WHO good manufacturing practices: specific pharmaceutical products
Sterile pharmaceutical products
Investigational pharmaceutical products for clinical trials in humans
Herbal medicinal products
1. Scope of these guidelines
4. Premises and equipment
5. Animal quarters and care
8. Lot processing records (protocols) and distribution records
9. Quality assurance and quality control
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.
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).
3.1 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).
6.1 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.
7.1 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.
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 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.
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.