<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE root>
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="research-article" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Current Pharmaceutical Biotechnology</journal-id><journal-title-group><journal-title xml:lang="en">Current Pharmaceutical Biotechnology</journal-title><trans-title-group xml:lang="ru"><trans-title>Current Pharmaceutical Biotechnology</trans-title></trans-title-group></journal-title-group><issn publication-format="print">1389-2010</issn><issn publication-format="electronic">1873-4316</issn><publisher><publisher-name xml:lang="en">Bentham Science</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">644789</article-id><article-id pub-id-type="doi">10.2174/1389201024666230726152629</article-id><article-categories><subj-group subj-group-type="toc-heading"><subject>Biotechnology</subject></subj-group><subj-group subj-group-type="article-type"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title xml:lang="en">Genotoxic Impurities in Critical Analysis of Product Development: Recent Advancements, Patents, and Current Challenges</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Swain</surname><given-names>Suryakanta</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><name><surname>Jena</surname><given-names>Bikash Ranjan</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff2"/></contrib><contrib contrib-type="author"><name><surname>Rao</surname><given-names>Areti</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><name><surname>Malothu</surname><given-names>Narender</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff4"/></contrib><contrib contrib-type="author"><name><surname>Kothakota</surname><given-names>Naga</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff5"/></contrib><contrib contrib-type="author"><name><surname>Tripathy</surname><given-names>Satya</given-names></name><email>info@benthamscience.net</email><xref ref-type="aff" rid="aff2"/></contrib></contrib-group><aff id="aff1"><institution>Department of Pharmaceutics, School of Pharmacy and Paramedical Sciences, K. K. University</institution></aff><aff id="aff2"><institution>Department of Pharmacy, School of Pharmacy and Life Sciences, Centurion University of Technology and Management</institution></aff><aff id="aff3"><institution>Department of Pharmacy, KL College of Pharmacy, Koneru Lakshmaiah Education Foundation</institution></aff><aff id="aff4"><institution>Department of Pharmacy, Koneru Lakshmaiah Education Foundation</institution></aff><aff id="aff5"><institution>Department of Forensics, School of Forensic Sciences, Centurion University of Technology and Management</institution></aff><pub-date date-type="pub" iso-8601-date="2024-02-15" publication-format="electronic"><day>15</day><month>02</month><year>2024</year></pub-date><volume>25</volume><issue>4</issue><issue-title xml:lang="ru"/><fpage>385</fpage><lpage>395</lpage><history><date date-type="received" iso-8601-date="2025-01-07"><day>07</day><month>01</month><year>2025</year></date></history><permissions><copyright-statement xml:lang="en">Copyright ©; 2024, Bentham Science Publishers</copyright-statement><copyright-year>2024</copyright-year><copyright-holder xml:lang="en">Bentham Science Publishers</copyright-holder><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/"/></permissions><self-uri xlink:href="https://journals.eco-vector.com/1389-2010/article/view/644789">https://journals.eco-vector.com/1389-2010/article/view/644789</self-uri><abstract xml:lang="en"><p id="idm46041443582128">The current review intends to regulate and accurately evaluate genotoxic contaminants in drug substance and drug product method and formulation process development, validation, and degradation pathways. The Quality by Design (QbD) principles can be applied to the systematic evaluation and control of impurities enabled by the development of modern analytical techniques, including the performance of risk assessment, the screening of Critical Process Parameters (CPPs), and the identification of the most influential variables in the optimization of the evaluation and control methods. Current difficulties in removing genotoxic contaminants and the procedures for doing so have been outlined in this review, along with the steps necessary to acquire optimum techniques and the most acceptable formulations. In addition to this, division, characterization, assessment, quantification, and formation of genotoxic impurities sources and control strategy for genotoxic impurities, handling of nitrosamine assay content of drug products in different industrial methodologies and their chemometric prospects and associated recent patents are also explored.</p></abstract><kwd-group xml:lang="en"><kwd>Genotoxic</kwd><kwd>validation</kwd><kwd>risk assessment</kwd><kwd>control strategy</kwd><kwd>chemometrics</kwd><kwd>recent patents.</kwd></kwd-group></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>Genotoxic impurities in pharmaceutical products. https://www.europeanpharmaceuticalreview.com/article/108031/genotoxic-impurities-in-pharmaceutical products/</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>Andrew, T.; David, E.; Sou-Jen, C.; Sophie, W.; Richard, T.; Nancy, B.; Ignacio, H.; Sanchez, F. Risk assessment of genotoxic impurities in new chemical entities: Strategies to demonstrate control. Org. Process Res. Dev., 2013, 17, 221-230.</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>Müller, L.; Mauthe, R.J.; Riley, C.M.; Andino, M.M.; Antonis, D.D.; Beels, C.; DeGeorge, J.; De Knaep, A.G.M.; Ellison, D.; Fagerland, J.A.; Frank, R.; Fritschel, B.; Galloway, S.; Harpur, E.; Humfrey, C.D.N.; Jacks, A.S.; Jagota, N.; Mackinnon, J.; Mohan, G.; Ness, D.K.; ODonovan, M.R.; Smith, M.D.; Vudathala, G.; Yotti, L. A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regul. Toxicol. Pharmacol., 2006, 44(3), 198-211. doi: 10.1016/j.yrtph.2005.12.001 PMID: 16412543</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>ICH Q3 A (R2). Impurities in New Drug substances. 2006.https://www.gmp-compliance.org/files/guidemgr/ICH Q3A R2.pdf</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>Helleday, T.; Eshtad, S.; Nik-Zainal, S. Mechanisms underlying mutational signatures in human cancers. Nat. Rev. Genet., 2014, 15(9), 585-598. doi: 10.1038/nrg3729 PMID: 24981601</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>Shaikh, T.; Hussain, S.; Tabrez, S. Genotoxic impurities and its risk assessment in drug compounds. DDIPIJ, 2018, 2(4), 227-232. doi: 10.32474/DDIPIJ.2018.02.000143</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>Robinson, D.I. Control of genotoxic impurities in active pharmaceutical ingredients: a review and perspective. Org. Process Res. Dev., 2010, 14(4), 946-959. doi: 10.1021/op900341a</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>Genotoxic impurities in pharmaceutical products regulations and analysis. https://www.agilent.com/cs/library/primers/public/5991-1876EN.pdf</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>The determination and control of genotoxic impurities in APIs. Pharm. Technol., 2011, (5)</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>Kieffer, J.; Brémond, É.; Lienard, P.; Boccardi, G. In silico assessment of drug substances chemical stability. J. Mol. Struct. THEOCHEM, 2010, 954(1-3), 75-79. doi: 10.1016/j.theochem.2010.03.032</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>Sharp, T.R. Calculated carbonhydrogen bond dissociation enthalpies for predicting oxidative susceptibility of drug substance molecules. Int. J. Pharm., 2011, 418(2), 304-317. doi: 10.1016/j.ijpharm.2011.04.063 PMID: 21575693</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>Sudheer, B. Genetic toxicology. Samuel, C.; David, R.; Simon, E. In: Reference module in chemistry, molecular sciences and chemical engineering; Elsevier, 2017; pp. 195-203. doi: 10.1016/B978-0-12-409547-2.12381-9</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>ICH S2 (R1) Genotoxicity testing and data interpretation for pharmaceuticals intended for human use - Scientific guideline European Medicines Agency, 2012.</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>ICH M7. Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, Business Plan, 2010; Position Paper, 2010.</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>ICH Q2 (R1), Validation of analytical procedures: Definitions and methodology, geneva, 2005, in 2005 incorporated in Q2 (R1). In: International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use,; , 2005.</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>Q3C(R4): impurities: guideline for residual solvents. International Conference on Harmonisation, 2009.http://www.ich.org/LOB/media/MEDIA5254.pdf</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>FDA draft guidance, genotoxic and carcinogenic impurities in drug substances and products: Recommended approaches; Food and Drug Administration, 2008.</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>EMEA. EMEA, Safety working group, questions and answers on the guideline on the limits of genotoxic impurities, EMA, 2008 and 2009. 2010.http://www.ema.europa.eu/ema</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>Sedlo, I. Kolonić, T.; Tomić, S. Presence of nitrosamine impurities in medicinal products. Archives of Industrial Hygiene and Toxicology, 2021, 72(1), 1-5. doi: 10.2478/aiht-2021-72-3491 PMID: 33787187</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>ulc, M.; Hodek, P.; Stiborová, M. The binding affinity of carcinogenic N-nitrosodimethylamine and N-nitrosomethylaniline to cytochromes P450 2B4, 2E1 and 3A6 does not dictate the rate of their enzymatic N-demethylation. Gen. Physiol. Biophys., 2010, 29(2), 175-185. doi: 10.4149/gpb_2010_02_175 PMID: 20577029</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>Krul, C.A.M.; Zeilmaker, M.J.; Schothorst, R.C.; Havenaar, R. Intragastric formation and modulation of N-nitrosodimethylamine in a dynamic in vitro gastrointestinal model under human physiological conditions. Food Chem. Toxicol., 2004, 42(1), 51-63. doi: 10.1016/j.fct.2003.08.005 PMID: 14630130</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>Nitrosamine impurities; European Medicines Agency (EMA),, 2020.</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>Nitrosamine impurities. https://cdnmedia.eurofins.com/european-west/media/12148099/ebr_nitrosamine_impurities_article.pdf</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>Delley, B. From molecules to solids with the DMol3 approach. J. Chem. Phys., 2000, 113(18), 7756-7764. doi: 10.1063/1.1316015</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>Wichard, J.D. In silico prediction of genotoxicity. Food Chem Toxicol., 2017, 106(Pt B), 595-599. doi: 10.1016/j.fct.2016.12.013</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>Barber, C.; Amberg, A.; Custer, L.; Dobo, K.L.; Glowienke, S.; Van Gompel, J.; Gutsell, S.; Harvey, J.; Honma, M.; Kenyon, M.O.; Kruhlak, N.; Muster, W.; Stavitskaya, L.; Teasdale, A.; Vessey, J.; Wichard, J. Establishing best practise in the application of expert review of mutagenicity under ICH M7. Regul. Toxicol. Pharmacol., 2015, 73(1), 367-377. doi: 10.1016/j.yrtph.2015.07.018 PMID: 26248005</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>Barber, C.; Antonucci, V.; Baumann, J.C.; Brown, R.; Covey-Crump, E.; Elder, D.; Elliott, E.; Fennell, J.W.; Gallou, F.; Ide, N.D.; Jordine, G.; Kallemeyn, J.M.; Lauwers, D.; Looker, A.R.; Lovelle, L.E.; McLaughlin, M.; Molzahn, R.; Ott, M.; Schils, D.; Oestrich, R.S.; Stevenson, N.; Talavera, P.; Teasdale, A.; Urquhart, M.W.; Varie, D.L.; Welch, D. A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies. Regul. Toxicol. Pharmacol., 2017, 90, 22-28. doi: 10.1016/j.yrtph.2017.08.008 PMID: 28822875</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>Kragelj Lapanja, N. Toplak Časar, R.; Jurca, S.; Doljak, B. Theoretical purge factor determination as a control strategy for potential mutagenic impurities in the synthesis of drug substances. Acta Chim. Slov., 2017, 64(1), 1-14. doi: 10.17344/acsi.2016.2840 PMID: 28380232</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>Programmable genotoxic agents and uses therefor. Patent USOO5882941A, 1999.</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>Highly pure salts of clopidogrel free of genotoxic impurities. Patent WO2012123958A1, 2012.</mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation>Method for measuring genotoxic impurities in pradaxa. Patent CN105092720A, 2015.</mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation>Process for the production of ralfinamide salts substantially free from impurities having genotoxic effects. Patent US9505708B2, 2011.</mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation>Detection method of parecoxib sodium genotoxicity impurity and application thereof. Patent CN105372376A, 2016.</mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation>Method for detecting suspected genotoxic impurity of tofacitinib citrate. Patent CN107064350A, 2017.</mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation>Sarpogrelate hydrochloride genetoxic impurity V and preparation method thereof, detection method, application. Patent CN107382911A, 2017.</mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation>The high-sensitivity analysis method of genotoxicity impurity in ethyl sulfonic acid Nintedanib. Patent CN106841495A, 2017.</mixed-citation></ref><ref id="B37"><label>37.</label><mixed-citation>Polybenzimidazole polymer with e'unctionalized spacer chain and its method of preparation for removal of genotoxic impurities. Patent WO2017222402, 2017.</mixed-citation></ref><ref id="B38"><label>38.</label><mixed-citation>HPLC method for detecting genotoxic impurities in candesartan cilexetil. Patent CN111965273A, 2019.</mixed-citation></ref><ref id="B39"><label>39.</label><mixed-citation>Method for determining genotoxic impurities in rivaroxaban. Patent CN111721858A, 2020.</mixed-citation></ref><ref id="B40"><label>40.</label><mixed-citation>Method for analyzing genotoxic impurities in moxifloxacin hydrochloride starting material. Patent CN111855848A, 2020.</mixed-citation></ref><ref id="B41"><label>41.</label><mixed-citation>Method for simultaneously detecting genotoxic impurities 5- isoquinoline sulfonic acid methyl ester and 5-isoquinoline sulfonic acid ethyl ester in fasudil hydrochloride. Patent CN111624276A, 2020.</mixed-citation></ref><ref id="B42"><label>42.</label><mixed-citation>Method for detecting content of genotoxic impurities in tenofovir alafenamide. Patent CN111239285A, 2020.</mixed-citation></ref><ref id="B43"><label>43.</label><mixed-citation>Method for detecting isocyanate potential genotoxic impurities in glimepiride tablet. Patent CN113866329A, 2021.</mixed-citation></ref><ref id="B44"><label>44.</label><mixed-citation>HPLC detection method for genotoxic impurities in clotrimazole raw material and methodological verification. Patent CN113834885A, 2021.</mixed-citation></ref><ref id="B45"><label>45.</label><mixed-citation>Preparation method for N-nitrosamine genotoxic impurity of varenicline tartrate. Patent CN113788829A, 2021.</mixed-citation></ref><ref id="B46"><label>46.</label><mixed-citation>Method for detecting genotoxic impurity in pentoxifylline. Patent CN113686981A, 2021.</mixed-citation></ref><ref id="B47"><label>47.</label><mixed-citation>Analysis method for improving recovery rate of genotoxic impurity n-propyl bromide in sodium valproate. Patent CN113624867A, 2021.</mixed-citation></ref><ref id="B48"><label>48.</label><mixed-citation>Method for separating and determining two genotoxic impurities in topiromilast. Patent CN113466378A, 2021.</mixed-citation></ref><ref id="B49"><label>49.</label><mixed-citation>Method for determining residual content of 4-methylpiperazine-1- formate genotoxic impurities in zopiclone. Patent CN113552241A, 2021.</mixed-citation></ref><ref id="B50"><label>50.</label><mixed-citation>Method for separating and determining two genotoxic impurities in flurbiprofen axetil. Patent CN113008999A, 2021.</mixed-citation></ref><ref id="B51"><label>51.</label><mixed-citation>Method for detecting arylamine and aromatic hydrazine genotoxic impurities in celecoxib. Patent CN112986410A, 2021.</mixed-citation></ref><ref id="B52"><label>52.</label><mixed-citation>Method for analyzing latent genotoxic impurities of lamotrigine. Patent CN112816604A, 2021.</mixed-citation></ref><ref id="B53"><label>53.</label><mixed-citation>Quantitative determination method for trace genotoxic impurity trifluoromethanesulfonate in medicine. Patent CN112782303A, 2021.</mixed-citation></ref><ref id="B54"><label>54.</label><mixed-citation>Method for testing genotoxic impurity in sacubitril valsartan sodium starting material. Patent CN112611813A, 2021.</mixed-citation></ref><ref id="B55"><label>55.</label><mixed-citation>Preparation of metformin hydrochloride free from genotoxic impurity. Patent 20210380529, 2021.</mixed-citation></ref><ref id="B56"><label>56.</label><mixed-citation>Method for detecting the content of genotoxic impurity benzyl bromide in drug. Patent CN112305100A, 2021.</mixed-citation></ref><ref id="B57"><label>57.</label><mixed-citation>Method for detecting potential genotoxic impurities of esomeprazole sodium. Patent CN112229920A, 2021.</mixed-citation></ref></ref-list></back></article>
