Is monitoring (of germs and particles) required in "unclean airlock areas" of category E/F for non-sterile production? If so, what limits need to be set? Can ISO Class 8 be used as a reference if necessary?
We have forwarded these questions to several authors of our team of experts. The question of particle monitoring in non-sterile areas is obviously a "grey area", which is revealed by the following extract from the answers that we have received:
Point 4.12 of Aide-Mémoire (AiM) 07121105 of the German GMP inspectorates presents the authorities’ opinion including possible limits (see Figure 1).
Figure 1: Microbiological air quality in production rooms for non-sterile medicinal products (AIM 07121105)
The AiM is very helpful, even if it doesn't state anything directly about the particles.
There is currently no commitment to ISO 8 in place. Values such as those specified by the WHO in their Technical Report Series can be considered as recommendations.
The ISO 8 requirement for E/F is subjective and does not take into account, for example, the aspects of at rest/in operation differences in the measurements. Since the E/F categories (or the corresponding dosage forms or specific plants/processes) are not defined in official regulations either, this results in a large scope for interpretation and risk-based opportunities for the manufacturing companies to achieve a specifically suitable definition.
However, it must also be clearly stated that this additionally refers to a qualification according to ISO 14644 and that corresponding limit values, sampling points and frequencies must be defined in the monitoring procedure.
Contrary to widespread opinion, the GMP ABC does not end at the D limit. The continuation is "just" the consequent thought process reaching beyond cleanliness classification (incl. e.g. the pressure cascade). This train of thought is welcomed by the supervising authorities!
As a general rule, classification is "merely" directly required in sterile areas. Nevertheless, such classifications can also be used in other business areas. This is often employed in areas of "non-sterile" production.
From my point of view, particle control is also mandatory in manufacturing of non-sterile dosage forms. ISO 8 is chosen because ISO 9 – with its very high particle limits – is too prone to risks. It is also possible to define specific particle limits. However, derivation is very difficult. For this reason, the option of applying ISO 8 is often used.
Continuation of the division of the hygiene classes by letters in other areas is possible and reasonable. Particle control and thus the definition of limit values depend on the production of the dosage forms. In the example stated, particle control is mandatory! The requirements for "microbiological purity" include particle control, because airborne particles often carry along germs.
Annex 1 (EU-GMP) and the "Aseptic Guide" (US-FDA) do not use room classes E and F.
In 2010, ZLG published an Aide-Mémoire for the "Inspection of Qualification and Validation in Pharmaceutical Manufacturing and Quality Control" (AiM 07121105). The section on qualification requirements for production rooms contains a table with reference values as an example of microbiological air quality for the production of non-sterile medicinal products (see Figure 1). By analogy with Annex 1 of the EU GMP Guidelines, the classifications for class E and F are given as examples. No particle concentrations or limits are given, only the recommended CFU/m³ concentrations for the "at rest" and "in operation" status.
However, a cleanroom classification that only refers to germ counts cannot be compared with an ISO class. The ISO classification always contains "all" particles – both "living" (germs) and "non-living" (dust, fibres, etc.). Clear and unambiguous ISO classification requires 2 additional parameters:
...and does not state any guide values for germ counts – as in pharmaceutical classifications.
In order to achieve the microbiological values stated in the ZLG document, a ventilation system can be assumed which meets the requirements of EU GMP Class D (i.e. air exchange determined according to the thermal load, or approx. 8-12 times).
By definition, airlocks must not be considered "clean rooms" (or is production taking place there?). They are exclusively used to safely separate different cleanroom classes on the air side and to control material and staff traffic. "In at-rest condition, airlocks must meet the purity class of the adjacent cleanroom", states the definition. However, this repeatedly results in purity classes being defined for airlocks that correspond to those of the adjacent cleanroom. Most SOPs describe the monitoring activities for "this" cleanroom class and that is also applied to the airlocks.
In my opinion it is a feasible approach to "validate" the access and thus the airlock procedure. This is used to measure a worst-case scenario (maximum person and/or material traffic) ([particles and] germs) and to determine the time it takes to reach the desired degree of purity. Then the access to the clean room is allowed (time lapse controlled by clock and training of the personnel, or automatically by the door locks). "Revalidation" would only be necessary if the parameters (room equipment, ventilation system, number of persons and material, etc.) have changed compared to the initial validation.
I therefore do not see the necessity of (particle and/or germ) monitoring in airlocks in this context.
However, I would like to additionally point out the responsibility of the manufacturer, who has to assess the risk for this purpose. Guidelines and standards can only provide assistance in this respect, but cannot establish "legally binding specifications".