LC-MS/MS method for the quantification of 10 nitrosamine impurities in metformin

Introduction

Since 2018, multiple batches of drug products, including angiotensin receptor blockers1 (ARBs) and the histamine blocker ranitidine2 (commonly known as Zantac™), have been recalled due to the presence of nitrosamines at unacceptable amounts. Scientists at the Center for Drug Evaluation and Research (CDER) division of the U.S. Food and Drug Administration (FDA) have published multiple methods to test these products for the presence of nitrosamines, including gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-MS (LC-MS) technologies. These methods are specific for detecting and quantifying up to eight different nitrosamines in these drug products, even if present at amounts well below the allowable intake level. The FDA was notified by international regulators of the presence of nitrosamines, particularly N-nitrosodimethylamine (NDMA) in metformin3, a biguanides drug product and the first-line medication for the treatment of type 2 diabetes. Using the expertise gained in detecting nitrosamines in other products (e.g., ARBs and ranitidine), the FDA developed and validated two different and complementary methods to test for multiple nitrosamines in metformin products.