A physiological state-based approach to the development and control of mammalian cell culture processes

对大量生物药物的需求日益增长，正在开发的哺乳动物细胞产品的数量越来越多，以及需要现代化和加快生产应对大流行的疫苗，这些都推动了开发高效、成本效益高和强大的细胞培养过程的需要。尽管哺乳动物细胞技术取得了进展，但仍然存在重大挑战；由于控制细胞生长、新陈代谢和生产力的众多参数，目前对哺乳动物细胞在培养中的复杂行为只有部分了解。反过来，这种知识的缺乏阻碍了有效控制战略的制定，这些战略对于降低生产成本、确保高产量和保持产品质量至关重要。因此，这一领域的进展对于缩短上市时间和增加临床和市场上急需的新的治疗药物的供应是必要的和关键的。拟议的研究旨在了解和表征细胞代谢和生理学，作为开发和控制哺乳动物细胞培养过程的合理基础。拟议的研究计划将专门调查：A)开发能够提供对细胞生理状态的定量描述的准确代谢模型；B)描述细胞对工艺条件变化的生理反应以及随之而来的对生产力的影响；以及C)制定控制培养中细胞的生理状态和生产力的策略。这一方法将应用于两个工业相关系统：干扰素-α的生产和腺病毒疫苗的生产。该方法将基于数学建模和质谱分析相结合。通过解决加速工艺开发的需要，这项研究可以帮助缓解蛋白质生产的瓶颈，并应对加拿大人的健康和福利产生积极影响。由于其很强的跨学科性质，这项研究还将为学生提供广泛的生物技术方面的培训，并为他们在生物化学工程领域的不同职业做好准备。

The growing demand for large amounts of biopharmaceuticals, the increasing number of mammalian cell products in development and the necessity to modernize and speed up the production of vaccines for pandemic readiness are driving the need to develop efficient, cost-effective and robust cell culture processes. Despite progress in mammalian cell technologies, significant challenges still remain; the complex behaviour of mammalian cells in culture is currently only partially understood because of the multitude of parameters governing cell growth, metabolism and productivity. In turn, this lack of knowledge has hindered the development of effective control strategies, which are vital for reducing production costs, ensuring high yields and maintaining product quality. Advancements in this area are thus needed and crucial to reduce the time-to-market and increase the supply of new and much needed therapeutic agents to the clinic and market.The proposed research aims at understanding and characterising the cellular metabolism and physiology as a rational basis for the development and control of mammalian cell culture processes. The proposed research program will specifically investigate: A) the development of an accurate metabolic model able to provide a quantitative description of the cells' physiological state; B) the characterisation of the cellular physiological response to changes in process conditions and the ensuing effects on productivity; and C) the development of strategies to control the physiological state and productivity of cells in culture. This approach will be applied to two industrially relevant systems: the production of Intereferon-alpha and the production of adenovirus vaccine. The methodology will be based on mathematical modeling combined with mass spectrometry analysis. By addressing the need to accelerate process development, this research can contribute to alleviate the bottleneck in protein production and should impact positively on the health and welfare of Canadians. Due to its strong interdisciplinary nature, this study will additionally provide students with training in broad aspects of biotechnology and prepare them for diverse careers in biochemical engineering.