Analysis of imprecision in incurred sample reanalysis for small molecules

Area of Science:

• Bioanalytical Chemistry
• Pharmacokinetics
• Drug Development

Background:

• Incurred sample reanalysis (ISR) is crucial for validating bioanalytical measurements.
• Current acceptance criteria for small molecules require 67% of reanalyzed samples within 20% of original values.
• Understanding sample size and incurred sample imprecision is key for reliable ISR studies.

Purpose of the Study:

• To evaluate the impact of incurred sample imprecision and sample size on ISR pass rates.
• To assess the relevance of ISR acceptance criteria and determine optimal sample sizes.
• To provide a framework for selecting appropriate sample sizes in ISR studies.

Main Methods:

• Simulated ISR studies were conducted to analyze ISR pass rates.
• The probability of passing ISR acceptance criteria was modeled as a function of incurred sample imprecision (%CV) and sample size.
• The influence of systematic bias on ISR pass rates was also investigated.

Main Results:

• Low incurred sample imprecision (≤10% CV) achieved high ISR pass rates (≥99%) with fewer than 50 samples.
• Intermediate imprecision (7-12% CV) required 80-160 samples for high ISR pass rates.
• High imprecision significantly decreased ISR pass rates, with sample size becoming ineffective.

Conclusions:

• Incurred sample imprecision is a critical factor influencing ISR pass rates.
• Sample size requirements vary significantly based on the level of incurred sample imprecision.
• The study provides a framework for optimizing sample size selection in ISR studies for reliable bioanalytical data.