Quantitative Analysis of NDMA in Drug Products: A Proposed High-Throughput Approach Using Headspace–SIFT-MS

Abstract

Since the initial 2018 recall of angiotensin receptor blockers due to unacceptable levels of mutagenic N-nitrosodimethylamine (NDMA) impurity, numerous drug products delivering diverse active pharmaceutical ingredients (APIs) have been recalled. Regulators and the industry are working together to understand and address this widescale problem. Conventional analysis of NDMA utilizes liquid or gas chromatography-based procedures that can involve complicated sample preparation and slow sample analysis. Selected ion flow tube mass spectrometry (SIFT-MS) analyses NDMA directly in the gas phase using soft chemical ionization, with an LOQ of 2 ng g−1. Through the novel application of the multiple headspace extraction (MHE) technique, NDMA was quantified directly and rapidly from the drug product without dissolution, at levels well below the regulatory acceptable intake of 96 ng day−1. A comparative analysis of recalled metformin using MHE-SIFT-MS and a conventional liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS) method showed good agreement. Use of the novel MHE-SIFT-MS approach may enable a wider screening of drug products to be conducted, since it provides around a three-fold increase in daily sample throughput.