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WHO good manufacturing practices: specific pharmaceutical products
Sterile pharmaceutical products
Biological products
Investigational pharmaceutical products for clinical trials in humans
Herbal medicinal products
Biological products 3
1. Scope of these guidelines 2. Principles 3. Personnel
4. Premises and equipment 5. Animal quarters and care 6.
Production 7. Labelling 8. Lot processing records
(protocols) and distribution records 9. Quality assurance and
quality control Authors Acknowledgements References
1. Scope of these guidelines
These guidelines are intended to complement those provided in
"Good manufacturing practices for pharmaceutical
products"(1).
The regulatory procedures necessary to control biological
products are in large part determined by the sources of products and
methods of manufacture. Manufacturing procedures within the scope of
these guidelines include:
— growth of strains of microorganisms and eukaryotic cells,
— extraction of substances from biological tissues, including
human, animal and plant tissues (allergens),
— recombinant DNA (rDNA) techniques,
— hybridoma techniques,
— propagation of microorganisms in embryos or
animals.
Biological products manufactured by these methods include
allergens, antigens, vaccines, hormones, cytokines, enzymes, human
whole blood and plasma derivatives, immune sera, immunoglobulins
(including monoclonal antibodies), products of fermentation
(including products derived from rDNA) and diagnostic agents for
in vitro use.
2. Principles
The manufacture of biological products shall be undertaken in
accordance with the basic principles of good manufacturing practices
(GMP). The points covered by these guidelines should therefore be
considered supplementary to the general requirements set out in
"Good manufacturing practices for pharmaceutical products"
(1), and relate specifically to the production and control of
biological products. In drawing up these guidelines, due
consideration was given to the draft "Guidelines for national
authorities on quality assurance for biological products", the final
version of which appears as Annex 2 to the forty-second report of
the WHO Expert Committee on Biological Standardization
(2).
The way in which biological products are produced, controlled and
administered makes some particular precautions necessary. Unlike
conventional pharmaceutical products, which are normally produced
and controlled using reproducible chemical and physical techniques,
biological products are manufactured by methods involving biological
processes and materials, such as cultivation of cells or
extraction of material from living organisms. These processes
display inherent variability, so that the range and nature of
by-products are variable. For this reason, in the manufacture of
biological products full adherence to GMP is necessary for all
production steps, beginning with those from which the active
ingredients are produced.
Control of biological products nearly always involves biological
techniques that have a greater variability than physicochemical
determinations. In-process controls take on a great importance in
the manufacture of biological products because certain deficiencies
may not be revealed by testing the finished product.
The present guidelines do not lay down detailed requirements for
specific classes of biological products, and attention is therefore
directed to other guidance issued by WHO, and in particular to the
Requirements for Biological Substances, which include requirements
for vaccines (2, Annex 7).
3. Personnel
3.1 The manufacturing establishment and its personnel shall be
under the authority of a person who has been trained in the
techniques used in manu-facturing biological substances and who
possesses the scientific knowledge upon which the manufacture of
these products is based. The personnel shall include specialists
with training appropriate to the products made in the
establishment.
3.2 Personnel required to work in clean and aseptic areas should
be selected with care, to ensure that they may be relied upon to
observe the appropriate codes of practice and are not subject to any
disease or condition that could compromise the integrity of the
product microbiologically or otherwise. High standards of personal
hygiene and cleanliness are essential. Staff should be instructed to
report any conditions (e.g. diarrhoea, coughs, colds, infected skin
or hair, wounds, fever of unknown origin) that may cause the
shedding of abnormal numbers or types of organisms into the working
environment. Health checks on personnel for such conditions should
be required before employment and periodically thereafter. Any
changes in health status that could adversely affect the quality of
the product shall preclude the person concerned from working in the
production area.
3.3 Only the minimum number of personnel required should be
present in clean and aseptic areas when work is in progress.
Inspection and control procedures should be conducted from
outside these areas as far as possible.
3.4 During the working day, personnel shall not pass from areas
where live microorganisms or animals are handled to premises where
other products or organisms are handled unless clearly defined
decontamination measures, including a change of clothing and shoes,
are followed. Persons not concerned with the production process
should not enter the production area except for essential purposes,
and in that case they shall be supplied with sterile protective
clothing.
3.5 The staff engaged in the manufacturing process should be
separate from the staff responsible for animal care.
3.6 The names and qualifications of those responsible for
approving lot processing records (protocols) should be registered
with the national control authority.
3.7 To ensure the manufacture of high-quality products, personnel
should be trained in good manufacturing and laboratory practices in
appropriate fields such as bacteriology, virology, biometry,
chemistry, medicine, immunology and veterinary medicine.
3.8 Training records should be maintained and periodic
assessments of the effectiveness of training programmes should be
made.
3.9 All personnel engaged in production, maintenance, testing and
animal care (and inspectors) should be vaccinated with appropriate
vaccines and, where appropriate, be submitted to regular testing for
evidence of active tuberculosis. Apart from the obvious problem of
exposure of staff to infectious agents, potent toxins or allergens,
it is necessary to avoid the risk of contamination of a production
batch with these agents.
3.10 Where BCG vaccines are being manufactured, access to
production areas shall be restricted to staff who are carefully
monitored by regular health checks. In the case of manufacture of
products derived from human blood or plasma, vaccination of workers
against hepatitis B is recommended.
4. Premises and equipment
4.1 As a general principle, buildings must be located, designed,
constructed, adapted and maintained to suit the operations to be
carried out within them. Laboratories, operating rooms and all other
rooms and buildings (including those for animals) that are used for
the manufacture of biological products shall be designed and
constructed of materials of the highest standard so that
cleanliness, especially freedom from dust, insects and vermin, can
be maintained.
4.2 Interior surfaces (walls, floors and ceilings) shall be
smooth and free from cracks; they shall not shed matter and shall
permit easy cleaning and disinfection. Drains should be avoided
wherever possible and, unless essential, should be excluded from
aseptic areas. Where installed they should be fitted with effective,
easily cleanable traps and with breaks to prevent back-flow. The
traps may contain electrically operated heating devices or other
means for disinfection. Any floor channels should be open, shallow
and easily cleanable and be connected to drains outside the area in
a manner that prevents ingress of microbial contaminants.
4.3 Sinks shall be excluded from aseptic areas. Any sink
installed in other clean areas shall be of suitable material such as
stainless steel, without an overflow, and be supplied with water of
potable quality. Adequate precautions shall be taken to avoid
contamination of the drainage system with dangerous effluents.
Airborne dissemination of pathogenic microorganisms and viruses used
for production and the possibility of contamination by other types
of viruses or substances during the production process, including
those from personnel, shall be avoided.
4.4 Lighting, heating, ventilation and, if necessary,
air-conditioning should be designed to maintain a satisfactory
temperature and relative humidity, to minimize contamination and to
take account of the comfort of personnel working in protective
clothing. Buildings shall be in a good state of repair. The
condition of the buildings should be reviewed regularly and repairs
carried out when and where necessary. Special care should be
exercised to ensure that building repair or maintenance operations
do not compromise products. Premises should provide sufficient space
to suit the operations to be carried out, allowing an efficient flow
of work and effective communication and supervision. All buildings
and rooms shall be clean and sanitary at all times. If rooms
intended for the manufacture of biological substances are used for
other purposes, they shall be cleaned thoroughly and, if necessary,
sanitized before the manufacture of biological substances is
resumed. Areas used for processing animal tissue materials and
microorganisms not required for the current manufacturing process
and for performing tests involving animals or microorganisms must be
separated from premises used for manufacturing sterile biological
products and have completely separate ventilation systems and
separate staff.
4.5 If certain products are to be produced on a campaign basis,
the layout and design of the premises and equipment shall permit
effective decontamination by fumigation, where necessary, as well as
cleaning and sanitizing after the production campaign.
4.6 Seed lots and cell banks used for the production of
biological products should be stored separately from other material.
Access should be restricted to authorized personnel.
4.7 Live organisms shall be handled in equipment that ensures
that cultures are maintained in a pure state and are not
contaminated during processing.
4.8 Products such as killed vaccines, including those made by
rDNA techniques, toxoids and bacterial extracts may after
inactivation be dispensed into containers on the same premises as
other sterile biological products, providing that adequate
decontamination measures are taken after filling, including, if
appropriate, sterilization and washing.
4.9 Spore-forming organisms shall be handled in facilities
dedicated to this group of products until the inactivation process
is accomplished. For Bacillus anthracis, Clostridium
botulinum and Clostridium tetani, strictly dedicated
facilities should be utilized for each individual product. Where
campaign manufacture of spore-forming organisms occurs in a facility
or suite of facilities, only one product should be processed at any
one time.
4.10 Dedicated facilities and equipment shall be used for the
manufacture of medicinal products derived from human blood or
plasma.
4.11 All containers of biological substances, regardless of the
stage of manu-facture, shall be identified by securely attached
labels. Cross-contamination should be prevented by adoption of some
or all of the following measures:
— processing and filling in segregated areas;
— avoiding manufacture of different products at the same time,
unless they are effectively segregated;
— containing material transfer by means of airlocks, air
extraction, clothing change and careful washing and
decontamination of equipment;
— protecting against the risks of contamination caused by
recirculation of untreated air, or by accidental re-entry of
extracted air;
— using "closed systems" of manufacture;
— taking care to prevent aerosol formation (especially by
centrifugation and blending);
— excluding pathological specimens sent in for diagnosis from
areas used for manufacturing biological substances;
— using containers that are sterilized or are of documented low
"bioburden".
4.12 Positive-pressure areas should be used to process sterile
products, but negative pressure is acceptable in specific areas
where pathogens are processed. In general, any organisms considered
to be pathogenic should be handled within specifically designed
areas under negative pressures, in accordance with containment
requirements for the product concerned.
4.13 Air-handling units should be dedicated to the processing
area concerned. Air from operations involving pathogens shall not be
recirculated and, in the cases of organisms in a group above
Risk Group 2 (3), shall be exhausted through sterilizing
filters that are regularly checked for performance.
4.14 Specific decontamination systems should be considered for
effluent when infectious and potentially infectious materials are
used for production.
4.15 Pipework, valves and vent filters shall be properly designed
to facilitate cleaning and sterilization. Valves on fermentation
vessels shall be completely steam-sterilizable. Air-vent filters
shall be hydrophobic and shall be validated for their designated
use.
4.16 Small stocks of substances that have to be measured or
weighed during the production process (e.g. buffers) may be kept in
the production area, provided that they are not returned to the
general stocks. Otherwise, dry materials used to formulate buffers,
culture media, etc. should be weighed and put into solution in a
contained area outside the purification and aseptic areas in order
to minimize particulate contamination of the
product.
5. Animal quarters and care (General requirements for animal quarters, care and
quarantine are given in reference 4.)
5.1 Animals are used for the manufacture and control of a number
of biological products. Animals shall be accommodated in separate
buildings with self-contained ventilation systems. The buildings'
design and construction materials shall permit maintenance in a
clean and sanitary condition free from insects and vermin.
Facilities for animal care shall include isolation units for
quarantine of incoming animals and provision for vermin-free food
storage. Provision shall also be made for animal inoculation rooms,
which shall be separate from the postmortem rooms. There shall be
facilities for the disinfection of cages, if possible by steam, and
an incinerator for disposing of waste and of dead animals.
5.2 The health status of animals from which starting materials
are derived and of those used for quality control and safety testing
should be monitored and recorded. Staff employed in animal quarters
must be provided with special clothing, changing facilities and
showers. Where monkeys are used for the production or quality
control of biological products, special consideration is required,
as laid down in the revised Requirements for Biological Substances
No. 7 (Requirements for Poliomyelitis Vaccine (Oral))
(5).
6. Production
6.1 Standard operating procedures shall be available and
maintained up to date for all manufacturing operations.
6.2 Specifications for starting materials should include details
of their source, origin and method of manufacture and of the controls
applied, in particular microbiological controls, to ensure their
suitability for use. Release of a finished product is conditional on
satisfactory results being obtained in the tests on starting
materials.
6.3 Media and cultures shall be added to fermenters and other
vessels under carefully controlled conditions to avoid
contamination. Care shall be taken to ensure that vessels are
correctly connected when cultures are added.
6.4 If possible, media should be sterilized in situ.
In-line sterilizing filters for routine addition of gases, media,
acids, alkalis, defoaming agents, etc. to fermenters should be used
where possible.
6.5 Careful consideration should be given to the validation of
sterilization methods.
6.6 When an inactivation process is performed during manufacture,
measures should be taken to avoid the risk of cross-contamination
between treated and untreated products.
6.7 A wide variety of equipment is used for chromatography; in
general such equipment should be dedicated to the purification of
one product and should be sterilized or sanitized between batches.
Problems of decontamination and purification may arise through
repeated use of the same equipment at the same or different stages
of processing. The life span of columns and the sterilization method
shall be defined. Particular care should be given to monitoring
microbial loads and endotoxins.
7. Labelling
7.1 All products shall be clearly identified by labels. The
labels used must remain permanently attached to the containers under
all storage conditions and an area of the container should be left
uncovered to allow inspection of the contents. If the final
container is not suitable for labelling (for example a capillary
tube), it should be in a labelled package.
7.2 The information given on the label on the container and the
label on the package shall be approved by the national control
authority.
7.3 The label on the container shall show:
— the name of the drug product;
— a list of the active ingredients and the amount of each
present, with a statement of the net contents, e.g. number of
dosage units, weight or volume;
— the batch or final lot number assigned by the
manufacturer;
— the expiry date;
— recommended storage conditions or handling precautions that
may be necessary;
— directions for use, and warnings and precautions that may be
necessary;
— the nature and amount of any substance used in the
preparation of the biological product that is likely to give rise
to an adverse reaction in some recipients;
— the name and address of the manufacturer or the company
and/or the person responsible for placing the drug on the
market.
7.4 The label on the package shall, in addition to the
information shown on the label on the container, show at least the
nature and amount of any preservative or additive in the
product.
7.5 The leaflet in the package should provide instructions for
the use of the product, and mention any contraindications or
potential adverse reactions.
8. Lot processing records (protocols) and distribution
records
8.1 Processing records of regular production lots must provide a
complete account of the manufacturing history of each lot of a
biological preparation, showing that it has been manufactured,
tested, dispensed into containers and distributed in accordance with
the licensed procedures.
8.2 A separate processing record should be prepared for each lot
of biological product, and should include the following
information:
— the name and dosage of the product;
— the date of manufacture;
— the lot identification number;
— the complete formulation of the lot, including identification
of seed or starting materials;
— the batch number of each component used in the
formulation;
— the yield obtained at different stages of manufacture of the
lot;
— a duly signed record of each step followed, precautions taken
and special observations made throughout the manufacture of the
lot;
— a record of all in-process control tests and of the results
obtained;
— a specimen of the label;
— identification of packaging materials, containers and
closures used;
— a dated signature of the expert responsible for approving the
manufacturing operations;
— an analytical report, dated and signed by the responsible
expert, showing whether the lot complies with the specifications
described in the standard operating procedure registered with the
national control authority;
— a record of the decision regarding the release or rejection
of the lot by the quality control department and, if the lot is
rejected, a record of its disposal or utilization.
8.3 The records shall be of a type approved by the national
control authority. They shall be retained for at least two years
after the expiry date of a lot or batch of a biological product and
be available at all times for inspection by the national control
authority.
8.4 Records must make it possible to trace all steps in the
manufacture and testing of a lot, and should include records of
sterilization of all apparatus and materials used in its
manufacture. Distribution records must be kept in a manner that
permits rapid recall of any particular lot, if
necessary.
9. Quality assurance and quality control
9.1 The quality assurance and/or quality control department
should have the following principal duties:
— to prepare detailed instructions for each test and
analysis;
— to ensure adequate identification and segregation of test
samples to avoid mix-up and cross-contamination;
— to ensure that environmental monitoring and equipment
validation are conducted as appropriate for evaluating the
adequacy of the manufacturing conditions;
— to release or reject raw materials and intermediate products,
if necessary;
— to release or reject packaging and labelling materials and
the final containers in which drugs are to be placed;
— to release or reject each lot of finished preparation;
— to evaluate the adequacy of the conditions under which raw
materials, intermediate products, and finished biological
preparations are stored;
— to evaluate the quality and stability of finished products
and, when necessary, of raw materials and intermediate
products;
— to establish expiry dates on the basis of the validity period
related to specified storage conditions;
— to establish and, when necessary, revise control procedures
and speci-fications; and
— to be responsible for the examination of returned
preparations to determine whether such preparations should be
released, reprocessed or destroyed; adequate records of the
distribution of such preparations should be
maintained.
9.2 A manufacturer's quality control laboratory shall be
separated from the production area and ideally should be in a
separate building. The control laboratory should be designed and
equipped and of such a size as to be a self-contained entity, with
adequate provision for the storage of documents and samples,
preparation of records and performance of the necessary tests.
9.3 In-process controls play a specially important role in
ensuring the consistent quality of biological products. Tests that
are crucial for quality control but that cannot be carried out on
the finished product shall be performed at an appropriate stage of
production.
9.4 Performance of all qualitative and quantitative tests
mentioned in the specifications for starting materials may be
replaced by a system of certificates issued by the producer of the
starting material, provided that:
— there is a history of reliable production,
— the producer is regularly audited, and
— at least one specific identity test is conducted by the
manufacturer of the final product.
9.5 Samples of intermediate and final products shall be retained
in sufficient amount and under appropriate storage conditions to
allow the repetition or confirmation of a batch control. However,
reference samples of certain starting materials, e.g. components of
culture media, need not necessarily be retained.
9.6 Certain operations require the continuous monitoring of data
during a production process, for example monitoring and recording of
physical parameters during fermentation.
9.7 Special consideration needs to be given to the quality
control requirements arising from production of biological products
by continuous culture.
Authors
The first draft of "Good manufacturing practices for biological
products" was prepared in January 1991 by Dr V. P. Grachev,
Scientist and Dr D. I. Magrath, Chief, Biologicals, WHO, Geneva,
Switzerland.
Acknowledgements
Acknowledgements are due to the following experts for their
comments and advice on the draft of "Good manufacturing practices
for biological products": Professor I. Addae-Mensah, Chemistry
Department, University of Ghana, Accra, Ghana; Professor H. Blume,
German Pharmacists' Central Laboratory, Eschborn, Germany; Dr A.
Fenyves, Paul Ehrlich Institute, Langen, Germany; Dr C. Guthrie,
General Manager, Blood Products Division, CSL Ltd., Parkville,
Australia; Dr U. Ihrig, German Pharmacists' Central Laboratory,
Eschborn, Germany; Mr K. Kawamura, Takeda Chemical Industries Ltd.,
Nihonbashi, Chuo-ku, Tokyo, Japan; Mr L. G. Kinnander, Chief
Pharmaceutical Inspector, Medical Products Agency, Uppsala, Sweden;
Mrs S. F. Langlois, Director, Regulatory Affairs, Connaught
Laboratories Ltd., A Pasteur Mйrieux Company, Willowdale, Ontario,
Canada; Mr P. Lemoine, Institute of Hygiene and Epidemiology,
Brussels, Belgium; Mr J. Lyng, State Serum Institute, Copenhagen,
Denmark; Professor N. V. Medunitsin, Director, Tarasevich State
Institute for the Standardization and Control of Medical Biological
Preparations, Moscow, USSR; Dr R. Netter, Paris, France; Professor
A. A. Olaniyi, Pharmaceutical & Chemistry Department, Faculty of
Pharmacy, University of Ibadan, Ibadan, Nigeria.
References
1. Good manufacturing practices for pharmaceutical products.
In: WHO Expert Committee on Specifications for Pharmaceutical
Preparations. Thirty-second report. Geneva, World Health
Organization, 1992 (WHO Technical Report Series, No. 823), Annex
1.
2. WHO Expert Committee on Biological Standardization.
Forty-second report. Geneva, World Health Organization, 1992
(WHO Technical Report Series, No. 822).
3. Laboratory biosafety manual, 2nd ed. Geneva, World
Health Organization, 1993.
4 Quality management for chemical safety testing.
Geneva, World Health Organization, 1992 (Environmental Health
Criteria, No. 141).
5. WHO Expert Committee on Biological Standardization.
Fortieth report. Geneva, World Health Organization, 1990 (WHO
Technical Report Series, No. 800), Annex
1.
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