Integrative in-silico models for mammalian cell cultures in single-use bioreactors: Bridging hydrodynamics, kinetics, and process control across scales

Abstract

This study presents a novel hybrid computational fluid dynamics (CFD) model that integrates hydrodynamics, kinetics, and auxiliary control systems for a mammalian bioprocess across scales. The CFD model simulates the entire 14-day bioprocess at three different scales (250 mL, 1000 L, and 2000 L). The combination of hydrodynamic and kinetic assessment at each timestep allows for an optimization of feed delivery and implementation of feed control systems, with PID parameters tuned within the simulation, resulting in computational methods for bioreactor optimization. Using this model and CHO fed-batch experimental data, this study reveals the cell growth profile was minimally sensitive to glucose concentration, while glutamine concentration had a large impact. This model’s scale-up utility is demonstrated by showing similar cell growth profiles across scales by tuning feeding rates. This assessment was completed in one-tenth of the time typically required to simulate such a process by leveraging the time scale difference between “fast” fluid dynamics and “slow” cell kinetics.