Quantitation of 6 N-Nitrosamines in Metformin and 5 Sartan APIs as per the EDQM method Procedure C

User Benefits

- EDQM method (Procedure C) applicability for Nitrosamine determination in Metformin in addition to Sartan APIs. - The GCMS-TQ8050 NX with AOC-20i+s Plus system achieves LOQ much lower than the EDQM method (Procedure C) meeting the defined criteria of S/N and recovery.

Introduction

Overview : The Drug Regulatory Authorities first noticed the presence of the N-Nitrosamine impurity (NSA), N- Nitrosodimethylamine (NDMA) in products containing valsartan in July 2018. Valsartan is an Angiotensin II Receptor Blocker (ARB) and belongs to a family of analogue compounds commonly referred to as the Sartans. Similarly, NSA has also been detected in other drug products such as Metformin. Metformin is a prescription drug used to control high blood sugar in patients with Type 2 diabetes. Considering the significance of these drugs, it is crucial to make Sartans and Metformin available with safe levels of NSA. What are NSA? : NSA are organic compounds of the chemical structure R₂N−N=O, where R is usually an alkyl group. These compounds are listed as Class 1 mutagens in ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to limit potential carcinogenic risk. As a result of the significant toxicity associated with these impurities, it is recommended to take steps to control and limit their presence in pharmaceutical materials. Like USFDA, European Directorate for the Quality of Medicines & Healthcare (EDQM) ensure access to good quality medicines in Europe. EDQM has been working actively at various levels to address the presence of Nitrosamines in active substances and medicines. EDQM has been regularly informing all stakeholders, from national authorities to manufacturers, on the state of the works and on initiatives taken. EDQM procedure for NSA: EDQM enlists 3 procedures for determination of NSA viz procedure A, B & C for LCMS/MS, GCMS & GCMS/MS, respectively. Procedures A and B have been validated as limit tests (30 ppb) and procedure C has been validated as a quantitative test. This application note describes analytical procedures for the detection of various N- Nitrosamines in Sartan & Metformin APIs by procedure C. The scope of each procedure is defined in Table 1. With these three procedures, it is possible to analyse the following N- nitrosamines: N-nitroso-dimethylamine (NDMA); N-nitroso- diethylamine (NDEA); N-nitroso-dibutylamine (NDBA); N- nitroso-N-methyl-4-aminobutyric acid (NMBA); N-nitroso- diisopropylamine (NDIPA); N-nitroso-ethyl-isopropylamine (NEIPA) and N-nitroso-dipropylamine (NDPA). Procedure A uses deuterated N-nitroso-diethylamine (NDEA-d10) as internal standard. Procedures B and C use N-nitroso-ethylmethylamine (NEMA) as internal standard. When a procedure is applied to substances outside of the scope covered by the initial validation (Table 1) or to medicinal products or if procedure A or B is used quantitatively, then it must be validated.

December 28, 2021 GMT