Validation of a CFD model for cell culture bioreactors at large scale and its application in scale-up

Abstract

Among all the operating parameters that control the cell culture environment inside bioreactors, appropriate mixing and aeration are crucial to ensure sufficient oxygen supply, homogeneous mixing, and CO₂ stripping. A model-based manufacturing facility fit approach was applied to define agitation and bottom air flow rates during the process scale-up from laboratory to manufacturing, of which computational fluid dynamics (CFD) was the core modeling tool. The realizable k-ε turbulent dispersed Eulerian gas-liquid flow model was established and validated using experimental values for the volumetric oxygen transfer coefficient (k_La). Model validation defined the process operating parameter ranges for application of the model, identified mixing issues (e.g., impeller flooding, dissolved oxygen gradients, etc.) and the impact of antifoam on k_La. Using the CFD simulation results as inputs to the models for oxygen demand, gas entrance velocity, and CO₂ stripping aided in the design of the agitation and bottom air flow rates needed to meet cellular oxygen demand, control CO₂ levels, mitigate risks for cell damage due to shear, foaming, as well as fire hazards due to high O₂ levels in the bioreactor gas outlet. The recommended operating conditions led to the completion of five manufacturing runs with a 100% success rate. This model-based approach achieved a seamless scale-up and reduced the required number of at-scale development batches, resulting in cost and time savings of a cell culture commercialization process.