Issue link: https://www.e-digitaleditions.com/i/1373953
Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING EBOOK 2021 5 test pre-use, without specifying whether pre- or post-sterilization (2–5). Both EU Annex 1 (6) and proposed revisions to that code, advanced in 2020, endorse the pre-use/post-sterilization integrity test, despite the risks it poses (7–9). In fact, since 2007, European regulators have in- creased enforcement of PUPSIT, despite the risks it presents. According to the European Medicines Agency (EMA) (10), during use, a flawed filter may come into contact with a fluid that results in a high level of fouling, which could mask the filter's f law and result in a false positive post-use test result. In 2017, the Sterile Filtration Quality Risk Man- agement (SFQRM) consortium was established by the Parenteral Drug Association (PDA) and Bio- Phorum, to better understand the science behind this theory. The group includes representatives of Big Pharma companies, major filter manufactur- ers, and consulting companies. What began as an effort to focus on PUPSIT and potential filter f law masking, became a comprehensive project whose goal is to improve sterility assurance through the establishment of a holistic, end-to-end control strategy for sterile filtration. The overall goal was better risk assessments and the development of control strategies to prevent filter failure as well as best practices for the use of detection controls (e.g., PUPSIT). Overall, the group's approach has been to focus on prevention, to prevent conditions that could result in f laws and f law masking, using quality risk manage- ment (QRM) principles and practices, instead of detecting f laws after they have been created. This article describes the overall effort and some of the approaches used. Eventually, the scope of the consortium's activi- ties grew to include the following, all of which have been distilled in an executive summary: • Developing a masking study protocol and per- forming studies using flawed filters to uncover the conditions under which filter f law mask- ing might occur • Mining data (e.g., historical product bacterial retention studies and integrity test data) to de- termine whether integrity test data had shifted, which could indicate masking • Developing risk assessments, guides, and re- lated control strategies for filter manufactur- ing, handling, shipping, sterilization, usage, and integrity testing • Publishing best practices for the design, imple- mentation, and use of PUPSIT, detailing the complexities involved. Masking study The goal of this work was to conduct filter masking studies on pre-use f lawed filters to check whether they could pass post-use integrity tests. If it was found that they resulted in false pass, the efforts would move to establishing risk levels and suggest- ing changes to the design of the filtration setup or usage. This portion of the work was supported by key sterile filter manufacturing companies. A test protocol was developed and reviewed by working group members and international regula- Debate and discussion over the use of PUPSIT may continue, but the SFQRM's efforts have replaced anecdotes and hearsay with scientific and data-based evidence.