Intensification and control of cell culture processes

哺乳动物细胞培养是生产单抗、重组蛋白和疫苗的主要表达平台。随着数百种抗体产品目前处于临床试验中，以及预计将出现许多轰动一时的生物仿制药，生物治疗市场预计将在未来十年继续呈指数级增长。对于这些新的生物疗法中的许多，以经济高效的方式大规模生产它们的能力将是它们成功转化为临床和市场的关键因素。补料分批仍然是大规模生物制造的主要生产模式，因为它允许延长生产阶段并达到更高的产品效价。然而，随着时间的推移，延长培养时间往往会导致产品一致性和质量发生不希望看到的变化。尽管产品异质性具有重要的影响，但大多数上游工艺开发工作仍然集中在细胞生长和生产率上。这主要是因为在生产过程中缺乏监测和调节产品质量的系统办法。该研究计划的中心目标是通过开发创新的、健壮的、可扩展的和低成本的高细胞密度培养过程来加强生物疗法的生产。这项研究将针对一个与工业相关的应用，即利用中国仓鼠卵巢(CHO)细胞生产单克隆抗体，因为这些细胞是生物制药行业的主要主力。更具体地说，该研究计划的目标将是：i)开发能够在高培养产量和产品质量方面实现最佳性能的强化高细胞密度培养工艺；ii)开发一种分析方法来快速评估培养过程中的产品质量；iii)设计并实施基于模型的产品控制策略。该方法将以先进和新兴的分析方法为基础，包括使用质谱分析和同位素示踪剂进行代谢研究，以及使用表面等离子激元共振(SPR)对产品质量属性进行快速在线评估。这项研究预计将为生物疗法制造领域带来重大贡献，这是一个具有相当重要经济意义的领域，对加拿大公民的健康和福利有直接影响。通过满足对改进和高效生物过程的需求，这些研究工作可以帮助减少将急需的新生物疗法推向临床和市场的成本和时间，从而最终使患者和行业受益。这项研究计划还将有助于培训高素质的人员，这被认为是促进加拿大生物制造行业发展的重要组成部分。

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.