Department of Chemical Engineering, Northeastern University, Boston, Massachusetts.
Biologics Development, Global Product Development and Supply, Bristol-Myers Squibb Company, Devens, Massachusetts.
Biotechnol Bioeng. 2018 Jul;115(7):1646-1665. doi: 10.1002/bit.26587. Epub 2018 Mar 31.
Controlling the charge profile of therapeutic protein is a critical challenge in the current quality-by-design (QbD) paradigm, throughout all phases of biologics process development (PD): cell line development, upstream cell culture, recovery process, downstream purification, and analytical characterization. Charge variant profiles may influence efficacy and/or lead to unintended side-effects. Thus, maintaining a consistent charge profile is of tremendous importance, and increasingly, researchers have focused efforts toward developing strategies to mitigate variability during cell culture and to improve separation and detection of charge variants. Current understanding of factors affecting charge variant formation during manufacturing remains inadequate, and sometimes, even substantial commitment of resources may still not fully achieve the desired or consistent profiles. As such, this review attempts to provide a comprehensive resource for the biologics community by summarizing the impact of charge variants and CQA management, analytical methods for charge variant detection, as well as strategies in downstream and upstream PD for controlling charge variant profiles.
控制治疗性蛋白的电荷特征是当前质量源于设计（QbD）范式中的一个关键挑战，贯穿于生物制品工艺开发（PD）的所有阶段：细胞系开发、上游细胞培养、恢复过程、下游纯化和分析特性。电荷变异体的特征可能会影响疗效和/或导致意外的副作用。因此，保持一致的电荷特征非常重要，研究人员越来越关注开发策略来减轻细胞培养过程中的变异性，并提高电荷变异体的分离和检测能力。目前对制造过程中影响电荷变异体形成的因素的了解还不够充分，有时，即使投入大量资源，也可能仍无法完全实现所需的或一致的特征。因此，本文通过总结电荷变异体和关键质量属性（CQA）管理、电荷变异体检测的分析方法以及下游和上游 PD 中控制电荷变异体特征的策略，为生物制品界提供了一个全面的资源。
