (for example, bacille Calmette–Guérin (BCG) or cholera), may not be sterilized by filtration processes. For these axenic products, processing should be conducted aseptically to minimize the introduction of contaminants from the point where a potential contamination cannot be removed from the manufacturing process. Relevant WHO documents should be consulted on the validation of specific manufacturing steps such as virus removal or inactivation. Robust environmental controls and monitoring and, wherever feasible, in situ cleaning and sterilization systems, together with the use of closed systems can significantly reduce the risk of accidental contamination and cross-contamination.

Control usually involves biological analytical techniques, which typically have a greater variability than physicochemical determinations. The combination of variability in starting materials and the potential for subtle changes during the manufacturing process of biological products also requires an emphasis on production consistency. This is of particular concern because of the need to link consistency to original clinical trials documenting the product’s safety and efficacy. A robust manufacturing process is therefore crucial and in-process controls take on a particular importance in the manufacture of biological active substances and medicinal products.

Because of the risks inherent in producing and manipulating pathogenic and transmissible microorganisms during the production and testing of biological materials, GMP should prioritize the safety of the recipient to whom the biological product is administered, the safety of personnel during operation and the protection of the environment.

Biosafety considerations should follow national guidelines and (if applicable and available) international guidelines. In most countries, the regulation of GMP and biosafety are governed by different institutions. In the context of manufacturing pathogenic biological products of Biosafety Risk Group 3 and 4, close collaboration between such institutions is especially required to assure that both product contamination and environmental contamination levels are controlled within acceptable limits. Specific recommendations regarding containment are outlined below in section 10.

5. Pharmaceutical quality system and quality risk management

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QRM principles should be used to develop the control strategy across all manufacturing and control stages – including materials sourcing and storage, personnel and materials flow, manufacture and packaging, quality control, quality assurance, storage and distribution activities, as described in relevant WHO guidelines and other documents. Due to the inherent variability of biological processes and starting materials, ongoing trend analysis and periodic review are particularly important elements of PQS. Thus, special attention should be paid to starting material controls, change control, trend analysis and deviation management in order to ensure production consistency. Monitoring systems should be designed so as to provide early detection of any unwanted or unanticipated factors that may affect the quality, safety and efficacy of the product. The effectiveness of the control strategy in monitoring, reducing and managing such risks should be regularly reviewed and the systems updated as required taking into account scientific and technical progress.

6. Personnel

6.1. Personnel responsible for production and control should have an adequate background in relevant scientific disciplines such as microbiology, biology, biometry, chemistry, medicine, pharmacy, pharmacology, virology, immunology, biotechnology and veterinary medicine, together with sufficient practical experience to enable them to perform their duties.

6.2. The health status of personnel should be taken into consideration as part of ensuring product safety. Where necessary, personnel engaged in production, maintenance, testing and animal care (and inspections) should be vaccinated with appropriate specific vaccines and have regular health checks. Any changes in the health status of personnel which could adversely affect the quality of the product should preclude their working in the production area, and appropriate records kept. The scope and frequency of health monitoring should be commensurate with the risk to the product and personnel.

6.3. Training in cleaning and disinfection procedures, hygiene and microbiology should emphasize the risk of microbial and adventitious contamination and the nature of the target microorganisms and growth media routinely used.

6.4. Where required to minimize the opportunity for cross-contamination, restrictions on the movement of all personnel (including quality control, maintenance and cleaning staff) should be defined on the basis of QRM principles. In general, all personnel including those not routinely involved in the production operation (such as management, engineering staff and validation staff or auditors) should not pass from areas with exposure to live microorganisms, genetically modified microorganisms, animal tissue, toxins, venoms or animals to areas where other products (inactivated or sterile) or different organisms are handled. If such passage is unavoidable during a working day, then contamination control measures (for example, clearly defined decontamination measures such as a complete change of appropriate clothing and shoes, and showering if applicable) should be followed by all personnel visiting any such production area unless otherwise justified on the basis of QRM.

6.5. Because the risks are difficult to manage, personnel working in an animal facility should be restricted from entering production areas where potential risks of cross-contamination exist.

6.6. Staff assigned to the production of BCG products should not work with other infectious agents. In particular, they should not work with virulent strains of Mycobacterium tuberculosis, nor should they be exposed to a known risk of tuberculosis infection (23). Additionally, they should be carefully monitored, with regular health checks that screen for tuberculosis infection.

6.7. If personnel working in BCG manufacturing and in animal quarters need to be reassigned to other manufacturing units they should not be allowed into such units until they pass their health check.

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7.1. The source, origin and suitability of active substances, starting materials (for example, cryo-protectants and feeder cells), buffers and media (for example, reagents, growth media, serum, enzymes, cytokines, growth factors and amino acids) and other components of the finished product should be clearly defined and controlled according to the principles set out in WHO guidance on GMP for pharmaceutical products.

7.2. Manufacturers should retain information describing the source and quality of the biological materials used for at least 1 year after the expiry date of the finished products and according to local regulations concerning biological products. It has been found that documents retained for longer periods may provide useful information related to adverse events following immunization (AEFIs) and other investigations.

7.3. All starting material suppliers (that is, manufacturers) should be initially qualified on the basis of documented criteria and a risk-based approach. Regular assessments of their status should also be carried out. Particular attention should be given to the identification and monitoring of any variability that may affect biological processes. When starting materials are sourced from brokers who could increase the risk of contamination by performing repackaging operations under GMP they should be carefully qualified; an audit may form part of such qualification, as needed.

7.4. An identity test, or equivalent, should be performed on each batch of received starting materials prior to release. The number of containers sampled should be justified on the basis of QRM principles and in agreement with all applicable guidelines (2). The identification of all starting materials should be in compliance with the requirements appropriate to the stage of manufacture. The level of testing should be commensurate with the qualification level of the supplier and the nature of the materials used. In the case of starting material used to manufacture active substances the number of samples taken should be based on statistically recognized criteria and QRM principles. However, for starting materials and intermediates used in the formulation of finished product each container should be sampled for identity testing in accordance with the main principles of GMP for pharmaceutical products unless reduced testing has been validated.

7.5. The sampling process should not adversely affect the quality of the product. Incoming starting materials should be sampled under appropriate conditions in order to prevent contamination and cross-contamination.

7.6. Where justified (such as the special case of sterile starting materials) it may be acceptable to reduce the risk of contamination by not performing sampling at the time of receipt but to perform the testing later on samples taken at the time of use. In such cases, release of the finished product is conditional upon satisfactory results of these tests.

7.7. Where the necessary tests for approving starting materials take a significantly long time, it may be permissible by exception to process starting materials before the test results are available. The use of these materials should be clearly justified in a documented manner, and the risks should be understood and assessed under the principles of QRM. In such cases, release of the finished product is conditional upon satisfactory results from the tests. It must be ensured that this is not standard practice and occurs only with justification of the risk taken.

7.8. The risk of contamination of starting materials during their passage along the supply chain should be assessed, with particular emphasis on adventitious agents such as those causing TSEs (24). Other materials that come into direct contact with manufacturing equipment and/or with potential product contact surfaces (such as filter media, growth media during aseptic process simulations and lubricants) should also be controlled. A quality risk assessment should be performed to evaluate the potential for adventitious agents in biological starting materials.

7.9. Where required, the sterilization of starting materials should be carried out by heat whenever possible. Where necessary, other appropriate validated methods may also be used for this purpose (such as irradiation and filtration).

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7.11. The transport of critical materials, reference materials, active substances, human tissues and cells to the manufacturing site should be controlled as part of a written quality agreement between the responsible parties if they are different commercial entities. Manufacturing sites should have documentary evidence of adherence to the specified storage and transport conditions, including cold chain requirements, if required. The required traceability – starting at tissue establishments through to the recipient(s), and including the traceability of materials in contact with the cells or tissues – should be ensured, maintained and documented.

8. Seed lots and cell banks

8.1. The recommendations set out in WHO good manufacturing practices for active pharmaceutical ingredients should be followed – specifically section 18 on specific guidance for active pharmaceutical ingredients manufactured by cell culture/fermentation.

8.2. Where human or animal cells are used as feeder cells in the manufacturing process, appropriate controls over their sourcing, testing, transport and storage should be in place.

8.3. In order to prevent the unwanted drift of genetic properties which might result from repeated subcultures or multiple generations, the production of biological products obtained by microbial culture, cell culture or propagation in embryos and animals should be based on a system of master and working seed lots and/or cell banks; which is the beginning of the manufacturing process of certain biological products (for example, vaccines).

8.4. The number of generations (expressed as passages or doublings) between the seed lot or cell bank and the finished product, defined as maximum, should be consistent with the marketing authorization dossier and should not be exceeded.

8.5. Cell-based medicinal products are often generated from a cell stock obtained from a limited number of passages. In contrast with the twotier system of MCBs and WCBs, the number of production runs from a cell stock is limited by the number of aliquots obtained after expansion and does not cover the entire life-cycle of the product. Cell stock changes should be covered by a validation protocol and communicated to the NRA, as applicable.

8.6. Establishment and handling of the MCBs and WCBs should be performed under conditions which are demonstrably appropriate. These should include an appropriately controlled environment to protect the seed lot and the cell bank, and the personnel handling them. To establish the minimum requirements for clean room grade and environmental monitoring in the case of vaccines see the WHO Environmental monitoring of clean rooms in vaccine manufacturing facilities: points to consider for manufacturers of human vaccines. During the establishment of the seed lot and cell bank, no other living or infectious material (such as viruses, cell lines or microbial strains) should be handled simultaneously in the same area or by the same persons, as set out in current WHO Recommendations.

8.7. Quarantine and release procedures for master and working cell banks/seed lots should be followed, including adequate characterization and testing for contaminants. Initially, full characterization testing of the MCB should be done, including genetic identification. A new MCB (from a previous initial clone, MCB or WCB) should be subjected to the same established testing as the original MCB, unless otherwise justified. Thereafter, the viability, purity and other stability-indicating attributes of seed lots and cell banks should be checked regularly according to justified criteria. Evidence of the stability and recovery of the seed lots and banks should be documented and records should be kept in a manner that permits trend evaluation.

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8.9. Seed lots and cell banks should be stored and used in such a way as to minimize the risks of contamination or alteration (for example, stored in qualified ultra-low temperature freezers or liquid nitrogen storage containers). Control measures for the storage of different seeds and/or cells in the same area or equipment should prevent mix-up and should take into account the infectious nature of the materials in order to prevent cross-contamination.

8.10. MSLs, MCBs, and preferably also WSLs and WCBs, should be stored in two or more controlled separate sites in order to minimize the risk of total loss due to natural disaster, equipment malfunction or human error. A contingency plan should be in place.

8.11. The storage and handling conditions for the cell or seed banks should be defined. Access should be controlled and restricted to authorized personnel, and appropriate access records maintained. Records of location, identity and inventory of individual containers should also be kept. Once containers are removed from the seed lot/cell bank management system they should not be returned to stock.

9. Premises and equipment

9.1. In general, preparations containing live microorganisms or live viruses should not be manufactured and containers should not be filled in areas used for the processing of other pharmaceutical products. However, if the manufacturer can demonstrate and validate effective containment and decontamination of the live microorganisms and viruses then the use of multi-product facilities may be justifiable. In such cases, measures such as campaign production, closed systems and/or disposable systems should be considered and should be based on QRM principles (see sections 10 and 13 below on containment and campaign production respectively).

9.2. Documented QRM should be carried out for every additional product in a biological manufacturing multi-product facility, which may include a potency and toxicological evaluation based on cross-contamination risks. Other factors to be taken into account include facility/equipment design and use, personnel and material flows, microbiological controls, physicochemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from product evaluation. The outcome of the QRM process should be the basis for determining the necessity for premises and equipment to be dedicated to a particular product or product family, and the extent to which this should be the case. This may include dedicating specific product-contact parts. The NRA should approve the use of a manufacturing facility for the production of multiple products on case-to-case basis.

9.3. Killed vaccines, antisera and other biological products – including those made by rDNA techniques, toxoids and bacterial extracts – may, following inactivation, be manufactured on the same premises provided that adequate decontamination and cleaning measures are implemented on the basis of QRM.

9.4. Cleaning and sanitization should take into account the fact that processes often include the handling of growth media and other growth-promoting agents. Validation studies should be carried out to ensure the effectiveness of cleaning, sanitization and disinfection, including elimination of residues of used agents. Environmental and personnel safety precautions should be taken during the cleaning and sanitization processes. The use of cleaning and sanitizing agents should not pose any major risk to the performance of equipment.

The use of closed systems to improve asepsis and containment should be considered where practicable. Where open systems are utilized during processing (for example, during addition of growth supplements, media, buffers and gases, and during sampling and aseptic manipulations during the handling of live cells such as in cell-therapy products) control measures should be put in place to prevent contamination, mix-up and cross-contamination. Logical and unidirectional flows of personnel, materials and processes, and the use of clean-in-place and sterilize-in-place systems, should be considered wherever possible. Where sterile single-use systems such as bags and connectors are utilized, they should be qualified with respect to suitability, extractables, leachables and integrity.

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9.6. In manufacturing facilities, the mix-up of entry and exit of personnel should be avoided through the use of separate changing rooms or through procedural controls where Biosafety Risk Group 3 or 4 organisms are handled.

10. Containment

10.1. Airborne dissemination of live microorganisms and viruses used for the production process, including those from personnel, should be avoided.

10.2. Adequate precautions should be taken to avoid contamination of the drainage system with dangerous effluents.

10.3. Dedicated production areas should be used for the handling of live cells capable of persistence in the manufacturing environment, for pathogenic organisms of Biosafety Risk Group 3 or 4 and/or for spore-forming organisms until the inactivation process is accomplished and verified. For Bacillus anthracis, Clostridium tetani and Clostridium botulinum strictly dedicated facilities should be utilized for each individual product. Up-to-date information on these and other high-risk or “special” agents should be sought from major information resources. Where campaign manufacture of spore-forming organisms occurs in a facility or suite of facilities only one product should be processed at any one time.

Use of any pathogenic organism above Biosafety Risk Group 3 may be permitted by the NRA according to the biohazard classification of the organism, the risk assessment of the biological product and its emergency demand.

10.4. Production of BCG-related product should take place in a dedicated area and by means of dedicated equipment and utilities (such as heating, ventilation and air conditioning (HVAC) systems) in order to minimize the hazard of cross-contamination.

10.5. Specific containment requirements apply to poliomyelitis vaccine in accordance with the WHO global action plan to minimize poliovirus facility-associated risk and with WHO Guidelines for the safe production and quality control of inactivated poliomyelitis vaccine manufactured from wild polioviruses. The measures and procedures necessary for containment (that is, for protecting the environment and ensuring the safety of the operator) should not conflict with those for ensuring product quality.

10.6. Air-handling systems should be designed, constructed and maintained to minimize the risk of cross-contamination between different manufacturing areas as required. The need for dedicated air-handling units or singlepass systems should be based on QRM principles, taking into account the biohazard classification and containment requirements of the relevant organism, and process and equipment risks. In the case of Biosafety Risk Group 3 organisms, air should not be recirculated to any other area in the facility and should be exhausted through high-efficiency particulate air (HEPA) filters that are regularly checked for performance. A dedicated non-recirculating ventilation system and HEPA-filtering of exhaust air are required when handling Biosafety Risk Group 4 organisms.

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10.8. Activities associated with the handling of live biological agents (such as centrifugation and blending of products which can lead to aerosol formation) should be contained in such a way as to prevent contamination of other products or the egress of live agents into the working and/or outside environment. The viability of such organisms and their biohazard classification should be taken into consideration as part of the management of such risks.

Accidental spillages, especially of live organisms, must be dealt with quickly and safely. Validated decontamination measures should be available for each organism or groups of related organisms. Where different strains of a single bacteria species or very similar viruses are involved, the decontamination process may be validated with one representative strain, unless the strains vary significantly in their resistance to the decontaminating agent(s) used.

10.9. Areas where Biosafety Risk Group 3 or 4 organisms are handled should always have a negative air pressure relative to the environment. This will ensure the containment of the organism in unlikely events such as failure of the door interlock. Air-lock doors should be interlocked to prevent them being opened simultaneously. Differential pressure alarms should be present wherever required, and should be validated and monitored.

10.10. Air-vent filters should be hydrophobic and subject to integrity testing at intervals determined by a QRM approach.

10.11. Where the filtration of exhaust air is necessary, the safe changing of filters should be ensured or bag-in-bag-out housings should be employed. Once removed, filters should be decontaminated and properly destroyed. In addition to HEPA filtration other inactivation technologies such as heat inactivation and steam scavenging may be considered for exhaust air to ensure effective inactivation of pathogenic organisms of Biosafety Risk Group 3 and/or 4.

11. Clean rooms

11.1. The WHO good manufacturing practices for sterile pharmaceutical products defines and establishes the required class/grade of clean areas for the manufacture of sterile products according to the operations performed, including final aseptic fill. Additionally, in order to address the specific manufacturing processes involved in the production of biological products, and particularly vaccines, the WHO Environmental monitoring of clean rooms in vaccine manufacturing facilities: points to consider for manufacturers of human vaccines guidance document may be used to develop the environmental classification requirements for biological manufacturing processes.

As part of the control strategy, the degree of environmental control of particulate and microbial contamination of the production premises should be adapted to the intermediate or finished product, and also to the production step, taking into account the potential level of contamination of the starting materials and the risks to the finished product.

11.2. The environmental monitoring programme should be supplemented with methods to detect the presence of the specific microorganisms used for production (for example, recombinant yeast and toxin- or polysaccharideproducing bacteria). The environmental monitoring programme may also include detection of the produced organisms and adventitious agents of production organisms, especially when campaign manufacture is applied on the basis of QRM principles.

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12.1. Since cultivation conditions, media and reagents are designed to promote the growth of cells or microbial organisms, typically in an axenic state, particular attention should be paid to the control strategy for ensuring that effective steps are in place for preventing or minimizing the occurrence of unwanted bioburden, endotoxins, viruses of animal and human origin, and associated metabolites.

12.2. The QRM process should be the basis for implementing the technical and organizational measures required to control the risks of contamination and cross-contamination. These could include, though are not limited to:

- carrying out processing and filling in segregated areas;

- containing material transfer by means of an airlock and appropriate type of pass box with validated transfer procedures, clothing change and effective washing and decontamination of equipment;

- recirculation of only treated (HEPA-filtered) air;

- acquiring knowledge of the key characteristics (for example, pathogenicity, detectability, persistence and susceptibility to inactivation) of all cells, organisms and any adventitious agents within the same facility;

- when considering the acceptability of concurrent work in cases where production is characterized by multiple small batches from different starting materials (for example, cell-based products) taking into account factors such as the health status of donors and the risk of total loss of a product from or for specific patients during development of the cross-contamination control strategy;

- preventing the risk of live organisms and spores entering non-related areas or equipment by addressing all potential routes of crosscontamination (for example, through the HVAC system) through the use of single-use components and closed systems;

- conducting environmental monitoring specific to the microorganism being manufactured in adjacent areas while paying attention to cross-contamination risks arising from the use of certain monitoring equipment (such as that used for airborne particle monitoring) in areas handling live and/or spore-forming organisms;

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12.3. When applicable, the inoculum preparation area should be designed so as to effectively control the risk of contamination, and should be equipped with a biosafety hood for primary containment.

12.4. If possible, growth media should be sterilized in situ by heat or in-line microbial-retentive filters. Additionally, in-line microbial-retentive filters should be used for the routine addition of gases, media, acids, alkalis and so on to fermenters or bioreactors.

12.5. Data from continuous monitoring of certain production processes (such as fermentation) should form part of the batch record. Where continuous culture is used, special consideration should be given to parameters such as temperature, pH, pO2, CO2 and the rate of feed or carbon source with respect to growth of cells.

12.6. In cases where a viral inactivation or removal process is performed, measures should be taken (for example, in relation to facility layout, unidirectional flow and equipment) to avoid the risk of recontamination of treated products by non-treated products.

12.7. A wide variety of equipment and components (for example, resins, matrices and cassettes) are used for purification purposes. QRM principles should be applied to devise the control strategy regarding such equipment and associated components when used in campaign manufacture and in multi-product facilities. The reuse of components at different stages of processing of one product is discouraged but, if performed, should be validated. Acceptance criteria, operating conditions, regeneration methods, lifespan and sanitization or sterilization methods, cleaning process, and hold time between the use of reused components should be defined and validated. The reuse of components for different products is not acceptable.

12.8. Where adverse donor (human or animal) health information becomes available after procurement and/or processing, and this information relates to product quality, then appropriate measures should be taken – including product recall, if applicable.

12.9. Antibiotics may be used during the early stages of production to help prevent inadvertent microbial contamination or to reduce the bioburden of living tissues and cells. In this case, the use of antibiotics should be well justified, and they should be cleared from the manufacturing process at the stage specified in the marketing authorization. Acceptable residual levels should be defined and validated. Penicillin and other beta-lactam antibiotics should not be used at any stage of the process.

12.10. A procedure should be in place to address equipment and/or accessories failure (such as air vent filter failure) which should include a product impact review. If such failures are discovered following batch release the NRA should be notified and the need for a batch recall should be considered.

13. Campaign production

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13.2. For downstream operations of certain products (for example, pertussis or diphtheria vaccines) campaign production may be acceptable if well justified. For finishing operations (formulation and filling) the need for dedicated facilities or the use of campaigns in the same facility will depend on the specific characteristics of the biological product, on the characteristics of the other products (including any non-biological products), on the filling technologies used (such as single-use closed systems) and on local NRA regulations. Labelling and packaging operations can be carried out in a multi-product facility.

13.3. Campaign changeover involves intensive decontamination/sterilization (if required) and cleaning of the equipment and manufacturing area. Decontamination/sterilization (if required) and cleaning should include all equipment and accessories used during production, as well as the facility itself. The following recommendations should be considered:

- waste should be removed from the manufacturing area or sent to the bio-waste system in a safe manner;

- materials should be transferred by a validated procedure;

- the Quality Unit should confirm area clearance by inspection, and review the campaign changeover data (including monitoring results) prior to releasing the area for the next product.

13.4. When required, the corresponding diluent for the product can be filled in the same facility in line with the defined campaign production strategy for finished product.

13.5. When campaign-based manufacturing is considered, the facility layout and the design of the premises and equipment should permit effective cleaning and decontamination/sterilization (if required) based on QRM principles and validated procedures following the production campaign. In addition, consideration may need to be given at the design stage of facility layout to the possible need for fumigation.

14. Labelling

14.1. The information provided on the inner label (also called the container label) and on the outer label (on the packaging) should be readable and legible, and the content approved by the NRA.

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14.3. The suitability of labels for low and ultra-low storage temperatures should be verified, if applicable. The label should remain properly attached to the container under different storage conditions during the shelf-life of the product. The label and its adhesive should have no adverse effect on the quality of the product caused by leaching, migration and/or other means.

15. Validation

15.1. Biological processes, handling of live materials and using campaign-based production, if applicable, are the major aspects of biological product manufacturing which require process and cleaning validation. The validation of such processes – given the typical variability of biological products, the possible use of harmful and toxic materials and the need for inactivation processes – plays an important role in demonstrating production consistency and in proving that the critical process parameters and product attributes are controlled. Where available, WHO guidance documents should be consulted on the validation of specific manufacturing methods (for example, virus removal or inactivation).

15.2. A QRM approach should be used to determine the scope and extent of validation.

15.3. All critical biological processes (including inoculation, multiplication, fermentation, cell disruption, inactivation, purification, virus removal, removal of toxic and harmful additives, filtration, formulation and aseptic filling) are subject, as applicable, to process validation. Manufacturing control parameters to be validated may include specific addition sequences, mixing speeds, time and temperature controls, limits of light exposure and containment.

15.4. After initial process validation studies have been finalized and routine production has begun, critical processes should be subject to monitoring and trending with the objective of assuring consistency and detecting any unexpected variability. The monitoring strategy should be defined, taking into consideration factors such as the inherent variability, complexity of quality attributes and heterogeneity of biological products. A system or systems for detecting unplanned departures from the process as designed should be in place to ensure that the process remains in a state of control. Collection and evaluation of information and data on the performance of the process will allow for detection of undesired process variability and will determine whether action should be taken to prevent, anticipate and/or correct problems so that the process remains under control.

15.5. Cleaning validation should be performed in order to confirm the effectiveness of cleaning procedures designed to remove biological substances, growth media, process reagents, cleaning agents, inactivation agents and so on. Careful consideration should be given to cleaning validation when campaign-based production is practised.

15.6. Critical processes for inactivation or elimination of potentially harmful microorganisms of Biosafety Risk Group 2 or above, including genetically modified ones, are subject to validation.

15.7. Process revalidation may be triggered by a process change as part of the change-control system. In addition, because of the variability of processes, products and methods, process revalidation may be conducted at predetermined regular intervals according to risk considerations. A detailed review of all changes, trends and deviations occurring within a defined time period – for example, 1 year, based on the regular product quality review (PQR) – may indicate a need for process revalidation.

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16. Quality control

16.1. As part of quality control sampling and testing procedures for biological materials and products, special consideration should be given to the nature of the materials being sampled (for example, the need to avoid contamination, ensure biocontainment and/or cold chain requirements) in order to ensure that the testing carried out is representative.

16.2. Samples for post-release use typically fall into one of two categories – reference samples or retention samples – for the purposes of analytical testing and identification respectively. For finished products the reference and retention samples will in many instances be presented identically as fully packaged units. In such circumstances, reference and retention samples may be regarded as interchangeable.

Reference samples of biological starting materials should be retained under the recommended storage conditions for at least 1 year beyond the expiry date of the corresponding finished product. Reference samples of other starting materials (other than solvents, gases and water) as well as intermediates for which critical parameters cannot be tested in the final product should be retained for at least 2 years after the release of the product if their stability allows for this storage period. Certain starting materials such as components of growth media need not necessarily be retainedRetention samples of a finished product should be stored in their final packaging at the recommended storage conditions for at least 1 year after the expiry date.

16.3. For cell-based products, microbiological tests (for example, sterility tests or purity checks) should be conducted on cultures of cells or cell banks free of antibiotics and other inhibitory substances in order to provide evidence of the absence of bacterial and fungal contamination, and to be able to detect fastidious organisms where appropriate. Where antibiotics are used, they should be removed by filtration at the time of testing.

16.4. The traceability, proper use and storage of reference standards should be ensured, defined and recorded. The stability of reference standards should be ensured, defined and recorded. The WHO Recommendations for the preparation, characterization and establishment of international and other biological reference standards should be followed.

16.5. All stability studies – including real-time/real-condition stability, accelerated stability and stress testing – should be carried out according to relevant WHO and other guidelines or other recognized documents. Trend analysis of the test results from the stability monitoring programme should assure the early detection of any process or assay drift, and this information should be part of the PQR of biological products.

16.6. For products where ongoing stability monitoring would normally require testing using animals, and no appropriate alternative or validated techniques are available, the frequency of testing may take into account a risk-based approach. The principle of bracketing and matrix designs may be applied if scientifically justified in the stability protocol.

16.7. All analytical methods used in the quality control and in-process control of biological products should be well characterized, validated and documented to a satisfactory standard in order to yield reliable results. The fundamental parameters of this validation include linearity, accuracy, precision, selectivity/specificity, sensitivity and reproducibility.

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In addition to the common parameters typically used for validating assays (such as accuracy and precision) additional measurements (for example, of the performance of references, critical reagents and/or cell lines) should be considered during the validation of bioassays based on the biological nature of the assay and reagents used.

17. Documentation (batch processing records)

17.1. In general, the processing records of regular production batches should provide a complete account of the manufacturing activities of each batch of biological product showing that it has been produced, tested and dispensed into containers in accordance with the approved procedures.

In the case of vaccines, a batch processing record and a summary protocol should be prepared for each batch for the purpose of lot release by the NRA. The information included in the summary protocol should follow the WHO Guidelines for independent lot release of vaccines by regulatory authorities. The summary protocol and all associated records should be of a type approved by the NRA.

17.2. Manufacturing batch records should be retained for at least 1 year after the expiry date of the batch of the biological product and should be readily retrievable for inspection by the NRA. It has been found that documents retained for longer periods may provide useful information related to AEFI and other investigations.

17.3. Starting materials may require additional documentation on source, origin, supply chain, method of manufacture and controls applied in order to ensure an appropriate level of control, including of microbiological quality if applicable.

17.4. Some product types may require a specific definition of what materials constitute a batch – particularly somatic cells in the context of ATMPs. For autologous and donor-matched situations, the manufactured product should be viewed as a batch.

18. Use of animals

18.1. A wide range of animals is used for the manufacture or quality control of biological products. Special considerations are required when animal facilities are present at a manufacturing site.

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18.3. Areas used for performing tests involving animals or microorganisms should be well separated from premises used for the manufacturing of products and should have completely separate ventilation systems and separate staff. The separation of different animal species before and during testing should be considered, as should the necessary animal acclimatization process, as part of the test requirements.

18.4. In addition to monitoring compliance with TSE regulations (24) other adventitious agents that are of concern (including those causing zoonotic diseases and diseases in source animals) should also be monitored and recorded in line with specialist advice on establishing such programmes. Instances of ill health occurring in the source/donor animals should be investigated with respect to their suitability, and the suitability of in-contact animals, for continued use (for example, in manufacture, as sources of starting materials, and for quality control and safety testing). Decisions should be documented.

18.5. A look-back procedure should be in place in relation to the decisionmaking process used to evaluate the continued suitability of the biological active substance or finished product in which animal-sourced starting materials have been used or incorporated. This decision-making process may include the retesting of reference samples from previous collections from the same donor animal (where applicable) to establish the last negative donation. The withdrawal period of therapeutic agents used to treat source/donor animals should be documented and should be taken into account when considering the removal of those animals from the programme for defined periods.

18.6. Particular care should be taken to prevent and monitor infections in source/donor animals. Measures taken should cover aspects such as sourcing, facilities, husbandry, biosafety procedures, testing regimes, control of bedding and feed materials, 100% fresh air supply, appropriate design of the HVAC system, water supply and appropriate temperature and humidity conditions for the species being handled. This is of special relevance to SPF animals where pharmacopoeial monograph requirements should be met. Housing and health monitoring should also be defined for other categories of animals (for example, healthy flocks or herds).

18.7. For products manufactured from transgenic animals, traceability should be maintained in the creation of such animals from the source animals. Note should be taken of national requirements for animal quarters, care and quarantine.

18.8. For different animal species and lines, key criteria should be defined, monitored and recorded. These may include the age, sex, weight and health status of the animals.

18.9. Animals, biological agents and tests carried out should be appropriately identified to prevent any risk of mix-up and to control all identified hazards.

18.10. The facility layout should ensure a unidirectional and segregated flow of healthy animals, inoculated animals and waste-decontamination areas. Personnel and visitors should also follow a defined flow in order to avoid cross-contamination.

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APPENDIX II

WHO GOOD MANUFACTURING PRACTICES FOR BIOLOGICAL MEDICINAL PRODUCTS DERIVED FROM HUMAN BLOOD OR PLASMA
(Enclosed with the Circular No. 35/2018/TT-BYT dated November 22, 2018 of the Minister of Health)

Glossary and abbreviations

1. Quality management

2. Personnel

3. Documentation

4. Premises and equipment

5. Qualification and validation

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7. Manufacturing

8. Contract manufacturing, analysis and services

Glossary and abbreviations

The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts.

apheresis

The process by which one or more blood components are selectively obtained by withdrawing whole blood, separating it by centrifugation and/or filtration into its components.

blood collection

The procedure whereby a single donation of blood is collected in an anticoagulant and/or stabilizing solution, under conditions designed to minimize microbial contamination, cellular damage and/or coagulation activation of the resulting blood donation.

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A constituent of blood (erythrocytes, leukocytes, platelets, cryoprecipitate and plasma) that can be prepared by various separation methods and under such conditions that it can be used either directly for therapeutic purposes or for further processing/manufacturing.

blood establishment

Any structure, facility or body that is responsible for any aspect of the collection, testing, processing, storage, release and/or distribution of human blood or blood components when intended for transfusion or further industrial manufacturing.

blood products

Any therapeutic substances derived from human blood, including whole blood, blood components and plasma-derived medicinal products.

calibration

The set of operations which establish, under specified conditions, the relationship between values indicated by a measuring instrument or measuring system, or values represented by a material measure, and the corresponding known values of a reference standard.

CJD / vCJD

Creutzfeld-Jakob-Disease/variant Creutzfeld-Jakob-Disease.

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A system developed for aseptic collection and separation of blood and blood components, manufactured under clean conditions, sealed to the external environment and sterilized by a validated and approved method.

computerized system

A system including the input of data, electronic processing and the output of information to be used either for reporting or for automatic control.

contract acceptor

An establishment or institution that performs particular work or services under a contract for a different institution.

contract giver

An establishment or institution that is subcontracting particular work or services to a different institution and sets up a contract defining the duties and responsibilities of each side.

donor

A person in defined good health conditions who voluntarily donates blood or blood components, including plasma for fractionation.

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The act of delivery of blood and blood components to other blood establishments, hospital blood banks or manufacturers of blood- and plasma-derived medicinal products. It does not include the issuing of blood or blood components for transfusion.

first-time (tested) donor

A donor whose blood or plasma is tested for the first time for infectious disease markers in a blood establishment.

good manufacturing practice (GMP)

All elements in the established practice that will collectively lead to final products or services that consistently meet appropriate specifications and compliance with defined regulations.

HAV, hepatitis A virus

A non-enveloped single-stranded RNA virus that is the causative agent of hepatitis A.

HBsAg, hepatitis B surface antigen

The antigen on the periphery of the hepatitis B virus.

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An enveloped double-stranded DNA virus that is the causative agent of hepatitis B.

HCV, hepatitis C virus

An enveloped single-stranded, RNA virus that is the causative agent of hepatitis C.

HIV, human immunodeficiency virus

An enveloped, single-stranded RNA virus that is the causative agent of the acquired immunodeficiency syndrome (AIDS).

HTLV 1 and 2, human T-cell lymphotropic virus, types 1 and 2

Enveloped, single stranded RNA viruses that are typically cell-associated.

manufacture

All operational processes or steps - including purchase or selection of materials and products, production, quality control, release, storage and distribution of products and the related controls - used to produce a blood product. This includes also the donation process.

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A unit or site used for the collection of blood and/or blood components, operating temporarily or at movable locations off-site from a permanent collection site, under the responsibility of a blood establishment.

nucleic acid amplification techniques (NAT)

A testing method to detect the presence of a targeted area of a defined microbial genome that uses amplification techniques such as polymerase chain reaction (PCR).

near-miss event

An incident that, if not detected in a timely manner, would have affected the safety of the recipients or donors.

national regulatory authority (NRA)

WHO terminology for national medicines regulatory authorities. NRAs should promulgate and enforce medicines regulations.

plasma for fractionation

The liquid part of human blood remaining after separation of the cellular elements from blood collected in a container containing an anticoagulant, or separated by continuous filtration and/or centrifugation of anticoagulated blood in an apheresis procedure, intended for further manufacturing.

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All operations involved in the preparation of blood components, from collection through processing to completion as a finished product (blood component).

qualification

A set of actions used to provide documented evidence that any piece of equipment, critical material or reagent used to produce the final product and that might affect the quality or safety of a product works reliably as intended or specified and leads to the expected results.

quality

The total set of characteristics of an entity that affect its ability to satisfy stated and implied needs, and the consistent and reliable performance of services or products in conformity with specified requirements. Implied needs include safety and quality attributes of products intended both for therapeutic use and as starting materials for further manufacturing.

quality assurance

A part of quality management focused on providing confidence that quality requirements will be met.

quality management

The coordinated activities that direct and control an organization with regard to quality.

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A management system that directs and controls an organization with respect to quality and that ensures that steps, processes, procedures and policies related to quality activities are being followed.

quality risk management (QRM)

A systematic process for the assessment, control, communication and review of risks to the quality of the product across the product’s life cycle.

quarantine

The status of starting or packaging materials, intermediate, bulk or finished products that are isolated physically or by other means while a decision is awaited on their release for use or rejection.

regular donor

A person who routinely donates blood, blood components or plasma in the same blood establishment in accordance with the minimum time intervals.

repeat donor

A person who has donated before in the same establishment but not within the period of time considered as regular donation.

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A donation is considered to be repeatedly reactive if it is found reactive in a screening test, is retested in duplicate using the same assay, and at least one of the repeat tests is also reactive.

validation

Actions for proving that any operational procedure, process, activity or system leads to the expected results. Validation work is normally performed in advance according to a defined and approved protocol that describes tests and acceptance criteria.

WNV, West Nile Virus

An enveloped single-stranded RNA virus that is the causative agent of West Nile fever.

1. Quality management

Principles

Quality is the responsibility of all persons involved in the various processes of the blood establishment. The management of the blood establishment is responsible for a systematic approach to quality and the implementation and maintenance of a quality management system. A quality programme should be designed to ensure that each product (including plasma for fractionation) is manufactured in the same manner from donor selection through to distribution of the final product.

Quality management involves all activities that determine the quality policy, objectives and responsibilities, and their implementation through quality planning, quality control, quality assurance and quality improvement in order to assure the quality and safety of blood and blood components.

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Within the organizational structure of the blood establishment there should be a quality management unit comprising one or more persons. The quality management personnel should be responsible for ensuring that there is documented evidence that the quality policies, procedures and practices are being fulfilled. Senior management, in coordination with the quality management unit, should develop and implement quality assurance policies and objectives in a manner that provides clear direction to all staff. The quality assurance policies and objectives should be designed to ensure the highest levels of safety and quality in the blood components that are produced from each collection. The policies and procedures should comply with all national and, where appropriate, international regulations and requirements.

Staff should be able to understand the intent of the quality objectives and their own role in accomplishing the objectives. The performance of the quality management system should be evaluated periodically by determining whether the objectives have been or are continuously being met. If there are shortcomings in the quality system, corrections should be made and the quality management unit should be held responsible for monitoring corrective action and continued compliance.

Within any blood establishment there should be independent functions for fulfilling quality assurance and quality control responsibilities. The quality assurance function should be independent of manufacturing operations and should assure that all processes are performed and documented. The quality assurance function should be involved in all quality-related matters and in the review and approval of all quality-related documents.

1.2. Quality assurance

Quality assurance is a wide-ranging concept covering all matters that individually or collectively influence the quality of the product. It is the totality of arrangements that are made with the purpose of ensuring that products are of the quality required for their intended use. Quality assurance therefore incorporates GMP, and other elements, including those outside the scope of this guideline - such as product design and development [7].

Quality assurance is that part of quality management that ensures that all critical processes are appropriately described in written instructions (see chapter 5), are performed in accordance with the principles of GMP and comply with the appropriate regulations. The quality assurance system should be fully documented, distributed and explained to everyone involved in the manufacturing processes.

All parts of the quality assurance system should be adequately resourced with competent personnel, suitable premises, and suitable and sufficient equipment and facilities to enable the manufacturing steps to be completed in a safe and quality-compliant manner.

1.2.1. Good manufacturing practice in blood establishments

GMP is the part of quality assurance that ensures that blood products are consistently produced and controlled to the quality standards appropriate to their intended use, as required by predefined specifications and, if applicable, by the marketing authorization. GMP is aimed primarily at diminishing the risks inherent in any blood establishment operation - such as contamination (including cross-contamination), mix-ups, disease transmission or other unexpected adverse outcomes resulting from the use of blood products.  GMP is concerned with both production and quality control.

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• All manufacturing processes are clearly defined by policies and standard operating procedures, are systematically reviewed in the light of experience, and are shown to be capable of consistently manufacturing products of the required quality that comply with their specifications.

• Qualification of equipment and reagents and validation of processes and methods are performed prior to use in the manufacture of products intended for transfusion or further manufacturing.

• All necessary resources are provided — including appropriately qualified and trained personnel, adequate premises, suitable equipment, appropriate materials, approved procedures and instructions, suitable storage and transport.

• A system is available to maintain traceability of all released products in order to facilitate recall, if necessary, of any product suspected of not conforming to standards, and there is also a system to handle complaints.

• A system is available that addresses process and quality improvement functions and activities.

1.2.2. Quality control

Quality control is that part of GMP which is concerned with specifications, sampling and testing. Quality control is also concerned with the organization, documentation and release procedures which ensure that the necessary and relevant tests are carried out and that neither materials are released for use nor products released for supply until their quality has been judged to be satisfactory [7]. For quality control programmes in blood establishments, refer to sections 9.5 and 9.6.

1.3. Product quality review

Regular periodic or rolling quality reviews should be conducted with the objective of verifying the consistency of the existing process and the appropriateness of current specifications in order to highlight trends and to identify improvements in both product and process.

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- review of starting materials;

- review of critical in-process controls;

- review of results of quality control and quality monitoring;

- review of all changes;

- review of the qualification status of equipment;

- review of technical agreements and contracts;

- review of all significant deviations, errors and non-conformances, and the corrective actions implemented;

- review of the findings of internal audits and other inspections, and the corrective actions implemented;

- review of complaints and recalls;

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- review of donor deferrals;

- review of look-back cases.

1.4. Quality risk management

Blood establishments should ensure that blood components manufactured in their facilities are of the quality required for their intended use, comply with quality standard requirements, and do not place recipients at risk due to inadequate safety, quality or efficacy throughout the life-cycle of the product. In order to reliably achieve the quality objective, there should be a comprehensively designed and correctly implemented system of quality assurance that incorporates GMP, quality control and quality risk management (QRM).

An effective QRM approach can ensure the quality of a product by providing proactive means to identify and control potential quality issues. It can also facilitate and improve the decision-making process in cases when quality problems or deviations from standard processes and specifications have to be assessed or planned changes need to be evaluated. The two primary principles of QRM are:

• The evaluation of the risk to quality and safety should be based on scientific knowledge and ultimately linked to the protection of the donor and/or recipient.

• The level of effort, formality and documentation of the QRM process should be commensurate with the level of risk.

Examples of the QRM processes and applications can be found in guidelines on QRM, such as the Q9 guideline of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [8]. This describes processes and offers a selection of methods and tools for applying the QRM principles.

1.5. Change control

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After the implementation of a change, a post-implementation evaluation should be carried out in order to determine whether the introduction of the change has been successful and effective.

The introduction of new equipment, processes and methods should be treated as a change.

1.6. Deviation evaluation and reporting

Any deviation from standard operating procedures, validated processes, or non-conformances with specifications or other quality-related requirements should be recorded and investigated. The potential impact on the quality of the product in question, or on other products, should be evaluated.

The evaluation of the cause of the deviation and of related processes that may also be implicated in the deviation should be documented. Review and approval of the investigation as completed should be documented by the quality assurance and/or quality control department as appropriate.

All deviations and non-conformances should be logged in a system that allows for appropriate data review. A data review should be carried out periodically in a manner that allows for tracking and trending of data and that facilitates process improvement.

The handling of deviations and non-conformances should be defined in writing. Actions should be taken within a reasonable time frame in order to avoid any impact on other products manufactured within the same establishment.

Under certain circumstances a product may be accepted after evaluation of a deviation. The documentation should include the justification or rationale for accepting a product manufactured in deviation from a specified requirement, and should be signed by the responsible person.

1.7. Corrective and preventive actions

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The corrective and preventive action system should ensure that each quality problem is addressed and corrected and that recurrence of the problem is prevented. Actions should be carried out within a reasonable predefined time frame. The management of the blood establishment should be involved in the review of corrective and preventive actions.

The blood establishment should have methods and procedures in place to collect, document and evaluate data on quality. Product or quality problems should be entered into the corrective and preventive action system. Quality data include all errors, deviations, non-conformances, accidents, near-miss events and complaints. Quality data also include the results of quality control tests 162 and monitoring activities. Quality data should be reviewed at defined intervals in order to identify product and quality problems that may require corrective action and to identify unfavourable trends that may require preventive action.

1.8. Internal audits

In order to monitor implementation and compliance with the quality management system, regular internal audits should be performed according to an established procedure. Internal audits should be conducted by trained, independent and competent persons under the responsibility of the organization’s quality assurance unit.

Internal audits should be arranged according to a schedule and should cover all parts of the operations, including data processing systems. Each audit should be carried out according to an approved audit plan that assesses compliance with internal requirements and applicable national and/or international regulations.

All audit results should be documented and reported to the management.

Appropriate corrective and preventive actions should be taken in a timely and effective manner and should be assessed for effectiveness after implementation.

The quality assurance department, where the internal audit function resides, should not audit itself but should be subject to an independent audit.

Internal audits are not a substitute for official inspections performed by the competent national authorities who check compliance with national regulations.

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1.9.1. Complaints

There should be a system in place to ensure that all complaints are handled according to written - and approved - standard operating procedures. The review of the complaint should take account of whether the complaint relates to a quality defect in a blood component. The blood establishment should determine whether a recall should be initiated. The process should be defined in a standard operating procedure. Complaints, adverse events or reactions, as well as any information concerning potentially defective products, should be carefully reviewed and thoroughly investigated in order to find the root cause of the problem. Consideration should be given to determining whether other products are also affected. All investigations and actions should be carried out in a timely manner to ensure that the safety of the recipient is not compromised and that other products manufactured within the same establishment are not affected.

Immediate corrective actions should be taken to address the root cause of the problem, and actions should be taken to prevent it from recurring. There should be active follow-up of the implementation of corrective actions (see section 3.7).

Designated personnel should be responsible for managing complaints and coordinating investigations, actions and measures to be taken within a defined time frame. The unit responsible for quality should be included in this process.

All complaints, with the original details, should be recorded. Records should be retained of all the decisions, investigations and measures taken as a result of a complaint. Complaint records should be reviewed regularly in order to check for unfavourable trends or recurring problems and to ensure continuous quality improvement.

Depending on the national requirements the NRA should be informed.

1.9.2. Recalls

An effective written recall procedure should be in place, including a description of the responsibilities and actions to be taken. A recall should always be initiated whenever it is discovered that a product does not meet the release criteria of the blood establishment and NRA. This may happen when information is obtained subsequent to the release of a product and, had this information been known in advance, it would have prevented the blood component from being released. A recall may also be indicated when it is discovered that personnel did not follow standard operating procedures. Corrective actions should take place within predefined time periods and should include the traceability of all relevant components and, where applicable, look-back procedures (see section 3.11).

A qualified person within the blood establishment should be nominated to assess the need for product recall and to initiate, coordinate and document the necessary actions.

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Recalled products should be destroyed. If recalled products are not destroyed, they should be clearly identified and stored separately in a secure area.

1.10. Process improvement

Ideas for potential improvements to any of the systems may come from research, development, brainstorming, or from the management of non 164 conformances, events and complaints, from internal or external audit or inspection findings, and from deviations detected during quality monitoring activities.

The process should track corrective or preventive actions that are developed and implemented. An effectiveness check should be in place to determine the impact or effectiveness of any changes. These activities should be documented and reported at least annually to the executive management (in the quality management review report).

1.11. Look-back

A written system should be in place for carrying out a look-back procedure. This process should be able to trace the products collected from a donor to the final recipients and from the recipient back to the donor, preferably by means of a computer database.

This standard operating procedure should be followed when it is determined retrospectively that a blood or plasma donation should have been excluded from processing - for instance, because the unit was collected from a donor who was subsequently rejected for reactive viral marker, high-risk behaviour, exposure to CJD/vCJD or other risks related to infectious diseases (donor look-back).

If a donor is confirmed to have a disease that is transmissible by blood products or has high-risk behaviour, the donor should be permanently excluded from further donation. All donations from such a donor should be traced and prevented from being used or further manufactured unless they have expired and therefore have already been destroyed. If donations have been used or further processed, procedures should be in place to define appropriate actions. Donor notification and counselling is recommended for purposes of donor health and for the safety of the blood supply.

There should be a process in place for investigating a report of a suspected transfusion-associated reaction in a recipient, in order to identify a potentially implicated donor (recipient look-back). The donor of products implicated in transmitting disease or causing recipient harm should be excluded from further donations. All other donations from the implicated donor should be traced and blood components removed from the inventory and recalled, if within the expiry date.

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The recipients of any products identified in the look-back process should be counselled about the risk of having contracted a disease from the potentially contaminated products and should be offered disease marker testing, consultation and medical treatment if indicated. For plasma used for fractionation, the manufacturer of the medicinal product should be notified in case of a look-back.

2. Personnel

Sufficient personnel should be available and should be qualified to perform their tasks. They should have the appropriate qualifications and experience and should be given initial and continuous training in order to assure the quality and safety of blood and blood components.

Only persons who are competent in the manufacturing process and have read and understood all relevant standard operating procedures should be involved in the manufacturing and distribution processes, including collection, quality control and quality assurance.

2.1. Organization and responsibilities

Tasks and responsibilities should be clearly documented and understood. Personnel should have clear, current and written job descriptions. There should be an organizational chart showing the hierarchical structure of the blood establishment with clear delineation of lines of responsibility and reporting.

Key personnel include the following functions and their substitutes:

- a “responsible person” (see functions and qualifications below);

- a processing or operations manager, responsible for all processing and operations activities;

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- a quality assurance manager, reporting findings or quality issues directly to the responsible person and empowered to discontinue operations if quality and safety expectations are not being fulfilled;

- a physician with the responsibility to ensure the safety of donors and the safety of the distributed blood components.

The blood establishment should nominate a “responsible person” who will be responsible for:

- ensuring that approved donor selection criteria are followed;

- ensuring that every unit of blood or blood components has been collected, tested, processed, stored and distributed in compliance with the national regulations in force;

- providing information to the competent national authority;

- ensuring that the required initial and ongoing training of personnel is carried out;

- ensuring that a quality management system and a haemovigilance system (ensuring traceability as well as notification of serious adverse events and reactions) is in place in the blood establishment.

The responsible person should fulfil the qualification requirements according to the national regulations, or should fulfil the following minimum conditions of qualification:

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• He/she should have practical experience in relevant areas, preferably for at least two years, in one or more establishments which are authorized to undertake activities related to collection, testing, preparation, storage and distribution of blood and blood components.

Depending on the national legislation, the name of the responsible person may need to be communicated to the NRA.

The quality assurance manager and the processing or operations manager should be different persons, functioning independently. The quality assurance manager is responsible for ensuring that there are appropriate quality systems and protocols in place for the safe and secure release of all materials, equipment, reagents and blood and blood components.

The processing or operations manager is responsible for ensuring that there are appropriate manufacturing and technical processes and procedures in place for the production of blood or blood components.

The physician should hold a relevant medical degree awarded on completion of a university course of study and should hold any registration or licensure that is required by the national authority

Responsibilities should be delegated only to individuals who have been trained for the task. Delegation should be in written form and should be reviewed regularly.

2.2. Training

Personnel should receive initial and continuous training that is appropriate to their specific tasks. This training should be carried out by qualified personnel or trainers and should follow prearranged written programmes. Approved training programmes should be in place and should also include:

- relevant principles of transfusion medicine;

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- relevant knowledge in microbiology and hygiene. Training should be documented and training records should be retained.

2.2.1. Initial training

Programmes for the initial training of newly recruited personnel or personnel taking over new functions should take into account all relevant tasks and procedures, including general topics such as quality assurance, GMP and computerized systems. The same topics and principles apply to training aimed to reintroduce personnel after a longer absence from the workplace. The time frames should be defined.

The training records should identify at least the trainer, all the specified tasks (including the relevant standard operating procedures) and when the training was completed. The records should be signed by both the trainee and the trainer. Upon completing the training, the personnel should be competent in the tasks in which they have been trained. If a database is used the personnel training profile should be updated annually.

2.2.2. Continuous training

Continuous training programmes (theoretical and/or practical training) should be in place to ensure that personnel keep up the skills to carry out their assigned tasks. Such training programmes should take technical and scientific developments into account. Training should also include any changes to standard operating procedures and personnel requirements. Both internal and external training courses may be useful here.

2.2.3. Competency

The overall competency of personnel is a result of education, experience and training. As a key factor for the quality and safety of blood and blood products, competency has to be carefully evaluated and continuously monitored.

Upon completion of the initial training, the competency of the personnel should be evaluated and documented. After the initial competency is determined, there should be periodic assessment of competency. The contents of training programmes and their effectiveness should be periodically reviewed and assessed.

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All personnel, prior to being hired and during employment, as appropriate, should undergo health examinations. Any person shown at any time to have an illness or open lesions that may adversely affect the quality of the products and/or the safety of the donors should be excluded from the establishment’s manufacturing processes until that person’s condition is no longer judged to be a risk.

All personnel should be trained in personal hygiene. In particular, personnel should be instructed to wash and disinfect their hands before, during and after activities such as blood collection and production.

Special attention should be drawn to the need to protect donors, employees and products from contamination - especially with blood and any other material of human origin.

To ensure protection of products, donors and employees from contamination, personnel should wear clean protective clothing appropriate for the duties they perform. Soiled protective clothing, if reusable, should be stored in a separate closed container until properly laundered and, if necessary, disinfected or sterilized. Where appropriate, disposable or sterile gloves should be worn when handling items that may come in contact with any blood or blood components.

Smoking, eating, drinking, chewing, and keeping plants, food, drinks, smoking material and personal medicines should not be permitted in areas used for production, testing, storage or distribution, or in other areas where they might adversely affect product quality. Personal hygiene procedures, including the use of appropriate protective clothing and equipment, should apply to all persons entering production areas.

3. Documentation

The documentation of procedures and records is essential to the quality assurance system. It ensures that work is performed in a standardized and uniform manner and ensures the traceability of all steps. Written instructions should include all applicable methods and procedures and should be accessible to all authorized personnel.

3.1. Standard operating procedures and records

3.1.1. Standard operating procedures

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All activities should be carried out according to the standard operating procedures. The standard operating procedures and the processes should be regularly reviewed and updated as necessary in order to improve the quality of products and services delivered. The document review process should itself be documented.

3.1.2. Records

Each activity that may affect the quality of blood and blood components should be documented and recorded at the time it takes place. Critical activities should be double-checked, either by a second person or electronically. There should be documentation to ensure that work is performed in a standardized manner according to standard operating procedures and that all critical steps in the process are traceable - especially those that have the potential to affect the quality of the product. The documentation should allow all steps and all data to be confirmed by independent review. All documentation should indicate the person performing the action, the date of the action and the equipment used in the action, where applicable.

Records should be legible, accurate, reliable and a true representation of the results and entries. The legibility of records is of great importance. Handwritten entry of data should be clear. Corrections to any records should be made in a manner that permits the reading and review of the previous entry, the correction, the date of correction and the person responsible for the correction.

Critical manufacturing and laboratory testing records should be reviewed frequently for completeness, legibility and, when appropriate, accuracy by the manager or other designated person.

3.2. Document control

All documents should be laid out in an orderly manner with a unique title and reference number, and should indicate the version and the effective date. The content of the document should be clear and should not include superfluous information. Title, nature, purpose and scope should be clearly outlined.

Documents should be reviewed, approved, signed and dated by authorized persons. An audit trail should indicate the person responsible for each step of document control.

3.2.1. Document management

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There should be a record of the distribution of each document which also shows at least the work areas or tasks affected by the document. All changes to documents should be acted upon promptly and should be reviewed, dated and signed by a person authorized to do so. Standard operating procedures should be designed, developed and approved, and personnel trained in a consistent manner, prior to implementation.

3.2.2. Record retention and archiving

All records, including raw data, which are critical to the safety and quality of blood or blood components, should be kept in a secured storage area according to national regulations, or preferably for at least 10 years. A longer period for retention of records may be required by NRAs, international requirements or by specific contractual agreements. Records of permanently deferred donors should be kept indefinitely.

Outdated standard operating procedures should also be kept in a historic file system. Documents should be archived in a secured area and should be readily accessible for retrieval by authorized personnel if required. The archival and retrieval process, especially if computerized systems are used, should be validated to ensure that all information can be retrieved and read at any time until the end of the required period of retention.

4. Premises and equipment

4.1. Premises

4.1.1. Design and construction

Premises should be located, constructed, adapted and maintained to suit the operations that are to be carried out in them. Premises should be designed to permit effective cleaning and maintenance to minimize risk of contamination. The workflow should be designed and arranged to allow for a logical flow of staff, donors and products in order to minimize the risk of errors. Working areas should not be used as passageways or storage areas.

Ancillary areas should be separated from the donor evaluation area, and from the screening, collection and manufacturing areas. Washing and toilet facilities and, if required, facilities for changing or eating should be maintained in a hygienic and tidy condition.

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Lighting, temperature, humidity and ventilation should be appropriate and should not adversely affect production or storage. Premises should be designed and equipped so as to afford maximum protection against the entry of animals, including insects.

Premises should be carefully maintained and cleaned (see sections 6.2.2 and 6.2.3) and where appropriate disinfected according to detailed written standard operating procedures. Cleaning records should be retained.

4.1.2. Donor areas

The area for blood donors should be separated from all production and testing areas.

The design of premises should be adequate for the conduct of operations and should allow for the logical flow of donors, in one direction if possible, so that donors who have passed reception, screening and donation do not have to return to a previous area.

The area for donor selection should permit confidential personal interviews to take place with due consideration for the safety of donors and personnel.

Rest and refreshment rooms for donors should be separated from donation or storage areas.

4.1.3. Production areas

Blood processing should be carried out in adequate facilities that are suitable for the purpose. The donor area, and production and testing areas should be separated from each other.

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When the use of a closed system is not possible or not appropriate, the risk of contamination or cross-contamination needs to be minimized. Therefore, the premises used for the processing of blood components in an open process should be designed and qualified as a grade A environment with a grade B background, as defined in the WHO GMP for sterile pharmaceutical products. A less stringent environment may be acceptable if the preparation of the product is directly combined with additional safety measures - such as immediate transfusion within a defined and limited time period after processing, or placing the product immediately into storage conditions that prohibit microbial growth. Personnel performing open processing should wear appropriate clothing (i.e. suitable coats, masks or gloves) and should receive regular training in aseptic manipulations. Aseptic processing should be validated. Environmental monitoring protocols should be applied and evaluated by the quality assurance unit.

The premises used for processing blood components should be kept in a clean and hygienic condition. Monitoring of the microbiological contamination load should be considered for critical equipment surfaces and environments where appropriate, according to a risk-based assessment of the process. Records should be available.

Each area of processing and storage should be secured against entry by unauthorized persons and should be used only for the intended purpose.

4.1.4. Storage areas

Storage areas should provide adequate space and should be arranged in a way that allows for dry and orderly placement of stored materials.

Storage conditions should be controlled, monitored and documented to show compliance with the specifications. Equal distribution of temperature throughout the storage facility should be guaranteed and documented. This is particularly important for the critical materials used in processing blood and blood components. Temperature checks should be carried out and recorded at least daily. Appropriate alarms at upper and lower temperature limits should be present and should be regularly checked; the checks should be recorded. Appropriate actions to be taken when there is an alarm should be defined in writing

Intermediate storage and transport should be carried out under defined conditions to ensure that specifications are met.

Storage areas should provide effective segregation of quarantined and released materials or components. There should be a separate area for rejected components and materials.

4.1.5. Laboratories

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4.1.6. Mobile collection sites

Premises for mobile collection sites should be adequate in design for the conduct of operations and should allow for the logical flow of staff, donors and products in order to minimize the risk of errors. The blood collection at mobile sites should be planned thoroughly. Ancillary areas (rest and refreshment rooms) should be separated from donation or storage areas, but observation of donors during post-donation refreshment should still be ensured.

Before premises are accepted for mobile donor sessions their suitability should be assessed against the following criteria:

- sufficient size to allow proper operation and ensure donor privacy;

- safety for staff and donors;

- ventilation, electrical supply, lighting, hand-washing facilities, reliable communication, sufficient space for blood storage and transport, and suitable temperature conditions.

Each site should have an approved plan that details the site layout. The set-up of the mobile collection site should be carried out according to the approved plan.

4.2. Equipment

4.2.1. Design and construction

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Equipment should be located in a suitable position (e.g. a balance should be positioned on a suitable even surface) where there is no negative impact from the surrounding environment (e.g. direct sunlight may have an impact on optical instruments such as apheresis systems or balances).

4.2.2. Maintenance

Maintenance, cleaning and calibration should be performed regularly and should be recorded. Maintenance of equipment should be carried out at intervals according to a documented schedule.

The maintenance programmes should be established on the basis of qualification activities. The intervals should be defined according to the instructions of the manufacturer of the equipment. Where intervals are not defined by the equipment manufacturer, maintenance should be carried out at least annually Different intervals may be defined on the basis of a risk assessment. If no regular maintenance activities are recommended by the manufacturer, at least a functional control should be performed according to documented procedures. All maintenance activities should be documented. The maintenance reports of external technical services should be checked and countersigned by the staff of the blood establishment in order to decide if action needs to be taken as a result of the maintenance outcome. The maintenance documents should include sufficient information to determine what types of checks have been performed.

Maintenance should also be carried out on equipment that is not in regular use, including back-up systems.

Instructions for use, maintenance, service, cleaning and sanitization should be available in a language that is understood by the user. There should be written procedures for each type of equipment, detailing the actions to be taken when malfunctions or failures occur. Defective equipment, or equipment that is not in service, should be clearly labelled and if possible removed from the working area.

The maintenance of sterile connecting devices should include a check of the tensile strength. Furthermore, as it is a very critical piece of equipment, there should be regular functional checks of the integrity of the tubing weld.

In general, functional tests should also be considered for other pieces of equipment - such as for balances before use after they have been moved or transported to a mobile site.

A regular maintenance programme, including appropriate intervals, should be in place for all critical laboratory equipment or systems. A procedure should be implemented for releasing equipment after maintenance or intervention.

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4.2.3. Cleaning

Cleaning procedures should be established and described in a standard operating procedure. Cleaning of equipment should take into consideration the instructions of the manufacturer. A schedule for regular cleaning and disinfection, if necessary, is recommended for all surfaces with direct contact with the bag system (e.g. centrifuge, separator, storage shelves).

Disinfectant solutions with sufficient and approved antimicrobial activity should be used. A cleaning plan should be established that specifies the cleaning intervals and methods to be used for the different equipment and premises. The cleaning procedures should not impact negatively on the equipment or blood components. Cleaning activities should be documented.

4.2.4. Calibration

Measuring instruments and measuring systems used for the collection and further separation of blood and for quality control testing should be calibrated regularly according to the instructions of the manufacturer. Calibration should be carried out and documented according to established standard operating procedures and national regulations. Regular calibration is necessary for temperature probes (e.g. in refrigerators), pipettes, balances, timing devices and haemoglobinometer devices (using control blood and/or cuvettes from the manufacturer). The devices used for calibration, such as the control weight used for the calibration of balances, should be certified for accuracy (by testing against a known standard). If the calibration consists of using a comparison measurement approach with a second device, then the maximum allowed deviation between the two measurements should be defined.

4.3. Computerized systems

A computerized system may be described as a functional unit consisting of one or more computers and associated peripheral input and output devices, and associated software that uses common storage for all or part of a programme and for all parts of the data necessary for the execution of the programme. A computerized system executes user-written or user-designated programmes, performs user-designated data manipulation (including arithmetic operations and logic operations), and it can execute programmes that modify themselves during their execution. A computer system may be a stand-alone unit or may consist of several interconnected units.

Hardware and software should be protected against unauthorized use or changes.

Critical computerized systems should be validated before use. The system is considered critical if:

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- it is used to handle or manipulate the related information;

- it has an impact on product quality, information management, storage, or tools for operational decision-making and control.

Periodic revalidation or annual checks to ensure reliability should be performed on the basis of a risk assessment.

There should be procedures for each type of software and hardware, detailing the action to be taken when malfunctions or failures occur. A back-up procedure should be in place to prevent loss of records in case of expected or unexpected downtime or function failures. The archival and retrieval process should be validated to ensure the accuracy of the stored and retrieved data.

Once in routine operation, critical computer systems should be maintained in a validated state. Any change should be handled through the formal change control system which includes qualification and/or validation activities. Applicable documentation should be revised and personnel should be trained before the change is introduced into routine use. Any software updates should be evaluated in advance and there should be procedures to validate or verify the acceptability of the update installation.

The manual entry of critical data, such as laboratory test results, should require independent verification and release by a second person. When a computerized system is used, an audit trail should be guaranteed.

5. Review and validation

5.1. Qualification of equipment

All equipment should be qualified and used in accordance with validated procedures.

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The extent of qualification depends on the critical nature and complexity of the equipment. For some equipment, installation qualification and calibration may be sufficient. More complex equipment may need a more thorough approach to qualification and validation and should include the instruments, the associated operation(s) and the software involved.

Further guidance on qualification and validation is given in the WHO guidelines on validation and in the Pharmaceutical Inspection Cooperation Scheme (PIC/S) Recommendations on validation master plan, installation and operational qualification, non-sterile process validation, cleaning validation.

5.2. Validation of manufacturing processes

All critical processes in the manufacture of blood and blood components should be validated before implementation according to a predefined protocol of tests and acceptance criteria. Critical processes include donor selection and determination of suitability, component preparations, donor testing for infectious diseases (see also section 7.3), ABO blood typing and antibody screening where applicable (e.g. for red-cell concentrates), labelling, storage and distribution.

Validation studies, including statistically based sampling where feasible, should be conducted to ensure that products are produced with consistent quality characteristics. Acceptance criteria should be based on a defined set of specifications for each blood component, including a set of quality control tests - such as measurement of weight respective to volume, residual blood cells (depending on product specifications), haemoglobin, and relevant coagulation factors (e.g. Factor VIII) and/or total protein/IgG content where applicable - established by the blood establishment or the NRA (see also sections 9.4.3 and 9.6). Data should be available to ensure that the final product is able to meet specifications.

Likewise, apheresis systems, including software, should be qualified and maintained. Apheresis procedures should be validated. Validation criteria with regard to the quality of blood components may, depending on the product, include weight, yield, content of residual white blood cells, haemoglobin and relevant coagulation factors. Validation studies of new apheresis procedures should also evaluate possible risks of activation of the coagulation, fibrinolysis, and complement systems potentially induced by the material in contact with blood. Such studies are usually performed by the manufacturer of the apheresis systems to support the licensing by the regulatory authorities.

5.3 Choosing an appropriate test system to screen for infectious disease

The quality of the screening of blood donations for markers of infection depends on a number of conditions being fulfilled:

• Only test systems designed and validated for blood donor screening should be used. Other systems, such as tests validated for diagnostic purposes only, should not be used.

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• Before implementing a test system for routine analysis, the laboratory should prove by validation that the manufacturer’s specifications are met (in principle this also applies if in-house tests are used).

• The laboratory should show that, on routine application of test systems, specified performance is reached and is consistently maintained.

Screening of blood donations generally requires such test systems to aim for high sensitivity even though this may be achieved at the expense of specificity. Although this may result in an increased proportion of false positive results, it is important in ensuring that all components with true positive test results are detected and not released. In case of new assays or techniques, precise specifications must be established by testing samples of appropriate populations (e.g. donors, recipients, seroconverted recipients) and by comparing the results generated by the existing test system and by the new one.

Validation of a test system involves four main elements:

- assay reagents which should include quality control material (e.g. positive quality control sample, negative quality control sample, calibrators);

- equipment;

- software, if applicable;

- procedure and handling (test method).

Validation records should not only present proof that the scope and desired specifications are met, but should also provide precise descriptions of all key material, key equipment and conditions of processing (e.g. temperature and time of incubation, rounds per minute in centrifugation). In addition, instructions for handling and processing, by which assay specifications are met, should be put in writing and should be provided with the test system.

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- specificity;

- sensitivity;

- accuracy (degree of closeness of measurements to the true value);

- repeatability (replicates of series);

- reproducibility (replicates of series, variation by operator, by day or by lot of reagents);

- known interferences (e.g. haemolytic sera, lipemic sera);

- lower and upper limits of detection (serial dilution).

Apart from testing appropriate donor/recipient populations, appropriate reference materials should be used to define the performance specifications of a test system. These reference materials should be traceable to the WHO international standard or reference reagents, when available for a specific marker.

The necessary documentation should be available for each test system and should include at least the following information:

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- safety instructions;

- a description of the assay principle;

- specifications;

-  a description of the sampling procedure, sampling plan, sample handling and test procedure;

-  internal quality controls (positive and negative), run with every series of donor samples;

-  recommended calibration material and calibration frequency (e.g. change of reagent lot);

-  primary reading of measurement (format e.g. optical density);

-  interpretation of the measurement and/or conversion to result;.

-  acceptance criteria, cut-off, reference values, limits, pro-zone, grey zone..

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5.4 Assay performance validation

In addition to the validation of the test system by the manufacturer, an onsite validation of the test system in the laboratory is required prior to its use in routine testing. This validation should demonstrate, that:

- the performance specifications of the system established by the kit manufacturer are met by the laboratory;

- laboratory personnel are thoroughly instructed, trained and competent to operate the test system.

Prior to first-time use, critical equipment, including related computer systems, should be thoroughly qualified. Installation qualification, operational qualification and performance qualification should be carried out and fully documented. This work may involve suppliers and/or third parties. It is strongly recommended that any performance qualification should be performed by the end-user (and not by a third party) since this is intended to demonstrate that the process works as designed.

In addition, a demonstration showing that the test system performance specifications are constantly met in routine donor testing is required. The means by which this may be achieved are:

- inclusion of internal and external quality control materials with every test series;

- previously tested samples collected for use as an internal panel for periodical in-process quality control;

- monitoring measurements of controls (for instance, graphically by using a Levi-Jennings diagram);

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- implementation of deviation rules (warning range, control range, Westgard rules) to govern corrective actions;

- monitoring trends in control measurements on external standard or reference material;

- successful participation in external quality assessment schemes (proficiency testing) by all qualified members of staff.

6. Management of materials and reagents

6.1. Materials and reagents

Only reagents and materials from approved suppliers that meet documented requirements and specifications should be used. Materials and reagents should meet the legal requirements for medical devices. The management procedures for materials, reagents and supplies should define the specifications for acceptance of any elements that may influence the quality of the final blood component. Receipt logs or records for these critical materials should indicate their acceptability on the basis of the defined specifications and should identify the person accepting them

6.2. Receipt and quarantine

Appropriate checks (e.g. attached certificates, expiry date, lot number, defects) should be performed on received goods in order to confirm that they correspond to the order and meet the specifications. Damaged containers should be carefully checked to detect possibly affected materials. Incoming critical materials (such as sterile solutions, blood bag systems and testing reagents) should be physically or administratively quarantined immediately after receipt and until they are released for use. Where the quarantine status is ensured by storage in separate areas, these areas should be clearly marked and their access restricted to authorized personnel. When labels are applied to the containers to indicate their status, the use of different colours may be helpful. Any system replacing physical quarantine (e.g. a computerized system) should provide equivalent security.

6.3. Release of incoming production material and test reagents

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The manufacturers of sterile materials (e.g. blood bag systems, anticoagulant solutions) should provide a certificate of release for each batch. The blood establishment should define acceptance criteria for such certificates in writing, and should include at least the name of the material, the manufacturer, compliance with the relevant requirements (e.g. pharmacopoeia or medical device regulations) and confirmation that the materials are sterile and pyrogen-free.

6.4. Storage

Materials and reagents should be stored under the conditions established by the manufacturer and in an orderly manner that permits segregation by batch or lot and stock rotation. Storage and use should follow the “first-expiring first-out” principle (i.e. the material that entered storage first should be used first).

The use of the expiry date as an alternative inventory management technique is also acceptable.

6.5. Traceability of materials and reagents

Inventory records should be kept for traceability. The records should document which batch or lot of materials or reagents have been used for the collection, processing or testing of the blood units or blood components. Inventory of critical supplies such as donation labels with serial numbers should be strictly controlled to avoid mix-ups or mislabelling due to uncontrolled excess labels.

6.6. Supplier/vendor management

All materials and reagents relevant for the quality of the products should be purchased or obtained only from qualified suppliers. The relationship between the two parties (i.e. contract giver and contract acceptor) should be defined in a contract. The blood establishment as contract giver is responsible for assessing the competence of the supplier (contract acceptor).

The contracting process should include:

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- the setting of appropriate specifications that adequately define the quality of the service or goods;

- appropriate checks on received goods to confirm that they meet specifications;

- checks to ensure that goods in use continue to meet specifications;

- notification of changes to requirements from either party prior to implementing any changes that may affect the quality of the services or goods provided;

- regular contact with suppliers in order to help understand and resolve problems.

7. Manufacturing

7.1. Donor registration

Upon presentation at the blood establishment, donors should positively identify themselves by stating their full name, address and date of birth. Each donor should also provide proof of a permanent place of residence, including a telephone number where appropriate, so that they can be contacted after donation, if necessary.

Proof of identity with a photograph - such as an identity card, passport or driver’s licence - should be provided, especially in the case of first-time donors. A careful check of the identity of the donor should be repeated prior to each step that is relevant to the quality of the products and the safety of donors, but at least before donor selection and venipuncture.

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7.2. Donor selection

Blood and blood components should be obtained from healthy donors who are carefully selected using a systematic and validated process consisting of review of the donor’s health assessment, social behaviour history (the donor questionnaire) and medical examination. This evaluation, along with a review of the results of the infectious disease screening laboratory test, should be used to make sure, prior to the release of any blood component, that the donor presents no increased risk for transmission of infectious agents. NRAs are pivotal in establishing a harmonized framework for donor selection criteria, taking into consideration the types of products, the relevant infectious risks, and the epidemiological data for disease prevalence in the country. The review of these combined data may be used in developing donor selection criteria. The NRA should also be part of any decision-making process intended to modify the donor selection and donation-testing procedures.

Regulatory agencies and professional organizations have respectively published regulations and recommendations on the criteria for the selection of donors of whole blood and blood components (see, for instance, the Council of Europe’s Guide to the preparation, use and quality assurance of blood components) that can be used as a reference. Such guidance documents also explain critical points that should be considered when processing blood and blood components.

Whenever possible, blood donations should be collected through a donation system involving regular and repeat donors. Obtaining blood from regular and repeat donors is a major contribution to ensuring optimal historical medical information about the donors, and therefore to detecting potential risk factors.

7.2.1. Epidemiological surveillance of the donor population

To ensure optimal long-term safety of blood components, blood establishments should maintain continuous epidemiological surveillance of the donor population. The objective of this surveillance is to know, as precisely as possible, the prevalence and incidence, and their respective trends, of infectious markers that are relevant to the safety of blood components. This enables countermeasures to be taken in a timely manner. The system should be able to gather epidemiological data not only at national/regional levels but also among donor populations that provide blood at individual blood establishments within a country or region. Consideration should be given to the travelling patterns of the donor population with respect to possible transmission of infectious diseases (i.e. malaria, Chagas disease, vCJD, etc.).

The information from epidemiological surveillance can furthermore be used:

- to detect, among donor populations of various collection centres, differences that may be associated with objective differences in viral markers within donor populations;

- to detect differences in the donor selection and screening processes at collection centres;

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- to assess the relevance of any preventive measures such as a strengthened donor selection process, additional deferral criteria, or implementation of additional screening tests to avoid contamination of blood components.

When donations from first-time donors are used to prepare blood components, epidemiological data on this specific donor group should be included in the estimate of the risk for infectious diseases transmitted by blood. It has been shown that first-time donors, who may occasionally include test-seeking persons, constitute a group that in some situations is more likely to have bloodborne viral markers than regular donors who have already gone through a selection/deferral process.

It is currently advisable to collect and analyse epidemiological data at the collection sites for HIV1/HIV2, hepatitis C virus (HCV) and hepatitis B virus (HBV) since they historically represent the major pathogenic risks associated with blood components. It is the responsibility of the NRA to define whether this list should be modified or should include additional criteria such as emerging infectious agents, on the basis of local or regional epidemiology

For the current three recommended markers, only confirmed positive tests (i.e. tests which are repeatedly reactive in a screening test and positive in at least one confirmatory test) should be recorded, reported and analysed.

7.2.2. Information to donors

Potential new donors should be informed (ideally both verbally and in writing) that it is necessary to respond to questions about their medical history and personal behaviour so that it can be determined whether they are eligible for blood donation. Written information can be a leaflet explaining infectious risks associated with blood products, and the impact of social behaviour on infectious risks or infectious risk factors. This information is usually provided by a licensed physician, or by a designated qualified person under the direct supervision of a licensed physician. The information should clearly explain the deferral criteria that exclude a donor from donating blood or plasma. It is important to ensure that the reasons for deferral are well understood by the candidate donor.

The candidate donor should be asked to sign a form of informed consent to give blood in which he/she acknowledges understanding the moral and legal responsibilities and possible risks associated with donating blood, as well as the occasional complications that may occur. The declaration of consent should also include a statement that the donor authorizes the release of his/ her blood and blood components for transfusion or further manufacturing.

Donors should be informed to contact the blood establishment if there is an unexpected event after the donation, such as illness or the discovery of new information not disclosed during the health screening.

7.2.3. Questionnaire and interview

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The questionnaire should cover questions about the medical history of the donor, his/her travel habits, risk behaviours, use of medication, and other medical treatment. A list of countries may be provided to assist the donor to complete the questionnaire with regard to earlier residency or travel.

Similarly, a list of drugs that may pose a threat to the recipient or may be an indication of poor donor health may also be provided. The NRA may provide requirements for such lists.

The questions should be drafted in such a way that donors may easily identify whether they are in good health. The questionnaire may be administered in several ways, such as:

- by a person reading questions to the donor and recording the responses;

- by the donor reading the questions and recording the responses;

- by computerized written questions presented to the donor with the donor recording the responses;

- by the computer reading the questions to the donor and the donor recording the responses;

- by other validated methods that ensure that the donor understands the question, how to completely answer the question and how to record the response to the question.

There should be a link between the donor, the donor questionnaire and the collected products. After the donor’s history has been reviewed, the collected components should be identified in a way that links the products to the history records but maintains the confidentiality of the donor. The product should be identified by a unique donation number linked to the donor name but the product information should not include the donor name except as required by the NRA in cases such as autologous donations.

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Donor identification and information, the donor selection interview and the donor assessment should all take place before each donation. The premises and layout of the blood establishment (or the mobile collection unit) should allow for adequate confidentiality during the donor interview and selection process so as not to discourage the candidate donor from answering questions about personal or private behaviour; otherwise the safety of the blood donation could be compromised.

The minimum intervals between two donations should be defined and should then be audited or reviewed for compliance with the waiting period prior to each donation.

7.2.4. Deferral policy and deferral criteria

As part of the blood establishment’s deferral policy, a list of permanent or temporary deferral criteria used for potential donors should be clearly defined, made public, and incorporated in the educational material for donors and the establishment’s procedures. It should also be determined whether the donor has previously been deferred, and reasons for any deferral should be reviewed so that a decision may be made on whether to accept the donor for current donation. A donor who is deferred should be informed of the reason for deferral, encouraged not to donate at other facilities while deferred and informed that the reason for the deferral may be shared with other health professionals or government agencies according to NRA recommendations or other legal requirements.

Both acceptance and deferral criteria for the donation of blood should be formulated by the NRA and should be national requirements that are applied nationwide. Within the scope of their role of establishing and implementing effective national regulations, NRAs should enforce such criteria.

Examples of the major permanent deferral criteria found in international guidelines include:

- clinical or laboratory evidence of bloodborne infectious diseases such as acute or chronic infection with HIV, HCV or HBV (in certain jurisdictions donors with elevated titres of anti-HBs may be acceptable);

- past or present intravenous drug use;

- persistent bacterial or protozoal infections.

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- a sexual relationship between men;

- men or women who are engaged in prostitution;

- subjects with haemophilia or other clotting-factor defects;

- sexual partners of any of the above or of someone the donor suspects may carry the above risk factors;

- jaundice within the 12 months prior to donation, since this may be a clinical sign of hepatitis A, B or C;

- transfusion with blood, blood components, plasma products, cellular therapy products or vascularized tissue transplant in the 12 months prior to donation, as blood transfusion and transplantations are risk factors for all bloodborne infections;

- exposure to someone else’s blood, including an accidental needle stick in the 12 months prior to donation;

- tattooing, scarification, ear-piercing or acupuncture in the 12 months prior to donation (since these practices may be vehicles for transmission of viral diseases) unless clear evidence is provided that it was carried out under sterile conditions;

- risk factors for Human T-cell lymphotropic virus (HTLV) infection;

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- a confirmed family history of CJD;

- imprisonment longer than three days within the 12 months prior to donation.

When temporary deferral criteria are used, a specific procedure involving trained personnel should be in place for the reinstatement of donors. There are deferral criteria that are temporary (as long as a risk factor has been identified) but that can be waived after additional controls have been carried out on the donor or the period of deferral has passed. NRAs may recommend or define different deferral criteria and timelines, e.g. when implementing NAT testing for the relevant viruses.

7.2.5. Physical examination, donor health criteria and donor acceptance

A targeted physical examination should be carried out by a licensed physician according to an established procedure prior to the first donation and thereafter before subsequent blood donations, and in case of special apheresis programmes at regular intervals. Depending on national regulations established by the NRA, the physical examination may be performed by a suitably educated and trained physician substitute under the supervision of a licensed physician. NRAs should, usually after consultation with the blood establishment, determine the health criteria and the acceptable limits taken into account during the physical examination - such as measurement of haemoglobin, blood pressure, weight, age, pulse rate and temperature, or any other criteria considered to be of concern for the safety of blood components or donors.

A written standard operating procedure based on the relevant acceptance/ deferral criteria should be in place at the blood establishment to control donor acceptance and deferral criteria, in compliance with the NRA. Abnormal donor findings should be referred to the physician who has the responsibility of making the final decision about the donor’s eligibility on the basis of current medical knowledge and national regulations. If the physician has any doubt about the donor’s eligibility, the donor should be deferred.

An appropriate computerized record system (or, if that is not available, a manual system) should be in place for donor records (including their medical history and health status), and for the purpose of ensuring traceability of all donations. Such information provides historical perspective of the health status of donors, including previous temporary deferrals, and contributes to reinforcing the judgement about whether the donation would create a risk to the quality and safety of the blood components.

Records should be kept for each activity associated with the selection of the donor. The record should reflect the decision to accept the donor, taking into consideration the medical history, donor deferral history, the donation interval, the answers given in the interview or questionnaire, and the results of the physical examination. The rejection of a donor and the reason for the deferral should be recorded. An authorized interviewer should sign the donor selection records and the final assessment of the donor’s suitability.

As with all other manufacturing steps under GMP, donor selection and acceptability procedures should be followed at all times using the validated methods. Any deviations from established procedures and processes may result in products not meeting specifications so such products should be considered as non-conforming products and must not be released for distribution.

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7.3.1 Whole blood collection

Donors should confirm their identity (by a method such as stating name and date of birth) immediately prior to venipuncture. Also prior to venipuncture, a check should be made to ensure that the collection system to be used is not damaged or contaminated, and that it is appropriate for the intended collection. Any abnormal moisture or discoloration suggests a defect and in such a case the collection system should be discarded. An investigation should be conducted to evaluate the extent of the problem and appropriate corrective actions should be taken. The collection systems should be used in accordance with the instructions of the manufacturer. Appropriate hand disinfection and personal hygiene procedures should be in place and should be performed by the personnel before each donation.

A standardized and validated procedure for the preparation of the phlebotomy site should be followed using a suitable disinfection solution which should be allowed to dry depending on the type of disinfectant. The expiry date of the disinfectant should be checked. If refillable bottles are used, they should be cleaned before being refilled. The date of manufacture and the date of opening of in-house disinfectants should be stated on the label. The prepared skin area should not be touched after the disinfection and before the needle has been inserted. Care should be taken not to lean over or speak over the disinfected skin.

For blood donations, laboratory samples should be taken at the time of donation. Procedures should be designed to minimize the risk of microbial contamination to the unit, such as diverting at least the first 10 ml collected in the tubing into test tubes for testing. Methods should be implemented to minimize the deterioration of the sample, such as refrigeration of the sample if required by the manufacturer’s instructions for the sample tube or test kit. The sample labelling process should include steps (such as labelling the tubes immediately at the chair side) to prevent the misidentification of samples. The test samples should be labelled immediately in a manner that links the donor, the samples and the blood component without breaching the confidentiality of the donor.

As soon as the collection process starts, good mixing of the blood with the anticoagulant solution should be ensured to avoid risks of activation of the coagulation cascade. The collection bag should be mixed gently at regular intervals thereafter. The mixing can be done by using a continuously running automatic mixing balance or by periodic manual mixing of the unit at least every 90 seconds. Collection of one standard unit of whole blood should be achieved within 12-15 minutes (depending on the component to be prepared later on), as longer durations may result in activation of the coagulation factors and cellular components.

Records should be kept for each activity associated with the donation, including identification of the person who performed the venipuncture. Records should also show any unsuccessful donation, adverse reactions or adverse events.

The maximum collection time for acceptance of the donation for component processing should be specified and controlled. Donations that exceed the maximum time period should be recorded and discarded.

The integral blood bag collection tubing should be sealed off at the end as close as possible to the blood bag and then removed.

A system of unique donation numbers should be used to identify each donor and the related donation, all associated components, samples and records, and to link each one to the others.

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A standard operating procedure should be in place describing the actions to be taken following an unsuccessful donation. It should specify how to handle already labelled material and the circumstances under which a second venipuncture might be possible.

As with other GMP manufacturing steps, the donor product collection process should be followed at all times using the validated methods. Any deviations from these established procedures and processes may result in products not meeting specifications and therefore such products should be considered non-conforming products and should not be released for distribution.

7.3.2. Collection by apheresis

In automated procedures, whole blood is collected from the donor, mixed with anticoagulant, and passed through an automated apheresis device. The blood component of choice is separated from the other blood components which are returned to the donor in a series of collection/separation and return cycles. The operational parameters of the apheresis system should be implemented in compliance with the instructions of the equipment manufacturer and in compliance with any specified safety requirements of the NRA. In general, the anticoagulant - often 4% sodium citrate or anticoagulant citrate dextrose solution A (ACD-A) - is delivered at a rate that will yield a specified ratio of anticoagulant to blood. The volume of the component collected from the donor during one procedure and over a period of time should be regulated by internal policies based on current medical knowledge and on national regulations set by the NRA. The number of collection/separation and return cycles for each donor depends on the total volume of the component that is to be harvested. To determine the number of cycles to be employed, the equipment requires programming with data inputs such as donor weight, height and haemoglobin values, and the pre-donation platelet count if platelets are to be collected. The amount of time required for the donation procedure depends on the number of cycles. An adequately trained physician should be available during apheresis sessions. The donor apheresis collection process should be followed at all times using validated methods. Any deviations from the established procedures and processes may result in products not meeting specifications and therefore they should be considered non-conforming products and must not be released for distribution.

7.3.3. Safety of donors

All measures should be taken to avoid anything that could adversely affect the donor before, during and after the donation. Special attention should be drawn to the potential risk of transmission of diseases or infections during the collection and sampling processes.

Donors should be given post-donation instructions regarding a period of recovery, such as refraining from certain activities for a while, drinking more fluids than usual and making sure to eat appropriately after the donation. Donors should be advised to refrain from activities such as heavy lifting, operating large items of equipment and other strenuous activities for a period of time until their blood volume has recovered. Donors should also be provided with information on how to obtain medical advice if they experience an adverse donor reaction after leaving the blood establishment.

Throughout the procedure of withdrawal of blood or blood components, the donor should be monitored. Personnel should be educated to provide appropriate aid in case of any adverse reaction. Donors should be kept under post-donation observation (e.g. for 15 minutes or more) prior to leaving the blood establishment and should be offered refreshment to replace fluid loss. If medically required, drinks may be provided to donors during collection (e.g. apheresis). In these circumstances, a suitable container for the drink is required. Donors should remain under observation for anticipated reactions to donation until they are able to articulate that they feel well enough to leave and be unattended. Immediate care should be given to the donor if there is a donor reaction. Information regarding donor reactions and a process to track and trend reactions should be in place in order to evaluate the number, type and severity of reactions. This information should be used to improve donor safety.

7.4. Component preparation

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7.4.1. Starting material

The starting materials for preparation of blood components are blood donations collected from suitable donors. Conditions of storage or transport, and the time prior to processing, are contributing factors to the quality of the product. Delays in preparation or unsuitable conditions of storage or transport may adversely affect the quality of the final product. Blood and blood components should be placed in controlled and validated conditions as soon as possible after venipuncture.

Donations and samples should be transported to the processing site in accordance with procedures that ensure both a constant approved temperature and secure confinement. This is especially important when blood is transported from distant collection sites.

Product transport or shipping at appropriate temperatures and temperature monitoring are important to ensure optimal quality. One way to ensure the temperature of products is to use packaging methods validated to keep the blood within the required temperature limits. There should be validation data to demonstrate that the method of transport maintains the blood within the specified temperature range throughout the period of transportation. Alternatively, portable temperature loggers may be used to record the temperature during the transportation of blood to the processing site. Where the blood is not transported by the processing establishment itself, the responsibilities of the transport company should be clearly defined and periodic audits should be conducted to ensure compliance.

7.4.2. Methods of production

Blood components may be prepared by using a centrifugation step with subsequent separation, by using another validated preparation method, or by apheresis technology during collection.

Although the use of closed systems is strongly recommended for all steps in component processing, open systems may exceptionally be necessary due to local constraints in an environment specifically designed to minimize the risk of bacterial contamination. When open systems are used, careful attention should be given to the use of aseptic procedures.

Where sterile connecting devices are used to maintain a functionally closed system they should be correctly used in accordance with a validated procedure. The resulting weld should be checked for satisfactory alignment and for validated integrity.

The critical equipment used for the preparation of blood components should be traceable to the corresponding manufacturing records.

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The centrifugation parameters (revolutions per minute, temperature, time, acceleration, deceleration) are important for the composition and characteristics of the specific components. These critical parameters should be defined on the basis of validation data that demonstrate a process that consistently produces quality products. For each run, the centrifugation records should identify the operator and confirm that the centrifugation process was performed according to specifications.

7.4.2.2. Separation

After centrifugation, the bag system should be carefully removed from the centrifuge and placed into a plasma expressor or blood separation system. The different layers of the components (red cells, platelets, plasma) should be transferred to the satellite bags within the closed systems, in a manner designed to optimize the harvest of the intended component while minimizing the carry-over of other component fractions.

Alternatively, blood components can be separated during collection by apheresis technology (see section 9.3.2.).

7.4.2.3. Freezing

Freezing is an important processing step that has an impact on quality, especially of plasma. The rate at which freezing proceeds and the core temperature are both considered to be important parameters. Rapid plasma freezing prevents or reduces the loss of critical constituents such as Factor VIII in frozen plasma that is either recovered or obtained by apheresis.

A system should be in place for ensuring that plasma is frozen to the specified core temperature within the time limit, keeping in mind that the freezing speed will be influenced by the type of plasma container, the freezing equipment and the loading pattern, as well as by the volume of plasma. The validation of the freezing process should consider worst-case scenarios that take into account both minimum and maximum loads and positions in the freezer. Recording the temperature of plasma units and the freezing time during a freezing process allows one to evaluate the freezing capacity of the equipment and ensures a standardized freezing process. Validation studies should be available and should demonstrate that the temperature of a frozen pack reaches the proposed storage temperature following the specifications. As indicated above, the aim is to achieve rapid freezing and thereafter to minimize temperature changes to the frozen plasma. Freezing of cellular components such as red cells or cellular therapy should follow a well defined, validated procedure that ensures the recovery and viability of the intended cellular product during thawing and final preparation steps.

7.4.2.4. Leukocyte reduction

Whole blood may be filtered for leukocyte reduction prior to centrifugation. Filtration of whole blood reduces the level of platelet and leukocyte contamination in plasma and red-cell concentrate preparations. Alternatively, components (e.g. red cells, platelets) may be filtered after separation. The introduction of any leukocyte reduction process either by filtration or special centrifugation technique requires careful validation that takes national requirements into account.

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Special centrifugation or filtration techniques of leukocyte reduction are used in several apheresis systems. When a standardized procedure is established on the apheresis system, the method should be validated under the conditions to be used.

An appropriate method should be used for leukocyte counting after leukocyte reduction. The method should be validated to ensure linearity, accuracy and reproducibility.

7.4.2.5. Irradiation

Regular dose-mapping of irradiation equipment should be performed. The exposure time should be set to ensure that all blood and blood components receive the specified recommended minimum dose, with no part receiving more than the maximum recommended dose. The common recommended minimum dose is 25 Gy (2500 cGy).

Care should be taken regarding the increased potassium leakage from red cells after their irradiation, either by limiting the shelf-life of the red-cell concentrate or by further manufacturing steps such as washing. For the radioactive source, allowance should be made at least annually for source decay. A second independent timing device should be used to monitor exposure time.

Radiation indicators should be used as aids to differentiating between irradiated and non-irradiated blood and blood components. A defined procedure should ensure the separation of components that have not been irradiated from those that have been irradiated, and should ensure they have distinctive labelling.

7.4.3. Blood and blood components

Blood components may be obtained using the methods described in section 9.4.2. However, the sequence and the combination of the methods used in the production of blood components may vary from one product to another.

The collection process itself is already crucial for the quality of blood components. Measures such as a reliable arm-cleaning and disinfection procedure, the use of closed and sterile collection systems, and appropriate microbiological controls should be implemented. Time limits should be defined for the processing of blood components.

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7.4.3.1. Whole blood

Whole blood for transfusion is blood that is taken from a donor who has been assessed and found suitable as meeting the blood establishment and NRA acceptance criteria. Whole blood is collected in sterile and pyrogenfree containers with a suitable anticoagulant. It may be used without further processing. In some cases, whole blood for transfusion may also be used after leukocyte reduction. The temperature of whole blood stored for transfusion should remain controlled between 1° and 6°C or in a more stringent range defined by the NRA. The storage time depends on the anticoagulant/preservative solution used.

Periodic quality control should be performed on the final product to ensure that the manufacturing process is consistent (see 9.6). At a minimum, the following critical parameters should be checked during the quality control assays:

- volume;

- haemoglobin or haematocrit;

- haemolysis at the end of storage.

The primary use of whole blood is as a source material for the preparation of blood components. Transportation and further manufacturing processes should be developed to maximize the number of components that may be produced from a whole blood donation. After collection, whole blood should be kept at a controlled temperature appropriate to the intended component manufacture and should be delivered to the production site as quickly as possible. If whole blood is collected away from the production site, the validated transport systems should ensure that correct temperatures are maintained throughout the process and that the product is delivered within 24 hours. The period between collection and further processing depends on the product but should not exceed 24 hours. The whole blood may also be filtrated to reduce leukocyte content prior to further processing.

Components should be manufactured by a method validated as meeting the predefined product specifications.

7.4.3.2. Red-cell concentrate

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Red-cell concentrates are stored under the same storage conditions as whole blood. The storage time depends on the anticoagulant/preservative solution used.

Further methods of preparation, such as irradiation or washing, are applied to obtain specific red-cell products, depending on the clinical indication.

Periodic quality control should be performed on the final product to ensure that the manufacturing process is consistent (see 9.6). Parameters measured depend on the type of red-cell concentrate product obtained. At a minimum, the following critical parameters should be checked during the quality control assays:

- volume;

- haemoglobin or haematocrit;

- haemolysis at the end of storage;

- residual leukocytes, if leukocyte reduction is performed.

7.4.3.3. Platelet concentrate

Platelet concentrates are derived from whole blood or are obtained by apheresis.

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In special circumstances, volume-reduced, split, washed or irradiated platelet concentrates can be prepared for specific treatments.

Periodic quality control should be performed on the final product to ensure that the manufacturing process is consistent (see 9.6). At a minimum, the following critical parameters should be checked during the quality control assays:

- volume;

- platelet content;

- residual leukocytes, if leukocyte reduction is performed;

- pH, measured at the end of the recommended shelf-life.

7.4.3.4. Plasma for transfusion and Plasma for fractionation

Plasma for transfusion is prepared either from whole blood or from plasma collected by apheresis, and is frozen within a defined period of time to a temperature that should adequately maintain the labile coagulation factors in a functional state, consistent with the intended use of the plasma. In particular, Factor VIII content is critical both as a quality indicator and to assure the efficacy of cryoprecipitate.

If plasma is separated from a unit of whole blood that is refrigerated to 4°C, centrifugation should preferably take place within eight hours of collection.

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If plasma is collected by apheresis, the freezing process should begin as soon as possible, and ideally not later than six hours after the completion of the apheresis process. In compliance with NRA requirements, consideration should be given to the time frames of processing with respect to the anticoagulant and device used and the product to be manufactured. The freezing process should be validated and should take place in a system that will allow complete freezing to a predefined core temperature in a predefined time (see section 9.4.2.3).

Product stability is dependent on the storage temperature. Storage temperature and shelf-life depend on the intended use of the product. For long-term storage (more than one year) the optimal storage temperature is minus 25°C or colder.

Periodic quality control should be performed on the final product to ensure that the manufacturing process is consistent (see 9.6). At a minimum, the following critical parameters should be checked during the quality control assays:

- volume;

- factor VIII activity (especially if plasma is used to treat Factor VIII deficiencies);

- residual leukocytes, if leukocyte reduction is performed;

- leakage;

- visual changes.

Virus inactivation and/or quarantine of plasma for transfusion are applied in some countries. Further complementary guidance with respect to virus inactivation is available in WHO guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood plasma products, and in other publications.

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7.4.3.5. Cryoprecipitate and Cryo-poor plasma

Cryoprecipitate is the cryoglobulin fraction of plasma and contains a major portion of the Factor VIII, von Willebrand factor, fi brinogen, Factor XIII and fibronectin present in plasma. Cryoprecipitate is obtained from fresh frozen plasma that is prepared in a way that protects Factor VIII stability. Plasma is allowed to thaw either overnight at 2-6°C or by a rapid-thaw technique. Following thawing, the supernatant cryo-poor plasma and the cryoprecipitate are separated by hard-spin centrifugation. The cryo-poor plasma is then expressed into a transfer bag. The two components are refrozen to the appropriate core temperature.

Stability during storage depends on the storage temperature. Storage temperature and shelf-life depend on the intended use of the product. For long-term storage (for two years or longer) the optimal storage temperature is minus 25°C or colder.

Periodic quality control should be performed on the final product to ensure that the manufacturing process is consistent (see 9.6). At a minimum, the following critical parameters should be checked during the quality control assays of cryoprecipitate:

- volume;

- Factor VIII activity;

- clottable fibrinogen;

- von Willebrand factor activity (if applicable).

Virus inactivation and/or quarantine are applied in some countries.

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7.5. Laboratory testing

7.5.1. Screening tests for infectious disease markers

7.5.1.1. Testing requirements

The following tests, which are considered mandatory by all regulatory agencies, are relevant to the preparation of blood components and should be performed on each individual blood donation:

- an approved test for Hepatitis B surface antigen (HBsAg);

- an approved test for anti-HIV1/HIV2;

- an approved test for anti-HCV.

All three tests have to be negative. Initially reactive donations should be retested in duplicate by the same assay. Products from a repeatedly reactive donation should not be used for therapeutic applications and should normally be destroyed unless useful for non-therapeutic purposes or investigations. A sample of the donation should be evaluated by a confirmatory test. There should be a system for notifying and counselling the donor if confirmation is positive. It is recommended that national algorithms should be developed and used to enable consistent resolution of discordant/indeterminate or unconfirmed results. In some countries, additional serological testing is required - for instance, anti-HBc testing may be performed on whole blood donations in order to further reduce the risk of exposure of recipients to HBV by contaminated blood or blood components. Additional testing for other agents or markers - such as anti-HTLV I/II, anti-T.cruzi or West Nile Virus (WNV) - may be required by the NRA, taking into account the epidemiological situation in any given region or country or the frequency of donating blood. In addition to testing for immunochemical-serological infectious disease markers, NAT testing of blood donations for the virus genomes has been introduced in some countries to increase the chance of identifying infected donors.

During the natural course of infection, viraemia usually occurs significantly at a point earlier than that at which immunochemical markers (antibodies) can be detected in the infected serum. Thus, infection may be detected by NAT up to 50–60 days before seroconversion (i.e. to HCV) occurs. Testing for the presence of nucleic acid may be performed for viruses such as HCV, HBV, HIV, HAV, WNV (where appropriate) and/or Parvovirus B19, and the application of this technology may be extended to other transmissible microbes. NATs require a particularly sophisticated laboratory environment, special equipment and specially trained laboratory personnel. Mainly because of an extraordinary risk of false-positive results due to the so-called “carry-over” (inadvertent transfer of the amplification product DNA to neat donor samples), very stringent handling and logistics are mandatory. In contrast to testing for the serological markers of individual donor specimens, NAT testing may be performed following current practices by assembling various samples in mini-pools. However, this requires a thoroughly validated system of sample labelling/identification, a validated strategy and pooling process, and a validated algorithm to resolve pool results to individual donors. Hence, a specific logistics system may have to be established not only in the laboratory but also at the blood establishment in order to collect and suitably label samples. Contiguously tracing samples through the whole process from the donor, through pooling (if applicable), testing and release of the donation may present a particularly demanding challenge.

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7.5.1.2. Handling of samples and data

Multiple specimens may be collected from a donor in order to meet all testing requirements (i.e. ABO typing, viral markers, NAT testing). There should be written standard operating procedures that clearly describe the collection, transportation and labelling of donor samples (i.e. whole blood, sera, anticoagulant, container tubes etc.) and which define the sampling procedure performed on material for analysis (e.g. how and by whom it is done, transfer of samples, accountability of samples). All screening activities, handling of donor specimens, sampling, analysis and data processing should be separated from patient diagnostic testing. Sample labelling at the site of collection and identification during all subsequent processing is critical and should be under control at all times. Each step of handling and processing should be described, as should the conditions of pre-analytical treatment of specimens (e.g. centrifugation), storage and transportation (duration, temperature, type of container, storage after testing).

Serological testing should be performed on samples transferred directly into the analyser from the original sample tube.

Secondary aliquot samples may be used for NAT testing of mini-pools of individual samples.

The following practical points should be considered in order to ensure the traceability and integrity of samples and data:

• At receipt of specimens at the laboratory, positive identification of those received versus those expected should be performed. The integrity of the sample should be checked for compliance with the recommendations made by the manufacturer of the test kit.

• Aliquot samples for analysis should be withdrawn from the donor sample preferably by automated pipetting equipment.

• To provide for positive identification of all aspects (donation, donor specimen, aliquot samples etc.) it may be advisable to use a barcode system. Hence, starting with the donation, barcodes should be used for labelling. In case of failure of the automatic barcode reader system and/or data processors, an appropriate system should be available for manual entry and tracing of data throughout the whole process until release of donations for transfusion. Manual handling of data should include independent repeat entry into the database; the data format should include a check-digit algorithm or an automated test for identity of the two sets of data.• Pipetting devices and machines should be validated before routine use, and validation reports should be available.

• Calibration of the pipetting devices should be performed periodically and should be documented.

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Testing of blood components should be carried out in accordance with the recommendations of the manufacturer of reagents and test kits. Modifications to the manufacturer’s instructions or reagents for donor screening tests should be validated. Where required, prior approval of the NRA should be obtained before the modified method is used for release of a blood component. Laboratory reagents intended for prolonged use should be marked with the preparation date, expiry date, specific storage conditions and signature of the person who prepared them. Instructions for use and storage should be followed. Screening algorithms should be precisely defined in writing (i.e. standard operating procedures) to deal with initially reactive specimens and to resolve discrepancies in results after retesting. All available measures should be taken to ensure that blood and blood components that are repeat reactive upon screening for an infectious disease marker are excluded from therapeutic use. Repeat reactive material should be stored away from all other blood components in a separate dedicated storage area. Such material should eventually be destroyed to prevent inadvertent re-entry into the transfusion chain. Test algorithms should provide details for appropriate confirmatory testing. In the case of repeatedly reactive results, clearly defined follow-up instructions should be followed. Actions include:

- notification and deferral of the donor;

- disposal of the indicated donation and of concurrent products;

- tracing and destruction of products which have not yet expired.

If products from the donor have been processed for further manufacture, there should be a procedure in place to assess both the safety of the manufactured products and whether a recall is needed.

Procedures for donor- and/or recipient-initiated look-backs should also be defined. Look-backs should be designed in such a way that the transfusion chain of donor–blood (or blood product)–recipient can be unequivocally reconstructed. The procedure should comprise notification and counselling action where indicated.

The following practical points should be considered in order to ensure that the equipment used for virology testing performs appropriately:

• There should be a mechanism to ensure positive sample identification and linkage to the donor. The preferred method is by sample tubes with barcodes.

• Ideally, the addition of reagent and samples and the testing process should be automated, in order to minimize risk of human errors and to ensure full traceability of the testing process.

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7.5.1.4. Test interpretation and follow-up of reactive results

The transfer and interpretation of raw data is a critical step and should therefore be documented and reviewed by a responsible person, as should the test parameters. Traceability and archiving of raw data should be guaranteed (see section 5.2).

The data should be examined by the supervisor, or by another person authorized to do so, before being officially accepted. If computerized systems are used, accepted data should be downloaded directly to the server, or there should be a secure system for manual download which ensures positive release. Manual transcription of results is discouraged as mistakes may be introduced.

Acceptance and rejection criteria should be specified:

• Initial reactive results should be identified by means of a secure and validated system.

• An acceptable system should be in place to confirm repeat reactive results, including sampling, labelling, testing and entry of results.

• Computer algorithms should edit reactive status to repeat reactive, or the editing should be performed by two authorized staff members.

• An appropriate deferral system should exist for repeat reactive results.

• There should be appropriate documentation justifying the re-entry of deferred donors.

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7.5.2. Blood group typing

Each donation should be tested for ABO and RhD blood groups and at least all first-time donors should be tested for clinically significant irregular redcell antibodies. When plasma is used for fractionation it should be tested in compliance with the specifications of the fractionator as agreed by the relevant NRA. Testing should be carried out in accordance with the recommendations of the manufacturer of reagents and test kits. Molecular methods may be used to determine blood groups, as necessary. The ABO and RhD blood group should be verified on each subsequent donation. A comparison should be made with the historically determined blood group. If a discrepancy is found, the applicable blood components should not be released until the discrepancy has been unequivocally resolved. Donors with a history of transfusions or pregnancy since the last donation should be tested for clinically significant irregular red-cell antibodies. If clinically significant red-cell antibodies are detected, and where applicable, the blood or blood component should be labelled accordingly.

NRAs may set different (stronger) requirements.

The ABO/RhD labelling of the red-cell concentrates of all first-time donations should be based on two independent ABO/RhD tests.

7.5.3. Retention samples

As specified by the NRA, an aliquot of the original testing sample should be retained from each donation and stored under conditions recommended by the test manufacturer that would permit retesting if indicated. The procedure for additional testing should be validated to ensure the integrity of the sample (including storage conditions) and the test results. The sample volume, the retention vial, the kind of specimen (serum or plasma), the storage conditions and length of storage should each be defined and should be included in the validation to ensure the integrity of test results.

7.6. Quality monitoring of blood and blood components

Quality control data should demonstrate that critical manufacturing processes are under control. Blood and blood components should comply with specifications and their testing should be performed using test methods approved by the NRA. All processes - including data transfers and computerized systems - that have an influence on the quality of the products in the area of collection, preparation or testing of blood and blood components should be validated. For critical processes such as rapid freezing of plasma, the need for revalidation should be defined. Quality control of blood and blood components should be carried out according to a defined sampling plan based on statistical methods. The sampling plan should take into account different collection and production sites, transport, methods of preparation and equipment used. Acceptance criteria should be based on a defined specification for each type of blood component. As an example for fresh frozen plasma, these data may include monitoring of weight/volume, sterility, Factor VIII activity and residual cell counts (platelets, leukocytes, erythrocytes). The sampling plan for testing of blood or blood components should take into account that most components are derived from one donor, and should be considered as a single batch. Whole blood or blood components should not be released for use if the quality control test indicates that the integrity of the product has been compromised.

The work record should identify the test(s) employed so as to ensure that entries, such as the calculation of results, are available for review.

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Where applicable, the practice of pooling samples before testing should be clearly stated and the donations used in the pooled sample should be recorded. Pooling of samples, such as for the measurement of Factor VIII activity in plasma, is acceptable only where comparative data of pooled samples and individual samples have demonstrated assurance of equivalence. The results of quality monitoring testing should be subject to periodic review and trend analysis. If the results of quality monitoring suggest that the process is not meeting validated parameters and specifications, then corrective and preventive actions should be taken to correct identified problems before product manufacturing and distribution is continued.

7.7. Labelling

7.7.1. Label information

The collected blood, as well as intermediate and finished blood components, should be labelled with relevant information regarding their identity and release status. The type of label to be used, as well as the labelling methodology, should be established in written standard operating procedures. Whenever possible, machine-readable labels (barcodes) should be used. The label for a finished blood component should comply with the requirements of the NRA or contain at least the following information:

- the unique donation number (through the use of this number there should be traceability to the donor and all records of the manufacturing steps through to the final product);

- the product name (see section 9.7.2.);

- the required storage conditions;

- the expiry date and, where appropriate, time (see section 9.7.3.);

- the date of collection of the donation(s) from which the blood component was prepared and/or the production date and time (where appropriate);

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- the ABO and RhD blood group (where appropriate);

- the name or other identification of the component preparation site.

Information regarding the use of the blood product may also be applicable.

For autologous blood components, the label should additionally contain the name and unique identification of the patient as well as the statement “Autologous donation”. In some countries the signature of the donor is also required.

7.7.2. Product name

The name of the blood component should be clearly stated on the label and should indicate any further processing such as leukocyte reduction or irradiation.

In addition, the anticoagulant and/or any nutrient or preservative solution should be mentioned on the label.

7.7.3. Expiry date

Any final blood product should have its expiry date on its label. It should be also kept in mind that certain processing steps, such as irradiation, have an influence on the expiry date so that relabelling becomes necessary.

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7.8. Release of product

Each blood establishment should be able to demonstrate that a blood component has been evaluated and approved for release by an authorized person, preferably assisted by validated computerized systems. The release criteria and specifications of blood components should be defined, validated, documented and approved by quality assurance. There should be a standard operating procedure that details the actions and criteria that determine whether the blood or blood component can be released. The decision to release the blood components should be made by the responsible person of the establishment; it should be clearly documented and traceability should be ensured. Electronic release of products should be fully validated. The documented manufacturing processes should be followed at all times using validated methods and procedures. Any deviations from these established procedures and processes may result in products not meeting specifications, in which case they should be considered non-conforming products and must not be released for distribution.

A review of the donor health record, collection and phlebotomy records, consent forms, records of production and test results should be performed and accepted (and should be recorded) prior to the release of the components. The release of products should be arranged in such a way that each component from the donation has been evaluated to ensure conformance with product specifications - such as platelet content in apheresis units, volume in plasma products or appearance for red blood cells - prior to release for distribution. The decision to release the component should not be made on the basis of a review of the collection processes alone.

There should be a system of administrative and physical quarantine for blood and blood components to ensure that components cannot be released until all mandatory requirements have been met.

In the absence of a computerized system for product status control:

- the label of a blood component should identify the product status and should clearly distinguish released products from non-released (quarantined) ones;

- records should demonstrate that, before a component is released, all current donor health records, collection and phlebotomy records, consent forms and test results have been verified and accepted by an authorized person.

If blood or blood components have been prepared from a donor who has donated on previous occasions, a comparison with previous records - specifically the ABO/RhD and infectious disease marker test results - should be made before final product release to ensure that current records accurately reflect the donor history.

Where release is subject to computer-derived information, the following points should be checked:

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• The manual entry of critical data, such as laboratory test results, should require independent verification by a second authorized person.

• There should be a hierarchy of permitted access to enter, amend, read or print data. Methods of preventing unauthorized entry should be in place, such as personal identity codes or passwords which are changed on a regular basis.

• Computer systems should prevent the release of all blood or blood components considered not acceptable for release. It should be possible to prevent the release of any future donation from a donor

In the event that the final product fails release due to noncompliance with the specified requirements and therefore due to potential impact on recipient safety, all other implicated components should be identified and appropriate action should be taken. A check should be made to ensure that (if relevant) other components from the same donation(s) and components prepared from previous donations given by the donor(s) are identified. There should be an immediate updating of the donor record(s) to ensure that the donor(s) cannot make any further donation, if appropriate.

There should be a defined procedure for the exceptional release of nonstandard blood and blood components under a planned non-conformance system. The decision to allow such a release should be made by the responsible person; the decision should be clearly documented and traceability should be ensured. Products that cannot be released should be destroyed and the record of destruction should be retained.

7.9. Storage

Standard operating procedures should describe the receipt, handling and storage of material, blood and blood components. There should be a system in place to maintain and control storage conditions, including any transportation that may be required. Autologous blood and blood components should be stored separately. Storage areas for blood components to be dispatched should be located near an entrance or exit to facilitate dispatch and to limit the number of persons entering the main working areas. Only authorized persons should have access to storage areas.

Storage conditions should be controlled, monitored and checked. The personnel authorized should be trained to be aware of the correct storage temperature ranges and alarm settings. Temperature records should be available to demonstrate that the blood components are stored at the required temperature throughout the storage area. A temperature monitoring and recording system that is independent from the temperature regulation system should be in place. Appropriate alarms should be present (upper and lower limits) and regularly checked; the checks should be recorded. Depending on the method of measuring the temperature, a delay of the alarm may be acceptable in order to avoid an alarm being triggered by opening a door or taking out a product, but any such delay should be reasonably justified. If the temperature sensor is placed in a reference solution, no delay of the alarm should be accepted. Appropriate actions on alarms should be defined, and a person should be authorized to decide on the use or rejection of affected products. Temperature excursions may occur and each event should be evaluated using the deviation management system (see section 3.5).

An alternative storage area of appropriate temperature is recommended for recovery in case of temperature control failure of the primary system. Areas for storage should be secured against the entry of unauthorized persons and should be used only for the intended purpose. Storage areas should provide effective segregation of quarantined and released materials or components. There should be a separate area for rejected components and material. If a temporary mechanical or electrical failure affects control of storage temperatures, an examination of the records should be made to evaluate the impact on plasma or blood component quality

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- red-cell concentrate: 1–6°C;

- plasma for transfusion: minus 25°C or colder;

- platelets: 20–24°C;

or in a more stringent range defined by the NRA.

Higher storage temperatures (e.g. minus 20°C) might be acceptable for plasma for transfusion but may result in a significantly shorter shelf-life.

Storage of platelets should also be controlled. Besides the temperature, the continuous agitation is very important. Based on the manufacturer’s instructions, the moving velocity should be set in a way that obtains an optimal quality of the product. The moving velocity should be part of the qualification of the equipment.

During the whole collection and manufacturing process it should be ensured that blood or blood components are never placed in direct sunlight or near a heating source.

All storage equipment should be subject to qualification, cleaning and preventive maintenance. Thermometers or temperature sensors should be calibrated annually. The temperature deviation to the standard measuring device should not exceed 1°C.

7.10. Distribution

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7.11. Shipping

Distribution should take place in a safe and controlled way in order to assure product quality during transport. All transportation and intermediate storage actions, including receipt and distribution, should be defined by written standard operating procedures and specifications. The shipping containers should be of sturdy construction in order to resist damage and should be validated to maintain acceptable storage conditions for the blood and blood components (e.g. by using appropriate cooling elements or insulation during transport). The transportation and storage conditions for blood components, the packaging format and the responsibilities of the persons involved should be in accordance with standard operating procedures agreed between the sites in question.

7.12. Returns

Blood components should not be returned to stock for subsequent distribution, unless:

- the procedure for return of a blood component is regulated by contract;

- for each returned blood component, it is proven that the agreed storage conditions have consistently been met;

- the integrity of the container has been maintained (i.e. unopened);

- sufficient material is available for compatibility testing.

In case of medical urgency, components may be returned and subsequently distributed using a defined procedure.

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8. Contract manufacturing, analysis and services

In blood establishments, all tasks that have an influence on the quality of collected blood and the manufacture of blood components - such as component processing, testing or information technology support - and which are performed externally by another party, should be subject to a specific written contract. The contract should ensure that the contract acceptor meets GMP requirements in all disciplines relevant to the contract giver’s activities. The contract giver is ultimately responsible for ensuring that processes are in place to assure the control of outsourced activities and the quality of purchased materials. These processes should incorporate QRM and should include:

- assessing (prior to outsourcing operations or selecting material suppliers) the suitability and competence of the other party to carry out the activity or provide the material using a defined supply chain (e.g. audits, material evaluations, qualification);

- defining the responsibilities and communication processes for quality related activities of the parties concerned;

- monitoring and review of the performance of the contract acceptor or the quality of the material from the provider, and identification and implementation of any improvements needed;

- monitoring of incoming ingredients and materials to ensure that they are from approved sources using the agreed supply chain.

 Details should be specified in a technical quality agreement or contract:

The contract or agreement should:

- clearly establish the duties of each party;

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- mention any technical arrangements;

- define the flow of information, especially regarding deviations and changes;

- define the handling and archiving of documents, samples and other relevant materials and information;

- state that any of the duties given to the contract acceptor should not be passed to a third party without evaluation and approval of the contract giver;

- permit the contract giver and competent authorities to visit and inspect the facilities of the contract acceptor.

The contract giver should provide the contract acceptor with all necessary information to enable compliance with expectations regarding services or goods. This assures that the work or service is performed in compliance with existing regulations. The overall responsibility for the work and duties carried out externally lies always with the contracting company. The contract should be agreed and signed by quality assurance representatives from both parties and should be kept up to date.

APPENDIX III

PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME (PIC/S) GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS
(Enclosed with the Circular No. 35/2018/TT-BYT dated November 22, 2018 of the Minister of Health)

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PART I. GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS - BASIC REQUIREMENTS

Chapter I. PHARMACEUTICAL QUALITY SYSTEM

Chapter II. PERSONNEL

Chapter III. PREMISES AND EQUIPMENT

Chapter IV. DOCUMENTATION

Chapter V. PRODUCTION

Chapter VI. QUALITY CONTROL

Chapter VII. OUTSOURCED ACTIVITIES

Chapter VIII. COMPLAINTS AND PRODUCT RECALL

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PART II. GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS - BASIC REQUIREMENTS FOR APIs

1. Introduction

2. Quality management

3. Personnel

4. Building and facilities

5. Process equipment

6. Documentation and records

7. Materials management

8. Production and in-process controls

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10. Storage and distribution

11. Laboratory controls

12. Validation

13. Change control

14. Rejection and re-use of materials

15. Complaints and recalls

16. Contract manufacturers (including laboratories)

17. Agents, brokers, traders, distributors, repackers and relabellers

18. Specific guidance for APIs manufactured by cell culture/ fermentation

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20. Glossary

PART I

GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS - BASIC REQUIREMENTS

Chapter I

PHARMACEUTICAL QUALITY SYSTEM

Principle

The holder of a Manufacturing Authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorisation or Clinical Trial Authorisation, as appropriate, and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company’s suppliers and by its distributors. To achieve this quality objective reliably there must be a comprehensively designed and correctly implemented Pharmaceutical Quality System incorporating Good Manufacturing Practice and Quality Risk Management. It should be fully documented and its effectiveness monitored. All parts of the Pharmaceutical Quality System should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the Manufacturing Authorisation and for the Authorised Person(s).

The basic concepts of Quality Management, Good Manufacturing Practice (GMP) and Quality Risk Management are inter-related. They are described here in order to emphasise their relationships and their fundamental importance to the production and control of medicinal products.

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Quality Management is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Management therefore incorporates Good Manufacturing Practice.

1.2. GMP applies to the lifecycle stages from the manufacture of investigational medicinal products, technology transfer, commercial manufacturing through to product discontinuation. However the Pharmaceutical Quality System can extend to the pharmaceutical development lifecycle stage as described in ICH Q10, which while optional, should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities.

1.3. The size and complexity of the company’s activities should be taken into consideration when developing a new Pharmaceutical Quality System or modifying an existing one. The design of the system should incorporate appropriate risk management principles including the use of appropriate tools. While some aspects of the system can be company-wide and others site-specific, the effectiveness of the system is normally demonstrated at the site level.

1.4. A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that:

(i) Product realisation is achieved by designing, planning, implementing, maintaining and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes;

(ii) Product and process knowledge is managed throughout all lifecycle stages;

(iii) Medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice;

(iv) Production and control operations are clearly specified and Good Manufacturing Practice adopted;

(v) Managerial responsibilities are clearly specified;

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(vii) Processes are in place to assure the management of outsourced activities;

(viii) A state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality;

(ix) The results of product and processes monitoring are taken into account in batch release, in the investigation of deviations, and, with a view to taking preventive action to avoid potential deviations occurring in the future;

(x) All necessary controls on intermediate products, and any other in-process controls and validations are carried out;

(xi) Continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge;

 (xii) Arrangements are in place for the prospective evaluation of planned changes and their approval prior to implementation taking into account regulatory notification and approval where required. After implementation of any change, an evaluation is undertaken to confirm the quality objectives were achieved and that there was no unintended deleterious impact on product quality;

(xiii) After implementation of any change, an evaluation is undertaken to confirm the quality objectives were achieved and that there was no unintended deleterious impact on product quality;

(xiv) An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems.

This can be determined using Quality Risk Management principles. In cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those. Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present. Appropriate corrective actions and/or preventive actions (CAPAs) should be identified and taken in response to investigations. The effectiveness of such actions should be monitored and assessed, in line with Quality Risk Management principles;

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(xvi) Satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subs

(xvii) There is a process for self-inspection and/or quality audit, which regularly appraises the effectiveness and applicability of the Pharmaceutical Quality System.

1.5. Senior management has the ultimate responsibility to ensure an effective Pharmaceutical Quality System is in place, adequately resourced and that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organisation. Senior management’s leadership and active participation in the Pharmaceutical Quality System is essential. This leadership should ensure the support and commitment of staff at all levels and sites within the organisation to the Pharmaceutical Quality System.

1.6. There should be periodic management review, with the involvement of senior management, of the operation of the Pharmaceutical Quality System to identify opportunities for continual improvement of products, processes and the system itself.

1.7. The Pharmaceutical Quality System should be defined and documented. A Quality Manual or equivalent documentation should be established and should contain a description of the quality management system including management responsibilities.

GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (GMP)

1.8. Good Manufacturing Practice is that part of Quality Management which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation, Clinical Trial Authorisation or product specification. Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that:

(i) All manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications;

(ii) Critical steps of manufacturing processes and significant changes to the process are validated;

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· Appropriately qualified and trained personnel;

· Adequate premises and space;

· Suitable equipment and services;

· Correct materials, containers and labels;

· Approved procedures and instructions, in accordance with the Pharmaceutical Quality System;

· Suitable storage and transport; and

(iv) Instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided;

(v) Procedures are carried out correctly and operators are trained to do so;

(vi) Records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected;

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(viii) Records of manufacture including distribution which enable the complete history of a batch to be traced are retained in a comprehensible and accessible form;

(ix) The distribution of the products minimises any risk to their quality and takes account of good distribution practice;

(x) A system is available to recall any batch of product, from sale or supply;

(xi) Complaints about products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent reoccurrence.

Quality control

1.9. Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. The basic requirements of Quality Control are that:

(i) Adequate facilities, trained personnel and approved procedures are available for sampling and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes;

(ii) Samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by approved personnel and methods;

(iii) Test methods are validated;

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(v) The finished products contain active ingredients complying with the qualitative and quantitative composition of the Marketing Authorisation or Clinical Trial Authorisation, are of the purity required, and are enclosed within their proper containers and correctly labelled;

(vi) Records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;

(vii) No batch of product is released for sale or supply prior to certification by an Authorised Person that it is in accordance with the requirements of the relevant authorisations;

(viii) Sufficient reference samples of starting materials and products are retained in accordance with Annex 19 to permit future examination of the product if necessary and that the sample is retained in the final pack.

Product quality review

1.10. Regular periodic or rolling quality reviews of all authorised medicinal products, including export only products, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least:

(i) A review of starting materials including packaging materials used in the product, especially those from new sources and in particular the review of supply chain traceability of active substances;

(ii) A review of critical in-process controls and finished product results;

(iii) A review of all batches that failed to meet established specification(s) and their investigation;

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(v) A review of all changes carried out to the processes or analytical methods;

(vi) A review of Marketing Authorisation variations submitted, granted or refused, including those for third country (export only) dossiers;

(vii) A review of the results of the stability monitoring programme and any adverse trends;

(viii) A review of all quality-related returns, complaints and recalls and the investigations performed at the time;

(ix) A review of adequacy of any other previous product process or equipment corrective actions;

(x) For new Marketing Authorisations and variations to Marketing Authorisations, a review of post-marketing commitments;

(xi) The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc., and reporting thereof;

(xii) A review of any contractual arrangements as defined in Chapter 7 to ensure that they are up to date.

1.11. The manufacturer and, where different, Marketing Authorisation holder should evaluate the results of the review and an assessment made as to whether corrective and preventive action or any revalidation should be undertaken, under the Pharmaceutical Quality System. There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self-inspection. Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc. where scientifically justified.

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Quality risk management

1.12. Quality Risk Management is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively.

1.13. The principles of Quality Risk Management are that:

(i) The evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient;

(ii) The level of effort, formality and documentation of the Quality Risk Management process is commensurate with the level of risk.

Examples of the processes and applications of Quality Risk Management can be found inter alia in Annex 20 or ICHQ9.

Chapter II

PERSONNEL

Principle

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General

2.1. The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. Senior management should determine and provide adequate and appropriate resources (human, financial, materials, facilities and equipment) to implement and maintain the Pharmaceutical Quality System and continually improve its effectiveness. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.

2.2. The manufacturer must have an organisation chart in which the relationships between the heads of Production, Quality Control and where applicable Head of Quality Assurance or Quality Unit referred to in point 2.5 and the position of the Authorised Person(s) are clearly shown in the managerial hierarchy.

2.3. People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice.

2.4. Senior management has the ultimate responsibility to ensure an effective Pharmaceutical Quality System is in place to achieve the quality objectives, and, that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organisation. Senior management should establish a quality policy that describes the overall intentions and direction of the company related to quality and should ensure continuing suitability and effectiveness of the Pharmaceutical Quality System and GMP compliance through participation in management review.

Key personnel

2.5. Senior Management should appoint Key Management Personnel including the head of Production, the head of Quality Control, and if at least one of these persons is not responsible for the release of products the Authorised Person(s) designated for the purpose. Normally, key posts should be occupied by full-time personnel. The heads of Production and Quality Control must be independent from each other. In large organisations, it may be necessary to delegate some of the functions listed in 2.7, 2.8 and 2.9. Additionally, depending on the size and organisational structure of the company, a separate Head of Quality Assurance or Head of the Quality Unit may be appointed. Where such a function exists usually some of the responsibilities described in 2.7, 2.8 and 2.9 are shared with the Head of Quality Control and Head of Production and senior management should therefore take care that roles, responsibilities, and authorities are defined.

2.6. The duties of the Authorised Person(s) are described in the national requirements and can be summarised as follows:

a) An Authorised Person must ensure that each batch of medicinal products has been manufactured and checked in compliance with the laws in force in that country and in accordance with the requirements of the Marketing Authorisation;

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c) The responsibilities of an Authorised Person may be delegated, but only to other Authorised Person(s).

2.7. The head of Production generally has the following responsibilities:

(i) To ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality;

(ii) To approve the instructions relating to production operations and to ensure their strict implementation;

(iii) To ensure that the production records are evaluated and signed by an authorised person;

(iv) To ensure the qualification and maintenance of his department, premises and equipment;

(v) To ensure that the appropriate validations are done;

(vi) To ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.

2.8. The head of Quality Control generally has the following responsibilities:

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(ii) To ensure that all necessary testing is carried out and the associated records evaluated;

(iii) To approve specifications, sampling instructions, test methods and other Quality Control procedures;

(iv) To approve and monitor any contract analysts;

(v) To ensure the qualification and maintenance of his/her department, premises and equipment;

(vi) To ensure that the appropriate validations are done;

(vii) To ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.

Other duties of Quality Control are summarised in Chapter 6.

2.9. The heads of Production, Quality Control and where relevant, Head of Quality Assurance or Head of Quality Unit, generally have some shared, or jointly exercised, responsibilities relating to quality including in particular the design, effective implementation, monitoring and maintenance of the Pharmaceutical Quality System. These may include, subject to any national regulations:

(i) The authorisation of written procedures and other documents, including amendments;

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(iii) Plant hygiene;

(iv) Process validation;

(v) Training;

(vi) The approval and monitoring of suppliers of materials;

(vii) The approval and monitoring of contract manufacturers and providers of other GMP related outsourced activities;

(viii) The designation and monitoring of storage conditions for materials and products;

(ix) The retention of records;

(x) The monitoring of compliance with the requirements of Good Manufacturing Practice;

(xi) The inspection, investigation, and taking of samples, in order to monitor factors which may affect product quality;

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(xiii) Ensuring that a timely and effective communication and escalation process exists to raise quality issues to the appropriate levels of management.

Training

2.10. The manufacturer should provide training for all the personnel whose duties take them into production and storage areas or into control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product.

2.11. Besides the basic training on the theory and practice of the Pharmaceutical Quality System and Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by either the head of Production or the head of Quality Control, as appropriate. Training records should be kept.

2.12. Personnel working in areas where contamination is a hazard, e.g. clean areas or areas where highly active, toxic, infectious or sensitising materials are handled, should be given specific training.

2.13. Visitors or untrained personnel should, preferably, not be taken into the production and quality control areas. If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised.

2.14. The Pharmaceutical Quality System and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions.

Personnel hygiene

2.15. Detailed hygiene programmes should be established and adapted to the different needs within the factory. They should include procedures relating to the health, hygiene practices and clothing of personnel. These procedures should be understood and followed in a very strict way by every person whose duties take him into the production and control areas. Hygiene programmes should be promoted by management and widely discussed during training sessions.

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2.17. Steps should be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products.

2.18. Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out.

2.19. Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas should be prohibited. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected should be forbidden.

2.20. Direct contact should be avoided between the operator’s hands and the exposed product as well as with any part of the equipment that comes into contact with the products.

2.21. Personnel should be instructed to use the hand-washing facilities.

2.22. Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the annexes.

Consultants

2.23. Consultants should have adequate education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.

Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.

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PREMISES AND EQUIPMENT

Principle

Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out.

Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt and, in general, any adverse effect on the quality of products.

Premises

General

3.1. Premises should be situated in an environment which, when considered together with measures to protect the manufacture, presents minimal risk of causing contamination of materials or products.

3.2. Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures.

3.3. Lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment.

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3.5. Steps should be taken in order to prevent the entry of unauthorised people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them.

Production Area

3.6. In order to minimise the risk of a serious medical hazard due to crosscontamination, dedicated and self-contained facilities must be available for the production of particular medicinal products, such as highly sensitising materials (e.g. penicillins) or biological preparations (e.g. from live micro-organisms).

The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities. For those products, in exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of medicinal products.

3.7. Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.

3.8. The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimise the risk of confusion between different medicinal products or their components, to avoid cross-contamination and to minimise the risk of omission or wrong application of any of the manufacturing or control steps.

3.9. Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection.

3.10. Pipe work, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.

3.11. Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.

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3.13. Weighing of starting materials usually should be carried out in a separate weighing room designed for such use.

3.14. In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.

3.15. Premises for the packaging of medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.

3.16. Production areas should be well lit, particularly where visual on-line controls are carried out.

3.17. In-process controls may be carried out within the production area provided they do not carry any risk to production.

Storage Areas

3.18. Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled.

3.19. Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored.

3.20. Receiving and dispatch bays should protect materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.

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3.22. There should normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.

3.23. Segregated areas should be provided for the storage of rejected, recalled or returned materials or products.

3.24. Highly active materials or products should be stored in safe and secure areas.

3.25. Printed packaging materials are considered critical to the conformity of the medicinal products and special attention should be paid to the safe and secure storage of these materials.

Quality control areas

3.26. Normally, Quality Control laboratories should be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals and radioisotopes, which should also be separated from each other.

3.27. Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and crosscontamination. There should be adequate suitable storage space for samples and records.

3.28. Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity, etc.

3.29. Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples.

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3.30. Rest and refreshment rooms should be separate from other areas.

3.31. Facilities for changing clothes, and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas.

3.32. Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.

3.33. Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.

Equipment

3.34. Manufacturing equipment should be designed, located and maintained to suit its intended purpose.

3.35. Repair and maintenance operations should not present any hazard to the quality of the products.

3.36. Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition.

3.37. Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.

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3.39. Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.

3.40. Balances and measuring equipment of an appropriate range and precision should be available for production and control operations.

3.41. Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.

3.42. Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the direction of flow.

3.43. Distilled, deionized and, where appropriate, other water pipes should be sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

3.44. Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective.

Chapter IV

DOCUMENTATION

Principle

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There are two primary types of documentation used to manage and record GMP compliance: instructions (directions, requirements) and records/reports. Appropriate good documentation practice should be applied with respect to the type of document.

Suitable controls should be implemented to ensure the accuracy, integrity, availability and legibility of documents. Instruction documents should be free from errors and available in writing. The term “written” means recorded, or documented on media from which data may be rendered in a human readable form.

Required GMP documentation (by type)

Site Master File: A document describing the GMP related activities of the manufacturer.

Instructions (directions, or requirements) type:

Specifications: Describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform.  They serve as a basis for quality evaluation.

Manufacturing Formulae, Processing, Packaging and Testing Instructions: Provide detail all the starting materials, equipment and computerised systems (if any) to be used and specify all processing, packaging, sampling and testing instructions. In-process controls and process analytical technologies to be employed should be specified where relevant, together with acceptance criteria.

Procedures: (Otherwise known as Standard Operating Procedures, or SOPs), give directions for performing certain operations.

Protocols: Give instructions for performing and recording certain discreet operations.

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Record/Report type:

Records: Provide evidence of various actions taken to demonstrate compliance with instructions, e.g. activities, events, investigations, and in the case of manufactured batches a history of each batch of product, including its distribution. Records include the raw data which is used to generate other records. For electronic records regulated users should define which data are to be used as raw data. At least, all data on which quality decisions are based should be defined as raw data.

Certificates of Analysis: Provide a summary of testing results on samples of products or materials1 together with the evaluation for compliance to a stated specification.

Reports: Document the conduct of particular exercises, projects or investigations, together with results, conclusions and recommendations.

Generation and control of documentation

4.1. All types of document should be defined and adhered to. The requirements apply equally to all forms of document media types. Complex systems need to be understood, well documented, validated, and adequate controls should be in place. Many documents (instructions and/or records) may exist in hybrid forms, i.e. some elements as electronic and others as paper based. Relationships and control measures for master documents, official copies, data handling and records need to be stated for both hybrid and homogenous systems. Appropriate controls for electronic documents such as templates, forms, and master documents should be implemented. Appropriate controls should be in place to ensure the integrity of the record throughout the retention period.

4.2. Documents should be designed, prepared, reviewed, and distributed with care. They should comply with the relevant parts of Product Specification Files, Manufacturing and Marketing Authorization dossiers, as appropriate. The reproduction of working documents from master documents should not allow any error to be introduced through the reproduction process.

4.3. Documents containing instructions should be approved, signed and dated by appropriate and authorized persons. Documents should have unambiguous contents and be uniquely identifiable. The effective date should be defined.

4.4. Documents containing instructions should be laid out in an orderly fashion and be easy to check. The style and language of documents should fit with their intended use. Standard Operating Procedures, Work Instructions and Methods should be written in an imperative mandatory style.

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4.6. Documents should not be hand-written; although, where documents require the entry of data.. Sufficient space should be provided for such entries.

Good documentation practices

4.7. Handwritten entries should be made in clear, legible, indelible way.

4.8. Records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable.

4.9. Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

Retention of documents

4.10. It should be clearly defined which record is related to each manufacturing activity and where this record is located. Secure controls must be in place to ensure the integrity of the record throughout the retention period and validated where appropriate.

4.11. Specific requirements apply to batch documentation which must be kept for one year after expiry of the batch to which it relates or at least five years after certification of the batch by the Authorised Person, whichever is the longer. For investigational medicinal products, the batch documentation must be kept for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used. Other requirements for retention of documentation may be described in legislation in relation to specific types of product (e.g. Advanced Therapy Medicinal Products) and specify that longer retention periods be applied to certain documents.

4.12. For other types of documentation, the retention period will depend on the business activity which the documentation supports. Critical documentation, including raw data (for example relating to validation or stability), which supports information in the Marketing Authorisation should be retained whilst the authorisation remains in force. It may be considered acceptable to retire certain documentation (e.g. raw data supporting validation reports or stability reports) where the data has been superseded by a full set of new data.

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The following section gives some examples of required documents. The quality management system should described all documents required to ensure product quality and patient safety.

Specifications

4.13. There should be appropriately authorised and dated specifications for starting and packaging materials, and finished products.

Specifications for starting and packaging materials

4.14. Specifications for starting and primary or printed packaging materials should include or provide reference to, if applicable:

a) the designated name (even INN, if available) and the internal code reference;

b) the reference, if any, to a pharmacopoeial monograph

c) qualitative and quantitive requirements with acceptance limits.

d) The maximum period of storage before re-examination.:

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f) a specimen of printed materials;

g) directions for sampling and testing, or reference to the procedure;

h) storage conditions and precautions;

i) the maximum period of storage before re-examination.

Specifications for intermediate and bulk products

4.15. Specifications for intermediate and bulk products should be available for critical steps or if these are purchased or dispatched. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.

Specifications for finished products

4.16. Specifications for finished products should include or provide reference to:

a) The designated name of the product and the code reference where applicable;

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c) The formula or reference to the formula;

d) A description of the pharmaceutical form and package details;

e) Directions for sampling and testing, or reference to the procedure;

f) The qualitative and quantitative requirements, with the acceptance limits;

g) Storage conditions and precautions where applicable;

h) The shelf-life.

Manufacturing formula and processing instructions

Approved, written manufacturing formula and processing instructions should exist for each product and batch size to be manufactured.

4.17. The manufacturing formula should include:

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b) A description of the pharmaceutical form, strength of the product and batch size;

c) A list of all starting materials to be used, with the amount of each, described; mention should be made of any substance that may disappear in the course of processing;

d) A statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.

4.18. The Processing Instructions should include:

a) A statement of the processing location and the principal equipment to be used;

b) The methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilising);

c) Detailed stepwise processing instructions [e.g. checks on materials, pretreatments, sequence for adding materials, critical process parameters (time, temp, etc.)];

d) The instructions for any in-process controls with their limits;

e) Where necessary, the requirements for bulk storage of the products; including the container, labeling and special storage conditions where applicable;

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Packaging Instructions

4.19. Approved Packaging Instructions for each product, pack size and type should exist. . These should include, or have a reference to, the following:

a) Name of the product;

b) ) Description of its pharmaceutical form, and strength where applicable;

c) The pack size expressed in terms of the number, weight or volume of the product in the final container;

d) A complete list of al the packaging materials required, including quantities, sizes and types, with the code or reference number relating to the specifications of each packaging material;

e) Where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf life of the product;

f) Checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations (line clearance), and that equipment is clean and suitable for use;

f) Special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin;

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h) Details of in-process controls with instructions for sampling and acceptable limits.

Batch processing record

4.20. A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved manufacturing formula and processing instructions, and should contain the following information:

a) The name and batch number of the product;

b) Dates and times of commencement, of significant intermediate stages and of completion of production;

c) The name of the person responsible for each stage of production;;

c) Identification (initials) of the operator(s) who performed each significant step of the process and, where appropriate, the name of any person who checked these operations;

e) The batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);

f) Any relevant processing operation or event and major equipment used;

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h) the amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanations for significant deviations from the expected yield;

i) notes on special problems including details, with signed authorization for any deviation from the master formula.

Note: Where a validated process is continuously monitored and controlled, then automatically generated reports may be limited to compliance summaries and exception/out-of-specification (OOS) data reports.

Batch packaging record

4.21. A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions. The batch packaging record should contain the following information:

a) the name of the product, the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained, the quantity actually obtained and the reconciliation;

b) the date(s) and time(s) of the packaging operations;

c) the name of the responsible person carrying out the packaging operation;

d) the initials of the operators of the different significant steps;

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f) details of the packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping the product if it is unpacked or a record of returning product has not been packaged to the storage area;

g) whenever possible, samples of the printed packaging materials used, including specimens bearing the approval for the printing of and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting;

h) Notes on any special problems, including details of any deviation from the packaging instructions, with written authorization by an appropriate person;

i) The quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of product obtained to permit an adequate reconciliation.

Standard operating procedures and records

Receipt

4.22. There should be written procedures and records for the receipt of each delivery of each starting material, (including bulk, intermediate or finished goods), primary, secondary and printed packaging materials.

4.23. The records of the receipts should include:

a) The name of the material on the delivery note and the containers;

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c) Date of receipt;

d) Supplier’s name and manufacturer’s name;

e) Manufacturer’s batch or reference number;

f) Total quantity and number of containers received;

g) The batch number assigned after receipt;

h) Any relevant comment (e.g. state of the containers).

4.24. There should be written procedures for the internal labeling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.

Sampling

4.25. There should be written procedures for sampling, which include the methods and equipment to be used, the amounts to be taken and any precautions to be observed to avoid contamination of the material or any deterioration in its quality.

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4.26. There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded.

Other

4.27. Written release and rejection procedures should be available for materials and products, and in particular for the certification for sale of the finished product by the Authorised Person(s). All records should be available to the Authorised Person.

A system should be in place to indicate special observations and any changes to critical data.

4.28. Records should be maintained for the distribution of each batch of a product in order to facilitate recall of any batch, if necessary.

4.29. There should be written policies, procedures, protocols, reports and the associated records of actions taken or conclusions reached, where appropriate, for the following examples:

- Validation and qualification of processes, equipment and systems;

- Equipment assembly and calibration;

- Technology transfer;

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- Personnel matters including signature lists, training in GMP and technical matters, clothing and hygiene and verification of the effectiveness of training;

- Environmental monitoring;

- Pest control;

- Complaints;

- Recalls;

- Returns;

- Change control;

- Investigations into deviations and non-conformances;

- Internal quality/GMP compliance audits;

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- Supplier audits.

4.30. Clear operating procedures should be available for major items of manufacturing and test equipment.

4.31. Logbooks should be kept for major or critical analytical testing, production equipment, and areas where product has been processed. They should be used to record in chronological order, as appropriate, any use of the area, equipment/method, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations out.

4.32. An inventory of documents within the Quality Management System should be maintained.

Chapter V

PRODUCTION

Principle

Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorisations.

General

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5.2. All handling of materials and products, such as receipt and quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded.

5.3. All incoming materials should be checked to ensure that the consignment corresponds to the order. Containers should be cleaned where necessary and labelled with the prescribed data.

5.4. Damage to containers and any other problem which might adversely affect the quality of a material should be investigated, recorded and reported to the Quality Control Department.

5.5. Incoming materials and finished products should be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution.

5.6. Intermediate and bulk products purchased as such should be handled on receipt as though they were starting materials.

5.7. All materials and products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation.

5.8. Checks on yields, and reconciliation of quantities, should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.

5.9. Operations on different products should not be carried out simultaneously or consecutively in the same room unless there is no risk of mix-up or crosscontamination.

5.10. At every stage of processing, products and materials should be protected from microbial and other contamination.

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5.12. At all times during processing, all materials, bulk containers, major items of equipment and where appropriate rooms used should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication should also mention the stage of production.

5.13. Labels applied to containers, equipment or premises should be clear, unambiguous and in the company's agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (for example, quarantined, accepted, rejected, clean, ...).

5.14. Checks should be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner.

5.15. Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occur, it should be approved in writing by a competent person, with the involvement of the Quality Control Department when appropriate.

5.16. Access to production premises should be restricted to authorised personnel.

5.17. Normally, the production of non-medicinal products should be avoided in areas and with the equipment destined for the production of medicinal products.

Prevention of cross-contamination in production

5.18. Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapours, sprays or organisms from materials and products in process, from residues on equipment, and from operators' clothing. The significance of this risk varies with the type of contaminant and of product being contaminated. Amongst the most hazardous contaminants are highly sensitising materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection, those given in large doses and/or over a long time.

5.19. Cross-contamination should be avoided by appropriate technical or organisational measures, for example:

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b) production by campaign (separation in time) followed by appropriate cleaning;

c) providing appropriate air-locks and air extraction;

d) minimising the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated air;

e) keeping protective clothing inside areas where products; or materials are processed;

f) using cleaning and decontamination procedures of known effectiveness;

g) using "closed systems" of production;

h) testing for residues;

i) use of cleaning status labels on equipment.

5.20. Measures to prevent cross-contamination and their effectiveness should be checked periodically according to set procedures.

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5.21. Validation studies should reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions should be recorded.

5.22. When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality.

5.23. Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process should be validated.

5.24. Processes and procedures should undergo periodic critical revalidation to ensure that they remain capable of achieving the intended results.

Starting materials

5.25. The purchase of starting materials is an important operation which should involve staff who have a particular and thorough knowledge of the suppliers.

5.26. Starting materials should only be purchased from approved suppliers named in the relevant specification and, where possible, directly from the producer. It is recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all aspects of the production and control of the starting material in question, including handling, labelling and packaging requirements, as well as complaints and rejection procedures are discussed with the manufacturer and the supplier.

5.27. For each delivery, the containers should be checked for integrity of package and seal and for correspondence between the delivery note and the supplier's labels.

5.28. If one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing and release.

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- the designated name of the product and the internal code reference where applicable;

- a batch number given at receipt;

- where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected);

- where appropriate, an expiry date or a date beyond which retesting is necessary.

When fully computerised storage systems are used, all the above information should not necessarily be in a legible form on the label.

5.30. There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified (see Chapter 6, Item 13).

5.31. Only starting materials which have been released by the Quality Control Department and which are within their shelf-life should be used.

5.32. Starting materials should only be dispensed by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labelled containers.

5.33. Each dispensed material and its weight or volume should be independently checked and the check recorded.

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Processing operations - intermediate and bulk products

5.35. Before any processing operation is started, steps should be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation.

5.36. Intermediate and bulk products should be kept under appropriate conditions.

5.37. Critical processes should be validated (see "VALIDATION" in this Chapter).

5.38. Any necessary in-process controls and environmental controls should be carried out and recorded.

5.39. Any significant deviation from the expected yield should be recorded and investigated.

Packaging materials

5.40. The purchase, handling and control of primary and printed packaging materials should be accorded attention similar to that given to starting materials.

5.41. Particular attention should be paid to printed materials. They should be stored in adequately secure conditions such as to exclude unauthorised access. Cut labels and other loose printed materials should be stored and transported in separate closed containers so as to avoid mix-ups. Packaging materials should be issued for use only by authorised personnel following an approved and documented procedure.

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5.43. Outdated or obsolete primary packaging material or printed packaging material should be destroyed and this disposal recorded.

Packaging operations

5.44. When setting up a programme for the packaging operations, particular attention should be given to minimising the risk of cross-contamination, mix-ups or substitutions. Different products should not be packaged in close proximity unless there is physical segregation.

5.45. Before packaging operations are begun, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance should be performed according to an appropriate check-list.

5.46. The name and batch number of the product being handled should be displayed at each packaging station or line.

5.47. All products and packaging materials to be used should be checked on delivery to the packaging department for quantity, identity and conformity with the Packaging Instructions.

5.48. Containers for filling should be clean before filling. Attention should be given to avoiding and removing any contaminants such as glass fragments and metal particles.

5.49. Normally, filling and sealing should be followed as quickly as possible by labelling. If it is not the case, appropriate procedures should be applied to ensure that no mix-ups or mislabelling can occur.

5.50. The correct performance of any printing operation (for example code numbers, expiry dates) to be done separately or in the course of the packaging should be checked and recorded. Attention should be paid to printing by hand which should be re-checked at regular intervals.

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5.52. Checks should be made to ensure that any electronic code readers, label counters or similar devices are operating correctly.

5.53. Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing.

5.54. On-line control of the product during packaging should include at least checking the following:

a) general appearance of the packages;

b) whether the packages are complete;

c) whether the correct products and packaging materials are used;

d) whether any over-printing is correct;

e) correct functioning of line monitors. Samples taken away from the packaging line should not be returned.

5.55. Products which have been involved in an unusual event should only be reintroduced into the process after special inspection, investigation and approval by authorised personnel. Detailed record should be kept of this operation.

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5.57. Upon completion of a packaging operation, any unused batch-coded packaging materials should be destroyed and the destruction recorded. A documented procedure should be followed if uncoded printed materials are returned to stock.

Finished products

5.58. Finished products should be held in quarantine until their final release under conditions established by the manufacturer.

5.59. The evaluation of finished products and documentation which is necessary before release of product for sale are described in Chapter 6 (Quality Control).

5.60. After release, finished products should be stored as usable stock under conditions established by the manufacturer.

Rejected, recovered and returned materials

5.61. Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorised personnel.

5.62. The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. Record should be kept of the reprocessing.

5.63. The recovery of all or part of earlier batches, which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture should be authorised beforehand. This recovery should be carried out in accordance with a defined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded.

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5.65. Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; they may be considered for re-sale, re-labelling or recovery with a subsequent batch only after they have been critically assessed by the Quality Control Department in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for re-issue or re-use, although basic chemical reprocessing to recover active ingredients may be possible. Any action taken should be appropriately recorded.

Chapter VI

QUALITY CONTROL

Principle

Quality Control is concerned with sampling, specifications and testing as well as the organisation, documentation and release procedures which ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality Control is not confined to laboratory operations, but must be involved in all decisions which may concern the quality of the product. The independence of Quality Control from Production is considered fundamental to the satisfactory operation of Quality Control (see also Chapter 1).

General

6.1. Each holder of a manufacturing authorisation should have a Quality Control Department. This department should be independent from other departments, and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal. Adequate resources must be available to ensure that all the Quality Control arrangements are effectively and reliably carried out.

6.2. The principal duties of the head of Quality Control are summarised in Chapter 2. The Quality Control Department as a whole will also have other duties, such as to establish, validate and implement all quality control procedures, keep the reference samples of materials and products, ensure the correct labelling of containers of materials and products, ensure the monitoring of the stability of the products, participate in the investigation of complaints related to the quality of the product, etc. All these operations should be carried out in accordance with written procedures and, where necessary, recorded.

6.3. Finished product assessment should embrace all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with Finished Product Specification and examination of the final finished pack.

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Good quality control laboratory practice

6.5. Control Laboratory premises and equipment should meet the general and specific requirements for Quality Control areas given in Chapter 3.

6.6. The personnel, premises, and equipment in the laboratories should be appropriate to the tasks imposed by the nature and the scale of the manufacturing operations. The use of outside laboratories, in conformity with the principles detailed in Chapter 7, Contract Analysis, can be accepted for particular reasons, but this should be stated in the Quality Control records.

Documentation

6.7. Laboratory documentation should follow the principles given in Chapter 4. An important part of this documentation deals with Quality Control and the following details should be readily available to the Quality Control Department:

- specifications;

- procedures describing sampling, testing, records (including test worksheets and/or laboratory notebooks), recording and verifying;

- procedures for and records of the calibration/qualification of instruments and maintenance of equipment;

- a procedure for the investigation of Out of Specification and Out of Trend results;

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- data from environmental (air, water and other utilities) monitoring, where required;

- validation records of test methods, where applicable.

6.8. Any Quality Control documentation relating to a batch record should be retained following the principles given in Chapter 4 on retention of batch documentation.

6.9. Some kinds of data (e.g. tests results, yields, environmental controls) should be recorded in a manner permitting trend evaluation. Any Out of Trend or Out of Specification data should be addressed and subject to investigation.

6.10. In addition to the information which is part of the batch documentation, other raw data such as laboratory notebooks and/or records should be retained and readily available.

Sampling

6.11. The sample taking should be done and recorded in accordance with approved written procedures that describe:

- The method of sampling;

- The equipment to be used;

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- Instructions for any required sub-division of the sample;

- The type and condition of the sample container to be used;

- The identification of containers sampled;

- Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials;

- The storage conditions;

- Instructions for the cleaning and storage of sampling equipment.

6.12. Samples should be representative of the batch of materials or products from which they are taken. Other samples may also be taken to monitor the most stressed part of a process (e.g. beginning or end of a process). The sampling plan used should be appropriately justified and based on a risk management approach.

6.13. Sample containers should bear a label indicating the following information:

a) The name of the materials sampled;

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c) The date of sampling;

d) The number of containers from which samples have been drawn;

They should be managed in a manner to minimize the risk of mix-up and to protect the samples from adverse storage conditions.

6.14. Further guidance on reference and retention samples is given in Annex 19.

Testing

6.15. Testing methods should be validated. A laboratory that is using a testing method and which did not perform the original validation, should verify the appropriateness of the testing method. All testing operations described in the Marketing Authorisation or technical dossier should be carried out according to the approved methods.

6.16. The results obtained should be recorded. Results of parameters identified as critical quality attributes should be trended and checked to make sure that they are consistent with each other. Any calculations should be critically examined.

6.17. The tests performed should be recorded and the records should include at least the following data:

a) Name of the material or product and, where applicable, dosage form;

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c) References to the relevant specifications and testing procedures;

d) Test results, including observations and calculations, and reference to any certificates of analysis;

e) Dates of testing;

f) Initials of the persons who performed the testing;

g) Initials of the persons who verified the testing and the calculations, where appropriate;

h) A clear statement of approval or rejection (or other status decision) and the dated signature of the designated responsible person;

i) Reference to the equipment used.

6.18. All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved by Quality Control and the results recorded.

6.19. Special attention should be given to the quality of laboratory reagents, solutions, glassware, reference standards and culture media. They should be prepared and controlled in accordance with written procedures. The level of controls should be commensurate to their use and to the available stability data.

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6.21. Where necessary, the date of receipt of any substance used for testing operations (e.g. reagents and reference standards) should be indicated on the container. Instructions for use and storage should be followed. In certain cases it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use.

6.22. Where necessary, the date of receipt of any substance used for testing operations (e.g. reagents and reference standards) should be indicated on the container. Instructions for use and storage should be followed. Instructions for use and storage should be followed. In certain cases it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use.

6.23. Culture media should be prepared in accordance with the media manufacturer’s requirements unless scientifically justified. The performance of all culture media should be verified prior to use.

6.24. Used microbiological media and strains should be decontaminated according to a standard procedure and disposed of in a manner to prevent the crosscontamination and retention of residues. The in-use shelf life of microbiological media should be established, documented and scientifically justified.

6.25. Animals used for testing components, materials or products, should, where appropriate, be quarantined before use. They should be maintained and controlled in a manner that assures their suitability for the intended use. They should be identified, and adequate records should be maintained, showing the history of their use.

On-going stability programme

6.26. After marketing, the stability of the medicinal product should be monitored according to a continuous appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of impurities or dissolution profile) associated with the formulation in the marketed package.

6.27. The purpose of the on-going stability programme is to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifications under the labelled storage conditions.

6.28. This mainly applies to the medicinal product in the package in which it is sold, but consideration should also be given to the inclusion in the programme of bulk product. For example, when the bulk product is stored for a long period before being packaged and/or shipped from a manufacturing site to a packaging site, the impact on the stability of the packaged product should be evaluated and studied under ambient conditions. In addition, consideration should be given to intermediates that are stored and used over prolonged periods. Stability studies on reconstituted product are performed during product development and need not be monitored on an on-going basis. However, when relevant, the stability of reconstituted product can also be monitored.

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a) Number of batch(es) per strength and different batch sizes, if applicable

b) Relevant physical, chemical, microbiological and biological test methods

c) Acceptance criteria

d) Reference to test methods

e) Description of the container closure system(s)

f) Testing intervals (time points)

g) Description of the conditions of storage (standardised ICH/VICH conditions for long term testing, consistent with the product labelling, should be used);

h) Other applicable parameters specific to the medicinal product.

6.30. The protocol for the on-going stability programme can be different from that of the initial long term stability study as submitted in the Marketing Authorisation dossier provided that this is justified and documented in the protocol (for example the frequency of testing, or when updating to ICH/VICH recommendations).

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6.32. In certain situations, additional batches should be included in the on-going stability programme. For example, an on-going stability study should be conducted after any significant change or significant deviation to the process or package. Any reworking, reprocessing or recovery operation should also be considered for inclusion.

6.33. Results of on-going stability studies should be made available to key personnel and, in particular, to the authorised person(s). Where on-going stability studies are carried out at a site other than the site of manufacture of the bulk or finished product, there should be a written agreement between the parties concerned. Results of on-going stability studies should be available at the site of manufacture for review by the competent authority.

6.34.a procedure for the investigation of Out of Specification and Out of Trend results; Results of on-going stability studies should be available at the site of manufacture for review by the competent authority. The possible impact on batches on the market should be considered in accordance with chapter 8 of the GMP Guide and in consultation with the relevant competent authorities.

6.35. A summary of all the data generated, including any interim conclusions on the programme, should be written and maintained. This summary should be subjected to periodic review

Technical transfer of testing methods

6.36. Prior to transferring a test method, the transferring site should verify that the test method(s) comply with those as described in the Marketing Authorisation or the relevant technical dossier. The original validation of the test method(s) should be reviewed to ensure compliance with current ICF/VICH requirements. A gap analysis should be performed and documented to identify any supplementary validation that should be performed, prior to commmencing the technical transfer process.

6.37. The transfer of testing methods from one laboratory (transferring laboratory) to another laboratory (receiving laboratory) should be described in a detailed protocol.

6.38. The transfer protocol should include, but not be limited to, the following parameters:

(i) Identification of the testing to be performed and the relevant test method(s) undergoing transfer;

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(iii) Identification of standards and samples to be tested;

(iv) Identification of any special transport and storage conditions of test items;

(v) The acceptance criteria which should be based upon the current validation study of the methodology and with respect to ICH/VICH requirements.

6.39. Deviations from the protocol should be investigated prior to closure of the technical transfer process. The technical transfer report should document the comparative outcome of the process and should identify areas requiring further test method revalidation, if applicable.

6.40. Where appropriate, specific requirements described in other guidelines should be addressed for the transfer of particular testing methods (e.g. Near Infrared Spectroscopy).

Chapter VII

OUTSOURCED ACTIVITIES

Principle

Contract manufacture and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings which could result in a product or work of unsatisfactory quality. There must be a written contract between the Contract Giver and the Contract Acceptor which clearly establishes the duties of each party. The contract must clearly state the way in which the authorised person releasing each batch of product for sale exercises his full responsibility.

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Note:

This Chapter deals with the responsibilities of manufacturers towards the Competent Regulatory Authorities with respect to the granting of marketing and manufacturing authorisations. It is not intended in any way to affect the respective liability of Contract Acceptors and Contract Givers to consumers; this is governed by other provisions of national law.

General

7.1. There should be a written contract covering the outsourced activities, the products or operations to which they are related, and any technical arrangements made in connection with it.

7.2. All arrangements for the outsourced activities including any proposed changes in technical or other arrangements should be in accordance with regulations in force, and the Marketing Authorisation for the product concerned, where applicable.

7.3. Where the Marketing Authorisation holder and the manufacturer are not the same, appropriate arrangements should be in place, taking into account the principles described in this chapter.

The contract giver

7.4. The Pharmaceutical Quality System of the Contract Giver should include the control and review of any outsourced activities. The Contract Giver is ultimately responsible to ensure processes are in place to assure the control of outsourced activities. Theses processes should incorporate quality risk management principles and notably include:

7.4.1. Prior to outsourcing activities, the Contract Giver is responsible for assessing the legality, suitability and the competence of the Contract Acceptor to carry out successfully the outsourced activities. The Contract Giver is also responsible for ensuring by means of the contract that the principles and guidelines of GMP as interpreted in this Guide are followed;

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7.4.3. The Contract Giver should monitor and review the performance of the Contract Acceptor and the identification and implementation of any needed improvement.

7.5. The Contract Giver should be responsible for reviewing and assessing the records and the results related to the outsourced activities. He/she should also ensure, either by himself/herself, or based on the confirmation of the Contract Acceptor’s Authorised Person, that all products and materials delivered to him/her by the Contract Acceptor have been processed in accordance with GMP and the Marketing Authorisation.

The contract acceptor

7.6. The Contract Acceptor must be able to carry out satisfactorily the work ordered by the Contract Giver such as having adequate premises, equipment, knowledge, experience, and competent personnel.

7.7. The Contract Acceptor should ensure that all products, materials and knowledge delivered to him/her are suitable for their intended purpose.

7.8. The Contract Acceptor should not subcontract to a third party any of the work entrusted to him/her under the contract without the Contract Giver’s prior evaluation and approval of the arrangements. Arrangements made between the Contract Acceptor and any third party should ensure that information and knowledge, including those from assessments of the suitability of the third party, are made available in the same way as between the original Contract Giver and Contract Acceptor.

7.9. The Contract Acceptor should not make unauthorised changes, outside the terms of the Contract, which may adversely affect the quality of the outsourced activities for the Contract Giver.

7.10. The Contract Acceptor should understand that outsourced activities, including contract analysis, may be subject to inspection by the competent authorities.

The contract

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7.12. The contract should describe clearly which party to the contract has responsibility for conducting each step of the outsourced activity, e.g. knowledge management, technology transfer, supply chain, subcontracting, quality and purchasing of materials, testing and releasing materials, undertaking production and quality controls (including in-process controls, sampling and analysis).

7.13. All records related to the outsourced activities, e.g. manufacturing, analytical and distribution records, and reference samples, should be kept by, or be available to, the Contract Giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect or to investigating in the case of a suspected falsified product must be accessible and specified in the relevant procedures of the Contract Giver.

7.14. The contract should permit the Contract Giver to audit outsourced activities, performed by the Contract Acceptor or their mutually agreed subcontractors.

Chapter VIII

COMPLAINTS AND PRODUCT RECALL

Principle

All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures. In order to provide for all contingencies, a system should be designed to recall, if necessary, promptly and effectively products known or suspected to be defective from the market.

Complaints

8.1. A person should be designated responsible for handling the complaints and deciding the measures to be taken together with sufficient supporting staff to assist him. If this person is not the authorised person, the latter should be made aware of any complaint, investigation or recall.

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8.3. Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for Quality Control should normally be involved in the study of such problems.

8.4. If a product defect is discovered or suspected in a batch, consideration should be given to checking other batches in order to determine whether they are also affected. In particular, other batches which may contain reworks of the defective batch should be investigated.

8.5. All the decisions and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records.

8.6. Complaints records should be reviewed regularly for any indication of specific or recurring problems requiring attention and possibly the recall of marketed products.

8.7. Special attention should be given to establishing whether a complaint was caused because of counterfeiting.

8.8. The Competent Authorities should be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, detection of counterfeiting or any other serious quality problems with a product.

Recalls

8.9. A person should be designated as responsible for execution and co-ordination of recalls and should be supported by sufficient staff to handle all the aspects of the recalls with the appropriate degree of urgency. This responsible person should normally be independent of the sales and marketing organisation. If this person is not the authorised person, the latter should be made aware of any recall operation.

8.10. There should be established written procedures, regularly checked and updated when necessary, in order to organise any recall activity.

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8.12. All Competent Authorities of all countries to which products may have been distributed should be informed promptly if products are intended to be recalled because they are, or are suspected of, being defective.

8.13. The distribution records should be readily available to the person(s) responsible for recalls, and should contain sufficient information on wholesalers and directly supplied customers (with addresses, phone and/or fax numbers inside and outside working hours, batches and amounts delivered), including those for exported products and medical samples.

8.14. Recalled products should be identified and stored separately in a secure area while awaiting a decision on their fate.

8.15. The progress of the recall process should be recorded and a final report issued, including a reconciliation between the delivered and recovered quantities of the products.

8.16. The effectiveness of the arrangements for recalls should be evaluated regularly.

Chapter IX

SELF INSPECTION

Principle

Self inspections should be conducted in order to monitor the implementation and compliance with Good Manufacturing Practice principles and to propose necessary corrective measures.

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9.2. Self inspections should be conducted in an independent and detailed way by designated competent person(s) from the company. Independent audits by external experts may also be useful.

9.3. All self inspections should be recorded. Reports should contain all the observations made during the inspections and, where applicable, proposals for corrective measures. Statements on the action subsequently taken should also be recorded.

PART II.

GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS - BASIC REQUIREMENTS FOR APIs

1. Introduction

Objective

This document (Guide) is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the requirements for quality and purity.

In this Guide “manufacturing” includes all operations of receipt of materials, production, packaging, repackaging, labelling, relabelling, quality control, release, storage and distribution of APIs and the related controls. In this Guide the term “should” indicates recommendations that are expected to apply unless shown to be inapplicable, modified in any relevant annexes to the GMP Guide, or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance.

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This Guide is not intended to define registration requirements or modify pharmacopoeial requirements and does not affect the ability of the responsible competent authority to establish specific registration requirements regarding APIs within the context of marketing/manufacturing authorisations. All commitments in registration documents must be met.

1.2. Scope

This Guide applies to the manufacture of APIs for medicinal products for both human and veterinary use. It applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs being rendered sterile. The sterilisation and aseptic processing of sterile APIs are not covered, but should be performed in accordance with the principles and guidelines of GMP as laid down in national legislations and interpreted in the GMP Guide including its Annex 1.

In the case of ectoparasiticides for veterinary use, other standards than this Guide, that ensure that the material is of appropriate quality, may be used.

This Guide excludes whole blood and plasma as the PIC/S GMP Guide for Blood Establishments lays down the detailed requirements for the collection and testing of blood. However, it does include APIs that are produced using blood or plasma as raw materials. Finally, the Guide does not apply to bulk-packaged medicinal products. It applies to all other active starting materials subject to any derogations described in the annexes to the GMP Guide, in particular Annexes 2 to 7 where supplementary guidance for certain types of API may be found. The annexes will consequently undergo a review but in the meantime and only until this review is complete, manufacturers may choose to continue to use Part I of the basic requirements and the relevant annexes for products covered by those annexes, or may already apply Part II.

Section 19 contains guidance that only applies to the manufacture of APIs used in the production of investigational medicinal products although it should be noted that its application in this case, although recommended, is not required in PIC/S countries.

 An “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials normally have defined chemical properties and structure.

An “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials normally have defined chemical properties and structure.

Table 1 gives guidance on the point at which the API Starting Material is normally introduced into the process. From this point on, appropriate GMP as defined in this Guide should be applied to these intermediate and/or API manufacturing steps. This would include the validation of critical process steps determined to impact the quality of the API. However, it should be noted that the fact that a manufacturer chooses to validate a process step does not necessarily define that step as critical.

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This GMP Guide does not apply to steps prior to the introduction of the defined “API Starting Material”.

Table 1. Application of this Guide to API Manufacturing

Type of Manufacturing

Application of this Guide to steps (shown in grey) used in this type of manufacturing

Chemical Manufacturing

Production of the API Starting Material

Introduction of the API Starting Material into process

Production of Intermediate(s)

Isolation and purification

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API derived from animal sources

Collection of organ, fluid, or tissue

Cutting, mixing, and/or initial processing

Introduction of the API Starting Material into process

Isolation and purification

Physical processing, and packaging

API extracted from plant sources

Collection of plant

Cutting and initial extraction(s)

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Isolation and purification

Physical processing, and packaging

Herbal extracts used as API

Collection of plants

Cutting and initial extraction(s)

Further extraction

Physical processing, and packaging

API consisting of comminuted or powdered herbs

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Cutting/ comminuting

Physical processing, and packaging

Biotechnology: fermentation / cell culture

Establishment of master cell bank and working cell bank

Maintenance of working cell bank

Cell culture and/or fermentation

Isolation and purification

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“Classical” Fermentation to produce an API

Establishment of cell bank

Establishment of the cell bank

Introduction of the cells into fermentation

Isolation and purification

Physical processing, and packaging

2. Quality management

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2.10. Quality should be the responsibility of all persons involved in manufacturing.

2.11. Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.

2.12. The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented.

2.13. There should be a quality unit(s) that is independent of production and that fulfils both quality assurance (QA) and quality control (QC) responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

2.14. The persons authorised to release intermediates and APIs should be specified.

2.15. All quality related activities should be recorded at the time they are performed.

2.16. Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.

2.17. No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine as described in Section 10.20 or the use of raw materials or intermediates pending completion of evaluation).

2.18. Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g. quality related complaints, recalls, regulatory actions, etc.).

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2.2. Quality risk management

2.20. Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the active substance. It can be applied both proactively and retrospectively.

2.21. The quality risk management system should ensure that:

- the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient through communication with the user of the active substance.

- the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk.

 Examples of the processes and applications of quality risk management can be found, inter alia, in Annex 20.

2.3. Responsibilities of the Quality Unit(s)

2.30. The quality unit(s) should be involved in all quality-related matters.

2.31. The quality unit(s) should review and approve all appropriate quality-related documents.

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1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the manufacturing company;

2. Establishing a system to release or reject raw materials, intermediates, packaging and labelling materials;

3. Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution;

4. Making sure that critical deviations are investigated and resolved;

5. Approving all specifications and master production instructions;

6. Approving all procedures impacting the quality of intermediates or APIs;

7. Making sure that internal audits (self-inspections) are performed;

8. Approving intermediate and API contract manufacturers;

9. Approving changes that potentially impact intermediate or API quality;

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11. Making sure that quality related complaints are investigated and resolved;

12. Making sure that effective systems are used for maintaining and calibrating critical equipment;

13. Making sure that materials are appropriately tested and the results are reported;

14. Making sure that there is stability data to support retest or expiry dates and storage conditions on APIs and/or intermediates where appropriate;

15. Performing product quality reviews (as defined in Section 2.6).

2.4. Responsibility for Production Activities

The responsibility for production activities should be described in writing, and should include but not necessarily be limited to:

1. Preparing, reviewing, approving and distributing the instructions for the production of intermediates or APIs according to written procedures;

2. Producing APIs and, when appropriate, intermediates according to preapproved instructions;

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4. Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded;

5. Making sure that production facilities are clean and when appropriate disinfected;

6. Making sure that the necessary calibrations are performed and records kept;

7. Making sure that the premises and equipment are maintained and records kept;

8. Making sure that validation protocols and reports are reviewed and approved;

9. Evaluating proposed changes in product, process or equipment; and

10. Making sure that new and, when appropriate, modified facilities and equipment are qualified.

2.5. Internal Audits (Self Inspection)

2.50. In order to verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule.

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2.6. Product quality review

2.60. Regular quality reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least:

- A review of critical in-process control and critical API test results;

- A review of all batches that failed to meet established specification(s);

- A review of all critical deviations or non-conformances and related investigations;

- A review of any changes carried out to the processes or analytical methods;

- A review of results of the stability monitoring program;

- A review of all quality-related returns, complaints and recalls; and

- A review of adequacy of corrective actions.

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3. Personnel

3.1. Personnel Qualifications

3.10. There should be an adequate number of personnel qualified by appropriate education, training and/or experience to perform and supervise the manufacture of intermediates and APIs.

3.11. The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.

3.12. Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee's functions. Records of training should be maintained. Training should be periodically assessed.

3.2. Personnel hygiene

3.20. Personnel should practice good sanitation and health habits.

3.21. Personnel should wear clean clothing suitable for the manufacturing activity with which they are involved and this clothing should be changed when appropriate. Additional protective apparel, such as head, face, hand, and arm coverings, should be worn when necessary, to protect intermediates and APIs from contamination.

3.22. Personnel should avoid direct contact with intermediates or APIs.

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3.24. Personnel suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs. Any person shown at any time (either by medical examination or supervisory observation) to have an apparent illness or open lesions should be excluded from activities where the health condition could adversely affect the quality of the APIs until the condition is corrected or qualified medical personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs.

3.3. Consultants

3.30. Consultants advising on the manufacture and control of intermediates or APIs should have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.

3.31. Records should be maintained stating the name, address, qualifications, and type of service provided by these consultants.

4. Building and facilities

4.1. Design and construction

4.10. Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants as appropriate.

4.11. Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination.

4.12. Where the equipment itself (e.g., closed or contained systems) provides adequate protection of the material, such equipment can be located outdoors.

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4.14. There should be defined areas or other control systems for the following activities:

- Receipt, identification, sampling, and quarantine of incoming materials, pending release or rejection;

- Quarantine before release or rejection of intermediates and APIs;

- Sampling of intermediates and APIs;

- Holding rejected materials before further disposition (e.g., return, reprocessing or destruction);

- Storage of released materials;

- Production operations;

- Packaging and labelling operations; and

- Laboratory operations.

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4.16. Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, in particular those used for in-process controls, can be located in production areas, provided the operations of the production process do not adversely affect the accuracy of the laboratory measurements, and the laboratory and its operations do not adversely affect the production process or intermediate or API.

4.2. Utilities

4.20. All utilities that could impact on product quality (e.g. steam, gases, compressed air, and heating, ventilation and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available.

4.21. Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimise risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be given to areas where APIs are exposed to the environment.

4.22. If air is recirculated to production areas, appropriate measures should be taken to control risks of contamination and cross-contamination.

4.23. Permanently installed pipework should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control systems, or alternative means. Pipework should be located to avoid risks of contamination of the intermediate or API.

4.24. Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when appropriate.

4.3. Water

4.30. Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use.

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4.32. If drinking (potable) water is insufficient to assure API quality, and tighter chemical and/or microbiological water quality specifications are called for, appropriate specifications for physical/chemical attributes, total microbial counts, objectionable organisms and/or endotoxins should be established.

4.33. Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.

4.34. Where the manufacturer of a non-sterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug (medicinal) product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.

4.4. Containment

4.40. Dedicated production areas, which can include facilities, air handling equipment and/or process equipment, should be employed in the production of highly sensitizing materials, such as penicillins or cephalosporins.

4.41. Dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.

4.42. Appropriate measures should be established and implemented to prevent crosscontamination from personnel, materials, etc. moving from one dedicated area to another.

4.43. Any production activities (including weighing, milling, or packaging) of highly toxic non-pharmaceutical materials such as herbicides and pesticides should not be conducted using the buildings and/or equipment being used for the production of APIs. Handling and storage of these highly toxic non-pharmaceutical materials should be separate from APIs.

4.5. Lighting

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4.6. Sewage and refuse

4.60. Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in and from buildings and the immediate surrounding area should be disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified.

4.7. Sanitation and maintenance

4.70. Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.

4.71. Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.

4.72. When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labelling materials, intermediates, and APIs.

5. Process equipment

5.1. Design and construction

5.10. Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitization (where appropriate), and maintenance.

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5.12. Production equipment should only be used within its qualified operating range.

5.13. Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified.

5.14. Any substances associated with the operation of equipment, such as lubricants, heating fluids or coolants, should not contact intermediates or APIs so as to alter their quality beyond the official or other established specifications. Any deviations from this should be evaluated to ensure that there are no detrimental effects upon the fitness for purpose of the material. Wherever possible, food grade lubricants and oils should be used.

5.15. Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.

5.16. A set of current drawings should be maintained for equipment and critical installations (e.g., instrumentation and utility systems).

5.2. Equipment Maintenance and Cleaning

5.20. Schedules and procedures (including assignment of responsibility) should be established for the preventative maintenance of equipment.

5.21. Written procedures should be established for cleaning of equipment and its subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include:

- Assignment of responsibility for cleaning of equipment;

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- A complete description of the methods and materials, including dilution of cleaning agents used to clean equipment;

- When appropriate, instructions for disassembling and reassembling each article of equipment to ensure proper cleaning;

- Instructions for the removal or obliteration of previous batch identification;

- Instructions for the protection of clean equipment from contamination prior to use;

- Inspection of equipment for cleanliness immediately before use, if practical; and

- Establishing the maximum time that may elapse between the completion of processing and equipment cleaning, when appropriate.

5.22. Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.

5.23. Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants (e.g. degradants or objectionable levels of micro-organisms).

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5.25. Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified.

5.26. Equipment should be identified as to its contents and its cleanliness status by appropriate means.

5.3. Calibration

5.30. Control, weighing, measuring, monitoring and test equipment that is critical for assuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule.

5.31. Equipment calibrations should be performed using standards traceable to certified standards, if existing.

5.32. Records of these calibrations should be maintained.

5.33. The current calibration status of critical equipment should be known and verifiable.

5.34. Instruments that do not meet calibration criteria should not be used.

5.35. Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an impact on the quality of the intermediate(s) or API(s) manufactured using this equipment since the last successful calibration.

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5.40. GMP related computerized systems should be validated. The depth and scope of validation depends on the diversity, complexity and criticality of the computerized application.

5.41. Appropriate installation qualification and operational qualification should demonstrate the suitability of computer hardware and software to perform assigned tasks.

5.42. Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at time of installation, a retrospective validation could be conducted if appropriate documentation is available.

5.43. Computerized systems should have sufficient controls to prevent unauthorized access or changes to data. There should be controls to prevent omissions in data (e.g. system turned off and data not captured). There should be a record of any data change made, the previous entry, who made the change, and when the change was made.

5.44. Written procedures should be available for the operation and maintenance of computerized systems.

5.45. Where critical data are being entered manually, there should be an additional check on the accuracy of the entry. This can be done by a second operator or by the system itself.

5.46. Incidents related to computerized systems that could affect the quality of intermediates or APIs or the reliability of records or test results should be recorded and investigated.

5.47. Changes to the computerized system should be made according to a change procedure and should be formally authorized, documented and tested. Records should be kept of all changes, including modifications and enhancements made to the hardware, software and any other critical component of the system. These records should demonstrate that the system is maintained in a validated state.

5.48. If system breakdowns or failures would result in the permanent loss of records, a back-up system should be provided. A means of ensuring data protection should be established for all computerized systems.

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6. Documentation

6.1. Documentation System and Specifications

6.10. All documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved and distributed according to written procedures. Such documents can be in paper or electronic form.

6.11. The issuance, revision, superseding and withdrawal of all documents should be controlled with maintenance of revision histories.

6.12. A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-up reports, technical transfer reports, process validation reports, training records, production records, control records, and distribution records). The retention periods for these documents should be specified.

6.13. All production, control, and distribution records should be retained for at least 1 year after the expiry date of the batch. For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed.

6.14. When entries are made in records, these should be made indelibly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry. Corrections to entries should be dated and signed and leave the original entry still readable.

6.15. During the retention period, originals or copies of records should be readily available at the establishment where the activities described in such records occurred. Records that can be promptly retrieved from another location by electronic or other means are acceptable.

6.16. Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are used, suitable retrieval equipment and a means to produce a hard copy should be readily available.

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6.18. If electronic signatures are used on documents, they should be authenticated and secure.

6.2. Equipment Cleaning and Use Record

6.20. Records of major equipment use, cleaning, sanitization and/or sterilization and maintenance should show the date, time (if appropriate), product, and batch number of each batch processed in the equipment, and the person who performed the cleaning and maintenance.

6.21. If equipment is dedicated to manufacturing one intermediate or API, then individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately.

6.3. Records of Raw Materials, Intermediates, API Labelling and Packaging Materials

6.30. Records should be maintained including:

- The name of the manufacturer, identity and quantity of each shipment of each batch of raw materials, intermediates or labelling and packaging materials for API's; the name of the supplier; the supplier's control number(s), if known, or other identification number; the number allocated on receipt; and the date of receipt;

- The results of any test or examination performed and the conclusions derived from this;

- Records tracing the use of materials;

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- The final decision regarding rejected raw materials, intermediates or API labelling and packaging materials.

- 6.31. Master (approved) labels should be maintained for comparison to issued labels.

6.4. Master Production Instructions (Master Production and Control Records)

6.40. To ensure uniformity from batch to batch, master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit(s).

6.41. Master production instructions should include:

► The name of the intermediate or API being manufactured and an identifying document reference code, if applicable;

► A complete list of raw materials and intermediates designated by names or codes sufficiently specific to identify any special quality characteristics;

► An accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unit of measure. Where the quantity is not fixed, the calculation for each batch size or rate of production should be included. Variations to quantities should be provided they are justified;

► The production location and major production equipment to be used;

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- sequences to be followed,

- ranges of process parameters to be used,

- sampling instructions and in-process controls with their acceptance criteria, where appropriate,

- time limits for completion of individual processing steps and/or the total process, where appropriate; and

- expected yield ranges at appropriate phases of processing or time;

► Where appropriate, special notations and precautions to be followed, or cross-references to these; and

► The instructions for storage of the intermediate or API to assure its suitability for use, including the labelling and packaging materials and special storage conditions with time limits, where appropriate.

6.5. Batch Production Records

6.50. Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to assure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction. If the batch production record is produced from a separate part of the master document, that document should include a reference to the current master production instruction being used.

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6.52. Documentation of completion of each significant step in the batch production

- Dates and, when appropriate, times;

- Identity of major equipment (e.g., reactors, driers, mills, etc.) used;

- Specific identification of each batch, including weights, measures, and batch numbers of raw materials, intermediates, or any reprocessed materials used during manufacturing;

- Actual results recorded for critical process parameters;

- Any sampling performed;

- Signatures of the persons performing and directly supervising or checking each critical step in the operation;

- In-process and laboratory test results;

- Actual yield at appropriate phases or times;

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- Representative label of API or intermediate if made commercially available;

- Any deviation noted, its evaluation, investigation conducted (if appropriate) or reference to that investigation if stored separately; and

- Results of release testing.

6.53. Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.

6.6. Laboratory Control Records

6.60. Laboratory control records should include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays, as follows:

- A description of samples received for testing, including the material name or source, batch number or other distinctive code, date sample was taken, and, where appropriate, the quantity and date the sample was received for testing;

- A statement of or reference to each test method used;

- A statement of the weight or measure of sample used for each test as described by the method; data on or cross-reference to the preparation and testing of reference standards, reagents and standard solutions;

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- A record of all calculations performed in connection with the test, including, for example, units of measure, conversion factors, and equivalency factors;

- A statement of the test results and how they compare with established acceptance criteria;

- The signature of the person who performed each test and the date(s) the tests were performed; and

- The date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

6.61. Complete records should also be maintained for:

- Any modifications to an established analytical method;

- Periodic calibration of laboratory instruments, apparatus, gauges, and recording devices;

- All stability testing performed on APIs; and

- Out-of-specification (OOS) investigations.

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6.70. Written procedures should be established and followed for the review and approval of batch production and laboratory control records, including packaging and labelling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed.

6.71. Batch production and laboratory control records of critical process steps should be reviewed and approved by the quality unit(s) before an API batch is released or distributed. Production and laboratory control records of non-critical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit(s).6.72. All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released.

6.73. The quality unit(s) can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company.

7. Materials management

7.1. General Controls

7.10. There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

7.11. Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials.

7.12. Materials should be purchased against an agreed specification, from a supplier or suppliers approved by the quality unit(s).

7.13. If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.

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7.2. Receipt and Quarantine

7.20. Upon receipt and before acceptance, each container or grouping of containers of materials should be examined visually for correct labelling (including correlation between the name used by the supplier and the in-house name, if these are different), container damage, broken seals and evidence of tampering or contamination. Materials should be held under quarantine until they have been sampled, examined or tested as appropriate, and released for use.

7.21. Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in silos), they should be identified as correct, tested, if appropriate, and released. Procedures should be available to prevent discharging incoming materials wrongly into the existing stock.

7.22. If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross-contamination from the tanker. Means of providing this assurance could include one or more of the following:

- certificate of cleaning

- testing for trace impurities

- audit of the supplier.

7.23. Large storage containers, and their attendant manifolds, filling and discharge lines should be appropriately identified.

7.24. Each container or grouping of containers (batches) of materials should be assigned and identified with a distinctive code, batch, or receipt number. This number should be used in recording the disposition of each batch. A system should be in place to identify the status of each batch.

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7.30. At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described below in 7.32. A supplier's Certificate of Analysis can be used in place of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers.

7.31. Supplier approval should include an evaluation that provides adequate evidence (e.g., past quality history) that the manufacturer can consistently provide material meeting specifications. Full analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a full analysis should be performed at appropriate intervals and compared with the Certificates of Analysis. Reliability of Certificates of Analysis should be checked at regular intervals.

7.32. Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company’s control do not need to be tested if the manufacturer’s Certificate of Analysis is obtained, showing that these raw materials conform to established specifications. Visual examination of containers, labels, and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented.

7.33. Samples should be representative of the batch of material from which they are taken. Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based upon a sampling plan that takes into consideration the criticality of the material, material variability, past quality history of the supplier, and the quantity needed for analysis.

7.34. Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.

7.35. Containers from which samples are withdrawn should be opened carefully and subsequently reclosed. They should be marked to indicate that a sample has been taken.

7.4. Storage

7.40. Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination.

7.41. Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection.

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7.43. Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use.

7.44. Rejected materials should be identified and controlled under a quarantine system designed to prevent their unauthorised use in manufacturing.

7.5. Re-evaluation

7.50. Materials should be re-evaluated as appropriate to determine their suitability for use (e.g., after prolonged storage or exposure to heat or humidity).

8. Production and in-process controls

8.1. Production operations

8.10. Raw materials for intermediate and API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use. Weighing and measuring devices should be of suitable accuracy for the intended use.

8.11. If a material is subdivided for later use in production operations, the container receiving the material should be suitable and should be so identified that the following information is available:

- Material name and/or item code;

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- Weight or measure of material in the new container; and

- Re-evaluation or retest date if appropriate.

8.12. Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Prior to use, production personnel should verify that the materials are those specified in the batch record for the intended intermediate or API.

8.13. Other critical activities should be witnessed or subjected to an equivalent control.

8.14. Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data. Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.

8.15. Any deviation should be documented and explained. Any critical deviation should be investigated.

8.16. The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means.

8.17. Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.

8.2. Time Limits

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8.21. Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use.

8.3. In-process Sampling and Controls

8.30. Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the development stage or historical data.

8.31. The acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product’s quality. Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps (e.g., isolation and purification steps).

8.32. Critical in-process controls (and critical process monitoring), including the control points and methods, should be stated in writing and approved by the quality unit(s).

8.33. In-process controls can be performed by qualified production department personnel and the process adjusted without prior quality unit(s) approval if the adjustments are made within pre-established limits approved by the quality unit(s). All tests and results should be fully documented as part of the batch record.

8.34. Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs. Sampling plans and procedures should be based on scientifically sound sampling practices.

8.35. In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other intermediates or APIs. Procedures should be established to ensure the integrity of samples after collection.

8.36. Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.

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8.40. For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part of the production process and is not considered to be blending.

8.41. Out-Of-Specification batches should not be blended with other batches for the purpose of meeting specifications. Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.

8.42. Acceptable blending operations include but are not limited to:

- Blending of small batches to increase batch size;

- Blending of tailings (i.e., relatively small quantities of isolated material) from batches of the same intermediate or API to form a single batch;

8.43. Blending processes should be adequately controlled and documented and the blended batch should be tested for conformance to established specifications where appropriate.

8.44. The batch record of the blending process should allow traceability back to the individual batches that make up the blend.

8.45. Where physical attributes of the API are critical (e.g., APIs intended for use in solid oral dosage forms or suspensions), blending operations should be validated to show homogeneity of the combined batch. Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and tap density) that may be affected by the blending process.

8.46. If the blending could adversely affect stability, stability testing of the final blended batches should be performed.

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8.5. Contamination Control

8.50. Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile.

8.51. Production operations should be conducted in a manner that will prevent contamination of intermediates or APIs by other materials.

8.52. Precautions to avoid contamination should be taken when APIs are handled after purification.

9. Packaging and identification labelling of APIs and intermediates

9.1. General

9.10. There should be written procedures describing the receipt, identification, quarantine, sampling, examination and/or testing and release, and handling of packaging and labelling materials.

9.11. Packaging and labelling materials should conform to established specifications. Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable.

9.12. Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.

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9.20. Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and recommended storage.

9.21. Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use. These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the specified limits.

9.22. If containers are re-used, they should be cleaned in accordance with documented procedures and all previous labels should be removed or defaced.

9.3. Label Issuance and Control

9.30. Access to the label storage areas should be limited to authorised personnel.

9.31. Procedures should be used to reconcile the quantities of labels issued, used, and returned and to evaluate discrepancies found between the number of containers labelled and the number of labels issued. Such discrepancies should be investigated, and the investigation should be approved by the quality unit(s).

9.32. All excess labels bearing batch numbers or other batch-related printing should be destroyed. Returned labels should be maintained and stored in a manner that prevents mix-ups and provides proper identification.

9.33. Obsolete and out-dated labels should be destroyed.

9.34. Printing devices used to print labels for packaging operations should be controlled to ensure that all imprinting conforms to the print specified in the batch production record.

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9.36. A printed label representative of those used should be included in the batch production record.

9.4. Packaging and Labelling Operations

9.40. There should be documented procedures designed to ensure that correct packaging materials and labels are used.

9.41. Labelling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs.

9.42. Labels used on containers of intermediates or APIs should indicate the name or identifying code, the batch number of the product, and storage conditions, when such information is critical to assure the quality of intermediate or API.

9.43. If the intermediate or API is intended to be transferred outside the control of the manufacturer’s material management system, the name and address of the manufacturer, quantity of contents, and special transport conditions and any special legal requirements should also be included on the label. For intermediates or APIs with an expiry date, the expiry date should be indicated on the label and Certificate of Analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or Certificate of Analysis.

9.44. Packaging and labelling facilities should be inspected immediately before use to ensure that all materials not needed for the next packaging operation have been removed. This examination should be documented in the batch production records, the facility log, or other documentation system.

9.45. Packaged and labelled intermediates or APIs should be examined to ensure that containers and packages in the batch have the correct label. This examination should be part of the packaging operation. Results of these examinations should be recorded in the batch production or control records.

9.46. Intermediate or API containers that are transported outside of the manufacturer's control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered.

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10.1. Warehousing Procedures

10.10. Facilities should be available for the storage of all materials under appropriate conditions (e.g. controlled temperature and humidity when necessary). Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.

10.11. Unless there is an alternative system to prevent the unintentional or unauthorised use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision as to their future use has been taken.

10.2. Distribution Procedures

10.20. APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit(s). APIs and intermediates can be transferred under quarantine to another unit under the company’s control when authorized by the quality unit(s) and if appropriate controls and documentation are in place.

10.21. APIs and intermediates should be transported in a manner that does not adversely affect their quality.

10.22. Special transport or storage conditions for an API or intermediate should be stated on the label.

10.23. The manufacturer should ensure that the contract acceptor (contractor) for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.

10.24. A system should be in place by which the distribution of each batch of intermediate and/or API can be readily determined to permit its recall.

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11.1. General Controls

11.10. The independent quality unit(s) should have at its disposal adequate laboratory facilities.

11.11. There should be documented procedures describing sampling, testing, approval or rejection of materials, and recording and storage of laboratory data. Laboratory records should be maintained in accordance with Section 6.6.11.12. All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit(s).

11.13. Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include a control of the impurities (e.g. organic impurities, inorganic impurities, and residual solvents). If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met.

11.14. Laboratory controls should be followed and documented at the time of performance. Any departures from the above described procedures should be documented and explained.

11.15. Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should require analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any resampling and/or retesting after OOS results should be performed according to a documented procedure.

11.16. Reagents and standard solutions should be prepared and labelled following written procedures. “Use by” dates should be applied as appropriate for analytical reagents or standard solutions.

11.17. Primary reference standards should be obtained as appropriate for the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognised source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.11.18. Where a primary reference standard is not available from an officially recognized source, an “in-house primary standard” should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.

11.19. Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol.

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11.20. For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.

11.21. An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the identity or some qualitative analytical designation (e.g. retention time), the range of each impurity observed, and classification of each identified impurity (e.g. inorganic, organic, solvent). The impurity profile is normally dependent upon the production process and origin of the API. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH Guideline Q6B.

11.22. The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data in order to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.

11.23. Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.

11.3. Validation of Analytical Procedures - see Section 12

11.4. Certificates of Analysis

11.40. Authentic Certificates of Analysis should be issued for each batch of intermediate or API on request.

11.41. Information on the name of the intermediate or API including where appropriate its grade, the batch number, and the date of release should be provided on the Certificate of Analysis. For intermediates or APIs with an expiry date, the expiry date should be provided on the label and Certificate of Analysis. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or Certificate of Analysis.

11.42. The Certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained (if test results are numerical).

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11.44. If new Certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these Certificates should show the name, address and telephone number of the laboratory that performed the analysis. They should also contain a reference to the name and address of the original manufacturer and to the original batch Certificate, a copy of which should be attached.

11.5. Stability Monitoring of APIs

11.50. A documented, on-going testing program should be designed to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.

11.51. The test procedures used in stability testing should be validated and be stability indicating.

11.52. Stability samples should be stored in containers that simulate the market container. For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in smaller-scale drums of similar or identical material composition to the market drums.

11.53. Normally the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. However, where data from previous studies show that the API is expected to remain stable for at least two years, fewer than three batches can be used.

11.54. Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.

11.55. For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first three months, and at three month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g. 9 month testing) can be considered.

11.56. Where appropriate, the stability storage conditions should be consistent with the ICH guidelines on stability.

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11.60. When an intermediate is intended to be transferred outside the control of the manufacturer’s material management system and an expiry or retest date is assigned, supporting stability information should be available (e.g. published data, test results).

11.61. An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date.

11.62. Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale; and (2) the quality of the API represents the material to be made on a commercial scale.

11.63. A representative sample should be taken for the purpose of performing a retest

11.7. Reserve/Retention Samples

11.70. The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.

11.71. Appropriately identified reserve samples of each API batch should be retained for one year after the expiry date of the batch assigned by the manufacturer, or for three years after distribution of the batch, whichever is the longer. For APIs with retest dates, similar reserve samples should be retained for three years after the batch is completely distributed by the manufacturer.

11.72. The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system. Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses.

12. Validation

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12.10. The company's overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval and documentation of each validation phase, should be documented.

12.11. The critical parameters/attributes should normally be identified during the development stage or from historical data, and the ranges necessary for the reproducible operation should be defined. This should include:

- Defining the API in terms of its critical product attributes;

- Identifying process parameters that could affect the critical quality attributes of the API;

- Determining the range for each critical process parameter expected to be used during routine manufacturing and process control.

12.12. Validation should extend to those operations determined to be critical to the quality and purity of the API.

12.2. Validation Documentation

12.20. A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units.

12.21. The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g. retrospective, prospective, concurrent) and the number of process runs.

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12.23. Any variations from the validation protocol should be documented with appropriate justification.

12.3. Qualification

12.30. Before starting process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:

- Design Qualification (DQ): documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose.

- Installation Qualification (IQ): documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or user requirements.

- Operational Qualification (OQ): documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges.

- Performance Qualification (PQ): documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications.

12.4. Approaches to Process Validation

12.40. Process Validation (PV) is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.

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12.42. Prospective validation should normally be performed for all API processes as defined in 12.12. Prospective validation performed on an API process should be completed before the commercial distribution of the final drug product manufactured from that API.

12.43. Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.

12.44. An exception can be made for retrospective validation for well established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:

1) Critical quality attributes and critical process parameters have been identified;

2) Appropriate in-process acceptance criteria and controls have been established;

3) There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability; and

4) Impurity profiles have been established for the existing API.

12.45. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Retained samples can be tested to obtain data to retrospectively validate the process.

12.5. Process Validation Program

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12.51. Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.

12.52. Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to or better than historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.

12.6. Periodic Review of Validated Systems

12.60. Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.

12.7. Cleaning Validation

12.70. Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality. For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps.

12.71. Validation of cleaning procedures should reflect actual equipment usage patterns. If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.

12.72. The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples to be obtained and how they are collected and labelled.

12.73. Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).

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12.75. Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g., non-sterile APIs used to manufacture sterile products).

12.76. Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production. Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.

12.8. Validation of Analytical Methods

12.80. Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognised standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented.

12.81. Methods should be validated to include consideration of characteristics included within the ICH guidelines on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

12.82. Appropriate qualification of analytical equipment should be considered before starting validation of analytical methods.

Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.

13. Change control

13.10. A formal change control system should be established to evaluate all changes that may affect the production and control of the intermediate or API.

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13.12. Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organisational units, and reviewed and approved by the quality unit(s).

13.13. The potential impact of the proposed change on the quality of the intermediate or API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g. as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgement should determine what additional testing and validation studies are appropriate to justify a change in a validated process.

13.14. When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.

13.15. After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.

13.16. The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.

13.17. Current dosage form manufacturers should be notified of changes from established production and process control procedures that can impact the quality of the API.

14. Rejection and re-use of materials

14.1. Rejection

14.10. Intermediates and APIs failing to meet established specifications should be identified as such and quarantined. These intermediates or APIs can be reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.

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14.20. Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.

14.21. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing.

14.22. Introducing unreacted material back into a process and repeating a chemical reaction is considered to be reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful evaluation to ensure that the quality of the intermediate or API is not adversely impacted due to the potential formation of by-products and over-reacted materials.

14.3. Reworking

14.30. Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for non-conformance should be performed.

14.31. Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is often the appropriate validation approach for rework procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, then a report can be written and the batch released once it is found to be acceptable.

14.32. Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.

14.4. Recovery of Materials and Solvents

14.40. Recovery (e.g. from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.

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14.42. Fresh and recovered solvents and reagents can be combined if adequate testing has shown their suitability for all manufacturing processes in which they may be used.

14.43. The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.

14.5. Returns

14.50. Returned intermediates or APIs should be identified as such and quarantined.

14.51. If the conditions under which returned intermediates or APIs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned intermediates or APIs should be reprocessed, reworked, or destroyed, as appropriate.

14.52. Records of returned intermediates or APIs should be maintained.  For each return, documentation should include:

- Name and address of the consignee

- Intermediate or API, batch number, and quantity returned

- Reason for return

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15. Complaints and recalls

15.10. All quality related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.

15.11. Complaint records should include:

- Name and address of complainant;

- Name (and, where appropriate, title) and phone number of person submitting the complaint;

- Complaint nature (including name and batch number of the API);

- Date complaint is received;

- Action initially taken (including dates and identity of person taking the action);

- Any follow-up action taken;

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- Final decision on intermediate or API batch or lot.

15.12. Records of complaints should be retained in order to evaluate trends, product related frequencies, and severity with a view to taking additional, and if appropriate, immediate corrective action.

15.13. There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.

15.14. The recall procedure should designate who should be involved in evaluating the information, how a recall should be initiated, who should be informed about the recall, and how the recalled material should be treated.

15.15. In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.

16. Contract manufacturers (including laboratories)

16.10. All contract manufacturers (including laboratories) should comply with the GMP defined in this Guide. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.

16.11. Contract manufacturers (including laboratories) should be evaluated by the contract giver to ensure GMP compliance of the specific operations occurring at the contract sites.

16.12. There should be a written and approved contract or formal agreement between the contract giver and the contract acceptor that defines in detail the GMP responsibilities, including the quality measures, of each party.

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16.14. Where subcontracting is allowed, the contract acceptor should not pass to a third party any of the work entrusted to him under the contract without the contract giver's prior evaluation and approval of the arrangements.

16.15. Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.

16.16. Changes in the process, equipment, test methods, specifications, or other contractual requirements should not be made unless the contract giver is informed and approves the changes.

17. Agents, brokers, traders, distributors, repackers and relabellers

17.1. Applicability

17.10. This section applies to any party other than the original manufacturer who may trade and/or take possession, repack, relabel, manipulate, distribute or store an API or intermediate.

17.11. All agents, brokers, traders, distributors, repackers, and relabellers should comply with GMP as defined in this Guide.

17.2. Traceability of Distributed APIs and Intermediates

17.20. Agents, brokers, traders, distributors, repackers, or relabellers should maintain complete traceability of APIs and intermediates that they distribute. Documents that should be retained and available include: Documents that should be retained and available include:

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- Address of original manufacturer

- Purchase orders

- Bills of lading (transportation documentation)

- Receipt documents

- Name or designation of API or intermediate

- Manufacturer’s batch number

- Transportation and distribution records

- All authentic Certificates of Analysis, including those of the original manufacturer

- Retest or expiry date

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17.30. Agents, brokers, traders, distributors, repackers, or relabellers should establish, document and implement an effective system of managing quality, as specified in Section 2.

17.4. Repackaging, Relabelling and Holding of APIs and Intermediates

17.40. Repackaging, relabelling and holding of APIs and intermediates should be performed under appropriate GMP controls, as stipulated in this Guide, to avoid mix-ups and loss of API or intermediate identity or purity.

17.41. Repackaging should be conducted under appropriate environmental conditions to avoid contamination and cross-contamination.

17.5. Stability

17.50. Stability studies to justify assigned expiration or retest dates should be conducted if the API or intermediate is repackaged in a different type of container than that used by the API or intermediate manufacturer.

17.6. Transfer of Information

17.60. Agents, brokers, distributors, repackers, or relabellers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.

17.61. Agents, brokers, distributors, repackers, or relabellers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.

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17.7. Handling of Complaints and Recalls

17.70. Agents, brokers, traders, distributors, repackers, or relabellers should maintain records of complaints and recalls, as specified in Section 15, for all complaints and recalls that come to their attention.

17.71. If the situation warrants, the agents, brokers, traders, distributors, repackers, or relabellers should review the complaint with the original API or intermediate manufacturer in order to determine whether any further action, either with other customers who may have received this API or intermediate or with the regulatory authority, or both, should be initiated. The investigation into the cause for the complaint or recall should be conducted and documented by the appropriate party.17.72. Where a complaint is referred to the original API or intermediate manufacturer, the record maintained by the agents, brokers, traders, distributors, repackers, or relabellers should include any response received from the original API or intermediate manufacturer (including date and information provided).

17.8. Handling of Returns

17.80. Returns should be handled as specified in Section 14.52. The agents, brokers, traders, distributors, repackers, or relabellers should maintain documentation of returned APIs and intermediates.

18. Specific guidance for APIs manufactured by cell culture/fermentation

18.1. General

18.10. Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms and that have not been covered adequately in the previous sections. It is not intended to be a stand-alone Section. In general, the GMP principles in the other sections of this document apply. Note that the principles of fermentation for “classical” processes for production of small molecules and for processes using recombinant and non-recombinant organisms for production of proteins and/or polypeptides are the same, although the degree of control will differ. Where practical, this section will address these differences. In general, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.

18.11. The term “biotechnological process” (biotech) refers to the use of cells or organisms that have been generated or modified by recombinant DNA, hybridoma or other technology to produce APIs. The APIs produced by biotechnological processes normally consist of high molecular weight substances, such as proteins and polypeptides, for which specific guidance is given in this Section. Certain APIs of low molecular weight, such as antibiotics, amino acids, vitamins, and carbohydrates, can also be produced by recombinant DNA technology. The level of control for these types of APIs is similar to that employed for classical fermentation.

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18.13. Production of APIs or intermediates from cell culture or fermentation involves biological processes such as cultivation of cells or extraction and purification of material from living organisms. Note that there may be additional process steps, such as physicochemical modification, that are part of the manufacturing process. The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary.

18.14. Appropriate controls should be established at all stages of manufacturing to assure intermediate and/or API quality. While this Guide starts at the cell culture/fermentation step, prior steps (e.g. cell banking) should be performed under appropriate process controls. This Guide covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use in manufacturing.

18.15. Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems).

18.16. In general, process controls should take into account:

-  Maintenance of the Working Cell Bank (where appropriate);

-  Proper inoculation and expansion of the culture;

- Control of the critical operating parameters during fermentation/cell culture;

-  Monitoring of the process for cell growth, viability (for most cell culture processes) and productivity where appropriate;

- Harvest and purification procedures that remove cells, cellular debris and media components while protecting the intermediate or API from contamination (particularly of a microbiological nature) and from loss of quality;

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- Viral safety concerns as described in ICH Guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin.

18.17. Where appropriate, the removal of media components, host cell proteins, other process-related impurities, product-related impurities and contaminants should be demonstrated.

18.2. Cell Bank Maintenance and Record Keeping

18.20. Access to cell banks should be limited to authorized personnel.

18.21. Cell banks should be maintained under storage conditions designed to maintain viability and prevent contamination.

18.22. Records of the use of the vials from the cell banks and storage conditions should be maintained.

18.23. Where appropriate, cell banks should be periodically monitored to determine suitability for use.

18.24. See ICH Guideline Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion of cell banking.

18.3. Cell Culture/Fermentation

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18.31. Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.

18.32. Personnel should be appropriately gowned and take special precautions handling the cultures.

18.33. Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) should be monitored to ensure consistency with the established process. Cell growth, viability (for most cell culture processes), and, where appropriate, productivity should also be monitored. Critical parameters will vary from one process to another, and for classical fermentation, certain parameters (cell viability, for example) may not need to be monitored.

18.34. Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, and sanitized or sterilized.

18.35. Culture media should be sterilized before use when appropriate to protect the quality of the API.

18.36. There should be appropriate procedures in place to detect contamination and determine the course of action to be taken. This should include procedures to determine the impact of the contamination on the product and those to decontaminate the equipment and return it to a condition to be used in subsequent batches. Foreign organisms observed during fermentation processes should be identified as appropriate and the effect of their presence on product quality should be assessed, if necessary. The results of such assessments should be taken into consideration in the disposition of the material produced.

18.37. Records of contamination events should be maintained.

18.38. Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of crosscontamination.

18.4. Harvesting, Isolation and Purification

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18.41. Harvest and purification procedures that remove or inactivate the producing organism, cellular debris and media components (while minimizing degradation, contamination, and loss of quality) should be adequate to ensure that the intermediate or API is recovered with consistent quality.

18.42. All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.

18.43. If open systems are used, purification should be performed under environmental conditions appropriate for the preservation of product quality.

18.44. Additional controls, such as the use of dedicated chromatography resins or additional testing, may be appropriate if equipment is to be used for multiple products.

18.5. Viral Removal/Inactivation Steps

18.50. See the ICH Guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin for more specific information.

18.51. Viral removal and viral inactivation steps are critical processing steps for some processes and should be performed within their validated parameters.

18.52. Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.

18.53. The same equipment is not normally used for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.

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19.1. General

19.10. Not all the controls in the previous sections of this Guide are appropriate for the manufacture of a new API for investigational use during its development. Section 19 provides specific guidance unique to these circumstances.

19.11. The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.

19.2. Quality

19.20. Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a suitable mechanism of approval of each batch.

19.21. A quality unit(s) independent from production should be established for the approval or rejection of each batch of API for use in clinical trials.

19.22. Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.

19.23. Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.

19.24. Process and quality problems should be evaluated.

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19.3. Equipment and Facilities

19.30. During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.

19.31. Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.

19.4. Control of Raw Materials

19.40. Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier’s analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.

19.41. In some instances, the suitability of a raw material can be determined before use based on acceptability in small-scale reactions (i.e., use testing) rather than on analytical testing alone.

19.5. Production

19.50. The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.

19.51. Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.

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19.60. Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a single API batch is produced or where process changes during API development make batch replication difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment qualification assures API quality during this development phase.

19.61. Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.

19.7. Changes

19.70. Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded.

19.8. Laboratory Controls

19.80. While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound.

19.81. A system for retaining reserve samples of all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application.

19.82. Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.19.9. Documentation

19.90. A system should be in place to ensure that information gained during the development and the manufacture of APIs for use in clinical trials is documented and available.

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19.92. A system for retaining production and control records and documents should be used. This system should ensure that records and documents are retained for an appropriate length of time after the approval, termination, or discontinuation of an application.

20. Glossary

Acceptance Criteria

Numerical limits, ranges, or other suitable measures for acceptance of test results.

Active Pharmaceutical Ingredient (API) (or Drug Substance)

Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.

API Starting Material

A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API Starting Materials are normally of defined chemical properties and structure.

Batch (or Lot)

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Batch Number (or Lot Number)

A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.

Bioburden

The level and type (e.g. objectionable or not) of micro-organisms that can be present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be considered contamination unless the levels have been exceeded or defined objectionable organisms have been detected.

Calibration

The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements.

Computer system

A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions.

Computerized system

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Contamination

The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging or repackaging, storage or transport.

Contract manufacturer

A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer.

Critical

Describes a process step, process condition, test requirement, or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the API meets its specification.

Cross-Contamination

Contamination of a material or product with another material or product.

Deviation

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Drug (Medicinal) Product

The dosage form in the final immediate packaging intended for marketing. (Reference Q1A)

Drug Substance

See Active Pharmaceutical Ingredient.

Expiry Date (or Expiration Date)

The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf life specifications if stored under defined conditions, and after which it should not be used.

Impurity

Any component present in the intermediate or API that is not the desired entity.

Impurity Profile

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In-Process Control (or Process Control)

Checks performed during production in order to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API conforms to its specifications.

Intermediate

A material produced during steps of the processing of an API that undergoes further molecular change or purification before it becomes an API. Intermediates may or may not be isolated. (Note: this Guide only addresses those intermediates produced after the point that the company has defined as the point at which the production of the API begins.)

Lot

See Batch.

Lot Number

See Batch Number.

Manufacture

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Material

A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, APIs and packaging and labelling materials.

Mother Liquor

The residual liquid which remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the API and/or impurities. It may be used for further processing.

Packaging Material

Any material intended to protect an intermediate or API during storage and transport.

Procedure

A documented description of the operations to be performed, the precautions to be taken and measures to be applied directly or indirectly related to the manufacture of an intermediate or API.

Process Aids

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Process Control

See In-Process Control.

Production

All operations involved in the preparation of an API from receipt of materials through processing and packaging of the API.

Qualification

Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.

Quality Assurance (QA)

The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.

Laboratory control

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Quality Unit(s)

An organizational unit independent of production which fulfils both Quality Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

Quarantine

The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.

Raw Material

A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.

Reference Standard, Primary

A substance that has been shown by an extensive set of analytical tests to be authentic material that should be of high purity. This standard can be: (1) obtained from an officially recognised source, or (2) prepared by independent synthesis, or (3) obtained from existing production material of high purity, or (4) prepared by further purification of existing production material.

Reference Standard, Secondary

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Reprocessing

Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process. Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process, and not reprocessing.

Retest Date

The date when a material should be re-examined to ensure that it is still suitable for use.

Reworking

Subjecting an intermediate or API that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with a different solvent).

Signature (signed)

See definition for signed.

Signed (signature)

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Solvent

An inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacture of an intermediate or API.

Specification

A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. “Conformance to specification” means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

Validation

A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria.

Validation Protocol

A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters/operating ranges, product characteristics, sampling, test data to be collected, number of validation runs, and acceptable test results.

Yield, Expected

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Yield, Theoretical

The quantity that would be produced at any appropriate phase of production, based upon the quantity of material to be used, in the absence of any loss or error in actual production.

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