Nitrosamines in Medicines: From Risk to Control

Why nitrosamines remain a critical issue

The presence of nitrosamines in medicines has been a major concern since the first recalls in 2018. These compounds are classified as probable human carcinogens, and even trace amounts can raise questions about patient safety. Regulators across the world, including the European Medicines Agency and the Food and Drug Administration, have issued strict guidance to control the presence of nitrosamine impurities in both active substances and finished products (European Medicines Agency, 2025; U.S. Food and Drug Administration, 2023).

The issue is not limited to one therapeutic class. It spans small molecules, complex generics, and even some biological products. The challenge lies in the many possible routes for nitrosamine formation during synthesis, formulation, packaging, and storage. These risks demand a structured, science-based approach that covers the entire product lifecycle.

Regulatory expectations and acceptable intake limits

Authorities have set acceptable intake limits for individual nitrosamines based on lifetime cancer risk models. These limits are extremely low, often in the nanogram per day range. For example, the AI for N-nitrosodimethylamine (NDMA) is 96 ng/day for chronic exposure. When nitrosamine levels exceed these thresholds, companies must act quickly to protect patients and maintain compliance (European Medicines Agency, 2025).

The EMA and the FDA both require marketing authorisation holders to perform risk assessments, confirmatory testing, and implement corrective actions. These steps are not one-off exercises. They form part of a continuous monitoring process because new information, new suppliers, or changes in manufacturing can alter the risk profile.

How nitrosamines enter the picture

Understanding the chemistry is key. Nitrosamine formation often involves secondary or tertiary amines reacting with nitrosating agents such as nitrite under acidic conditions. This can happen in the API synthesis route, during recovery of solvents, or through contaminated raw materials.

Excipients can also contribute. Some contain trace nitrite, which can react with amines in the formulation. Packaging is another source. Certain lidding foils, inks, and adhesives may release nitrite or nitrogen oxides into the headspace of a sealed pack.

Even storage conditions matter. Heat and humidity can accelerate reactions that create nitrosamine impurities over time.

A structured approach to risk assessment

The first step is a thorough risk evaluation. Map every plausible pathway for nitrosamine formation across the manufacturing process and supply chain.

Consider starting materials, reagents, catalysts, and recycled solvents. Review excipient specifications for nitrite content. Audit packaging components for potential migration.

Once the map is complete, prioritise scenarios by likelihood and patient exposure. High-risk cases move to confirmatory testing. This testing must use sensitive and selective methods. For volatile nitrosamines like NDMA, GC–MS with headspace sampling is common.

For non-volatile species, LC–HRMS or LC–MS/MS is preferred. Detection limits should be well below the AI to provide confidence in results.

Controlling nitrosamine levels in practice

When testing confirms the presence of nitrosamines, companies must act. The most effective strategy is to remove the root cause.

This could mean switching to low-nitrite excipients, tightening pH control, or replacing a reagent. In some cases, adding scavengers or antioxidants can help. Packaging changes may also be necessary, such as moving to foils with proven low migration.

Process adjustments should be documented and justified with data. Each change must show a measurable reduction in nitrosamine levels. End-product testing alone is not enough. Regulators expect a control strategy that prevents formation rather than relying on detection after the fact.

Risk does not end after implementation. Companies must trend results over time to confirm that controls remain effective. This includes routine testing of high-risk products, periodic checks on excipient lots, and monitoring of packaging suppliers. Trending helps detect early signals of drift and supports decisions on shelf-life or storage conditions.

The EMA’s Q&A guidance stresses that marketing authorisation holders remain responsible for ongoing vigilance. The FDA echoes this in its updates, reminding firms that presence of nitrosamine impurities can occur even after years on the market if processes or materials change (European Medicines Agency, 2025; U.S. Food and Drug Administration, 2023).

Documentation that stands up to inspection

Regulators expect clear, concise evidence. Keep three core files ready:

A live risk assessment with dates and rationales.
Analytical reports with method details, validation data, and raw results.
A control strategy that links each mitigation to its effect on nitrosamine levels.

When acceptable intake limits cannot be met immediately, companies may apply for temporary measures under less-than-lifetime exposure principles. These cases require strong justification and a clear timeline for corrective action.

Common pitfalls to avoid

One frequent error is assuming that absence of nitrite equals zero risk. Trace amounts can vary between lots and still drive nitrosamine formation under the right conditions. Another mistake is overlooking packaging.

Migration from foils or inks has caused several confirmed cases. Finally, some firms treat the initial assessment as a one-time task. In reality, this is a lifecycle obligation that demands periodic review.

Why this matters for global compliance

Both EMA and FDA align on the fundamentals: science-based risk assessment, sensitive testing, and proactive control. Other agencies, supported by the World Health Organization, follow similar principles to protect patients worldwide. For companies, this means a harmonised approach can satisfy multiple markets and reduce duplication. For patients, it means safer medicines and fewer recalls.

How TechnoLynx can help

TechnoLynx works with pharmaceutical companies to design and implement robust nitrosamine control programmes. We start with a detailed risk map tailored to your processes and materials. Our team develops and validates advanced analytical methods for trace detection, including LC–HRMS and GC–MS workflows.

We also build trending dashboards that link results to suppliers, batches, and packaging lots. Every solution comes with audit-ready documentation and a lifecycle monitoring plan. This ensures compliance with EMA, FDA, and other global requirements while keeping your products safe for patients.

References

European Medicines Agency (2025) Nitrosamine impurities: guidance for marketing authorisation holders. Available at: https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/referral-procedures-human-medicines/nitrosamine-impurities/nitrosamine-impurities-guidance-marketing-authorisation-holders (Accessed: 26 September 2025).
European Medicines Agency (2025) Q&A on the CHMP Article 5(3) opinion on nitrosamine impurities. Available at: https://www.ema.europa.eu (Accessed: 26 September 2025).
U.S. Food and Drug Administration (2023) Control of nitrosamine impurities in human drugs. Available at: https://www.fda.gov (Accessed: 26 September 2025).
World Health Organization (2023) Medication safety and nitrosamine risk management. Available at: https://www.who.int (Accessed: 26 September 2025).
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