BUILDINGS AND FACILITIES
Design and Construction
Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants as appropriate.
Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination.
Where the equipment itself (e.g., closed or contained systems) provides adequate protection of the material, such equipment can be located outdoors.
The flow of materials and personnel through the building or facilities should be designed to prevent mix-ups or contamination.
There should be defined areas or other control systems for the following activities:
− Receipt, identification, sampling, and quarantine of incoming materials, pending release or rejection;
− Quarantine before release or rejection of intermediates and APIs;
− Sampling of intermediates and APIs;
− Holding rejected materials before further disposition (e.g., return, reprocessing or destruction);
− Storage of released materials;
− Production operations;
− Packaging and labelling operations; and
− Laboratory operations.
Adequate, clean washing and toilet facilities should be provided for personnel. These washing facilities should be equipped with hot and cold water as appropriate, soap or detergent, air driers or single service towels. The washing and toilet facilities should be separate from, but easily accessible to, manufacturing areas. Adequate facilities for showering and/or changing clothes should be provided, when appropriate.
Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, in particular those used for in-process controls, can be located in production areas, provided the operations of the production process do not adversely affect the accuracy of the laboratory measurements, and the laboratory and its operations do not adversely affect the production process or intermediate or API.
All utilities that could impact on product quality (e.g. steam, gases, compressed air, and heating, ventilation and air conditioning) should be qualified and appropriately monitored and action should be taken when limits are exceeded. Drawings for these utility systems should be available.
Adequate ventilation, air filtration and exhaust systems should be provided, where appropriate. These systems should be designed and constructed to minimise risks of contamination and cross-contamination and should include equipment for control of air pressure, microorganisms (if appropriate), dust, humidity, and temperature, as appropriate to the stage of manufacture. Particular attention should be given to areas where APIs are exposed to the environment.
If air is recirculated to production areas, appropriate measures should be taken to control risks of contamination and cross-contamination.
Permanently installed pipework should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control systems, or alternative means. Pipework should be located to avoid risks of contamination of the intermediate or API.
Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when appropriate.
Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use.
Unless otherwise justified, process water should, at a minimum, meet World Health Organization (WHO) guidelines for drinking (potable) water quality.
If drinking (potable) water is insufficient to assure API quality, and tighter chemical and/or microbiological water quality specifications are called for, appropriate specifications for physical/chemical attributes, total microbial counts, objectionable organisms and/or endotoxins should be established.
Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.
Where the manufacturer of a non-sterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug (medicinal) product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.
Dedicated production areas, which can include facilities, air handling equipment and/or process equipment, should be employed in the production of highly sensitizing materials, such as penicillins or cephalosporins.
Dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.
Appropriate measures should be established and implemented to prevent cross-contamination from personnel, materials, etc. moving from one dedicated area to another.
Any production activities (including weighing, milling, or packaging) of highly toxic non-pharmaceutical materials such as herbicides and pesticides should not be conducted using the buildings and/or equipment being used for the production of APIs. Handling and storage of these highly toxic non-pharmaceutical materials should be separate from APIs.
Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.
Sewage and Refuse
Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from manufacturing) in and from buildings and the immediate surrounding area should be disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified.
Sanitation and Maintenance
Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition.
Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.
When necessary, written procedures should also be established for the use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents to prevent the contamination of equipment, raw materials, packaging/labelling materials, intermediates, and APIs.