Risk Evaluation of N-Nitrosamines in Drug-Linker Intermediates Used To Generate Antibody–Drug Conjugates,Organic Process Research & Development

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Risk Evaluation of N-Nitrosamines in Drug-Linker Intermediates Used To Generate Antibody–Drug Conjugates
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-07-25 , DOI: 10.1021/acs.oprd.4c00255
Osama Chahrour ₁ , Paul G. Bulger ₂ , Olivier Dirat ₃ , Kate Schrier ₄ , Andrew T. Parsons ₅ , J. Gair Ford ₆ , Frank Bernardoni ₂ , Evan M. Hetrick ₇ , Llorente R. Bonaga ₈ , Kevin P. Cole ₇ , Joy Miller ₉ , Qunying Zhang ₁₀ , Michael T. Jones ₁₁

Affiliation

Chemical Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield SK10 2NA, U.K.
Department of Analytical Research & Development, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
Pfizer Global Regulatory Sciences, CMC Advisory Office, Sandwich CT13 9NJ, United Kingdom
CMC Regulatory Affairs, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States
Process Development, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States
CMC Regulatory Affairs, AstraZeneca, Macclesfield SK10 2NA, U.K.
Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana 46285, United States
GRACS CMC, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
Analytical Development, Takeda Pharmaceuticals, 200 Shire Way, Lexington, Massachusetts 02421, United States
Analytical Research & Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
Pharmaceutical Sciences, Pfizer Inc., 875 Chesterfield Parkway West, Chesterfield, Missouri 63017, United States

This position study provides a science-based, holistic approach to evaluating the risks of nitrosamine presence in drug-linkers as intermediates toward antibody–drug conjugate (ADC) drug substances. The evaluation of 47 different ADC drug substances, which have a recommended dose available in the public domain, supports the conclusion that the chemically synthesized fragments of ADCs are unlikely to lead to nitrosamine presence in the final drug product. Hence, it can be concluded that for most ADCs there are few nitrosamine risks introduced by the drug-linkers and their impurities. An abbreviated workflow for quality risk management of nitrosamine in drug-linkers is therefore proposed.

中文翻译：

用于生成抗体-药物偶联物的药物连接体中间体中 N-亚硝胺的风险评估

这项立场研究提供了一种基于科学的整体方法来评估药物接头中亚硝胺作为抗体药物偶联物 (ADC) 原料药中间体存在的风险。对 47 种不同 ADC 原料药（在公共领域有推荐剂量）的评估支持了这样的结论：化学合成的 ADC 片段不太可能导致最终药品中出现亚硝胺。因此，可以得出结论，对于大多数 ADC，药物连接体及其杂质引入的亚硝胺风险很少。因此，提出了药物接头中亚硝胺质量风险管理的简化工作流程。

更新日期：2024-07-25

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