The Nitrosamine challenge in pharmaceuticals 

The concern about potential risk of nitrosamines in excipients has changed gradually from the possible presence of nitrosamines as impurities of the excipient to the presence of nitrosating agents (like nitrites) present at low concentrations in the excipient that can act as nitrosating agents in the finished product.

Already in 2011 it was known that pharmaceutical compounds containing amino groups have the potential to form N-Nitroso compounds as degradates in the drug product due to interactions with nitrite impurities in the excipients (Wu et al., 2011).

Also, regulatory authorities like the FDA have confirmed that “In some cases, the root cause of Nitrosamine Drug Substance Related Impurities (NDSRI) formation has been attributed to nitrite impurities present in excipients at parts-per-million amounts. Nitrite impurities have been observed in a range of commonly used excipients (as well as water) and may lead to the formation of NDSRIs in certain drug products" (https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drug-substance-related-impurities, accessed 31/07/2023).  

In a recent article it has been concluded that about 40.4 % of the analysed APIs and 29.6 % of the API impurities are potential nitrosamine precursors. Most structures identified could form complex API-related nitrosamines, so-called nitrosamine drug substance related impurities (NDSRIs)” therefore there is a risk of nitrosamine formation (NDSRIs) in those APIs if the excipients in which they are formulated contain nitrites. As it is not possible to remove from the market 40% of the small molecule API’s it is not possible to eliminate such hazard (Schlingemann et al., 2023). 

A very recent article came to the same conclusion, i.e., that pharmaceuticals cannot be made “nitrosamine-free” but that at the same time there is a need to protect patients from true cancer risk and secure access to important medicines and thereby manufacturers and health authorities need to pursue all efforts to implement nitrosamines control strategies to deliver safe and effective medicines (Nudelman et al., 2023).

Despite nitrites, it is also known that is possible to form N-nitrosamines at pH>6 under the action of certain catalysts like formaldehyde (Cioc et al., 2023; Consumer Safety Scientific Committee, 2011). Formaldehyde is a commo impurity in many excipients, particularly alkoxylates like polyethylene glycols and polysorbates as it can be formed as degradant from the oxyethylene chain.

Also, peroxides in excipients could be involved in the generation of nitrosating agents and/or vulnerable amines and/or acidic degradants that catalyse amine nitrosation. Peroxides may also favour N-Nitrosation at atypical pH values by producing catalytically active aldehydes (Cioc et al., 2023).

So far, the information available on the levels of nitrites in excipients is focused on excipients used in oral solid dosage formulations like microcrystalline cellulose, hypromellose, povidone, magnesium stearate, lactose monohydrate or corn starch (Boetzel et al., 2023) but there is no data available on widely used lipid derived excipients such as polysorbates. 

Croda has tested for nitrites content our range of high purity Super Refined Polysorbate  grades using an analytical method developed in-house (Ion Chromatography - MS) and results confirm absence of nitrites below 0.05 ppm’s.

 ND = Not Detected

Furthermore, our Super Refined PEG and Polysorbate grades have low aldehydes and peroxides content and therefore are the perfect choice to minimize the risk of formation of NDSRIs in drug product formulations.

References:
Boetzel, R., Schlingemann, J., Hickert, S., Korn, C., Kocks, G., Luck, B., Blom, G., Harrison, M., François, M., Allain, L., Wu, Y., & Bousraf, Y. (2023). A Nitrite Excipient Database: A Useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products. Journal of Pharmaceutical Sciences, 112(6). https://doi.org/10.1016/j.xphs.2022.04.016
Cioc, R. C., Joyce, C., Mayr, M., & Bream, R. N. (2023). Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies. Organic Process Research & Development. https://doi.org/10.1021/acs.oprd.3c00153
Consumer Safety Scientific Committee. (2011). Opinion on Nitrosamines and Secondary Amines in Cosmetic Products. European Commission, March.
Nudelman, R., Kocks, G., Mouton, B., Ponting, D. J., Schlingemann, J., Simon, S., Smith, G. F., Teasdale, A., & Werner, A.-L. (2023). The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny. Organic Process Research & Development. https://doi.org/10.1021/acs.oprd.3c00100
Schlingemann, J., Burns, M. J., Ponting, D. J., Martins Avila, C., Romero, N. E., Jaywant, M. A., Smith, G. F., Ashworth, I. W., Simon, S., Saal, C., & Wilk, A. (2023). The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals. Journal of Pharmaceutical Sciences, 112(5). https://doi.org/10.1016/j.xphs.2022.11.013
Wu, Y., Levons, J., Narang, A. S., Raghavan, K., & Rao, V. M. (2011). Reactive impurities in excipients: Profiling, identification and mitigation of drug-excipient incompatibility. In AAPS PharmSciTech (Vol. 12, Issue 4). https://doi.org/10.1208/s12249-011-9677-z