Analytical Sciences, GlaxoSmithKline Pharmaceutical Research and Development, 709 Swedeland Road, King of Prussia, PA 19406, USA.
J Pharm Biomed Anal. 2010 Apr 6;51(5):999-1014. doi: 10.1016/j.jpba.2009.11.009. Epub 2009 Nov 13.
Genotoxic impurities (GTIs) in pharmaceuticals at trace levels are of increasing concerns to both pharmaceutical industries and regulatory agencies due to their potentials for human carcinogenesis. Determination of these impurities at ppm levels requires highly sensitive analytical methodologies, which poses tremendous challenges on analytical communities in pharmaceutical R&D. Practical guidance with respect to the analytical determination of diverse classes of GTIs is currently lacking in the literature. This article provides an industrial perspective with regard to the analysis of various structural classes of GTIs that are commonly encountered during chemical development. The recent literatures will be reviewed, and several practical approaches for enhancing analyte detectability developed in recent years will be highlighted. As such, this article is organized into the following main sections: (1) trace analysis toolbox including sample introduction, separation, and detection techniques, as well as several 'general' approaches for enhancing detectability; (2) method development: chemical structure and property-based approaches; (3) method validation considerations; and (4) testing and control strategies in process chemistry. The general approaches for enhancing detection sensitivity to be discussed include chemical derivatization, 'matrix deactivation', and 'coordination ion spray-mass spectrometry'. Leveraging the use of these general approaches in method development greatly facilitates the analysis of poorly detectable or unstable/reactive GTIs. It is the authors' intent to provide a contemporary perspective on method development and validation that can guide analytical scientists in the pharmaceutical industries.
由于具有潜在的人类致癌性，痕量水平的药品中遗传毒性杂质（GTIs）引起了制药行业和监管机构的越来越多的关注。这些杂质在 ppm 水平的测定需要高度灵敏的分析方法，这给制药研发领域的分析界带来了巨大的挑战。目前文献中缺乏关于各种 GTIs 类别的分析测定的实用指南。本文从化学开发过程中常见的各种结构类别的 GTIs 分析角度，提供了工业界的观点。本文将综述近期文献，并重点介绍近年来开发的几种提高分析物检测灵敏度的实用方法。因此，本文主要分为以下几个部分：（1）痕量分析工具箱，包括样品引入、分离和检测技术，以及几种提高检测灵敏度的“通用”方法；（2）方法开发：基于化学结构和性质的方法；（3）方法验证考虑因素；（4）过程化学中的测试和控制策略。讨论的提高检测灵敏度的一般方法包括化学衍生化、“基质失活”和“配位离子喷雾质谱”。在方法开发中利用这些通用方法可以极大地促进对检测困难或不稳定/反应性 GTIs 的分析。本文的目的是提供一种现代的方法开发和验证观点，以指导制药行业的分析科学家。
