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

Area of Science:

• Pharmaceutical Science
• Analytical Chemistry
• Toxicology

Background:

• The Analytical Evaluation Threshold (AET) is crucial for patient safety in evaluating drug product leachables.
• Large dosing volumes and complex drug matrices pose significant analytical challenges, hindering AET achievement.
• Industry perspectives highlight the need for alternative strategies when conventional methods fall short.

Purpose of the Study:

• To review challenges in achieving AET for leachables in drug products.
• To present industry perspectives and propose scientifically justified approaches for patient safety.
• To identify common hurdles and alternative risk assessment methods used in the pharmaceutical industry.

Main Methods:

• An industry-wide survey conducted by the ELSIE Consortium among 23 member companies.
• Supplementation of survey findings with case studies and a review of analytical and regulatory strategies.
• Analysis of reported limits of quantification (LOQs) in relation to matrix complexity.

Main Results:

• Large dosing volumes (74%) and matrix complexity (68%) were identified as primary drivers for unachievable AETs.
• Matrix complexity significantly impacts LOQs, with values ranging from <10 ppb to >100 ppb.
• Key analytical difficulties include identifying unknowns, background interference, and distinguishing artifacts.

Conclusions:

• When AET is unachievable, alternative approaches like targeted studies, simulation, and predictive modeling are essential.
• For life-threatening conditions, risk-benefit analysis using the 'less than lifetime' (LTL) concept may justify higher thresholds.
• Rigorous method development and scientific justification are critical for regulatory alignment and patient safety.