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.

中文翻译：

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基于模型的小规模集成连续端到端 mAb 平台的设计和控制。

从工艺开发的最早阶段就可以使用连续集成生物工艺，可以更轻松、更高效、更快速地开发和表征集成工艺以及小规模候选药物的生产。本文介绍的过程是基于 200 ml 交替切向流过滤灌注生物反应器的小规模连续端到端单克隆抗体生产平台的概念验证，并与具有模型的纯化过程相结合——基于设计和控制。由周期性双柱蛋白 A 捕获、病毒灭活、CEX 柱和 AEX 柱组成的下游过程在单个色谱系统中紧凑地实施，纯化时间少于 4 小时。单克隆抗体在 CHO 细胞的高细胞密度灌注培养中产生 17 天，滴度高达 1.0 mg/ml。通过对所有色谱步骤进行建模，创建了下游过程的数字孪生。这些模型通过实施控制策略来实现实时决策，以实现过程操作的自动化和优化。该过程的稳态操作确保了纯化产物的一致糖基化模式。关于杂质的去除，HCP 水平至少降低了 4-log。回收率高达60%，纯化产物的最大生产率为0.8mg/ml/天。通过对所有色谱步骤进行建模，创建了下游过程的数字孪生。这些模型通过实施控制策略来实现实时决策，以实现过程操作的自动化和优化。该过程的稳态操作确保了纯化产物的一致糖基化模式。关于杂质的去除，HCP 水平至少降低了 4-log。回收率高达60%，纯化产物的最大生产率为0.8mg/ml/天。通过对所有色谱步骤进行建模，创建了下游过程的数字孪生。这些模型通过实施控制策略来实现实时决策，以实现过程操作的自动化和优化。该过程的稳态操作确保了纯化产物的一致糖基化模式。关于杂质的去除，HCP 水平至少降低了 4-log。回收率高达60%，纯化产物的最大生产率为0.8mg/ml/天。关于杂质的去除，HCP 水平至少降低了 4-log。回收率高达60%，纯化产物的最大生产率为0.8mg/ml/天。关于杂质的去除，HCP 水平至少降低了 4-log。回收率高达60%，纯化产物的最大生产率为0.8mg/ml/天。