Air-Tightness of GMP Cleanrooms

There are various directives and standards that define the air-tightness of rooms and their testing in different ways. For example, for the tightness of ventilation ducts there are the tightness classes A to D according to DIN EN 15727, which have nothing to do with the EU GMP cleanroom classes A to D according to Annex 1. VDI Guideline 2083 Sheet 19 lists leakage classes from 0 to 7. So how tight do rooms or ventilation systems actually have to be for GMP production?

There are no specifications in the GMP regulations. The state of the art applies and this is usually found in technical standards and guidelines, such as the aforementioned documents DIN EN 15727 and VDI 2083 Sheet 19. There is a need for a unified definition and testing of the air-tightness of rooms, simply because of the increasing use of hydrogen peroxide for decontamination and the rising number of highly active substances in API and pharmaceutical production. Air-tightness also plays a significant role in energy efficiency requirements.

Thus, air-tightness should be considered in a defined way across all project phases. Problems are very often caused by unspecified "airtight" rooms and ventilation systems that then fail the air-tightness test during acceptance. Detailed work is then required to detect and close the leaks responsible for this. This is all the more difficult if the spots are no longer accessible. Frequent weak spots are, for example, ventilation outlets and flanges in the ventilation network, as well as door hinges, joints in the wall/ceiling system or pipe/cable ducts.

The regulations and standards available so far describe different procedures for carrying out leakage measurements and are not directly comparable with regard to their measurement results. VDI Guideline 2083 Sheet 19 can be used here. This guideline specifies a procedure for testing and classifying the tightness of isolators, cleanrooms and air ducts and contains instructions for producing tight cleanrooms. It applies to all rooms that are operated in positive or negative pressure relative to the environment, both for the protection of persons and for the protection of products.

The air duct tightness classes A to D according to DIN EN 15727 are integrated into the tightness classes shown in the VDI Guideline and are identical to the tightness classes 1 to 4. The guideline gives the following recommendations for the tightness classes:

• Class 0: For ventilated rooms with lower requirements than ISO 9 or energy efficiency requirements in general (can be used in a GMP facility). 
• Class 1: Cleanrooms ISO 7 to 9 or classes C and D according to EU GMP 
• Class 2: Rooms that are kept under negative pressure in a controlled manner during a gassing process. 
• Class 3: Cleanrooms <= ISO 6 - i.e. class B and better according to EU GMP 
• Class 4: BSL3 safety laboratories; sterile isolators and rooms that are fumigated 
• Class 5: Safety laboratories BSL4, active substance isolators (High Potent) 
• Class 6 / 7: Project-specific special requirements for rooms with extremely high demands on air-tightness, e.g. high-security laboratories (usually not found in a GMP facility)