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Model-based design and control of a small-scale integrated continuous end-to-endmAbplatform

机译：基于模型的设计与控制小型集成连续端到endMabplatform

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摘要

A continuous integrated bioprocess available from the earliest stages of process development allows for an easier, more efficient and faster development and characterization of an integrated process as well as production of small-scale drug candidates. The process presented in this article is a proof-of-concept of a continuous end-to-end monoclonal antibody production platform at a very small scale based on a 200 ml alternating tangential flow filtration perfusion bioreactor, integrated with the purification process with a model-based design and control. The downstream process, consisting of a periodic twin-column protein A capture, a virus inactivation, a CEX column and an AEX column, was compactly implemented in a single chromatography system, with a purification time of less than 4 hr. Monoclonal antibodies were produced for 17 days in a high cell density perfusion culture of CHO cells with titers up to 1.0 mg/ml. A digital twin of the downstream process was created by modelling all the chromatography steps. These models were used for real-time decision making by the implementation of control strategies to automatize and optimize the operation of the process. A consistent glycosylation pattern of the purified product was ensured by the steady state operation of the process. Regarding the removal of impurities, at least a 4-log reduction in the HCP levels was achieved. The recovery yield was up to 60%, and a maximum productivity of 0.8 mg/ml/day of purified product was obtained.
机译：从最早的过程开发阶段提供的连续综合生物过程允许更容易，更高效，更快地开发和表征综合过程以及生产小规模的药物候选者。本文中提出的方法是基于200mL交替切向流过滤灌注生物反应器的基于200mL交替的切向流动过滤灌注生物反应器的连续端到端单克隆抗体生产平台概念。基于设计和控制。由周期性双柱蛋白A捕获，病毒失活，CEX柱和AEX柱组成的下游工艺在单个色谱系统中紧凑地实施，纯化时间小于4小时。在CHO细胞密度灌注培养的CHO细胞密度灌注培养中制备单克隆抗体17天，其滴度高达1.0mg / mL。通过建模所有色谱步骤来创建下游过程的数字双胞胎。这些模型用于通过实施控制策略来自动化和优化过程的操作来实时决策。通过该方法的稳态操作确保了纯化产物的一致糖基化图案。关于去除杂质，实现了HCP水平的至少4次降低的降低。回收率高达60％，获得0.8mg / ml /毫升纯化产物的最大生产率。

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