Assessment of Genotoxic Impurities

The US Food and Drug Administration (FDA) finalized International Conference on Harmonization (ICH) guidance on DNA-reactive substances that could potentially cause damage when present at low levels and potentially cause cancer.

A potential genotoxic impurity (PGI) has been defined as an “Impurity that shows a structural alert for genotoxicity but that has not been tested in an experimental test model. Here potentially relates to genotoxicity, not to the presence or absence of this impurity”. Genotoxic impurities impact the genetic material using mutations through chromosomal breaks, rearrangements, covalent binding, or insertion into the DNA during replication which may result in carcinogenesis.

The guidance document features sections on considerations for marketed products, drug substance, and drug product impurity assessments, hazard assessment elements, risk characterization, control, documentation, and three appendices on scenarios for the application of ICH M7, case examples to illustrate potential control approaches and an addendum to M7.

Sources of Genotoxic Impurities:

Genotoxic impurities (GTI’s) are expected to get into drug substances through several sources, the main source is starting material and its impurities. Also, genotoxic intermediate and by-products formed in the synthesis process may get be carried forward to the drug substances as genotoxic impurities. In addition to these, solvents, catalysts, and reagents used in the synthesis process can also be a probable source of genotoxic impurities in drug substances.

Degradation products generated on storage and shipment or exposure to light, air oxidation, or hydrolysis contribute to the generation of impurities in drug substances. Beside these excipients and their impurities, extractable and leachable can also contribute to genotoxic impurities in drug products

Control of selected Genotoxic Impurities in APIs:

GTIs can be well controlled by the process, without affecting quality, by modifying the route of synthesis. Methods for controlling sulfonates and alkylating agents.

Limits for Impurities:

Guidelines from the ICH and EMA provide the limits for impurities in drug substances and drug products. These limits do not apply to GTIs because of their adverse effects; hence it is necessary to determine limits based on the daily dose of the drug substance. This task drains process-development resources. To overcome this problem, scientists have to identify GTIs early in process development, develop analytical methods (i.e., for quantifying the genotoxic impurity), and demonstrate the necessary synthetic process controls.

Different Classes of Mutagenic Impurities with Control Strategies:

In silico structure-based assessments, i.e. Derek Nexus, Sarah Nexus, etc., are used for predicting mutagenicity based upon QSAR (quantitative structure-activity relationships) approaches. These findings are then reviewed by toxicology experts to provide any additional understanding as to the relevance of these predictions (both positive and negative), and in the case of contradictory outcomes to understand those differences. Based on this assessment, impurities are categorized into 5 different classes in order of decreasing regulatory concern.

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Created on Mar 8th 2021 01:13. Viewed 303 times.

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