A Risk-Based Approach for Pre-Use/Post-Sterilization Integrity Test Simulation During Bacterial Retention Testing as Part of the Process-Specific Filter Validation of Sterilizing Grade Filters

Abstract

Pre-use post-sterilization integrity testing is implemented in sterile filtration applications by drug manufacturers using a risk-based approach with consideration of the stipulation in Eudralex Volume 4, Annex 1, Manufacture of Sterile Medicinal Products, which states that "The integrity of the sterilizing filter should be verified before use". Within the bacterial retention test design, performed as part of the process-specific sterile filter validation, it is important to simulate the filtration process under evaluation as closely as possible. Worst-case conditions experienced by the process filter during routine use that may impact the process filters' ability to produce a sterile effluent should be accounted for in the study. As performing pre-use post-sterilization integrity tests introduces additional mechanical stress on the process filter and a new potential route for the introduction of bioburden into the process fluid flow path related to the filter wetting procedure, a risk-based bacterial retention test design incorporating a pre-use post-sterilization integrity test simulation phase should be considered after a thorough evaluation of the process-specific conditions. The risk assessment should include evaluation of process pre-use post-sterilization integrity test conditions, including but not limited to the integrity test method and specifications, the wetting fluid type, the maximum allowable number of pre-use post-sterilization integrity test repetitions, as well as the permitted bioburden level of the pre-use post-sterilization integrity test wetting fluid. The outcome of the assessment provides a basis for the process-specific bacterial retention test design. In the following, we present our perspective on the topic as well as detailed insight into various aspects of pre-use post-sterilization integrity test simulation test design for consideration. Finally, we present all three PUPSIT-BCT approaches described (non-bactericidal, partially bactericidal, and bactericidal). Executed studies yielded acceptable results. Target parameters agreed upon were met.

Keywords: Annex 1; Bacterial challenge test; Bacterial retention test; Filter validation; PUPSIT; PUPSIT simulation; Sterile drug products; Sterilizing grade filters.