A mechanistic-empirical model of central metabolism, signaling, and the reactor environment for bioprocesses

Abstract

This model was built and optimized to reproduce the variability inherent to many industrial cell-culture processes. Classically, fed-batch Chinese Hamster Ovary (CHO) cell cultures will initially produce lactate in the early phase of culture before switching to lactate consumption. However, some processes may revert to lactate production in the late stage of culture, driving up osmolarity while reducing viable cell density, and ultimately lowering process performance. This phenomenon may occur in only some runs of a manufacturing processes and even may differ among runs with similar initial conditions and trajectories, leading to longstanding questions about the mechanisms driving this switch. By simulating cultures which were exposed to different amounts of stress before the production bioreactor we show that similar starting conditions in the bioreactor environment can lead to variability in metabolic shift. We provide this model as a tool to demonstrate this metabolic variability and provide a platform for hypothesis testing, in silico bioprocess optimization, and simulation of reactor scale-up and scale-down.