RESUMO
Eudralex volume 4, Annex 1, the European Union Good Manufacturing Practice for sterile products, requires that "The integrity of the sterilised filter should be verified before use" (1). Implicit in this requirement for a PUPSIT is the rationale that the sterilizing filter could sustain damage during sterilization or use (i.e., subsequent to any pre-use test conducted prior to sterilization), causing a defect which would not be detected by the post-use integrity ("masked" during filtration). To assess whether a filter defect could be masked by partial filter plugging, we evaluated the impact of the bacterial challenge test (BCT) on the bubble point (BP) of the test filters. The BP tests that are conducted before and after the BCT have been collected and compared for 2086 filters (1571 × test filters and 515 × control filters), representing 531 BCTs on 518 different pharmaceutical products, buffers, and in-process fluids. These tests comprise a cross section of fluids from multiple firms spanning the pharmaceutical and biotechnology industry. A posttest to pretest BP ratio was calculated for each filter and the distribution of these ratios examined to determine whether there were cases of elevation of the BP because of bacterial loading to the point where masking of a filter defect could occur; that is, if a defective filter could pass integrity testing due to apparent reduction in filter pore size because of the bacteria retained during the BCT. Ratios were averaged across all tests for the same test fluid. The mean average ratio was 1.00 ± 0.15, indicating that on the average, elevation of the BP does not occur. To assess the risk of masking a filter defect, observed BP ratios were compared to the ratio of the minimum BP specification of a 0.2 µm filter to that of a 0.45 µm filter of the same membrane type. The lowest such ratio for any membrane type was 1.33. A BP ratio equal to or higher than this ratio was considered a risk for masking, because a 0.45 µm filter could appear to meet the specifications of a 0.2 µm filter. Out of 518 average BP ratios, only eight fluids (1.5%) produced BP ratios meeting this criterion for a masking risk. Potential risk factors associated with these cases are discussed. We conclude that filtration processes producing BP changes sufficient to present a risk of masking defects are not common, and are detectable during the routine BCT. The BP ratios observed during routine BCT are one means to assess the potential of a given filtration process to mask defects and can be considered when determining whether a PUPSIT should be implemented.