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For hydrophilic filters, there are two frequently used integrity tests:
- The diffusion test, also called forward flow, consists of measuring the gas flow through the wet membrane at a defined differential pressure.
- The bubble point consists of detecting the differential pressure at which a disproportionate increase in gas flow occurs as the wetting liquid is expelled from the largest pores of the membrane.
A combined diffusion and bubble point test can also be performed, but it is not a regulatory requirement to conduct both.
For hydrophobic filters, there are three frequently used integrity tests:
- The water intrusion test (WIT) consists of measuring the amount of water that evaporates from the upstream to the downstream side of the membrane at a defined test pressure. If the size of the filter allows for WIT, this is the preferred method.
- The diffusion test is performed after wetting the hydrophobic membrane with, for example, 60% IPA, 70% IPA, or another suitable low surface tension liquid. It is a good alternative if the WIT fails twice.
- The bubble point test is also performed after wetting the hydrophobic membrane with a suitable low surface tension liquid (e.g., 60% or 70% IPA). Like the diffusion test, it is a good alternative if the WIT fails twice.
The bubble point is the differential pressure at which the wetting liquid is expelled from the largest pores. It is correlated with the size of the largest pores in the membrane. From a general perspective, the diffusion test is considered more sensitive, even though it is not correlated with pore size. It should be recognized that each method has strengths and limitations that must be evaluated based on the specific circumstances of the test.
Annex 1 of EudraLex Volume 4, released in August 2022, is currently the most frequently discussed GMP guideline in filter integrity testing. Other relevant guidance documents include:
- WHO Annex 2, TRS 1044 (October 2022)
- FDA Guidance for Industry (September 2004)
Pre-use post sterilization integrity testing (PUPSIT) refers to verifying the integrity of a sterilizing-grade filter after sterilization and before use, as required by EU Annex 1 and WHO Annex 2. Pre-use testing of sterilized filters was first introduced in EU Annex 1 in 1996 (Section 85), although the term PUPSIT was not used until the version released in 2022.
Integrity testing is a regulatory requirement and a fundamental element of sterility assurance, but by itself, it is of limited value. In fact, a sterilizing-grade filter can only be considered effective if the integrity test is passed, if assurance is given that the result is not a false pass, if the filter type has been validated with a bacterial challenge test under process conditions, and if the filter supplier has a solid quality management system in place to ensure reproducible filters.
