(597c) Managing Simultaneous Manufacturing, Process Development, and Technology Transfer Challenges for a Sensitive CHO Process With Rapid Timelines

For monoclonal antibody products, early stage process development typically focuses on rapid cell line development, clone selection, and production of material for clinical trials, without the final large scale manufacturing site in mind. For robust Chinese hamster ovary (CHO) cell lines, the risk associated with this approach is usually minimal, as the cells typically perform similarly under a moderate range of bioreactor operating parameters and facility configurations. However, for a more sensitive cell line, relatively small changes in mixing and sparging strategy may significantly impact overall performance. This case study highlights the challenges encountered for a sensitive CHO cell line which led to decreased viability and 35% lower titer upon scale-up. Subsequent lab scale experiments and statistical analysis demonstrated that the reduced titer was correlated to high power input per unit volume, high gas sparge rates, and high dissolved CO2 in the culture medium. To address these limitations, the relationships among power input, sparge rate, and kLa were modeled to identify the feasible process design space for a target manufacturing site. Based on the model, a comprehensive DOE was performed to investigate and decouple these parameters at lab scale and identify those with the highest overall impact to dissolved CO2, viability, and titer. As a result, competing factors, including multiple process sensitivities and facility fit restrictions, were mitigated in a short timeframe to maintain supply for ongoing clinical trials and improve productivity.