Pre-use post-sterilization integrity test (PUPSIT)

As a requirement of the most recent updated version of EU GMP Volume 4 – Annex 1 (2022) “Manufacture of Sterile Medicinal Products” and WHO TRS 1044 – Annex 2 “good manufacturing practices for sterile pharmaceutical products”; verification of the integrity of the sterilized filter assembly should be done before use by Pre-use post-sterilization integrity test (PUPSIT) to ensure no damage or loss of integrity occurred during preparation of filter prior to use.

The abbreviation (PUPSIT) was just a new terminology introduced in the current versions but the testing itself was a requirement stated in the previous versions (i.e. EU GMP Volume 4 – Annex 1 (2008) and WHO Technical Report Series, No. 961, 2011 – Annex 6). The phrase “sterilised filter” in the previous versions, indicates that filter integrity test must be performed post the sterilisation process but prior to the filtration of product.

Examples of tests used include bubble point, diffusive flow or pressure hold test. In addition to the new versions introduced another acceptable test to be used (i.e. water intrusion which tests the volume of water that penetrates the membrane of a hydrophobic filter under a specific amount of pressure for a particular amount of time. The correct amount of pressure will penetrate the membrane but not get it wet).

It's noted that Egyptian Drug Authority (EDA) published their own draft guideline for Good manufacturing practices on 1st December 2022. The draft guideline not included PUPSIT as a requirement. It’s acceptable that integrity of the filter to be confirmed immediately at least after use.

The benefits coming from PUPSIT is that it measures the integrity of the sterilizing filter and all the components (filter housing, connections, and support structures) after installation and sterilization, but before the drug manufacturers use it. As there are possible risks associated with installation and sterilization regarding inability to detect microscopic flaws in the post-use test if we depend on it alone. Flaws may arise during the in-line steam sterilization process allowing contaminants to pass through during the filtration process. but clogging during filtration would result in a passed integrity post-use. This theoretical “filter flaw masking” could have serious consequences for downstream processing, significantly affecting the quality of the final product, and potentially putting patients at risk.

The following aspects should be considered for PUPSIT to avoid introducing additional contaminants to the process or the product, negating any benefit of the PUPSIT process:

??Maintaining sterile conditions during Wetting the filter to be tested and evacuating the wetting liquid.

??Adding complex filtration systems with additional components and connections (i.e. T-pieces and connectors) should not negatively impact aseptic process.

??Operators’ interventions that may negatively impact aseptic handling.

It's acceptable that PUPSIT may not always be possible after sterilization due to process constraints (such as the filtration of very small volumes of solution). The use of an alternative approach may be taken provided that a thorough risk assessment has been performed and compliance is achieved by the implementation of appropriate controls to mitigate any risk of a non-integral filtration system. This should be considered in contamination control strategy (CCS).

Points to be considered in the risk assessment should include:

??In-depth knowledge and control of the filter sterilization process to ensure that the potential for damage to the filter is minimized.

??In-depth knowledge and control of the supply chain to include: contract sterilization facilities, defined transport mechanisms, packaging of the sterilized filter to prevent damage to the filter during transportation and storage.

??In-depth process knowledge, such as: the specific product type, including particle burden and whether there exists any risk of impact on filter integrity values, such as the potential to alter integrity testing values and therefore prevent the detection of a non-integral filter during a post-use filter integrity test, prefiltration and processing steps, prior to the final sterilizing grade filter, which would remove particle burden and clarify the product prior to the sterile filtration.

?Conclusion:

Testing integrity of sterilized filter before use is not a new regulatory requirement, the term “PUPSIT” just recently introduced. Some regulatory agencies do not mandate testing integrity of sterilized filter before use and others do not require the filter under integrity testing to be sterilized (i.e., integrity test done before sterilization).?

Although there are risks associated with PUPSIT regarding impacting aseptic process, it's still more beneficial to perform PUPSIT to eliminates any risk associated with damage or loss of integrity of the filter which will lead to undesired consequences on product safety and sterility.

References:

• ?EU GMP Volume 4 – Annex 1 (2022) “Manufacture of Sterile Medicinal Products”
• EU GMP Volume 4 – Annex 1 (2008) “Manufacture of Sterile Medicinal Products”.
• WHO TRS 1044 – Annex 2 “good manufacturing practices for sterile pharmaceutical products”.
• WHO Technical Report Series, No. 961, 2011 – Annex 6 “good manufacturing practices for sterile pharmaceutical products”.
• FDA guidance for industry, Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice 2004.
• PS/INF 26/2022 (Rev. 1): REVISED ANNEX 1 (MANUFACTURE OF STERILE MEDICINAL PRODUCTS) TO GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS – 2022
• EDA draft guideline for Good manufacturing practices, 2022.
• The Complete Guide to Pre-Use, Post-Sterilization Integrity Testing (PUPSIT), Sartorius Site: