Advancements in the Manufacture of Monoclonal Antibodies and Other Large Molecule Protein Therapeutics: Recent Innovations in Cell Culture Technology Enabling Process Intensification

This chapter on recent advances in upstream process development will discuss the limitations of fed-batch processes, the recent resurgence of interest in traditional “classical steady-state” perfusion in which viable cell density is held nearly constant, and the development of non-conventional “dynamic” perfusion processes in which viable cell density is allowed to peak and decline. Many variants and hybrid processes that combine elements of both perfusion and fed-batch, or even link bioreactors together for a unique, isolated control of the growth phase and the more quiescent production phase will be explored. Other process intensification methodologies such as N-1 perfusion for high-density production reactor inoculation will also be examined. A section on the pragmatic control of mammalian cell metabolism will explain recent advances designed to precisely control lactic acid formation and limit ammonium ion accumulation. Genetic engineering approaches such as enzyme knock outs and catabolic pathway reconstitution to limit the formation of previously unknown growth-inhibitory by-products of metabolism will also be delineated.