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.