Toxicological Assessment of Potential Leachables in Parenteral Drug Products: Bioavailability Adjustment Considerations.

Leachables are chemicals that can potentially occur in a drug product; therefore, it is important for patient safety to assess potential toxicity risk. Many parenteral drug products are liquid formulations and have an increased likelihood for leachables compared to other dosage forms. One approach for the safety assessment of potential leachables is to derive a Permitted Daily Exposure (PDE) from toxicity data. However, there is often a lack of availability of parenteral repeat dose toxicity studies to facilitate the assessment. In lieu of parenteral data, a bioavailability adjustment factor (BAF) can be incorporated to account for anticipated toxicokinetic differences resulting from an alternate route of administration. Determination of an appropriate and acceptable BAF can be a challenge due to several factors, such as experimental data availability and reliability. As such, in this work a flowchart is designed to encourage harmonization across toxicologists when selecting an appropriate BAF by considering the availability and reliability of experimental data, bioavailability read-across surrogates and an existing physicochemical prediction tool based on LogP and molecular weight. Case studies are presented to illustrate how these approaches can be integrated into the leachables safety assessment when a bioavailability adjustment is pertinent and the importance of expert review.