{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T08:13:56Z","timestamp":1791015236532,"version":"4.1.0"},"reference-count":107,"publisher":"Elsevier BV","issue":"5","license":[{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/100009945","name":"Merck KGaA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002873","name":"Chulalongkorn University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002873","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jpharmsci.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pharmaceutical Sciences"],"published-print":{"date-parts":[[2023,5]]},"DOI":"10.1016\/j.xphs.2023.01.028","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T20:30:29Z","timestamp":1675456229000},"page":"1192-1209","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":38,"title":["Current Threat of Nitrosamines in Pharmaceuticals and Scientific Strategies for Risk Mitigation"],"prefix":"10.1016","volume":"112","author":[{"given":"Bodin","family":"Tuesuwan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5352-7506","authenticated-orcid":false,"given":"Vorasit","family":"Vongsutilers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.xphs.2023.01.028_bib0001","series-title":"Overall Evaluations of Carcinogenicity: an Updating of IARC Monographs Volumes 1 to 42.7","year":"1987"},{"key":"10.1016\/j.xphs.2023.01.028_bib0002","unstructured":"European Medicines Agency. EMA reviewing medicines containing valsartan from Zhejiang Huahai following detection of an impurity: some valsartan medicines being recalled across the EU. Press release. https:\/\/www.ema.europa.eu\/en\/news\/ema-reviewing-medicines-containing-valsartan-zhejiang-huahai-following-detection-impurity-some. Published 2018. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0003","unstructured":"U.S. Food & Drug Administration. FDA announces voluntary recall of several medicines containing valsartan following detection of an impurity. Press release. https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-announces-voluntary-recall-several-medicines-containing-valsartan-following-detection-impurity. Published 2018. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0004","unstructured":"European Medicines Agency. EMA to review ranitidine medicines following detection of NDMA. Press release. https:\/\/www.ema.europa.eu\/en\/news\/ema-review-ranitidine-medicines-following-detection-ndma. Published 2019. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0005","unstructured":"European Medicines Agency. Suspension of ranitidine medicines in the EU. Press release. https:\/\/www.ema.europa.eu\/en\/news\/suspension-ranitidine-medicines-eu. Published 2020. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0006","unstructured":"U.S. Food & Drug Administration. FDA requests removal of all ranitidine products (Zantac) from the market. Press release. https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-requests-removal-all-ranitidine-products-zantac-market. published 2020. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0007","unstructured":"U.S. Food & Drug Administration. FDA updates and press announcements on NDMA in metformin. Press announcement."},{"key":"10.1016\/j.xphs.2023.01.028_bib0008","unstructured":"U.S. Food & Drug Administration. Questions and Answers: NDMA impurities in metformin products. Q&A. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/questions-and-answers-ndma-impurities-metformin-products. Published 2020. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0009","unstructured":"European Medicines Agency. EMA update on metformin diabetes medicines. Press release. https:\/\/www.ema.europa.eu\/en\/news\/ema-update-metformin-diabetes-medicines. Published 2019. Accessed May 11, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0010","unstructured":"European Medicines Agency. Assessment report: Nitrosamine impurities in human medicinal products procedure number: EMEA\/H\/A-5. https:\/\/www.ema.europa.eu\/en\/human-regulatory\/post-authorisation\/referral-procedures\/nitrosamine-impurities 3(1490) 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0011","unstructured":"European Medicines Agency. EMA advises companies on steps to take to avoid nitrosamines in human medicines. Press release. https:\/\/www.ema.europa.eu\/en\/news\/ema-advises-companies-steps-take-avoid-nitrosamines-human-medicines. Published 2019. Accessed May 19, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0012","unstructured":"European Medicines Agency. Sartan medicines: Companies to review manufacturing processes to avoid presence of nitrosamine impurities. Press release. https:\/\/www.ema.europa.eu\/en\/news\/sartan-medicines-companies-review-manufacturing-processes-avoid-presence-nitrosamine-impurities. Published 2019. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0013","unstructured":"European Medicines Agency. CHMP list of questions to be addressed by the API manufacturers for valsartan-containing medicinal products. https:\/\/www.ema.europa.eu\/en\/documents\/referral\/valsartan-article-31-referral-chmp-list-questions-be-addressed-api-manufacturers-valsartan_en.pdf. 2018."},{"key":"10.1016\/j.xphs.2023.01.028_bib0014","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.jpba.2019.05.022","article-title":"The contamination of valsartan and other sartans, Part 1: new findings","volume":"172","author":"S\u00f6rgel","year":"2019","journal-title":"J Pharm Biomed Anal"},{"issue":"6","key":"10.1016\/j.xphs.2023.01.028_bib0015","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1021\/acs.jmedchem.0c02120","article-title":"Critical analysis of drug product recalls due to nitrosamine impurities","volume":"64","author":"Bharate","year":"2021","journal-title":"J Med Chem"},{"issue":"9","key":"10.1016\/j.xphs.2023.01.028_bib0016","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1248\/cpb.c21-00289","article-title":"N-Nitrosodimethylamine (NDMA) formation from ranitidine impurities: possible root causes of the presence of NDMA in ranitidine hydrochloride","volume":"69","author":"Yokoo","year":"2021","journal-title":"Chem Pharm Bull"},{"issue":"10","key":"10.1016\/j.xphs.2023.01.028_bib0017","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1248\/cpb.c20-00431","article-title":"Temperature-dependent formation of N-nitrosodimethylamine during the storage of ranitidine reagent powders and tablets","volume":"68","author":"Abe","year":"2020","journal-title":"Chem Pharm Bull"},{"key":"10.1016\/j.xphs.2023.01.028_bib0018","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpba.2020.113877","article-title":"Insight into the formation of N-nitrosodimethylamine in metformin products","volume":"195","author":"Jire\u0161","year":"2021","journal-title":"J Pharm Biomed Anal"},{"key":"10.1016\/j.xphs.2023.01.028_bib0019","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijpharm.2022.121687","article-title":"Nitrocellulose blister material as a source of N-nitrosamine contamination of pharmaceutical drug products","volume":"618","author":"Golob","year":"2022","journal-title":"Int J Pharm"},{"key":"10.1016\/j.xphs.2023.01.028_bib0020","doi-asserted-by":"crossref","unstructured":"World Health Organization (WHO). I.A.R.C. monographs on the evaluation of the carcinogenic risk of chemicals to humans: some N-Nitroso compounds. 17. France. 1978.","DOI":"10.1016\/0015-6264(79)90217-7"},{"key":"10.1016\/j.xphs.2023.01.028_bib0021","series-title":"14th Report on Carcinogens","year":"2017"},{"key":"10.1016\/j.xphs.2023.01.028_bib0022","unstructured":"World Health Organization (WHO). List of classifications. Agents classifed by the I.A.A.C. monographs, Volumes 1\u2013132. List of Classifications. https:\/\/monographs.iarc.who.int\/list-of-classifications. Published 2022. Accessed November 27, 2022."},{"issue":"22","key":"10.1016\/j.xphs.2023.01.028_bib0023","doi-asserted-by":"crossref","DOI":"10.3390\/molecules25225304","article-title":"N-Nitrosodimethylamine contamination in the metformin finished products","volume":"25","author":"Zmys\u0142owski","year":"2020","journal-title":"Molecules"},{"key":"10.1016\/j.xphs.2023.01.028_bib0024","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijpharm.2022.121740","article-title":"Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite","volume":"620","author":"Schlingemann","year":"2022","journal-title":"Int J Pharm"},{"issue":"3","key":"10.1016\/j.xphs.2023.01.028_bib0025","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1208\/s12248-022-00702-4","article-title":"International regulatory collaboration on the analysis of nitrosamines in metformin-containing medicines","volume":"24","author":"Keire","year":"2022","journal-title":"AAPS J"},{"key":"10.1016\/j.xphs.2023.01.028_bib0026","unstructured":"U.S. Food & Drug Administration. Questions and Answers: NDMA impurities in ranitidine (commonly known as Zantac). https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/questions-and-answers-ndma-impurities-ranitidine-commonly-known-zantac. Published 2020. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0027","unstructured":"Therapeutic Goods Administration (TGA). Ranitidine update 2 - contamination with N-nitrosodimethylamine. Press release. https:\/\/www.tga.gov.au\/news\/safety-alerts\/ranitidine-0. Published 2020. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0028","unstructured":"U.S. Food & Drug Administration. Laboratory analysis of rifampin\/rifapentine products. Press release. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/laboratory-analysis-rifampinrifapentine-products. Published 2021. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0029","unstructured":"World Health Organization (WHO). Nitrosamine concerns for rifapentine and rifampicin update and FAQs. Press release. https:\/\/extranet.who.int\/pqweb\/sites\/default\/files\/documents\/FAQ_Nitrosamine_18Dec2020.pdf. Published 2020. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0030","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpba.2021.114205","article-title":"The nitrosamine contamination of drugs, part 3: quantification of 4-methyl-1-nitrosopiperazine in rifampicin capsules by LC-MS\/HRMS","volume":"203","author":"Wohlfart","year":"2021","journal-title":"J Pharm Biomed Anal"},{"key":"10.1016\/j.xphs.2023.01.028_bib0031","doi-asserted-by":"crossref","unstructured":"van Haarst A, Smith S, Garvin C, Benrimoh N, Paglialunga S. Rifampin drug\u2013drug\u2013interaction studies: reflections on the nitrosamine impurities issue. Clin Pharmacol Ther. n\/a. doi:10.1002\/cpt.2652.","DOI":"10.1002\/cpt.2652"},{"key":"10.1016\/j.xphs.2023.01.028_bib0032","unstructured":"European Medicines Agency. Highlights from the second meeting of the Nitrosamine Implementation Oversight Group (NIOG). Press release. https:\/\/www.ema.europa.eu\/en\/documents\/report\/highlights-second-meeting-nitrosamine-implementation-oversight-group-niog_en.pdf. Published 2021. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0033","unstructured":"U.S. Food & Drug Administration. Pfizer voluntary nationwide recall of lots of accuretic (quinapril HCl\/hydrochlorothiazide), quinapril and hydrochlorothiazide tablets, and quinapril HCl\/hydrochlorothiazide tablets due to N-nitroso-quinapril content. Company announcement. https:\/\/www.fda.gov\/safety\/recalls-market-withdrawals-safety-alerts\/pfizer-voluntary-nationwide-recall-lots-accuretic-quinapril-hclhydrochlorothiazide-quinapril-and. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0034","unstructured":"Therapeutic Goods Administration (TGA). Quinapril low levels of contamination with N-nitroso-quinapril. Press announcement. https:\/\/www.tga.gov.au\/news\/safety-alerts\/quinapril#:\u223c:text=N-Nitroso-quinaprilisa,water%2Candinairpollution. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0035","unstructured":"Health Canada. Pfizer recalls Accupril blood pressure tablets due to a nitrosamine impurity. Public advisory. https:\/\/recalls-rappels.canada.ca\/en\/alert-recall\/pfizer-recalls-accupril-blood-pressure-tablets-due-nitrosamine-impurity. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0036","unstructured":"U.S. Food & Drug Administration. FDA updates and press announcements on nitrosamine in Varenicline (Chantix). Press announcement. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0037","unstructured":"U.S. Food & Drug Administration. FDA works to avoid shortage of sitagliptin following detection of nitrosamine impurity. Press announcement. https:\/\/www.fda.gov\/drugs\/drug-safety-and-availability\/fda-works-avoid-shortage-sitagliptin-following-detection-nitrosamine-impurity. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0038","unstructured":"Therapeutic Goods Administration (TGA). Sitagliptin Safety advisory - low levels of contamination with a nitrosamine impurity. Press announcement. https:\/\/www.tga.gov.au\/news\/safety-alerts\/sitagliptin. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0039","unstructured":"Health Sciences Authority. Update on nitrosamine impurity in sitagliptin products. Press announcement. https:\/\/www.hsa.gov.sg\/announcements\/safety-alert\/update-on-nitrosamine-impurity-in-sitagliptin-products. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0040","unstructured":"European Medicines Agency. Questions and answers for marketing authorisation holders\/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) https:\/\/www.ema.europa.eu\/en\/documents\/referral\/nitrosamines-emea-h-a53-1490-questions-answers-marketing-authorisation-holders\/applicants-chmp-opinion-article-53-regulation-ec-no-726\/2004-referral-nitrosamine-impurities-human-medicinal-products_en.pdf. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0041","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2020.104749","article-title":"Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data","volume":"116","author":"Thresher","year":"2020","journal-title":"Regul Toxicol Pharmacol"},{"issue":"3-4","key":"10.1016\/j.xphs.2023.01.028_bib0042","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0165-1218(91)90123-4","article-title":"Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential","volume":"259","author":"Tricker","year":"1991","journal-title":"Mutat Res"},{"key":"10.1016\/j.xphs.2023.01.028_bib0043","unstructured":"Therapeutic Goods Administration (TGA). Nitrosamine impurities in medicines - information for sponsors and manufacturers. Press announcement. https:\/\/www.tga.gov.au\/news\/safety-alerts\/nitrosamine-impurities-medicines-information-sponsors-and-manufacturers. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0044","unstructured":"The international council for harmonisation of technical requirements for pharmaceuticals for human use (ICH). ICH M7 assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk - Step 5.; 2017."},{"key":"10.1016\/j.xphs.2023.01.028_bib0045","unstructured":"U.S. Food & Drug Administration. Control of Nitrosamine Impurities in Human Drugs. Guidance for industry. https:\/\/www.fda.gov\/media\/141720\/download. Published 2021. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0046","unstructured":"Lhasa Limited. Lhasa carcinogenicity database. Database. https:\/\/www.lhasalimited.org\/products\/lhasa-carcinogenicity-database.htm#LhasaTD50. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0047","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2021.104926","article-title":"Use of less-than-lifetime (LTL) durational limits for nitrosamines: case study of N-nitrosodiethylamine (NDEA)","volume":"123","author":"Bercu","year":"2021","journal-title":"Regul Toxicol Pharmacol"},{"issue":"2","key":"10.1016\/j.xphs.2023.01.028_bib0048","first-page":"6415","article-title":"Effects on 4080 rats of chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine: a detailed dose-response study","volume":"51","author":"Peto","year":"1991","journal-title":"Cancer Res"},{"key":"10.1016\/j.xphs.2023.01.028_bib0049","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.dnarep.2014.03.009","article-title":"Inter-individual variation in DNA repair capacity: a need for multi-pathway functional assays to promote translational DNA repair research","volume":"19","author":"Nagel","year":"2014","journal-title":"DNA Repair"},{"issue":"11","key":"10.1016\/j.xphs.2023.01.028_bib0050","doi-asserted-by":"crossref","first-page":"2216","DOI":"10.1158\/1055-9965.EPI-06-0455","article-title":"Genes involved in DNA repair and nitrosamine metabolism and those located on chromosome 14q32 are dysregulated in nasopharyngeal carcinoma","volume":"15","author":"Dodd","year":"2006","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"5","key":"10.1016\/j.xphs.2023.01.028_bib0051","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3109\/1354750X.2011.577237","article-title":"Evaluating the effects of genetic variants of DNA repair genes using cytogenetic mutagen sensitivity approaches","volume":"16","author":"Abdel-Rahman","year":"2011","journal-title":"Biomarkers"},{"key":"10.1016\/j.xphs.2023.01.028_bib0052","unstructured":"U.S. Food & Drug Administration. AAM\/CHPA\/PhRMA questions for May 4th FDA-industry meeting to discuss nitrosamine impurities in pharmaceuticals. Presented at the: https:\/\/www.fda.gov\/media\/150864\/download."},{"key":"10.1016\/j.xphs.2023.01.028_bib0053","unstructured":"U.S. Food & Drug Administration. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) method for the determination of NDMA in metformin drug substance and drug product. Test method. https:\/\/www.fda.gov\/media\/134914\/download. Published 2020. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0054","unstructured":"European Medicines Agency. Vildagliptin\/metformin hydrochloride Accord 50 mg\/850 mg film-coated tablets vildagliptin\/metformin hydrochloride Accord 50 mg\/1000 mg film-coated tablets. Summary of product characteristic. https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/vildagliptin\/metformin-hydrochloride-accord-epar-product-information_en.pdf. Accessed November 27, 2022."},{"issue":"4","key":"10.1016\/j.xphs.2023.01.028_bib0055","doi-asserted-by":"crossref","DOI":"10.1002\/ardp.202100435","article-title":"Risk assessment for nitrosated pharmaceuticals: a future perspective in drug development","volume":"355","author":"Schmidtsdorff","year":"2022","journal-title":"Arch Pharm"},{"key":"10.1016\/j.xphs.2023.01.028_bib0056","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.jpba.2017.10.035","article-title":"Artifactual degradation of secondary amine-containing drugs during accelerated stability testing when saturated sodium nitrite solutions are used for humidity control","volume":"149","author":"Sluggett","year":"2018","journal-title":"J Pharm Biomed Anal"},{"key":"10.1016\/j.xphs.2023.01.028_bib0057","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpba.2022.114872","article-title":"N-nitrosation in the absence of nitrosating agents in pharmaceuticals?","volume":"218","author":"Jire\u0161","year":"2022","journal-title":"J Pharm Biomed Anal"},{"issue":"9","key":"10.1016\/j.xphs.2023.01.028_bib0058","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1021\/acs.oprd.0c00323","article-title":"Pathways for N-nitroso compound formation: secondary amines and beyond","volume":"24","author":"L\u00f3pez-Rodr\u00edguez","year":"2020","journal-title":"Org Process Res Dev"},{"issue":"3","key":"10.1016\/j.xphs.2023.01.028_bib0059","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0041-008X(75)90255-0","article-title":"Formation of N-nitroso compounds: Chemistry, kinetics, and in vivo occurrence","volume":"31","author":"Mirvish","year":"1975","journal-title":"Toxicol Appl Pharmacol"},{"issue":"6","key":"10.1016\/j.xphs.2023.01.028_bib0060","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1248\/cpb.47.819","article-title":"Reaction of secondary and tertiary amines with nitric oxide in the presence of oxygen","volume":"47","author":"Itoh","year":"1999","journal-title":"Chem Pharm Bull"},{"issue":"9","key":"10.1016\/j.xphs.2023.01.028_bib0061","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1021\/acs.oprd.0c00224","article-title":"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","volume":"24","author":"Ashworth","year":"2020","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2023.01.028_bib0062","unstructured":"World Health Organization (WHO). Information note: Update on nitrosamine impurities. https:\/\/www.who.int\/medicines\/publications\/drugalerts\/InformationNote_Nitrosamine-impurities\/en\/. Published 2019. Accessed May 9, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0063","unstructured":"U.S. Food & Drug Administration. FDA provides update on its ongoing investigation into valsartan products; and reports on the finding of an additional impurity identified in one firm's already recalled products. Press release. https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-provides-update-its-ongoing-investigation-valsartan-products-and-reports-finding-additional. Published 2018. Accessed December 1, 2020."},{"key":"10.1016\/j.xphs.2023.01.028_bib0064","unstructured":"B\u00fchlmayer P, Ostermayer F, Schmidlin T. Acyl compounds. 1991."},{"issue":"8","key":"10.1016\/j.xphs.2023.01.028_bib0065","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1021\/jm00112a031","article-title":"Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives","volume":"34","author":"Carini","year":"1991","journal-title":"J Med Chem"},{"issue":"22","key":"10.1016\/j.xphs.2023.01.028_bib0066","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1021\/jm00074a018","article-title":"A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists","volume":"36","author":"Bernhart","year":"1993","journal-title":"J Med Chem"},{"key":"10.1016\/j.xphs.2023.01.028_bib0067","unstructured":"Bernhart C, Breliere J-C, Clement J, et al. N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present. 1991."},{"key":"10.1016\/j.xphs.2023.01.028_bib0068","unstructured":"Naka T, Nishikawa K, Kato T. Benzimidazole derivatives, their production and use. 1991."},{"issue":"10","key":"10.1016\/j.xphs.2023.01.028_bib0069","doi-asserted-by":"crossref","DOI":"10.3390\/separations8100162","article-title":"Determination of genotoxic azide impurity in cilostazol API by ion chromatography with matrix elimination","volume":"8","author":"P\u00e1ll","year":"2021","journal-title":"Separations"},{"key":"10.1016\/j.xphs.2023.01.028_bib0070","series-title":"Heterocyclic Drug Discovery","first-page":"221","article-title":"Chapter 8 - FDA approved six-membered ring fused pyrimidine-based derivatives","author":"Arora","year":"2023"},{"issue":"7","key":"10.1016\/j.xphs.2023.01.028_bib0071","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1016\/j.watres.2013.02.017","article-title":"NDMA formation from amine-based pharmaceuticals - impact from prechlorination and water matrix","volume":"47","author":"Shen","year":"2013","journal-title":"Water Res"},{"key":"10.1016\/j.xphs.2023.01.028_bib0072","unstructured":"European Medicines Agency. Lessons learnt from presence of N-nitrosamine impurities in sartan medicines. https:\/\/www.ema.europa.eu\/en\/documents\/report\/lessons-learnt-presence-n-nitrosamine-impurities-sartan-medicines_en.pdf.2020."},{"issue":"1","key":"10.1016\/j.xphs.2023.01.028_bib0073","doi-asserted-by":"crossref","first-page":"39","DOI":"10.38212\/2224-6614.1133","article-title":"N-nitrosodimethylamine (NDMA) contamination of ranitidine products: a review of recent findings","volume":"29","author":"Aldawsari","year":"2021","journal-title":"J Food Drug Anal"},{"issue":"10","key":"10.1016\/j.xphs.2023.01.028_bib0074","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1016\/j.watres.2011.03.035","article-title":"Chloramination of nitrogenous contaminants (pharmaceuticals and pesticides): NDMA and halogenated DBPs formation","volume":"45","author":"Le Roux","year":"2011","journal-title":"Water Res"},{"issue":"2","key":"10.1016\/j.xphs.2023.01.028_bib0075","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1016\/j.watres.2010.09.036","article-title":"Demonstration of 20 pharmaceuticals and personal care products (PPCPs) as nitrosamine precursors during chloramine disinfection","volume":"45","author":"Shen","year":"2011","journal-title":"Water Res"},{"issue":"17","key":"10.1016\/j.xphs.2023.01.028_bib0076","doi-asserted-by":"crossref","first-page":"5687","DOI":"10.1016\/j.watres.2011.08.034","article-title":"NDMA formation kinetics from three pharmaceuticals in four water matrices","volume":"45","author":"Shen","year":"2011","journal-title":"Water Res"},{"key":"10.1016\/j.xphs.2023.01.028_bib0077","article-title":"Ranitidine: a proposed mechanistic rationale for NDMA formation and a potential control strategy","author":"Harmon","year":"2022","journal-title":"J Pharm Sci"},{"key":"10.1016\/j.xphs.2023.01.028_bib0078","article-title":"Trace aldehydes in solid oral dosage forms as catalysts for nitrosating secondary amines","author":"Harmon","year":"2022","journal-title":"J Pharm Sci"},{"issue":"12","key":"10.1016\/j.xphs.2023.01.028_bib0079","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1021\/acs.oprd.0c00462","article-title":"Ranitidine\u2014investigations into the root cause for the presence of N-nitroso-N,N-dimethylamine in ranitidine hydrochloride drug substances and associated drug products","volume":"24","author":"King","year":"2020","journal-title":"Org Process Res Dev"},{"issue":"4","key":"10.1016\/j.xphs.2023.01.028_bib0080","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1208\/s12249-011-9677-z","article-title":"Reactive impurities in excipients: profiling, identification and mitigation of drug-excipient incompatibility","volume":"12","author":"Wu","year":"2011","journal-title":"AAPS PharmSciTech"},{"key":"10.1016\/j.xphs.2023.01.028_bib0081","article-title":"A nitrite excipient database: a useful tool to support N-nitrosamine risk assessments for drug products","author":"Boetzel","year":"2022","journal-title":"J Pharm Sci"},{"key":"10.1016\/j.xphs.2023.01.028_bib0082","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpba.2022.114677","article-title":"Nitrites as precursors of N-nitrosation in pharmaceutical samples - a trace level analysis","volume":"213","author":"Jire\u0161","year":"2022","journal-title":"J Pharm Biomed Anal"},{"issue":"2","key":"10.1016\/j.xphs.2023.01.028_bib0083","doi-asserted-by":"crossref","first-page":"e06179","DOI":"10.1016\/j.heliyon.2021.e06179","article-title":"Determination of dimethylamine and nitrite in pharmaceuticals by ion chromatography to assess the likelihood of nitrosamine formation","volume":"7","author":"Hu","year":"2021","journal-title":"Heliyon"},{"issue":"3","key":"10.1016\/j.xphs.2023.01.028_bib0084","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1007\/s10973-011-1746-8","article-title":"Degradation of aged nitrocellulose investigated by thermal analysis and chemiluminescence","volume":"107","author":"Rychl\u00fd","year":"2012","journal-title":"J Therm Anal Calorim"},{"key":"10.1016\/j.xphs.2023.01.028_bib0085","unstructured":"National Institutes of Health (NIH). N-Nitrosodimethylamine. PubChem. https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/6124#section=Boiling-Point. Published 2022. Accessed November 26, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0086","unstructured":"National Institutes of Health (NIH). N-Nitrosodiethylamine. PubChem. https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/5921#section=Boiling-Point. Published 2022. Accessed November 26, 2022."},{"issue":"2","key":"10.1016\/j.xphs.2023.01.028_bib0087","doi-asserted-by":"crossref","first-page":"136","DOI":"10.5731\/pdajpst.2021.012645","article-title":"Evaluating nitrosamines from elastomers in pharmaceutical primary packaging","volume":"76","author":"Boltres","year":"2022","journal-title":"PDA J Pharm Sci Technol"},{"key":"10.1016\/j.xphs.2023.01.028_bib0088","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpba.2020.113460","article-title":"Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography\u2013tandem mass spectrometry","volume":"189","author":"Lim","year":"2020","journal-title":"J Pharm Biomed Anal"},{"key":"10.1016\/j.xphs.2023.01.028_bib0089","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejps.2021.106026","article-title":"NDMA analytics in metformin products: comparison of methods and pitfalls","volume":"168","author":"Fritzsche","year":"2022","journal-title":"Eur J Pharm Sci"},{"key":"10.1016\/j.xphs.2023.01.028_bib0090","doi-asserted-by":"crossref","DOI":"10.1016\/j.jpba.2020.113582","article-title":"HS-SPME-GC-MS as an alternative method for NDMA analysis in ranitidine products","volume":"191","author":"Alshehri","year":"2020","journal-title":"J Pharm Biomed Anal"},{"issue":"4","key":"10.1016\/j.xphs.2023.01.028_bib0091","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1208\/s12248-020-00473-w","article-title":"A cautionary tale: quantitative LC-HRMS analytical procedures for the analysis of N-nitrosodimethylamine in metformin","volume":"22","author":"Yang","year":"2020","journal-title":"AAPS J"},{"key":"10.1016\/j.xphs.2023.01.028_bib0092","unstructured":"The international council for harmonisation of technical requirements for pharmaceuticals for human use (ICH). ICH Q2 (R1) validation of analytical procedures: text and methodology. https:\/\/database.ich.org\/sites\/default\/files\/Q2%28R1%29Guideline.pdf. 2005."},{"key":"10.1016\/j.xphs.2023.01.028_bib0093","unstructured":"AOAC. Guidelines for standard method performance requirements. http:\/\/www.eoma.aoac.org\/app_f.pdf. 2019."},{"key":"10.1016\/j.xphs.2023.01.028_bib0094","unstructured":"U.S. Food & Drug Administration. Combined headspace N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NEIPA), and N-nitrosodiisopropylamine (NDIPA) impurity assay by GC-MS.MS 2019. https:\/\/www.fda.gov\/media\/124025\/download."},{"issue":"1","key":"10.1016\/j.xphs.2023.01.028_bib0095","doi-asserted-by":"crossref","first-page":"150","DOI":"10.38212\/2224-6614.3400","article-title":"A substructure-based screening approach to uncover N-nitrosamines in drug substances","volume":"30","author":"Kao","year":"2022","journal-title":"J Food Drug Anal"},{"key":"10.1016\/j.xphs.2023.01.028_bib0096","article-title":"The landscape of potential small and drug substance related nitrosamines in pharmaceuticals","author":"Schlingemann","year":"2022","journal-title":"J Pharm Sci"},{"key":"10.1016\/j.xphs.2023.01.028_bib0097","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.yrtph.2015.12.006","article-title":"Evaluation of a statistics-based Ames mutagenicity QSAR model and interpretation of the results obtained","volume":"76","author":"Barber","year":"2016","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.xphs.2023.01.028_bib0098","doi-asserted-by":"crossref","DOI":"10.1016\/j.comtox.2021.100186","article-title":"Developing structure-activity relationships for N-nitrosamine activity","volume":"20","author":"Cross","year":"2021","journal-title":"Comput Toxicol"},{"issue":"11","key":"10.1016\/j.xphs.2023.01.028_bib0099","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1021\/acs.chemrestox.2c00199","article-title":"What makes a potent nitrosamine? Statistical validation of expert-derived structure\u2013activity relationships","volume":"35","author":"Thomas","year":"2022","journal-title":"Chem Res Toxicol"},{"issue":"4","key":"10.1016\/j.xphs.2023.01.028_bib0100","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1021\/acs.oprd.1c00494","article-title":"Reaction of irbesartan with nitrous acid produces irbesartan oxime derivatives, rather than N-nitrosoirbesartan","volume":"26","author":"Lin","year":"2022","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2023.01.028_bib0101","doi-asserted-by":"crossref","DOI":"10.1016\/j.bpc.2020.106539","article-title":"Clues to the non-carcinogenicity of certain N-nitroso compounds: role of alkylated DNA bases","volume":"271","author":"Salam","year":"2021","journal-title":"Biophys Chem"},{"key":"10.1016\/j.xphs.2023.01.028_bib0102","doi-asserted-by":"crossref","DOI":"10.1016\/j.yrtph.2021.105042","article-title":"In silico assessment of genotoxicity. Combinations of sensitive structural alerts minimize false negative predictions for all genotoxicity endpoints and can single out chemicals for which experimentation can be avoided","volume":"126","author":"Benigni","year":"2021","journal-title":"Regul Toxicol Pharmacol"},{"key":"10.1016\/j.xphs.2023.01.028_bib0103","unstructured":"European Medicines Agency. Nitrosamine impurities. https:\/\/www.ema.europa.eu\/en\/human-regulatory\/post-authorisation\/referral-procedures\/nitrosamine-impurities. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0104","unstructured":"Health Canada. Guidance on nitrosamine impurities in medications. Guidance. https:\/\/www.canada.ca\/en\/health-canada\/services\/drugs-health-products\/compliance-enforcement\/information-health-product\/drugs\/nitrosamine-impurities\/medications-guidance.html. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0105","unstructured":"Swissmedic. Potential nitrosamine contamination\u2013Harmonised implementation (update). Guidance. https:\/\/www.swissmedic.ch\/swissmedic\/en\/home\/news\/mitteilungen\/potentielle-verunreinigungen-nitrosaminen-update.html. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0106","unstructured":"Therapeutic Goods Administration (TGA). Nitrosamine impurities in medicines - information for sponsors and manufacturers. Guidance. https:\/\/www.tga.gov.au\/news\/safety-alerts\/nitrosamine-impurities-medicines-information-sponsors-and-manufacturers. Published 2022. Accessed November 27, 2022."},{"key":"10.1016\/j.xphs.2023.01.028_bib0107","unstructured":"Japanese Pharmaceuticals and Medical Devices Agency. Self-inspection on risks of contamination with nitrosamines in drugs. Guidance. https:\/\/www.pmda.go.jp\/files\/000243438.pdf. Published 2021. Accessed November 27, 2022."}],"container-title":["Journal of Pharmaceutical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022354923000308?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0022354923000308?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T09:41:16Z","timestamp":1758361276000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0022354923000308"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5]]},"references-count":107,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,5]]}},"alternative-id":["S0022354923000308"],"URL":"https:\/\/doi.org\/10.1016\/j.xphs.2023.01.028","relation":{},"ISSN":["0022-3549"],"issn-type":[{"value":"0022-3549","type":"print"}],"subject":[],"published":{"date-parts":[[2023,5]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Current Threat of Nitrosamines in Pharmaceuticals and Scientific Strategies for Risk Mitigation","name":"articletitle","label":"Article Title"},{"value":"Journal of Pharmaceutical Sciences","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.xphs.2023.01.028","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.","name":"copyright","label":"Copyright"}]}}