Quantitative Aspects of Non-targeted Analysis for Organic Extractables/Leachables; Insights Secured by Considering the FDA CLAP List Compounds.

Authors

Dennis Jenke, Piet Christiaens, Jan Baeten, Philippe Verlinde

Published in

PDA journal of pharmaceutical science and technology. Sep 12, 2026. Epub Sep 12, 2026.

Abstract

Substances released from a drug product's manufacturing, packaging, and delivery system are termed leachables. Medical device leachables are released during their clinical use. Packaged drug products and medical devices are profiled for leachables (and/or extractables as probable leachables) by screening the drug product or extracts via non-targeted analysis (NTA) employing chromatography coupled with mass spectrometric detection.A leachable's concentration is important as concentration is establishes a patient's exposure to leachables during the clinical use of a drug product or medical device.Two issues are relevant when quantifying extractables or leachables (E/L) during NTA: when is quantitation necessary, and how is quantitation accomplished? Quantitation for toxicological safety risk assessment is necessary if the E/L is present at a level that exceeds the Analytical Evaluation Threshold (AET). To address compound-to-compound variation in analytical response, the AET is lowered via an Uncertainty Factor (UF).Estimated concentrations for identified E/Ls are accurate if either a reference standard is available for the E/L or the E/L can be linked to a surrogate reference compound. However, these approaches are not applicable to unidentified E/Ls or when reference compounds are unavailable.The means for calculating the UF and the use of a universal quantitation surrogate, specifically the median relative response factor (RRF) of a data set of compounds, to estimate the concentration of unidentified E/L are considered herein. Using the FDA CLAP list as a reference, this manuscript concludes that the proper calculation of the UF involves the median RRF and the RRF at the 16% percentile. Furthermore, this manuscript establishes that methods coupling liquid chromatography with mass spectrometric detection (electrospray ionization, ESI) are inaccurate when quantifying unidentified E/Ls given the large variation in RRF values. However, as RRF values for GC/MS are less variable, concentrations estimated for unidentified E/Ls using RRF_median can be accurate and protective.

PMID:
42731873
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.