In the discussion on integrity testing of liquid filters (for review, please refer to: Understanding Integrity Testing in One Minute), we have learned that the main principle is to measure the gas flow rate through a wetted membrane under a certain test pressure. Different testing methods can be used to obtain the bubble point value and the diffusive flow. These testing methods are also applicable to hydrophobic gas filters; by wetting them with a low-surface-tension liquid (commonly alcohol solutions), the corresponding bubble point and diffusive flow tests can be performed.
The integrity testing of hydrophobic filters can also be determined by the resistance of a dry membrane to water under a certain pressure, which is known as the Water Intrusion Test. Compared to bubble point and diffusive flow tests using alcohol solutions, this method keeps the membrane dry, shortens the drying time required after testing, and avoids the introduction of alcohol solutions, thereby preventing contamination of the filter.
The principle of the Water Intrusion Test is that the pore structure of a dry membrane can prevent water flow under lower test pressures. At the breakthrough pressure (the pressure that forces water through the membrane pores), a very small but measurable water flow occurs, similar to the diffusive flow in traditional integrity tests of wetted membranes. This flow is proportional to the membrane surface area and the open porosity. If the measured water intrusion flow rate is lower than the maximum allowable flow rate given for the condition (i.e., the standard test specification), the test passes, proving that the filter element is intact.
Key Considerations for Implementing the Water Intrusion Test
• Ensure the system is leak-tight.
• Ensure the filter is dry before testing.
• Maintain a stable temperature during the test.
• Use high-quality water (to prevent changes in surface tension due to contaminants).
• Allow sufficient stabilization time, including the time for gas introduced by the automated tester to fully diffuse into the water.
• Due to the small water flow rate, use high-sensitivity flow meters or pressure sensors, typically 0.1 mL/min.
• When using upstream pressure to calculate flow values, ensure that the upstream volume can be accurately measured for each test.
• Limits and ranges may need to be adjusted for different integrity testers.
Advantages of the Water Intrusion Test
• Avoids the introduction of flammable, explosive, or potentially contaminating solutions.
• Shortens the drying time required after testing.
• Test results are correlated with bacterial retention.
Limitations of the Water Intrusion Test
• If a filter is not completely dried after steam sterilization, it may affect the test, causing false failures.
• If the filter is contaminated, causing part of the membrane surface to become hydrophilic, it may also affect the test, causing false failures.
• Due to the very small measurable water flow rate, this test may not be applicable to small filters (typically less than 0.5 ft², approx. 460 cm²).
When Should Integrity Testing of Gas Filters Be Performed?
China
Filters for gases that are in direct contact with sterile drug solutions or sterile equipment surfaces should be integrity tested after each batch or at the end of continuous multi-batch production. For other applications, the frequency of integrity testing can be determined based on risk assessment results.
— Guide on Sterile Filtration Technology and Application, 2018
United States
We recommend that filters that serve as sterile boundaries or supply sterile gases that can affect product be integrity tested upon installation and periodically thereafter (e.g., end of use). Integrity tests are also recommended after activities that may damage the filter. Integrity test failures should be investigated, and filters should be replaced at appropriate, defined intervals.
— FDA cGMP Sterile Drug Products Produced by Aseptic Processing, 2004
European Union
6.11 Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should be sterilized and the integrity of the filter tested before installation and after removal following use.
6.19 Gases used in aseptic processes should be filtered through a sterilizing filter (with a nominal pore size of a maximum of 0.22 μm) at the point of use. Where the filter is used on a batch basis (e.g. for filtration of gas used for overlay of aseptically filled products) or as product vessel vent filter, then the filter should be integrity tested and the results included as part of the batch certification process.
— EU GMP Annex 1 Manufacture of Sterile Medicinal Products, draft version 2020