A Computational Approach for Deriving Acceptable Intake (AI) of Nitrosamine Drug Substance Related Impurities (NDSRIs): A Read-Across and QSAR Based Framework
Main Article Content
Abstract
Background: N-nitrosamines, particularly nitrosamine drug substance-related impurities (NDSRIs), have become an important pharmaceutical safety concern following recalls of several medicines. Although acceptable intake (AI) values are established for some simple nitrosamines, approaches for deriving AI values for structurally complex NDSRIs remain limited.
Methods: A literature-based dataset of 25 commonly prescribed active pharmaceutical ingredients (APIs) with potential nitrosamine risk was assembled. Carcinogenicity and mutagenicity were evaluated using DEREK Nexus®, SARAH Nexus®, Case Ultra®, and complementary freely accessible computational tools. Structural read-across was employed to identify compounds with available carcinogenicity information, including TD50 values. Where applicable, AI values were derived according to the ICH M7 principle (AI = TD50/50,000). Losartan and ranitidine were used as representative examples to examine the applicability of the computational framework.
Results: The integrated read-across and QSAR-based approach enabled computational assessment of carcinogenicity and mutagenicity and supported the derivation of AI values for selected NDSRIs. The framework provided a organised and comparatively resource-efficient approach for prioritizing compounds requiring further confirmatory evaluation.
Conclusion: The proposed computational framework provides a transparent and scalable strategy for preliminary AI derivation and risk assessment of NDSRIs. It may assist pharmaceutical manufacturers and regulatory scientists in identifying potential nitrosamine-related risks and prioritizing compounds for further experimental and regulatory assessment.
Downloads
Article Details
Section
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The Journal is owned, published and copyrighted by the Nigerian Medical Association, River state Branch. The copyright of papers published are vested in the journal and the publisher. In line with our open access policy and the Creative Commons Attribution License policy authors are allowed to share their work with an acknowledgement of the work's authorship and initial publication in this journal.
This is an open access journal which means that all content is freely available without charge to the user or his/her institution. Users are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles in this journal without asking prior permission from the publisher or the author.
The use of general descriptive names, trade names, trademarks, and so forth in this publication, even if not specifically identified, does not imply that these names are not protected by the relevant laws and regulations. While the advice and information in this journal are believed to be true and accurate on the date of its going to press, neither the authors, the editors, nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.
TNHJ also supports open access archiving of articles published in the journal after three months of publication. Authors are permitted and encouraged to post their work online (e.g, in institutional repositories or on their website) within the stated period, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access). All requests for permission for open access archiving outside this period should be sent to the editor via email to editor@tnhjph.com.
How to Cite
References
Kashinath KP, Sardar MS, Roy S, Kumar A, Kaity S. Pharmaceutical Nitrosamines: A Comprehensive Review of Health Risks, Detection, Mitigation Strategies Supplemented with CYP450 Interactions as Molecular Simulations for Mechanistic Insight into Carcinogenicity. Molecular Pharmaceutics. 2025 Jul 25;22(9):5139-64. https://doi.org/10.1021/acs.molpharmaceut.4c01173
Snodin DJ. Mutagenic impurities in pharmaceuticals: A critical assessment of the cohort of concern with a focus on N-nitrosamines. Regulatory Toxicology and Pharmacology. 2023 Jun 1;141:105403. https://doi.org/10.1016/j.yrtph.2023.105403
Bhirud D, Agrawal G, Shah H, Patel A, Palkar MB, Bhattacharya S, Prajapati BG. Nitrosamine impurities in pharmaceuticals: an empirical review of their detection, mechanisms, and regulatory approaches. Current Topics in Medicinal Chemistry. 2024 Mar 1;24(6):503-22. https://doi.org/10.2174/0115680266278636240125113509
Vogel M, Norwig J. Analysis of genotoxic N-nitrosamines in active pharmaceutical ingredients and market authorized products in low abundance by means of liquid chromatography–tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis. 2022 Sep 20;219:114910. https://doi.org/10.1016/j.jpba.2022.114910
Manchuri KM, Shaik MA, Gopireddy VS, Sultana N, Gogineni S. Analytical methodologies to detect n-nitrosamine impurities in active pharmaceutical ingredients, drug products and other matrices. Chemical Research in Toxicology. 2024 Aug 19;37(9):1456-83. https://doi.org/10.1021/acs.chemrestox.4c00234
Tuesuwan B, Vongsutilers V. Nitrosamine contamination in pharmaceuticals: threat, impact, and control. Journal of Pharmaceutical Sciences. 2021 Sep 1;110(9):3118-28. https://doi.org/10.1016/j.xphs.2021.04.021
Johnson GE, Dobo K, Gollapudi B, Harvey J, Kenny J, Kenyon M, Lynch A, Minocherhomji S, Nicolette J, Thybaud V, Wheeldon R. Permitted daily exposure limits for noteworthy N‐nitrosamines. Environmental and molecular mutagenesis. 2021 Jun;62(5):293-305. https://doi.org/10.1002/em.22446
Santos CE. *Strategies of development, assessment and application of in silico models for toxicity assessment of chemical structures of toxicological interest* (Doctoral dissertation, Universidade de São Paulo). https://doi.org/11606/T.60.2024.tde-22052025-095604
Woolley DR, Johnson GE, Cross KP. Risk (Re) Assessment of N-Methyl-N-nitrosophenethylamine for use in computing risk levels of N-Nitrosamine Drug Substance Related Impurities. Regulatory Toxicology and Pharmacology. 2025 Jun 16:105888. https://doi.org/10.1016/j.yrtph.2025.105888
Charoo NA, Dharani S, Khan MA, Rahman Z. Nitroso impurities in drug products: an overview of risk assessment, regulatory milieu, and control strategy. AAPS PharmSciTech. 2023 Feb 9;24(2):60. https://doi.org/10.1208/s12249-023-02523-w
Khare R. Quality Risk Analysis: The Key to Failure Prevention. InApproved: The Life Cycle of Drug Development 2025 Apr 30 (pp. 531-547). Cham: Springer Nature Switzerland. https://doi.org/10.1007/978-3-031-81787-8_16
Dhansekar N, Rale P, Ghalsasi Y. The Presence of Nitrosamines and Nitrosamine Drug-Related Substances in Pharmaceutical Products: An Overview of Regulatory Concerns, Analytical Methodologies, and Control Strategies. Current Drug Safety. 2025 Nov;20(4):404-14. https://doi.org/10.2174/0115748863324951241028050225
Slagboom TN, van Bunderen CC, De Vries R, Bisschop PH, Drent ML. Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines. Pituitary. 2023 Aug;26(4):319-32. https://doi.org/10.1007/s11102-023-01322-7
Chushak Y, Keebaugh A, Clewell RA. Prediction of Respiratory Irritation and Respiratory Sensitization of Chemicals Using Structural Alerts and Machine Learning Modeling. Toxics. 2025 Mar 25;13(4):243. https://doi.org/10.3390/toxics13040243
Danieli A, Colombo E, Raitano G, Lombardo A, Roncaglioni A, Manganaro A, Sommovigo A, Carnesecchi E, Dorne JL, Benfenati E. The VEGA tool to check the applicability domain gives greater confidence in the prediction of in silico models. International Journal of Molecular Sciences. 2023 Jun 8;24(12):9894. https://doi.org/10.3390/ijms24129894
Schultz TW, Chapkanov A, Kutsarova S, Mekenyan OG. Assessment of uncertainty and credibility of predictions by the OECD QSAR Toolbox automated read-across workflow for predicting acute oral toxicity. Computational Toxicology. 2022 May 1;22:100219. https://doi.org/10.1016/j.comtox.2022.100219
Aishwarya D, RamakantDhampalwar V, Pallaprolu N, Peraman R. Nitrosamine Drug Substance-Related Impurities (NDSRIs) in Pharmaceuticals: Formation, Mitigation Strategies, and Emphasis on Mutagenicity Risks. Pharmaceutical Research. 2025 Apr 23:1-32. https://doi.org/10.1007/s11095-025-03857-9
Bercu JP, Masuda-Herrera M, Trejo-Martin A, Sura P, Jolly R, Kenyon M, Thomas R, Ponting DJ, Snodin D, Tuschl G, Simon S. Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs). Regulatory Toxicology and Pharmacology. 2023 Aug 1;142:105415. https://doi.org/10.1016/j.yrtph.2023.105415
Glevitzky M, Glevitzky I, Mucea-Ștef P, Popa M, Dumitrel GA, Vică ML. Integrated Risk Framework (IRF)—interconnection of the Ishikawa diagram with the enhanced HACCP system in risk assessment for the sustainable food industry. Sustainability. 2025 Jan 12;17(2):536. https://doi.org/10.3390/su17020536
Solikha NR, Marodiyah I. Risk Management in Production using Quality Risk Approach and FMEA. Indonesian Journal of Law and Economics Review. 2024 Oct 3;19(4):10-21070. https://doi.org/10.21070/ijler.v19i4.1169