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ItalianoIn short: Since 25 August 2023, the revised Annex 1 of the EU GMP Guidelines applies to the manufacture of sterile medicinal products. It sets cleanliness grades, pressure differentials, airflow and test intervals that directly shape the ventilation design. Building these values into design and documentation from the start makes qualification straightforward – including when converting cleanrooms during operation.
Who Annex 1 applies to
Annex 1 governs the manufacture of sterile products. Manufacturers may also apply some of its principles to non-sterile products where microbial and particulate contamination matters, for example certain liquids, creams or ointments. They must then document which principles they apply.
The basis is a Contamination Control Strategy (CCS) for the whole facility. It justifies the ventilation design.
Cleanliness grades A to D
Annex 1 sets maximum particle concentrations per cubic metre of air, both “at rest” and “in operation”. The number of sampling locations follows ISO 14644-1.
| Grade | ≥ 0.5 µm, at rest | ≥ 0.5 µm, in operation | ≥ 5 µm, at rest | ≥ 5 µm, in operation |
|---|---|---|---|---|
| A | 3,520 | 3,520 | not specified | not specified |
| B | 3,520 | 352,000 | not specified | 2,930 |
| C | 352,000 | 3,520,000 | 2,930 | 29,300 |
| D | 3,520,000 | set by the manufacturer | 29,300 | set by the manufacturer |
For grade D, the manufacturer sets the in-operation limits based on risk assessment.
Pressure cascade
- Overpressure: cleanrooms are supplied with filtered air that maintains a positive pressure or directed airflow relative to the surrounding lower grade.
- Guidance value: between adjacent rooms of different grades, Annex 1 states a pressure difference of at least 10 Pa.
- Containment exception: where hazardous materials must be contained, airlocks may also be negatively pressurised.
- For the design this means: a pressure concept for each room with direction and differential, plus doors and airlocks that maintain it in operation.
Airflow and recovery
- Unidirectional airflow: unidirectional airflow systems (grade A) should provide a homogeneous air speed of 0.36 to 0.54 m/s at the working position. This is a guidance value; deviations must be scientifically justified.
- Airflow patterns: they are visualised at rest and in operation and recorded on video.
- Recovery: after operations, a room must return to the at-rest state. Annex 1 gives a guidance value of less than 20 minutes; the actual time is determined during qualification.
Qualification and requalification
Qualification. Annex 15 of the EU GMP Guidelines (in force since 1 October 2015) describes the stages from user requirements (URS) through design, installation and operational qualification (DQ, IQ, OQ) to performance qualification (PQ). The design documents are the basis against which testing is done.
Requalification. Cleanrooms are requalified periodically, with at least these tests:
- classification (particle concentration),
- integrity test of final filters,
- airflow volume measurement,
- verification of pressure differentials,
- air velocity or recovery test.
Maximum intervals: grades A and B 6 months, grades C and D 12 months.
Conversions during operation
If a cleanroom is extended or converted while production continues next door, three questions are added:
- Separation: how do the operating areas keep their grade during construction? This concerns construction phases, temporary partitions and pressure control of the existing rooms.
- Interventions in the ventilation: which systems serve both areas, and when may work be done on them?
- Requalification: after changes, qualification has to be repeated. This belongs in the construction schedule, not at the end.
Design checklist
- Contamination control strategy and URS are available
- Cleanliness grade per room, at rest and in operation
- Pressure concept with direction and differential per room, airlocks
- Airflow type per area, air speed for unidirectional airflow
- Recovery time as a design target
- Monitoring: particles, pressure, temperature, humidity, alarms
- Design documents structured so that DQ, IQ and OQ can build on them
- For conversions: construction phases, partitions, requalification in the schedule
Frequently asked questions
Since when does the new Annex 1 apply?
Since 25 August 2023. For a single point on lyophilisation (8.123), the date is 25 August 2024.
Are 10 Pa pressure differential mandatory?
Annex 1 states at least 10 Pa between adjacent rooms of different grades as a guidance value. Where hazardous materials must be contained, Annex 1 explicitly provides for different pressure regimes, such as negatively pressurised airlocks. The basis is the risk assessment in the contamination control strategy.
How often must cleanrooms be requalified?
Grades A and B at most every 6 months, grades C and D at most every 12 months. In addition after remedial actions and after changes to equipment, facility or processes, where change management classifies them as significant.
Sources
- EudraLex Volume 4, EU GMP Guidelines, Annex 1 “Manufacture of Sterile Medicinal Products” (2022), sections 1, 4.14, 4.23–4.32, Table 1
- EudraLex Volume 4, Annex 15 “Qualification and Validation” (in force since 1 October 2015)
- ISO 14644-1, Cleanrooms and associated controlled environments – Classification of air cleanliness by particle concentration
