Analytical Research & Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
Baertschi Consulting LLC, Carmel, IN 46033, USA.
J Pharm Sci. 2023 Dec;112(12):2948-2964. doi: 10.1016/j.xphs.2023.09.003. Epub 2023 Sep 9.
Forced degradation (i.e., stress testing) of small molecule drug substances and products is a critical part of the drug development process, providing insight into the intrinsic stability of a drug that is foundational to the development and validation of stability-indicating analytical methods. There is a lack of clarity in the scientific literature and regulatory guidance as to what constitutes an "appropriate" endpoint to a set of stress experiments. That is, there is no clear agreement regarding how to determine if a sample has been sufficiently stressed. Notably, it is unclear what represents a suitable justification for declaring a drug substance (DS) or drug product (DP) "stable" to a specific forced degradation condition. To address these concerns and to ensure all pharmaceutically-relevant, potential degradation pathways have been suitably evaluated, we introduce a two-endpoint classification designation supported by experimental data. These two endpoints are 1) a % total degradation target outcome (e.g., for "reactive" drugs) or, 2) a specified amount of stress, even in the absence of any degradation (e.g., for "stable" drugs). These recommended endpoints are based on a review of the scientific literature, regulatory guidance, and a forced degradation data set from ten global pharmaceutical companies. The experimental data set, derived from the Campbell et al. (2022) benchmarking study, provides justification for the recommendations. Herein we provide a single source reference for small molecule DS and DP forced degradation stress conditions and endpoint best practices to support regulatory submissions (e.g., marketing applications). Application of these forced degradation conditions and endpoints, as part of a well-designed, comprehensive and a sufficiently rigorous study plan that includes both the DS and DP, provides comprehensive coverage of pharmaceutically-relevant degradation and avoids unreasonably extreme stress conditions and drastic endpoint recommendations sometimes found in the literature.
强制降解（例如，应力测试）是小分子药物物质和产品开发过程中的关键部分，提供了对药物固有稳定性的深入了解，这是开发和验证稳定性指示分析方法的基础。在科学文献和监管指南中，对于什么构成一组应力实验的“适当”终点存在一定程度的不明确性。也就是说，对于如何确定一个样品是否已经受到足够的应力，没有明确的共识。值得注意的是，对于宣布药物物质（DS）或药物产品（DP）在特定强制降解条件下“稳定”，缺乏合适的理由。为了解决这些问题，并确保所有与药物相关的潜在降解途径都得到适当评估，我们引入了一个由实验数据支持的双终点分类指定。这两个终点是 1）总降解目标百分比（例如，对于“反应性”药物）或 2）指定的应力量，即使没有任何降解（例如，对于“稳定”药物）。这些建议的终点是基于对科学文献、监管指南和来自十家全球制药公司的强制降解数据集的审查。实验数据集源自 Campbell 等人（2022 年）基准研究，为这些建议提供了依据。本文为小分子 DS 和 DP 强制降解应激条件和终点最佳实践提供了单一来源参考，以支持监管提交（例如，营销申请）。这些强制降解条件和终点的应用，作为精心设计、全面和足够严格的研究计划的一部分，该计划包括 DS 和 DP，可以全面涵盖与药物相关的降解，并避免在文献中有时发现的不合理的极端应激条件和剧烈的终点建议。
