(233a) QbD for Biotherapeutics: Opportunities and Challenges -- An Industrial View Point

This paper will present an industrial viewpoint of the opportunities and challenges that have surfaced to date in the application of quality by design (QbD) principles in the development of biologics for human therapy. While a number of tools of product and process design already have a long tradition in the development of drugs derived by biotechnology, the development of the more recent ICH guidelines Q8, Q9 and Q10 has provided a regulatory framework for a comprehensive and prospective quality by design approach that fully integrates product and process development with the principles of quality risk management and quality systems. Quality by design can be applied throughout the lifecycle of a product. While QbD can begin as early as in the first stages of the engineering of the biotherapeutic itself and its formulation, extensive process design studies are typically not undertaken until the product reaches proof of concept in clinical trials. Case studies will be presented and some of the challenges of applying QbD to multiple unit operations and identifying the functional relationships between process input parameters and quality attributes of the drug will be highlighted. Different ways of developing and presenting a multidimensional manufacturing design space will be shown. Since the sources of heterogeneity of a biotherapeutic compound, such as a glycosylated protein, primarily originate in the drug substance manufacturing process, this presentation will focus on the production and purification of bulk formulated drug substance. Differences in the approaches that might be taken for a pre-approval versus a marketed product will also be illustrated. Well-characterized biologics, such as monoclonal antibodies, are good candidates for a comprehensive QbD approach, however, the stage of development, the type of anticipated post-approval changes, and a variety of other technical and business aspects will impact the decision of how thoroughly the design space will be explored prior to marketing approval. Both the advantages of increased process understanding and the outlook of reduced regulatory hurdles to continuous process improvement justify working through the challenges. Developing a process design space and control strategy that in the future may underwrite, for example, changes in equipment, process scale, or manufacturing site are often high on the priority list for manufacturers of biologics.