De Palma Ryan, Patel Vikram, Florian Jeffry, Keire David, Selaya Daniela, Strauss David G, Rouse Rodney, Matta Murali K
Division of Applied Regulatory Science, Office of Clinical Pharmacology, Center for Drugs Evaluation and Research, US Food and Drug Administration, United States.
Office of Testing and Research, Center for Drugs Evaluation and Research, US Food and Drug Administration, United States.
J Pharm Sci. 2023 May;112(5):1315-1323. doi: 10.1016/j.xphs.2023.01.026. Epub 2023 Feb 1.
Control of N-nitrosoamine impurities is important for ensuring the safety of drug products. Findings of nitrosamine impurities in some drug products led FDA to develop new guidance providing recommendations for manufacturers towards prevention and detection of nitrosamine impurities in pharmaceutical products. One of these products, ranitidine, also had a published in vivo study, which has since been retracted by its authors, suggesting a potential for in vivo conversion of ranitidine to the probable human carcinogen, N-nitrosodimethylamine (NDMA). FDA subsequently initiated a randomized, double-blind, placebo-controlled, crossover clinical investigation to assess the potential for in vivo conversion of ranitidine to NDMA with different meals. A bioanalytical method toward characterization of NDMA formation was needed as previously published methods did not address potential NDMA formation after biofluid collection. Therefore, a bioanalytical method was developed and validated as per FDA's Bioanalytical Method Validation guidance. An appropriate surrogate matrix for calibration standards and quality control sample preparation for both liquid matrices (human plasma and urine) was optimized to minimize the artifacts of assay measurements and monitor basal NDMA levels. Interconversion potential of ranitidine to NDMA was monitored during method validation by incorporating the appropriate quality control samples. The validated methods for NDMA were linear from 15.6 pg/mL to 2000 pg/mL. Low sample volumes (2 mL for urine and 1 mL for plasma) made this method suitable for clinical study samples and helped to evaluate the influence of ranitidine administration and meal types on urinary excretion of NDMA in human subjects.
控制亚硝胺杂质对于确保药品安全至关重要。一些药品中发现的亚硝胺杂质促使美国食品药品监督管理局（FDA）制定新的指南，为制造商提供有关预防和检测药品中亚硝胺杂质的建议。其中一种产品雷尼替丁，曾有一项已发表的体内研究，但其作者后来撤回了该研究，该研究表明雷尼替丁在体内可能会转化为可能的人类致癌物N-亚硝基二甲胺（NDMA）。FDA随后启动了一项随机、双盲、安慰剂对照、交叉临床研究，以评估雷尼替丁在不同饮食情况下体内转化为NDMA的可能性。由于先前发表的方法未涉及生物流体采集后潜在的NDMA形成问题，因此需要一种用于表征NDMA形成的生物分析方法。因此，根据FDA的生物分析方法验证指南开发并验证了一种生物分析方法。针对两种液体基质（人血浆和尿液）的校准标准品和质量控制样品制备，优化了合适的替代基质，以尽量减少测定测量的假象并监测基础NDMA水平。在方法验证过程中，通过加入适当的质量控制样品来监测雷尼替丁向NDMA的相互转化潜力。验证后的NDMA方法在15.6 pg/mL至2000 pg/mL范围内呈线性。低样本量（尿液2 mL，血浆1 mL）使该方法适用于临床研究样本，并有助于评估雷尼替丁给药和饮食类型对人体受试者尿液中NDMA排泄的影响。
