GMP Cleanroom Requirements for Grade A, B, C, and D Facility
Regulatory bodies established for ensuring the quality of the products being manufactured. They put stringent regulations for drug
manufacturing facilities.
The Good Manufacturing Practices (GMP) for manufacturing sterile medicinal products were created to ensure that the drugs are safe
and contain the ingredients and amounts they claim. These criteria are intended to reduce the risk of microbiological, particle, and
pyrogen contamination.
Cleanrooms do not entirely remove contamination; instead, they regulate it to a tolerable level. In cases where operations are likely to
cause defects in the final product, a higher degree of cleanliness is required to avoid contamination.
Under the GMP requirements, the manufacturing of sterile medicinal products can be distinguished into 4 grades: Grade A, B, C & D.
Examples of operations and grades for aseptic preparation and processing operations
• Aseptic assembly of filling equipment.
• Connections made under aseptic conditions (where sterilized
product contact surfaces are exposed) that are post the final
sterilizing grade filter. These connections should be sterilized by
• Sinks and drains prohibited in Grade A
steam-in-place whenever possible.
• High-risk operations (filling zone, stopper
• Aseptic compounding and mixing.
bowls, open ampoules, and vials, making
aseptic connections) • Replenishment of sterile bulk product, containers, and closures.
Grade A
• Laminar airflow cabinet can obtain Grade A • Removal and cooling of unprotected (e.g., with no packaging)
cleanliness in Grade B background. items from sterilizers
• Equivalent to an ISO 5 cleanroom • Staging and conveying of sterile primary packaging components
environment (at rest and in operation) in the aseptic filling line while not wrapped.
• Aseptic filling, sealing of containers such as ampoules, vial
closure, transfer of open or partially stoppered vials.
• Loading of a lyophilizer.
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• Sinks and drains are prohibited in Grade B
• ISO 5 at rest, ISO 7 in operation • Background support for grade A (when not in an isolator).
• Particle monitoring system with alarm if limits • Conveying or staging, while protected from the surrounding
Grade B
are exceeded is required. environment, of equipment, components, and ancillary items for
• Background zone for Grade A introduction into grade A.
• Used for aseptic preparation and filling
• Less critical operations
• ISO 7 at rest, ISO 8 in operation
• Monitoring depends on quality risk • Preparation of solutions to be filtered including sampling and
Grade C
management. dispensing.
• Used for filling of products for terminal
sterilization (at least in a Grade C)
• Cleaning of equipment.
• Less critical operations • Handling of components, equipment, and accessories after
cleaning.
• ISO 8 at rest, not defined for in operation.
Grade D • Assembly under HEPA filtered airflow of cleaned components,
• Dirtiest area of GMP guidelines
equipment, and accessories prior to sterilization.
• Assembly of closed and sterilized SUS using intrinsic sterile
connection devices
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Grade A:
A cGMP Grade A environment is equivalent to an ISO 5, for both at rest and in operation. This means that whether employees are
working or not, the cleanliness inside the cleanroom must maintain Grade A levels (ISO 5).
The required level of cleanliness for a Grade A area is obtained using a laminar flow cabinet or a laminar airflow hood (LAF). If the
surrounding air is preserved and classed as Grade B, a laminar flow cabinet can attain a cleanliness classification of Grade A.
To achieve Grade A cleanliness level, the number of airborne particles is according to below table
Maximum permitted number of Maximum permitted number of
particles ≥ 0.5 μm/m3 particles ≥ 0.5 μm/m3 ISO Class
Grade
At Rest/In Operation
At rest In operation
Grade A 3 520 3 520 ISO 5/ ISO 5
The Grade A area is dedicated to high-risk operations such as fill/finish (filling zone), stopper bowls, open ampoules, vials, and making
aseptic connections.
Grade B:
The Grade B cleanroom, in operation, is equivalent to an ISO 7 environment, while at rest, it corresponds to an ISO 5 cleanroom. At
rest, the Grade B cleanroom needs to meet a maximum of 3,520 particles (0.5 μm) per cubic meter. In operation, the number of
permitted airborne particles increases to 352,000 (0.5 μm) for each cubic meter of air.
Maximum permitted number of Maximum permitted number of
particles ≥ 0.5 μm/m3 particles ≥ 0.5 μm/m3 ISO Class
Grade
At Rest/In Operation
At rest In operation
Grade B 3 520 352 000 ISO 5/ ISO 7
Sinks and drains are not permitted in Grade A and B areas. The Grade B room of your GMP facility must be equipped with a particle
monitoring system including an alarm if limits are exceeded. The Grade B cleanroom environment of your GMP facility is used for
aseptic preparation and filling.
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Grade C:
The Grade C cleanroom spaces are for performing less stringent steps of sterile product manufacturing. The airborne particle
classification equivalent for Grade C (at rest and in operation) is ISO 7 and ISO 8, respectively.
At rest, the number of particles allowed for each cubic meter is 352,000, while the number is 3,520, 000 in operation.
Maximum permitted number of Maximum permitted number of
particles ≥ 0.5 μm/m3 particles ≥ 0.5 μm/m3 ISO Class
Grade
At Rest/In Operation
At rest In operation
Grade C 352 000 3 520 000 ISO 7/ ISO 8
The monitoring of the Grade C area should be implemented in line with quality risk management principles, the systematic method for
assessing, controlling, communicating, and reviewing risks to the quality of a medicinal product throughout its lifespan.
Grade D:
For Grade D, the airborne particle classification is the equivalent of an ISO 8 cleanroom at rest. While in operation, the particle
classification is not predefined; it will depend on the nature of the processes taking place inside the zone. This is what we call a Clean
Non-Classified / Controlled Not Classified (CNC) area.
Maximum permitted number of Maximum permitted number of
particles ≥ 0.5 μm/m3 particles ≥ 0.5 μm/m3 ISO Class
Grade
At Rest/In Operation
At rest In operation
Grade D 3 520 000 Not defined (CNC) ISO 8/ – not defined
Like the Grade C cleanroom of a GMP facility, the Grade D area is used to perform less critical steps in manufacturing sterile drugs.
The Grade D environment can be a background zone, depending on how your cleanroom is designed. This is the least clean area of
the GMP requirements for sterile products.
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