Optimizing performance of semi-continuous cell culture in an ambr15™ microbioreactor using dynamic flux balance modeling.

The ambr bioreactors are single-use microbioreactors for cell line development and process optimization. With operating conditions for large-scale biopharmaceutical production properly scaled down, microbioreactors such as the ambr15™ can potentially be used to predict the effect of process changes such as modified media or different cell lines. While there have been some recent studies evaluating the ambr15™ technology as a scale-down model for fed-batch operations, little has been reported for semi-continuous or continuous operation. Gassing rates and dilution rates in the ambr15™ were varied in this study to attempt to replicate performance of a perfusion process at the 5 L scale. At both scales, changes to metabolite production and consumption, and cell growth rate and therapeutic protein production were measured. Conditions were identified in the ambr15™ bioreactor that produced metabolic shifts and specific metabolic and protein production rates that are characteristic of the corresponding 5 L perfusion process. A dynamic flux balance (DFB) model was employed to understand and predict the metabolic changes observed. The DFB model predicted trends observed experimentally, including lower specific glucose consumption and a switch from lactate production to consumption when dissolved CO2 was maintained at higher levels in the broth.