Cell substrates: where do we stand after 50 years of discussion?

The issue of which cells are acceptable as substrates for the production of biological products, and especially vaccines, has been with us in one form or another since the development of cell cultures in the 1950s. The major cell substrate events that occurred over the past 50 years are reviewed briefly, including the outcomes of the seven most significant meetings. Cell DNA has been discussed for 30 years with incomplete resolution of some aspects of the issue. The currently available information on the potential oncogenicity of cellular DNA derived from continuous cell lines for which there is no evidence of either viral integration or extrachromosomal viral elements is reviewed. Issues associated with the continuing regulatory uncertainty about cell DNA are discussed. A perspective is provided on the answers to four questions: (i) what do we know now about the DNA issue? (ii) what can we conclude from what we know now? (iii) what more information, if any, is needed to provide updated guidance? and how do we reach a consensus and updated guidance? And finally, a way forward is presented.