Practical Implementation to Mitigating Nitrosamine Risk

Nitrosamine have been a problem in pharmaceutical manufacturing since approximately 2018, after the carcinogenic impurities were found in statin drugs. Since then, regulators and pharmaceutical manufacturers have been working to mitigate the risk of nitrosamines in drugs.^1,2

PharmTech spoke with Bram Baert, global head of Regulatory Affairs at Capsugel, and Sandrine Picco, senior analytical Ssecialist on Capsugel's Innovaform Accelerator team, to find out about Capsugel’s approach to nitrite and nitrosamine risk ahead of their CPHI Milan 2026 presentation, “Nitrosamine Risk Mitigation: From Regulatory Expectations to Practical Implementation.”

PharmTech: Why has the industry gravitated toward a “how low is low enough” framing, and what's the risk of chasing the lowest reported nitrite number rather than a number you can trust?

Baert: So, once we understood that nitrite, which can naturally be present in some excipients, can contribute to the formation of these potentially harmful nitrosamines in medicines, the obvious solution seemed to be, we simply eliminate nitrite from the excipient. However, in practice, it is not that simple.

Nitrite can occur intrinsically in many materials, so reducing its level to zero can be extremely difficult, and gelatin capsules are, in fact, a good example. There are ways to reduce nitrite levels in the capsule, but doing so can add significant complexity and cost to the manufacturing process.

Now, at the same time, we also know that many medicines can safely tolerate a certain amount of nitrite without creating a significant risk. So, rather than pursuing this sometimes unrealistic goal of extremely low nitrite levels, a more practical and science-based approach is actually to determine what level is acceptable from a safety perspective and then make sure that the excipient consistently stays below that limit.

So, in other words, the goal is not necessarily to go for a zero nitrite at any cost, but to control the nitrite to a level that is scientifically justified and that is, of course, appropriate for the overall risk. This key observation is very important for our new integrated offering that we just launched to help pharmaceutical companies navigate these increasingly complex nitrosamine assessments.

How are analytical confidence, manufacturing reproducibility, and supply chain robustness important to sustainable risk reduction?

Picco: Nitrite is an environmental contaminant that may be present at trace levels throughout daily life, including in excipients, APIs, manufacturing environments, and on material surfaces. And because of its diverse origins and heterogeneity distribution, controlling nitrite contamination remains a significant challenge for the pharmaceutical industry.

So, while the industry continues to investigate manufacturing and environmental sources of nitrites, we must also at the same time provide effective mitigation strategies to our customers. Fundamental measures, including controlling nitrite levels in raw materials and ensuring robust and standardized mass manufacturing processes, for example. However, these efforts alone may not be sufficient, as storage conditions and primary packaging should also be considered because nitrite can migrate over time.

And despite growing interest in this topic, very limited scientific data have been published, and to the best of my knowledge, none have assessed the risk associated with packaging materials yet. At the same time, pharmaceutical manufacturers are increasingly asking which packaging solution could best minimize this risk. So, to address this knowledge gap, we initiated a comparative study of various packaging and product contact materials, including polymeric containers and manufacturing consumables, like gloves, for example, with the goals of better controlling the potential for nitrite migration.

In summary, we can say that nitrites are everywhere. Managing their impact requires a holistic approach that extends across the entire pharmaceutical supply chain, from raw materials and manufacturing processes to the storage and packaging.

Regarding nitrite testing methodologies harmonization, how can the pharmaceutical industry manage the current diversity of strategies?

Picco: When assessing nitrite results, numbers alone do not tell us the full story, because nitrite is an environmental trace residue that can be unevenly distributed within materials. Also, published studies have demonstrated considerable viability between batches and even between laboratories analyzing the same batch. As a result, comparing nitrite values without considering the context can be misleading. Key questions that must first be addressed include: was the method fit for purpose and properly validated? How were the samples stored prior to analysis? What comparison approach and specifications should be used?

At Capsugel, our first step is always to understand how the data were generated, which is foundational part of our new integrated offering for nitrosamine risk mitigation that combines the analytical method with scientific interpretation and regulatory support. Only then can we ensure meaningful comparisons and provide robust support for customer decision-making.

Can low nitrite guarantee low nitrosamines?

Picco:This is an important area being discussed widely among the pharmaceutical community today to address this challenge. It’s important to recognize that nitrosation reaction can be triggered by nitrosating agents other than nitrate itself. In fact, cases have been documented when a nitrosamine formation occurred even through no nitrite was even detected.

So, from a global perspective, any excipient identified as posing a potential nitrosamine risk for a given API should be carefully evaluated and should contain the lowest possible nitrate level. In addition, nitrate risks evaluation cannot be generic. This should be established on a case-by-case basis, taking into account both the API’s characteristics and the formulation composition.

While nitrate limits were historically discussed at the parts-per-million (PPM) level, the pharmaceutical industry is now operating at a parts-per-billion (PPB) range. Therefore, the theoretical nitrosamine risk can be assessed based on the API and formulation composition. However, this assessment does not account for environmental factors. As a result, ensuring a low nitrate product is not only a matter of controlling raw material quality; this also requires appropriate manufacturing, handling, and storage conditions to minimize the potential for nitrosamine formation throughout the product life cycle.

What are some hurdles in getting from a target specification to a reproducible process at scale?

Picco: Our conversation at CPHI outlined how to overcome key challenges in order to move from a target specification to a robust and reproducible manufacturing process at commercial scale. For example, nitrates are present everywhere in the environment, and their cumulative contribution makes a zero-nitrate strategy practically impossible. As a result, manufacturers can only focus on minimizing nitrate content and controlling the factors that promote nitrate formation.

First, the nitrate analytical method must be sensitive and robust, and second, also, controlling sources of viability becomes critical, including raw material quality, supplier-to-supplier differences, and process parameters. Finally, as production is scaled up, it’s essential to ensure that the process remains capable of consistently meeting the specification while maintaining also efficiency and regulatory compliance. Effective nitrate control isn’t a one-size-fits-all approach, and our integrated offering addresses these challenges in a product-specific way.

What does “confidence” actually mean in practice? How do you demonstrate it?

Picco: Several scientific publications have reported nitrate determination methods with sensitivities in the PPM range. However, current pharmaceutical requirements demand excipients with nitrate levels controlled now at the PPB range. In consequence, these analytical techniques had to be further optimized, not only to lower their limit of quantification, but also to ensure robustness against matrix effects.

Pharmaceutical companies need excipients that are characterized using reliable analytical methods, especially when no official regulatory methods and limits have been yet established for the nitrate contents in excipients. So, to navigate this regulatory gray area, we developed and implemented a consistent, validated method for reliable trace-level nitrate measurements.

This method was then validated in accordance with the pharmaceutical ICH Q2 [R2] guideline and showed that all the lights were green. The validation demonstrated a limit of quantification as low as a hundred PPB, and we also confirmed a strong analytical performance in term of linearity, precision, accuracy, robustness, and repeatability. In summary, this method is fully suitable for trace-level nitrate analysis, whether for routine release testing, customer support, scientific decision-making, or investigations.

When it comes to customer-specific risk assessment, how does nitrosamine risk mitigation differ from one customer's product to another?

Baert: So, as Sandrine just outlined, we apply a strong analytical validation to our approach for the customers. And to build on that, it is really important to look at this as more than just a customer-specific question. The potential for nitrosamines in a direct product depends on a number of things. There’s the raw materials, there’s the formulation, the manufacturing process, the packaging, and how all of these factors interact.

So, the nitrites, they are just only one piece of the puzzle, and the nitrite level that is acceptable can actually be different from one product to another. And that is why we do not believe in simply setting one fixed nitrite limit for every product. Instead, we look at the science, and we assess together with our customers what level is really needed for their specific product, and then we make sure, of course, that we can consistently control our capsules to that level.

What does cross-functional collaboration across the value chain look like? Which functions or external partners need to be at the table, and what breaks down when they aren't?

Baert: So, nitrosamine risk mitigation is a pressing issue that we must address all together. So, one of the biggest lessons from nitrosamines is that you really cannot look at the risk in isolation. You cannot just look at one ingredient or one step in the manufacturing process. Instead, you need to bring together the different people, the API and the excipient manufacturer, the formulation and the manufacturing teams, the analytical experts, as well as the quality and the regulatory specialists, and where relevant, even the packaging material suppliers need to be involved. And key is that everyone sees a different part of the picture, and if one of those pieces is missing, you may have a good assessment of one part of the process, but you may still miss the overall risk to the patient.

References

1. Zeleznik J, Badger S, Ghimire M. Excipient selection strategies to mitigate nitrosamine risk. PharmTech Ingredient Innovations eBook. April 8, 2026. https://www.pharmtech.com/view/excipient-selection-strategies-to-mitigate-nitrosamine-risks
2. FDA statement on the FDA’s ongoing investigation into Valsartan and ARB Class impurities and the agency’s steps to address the root causes of the safety issues. Press release. FDA. January 25, 2019.