Manufacturing issues with combining different antigens: a regulatory perspective.

The regulation of biological products is conducted within the framework Title 21 of the US Code of Federal Regulations (CFR). These regulations describe product and clinical testing requirements for drugs and biological products, as well as the requirements for licensure of such products. The requirements outlined in the CFR also apply to combination vaccines. In addition, the Center for Biologics Evaluation and Research has issued a Guidance to Industry document that discusses the manufacturing, testing, and clinical evaluation of combination vaccines. However, as the complexity of mixing the different antigens increases, the challenges associated with product development (e.g., demonstration of comparability of the components and lot consistency) require early interactions with the US Food and Drug Administration. The many areas of difficulty in the arena of combination vaccine development underscore the need for continued reevaluation of current guidance documents in addressing the increasing complexity of vaccines.