An analytical lab working on the behalf of a pharmaceuticals company.
ICH defines a Permitted Daily Exposure (PDE) as a pharmaceutically acceptable intake “protective of public health for all patient populations” and provides specific guidance on the derivation of PDEs for threshold toxins identified as residual solvents (Q3C guideline) and elemental impurities (Q3D guideline) in pharmaceuticals. Generally, a chemical intake below the appropriate PDE for that route of exposure would be considered tolerable for patients exposed over the duration of a lifetime. At the time of drafting (August 2022), there is no official guidance from ICH on the derivation of PDE values for extractables and leachables, although this is in development. It is assumed by bibra that the principles of the Q3C and Q3D guidelines would apply.
For the current project, bibra was asked to apply ICH principles to calculate a PDE for a leachable identified by the client from vials used to contain an intravenous anticancer drug. The client advised bibra on the specific exposure scenario and maximum daily dose.
 The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.
To identify toxicity data relevant to the leachable, derive an appropriate PDE, and use this to assess the risks posed to patients who may be exposed to this compound by injection. All relevant routes of exposure and endpoints of interest (including sensitisation, acute and repeated-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity) were considered.
Approach and outcome
Comprehensive toxicity and ADME data searches were undertaken using bibra’s in-house TRACE database, PubMed, PubChem, eChemPortal, the ECHA Information on Chemicals database, the Lhasa Carcinogenicity Database and the Registry of Toxic Effects of Chemical Substances RTECS. Appropriate well-studied read-across candidates were also identified to fill data gaps, and were subject to pragmatic data searches, driven by Expert Group opinions and conclusions.
Bibra then compiled a comprehensive report summarising the available toxicity data on the detected leachable. The weight of evidence, including Expert Group consensus, confirmed that the chemical of interest is a threshold toxin, and that the derivation of a parenteral PDE is appropriate. Existing tolerable exposures for different routes, as defined by Expert Groups, were considered alongside the summarised dataset. A No-Observed-Adverse-Effect Level (NOAEL) from an oral study in rats was selected as the critical Point of Departure (PoD) for PDE derivation, and appropriate uncertainty factors for interspecies and intraspecies variation, and for study duration, were selected in line with ICH guidance. Study limitations and route-to-route differences (informed by absorption and metabolism data and the physicochemical properties of the chemical) were also considered. The derived PDE was over 1000-fold higher than the estimated exposure level for patients, meaning that no adverse effects are expected.