(1993; 36 pages)
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 manufacture, 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.