PREMISES

PRINCIPLE

Premises must be located, designed, constructed, adapted and maintained to facilitate proper operations. Their layout and design must aim to minimize risk of confusion, cross-contamination and other error and permit effective cleaning, sanitation 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.

GENERAL

Premises should be located as to avoid contamination from the surrounding environment such as air, earth and water pollutant as well as from nearby activities which could adversely affect the quality of products. If the premises were unsuitably located, effective measures should be taken to avoid such contamination.
Premises should be so constructed, equipped and maintained to afford maximum protection against weather, flood, ground seepage and the access entry and harbouring of insects, birds, rodents, vermin, or other animals. There should be a procedure for rodent and pest control.
Premises should be carefully maintained. They should be cleaned and, where applicable, disinfected according to detailed written procedures. Records should be maintained.
All premises, including production areas, laboratories, stores, passage ways and external surroundings should be maintained in a clean and tidy condition. The conditions of buildings should be reviewed regularly, and repaired where necessary. Special care should be exercised to ensure that building repair or maintenance operations do not adversely affect the products.
Electrical supply, lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment.
The premises design and lay-out should ensure :
the compatibility of other manufacturing operations that may be carried out in the same or adjacent premises; and
avoiding use of production areas as a general traffic for personnel and materials or for storage other than the materials in process.
Steps should be taken in order to prevent the entry of unauthorized people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them.
Defined areas for the following operations are required :
materials receiving;
incoming goods quarantine;
starting materials storage;
weighing and dispensing;
processing;
equipment washing;
equipment storage;
storage of bulk products;
packaging;
quarantine storage before the final release of finished products;
product shipping; and
control laboratory

WEIGHING AREAS

The weighing of starting materials and the estimation of yield by weighing should be carried out in separate weighing areas specially designed for that use. Such areas may be part of either storage or production areas.

PRODUCTION AREAS

In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials.
The production of other products, such as certain antibiotics (e.g. penicillins), sex hormones, certain cytotoxics, certain highly active drugs, biological preparations (e.g. from live micro-organisms) and non-pharmaceutical products, should be conducted in separate buildings.
The production of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of pharmaceutical products.
Premises should 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, the requisite cleanliness levels;
to avoid crowding and disorder; and
to allow effective communication and supervision.
The adequacy of the working and in-process storage space should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different pharmaceutical products or their components, to avoid cross-contamination and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection.
The floor in processing areas should be made of impervious materials, laid to an even surface and should allow prompt and efficient removal of any spillages. The coving of junctions between walls and floors in processing areas is necessary.
Pipe work, light fittings, ventilation points and other services should be designed and installed in such a way to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the production areas.
Exposed pipes should not touch walls but be suspended from or be supported by brackets, sufficiently separated to allow thorough cleaning.
Exposed overhead roof joints, pipes and ducts should be avoided. Where they are unavoidable, special cleaning procedures and schedules should be prepared and followed.
Air intakes and exhausts, and associated pipe work and ducting should be installed in such a way to avoid product contamination.

Drains should be of adequate size, designed and equipped with trapped gullies to prevent back-flow. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.
Production areas should be effectively ventilated, with air control facilities including filtration of air to a sufficient level to prevent contamination and cross-contamination, as well as control of temperature and, where necessary, humidity appropriate both to the products handled and to the operations undertaken within them and to the external environment. These areas should be regularly monitored during both production and non-production periods to ensure compliance with their design specifications.
In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.
Premises for the packaging of pharmaceutical products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.
Productions areas should be well lit, particularly where visual on-line controls are carried out.
In-process controls may be carried out within the production area provided they do not carry any risk for the production.
Doors that lead from production areas directly to the outside, e.g. fire exits, should be sealed. They should be secured in such a way that they can be used only as an emergency exit. Where internal doors are a barrier to cross contamination, they should be closed when not in use.

STORAGE AREAS

Storage areas should 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, returned or recalled.
Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean, dry and sufficiently lit and maintained within specified temperature limits.
Where special storage conditions are required (e.g. temperature, humidity) these should be provided, controlled, monitored and recorded where appropriate.
Receiving and dispatch bays should protect materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.
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 should give equivalent security.
There should normally be a separate sampling area for starting materials in a controlled environment. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination. Adequate cleaning procedures should be in place for the sampling areas.
Segregated and locked areas should be provided for the storage of rejected, recalled or returned materials and products.
Highly active materials and radioactive materials, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire or explosion should be stored in safe and secure areas. Narcotics and other dangerous drugs should be stored under lock.
Printed packaging materials are considered critical to the conformity of the pharmaceutical products to its labelling and special attention should be paid to the safe and secure storage of these materials; particularly, labels should be stored under lock.

QUALITY CONTROL AREAS

Quality control laboratories should be separated from production areas. Areas where biological, microbiological or radioisotope test methods are employed should be separated from each other.
Quality control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples, reference standards (if necessary, under controlled temperature), solvents, reagents and records.
A separate room may be needed for instruments to protect them against electrical interference, vibration, contact with excessive moisture (humidity) and other external factors, or where it is necessary to isolate the instruments.
The design of the laboratories should take into account the suitability of construction materials, prevention of fumes and ventilation. There should be separate air supply to laboratories and production areas. Separate air-handling units and other provisions are needed for biological, microbiological and radioisotope laboratories.

ANCILLARY AREAS

Rest and refreshment rooms should be separated from production and quality control laboratory areas.
Facilities for changing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas. Changing rooms should be directly connected to but separated from production areas.
Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.
Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.