Unseen Threats: Nitrosamine Impurities in Pharmaceuticals

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A Sudden Jolt: When the Medicine Became the Risk

In July 2018, the pharmaceutical industry experienced a significant disruption when batches of valsartan, a widely used antihypertensive, were found to contain an unexpected impurity — N-nitrosodimethylamine (NDMA), a probable human carcinogen. Regulatory agencies, manufacturers, and healthcare providers were prompted to act swiftly.

This contamination was not due to the drug substance itself but traced back to a change in the manufacturing process. Conditions conducive to the formation of nitrosamines — particularly NDMA — had inadvertently been introduced. What followed was a series of global recalls, not only for valsartan but later for other drugs including losartan, irbesartan, ranitidine, metformin, and rifampin.

These events brought nitrosamine impurities — previously associated more with food and environmental exposure — into the spotlight of pharmaceutical quality assurance. The industry began to recognize the need for enhanced scrutiny, particularly regarding how certain conditions or raw materials could lead to the formation of these potentially harmful impurities in medicinal products.

 

What Are Nitrosamines — And Why Do They Matter?

Nitrosamines are a class of chemical compounds containing a nitroso group (-N=O) bonded to an amine. Many nitrosamines are considered genotoxic and carcinogenic, having demonstrated mutagenic effects in both in vitro and in vivo studies. NDMA, N-nitrosodiethylamine (NDEA), and N-nitrosodiisopropylamine (DIPNA) are among the better-known members of this class.

These compounds are not typically added intentionally to pharmaceutical products. Rather, they are formed as byproducts when secondary or tertiary amines come into contact with nitrosating agents — such as nitrites — under specific environmental or processing conditions (e.g., acidic pH or elevated temperatures).

While nitrosamines have long been studied in the context of food safety, tobacco products, and industrial processes, their presence in pharmaceutical products at unacceptable levels became a more widely acknowledged concern only after the events of 2018.

 

 

How Were They Discovered in Medicines?

The initial detection of NDMA in valsartan was the result of routine quality control and impurity profiling. A laboratory in the European Union identified an unexpected peak during chromatographic analysis, which was later confirmed as NDMA. Investigation revealed that a change in the API synthesis route — specifically, the use of sodium nitrite in the presence of dimethylamine under acidic conditions — had inadvertently led to NDMA formation.

Subsequent testing by regulatory bodies and independent laboratories expanded the scope of concern. Ranitidine, for example, was found to potentially generate NDMA under storage conditions, particularly when exposed to heat. This led to widespread recalls and, in some regions, withdrawal from the market.

These incidents underscored the potential for nitrosamines to arise from a variety of sources — not only API synthesis, but also from excipients, packaging materials, or storage conditions.

 

The Wake-Up Call: Nitrosamines Are Everyone’s Responsibility

In response to these findings, global regulatory authorities issued comprehensive guidance. Agencies such as the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), Australia’s Therapeutic Goods Administration (TGA), Health Canada, and others mandated risk assessments for all medicinal products — including active pharmaceutical ingredients (APIs), excipients, and final dosage forms.

Manufacturers across the supply chain were asked to evaluate their products for the potential presence and formation of nitrosamines, and to take corrective or preventive actions where necessary. The responsibility to ensure the safety of drug products — with respect to nitrosamine contamination — now clearly extended to both upstream and downstream participants in pharmaceutical manufacturing.

 

How Do You Know If Your Product Is at Risk?

Determining whether a product is susceptible to nitrosamine formation involves a structured risk assessment. This process typically includes a detailed evaluation of all raw materials, manufacturing steps, storage conditions, and packaging components.

Several key factors contribute to nitrosamine formation:

Presence of amines: APIs or excipients containing secondary or tertiary amine functional groups can act as nitrosamine precursors.

Use of nitrosating agents: Compounds such as nitrites or nitrates, especially in acidic environments, can initiate nitrosation.

Trace contaminants: Even low levels of nitrites in water, solvents, or excipients can be sufficient to drive nitrosamine formation.

Process conditions: Elevated temperatures, low pH, or the use of certain catalysts can increase formation risk.

Packaging interactions: Some packaging components or adhesives may contribute nitrosating agents over time.

Example: The Influence of Excipients

Consider a formulation where the API contains a secondary amine group, and a commonly used excipient like starch or povidone contains trace levels of nitrite (e.g., 50–200 ppm). If the product undergoes wet granulation or is exposed to heat during drying, conditions may become favorable for NDMA or other nitrosamines to form — even without direct addition of any nitrosating agent.

Trace nitrite is common (ppm level) in many excipients (e.g. microcrystalline cellulose, lactose, starches, povidone). For instance, surveys found nitrite up to ~285 ppm in one batch of sodium starch glycolate and up to ~184 ppm nitrate.

Therefore, excipient selection and characterization are now critical. Suppliers are increasingly being asked to provide detailed information on residual nitrite and nitrate levels, as well as data on the material’s suitability for use in nitrosamine-sensitive formulations.

 

Risk Assessment in Drug Manufacturing

Regulatory agencies now require formal nitrosamine risk assessments for all affected drugs. For approved products, this was initially framed as a “call for review” by EMA and parallel requirements by FDA, Health Canada, etc. In the EU, for example, marketing authorization holders (MAHs) must complete a three-step process: (1) a comprehensive risk evaluation of APIs, excipients, and process, (2) confirmatory testing for suspected nitrosamines, and (3) update authorizations if changes are made. EMA explicitly reminds MAHs of this ongoing obligation, even after original deadlines passed. Similarly, the FDA guidance calls for manufacturers to “take appropriate measures” to prevent unacceptable nitrosamine levels, including risk-based safety assessments.

Key principles from guidance: prioritize products with highest risk factors – chronic use and high doses. For instance, drugs with long-term indication (e.g. hypertension, diabetes) or large daily dose warrant early review. Regulators advise considering the population size and duration of exposure in risk ranking. In practice, companies often list whether the API has a nitrosatable amine or amide, whether sodium nitrite (or reagents that can generate nitrosating species) is used, and whether any excipient or container could introduce nitrites.

Risk assessments should involve both API and drug product manufacturers working with excipient suppliers. TGA (Australia) guidance emphasizes that sponsors must “ensure that they… have access to relevant information from the API manufacturer regarding potential formation of nitrosamine impurities, as well as the potential for cross-contamination”. IPEC (excipients council) also underscores that excipients are one factor in the overall drug product risk assessment. In other words, the finished‑product sponsor bears ultimate responsibility: even if an excipient has low ppm nitrites, the sponsor must evaluate if those levels combined with the API chemistry pose a real risk.

If a risk is identified, agencies require confirmatory testing. EMA’s Q&A guidance tells MAHs to report to authorities if any nitrosamine is detected, and to carry out appropriate tests. In Australia, TGA guidance states: “if a known, plausible or potential cause of nitrosamine impurities is present, sponsors should undertake further investigation” – typically a formal lab analysis for specific nitrosamines. Data from regulators (FDA, TGA, etc.) show that sponsors are doing these risk assessments for all new and existing products, including sometimes after changes in suppliers or process.

Depending on the outcome, risk assessments lead to one of two paths: if testing confirms a nitrosamine above the acceptable limit, manufacturers must implement corrective actions (reformulation, process change, new controls) and notify regulators. If levels are below the limit, the process may be validated by routine testing and inclusion of nitrosamine spec in release (often when levels approach ~10% of the AI). Throughout, sponsors must document all findings and corrective/preventive actions (CAPAs) – for example, replacing a raw material, improving purification, or changing a reactor cleaning protocol. Notably, guidance advises that risk assessments be revisited periodically: changes in synthesis, materials, or new scientific data should trigger an update of the nitrosamine risk profile.

 

How Are Nitrosamines Detected?

Detecting these impurities is no easy task. Regulatory limits are in the nanogram-per-day range — so analytical methods need extraordinary sensitivity.

Techniques like:

Gas Chromatography–Mass Spectrometry (GC-MS) for volatile nitrosamines like NDMA.

Liquid Chromatography–Tandem MS (LC-MS/MS) for less volatile compounds.

Headspace analysis and solid-phase extraction for trace-level enrichment.

Regulators like the FDA and EMA have published validated methods for drugs like valsartan, metformin, and rifampin. But in most cases, manufacturers need to develop their own validated methods tailored to their product — often using stable isotope-labeled standards for precise quantification.

And the bar is high. If a product contains more than 10% of the acceptable limit, ongoing testing is usually required. Above the limit? The product cannot be released — and the manufacturer must take corrective action.

 

What Should Manufacturers and Excipient Suppliers Do?

This is not just a one-time fix — it’s an ongoing responsibility. Here’s what every stakeholder must consider:

For API Manufacturers:

Review synthetic routes for nitrosating agents or amines.

Avoid nitrite/nitrate-containing reagents or quenching steps.

Control recycled solvents and purification methods.

For Finished Product Manufacturers:

Perform detailed risk assessments covering all materials.

Collaborate with suppliers on nitrite/nitrate data.

Use sensitive analytical methods where needed.

Redesign formulations or processes if needed.

For Excipient Suppliers:

Monitor and disclose nitrite/nitrate levels in excipients.

Avoid cross-contamination and ensure consistent quality.

Support risk assessments with detailed CoAs and data.

Industry groups like IPEC (International Pharmaceutical Excipients Council) have published best practices for managing excipient-related nitrosamine risks — emphasizing transparency and proactive communication across the supply chain.

 

Final Thoughts: Learning from the Crisis

The nitrosamine crisis has been a wake-up call — not just about impurities, but about how tightly connected every part of the pharmaceutical supply chain is. A seemingly minor change in process or material can trigger a cascade of risk.

Through smart chemistry, robust supplier qualification, and modern analytics, we can prevent nitrosamine formation — and continue to deliver safe, effective medicines to patients around the world.

What began as a crisis is now a catalyst — pushing the industry toward better science, better controls, and better collaboration.

Commitment Vikram Thermo

At Vikram Thermo (India) Ltd., we recognize that our role is central in ensuring nitrosamine-free medicines. We have implemented stringent controls across our raw material sourcing, manufacturing, and quality systems to minimize the risk of nitrite or nitrate contamination. Every batch of our excipients is subject to rigorous testing, with close monitoring of trace nitrite/nitrate levels using validated, highly sensitive analytical methods. We work proactively with our partners by providing detailed data on residual nitrites/nitrates, and full traceability of our supply chain. Beyond compliance, our approach is preventive — from designing controlled processes and avoiding cross-contamination risks, to continuous improvement through supplier audits and risk reviews. This commitment ensures that Vikram Thermo (India) Ltd. Consistently supports customers in developing safe, compliant, and patient-centric drug products, reinforcing trust at every step of the supply chain.

 

Source: Vikram Thermo

 

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