A pharmaceutical company.


Following analytical studies on an intravenous drug product, an organic leachable from the container‑closure system (CCS) was detected, identified and quantified.

Project goals

As this leachable would be infused into the patient along with the drug product, bibra was asked to evaluate the possible associated health risks, considering both short- and long-term treatments.

Approach and outcome

As an impurity in a pharmaceutical product, guidance issued by the ICH was key in establishing a Permitted Daily Exposure (PDE) for the leachable compound. The first step in any health risk assessment is to gather all relevant data, e.g., by conducting literature searches. However, no toxicity data were available for this particular chemical.

Bibra therefore adopted a “read-across” approach. By considering the chemical structure of the “target” compound (the untested leachable), as well as its likely metabolism in the human body, several possible “surrogate” (“source”) compounds were identified. Literature searches were therefore conducted on these related chemicals, and toxicity data suitable for a PDE derivation were identified for one of the candidates. The ECHA Read-Across Assessment Framework (RAAF) was borne in mind in assessing the tested compound’s suitability as a surrogate.

By evaluating the toxicity data on the key surrogate compound, a PDE was subsequently derived following ICH guidelines. Certain (Q)SAR tools were also applied in support. Furthermore, bibra justified the “read-across” approach by showing that the “target” and “surrogate” compounds would likely share a common toxicological mode-of-action (MoA) and metabolism. As a health-precautionary measure, an Uncertainty Factor (UF) was applied to the PDE to account for any uncertainties in applying the read-across approach.

Bibra project team

James Hopkins1

James Hopkins

Toxicology Director and Chairman

RSB/BTS and European Registered Toxicologist
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Beth O Connell

Beth O’Connell

Principal Toxicologist

RSB/BTS and European Registered Toxicologist
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