Some time ago, I received a very interesting request that I’d like to use as an opportunity for writing this blog article.

The question

According to the draft of the revised Annex 1 "Manufacture of Sterile Medicinal Products" of the EU GMP guidelines, sterile filters should be discarded after having been used. Multiple use is excluded, with the exception that a use for more than one working day has been validated. This phrasing is not quite unambiguous. So how should we interpret the following requirement "Liquid sterilizing filters should be discarded after the processing of a single lot. The same filter should not be used for more than one working day unless such use has been validated." (8.89)?

As part of the release testing of parenteral pharmaceuticals, sterility of the pharmaceuticals must be ensured after filling. Since a direct check of every filled vial or every syringe cannot be performed, the sterile filters are checked for their integrity, more precisely for their pore diameter, instead. According to the specifications of the WHO, a pore diameter of maximum 0.2 µm is allowed for sterile filtration [1]; accordingly, filtration with a sterile filter possessing a pore diameter of 0.2 µm or less results in a sterile filtrate.

Recently, I've been asked if I know why the ASTM F838 bacterial challenge test sets a maximum pressure of 30 psi (= 2.07 bar). Should this limit not be exceeded as no retention capability of the filter upwards can be provided? The answer to this question is a clear no. Filter membranes are still bacteria-retaining even at much higher pressures.

For pharmaceutical companies that manufacture their products under aseptic conditions, sterile filtration is the last step before filling. The validation of the manufacturing process also includes the step of sterile filtration. Accordingly, it must be demonstrated by filter validation that the filter is able to retain bacteria and thus ensure the sterility of the product. This evidence is provided by a bacterial challenge test according to ASTM F838-20. But, before this bacterial challenge test can be performed, it must be checked by a viability test that the product solution has no negative effect on the bacterium used in the bacterial challenge test. That sounds complicated? It shouldn’t - just imagine what would happen if your product solution is killing the test bacteria...