Confessions of a Cell Culture Engineer: Process Impact on Protein Products in a QbD World

In producing therapeutic proteins from cell culture processes, it is necessary to develop processes capable of delivering consistent protein characteristics, particularly those that could affect the structure or function of the biomolecule and potentially impact the product safety or efficacy. Over the past thirty years, cell culture scientists and engineers have navigated the waters of process understanding in tackling protein product quality challenges. In many cases, the root cause of protein product attribute variation is related to cell culture process conditions.

The impacts of process conditions on protein attributes may be due to biosynthetic (biological origin) or degradative (chemical or physical origin) effects, and these effects may be driven by intracellular or extracellular factors. This presentation will review industrially relevant experiences, and discuss approaches toward better understanding and control of recombinant protein product characteristics through cell culture manipulations. Specific protein attribute variation addressed may include amino acid sequence, glycosylation (micro and macroheterogeneity), and charge variant distributions, and their potential for impact on various aspects of protein quality. The linkage between this process knowledge and today’s Quality by Design (QbD) approaches to process and product development will be discussed.