Transfer of continuous manufacturing process principles for mAb production in a GMP environment: A step in the transition from batch to continuous
Transfer of continuous manufacturing process principles for mAb production in a GMP environment: A step in the transition from batch to continuous
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在 GMP 环境中转移 mAb 生产的连续制造工艺原理：从批量到连续的过渡的一步
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发表时间：
2022
期刊：
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通讯作者：
Jean
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作者：
Kevin Botelho Ferreira;Asma Benlegrimet;Gabriel Diane;Victor Pasquier;Raphaël Guillot;Marc De Poli;Loïc Chappuis;N. Vishwanathan;J. Souquet;H. Broly;Jean
实施连续替代分批上游工艺（USP）和下游工艺（DSP）生产重组治疗性蛋白是一个重大的范式变化。本报告描述了如何使用最初设计用于批量操作的设备同时使用连续生产工艺和原理生产第一公斤单克隆抗体。交付临床材料的项目时间表推动了这一目标，并帮助了过渡。然而，由于设备的可用性，必须在设想的连续下游工艺（cDSP）操作和本文中描述的操作之间进行权衡。在用于临床试验的两次GMP运行中共生产了2.1 kg单克隆抗体。对于USP，升级了200 L一次性中试规模生物反应器，以实现灌注操作。DSP步骤设计为易于转移至cDSP，用于后续临床或商业生产。以不连续的方式测试了在线调节缓冲液制备策略，以证明其有效性，并在连续收集含抗体细胞培养上清液的同时构建了纯化级联。该策略将避免在随后转移至当前正在确认的连续设备时发生任何工艺变更。小规模参考运行与GMP运行在生产率和质量方面的一致性证实了所提出的方法是有效的。因此，我们证明了现有的补料分批基础设施可以适应连续生产，而无需大量额外投资。这种方法有助于在进行大规模投资之前评估下一代制造工艺。
Implementation of continuous in lieu of batch upstream processing (USP) and downstream process (DSP) for the production of recombinant therapeutic protein is a significant paradigm change. The present report describes how the first kilograms of monoclonal antibody were produced with equipment originally designed for batch operations while using continuous manufacturing processes and principles. Project timelines for the delivery of clinical material have driven this ambition and helped the transition. Nevertheless, because of equipment availability, a tradeoff between the envisaged continuous downstream process (cDSP) operations and the ones described in this article had to be taken. A total of 2.1 kg of monoclonal antibody were produced in two GMP runs for clinical trials. For USP, a 200‐L single‐use pilot scale bioreactor was upgraded to enable perfusion operation. DSP steps were designed to be easily transferable to cDSP for later clinical or commercial productions. An in‐line conditioning buffer preparation strategy was tested in a discontinuous way to prove its efficiency and the purification cascade was structured in parallel to the continuous collection of antibody‐containing cell culture supernatant. This strategy will avoid any process change when later moving to the continuous equipment that is currently under qualification. Alignment between small‐scale references runs and the GMP runs in terms of productivity and quality confirmed that the presented approach was valid. Thus, we demonstrate that existing fed‐batch infrastructure can be adapted to continuous manufacturing without significant additional investments. Such approach is useful to evaluate next‐generation manufacturing processes before making large investments.