The Importance of Pre-Use Integrity Testing in Sterilizing Filtration - Pharmaceutical Technology

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The Importance of Pre-Use Integrity Testing in Sterilizing Filtration
Pre-use integrity testing of sterilizing-grade filters eliminates the potential adverse effects of filter loading on the integrity-test results, allowing unambiguous correlation with the integrity-test specification established during filter-validation studies.

Pharmaceutical Technology

Bacterial retention is assessed by challenging filters of the intended type having a range of integrity-test values and analyzing the bacterial-passage results. Ideally, the retention pattern observed will allow identification of physical integrity-test values above or below which, depending on the type of integrity test, there is virtually no probability of bacterial passage. For example, with a series of filters having a range of bubble points and equivalently challenged, there would be a value below which bacterial passage always occurred, a range where passage sometimes occurred, and a value above which passage never occurred.

It is important to identify the integrity values above and below which bacterial retention and bacterial passage can be expected. This ensures that the correlation between the integrity-test value and bacterial retention is valid and there are not other factors such as pore-size distribution and anisotropy that are potentially influencing the perceived correlation.

During development of what he referred to as the "forward flow" test in 1973, Dr. Pall performed bacterial-challenge testing on a series of 43 cartridges having water-wet forward air flow values ranging from 16 to 900 cm3/h at a pressure differential of 10 in of mercury (4.9 psi) (3). The results of this testing showed that no filter with a flow of less than 199 cm3/h allowed bacterial passage. On the basis of those results, he established a maximum flow limit of 100 cm3/h for an acceptable production filter element, building in a safety factor. However, the testing also showed that there were filters with forward-flow values of 210, 258, 450, and 645 cm3/h that retained the challenge organism and filters with forward-flow values of 199, 238, 471, and 600 cm3/h that allowed bacterial passage. The study did not establish a point above which bacterial passage always occurred; therefore the correlation between the integrity-test value and bacterial retention was not fully elucidated.

Because the forward-flow test as described relies on diffusive flow, which in terms of the filter membrane is a function of porosity, area, and thickness and is not directly related to pore size, the bacterial-retention results obtained for the higher forward-flow values could be indicative of pore-size distribution differences (or possibly thickness variations) among the tested membranes. Had these tests been carried out at pressures closer to the bubble point as is done today, differences in pore-size distribution might have been revealed as a result of the pressure-induced thinning of the liquid layer in the larger pores and better correlation obtained with bacterial retention at the higher diffusive-flow values. Nonetheless, Pall's efforts served as the basis for developing the automated filter-integrity tests in use today. These tests operate at considerably higher pressures, capturing the influence of the knee area and providing effective correlation between bacterial retention and the integrity-test value.

It is important to note that the integrity-test values were obtained on clean filters, before commencing the bacterial-retention tests, eliminating the influences of filter loading on filter porosity and diffusive-flow values.

Another validation consideration is to test the filters after sterilization and bacterial-challenge testing to evaluate the influences of filter loading and the sterilization process on the integrity-test values.

Filter loading

The sterilizing filtration process is designed to remove viable and nonviable particles from the fluid passing through the filter. The particles removed from the fluid either remain on the surface of the filter membrane or are trapped within the membrane matrix.


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