Analysis of Virus Clearance for Biotechnology Manufacturing Processes from Early to Late Phase Development.

The risk for virus contamination in biotechnology products (e.g., monoclonal antibodies, fusion proteins, or antibody-drug conjugates) derived from mammalian cell lines is a safety concern that must be evaluated from the early stages of development. The regulatory requirement for virus clearance that assesses the capacity of purification processes to remove endogenous and adventitious viruses is aimed at mitigating viral safety risk. A virus clearance database, containing virus clearance study data from biological license applications and investigational new drug submissions, has been maintained by the Food and Drug Administration's Center for Drug Evaluation and Research for over 15 years. Herein, an update is provided with regard to the impacts of process changes on the virus clearance during the product development cycle of biotechnology drug products based on the investigational new drug submissions received between January 1986 through March 2024. The current data demonstrated continuous robust removal of retroviruses and parvoviruses by chemical inactivation and virus-retentive filtration unit operations, respectively. Additional virus removal was supported by inclusion of one or more chromatography processes unit operations. For these processes, interactive process parameter effects were investigated for impacts on the reported virus clearance. The data reported here demonstrated that process- and product- specific considerations needed to be evaluated on a case-by-case basis to achieve robust and effective virus clearance for mammalian-cell-derived biotechnology products.