Regarding microbiological monitoring of sterile manufacturing operations, differences exist between European and US requirements: In its Guidance for Industry on Sterile Drug Products Produced by Aseptic Processing, FDA requires only the active sampling of airborne microorganisms, complemented by measurement of microbial sedimentation as an optional test. Annex 1 to the EU GMP Guide, on the other hand, includes the sedimentation test into the specified monitoring parameters, and also requires surface cleanliness tests of critical processing areas as well as the testing of sterile gloves if they serve for interference into Grade A areas.
Very comprehensive guidance on microbiological monitoring is compiled in the informative chapter <1116> of the U.S. Pharmacopoeia. This chapter has been completely revised for USP 35 and was renamed to “Microbiological control and Monitoring of Aseptic Process Environment”. At this time, an entirely different approach has been adopted for the establishment of microbiological limit values for sterile production processes. Instead of setting limit counts of colony forming units, preference is given to assessing the percentage of samples (identified as incident rate) on which microbiological contamination has been detected after due incubation. The following definition is given: “The incident rate is the rate at which environmental samples are found to contain microbial contamination. For example, an incident rate of 1 % would mean that only 1 % of the samples taken show any contamination regardless of the colony number. In other words, 99 % of the samples taken are completely free of (microbiological) contamination”. The contamination incident rates recommended in the informative chapter <1116> are given in figure 1.
Figure 1 Recommended contamination incident rates according to the USP Informative Chapter <1116>
The frequency of microbiological sampling should be determined according to the level of risk and can vary from more than once per batch or shift to once every three months or every half year. USP, for instance, recommends in its informative chapter <1116> the sampling frequencies given in figure 2 for aseptic processing areas.
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