At our GMP Conference, the “GMP-BERATER Tage“, in October 2019 we presented a GMP dialogue on "Microbiological Monitoring in non-sterile areas". Questions on the topic were asked by participants and answered by GMP inspector Franz Schönfeld, PhD and microbiologist Frank Mertens, PhD in a lively discussion.
The GMP requirements for microbiological monitoring in the sterile production areas are laid down in several regulations. However, hardly anything is defined for non-sterile zones. How should microbiological monitoring be established there? How and how often do you check the air quality? Which methods are used? May rapid methods be used? Which limit values can be applied?
Microbiological monitoring and trending are increasingly replacing individual tests against limit values. Qualitative assessment is becoming increasingly important: Which microorganisms occur frequently? In what places? And where are the sources of entry?
From this point of view, it may well make sense to create a microbial library, even if this is not stipulated anywhere. However, one should only concentrate on conspicuous findings. This library can also be used for culture media testing (growth controls). Another area of application is qualification: In the qualification of rooms and water installations, the microbial (initial) status is determined. However, changes can only be detected if the microbial spectrum is known. Here too, a microbial library provides useful services.
The permissible bacterial count for non-sterile products is specified in the pharmacopoeias. It is up to you to determine the appropriate environmental conditions with which the required microbial status of the product is reliably achieved. Since every product and every production facility is different, there are no generally applicable guidelines for this.
If monitoring reveales deviations that do not affect the microbial status of the finished product, the self-defined limit values are probably too strict. In practice, decision-makers often lack the necessary expertise in this area. Often too much of a good thing is then done out of misunderstood risk awareness.
In this case, the experts recommend evaluating the existing monitoring data and carrying out a risk analysis on the basis of the trend analysis, which has to be carried out regularly anyway. Based on this, a new concept can be developed in which limit values, sampling points and examination frequencies are defined or adapted on a risk-based basis.
The following applies to risk analysis:
The risk priority number (RPN) is the product oft he three factors: severity, probability of occurrence and probability of detection.
If the probability of occurrence is reduced by (additional) preventive measures, the scope of monitoring can be reduced.
As Dr Franz Schönfeld reported from his inspection practice, risk analysis, especially FMEA, is often not applied correctly in practice. For example, too little is asked about the objective of the measures (the objective is the microbial status in the product!). Moreover, too little attention is often paid to the real risks. For example, there is hardly any distinction between the production of liquid, semi-solid or solid pharmaceutical forms, but everything is dealt with according to the same scheme.
Here, too, the aim of the measures must be kept in mind, namely the microbial status of the finished product. In order to be able to assess whether this is negatively influenced by the microbial status of the production environment, sampling must be carried out in operation, i.e. during ongoing production.
In the production of active substances, the monitoring effort can be reduced compared to the production of medicinal products. The active substance is homogeneous and the samples are therefore representative. Contract givers often make excessive and unjustified demands - here too, a lack of microbiological expertise is often the reason.
According to the experts, this requirement is excessive - at least in the European area. However, in other cultures and countries where daily showers are not part of the general understanding of hygiene, wearing overalls in class D can be useful.
To use clean room class D with all its consequences regarding classification, qualification and monitoring for the production of non-sterile products is certainly too excessive. However, depending on the dosage form, it may be useful to define the monitoring parameters "based on class D". Competent risk management is also required here!
This question can be clearly answered with "no": "spore-free" does not mean "sterile".
For environmental monitoring of non-sterile medicinal products, the methodology for the detection of specified microorganisms is not specified. Detective work is often called for, especially in problem cases. This is where professional competence is required - and with it the whole range of microbiological methods.
Doris Borchert, PhD
GMP-Verlag Peither AG, Schopfheim
You need more information about microbiological monitoring?
Then we recommend chapter 10.E Microbiological Monitoring of the GMP Compliance Adviser, the most comprehensive GMP online knowledge portal worldwide.