The imminent patent expiration of many biopharmaceutical products will produce the possibility for generic versions of these therapeutic agents (i.e. biosimilars). However, there are a number of issues that will make approval of biosimilars much more complicated than the approval of generic equivalents of conventional pharmaceuticals. These issues centre on the intrinsic complexity of biopharmaceutical agents, which are recombinant proteins in most cases, and the heterogeneity of proteins produced by different manufacturing processes (i.e. differences in host cells, purification and processing, formulation and packaging). The increased occurrence of antibody (Ab)-mediated pure red cell aplasia (PRCA) associated with a change in the formulation of one particular epoetin-alpha. product highlights the potential for increased immunogenicity of recombinant proteins with different formulations, or those manufactured by different processes. Thus, verification of the similarity to or substitutability of biosimilars with reference innovator biopharmaceutical products will require much more than a demonstration of pharmacokinetic similarity, which is sufficient for conventional, small molecule generic agents. Regulatory requirements for the approval of biosimilars have not yet been fully established, but preliminary guidelines from the European Agency for the Evaluation of Medicinal Products (EMEA) state that the complexity of the product, the types of changes in the manufacturing process, and differences in quality, safety and efficacy must be taken into account when evaluating biosimilars. For most products, results of clinical trials demonstrating, safety and efficacy are likely to be required. In addition, because of the unpredictability of the onset and incidence of immunogenicity, extended post-marketing surveillance is also important and may be required.
