28/29 April 2021
The premises dedicated to the manufacture of medicinal products have to be monitored. Depending on the type of product to manufacture and whether it is a sterile or a non-sterile medicinal product, the requirements are more or less demanding. Besides, the amount of rules to be respected also increases the greater the risk of contamination for the product is. Consequently, most regulations and the most demanding requirements exist for the monitoring of rooms dedicated to the production of sterile medicinal products.
The substantial size for room/cleanroom monitoring is the particle concentration. It determines the cleanroom class which has to be first demonstrated in the qualification and reiterated in the context of re-requalification. Where and how particles in the critical zone A (= ISO class 4.8) have to be measured is directly laid down in Annex 1 of the EU GMP Guide.
With regard to the turbulent streamed rooms (B, C, D) that surround the sterile core A, Annex 1 requires the use of ISO 14644-1 (2015). By naming it in a mandatory GMP regulation, this ISO standard is also mandatory but only for sterile manufacturing. ISO 14644-1 (2015) contains a table listing the number of measuring points depending on the room size but only for the measurements concerning the qualification/re-qualification of the cleanroom determination with regard to particle concentration.
However, a risk-based approach should define the number and positions of the measuring points. Here, ISO 14644-2 applies. According to the technical interpretation of Annex 1 (PIC/S PI 032-2), permanent particle monitoring is required for zone A and indirectly for zone B too.
Microbiological monitoring is also described in a standard. But DIN EN ISO 14698 provides no details about the number of measuring points per area but requires a risk-based approach.
The temperature and humidity also have to be measurable. No binding specification about the number of measuring points and their positioning is available, though. Here again, a risk-based approach is required in diverse regulations. Theoretically, one single measuring point would be sufficient - but only in an ideal case where the room conditions are identical all over the room. Such an ideal case doesn't exist in reality. So usually worst case points are considered.
With regard to the manufacture of non-sterile forms, there are far fewer regulations. However, this greater degree of freedom often leads to uncertainties. Usually, one leans against the classification A-D and defines own zones such as D', E and F where each zone has an own and separated monitoring concept.