Nitrosamine Impurities: Sources and Control

Abstract

In June 2018, FDA was informed of the presence of an impurity identified as N-nitrosodimethylamine (NDMA) in the angiotensin II receptor blockers (ARB) valsartan. Through investigation, the Agency determined that numerous lots of valsartan and a few other ARB drug products from different manufacturers contained unacceptable levels of nitrosamines. The drug product manufacturers voluntarily recalled the affected batches of these drug products.

In September 2019, FDA learned that some common heartburn products (ranitidine, commonly known as Zantac, and nizatidine, commonly known as Axid) contained unacceptable levels of NDMA. FDA recommended that manufacturers voluntarily recall ranitidine and nizatidine products with NDMA levels above what the Agency considers acceptable. FDA’s testing suggests that NDMA levels increase with storage time. On April 1, 2020, FDA requested that all ranitidine products be withdrawn from the U.S. market.

In May 2020, FDA testing revealed that certain lots of metformin extended-release formulation contained NDMA above the Agency’s recommended acceptable intake limit. Based on that testing, FDA requested that identified applicants voluntarily recall these lots of the extended-release metformin.

FDA and other regulatory authorities have partnered to share information and to develop guidelines to mitigate the risk of nitrosamine impurities in drug products.

In this article, sources of nitrosamine and mitigation measures are discussed based on regulatory guidelines.