Abstract
This work presents the dynamic optimization of glucose feed in cell cultivation considering the balance between productivity and impurity generation. We first developed a mechanistic model considering cell growth promotion by glucose and cell growth inhibition by osmolarity for a newly developed, high-productivity CHO-MK cell line. For model development, fed-batch cultivation experiments were conducted at a 250 mL scale under three different glucose feeding profiles. Results from a single-objective dynamic optimization, using the glucose feed profile as a design variable, were compared to those from multi-objective problem settings with varying weights assigned to productivity and final impurity concentrations. Simulation results suggested different glucose feed profiles depending on the priority given to the mAb and impurities, where the main difference was in the generated viable cell density profiles. Productivity-focused profiles employed a low-high-intermediate feeding strategy, in which the total glucose feed over the cultivation period was set to a balanced level, with an initially low rate, followed by a gradual increase, and a later decrease. Profiles focusing on impurity reduction adopted a feeding strategy that maintained a high glucose feed throughout the cultivation period. This work demonstrated the power of mechanistic-model-based process design and is expected to encourage further model-based process design in biopharmaceutical manufacturing.