Feature article - Nitrosamine mitigation: Delivering a dose of clarity in three key questions

Amit Chivate, senior market manager, Greater Asia & China, at Roquette Health & Pharma Solutions looks at practical strategies pharma producers can adopt to simplify their nitrosamine compliance processes and continue to assure patient safety

More than half a decade since it first appeared on formulators’ radars, the issue of nitrosamine content in pharmaceuticals is still evolving. Drug manufacturers have since become well versed in the shifting regulatory standards for risk assessments, testing and safe consumption levels. 

Now yet another consideration has been added to the roster. Published in January 2025, the US FDA’s Carcinogenic Potency Categorisation Approach (CPCA) offers a comprehensive framework for assessing the carcinogenic potential of and acceptable intake (AI) limits for N-nitrosamine drug substance-related impurities (NDSRIs).1

Though its aim is to provide a more adaptable and accurate method with which to establish safe consumption limits, it means pharma producers are faced with a new paradigm for classifiying nitrosamine risk, and potentially renewed efforts to test, certify and ensure their products remain compliant. 

Here, we aim to bring a dose of certainty amid the speculation, offering an overview of the regulatory landscape and tangible advice drug developers can use to streamline compliance processes in the form of three essential questions and their answers:

• How do NDSRIs form, and what makes them so concerning?
• What are the most important regulatory guidelines surrounding nitrosamines that pharmaceutical producers must ensure they follow?
• How can drug developers guard against the formation of nitrosamines in their formulations and manufacturing processes?

The problem

NDSRIs are a class of genotoxic impurities found in pharmaceutical products. They typically form when secondary or tertiary amines, present in the API, interact with a nitrosating agent. 

As is often the case in pharma, however, the baseline definition is only a small part of the picture. The highest likelihood of NDSRI formation occurs during drug manufacturing, when nitrosating agents within excipients come into contact with API amines. 

The risks do not stop at the end of the production line either. Packaging materials, such as certain types of plastics or rubber stoppers, can also leach nitrosating agents into the drug product, while exposure to excess heat, light, or acidity during manufacturing and storage can equally exacerbate degradation pathways. 

Nitrosamines in any form are a significant concern because they are probable human carcinogens, as classified by the International Agency for Research on Cancer (IARC), and as such must be limited to assure long-term patient safety. The question therefore becomes, why do NDSRIs require special attention? 

In contrast to simpler and more predictable small-molecule nitrosamines, NDSRIs exhibit complex chemical structures that mirror that of a specific API. It’s this variation that makes the task of establishing acceptable intake limits that much more difficult—and is also why NDSRIs garner intense regulatory scrutiny. 

The regulations

The first phase of the nitrosamine conversation should have ended on 1 October 2023. This as the deadline set by both the FDA and European Medicines Agency (EMA) by which drug producers must have completed confirmatory product testing and submitted details of any changes required to lower the risk of nitrosamine formation.2,3

However, in response to growing awareness of NDSRIs and their unique complexity, the FDA granted pharmaceutical players additional time until 1 August 2025, to assure their products meet the organisation’s recommended AI limits, as determined by its newly characterided carcinogenic potency categories. 

Enter the CPCA. It proposes a new protocol for NDSRI assessment that does not rely on difficult-to-source historical data, but instead predicts carcinogenic potency based on chemical structure.4 Using available epidemiological data from animal and human studies, the CPCA determines the relative, probable risk associated with each nitrosamine compound. 

Once this is established, the approach then awards scores based on the structure of ?-hydrogen atoms within the compound, while also considering the presence of activating or deactivating features. The resulting scores are combined to assign the NDSRI to a potency category, which, in turn, dictates its acceptable daily intake limit. 

Clear, concise and widely applicable, the CPCA represents a real breakthrough in the regulatory attitude towards NDSRIs and their mitigation. With such a protocol now established, the 1 August deadline is the first that feels at least somewhat definitive, even if it is unlikely to be the last the industry ever hears on the topic of nitrosamines. 

Guarding against NDSRIs

Last, and far from least, we turn to the practicalities of managing NDSRIs. The most obvious place to start is with the ingredients—both active and excipient. Fillers, binders, diluents and other excipients can constitute as much as 90% of drug products by volume, yet these ingredients have so far been exempt from official assessments designed to limit nitrosamine risk.5,6 

Fewer regulatory mandates means less information available to producers on which excipients pose the lowest risk in terms of nitrosating agents, but some suppliers have taken this challenge into their own hands. Roquette, for instance, has undertaken extensive testing beyond that required by FDA and EMA guidelines to confirm the safety and quality of its solutions, and offer producers a wide array of low nitrite excipients for optimal flexibility and functionality, as well as safety.

Following formulation, the next biggest site of nitrosamine risk is the production line. Even when care has been taken to use low nitrite ingredients, exposure to moisture, high temperatures, or pH levels lower than 5 act as the perfect conducive environment for nitrosating agents to react with amines, leading to the formation of significant contaminants. 

Optimising processes for direct compression, as opposed to wet granulation, is therefore an effective route for risk mitigation. Direct compression lowers the risk of nitrosamine formation in two ways: by reducing exposure to moisture levels during processing and eliminating exposure to high temperatures during the drying step. 

In addition to this, drug producers can limit risk through the use of excipients with either low water activity, or low water activity combined with water-scavenging properties. These solutions further decrease the likelihood of nitrosating agents coming into contact with amines from APIs and forming contaminants. 

Another example of an effective nitrosamine-tackling intervention is the use of plant-based film coatings for tablets. Such solutions unlock the potential to coat at significantly lower product temperatures than conventional approaches, thereby minimising exposure to high temperatures during production. 

Manufactures can also take advantage of improved packaging materials that are better able to shield finished products from light, heat, and physical degradation. Adaptations like this can never remove the risk of nitrosamine formation entirely, but they can give producers and patients the much-needed peace of mind that their products fall well within the safe and compliant category. 

The only constant is change

The beauty of science is that nothing is ever truly certain. Theories emerge and become accepted, but there is always room for new discoveries to completely shift our perspective. 

The story of nitrosamines in pharma from 2019 to now exemplifies this journey from established theory, to new challenge, and back to a new normal. As the industry gets to grips with the CPCA ahead of the FDA’s final testing deadline in August, we are entering into a more stable phase of the nitrosamine conversation—but this will not last forever. 

In the spirit of scientific curiosity and an unwavering dedication to patient safety, regulators and producers will almost certainly discover new strategies for tackling the risks posed by nitrosamines, kicking off a whole new cycle of change. This tension between constant evolution and the need to assure safety is the dilemma at the heart of pharmaceuticals, but is also the fuel that drives life-saving innovation. 

For more information: https://www.roquette.com/pharma/nitrosamine-mitigation-low-nitrite-excipients

References: 

1. https://www.fda.gov/drugs/spotlight-cder-science/determining-recommended-acceptable-intake-limits-n-nitrosamine-impurities-pharmaceuticals
2. Covington, August 2023: https://www.cov.com/en/news-and-insights/insights/2023/08/fda-releases-final-guidance-on-recommended-acceptable-intake-limits-for%20nitrosamines#layout=card&numberOfResults=12
3. EMA Nitrosamine impurities: https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/referral-procedures-human-medicines/nitrosamine-impurities
4. https://www.fda.gov/drugs/spotlight-cder-science/determining-recommended-acceptable-intake-limits-n-nitrosamine-impurities-pharmaceuticals
5. C.G. Abrantes, D. Duarte & C.P. Reis, J. Pharm. Sci. 2016, 105, 2019–2026: doi: 10.1016/j.xphs.2016.03.019
6. A. Haywood & B.D. Glass, Aust. Prescr. 2011, 34, 112–114: doi: 10.18773/austprescr.2011.060