The transition to continuous biomanufacturing is considered the next step to reduce costs and improve process robustness in the biopharmaceutical industry, while also improving productivity and product quality. The platform production process for monoclonal antibodies (mAbs) is eligible for continuous processing to lower manufacturing costs due to patent expiration and subsequent growing competition. One of the critical quality attributes of interest during mAb purification is aggregate formation, with several processing parameters and environmental factors known to influence antibody aggregation. Therefore, a real-time measurement to monitor aggregate formation is crucial to have immediate feedback and process control and to achieve a continuous downstream processing. Miniaturized biosensors as an in-line process analytical technology tool could play a pivotal role to facilitate the transition to continuous manufacturing. In this review, miniaturization of already well-established methods to detect protein aggregation, such as dynamic light scattering, Raman spectroscopy and circular dichroism, will be extensively evaluated for the possibility of providing a real-time measurement of mAb aggregation. The method evaluation presented in this review shows which limitations of each analytical method still need to be addressed and provides application examples of each technique for mAb aggregate characterization. Additionally, challenges related to miniaturization are also addressed, such as the design of the microfluidic chip and the microfabrication material. The evaluation provided in this review shows why the development of microfluidic biosensors is considered the key for real-time measurement of mAb aggregates and how it can contribute to the transition to a continuous processing. © 2021 The Authors. Journal of Chemical Technology and Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry (SCI).

中文翻译：

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用于连续下游处理中单克隆抗体聚集体检测的过程分析技术 (PAT) 小型化

向连续生物制造的过渡被认为是降低成本和提高生物制药行业工艺稳健性的下一步，同时也提高了生产力和产品质量。由于专利到期和随之而来的日益激烈的竞争，单克隆抗体 (mAb) 的平台生产过程符合连续加工的条件，以降低制造成本。mAb 纯化过程中关注的关键质量属性之一是聚集体的形成，已知有几个工艺参数和环境因素会影响抗体聚集。因此，监测骨料形成的实时测量对于获得即时反馈和过程控制以及实现连续的下游加工至关重要。作为在线过程分析技术工具的微型生物传感器可以在促进向连续制造过渡方面发挥关键作用。在这篇综述中，将广泛评估已经成熟的检测蛋白质聚集方法的小型化，如动态光散射、拉曼光谱和圆二色性，以提供实时测量 mAb 聚集的可能性。本综述中介绍的方法评估显示了每种分析方法的哪些局限性仍需要解决，并提供了用于 mAb 聚集体表征的每种技术的应用示例。此外，还解决了与小型化相关的挑战，例如微流控芯片和微加工材料的设计。本综述中提供的评估显示了为什么微流控生物传感器的开发被认为是 mAb 聚集体实时测量的关键，以及它如何有助于向连续处理的过渡。© 2021 作者。John Wiley & Sons Ltd 代表化学工业协会 (SCI) 出版的《化学技术和生物技术杂志》。