A REVIEW ON ANALYTICAL CHALLENGES IN MONITORING AND CONTROLLING GENOTOXIC IMPURITIES
Keywords:Column liquid chromatography, Genotoxic impurities, Analytical methods and challenges, Nitrosamines, World health organization
Genotoxic impurities (GIs) are chemical agents that have a DNA-interaction characteristic which can ultimately lead to cancer. Their presence in various drug substances had driven various regulatory authorities to guide monitor, control, and to limit their level in various drug products. The objective of this article is to review the analytical approaches and challenges faced while accessing, monitoring, and controlling GIs in pharmaceuticals and also a brief explanation such as low limits of GIs, matrix interference, non-volatility, and environmental conditions encountered during the analysis of GIs are also discussed in this paper. At present, several modern analytical techniques are being used for the analysis of GIs such as high-performance liquid chromatography, liquid chromatography-mass spectrometry, and gas chromatography-mass spectroscopy that have high selectivity and sensitivity, but at the same time, many researchers have reported several challenges while using these techniques. Impacts of GIs are very important and various international organizations such as the World Health Organization have set out rules for regulating these chemicals. Hence, we can conclude that analytical approaches and their challenges are essential to understand because they play a key role to develop robust analytical methods.
Liu DQ, Sun M, Kord AS. Recent advances in trace analysis of pharmaceutical genotoxic impurities. J Pharm Biomed Anal 2010;51:999-1014.
Qiu F, Norwood DL. Identification of pharmaceutical impurities. J Liq Chromatogr Relat Technol 2007;30:877-935.
Committee for Human Medicinal Products. ICH Guideline M7 (R1) on the Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. Geneva, Switzerland: International Conference on Harmonisation; 2015. p. 1-110.
Leistner A, Haerling S, Kreher JD, Becker I, Jung D, Holzgrabe U. Risk assessment reports of potential impurities in cetirizine dihydrochloride. J Pharm Biomed Anal 2020;189:1-13.
Holm R, Elder DP. Analytical advances in pharmaceutical impurity profiling. Eur J Pharm Sci 2016;87:118-35.
Pounikar AR, Umekar MJ, Gupta KR. Genotoxic impurities: An important regulatory aspect. Asian J Pharm Clin Res 2020;13:10-25.
Rahman N, Azmi SN, Wu HF. The importance of impurity analysis in pharmaceutical products: An integrated approach. Accredit Qual Assur 2006;11:69-74.
Kasper P, Muller L. Genotoxic impurities in pharmaceuticals. Genotoxicity Carcinog Test Pharm 2015;2015:55-74.
Munro IC, Renwick AG, Danielewska NB. The threshold of toxicological concern (TTC) in risk assessment. Toxicol Lett 2008;180:151-6.
European Medicines Agency. Guidelines on the Limit of Genotoxic Impurities, CPMP/SWP/5199/02, EMEA/CHMP/QWP/251344/2006. European Medicines Agency; 2006. Available from: https://www. ema.europa.eu/en/documents/scientific-guideline/guideline-limits-genotoxic-impurities_en.pdf. [Last accessed on 2020 Jun 21].
Kroes R, Kleiner J, Renwick A. The threshold of toxicological concern concept in risk assessment. Toxicol Sci 2005;86:226-30.
Raman NV, Prasad AV, Reddy KR. Strategies for the identification, control, and determination of genotoxic impurities in drug substances. J Pharm Biomed Anal 2011;55:662-7.
Yuabova ZY, Holschlag DR, Rodriguez SA, Qin C, Papov VV, Qiu F, et al. Genotoxic impurities: A quantitative approach. J Liq Chromatogr Relat Technol 2008;31:2318-30.
Wang J, Yang S, Zhang K. A simple and sensitive method to analyze genotoxic impurity hydrazine in pharmaceutical materials. J Pharm Biomed Anal 2016;126:141-7.
Soni LK, Sanjay J. Optimization and validation of RP-HPLC method for the estimation of meloxicam and paracetamol with its genotoxic impurity (p-amino phenol) in bulk and pharmaceutical drug product using PDA detector. Asian J Biomed Pharm Sci 2016;6:21-6.
Dousa M, Doubsky J, Srbek J. Utilization of photochemically induced fluorescence detection for HPLC determination of genotoxic impurities in the vortioxetine manufacturing process. J Chromatogr Sci 2016;54:1625-30.
Olsen BA, Castle BC, Myers DP. Advances in HPLC technology for the determination of drug impurities. Trends Anal Chem 2006;25:796-805.
Teasdale A, Elder DP. Analytical control strategies for mutagenic impurities. Trends Anal Chem 2018;101:66-84.
Raman NV, Prasad AV, Reddy KR. Sensitive derivatization methods for the determination of genotoxic impurities in drug substances using hyphenated techniques. J Pharm Biomed Anal 2014;89:276-81.
Reddy AV, Jaafar J, Umar K, Majid ZA, Bin AA, Talib J, et al. Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals. J Sep Sci 2015;38:764-79.
Mattrey FT, Makarov AA, Regalado EL, Bernardoni F, Figus M, Hicks MB, et al. Current challenges and future prospects in chromatographic method development for pharmaceutical research. Trends Anal Chem 2017;95:36-46.
Al-Sabti B, Harbali J. Trace analysis of potential genotoxic impurity N, N -dimethylaniline in linagliptin active pharmaceutical ingredient using HPLC. Sep Sci Plus 2020;3:1-7.
Anerao A, Solase V, Gadhave T, More A, Pradhan N. Quantification of genotoxic impurities in key starting material of sertraline hydrochloride by simple and sensitive liquid chromatography technique. Curr Pharm Anal 2018;16:110-6.
Landge SB, Dahale SB, Devadhe SJ, Desmukh DG, Solanki PV, Jadhav SA, et al. Separation and quantification of structurally similar impurities by HPLC method of vortioxetine hydrobromide: An antidepressant drug. Eur Chem Bull 2020;9:114-8.
Senthil KS, Srivastava RK, Srinivas RV. Determination of 2-cyano-4’- bromomethyl biphenyl genotoxic impurity in irbesartan drug substances using HPLC technique. Int J Pharm Pharm Sci 2016;8:225-30.
Kumar T, Ramya M, Srinivasan V, Xavier N. A simple and direct LC-MS method for determination of genotoxic impurity hydroxylamine in pharmaceutical compounds. J Chromatogr Sci 2017;55:683-9.
Singh S, Handa T, Narayanam M, Sahu A, Junwal M, Shah RP. A critical review on the use of modern sophisticated hyphenated tools in the characterization of impurities and degradation products. J Pharm Biomed Anal 2012;69:148-73.
Lee H, Shen S, Grinberg N. Identification and control of impurities for drug substance development using LC-MS and GC-MS. J Liq Chromatogr Relat Technol 2008;31:2235-52.
Devanshu S, Rahul M, Annu G, Kishan S, Anroop N. Quantitative bioanalysis by LC-MS/MS. J Pharm Biomed Sci 2010;7:1-8.
Lee MS. LC-MS Applications in Drug Development. United States: Wiley, Interscience Series on Mass Spectrometry; 2002. p. 39-41.
Szekely G, Henriques B, Gil M, Ramos A, Alvarez C. Design of experiments as a tool for LC-MS/MS method development for the trace analysis of the potentially genotoxic 4-dimethylamino pyridine impurity in glucocorticoids. J Pharm Biomed Anal 2012;70:251-8.
Venugopal N, Vijaya BR, Gangadhar RK, Madhavi V, Madhavi G. Method development and validation study for the quantitative determination of 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride a genotoxic impurity in pantoprazole active pharmaceutical ingredient by LC-MS/MS. J Pharm Biomed Anal 2012;70:592-7.
Chen Y, Wu S, Yang Q. Development and validation of LC-MS/MS for analyzing potential genotoxic impurities in pantoprazole starting materials. J Anal Methods Chem 2020;2020:1-8.
Liu DQ, Chen TK, McGuire MA, Kord AS. Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process. J Pharm Biomed Anal 2009;50:144-50.
David F, Jacq K, Sandra P, Baker A, Klee MS. Analysis of potential genotoxic impurities in pharmaceuticals by two-dimensional gas chromatography with deans switching and independent column temperature control using a low-thermal-mass oven module. Anal Bioanal Chem 2010;396:1291-300.
Van WA, Niederlander HA, Siebum AH, Vervaart MA, De JG. A new derivatization reagent for LC-MS/MS screening of potential genotoxic alkylation compounds. J Pharm Biomed Anal 2013;74:133-40.
Suryakala D, Susarla S, Rao BM. LC-MS method development for the quantitation of potential genotoxic impurity 2-methyl-6-nitro aniline in telmisartan API. J Appl Pharm Sci 2020;10:92-6.
Ramachandra B. Development of impurity profiling methods using modern analytical techniques. Crit Rev Anal Chem 2017;47:24-36.
Baldwin S, Bristow T, Ray A, Rome K, Sanderson N, Sims M, et al. Applicability of GC/quadrupole-orbitrap mass spectrometry in support of pharmaceutical research and development. Rapid Commun Mass Spectrom 2016;30:873-80.
Sun M, Bai L, Liu DQ. A generic approach for the determination of trace hydrazine in drug substances using in situ derivatization-headspace GC-MS. J Pharm Biomed Anal 2009;49:529-33.
Prasannakumar PB, Balamuralidhara V, Gowrav MP, Venkatesh MP. Nitrosamines in Drug substance and drug product: A regulatory challenge. Int J Res Pharm Sci 2020;11:2123-30.
Wollein U, Schramek N. Simultaneous determination of alkyl mesilates and alkyl besilates in finished drug products by direct injection GC-MS. Eur J Pharm Sci 2012;45:201-4.
Ho TD, Yehl PM, Chetwyn NP, Wang J, Anderson JL, Zhong Q. Determination of trace level genotoxic impurities in small molecule drug substances using conventional headspace gas chromatography with contemporary ionic liquid diluents and electron capture detection. J Chromatogr A 2014;1361:217-28.
Raghavender RS, Hussain RK, Narendra KM, Madhava RP, Venkata RR, Sharma HK. A validated GC-MS method for the determination of genotoxic impurities in divalproex sodium drug substance. J Chromatogr Sci 2019;57:101-7.
Chen L, Zhang W, Hu S. Determination of genotoxic epoxide at trace level in drug substance by direct injection GC-MS. J Pharm Biomed Anal 2017;146:103-8.
Ahirrao VK, Jadhav RA, Rane VP, Bhamare HR, Yeole RD. Time dependent selected reaction monitoring based GC-MS/MS method for estimation of genotoxic impurities in new antibacterial agent alalevonadifloxacin mesylate. J Anal Sci Technol 2020;11:2-9.
Anerao A, Patil B, Pradhan N. Determination of residual dimethyl sulfate in methoxsalen drug substance by pre-column derivatization with static headspace gas chromatography. Int J Pharm Pharm Sci 2018;10:84-9.
World Health Organization. Update on Nitrosamine Impurities, EMP/ RHT/Information Note-nitrosamine Impurities. Geneva: World Health Organization; 2019. Available from: https://www.who.int/medicines/ publications/drugalerts/InformationNoteNitrosamine-impurities_ Nov2019.pdf. [Last accessed on 2020 Jun 18].
European Medicines Agency. To Review Ranitidine Medicines Following the Detection of NDMA, EMA/503622/2019. Netherlands: European Medicines Agency; 2019. Available from: https://www. ema.europa.eu/en/documents/press-release/ema-review-ranitidine-medicines-following-detection-ndma_en.pdf. [Last accessed on 2020 Jun 18].
European Medicines Agency. Information on Nitrosamines for Marketing Authorization Holders, EMA/189634/2019. European Medicines Agency; 2019. Available from: https://www.ema.europa. eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders_en.pdf. [Last accessed on 2020 Jun 18].
Charrois JW, Arend MW, Froese KL, Hrudey SE. Detecting N-nitrosamines in drinking water at nanogram per liter levels using ammonia positive chemical ionization. Environ Sci Technol 2004;38:4835-41.
Kodamatani H, Roback SL, Plumlee MH, Ishida KP, Masunaga H, Maruyama N, et al. An inline ion-exchange system in a chemiluminescence-based analyzer for direct analysis of N-nitrosamines in treated wastewater. J Chromatogr A 2018;1553:51-6.
Mullett WM, Levsen K, Borlak J, Wu J, Pawliszyn J. Automated in-tube solid-phase microextraction coupled with HPLC for the determination of N-nitrosamines in cell cultures. Anal Chem 2002;74:1695-701.
Qian Y, Wu M, Wang W, Chen B, Zheng H, Krasner SW, et al. Determination of 14 nitrosamines at nanogram per liter levels in drinking water. Anal Chem 2015;87:1330-6.
Sieira BJ, Carpinteiro I, Rodil R, Quintana JB, Cela R. Determination of N-nitrosamines by gas chromatography coupled to quadrupole-time-of-flight mass spectrometry in water samples. Separations 2020;7:1-12.
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