Virus safety of biotech- and plasma-derived therapeutics is ensured through complementary manufacturing and quality control measures that include the control and monitoring of raw materials, the validation and implementation of effective virus clearance technology, and the monitoring of final filled product for the presence of virus. Virus filtration, which is considered a robust and effective virus clearance technology, is a common unit operation in the manufacture of biologicals. In this article, we review the points that need to be considered when selecting a virus retentive filter. The areas covered include regulatory considerations; selecting, optimizing, and validating a virus filtration step; and process scale implementation—areas that are of critical importance to users of virus filters.
Some biological therapeutic products are produced using mammalian cell lines or human plasma. The risk of contamination with either known or unknown viruses in these products has been demonstrated; hence, regulatory agencies have mandated that manufacturers evaluate the risks of virus contamination and take necessary measures to mitigate these risks. In addition to ensuring the purity of source materials, manufacturers are encouraged to institute steps in the purification process that will clear endogenous and adventitious viruses. Filtration has been successfully used in numerous processes as a robust step for virus clearance.To implement virus retentive filtration successfully within a process, several points should be considered. These can be broadly categorized as follows:
This article reviews each of these categories and suggests factors to consider when selecting and implementing a virus filter.
To ensure the virological safety of biological therapeutics, regulatory guidance advocates virus control at various stages of the drug manufacturing process. Specifically, manufacturers should (a) select and test source materials for the absence of viruses; (b) test the capacity of the production process to remove or inactivate viruses; and (c) test the product at appropriate stages of production for freedom from detectable viruses.1
Regulators require that an overall safety margin, such as <1 virus particle per 106 doses, be used to demonstrate the virus safety of the manufacturing process. The drug manufacturer is required to quantify the virus "load" in the process. For biotech products derived from murine cell lines such as Chinese hamster ovaries (CHO) and nonsense oligonucleotide (NSO), this typically translates to ~12–18 log10 clearance for endogenous retroviruses and ~6 log10 removal for adventitious viruses. The following is a composite summary of regulatory guidance on virus clearance, with an emphasis on how the guidance relates to virus filtration. 2–5
Depending on regulatory requirements, one needs to consider if the process requires retrovirus clearance, or retrovirus and parvovirus removal. Virus clearance filters are broadly classified into two categories: