What to Check When Choosing a Sterilizing-Grade Filter

What "Sterilizing Grade" Means

A sterilizing-grade filter is a filter that has been validated to reproducibly remove viable microorganisms from the process fluid and produce a sterile filtrate.[1][2] The nominal pore size is stated as "usually 0.2 µm or smaller" in the U.S. FDA guidance and as "a maximum of 0.22 µm" in EU GMP Annex 1.[1][2] The FDA guidance regards 0.2 µm and 0.22 µm as interchangeable nominal ratings.[1]

However, the grade is not determined by the pore size number alone. The criterion is the bacterial challenge test. When the filter is challenged with at least 10^7 Brevundimonas diminuta (ATCC 19146) per cm² of effective filtration area, the test organism must not pass through.[1][3][4]

Standard Tests and Process-Specific Validation Are Different

ASTM F838-20 is a test method for evaluating the bacterial retention performance of a filter under standard conditions, and it states itself that it is not intended for product- or process-specific validation.[3] Regulatory documents recommend performing bacterial retention testing under worst-case conditions using the actual product (or, where it cannot be used, a justified surrogate fluid).[1][2] A standard test report is therefore the starting point for selection and does not replace validation under your own product and process conditions.[1][3]

Complex testing is often performed by outside laboratories or filter manufacturers, but the filter user is responsible for reviewing whether those data apply to its own product and conditions of use.[1][4]

Membrane Material and Product Compatibility

• Compatibility: the filter must be compatible with the fluid to be filtered and must not be damaged by the product.[1][2][4]
• Adsorption: the extent to which product components adsorb to the filter must be evaluated.[2] In a study comparing two sterilizing filters of different materials, the amount of protein adsorbed differed between the filters.[6]
• Extractables/leachables: components that may migrate from the filter into the product must be evaluated.[2][4]
• Process conditions: pressure, flow rate, maximum filtration time and temperature are factors that affect filter performance and are addressed in validation.[1][2] The FDA guidance also lists viscosity and surface tension, pH, osmolality and hydraulic shock.[1]

Integrity Testing

An integrity test is a test that checks a filter for damage without destroying it. Bubble point, diffusive flow (or forward flow) and pressure hold tests are used.[1][2][4] The test specification values must be linked to the bacterial retention validation data.[1][2][4]

Both U.S. and European documents recommend performing post-use integrity testing routinely.[1][2] For pre-use testing the wording differs. The FDA guidance states that it "can be performed",[1] while EU GMP Annex 1 (2022) calls for pre-use post-sterilization integrity testing (PUPSIT) to be performed but, where this is not possible due to the process, accepts an alternative on the condition of a thorough risk assessment.[2] The revised Annex 1 of the PIC/S GMP Guide also entered into force on August 25, 2023,[2][5] and in Korea a revision of the GMP notification for sterile medicinal products reflecting the PIC/S standard has been in progress, so the timing of application must be confirmed against the latest original text of the notification.[8][9][10]

Sizing and Conditions of Use

The required filtration area is estimated by small-scale filtration trials with the actual process fluid. One example is the Vmax method, which determines the maximum throughput by measuring flow decay at constant pressure.[6][7] The maximum filtration volume, filtration time and operating pressure are established in validation, and the process is run within those ranges.[1][2] As a rule, sterilizing filters for liquids are discarded after processing one batch, and repeated use requires separate validation.[1][2]

Data to Request from the Supplier

Sources