Kopp Marie R G, Grigolato Fulvio, Zürcher Dominik, Das Tapan K, Chou Danny, Wuchner Klaus, Arosio Paolo
Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
Bristol Myers Squibb, Warren, NJ, USA.
J Pharm Sci. 2023 Feb;112(2):377-385. doi: 10.1016/j.xphs.2022.10.009. Epub 2022 Oct 9.
Protein stability against aggregation is a major quality concern for the production of safe and effective biopharmaceuticals. Amongst the different drivers of protein aggregation, increasing evidence indicates that interactions between proteins and interfaces represent a major risk factor for the formation of protein aggregates in aqueous solutions. Potentially harmful surfaces relevant to biologics manufacturing and storage include air-water and silicone oil-water interfaces as well as materials from different processing units, storage containers, and delivery devices. The impact of some of these surfaces, for instance originating from impurities, can be difficult to predict and control. Moreover, aggregate formation may additionally be complicated by the simultaneous presence of interfacial, hydrodynamic and mechanical stresses, whose contributions may be difficult to deconvolute. As a consequence, it remains difficult to identify the key chemical and physical determinants and define appropriate analytical methods to monitor and predict protein instability at these interfaces. In this review, we first discuss the main mechanisms of surface-induced protein aggregation. We then review the types of contact materials identified as potentially harmful or detected as potential triggers of proteinaceous particle formation in formulations and discuss proposed mitigation strategies. Finally, we present current methods to probe surface-induced instabilities, which represent a starting point towards assays that can be implemented in early-stage screening and formulation development of biologics.
蛋白质抗聚集稳定性是安全有效生物制药生产中的一个主要质量问题。在蛋白质聚集的不同驱动因素中，越来越多的证据表明，蛋白质与界面之间的相互作用是水溶液中蛋白质聚集体形成的一个主要风险因素。与生物制品制造和储存相关的潜在有害表面包括气 - 水和硅油 - 水界面以及来自不同加工单元、储存容器和输送装置的材料。其中一些表面的影响，例如源自杂质的影响，可能难以预测和控制。此外，界面、流体动力学和机械应力的同时存在可能会使聚集体的形成更加复杂，其各自的作用可能难以区分。因此，仍然难以确定关键的化学和物理决定因素，并定义适当的分析方法来监测和预测这些界面处的蛋白质不稳定性。在这篇综述中，我们首先讨论表面诱导蛋白质聚集的主要机制。然后，我们回顾了被确定为潜在有害或在制剂中被检测为蛋白质颗粒形成潜在触发因素的接触材料类型，并讨论了提出的缓解策略。最后，我们介绍了探测表面诱导不稳定性的当前方法，这些方法是朝着可用于生物制品早期筛选和制剂开发的检测方法迈出的第一步。
