Strategies for Mitigating Nitrosamine Risk

n-nitrosodimethylamine molecular structure, 3d model molecule, n-nitrosamines, structural chemical formula view from a microscope | Image Credit: © Сергей Шиманович - stock.adobe.com

In January 2025, FDA posted “Determining Recommended Acceptable Intake Limits for N-nitrosamine Impurities in Pharmaceuticals: Development and Application of the Carcinogenic Potency Categorization Approach” in the Spotlight on CDER Science section of the FDA.gov website (1). The presence of nitrosamines, which are cancer causing chemicals, in pharmaceuticals has been an ongoing concern since 2018 (2).

Pharmaceutical Technology® asked Amit Chivate, senior market manager, Greater Asia and China, Roquette, to give us his perspective on FDA’s recommendations on how manufacturers should approach nitrosamines.

PharmTech: What can you tell us about the recommendations FDA published in January 2025 for the development and application of the Carcinogenic Potency Categorization Approach (CPCA) to nitrosamines?

Chivate:The CPCA provides a comprehensive framework for assessing the carcinogenic potential of and acceptable intake limits for N-nitrosamine drug substance-related impurities (NDSRIs) (1). The need for such specific advice stems from the fact that, in contrast to simpler, small-molecule nitrosamines, NDSRIs present complex and unique chemical structures, which make the establishment of accurate acceptable limits (AI) particularly challenging. The CPCA proposes a new protocol that predicts the carcinogenic potency of an NDSRI by analyzing its chemical make-up—whether known or merely theoretical. The first step is a review of available science from animal studies and human epidemiological data to determine the relative risk associated with each nitrosamine compound. Next, scores are awarded according to the structure of α-hydrogen atoms, and the presence of activating or deactivating features are combined to assign the NDSRI to a potency category, which then dictates its acceptable daily intake limit. This approach represents a notable breakthrough because it allows for a precise, risk-based assessment—even in the absence of specific long-term carcinogenicity data for a particular NDSRI–—making it an ideal case study for how regulatory updates can simplify the drug development process.

The CPCA also brings a dose of much needed clarity and transparent scientific process to the field of nitrosamine mitigation, making it a win for consistency, quality and— above all—patient safety.

PharmTech: What makes determining acceptable intake so challenging?

Chivate: Determining an acceptable daily exposure limit for any given drug impurity is an incredibly complex task—especially in the case of NDSRIs, which are usually unique to each individual drug. Extreme specificity, in this instance, means increased uncertainty, as there is unlikely to be enough tailored safety information on each NDSRI for manufacturers to determine safe exposure levels. As a result, formulators often turn to information gathered on structurally similar compounds or apply a conservative default acceptable intake limit, neither of which yield perfectly accurate results and can force drug companies to make unnecessary changes to their production practices to meet disproportionately strict standards.

Inconsistent regulatory guidelines across different countries, limited long-term epidemiological data, and the difficulty of quantifying cumulative risk from multiple sources all add another layer of complexity. FDA, for instance, sets its AI limits based on safety assessments that evaluate the mutagenic and carcinogenic potential of nitrosamines. Here, it uses rodent carcinogenic potency data or structure-activity relationships (SAR) to identify comparable compounds in the absence of robust data. In contrast, the European Medicines Agency (EMA) predicts carcinogenic potency categories and corresponding AI limits based on the presence of activating or deactivating structural features in the molecule, which influence carcinogenic potency. The recently published CPCA was developed to harmonize and simplify these approaches, with the aim of giving drug manufacturers a simpler, faster and more precise strategy for remaining compliant and protecting patients, without always having to resort to the most extreme safety measures.

PharmTech: What are NDSRIs?

Chivate:NDSRIs are a subset of nitrosamine genotoxic impurities with complex chemical structures that typically mirror that of an API. They form when secondary or tertiary amines in the drug substance or formulation interact with nitrosating agents during manufacturing and storage. NDSRIs are particularly concerning because they are probable human carcinogens, as classified by the International Agency for Research on Cancer. In contrast to simpler, small-molecule nitrosamines, which are more general contaminants that can affect any drug formulation, NDSRIs are formed through the nitrosation of the API in response to specific production or storage conditions. In short, NDSRIs are complex, unique, and, therefore, more difficult to manage.

PharmTech: What can pharma manufacturers do to manage the nitrosamine risk?

Chivate: At this point, manufacturers are well versed in nitrosamine risk mitigation, but there are some underreported strategies that we think should be brought into the spotlight. First is the benefit of weaving the compliance process throughout the entire production line, start to finish. Though testing to determine whether drugs meet AI limits is typically carried out on finished products, we advise that all raw materials should first be evaluated for their potential to introduce nitrosamine impurities—either during production or on their way to patients’ medicine cabinets. This initial step can help save time and potential expense through the early identification of contaminated raw materials, as well as speed up the verification process of the final product.

Excipients are another essential, yet often overlooked, element to the nitrosamine compliance conversation. Fillers, binders, disintegrants, and diluents make up as much as 90% of a drug’s overall volume, so it stands to reason they receive at least some of the scrutiny when it comes to product safety (3,4).One of the simplest and most effective safeguarding options for pharma producers is to select excipients with a demonstrated low nitrate content. The drawback with this strategy, however, is that since regulators do not yet mandate their assessment for nitrosamine risk, comprehensive or consistent data on the nitrite content of many excipients can be hard to pin down. This is where the support of an experienced formulation partner can be invaluable, not only for providing drug manufacturers with high-quality information and products, but also with tailored advice on how to optimize production conditions, for safety and productivity.

References

1. FDA. Determining Recommended Acceptable Intake Limits for N-nitrosamine Impurities in Pharmaceuticals: Development and Application of the Carcinogenic Potency Categorization Approach. Spotlight on CDER Science. FDA.gov. Jan. 10, 2025. https://www.fda.gov/drugs/spotlight-cder-science/determining-recommended-acceptable-intake-limits-n-nitrosamine-impurities-pharmaceuticals
2. FDA. 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. Jan. 25, 2019.
3. Abrantes, C.G.; Duarte, D.; Reis, C.P. An Overview of Pharmaceutical Excipients: Safe or Not Safe. J. Pharm. Sci. 2016;105:2019–2026. DOI: 10.1016/j.xphs.2016.03.019
4. Haywood, A.; Glass, B.D. Pharmaceutical Excipients—Where Do We Begin? Aust. Prescr. 2011;34:112–114. DOI: 10.18773/austprescr.2011.060

About the speaker

Amit Chivate is senior market manager, Greater Asia and China, at Roquette.

Amit holds an MBA and a PhD in pharmaceutical drug delivery, and has more than 20 years of experience working across R&D, strategy, sales, marketing, and product management in both India and the United States. At Roquette, Amit serves as the senior marketing manager for the APAC region, leveraging his technical and business expertise to drive marketing initiatives and strategic growth.