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Recommendations for the Bioanalytical Method Validation of Ligand-Binding Assays to Support Pharmacokinetic Assessments of Macromolecules

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Abstract

Purpose.With this publication a subcommittee of the AAPS Ligand Binding Assay Bioanalytical Focus Group (LBABFG) makes recommendations for the development, validation, and implementation of ligand binding assays (LBAs) that are intended to support pharmacokinetic and toxicokinetic assessments of macromolecules.

Methods. This subcommittee was comprised of 10 members representing Pharmaceutical, Biotechnology, and the contract research organization industries from the United States, Canada, and Europe. Each section of this consensus document addresses a specific analytical performance characteristic or aspect for validation of a LBA. Within each section the topics are organized by an assay's life cycle, the development phase, pre-study validation, and in-study validation. Because unique issues often accompany bioanalytical assays for macromolecules, this document should be viewed as a guide for designing and conducting the validation of ligand binding assays.

Results. Values of ±20% (25% at the lower limit of quantification [LLOQ]) are recommended as default acceptance criteria for accuracy (% relative error [RE], mean bias) and interbatch precision (%coefficient of variation [CV]). In addition, we propose as secondary criteria for method acceptance that the sum of the interbatch precision (%CV) and the absolute value of the mean bias (%RE) be less than or equal to 30%. This added criterion is recommended to help ensure that in-study runs of test samples will meet the proposed run acceptance criteria of 4-6-30. Exceptions to the proposed process and acceptance criteria are appropriate when accompanied by a sound scientific rationale.

Conclusions. In this consensus document, we attempt to make recommendations that are based on bioanalytical best practices and statistical thinking for development and validation of LBAs.

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Authors and Affiliations

  1. Amgen Inc, Thousand Oaks, California

    Binodh DeSilva

  2. Lilly Research Laboratories, Greenfield, Indiana

    Wendell Smith

  3. Bristol-Myers Squibb, Princeton, New Jersey

    Russell Weiner

  4. Johnson and Johnson Pharmaceutical, Raritan, New Jersey

    Marian Kelley

  5. Alta Analytical Laboratory, San Diego, California

    JoMarie Smolec

  6. Pfizer Global Research and Development, Ann Arbor, Michigan

    Ben Lee

  7. Covance Laboratories, Chantilly, Virginia

    Masood Khan

  8. PPD Development, Richmond, Virginia

    Richard Tacey

  9. HLS, Cambridgeshire, UK

    Howard Hill

  10. Millennium Pharmaceuticals, Cambridge, Massachusetts

    Abbie Celniker

Authors
  1. Binodh DeSilva
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  2. Wendell Smith
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  3. Russell Weiner
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  4. Marian Kelley
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  5. JoMarie Smolec
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  6. Ben Lee
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  7. Masood Khan
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  8. Richard Tacey
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  9. Howard Hill
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  10. Abbie Celniker
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Corresponding author

Correspondence to Marian Kelley.

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DeSilva, B., Smith, W., Weiner, R. et al. Recommendations for the Bioanalytical Method Validation of Ligand-Binding Assays to Support Pharmacokinetic Assessments of Macromolecules. Pharm Res 20, 1885–1900 (2003). https://doi.org/10.1023/B:PHAM.0000003390.51761.3d

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  • DOI: https://doi.org/10.1023/B:PHAM.0000003390.51761.3d

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