Genotoxic Impurities (GTIs) in pharmaceutical products at trace levels are of concern due to human carcinogen and their detection at trace levels are of increasing concern to pharmaceutical industries and regulatory agencies. Pharmaceutical regulatory agencies Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have raised concerns about the presence of low levels of genotoxic impurities (GTIs) in APIs or in drug products.
Genotoxic impurities (GTIs) in pharmaceuticals at trace levels are of increasing concern to both pharmaceutical industries and regulatory agencies due to their potential for human carcinogens. Determination of these impurities at ppm levels requires highly sensitive analytical technique and methodology, which poses tremendous challenges to scientists in the pharmaceutical Industry. Pharmaceutical genotoxic impurities (GTIs) may induce genetic mutations, chromosomal breaks, or chromosomal rearrangements, and have the potential to cause cancer in humans. Therefore exposure to even low levels of such impurities present in final active pharmaceutical ingredient (API) or in drug products may be of significant toxicological concern. Therefore, it is important for process chemists to explore possible opportunities to avoid the use and generation of these genotoxic materials in the manufacturing process. Although present at trace levels, GTIs can be critical in drug development and if not addressed correctly could delay approval from regulatory agencies.
Genotoxic Impurities:
The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids. Genotoxic impurities GTIs can generate through various sources, starting material its impurities, intermediate, process-related by-products in the synthesis process, and also solvents, catalysts, and reagents used in drug synthesis. Further, degradation of the drug in storage, exposure to light, and air oxidation result in the generation of impurities in drug substances.
In API and pharmaceutical products, genotoxic impurities may have the potential carcinogenic or mutagenic effect and the reason levels of these impurities need to be controlled in a range that is safe for human consumption. The level of impurities may project a high impact on the safety, and in-process time of development. Sometimes it takes significant time to carry out multiple attempts to characterize and remove impurities to acceptable levels. Further ICH M7(R1) classifies impurities with respect to mutagenic and carcinogenic potential and resulting control actions as.
Class 1: Impurities are known to be both genotoxic and carcinogenic;
Class 2: Impurities are genotoxic but with unknown carcinogenic potential;
Class 3: Impurities are structural alerts with unknown genotoxic potential (namely potential genotoxic impurities) and for which the structures are unrelated to the API structure;
Class 4: Impurities are structural alerts but share the alerting structure with the API (and can be qualified via a determination of the absence of genotoxicity of the API;
Class 5: Impurities are not structural alerts, thus controlled as ordinary impurities covered by ICH Q3 guidelines.
Regulatory guidelines:
International Council for Harmonisation (ICH):
This M7 (R1) guideline emphasizes considerations of both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose a negligible carcinogenic risk. It outlines recommendations for the assessment and control of mutagenic impurities that reside or are reasonably expected to reside in the final drug substance or product, taking into consideration the intended conditions of human use. ICH Q3A(R2): Impurities in New Drug Substances and Q3B(R2): Impurities in New Drug Products (Ref. 1, 2) provide guidance for qualification and control for the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive.
United States Food and Drug Administration (USFDA):
In Dec 2008 the US Food & Drug Administration (FDA) issued a new document with recommendations regarding limits for genotoxic and carcinogenic impurities in drug substances and products in clinical trials and after the authorization was granted. This draft guidance contains precise proposals for the qualification of these impurities with respect to their carcinogenic risk. It is intended as an addition to the ICH guidelines Q3A, Q3B, and Q3C comprising rather general requirements.
Genotoxic impurities (GTIs) in pharmaceuticals at trace levels are of increasing toxicological concern to regulatory agencies due to human carcinogens. The exposure of these impurities even at ppm level in active pharmaceutical ingredients (API) or in drug products may be of significant toxicological concern. The ICH M7 guideline outlines the recommendations for the assessment and control of mutagenic impurities that reside or are reasonably expected to reside in the final drug substance or product, taking into consideration the intended conditions of human use.
References:
- David Q Liu et., al Recent advances in trace analysis of pharmaceutical Genotoxic impurities, Journal of Pharmaceutical and Biomedical Analysis 51 (2010) 999–1014.
- Gyorgy Szekely et., al Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation. Chem. Rev. 2015, 115, 16, 8182–8229.
ICH M7 guideline: Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk.
- FDA draft guidance regarding genotoxic and carcinogenic impurities is available at: https://www.gmp-compliance.org/gmp-news/fda-issues-new-draft-guidance-regarding-genotoxic-and-carcinogenic-impurities-in-drug-substances-and-products
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