Analytical Sciences Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
J Pharm Sci. 2013 May;102(5):1404-18. doi: 10.1002/jps.23462. Epub 2013 Feb 21.
The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data.
本文介绍了礼来公司为满足欧洲药品管理局和美国食品药品监督管理局关于控制遗传毒性杂质 (GTI) 的要求而实施的策略。这些策略旨在提供有关与开发和上市化合物相关的风险和潜在责任的理解。这些策略系统地评估了杂质的遗传毒性潜力，既考虑了实际杂质，也考虑了潜在杂质。活动的时间安排旨在尽量减少对开发时间表的影响，同时建立足够的数据包，以消除潜在 GTI 形成的风险，或支持实施长期控制所需的规范。本文介绍了与 GTI 控制相关的背景、应评估的杂质类型，以及发现杂质具有遗传毒性时应采取的措施。本文还概述了一种用于定义来自于稳定性研究的潜在降解产物的系统方法，并提出对这些杂质进行遗传毒性风险评估。最后，提出了一种基于阿伦尼乌斯的策略，用于快速评估潜在降解杂质在商业药物产品制剂中形成的可能性。重要的是，本文提出了一种利用支持性数据来降低潜在 GTI 风险的建议。
