PDA TR 41

TR-41 provides a framework of the principles of operation, types of configuration, and materials of construction of virus-retentive filters and presents best practices for their design, operation, and validation in various applications; key literature references are noted. A QbD approach to virus safety assurance is described that starts with identification of critical process parameters related to virus filtration and discusses design space and operation within the proven acceptable range and normal acceptable range. Challenges to specific applications, such as large and small virus-retentive filters used for downstream processing of biopharmaceuticals, ATMPs, and plasma-derived products, as barrier technology prior to mammalian bioreactor cell culture, or for treating growth media for production of ATMPs, are also addressed. Additional sections examine critical considerations for evaluation and virus clearance validation studies, integrity testing, and sterilization. The final section focuses on future manufacturing technologies under development, such as the integration of virus filtration into continuous bioprocessing applications. Appendix I (Section 12.0) provides additional information-risk evaluation and risk-ranking tools, including a model failure mode and effects analysis (FMEA)-that can be used prior to implementing virus filtration. Appendix II provides an overview and background for evaluating virus filters, and procedures for preparing and enumerating bacteriophage. Detailed, product-specific protocols for filtration and use or recommendation of specific filters over others are out of scope for this document. Manufacturing operational and process topics (e.g., manual vs. automated operation, pressure vs. pump) are also not discussed and should be assessed on an individual basis.