Cleanroom GMP grades: Grade A to Grade D
In sterile pharmaceutical manufacturing, a GMP grade describes the level of environmental control required for a specific process. Particle concentration is part of that classification, but it is not the whole definition. EU GMP Annex 1 also considers microbial contamination, gowning, airflow, pressure, barrier technology and the condition of the room during production. This is why the same cleanroom can have different particle limits at rest and in operation.
For cleanroom design, the grade therefore needs to be established at the beginning of the project. At ABN Cleanroom Technology, this requirement is incorporated into the Configure to Order+ approach so that each zone is developed around the conditions it must maintain during the intended manufacturing proces
The four GMP grades
EU GMP Annex 1 defines Grades A, B, C and D for the manufacture of sterile medicinal products. The level of control increases with the risk of contamination. Operations in which sterile product or critical surfaces are directly exposed require the highest level of protection, while activities with a lower contamination risk can take place in lower grade environments.
Grade A
Grade A is used for the most critical aseptic operations, including aseptic filling, open primary packaging and aseptic connections. These conditions are normally created through localised protection, such as unidirectional airflow within a RABS or an isolator. The airflow must be qualified to protect the critical zone, and the design should minimise direct operator intervention wherever possible.
Grade B
When an isolator is not used, Grade B normally provides the background environment for a Grade A zone during aseptic preparation and filling. With isolator technology, a lower background grade may be acceptable depending on the type of isolator, the risk assessment and the contamination control strategy, known as the CCS.
Grade C/D
Grades C and D are used for less critical stages of sterile manufacture, including preparation activities and processes involving terminal sterilisation. They can also provide the background for isolators where permitted by Annex 1. The required grade is determined by the process, the level of product exposure and the associated contamination risk.
At rest and in operation
A cleanroom behaves differently during production than it does when it is empty, so Annex 1 distinguishes between two states. At rest means that the installation and utilities are complete, the HVAC system is operating and the main manufacturing equipment is installed, but the equipment is not operating and no personnel are present. In operation means that the HVAC system is fully operational, the equipment is running in its defined operating mode and the maximum number of personnel are present while carrying out or simulating routine work.
This difference is reflected in the particle limits. During production, people move, equipment operates and materials enter and leave the room, all of which can increase contamination. After operations and the associated line clearance or cleaning activities have finished, the room is expected to return to its qualified at rest particle limits. Annex 1 gives a guidance value of less than 20 minutes for this clean up period, while the actual recovery time must be established during qualification and documented in the relevant procedures.
Particle limits for cleanroom classification
Annex 1 defines maximum airborne particle concentrations for cleanroom classification. The limits in Table 1 of Annex 1 are shown below.
Where the table states “not specified”, Annex 1 does not set a classification limit for 5 µm particles. Classification including this particle size may still be considered when indicated by the CCS or by historical trends. For Grade D in operation, “not predetermined” means that Annex 1 does not prescribe a fixed particle limit. Appropriate limits are established by the manufacturer according to the process and risk assessment.
How GMP grades relate to ISO classes
GMP grades and ISO classes both use airborne particle concentration, but they serve different purposes. ISO 14644 1 classifies air cleanliness by particle concentration, while EU GMP Annex 1 applies that control within the wider context of sterile pharmaceutical manufacturing, including microbial control, gowning, qualification and operating practices.
At 0.5 µm, the Annex 1 limits correspond numerically with familiar ISO 14644 1 concentrations. Grade A and Grade B at rest correspond numerically with ISO Class 5. Grade B in operation and Grade C at rest correspond numerically with ISO Class 7, while Grade C in operation and Grade D at rest correspond numerically with ISO Class 8. These are useful numerical comparisons, but they are not formal regulatory equivalences. Meeting an ISO particle class alone does not mean that a cleanroom satisfies the requirements of a GMP grade.
Microbial control
Particle classification alone cannot demonstrate full GMP control. Annex 1 also sets microbial contamination limits for cleanroom qualification, because viable contamination can be influenced by personnel, gowning, material transfer and working practices even when airborne particle levels remain within specification. Routine environmental monitoring is addressed separately in section 9 of Annex 1 and continues during manufacturing to demonstrate that the controlled environment remains in an appropriate state.
How the grades are used in production
The role of each grade becomes clearer when it is connected to the manufacturing process.
- In aseptic processing, Grade A covers operations where sterile product, sterile components or critical surfaces are exposed. This includes activities such as aseptic filling, aseptic compounding and mixing, certain aseptic connections after the final sterilising grade filter, staging of unwrapped sterile primary packaging and loading a lyophiliser.
- Grade B supports Grade A when an isolator is not used and can also be used for protected staging or movement of equipment and components before they enter Grade A.
- Grade C is used for activities such as preparing solutions that will subsequently be filtered, including sampling and dispensing.
- Grade D covers activities including equipment cleaning, handling cleaned components and assembling cleaned items under HEPA filtered airflow before sterilisation.
- For terminally sterilised products, the process allows different grades because a sterilisation step follows filling. Preparation of solutions and components for subsequent filling is generally carried out in Grade D, while filling is generally performed in Grade C. Where the product presents an unusual contamination risk, a higher grade may be required.
Barrier technology also influences the required background. Annex 1 states that open isolators generally require at least Grade C, closed isolators at least Grade D, and RABS used for aseptic processing at least Grade B. The final design must be supported by the risk assessment and the CCS.
Gowning by grade
Personnel are an important source of contamination, so gowning becomes more stringent as the required level of environmental control increases. In Grade D, hair, beards and moustaches are covered and personnel wear a general protective suit with appropriately disinfected shoes or overshoes. Grade C requires similar hair and facial hair coverage together with a single piece or two piece trouser suit, gathered at the wrists and with a high neck, as well as appropriately disinfected footwear.
Grade B, including access or interventions into Grade A, requires sterilised cleanroom garments over dedicated undergarments, together with sterile headgear, a sterile facemask, sterile eye coverings, sterilised footwear and sterile gloves. A second pair of sterile gloves is worn over the pair used during gowning. Personnel entering Grade A and B areas must also be trained in aseptic gowning and behaviour, with gowning compliance reassessed at least annually using visual and microbial assessment.
Pressure, airflow and airlocks
The required cleanliness depends not only on filtration, but also on controlling how air moves through the facility. Annex 1 gives 10 Pa as a guidance value for the pressure difference between adjacent rooms of different grades. Under normal conditions, cleaner rooms are maintained at positive pressure relative to lower grade background areas so that airflow moves in the intended direction. Where containment is required, a different pressure strategy may be justified according to the process risk.
For unidirectional airflow, Annex 1 gives a guidance range of 0.36 to 0.54 m/s at the working position unless another value is scientifically justified in the CCS. Airflow visualisation studies are used to confirm that the airflow protects critical areas and that air from a lower grade environment does not compromise a cleaner zone.
Airlocks maintain these pressure and cleanliness relationships while personnel and materials move between areas. Entry and exit doors should not be opened at the same time. Airlocks leading to Grade A and B areas should use an interlocking system, while Grade C and D airlocks require a visual or audible warning system as a minimum. At rest, the final stage of the airlock should have the same cleanliness grade as the room it leads into.
Requalification
Grade C and D areas have a maximum interval of twelve months. Requalification includes cleanroom classification, final filter integrity testing, airflow volume measurement and verification of pressure differences between rooms. Air velocity testing is included where relevant, while recovery testing is used in non unidirectional airflow areas. Requalification is also required after relevant changes or remedial actions that could affect cleanroom performance.
These requirements should be considered during design, because access to filters, test ports and measurement points directly affects how efficiently the cleanroom can be tested and maintained throughout its operating life.
This requirement has an important consequence for design. Filters, test ports and measurement points need to remain accessible throughout the life of the facility. Thinking about testing only after construction can make routine qualification unnecessarily difficult, while designing for it from the beginning makes long term compliance much easier to manage.
Designing for the process, not just the number
The main lesson is that a GMP grade describes a controlled manufacturing environment rather than a particle count on a certificate. The room has to achieve the required conditions for the process and state in which it is intended to operate.
This means that particle concentration, microbial control, airflow, pressure cascades, gowning, material flow, operator behaviour and barrier technology cannot be designed as separate subjects. They influence one another, and together they determine whether the cleanroom can maintain the required state of control during real production. Passing an at rest classification test is important, but it is only one part of that wider picture.
At ABN Cleanroom Technology, these requirements are translated into the cleanroom design through the Configure to Order+ approach, combining pre-engineered and validate building blocks with project specific engineering so that the facility can be aligned with the process, the required grade.