Regulation and Control of Room Pressure in the Sterile Pharmaceutical Manufacture: Requirements and Technical Implementation
The regulation and control of pressure differences between rooms with different cleanliness grades and between different production areas is an essential element of the sterile pharmaceutical manufacture. It serves to direct the airflow in a precise way in order to protect the product from contamination, to minimise the risk of cross contamination and to guarantee the required personnel protection. This means that a well-planned pressure management guarantees personnel protection, product quality as well as compliance with the regulatory requirements as specified in the GMP Guidelines. But issues arise repeatedly concerning details regarding the dimensioning of differential pressures between different cleanliness areas or rooms or openings for the transfer of material (such as pass-through hatches, mouseholes). The most important requirements as well as possibilities for the technical implementation will be explained more in detail in the following.
Pressure Cascades and Room Airflow
Pressure conditions in sterile manufacturing areas must be designed in such a way that the air flows from higher classified rooms (e.g. grade A) to less critical areas (e.g. grade D or unclassified). This is achieved by setting up pressure cascades:
- Higher cleanliness grades (e.g. grade A): Highest pressure to protect the product and the environment.
- Lower grades (e.g. grade D): Lower pressure in order to prevent the air from penetrating into higher classified areas.
- Rooms with the same classifications may also present a pressure difference if this is required for process-technical reasons.
Specific Requirements concerning Pressure Differences
The minimum differences are clearly specified:
- In the case of a standard cascade between rooms with two grades (for instance from grade C to grade D): At least 15 Pa distributed across both doors of an airlock.
- Between rooms with different grades: At least 7.5 Pa for each door in airlocks.
- Pressure differences should not exceed 37 Pa in order to avoid problems such as the difficult opening of doors, noise exposure or air balancing problems.
Recommendation
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Monitoring and Alarm Management
Continuous monitoring of the pressure conditions is required in order to guarantee conformity with GMP.
- Critical rooms (e.g. grades A and B): Pressure differences as well as other parameters such as temperature and air humidity must be measured continuously and require documentation. Deviations must be indicated by means of alarms.
- Rooms not critical according to GMP (e.g. grades C and D): Pressure differences in these rooms may also be monitored in order to maintain the cleanliness grade but usually they are not considered as being critical to quality.
- Pressure alarms should be set in such a way that they provide early warnings with regard to potential problems. Typical alert limits for rooms with grade C or D are at 4 Pa (+/-2Pa).
Material Transfer and Airlocks
Material transfer between rooms with different grades is often carried out by means of so-called mouseholes. Special requirements apply in this case:
- The airflow must always be directed from the cleaner area into the less clean room.
- The positive airflow is verified by means of visualisation (smoke studies).
- The construction of mouseholes must guarantee that a sufficient amount of filtered air is provided for the differential pressure even if it is not possible to completely achieve a unidirectional flow.
Further Critical Parameters
Apart from pressure differences there are also other room related parameters that have to be monitored:
- Temperature and relative air humidity: They must be monitored especially in rooms with grade A and grade B if the product quality might be influenced by deviations.
- Failure of air supply: The failure of air supply in a sterile grade A area is considered to be a critical event and has to be monitored.
Data Archiving and Documentation
The results of the monitoring of pressure as well as of other room related parameters must be documented in accordance with the GMP guidelines:
- Archiving: All relevant data must be available in order to be able to prove compliance with requirements in the course of audits or inspections.
- Merging of data: In the case of less complex equipment the pressure differences may also be determined by means of a calculation on the basis of measurements at reference points, provided this data stems from a single control unit and appropriate alert limits are in place.
Summary: Regulation of Differential Pressure in Rooms and Triggering of Alarms
The control of room pressures and pressure differences in sterile manufacturing areas is a central measure in order to prevent cross contamination and to guarantee the quality of the pharmaceutical products. Regulatory requirements can be met and risks can be minimised by complying with the defined pressure differences, by monitoring them continuously and by means of documentation. A robust pressure management is especially important in complex equipment with many interfaces. This applies to isolators, RABS or airlocks with openings for material transfer.
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The following table shows how pressure cascades including the triggering of alarms can be designed between rooms with different cleanliness classes.
1 The minimum differential pressure between process rooms and corridors applies to all grades. If airlocks are in place the minimum differential pressure applies from room to room across the airlock. For the grades D and C with a minimum differential pressure of 15 Pa the minimum pressure at each door of the lock is 7.5 Pa for example.
2 The differential pressure can be considered to be critical if this is required in order to prevent cross contamination.
Higher differential pressures might be required for areas with complex pressure systems. This applies to isolators or RABS.
References:
EU GMP Annex 1
ISPE Baseline® Guide: Volume 3 - Sterile Product Manufacturing Facilities
ISPE Good Practice Guide: Heating, Ventilation, & Air Conditioning
About the Author
Nikolaus Ferstl carried out pharmaceutical projects worldwide as branch manager of LSMW/M+W (now Exyte) in Vienna. From 2009 to 2024, he was technical director of Regensburg University Hospital. Today, he is managing director of Facility Engineering Services GmbH.
