A global manufacturer of pharmaceuticals.


The client presented us with the structures of a number of impurities in a medicine currently in development for advanced cancer indications.

ICH guidelines M7, Q3A and Q3B provide a framework for the assessment of pharmaceutical impurities. ICH M7 requires that manufacturers demonstrate that the impurities are not capable of inducing point mutations (by testing or by (Q)SAR analysis) or that they are controlled to an acceptable level. ICH Q3A and Q3B provide the framework for the qualification of non-mutagenic impurities in drug substances and drug products, respectively.

Project goals

We were asked to assess eight compounds (unreacted starting materials, reagents, intermediates and degradants) identified in the drug product following ICH guidance to reach a conclusion on whether they could be considered qualified.

Approach and outcome

We applied our well-established protocol for the assessment and qualification of pharmaceutical impurities.

The first step was to consider which of the impurities might be mutagenic, and therefore subject to ICH M7. Comprehensive literature searches were conducted, including in bibra’s in-house database, TRACE, and in silico predictions were carried out using Toxtree and Leadscope. As all of the impurities were determined to be non-mutagenic, the second step was to identify which compounds required qualification based on the thresholds established in ICH Q3A and Q3B. One of the eight impurities was excluded from risk assessment on this basis.

One further impurity had sufficient substance-specific toxicity data available to allow a health risk assessment to be carried out and to conclude on the qualification. Another impurity was identified as a rapid and extensive mammalian metabolite of the active ingredient, and was considered qualified on this basis.

As a final step, estimated patient exposures were compared to the health-precautionary Threshold of Toxicological Concern benchmarks. This highlighted two impurities for which major systemic toxicity would not be expected. The remaining three compounds could not be qualified, and further investigation was considered necessary.

Bibra project team

James Hopkins1

James Hopkins

Toxicology Director and Chairman

RSB/BTS and European Registered Toxicologist
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Chris Waine

Chris Waine

Principal Toxicologist

RSB/BTS and European Registered Toxicologist
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