N-nitrosamine impurity; Risk assessment; Carcinogenicity; Pharmaceuticals; FDA; EMA
Precision for document type :
Review article
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Zhang, Yue ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Widart, Joëlle ; Université de Liège - ULiège > Département de pharmacie
Ziemons, Eric ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Hubert, Philippe ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Hubert, Cédric ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Language :
English
Title :
N-nitrosamine risk assessment in pharmaceuticals: Where are we from a regulatory point of view in 2025?
Publication date :
21 July 2025
Journal title :
Journal of Pharmaceutical and Biomedical Analysis Open
U.S. Food & Drug Administration. Control of Nitrosamine Impurities in Human Drugs Guidance for Industry, Revision 2. 2024.
Beard, J.C., Swager, T.M., An organic chemist's guide to N-nitrosamines: their structure, reactivity, and role as contaminants. J. Org. Chem. 86 (2021), 2037–2057, 10.1021/acs.joc.0c02774.
Park, J.E., Seo, J.E., Lee, J.Y., Kwon, H., Distribution of seven N-nitrosamines in food. Toxicol. Res. 31 (2015), 279–288, 10.5487/TR.2015.31.3.279.
International Agency for Reserach on Cancer, List of Classifications, 2024. 〈https://monographs.iarc.who.int/list-of-classifications〉 (Accessed 13 November 2024).
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH M7(R2) Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, 2023.
Martin, J., Krum, H., Role of valsartan and other angiotensin receptor blocking agents in the management of cardiovascular disease. Pharmacol. Res. 46 (2002), 203–212, 10.1016/S1043-6618(02)00092-0.
European Medicines Agency. Assessment Report – Referral Under Article 31 of Directive 2001/83/EC Angiotensin-II-receptor Antagonists (Sartans) Containing a Tetrazole Group. 2019.
U.S. Food & Drug Administration. FDA Statement on FDA's Ongoing Investigation Into Valsartan Impurities and Recalls and an Update on FDA's Current Findings, 2018 (〈 https://www.fda.gov/news-events/press-announcements/fda-statement-fdas-ongoing-investigation-valsartan-impurities-and-recalls-and-update-fdas-current〉 (Accessed 13 November 2024)).
U.S. Food & Drug Administration. FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan), 2019 (〈 https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan〉 (Accessed 13 November 2024)).
U.S. Food & Drug Administration, FDA Updates and Press Announcements on NDMA in Zantac (ranitidine), 2020. 〈https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine〉 (Accessed 13 November 2024).
European Medicines Agency, Ranitidine-containing medicinal products – referral, n.d. 〈https://www.ema.europa.eu/en/medicines/human/referrals/ranitidine-containing-medicinal-products〉 (Accessed 13 November 2024).
U.S. Food & Drug Administration, FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended-Release Products, FDA Alerts Patients and Health Care Professionals to Nitrosamine Impurity Findings in Certain Metformin Extended-Release Products, 2020. (Accessed 13 November 2024).
European Medicines Agency. Nitrosamine Impurities: The Network's Response. 2019 〈https://www.ema.europa.eu/en/annual-report/2019/nitrosamine-impurities-networks-response.html〉 (Accessed 13 November 2024).
U.S. Food & Drug Administration, FDA Updates and Press Announcements on Nitrosamines in Rifampin and Rifapentine, 2021. 〈 https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamines-rifampin-and-rifapentine#:∼:text=Theacceptableintakelimitsare,partspermillion(ppm)〉. (Accessed 13 November 2024).
U.S. Food & Drug Administration. Laboratory Analysis of Valsartan Products, 2019 (〈 https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-analysis-valsartan-products〉 (Accessed 13 November 2024)).
U.S. Food & Drug Administration. Laboratory Tests. 2019, Ranitidine (〈 https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-ranitidine#:∼:text=NDMAwaspresentinall,ingestionbasedonlifetimeexposure〉 (Accessed 13 November 2024)).
U.S. Food & Drug Administration. Laboratory Tests. 2020, Metformin 〈https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-tests-metformin〉 (Accessed 13 November 2024).
U.S. Food & Drug Administration. Laboratory Analysis of Rifampin/Rifapentine Products, 2021 (〈 https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-analysis-rifampinrifapentine-products〉 (Accessed 13 November 2024)).
U.S. Food & Drug Administration. FDA Updates and Press Announcements on Nitrosamine in Varenicline (Chantix). 2022 (〈 https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix#:∼:text=Updat%5B9%2F17%2F2021,N-nitroso-vareniclinelevels〉 (Accessed 13 November 2024)).
Bulger, P.G., Jones, M.T., Ford, J.G., Schrier, K., Cole, K.P., Bernardoni, F., Dirat, O., Zhang, Q., Chahrour, O., Miller, J., Bonaga, L., Parsons, A.T., Yang, L., Risk assessment and control of N-nitrosamines in antibody-drug conjugates: current industry practices. Org. Process Res. Dev. 28 (2024), 3078–3084, 10.1021/acs.oprd.4c00254.
Chahrour, O., Bulger, P.G., Dirat, O., Schrier, K., Parsons, A.T., Ford, J.G., Bernardoni, F., Hetrick, E.M., Bonaga, L.R., Cole, K.P., Miller, J., Zhang, Q., Jones, M.T., Risk evaluation of N-nitrosamines in drug-linker intermediates used to generate antibody-drug conjugates. Org. Process Res. Dev. 28 (2024), 3085–3093, 10.1021/acs.oprd.4c00255.
United States Pharmacopoeia, Nitrosamines Exchange, n.d. 〈https://nitrosamines.usp.org/〉 (Accessed 13 November 2024).
Vikram, H.P.R., Kumar, T.P., Kumar, G., Beeraka, N.M., Deka, R., Suhail, S.M., Jat, S., Bannimath, N., Padmanabhan, G., Chandan, R.S., Kumar, P., Gurupadayya, B., Nitrosamines crisis in pharmaceuticals − Insights on toxicological implications, root causes and risk assessment: a systematic review. J. Pharm. Anal., 14, 2024, 100919, 10.1016/j.jpha.2023.12.009.
United States Pharmacopoeia, Nitrosamine impurities, n.d. 〈https://www.usp.org/impurities/nitrosamine-impurities〉 (Accessed 13 November 2024).
U.S. Food & Drug Administration. Control of Nitrosamine Impurities in Human Drugs Guidance for Industry, Revision 1. 2021.
World Health Organization, WHO good manufacturing practices considerations for the prevention and control of nitrosamine contamination in pharmaceutical products, draft working document for comments, 2024.
European Medicines Agency, Questions and answers for marketing authorisation 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, Revision 21, 2024.
United States Pharmacopeial Convention. <1469> Nitrosamine impurities. United States Pharmacopoeia, 2024.
European Directorate for the Quality of Medicines & HealthCare, 2.5.42. N-nitrosamines in active substances, in: Eur. Pharmacopoeia, 11.0, n.d., pp. 199–203.
Parr, M.K., Joseph, J.F., NDMA impurity in valsartan and other pharmaceutical products: analytical methods for the determination of N-nitrosamines. J. Pharm. Biomed. Anal. 164 (2019), 536–549, 10.1016/j.jpba.2018.11.010.
Manchuri, K.M., Shaik, M.A., Gopireddy, V.S.R., Sultana, N., Gogineni, S., Analytical methodologies to detect N-nitrosamine impurities in active pharmaceutical ingredients, drug products and other matrices. Chem. Res. Toxicol. 37 (2024), 1456–1483, 10.1021/acs.chemrestox.4c00234.
Akkaraju, H., Tatia, R., Mane, S.S., Khade, A.B., Dengale, S.J., A comprehensive review of sources of nitrosamine contamination of pharmaceutical substances and products. Regul. Toxicol. Pharm., 139, 2023, 105355, 10.1016/j.yrtph.2023.105355.
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. 31 (2023), 295–311, 10.1016/j.jsps.2022.12.010.
Tsuji, G., Yokoo, H., Demizu, Y., Abe, Y., Masada, S., Uchiyama, N., Tsutsumi, T., Yamamoto, E., Nitrosamine contamination of pharmaceuticals: cases in Japan, formation mechanisms, detection methods, regulatory perspectives, and insights. J. Pharm. Biomed. Anal. Open, 4, 2024, 100034, 10.1016/j.jpbao.2024.100034.
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., The landscape of potential small and drug substance related nitrosamines in pharmaceuticals. J. Pharm. Sci. 112 (2023), 1287–1304, 10.1016/j.xphs.2022.11.013.
S. Cloëz, M. Frick, TAG Information Note: N-nitrosamines and Tuberculosis Medicines Rifampicin and Rifapentine, 2021.
U.S. Food & Drug Administration. CDER Nitrosamine Impurity Acceptable Intake Limits, 2025 (〈 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits〉 (Accessed 20 April 2025)).
FDA guidance document, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs), Guidance for Industry, 2023.
Kruhlak, N.L., Schmidt, M., Froetschl, R., Graber, S., Haas, B., Horne, I., Horne, S., King, S.T., Koval, I.A., Kumaran, G., Langenkamp, A., McGovern, T.J., Peryea, T., Sanh, A., Siqueira Ferreira, A., van Aerts, L., Vespa, A., Whomsley, R., Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: development and application of the Carcinogenic Potency Categorization Approach (CPCA). Regul. Toxicol. Pharm., 150, 2024, 105640, 10.1016/j.yrtph.2024.105640.
Chakravarti, S., Saiakhov, R.D., Girireddy, M., Confidence score calculation for the carcinogenic potency categorization approach (CPCA) predictions for N-nitrosamines. Comput. Toxicol., 29, 2024, 100298, 10.1016/j.comtox.2023.100298.
Gold, L.S., Slone, T.H., Bernstein, L., Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database. Environ. Health Perspect. 79 (1989), 259–272, 10.1289/ehp.8979259.
Gold, L.S., Slone, T.H., Manley, N.B., Garfinkel, G.B., Hudes, E.S., Rohrbach, L., Ames, B.N., The Carcinogenic Potency Database: analyses of 4000 chronic animal cancer experiments published in the general literature and by the U.S. National Cancer Institute/National Toxicology Program. Environ. Health Perspect. 96 (1991), 11–15, 10.1289/ehp.919611.
Organisation for Economic Co-operation and Development. Test Guideline No. 488: Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays. OECD Guidel. Test. Chem. Sect., 4, 2025, 10.1787/9789264203907-en.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH Q2(R2) Validation of Analytical Procedures, 2023.
Zhang, Y., Houari, S., Van Laethem, T., Dispas, A., Ziemons, E., Hubert, P., Hubert, C., Innovative QSRR modeling approach for the development of an ultra-sensitive LC-MS/MS method for trace analysis of N-nitrosamines. J. Pharm. Biomed. Anal. Open, 5, 2025, 100064, 10.1016/j.jpbao.2025.100064.
Luo, F., Liu, Y., Xie, Y., Hou, W., Zhang, L., Zhang, Z., Simultaneous determination of 13 nitrosamine impurities in biological medicines using salting-out liquid-liquid extraction coupled with liquid chromatography tandem mass spectrometry. J. Pharm. Biomed. Anal., 218, 2022, 114867, 10.1016/j.jpba.2022.114867.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, 2000.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH Q3A(R2) Impurities in new Drug Substances, 2006.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH Q3B(R2) Impurities in New Drug Products, 2006.
Baumann, M., Baxendale, I.R., Ley, S.V., Nikbin, N., An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals. Beilstein J. Org. Chem. 7 (2011), 442–495, 10.3762/bjoc.7.57.
Snodin, D.J., Elder, D.P., Short commentary on NDMA (N-nitrosodimethylamine) contamination of valsartan products. Regul. Toxicol. Pharm. 103 (2019), 325–329, 10.1016/j.yrtph.2019.01.007.
Ray, A., Atal, S., Sadasivam, B., Understanding the molecular-pharmaceutical basis of sartan recalls focusing on valsartan. Glob. Cardiol. Sci. Pract., 25, 2020, 10.21542/gcsp.2020.25.
Burns, M.J., Teasdale, A., Elliott, E., Barber, C.G., Controlling a cohort: use of mirabilis-based purge calculations to understand nitrosamine-related risk and control strategy options. Org. Process Res. Dev. 24 (2020), 1531–1535, 10.1021/acs.oprd.0c00264.
Jireš, J., Douša, M., Gibala, P., Kubelka, T., N-nitrosation in the absence of nitrosating agents in pharmaceuticals?. J. Pharm. Biomed. Anal., 218, 2022, 114872, 10.1016/j.jpba.2022.114872.
Kosuri, E.R., Bhanti, M., Jaywant, M.A., Han, M., Wang, X., Obeng, M., A GC-MS/MS method for trace level quantification of six nitrosamine impurities (NDMA, NDEA, NEIPA, NDIPA, NDPA, and NDBA) in commercially used organic solvents: dichloromethane, ethyl acetate, toluene, and o-xylene. J. Pharm. Sci. 112 (2022), 1225–1230, 10.1016/j.xphs.2022.11.024.
Jireš, J., Douša, M., Nitrites as precursors of N-nitrosation in pharmaceutical samples – a trace level analysis. J. Pharm. Biomed. Anal., 213, 2022, 114677, 10.1016/j.jpba.2022.114677.
Baumann, M., Näf, K., Quantification of nitrite in excipients and chemicals: a versatile and highly sensitive method using headspace gas chromatography coupled to mass spectrometry. Org. Process Res. Dev. 28 (2024), 3217–3228, 10.1021/acs.oprd.4c00115.
Dirat, O., Urquhart, M.W., Akehurst, H., Burns, M.J., Dobo, K.L., Harvey, J., Kuhl, N., Schlingemann, J., Tomlin, P., Wetter, C., Drug substance and drug product workflows for quality risk management for the presence of nitrosamines in medicines. Org. Process Res. Dev. 29 (2025), 1538–1553, 10.1021/acs.oprd.5c00097.
Narang, A.S., Mantri, R.V., Raghavan, K.S., Excipient compatibility and functionality. Dev. Solid Oral Dos. Forms Pharm. Theory Pract. Second Ed., Second Edi, 2017, 151–179, 10.1016/B978-0-12-802447-8.00006-6.
Boetzel, R., Schlingemann, J., Hickert, S., Korn, C., Kocks, G., Luck, B., Blom, G., Harrison, M., François, M., Allain, L., Wu, Y., Bousraf, Y., A nitrite excipient database: a useful tool to support n-nitrosamine risk assessments for drug products. J. Pharm. Sci. 112 (2023), 1615–1624, 10.1016/j.xphs.2022.04.016.
Schlingemann, J., Hickert, S., Blom, G., Kocks, G., Allain, L., Letter to the editor of Heliyon re: determination of dimethylamine and nitrite in pharmaceuticals by ion chromatography to assess the likelihood of nitrosamine formation Heliyon. 2021; 77: e06179. Heliyon, 8, 2022, e09607, 10.1016/j.heliyon.2022.e09607.
Schlingemann, J., Boucley, C., Hickert, S., Bourasseau, L., Walker, M., Celdran, C., Chemarin, T., Pegues, C., Fritzsche, M., Keitel, J., Goettsche, A., Seegel, M., Leicht, S., Guessregen, B., Reifenberg, P., Wetzel, S., Müller, T., Schooren, F., Schuster, T., Liebhold, M., Kirsch, A., Krueger, P., Saal, C., Mouton, B., Masanes, S., Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite. Int. J. Pharm., 620, 2022, 121740, 10.1016/j.ijpharm.2022.121740.
Nawrocki, J., Andrzejewski, P., Nitrosamines and water. J. Hazard. Mater. 189 (2011), 1–18, 10.1016/j.jhazmat.2011.02.005.
European Medicines Agency, EMA/369136/2020 Assessment report, Procedure under Article 5(3) of Regulation EC (No) 726/2004 Nitrosamine impurities in human medicinal products, 2020.
Xu, B., Chen, Z., Qi, F., Ma, J., Wu, F., Rapid degradation of new disinfection by-products in drinking water by UV irradiation: N-nitrosopyrrolidine and N-nitrosopiperidine. Sep. Purif. Technol. 69 (2009), 126–133, 10.1016/j.seppur.2009.07.004.
Stefan, M.I., Bolton, J.R., UV direct photolysis of N-nitrosodimethylamine (NDMA): kinetic and product study. Helv. Chim. Acta 85 (2002), 1416–1426, 10.1002/1522-2675(200205)85:5<1416::AID-HLCA1416>3.0.CO;2-I.
Suresh Kumar, A.B., Dey, D., Balaji, T.S., Karthik, H., Sathishkumar, K., McDaid, P., Fitzpatrick, B., Awasthi, A., Davies, S., Dirat, O., Nitrite in pharmaceutical manufacturing water: development of an ultra-sensitive analytical method, typical data, and discussion of potential nitrosamine formation in drug substance and drug product from water. Org. Process Res. Dev. 28 (2024), 2614–2622, 10.1021/acs.oprd.4c00037.
Cioc, R.C., Joyce, C., Mayr, M., Bream, R.N., Formation of N-nitrosamine drug substance related impurities in medicines: a regulatory perspective on risk factors and mitigation strategies. Org. Process Res. Dev. 27 (2023), 1736–1750, 10.1021/acs.oprd.3c00153.
Tank, D., Karan, K., Gajera, B.Y., Dave, R.H., Investigate the effect of solvents on wet granulation of microcrystalline cellulose using hydroxypropyl methylcellulose as a binder and evaluation of rheological and thermal characteristics of granules. Saudi Pharm. J. 26 (2018), 593–602, 10.1016/j.jsps.2018.02.007.
Brickman, K.T., How Jet Milling Improves Pharmaceutical Particle Size Reduction, 2024 (〈 https://www.customprocessingservices.com/blog/5-ways-jet-milling-improves-pharmaceutical-particle-size-reduction〉 (Accessed 19 November 2024)).
Amarji, B., Kulkarni, A., Deepika, P.K.Deb, Maheshwari, R., Tekade, R.K., Package development of pharmaceutical products: aspects of packaging materials used for pharmaceutical products. Dos. Form Des. Parameters, II, 2018, 521–552, 10.1016/B978-0-12-814421-3.00015-4.
United States Pharmacopeial Convention. 〈1381〉 Assessment of Elastomeric Component Used in Injectable Pharmaceutical Product Packaging/delivery Systems., 2020, United States Pharmacopoeia.
United States Pharmacopeial Convention. 〈1664.1〉 Orally Inhaled and Nasal Drug Products., 2015, United States Pharmacopoeia.
Zheng, J., Brookes, A., Moser, J., Pfeffer, H., Smith, A., On the risk of nitrosamine contamination during drug product blister packaging. J. Pharm. Sci. 112 (2023), 2321–2325, 10.1016/J.XPHS.2023.07.014.
Golob, N., Grahek, R., Ross, M., Roškar, R., Nitrocellulose blister material as a source of N-nitrosamine contamination of pharmaceutical drug products. Int. J. Pharm., 618, 2022, 121687, 10.1016/j.ijpharm.2022.121687.
Boltres, B., Evaluating nitrosamines from elastomers in pharmaceutical primary packaging. PDA J. Pharm. Sci. Technol. 76 (2022), 136–150, 10.5731/pdajpst.2021.012645.
Jireš, J., Douša, M., Gibala, P., Doubský, J., Pěček, D., Mervart, D., Kluk, A., Veseli, A., Kalášek, S., Řezanka, P., Comprehensive UHPLC–MS screening methods for the analysis of triazolopyrazine precursor and its genotoxic nitroso-derivative in sitagliptin pharmaceutical formulation. J. Pharm. Biomed. Anal., 238, 2024, 115861, 10.1016/j.jpba.2023.115861.
European Directorate for the Quality of Medicines & HealthCare, Metformin hydrochloride, in: Eur. Pharmacopoeia, 11.0, n.d., pp. 3359–60.
Hao, G., Hu, R., Wang, X., Gao, P., Wang, L., Jiang, M., Xin, L., Tan, G., Zhao, Y., Sun, F., Chu, D., Lv, J., You, J., Huang, F., Song, X., N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: effects of metformin and hypromellose used in drug product formulation. J. Pharm. Biomed. Anal., 222, 2023, 115066, 10.1016/j.jpba.2022.115066.
Tian, Y., Tao, X., Feng, Y., Yin, L., Ning, B., Investigation into the genotoxic impurity, 1-methyl-4-nitrosopiperazine, in rifampicin. J. Pharm. Biomed. Anal., 248, 2024, 116303, 10.1016/j.jpba.2024.116303.
Zhu, K., Kerry, M., Serr, B., Mintert, M., Pursch, M., Eeltink, S., Desmet, G., Highly sensitive two-dimensional ion chromatography mass spectrometry method for nitrite determination in hydroxypropyl methylcellulose. J. Pharm. Biomed. Anal., 248, 2024, 116330, 10.1016/j.jpba.2024.116330.
Yamamoto, H., Kagawa, C., Nakajima, T., Nakagomi, J., Kunikyou, S., Kitagawa, T., Mimura, H., Quantitation of reactive nitrosating agents in pharmaceutical excipients for N-nitrosamine risk Assessments. Org. Process Res. Dev. 27 (2023), 1767–1772, 10.1021/acs.oprd.2c00402.
International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans—Some Pharmaceutical Drugs. 1980, WHO, Geneva, Switzerland.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, The Common Technical Document, n.d. 〈 https://www.ich.org/page/ctd〉 (Accessed 10 April 2025).
Schmidtsdorff, S., Neumann, J., Schmidt, A.H., Parr, M.K., Risk assessment for nitrosated pharmaceuticals: a future perspective in drug development. Arch. Pharm. 355 (2022), 1–10, 10.1002/ardp.202100435.
Nitish, S., Rashi, P., Tejaswini, B., Sonali, J., Ravi, P.S., Modified NAP test: a simple and responsive nitrosating methodology for risk evaluation of NDSRIs. J. Pharm. Sci. 112 (2023), 1333–1340, 10.1016/j.xphs.2023.02.024.
Ames, B.N., Mccann, J., Yamasaki, E., Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat. Res. 31 (1975), 347–364, 10.1016/0165-1161(75)90046-1.
Heflich, R.H., Bishop, M.E., Mittelstaedt, R.A., Yan, J., Guerrero, S.K., Sims, A.M., Mitchell, K., Moore, N., Li, X., Mei, N., Elespuru, R.K., King, S.T., Keire, D.A., Kruhlak, N.L., Dorsam, R.T., Raw, A.S., Davis Bruno, K.L., McGovern, T.J., Atrakchi, A.H., Optimizing the detection of N-nitrosamine mutagenicity in the Ames test. Regul. Toxicol. Pharm., 153, 2024, 105709, 10.1016/j.yrtph.2024.105709.
Organisation for Economic Co-operation and Development. Test guideline no. 471: bacterial reverse mutation test. OECD Guidel. Test. Chem. Sect. 4, 2020, 10.1787/9789264071247-en.
McCann, J., Gold, L.S., Horn, L., McGill, R., Graedel, T.E., Kaldor, J., Statistical analysis of Salmonella test data and comparison to results of animal cancer tests. Mutat. Res. 205 (1988), 183–195, 10.1016/0165-1218(88)90017-1.
Bogen, K.T., Improved prediction of carcinogenic potencies from mutagenic potencies for chemicals positive in rodents and the Ames test. Environ. Mol. Mutagen. 25 (1995), 37–49, 10.1002/em.2850250107.
Li, X., Le, Y., Seo, J.E., Guo, X., Li, Y., Chen, S., Mittelstaedt, R.A., Moore, N., Guerrero, S., Sims, A., King, S.T., Atrakchi, A.H., McGovern, T.J., Davis-Bruno, K.L., Keire, D.A., Elespuru, R.K., Heflich, R.H., Mei, N., Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol in bacterial and human in vitro assays. Regul. Toxicol. Pharm., 141, 2023, 105410, 10.1016/j.yrtph.2023.105410.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, ICH Q1A(R2) Stability Testing of New drug Substances and Products, 2003.
Jain, D., Basniwal, P.K., Forced degradation and impurity profiling: recent trends in analytical perspectives. J. Pharm. Biomed. Anal. 86 (2013), 11–35, 10.1016/j.jpba.2013.07.013.
Blessy, M., Patel, R.D., Prajapati, P.N., Agrawal, Y.K., Development of forced degradation and stability indicating studies of drugs - a review. J. Pharm. Anal. 4 (2014), 159–165, 10.1016/j.jpha.2013.09.003.
Pharma, Emery, Pharma, Emery, Ranitidine: FDA Citizen Petition. 2020 〈https://emerypharma.com/news/emery-pharma-ranitidine-fda-citizen-petition/#:∼:text=Alameda%2C CA _ On January 2%2Cbrand names%2C including Zantac%AE〉 (Accessed 20 November 2024).
United States Pharmacopeial Convention. 〈1663〉 Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, 2020, United States Pharmacopoeia.
United States Pharmacopeial Convention. 〈1664〉 Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems, 2024, United States Pharmacopoeia.
Dalkılıç, O., Demircioğlu, İ.H., Çelik, S., Can, H., Akman, T.C., Atila, A., Kılıç, H., Kandemir, L., Method development and validation for determination of N-nitrosamines in pharmaceutical preparations by LC-MS/MS: application to extractables and leachables studies. J. Chromatogr. A, 1745, 2025, 465741, 10.1016/j.chroma.2025.465741.
Murphy, N.S., O'Connor, D.C., Gavins, G.C., James, L., Lockett, J.P., McManus, J.A., Packer, G., Lopez-Rodríguez, R., Webb, S.J., Burns, M.J., Identifying the risk of formation of nitrosamines and other potentially mutagenic impurities during API manufacture using in silico risk assessment. Org. Process Res. Dev. 27 (2023), 1812–1819, 10.1021/acs.oprd.3c00118.
Lhasa Limited, 10 FAQs About Mirabilis: Pharmaceutical Impurity Control Using In Silico Tools, 2024. 〈https://www.lhasalimited.org/blog/10-faqs-about-mirabilis-pharmaceutical-impurity-control-using-in-silico-tools/〉 (Accessed 21 November 2024).
Borths, C.J., Burns, M., Curran, T., Ide, N.D., Nitrosamine reactivity: a survey of reactions and purge processes. Org. Process Res. Dev. 25 (2021), 1788–1801, 10.1021/acs.oprd.1c00162.