Nitrosamine contamination in medicines has sparked concern, triggering recalls and regulatory overhauls. But has theoretical risk been allowed to outweigh practical clinical need in some circumstances? In his latest commentary, Professor Alain Astier explores the science and consequences of the ‘precautionary principle’ in pharmaceutical regulation.
Nitrosamines are a class of chemical compounds formed via nitrosation – the reaction of a nitroso group (–NO) with an amine. This process typically occurs in the presence of nitrosating agents, most notably nitrites.
Nitrites are widespread environmental contaminants, often stemming from agricultural run-off involving nitrate-based fertilisers. These nitrates convert into nitrites, which can leach into groundwater and eventually enter public water supplies. Consequently, nitrosamines are found in various sources including food, drinking water, cosmetics, tobacco smoke and industrial products such as latex and pesticides.
Dietary exposure is especially notable; nitrosamines are frequently produced during the high-temperature cooking of meats and protein-rich foods.
Based on animal studies, nitrosamines are classified as possible human carcinogens.1 Evidence suggests that prolonged exposure to nitrosamines above specific thresholds may elevate cancer risk. However, considering the multitude of environmental and dietary exposure sources, the additional contribution from the trace levels found in medicines is generally regarded as minimal. Therefore, the cancer risk from medicinal exposure alone is considered low.
The ‘sartan’ crisis turning point
Nitrosamine contamination in pharmaceuticals first drew widespread attention in 1977 when Germany’s former Federal Health Agency recommended withdrawing amidopyrine-containing analgesics due to the detection of up to 340 µg/kg of N-nitrosodimethylamine (NDMA) in some active pharmaceutical ingredient (API) batches.2
Subsequent analyses, including a study by Krull et al, found no NDMA contamination among 73 tested products.3 However, further research identified that certain drug substances, particularly those with primary or secondary nitrosatable amine groups, were susceptible to contamination. This included antibiotics such as erythromycin and tetracyclines and other compounds such as imipramine.4
The issue reached crisis point in July 2018 with the discovery of NDMA in certain angiotensin II receptor blockers (ARBs), or sartans, which share a tetrazole ring structure.
A referral procedure known as EMEA/H/A-31/1471 was launched under Article 31 of Directive 2001/83/EC of the European Parliament to evaluate valsartan’s benefit–risk profile.5 This referral was later expanded to include all EU-authorised tetrazole-containing ARBs: losartan, olmesartan, candesartan, irbesartan.6
By early 2019, the European Medicines Agency (EMA) set interim limits for nitrosamines in APIs, allowing a two-year transition before stricter thresholds took effect.7 A similar review was also initiated for ranitidine after NDMA was detected in both the API and the finished product.8
Sources of NDMA contamination
Although the contamination in sartans originated from the synthesis, nitrosamines in other drugs can stem from diverse sources:
- Raw materials: synthesis precursors, intermediates and solvents can contain nitrosamines or their precursors
- Nitrites in materials: present in many raw materials, nitrites can react with amines, which are common in APIs and reagents, to form nitrosamines
- Solvents: chemicals such as dimethylacetamide and dimethylformamide may contain or form nitrosatable amines including dimethylamine and diethylamine
- Water: an often-overlooked contributor, water can contain nitrites or form nitrosamines during chloramine or ozone-based disinfection9
- Excipients and packaging: tablet excipients such as lactose, pregelatinised starch, polyvinylphenol and sodium starch glycolate can carry nitrite residues. Packaging components such as nitrocellulose blister materials combined with certain inks may also promote nitrosamine formation.10
Advanced analytical methods such as liquid chromatography-mass spectrometry now allow the detection of nitrosamines at ultra-trace levels, which has helped uncover these varied contamination pathways.11
Evaluating the risk: what do we really know about nitrosamines?
Despite widespread concern, the actual clinical risk from nitrosamine-contaminated drugs remains unclear. A Danish study found no increase in cancer incidence.12 In contrast, a French epidemiological study based on 1.4 million valsartan users from 2013-17 found no increase in overall cancer risk but observed slightly higher incidences of liver cancer (hazard ratio (HR) 1.12) and melanoma (HR 1.10) among those exposed to NDMA-contaminated valsartan.13 This corresponded to 3.7 and 5.8 additional cases per 100,000 person-years, respectively.
However, the study did not account for external nitrosamine sources such as diet, tobacco or UV exposure, which is especially relevant for melanoma. Furthermore, any direct mechanistic link between ingested nitrosamines and skin cancer remains unclear.
Precaution vs practicality
The ‘precautionary principle’ led to widespread recalls, forcing significant numbers of patients to change or suspend treatments abruptly. While intended to protect public health, such decisions may have inadvertently posed greater risks by disrupting effective therapies.
Stricter regulatory requirements compel manufacturers to alter synthesis pathways, which can be prohibitively expensive, particularly for mature, off-patent drugs. This has led some API suppliers to exit the market, exacerbating drug shortages.14
Furthermore, even revised synthesis methods may not eliminate contamination risks if raw materials, solvents or water are contributing factors.
Given that pharmaceutical-grade solvents are often unavailable due to limited demand, suppliers have little incentive to meet elevated purity standards. The result is a regulatory environment that may inadvertently accelerate the abandonment of essential but low-margin medicines.
Another challenge is determining safe exposure limits. As nitrosamines comprise a large, structurally diverse group of compounds, their individual toxicities vary. The type and amount of nitrosamines present depend on the drug’s chemical structure and synthesis, hence, setting uniform thresholds is difficult. An approach using the total amount of nitrosamine may be more realistic.
Ensuring a balanced approach to nitrosamines
Minimising nitrosamine exposure remains a legitimate and essential goal. The EMA has stated that manufacturing processes must align with the latest scientific knowledge, requiring marketing authorisation holders to mitigate nitrosamine contamination wherever feasible.15
However, the escalating regulatory burden, particularly on mature drugs, demands reassessment. Excessively rigid implementation of the precautionary principle without considering economic feasibility and clinical necessity may worsen drug shortages and undermine patient care.
Conclusion
As healthcare professionals, our foremost obligation is to ensure that our patients continue receiving effective, essential therapies. This imperative must be carefully balanced against theoretical risks from trace contaminants.
The potential long-term harm from drug shortages and treatment interruptions may be more immediate than the risks posed by ultra-low levels of nitrosamines. Regulatory vigilance is vital alongside further epidemiological research and refined risk models to guide balanced, science-based decisions.
Author
Alain Astier PharmD PhD
Honorary head of the Department of Pharmacy, Henri Mondor University Hospital, and French Academy of Pharmacy, Paris, France
References
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5 EMEA/H/A-31/1471. EC decision number (2019) 2698 of 02 Apr 2019. Referral under Article 31 of Directive 2001/83/EC angiotensin-II-receptor antagonists (sartans) containing a tetrazole group.
6 EMA/351053/2019 rev 1. Temporary interim limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines.
7 EMEA/H/A-31/1491. EMA Referral under Article 31 of Directive 2001/83/EC.
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13 Mansouri I et al. N‐nitrosodimethylamine-Contaminated Valsartan and Risk of Cancer: A Nationwide Study of 1.4 million Valsartan Users. Am Heart Assoc 2022;11:e8067.
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15 European Medicines Agency. Article 23 and Annex I of Directive 2001/83/EC and Article 16 of Regulation (EC) No 726/2004.
