Quality Issues for Multiregional Clinical-Trial Materials - Pharmaceutical Technology

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Quality Issues for Multiregional Clinical-Trial Materials
The authors examine risk management relating to the quality issues of clinical-trial materials and discuss areas that would benefit from additional consideration and harmonization.


Pharmaceutical Technology
Volume 35, Issue 10, pp. 124-132

Genotoxic impurities

Compounds that have been shown to induce genetic mutations, chromosomal breaks, and/or chromosomal rearrangements are considered genotoxic and have the potential to cause cancer in humans. Regulatory authorities consider that exposures to even low levels of these impurities may be of significant concern. Current guidances that address issues related to impurities include ICH Q3A (R2) Impurities for New Drug Substances and Q3B (R2) Impurities in New Drug Products, and EMA's Committee for Medicinal Products for Human Use's guideline on the limits of genotoxic impurities (GTIs) (6, 8, 9).

The ICH guidances define an impurity as any component of the drug substance or drug product other than the chemical entity that makes up the drug substance or an excipient in the drug product. Depending on the quantity of drug substance or drug product to which a patient is exposed, these guidances recommend thresholds for the identification, reporting, and qualification of impurities. The identification limits provided in ICH Q3A (R2) and ICH Q3B (R2), however, may not be acceptable for genotoxic or carcinogenic impurities.

The EMA guideline recommends that the level for GTIs should be "as low as reasonably practicable" (ALARP). According to this principle, manufacturers should strive to achieve the lowest levels of genotoxic or carcinogenic impurities that are technically feasible and/or levels that convey no significant cancer risk. For example, alternative synthetic routes that do not lead to genotoxic residues should be used if practical. However, according to EMA, the ALARP principle does not need to be applied to impurities that do not exceed the threshold of toxicological concern (TTC) (10).

The ICH guidances on impurities do not apply to drug substances or drug products used during the clinical research. Issues regarding the presence of genotoxic or carcinogenic impurities, however, often occur during clinical development. In cases where the presence of an impurity with genotoxic or carcinogenic potential is identified or where such an impurity may be expected based on the synthetic pathway, steps should be taken during the clinical development to address safety concerns associated with these impurities. The EMA guideline provides recommendations for acceptable exposure thresholds during clinical development as well as for marketing applications.

The concept of TTC for genotoxic compounds was developed for the EMA guideline and a draft FDA guideline, Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches (9–11). The guidelines stipulate that exposure to a GTI must be below 1.5 μg/day, which represents a 1 in 100,000 incremental lifetime cancer risk. This level does not apply to the most potent carcinogens or to GTIs for which safe limits already exist based on evidence of a threshold mechanism for genotoxicity. The TTC comes from an analysis of 730 compounds and related carcinogenicity data in the Carcinogenic Potency Database housed at the University of California, Berkeley (12). Originally proposed by regulators as a 0.15-μg limit on carcinogenic impurities in food, the value was adjusted upward for pharmaceuticals because of the benefit gained from taking medications. Even so, the 1.5 μg limit is about 1000 times lower than typical thresholds on impurities.

Alternatives to the TTC approach may be used. If there are adequate safety data for a known GTI, the data can be used to set limits that may differ from the TTC. Lacking data, drug developers have the option to conduct toxicological studies with a GTI to enable an estimation of a compound-specific limit or to default to the TTC. With impurities suspected to be GTIs, drug developers may not bother to classify them depending on the expected risk, needed analytical efforts, and considerations for controlling the impurity. If no testing is done, potential GTIs must be controlled at or below the TTC. If testing finds that a potential GTI is genotoxic, either the TTC or a level based on safety data must be used. If it is not genotoxic, the impurity is handled like any impurity.

Although avoidance of GTIs as reagents, starting materials, synthetic intermediates, and byproducts in chemical processing is an important consideration, it is not always feasible or desirable. Functional groups that render starting materials and synthetic intermediates useful as reactive building blocks may also be responsible for their genotoxicity. Avoidance of mesylate or tosylate salt isolations (i.e., to avoid potential mesylate and tosylate ester GTIs) may limit opportunities for optimal purification, physical properties, stability, or bioavailability of an API. The alternative to avoiding GTIs is to assess and manage potential risk through appropriate application of chemical process design and analytical testing.


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