Folmsbee Martha, Moussourakis Michael
Pall Corporation, 25 Harbor Park Dr., Port Washington, NY 11050.
PDA J Pharm Sci Technol. 2012 Mar-Apr;66(2):161-7. doi: 10.5731/pdajpst.2012.00771.
Bacterial penetration of integral sterilizing-grade 0.2 μm rated filters, although rare, is not a new phenomenon in the biopharmaceutical industry. It is recognized by both the Parenteral Drug Association and the Food and Drug Administration via recommended bacterial retention qualification (also commonly called filter validation) performed in relevant product fluids or suitable surrogates when necessary (1-3). As noted in recent work, formulations such as some adjuvanted vaccines, liposome-based drug delivery solutions, and similar surfactant or emulsion-based product fluids increase the likelihood of such penetration events (4). Here we demonstrate that some 0.2 μm rated sterilizing-grade filters from different filter manufacturers may perform less effectively than expected when their membranes are challenged with one of these bacterial penetration risk-related solutions. Some filters provided very little sterility assurance (titer reductions < 6 logs) and others provided substantial sterility assurance (titer reduction > 8 log). From this, it is clear that the product formulation most likely to lead to filter penetration must be identified early in the design process to facilitate process design and minimize qualification costs. In this way, the solution can be matched with the appropriate sterilizing-grade filter and the appropriate process conditions.
Bacterial penetration of intact sterilizing-grade filters during filter qualification, although rare, is not a new phenomenon in the biopharmaceutical industry. Because these incidences are identified in the filter validation process, there is no risk to the drug product end-user, but these failures do incur additional expense to the pharmaceutical manufacturer and could prevent the manufacture of very important drug formulations. Formulations such as some adjuvanted vaccines, liposome-based drug delivery solutions, and similar surfactant or emulsion-based product fluids have been documented to lead to an increased risk of penetration events. Here we demonstrate that some sterilizing-grade filters may perform differently from expected when their membranes are challenged with one of these solutions related to bacterial penetration risk. Some filters provided very little sterility assurance and others provided substantial sterility assurance. From this, it is clear that the pharmaceutical products and product formulation most likely to lead to filter penetration must be identified early in the design process to facilitate process design and minimize qualification costs. Moreover, that solution should be matched with the appropriate sterilizing-grade filter and process conditions to ensure expected sterility.
细菌穿透整级的0.2μm额定除菌过滤器，虽然罕见，但在生物制药行业并非新现象。肠胃外药物协会和食品药品管理局都认可，在相关产品流体或必要时合适的替代物中进行推荐的细菌截留鉴定（通常也称为过滤器验证）（1-3）。如近期研究所述，某些佐剂疫苗、基于脂质体的药物递送溶液以及类似的基于表面活性剂或乳液的产品流体等制剂会增加此类穿透事件的可能性（4）。在此我们证明，当不同过滤器制造商生产的一些0.2μm额定除菌过滤器的膜受到这些与细菌穿透风险相关的溶液之一的挑战时，其性能可能不如预期。一些过滤器提供的无菌保证很少（滴度降低<6个对数），而其他过滤器提供了大量的无菌保证（滴度降低>8个对数）。由此可见，在设计过程的早期必须确定最有可能导致过滤器穿透的产品配方，以促进工艺设计并最小化鉴定成本。通过这种方式，可以将溶液与合适的除菌级过滤器和合适的工艺条件相匹配。
在过滤器鉴定过程中，完整的除菌级过滤器出现细菌穿透，虽然罕见，但在生物制药行业并非新现象。由于这些情况是在过滤器验证过程中发现的，对药品最终用户没有风险，但这些失败确实会给制药商带来额外费用，并可能阻碍非常重要的药物制剂的生产。已记录某些佐剂疫苗、基于脂质体的药物递送溶液以及类似的基于表面活性剂或乳液的产品流体等制剂会导致穿透事件风险增加。在此我们证明，当一些除菌级过滤器的膜受到这些与细菌穿透风险相关的溶液之一的挑战时，其性能可能与预期不同。一些过滤器提供的无菌保证很少，而其他过滤器提供了大量的无菌保证。由此可见，在设计过程的早期必须确定最有可能导致过滤器穿透的药品和产品配方，以促进工艺设计并最小化鉴定成本。此外，该溶液应与合适的除菌级过滤器和工艺条件相匹配，以确保预期的无菌性。
