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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. 13/VBHN-BYT
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Hanoi, November 02, 2023
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CIRCULAR
GUIDELINES ON GOOD MANUFACTURING PRACTICES (GMP) FOR HEALTH
SUPPLEMENTS
The Circular No.
18/2019/TT-BYT dated July 17, 2019 of the Minister of Health on guidelines on
Good Manufacturing Practices (GMP) for health supplements, which has been
effective since July 17, 2019, is amended by:
The Circular No.
17/2023/TT-BYT dated September 25, 2023 of the Minister of Health on amendments
to and annulment of certain legislative documents on food safety promulgated by
the Minister of Health, which has been effective since November 09, 2023.
Pursuant to the Law on
Food Safety dated June 17, 2010;
Pursuant to the
Government’s Decree No. 15/2018/ND-CP dated February 02, 2018 on elaboration of
some Articles of the Law on Food Safety;
Pursuant to the
Government’s Decree No. 75/2017/ND-CP dated June 20, 2017 defining the
functions, tasks, powers and organizational structure of the Ministry of
Health;
At the request of the
Director of the Vietnam Food Administration;
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Article
1. Scope
This Circular provides
for:
1. Principles and
requirements of Good Manufacturing Practices (GMP) for health supplements and
application of GMP by domestic manufacturers of health supplements.
2. Certificates
equivalent to the Certificate of compliance with GMP for imported health
supplements.
Article
2. Regulated entities
This Circular applies to
organizations and individuals that manufacture or sell health supplements in
Vietnam and other relevant organizations and individuals.
Article
3. Principles and requirements of GMP for health supplements and application of
GMP by domestic manufacturers of health supplements
1. Domestic manufacturers
of health supplements shall satisfy food safety conditions specified in Clause
1 Article 28 of the Government’s Decree No. 15/2018/ND-CP dated February 02,
2018 on elaboration of some Articles of the Law on Food Safety and the
following principles and requirements of GMP for health supplements:
a) Health supplements are
manufactured in such a way 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. To achieve the quality
objective reliably, there must be a comprehensively designed and correctly
implemented system of quality assurance incorporating GMP and quality control.
It should be fully documented and its effectiveness monitored. All parts of the
quality assurance system should be adequately staffed with competent personnel,
and should have suitable and sufficient premises, equipment, and facilities;
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c) Premises and
manufacturing equipment must be located, designed, constructed, adapted and
maintained to suit the operations to be carried out. The layout and design of
premises 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;
d) A high level of
sanitation and hygiene should be practiced in every aspect of the manufacture
of health supplements. The scope of sanitation and hygiene covers personnel,
premises, equipment and apparatus, products for cleaning and disinfection, and
anything that could become a source of contamination to the product;
dd) Every manufacturer
should establish a system of clearly written documentation that consists of
procedures, standards, manufacturing formulae, processing and packaging
instructions, is able to record executed activities for manufacturing, quality
control, distribution and other matters linked to GMP, and permits tracing of
batch history of the product, from receiving of starting materials to the
distribution of finished products.
e) There must be an
authorized manufacturing process existing for each product, including detailed
regulations on manufacturing and quality control, with the objective of
obtaining a product of the requisite quality, consistent with the approved
specifications. Executed activities for each batch should be sufficiently and
clearly documented and retained as prescribed;
g) Every manufacturer
should have a quality control system so designed as to ensure that the
production and the quality control departments are independent of each other
and that the products are manufactured in accordance with adequate conditions
and procedures and continue to meet the established specifications;
h) If a product is
manufactured and/or analyzed under a contract, the contract manufacture and/or
analysis must be correctly defined, agreed and controlled. The contract must
clearly establish the duties and responsibilities of each party and clearly
state the way in which the authorized person releasing each batch of product
for sale exercises his full responsibility.
i) All complaints and
other information concerning potentially defective products must be kept and
reviewed according to written procedures. A system shall be designed to recall
promptly and effectively products known or suspected to be defective from the
market.
k) Self-inspections shall
be conducted in order to monitor the implementation and compliance with Good
Manufacturing Practice principles and to propose necessary corrective measures.
l) Detailed contents of
GMP for health supplements are provide in the Appendix hereof.
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3. Any manufacturer of
herbal medicinal products and traditional medicinal products that has been
issued with the effective Certificate of compliance with GMP for herbal
medicinal products and traditional medicinal products by the Drug
Administration of Vietnam - the Ministry of Health or the Traditional Medicine
Administration of Vietnam - the Ministry of Health in accordance with
regulations of law on pharmacy is entitled to manufacture health supplements
whose dosage forms are equivalent to those that have been certified and is not
required to apply for issuance of the Certificate of GMP compliance with health
supplements. The provisions of this Clause shall come into force on the
effective dates of the legislative documents mentioned in Clause 2 Article 5 of
this Circular.
Article
4. Application of GMP and certificates equivalent to the Certificate of
compliance with GMP for imported health supplements 2
1. Imported health
supplements shall be manufactured by a manufacturer that has been granted one
of the following certificates with forms equivalent to those of the imported
health supplements by a competent authority of the manufacturing country or
organization designated or acknowledged by the regulatory authority of the
manufacturing country:
a) Certificate of GMP
compliance if it is a manufacturer of health supplements;
b) Certificate of
compliance with GMP for a manufacturer of pharmaceutical products or food;
c) Regarding the
countries or territories that do not issue the certificates specified in Points
a and b of this Clause, a certificate which contains at least one of the
following is required:
- Compliance with HACCP -
Hazard Analysis and Critical Control Point;
- Compliance with ISO
22000 - International Organization for Standardization 22000;
- Compliance with IFS -
International Food Standard;
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- Compliance with FSSC
22000 - Food Safety System Certification 22000.
d) Regarding the
countries or territories that do not issue the certificates specified in Points
a, b and c Clause 1 of this Article, a certificate or written certification
which demonstrates that the manufacturer meets the legislation of that country
or territory is required.
2. The certificate
specified in clause 1 of this Article shall at least contain:
a) Name of the issuing
authority;
b) Date of issue;
c) Expiration date (if
the expiration date is not written on the certificate, an assessment report or
periodic inspection record is required to prove that the manufacturer still
maintains its fulfillment of food safety conditions, or prescribes a time limit
for periodic inspection, or assesses the food according to legislation of the
country of origin/manufacture);
d) Full name and
signature of the issuing person;
dd) Name and address of
the certificate holder;
e) Scope covered by the
certificate and product types.”
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1. This Circular comes
into force from July 17, 2019.
Article
6. Transitional clauses
1. Regarding domestically
manufactured or imported health supplements issued with the Certificate of
Declaration of conformity with food safety regulations or Certificate of
registered product declaration that remains effective but not issued with the
Certificate of compliance with GMP for health supplements or an equivalent
certificate as prescribed in this Circular:
a) The products
manufactured before July 01, 2019 shall be sold until their expiration date;
b) From July 01, 2019,
every organization and individual shall submit a copy (authenticated by the health
supplement manufacturer) of the Certificate of compliance with GMP for health
supplements or equivalent certificate as prescribed in this Circular prior to
manufacturing.
2. Applications for
registration of the health supplement declaration submitted before July 01,
2019 (including those submitted before July 01, 2019 and revised after July 01,
2019) shall be processed as prescribed in Article 8 of the Government’s Decree
No. 15/2018/ND-CP.
Article
7. Responsibility for implementation
1. The Vietnam Food
Administration shall:
a) take charge and
cooperate with relevant units in disseminating, providing guidance and
implementing this Circular;
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c) cooperate with the
Drug Administration of Vietnam, Traditional Medicine Administration of Vietnam
and Inspectorate of the Ministry of Health in inspecting the compliance with
principles and requirements of GMP for health supplements by manufacturers of
herbal ingredients, semi-finished herbal ingredients, herbal medicinal products
and traditional medicinal products that have been issued with the Certificate
of eligibility for pharmacy business or Certificate of compliance with GMP for
medicinal products and medicinal materials.
2. The Drug
Administration of Vietnam and Traditional Medicine Administration of Vietnam
shall, within their jurisdiction, take charge or cooperate with the Vietnam
Food Administration in inspecting the compliance with principles and
requirements of GMP for health supplements by manufacturers of herbal
ingredients, semi-finished herbal ingredients, herbal medicinal products and
traditional medicinal products that have been issued with the Certificate of
eligibility for pharmacy business or Certificate of compliance with GMP for
medicinal products and medicinal materials, which allows manufacturing of
health supplements.
3. Organizations and
individuals that manufacture or sell health supplements shall:
a) comply with
regulations of this Circular;
b) maintain their
compliance with principles and requirements of GMP for health supplements
according to the Certificate of compliance with GMP for health supplements or
the equivalent certificate that has been granted and acknowledged throughout
their operations.
4. The Director of the
Vietnam Food Administration, Chief of the Ministry Office, Chief Inspector of
the Ministry of Health, Directors and General Directors of Departments and
General Departments affiliated to the Ministry of Health and relevant
organizations and individuals are responsible for the implementation of this
Circular.
Difficulties that arise
during the implementation of this Circular should be reported to the Ministry
of Health (Vietnam Food Administration) for consideration./.
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PP. THE MINISTER
THE DEPUTY MINISTER
Do Xuan Tuyen
APPENDIX:
PRINCIPLES AND REQUIREMENTS OF
GMP FOR HEALTH SUPPLEMENTS
(Enclosed with the Circular No. 18/2019/TT-BYT dated July 17, 2019 of
the Minister of Health)
Page
Acronyms
Glossary
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I. Quality
management
Principle
Quality assurance
Quality control
Product quality review
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II. Personnel
Principle
Organization, qualification
and responsibilities
Training
III. Premises and
equipment
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Principle
Premises
General
Production areas
Storage areas
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Quality control areas
Ancillary areas
Equipment
IV. Sanitation and
hygiene
Principle
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Personnel
Premises
Equipment and utensils
V. Documentation
Principle
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General
Quality control
documents
Specifications
Specifications for
natural materials
Specifications for
starting materials and packaging materials
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Specifications for
intermediate and bulk products
Specifications for
finished products
Production documents
Manufacturing Formula
and Processing Instructions
Packaging Instructions
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Batch processing
records
Batch packaging records
Standard Operating
Procedures (SOPs) and records
VI. Production
Principle
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General
Verification
Prevention of
cross-contamination in production
Starting materials
Processing operations:
Intermediate and bulk products
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Packaging materials
Packaging Operations
Finished products
Rejected, recovered and
returned materials
VII. Quality control
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Principle
General
Sampling
Testing
Ongoing stability
programme
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VIII. Contract
manufacture and analysis
Principle
Contract
manufacture
Contract analysis
The contract
giver
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The Contract Acceptor
The Contract
IX. Complaints and
product recalls
Principle
Product complaints
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Product recalls
Complaints on adverse product
reactions
X.
Self-inspection
Principle
XI. Other
contents:
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List of internationally
accepted references for test methods
Verification
Guidelines on stability
study and shelf-life of health supplements
Self-inspection checklist
Templates for
Manufacturing processes, Batch processing/packaging records and List of
finished product batch records
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Acronyms:
1. ASEAN: Association of
South East Asian Nations
2. ATTP: An toàn thực phẩm
(“Food safety”)
3. FEFO: First Ended, First
Out
4. FEFO: First In, First
Out
5. GMP: Good
Manufacturing Practice
6. HEPA: High Efficiency
Particulate Air
7. HVAC: Heating
Ventilation and Air Conditioning System, which is able to:
● Air ventilation
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● Dust filtering (if
required)
8. NRA: National
Regulatory Authority
9. QA: Quality Assurance
10. QC: Quality Control
11. SOP: Standard
Operating Procedure
12. VAFF: Vietnam
Association of Functional Food.
13. WHO: World Health
Organization
Glossary:
For the purposes of this
Appendix, the terms below shall be construed as follows:
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2. Packaging Material: Material
that contains foods, encloses foods completely or partially and is divided into
02 categories:
- Consumer
packaging, which is directly attached to goods and sold together with goods to
consumers, and include:
+ Primary packaging,
which is designed to contain goods, comes into direct contact with goods,
shapes goods or encloses goods in the shape of goods.
+ Secondary packaging,
which is designed to contain one or more primary packaging materials together.
- Non-consumer packaging,
which is not retailed together with goods, has various types and used for
transportation and storage of goods on vehicles or warehouses.
3. Quarantine or
separation: The status of starting materials, intermediate, bulk and finished
products set apart physically or by system while awaiting a decision on their
suitability for processing, packaging, distribution, reprocessing or rejection.
4. National Regulatory
Authority: It is the country regulatory authority which exercises a legal right
to control the import, manufacture and export and which may take regulatory
action to ensure that the health supplement products marketed within its
jurisdiction comply with regulatory requirement.
5. Qualification: Action
approving and documenting the equipment or ancillary systems are properly
installed, work correctly and actually lead to expected results.
6. Packaging: All
operations, including filling and labeling, that a bulk product has to undergo
in order to become a finished product.
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8. Expiry Date: A date
fixed for each individual batch before which the batch still meets the required
standard specifications for quality. After this date, the batch is not
permitted for sale.
9. Sanitation: Hygienic
control on manufacturing processes, including personnel, premises, equipment
and handling of materials from starting materials to finished products.
10. Documentation: Any
document that shows results obtained or provides evidence of the activities
performed.
11. Control: Any
necessary activity performed to ensure maintenance of standards specified in
the manufacturing process.
12. 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.
13. Batch (or Lot): A
quantity of any health supplement produced during a given cycle of manufacture
and from a specific formulation order, that is uniform in character and quality
(the essence of a manufacturing batch is its homogeneity).
14. Rejected: The status
of starting materials, intermediate, bulk or finished products which are not
permitted to be used for processing, packaging or distribution and shall be
discarded in a safe manner.
15. Reference sample: A
sample is representative of the batch of starting/packaging materials or
intermediate/finished products from which they are taken, stored for the
purpose of being analyzed shall the need arise during the shelf life of the
batch concerned.
16. Hazard: A biological,
chemical or physical agent in a food with the potential to cause an adverse
health effect.
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18. Authorized Person: A
person who is formally and properly empowered and has the authority to perform
specified duties associated with the company.
19. Risk: The chance or
(probability) that a hazard will occur.
20. Starting Materials:
Any substance or mixture of substances (pre-mix) used in the production of a
traditional medicine or health supplement excluding packaging material.
21. Raw Materials: All
materials whether active or inactive that are employed in the processing of
health supplements.
22. Natural raw
materials: materials used in the manufacture of health supplements and existing
in a natural state and unprocessed form.
23. Natural Materials:
Comminuted or powdered natural materials, extracts, tinctures, fatty or
essential oils, resins, gums, balsams, expressed juices, etc. prepared from
plant, animal or mineral, and preparations whose production involves a
fractionation, purification or concentration process, excluding chemically
defined isolated constituents.
24. Contamination: The
introduction of any foreign matter (food contaminants may be biological,
chemical or physical agent) into a food.
25. Product: The result
of a process or of a set of activities that are interrelated or that interact
with one another.
26. Intermediate Product:
Any material or mixture of materials which have to undergo one or more stages of
processing to become a bulk or finished product.
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28. Reprocessing: A
method of repeating the process of all or part of a batch with an unacceptable
quality to undergo special or additional processing before release.
29. Finished Product: A
product which has undergone all the stages of manufacture, including packaging
in its final container and labelling.
30. Verification:
Confirmation, through the provision of objective evidence, that the
requirements for any procedure, process, equipment, material, activity or
system have been fulfilled.
31. Product Recall: It is
an action taken to remove a product from the market. Recalls maybe initiated by
the NRA or a voluntary action on the part of manufacturer and distributor to
carry out their responsibility to protect the public health and well-being from
products that present a risk of injury or gross deception or are otherwise
deceptive.
324. (repealed)
33. Packaging Materials:
Any material, including printed material, employed in the packaging of a health
supplement, such as containers, closures, bags, packing, label materials,
seals, binding materials, adhesives and tapes.
34. Released or Passed:
The status of starting materials, intermediate, bulk or finished products which
are allowed to be used for processing, packaging or distribution.
I.
Quality management
Principle
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1.1. The basic concept of
Quality Assurance, Good Manufacturing Practice and Quality Control are
inter-related. They are described here in order to emphasise their
relationships and their fundamental importance to the production and control of
health supplements.
Quality assurance
1.2. Quality Assurance 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
organized arrangements made with the object of ensuring the products are of the
quality required for their intended use. Quality assurance therefore
incorporates Good Manufacturing Practice plus other factors outside the scope
of these guidelines.
The system of Quality
Assurance appropriate for the manufacture of health supplements shall ensure
that:
1.2.1. Health supplements
are designed and developed in a way that takes account of the requirements of
GMP.
1.2.2. Production and
control operations are clearly specified and GMP adopted.
1.2.3. Managerial
responsibilities are clearly specified.
1.2.4. Arrangements are
made for the manufacture, supply and use of the correct starting and packaging
materials.
1.2.5. All necessary
controls on starting materials, intermediate products, and bulk products and
other in-process controls, calibrations and validations are carried out.
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1.2.7. Health supplements
are not sold or supplied before a head of Quality Control has certified that
each production batch has been produced and controlled in accordance with the
marketing authorization and any other procedures relevant to the production,
control and release of health supplements.
1.2.8. Satisfactory
arrangements exist to ensure, that the health supplements are stored,
distributed and subsequently handled so that quality is maintained throughout
their shelf life.
1.2.9. There is a
procedure for self-inspection and/or quality audit, which regularly appraises
the effectiveness and applicability of the Quality Control system.
1.3. Good Manufacturing
Practice is that part of Quality Assurance which ensures that products are
consistently manufactured and controlled to the quality standards appropriate
to their intended use and as required by the marketing authorization or product
specification. Good Manufacturing Practice is concerned with both production
and quality control. The basic requirements of GMP are that:
1.3.1. All manufacturing
processes are clearly defined, systematically reviewed in the light of
experience and shown to be capable of consistently manufacturing health
supplements of the required quality and complying with their specifications.
1.3.2. Critical steps of
manufacturing processes and significant changes to the process are verified.
1.3.3. All necessary
facilities for GMP are provided including:
1.3.3.1. Sufficient and
appropriately qualified and trained personnel;
1.3.3.2. Adequate
premises and space;
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1.3.3.4. Appropriate
materials, containers and labels;
1.3.3.5. Approved
procedures and instructions;
1.3.3.6. Suitable storage
and transport.
1.3.4. Instructions and
procedures are written in clear and unambiguous language, specifically
applicable to the facilities provided.
1.3.5. Operators are
trained to carry out procedures correctly.
1.3.6. 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 products as expected. Any
significant deviations are fully recorded and investigated.
1.3.7. Records covering
manufacture and distribution, which enable the complete history of a batch to
be traced, are retained in a comprehensible and accessible form.
1.3.8. The proper storage
and distribution of the products minimizes any risk to their quality.
1.3.9. A system is
available to ensure that any batch of product should be recalled from sale as
soon as possible.
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Quality control
1.4. Quality Control is
the part of Good Manufacturing Practice concerned with: (i) Specifications and
testing, (ii) Sampling and (iii) Tests carried out in accordance with
regulations, and with the organization, 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:
1.4.1. Adequate
facilities, trained personnel and approved procedures are available for
sampling, inspecting and testing starting materials, packaging materials,
intermediate, bulk, and finished products, and where appropriate for monitoring
environmental conditions for GMP.
1.4.2. Samples of
starting materials, packaging materials, intermediate products, bulk products
and finished products must be taken by methods and personnel approved of by the
quality control department.
1.4.3. Test methods are
either internationally accepted or other validated methods (refer to Section
11.1).
1.4.4. 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;
1.4.5. 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 labeled.
1.4.6. 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.
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1.4.8. 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 in
its final pack unless the pack is exceptionally large.
Product quality review
1.5. Regular periodic or
rolling quality reviews of all health supplements, including export only
products, shall 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 shall normally be conducted and documented
annually, taking into account previous reviews, and shall include at least:
1.5.1. A review of
starting materials and packaging materials used for the product, especially
those from new sources;
1.5.2. A review of
critical in-process controls and finished product results;
1.5.3. A review of all
batches that failed to meet established specification(s) and their
investigation;
1.5.4. A review of all
significant deviations or non -conformances, their related investigations, and
the effectiveness of resultant corrective and preventative actions taken;
1.5.5. A review of all
changes carried out to the processes or analytical methods;
1.5.6. A review of
product authorization variations (submitted/granted/ refused), including those for
third country (export only) dossiers;
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1.5.8. A review of all
quality-related returns, complaints and recalls and the investigations
performed at the time;
1.5.9. A review of
adequacy of any other previous product process or equipment corrective actions;
1.5.10. The qualification
status of relevant equipment and utilities, e.g. Heating, Ventilation and Air
Conditioning (HVAC), water, compressed gases, etc.;
1.5.11. A review of
Contractual Agreements to ensure that they are up to date;
1.5.12. A review of
post-marketing commitment for new product/variation.
1.6. The manufacturer and
manufacturing authorization holder shall evaluate the results of this review and
an assessment shall be made whether corrective and preventive action shall be
undertaken. Agreed corrective and preventive actions shall be completed in a
timely and effective manner. There shall 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, etc. where
scientifically justified.
1.7. Where the product
owner is not the manufacturer, there shall be a technical agreement/contract in
place between the various parties that defines their respective
responsibilities in producing the quality review. The authorised person
responsible for final batch certification together with the product owner shall
ensure that the quality review is performed in a timely manner and is accurate.
II.
Personnel
Principle
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Staff at all levels
should receive initial and continuing training in the principles of GMP and for
the tasks and responsibilities assigned to them so that they have the attitudes
for achieving the goals of Good Manufacturing Practice.
Organization,
qualification and responsibilities
2.1. The manufacturer
shall have an organization chart. People in responsible positions shall have
specific duties recorded in written job descriptions and adequate authority to
carry out their responsibilities. There shall be no gaps or unexplained
overlaps in the responsibilities of those personnel concerned with the
application of Good Manufacturing Practice. Key personnel include the head of
production department and the head of quality control department (or including
the head of production department, head of testing department and head of
quality assurance department). Key posts should be occupied by full-time
personnel having knowledge, skill and capabilities relevant to their assigned
function, and capable of handling their duties properly. The heads of
production and quality control departments should be independent of each other.
In large organizations, it may be necessary to delegate some of the functions
(mentioned in sections 2.2, 2.3 and 2.4 below); however, the responsibility
cannot be delegated.
2.2. The head of
production department shall have full authority and responsibilities to manage
production of products covering operations, equipment, production personnel,
production area and records.
The head of the
production department generally has the following responsibilities:
2.2.1. To ensure those
products are manufactured and stored according to the appropriate documentation
in order to obtain the required quality;
2.2.2. To approve the
instructions relating to production operations, including the in -process
controls and to ensure their strict implementation;
2.2.3. To ensure that the
production records are evaluated and signed by a designated person before they
are made available to the Quality Control Department;
2.2.4. To check the
maintenance of the department, premises and equipment;
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2.2.6. To ensure that the
required initial and continuing training of production personnel is carried out
and adapted according to need.
2.3. The head of Quality
Control Department shall have adequate training and practical experience, which
can enable the person to perform the functions effectively. He/She shall be
given full authority and responsibility in all quality control duties such as
establishment, verification and implementation of all quality control
procedures. He /She shall have the sole authority to approve starting
materials, intermediates, bulk and finished products that meet the
specification or to reject those which do not conform to the relevant
specification or which were not manufactured in accordance with approved
procedures and under the defined conditions.
The head of Quality
Control shall have the following responsibilities:
2.3.1. To approve or
reject starting materials, packaging materials and intermediate, bulk and
finished products;
2.3.2. To evaluate batch
records;
2.3.3. To ensure that all
necessary testing is carried out;
2.3.4. To ensure that the
critical processes are appropriately verified;
2.3.5. To approve
sampling instructions, specification, test methods, and other quality control
procedures;
2.3.6. To approve and monitor
tests carried out under contract;
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2.3.8. To establish
expiration date and shelf life specifications on the basis of stability test or
available stability data related to storage conditions;
2.3.9. To approve those
suppliers of raw materials and packaging materials;
2.3.10. To evaluate all
complaints received or deficiencies noted about any batch, if necessary in
conjunction with other departments, and to take appropriate action accordingly;
2.3.11. To maintain
adequate analytical records concerning the examinations of all samples taken;
2.3.12. To recommend
contract-manufacturing operations;
2.3.13. To ensure that
the required initial and continuing training of his department personnel is
carried out and adapted according to need.
2.4. The heads of
Production Department and Quality Control Department shall share a joint
responsibility:
2.4.1. To authorize
written procedures and relevant document including amendments;
2.4.2. To monitor and
control the manufacturing environment, sanitation and hygiene;
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2.4.4. To verify critical
processes;
2.4.5. To approve and
monitor the suppliers of materials and contract manufacturers;
2.4.6. To establish and
monitor the storage conditions for materials and products;
2.4.7. To retain records;
2.4.8. To monitor
compliance with the requirements of Good Manufacturing Practice;
2.4.9. To inspect, investigate
and take samples, in order to monitor factors which may affect product quality.
Training
2.5. All personnel shall
be trained in the particular operations and in the principles of Good
Manufacturing Practice.
2.6. Training in Good
Manufacturing Practice shall be on a continuing basis and with adequate
frequency to assure that employees remain familiar with Good Manufacturing
Practices requirements relevant to their functions. Training in Good
Manufacturing Practice shall be in accordance with written programmes approved
by the head of Production Department and the head of Quality Control
Department.
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2.8. The concept of
Quality Assurance and all the measures capable of improving its understanding
and implementation shall be fully discussed during the training sessions.
III.
Premises and equipment
Principle
Premises and
manufacturing equipment must be located, designed, constructed, adapted and
maintained to suit the operations to be carried out. Their layout and design
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.
Premises: General
3.1. Premises for
manufacturing shall be of suitable size, design, construction and location to facilitate
proper operation, cleaning and maintenance.
3.2. Premises shall be
carefully maintained, ensuring that repair and maintenance operations do not
present any hazard to the quality of products. They shall be cleaned and, where
applicable, disinfected according to detailed written procedures.
3.3. Steps shall be taken
in order to prevent the entry of unauthorized people. Production, storage and
quality control areas shall not be used as a right of way by personnel who do
not work in them.
3.4. Lighting,
temperature, humidity and ventilation shall be appropriate and such that they
do not adversely affect, directly or indirectly, either the products during
their manufacture and storage, or the accurate functioning of equipment.
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3.6. Premises shall 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.
3.7. In case the health
supplements, herbal medicinal products and traditional medicinal products are
manufactured on the same line, appropriate measures must be taken to prevent
confusion, contamination and cross-contamination (refer to section 6.19).
3.8. Premises shall be
designed, constructed and maintained to protect against access and harboring of
vermin, rodents, birds, insects or other animals.
3.9. Design shall
consider prevention of mix-up between different products or their components
and the possibility of cross contamination by other substances.
3.10. Special attention
must be given for processing operations that generate dust. Measures shall be
taken to prevent the generation and dissemination of dust.
3.11. Defined areas for
the following operations are required:
3.11.1. Receiving and
quarantine of incoming material;
3.11.25 (repealed)
3.11.3. Storage of
starting and packaging materials;
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3.11.5. Processing;
3.11.6. Storage of
bulk/intermediate products;
3.11.7. Packaging;
3.11.8. Equipment
washing;
3.11.9. Storage of
quarantine finished products;
3.11.10. Storage of
approved finished products;
3.11.11. Designated area
for quality control.
Where quarantine status
is ensured by storage in separate areas, these areas must be clearly marked and
their access restricted to authorized personnel. Any system replacing the
physical quarantine shall give equivalent security.
Production areas
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3.13. Any open channels
shall be avoided, but if required they shall be shallow enough to facilitate
cleaning and disinfecting. All drainage shall have trapped gullies.
3.14. Buildings shall be
effectively ventilated with air control facilities (including temperature,
humidity and filtration), appropriate both to the operations undertaken within
and to the external environment.
3.15. Production areas
shall be well lit, particularly where visual on-line controls are carried out.
3.16. Pipework, light
fittings, ventilation points and other services shall be designed and sited to
avoid the creation of recesses which are difficult to clean. As far as possible,
for maintenance purposes, they shall be accessible from outside the
manufacturing areas.
3.176. (repealed)
3.18. In cases where dust
is generated (e.g. during sampling, weighing, mixing and processing operations,
packaging of dry products), specific provisions shall be taken to avoid
cross-contamination and facilitate cleaning.
3.19. Premises for the
packaging of health supplements shall be specifically designed and laid out so
as to avoid mix-ups or cross-contamination.
3.20. Premises shall
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.
3.21. Adequacy of working
space, which shall allow orderly and logical placement of equipment and
materials and to suit the operation, efficient flow of work, effective
communication and supervision as well as to avoid crowding and disorders.
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3.23. Changing rooms into
the production areas shall have adequate hand washing and/or sanitizing
facilities.
Storage areas
3.24. Storage areas shall
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 or recalled.
3.25. Storage areas shall
be designed or adapted to ensure good storage conditions. In particular, they
shall be clean and dry and maintained within acceptable temperature limits.
Where special storage conditions are required (e.g. temperature, humidity)
these shall be provided, checked and monitored.
3.26. Segregated and
secure areas shall be provided for the storage of rejected, recalled or
returned materials or products. Products rejected during a manufacturing
process should not be stored in the production facility but marked, entered
into a logbook and returned to stock after each production shift to prevent
mistakes.
3.27. Highly active
materials or products (e.g. flammable, explosive or toxic substances) shall be
stored in separate, safe and secure areas.
3.28. Receiving and
dispatch bays shall protect materials and products from the weather. Reception
areas shall be designed and equipped to allow containers of incoming materials
to be cleaned where necessary before storage.
3.297. (repealed)
3.30. Printed packaging
materials are considered critical to the conformity of the products, and
special attention shall be paid to the safe and secure storage of these
materials.
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3.32. Special attention
shall be paid to the cleanliness and good maintenance of the storage areas
particularly when dust is generated.
3.33. Storage of plant
materials, animal materials including parts, microorganisms, extracts,
tinctures and other preparations that require special conditions of
temperature, humidity or light protection; these conditions shall be provided
and monitored.
Quality control areas
3.34. If tests are
carried out at production facilities, quality control laboratories, especially
laboratories where microbiological test methods are employed, should be
separated from production areas.
3.35. Control
laboratories shall be designed to suit the operations to be carried out in
them. Sufficient space shall be given to avoid mix-ups and cross-contamination.
There shall be adequate suitable storage space for samples and records.
3.36. Separate rooms may
be necessary to protect sensitive instruments from vibrations, electrical
interference, humidity, etc.
3.37. Special
requirements are needed in laboratories handling particular substances such as
microorganism samples.
Ancillary areas
3.38. Rest and
refreshment rooms and toilets shall be separated from other areas and shall not
have direct access to controlled areas (e.g. production and storage areas).
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3.40. Maintenance
workshops shall be separated from production areas. Whenever parts and tools
are stored in the production area, they shall be kept in rooms or lockers
reserved for that use.
3.41. Animal houses shall
be well isolated from other areas, with separate entrance and air handling
facilities. Warehouses of explosive and flammable substances, waste storage
areas, waste treatment system and boilers (if any) shall be located far away
from production, testing and storage areas so as to ensure safety and hygiene.
Equipment
3.42. Manufacturing
equipment shall be designed, placed and maintained to suit its intended and
ensure safety of employees. The maintenance and replacement of accessories
shall comply with the approved plan and requirements of the equipment
manufacturer.
3.43. Manufacturing
equipment shall be installed so as to prevent contamination or minimize the
risk of error and, where necessary, tested to ensure the equipment operate
appropriately.
3.44. Manufacturing
equipment shall be located at a distance from other equipment sufficient to
avoid congestion and cross contamination.
3.45. Fixed pipework
shall be clearly labelled to indicate the contents and direction of flow.
3.46. Balances and
measuring equipment of an appropriate range and precision shall be available
for production and control operation.
3.47. Measuring,
weighing, recording and control equipment shall be calibrated and checked at
defined intervals by appropriate methods. Adequate records of such tests shall
be maintained.
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3.498 (repealed)
3.50. Defective equipment
shall, if possible, be removed from production and quality control areas, or at
least be clearly labelled as defective.
3.51. Repair and
maintenance operations shall not present hazard to the quality of the products.
Any missing components such as nuts, springs, clips, etc. shall be reported and
investigated immediately.
3.52. Production
equipment (including transfer pipes and hoses) shall 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.
3.53. Pipes, hoses, pumps
and valves used for treated water, starting materials and the products shall be
cleaned and sanitized according to written procedures that detail the action
limits for microbiological contamination and the measures to be taken.
IV.
Sanitation and hygiene
Principle
A high level of
sanitation and hygiene shall be practiced in every aspect of the manufacturing
of health supplements.
The scope of sanitation
and hygiene covers personnel, premises, equipment and utensils; in fact,
anything that could become a source of contamination to the product.
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Personnel
4.1. All personnel, prior
to employment shall undergo health examinations. During the course of their
employment they shall also routinely undergo health examinations which shall
include relevant examinations appropriate to the tasks that they are required
to perform.
4.2. All personnel shall
practice good personal hygiene. They shall be trained in the practices of
personal hygiene.
4.3. Any person shown at
any time to have an apparent illness or open lesions or disease such as active
tuberculosis, acute diarrhea, cholera, dysentery, typhoid, acute hepatitis A or
E, acute respiratory tract infection or acute dermatitis or skin infection that
may adversely affect the quality of products shall not be allowed to handle raw
materials, packaging materials, in-process materials, and finished products
until the condition is improved.
4.4. Direct contact shall
be avoided between the operator's hands and raw materials, intermediate or bulk
product. Proper washing of hands and wearing of gloves shall be used if contact
with hands is unavoidable.
4.5. To assure protection
of the product from contamination as well as the safety of the personnel,
appropriate protective garments shall be worn. Soiled uniforms shall be stored
in closed containers until properly laundered.
4.6. Only authorised
personnel shall be allowed to enter production areas. Visitors or untrained
personnel shall, preferably, not be taken into the production and quality
control areas. If this is unavoidable, they shall be given information in
advance, particularly about personal hygiene and the prescribed protective
clothing. They shall be closely supervised.
4.7. Smoking, eating,
drinking and chewing or keeping of plants, food, drink, smoking materials and
personal medicines shall be restricted to specific areas and not permitted in
production, laboratory, storage or other areas where they might adversely
influence product quality.
4.8. The wearing of
makeup, wrist watches and jewellery shall be prohibited in the production area
however for jewellery or objects that cannot be removed; it must be covered by
material that is maintained in an intact, clean and sanitary condition.
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4.9. Premises used for
the manufacturing of products shall be of suitable design and construction so
as to facilitate good sanitation.
4.10. Adequate employee's
washing and well ventilated toilet facilities and changing rooms shall be
provided at suitable locations.
4.11. Suitable locker
facilities shall be provided at appropriate locations for the storage of
employees clothing and personal property.
4.12. The preparation, storage
and consumption of food and beverages shall be restricted to specific areas,
such as meal rooms and canteen. Facilities in such rooms must meet sanitary
standards. Meal rooms and canteen rooms shall not have direct access to
controlled areas such as production area and areas use to store materials used
for production and finished products.
4.13. Waste material
shall not be allowed to accumulate. It shall be collected in suitable
receptacles for removal to collection points outside the buildings and disposed
off safely and in a sanitary manner at regular and frequent intervals.
4.14. Rodenticide,
insecticides, fumigating agents and sanitizing materials used must not
contaminate equipment, raw materials, packaging materials, in-process materials
or finished products. There shall be a pest control programme, documents such
as layout, trending and expectations. Contract agreements shall be established,
where applicable.
4.15. There shall be
written procedures assigning responsibility for sanitation and describing
cleaning schedules, methods, equipment, materials to be used and facilities to
be cleaned in sufficient detail. Such written procedures shall be followed.
4.16. Pets are not
allowed within the vicinity of the manufacturing plant.
Equipment and utensil
cleaning
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4.18. Vacuum or wet
cleaning methods are to be preferred. Compressed air and brushes shall be used
with care or avoided if possible, as they increase the risk of product
contamination.
4.19. Cleaning agents,
washing and cleaning equipment shall not be a source of contamination. The
choice of cleaning method and agents shall be carefully considered and
justified.
4.20. Adequate space,
preferably separated from processing areas, shall be provided for cleaning and
storing mobile equipment and utensils including the storage of cleaning
materials.
4.21. Written procedures
shall be established and followed for cleaning and sanitising of equipment,
utensils and containers used in the manufacture of health supplements. Such
written procedures shall be followed.
4.22. These procedures
shall be prepared to prevent equipment contamination by cleaning or sanitising
agents and shall at least include the following:
4.22.1. Responsibility
for cleaning;
4.22.2. Cleaning
schedule;
4.22.3. Cleaning methods;
4.22.4. Equipment and
materials used in cleaning operations;
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4.22.6. Removal of
previous batch identification;
4.22.7. Protection of clean
equipment and utensils from contamination prior to use.
4.23. Records of
cleaning, including the appropriate sanitizing and inspection conducted prior
to use shall be maintained.
V.
Documentation
Principle
Good documentation
constitutes an essential part of the quality assurance system. Clearly written
documentation prevents errors from spoken communication and permits tracing of
batch history of the product, from receiving of starting materials to the
distribution of finished products. It shall be able to record executed
activities for maintenance, storage, quality control, distribution and other
specific matters linked to GMP.
For manufacturing
activities, a documentation system must be prepared. The system consisting of
manufacturing formulae and instructions, specifications, procedures and records
must be free from errors and clearly established.
General
5.1. The system of
documentation shall be able to record the complete history of each batch. It
shall be adequate to permit investigation and tracing of any defective
products.
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5.3. Product related
records shall be retained for at least one (01) year after the expiry date of
the finished product.
5.4. Documents shall be
designed, prepared, reviewed and distributed with care. The reproduction of working
documents from master documents must not allow any error to be introduced
through the reproduction process. Reproduced documents shall be clear, legible
and duly authorized for reproduction.
5.5. Documents shall be
approved, signed and dated by appropriate and authorized person.
5.6. Documents shall have
unambiguous contents; title, nature and purpose shall be clearly stated. They
shall be laid out in an orderly fashion and easy to be checked.
5.7. Documents shall be
regularly reviewed and kept up to date. When a document has been revised,
systems shall be operated to prevent inadvertent use of superseded documents.
5.8. Documents shall not
be hand-written, except in the case where documents require the entry of data.
These entries may be made in clear, legible, and indelible handwriting.
Sufficient space shall not be provided for data.
5.9. Any alteration made
to the entry on a document shall be signed and dated. The reason of the
alteration should be recorded. The alteration shall permit the reading of the
original information.
5.10. The records shall
be made or completed at the time each action is taken and in such a way that
all significant activities concerning the manufacture the product are
traceable.
5.11. Data may be
recorded by electronic data processing systems, photographic or other reliable
means, but detailed procedure relating to the system in use shall be available
and the accuracy of the records shall be checked and verified. If documentation
is handled by electronic data processing methods, only personnel who have been
authorized shall be able to enter or modify data in the computer and there
shall be a record of changes and deletions. Access shall be restricted by
passwords or other means and the result of entry of critical data shall be
independently checked and verified. Batch records electronically stored shall
be protected by back-up transfer. It is particularly important that, during the
period of retention, the data are readily available.
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Quality control
documents
5.13. The following shall
be readily available from the Quality Control Department:
5.13.1. Specifications;
5.13.2. Sampling
procedures;
5.13.3. Testing
procedures and records (including analytical worksheets/raw data and/or
laboratory notebooks);
5.13.4. Analytical
reports and/or certificates;
5.13.5. Data from
environmental monitoring, where appropriate;
5.13.6. Procedures for
and records of the calibration of instruments and maintenance of equipment;
5.14. Any Quality Control
documentation relating to a batch record shall be retained for at least one
(01) year after the expiry date of the finished product.
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5.15. The materials used
in the product shall be handled in an appropriate manner and manufactured in an
appropriate controlled condition to prevent cross-contamination. Documented
traceability of the material and suppliers is fundamental to the quality of the
finished products and shall be made available.
Specifications for
natural materials
5.16. The specifications
for natural material shall where appropriate include the following:
5.16.1. Scientific name
and if possible with reference to the authors;
5.16.2. Details to the
source of the natural material (country or region of origin, and cultivation,
time of harvesting, collection procedures, possible pesticides used, etc.);
5.16.3. Whether the whole
plant/animal or only a part is used;
5.16.4. When dried
plant/animal is purchased, drying system shall be specified;
5.16.5. Pictorial
demonstration/description of natural material; macroscopical and/or
microscopical examination;
5.16.6. Storage
conditions and precautions, when necessary;
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5.17. Testing procedures
shall be available if the following tests are conducted, where appropriate:
5.17.1. Identification
tests including, where possible, tests for known active constituents, or
markers;
5.17.2. Assay, where
possible, of constituents of known therapeutic activity or markers;
5.17.3. Limit tests such
as ash value, and presence of essential oils and loss on drying;
5.17.4. Tests for heavy
metals and for likely contaminants, foreign materials and adulterants;
5.17.5. Tests for
radioactivity, mycotoxin, fungal and microbial contamination;
5.17.6. Test for residual
solvents in extracts or finished products, where applicable;
5.17.7. Other tests, as
required.
Specifications for
starting materials and packaging materials
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5.18.1. A description of
the materials, including:
5.18.1.1. The designated
name and the internal code reference;
5.18.1.2. The reference,
if any, to a pharmacopoeia monograph;
5.18.1.3. The approved
suppliers and, if possible, the original producer of the products;
5.18.1.4. A specimen of
printed materials.
5.18.2. Directions for
sampling and testing or reference to procedures.
5.18.3. Qualitative and
quantitative requirements with acceptance limits.
5.18.4. Storage
conditions and precautions.
5.18.5. The maximum
period of storage before re-examination.
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5.19. Specifications for
intermediate and bulk products shall be available if these are purchased or
transferred, or if data obtained from intermediate products are used for the
evaluation of the finished product. The specifications shall be similar to specifications
for starting materials or for finished products, as appropriate.
Specifications for
finished products
5.20. The specifications
for finished product where appropriate shall include the following tests:
5.20.1. Microbial limits;
5.20.2. Heavy metals
limits;
5.20.3. Uniformity of
weight (for tablets and capsules), disintegration (for tablets, capsules and
pills), hardness and friability (for tablets), and viscosity (for internal and
external liquids);
5.20.4. Physical
appearance such as colour, taste, texture, size, etc.
5.20.5. Other tests, as
required.
5.21. Other contents:
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5.21.2. The formula or a
reference to;
5.21.3. A description of the
dosage form and package details;
5.21.4. Directions for
sampling and testing or a reference to procedures, where applicable;
5.21.5. The qualitative
and quantitative requirements, with the acceptance limits, where applicable;
5.21.6. The storage
condition and any special handling precautions, where applicable;
5.21.7. The shelf life.
Production documents (refer to section 11.5)
Manufacturing Formula
and Processing Instructions
Formally authorized
Manufacturing Formula and Processing Instructions shall exist for each product
and batch size to be manufactured. They are often combined in one document.
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5.22.1. The name of the
product, with a product reference code relating to its specification;
5.22.2. A description of
the product dosage form, strength of the product and batch size;
5.22.3. A list of all
starting materials to be used, with the amount of each, described using the
designated name and a reference which is unique to that material. Mention shall
be made of any substance that may disappear in the course of processing;
5.22.4. A statement of
the expected final yield with the acceptable limits, and of relevant
intermediate yields, where applicable.
5.23. The Processing
Instructions shall include:
5.23.1. A statement of
the processing location and the principal equipment to be used;
5.23.2. The methods, or
reference to the methods, to be used for setting up the equipment (e.g.
Cleaning, assembling, calibrating);
5.23.3. Detailed stepwise
processing instruction (e.g. Checks on materials, pre-treatments, sequence for
adding materials, mixing times, temperatures);
5.23.4. The instructions
for any in-process controls with their limits;
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5.23.6. Any special
precautions to be observed.
5.24. The processing
instructions shall describe the different operations carried out upon the crude
material such as sorting, cleaning, drying, crushing and sifting, and include
drying time and temperatures, and methods used to control fragment or particle
size. It shall also describe the sieving process or other methods of removing
foreign materials.
5.25. In particular,
there shall be written instructions and records, which ensure that each
container of the product is carefully examined to detect any
adulteration/substitution or presence of foreign matter, such as metal or glass
pieces, animal parts or excrement, stones, sand, etc., or rot and signs of
decay.
5.26. For product
preparation, instructions shall include details of base or solvent, time and
temperatures of extraction, details of any concentration stages and methods
used.
Packaging Instructions
5.27. There shall be formally
authorized Packaging Instructions for each product, pack size and type. These
shall normally include, or have a reference to the following:
5.27.1. Name of the
product;
5.27.2. Description of
its product dosage form, and strength where applicable;
5.27.3. The pack size
expressed in terms of the n umber, weight or volume of the product in the final
container;
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5.27.5. 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;
5.27.6. Special
precautions to be observed, including a careful examination of the area and
equipment in order to ascertain the line clearance before operations begin;
5.27.7. A description of
the packaging operation, including any significant additional operations, and
equipment to be used;
5.27.8. Details of
in-process controls with instructions for sampling and acceptance limits.
Batch processing
records
5.28. Batch Processing
Record is that part of Batch Manufacturing Record and shall be kept for each
batch processed. It shall be based on the relevant parts of the currently
approved Manufacturing Formula and Processing Instructions. The method of
preparation of such records shall be designed to avoid transcription errors.
The record shall carry the batch number of the product being manufactured.
5.29. Before any
processing begins, there shall be recorded verification that the equipment and
work station are clear of previous products, documents or materials not
required for the planned process, and that equipment is clean and suitable for
use.
5.30. During processing,
the following information shall be recorded at the time each action is taken
and, after completion, the record shall be dated and signed in agreement by the
person responsible for the processing operations:
5.30.1. Name of the
product;
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5.30.3. Name of the
person responsible for each stage of production;
5.30.4. Date and the
signature of the operator of different significant steps of production and,
where appropriate, of the person who checked each of these operations (e.g.
weighing);
5.30.5. 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 materials added);
5.30.6. Any relevant
processing operation or event and major equipment used;
5.30.7. A record of the
in-process controls and the date and signature of the person(s) carrying them
out, and the results obtained;
5.30.8. The product yield
obtained at different and pertinent stages of manufacture;
5.30.9. Notes on special
problems including details, with signed authorisation for any deviation from
the manufacturing formula and processing instructions.
Batch packaging
records
5.31. A Batch Packaging
Record is part of Manufacturing Record and shall be kept for each batch or part
of batch processed. It shall be based on the relevant parts of the Packaging
Instructions and the method of preparation of such records shall be designed to
avoid transcription errors. The record shall carry 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.
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5.33. The following
information shall be entered at the time each action is taken and, after
completion, the record shall be dated and signed in agreement by the person(s)
responsible for the packaging operations:
5.33.1. The name of the
product;
5.33.2. The date(s) and
times of the packaging operations. When there is the risk of contamination, the
packaging activity shall be done within the day itself.
5.33.3. The name of the
responsible persons carrying out the packaging operation;
5.33.4. The date and
signature of the operators of the different significant steps;
5.33.5. Records of
verification for identity and conformity with the packaging instructions
including the results of in-process controls;
5.33.6. Details of the
packaging operations carried out, including references to equipment and the
packaging lines used;
5.33.7. Whenever possible,
samples of printed packaging materials used, which include the batch/lot
number, expiry date and any additional overprinting;
5.33.8. Notes on any
special problems or unusual events including details, with date and signed
authorization from the manufacturing formula and processing instructions;
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Standard Operating
Procedures (SOPs) and records
5.34. There shall be
written procedures and records for the receipt of each delivery of each
starting materials and packaging material.
The records of the
receipts shall include:
5.34.1. The name of
material on the delivery note and the containers;
5.34.2. The “in-house”
name and /or code of material (if different from the name of the material on
the delivery note and the containers);
5.34.3. Date of receipt,
date and signature of the receiving staff;
5.34.4. Supplier’s name
and manufacturer’s name;
5.34.5. Manufacturer’s
batch or reference number;
5.34.6. Total quantity
and number of containers received;
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5.34.8. Any relevant
comment (e.g. State of the containers).
5.35. There shall be
written procedures for the internal labelling, quarantine and storage of
starting materials, packaging materials and other materials, as appropriate.
5.36. Standard operating
procedures shall be available for the operation of each equipment and placed in
close proximity to the instrument or equipment.
5.37. There shall be
standard operating procedures for sampling, which specify the person(s) authorized
to take samples, and the sampling instructions.
5.38. There shall be a
standard operating procedure describing the details of the batch/lot numbering
system, with the objective of ensuring that each batch of intermediate, bulk,
or finished product is identified with a specific batch number. The batch
numbering procedures shall assure that the same batch numbers will not be
repeatedly used; this applies also to reprocessing.
5.39. Batch number
allocation shall be immediately recorded, e.g. in a logbook. The record shall
include date of allocation, product identity, and size of batch.
5.40. The standard
operating procedures for batch numbering that are applied to the processing
stage and to the respective packaging stage shall be related to each other.
5.41. Written procedure
for quarantine, release and rejection shall be available for materials and
products, and in particular for the release for sale of the finished product by
the authorized person.
5.42. Records shall be
maintained of the distribution of each batch of a product in order to
facilitate the recall of the batch if necessary.
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5.43.1. Equipment assembly;
5.43.2. Operation of
analytical apparatus and calibration;
5.43.3. Maintenance,
cleaning, and sanitization of equipment and premises;
5.43.4. Personnel matters
including qualification, GMP training, clothing, and hygiene;
5.43.5. Environmental
monitoring;
5.43.6. Pest control;
5.43.7. Adverse product
reactions, complaints and product recalls;
5.43.8. Returns and
recovered products, rejected products/materials;
5.43.9. Disposal and
destruction of the rejected products/materials;
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5.44. Logbooks shall be
kept for major or critical equipment and shall record, as appropriate, any
calibrations, maintenance, cleaning, or repair operations, including dates and
the identity of the people who carried these operations out.
5.45. Logbooks shall be
recorded in chronological order for the use of all equipment and the areas
where the products have been processed.
5.46. Several of the
above- mentioned procedures, specifications and/or records may be combined
together in one specific document.
VI.
Production
Principle
With the premises and
equipment provided, the processes used in production shall be capable of
yielding finished products which conform to their specifications. Defined
manufacturing procedures are necessary to ensure that production, quality
control and other relevant personnel are instructed on the details of the
processes concerned.
General
6.1. Production shall be
performed and supervised by competent people.
6.2. All handling of
materials and products, such as receipt and quarantine, sampling, storage,
labelling, dispensing, processing, packaging and distribution shall be done in
accordance with written procedures or instructions and, where necessary,
recorded.
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6.4. Damage to containers
and any other problem, which might adversely affect the quality of a material,
shall be investigated, recorded and reported to the Quality Control Department.
6.5. Incoming materials
and finished products shall be physically or administratively quarantined
immediately after receipt or processing, until they have been released for use
or distribution.
6.6. Intermediate and
bulk products purchased as such shall be handled on receipt as though they were
starting materials.
6.7. All materials and
products shall be stored under the appropriate conditions established by the
manufacturer and in an orderly fashion to permit batch segregation and stock
rotation.
6.8. Checks on yields,
and reconciliation of quantities, shall be carried out as necessary to ensure
that there are no discrepancies outside acceptable limits.
6.9. Operations on
different products shall not be carried out simultaneously or consecutively in
the same room unless there is no risk of mix-up or cross - contamination.
6.10. At every stage of
processing, products and materials shall be protected from microbial and other
contamination. Any treatment used to reduce fungal/microbial contamination or
other infestation shall be documented.
6.11. When working with
dry materials and products, special precautions shall be taken to prevent the
generation and dissemination of dust.
6.12. At all times during
processing, all materials, bulk containers, major items of equipment and where
appropriate, rooms used shall be labelled or otherwise identified with an
indication of the product or material being processed, its strength (where
applicable) and batch number.
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6.14. Checks shall 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.
6.15. Access to
production premises shall be restricted to authorized personnel.
6.16. Water used as
ingredients or for final rinsing of production equipment shall be treated to
minimize microbial contamination
Verification
6.17. Verification work
that is needed to prove control of critical aspects of particular operations
shall be identified and documented. Significant changes to the facilities,
equipment and the processes which may affect the quality of the product shall
be verified. A risk assessment approach shall be used to determine the scope
and extent of verification.
(Refer to Section
11.2).
Prevention of
cross-contamination in production
6.18. Contamination of a
starting material or of a product by another material or product shall 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.
6.19. Cross-contamination
shall be avoided by appropriate technical or organizational measures, for
example:
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6.19.2. Providing
appropriate air-locks and air extraction.
6.19.3. Minimizing the
risk of contamination caused by recirculation or re - entry of untreated or
insufficiently treated air.
6.19.4. Keeping
protective clothing inside areas where products with special risk of
cross-contamination are processed.
6.19.5. Using the
approved cleaning and decontamination procedures of known effectiveness, as
ineffective cleaning of equipment is a common source of cross-contamination.
6.19.6. Using “closed
systems” of production.
6.19.7. Testing for
residues and use of cleaning status labels on equipment.
6.19.8. Specific
provisions for sampling, weighing, mixing and processing operations of crude
plants whenever dust is generated.
6.20. Measures to prevent
cross-contamination and their effectiveness shall be checked periodically
according to set procedures.
Starting materials
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6.22. Starting materials
shall only be purchased from approved suppliers and, where possible, directly
from the producer. It is recommended that the specifications established by the
manufacturer for the starting materials are 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 contractually agreed between
the manufacturer and the supplier. The supplier of the materials shall be
adequately assessed and the assessment shall be recorded.
The supplier assessment
programme shall include the establishment of an approved supplier list which
may include alternative supplier, initial assessment before placing the
supplier on the approved supplier list and periodic assessment thereafter,
provision for on-site audit of the supplier premises, etc.
6.23. For each delivery,
the containers shall be checked for integrity of package and seal and for
correspondence between the delivery note and the supplier's labels.
6.24. If one material
delivery is made up of different batches, each batch shall be considered as
separate for sampling, testing and release.
6.25. Starting materials
in the storage areas shall be appropriately labelled. Labels shall bear at
least the following information:
6.25.1. The designated
name of the product and the internal code reference where applicable;
6.25.2. A batch number
given at receipt;
6.25.3. Where
appropriate, the status of the contents (e.g. in quarantine, on test, released,
rejected);
6.26. There shall 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 shall be identified.
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6.28. Starting materials
shall 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.
6.29. Each dispensed
material and its weight or volume shall be independently checked and the check
recorded.
6.30. Materials dispensed
for each batch shall be kept together and conspicuously labelled as such.
Processing operations:
Intermediate and bulk products
6.31. Before the
introduction of a Master Formula it shall be evaluated sufficiently to
determine that it is suitable for routine processing operations, and the
ability of the process to be reproducible.
6.32. Production
personnel shall follow defined and authorized procedures for every stage of
each manufacturing process.
6.33. Any deviation from
defined procedures shall be recorded and agreed upon between the head of
Production Department and the head of Quality Control Department.
6.34. Before any manufacturing
begins, steps shall be taken to ensure that the work area and equipment are
free from any materials, products, or documents, not required for the current
operation.
6.35. Any necessary
in-process controls and environmental controls shall be carried out and
recorded.
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6.37. The final yield of
each production stage shall be recorded and checked against the theoretical
yield. In the event of a significant variation, steps shall be taken to prevent
release or further processing of the batch, until an appropriate investigation
is made.
6.38. Storage of
materials and bulk products must be under controlled condition.
Packaging materials
6.39. The purchase,
handling and control of primary and printed packaging material shall be
accorded attention similar to that given to starting materials.
6.40. Particular
attention shall be paid to printed materials. They shall be stored in adequately
secure condition such as to exclude unauthorized access. Cut labels and other
loose printed materials shall be stored and transported in separate closed
containers so as to avoid mix-ups. Packaging materials shall be issued for use
only by authorized personnel following an approved and documented procedure.
6.41. Each delivery or
batch of printed or primary packaging material shall be given a specific
reference number or identification mark.
6.42. Outdated or
obsolete primary packaging material or printed packaging material shall be
destroyed and this disposal recorded.
Packaging Operations
6.43. When setting up a
programme for the packaging operations, particular attention shall be given to
minimising the risk of the cross-contamination, mix-ups or substitutions.
Different products shall not be packaged in close proximity unless there is
physical segregation.
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6.45. The name and batch
number of the product being handled shall be displayed at each packaging
station or line.
6.46. All products and
packaging materials to be used shall be checked on delivery to the packaging
department for quantity, identity and conformity with the Packaging
Instructions.
6.47. Primary packaging
shall be clean prior to use. Measures shall be taken to prevent any
contaminants such as glass fragments and metal particles.
6.48. Normally, filling
and sealing shall be followed as quickly as possible by labelling. If it is not
the case, appropriate procedure shall be applied to ensure that no mix-ups or
mislabelling could occur.
6.49. The correct
performance of any printing operation (for example batch/lot numbers, expiry
dates) to be done separately or in the course of the packaging shall be checked
and recorded. Attention shall be paid to printing by hand which shall be re
-checked at regular intervals.
6.50. Special care shall
be taken when using cut-labels and when over-printing is carried out off-line.
Roll-feed labels are normally preferable to cut-labels, in helping to avoid
mix-ups.
6.51. Checks shall be
made to ensure that any electronic code readers, label counters or similar
devices are operating correctly.
6.52. Printed and embossed
information on packaging materials shall be distinct and resistant to fading or
erasing.
6.53. On-line control of
the product during packaging shall include at least checking the following:
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6.53.2. Whether the
packages are complete;
6.53.3. Whether the
correct products and packaging materials are used;
6.53.4. Whether any
over-printing is correct;
6.53.5. Correct
functioning of line monitors.
6.54. Samples taken away from
the packaging line shall not be returned.
6.55. Products which have
been involved in an unusual event shall only be reintroduced into the process
after special inspection, investigation and approval by authorized personnel.
Detailed record shall be kept of this operation.
6.56. Any significant or
unusual discrepancy observed during reconciliation of the amount of bulk
product and printed packaging materials and the number of units produced shall
be investigated and satisfactorily accounted for before release.
6.57. Upon completion of
a packaging operation, any unused batch-coded packaging materials shall be
destroyed and the destruction recorded. A documented procedure shall be
followed if uncoded printed materials are returned to stock.
Finished products
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6.59. The evaluation of
finished products and documentation which is necessary before release of
product for sale is described in Section VII. Quality Control.
6.60. After release,
finished products shall be stored as usable stock under conditions established
by the manufacturer.
Rejected, recovered
and returned materials
6.61. Rejected materials
and products shall be clearly marked as such and stored separately in
restricted areas. They shall either be returned to the suppliers or, where
appropriate, reprocessed or destroyed. Whatever action is taken shall be
approved and recorded by authorized personnel.
6.62. The reprocessing of
rejected products shall 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 authorized procedure after evaluation of
the risks involved. Record shall be kept of the reprocessing.
6.63. 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 the defined stage of
manufacture shall be authorized beforehand. This recovery shall be carried out
in accordance with a defined procedure after evaluation of the risks involved,
including any possible effect on shelf life. The recovery shall be recorded.
6.64. The need for
additional testing of any finished product which has been reprocessed, or into
which a recovered product has been incorporated, shall be considered by the
Quality Control Department.
6.65. Products returned
from the market and which have left the control of the manufacturer shall be
destroyed unless without doubt their quality is satisfactory. They may be
considered for re-sale, re-labelling or recovery in 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 shall all be taken into account in this assessment. Where
any doubt arises over the quality of the product, it shall not be considered
suitable for re-issue or re-use, although basic chemical reprocessing to
recover active ingredient may be possible. Any action taken shall be
appropriately recorded.
VII.
Quality control
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Every manufacturing
establishment shall have a quality control system so designed as to ensure that
the products are manufactured in accordance with adequate conditions and
procedures and continue to meet the established specifications.
Quality control is not
confined to laboratory operations, but must involve all decisions which may
concern the quality of the product.
For this purpose there
shall be an appropriate and independent Quality Control Department.
General
7.1. Quality control is
concerned with sampling, specifications, testing, organization, documentation
and release procedures which ensure that the necessary tests are in fact
carried out, and that the materials are not released for use, nor products
released for sale and supply until their quality has been assessed to be
satisfactory.
7.2. The Quality Control
Department shall have a designated area with sufficient and well trained staff
to perform any required analysis before, during and after manufacture.
7.3. If the in-house
Quality Control Department cannot perform certain specific analysis, the
services of accredited/ recognised external laboratory can be used to conduct
the tests.
7.4. Finished products
assessment shall embrace all relevant factors, including production condition,
results of in-process testing, a review of manufacturing (including packaging)
documentation, compliance with Finished Product Specification and examination
of final finished pack.
7.5. Quality Control
personnel shall have access to production areas for sampling and investigation
as appropriate.
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7.7. The identity and
quality of materials and finished products shall be checked/tested. The
presence of individual ingredient in pre-mixes shall be confirmed.
7.8. Besides these
principal duties, the Quality Control Department as a whole will also have
other duties, such as to establish 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, etc. All these operations shall be
carried out in accordance with written procedures and recorded.
7.9. The stability of the
finished product shall be monitored according to a continuous appropriate programme
that will permit the detection of any stability issue associated with the
formulation in the marketed package.
Sampling
7.10. Due to the fact
that crude material shall be an aggregate of individual natural materials i.e.
contain an element of heterogeneity, the sampling has to be carried out with
special care by competent personnel. Each batch shall be identified by its own
documentation.
7.119. Samples are taken at locations free of from
contamination, cross-contamination and mix-ups and following appropriate
procedures, including the following:
7.11.1. The method of
sampling;
7.11.2. The equipment to
be used;
7.11.3. The amount of the
sample to be taken;
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7.11.5. The type and
condition of the sample container to be used;
7.11.6. The
identification of containers sampled;
7.11.7. The storage
conditions;
7.11.7. Instructions for
the cleaning and the storage of sampling equipment.
7.12. Reference samples
shall 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).
7.13. Sample containers
shall bear a label indicating the contents, with the batch number, the date of
sampling and the containers from which samples have been drawn.
7.14. Reference samples
from each batch of finished products shall be retained till one year after the
expiry date. Finished products shall usually be kept in their final packaging
and stored under the recommended conditions. Samples of starting materials
(other than solvents, gases and water) shall be retained for at least two (02)
years after the release of the product if their stability allows. This period
may be shortened if their stability, as mentioned in the relevant
specification, is shorter. Reference samples of materials and products shall be
of a size sufficient to permit at least a full re-examination.
Testing
7.15. All testing
operations described in the marketing authorization shall be carried out
according to approved methods which shall be internationally accepted (refer to
section 11.1).
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7.17. The test performed
shall be recorded and the records shall include at least:
7.17.1. Name of the
material or product and, where applicable, dosage form;
7.17.2. Batch number and,
where appropriate, the manufacturers and/or supplier;
7.17.3. References to the
relevant specifications and testing procedures;
7.17.4. Test results,
including observations and calculations, and reference to any certificates of
analysis;
7.17.5. Dates of testing,
the name of the analyst and the name of the external laboratory, if applicable;
7.17.6. Date and
signature of the persons who performed the testing;
7.17.6. Date and
signature of the persons who verified the testing and the calculations, where
appropriate;
7.17.7. A clear statement
of release or rejection (or other status decision) and the dated signature of
the designated responsible person.
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7.19. Special attention
shall be given to the quality of laboratory reagents, volumetric glassware and
solutions, reference standards and culture media. They shall be prepared in
accordance with written procedures and recorded.
7.20. Laboratory reagents
intended for prolonged use shall be marked with the preparation date and the
signature of the person who prepared them. The expiry date of unstable reagents
and culture media shall be indicated on the label, together with specific
storage conditions. In addition, for volumetric solutions, the last date of
standardization and the last current factor (F) shall be indicated.
7.21. For some kinds of
data (e.g. analytical test results, yields, environmental controls) it is
recommended that records in a manner permitting trend evaluation be kept.
7.22. In addition to the
information which is part of the batch record, other original data such as
laboratory notebooks and/or reports shall be retained and readily available.
Ongoing stability
programme
7.23. After marketing,
the stability of the product shall be monitored according to a continuous
appropriate programme that will permit the detection of any stability issue associated
with the formulation in the marketed package.
7.24. 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.
7.25. This mainly applies
to the product in the package in which it is marketed/sold, but consideration
shall 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 shall be evaluated and studied
under ambient conditions. In addition, consideration shall 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.
7.26. The on-going
stability programme shall be described in a written protocol and results
formalized as a report. The equipment used for the on-going stability programme
(stability chambers among others) shall be qualified and appropriately
maintained.
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7.27.1. Number of
batch(es) per strength and different batch sizes, where applicable;
7.27.2. Relevant
physical, chemical, microbiological and biological test methods, stability
indicating parameters, where applicable.
7.27.3. Acceptance
criteria;
7.27.4. Reference to test
methods;
7.27.5. Description of
the container closure system(s);
7.27.6. Testing intervals
(time points);
7.27.7. Description of
the conditions of storage;
7.27.8. Other applicable
parameters specific to the finished product.
7.28. The protocol for
the on-going stability program can be different from that of the initial
long-term stability study as submitted in the marketing authorization dossier
provided that this is justified and documented in the protocol.
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7.30. In certain
situations, additional batches shall be included in the on-going stability
program. For example, an on-going stability study shall be conducted after any
significant change or significant deviation to the process or package. Any
reworking, reprocessing or recovery operation shall also be considered for
inclusion.
7.31. Results of on-going
stability studies shall be made available to key personnel and, in particular,
to the authorized 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 shall be a written agreement between the parties concerned. Results of
on-going stability studies shall be available at the site of manufacture for
review by the competent authority.
7.32. Out of
specification or significant atypical trends shall be investigated. Any
confirmed out of specification result, or significant negative trend, shall be
reported to the relevant competent authorities. The possible impact on batches
on the market shall be considered in accordance section IX. Complaints and
Product Recalls of the GMP Guide and in consultation with the relevant
competent authorities
7.33. A summary of all
the data generated, including any interim conclusions on the programme, shall
be written and maintained.
7.34. For stability study
requirements, reference shall be made to section 11.3.
VIII.
Contract manufacture and analysis
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 and responsibilities of
each party. The contract must clearly state the way in which the authorized
person releasing each batch of product for sale exercises his full
responsibility.
Contract manufacture
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Contract analysis
8.2. Contract analysis must
have a written contract agreement between the Contract Giver and the Contract
Acceptor which clearly establishes the duties and responsibilities of each
party.
All arrangements for
contract analysis, including any proposed changes in technical or other
arrangements, shall be in accordance with the NRA requirements for the product
concerned.
The contract giver
8.4. The Contract Giver
shall be responsible for assessing the competency of the Contract Acceptor in
successfully carrying out the work/test required and for ensuring by means of
the contract that the principles of GMP described in these guidelines are
followed.
8.5. The Contract Giver
shall provide the Contract Acceptor with all the information necessary to carry
out the contracted operations correctly in accordance with the NRA
requirements. The Contract Giver shall ensure that the Contract Acceptor is
fully aware of any problems associated with the product or the work which might
pose a hazard to his premises, equipment, personnel, other materials or other
products.
8.6. The Contract Giver
shall ensure that all products and materials delivered by the Contract Acceptor
comply with their specifications.
The Contract Acceptor
8.7. The Contract
Acceptor has adequate premises, equipment, knowledge and experience, and
competent personnel to carry out satisfactorily the work ordered by the
Contract Giver. Contract manufacture shall be undertaken only by a manufacturer
who is the holder of a manufacturing authorization issued by the NRA.
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8.9. The Contract
Acceptor shall not pass to a third party any of the work entrusted to him under
the contract without the Contract Giver’s prior to evaluation and approval of
the arrangements. Arrangements made between the Contract Acceptor and any third
party shall ensure that the manufacturing and the analytical information is
made available in the same way as between the original Contract Giver and Contract
Acceptor.
8.10. The Contract
Acceptor shall refrain from any activity that may adversely affect the quality
of the product manufactured/tested for the Contract Giver.
The Contract
8.11. A contract shall be
drawn up between the Contract Giver and the Contract Acceptor, which specifies
their respective responsibilities relating to the manufacture and the control
of the product. Technical aspects of the contract shall be drawn up by
competent persons suitably knowledgeable in traditional medicines and health
supplements manufacturing, analysis and GMP. All arrangement for manufacture
and analysis must be in accordance with the NRA requirement and agreed by both
parties.
8.12. The contract shall
specify the way in which the head of Quality Control Department releasing the
batch for sale ensures that each batch has been manufactured and checked for
compliance with the requirements of the NRAs.
8.13. The contract shall
describe clearly who is responsible for purchasing materials, testing and
releasing materials, undertaking production and quality controls, including
in-process controls, and who has responsibility for sampling and analysis. In
case of contract analysis, the contract shall state whether or not the Contract
Acceptor shall take samples at the premises of the manufacturer.
8.14. Manufacturing,
analytical and distribution records, and reference samples shall 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 must be
accessible and specified in the defect/recall procedures of the Contract Giver.
8.15. The contract shall
permit the Contract Giver to visit the facilities of the Contract Acceptor.
8.16. In the case of
contract analysis, the Contract Acceptor shall understand that he is subject to
inspection by the competent Authorities.
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Principle
All complaints and other
information concerning potentially defective products must be kept and reviewed
according to written procedures. In order to provide for all contingencies, a
system shall be designed to recall, if necessary, promptly and effectively
products known or suspected to be defective from the market.
Product complaints
9.1. Product complaints
are usually concerned with the quality of the product such as its physical
properties, or condition of its packaging. Complaints (internal or external)
could be made to the manufacturer, verbally or in writing by consumers,
distributors or the NRA.
9.2. All complaints shall
be investigated and evaluated. Written procedures describing the handling of
all written and verbal complaints regarding the product shall be established
and followed. Such procedures shall include provisions for review by the
Quality Control unit. A written record of each complaint shall be maintained in
a file designated for product complaints.
9.3. A person shall be
designated responsible for handling the complaints.
9.4. There shall 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.
9.5. Any complaint
concerning a product defect shall be recorded with all the original details and
thoroughly investigated. The person responsible for Quality Control shall be
part of the team.
9.6. Special attention
shall be given in establishing whether the product which is the subject of a
complaint, genuine or is a counterfeit product.
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9.8. All decisions and
measures taken as a result of a complaint shall be recorded and referenced to
the corresponding batch records.
9.9. Complaint records
shall be reviewed regularly for any indication of specific or recurring
problems requiring attention and possibly the recall of marketed products.
9.10. For recurring
problem, a trending shall be established in order to identify the possible
systemic defects.
9.11. The NRA shall be
informed if a manufacturer is considering action following possibly faulty
manufacture, product deterioration, or any other serious quality problems with
a product.
9.12. The NRA and the
complainant shall be furnished with a summary of the action taken.
Product recalls
9.13. Responsibility and
procedures for recall of the product shall be established by the manufacturer
to facilitate the recall of a batch from any link of the distribution chain
when this becomes necessary.
9.14. The recall
procedures shall take into account the degree and level of recall which in line
with the NRA requirement.
9.15. Any action taken to
recall a product suspected or known to be defective or hazardous, shall be done
immediately and in accordance with a pre-determined plan. The procedures to be
followed shall be specified in writing and made known to all that may be
concerned.
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9.17. There shall be
established written procedures, regularly checked and updated when necessary,
in order to organize any recall activity.
9.18. Recall operation shall
be capable of being initiated immediately and at any time.
9.19. All NRA of all
countries to which products may have been distributed shall be informed
immediately if products are intended to be recalled because they are, or are
suspected of being defective.
9.20. The distribution
records shall be readily available to the person(s) responsible for recalls,
and shall contain sufficient information on distributor/retailer/wholesalers
and directly supplied customers (with latest and valid addresses, contact
number including mobile phone, phone and/or fax numbers inside and outside
working hours, batches and amounts delivered), including those for exported
products.
9.21. Recalled products
shall be identified, recorded and stored separately in a secure area while
awaiting a decision on their fate.
9.22. The progress of the
recall process shall be recorded and a final report issued, including
reconciliation between the delivered and recovered quantities of the products.
9.23. The effectiveness
of the arrangements for recalls shall be evaluated regularly.
Complaints on adverse
product reactions
9.24. Unexpected adverse
product reactions resulting from the use of the product must be thoroughly
investigated and documented. Reports of serious unexpected adverse reactions
shall be immediately forwarded to the NRA.
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Principle
Self-inspections shall be
conducted in order to monitor the implementation and compliance with Good
Manufacturing Practice principles and to propose necessary corrective measures.
10.1. Personnel matters,
premises, equipment, documentation, production, quality control, distribution
of the products, arrangements for dealing with complaints and recalls, and
self-inspection, shall be examined at intervals following a pre-arranged program
in order to verify their conformity with the principles of Quality Assurance.
10.2. Self-inspection
shall be conducted in an independent and detailed way by designated competent
person(s) from the company. The independent audits by external experts may also
be useful.
10.3. All
self-inspections shall be recorded. Reports shall contain all the observations
made during the inspections and, where applicable, proposals for corrective
actions and preventive actions, and corresponding time frames. Statements on
the actions subsequently taken shall also be recorded.
10.4. Reference shall be
made to section 11.4. Self-inspection checklist.
XI.
Other contents
11.1. List of
internationally accepted references for test methods
1) Internationally
accepted Pharmacopoeia including European Pharmacopoeia, US Pharmacopoeia,
British Pharmacopoeia, Japanese Pharmacopoeia.
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- ISO Standard - ICS 67 -
Food Technology;
- ISO Standard - ICS
67.050 - General methods of tests and analysis for food products.
3) American Herbal
Pharmacopoeia (AHP).
4) Food Chemicals Codex
(FCC).
5) Association of
Official Analytical Chemist International: Official Methods of Analysis.
6) Microbiologicals: US
Food and Drug Administration Bacteriological Analytical Manual.
7) Office of Dietary
Supplement, National Institute of Health. US: Dietary Supplement Analytical
Methods/ Reference Materials (AMRM) Program.
http://ods.od.nih.gov/Research/AMRMProgramWebsite.aspx.
8) WHO – Quality Control
Methods for Herbal Materials, 1998 (first version) and update version.
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Note: The use of this list is subject to the consideration,
regulations and prerogative of each national regulatory authority. Other
references may be considered by national regulatory authority, provided that
the test methods are validated against guidelines/parameters defined by
ICH/ASEAN Guidelines for Validation of Analytical Procedures.
11.2. Verification
Principle
11.2.1. This Appendix
describes the principles of verification which are applicable to the
manufacture of health supplements.
Accordingly, and in this
Appendix, verification shall refer to the documented act or conduct of
confirmation that the control or procedure required in a particular critical
aspect of manufacturing operation has been complied with or satisfactorily
implemented by the manufacturer based on risk assessment and risk management.
Re-verification shall be
performed if there are significant changes to the facilities, systems,
processes and equipment that may have impact on the quality of the finished
products, and the changes would require regulatory approval. Where there are no
significant changes, periodic review shall be performed to show that the
facilities, systems, processes and equipment continue to meet the prescribed
requirements.
Documentation
11.2.2. A verification
programme which includes written procedure(s) shall be established to specify
how the verification activities will be carried out. The documentation provided
will demonstrate the quality assurance systems needed to produce quality health
supplements. This includes the QA systems, which consist of elements that
address matters such as roles and responsibilities, employee training, document
management, equipment calibration and maintenance, manufacturing and laboratory
control procedures, and product shelf life evaluation.
A report that
cross-references the verification programme and procedure shall be prepared,
summarizing the results obtained, commenting on any deviations observed, and
drawing the necessary conclusions, including the recommending changes necessary
to correct the deficiencies.
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11.2.3. Equipment and
machinery shall be periodically verified to determine if they are still
operating in a valid state.
During verification, it
is important to use calibrated reference material e.g. NIST traceable
calibrated thermometer to verify the temperature of process to determine its
valid state.
Machinery and equipment
to be used shall have been verified prior to the verification of process and
staff taking part in verification work shall have been appropriately trained.
Verification of
process
11.2.4. General
Verification of process
contributes to assuring product quality and the basic principle of quality
assurance is that a product shall be produced under such condition that is fit
for its intended use.
The basic principle of quality
assurance is that a product shall be consistently produced and controlled to
the quality standards appropriate to their intended use and as required by the
marketing authorization and product specification.
11.2.5. Verification of process
may involve demonstration, testing & analysis and in-process control, or
other relevant to confirm that critical processes are kept under control. A
process verification report shall be prepared to provide evidence that the
process has been verified.
a) Demonstration
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Demonstrations can be
conducted in actual or simulated environments.
b) Testing and Analysis
Test is the application
of scientific principles and procedures to determine the properties or
functional capabilities of items.
Test is similar to
demonstration, but is more exacting, generally requiring specialized test
equipment/configuration/data/procedure in order to verify that the item
satisfies the requirement.
Analysis is the use of
established technical or mathematical models or simulations, algorithms, or
other scientific principles and procedures to provide evidence that the item
meets its stated requirements.
c) In-process control
Critical parameters shall
be determined and monitored, checks performed during production in order to
monitor and if necessary to adjust the process to ensure that the products
conform to its specification. The control of the environment or equipment may
also be regarded as a part of in-process control.
Change control
11.2.6. Written
procedures shall be in place to describe the actions to be taken if a change is
proposed to a starting material, product component, process equipment, process
environment (or site), method of production or testing or any other change that
may affect product quality or reproducibility of the process. Change control
procedures shall ensure that sufficient supporting data are generated to
demonstrate that the revised process will result in a product of the desired
quality, consistent with the approved specifications.
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11.3. Guidelines on
stability study and shelf-life of health supplements
Introduction
Stability is an essential
factor of quality in health supplements. It is determined by a series of
chemical, physical and microbiological tests conducted, namely to ensure
maintenance of the specifications of the finished product stored in the
established storage condition within the determined shelf-life.
Objective
This guideline is
intended to provide recommendations on the core stability study required for
products. Nevertheless it leaves sufficient flexibility to encompass the
variety of different practical situations that may be encountered due to
specific scientific considerations and characteristics of the products being
evaluated.
Design
11.3.1. General
The design of a stability
study for the product should be based on the nature of the product. It should
take into account of the following:
- Selection of batches;
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- Testing frequency;
- Container closure
system.
11.3.2. Selection of
batches
Stability data should be
provided for batches of the same formulation and dosage form in the container
closure system intended for marketing.
- Stability data from at
least two batches would be required, derived either from pilot scale, primary
scale, production scale or their combination.
- The manufacturing
process of batches used in stability studies should simulate that of production
batches and should be of the same quality as well as meet the same specification
as those batches intended for marketing.
- Stability studies
should be performed on individual strengths of the product and/or type of
container closure system in which the finished product is packed unless bracketing/matrixing
is applied as in the section “Reduced design”.
11.3.3. Specification and
testing parameters
A stability study should
cover the testing of the physical, chemical and microbiological properties of a
finished product that are susceptible to change during storage and are likely
to influence quality when changed.
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For a combination product
containing multiple active ingredients, although it may not be necessary to
assay all the active ingredients. It may be appropriate to assay one, and in
some cases, more than one active ingredient, or a surrogate marker that is
known to be susceptible to change under storage condition (such as temperature
and/or humidity) and is likely to influence the quality of the combination
product. A valid justification shall be submitted. For a product containing
ingredients without known marker(s), physical parameters may be used as
surrogate indicators during storage, when the use of such parameters can be
justified.
11.3.4. Testing frequency
For accelerated and real
time stability studies, frequency of testing should be sufficient to establish
the stability profile of the finished product. At the accelerated storage
condition, a minimum of three time points, including the initial and final time
points, for example, 0, 3, and 6 months for a 6-month study, is recommended.
The frequency of testing
at real time storage conditions should normally be every 3 months over the
first year, every 6 months over the second year and annually thereafter through
the proposed shelf-life.
Table 1: A typical
testing frequency
Storage condition
Testing frequency
Real time
0, 3, 6, 9, 12, 18, 24
months and annually thereafter through the proposed shelf-life
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0, 3 and 6 months
Reduced designs, i.e.,
matrixing or bracketing, where the testing frequency is reduced or certain factor
combinations are not tested at all, can be applied, if justified, as in the
section “Reduced design”.
Where an expectation
exists that outcomes from accelerated studies are likely to approach
significant change criteria, i.e. parameters tested are out of the
specifications set, it is advised an increased testing should be conducted
either adding samples at the final time point or by including a fourth time
point in the study design.
If the “significant change”
occurs within the first 3 months’ testing at the accelerated storage condition,
a justification should be provided to address the effect of short term
excursions outside the label storage condition, e.g, during shipping or
handling. This justification can be supported, if appropriate, by further
testing on a single batch of the product for a period shorter than 3 months but
with more frequent testing than usual. It is considered unnecessary to continue
to test a product through the remaining months when a “significant change” has
occurred within the first 3 months, and as such the shelf-life shall be based
on real time data.
If “significant change”
occurs between 3 and 6 months’ testing at the accelerated storage condition,
shelf-life shall be based on real time data (often found in preparations such
as cream or grease which cannot be tested under accelerated conditions).
11.3.5. Storage
conditions
In general, HS as a
finished product should be evaluated under its storage conditions (with
appropriate tolerances) that test its thermal stability under recommended
storage conditions and, if applicable, its sensitivity to moisture or potential
for solvent loss.
The storage conditions
and the lengths of studies chosen should be sufficient to cover storage, shipment,
and subsequent use, for example, after reconstitution or dilution as
recommended in the labeling.
Specific recommended
temperature and relative humidity conditions for storage applied to stability
studies and types of container closure system are based on the nature of the
products and the type of primary container used, in accordance with recommended
storage condition on product label. Common storage conditions are shown in
Table 2 below.
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Type of container closure system/study
Storage condition
Products in primary
containers permeable to water vapor
30°C±2°C; Relative
humidity 75% ±5%.
Products in primary
containers impermeable to water vapor
30oC±2oC
Accelerated studies
40°C±2°C; Relative
humidity 75% ±5%.
If submitted data is
based on conditions that are less stressful (e.g. 30°C/65% RH) than those
required, the data should be accompanied by appropriate complementary data
which will permit to conduct a proper scientific evaluation under the condition
recommended on the label (climate condition in the region/country where the
product is expected to be marketed). Factors to be taken into consideration
will include:
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● Whether data have also been
provided under accelerated conditions;
● The type of container
closure system.
Other storage conditions
are allowable, if justified. Examples would include:
● Heat sensitive products
which should be stored under lower temperature condition which will eventually
become the designated long term storage temperature.
- Products containing
less stable active ingredients and formulations not suitable for storage at
elevated temperature will need real time stability studies.
- When a lower
temperature condition is used, the 6 month accelerated testing should be
carried out at a temperature at least 150C above the expected actual
storage temperature (together with appropriate relative humidity conditions for
that temperature). For example, for a product to be stored long term under
refrigerated conditions, accelerated testing should be conducted at 25ºC ± 2ºC,
60% RH ± 5% RH. The designated real time testing conditions will be reflected
in the labelling and shelf-life (expiration date). Typical storage conditions
recommended for stability studies on products intended for storage in a
refrigerator as shown in Table 3 below.
● Products which change
physically or even chemically at lower storage temperature conditions e.g.,
suspensions or emulsions.
Table 3: Typical storage
conditions recommended for products intended in a refrigerator
Study
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Real time
5oC±3oC
Accelerated studies
25oC±2oC.
Relative humidity 60% ±5%
Data from the accelerated
stability studies can be used to evaluate the effect of short-term excursions
outside the label storage conditions such as during shipping. The data from
accelerated study and ongoing real time stability study can be used to justify
an interim extrapolated shelf-life. However, the actual shelf-life should be
based ultimately on the real time stability data at the recommended storage
conditions.
11.3.6. Container closure
system
Stability testing should be
conducted on the product packaged in the primary container closure system
proposed for marketing including, as appropriate, any secondary packaging.
Finished products packed
in moisture-impermeable primary containers are not required to be tested under high
humidity conditions. Generally considered moisture-impermeable containers
include aluminium/aluminium blisters, High Density Polyethylene (HDPE) or glass
bottles fitted with metal or HDPE closures.
When using
moisture-permeable containers for packaging, due to consideration should be
given to the stability of the contents under high humidity conditions. Moisture
may have an undesirable effect on chemical and physical stability of a finished
product.
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11.3.7. Evaluation
A systematic approach
should be adopted in the presentation and evaluation of the stability
information, which should include, as appropriate, results from the physical,
chemical and microbiological tests. Any evaluation should consider not only the
assay, but also other appropriate test attributes. A recommended presentation
of the summary table of stability results appears as in the section
“Recommended presentation of the summary table of stability results”.
11.3.8. Labelling
The storage conditions
that include temperature, light and humidity indicated on the label should be
based on the stability evaluation of the product. General precautionary
statements, such as “Protect from light” and/or “Store in a dry place”, may be
included, but should not be used to conceal stability problems of the finished
product. Specific instruction on storage condition should be provided. Terms
such as “ambient conditions” or “room temperature” should be avoided.
Glossary
For the purposes of this
Appendix, the terms below shall be construed as follows:
1. Assay: A test
procedure for measuring or determining the quantity of active ingredient or
marker in a finished product.
2. Batch: A defined
quantity of starting material, packaging material or product produced during a
given cycle (in a single process or series of processes) and from a specific
formulation order, that is uniform in character and quality (the essence of a
manufacturing batch is its homogeneity). 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.
3. Pilot scale batch: A
batch of substances or product manufactured by procedure fully representative
of and simulating that to be applied to a full production scale batch. A pilot
scale is generally, at minimum, one tenth that of a full production scale.
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5. Production scale
batch: A batch of product manufactured at production scale by using production
equipment in a production facility as specified in the application.
6. Specification: A list
of tests, references to analytical procedures, and appropriate acceptance
criteria which are numerical limits, ranges, or other criteria for the tests
described. Specification is used as the basis for quality assessment.
“Conformance to specification” means that the product, when tested according to
the listed analytical procedures, will meet the acceptance criteria. The set of
criteria to which a substance, product or material at stages of its manufacture
should conform to shall be considered acceptable for its intended use.
Specifications are critical quality standards that are proposed and justified
by the manufacturer and approved by regulatory authorities as conditions of
approval.
7. Stability study
protocol: A document describing rationale, goals, methodology, and statistical
methods of the stability study which specifies the terms and conditions under
which the stability study must be conducted and managed.
8. Stability studies:
Real time and accelerated studies/testing undertaken on primary batches
according to a prescribed stability protocol to establish or confirm the
re-test period of a substance or shelf-life of a finished product.
- Accelerated stability
studies: Studies designed to increase the rate of chemical degradation or
physical change of a finished product by using exaggerated storage conditions
as part of the formal stability studies. Data from these studies, in addition
to long-term stability studies, can be used to assess longer term chemical
effects at non-accelerated condition and to evaluate the effect of short term
excursions outside the label storage conditions such as might occur during
shipping. Results from accelerated testing studies are not always predictive of
physical changes.
- Real time stability
studies: stability studies under the recommended storage condition for the
re-test period or shelf-life proposed (or approved) for labeling.
9. Storage condition:
condition for intended storage of a finished product defined on the container
label based on the stability study.
Reduced design
A full study design is
one in which samples for very combination of all design factors are tested at
all time points. A reduced design is one in which samples for every factor
combination are not all tested at all time points. A reduced design can be a
suitable alternative to a full design when multiple design factors are
involved.
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During the course of a
reduced design study, a change to full testing or to a less reduced design can
be considered if justification is provided and the principles of full designs
and reduced design studies are followed. Proper adjustments should be made to
the statistical analysis, where applicable, to account for the increase in
sample size as a result of the change. Once the design is changed, full testing
or less reduced testing shall be carried out through the remaining time points
of the stability study.
Bracketing
Bracketing is the design
of a stability schedule such that only samples on the extremes of certain
design factors, for example, strength, container size and/or fill, are tested
at all time points as in a full design. The design assumes that the stability
of any intermediate levels is represented by the stability of the extremes
tested.
Design example
An example of a
bracketing design is given in Table 4 below. This example is based on a product
available in 3 strengths and 3 container sizes. In this example, it
demonstrated that the 15 ml and 500 ml high-density polyethylene container
sizes truly represent the extremes. The batches for each selected combination
should be tested at each time point as in a full design.
Table 4: Example of
Bracketing Design
Strength
50 mg
75 mg
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Batch
1
2
3
1
2
3
1
2
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Container size (ml)
15
T
T
T
T
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T
100
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500
T
T
T
T
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T
T = Sample tested
Matrixing
Matrixing is the design
of a stability schedule such that a selected subset of the total number of
possible samples for all factor combinations would be tested at a specified
time point. At a subsequent time point, another subset of samples for all factor
combinations would be tested.
The design assumes that
the stability of each subset of samples tested represents the stability of all
samples at a given time point.
The differences in the
samples for the same finished product should be identified as, for example,
covering different batches, different strengths, different sizes of the same
container closure system, and possibly, in some cases, different container
closure systems.
When a secondary
packaging system contributes to the stability of the finished product,
matrixing can be performed across the packaging systems. Each storage condition
should be treated separately under its own matrixing design. Matrixing should
not be performed across test attributes. However, alternative matrixing designs
for different test attributes can be applied if justified.
Design examples
Examples of matrixing
designs on time points for a product in two strengths (Sl and S2) are shown in
the Table below. The terms “one-half reduction” and “one-third reduction” refer
to the reduction strategy initially applied to the full study design. For
example, a “one- half reduction” initially eliminates one in every two time
points from the full study design and a “one-third reduction” initially removes
one in every three. In the examples shown below, the reductions are less than
one-third due to the inclusion of full testing of all factor combinations at
some time points. These examples include full testing at the initial, final,
and 12- month time points as shown in the table below.
...
...
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Time point (months)
0
3
6
9
12
18
24
36
...
...
...
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S1
Batch 1
T
T
T
T
T
...
...
...
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Batch 2
T
T
T
T
T
...
...
...
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Batch 1
T
T
T
T
T
...
...
...
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T
T
T
T
T
T
(T = Sample
tested)
...
...
...
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At least 4 out of 8 time points
● Example of Matrixing
Design on Time Points for a Product with Strengths “One-Third Reduction”
Time point (months)
0
3
6
9
...
...
...
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18
24
36
Strength
S1
Batch 1
T
T
T
...
...
...
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T
T
T
T
Batch 2
T
T
T
T
...
...
...
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T
T
S2
Batch 1
T
T
T
...
...
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T
T
T
Batch 2
T
T
T
T
...
...
...
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T
(T = Sample
tested)
At least 8 out of 12 time points
At least 6 out of 8 time points
● Example of Matrixing Design
on Time Points for a Product with three Strengths “One-Third Reduction”
Time point (months)
...
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3
6
9
12
18
24
36
Strength
S1
...
...
...
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T
T
T
T
T
T
T
Batch 2
...
...
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T
T
T
T
T
S2
Batch 1
...
...
...
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T
T
T
T
T
Batch 2
T
...
...
...
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T
T
T
T
S3
Batch 1
T
...
...
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T
T
T
T
T
T
Batch 2
T
T
...
...
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T
T
T
T
(T = Sample
tested)
At least 12 out of 18 time points
At least 8 out of 12 time points
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Recommended presentation
of the summary table of stability results:
Testing parameters
Organoleptic characteristic
Assay
Hardness/ friability
Dissolution/ disintegration
Water content
Viscosity
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Microbial content
Granules/Particle size
Resuspendability
Health supplement dosage form
Oral
powder
...
...
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Hard capsule
...
...
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Soft
capsule
...
...
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Coated
and uncoated tablet
...
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Coated
and uncoated pill/pellet
...
...
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...
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...
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Solution
...
...
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Emulsion
...
...
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Granules
...
...
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Recommended presentation
of the summary table of stability results
Product name:
……….
Storage condition:
……….
Dosage form:
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Batch No.
……….
Strength:
……….
Manufacturing date:
……….
Container:
……….
Date of report:
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Pack size:
……….
Period of the study:
……….
Testing parameters (as applicable)
Acceptance criteria
Testing frequency (months)
0
...
...
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6
9
12
18
24
…
Organoleptic
characteristic
...
...
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Strength
...
...
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Hardness
...
...
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Dissolution
...
...
...
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Humidity
...
...
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Microbial content
...
...
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…
...
...
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Conclusion:
……………………………………………………………………………………
Prepared by
Checked by
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11.4. Self-inspection
checklist
11.4.1. Purpose
The purpose of
self-inspection is to sufficiently determine information and evaluate the
compliance with GMP in order to detect any shortcomings and defects in the
implementation of GMP and to recommend the necessary corrective actions. The
procedure for self-inspection should be documented, including a detailed
self-inspection checklist.
In case of difference in
production lines, dosage form and investment scale, each manufacturer shall produce
and promulgate a self-inspection checklist appropriate to its condition. The
preparation and application of a selft-inspection checklist shall be relevant
to the objective and nature of the inspection (initial or repeated, periodic or
unscheduled, general or thematic evaluation). This checklist shall be developed
and/or adjusted according to the following self-inspection questionnaire.
11.4.2. Main contents
1) General information
about the Company
2) Quality management
3) Personnel and training
4) Premises and equipment
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6) Documentation
7) Manufacturing and
manufacturing process control
8) Quality control
9) Contract manufacture
and analysis
10) Complaints and
product recalls
11) Self-inspection
11.4.3. Guidance on
response to questionnaires
- Regarding open
questions: add details to the blank.
- Regarding closed-ended
questions, place a check mark “√” in the answer box.
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11.4.4. Contents
1. General information
about the Company
- Name/address: ………………………………………………………………
- Telephone/fax:
……………………………………………………………
- Place of manufacturing:
…………………………………………….……….
- Representative of the
company/position: ………………………………………….…….
- Total number of
employees: ……………………………………………………….
- Number of personnel
working in production areas: ………………………….…
- Authorization of the
National Regulatory Authority: …………………………
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- Organization chart:
…………………………………………………………….
- Training result:
………………………………………………………….
- Diagrams of production areas
(geographical premises; line arrangement; class of cleanliness; layout, raw
materials, bulk products, semi-finished products): ………………………………………………………………
- Diagram of ancillary
systems (air handling system, industrial water supply system, wastewater treatment
system, fire fighting system): ..…...
- Manufacturing
activities: product types, inspection during manufacturing process, supplier
evaluation: ………………………………….………..
- Quality assurance
system, quality control system: ………………………
- Internal audit: …………………………………………………………...
2. Self-inspection
questionnaire
No.
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Applicable
Not applicable
Pass
Fail
Quality management
1
Whether quality
policies and commitments are determined, and formally promulgated by
competent persons.
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2
Whether a quality
management system, including quality manual, procedures, resources and
organization structure concerned is established.
3
Whether managerial
responsibilities are clearly documented.
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4
Whether arrangements
are made for the manufacture, supply and use of the correct starting and
packaging materials.
5
Whether in-process
controls are established and maintained according to the approved procedures.
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6
Whether persons
responsible for batch certification are assigned.
7
Whether before release,
each batch is reviewed, certified and checked according to procedures and
specifications.
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8
Whether a plan for initial
or periodic verification of critical steps of a manufacturing process is
prepared.
9
Whether critical steps
or significant changes that affect product quality during the manufacturing
process are verified.
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10
Whether records
covering manufacture, which enable the complete history of a batch to be
traced are prepared.
11
Whether there are
adequate procedures for sampling, inspecting and testing starting materials,
intermediate, bulk, and finished products, and for monitoring environmental
conditions for GMP and checking measuring equipment.
...
...
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12
Whether quality control
is sufficiently documented.
13
Whether product quality
reviews are conducted according to GMP recommendations.
...
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14
Whether there are
self-inspection/internal audit programs.
I. Personnel
15
Whether the
organization chart is updated (by the time of self-inspection).
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16
Whether the
organization chart consists of the following (and the respective quantity):
Production department:
………………………………..… persons
Quality control
department: ………………….… persons
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Other departments
(please specify):
- ………………………………………………….
persons
- ………………………………………………….
persons.
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Whether the head of
Production Department and the head of Quality Control Department are
independent of each other.
18
Whether these key posts
are occupied by full-time personnel.
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Information about the
head of the production department:
- Knowledge (GMP,
manufacturing, etc.): …………..………………….
- Qualifications:
………………………….
- Skills:
……………………………………………………
- Experience (manufacturing,
manufacturing management): ……..
20
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- Knowledge (GMP,
testing, etc.): …………..………………….
- Qualifications:
………………………….
- Skills:
……………………………………………………
- Experience (testing,
testing management): ……………………………………………………
……………………………………………………
21
...
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Line-based (and the
respective quantity on each line):
- Line A:
……………………………………………………
- Line B:
……………………………………………………
Step-based (and the
respective quantity required for each step):
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- Preliminary
processing: ……………………………………………………..
- Processing:
…………………………………………………..
- Shaping:
………………………………………………….
- Primary packaging:
……………………………………………
- Secondary packaging:
……………………………………………
Combined line and step
(and the respective quantity):
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- Preliminary
processing line A: ……………………………………………………
- Processing line B:
……………………………………………………
22
Organization and operation
of the Quality Control Department [arranged by tests (chemical, physical,
physicochemical or microbiological test); by items (materials, packaging,
bulk or finished products); by activities (standard
establishment/verification, application registration, testing, stability
monitoring, production condition verification/assessment, inspection,
supervision), etc.] and respective quantity of each unit:
...
...
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23
In-process control
personnel belonging to:
- Quality Control
Department (and quantity): ……………..
- Or Production
Department (and quantity): ……………………..
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24
Job description of:
- Head of Production
Department: ………………………………….
- Head of Quality
Control Department: ……………………
- Head of another department:
………………………
25
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...
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- Group …:
………………………………………………….
- Group …:
………………………………………………….
26
Whether all personnel undergo
initial and regular health examinations and medical records are sufficiently
retained.
...
...
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27
Whether all personnel
receive training in GMP
28
Whether all personnel receive
training in SOPs, relevant professional operations and knowledge.
...
...
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29
Whether new personnel
training procedures are available.
30
Whether the training is
provided according to the approved plan, programme and contents.
...
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31
Whether trainers have
knowledge and experience and have provided training in GMP
32
Whether after each
training course, results and effectiveness of training are assessed and all
training records are retained.
...
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II. Premises and
equipment
Premises
33
Whether the
establishment manufactures products containing sensitizing materials such as
penicillins, hormones or live microorganisms or products intended for
external use.
34
Whether dedicated
facilities are available for the production of these products.
...
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35
Whether production,
testing, storage and ancillary areas are appropriately located and designed.
36
Premises are well
maintained.
...
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37
Whether design drawings
(general, detailed) are updated.
38
Whether relevant
parameters are verified and assessed again after changes are made.
...
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39
Whether there are adequate
toilets, which are well ventilated and separated from other areas, and do not
have direct access to production and storage areas.
40
Whether risk or
condition that insects or other animals access and harbor is available.
...
...
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41
Whether access to
relevant areas is restricted to authorized personnel.
Production areas
42
...
...
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43
Whether changing rooms are
directly connected to but separated from production areas.
44
...
...
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45
Whether production areas
provide adequate space for the installation/maintenance/repair of equipment,
production operations and easy cleaning.
46
...
...
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47
Whether pipework, light
fittings, ventilation points and other facilities shall be appropriately
sited to facilitate cleaning.
48
...
...
...
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- Information about
materials for walls/floors/ceilings: ….…/……/…..
- Information about
filter classes/pressure difference: ………/….……
49
Whether there is any
peeling paint or crack in these areas.
...
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50
Whether separate spaces
are created for cleaning of production equipment to avoid contaminating clean
areas.
51
Whether areas where for
containers for waste generated during the manufacturing process and waste
routes are appropriately defined to avoid contaminating products and clean
areas.
...
...
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52
Whether wastewater is
collected by anti-syphon traps.
53
Whether open channels
are shallow enough to facilitate cleaning.
...
...
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54
Whether parameters lighting
(a), temperature (b), humidity (c) and ventilation (d) are established,
assessed and maintained in a manner that is appropriate to steps of each
line:
a) Information about
Line 1:
Area/step
...
...
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Toilet and changing clothes
for the first time
...
...
...
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Weighing natural raw
materials and initiating preliminary processing
Changing clothes for
the second time
...
...
...
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Weighing raw materials
and initiating processing
...
...
...
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Shaping and primary
packaging
Secondary packaging
...
...
...
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b) Information about
Line 2: ……………………………………
55
Whether the
abovementioned parameters are monitored with appropriate frequency to maintain
to during the production.
Clearly specify control
measure: ………………………
...
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56
Whether a limit is
imposed on the abovementioned parameters and measures to be taken if such
limit is exceeded.
57
Whether the measurement
of particles in clean zones is carried out after completing the construction
of premise and installation of equipment, and are carried out at regular
intervals:
- Quantity/m3:
… (particles ≥ 0.5 µm); … (particles ≥ 5.0 µm)
...
...
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58
Whether special
requirements are imposed on controlled areas of facilities manufacturing
products at risk of generating microorganisms, such as soft pellets, syrups,
preparations extracted from herbal ingredients, etc.
- Clearly specify
control measure: ……………………
-
Maximum Colony Forming Units per volume of air
and/or surface area of equipment: …/ … /………
- Testing frequency:
……………
...
...
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59
Specify dust control
measures taken in production areas or products that may generate dust:
…………………………………………
Storage areas
60
Whether there are
separate areas for storage of starting materials, packaging materials and
finished products, which provide adequate space and are under appropriate temperature
and humidity conditions.
...
...
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61
Whether there are
separate areas for the receipt, quarantine, storage and release in the
abovementioned areas.
62
Whether if special storage
conditions are required (temperature, humidity or ventilation), these
conditions are monitored using calibrated equipment.
...
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63
Whether there are separate
areas for isolation and locks for printed packaging materials,
materials/rejected products, residues/scrap, recalled/returned products.
64
...
...
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65
Whether there are
separate areas for storage of crude natural materials, materials or flammable
substances.
Testing areas
...
...
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Whether there are laboratories
separated from production areas.
67
Whether there are
microbiological laboratories, which meet design requirements.
...
...
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Whether working rooms
are appropriately located and provide sufficient space. Information about rooms
and respective area: ………
69
Whether there are
sufficient equipment and utensils that basically meet requirements for
testing of materials, products, assessment/monitoring of
environment/production conditions and that undergo assessment prior to use.
List main analytical
equipment: ……………………
...
...
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Ancillary areas
70
Whether ancillary areas
are separated from production, testing and storage areas.
List ancillary areas:
……………………
...
...
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Whether ancillary areas
are located and designed in a safe and sanitary manner.
Equipment and
utensils
72
Whether there is
sufficient production equipment appropriate to current production line(s).
...
...
...
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73
Whether such equipment
is designed with appropriate power.
...
...
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74
Whether auxiliary parts
of production equipment such as exhaust pipe of capsule filling machine,
static drying chamber, motor/drive, etc. are appropriately covered and cleaned
at regular intervals.
75
Whether surface of
equipment, utensils, pipes and filters in direct contact with materials and
products is made of inert materials that are not additive and permit easy
cleaning.
...
...
...
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76
Whether equipment is
installed and located in a space wide enough for the operation, cleaning or
maintenance.
77
...
...
...
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78
Whether fixed pipes are
installed inclined to avoid the stagnation of rinsing water.
...
...
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79
Whether valves intended
for closing/opening flow of materials/liquid products are used. If available,
specify microbiological contamination control measure: …………
80
Whether fixed pipework
is clearly labeled to indicate the contents and direction of flow.
...
...
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81
Whether equipment is evaluated
and tested prior to use and periodic maintenance.
82
...
...
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83
Whether defective equipment
is removed from production areas or covered to avoid contamination or clearly
labeled as unusable in case of failure to move.
...
...
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Utility system
84
Whether ancillary utility
system is designed and installed in a manner that ensures integrity of
materials, in-process products and finished products.
List current utilities:
……………………
...
...
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Whether maintenance and
cleaning programme is designed for each ancillary system and complied with.
86
Whether there are
standards and written procedures for the operation of systems, sampling and
monitoring.
...
...
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87
Whether defined actions
are taken to handle the cases in which the standards are not met.
Air handling system
...
...
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Whether air handling
and supply system satisfies temperature, humidity and ventilation
requirements.
89
Whether system diagram is
located at locations that permit easy monitoring and handling in case of
incidents.
...
...
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Whether pipework is
clearly labeled to indicate the direction of air flow.
91
Whether exhaust gas is filtered
and/or appropriately handled before being released into the environment.
...
...
...
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Whether the air supply
system is periodically fumigated in areas at high risk of causing
microbiological contamination to products.
93
Whether pipework is
made of materials impermeable to disinfectants.
...
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Whether the ability to
filter air is appropriate to the expected cleanliness level and minimize the
effect of contamination and cross-contamination on operations.
95
Specify design value,
warning/action limits and recording/monitoring frequency corresponding to the
parameters: filter class (a), pressure difference before/after
intermediate/final filtration (b), pressure difference between rooms/halls in
areas which have various cleanliness levels or require various controls (c)
number of air exchanges (d), room temperature/humidity (dd) of the following
areas:
Warehouses storing
materials and packaging that only require air ventilation: ……
...
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Warehouses storing
materials and packaging that require temperature/humidity control: ….
Preliminary processing
areas: ………………………………………………
...
...
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Processing and primary packaging
areas (open materials/products):
……………………………………………………………….……
Secondary packaging
areas and finished product warehouse:
…………………..
...
...
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Microbiological
laboratories and sampling areas: ………………
Physicochemical laboratories
and sample retention rooms: …………………..
...
...
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96
Whether air handling
and supply system is verified prior to use, periodic assessment is carried
out, records are made and documents are retained.
97
Is HEPA filter installed
for air supplied to rooms/areas presenting high risk to materials and
products?
...
...
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98
Whether there are
appropriate monitoring and control measures for ensuring integrity of HEPA
filters.
99
Whether pre or intermediate
filters are periodically cleaned or appropriately replaced.
...
...
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Water treatment
system
100
Whether water treatment
and supply system is appropriate to its intended use.
101
Whether water used for cleaning
and preliminary processing of natural raw materials satisfies standards for
domestic water.
...
...
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102
Specify sources of
domestic water used by plants (well water, drilled well water, tap water,
etc.): ………………………
103
Whether water used for
processing (and rinsing equipment and utensils in clean areas) satisfies
standard for drinking water or standard for pure water according to Vietnam’s
pharmacopoeia.
...
...
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104
Specify the technology for
treating such kind of water: ………………………
105
Whether pipework is
clearly labeled to indicate the name and direction of flow.
...
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106
Whether pipework is
made of appropriate materials that are not reactive or additive to such an extent
that it will affect the quality of water.
107
Specify materials for
producing pipes conveying drinking water or pure water used for producing
products at high risk of causing microbiological contamination: ……………………….
...
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108
Whether there are
programmes and plans for sampling and water quality inspection.
109
Whether limit on
microbiological and physicochemical criteria are imposed and controlled
appropriately and effective measures are taken if such limit is exceeded.
...
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Compressed air
system
110
Whether the
establishment that uses compressed air for production:
Whether the
establishment uses compressed air for production, which:
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comes into contact with
products (extracting, packing, etc.) and/or clean utensils
111
or only supports
production (lifting, etc.) and does not come into contact with products.
Oil streaks
...
...
...
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Particles
Microbiological limit
...
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And humidity, when
necessary
112
Whether system diagram
is located at locations that permit easy monitoring and handling.
...
...
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113
Whether compressed air
is handled and filtered through appropriate filters.
114
Whether there are
compressed air monitoring and assessment programs.
...
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115
Whether this system has
its safety verified as prescribed
Water vapour
production system
116
Whether the establishment
that uses water vapor for production:
comes into contact with
product surface or surface of processing utensils in contact with products;
...
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or only supports
production (heating, etc.) and does not come into contact with products.
117
Clearly specify water
used for creating water vapour:
...
...
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For boilers for heating
purpose: ………………………………
118
...
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119
Whether pipes are made
of properly treated stainless steel.
Wastewater treatment
system
...
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Whether wastewater treatment
system is designed, constructed and operated in a manner that is appropriate
to the nature of wastewater and waste generated during production and
testing.
121
Whether wastewater treatment
system is confirmed by the supervisory environment authority.
...
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122
Whether fire fighting
system is intended for plants.
123
Whether there is a relevant
regulatory authority’s effective confirmation of operation of the fire
fighting system.
...
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V. Sanitary
conditions and sanitation control
Personnel
124
Whether personnel undergo
pre-employment medical examination and examination is done periodically.
125
Personnel are trained
in personal hygiene.
...
...
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126
Provide sufficient soaps,
hand dryers/washers for necessary areas.
127
...
...
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128
Whether personnel in
clean areas wear clean clothes, shoes/sandals and hats.
129
...
...
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130
Whether protective
garments are appropriately collected and washed in sanitary areas.
131
...
...
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132
Whether any personnel
suffering illness or open wound is found still engaging in production at stages
that may affect product quality.
133
...
...
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134
Whether visitors are given
information about personal hygiene and the prescribed protective clothing,
and are closely supervised.
135
...
...
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Premises
136
Whether there is a pest
control programme.
...
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Whether there are
measures/agents for cleaning/killing insects, which exert adverse effects on
products.
138
Whether insects or other
animals are found accessing or harboring in production, storage or testing
areas.
...
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Whether there are
premise cleaning procedures, which define responsibilities, schedules,
methods, cleaning agents, utensils, etc. appropriate to each area (clean,
controlled or exterior, etc.) and procedures are complied with.
140
Whether any dust is
found in production rooms in clean areas under non-operating conditions.
...
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Whether cleaning intervals
are defined to make sure they are not left unused for an excessive amount of
time.
142
Whether wastewater
collection and treatment system satisfies sanitary requirements or wastewater
treatment contract satisfies applicable regulations on environmental
protection.
...
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143
Whether there are
separate rooms for cleaning mobile equipment, removable parts and utensils to
avoid contaminating cleaned rooms/equipment/utensils.
144
Whether cleaned
equipment and utensils are stored in a clean and dry condition.
...
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145
Whether vacuum or wet
cleaning method with lint-free towel/cloth is to be preferred.
146
Whether compressed air
and brushes are used in clean areas.
Specify control
measures if compressed air and brushes are used: …..
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147
Whether quality of
compressed air is controlled in clean areas (particles) and compressed air comes
into direct contact with foods in clean areas (oil streaks).
Clearly specify
measures and implementing frequency: ……………………
148
Whether a list of
cleaning agents suitable for cleaning premises and equipment is compiled.
...
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149
Whether water used for
cleaning complies with applicable regulations.
150
Whether there are
cleaning procedures intended for each type of production equipment, which
define responsibilities, cleaning methods, agents, utensils and intervals, etc.
and procedures are complied with.
...
...
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151
Whether these
procedures permit effective cleaning of equipment and toughest stains.
Whether records of
assessment of cleaning effectiveness of these procedures are retained.
152
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153
Whether microbiological
limits are imposed on the system (pumps, pipes, couplings, filters, valves, hoses,
etc.) for distributing water, materials/liquid products.
154
...
...
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Materials, additives
and food processing aids
155
Whether materials are purchased
from approved suppliers.
...
...
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Whether the standard to
be satisfied by suppliers includes the following:
Manufacturer’s quality
management system;
Specifications for materials
(appropriate to expected quantity of final products);
...
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157
Whether every material
container in warehouses is labeled as quarantined, sampled, released or
rejected and put in separate areas.
158
...
...
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159
Specify measures for assuring
identity of the contents of each material container, including the container
from which samples are not taken:
...........................................................
160
...
...
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Specify measures:
……………………………………
161
Whether cut labels and
loose materials are stored in separate containers with identification labels.
...
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Whether appropriate control
measures are adopted to avoid mix-ups when dispensing or using printed
materials (especially those containing the products with the same name but
different contents) or batch numbers and expiry dates are assigned upon
packing or inkjet printing (especially the additional amount).
163
Whether material
containers are cleaned before being transported to a weighing room.
...
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Whether materials are
divided in clean areas and appropriately labeled.
165
Whether any material
that is not approved by QA/QC departments or has reached its expiry or retest
date is dispensed.
...
...
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Whether materials are
dispensed using the FEFO or FIFO method.
167
Whether the weighing and
dispensation are controlled in an independent manner.
...
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Specify measures for
controlling cross-contamination occurring during the processing of weighing,
dispensing or collecting samples of materials: ………………………
169
Whether materials
dispensed for each batch are kept together.
...
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Whether the
dispensation of additional materials or receipt of residual products is
approved by the head of the Production Department or Quality Control
Department and operations are carried out in the same manner as materials are
initially dispensed.
Documentation
Whether the
establishment has the following basic documents about
171
Personnel and training.
...
...
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172
Premises and results of
manufacturing environment monitoring and assessment.
173
Production equipment
and results of assessment and testing thereof.
...
...
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174
Cleaning and cleaning
procedure assessment.
175
Materials and supplier
assessment.
...
...
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176
Receipt, storage and
dispensation of materials and finished products.
177
Manufacturing and
manufacturing process assessment.
...
...
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178
Quality control
179
Change control
...
...
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180
Product distribution records
181
Complaint handling and
product recalls
...
...
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182
Contract manufacture
and analysis
183
Environmental safety
assurance and fire fighting
...
...
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184
Self-inspection
Documentation
185
Whether documentation
is prepared, checked/reviewed, approved, dated and signed by appropriate and
authorized person.
...
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186
Whether document is
laid out according to standard design(s) and has clear and unambiguous
contents.
187
Whether documentation
is updated and reviewed and remains effective.
...
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188
Whether effective
dispensation and recall measures are in place to make sure old versions are
not used.
Clearly specify such
measures: ……………………………………………………..
189
...
...
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190
Whether the recording
or entry of data is immediately carried out after performing each activity.
191
...
...
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192
Whether any relevant
documentation (production and quality control) is retained for at least 01
year after the expiry date of the finished product.
193
...
...
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Quality control
documents
194
Whether the Quality Control
Department has the following basic documents, including but not limited to:
Analyst training
records.
...
...
...
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Water records.
Specifications for
starting materials.
...
...
...
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Specifications for
packaging materials.
Specifications for
finished products.
...
...
...
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Records of verification
of analysis procedures (if any) and documents about test methods.
Procedures for taking samples
of raw materials, natural raw materials, packaging materials and
intermediate, bulk and finished products.
...
...
...
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Records of sampling and
results of monitoring/inspection (packaging and some certain types of
materials), analysis (intermediate products), testing (materials, bulk
products, finished products): Sample collection form, analyst’s book,
analysis report, test report, original test report, etc.
Procedures for and records
of the calibration/inspection of equipment/measuring instruments and
analytical equipment.
...
...
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Records of stability
monitoring and evaluation of trends in product quality.
Specifications
Specifications for
natural materials
195
Whether the establish
uses natural materials.
...
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Specify such natural
materials: ………………………
196
Whether information
about natural materials includes:
...
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Origin
(cultivation/harvesting area).
...
...
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Storage condition and
expiry date (if any).
...
...
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197
Whether there are
sufficient procedures for determining each type of natural material.
198
...
...
...
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Pictorial demonstration/description
and identification of active ingredient(s) or marker(s) (if any).
Assay of active
constituent(s) or marker(s) (if any).
...
...
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Limit tests:
- Impurities,
fragmentation or foreign materials.
- Loss on drying.
- Ash content.
- Mycotoxins,
microfungi.
- Heavy metals.
- Radioactivity.
...
...
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Other tests:
………………………………………………
Specifications for
other starting materials and packaging materials
199
Whether specifications are
established for other starting materials and packaging materials used in
plants.
...
...
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200
Whether specifications
for materials include:
Name, code, reference
to a pharmacopoeia monograph or other official documents.
Name of the manufacturer
and supplier.
...
...
...
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Reference to sampling
procedures.
Qualitative
requirements and acceptance limits.
...
...
...
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Qualitative
requirements and acceptance limits.
Residual solvents in extracts
or finished products.
...
...
...
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Storage condition and
expiry date or retest date.
A specimen of printed
materials.
...
...
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201
Whether water used for
processing complies with applicable regulations.
Specifications for
intermediate and bulk products
202
...
...
...
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203
Whether specifications
(tests and acceptance limits) established for these products are appropriate
to starting materials or respective finished products.
Specifications for
finished products
...
...
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204
Whether adequate specifications
are established for every finished product.
205
Whether specifications
established for each finished product include at least:
...
...
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Formula or a reference
to.
...
...
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Physical appearance.
Uniformity in weight or
volume.
...
...
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Qualitative
requirements and acceptance limits.
...
...
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Bacterial contamination
limits.
...
...
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Limits: Heavy metals,
residual solvents (if any)
Tests specific to each
type of dosage form: Dissolution, hardness, friability, viscosity, pH, etc.
...
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Other tests:
……………………………………………
...
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Reference to sampling
procedures and analysis procedures.
...
...
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Production documents
206
Whether production
documents are designed for each dosage form and each packaging specification in
accordance with regulations.
List current products
(for each specification): ……………
...
...
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Whether each production
procedure is evaluated prior to production to ensure suitability and
reproducibility of the procedure.
208
Whether documents are
up to date and closed managed to make sure ineffective old versions are not
used.
...
...
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Original formula and
processing/packaging instructions
209
Whether there are sufficient
original formulas and processing instructions for each finished product batch
size.
...
...
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Whether processing
instructions are stated in a clear, sufficient and stepwise manner.
211
Whether adequate information
or requirements for each operation or stage are available:
Quantity of each
material added;
...
...
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Name of equipment,
code, reference to SOP, parameters required (speed, times, etc.);
...
...
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Sampling, product
quality inspection (tests, reference to test methods), if any;
...
...
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Theoretical yields of
each step….
Batch
processing/packaging records
212
...
...
...
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213
Whether records are
prepared according to original formula and processing/packaging instructions,
and standard design for each dosage form and pack size.
214
...
...
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Justification:
……………………………………………………
215
Whether records are made
after carrying out each operation and completed after the end of each step.
...
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Whether each result of
operations carried out or actual value of each batch is recorded in
accordance with the original formula and processing/packaging instructions.
217
Whether a batch record
states:
...
...
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Name, code, content,
dosage form, product specification, batch size/number and expiry date.
Name, code, number/weight,
batch number, number of test report/acceptance report of every material
dispensed
...
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Sufficient about
starting/ending time and signature of the person carrying out the
activities/inspection.
Reconciliation between theoretical/actual
yields of residual products/scraps and rate % as requested
...
...
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Reconciliation
(received, used/defective/returned quantities) and specimen of primary
packaging, printed materials
Results of inspection carried
out before/during/after the manufacturing process of each step
...
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Report on test of
finished products prior to release
218
Whether activities
performed differently from standard procedure (batch size, quantity, temperature,
moisture content, times, etc.) are accepted by the heads of the
Production/Quality Control Departments.
...
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Whether deviations
(moisture content, content, weight, quantity, etc.) listed and used when
assessing batch records and monitoring quality trend.
Standard Operating
Procedures (SOPs) and records
220
Whether SOPs are
established for routine activities such as personal hygiene, protective garment
changing, operation of production equipment, sampling, etc.
Number of SOPs
(attached to the List): …………………………
...
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221
Whether training in
SOPs is provided to relevant personnel.
222
If a SOP is revised, whether
the old SOP is discarded and personnel are re-trained.
...
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223
Whether SOPs are
available at locations that permit easy reference.
224
Whether a SOP intended
for the receipt includes the following basic receipt requirements:
Name, code, batch
number, number/quantity of materials.
...
...
...
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Supplier’s name and
manufacturer’s name.
Packaging state and
storage conditions upon delivery/receipt.
...
...
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Check information
against invoice/delivery note.
Date, signature and
name of the person who delivers/receives.
...
...
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225
Whether materials and
finished products are released by taking the following steps:
Receipt, control
...
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Sampling, check,
testing
...
...
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226
Whether the following
basic requirements are imposed on release of a finished product batch:
Review of records and
conformity of results of in-process testing.
...
...
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Finished product
results. Production conditions (rooms, equipment).
Other activities and
deviations (if any).
...
...
...
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Batches are numbered so
that:
Whether each batch of materials,
in-process products and finished products is identified with a specific batch
number and same batch numbers will not be repeatedly used.
Whether the
traceability of any batches, including those containing residual products or reprocessed
products is permitted.
...
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Whether the batch
number allocation shall be immediately recorded (in blank documents, material
dispensation notes, labels, when inkjet printing, etc.), including batch
size.
I. Manufacturing
General
228
Whether all activities
related to the manufacturing of a batch of finished products are performed
according to procedures, documented and made into a batch record.
...
...
...
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229
Whether the receipt of residual
or reprocessed products or activities beyond the procedure are accepted by
the heads of the Production/Quality Control Departments.
230
Whether the rate % of
receipt, maximum retention period and tests if required are determined.
...
...
...
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231
Whether these
activities are documented, batches of these products or these products are
assigned a separate batch number for the purposes of monitoring and
additional testing.
232
Whether different
products are manufactured simultaneously or continuously in a room.
...
...
...
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233
Whether
cross-contamination or mix-ups may occur upon performing the abovementioned
manufacturing operation.
Specify control
measures, if available: ...............................................
...
...
...
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234
Whether there is a
record of checks, and the results obtained before an operation begins.
235
Whether a check
includes:
Status of the room
(line clearance performed, cleaned, meeting temperature and humidity
requirements, etc.);
...
...
...
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Status of equipment
(operational, properly connected, cleaned);
Patterns, parts, utensils,
sieve cloth, mortars and pestles, etc. (proper type, cleaned);
...
...
...
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Materials, products
(packaging, labels, physical appearance).
236
Whether all dispensed materials
and packaging, and intermediate and bulk products are closely packaged,
labeled and stored under appropriate storage conditions.
...
...
...
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237
Whether labels are
attached to all packaging or containers, including at least: name, batch number,
number/quantity used for batches of finished products.
238
Whether the name and
batch number of the product are displayed using signs at each packaging line.
...
...
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239
Whether there is a record
of the in-process controls, and the results obtained.
240
Whether in-process
controls include, but are not limited to:
Manufacturing
environment monitoring (temperature, humidity, pressure difference, etc.);
...
...
...
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Personal hygiene
control and compliance with manufacturing procedures by personnel.
Intermediate products
(extracts, granules, solutions, etc.): physical appearance, uniformity,
moisture content, viscosity, pH, content, etc.;
...
...
...
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Tablet: weight and
difference, hardness/friability, disintegration, etc.;
Soft capsule: weld
edge; moisture content, weight/thickness and difference in capsule size,
etc.;
...
...
...
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Bags, packs, bottles: proper
packaging, batch number, expiry dates, closeness, volume and difference, etc.
Boxes: proper
packaging, batch number, expiry dates, forms, etc.;
...
...
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241
Whether tested samples are
collected, labeled and transported to a location awaiting for destruction.
242
Whether there is a
record of checks, and the results obtained after each manufacturing step.
...
...
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243
The checks include, but
are not limited to, the following:
Integrity of sieve
cloth, mortars and pestles, etc.
...
...
...
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244
Whether residual
products, scraps or wastes are removed from premises after each production shift
and periodically handled or destroyed or handled under a contract and
documented.
245
...
...
...
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246
Whether final yield and
theoretical yield of each production stage and the whole manufacturing
process are balanced.
247
...
...
...
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248
Whether finished
products are held in quarantine until their final release under appropriate
conditions.
Cross-contamination
prevention
...
...
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Whether the
establishment conducts an assessment to determine the appearance or
likelihood of, but not limited to the following risks of cross-contamination:
Samples are taken
during the cleaning or when the cleaning has not been performed;
Weighing and
dispensation are performed during the cleaning or when the cleaning has not
been performed;
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Rooms, equipment and
utensils intended for producing/weighing/taking samples have not been
cleaned;
Protective garments are
intended for more than 1 product;
...
...
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The systems for
filtering, supplying/capturing air and controlling pressure difference fail
to comply with regulations;
Shared activities such as
in-process controls (rooms, personnel, utensils), corridors, washing rooms,
utensil cleaning rooms, rooms for temporary storage of materials awaiting for
processing or intermediate or bulk products, etc. are carried out.
...
...
...
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250
Specify cross-contamination
prevention or control measures that have been taken: …………….
II. Testing and
control of quality of materials, bulk products and finished products and
tests conducted by competent establishments
251
Whether there is a Quality
Control Department with sufficient personnel and appropriate equipment.
...
...
...
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252
In order to perform
basic tasks, including but not limited to:
Approve specifications
for materials, packaging and in-process products and finished products;
Take samples, conducts
necessary checks and tests ;
...
...
...
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Assess suppliers and
consider deciding to accept materials and packaging ;
Calibrate and
monitoring the calibration/inspection of necessary equipment and utensils ;
...
...
...
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Standardize conditions
for production, storage, assessment and monitoring ;
Assess (verify)
manufacturing process ;
...
...
...
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Assess batch records
and decide to release finished products ;
Monitor the stability
of products and study/determine shelf-life thereof when necessary.
...
...
...
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253
Whether the
abovementioned activities are performed according to SOPs, procedures or
protocol and sufficiently documented.
254
Whether the
establishment conducts all basic tests and conducts them on a frequent basis.
...
...
...
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255
Whether a contract
analysis is concluded to do any special test.
Specify names of the
tests and respective laboratories: ……
Sampling
...
...
...
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Whether samples are
taken at locations free from contamination or cross-contamination, by
designated persons wearing appropriate clothes and maintaining an appropriate
degree of personal hygiene, and according to a procedure.
257
Whether different
batches (of a material) are considered as separate for sampling.
...
...
...
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Whether samples are
sufficient and representative of the number of material and product
containers.
259
Whether material and product
containers from which samples have been drawn are identified.
...
...
...
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Whether samples are
packaged, labeled and stored under appropriate conditions to make sure their
status quo is maintained and they are stored for a given period of time.
Check/testing
261
Whether methods for
testing parameters of every material, bulk product and finished product are
assessed at least in terms of their specificity and accuracy.
...
...
...
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262
Whether methods for testing
parameters of every finish product are expected to be submitted in the
marketing authorization dossier or have been accepted by the licensing
authority as prescribed.
263
Whether all testing operations
are carried out according to approved methods.
...
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264
Whether reagents and
standard solutions are prepared, labeled and stored as prescribed.
265
Whether results of operations
carried out are documented and retained for a given period of time.
...
...
...
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Stability monitoring
266
Whether programmes or
protocols are designed, samples are taken and retained, and tests are conducted
to monitor the stability of products in order to determine their shelf-life.
267
Whether programmes or
protocols are designed, samples are taken and retained, and tests are
conducted to monitor the stability of products after being sold on the
market.
...
...
...
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268
Whether stability
protocols are established in accordance with regulations.
269
Whether results of
operations carried out are documented, processed and retained.
...
...
...
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III. Contract manufacture
and analysis
270
Whether the
establishment undertakes contract manufacture.
Specify products and
respective manufacturing steps: ………
271
...
...
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272
Whether the
establishment undertakes contract analysis.
Specify names of the
tests conducted under a contract: ……
...
...
...
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Whether the Contract
Acceptor has its manufacturing competency assessed and is a laboratory
acknowledged to carry out the contracted operations correctly.
274
Whether the contract
clearly states the way in which the authorized person releasing each batch of
product for sale exercises his full responsibility.
...
...
...
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Product complaints
and returned products
275
Whether there are SOPs
for handling product complaints and returned products.
276
Whether persons are
designated to be responsible for transferring, considering, assessing and
handling cases of product complaints and returned products.
...
...
...
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277
Whether any complaints
on adverse product reactions are received.
Please specify:
………………………
278
Whether quality control
and assurance departments are assigned to consider products returned from the
market due to complaints, defects, expiration or other reasons that may
affect product quality.
...
...
...
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279
Whether if the reason
for poor quality of a batch is uncovered, whether other relevant batches are
considered.
280
Whether products
returned from the market and which have left the control of the manufacturer are
destroyed unless without doubt (about origin, labeling, storage conditions,
etc.) their quality is satisfactory.
...
...
...
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281
Whether the receipt and
handling are documented.
Please specify:
……………………………
Product recalls
...
...
...
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Whether there is a
recall procedure, which describes the scope and degree of recall according to
the degree of poor quality and effects on users.
283
A system is available to
ensure that the recall is carried out in a fast and effective manner.
...
...
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Whether the person
responsible for recalls is independent of the sales organization and provided
with sufficient information about customers.
285
Whether there is a
final record, including a reconciliation between the delivered and recovered
quantities and measures to be taken.
Please specify:
………………………
...
...
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Self-inspection
286
Whether a
self-inspection team is established.
Specify names and
positions of members: ………………
287
Whether there are
self-inspection programmes and plans and items.
...
...
...
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288
Whether self-inspection
items includes:
Quality management
...
...
...
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Personnel
...
...
...
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Premises
Equipment
...
...
...
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Hygiene and sanitation
Documentation
...
...
...
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Manufacturing and
in-process controls
...
...
...
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Quality control
Contract manufacture
and analysis
...
...
...
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Complaints and product
recalls
Self-inspection
...
...
...
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Results of previous
self-inspections and remedial actions taken.
...
...
...
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Self-inspection is
documented. Whether there is a self-inspection report.
290
Whether self-inspection
results are considered to take necessary corrective actions.
Whether corrective
actions are monitored and assessed.
...
...
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11.5. Templates for
Manufacturing processes, Batch processing/packaging records and List of
finished product batch records
The following templates are
prepared under the guidance specified in Section 5.22 through Section 5.33 so
that health supplement manufacturers can reference to when establishing
manufacturing processes and prepare batch records. Manufacturers may develop
and/or create their own templates but should comply with GMP and other relevant
requirements. Manufacturers may develop and/or create their own forms but
should comply with GMP and other relevant requirements.
11.5.1. Template for
Manufacturing process
1. General information:
- Names, codes,
concentration/content and dosage forms of products: …………………
- Theoretical yields of a
standard batch and package details: ………………………
- Number of
procedure/version and date of issue/entry into force: ……………….
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No.
Material
Code
Amount
For smallest unit of finished product
For a batch of finished products (standard batch size)
Amount
Unit
Amount
...
...
...
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………..…
…...
………
…...
………
…...
……...…(*)
...
...
...
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………
…...
………
…...
Total:
………
…...
………
…...
...
...
...
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3. Specifications
(parameters, limits and reference to test methods):
- Materials, packaging:
………………………………………………………..……….
- Bulk/intermediate
products (if any): ………………………………...….
- Finished products:
………………………………………………………………………...
4. List of main equipment
(intended for the process):
No.
Name of equipment
Power
Note
...
...
...
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………………………………..
…………….
…………….
…
………………………………..
…………….
…………….
5. Manufacturing step diagram:
………………………………………………………………………...
6. Detail description of
manufacturing steps:
...
...
...
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No.
Requirement
1
Define
sufficient/specific requirements/activities that should be executed according
to GMP (Sections 5.22 to 5.33), such as: room/equipment check; order of
operations and respective requirements such as equipment, reference SOPs,
parameters (times, speed), amount of each material, in-process controls,
sampling, testing, acceptance limits; packaging, labeling, quarantine, input
quotas, etc.
…
…………………………………………………………………………………..
6.2. Processing step:
…………………………………………………………….
6.3. Shaping step:
…………………………………………………………….
6.4. Primary packaging
step: …………………………………………………………….
...
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Prepared by
(Date, signature and full name)
Checked by
(Date, signature and full name)
Approved by
(Date, signature and full name)
11.5.2. Batch
processing/packaging records
Product code and number
of respective manufacturing process: ……….
BATCH PROCESSING/PACKAGING RECORDS
Batch number: ……………
Expiry date: …….…
Name, content and
dosage form of product: ….….
Batch size and package
details: …………….……..
...
...
...
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1. Delivery/receipt of
materials:
No.
Name of material
Code
Amount required
Actual amount
For smallest unit of finished product
For a batch of finished products (standard batch size)
Amount
...
...
...
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Number of material batch
Number of test report (3) or acceptance report(4)
Amount
Unit
Amount
Unit
...
...
...
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1
A
a0
a1
o0
a2
o1
…..
…
...
...
...
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…..
…
B(1)
b0
b1
p0
b2
p1
…..
...
...
...
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…
…..
…
C(2)
...
...
...
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…
…
…..
Total:
z1
q0
z2
q1
…..
...
...
...
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(1): Any substance
that may disappear in the course of preliminary processing or processing;
(2): Residual products
from previous batch (if any);
(3): Test report of
the QC Department
(4): Acceptance
report of the QC or QA Department.
(specify date) ……/……/……
Delivered by
(Warehouse keeper)
...
...
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(Production personnel)
Controlled by
(IPC personnel)
2. Preliminary
processing:
Start at: ….. hour,
…../…../…. (specify date)
No.
Requirement
Activity
1
...
...
...
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Record the results
obtained: amount of materials used, actual parameters, testing results,
actual yield, etc. and other activities, deviations or unusual events, if
any.
End at: ….. hour,
…../…../…. (specify date)
(specify date) ……/……/……
Performed by
(Production personnel)
Controlled by
(Team leader)
3. Processing:
…………………………………………………..
4. Shaping:
………………………………………………….
...
...
...
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6. Second-level packaging
(secondary packaging) : ………………………………………………………….
7. Batch record review
(control of residual products/scraps, reconciliation between yields, other
activities, incidents, etc.): ………...
11.5.3. Template for
List of finished product batch records
LIST OF FINISHED PRODUCT BATCH RECORDS
Name of product:
……………………………………………………………………………
Manufacturing date: ……………
Expiry date: ………………..
Start at: ...………………… End
at:……………….…
This batch record
includes:
□ 1. Production order and
delivery note
...
...
...
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□ 2.1. Weighing and
dispensation of materials
□ 2.1.1. Note indicating
status of weighing room and related equipment
□ 2.1.2. Main material
test report (photocopy)
□ 2.1.3. Record of
material weighing and dispensation
□ 2.2. Preliminary
processing
□ 2.2.1. Note indicating
status of preliminary processing room and main production equipment
□ 2.2.2. Labels of
material(s) dispensed for preliminary processing and weighing note, if
available.
□ 2.2.3. In-process control
note
□ 2.2.4. Record of
preliminary processing step
...
...
...
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□ 2.3.1. Note indicating
status of processing room(s) and main production equipment
□ 2.3.2. Labels of
material(s) dispensed for processing and weighing note, if available.
□ 2.3.3. Labels of
intermediate products awaiting for processing, where applicable
□ 2.3.4. In-process
control note
□ 2.3.5. Record of
processing step
□ 2.3. Shaping
□ 2.4.1. Note indicating
status of shaping room(s) and main production equipment
□ 2.4.2. Labels of
material(s) dispensed for shaping and weighing note, if available.
□ 2.4.3. Labels of
intermediate products awaiting for shaping, where applicable
...
...
...
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□ 2.4.5. Record of
shaping step
□ 3. Packaging step
□ 3.1. Primary packaging
□ 3.1.1. Note indicating
status of primary packaging room(s) and main equipment
□ 3.1.2. Labels of bulk
products awaiting for primary packaging (where possible)
□ 2.2.3. In-process
control note
□ 3.1.4. Record of
primary packaging
□ 3.1.5. Specimen of
primary packaging printed/assigned batch number and expiry date
□ 3.1.6. Note of
dispensation/adjustment/reconciliation (received/used/rejected/returned) of
primary packaging
...
...
...
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□ 3.2.1. Note indicating
status of packaging room and secondary packaging equipment, if available
□ 3.2.2. Labels of bulk
products awaiting for secondary packaging (where possible)
□ 3.2.3. Record of batch
number/expiry date printing and secondary packaging
□ 3.2.4. Specimen of
secondary packaging printed/assigned batch number or expiry date
□ □ Box
□ Instructions for use
□ Container label (if available)
□ 3.2.5. Note of
dispensation/adjustment/reconciliation (received/used/rejected/returned) of
secondary packaging
□ 4. Batch record review
□ 4.1. Reconciliation
between yield of each step and yield of the whole manufacturing process
□ 4.2. Review of other
activities executed, deviations or unusual events (if available)
...
...
...
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□ 4.4. Finished product
release order and receipt note.
1 Prelude to the Circular No. 17/2023/TT-BYT dated
September 25, 2023 of the Ministry of Health on amendments to and annulment of
certain legislative documents on food safety promulgated by the Minister of
Health:
“The Law on
Promulgation of Legislative Documents No. 80/2-015/QH-13 dated June 22, 2015
and the Law dated June 18, 2020 on Amendments to the Law on Promulgation of
Legislative Documents No. 63/2020/QH-14;
The Law on Food Safety
No. 55/2010/QH10 dated June 17, 2010;
The Government’s Decree
No. 15/2018/ND-CP dated February 02, 2018 on elaboration of some Articles of
Law on Food Safety;
The Government's
Decree No. 95/2022/ND-CP dated November 15, 2022 on functions, tasks,
powers, and organizational structure of the Ministry of Health;
At the request of the
Director of the Vietnam Food Administration,
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2 This Article is amended by Clause 1 Article 3
of the Circular No. 17/2023/TT-BYT, which has been effective since November 09,
2023.
3 Articles 9, 10 and 11 of the Circular No.
17/2023/TT-BYT, which has been effective since November 09, 2023, stipulate
that:
Article 9. Terms of
reference
In case any of the
legislative documents referred to in this Circular are amended, supplemented,
or replaced, the new documents shall prevail.
Article 10. Effect
This Circular comes
into force as of November 9, 2023.
Article 11.
Responsibility for implementation
The Chief of Ministry
Office; Director of the Food Safety Administration; Ministerial Chief
Inspector; Heads of units affiliated to the Ministry of Health; Directors of
Health Departments of provinces and cities; Heads of food safety authorities
under People's Committees of provinces and centrally-affiliated cities; Heads
of health agencies of ministries and central authorities and relevant agencies,
organizations and individuals shall implement this Circular./.
4 The ordinal number 32nd is repealed
as prescribed in point c Clause 2 Article 7 of the Circular No. 17/2023/TT-BYT,
which has been effective since November 09, 2023.
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6 This section is repealed as prescribed in
point c Clause 2 Article 7 of the Circular No. 17/2023/TT-BYT, which has been
effective since November 09, 2023.
7 This section is repealed as prescribed in
point c Clause 2 Article 7 of the Circular No. 17/2023/TT-BYT, which has been
effective since November 09, 2023.
8 This section is repealed as prescribed in
point c Clause 2 Article 7 of the Circular No. 17/2023/TT-BYT, which has been
effective since November 09, 2023.
9 Title of this section is changed as prescribed
in Clause 2 Article 3 of the Circular No. 17/2023/TT-BYT, which has been
effective since November 09, 2023.