NDMA Formation Due to Active Ingredient Degradation and Nitrite Traces in Drug Product

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

“…As mentioned above, NDMA did not increase when the drug product was stored in the PTP sheet under the stability study conditions. Since there have been several reports of increased NDMA in stability tests of metformin drug products with nitrite-containing excipients, ,, we believe that the effect of the excipients was small in our case. In addition, despite the fact that the factories of Osaka and Yamagata manufactured the product under similar conditions using excipients from the same manufacturer, the product formulated at the Yamagata factory did not contain high levels of NDMA.…”

“…19 In the United States, 17 different drug manufacturers had recalled a total of 283 batches of metformin by January 2023. 20 NDMA contamination of metformin has a significant impact on both patients and drug manufacturers. Pharmaceutical companies searched for the root cause to avoid NDMA contamination 21,22 and have reported that nitrite in excipients, 23−25 nitrite in water used in manufacturing, 26 and nitrocellulose in packaging materials 27 may be nitrosating agents.…”

“…NDMA contamination of metformin has a significant impact on both patients and drug manufacturers. Pharmaceutical companies searched for the root cause to avoid NDMA contamination , and have reported that nitrite in excipients, − nitrite in water used in manufacturing, and nitrocellulose in packaging materials may be nitrosating agents. The conditions for the formation of nitroso amines have also been studied and reported. − …”

Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies

“…36 While it is demonstrated that the NDSRI formation due to secondary amine degradants is considerably less problematic than for secondary amine drug substances due to the lower secondary amine concentration, 25 information provided to EU regulators suggests that active substances containing tertiary amides are still at risk of N-nitrosamine formation, particularly when the amine degradant is a lowmolecular weight, volatile, and hence highly mobile compound. 44 Finally, peroxides could be directly involved in the formation of N-nitrosamines by oxidative processes in drug (degradant) molecules that bear a hydrazine or hydrazone moiety (e.g., gliclazide, rifampicin). 47,48…”

“…We refer again to the demonstrated examples of ranitidine and nizatidine. However, tertiary amines with at least one (hetero)­benzylic-type/allylic substituent might also be at risk. While the evidence so far relates to ranitidine and nizatidine, a more general possibility is the peroxide-promoted hydrolysis of tertiary amide bonds, a structural motif that is very common in drug substances, to afford secondary amines.…”