The document discusses design and construction features for buildings used in drug manufacturing. It states that buildings must be of suitable size and construction to allow for cleaning and prevent contamination. It also discusses the need for separate areas for different stages of production, including receiving, storage, manufacturing, packaging, and waste disposal. Finishes, lighting, ventilation, plumbing, and sanitation are also addressed to maintain a clean and suitable environment for drug production.

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3. DESIGN AND CONSTRUCTION FEATURES:
A. Any building or buildings used in the manufacture,
processing, packing or holding of drug product shall be of
suitable size, construction and location to facilitate
cleaning, maintenance, and proper operations.
Regarding buildings and facilities, there are two major
areas of concern:
• the external environment and
• the internal environment.
The external environment must be amenable to the
location of well-designed and constructed buildings.
It is not only sufficient that the buildings in which the
production operations are to occur are clean and orderly and
of suitable size and construction, but if the land, air, or water
resources that surround the plant offer the potential for
water damage, infestation, or contamination of any type, the
facilities are in jeopardy (danger) of being judged unsuitable.
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5. Pertinent (Relevant) consideration prior to purchase, construction, or
alteration of existing facilities includes the following:
1) Adequate space for future expansion.
2) Zoning laws to allow anticipated development while restricting undesirable
developments in the vicinity.
3) Availability of water (quality and quantity), power, fuel, sewage and
waste-stream removal.
4) Accessibility for employees (availability of public transportation),
materials, and visitors (customers, suppliers).
5) Environmental issues such as site history; soil, water, and air quality;
and geological and topological issues (potential for flooding, earthquakes,
foundation instability).
6) Proximity of undesirable activities likely to pollute or act as a source
of vermin, insects, odor, or microorganisms—such as other industries,
disposal sites, or open mining.
7) Availability of a suitable labor force (people, skills, wage expectations,
labor relations and attitudes, access to further education
sources).
8) Ability to provide adequate security arrangements.
9) Proximity or accessibility to interrelated operations of the company—
R&D, marketing, internally produced intermediates or components.
10) Political situation—government stability, trade policies and taxation
(for foreign based operations), financial incentives.
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6. Having identified a suitable location for the facility, the site
development plan is prepared and will include:
1) Compliance with appropriate laws and regulations and any
additional company standards.
2) Site resources and infrastructure such as amenities, green spaces,
parking (employees, delivery and distribution vehicles, visitors),
road and rail access, recreation areas, site utilities, tank farms
and other external storage, and protection of wetlands and other
restricted environments.
3) Stormwater and waste management.
4) Site security and access—fences, guard posts, cameras.
5) Buildings—siting, layout, usage, function interrelationships for
efficiency, possible expansion, surface finishes.
6) Utilities—design, layout, backup (especially for critical utilities as
electricity and nitrogen for some chemical operations).
7) Equipment—design, layout, spares, capacity.
8) Traffic flow—pedestrian and vehicular (internal and external).
9) Safety—for personnel and equipment, containment for hazardous
materials, sprinkler system, emergency egress (exit), and
emergency services access.
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7. 10)External architecture to take into account local environmental conditions
(wind, snow, humidity) and aesthetic appearance blending local
atmosphere, comparative image, and functionality.
11)Ease of maintenance—accessibility to services (service ducts), ease of
cleaning, access for equipment.
12)Selection and use of experienced contractors.
13)Identification of project management responsibility.
14)Validation plans and an effective change control procedure. Provision of
design and ‘‘as-built’’ drawings.
15)Construction materials.
a) Walls: The position of walls should provide an orderly movement of
materials and personnel and should also take into account noise
levels to provide acceptable working conditions. The
interrelationship of different operations should minimize the
potential for cross-contamination and for component mix-up during
storage and interdepartmental shipping.
Walls in manufacturing areas, corridors, and packaging areas should
be of plaster finish on high-quality concrete blocks or gypsum board. The finish
should be smooth, usually with enamel or epoxy paint.
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8. Prefabricated partitions may be used in packaging areas where
flexibility of layout is important. Prefabricated units have also been used in
other areas, including sterile suites where panel joints must be given
particular attention. Where possible, walls should be flush and projections
should be avoided.
b) Floors: Floor covering should be selected for durability as well as
cleanability and resistance to the chemicals with which it is likely to
come into contact.
i. Terrazzo provides a hard-wearing finish; both tiles and poured-in-
place finishes are available. The latter is preferable for
manufacturing areas, and if tiles are used, care must be taken to
ensure effective sealing between the tiles, which otherwise could
become a harboring area of dirt and microorganisms.
ii. Ceramic and vinyl tiles usually are not recommended for production
areas. However, if used, the between-tile sealing should be flush
and complete.
iii.Welded vinyl sheeting provides an even, easy to clean surface. This
is not practical for heavy traffic areas, but can be of value in
production areas, especially for injectables. Here the lack of joints
improves the ease of cleaning and sanitation.
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9. iv. Epoxy flooring provides a durable and readily cleanable surface.
However, the subsurface finish is extremely important.
c) Ceilings: Suspended ceilings may be provided in office areas,
laboratories, toilets, and cafeterias. They usually consist of layin
acoustical panels of nonbrittle, nonfriable, nonasbestos, and non-
combustible material.
Manufacturing areas require a smooth finish, often of seamless
plaster or gypsum board. All ceiling fixtures such as light fittings, air outlets
and returns, PA system and sprinkler heads should be designed to assure ease
of cleaning and to minimize the potential for accumulation of dust.
d) Services: In the building design, provisions must be made for drains,
water, steam, electricity, and other services to allow for ease of
maintenance. Access should, ideally, be possible without disruption of
activity within the actual rooms provided with the services.
B. Any such building shall have adequate space for the orderly placement of
equipment and materials to prevent mix-ups between different
components, drug product containers, closures, labeling, in-process
materials, or drug products, and to prevent contamination. The flow of
components, drug product containers, closures, labeling, in-process
materials, and drug products through the building or buildings shall be
designed to prevent contamination.
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10. Table: Typical Finishes for Various Operations
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11. C. Operations shall be performed within specifically defined areas
of adequate size. There shall be separate or defined areas or
other such control systems for the firm’s operations as are
necessary to prevent contamination or mix-ups during the
course of the following procedures:
1) Receipt, identification, storage, and withholding from use
of components, drug product containers, closures, and
labeling, pending the appropriate sampling, testing, or
examination by the quality control unit before release for
manufacturing or packaging;
2) Holding rejected components, drug product containers,
closures, and labeling before disposition;
3) Storage of released components, drug product containers,
closures, and labeling;
4) Storage of in-process materials;
5) Manufacturing and processing operations;
6) Packaging and labeling operations;
7) Quarantine storage before release of drug products;
8) Storage of drug products after release;
9) Control and laboratory operations.
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12. 10) Aseptic processing, which includes as appropriate:
i. Floors, walls, and ceilings of smooth, hard surfaces
that are easily cleanable;
ii. Temperature and humidity controls;
iii. An air supply filtered through high-efficiency
particulate air (HEPA) filters under positive pressure,
regardless of whether flow is laminar or non-laminar;
iv. A system for monitoring environmental conditions;
v. A system for cleaning and disinfecting the room and
equipment to produce aseptic conditions;
vi. A system for maintaining any equipment used to
control the aseptic conditions.
D. Operations relating to the manufacture, processing and
packing of penicillin shall be performed in facilities
separate from those used for other drug products for
human use.
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13. LIGHTING
Adequate lighting shall be provided in all areas. In order
to meet lighting requirements, it is necessary for the
manufacturer to define the term ‘‘adequate.’’ This may be done
by defining the amount of light (lux or foot-candles) reaching
the working surface for each area involved in the production of
pharmaceuticals. Public standards exist for some types of work.
Normally, a range of 30–50 foot-candles ensures worker
comfort and ability to perform efficiently and effectively;
however, 100 foot-candles may be needed in some areas, as
well as special lighting for some operations, such as inspection
of filled vials. Once the light levels have been defined, it is
necessary that they be measured periodically and the results
recorded. The specifications should call either for replacement
of light sources when some level above the established
minimum has been reached or, alternatively, routine
replacements of light sources on some schedule that has been
shown adequate to ensure that light levels do not drop below
the established minimum. 13

14. VENTILATION, AIR FILTRATION, AIR HEATING AND COOLING
a) Adequate ventilation shall be provided.
b) Equipment for adequate control over air pressure,
microorganisms, dust, humidity, and temperature shall be
provided when appropriate for the manufacture, processing,
packing, or holding of a drug product.
c) Air filtration systems, including prefilters and particulate
matter air filters, shall be used when appropriate on air
supplies to production areas. If air is recirculated to
production areas, measures shall be taken to control
recirculation of dust from production. In areas where air
contamination occurs during production, there shall be
adequate exhaust systems or other systems adequate to
control contaminants.
d) Air-handling systems for the manufacture, processing and
packing of penicillin shall be completely separate from those
for other drug products for human use.
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15. Air-handling systems should consider the following factors:
1) Placement of air inlet and outlet ports. These should be sited to
minimize the entry of airborne particulates or odors from the
surrounding areas. Outlets should not be sited near inlets.
2) Where recirculation of air is acceptable, adequate precautions must
be taken to ensure that particulates from a processing area are
removed. This will usually require an alarm system or an automatic
cutoff in the event that a filter develops a hole. Dust extraction
systems should be provided, where appropriate, to further minimize
this potential problem.
3) The degree of filtration and the air volumes should be matched to
the operations involved.
4) Temperature and humidity conditions should provide personnel
comfort—which will enhance employee performance.
5) Where differential pressures are required between adjacent areas,
suitable monitoring equipment must be provided. For example,
solids manufacturing areas are usually maintained at a negative
pressure in relation to adjacent rooms and corridors in order to
minimize the possibility of dust migration to these other areas.
6) The siting of final air filters close to each room being serviced
eliminates concerns regarding the possibility of small leaks in the air
duct system. Air usually enters rooms near the ceiling and leaves
from the opposite side near the floor.15

16. PLUMBING
a) Potable water shall be supplied under continuous positive pressure
in a plumbing system free of defects that could contribute
contamination to any drug product. Potable water shall meet the
standards prescribed in the Environmental Protection Agency’s
Primary Drinking Water Regulations set forth in 40 CFR Part 141.
Water not meeting such standards shall not be permitted in the
potable water system.
b) Drains shall be of adequate size and, where connected directly to
a sewer, shall be provided with an air break or other mechanical
device to prevent back-siphonage.
Where it is necessary to provide on-site potable water storage,
an automatic chlorination system should be installed, usually at 2–3
ppm.
Drains, particularly those in production areas, can be a
potential source of microbial hazard. The requirement to include an
air break between drain and sewer is an attempt to minimize this by
eliminating the chance of back-siphonage. Drains should also be
regularly disinfected. 16

17. SEWAGE AND REFUSE
Sewage, trash, and other refuse in and from the building and immediate
premises shall be disposed of in a safe and sanitary manner. A pharmaceutical
plant may consider disposal in several different ways:
1) Product disposal. Any product requiring disposal should initially be separated
from its packaging if appropriate. For example, any product to be disposed
of in an approved landfill site should not be left in impermeable glass,
plastic, or other containers which would significantly delay destruction.
Tipping of product to bulk or crushing would be viable pretreatments. There
are risks associated with the destruction of products—potential for the
product to get diverted, legitimately or otherwise, during the disposal
sequence and contamination of groundwater. Disposal procedures should
involve agents with a proven record of dealing with such sensitive materials
or the use of company personnel to accompany the material from plant to
disposal. Ideally, incineration procedures have preference over landfill.
Where incineration is used, product in plastic or other flammable packaging
may not need to be returned to bulk.
2) Printed packaging disposal. The disposal of printed packaging components
including labels, inserts, and cartons poses no health risk. However,
ineffective disposal, such as into public landfill, can give rise to public
concern that product may be associated with the packaging. Such materials
should preferably be incinerated.
3) General trash and sewage. Normal local services will usually be adequate for
trash and sewage. However, internal procedures should be sufficiently
rigorous and monitored, to ensure that product and packaging waste does
not get intermixed. Containers used within the plant to accumulate waste
materials should be clearly marked to denote their designated use.17

18. WASHING AND TOILET FACILITIES
Adequate washing facilities shall be provided,
including hot and cold water, soap or detergent, air driers or
single-service towels, and clean toilet facilities easily
accessible to working areas.
In addition to GMP regulations, Occupational Safety &
Health Administration (OSHA) regulations impact on washing
and toilet facilities. These require toilet rooms to be separate
for each sex except where individual locked toilet rooms are
available and also define the minimum number of water
closets based on the number of users.
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19. 1)Eating facilities:
a)Eating and drinking are permitted only in separate eating
facilities well segregated from all production areas.
Smoking is permitted only where an adequate disposal
device is provided and apart from production areas.
b)Prominent signs indicating these rules are posted at
entrances to production areas.
c)Enforcement procedures against violators are taken by
management.
d)Permanent facilities for breaks and people bringing
lunches are required. Cafeterias serving hot meals are
ideal to reduce the amount of food, a potential
contamination source, being brought into the plant.
2)For production and materials processing areas:
a) Drinking, eating, smoking, tobacco chewing, and
expectoration are prohibited.
b)Tissues and closed disposal containers are readily
available. 19

20. 3)Lavatories and lockers:
a) Adequate in number for the number of personnel employed.
b)Conveniently located to all areas.
c) Hot shower facilities are provided.
d) Disinfectant soaps are utilized.
e) Adequate ash and waste receptacles are provided.
f) Periodic cleaning of the area during each shift with logging of
times and conditions is mandatory.
g) Complete cleaning with cleansing and disinfectant agents daily.
Follow-up inspection by supervisory personnel is logged.
h) Specific rest areas for female employees are provided.
i) Eating and drinking are not permitted. Foods and beverages for
meals and breaks may be stored only in lockers and then
removed to a separate eating area.
j) Areas separated from all aseptic spaces by an air lock.
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21. SANITATION
a) Any building used in the manufacture, processing, packing, or
holding of a drug product shall be maintained in a clean and
sanitary condition. Any such building shall be free of infestation by
rodents, birds, insects and other vermin (other than laboratory
animals). Trash and organic waste matter shall be held and
disposed of in a timely and sanitary manner.
b) There shall be written procedures assigning responsibility for
sanitation and describing in sufficient detail the cleaning schedules,
methods, equipment, and materials to be used in cleaning the
buildings and facilities; such written procedures shall be followed.
c) There shall be written procedures for use of suitable rodenticides,
insecticides, fungicides, fumigating agents and cleaning and
sanitizing agents. Such written procedures shall be designed to
prevent the contamination of equipment, components, drug
product containers, closures, packaging, labeling materials, or drug
products and shall be followed. Rodenticides, insecticides and
fungicides shall not be used unless registered and used in
accordance with the Federal Insecticide, Fungicide, and
Rodenticide Act (7 U.S.C. 135).
d) Sanitation procedures shall apply to work performed by contractors
or temporary employees as well as work performed by full-time
employees during the ordinary course of operations.21

22. MAINTENANCE
Any building used in the manufacture, processing,
packing, or holding of a drug product shall be maintained in a
good state of repair.
Deterioration of buildings not only presents a poor
image of the facility, it can also impact on product quality.
Cracks and holes in walls, floors, or ceilings can provide access
for insects, rodents, birds, dirt, or microorganisms. They can
also hinder cleaning and sanitation, thereby increasing the
potential for cross-contamination or microbial multiplication.
Floor cracks can also become a safety hazard for people or
even dislodge materials from trucks.
The ingress of water from roof leaks can cause
significant damage to materials and equipment, give rise to
electrical failures and fires and result in damage to the basic
structure of the building. Additionally, holes in the roof or
near the tops of buildings provide ready access to birds, which
may then be encouraged to nest within the building.
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23. BUILDINGS AND FACILITIES
Damage to insulation or pipes and duct work will
detract from the basic purpose of such insulation. It may
also result in freezing and eventual leakage of pipes and in
the shedding of insulation material into product and
equipment.
Light fittings need regular cleaning to remove any
accumulated dust, which can act both as a potential source
of contamination and reduce light intensity.
Where the proper correction of building deficiencies
requires shut-down of the area, it may be necessary to
resort to temporary repair until adequate time can be made
to enact a permanent repair. Building inspection and
maintenance programs should be defined in writing and a
record kept confirming compliance and referencing any
repairs performed. 23

24. EXAMPLES OF OBSERVATIONS FROM FDA 483 CITATIONS
1)The sterility test room was not designed and
constructed to facilitate cleaning and disinfection.
2)The HVAC and dust collection systems are not
validated.
3)The direction of air flow is not monitored in the
manufacturing rooms.
4)There are no approved procedures for maintaining the
HVAC and dust control systems throughout the plant.
5)The WFI system is not designed in a manner to
minimize microbial contamination and endotoxin load.
For example, in the past year there have been ten
incidents of WFI samples that exceeded specifications
for microbial contamination.
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25. 6) The written procedures covering pest control within
the buildings are not signed or dated by the
personnel who prepared and authorized them.
7)Inspection of the reverse osmosis water system
revealed dead legs, which are potential sites for
microorganisms to lodge, multiply, and enter the
effluent.
8)There are no temperature or humidity specifications
for the area.
9)Sensors for monitoring warehouse temperature have
not been calibrated since their installation three
years ago.
10)Air recirculated in the compressing area has never
been tested for particulate matter. Validation of the
air handling system is inadequate—samples for cross
contamination were collected from only cubicles in
the compressing area. 25

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