The intact-mass MS measurements are becoming increasingly popular in characterization of a range of biopolymers, especially those of interest to biopharmaceutical industry. However, as the complexity of protein therapeutics and other macromolecular medicines increases, the new challenges arise, one of which is the high levels of structural heterogeneity that are frequently exhibited by such products. The very notion of the molecular mass measurement loses its clear and intuitive meaning when applied to an extremely heterogenous system that cannot be characterized by a unique mass, but instead requires that a mass distribution be considered. Furthermore, convoluted mass distributions frequently give rise to unresolved ionic signal in mass spectra, from which little-to-none meaningful information can be extracted using standard approaches that work well for homogeneous systems. However, a range of technological advances made in the last decade, such as the hyphenation of intact-mass MS measurements with front-end separations, better integration of ion mobility in MS workflows, development of an impressive arsenal of gas-phase ion chemistry tools to supplement MS methods, as well as the revival of the charge detection MS and its triumphant entry into the field of bioanalysis already made impressive contributions towards addressing the structural heterogeneity challenge. An overview of these techniques is accompanied by critical analysis of the strengths and weaknesses of different approaches, and a brief overview of their applications to specific classes of biopharmaceutical products, vaccines, and nonbiological complex drugs.

中文翻译：

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基于质谱的方法，用于在完整质量水平上表征高度异质的生物制药、疫苗和非生物复杂药物

完整质量 MS 测量在一系列生物聚合物的表征中变得越来越流行，尤其是那些生物制药行业感兴趣的生物聚合物。然而，随着蛋白质疗法和其他大分子药物的复杂性增加，新的挑战出现，其中之一是此类产品经常表现出的高水平结构异质性。当应用于无法用唯一质量来表征的极其异质的系统时，分子质量测量的概念就失去了其清晰和直观的含义，而是需要考虑质量分布。此外，复杂的质量分布经常会在质谱中产生未解析的离子信号，使用适用于均质系统的标准方法可以从中提取很少甚至没有有意义的信息。然而，过去十年取得了一系列技术进步，例如完整质量 MS 测量与前端分离的结合、MS 工作流程中离子淌度的更好集成、令人印象深刻的气相离子化学工具库的开发作为 MS 方法的补充，以及电荷检测 MS 的复兴及其成功进入生物分析领域，已经为解决结构异质性挑战做出了令人印象深刻的贡献。对这些技术的概述伴随着对不同方法的优点和缺点的批判性分析，并简要概述了它们在特定类别的生物制药产品、疫苗和非生物复合药物中的应用。