Catabolic control for animal cell culture processes

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Mammalian cell cultures are the dominant production system for the manufacturing of many important recombinant therapeutic proteins and vaccines. Despite significant advances in mammalian cell technologies, the lack of reliable sensors and the insufficient understanding of cell physiology and process dynamics have hampered the development of effective control strategies. These are vital and critically needed for enhancing yield, maintaining product quality and reducing process variability. The proposed research program aims at developing model-based control strategies enabling the robust, efficient and cost-effective development and operation of mammalian cell culture processes. More specifically, the research program will investigate 1) the kinetic modeling of cellular physiology using quantitative metabolomics and 13C-fluxomics 2) the on-line sensing and estimation of key physiological variables 3) the design and implementation of feeding strategies capable of maintaining the cells at a physiological state that ensures high growth and production rates at each stage of culture. The methodology will involve mathematical modeling based on extensive physiological characterization using mass spectrometry analysis and isotopomer/metabolite balancing techniques. The approach will be developed initially on industrially/clinically relevant model systems. The aims of this grant application are thus in direct line with the requirements of the recent "Process Analytical Technology" initiative by the Food and Drug Administration. Advancements in this area are crucial to increase the supply of new therapeutic agents to the clinic, while reducing the time-to-market. By producing both fundamental and practical benefits, the proposed research is expected to bring a significant contribution to the development and manufacturing of biotherapeutics, an area of considerable economic importance that directly impact the health and welfare of Canadians.