Analysis of Nitrosamine Impurities in Ranitidine

N-nitrosodimethylamine (NDMA) has been classified by the International Agency for Research on Cancer (IARC) as a probable human carcinogen even at low exposure levels. Therefore, regulatory agencies, European Medicines Agency (EMA) and U.S. Food and Drugs Administration (FDA) have been closely monitoring the levels of nitrosamine impurities to ensure medicinal products are of acceptable quality and are safe for patients to consume.

A year after the quality concerns over the valsartan crisis in 2018, the pesky NMDA is now causing problems in ranitidine. In 2019, FDA announced that low levels of NDMA was found in samples of some ranitidine medicine, an over-the-counter (OTC) and a H2 (histamine-2) blocker prescription drug, which relieves heartburn by decreasing the amount of acid created by the stomach. This resulted in FDA releasing testing methods to provide options for regulators and industry to detect nitrosamine impurities in ranitidine drug substance and drug product.

In GC-MS testing methods for nitrosamines impurities in ranitidine, N-nitroso-N-methyl-4-aminobutyric acid (NMBA) cannot be directly detected in certain angiotensin II receptor blocker (ARB) drug products. Thus, FDA developed and validated a single HRAM LC-MS method following ICH Q2(R1) that can quantify all six nitrosamine impurities simultaneously. The FDA method utilizes the exceptional acquisition speed, sensitivity, and resolving power of the Thermo Scientific^TM Q Exactive^TM Hybrid Quadrupole-Orbitrap^TM Mass Spectrometer or Q Exactive^TM HF-X Hybrid Quadrupole-Orbitrap^TM Mass Spectrometer system for the determination of these trace level genotoxic impurities.

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