告诫故事：二甲双胍中N-亚硝基二甲胺的定量LC-HRMS分析程序。,The AAPS Journal

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告诫故事：二甲双胍中N-亚硝基二甲胺的定量LC-HRMS分析程序。
The AAPS Journal ( IF 5.0 ) Pub Date : 2020-07-01 , DOI: 10.1208/s12248-020-00473-w
Jingyue Yang ₁ , Tim Andres Marzan ₁ , Wei Ye ₁ , Cynthia D Sommers ₁ , Jason D Rodriguez ₁ , David A Keire ₁

Affiliation

一家私人测试实验室在FDA的公民请愿书（CP）中报告说，他们测试的38种二甲双胍药品中，有16种的N-亚硝基二甲基胺（NDMA）含量超过了96 ng /天的允许摄入量（AI）。由于FDA一直在监测亚硝胺的药物，因此已经开发，验证并应用了正交分析程序来检测二甲双胍药品中的以下亚硝胺（如果存在）：（i）NDMA（采用专用方法）或（ii）NDMA（（使用第二种确认方法），N-亚硝基二乙胺（NDEA），N-乙基-N-亚硝基-2-丙胺（NEIPA），N-亚硝基二异丙胺（NDIPA），N-亚硝基二正丙基胺（ NDPA），N-亚硝基-甲基苯基胺（NMPA），N-亚硝基-二正丁基胺（NDBA）和N-亚硝基-N-甲基-4-氨基丁酸（NMBA）。与私人实验室的结果相反，FDA用正交程序对同一组38个样品进行的FDA测试发现，在38种产品中，只有8种产品的AI含量高于AI，并且通常观察到的值低于私人测试实验室的报告。如此处所述，对差异原因进行的调查显示，N，N-二甲基甲酰胺（DMF）可能会干扰NDMA测量。数据表明，在数据提取过程中使用足够的质量准确度以及在数据处理中使用适当的质量公差设置以确保在共洗脱DMF的情况下对NDMA进行质谱测量的选择性对于防止过高估计DMF的水平是必要的。二甲双胍药品中的NDMA。总体而言，应注意确保在分析程序中具有必要的特异性，以便对也含有DMF或其他潜在干扰物质的药品中的亚硝胺水平进行充分评估。

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A Cautionary Tale: Quantitative LC-HRMS Analytical Procedures for the Analysis of N-Nitrosodimethylamine in Metformin.

A private testing laboratory reported in a Citizen Petition (CP) to FDA that 16 of 38 metformin drug products they tested had N-nitrosodimethyl amine (NDMA) amounts above the allowable intake (AI) of 96 ng/day. Because the FDA had been monitoring drugs for nitrosamines, orthogonal analytical procedures had been developed, validated and applied to detect the following nitrosamines in metformin drug products (if present): (i) NDMA (with a dedicated method) or (ii) NDMA (with a second confirmatory method), N-nitroso-diethylamine (NDEA), N-ethyl-N-nitroso-2-propanamine (NEIPA), N-nitroso-diisopropylamine (NDIPA), N-nitroso-di-n-propylamine (NDPA), N-nitroso-methylphenylamine (NMPA), N-nitroso-di-n-butylamine (NDBA) and N-nitroso-N-methyl-4-aminobutyric acid (NMBA). In contrast to the private laboratory results, FDA testing on the same set of 38 samples with orthogonal procedures observed amounts over the AI in only 8 of the 38 products and generally observed lower values than reported by the private testing laboratory. As described here, the investigation into the cause of the discrepancy revealed that N,N-dimethylformamide (DMF) can interfere with NDMA measurements. The data showed that the use of sufficient mass accuracy in the data acquisition and appropriate mass tolerance setting in the data processing to assure the selectivity of mass spectrometry measurements of NDMA in the presence of co-eluting DMF was necessary to prevent overestimation of the level of NDMA in metformin drug products. Overall, care should be taken to assure the necessary specificity in analytical procedures for adequate assessment of the nitrosamine level in drug products that also contain DMF or other potential interfering substances.

更新日期：2020-07-01

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