CMC Considerations for Continuous Bioprocess Design, Development, and Manufacturing

This chapter describes monoclonal antibody (mAb) continuous bioprocess (CBP) from design, implementation to manufacturing based on the scientific understanding of mAb physicochemical properties, proven bioprocessing principles, available technologies, chemistry, manufacturing, and control (CMC) considerations, current industrial practices, regulatory guidelines, challenges, potential solutions, and future perspectives. The discussion addresses the conventional, intensified, integral, and/or fully automated end-to-end mAb CBP manufacturing process from cell line development (CLD); cell culture process development (e.g., upstream process); protein purification process development (e.g., downstream process); analytical method development, qualification, and validation for process performance; and product quality monitoring and control perspectives. The increasing interest in the application of CBP in biopharmaceutical manufacturing is associated with increased mAb market demand, demonstrated process consistency and product quality, and potential cost of goods (COGs) reduction. Some unprecedented challenges of CBP application are discussed. Some innovative technologies are assessed with practical solutions proposed. A case study is presented and discussed regarding a flowthrough mode of cation exchange chromatography for potential CBP implementation. The goal of this chapter is to propose a design and establish a fully automated CBP platform for an end-to-end mAb production from cell culture to drug substance (DS) formulation. Finally, the CBP technology is proposed for other bioprocess and manufacturing such as adeno-associated virus (AAV) vector for gene therapy.