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THE
MINISTRY OF HEALTH
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THE
SOCIALIST REPUBLIC OF VIETNAM
Independence - Freedom - Happiness
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No.
35/2018/TT-BYT
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Hanoi,
November 22, 2018
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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.
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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
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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.
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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,
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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
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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.