Testing considerations for novel cell substrates: a regulatory perspective

The development of new products for the prevention and treatment of current as well as emerging and re-emerging diseases has led to the introduction of novel cell substrates in biologics. Examples include the demand for large-scale production of pandemic influenza vaccines and for therapeutic proteins, and the use of novel vectors for AIDS vaccines and in cancer gene therapy. A major safety issue regarding the use of novel cell substrates is adventitious agents, including viruses that may have been exogenously introduced due to cell passage history or indigenous viruses that are naturally occurring in the species of cell origin due to infection, or endogenous retroviruses that exist as a normal part of the host cell DNA. Additionally, in the case of genetically engineered cells, there is a concern for recombinant viruses that may be generated de novo involving vector virus sequences. Furthermore, potential oncogenicity of residual cellular DNA remains a theoretical safety concern related to tumorigenic cell substrates. This paper discusses safety issues related to novel cell substrates with a focus on tumorigenic cells and genetically engineered cells and presents the current testing recommendations for general cell substrate safety with details on additional assays for consideration in testing some novel cell substrates including tumorigenic cells.