Updated: IPEC Position Paper on Role of Excipients in Determining N-Nitrosamine Risks for Drug Products

The updated IPEC Position paper is now available on the IPEC page. Please check the following article.

Position Paper is on the download page.

According to the position paper, the responsibility of assessing and potentially controlling nitrosamines lies with the drug product owner/manufacturer as part of a collaborative process. It’s the same as the old version. However, many excipient manufacturers provide information to
support drug product manufacturers’ risk assessments and mitigation strategies.

Detailed information is included in the updated document. I picked up some of them.

Nitrosamines in Excipients
To date, only one excipient has been known to contain a nitrosamine: trolamine (triethanolamine) with the nitrosamine impurity N-nitrosodiethanolamine. In the European Pharmacopeia, the limit for N-nitrosodiethanolamine is established at 24 ppb.9 While this particular excipient may contain a nitrosamine impurity, this vulnerability is known and understood. The risk of an excipient introducing a nitrosamine directly to a drug product is not currently envisaged for any other product.

Nitrosating Compounds in Excipients
Nitrates can react to form nitrite through enzymatic reduction, which then can form the reactive nitrous anhydride under acidic conditions. It is very unlikely during excipient and drug product manufacturing for enzymatic reduction of nitrates to nitrites to occur. Therefore, nitrate is not a significant contributor to nitrosamine formation in drug products. Further discussion will focus only on nitrites.

Consideration of Excipients for Mitigating Nitrosamine Formation in Drug Products
There are many opportunities for drug product manufacturers to select and utilize excipients to help reduce nitrosamine formation. Ideally this is best done as part of new product development (Quality by Design). Many new and novel nitrosamines are emerging and the scope of potential nitrosamines in commercial drug products is not yet fully understood. In the FDA provided updates on possible strategies to reduce the risk of nitrosamine impurities in drug products. Within the update, the FDA encourages drug product manufacturers to explore innovative strategies to reduce the formation of nitrosamines in drug products. This is aligned with the investigation presented by Nanda where excipients (e.g., antioxidants and amino acids) were used to prevent the formation of nitrosamines within tablet formulations. Additionally, certain amino acid and primary amine excipients have been shown not to be carcinogenic and/or to have scavenging and other nitrosamine inhibition formation properties.


A fine line in many of the statements from the updated document…

…it is in the interests of excipient manufacturers to provide information that would facilitate the safe use of their excipients generally, and equally for nitrosamines risk assessments; however, it should be made clear that excipient manufacturers are under no specific regulatory requirement to provide excipient risk assessments on nitrosamines…

…excipient manufacturers may be able to provide information that would potentially exclude the presence of nitrosamines, nitrosating agents (nitrites), or vulnerable amines, but they generally will not possess analytical testing data on these substances…

…The template can be used as a starting point for providing excipient information to customers…

…the excipient supplier should carefully evaluate the potential risks of its excipient. A risk assessment for an excipient is not a regulatory requirement for excipient suppliers…

…Excipient manufacturers are under no obligation to test excipients for these substances. Excipient manufacturers could voluntarily provide such data…

What has been your experience with your suppliers? Are they going the extra mile to support your risk assessment? What are your expectations?


Adding the references here for easy access:

  • Teasdale, A.; Popkin, M., Regulatory Highlights. Org.Process Res. Dev. 2019, 23 (7), 1292-1297. https://doi.org/10.1021/acs.oprd.9b00270
  • Ashworth, Dirat, Teasdale, and Whiting. (2020). Potential for the Formation of N‑Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water. Organic Process Research & Development; 24:1629-1646. https://doi.org/10.1021/acs.oprd.0c00224
  • Sluggett, et. al. (2018) Artifactual Degradation of Secondary Amine-Containing Drugs During Accelerated Stability Testing When Saturated Sodium Nitrite Solutions are Used for Humidity Control. Journal of Pharmaceutical and Biomedical Analysis. 149, 206-213. https://doi.org/10.1016/j.jpba.2017.10.035
  • Lundberg et al. Nature Reviews Microbiology, 2004. https://doi.org/10.1038/nrmicro929
  • Cioc, R., Joyce, C., Mayr, M., Bream, R. (2023) Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies. Organic Process Research & Development, 27 (10), 1736-1750. https://doi.org/10.1021/acs.oprd.3c00153
  • Boetzel, et al. (2022) A Nitrite Excipient Database: A Useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products. Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.xphs.2022.04.016
  • Song et al. (2015) Dietary Nitrates, Nitrites, and Nitrosamines Intake and the Risk of Gastric Cancer: A Meta-Analysis. Nutrients. 2015 Dec; 7(12): 9872–9895. https://doi.org/10.3390%2Fnu7125505
  • Wu et al, Reactive Impurities in Excipients, PharmSciTech, 2011 https://doi.org/10.1208%2Fs12249-011-9677-z
  • Nanda, et.al. (2021) Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study. Journal of Pharmaceutical Sciences; 110(12), 3773-3775. https://doi.org/10.1016/j.xphs.2021.08.010
  • Ohshima, H., Mahon, G. A. T., Wahrendorf, J. and Bartsch, H. (1983) Kinetic Model for Predicting Carcinogenic Effects Caused by Endogenous Nitrosation; Cancer Res.; 43, 50725076. http://cancerres.aacrjournals.org/content/43/11/5072
  • Garcia, H. and Lijinsky, W. (1973) Studies of the tumorigenic effect in feeding of nitrosamino acids and of low doses of amines and nitrite to rats. Zeitschrift fur Krebsforschung und Klinische Onkologie; 79, 141-144 https://link.springer.com/article/10.1007/BF00303670
  • Endo, H., Takahashi, K. and H. Aoyagi (1974) Screening of compounds structurally and functionally related to N-methyl-N’-nitro-N-nitrosoguanidine, a gastric carcinogen. GANN; 65, 45-54. https://pubmed.ncbi.nlm.nih.gov/4596583/
  • Kato, T. and Kikugawa, K. (1992) Proteins and amino acids as scavengers of nitrite: inhibitory effect on the formation of nitrosodimethylamine and diazoquinone. Food and Chem Tox, 30(7), 617-626. https://doi.org/10.1016/0278-6915(92)90196-R
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@Yosukemino, Meglumine is also one of the excipient used in the formulation containing Nitrosamine. N-Nitroso Meglumine have already added by EMA in their updated list.