Concepts for the Separation of Clean Rooms

Excerpt from the GMP Compliance Adviser, Chapter 3.C.2

3 min. reading time | by Raimund Brett
Published in LOGFILE 19/2024

A pressure cascade is required between cleanrooms of different cleanliness levels to prevent cross contamination. Annex 1 of the EU GMP Guide requires a pressure difference of at least 10 Pascal between two different cleanliness classes. Today’s feature explains how these pressure differences can be achieved and maintained for two different types of pressure cascade systems. 

It is an excerpt from the GMP Compliance Adviser, the most comprehensive GMP online knowledge portal worldwide.

Between rooms of different cleanliness grades, it is required to establish a pressure cascade to prevent cross contamination. Annex 1 of the EU GMP Guide requires a pressure difference of at least 10 Pascal between two different cleanliness classes. These pressures can be achieved if the structure (walls, ceiling, windows and doors) is tight. The pressure level is usually controlled in such a way that the supply air is kept constant, and the exhaust air is controlled via volume flow controllers to maintain the corresponding pressure difference. The pressure differences in a manufacturing area for sterile pharmaceuticals must be continuously measured and recorded. If a pressure drop occurs, an alarm must be triggered. This also applies to the airlocks.One can generally differentiate between two different types of pressure cascade systems:

• “bubble type” i.e. positive pressure system and   
• “sink type” i.e. negative pressure system

The bubble type system focuses on protecting the product from contamination from adjacent areas of lower cleanliness and from the employee. This is achieved by maintaining a higher static pressure in the clean rooms or clean room area than in the adjacent areas. Alternatively, the flow at leak points can be adjusted so that there is a flow from the clean area to the less clean area. These measures ensure that contaminations in the air always flow towards the less clean area. This prevents the ingress of contaminants from areas of low purity. The bubble type system is often used in the manufacture of liquid products. They are generally more susceptible to microbiological contamination.

Sink type systems are used where, in addition to protecting the product, it is important to protect the personnel and the environment. This is the case, for example, with highly active pharmaceutical ingredients (HAPI, high potent APIs) or radioactive substances. To prevent contaminated air from reaching adjacent areas, a negative pressure is created in the hazard zone relative to the surroundings/adjacent areas. This system is often used where dusty substances or products are processed.

To select the correct pressure system for the intended production, first the following steps are required:

• Analyze the entire production process and document all process steps required to determine the clean room grades.
• Perform a risk analysis:
  • What is the primary need for protection (product, personnel, environment)?
  • What are the contamination risks (particles, microbiology, endotoxins/pyrogens, chemicals)?
  • What are sources of contamination for the product?
  • Where is the greatest risk of contamination?
• Define the pressure levels for each area (airlocks, clean room, etc.)

Documentation should be carried out as part of the Contamination Control Strategy mentioned above.

The planning of a coherent cleanliness zone concept is a challenging task. To avoid errors, the following aspects in particular should be taken into account, which unfortunately are often forgotten during planning.

Important aspects for planning cleanliness zone concepts are:

• Separate airlocks for incoming and outgoing materials and/or waste and product if there is a risk of re-contamination
• Sufficient area for material transfer
• A Sufficient storage space even in classified areas – airlocks are not a storage area
• Separation of material with different status in the storage areas
• Separation of washing and process rooms – washing machines and sterilizers for pass-through operation are ideal
• Decontamination procedures must be followed when material is brought in
• Access controls for all areas

Do you have any questions or suggestions? Please contact us at: redaktion@gmp-verlag.de