Abstract
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 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.Lay abstract
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.