A cleanroom is a room in which the concentration of particles and microorganisms in the air and on surfaces is deliberately kept low and regularly demonstrated. For the manufacture of sterile medicinal products, EU GMP Annex 1 describes four cleanroom grades from A to D. Grade A is the critical zone for high-risk operations such as aseptic filling, Grade B is normally the background environment for it in aseptic manufacturing, and Grades C and D are used for less critical steps or as the surroundings of isolators. Service providers in this field design cleanrooms, qualify them and set up the environmental monitoring with which you show during routine operation that the room maintains its state.
What is regulated
Four cleanroom grades A to D with limits for particles and microorganisms, set out in EU GMP Annex 1.
Two states
Classification is performed in the at-rest state without personnel and in the in-operation state with ongoing or simulated work.
How often again
Requalification at least every 6 months for Grades A and B and every 12 months for Grades C and D.
What holds it all together
The contamination control strategy (CCS), which links design, procedures and monitoring for the entire site.
It is important to distinguish between three activities that are often mentioned in the same breath. Classification measures the particle concentration in the air against a specification. It is part of the broader qualification, which also tests filters, air volumes, pressure differentials, airflow patterns and microbial contamination. Finally, monitoring oversees the room during routine operation. Annex 1 explicitly requires qualification and monitoring to be kept clearly separate.
When you need this
The obvious occasion is new construction or a conversion, for example a new filling line, an additional isolator or upgrading an area to a higher grade. Here it pays to involve specialists early, because room layout, airlocks, airflow and pressure cascades can only be changed later at great expense. Just as often, the need concerns routine operation: requalifications must take place at fixed intervals, an unscheduled requalification may be needed after changes to equipment or ventilation, and conspicuous trends in monitoring call for an expert investigation.
Since the revision of Annex 1, the contamination control strategy has been added, and many manufacturers seek support in setting it up. Manufacturers of non-sterile products, for example certain liquids or creams, can also apply principles of the Annex, but must then document which ones they adopt and demonstrate compliance with them.
Legal basis and rules
EU GMP Guide, Annex 1
Governs the manufacture of sterile medicinal products. The revised version was published in August 2022 and has applied since 25 August 2023. It defines Grades A to D, the limits for particles and microorganisms in qualification and monitoring, and the maximum intervals for requalification.
EU GMP Guide, Annex 15
Describes qualification and validation. Annex 1 requires cleanrooms and clean air equipment to be qualified according to this methodology, that is, with requirements, planned tests and documented results.
ISO 14644-1:2015
International standard for classifying air cleanliness by particle concentration. Annex 1 refers to it for the minimum number and location of sampling points. The 2015 version was confirmed by ISO in 2021 and remains valid.
ISO 14644-2:2015
Sets minimum requirements for a monitoring plan that demonstrates the particle concentration during operation. This version was also confirmed in 2021.
AMWHV
The German Ordinance on the Manufacture of Medicinal Products and Active Substances (Arzneimittel- und Wirkstoffherstellungsverordnung, AMWHV) obliges manufacturers in Germany to follow Good Manufacturing Practice and refers to the EU GMP Guide and its annexes for interpretation.
Fixed maximum intervals for requalification
Under paragraph 4.32 of Annex 1, Grade A and B areas must be requalified at least every 6 months and Grade C and D areas at least every 12 months. This includes at least classification, integrity testing of the final filters, airflow volume, pressure differentials and, depending on the type of airflow, air velocity or recovery time. After remedial action or significant changes, for example to the ventilation or when the final filters are replaced, requalification may also be required outside this cycle.
How the work is organised
A cleanroom project follows the life cycle of the facility. Depending on your starting point, you outsource the whole project or only individual parts:
01
Requirements and design
The necessary grades, room sequences, airlocks and airflow are derived from the product, process and contamination risks. Annex 1 gives a guide value of a pressure differential of at least 10 pascals between adjacent rooms of different grades and requires the use of RABS or isolators to be considered in the CCS.
02
Qualification
Under Annex 15 and Annex 1, depending on the facility, tests include filter leakage, airflow volume and air velocity, pressure differentials, airflow direction with visualisation, temperature, humidity, recovery time and microbial contamination. Airflow patterns are examined in the at-rest and in-operation states and kept as video recordings.
03
Classification
Particles of 0.5 and 5 micrometres and larger are measured at rest and under simulated operation, with sampling points according to ISO 14644-1 and additional points at critical locations such as the filling point. After work has ended, the room must return to the at-rest state within a defined recovery time, with a guide value of less than 20 minutes.
04
Monitoring programme
Sampling locations, frequencies and methods are set on a risk basis, together with alert and action limits for particles and microorganisms. Grade A must be continuously monitored for particles during critical operations, with a sample flow of at least 28 litres per minute.
05
Routine and requalification
Trends are evaluated, excursions investigated and measures derived. Requalification follows at the prescribed intervals and after changes.
For Grade D, Annex 1 does not set fixed particle limits for the in-operation state; the manufacturer derives them from a risk assessment and its routine data. However much you outsource, approval of protocols and reports remains with the persons designated for this in your quality system.
What to look for when choosing a provider
Cleanroom services are offered by providers with very different focuses, from design and construction through pure measurement services to microbiological consulting. These questions help you find the right offer:
Questions to ask the provider
Does the provider have experience with the grade and technology concerned, for example isolators, RABS or Grade C and D areas?
Does it know the revised Annex 1 in detail, and can it help shape or assess your CCS?
Which tests does it perform itself, and which does it pass on to laboratories or other subcontractors?
Does it deliver protocols and reports that fit your qualification system under Annex 15?
Can it perform airflow visualisation with video recording, including under simulated interventions?
Does it support you in setting alert and action limits and in trend analysis?
Is it also available at short notice if requalification is needed after a deviation or a filter change?
Frequently asked questions
Is a room with an ISO class automatically a GMP cleanroom?
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No. ISO 14644-1 only classifies air cleanliness on the basis of particle concentration. Annex 1 sets its own limits for Grades A to D and also requires further tests, for example on microbial contamination, both at rest and in operation.
What is the difference between at rest and in operation?
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At rest, the facility is fully installed, the ventilation is running and the equipment is ready, but it is not operating and there are no personnel in the room. In operation, the equipment runs in the defined operating mode and the maximum intended number of personnel is working or simulating routine work.
How often must a cleanroom be requalified?
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Under Annex 1, at least every 6 months for Grades A and B and at least every 12 months for Grades C and D. In addition, requalification is required after remedial action and after significant changes, whose impact is assessed through change control.
What belongs in the contamination control strategy?
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Annex 1 lists, among other things, the design of plant and process, premises and equipment, personnel, utilities, raw material controls, suppliers, outsourced activities, cleaning and disinfection, monitoring, and measures for prevention and continuous improvement. The CCS must be reviewed regularly and is part of the management review.
Sources
Every statement in this text was checked against these primary sources (as of 10.11.2026). Laws, guidelines and authority websites, no advertising.