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PharmTech.com Quality and Regulatory Sourcebook eBook March 2024 Pharmaceutical Technology ® 13 Aseptic MAnufActuring the post-use integrity test. Such events would be an economical burden, but not a patient safety concern. PUPSIT is also recommended for gamma sterilized single-use filter assemblies, which represent a closed processing system, therefore, an enhancement to contamination control. However, performing PUPSIT requires downstream manipulation of the gamma sterilized filtrate side and an increase in complex- it y, meaning additional connections, vent f ilters, bags, tubing, f low-path redirection procedures, and so forth. The technical and patient safety enhance- ment of such closed systems is reduced by the uni- versal enforcement of PUPSIT, which does not make sense because regulatory authorities always expound "quality is designed into a process and not tested into a process". Moreover, section 8.82 states: "The filtra- tion systems should be designed to: … Minimize the number of aseptic connections required bet ween the final sterilizing grade filter and the final filling of the product" (1). Section 8.82 contradicts the uni- versal enforcement of PUPSIT, as the PUPSIT set-up is much more complex and requires a multitude of additional connections, filters, pipe or tubing, and vessels between the final sterilizing filter and final filling process. Clarity is required from the regula- tors of what statement prevails. Is the priority set on a robust, well designed, and minimalistic sterile boundary between the filter and the filling or a likely needless pre-use test, which increases the filtrate side complexity? The main reason why PUPSIT became an EU regu- lator enforcement topic is the fear that a minute f law of the filter membrane (present before use) is masked during the filtration process and not detected by the post-use integrit y test af ter the filtration process. Studies performed by the Parenteral Drug Associa- tion and BioPhorum showed that the masking theory is possible; however, the masking occurs extremely rarely and on ly >80 % f ilter block ing levels (3,4). T herefore, one would assume t hat f i ltration pro- cesses, which have f luid streams with low blocking propensities and/or are designed to only block the filter to a low level and/or have protective prefiltra- tion set-ups, may not need to utilize PUPSIT. Likewise, when there is proof that the handling, installation, and sterilization processes do not show the risk of damage of a filter, PUPSIT should be voided. Clarity is required here whether the EU regulatory authority sees it the same way? Most impor tant ly, t hough, is t he question and clarity requirement for thorough risk assessment ac- ceptance. Do the EU regulatory authorities respect a vigorous risk assessment, which shows that the risk of not performing PUPSIT is lower than performing PUPSIT? Currently, a strict reading of the updated language in Annex 1 section 8.87 might cause an inspector to only accept a risk assessment if PUPSIT is "not possible due to process constraints" (1), as op- posed to cases of sound technical argument where the extra testing adds no value and increases risk or complexity. This question is an essential one, as a risk assessment is much more valuable than a ge- neric enforcement of a test, which requires sterile filtrate manipulation and much higher downstream complexities. It must be emphasized that the sterilizing filter will always have a post-use integrity test, which pro- vides the ultimate assurance of patient safety by de- tecting any rare, non-retentive filters before a batch is released. However, such post-use testing can be performed off line, after the completion of the filtra- tion process, when there is no longer any risk of con- taminating the product during the integrity testing process itself. The arguments herein apply only to the perceived need for additional pre-use, post-steriliza- tion integrity testing of the same filter. Conclusion Although the revised EU Annex 1 guidance encom- passes enhanced process understanding and recog- nizes changes in regulatory and manufacturing envi- ronments, there are areas where the requirements for liquid sterilizing grade filtration testing do not align with technological advances and contamination con- trol assurance. It is crucial to review these discrepan- cies and seek clarification on certain aspects of liquid filtration requirements in Annex 1 to ensure patient safety. By acknowledging technology advances in filtration and providing clear guidance, the revised Annex 1 can facilitate the adoption of robust contam- ination control measures while utilizing new inno- vations in the field of filtration. However, the generic enforcement of an integrity test like PUPSIT does not align with the aim. Furthermore, clarity of crucial questions posted by the industry is needed to avoid confusion and risk elevation. References 1. European Commission. Annex 1: Manufacture of Sterile Medicinal Products. EudraLex Volume 4, Brussels, Aug. 22, 2022. 2. PDA. Points to Consider for Risks Associated with Sterilizing Grade Filters and Sterilizing Filtration. Parenteral Drug Association, July 2020. 3. Ferrante, S.; McBurnie, L.; Dixit, M.; Joseph, B.; Jornitz, M. W. Test Process and Results of Poten- tial Masking of Sterilizing Grade Filters. PDA JPST 2020, 74, 509–523. 4. Thome, B.; Joseph, B.; Dassu, D.; et al. Data Min- ing to Determine the Inf luence of Fluid Properties on the Integrity Test Values. PDA JPST 2020, 74, 524–562. ■