International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines

Abstract

Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches. Graphical abstract

Analysis of N‐nitrosodimethylamine in metformin hydrochloride products by high‐resolution accurate mass gas chromatography mass spectrometry

“…Comparatively, both limits are also on a par with the GC-MS/MS methods reported by some official medicines control laboratories in Europe and Canada, which have LOD values ranging from 5 to 10 ng/g. 5 We are aware the method LOD for immediate-release METs should be less than 10 ng/g due to the absence of the gelforming HPMC excipient, which has been reported at 5 ng/g in another study. 12 For operational use, an LOD of 10 ng/g was applied to both MET formulations.…”

“…METs have been used to treat patients with type‐2 diabetes, and are generally prescribed as tablet form (250–1000 mg) in immediate and extended‐release formulations. Based on a recent international collaborative study, 719 out of 875 METs (82.17%) are below the allowed intake (AI) limit of NDMA, 96 ng per day/3000 mg or 32 ng/g active pharmaceutical ingredient (API), whereas 175 METs (17.83%) have been found above the AI, 5 showing a significant variation of NDMA contents found in METs from different parts of the world.…”

“…National regulatory laboratories and pharmaceutical firms have been striving to develop analytical methods for NDMA in METs 5,12 . The main challenge was to develop and validate an analytical method for both immediate‐ and extended‐release METs within the short critical timeline.…”

“…National regulatory laboratories and pharmaceutical firms have been striving to develop analytical methods for NDMA in METs. 5,12 The main challenge was to develop and validate an analytical method for both immediate-and extended-release METs within the short critical timeline. Triple quadrupole mass spectrometers coupled with liquid and gas chromatography (LC-MS/MS and GC-MS/MS) have been preferred due to their exceptional sensitivity at subppb levels, 5,12 achieving the desired limits of detection and quantification (LOD and LOQ) below the AI limit.…”

“…5,12 The main challenge was to develop and validate an analytical method for both immediate-and extended-release METs within the short critical timeline. Triple quadrupole mass spectrometers coupled with liquid and gas chromatography (LC-MS/MS and GC-MS/MS) have been preferred due to their exceptional sensitivity at subppb levels, 5,12 achieving the desired limits of detection and quantification (LOD and LOQ) below the AI limit. Liquid-liquid extraction with the use of an isotopically labelled internal standard has been successfully applied in sample preparation.…”