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Assessment of incurred sample reanalysis for macromolecules to evaluate bioanalytical method robustness: effects from
Theingi M Thway1, Michael Eschenberg, Dominador Calamba
1Pharmacokinetics and Drug Metabolism, Amgen Inc, Thousand Oaks, California 91320, USA. tthway@amgen.com
The AAPS Journal
|April 5, 2011
Summary
Incurred sample reanalysis (ISR) ensures method reproducibility for drug development. Precision, not total error, is key for ligand-binding assays to pass ISR, with imprecision below 15% ensuring success.
Area of Science:
- Bioanalytical method validation
- Pharmacokinetics and toxicokinetics
- Ligand-binding assays
Background:
- Incurred sample reanalysis (ISR) is crucial for validating bioanalytical methods in drug development.
- Regulatory agencies require ISR to ensure reproducibility of pharmacokinetic and toxicokinetic data.
- Ligand-binding assays (LBAs) are commonly used but require robust validation for reliable results.
Purpose of the Study:
- To evaluate if total error (TE) predicts ISR success for LBAs.
- To assess the role of precision and accuracy in meeting ISR criteria using modified Bland-Altman (mBA) analysis.
- To determine minimum precision requirements for successful ISR in LBAs.
Main Methods:
- Modified Bland-Altman (mBA) analysis was employed to assess accuracy and precision.
- Simulated studies were conducted to establish precision thresholds for ISR success.
- Analyzed 37 ISR studies for LBAs with TEs ranging from 15% to 30%.
Main Results:
- All 37 ISR studies met regulatory criteria; all met the mBA accuracy threshold (≤30%).
- Two studies (5%) failed to meet the mBA precision threshold of 30%.
- Simulations indicated that ≤15% imprecision in LBAs leads to 99.9% ISR success for both regulatory and mBA criteria.
Conclusions:
- Method precision is a critical factor for LBA reproducibility and ISR success.
- Modified Bland-Altman analysis effectively evaluates ISR performance.
- Identifying and controlling imprecision is vital for methods likely to pass ISR.
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