Low Analytical Evaluation Threshold in Leachables Screening: Challenges, Potential Solutions and Alternative Approaches.

Achieving the Analytical Evaluation Threshold (AET) for leachables is critical in quantification for patient safety evaluation but presents challenges for drug products with large dosing volumes or complex matrices. This paper reviews these challenges, presents industry perspectives, and proposes scientifically justified approaches to ensure patient safety where the AET is not analytically achievable. An industry-wide survey conducted by the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium among 23 member companies identified common hurdles and alternative approaches used in leachables risk assessments. Findings were supplemented with case studies and a review of current analytical and regulatory strategies. The survey identified large dosing volumes (74% respondents) and matrix complexity (68% respondents) as the primary drivers for unachievable AETs. Matrix complexity was shown to significantly impact achievable limits of quantification (LOQs), with reported LOQs ranging from < 10 parts per billion (ppb) in simple aqueous solutions to > 100 ppb in complex matrices like protein-based or lipid-based formulations. Key analytical difficulties included identifying unknown leachables, background interference, and differentiating true leachables from analytical artifacts. When conventional screening methods cannot meet the AET, a robust, scientifically rationalized alternative approach is essential. Recommendations include implementing targeted leachable studies for enhanced sensitivity, using simulation studies to predict leachable profiles without matrix interference, and applying predictive modelling. For therapies addressing life-threatening conditions, a risk-benefit analysis leveraging the "less than lifetime" (LTL) concept may justify higher thresholds. Demonstrating rigorous method development efforts and providing scientific justification for the chosen strategy is crucial for regulatory alignment and ensuring patient safety.