Quantitation of NDMA and NDEA in Metformin and 5 SartanAPIs as per the EDQM method Procedure B

User Benefits

- This application note demonstrates applicability of EDQM method (Procedure B) for Metformin in addition to Sartan APIs. - The GCMS-QP2020 NX with AOC-30i system achieves LOQ lower than the EDQM method (Procedure B) 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. Like USFDA, European Directorate for the Quality of Medicines and 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 and C for LC-MS/MS, GC-MS and GC-MS/MS, respectively. Procedures A and B have been validated as limit tests (30 ppb) with recovery demonstrated at limit level. The procedure C has been validated as a quantitative test wherein a three-point calibration is plotted with recovery performed at limit level (30 ppb). This application news describes analytical procedures for the detection of 2 commonly found N-Nitrosamines namely N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) in Sartan and Metformin APIs by procedure B. The procedure B further describes 2 sample preparations procedures namely sample preparation 1 and 2. The sample preparation 1 is used for Valsartan, Losartan and Olmesartan additionally Metformin API is also analysed with this method. The sample preparation 2 is used for Candesartan and Irbesartan. When a procedure is applied to substances outside of the scope covered by the initial validation or to medicinal products or if procedure A or B is used quantitatively, then it must be validated.

February 9, 2023 GMT