Early clinical drug product shelf-life setting using accelerated predictive stability and metabolite data for impurity qualification: A case study

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-11-01 DOI:10.1016/j.xphs.2024.08.010
Jenny E. Ottosson , Angela Ku , Magnus Fransson , Carina Leandersson , Lars Weidolf , Jufang Wu Ludvigsson , Magnus Klarqvist
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Abstract

This case study demonstrates how knowledge of degradation products together with predictions can establish a lean stability strategy using the accelerated predictive stability (APS) principles. Applying all available data for AZD4831, (R)-1-(2-(1-aminoethyl)-4-chlorobenzyl)-2-thioxo-2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidin-4(5H)-one, a reliable predictive model was developed despite minor differences in technical batch tablet compositions. Early forced degradation studies were performed to map potential degradation pathways. The insights from these studies guided the design of an APS study, which in turn inform on a suitable clinical stability program, initial specification and shelf-life. The use of APS predictions of degradants as well as total impurities highlighted at an early stage, when designing the clinical stability program, the opportunity to identify which degradation product that would be shelf-life limiting. Hence, it was possible to guide the development stability activities and set an initial shelf-life of a tablet formulation. The presented study displays the importance of combining several sources of information in drug development, e.g., potential degradation pathways, accelerated stability, stability program design, metabolite data, and specification limits.

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利用加速预测稳定性和代谢物数据进行杂质鉴定,确定早期临床药物产品的保质期:案例研究。
本案例研究展示了降解产物知识和预测如何利用加速预测稳定性(APS)原理建立精益稳定性策略。应用 AZD4831((R)-1-(2-(1-氨基乙基)-4-氯苄基)-2-硫酮-2,3-二氢-1H-吡咯并[3,2-d]嘧啶-4(5H)-酮)的所有可用数据,建立了一个可靠的预测模型,尽管技术批次片剂成分略有不同。为绘制潜在降解途径图,进行了早期强制降解研究。这些研究为 APS 研究的设计提供了指导,而 APS 研究又为合适的临床稳定性计划、初始规格和保质期提供了信息。在设计临床稳定性方案的早期阶段,使用 APS 预测降解剂和杂质总量,可以确定哪种降解产物会对货架期产生限制。因此,有可能指导开发稳定性活动并设定片剂制剂的初始保质期。本研究显示了在药物开发过程中结合多种信息来源的重要性,例如潜在降解途径、加速稳定性、稳定性方案设计、代谢物数据和规格限值。
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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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