Modeling the coupled extracellular and intracellular environments in mammalian cell culture.

The regulation of metabolism in mammalian cell culture is closely linked to the process of apoptosis-programmed cell death. Apoptosis negatively impacts culture viability, product yield, and quality. An improved understanding of the interaction between apoptosis and metabolism will give rise to better control over the culture process, and thus improvements in product yield. This study presents a mathematical model that describes both the metabolic fluxes involving the extracellular metabolites and the progression of apoptosis in terms of intracellular caspases, and thus highlights the interactions between these two processes. The model is trained and validated against experimental observations of Chinese Hamster Ovary cell culture producing monoclonal antibody. Importantly, the model describes the continued production of monoclonal antibody in post exponential phase by incorporating different rates of antibody production for separate sub-populations within the culture. A parameter estimability test was applied on the combined model to assess the confidence in parameter estimates.