PREMISES - DESIGN,

CONSTRUCTION, LAYOUT AND

MAINTENANCE
Introduction
In any industry, manufacturing operations must be carried out under clean
and hygienic conditions. However, in the pharmaceutical industry, the condition
of the premises assumes critical importance because of the nature of the
products being manufactured. Both the external and internal environments must
be geared to be conducive to maintain the quality and safety of drug products.
Special care must also be taken to prevent contamination of the products and
therefore, the location, design, construction and layout of premises is a vital part
of the Good Manufacturing Practices (GMP) regulations. ‘Premises’ refers to the
buildings and facilities where pharmaceutical processing is done. These places
must comply with cGMP requirements.
8.1 LOCATION
Premises must be located in a site that is of a size suitable to house all the
different departments. The nature of manufacturing and testing to be
performed, the magnitude of the operation in terms of daily production levels,
the number of products that will be processed and the storage space required for
raw material, in-process and finished goods are some of the important factors to
be considered when choosing a location. Other factors such as availability of
power, water, labour workforce and closeness to transport hubs may also impact
this decision. From the GMP point of view, the most important factor is the
climatic condition, and hygiene levels in the surroundings. Pharmaceutical
premises must ideally be located away from polluting industries as otherwise, it
will burden the air handling and water handling systems.
According to Schedule M of the Drugs and Cosmetics Rules, factory buildings
must be situated in a place that avoids contamination risk from the external
environment (for example

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– from open drains, public lavatory, open sewage lines, or industry that
produces gaseous fumes or strong odours or generates smoke, dust or other
8.2 DESIGN AND CONSTRUCTION
chemical emissions).
The building used must be designed, constructed and maintained in a manner
that permits drug production under hygienic conditions. It must be suitable for
the operations being performed. The layout of the premises must be such that it
reduces risk of errors, and also avoids buildup of dirt and cross-contamination
that may affect drug product quality. Construction and layout of the building
must allow for a sequential and logical flow of the production process and
movement of personnel and materials. It must also permit regular cleaning,
repair and maintenance work without harming product quality.
Walls, ceilings and floors of the building must be smooth and crack-free, easy
to clean and disinfect. Surfaces must not shed particles; they must be kept
smooth and without any open joints where dust can accumulate.

8.3 UTILITIES
The building must be supplied with adequate light, water, power supply and
ventilation and must be fitted with systems to maintain the temperature and
humidity of different areas at desired levels. There must be arrangements to
protect against the entry of pests, insects, rodents etc.
The fittings, ducts, pipes and ventilation points must be designed in such a
way that they do not produce difficult-to-clean recesses. Such points must be
located to be easily accessible for maintenance work without having to enter the
manufacturing areas.
Sensitive drug manufacturing areas must be air-conditioned to achieve the
optimum temperature and humidity conditions. All areas must receive filtered air
– the filtration and air change rate must be designed to achieve the desired clean
area classification. Some of the important factors that influence this rate include
the quality of the input air, size of the room, heat load of the room, room
pressure to be maintained, dust generated during processing in that room,
number of personnel working in the room etc. An air change rate of 6 to 20 air
changes per hour is the norm.
Lighting facilities too must match requirements – for example, visual
inspection areas must be brightly lit; light-sensitive drug manufacturing requires
amber lighting provisions etc.
Water systems shall be installed to provide water of the quality
commensurate with requirements of the drug product. Potable water may be
used for washing and cleaning but better quality water as purified water or
distilled water must be used during the manufacturing and testing operations.
Water storage tanks must be designed to maintain the quality of the water and

8.4 SANITATION
prevent microbial growth.

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All areas inside the building must be cleaned regularly and cleaning records
must be maintained. Drains must be sized correctly and be designed to prevent
back-flow of contents. They must be closed as far as possible; if open channels
are unavoidable, they must be kept shallow to allow easy cleaning and
disinfection.
Wastes from manufacturing area must be disposed in keeping with
regulations of Environment Pollution Control Board. Waste materials that have to
be disposed must be stored in a safe manner. Any wastes that are inflammable,
hazardous or toxic must be stored in a segregated area while awaiting disposal.
Bio-medical waste must be disposed as per regulations of Bio-Medical Waste
(Management and Handling) Rules, 1996. Rejected drugs must be stored
separately and destroyed in keeping with regulations.
Restrooms, toilets and refreshment area must be located far from
manufacturing areas. They must not be in direct communication with areas
where materials are manufactured, tested or stored. Animal testing laboratories
too must be isolated from these areas, with separate entrance and dedicated air-
handling systems.
8.4.1 Sanitation of Sterile Areas
Sterile areas must be cleaned and sanitized often in keeping with an
approved cleaning protocol. More than one type of disinfectants must be used to
ensure effective bactericidal action. Regular monitoring of clean rooms must be
performed to detect presence of contaminating microorganisms. Cleaning
procedures must be validated to verify that disinfectant residues are detected
and removed during cleaning. Detergents and disinfectants used in sterile areas
must be sterile before use. For spaces that are inaccessible inside the sterile
room, fumigation may be used to reduce microbial contamination. Occasional
cleaning with a sporicidal agent must be part of the cleaning routine since spores
are resistant to the common disinfectants.
8.5 ENVIRONMENTAL CONTROL
The temperature and relative humidity of the premises must be controlled in
order to ensure the area complies with material and product requirements, as
well as regulatory requirements. Attention must also be given to operator
comfort wherever possible. Airlocks must be built to separate low-humidity areas
from higher humidity areas; this prevents the migration of moisture that would
otherwise overload the Heating Ventilation and Air Conditioning (HVAC) system.
The systems used for humidity control must be designed to avoid introducing
any contaminants.
Dust and vapours must be extracted at source and not allowed to travel
elsewhere. The dust extraction system must have adequate transfer velocity in
order to make sure that the dust is truly carried away and does not merely settle
into the ducting of the system.
General direction of airflow in a room must be designed to remove vapours
and dust generated in the area. It must also consider the location of the operator
to make sure he/she does not contribute to contamination. It is often preferred
to introduce air into the room
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using ceiling diffusers, and extract the room air through vents at low heights on
the wall to provide a flushing effect as the air moves out of the room. In case of
processes that generate a vapor that is lighter than air, the extraction grilles will

8.6 CONTAMINATION
need to be positioned at higher level.
World Health Organization (WHO) defines contamination as, “The undesired
introduction of impurities of a chemical or microbial nature, or of foreign matter,
into or on to a starting material or intermediate, during production, sampling,
packaging or repackaging, storage or transport.”
The most common sources of contamination are dust, skin, hair,
microorganisms, grease, chemicals and particulate matter. Such contamination
can be controlled by controlling the environmental conditions as well as
personnel factors.
Environment control is exerted by having a well-designed HVAC system that
efficiently removes the contaminants that may get introduced. Regular cleaning
and controlled entry and exit of materials and personnel into the clean areas can
also help avoid contamination.
Personnel hygiene is a must and they must be trained to follow the
prescribed dress code, procedures for entry and exit into clean rooms and
gowning procedures.
Cleanrooms:
Cleanroom refers to a controlled environment where level of contamination is
kept very low to meet requirements specified in terms of number of particulates
per cubic meter. To achieve this controlled environment, air enters the
cleanroom through High Efficiency Particulate Air (HEPA) filters that remove
particles greater than or equal to 0.3 micron in size.
US Food and Drug Administration Guideline for Air Classification
Microbiological Limit
Clean 0.5 µm 0.5 µm cfu/ ft3 cfu/ mt3
area particles particles
classificati /ft3 /mt3
on
100 100 3500 <1 <3
1000 1000 35000 <2 <7
10000 10000 350000 <3 < 18
100000 100000 3500000 < 25 < 88
Note : µm – micrometer, ft – cubic feet, mt – cubic meter, cfu – colony
3 3

forming unit
Cleanroom Classification as per Schedule M:

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Grade At rest In operation (a)

(b)
Maximum number of permitted particles per cubic
metre equal to or above
0.5 µm 5 µm 0.5 µm 5 µm
A 3520 29 3500 29
B (a) 35,200 293 3,52,000 2,930
C (a) 3,52,000 2,930 35,20,000 29,300
D (a) 35,20,000 29,300 Not defined (c) Not defined (c)

Grad Types of operations for aseptic

e preparations
A Aseptic preparations and filling.
B Background room conditions for activities requiring
Grade A.
C Preparation of solution to be filtered.
D Handling of components after washing.
WHO Air Classification System for Manufacture of Sterile Products
Grad Maximum number of Maximum number
e particle permitted of viable
per m3 microorganisms
per m3
0.5 – 5 µm > 5 µm
A (Laminar 3,500 None Less than 1
airflow
workstation)
B 3,500 None 5
C 3,50,000 2000 100
D 35,00,000 20,000 500

8.7 CROSS CONTAMINATION

WHO defines cross-contamination as, “Contamination of a starting material,
intermediate product or a finished product with another starting material or
material during production.”
Manufacturing areas must be designed to prevent both contamination of drug
product and cross contamination between products. Contamination may be
avoided by controlling the quality of air in a room and by ensuring hygiene and
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clothing change of workers entering into the manufacturing area. Cross-
contamination is a little more difficult to control.

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Risk of cross-contamination is greater when dry material processing takes

place because dust is generated and spreads rapidly. The most common sources
of cross-contamination include dust, vapors, gases, particles, sprays, residues on
equipment surfaces, operators clothing or skin.
The most dangerous contaminants include sensitizing materials, hormones,
living organisms, cytotoxic materials and highly active compounds.
8.7.1 Measures to Prevent/ Reduce Cross-contamination
1. Manufacturing the product in dedicated areas which are self-contained.
2. Manufacturing on a campaign basis – complete the production process
and then ensure a thorough cleaning before starting a new product batch
on the same line.
3. Using premises that are appropriately protected through airlocks, air-
extraction systems and pressure differentials.
4. Preventing re-entry or re-circulation of untreated air
5. Using protective clothing
6. Regular testing for presence of residues
8.7.2 Preventing Dust Migration in Non-dedicated Facilities
Sometimes, it may be necessary to manufacture different products in
different areas of the same premises. In such situations, care must be taken to
ensure dust from one area doesn’t move into another area where a different
product is being processed.
8.7.3 Air Containment
Containment of air is achieved by two methods – displacement or pressure
differential.
Displacement Concept:
This concept relies on maintaining a high airflow in combination with a low
pressure differential. It is often used in areas where dust generation is high. Air is
supplied into the corridor, from where it flows through the doorway and into the
room, and gets extracted out from the back of the room. The room door must be
kept closed and air entry is through a door grille. The air should move with a
velocity that’s high enough to ensure there is no turbulence in the doorway that
may cause dust to escape.
Pressure Differential Concept:
This relies on use of low airflow in combination with a high pressure
differential. This concept works best in areas that are no-dust or low-dust. The
pressure differential between clean and less-clean areas must be great enough to
ensure air containment and prevent reverse-flow of air; however, it must not be
high enough to cause turbulence in the area. Generally, pressure differentials of
5Pa to 20 Pa are acceptable; the most commonly maintained value is 15 Pa. Too
low pressure differentials must be avoided because they lead to reversal of air
flow, and contamination. If unavoidable, it is advised to simultaneously use
airlocks too.

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These areas must be fitted with devices to control and monitoring devices
that must be qualified before use. Regular calibration of these devices is also
necessary. There must also be an alarm system linked to the pressure controller
to alert personnel to any critical change in the pressure differentials.
8.7.4 Airlocks
The barrier which separates 2 controlled areas is called as an airlock. It
generally has two or more doors to regulate the movement of air. Airlocks can be
of 3 types – cascade type, bubble type and sink type.
Cascade airlocks: These airlocks have lower pressure on one side, and
higher pressure on the other side. For example, in tablet manufacturing areas,
corridor is at higher pressure, and cubicle where drug processing occurs is at
lower pressure. Thus, air moves from corridor to cubicle, and prevents dust
containing drug from entering into the corridor.
Bubble airlocks: These airlocks have higher pressure inside than on both
outer sides. For example, in parenteral manufacturing areas, the high pressure
inside drives air away from the room into the corridor. Thus, entry of
contaminants that may damage the drug inside the sterile clean room is
prevented.
Sink airlocks: Here, the pressure on both sides of the airlock is very high so
that no contaminant can escape from the cubicle. This type of system is used in
facilities used to manufacture harmful substances like toxins or poisons.
In all these airlocks, doors must open into the side having higher pressure so
that it will close automatically and faster. The airlock must be designed with an
interlocking system so that both doors cannot open at the same time. Opening of
either door must be linked to the sounding of an alarm.
Air changes must be carried out at higher rates within the airlock – generally,
20 air changes per hour is the minimum prescribed rate. Airlocks must be
empty; no material should be stored in them.

8.8 ADDITIONAL CONSIDERATIONS REGARDING PREMISES

8.8.1 Storage Areas
Storage areas must have sufficient space for the materials to be stored in a
systematic and organized manner according to their categories such as starting
materials, intermediates, bulk product, finished products, packaging materials,
released products, quarantined products, rejected products, recalled products
and returned products.
These areas must be clean, well-lit, dry, and be maintained at specified
temperatures. In case of special storage conditions (for example, cold
conditions), the conditions must be monitored and controlled.
Receiving bays must allow cleaning of incoming material if necessary. The
received material must be kept in quarantine until sampling, testing and
approval. Entry to this area must be restricted. Materials that have been rejected
or returned or recalled must be physically separated from other materials.
Separate storage areas must exist for holding

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materials that are dangerous or highly active (for example – narcotics, highly
inflammable solvents, radioactive materials, poisons etc).
Sampling areas for starting materials must be sufficiently separated to avoid
contamination or cross contamination.
8.8.2 Production Areas
Products that are highly active (such as hormones, antibiotics, cytotoxic
drugs) or highly sensitizing (penicillin, for example) must be manufactured in
dedicated facilities that are self- contained. Other products must not be
manufactured here.
In facilities where multiple product batches are being simultaneously
manufactured, there must be measures in place to prevent cross-contamination.
Besides, there must be sufficient in-process storage space to prevent the
occurrence of mix-ups.
8.8.3 Quality Control (QC) Laboratory Areas
QC laboratories must be located in an area separate from production. In the
laboratories, separate areas must exist for biological, microbiological, and
radioisotope testing and these areas must have dedicated air handling units.
Sufficient space must be provided for storing samples, solvents, reference
standards and laboratory records with no chances of mix-ups between different
samples drawn for testing. Air supply to QC laboratories must be separate from
the unit supplying air to production areas.
Instruments that are sensitive to temperature and humidity must be housed
in separate rooms. Care must be taken to prevent vibrations and electrical
interference from reaching them.
Pharmaceutical companies pay lot of attention to setting up quality
management systems and validation studies in order to ensure regulatory
compliance. Along with this, it is vital they pay attention to maintenance of their
facilities and premises so that there is no risk of product contamination which
may lead to damaging situations such a s a product recall. Having self-inspection
programmes, regular maintenance activity, and good housekeeping practices will
ensure that companies remain in compliance with regulatory requirements.

References
1. World Health Organization. (2007). Quality Assurance of Pharmaceuticals:
A Compendium of Guidelines and Related Materials. Vol 2, 2 nd Updated
Edition. Good Manufacturing Practices and Inspection. Available online at

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https://www.who.int/medicines/areas/quality_safety/quality_assurance/
QualityAssura ncePharmVol2.pdf
2. Potdar M.A. (2007). Pharmaceutical Quality Assurance. 2nd Edition. Nirali
Prakashan.
3. Sharma P. P. (2015). How to Practice GMPs: A Treatise on GMPs. 7 th
Edition. Vandana Publications.
4. Ministry of Health and Family Welfare, India. Schedule M: Drugs and
Cosmetics Rules, 1945. Available online at
https://ipapharma.org/wp- content/uploads/2019/02/schedule-m-1.pdf
5. United States Food and Drug Administration. 21 CFR Part 211. Available
online at
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?
CFRPart=21 1

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