Intensification and control of cell culture processes

哺乳动物细胞培养是生产单克隆抗体、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阶段，以及许多重磅生物仿制药的预期出现，生物治疗市场预计将在未来十年继续呈指数级增长。对于许多新的生物治疗药物来说，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滴度。然而，随着时间的推移，延长的培养时间往往会导致产品一致性和质量的不希望的变化。尽管产品异质性的关键含义，大多数上游工艺开发工作仍然集中在细胞生长和生产力。这主要是由于在生产过程中缺乏系统的方法来监测和调节产品质量。该研究项目的核心目标是通过开发创新的、稳健的、可扩展的和经济高效的高密度细胞培养工艺来加强生物治疗药物的生产。该研究将针对工业相关应用，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工业的主要主力。更具体地说，该研究计划的目标是：1)开发强化的高密度培养过程，在高培养产量和产品质量方面实现最佳性能；2)开发一种分析方法，在培养过程中快速评估产品质量；3)设计并实施基于模型的产品控制策略。该方法将基于先进的和新兴的分析方法，包括使用质谱分析和同位素示踪剂进行代谢研究，表面等离子体共振（SPR）用于产品质量属性的快速在线评估。预计这项研究将对生物治疗药品生产领域作出重大贡献，这是一个具有相当经济重要性并对加拿大公民的健康和福利有直接影响的领域。通过解决对改进和高效生物工艺的需求，这些研究工作可以帮助减少将急需的新生物治疗药物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。该研究项目还将有助于培养高素质人才，这被认为是促进加拿大生物制造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.