Nitrosamines, or more formally N-Nitrosamines, are organic substances having the chemical formula R2N=O, where R is often an alkyl group.10 They contain a Nitroso group (NO+) coupled to a deprotonated amine.11 Over a generation back, the chemical literature published the first characterization of a class of chemicals named nitrosamines. Since diethyl amine hydrochloride and sodium nitrite were combined to produce Nitrosodiethylamine (NDEA), nitrosamines have been well known. However, until 1954, the scientific community paid little attention to these chemicals.12 When two cases of liver cirrhosis among three persons working in a research facility at an industrial company where NDMA (N-Nitroso Dimethyl Amine) had been introduced as a solvent first appeared that year, John Barnes and Peter Magee reported that the compound had hepatotoxic effects. The hepato-carcinogenicity of NDMA in rats was also discovered a few years later, in 1956, by Barnes and Magee.13

The toxicity of N-Nitroso compounds attracted a tons of attention after it was discovered that NDMA was carcinogenic.13–15 The oral cavity, esophagus, stomach, urinary bladder, and brain are the most popular targets where tumors are formed in animals. Since NDMA was detected in some few valsartan products made in China in July 2018, pharma manufacturers and the FDA have been grappling with the issue of contamination with NDMA and related nitrosamine chemicals. Later, the recalls included losartan and irbesartan as additional ARBs (Angiotensin II receptor antagonists). In order to prevent the introduction of nitrosamines into these agents, the agency has been collaborating with manufacturers. Certain production procedures were deemed to be at fault. Angiotensin II Receptor Antagonists (ARBs), which include sartans like candesartan, irbesartan, losartan, olmesartan and valsartan, are being tested for the presence of NDMA. Patients with hypertension, as well as those with specific cardiac or renal conditions, are treated with these medications. When liver abnormalities were noticed in a variety of farm animals that had taken feeds containing herring that had been preserved by the addition of high amounts of sodium nitrite in the early 1960s, nitrosamines became a new topic of worry. It was possible to isolate and identify the harmful chemical in the diet as NDMA. The existence of that contaminant was later determined to be the consequence of an interaction between dimethylamine, an amine that naturally occurs in fish, and even a nitrosating agent created from sodium nitrite. As a result, scientists started to investigate if nitrosamines could also be present in food for humans. They then started to measure the levels of nitrosamines in the human food supply, which revealed that a number of different meals included some quantity of these contaminants. Tetrazole, a particular ring structure of these ARBs, has the potential to produce nitrosamine impurities during production. When particular reactions occur during the synthesis of ARBs, nitrosamines can emerge. The FDA had publicly revealed the procedure for checking ARBs against nitrosamine contaminants in the APIs, like valsartan, which has been the source of recalls and inquiries since 2018. However, the FDA has continuously exaggerated the risk that the contamination causes to the patients, citing studies that indicated a minimal to no increase in cancer risk. Nevertheless, ARB continued to issue additional recalls until 2019. Impurities containing nitrosamine have recently been observed in products containing pioglitazone and ranitidine.16

Ranitidine is a recent medication molecule that the FDA is closely monitoring for patient safety due to the high amounts of NDMA. According to the US Regulatory update from October 2, 2019, ranitidine formulations produced very high amounts of NDMA when tested at higher temperatures using a test method modified by a third-party laboratory. Ranitidine samples have so far tested positive for unacceptable amounts of NDMA in the agency’s preliminary, constrained testing. The FDA stated in its announcement of the ranitidine contamination that it was still assessing the degree of patient risk.16