N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO₂

Abstract

In 2019, N-nitrosodimethylamine (NDMA) exceeding the maximum allowable intake (96 ng/day) was detected in metformin drug products in Singapore, and since then, many of the drug products have been voluntarily recalled globally for the same reason. In our company, the analysis of the metformin drug products showed that small batches (1.9%) of products contained the excessive level of NDMA, so we investigated the root cause of NDMA formation. As a result, we found that dimethylamine (DMA) in the active pharmaceutical ingredient (API) used in the manufacturing process and nitrogen dioxide (NO 2 ) in the atmosphere had considerable influence on the formation of NDMA in metformin drug products. The results of a model experiment simulating a fluidized bed granulator also supported the hypothesis that atmospheric NO 2 introduced into the granulator Nnitrosated DMA in the API to form NDMA.

Simple and Practical Method for the Quantitative High-Sensitivity Analysis of N-Nitroso Duloxetine in Duloxetine Drug Products Utilizing LC-MS/MS

“…Under such circumstances, we have raised questions about commonly accepted beliefs on NDMA contamination in metformin drug products based on our findings that the amount of NDMA contamination varies among our manufacturing sites, even when the same raw materials were used. We successfully demonstrated the correlation between the concentration of atmospheric NO 2 around our factories and the NDMA content in metformin drug products, 10 suggesting that NO X , an air pollutant, may be closely related to the formation and contamination of NDMA.…”

Risk Assessment Study of Nitrosamines for the API Temozolomide Industrial Process

“…For the determination of the acceptable concentration limit of NDMA in Temozolomide, the acceptable intake was considered and the calculation was established by the regulatory authorities ANVISA, EMA, and FDA. In this case, the acceptable intake for NDMA is 96 ng/day and the treatment duration factor with Temozolomide is 13.3 (for 1 to 12 months of treatment). According to the Melazte leaflet, Temozolomide is administered orally through capsules, and the recommended daily dosage for patients with newly diagnosed high-grade glioma is 75 mg/m 2 , alongside focal radiotherapy, followed by 6 cycles.…”

“…Several batches of the sartan drugs Valsartan, Irbesartan, and Losartan faced a setback because of the detection of N -nitrosamines beyond the acceptable limits and this has greatly affected the market presence of sartans . For example, Valsartan was contaminated with N -nitrosamines ( N -nitrosodimethylamine (NDMA) and N -nitrosodiethylamine (NDEA)), which are probable human carcinogens, leading to a large-scale global recall . The nonsartan drug, pioglitazone, was later discovered to contain specific N -nitrosamine, and in September 2019, low levels of NDMA were found within ranitidine products and, on December of the same year, NDMA was detected in Metformin drug also …”

“…For example, Valsartan was contaminated with N -nitrosamines ( N -nitrosodimethylamine (NDMA) and N -nitrosodiethylamine (NDEA)), which are probable human carcinogens, leading to a large-scale global recall . The nonsartan drug, pioglitazone, was later discovered to contain specific N -nitrosamine, and in September 2019, low levels of NDMA were found within ranitidine products and, on December of the same year, NDMA was detected in Metformin drug also …”

“…In short, N -nitrosamines were detected at worrying levels in other drugs containing APIs such as Sartans, Ranitidine, Metformin, and Nizatidine, which triggered the recall of hundreds of batches of the related drugs from the worldwide market . Furthermore, there was the recall of Chantix (Varenicline) batches in the USA, Canada, and the EU in mid-2021 due to the presence of the N -nitrosamine drug substance-related impurity (NDSRI) Nitrosovarenicline .…”