(130e) A Model for Long-Term Dynamic Simulation of Cell Metabolism

Mammalian fed-batch cultures are used extensively in industry for the production of recombinant therapeutic proteins. Despite such continued use, the metabolism of cells in these processes remains poorly understood. With limited insight into the mechanisms behind major metabolic events, such as the lactate shift and recombinant protein productivity, process optimization typically involves extensive experimentation. The use of a detailed metabolic model capable of accurately describing the long-term dynamics of metabolic and biosynthetic pathways would be invaluable to process optimization; however, to date such comprehensive models do not exist. This paper presents a novel modeling framework for simulating pathway dynamics based on a global regulator, illustrated with a detailed model of CHO cell metabolism. Model simulations were compared to experimental data collected in fed-batch bioreactors. These comparisons showed that the simulations accurately predicted cell growth, recombinant protein, and metabolite concentration profiles, as well as the timing and magnitude of the metabolic shift, in response to variations in process parameters such as temperature shift, seed density, and nutrient concentrations. This model is the first to date to account for the combined effects of temperature, redox, metabolite concentrations, and regulation in CHO cell metabolism.