Excipient Selection Strategies to Mitigate Nitrosamine Risks

The pharmaceutical industry is faced with balancing science and innovation with patient safety. Among issues affecting drug product manufacturers, nitrosamine impurities have a unique focus due to their inherent risk to patient health. Why the concern? Evidence shows nitrosamines to be carcinogenic and associated with numerous cancer forms, including esophageal, stomach, liver, lung, and bladder.1 Still, other cancer forms, such as nasopharyngeal, colorectal, and brain, may be attributed to nitrosamine exposure.1 With this in mind, it is important to understand how nitrosamines form.

Pharmaceuticals — APIs and excipients — and their manufacturing processes can create an exposure risk. It is here that pharmaceutical companies have the ability to limit patient nitrosamine exposure.

The nitrosamine issue first emerged in June 2018, when N-nitrosodimethylamine (NDMA) was detected in valsartan. This was followed in the larger group of sartans in July 2018. Ranitidine and metformin followed in 2019.2 The initial focus was on tablets; however, other routes of administration, such as topical, transdermal, and parenteral, may also be a nitrosamine exposure risk. At risk APIs include secondary and tertiary amines and some amides.2

Nitrosamine Formation

Nitrosamine formation has been studied by industry, academia, and regulators hoping to better understand nitrosamine formation. Research shows that nitrosamines form through complex chemical pathways involving nitrosating agents (Figure 1),3 including the following:

• Nitrite-containing compounds
• Nitrogen dioxide
• Nitrous oxide
• Nitrous acid
• Nitrous trioxide

From the studies, stakeholders have identified seven nitrosamine compounds (Figure 2), specifically N-nitroso compounds (NOCs) associated with an increased health risk.

Today, more than 300 APIs have a potential for nitrosamine formation (Table I).4
While some drug products have been withdrawn from the market, not all have. Regulators have worked with industry to determine acceptable exposure levels and has published acceptable intake levels that vary from 26.6 ng/day to 1500 ng/day (Table II).5 The European Medicines Agency (EMA) has also established acceptable intake levels through their own studies as have PDMA (Japan), Health Canada, TGA (Australia), NMPA (China), and ANVISA (Brazil).

Mitigation Strategies: Excipient and Process Selection

Several nitrosating agent sources were mentioned earlier. There are others and can include packaging materials (nitrocellulose based), process water, solvents (recovered and recycled solvents), and excipients. Knowing that excipients may contribute to nitrosamine formation, excipient stakeholders are collaborating to better understand excipient impact. Excipient suppliers are examining product manufacturing processes to reduce nitrosating agents. Excipient manufacturers actively assessing nitrosating agent levels are BASF, DFE Pharma, Evonik, Lubrizol, and Roquette. Case studies show how excipient selection mitigates nitrosamine formation and patient risk.

Pearlitol (mannitol) is one example. Pearlitol’s chemical structure is nitrogen-free, and the manufacturing process does not introduce nitrosamines or nitrosating agents during production (Figure 3).

Another question is if there is a change in performance when controlling nitrite levels in excipients. Avicel PH exists in standard and low nitrite forms. The manufacturing process used to produce Avicel with low nitrite levels has been assessed and determined not to alter the compaction performance compared to the standard offering (Figure 4).

Process selection for drug product manufacture is also fundamental in mitigating nitrosamine formation. API characterization and a risk assessment can determine if the manufacturing process is a contributing factor. For example, wet granulation processes can prompt formation for at risk APIs. Additionally, elevated temperatures and humidities have demonstrated increased nitrosamine formation.6 Recovered and recycled solvent use, which has become more common, has demonstrated increased risk due to impurities present. Direct compression and dry granulation avoid conditions that might initiate formation (Figure 5).

EMA7 and the US Food and Drug Administration (FDA)8, in their respective guidance documents, provide a strategy for nitrosamine mitigation (Figure 6). This approach provides a strategy toward risk evaluation, identification and level determination, and mitigation implementation, which can include excipient and process selection, as well as using scavengers.

Scavengers have shown to reduce nitrosamines (Figure 7).9 The amino acids lysine, arginine, L-cysteine, and histidine have demonstrated nitrite scavenging as well as pH modification using caffeic and ferulic acid.10 Yet, not all scavengers are equally effective and should be assessed on their own merit as one study showed. For the model compound, ascorbic acid showed greater nitrosamine reduction than α-tocopherol with other options somewhere between.9

Nitrosamine Risk Evaluation

The International Pharmaceutical Excipients Council (IPEC) developed a questionnaire providing information about excipients to assist pharmaceutical companies with a risk evaluation of nitrosamine impurity presence in the final drug product (Figure 8).11 The questionnaire was adapted from the guidance from the EMA assessment report, Nitrosamine impurities in human medicinal products, the related EMA document, “Questions and answers for marketing authorization holders”, and the FDA Guidance for Industry, Control of Nitrosamine Impurities in Human Drugs.The questionnaire was developed as a harmonized approach to share information with drug product manufacturers.

Conclusion

With advances in instrumentation to aid with API characterization and nitrosamine detection, formulators are more prepared to implement nitrosamine mitigations strategies. Knowing whether an API is at risk is the first step and assists with excipient and process selection. Additionally, excipient manufacturers have responded to pharmaceutical industry needs by making low nitrite excipients available as well as those used as scavengers. Excipients for direct compression and roller compaction also can be used to avoid wet processes that promote nitrosamine formation.

References

1. Harshita Akkaraju, Ritik Tatia, Sayalee Sanjay Mane, Amol B. Khade, Swapnil J. Dengale. A comprehensive review of sources of nitrosamine contamination of pharmaceutical substances and products, Regulatory Toxicology and Pharmacology, 2023; 139.

2. Wichitnithad W, Nantaphol S, Noppakhunsomboon K, Rojsitthisak P. An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals. Saudi Pharm J. 2023 Feb;31(2):295-311. DOI: 10.1016/j.jsps.2022.12.010. Epub 2022 Dec 24. PMID: 36942272; PMCID: PMC10023554.

3. Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry.U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). September 2024, Revision 2.

4. FDA. CDER Nitrosamine Impurity Acceptable Intake Limits. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits#compound, Table 1

5. Recommended Acceptable Intake Limits for Nitrosamine Drug Substance Related Impurities (NDSRIs): Guidance for Industry. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). August 2023, Pharmacology/Toxicology.

6. Moser, Justin, et al. N-nitrosamine formation in pharmaceutical solid drug products: Experiment observations. Journal of Pharmaceutical Sciences 2003.

7. Questions and answers for marketing authorization holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. European Medicines Agency. EMA/409815/2020 Rev.23, 10 October 2025

8. Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry.U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). September 2024, Revision 2.

9. Homšak, M.; Trampuž, M.; Naveršnik, K.; Kitanovski, Z.; Žnidarič, M.; Kiefer, M.; Časar, Z. Assessment of a diverse array of nitrite scavengers in solution and solid state: A study of inhibitory effect on the formation of alkyl-aryl and dialkyl N-nitrosamine derivatives. Processes 2022;10, 2428.

10. Bayne, A-C V. et al. N-nitrosamine mitigation with nitrite scavengers in oral pharmaceutical drug products. Journal of Pharmaceutical Sciences. 112, 7, 1794 – 1800.

11. IPEC Questionnaire for Excipient Nitrosamine Risk Evaluation. IPEC https://ipecamericas.org/viewdocument/questionnaire-for-excipient-nitrosa

About the Authors

Joseph Zeleznik is the Technical Director – North America at IMCD. Joseph brings nearly four decades of experience in pharmaceutical excipients and formulation development. His expertise spans high-functionality and novel excipients, continuous manufacturing, and advanced formulation strategies.

Sydney Badger is a Technical Development Manager at IMCD. With over seven years of experience in the pharmaceutical excipient industry, Sydney has a strong background in oral solid dosage forms and formulation development. Leveraging her previous experience as an R&D formulator, she brings application-oriented technical expertise to her current role.

Dr. Manish Ghimire is the Director of Technical Development – North America at IMCD. Manish brings over 20 years of experience in pharmaceutical R&D and technical marketing, with deep expertise in solid dosage forms and advanced formulation strategies. He is a recognized thought leader known for translating complex scientific concepts into practical, commercially relevant solutions.