GMP Facility: Understanding Grade A, Grade B, Grade C & D

Understanding the GMP requirements and their grades can be challenging at times, especially with different regulatory bodies in other countries. What are the differences between a Grade A, Grade B, Grade C, or Grade D cleanroom environment? This article will cover:

  • The differences between the grades
  • Their ISO equivalent at rest/in operation
  • Examples of applications for each GMP grade
  • Graphic charts (number of airborne particles, etc.)

Regulators such as the FDA in the United States or Health Canada ensure the quality of drug products. They put strict and precise regulations for drug manufacturers in the pharma industry.

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.

Also known as the current Good Manufacturing Practices (cGMP), the regulations cover production processes, quality control, packaging, personnel, and GMP facility. This article will focus on the latter, the good manufacturing practices for the cleanroom environment of your GMP Facility.

GMP Cleanroom Requirements for Grade A, B, C, and D Facility 

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.

Some operations, such as the manufacturing of non-sterile pharmaceuticals, do not automatically require a cleanroom, whereas sterile drugs necessarily do. The GMP clean air grades and classifications define the environment in which sterile drugs and biological products should be manufactured.

Under the GMP requirements, the manufacturing of sterile medicinal products can be distinguished into 4 grades: Grade A, B, C & D.

 

cGMP Cleanroom Grades Summary

Grade A Grade B Grade C Grade D
Sinks and drains prohibited in Grade A

High-risk operations (filling zone, stopper bowls, open ampoules, and vials, making aseptic connections)

Laminar airflow cabinet can obtain Grade A cleanliness in Grade B background

Equivalent to an ISO 5 cleanroom environment (at rest and in operation)

Sinks and drains are prohibited in Grade B

ISO 5 in operation, ISO 7 at rest

Particle monitoring system with alarm if limits are exceeded is required

Background zone for Grade A

Used for aseptic preparation and filling

Less critical operations

ISO 7 in operation, ISO 8 at rest

Monitoring depends on the quality risk management

Used for filling of products for terminal sterilization (at least in a Grade C)

Preparation of solutions to be filtered, including weighing

Less critical operations

ISO 8 at rest, not defined for    in operation

Dirtiest area of GMP guidelines

 

 

 

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 smaller than 0.5 micrometers should not exceed 3,520 per cubic foot.

 

Grade Maximum permitted number of particles ≥ 0.5 μm/m3

At rest

Maximum permitted number of particles ≥ 0.5 μm/m3

In operation

ISO Class
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.

Tasks and applications to do in a Grade A area:

  • Aseptic assembly of filling equipment
  • Aseptic compounding and mixing
  • Replenishment of sterile bulk products, containers, and closures
  • Removal and cooling of unprotected items from sterilizers
  • Staging and conveying of sterile primary packaging components
  • Loading of a lyophilizer

Grade B

The Grade B cleanroom, in operation, is equivalent to an ISO 5 environment, while at rest, it corresponds to an ISO 7 cleanroom. At rest, the Grade B cleanroom needs to meet a maximum of 3,520 particles (0.5 μm) per cubic foot. In operation, the number of permitted airborne particles increases to 352,000 (0.5 μm) for each cubic foot of air.

Grade Maximum permitted number of particles ≥ 0.5 μm/m3

At rest

Maximum permitted number of particles ≥ 0.5 μm/m3

In operation

ISO Class
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.

Other tasks and applications in a Grade B area:

  • Background support for the Grade A zone
  • Transport (while protected from the surrounding environment) of equipment, components, and ancillary items for introduction into the Grade A zone.

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 foot is 352,000, while the number is 3,520, 000 in operation.

Grade Maximum permitted number of particles ≥ 0.5 μm/m3

At rest

Maximum permitted number of particles ≥ 0.5 μm/m3

In operation

ISO Class
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.

Examples of what activities should take place in a Grade C environment:

  • The filling of products for terminal sterilization (at least in a Grade C)
  • Preparation of components and most products should be done at least in a Grade D cleanroom. Still, some products with high or unusual risks of microbial contamination should be prepared in a Grade C area.
  • Preparation of solutions to be filtered, including weighing.

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 (CNC) area.

Grade Maximum permitted number of particles ≥ 0.5 μm/m3

At rest

Maximum permitted number of particles ≥ 0.5 μm/m3

In operation

ISO Class
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.

Here is a list of tasks that can be processed in a Grade D cleanroom:

  • Cleaning of equipment
  • Handling of components, equipment, and accessories after washing
  • Assembly of cleaned components, equipment, and accessories before sterilization
  • Assembly of closed and sterilized SUS using intrinsic aseptic connectors

Cleanroom Grade A, B, C, and D Classification Chart 

MAXIMUM PERMITTED NUMBER OF PARTICLES/M^3 EQUAL TO OR ABOVE
at rest (b) in operation Federal Standard 209E and the ISO classifications approximate equivalency
Grade 0,5m m 5m m 0,5m m 0,5m
A 3 500 0 3 500 0 100, ISO 5
B(a) 3 500 0 350 000 2 000 100, ISO 5
C(a) 350 000 2 000 3 500 000 20000 class 10000, ISO 7
D(a) 3 500 000 20 000 not defined (c) not defined (c) class 100000, ISO 8

This chart is intended for reference only. Make sure to follow protocol specific to your cleanroom. 

Notes:

(a) To reach the B, C, and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with appropriate filters such as HEPA for grades A, B, and C.

(b) The guidance given for the maximum permitted number of particles in the “at rest” condition corresponds approximately to the US Federal Standard 209E and the ISO classifications as follows: grades A and B correspond with class 100, M 3.5, ISO 5; grade C with class 10000, M 5.5, ISO 7 and grade D with class 100000, M 6.5, ISO 8.

(c) The requirement and limit for this area will depend on the nature of the operations carried out.

Sources:

  1. https://www.gmp-compliance.org/files/guidemgr/2020_annex1ps_sterile_medicinal_products_en.pdf
  2. https://www.gmp-compliance.org/files/guidemgr/annex%2001[2008].pdf
  3. https://picscheme.org/docview/4205
  4. https://ispe.org/pharmaceutical-engineering/march-april-2017/understanding-cleanliness-classifications-life-science
  5. https://www.canada.ca/content/dam/hc-sc/documents/services/drug-health-product-review-approval/compliance-enforcement/good-manufacturing-practices/guidance-documents/gmp-guidelines-annex-1-manufacture-sterile-drugs-0119/gui-0119-eng.pdf

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