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Can Redundant Filtration Make Sterility Assurance Double Sure?
As the market for biopharmaceuticals grows, manufacturers must be certain that they understand the regulatory guidelines for the production of these therapies. Because most biopharmaceuticals are administered by injection, their sterility is crucial to ensuring patients’ safety. Filtration is a central quality-assurance strategy for injectable drugs. In a 2004 guidance, FDA says that the “use of redundant sterilizing filters should be considered in many cases” (1). But not all manufacturers agree on what redundant filtration is.
A technical report published by the Parenteral Drug Association (PDA) provides some illumination. The report defines redundant filtration as “a type of serial filtration in which a second sterilizing-grade filter is used as a backup in the event of an integrity failure of the primary sterilizing filter” (2). The second sterilizing-grade filter is incorporated in line, usually upstream but possibly downstream, to provide additional assurance of sterilizing filtration, says Jerry Martin, senior vice-president of global scientific affairs at Pall Life Sciences and one of the authors of the PDA technical report.
“This approach is especially prudent when the final sterilizing filter is not preuse tested and batches are aseptically filled into small containers prior to filter-integrity testing postuse,” says Martin. “Such batches often cannot be reworked in the event of a sterilizing-filter integrity failure, so inclusion of a redundant sterilizing filter can save the batch in the event of one filter failing the postuse integrity test.”
Some professionals use the term to describe two filters, one of which is terminal, that are separated by a holding tank, but otherwise in close proximity in a processing train. “We prefer the more strict definition of two filters used in series to meet the objectives of a single processing step,” says Rick Friedman, associate director of FDA’s Office of Manufacturing and Product Quality. “But, in all cases, the key aspect is the risk mitigation afforded by using two sterilizing filters rather than one.”
Theoretically, redundant filtration is not necessary to achieve a sterile drug substance, but some drugmakers find that it improves product quality. Incorporating two 0.1-µm filters in a process helps cell culture media sterilization success rate, according to a manufacturing professional at a major biopharmaceutical company. “We did not really get to understand the mechanism why two 0.1-µm filters are better than one, but the result seems to be telling us that they’re better. It significantly reduced our cell culture contamination rate,” says the professional, who preferred to remain anonymous.
Others consider redundant filtration a waste. “The cost lies within the end-user’s court, and therefore redundant filtration should be reviewed critically,” says Maik Jornitz, senior vice-president of marketing bioprocess at Sartorius-Stedim North America. Besides increasing filter costs, redundant filtration may force the end-user to address concerns about hold-up volume, unspecific adsorption, and leachables. If two filters’ functions are not defined appropriately, a manufacturer must perform integrity testing on both of them, and cannot use one of them as insurance in the event that the other fails. Companies should ask themselves whether redundant filtration is truly necessary, whether the strategy is enacted to please regulators, or whether it is “a band-aid for a more serious penetration issue,” says Jornitz.
Manufacturers may find that redundant filtration has more value for some processes than for others. “The need for redundant filtration is process-dependent and should be based on a fully documented risk assessment that includes feed bioburden, filter-retention validation, filter-integrity history, processing time, product value, and reprocessing potential,” says Randy Wilkins, North American technical consulting team manager for EMD Millipore. “A thorough cost–benefit analysis is recommended for each specific application.”
Current regulations do not require redundant filtration, although guidance suggests that manufacturers consider it. “The requirement is for bioburden understanding and control, by whatever means are shown to be robust and validated,” says Wilkins. Thus, drugmakers are free to use their own discretion about the need for this strategy, even as they are bound to prove that their processes ensure the microbial safety of their products.
2. PDA, Technical Report No. 26, “Sterilizing Filtration of Liquids,” Revised 2008, PDA J. Pharm. Sci. Technol. 62 (S-5), 5 (2008).