Genotoxic impurities in pharmaceutical products – regulatory, toxicological and pharmaceutical considerations

Authors

DOI:

https://doi.org/10.20883/medical.e502

Keywords:

genotoxicity, impurities, legislation

Abstract

This article provides an overview of the most important aspects around the detecting and reporting of genotoxic impurities in the pharmaceutical industry. It focuses on relevant regulatory, toxicological, and pharmaceutical considerations. In this regard, the concept of Threshold of Toxicological Concern is explained and the most common genotoxic impurities are described. Furthermore, toxicological methods for genotoxic impurities screening are presented. Finally, the article emphasises several issues regarding further development.

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References

European Medicines Agency Guidelines: ICH (S2) R1 Genotoxicity testing and data interpretation for pharmaceuticals intended for human use. https://www.ema.europa.eu/en/ich-s2-r1-genotoxicity-testing-data-interpretation-pharmaceuticals-intended-human-use. Accessed 2021 January 12.

European Medicines Agency Guidelines: ICH M3 (R2) Non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. https://www.ema.europa.eu/en/ich-m3-r2-non-clinical-safety-studies-conduct-human-clinical-trials-pharmaceuticals. Accessed 2021 January 12.

Shaikh T. Genotoxic Impurities and Its Risk Assessment in Drug Compounds. Drug Designing & Intellectual Properties International Journal. 2018 Oct 23;2(4). https://doi.org/10.32474/ddipij.2018.02.000143

European Medicines Agency Guidelines: ICH M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. https://www.ema.europa.eu/en/ich-m7-assessment-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit-potential. Accessed 2021 January 12.

Snodin D, Elder D. Genotoxic Impurities Part 1: General Overview. Pharmaceutical Outsourcing. 2012 May 25;.

Savale SK. Genotoxicity of Drugs: Introduction, Prediction and Evaluation. Asian Journal of Biomaterial Research. 2018;4(6):1-29.

European Medicines Agency Guidelines: ICH Q3A(R2) Impurities in new drug substances and ICH Q3B (R2) Impurities in New Drug Products. https://www.ema.europa.eu/en/ich-q3a-r2-impurities-new-drug-substances. Accessed 2021 January 12.

Müller L, Mauthe RJ, Riley CM, Andino MM, Antonis DD, Beels C, DeGeorge J, De Knaep AG, Ellison D, Fagerland JA, Frank R, Fritschel B, Galloway S, Harpur E, Humfrey CD, Jacks AS, Jagota N, Mackinnon J, Mohan G, Ness DK, O’Donovan MR, Smith MD, Vudathala G, Yotti L. A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regulatory Toxicology and Pharmacology. 2006 Apr;44(3):198-211. https://doi.org/10.1016/j.yrtph.2005.12.001

R Pounikar A, J Umekar M, R Gupta K. Genotoxic impurities: an important regulatory aspect. Asian Journal of Pharmaceutical and Clinical Research. 2020 Apr 11;:10-25. https://doi.org/10.22159/ajpcr.2020.v13i6.37370

Maithani M, Raturi R, Gupta V, Bansal P. Evolution of regulatory aspects of genotoxic impurities in pharmaceuticals: Survival of the fittest. Journal of Liquid Chromatography & Related Technologies. 2017 Sep 14;40(15):759-769. https://doi.org/10.1080/10826076.2017.1357574

Dobo KL, Greene N, Cyr MO, Caron S, Ku WW. The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development. Regulatory Toxicology and Pharmacology. 2006 Apr;44(3):282-293. https://doi.org/10.1016/j.yrtph.2006.01.004

Elder D, Facchine KL, Levy JN, Parsons R, Ridge D, Semo L, Teasdale A. An Approach to Control Strategies for Sulfonate Ester Formation in Pharmaceutical Manufacturing Based on Recent Scientific Understanding. Organic Process Research & Development. 2012 Oct 12;16(11):1707-1710. https://doi.org/10.1021/op300216x

Elder DP, Snodin DJ. Drug substances presented as sulfonic acid salts: overview of utility, safety and regulation. Journal of Pharmacy and Pharmacology. 2009 Mar;61(3):269-278. https://doi.org/10.1211/jpp.61.03.0001

Ramakrishna K, Raman N, Rao KN, Prasad A, Reddy KS. Development and validation of GC–MS method for the determination of methyl methanesulfonate and ethyl methanesulfonate in imatinib mesylate. Journal of Pharmaceutical and Biomedical Analysis. 2008 Mar;46(4):780-783. https://doi.org/10.1016/j.jpba.2007.11.013

Snodin D, Elder D. Genotoxic Impurities Part 2: Toxicological Overview. Pharmaceutical Outsourcing. 2012 Sep 16;.

Snodin DJ. Genotoxic Impurities: From Structural Alerts to Qualification. Organic Process Research & Development. 2010 Jul 16;14(4):960-976. https://doi.org/10.1021/op100118e

Seifried HE, Seifried RM, Clarke JJ, Junghans TB, San RHC. A Compilation of Two Decades of Mutagenicity Test Results with the AmesSalmonella typhimuriumand L5178Y Mouse Lymphoma Cell Mutation Assays†. Chemical Research in Toxicology. 2006 May;19(5):627-644. https://doi.org/10.1021/tx0503552

OECD (2020), Test No. 471: Bacterial Reverse Mutation Test, OECD Guidelines for the Testing of Chemicals, Section 4. Paris: OECD Publishing; . https://doi.org/10.1787/9789264071247-en

Kroes R, Renwick A, Cheeseman M, Kleiner J, Mangelsdorf I, Piersma A, Schilter B, Schlatter J, van Schothorst F, Vos J, Würtzen G. Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet. Food and Chemical Toxicology. 2004 Jan;42(1):65-83. https://doi.org/10.1016/j.fct.2003.08.006

Scinto K. NDMA contamination in medications has caused concern among consumers, and health care professionals after WHO recalled 1159 lots of ARBs including valsartan, losartan, and irbesartan. https://www.pharmacytimes.com/view/updates-on-nmda-contaminations-in-medications. Accessed 2021 March 16.

European Medicines Agency: Questions and answers document on “Information on nitrosamines for marketing authorisation holders” to provide guidance on handling nitrosamine impurity testing for marketing authorization holders. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/referral-procedures/nitrosamine-impurities. Accessed 2021 January 5.

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Published

2021-03-30

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Review Papers

How to Cite

1.
Regulska K, Michalak M, Murias M, Stanisz B. Genotoxic impurities in pharmaceutical products – regulatory, toxicological and pharmaceutical considerations. JMS [Internet]. 2021 Mar. 30 [cited 2024 Jul. 19];90(1):e502. Available from: https://jms.ump.edu.pl/index.php/JMS/article/view/502
Received 2021-02-04
Accepted 2021-03-24
Published 2021-03-30