Fluctuations in dissolved oxygen concentration during a CHO cell culture process affects monoclonal antibody productivity and the sulfhydryl‐drug conjugation process

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Abstract

During a CHO cell culture production process, important parameters are generally well controlled by a feedback mechanism (PID loop) in order to ensure consistency in both productivity and product quality. These parameters typically include pH, dissolved oxygen (DO), and temperature. While most of these parameters are very well controlled within their specific deadband, stable DO control can be challenging. Oscillations in DO concentration are not uncommon and these fluctuations can be exacerbated with an efficient mass transfer aeration strategy. In this study, where an IgG₂ producing cell line was used, we observed increased lactate accumulation accompanied by decreased titer production in lots with fluctuations in DO concentration (DO_F ) when compared with lots with stable DO control (DO_S ). We demonstrate that DO_F had a greater impact on performance with respect to titer production and lactate accumulation than DO setpoint. Furthermore, we report that estimated specific oxygen uptake rates (qOURs) were lower in DO_F lots when compared with DO_S lots. We also report that purified mAb sourced from DO_F lots yielded lower drug-to-antibody ratio (DAR) after the sulfhydryl-targeted maleimide conjugation process when equivalent reducing agent was used. All mAb lots were within the analytical specifications for release, though a slight increase in measureable trisulfides were observed in DO_F mAb lots. DO control aimed to minimize fluctuations around DO setpoint was essential for us to produce consistent DAR without adjusting the conjugation process. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1427-1437, 2018.

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