An analytical laboratory, working for various pharmaceutical companies.


Chemicals that leach into drug products from processing or manufacturing equipment, drug delivery systems and/or packaging may pose a health risk to patients. The client has frequently identified a particular leachable in drug products designed for intravenous use, and required a tolerable exposure value against which to evaluate patient exposures.

Project goals

Bibra was asked to perform a hazard assessment for the leachable and derive a chronic parenteral Permitted Daily Exposure (PDE) value, following ICH[1] guidance, that would be tolerated by patients exposed to this leachable by daily intravenous injection.

[1] The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

Approach and outcome

The bibra toxicologists have many years of experience in the preparation of hazard reports and deriving PDEs on a range of chemicals. Comprehensive literature searches were conducted in order to identify any relevant toxicological data associated with the potential leachable. Initial searches were conducted using the bibra in-house database, TRACE. Where available, Expert Group reports formed the basis of the hazard review. Subsequent searches of the primary literature were then conducted in PubMed, PubChem, the European Chemicals Agency (ECHA) Information on Chemicals database, eChemPortal, the Lhasa Carcinogenicity Database, and the Registry of Toxic Effects of Chemical Substances (RTECS), in order to identify more recent data that would not have been considered by the Expert Groups. In the absence of substance-specific data for some endpoints, literature searches were also conducted on structurally similar (read-across) chemicals. Because of the well-studied nature of the selected read-across chemicals, these searches were limited to TRACE and PubMed only.

After summarising the available toxicity data, the bibra toxicologists identified two key studies that were deemed suitable for a PDE derivation. A No-Observed-Adverse-Effect Level (NOAEL) from a rat inhalation study and a Lowest-Observed-Adverse-Effect Level (LOAEL) from a rat oral study were selected as critical Points of Departure (PoDs), and appropriate modifying factors were applied following ICH guidance. From these, a final health-precautionary parenteral PDE for the leachable was proposed.

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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