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Ligand-Binding Assays: Development, Validation, and Implementation in the Drug Development Arena

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A consolidated and comprehensive reference on ligand-binding assays

Ligand-binding assays (LBAs) stand as the cornerstone of support for definition of the pharmaco-kinetics and toxicokinetics of macromolecules, an area of burgeoning interest in the pharmaceutical industry. Yet, outside of the Crystal City Conference proceedings, little guidance has been available for LBA validation, particularly for assays used to support macromolecule drug development. Ligand-Binding Assays: Development, Validation, and Implementation in the Drug Development Arena answers that growing need, serving as a reference text discussing critical aspects of the development, validation, and implementation of ligand-binding assays in the drug development field.

Ligand-Binding Assays covers essential topics related to ligand-binding assays, from pharmacokinetic studies, the development of LBAs, assay validation, statistical LBA aspects, and regulatory aspects, to software for LBAs and robotics and other emerging methodologies for LBAs. Highlights include:

  • A general discussion of challenges and proven approaches in the development of ligand-binding assays

  • More detailed examination of characteristics of these assays when applied to support of pharmacokinetic and toxicokinetic studies of compounds at different stages in the discovery or development timeline

  • A concise, but detailed, discussion of validation of ligand-binding assays for macromolecules

  • A practical approach to "fit-for-purpose" validation of assays for biomarkers, those molecules receiving increased attention as potentially demonstrating that the target chosen in discovery is being modulated by the candidate therapeutic, both in nonclinical and clinical studies

Written by a team of world-recognized authorities in the field, Ligand-Binding Assays provides key information to a broad range of practitioners, both in the pharmaceutical and allied industries and in related contract research organizations and academic laboratories and, perhaps, even in the field of diagnostics and clinical chemistry.

Author(s): Masood N. Khan, John W. Findlay
Edition: 1
Publisher: Wiley
Year: 2009

Language: English
Pages: 422

LIGAND-BINDING ASSAYS......Page 4
CONTENTS......Page 8
Preface......Page 14
Contributors......Page 18
1.1 General......Page 20
1.2 Historical Review......Page 21
1.3 LBAs for Macromolecules......Page 22
1.5 Ligand-Binding Assay Bioanalytical Focus Group of AAPS......Page 23
1.6 Scope of the Present Volume......Page 27
References......Page 30
2.1 Introduction......Page 34
2.2 Differences Between Low Molecular Weight Molecules and Macromolecules......Page 35
2.3 LBA Assay Considerations Relative to Research and Development Stage......Page 42
2.4 Critical Future Challenges for Ligand-Binding Assays......Page 49
References......Page 51
3.1 Introduction......Page 58
3.2 Inherent Complexities of Immunoassay Development......Page 61
3.3 Steps in the Development of a Validatable Immunoassay......Page 64
3.4 Development and Optimization of an Immunoassay......Page 77
3.6 Troubleshooting Immunoassays......Page 89
3.7. Conclusions......Page 94
References......Page 95
4.1 Introduction......Page 100
4.2 Assay Development and Validation Paradigm......Page 102
4.3 Prestudy Validation Phase......Page 103
4.4 Analytical Performance Characteristics......Page 104
4.5 In-Study Validation Phase......Page 124
4.6 Partial Validations/Method Transfer/Cross-Validation......Page 126
4.8 Conclusions......Page 127
References......Page 128
5.1 Introduction......Page 130
5.2 Objectives of Assay Validation......Page 132
5.3 Validation Criteria......Page 134
5.4 Estimating Assay Performance Characteristics......Page 138
5.5 Decision Rules and Risk Assessment in Prestudy Validation......Page 141
5.6 Decision Rules During In-Study Phase and Associated Risks......Page 142
5.7 Reconciling Validation and Routine Decision Rules......Page 143
References......Page 145
6.1 Introduction......Page 148
6.2 Preanalytical Considerations and Method Feasibility......Page 153
6.3 Method Development and Method Qualification for Exploratory Applications......Page 161
6.4 Method Development and Method Validation for Advanced Applications......Page 170
6.6 Documentation, Record Keeping, and Reporting......Page 173
6.7 Regulatory Issues......Page 174
6.8 In-study Validation......Page 175
6.9 Conclusions......Page 176
References......Page 177
7.1 Introduction......Page 182
7.2 Validation Definitions That May be Interpreted Inconsistently......Page 185
7.3 Validation Experiments......Page 187
7.4 Stability......Page 199
7.5 Reoptimizing Reagent Concentrations......Page 203
7.6 The Use of Commercial Kits for PK and TK Assays......Page 205
7.7 Matrix Problems......Page 208
7.8 Changing Method Protocol......Page 209
References......Page 210
8.1 Introduction......Page 212
8.2 Immunogenicity Risk-Based Strategy......Page 213
8.3 Regulatory Guidance......Page 214
8.4 Assay Design......Page 215
8.5 Optimization and Validation: Total Binding Antibody Assays......Page 223
8.6 Optimization and Validation: Neutralizing Antibody Assays......Page 232
8.7 Assays and Risk Assessment......Page 239
8.8 Application and Interpretation of Data......Page 243
8.9 Conclusions......Page 244
8.10 Appendix 8.A Illustration of Screening Cut Point Evaluation......Page 246
References......Page 253
9.1 Introduction......Page 258
9.2 United States Pharmacopeia......Page 260
9.3 Characterization of Non-USP Reference Standards......Page 264
9.4 The PK Assay......Page 276
9.5 Conclusions......Page 281
References......Page 282
10.1 Introduction......Page 284
10.2 Establishing Successful Working Relationships Between Laboratories......Page 286
10.3 Method Transfer......Page 291
10.4 Monitoring the Method Transfer Process......Page 296
10.5 Auditing CROs......Page 298
10.6 Method Troubleshooting......Page 300
10.7 Secrets of Successful Method Transfer......Page 304
References......Page 305
11.1 Introduction......Page 306
11.2 Implementing Automated Systems......Page 309
11.3 Specific Ligand-Binding Assay Automation Systems......Page 324
11.4 Automated Sample Dilutors......Page 326
11.5 Assay Robots......Page 336
11.6 Integration: Tying It All Together......Page 342
Acknowledgments......Page 344
References......Page 345
12.1 Regulatory Perspectives in the Documentation of Bioanalytical Data and Reports......Page 346
12.2 Recommendations for Development, Validation, Implementation, and Reporting Phases......Page 349
References......Page 359
13.1 Introduction......Page 362
13.2 Dissociation-Enhanced Lanthanide Fluoroimmunoassay......Page 363
13.3 Enzyme-Linked Immunospot Assay......Page 365
13.4 Immuno-Polymerase Chain Reaction......Page 367
13.5 Electrochemiluminescence-Based Ligand-Binding Assays......Page 369
13.6 Hybridization-Based Ligand-Binding Assays......Page 373
13.7 Molecularly Imprinted Polymers (Synthetic Antibodies)......Page 375
13.8 Surface Plasmon Resonance Methods......Page 377
13.9 Chromatography–Ligand-Binding Assay Coupled Methods, Immunoaffinity Systems, and Online (Flow-Injection) Ligand-Binding Assay Methods......Page 381
13.10 Future Trends and Directions for LBA Technologies......Page 384
References......Page 385
Index......Page 400