Highly sensitive and robust LC-MS/MS solution for quantitation of nitrosamine impurities in metformin drug products

Application benefits

•  Detection and quantitation of 10 nitrosamines with a single liquid chromatography triple quadrupole selected reaction monitoring mass spectrometry (LC-SRM-MS) method using both heated electrospray ionization (HESI) and atmospheric pressure chemical ionization (APCI)
•  Quantitation of nitrosamine impurities in metformin drug product below the daily acceptable intake level, meeting both European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) regulatory guidelines
•  Reproducible and accurate quantitative method suitable for routine screening of nitrosamine impurities in drug products
•  Use of the Thermo Scientific™ Chromeleon™ Chromatography Data System (CDS) for both data collection and processing in compliant environments with full data integrity and security capabilities for cGMP facilities, including 21 CFR part 11

Goal

To demonstrate robust and sensitive quantitation of 10 nitrosamines with a Thermo Scientific™ TSQ Quantis™ mass spectrometer, and the use of the LC-SRM-MS method to quantify nitrosamine impurities in metformin drug products.

Introduction

Nitrosamine contaminations in drug products

After the discovery of unacceptable levels of nitrosamine contaminations in certain drug products over the last two years, regulatory agencies around the world have mandated stringent guidelines and analytical testing of all pharmaceuticals, especially for chemically synthesized ones, to control and limit the level of these genotoxic impurities in drugs.^1-3 To ensure patient health and safety, and quality of these drugs, international regulators have set acceptable daily intake (AI) limits, and a total nitrosamine content of less than 30 ppb, based on the daily dose of the drug substance considering different strength availability of drug products.^2,3 Given these low AI limits, pharmaceutical manufacturers have to develop highly selective and sensitive methods for both the active pharmaceutical ingredients and finished drug products to meet the requirement, and to enable control of nitrosamine impurities within their supply chains.