Intensification and control of cell culture processes

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Mammalian cell culture is the dominant expression platform for the production of monoclonal antibodies, recombinant proteins and vaccines. With several hundreds of antibody products currently in clinical trials and with the anticipated emergence of many blockbuster biosimilars, the biotherapeutic market is expected to continue growing exponentially in the next decade. For many of these new biotherapeutics, the ability to mass produce them in a cost-efficient fashion will be a critical factor for their successful translation to the clinic and market. Fed-batch remains the predominant production mode for large-scale biomanufacturing, since it allows to extend the production phase and reach higher product titers. However, prolonged culture duration often leads to undesired changes to product consistency and quality over time. Despite the critical implications of product heterogeneity, most upstream process development efforts still concentrate on cellular growth and productivity. This is mainly due to the lack of a systematic approach to monitor and modulate product quality during production. The central goal of this research program is to intensify the production of biotherapeutics by developing innovative, robust, scalable and cost-efficient high-cell density culture processes. The research will 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. More specifically, the research program will aim to i) develop intensified high cell-density culture processes that can achieve an optimum performance in terms of both high culture yield and product quality ii) develop an analytical approach to rapidly assess product quality during a culture and iii) devise and implement a model-based product control strategy. 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 quality attributes. This research is expected to bring significant contributions to the field of biotherapeutics manufacturing, 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 much needed new biotherapeutics to the clinic and market, and will thus ultimately benefit both patients and industry. This research program will also contribute to the training of highly qualified personnel, which is recognized as an essential component to foster the development of the biomanufacturing industry in Canada.