Rational development of fed-batch mammalian cell culture processes

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Mammalian cell culture remains the dominant expression system for the manufacturing of recombinant proteins for clinical applications. With several hundreds of protein products currently in clinical trials and with the anticipated emergence of several blockbuster biosimilars, the biotherapeutics market is expected to grow exponentially within the next decade. For the majority of these novel bioproducts, the capacity to mass produce them in a cost-efficient manner will be a critical factor for their successful translation to the clinic and market.***The central goal of this NSERC Discovery Research Program is to devise innovative strategies that will enable the rapid development of robust and cost-effective cell culture-based manufacturing processes. To better cope with the inherent complexity of mammalian cell cultures, the research will be conducted following a multi-scale system's approach integrating information at the cellular and process levels. More specifically, the research program will aim to i) conduct comprehensive metabolic characterization of mammalian cells under relevant process conditions in order to guide and streamline optimization efforts ii) develop reliable mathematical models linking process conditions and cell culture state in order to simulate and predict process performance and iii) design and implement efficient model-based dynamic fed-batch strategies ensuring high product yield and consistency. ***The methodology will be based on advanced and emerging analytical methods, including the use of mass spectrometry analysis and isotopic tracers for conducting metabolic studies and surface plasmon resonance (SPR) for rapid at-line assessment of product bioactivity. The research will primarily target an industrially relevant application, the production of monoclonal antibodies by Chinese Hamster Ovary (CHO) cells, as these cells are the main workhorse of the biopharmaceutical industry. The research will also pursue the development of cell culture processes involving mammalian cells that have been engineered to possess an improved metabolic efficiency. ***The novelty of the research program lies not only in its anticipated outcomes, but also in the innovative application of a multi-scale systems approach combining cellular and process engineering strategies for conducting rational process development and generating new knowledge. This research is expected to bring a significant contribution to the development and manufacturing of biotherapeutics, an area of considerable economic importance and having a direct impact on the health and welfare of Canadian citizens. By addressing the needs for improved and efficient bioprocesses, these research efforts can help to reduce the cost and time in getting recombinant products to the clinic and market and will thus ultimately benefit both patients and industry.***********