Deputy Direct CDER/OPQ/OTR US Food and Drug Administration Silver Spring, Maryland
NDMA and other nitrosamines are common contaminants in low amounts in foods and beverages, cosmetics, water, tobacco products and consumer goods. More recently, in 2018 observations of NDMA and NDEA in angiotensin receptor blocker drugs (ARBs) led to recalls of batches of products which had unacceptable amounts of nitrosamines. Since the ARB nitrosamine impurities were discovered, there have been additional drugs found to contain nitrosamines in the parts-per-million to parts-per-billion range (e.g., ranitidine in 2019 or metformin in 2020(7)) each with unique properties in terms of the route and source of their presence. Key to detection of nitrosamines in each drug is the application of appropriate measurement technology focused on detecting low nanogram amounts of nitrosamines in solvents, intermediates, APIs and finished dosage forms. The risk in each unique manufacturing process, supply chain and drug product characteristics should be assessed early on in development. If a risk exists (e.g., a process that brings nitrite and secondary amines together under acidic conditions), then suitable testing to assure that their is minimal nitrosamine formation or maximal process nitrosamine purging capacity to minimize nitrosamines in the finished dosage forms that patients would be exposed to. Care should be taken to assess the potential for supply chains, finished dosage form manufacturing or packaging steps or drug product degradation over time to lead to contaminated with these impurities above acceptable intake amounts.
Define why nitrosamines at ppm or ppb amounts must be closely monitored and controlled in drug products.
Discuss what conditions can lead to the risk for nitrosamine formation.
Explore the lessons learned in the past two years of the discovery of nitrosamines in drugs.