A New Analytical LC-MS/MS Method for Determination of Eight Standard Nitrosamines (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, NDBA) in a Commercial Small Molecule Drug Product Capsules and its Active Pharmaeceutical Ingredient for Treatment of Fabry: A Rare Disease.

IF 3.5 3区医学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Pharmaceutical Research Pub Date : 2025-06-17 DOI:10.1007/s11095-025-03875-7

Krishnaiah Charagondla, Partha S Mukherjee, Kalyani Ginjupalli, Bing Hu, Simrat Kaur, Paresh Thanki, Tejas Tailor, Bhavin Prajapati, Saroj Ramdas

{"title":"A New Analytical LC-MS/MS Method for Determination of Eight Standard Nitrosamines (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, NDBA) in a Commercial Small Molecule Drug Product Capsules and its Active Pharmaeceutical Ingredient for Treatment of Fabry: A Rare Disease.","authors":"Krishnaiah Charagondla, Partha S Mukherjee, Kalyani Ginjupalli, Bing Hu, Simrat Kaur, Paresh Thanki, Tejas Tailor, Bhavin Prajapati, Saroj Ramdas","doi":"10.1007/s11095-025-03875-7","DOIUrl":null,"url":null,"abstract":"Purpose: This study aims to develop and validate a highly sensitive LC-MS/MS method for quantifying eight nitrosamine (NA) impurities NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA in a small molecule commercial Active Pharmaceutical Ingredients (API) and Drug Product (DP) capsules used for the treatment of Fabry rare disease in global patients.Methods: The method utilized gradient separation on a C18 column, ensuring optimum resolution between NAs and internal standards. Elution was monitored at precursor and product ions. The method was validated according to ICH Q2 (R1) guidelines, assessing specificity, linearity, recovery, and repeatability in both API and capsule matrices.Results: Quantification of NAs ranged from 0.0215 to 0.780 ppm in relation to a 20.5 mg/mL sample concentration. Linearity coefficients ranged from 0.99 to 1.00. The Detection Limit (DL) was 0.154-0.560 ng/mL, and the Quantitation Limit (QL) was 0.438-1.590 ng/mL. Mean recoveries for all NAs were between 90 and 107%, and repeatability was under 15%. An Analytical Target Profile (ATP) concept was successfully employed to monitor Analytical Method Performance Characteristics (AMPC).Conclusions: The validated LC-MS/MS method proved effective for quantifying NAs (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA) in both API and capsule matrices, with results consistently below the Quantitation Limit (QL) in confirmatory testing. This approach supports the elimination of routine NA testing, adhering to FDA and EMA's conservative Acceptable Intake (AI) limits, ensuring safety and regulatory compliance for global patients.","PeriodicalId":20027,"journal":{"name":"Pharmaceutical Research","volume":" ","pages":""},"PeriodicalIF":3.5000,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmaceutical Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11095-025-03875-7","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose: This study aims to develop and validate a highly sensitive LC-MS/MS method for quantifying eight nitrosamine (NA) impurities NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA in a small molecule commercial Active Pharmaceutical Ingredients (API) and Drug Product (DP) capsules used for the treatment of Fabry rare disease in global patients.

Methods: The method utilized gradient separation on a C18 column, ensuring optimum resolution between NAs and internal standards. Elution was monitored at precursor and product ions. The method was validated according to ICH Q2 (R1) guidelines, assessing specificity, linearity, recovery, and repeatability in both API and capsule matrices.

Results: Quantification of NAs ranged from 0.0215 to 0.780 ppm in relation to a 20.5 mg/mL sample concentration. Linearity coefficients ranged from 0.99 to 1.00. The Detection Limit (DL) was 0.154-0.560 ng/mL, and the Quantitation Limit (QL) was 0.438-1.590 ng/mL. Mean recoveries for all NAs were between 90 and 107%, and repeatability was under 15%. An Analytical Target Profile (ATP) concept was successfully employed to monitor Analytical Method Performance Characteristics (AMPC).

Conclusions: The validated LC-MS/MS method proved effective for quantifying NAs (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA) in both API and capsule matrices, with results consistently below the Quantitation Limit (QL) in confirmatory testing. This approach supports the elimination of routine NA testing, adhering to FDA and EMA's conservative Acceptable Intake (AI) limits, ensuring safety and regulatory compliance for global patients.

查看原文本刊更多论文

一种新的LC-MS/MS分析方法测定治疗罕见病法布里病市产小分子制剂胶囊中8种标准亚硝胺（NDMA、NMBA、NDEA、NEIPA、NDIPA、NMPA、NDPA、NDBA）及其活性成分

目的：本研究旨在建立并验证一种高灵敏度的LC-MS/MS方法，用于定量全球用于治疗法布里罕见病的小分子商业活性药物成分（API）和药物制品（DP）胶囊中8种亚硝胺（NA）杂质NDMA、NMBA、NDEA、NEIPA、NDIPA、NMPA、NDPA和NDBA。方法：采用C18色谱柱梯度分离，保证了NAs与内标之间的最佳分离。监测前体离子和产物离子的洗脱情况。根据ICH Q2 （R1）指南对该方法进行验证，评估原料药和胶囊基质的特异性、线性、回收率和可重复性。结果：相对于20.5 mg/mL的样品浓度，NAs的定量范围为0.0215 ~ 0.780 ppm。线性系数范围为0.99 ~ 1.00。检测限（DL）为0.154 ~ 0.560 ng/mL，定量限（QL）为0.438 ~ 1.590 ng/mL。所有NAs的平均回收率在90 ~ 107%之间，重复性低于15%。分析目标轮廓（ATP）的概念被成功地用于监测分析方法性能特征（AMPC）。结论：经验证的LC-MS/MS方法可有效定量测定原料药和胶囊基质中的NAs (NDMA、NMBA、NDEA、NEIPA、NDIPA、NMPA、NDPA和NDBA)，验证试验结果均低于定量限（QL）。该方法支持消除常规NA检测，遵守FDA和EMA的保守可接受摄入量（AI）限制，确保全球患者的安全性和法规合规性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pharmaceutical Research 医学-化学综合

CiteScore

6.60

自引率

5.40%

发文量

276

审稿时长

3.4 months

期刊介绍： Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to: -(pre)formulation engineering and processing- computational biopharmaceutics- drug delivery and targeting- molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)- pharmacokinetics, pharmacodynamics and pharmacogenetics. Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.