Genotoxic Impurities (GTIs) in pharmaceutical products at traces levels are of concern due to human carcinogen and their detection at traces 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 for the presence of low levels of genotoxic impurities (GTIs) in APIs or in drug product.
Genotoxic impurities (GTIs) in pharmaceuticals at trace levels are of increasing concerns to both pharmaceutical industries and regulatory agencies due to their potentials for human carcinogen. Determination of these impurities at ppm levels requires highly sensitive analytical technique and methodology, which poses tremendous challenges to scientists in pharmaceutical Industry. Pharmaceutical genotoxic impurities (GTIs) may induce genetic mutations, chromosomal breaks, or chromosomal rearrangements, and have the potential to cause cancer in human. Therefore exposure to even low levels of such impurities present in final active pharmaceutical ingredient (API) or in drug product 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 in approval from regulatory agencies.
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, catalyst, and reagent used in drug synthesis. Further, degradation of drug on storage, exposure to light, air oxidation results in 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. Level of impurities may project a high impact on the safety, in-process time on development. Sometimes it takes significant time to carry out multiple attempts to characterise 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 he 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.
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 negligible carcinogenic risk. It outlines recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in 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) provides guidance for qualification and control for the majority of the impurities, limited guidance is provided for those impurities that are DNA reactive.
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 authorisation 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 toxiclogical concerns to regulatory agencies due to human carcinogen. The exposure of these impurities even at ppm level in active pharmaceutical ingredient (API) or in drug product may be of significant toxicological concern. The ICH M7 guideline outlines the recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions of human use.