Volume : 10, Issue : 11, November – 2023
Title:
NAVIGATING NITROSAMINE IMPURITIES IN PHARMACEUTICAL INDUSTRY
Authors :
Mohit Bajaj, Ketaki Jawalekar, Krishna Vaishnav, Anuj Deshmukh
Abstract :
The discovery of N-nitrosamine impurities in medications and the subsequent appearance of nitrosamine drug substance related impurities (NDSRIs) have presented both regulators and drug product producers with significant challenges. Global regulators have lately taken action in response to the unexpected discovery of nitrosamine impurities in human medicines in order to comprehend the hazards these contaminations pose to patients and to limit their presence. NDSRIs are primarily connected to drug product reactions, which adds a special complication. There are known to be over 300 nitrosamines, several of which are powerful mutagenic carcinogens. The discovery of N-nitroso-dimethylamine (NDMA) in valsartan from one manufacturer in 2018 alerted regulators to the existence of nitrosamines in EU pharmaceuticals for the first time. N-nitroso dimethylamine (NDMA) and N-nitroso-diethylamine (NDEA) garnered significant attention. Since then, these have been verified in a variety of pharmaceuticals, including ranitidine and metformin. The present technical understanding of the various NDSRIs, impurity generation, risk factors, reaction conditions, analytical methods for detection, and potential mitigation strategies will all be covered in this study. We will explore the enormous gaps in mechanistic knowledge that still exist while also highlighting the scientific advancements that have been made in this area of study, which is currently under development.
KEYWORDS: N-nitrosamine, Sartans, Ranitidine, Metformin, Mutagenic impurities, Carcinogenicity.
Cite This Article:
Please cite this article in Mohit Bajaj et al, Navigating Nitrosamine Impurities In Pharmaceutical Industry, Indo Am. J. P. Sci, 2023; 10 (11).
Number of Downloads : 10
References:
1. World Health Organization (WHO). Information Note Nitrosamine impurities [displayed 24 September 2020]. Available at https://www.who.int/medicines/publications/ drug alerts/InformationNote_Nitrosamine-impurities/en.
2. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk [displayed 7 March 2021]. p. 6. Available at: https://www.ema.europa.eu/en/documents/ scientific-guideline/ich-guideline-m7r1-assessment-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit_ en.pdf
3. Brian Byrd, J., Chertow, G.M., Bhalla, V., 2019. Hypertension hot potato-Anatomy of the angiotensin-receptor blocker recalls. N. Engl. J https://doi.org/10.1056/NEJMp1901657
4. Shaikh T, Gosar A and Sayyed H. Nitrosamine Impurities in Drug Substances and Drug Products, Journal of Advances in Pharmacy Practices,2020;2(1): 48–57.
5. Shaik K, Sarmah B and Wadekar G. Regulatory Updates and Analytical Methodologies for Nitrosamine Impurities Detection in Sartans, Ranitidine, Nizatidine, and Metformin along with Sample Preparation Techniques, Critical Reviews in Analytical Chemistry,2020;1-9
6. Aloka Srinivasan (2019), “Proactive Evaluation of Possible Genotoxic Impurities during the Early Stages of Drug Development”, http://www.pharmtech.com.
7. G. Subba Rao (1980), “Nitrosarnines from drugs and nitrite: potential source of chemical carcinogens in humans”, Pharmacy International, Volume 1, pp. 187-190. 9. “Information on nitrosamines for marketing authorization holders”, European Medicines Agency, pp. 1-10, EMA/CHMP/428592/2019 Rev. 2.
8. U. S. Food and Drug Administration update (Jan 25, 2019), “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”, https://www.fda.gov.
9. EMA, “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral onnitrosamineimpuritiesinhumanmedicinalproducts.”202 0,5,726. EMA/409815 /2020
10. Taniguchi J, Alite H, Heinlein C and Cannon K. Nitrosamines in Pharmaceuticals: Toxicity, Risk Analysis, Chemistry, and Test Methods. American Pharmaceutical the Review of American Pharmaceutical Business & Technology,2020;23(1):42-48.
11. Park J, Jung-eun S, Jee-yeon L, Kwon H. Distribution of Seven N- Nitrosamines in Food, Toxicological Research,2015;31 (3):279-288.
12. Rao G.S. N-Nitrosamines from drugs and nitrite: potential source of chemical carcinogens in humans, Pharmacyinternational,2015;190:187-190.
13. European Medicines Agency (2019), “EMA advises companies on steps to take to avoid nitrosamines in human medicines”, https://www.ema.europa.e u, EMA/511347/2019
14. Mergens, W. J.; Newmark, H. L. Antioxidants as Blocking Agents Against Nitrosamine Formation BT-Autoxidation in Food and Biological Systems; Simic, M. G., Karel, M., Eds.; Springer US: Boston, MA, 1980; pp 387−403. DOI: 10.1007/978-1-4757-9351-2_21.
15. Lim, D. S.; Lim, S. K.; Kim, M. K.; Kwon, Y. C.; Roh, T. H.; Choi, S. M.; Yoon, S.; Kim, H. S.; Lee, B.-M. Formation and Inhibition of N-Nitroso diethanolamine in Cosmetics under PH, Temperature, and Fluorescent, Ultraviolet, and Visual Light. J. Toxicol. Environ. Heal. Part A 2018, 81 (9), 241−253.
16. Rőszer, T. The Biology of Subcellular Nitric Oxide; Springer: Dordrecht, Netherlands, 2012.
17. Rousseau, B.; Rosazza, J. P. N. Reaction of Ferulic Acid with Nitrite: Formation of 7-Hydroxy-6-Methoxy-1,2(4H)-Benzoxazin-4- One. J. Agric. Food Chem. 1998, 46 (8), 3314−3317.
18. Napolitano, A.; d’Ischia, M. New Insights into the Acid Promoted Reaction of Caffeic Acid and Its Esters with Nitrite: Decarboxylation Drives Chain Nitrosation Pathways toward Novel Oxime Derivatives and Oxidation/Fragmentation Products Thereof. J. Org. Chem. 2002, 67 (3), 803−810.
19. Beard JC, Swager TM. An organic chemist’s guide to N-nitrosamines: their structure, reactivity, and role as contaminants. J Org Chem. 2021;86(3):2037–2057.
20. Brambilla G, Martelli A. Genotoxic and carcinogenic risk to humans of drug −nitrite interaction products. Mutat Res/Rev Mutat Res. 2007;635(1):17–52.
21. Brambilla G, Martelli A. Update on genotoxicity and carcinogenicity testing of 472 marketed pharmaceuticals. Mutat Res. 2009;681(2-3):209–229
22. Abe, Y., Yamamoto, E., Yoshida, H., Usui, A., Tomita, N., Kanno, H., Masada, S., Yokoo, H., Tsuji, G., Uchiyama, N., Hakamatsuka, T., Demizu, Y., Izutsu, K.-I., Goda, Y., Okuda, H., 2020. Temperature-Dependent Formation of N-Nitroso dimethylamine during the Storage of Ranitidine Reagent Powders and Tablets. Chem. Pharm. Bull. 68, 1008–1012. https://doi.org/10.1248/cpb.c20- 00431.
23. European Medicines Agency (EMA). Angiotensin-II-receptor antagonists (sartans) containing a tetrazole group.2021. https://www. ema.europa.eu/en/medicines/human/referrals/angiotensin-ii-receptor-antagonists-sartancontaining-tetrazole-group.
24. European Medicines Agency (EMA). Ranitidine-containing medicinal products. 2020. https://www.ema.europa.eu/en/medicines/human/referrals/ranitidine-containing-medicinal-products
25. European Medicines Agency (EMA). Nitrosamine impurities in human medicinal products. Procedure under Article 5(3) of Regulation EC (No) 726/2004. 2020. https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490 assessment-report_en.pdf.
26. ICH guideline M7(R1) on assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. 2018. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-guideline-m7r1 assessment-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit_en.pdf.
27. 1. Solanki R. Impurity profiling of active pharmaceutical ingredients and finished drug products, International Journal of Drug Research and Technology, 2012; 2 (3):231-238
28. EMA, “Lessons learnt from presence of N-nitrosamine impurities in sartanmedicinesOverviewandrecommendations.”2019EM A/526934/2019
29. FDA Press Release (July, 2018), “FDA announces voluntary recall of several medicines containing valsartan following detection of an impurity,” APHA.
30. EMA Press Release (September 21, 2018), “Valsartan: Review of Impurities Extended to Other Sartan Medicines,” EMA, Available at https://www.ema.europa.eu.
31. Chang Chau Chan, Lee Y.C, Harman Lam, Xui Ming Zhang (2004), “Analytical method validation and instrument performance verification”, John Wiley and Sons. Pp. 320, ISBN: 978-0-471-25953-4
32. European Medicines Agency (2019), “Temporary interim limits for NMBA, DIPNA and EIPNA impurities in sartan blood pressure medicines”, EMA/351053/2019 rev. 1.
33. U. S. Food and Drug Administration (FDA). Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products. 2021. https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drugsubstance-relatedimpurities.
34. U.S. Food and Drug Administration Inactive Ingredients Database. https://www.fda.gov/drugs/drugapprovals-and-databases/inactive-ingredients-database-download