Chemmalil Letha, Prabhakar Tanushree, Kuang June, West Jay, Tan Zhijun, Ehamparanathan Vivekh, Song Yuanli, Xu Jianlin, Ding Julia, Li Zhengjian
BMS Analytical Method Development Group, Devens, Massachusetts.
BMS Manufacturing Science & Technology, Devens, Massachusetts.
Biotechnol Bioeng. 2020 Dec;117(12):3757-3765. doi: 10.1002/bit.27531. Epub 2020 Aug 24.
Process analytical technology (PAT) has been defined by the Food and Drug Administration as a system for designing, analyzing, and controlling manufacturing through timely measurements to ensure final product quality. Based on quality-by-design (QbD) principles, real-time or near-real-time data monitoring is essential for timely control of critical quality attributes (CQAs) to keep the process in a state of control. To facilitate next-generation continuous bioprocessing, deployment of PAT tools for real-time monitoring is integral for process understanding and control. Real-time monitoring and control of CQAs are essential to keep the process within the design space and align with the guiding principles of QbD. The contents of this manuscript are pertinent to the online/at-line monitoring of upstream titer and downstream product quality with timely process control. We demonstrated that an ultra-performance liquid chromatography (UPLC) system interfaced with a UPLC-process sample manager (UPLC-PSM) can be utilized to measure titer and CQAs directly from bioreactors and downstream unit operations, respectively. We established online titer measurements from fed-batch and perfusion-based alternating tangential flow bioreactors as well as product quality assessments of downstream operations for real-time peak collection. This integrated, fully automated system for online data monitoring with feedback control is designed to achieve desired product quality.
美国食品药品监督管理局将过程分析技术（PAT）定义为一种通过及时测量来设计、分析和控制生产过程以确保最终产品质量的系统。基于质量源于设计（QbD）原则，实时或近实时数据监测对于及时控制关键质量属性（CQA）以保持过程处于受控状态至关重要。为促进下一代连续生物加工，部署用于实时监测的PAT工具对于过程理解和控制不可或缺。对CQA进行实时监测和控制对于使过程保持在设计空间内并符合QbD的指导原则至关重要。本手稿的内容与上游滴度和下游产品质量的在线/在线监测以及及时的过程控制相关。我们证明，与超高效液相色谱（UPLC）过程样品管理器（UPLC-PSM）连接的UPLC系统可分别用于直接测量生物反应器中的滴度和下游单元操作中的CQA。我们建立了补料分批培养和基于灌注的交替切向流生物反应器的在线滴度测量方法，以及下游操作的产品质量评估以进行实时峰收集。这种具有反馈控制的用于在线数据监测的集成全自动系统旨在实现所需的产品质量。
