As part of mitigating the risk of introducing viral contaminants into a product during manufacturing, biopharma companies must assess the overall risk from a variety of sources (cell substrate, animal-derived raw materials, upstream and downstream processes, etc.) and consider options for reducing such risk. For global submissions, this requirement is formalized within EP 5.1.7 Viral Safety. For domestic submissions, such risk assessment and mitigation is consistent with the philosophy of the US FDA as formalized within the 1993 Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals; and ICH Q5A (R1) Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin.
A photomicrograph of the HIV virus from the CDC
• Selection of a cell substrate with low inherent viral risk, and adequate characterization of the manufacturing cell substrate will reduce the risk associated with this important reagent.
• Elimination of the use of animal-derived raw materials and excipients will greatly reduce the risk of introduction of a virus, but of course this is not always possible.
• Where it is necessary to use an animal-derived material (ADM) in the manufacturing process, the following steps should be taken: (1) evaluate the viral risk associated with the ADM; (2) mitigate the viral risk through sourcing strategies, quality control testing at the source and/or at the biopharma, and implementation, where possible, of viral inactivation treatment (e.g., gamma-irradiation) of the ADM.
• Once an ADM has been incorporated into a reagent such as a culture medium, the reagent itself may be subjected to viral inactivation strategies such as UVC-treatment or high-temperature short-time (HTST) treatment.
• Avoidance of the use of open-vessel operations during upstream processes, as they provide entrance points for viruses.
• Implementation of in-process and lot release viral detection tests to provide early indications of a viral infection in an upstream process.
• Implementation and characterization of robust and efficacious viral purification strategies during downstream processing of the biologic.
It is an expectation of the regulatory agencies that each biopharma will employ a combination of the above options in order to assure the viral safety of their biological products. If a viral contamination event should occur during a manufacturing run, it should be thoroughly investigated, with the aim of identifying the source(s) of the contamination. The information learned during the course of investigation should be used to eliminate the source of the contamination, and mitigate the risk of any future similar recurrences of the contamination.
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