Criteria for investigation of the product equivalence of monoclonal antibodies for therapeutic and in vivo-diagnostic use in case of introduction of changes in the manufacturing process.

The development of a monoclonal antibody for therapeutic or in vivo-diagnostic use from the first description to clinical trials and compilation of the dossier for granting the license requires a time consuming and expensive program. Due to its long development time, a particular monoclonal antibody can be subjected to a series of changes and improvements in manufacturing technology before licensure. In addition, the application for marketing authorization of biotechnology-derived medicinal products is not to be considered as an endpoint of a drawn-out development process which ends with license, because changes, amendments or improvements of the manufacturing process occur after a marketing authorization for a monoclonal antibody has been granted. Most of these changes, even minor qualitative and quantitative changes in the active substance itself, would require a new application according to the legal regulations of the European Union and of the national drug laws of the Member States. The paper proposes a procedure to take previously evaluated development-related data into account by evaluation of the product equivalence of both antibody forms ascertained before and after introduction of changes in the manufacturing process. The thorough in vitro analysis of parameters such as isotype, subclass, affinity, microheterogeneity, molecular weight, primary and secondary structure, structural integrity of the antibody molecule, glycosylation pattern, specificity, cross-reactivity and biological potency with subsequently performed pharmacological/toxicological evaluation of biodistribution, half life and safety provide sufficient data for decision on the need for further clinical trials.