Consideration of the production methods and safety evaluation of cytokines.

Cytokines are natural endogenous substances whose biological effects in humans are little known when given in therapeutic rather than physiologic doses. Yet, there is intense interest in seeking their possible clinical use. While E. coli are effective in making "simple proteins" with few disulfide bonds, mammalian cells are becoming more generally used for the production of "complex proteins" with multiple disulfide bonds and glycoproteins. There appears to be much less concern about the safety of possibly oncogenic residual DNA from transformed cell lines, but viral contamination of products continues to be an active concern. Both physicochemical and biological methods are necessary to establish the identity, purity and potency of biological drugs. For proteins to manifest their proper biological and therapeutic effects in humans, their correct conformation must be maintained throughout production, purification and formulation. Regulating novel biological drugs such as the cytokines might raise new scientific issues that are not currently apparent, but the basic principles involved will be consistent with those used to evaluate other biologics, e.g., sound scientific principles, flexibility, case-by-case approach, good common sense and risk vs benefit assessment.