Safety assurance for biologics manufactured in mammalian cell cultures: a multitiered strategy.

Contamination by viral and microbial agents is a serious risk for biopharmaceuticals produced by mammalian cell culture processes. In order to effectively mitigate the risk and minimize the occurrence of such contamination events, a multi-tiered approach has been adopted to safeguard the manufacturing processes from A to Z. The multi-tiered approach consists of three separate, yet complementary, elements: (1) control and testing of raw materials in general, and animal sourced materials (ASM) in particular; (2) in-process and release testing for adventitious agents with emphasis on viruses based on risk assessment; and (3) demonstration of an adequate, robust, and consistent viral clearance capability by the downstream purification process. The implementations of these measures will be described in the context of regulatory compliance and GMP manufacturing.