The Nitrosamine puzzle: What We Learned in the Last Five Years

The Nitrosamine Puzzle: What We Learned in the Last Five Years

Unraveling the Nitrosamine Puzzle: A Brief Overview

The Nitrosamine (NA) issue, often termed the “Saga,” has been a focal point of attention for both the pharmaceutical sector and regulatory entities over the past half-decade. And this also has been discussed very well in the recent article in OPRD. This intricate puzzle began unfolding in 2018 when N-nitrosodimethylamine (NDMA) was detected in valsartan. As if unraveling a mystery, subsequent discoveries of NDMA in other pharmaceutical components, including piaglitazone, ranitidine, and metformin, added layers to the complexity. The situation escalated with the 2021 recall of Chantix (varenicline) due to the presence of a nitrosamine drug-substance-related impurity (NDSRI) named nitrosovarenicline. This significant development was quickly succeeded by recalls of other medications, such as propranolol, quinapril, and orphenadrine, each associated with their specific NDSRIs. This revelation was soon followed by recalls of other medications, such as propranolol, quinapril, and orphenadrine, each linked to their specific NDSRIs.

Nitrosamines on Our Plates: A Glimpse Beyond Pharmaceuticals

For ages, nitrosamines have silently nestled in various food sources. Recent scholarly endeavors have spotlighted that certain food categories, notably fats, oils, sweets, meats, fish, and vegetables, are teeming with the highest total NA content. NDMA, one of the most prominent NAs, suggests a daily intake that might exceed 2 µg/day from an average diet. Moreover, indulging in beer or other malt beverages could add an extra 1 µg/day to this exposure. The vigilant European Food Safety Authority (EFSA) has meticulously assessed the potential risks tied to NAs in our food, focusing on ten carcinogenic NAs.

The Indispensable Role of Secondary Amines: A Pharmaceutical Perspective

In pharmaceuticals, secondary amines are pivotal players in the synthesis of active pharmaceutical ingredients (APIs). Their unparalleled properties render them indispensable. However, under certain conditions, these very amines can pave the way for the formation of NAs in drug concoctions. While the scientific community is ardently striving to curtail nitrite levels, entirely thwarting the formation of NAs remains a Herculean task. The pharmaceutical vanguard remains unwavering in its commitment to safeguarding the medicines it dispenses. When genuine safety alarms ring, decisive actions, even as stern as product recalls, stand ready to be executed.

The Silent Exposure: Nitrosamines Within Us

Beyond the external sources like food and medicines, there’s a silent, endogenous exposure to NAs that often goes unnoticed. The human gastrointestinal (GI) tract, a site enriched with nitrate and nitrite from our diets, emerges as a significant crucible for endogenous NA genesis. Certain biogenic amines, notably spermidine and putrescine, have been spotlighted as precursors of specific volatile nitrosamines. The magnitude of this endogenous exposure is nothing short of astonishing. Some scholarly estimates even posit that it might overshadow external exposure, relegating the contribution from pharmaceuticals to a mere footnote in the grand narrative.


The Nitrosamine conundrum has illuminated the pharmaceutical landscape’s intricate challenges in its quest for medicinal safety. As the industry and regulatory torchbearers collaboratively navigate this labyrinth, it’s paramount to fathom the broader tapestry of NA exposure, encompassing both external and internal realms. The unwavering allegiance to patient safety remains the North Star, guiding relentless endeavors to sculpt effective and pragmatic NA control blueprints.

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