A human health risk assessment of API-related impurities

Client

A pharmaceutical company.

Background

Whilst developing an inhalation spray drug product, the client identified two impurities with chemical structures related to the Active Pharmaceutical Ingredient (API).

Project goals

Bibra was asked to assess the health risks posed to patients by the presence of the two impurities within the drug product, and to evaluate whether the impurities could be qualified at levels of up to 3% of the API.

Approach and outcome

Several approaches to the health risk assessment were considered. The first involved conducting searches for relevant systemic toxicity data on the two impurities, however, none were identified. Secondly, (Quantitative) Structure-Activity Relationship ((Q)SAR) analyses were performed using Leadscope’s expert-rule and statistical based models for bacterial mutagenicity, which predicted both impurities to be non-mutagenic. The bibra team therefore turned to guidance from EMA and ICH on the assessment of non-mutagenic impurities, which recommend considering the metabolic relationship and the structural similarities and differences between the API and impurities. As the impurities were found to be hydrolysis products of the API, they were shown to be both structurally similar (with no new toxicophores) and metabolically related. Finally, an assessment applying the Threshold of Toxicological Concern (TTC) provided reassurance that the estimated exposures to the impurities would not be expected to pose a health risk to patients.

The result

Based on the overall weight-of-evidence, it was concluded that both impurities could be considered qualified at the proposed levels.

Why bibra?

• An extensive in-house database TRACE enables comprehensive literature searching 
• All of our senior team are UK and European Toxicologists 
• Bibra has been providing expert, industry-leading toxicology consulting for the pharmaceutical indsutry for decades, and we have established ourselves as authorities in this area 

Learn more about our work in pharmaceutical toxicology

We have many years of experience in preparing toxicological assessments required in the pharmaceutical sector. We regularly provide our clients with assessments of novel or unexpected impurities, excipients and other intentionally-added substances, and extractables and leachables. Get in touch if we can help you!