Contents

Cover

Title Page

Copyright

Preface

Contributors

Abbreviations

Part I: Overview Of LC-MS Bioanalysis

Chapter 1: Roles of LC-MS Bioanalysis in Drug Discovery, Development, and Therapeutic Drug Monitoring

1.1 INTRODUCTION

1.2 LC-MS BIOANALYSIS IN DRUG DISCOVERY

1.3 LC-MS BIOANALYSIS IN PRECLINICAL DEVELOPMENT OF DRUGS

1.4 LC-MS BIOANALYSIS IN CLINICAL DEVELOPMENT OF DRUGS

1.5 LC-MS BIOANALYSIS OF LARGE MOLECULE DRUGS AND BIOPHARMACEUTICALS

1.6 GUIDANCE AND REGULATIONS FOR LC-MS BIOANALYSIS

1.7 GENERAL CONSIDERATIONS OF A ROBUST LC-MS BIOANALYTICAL METHOD

1.8 CONCLUSIONS

REFERENCES

Chapter 2: Overview: Fundamentals of a Bioanalytical Laboratory

2.1 INTRODUCTION

2.2 KEY ELEMENTS OF A BA LABORATORY

2.3 QUALITY ASSURANCE

2.4 SUPPORTING FUNCTIONS

2.5 CRO MONITORING

2.6 CONCLUSIONS

REFERENCES

Chapter 3: International Regulations and Quality Standards of Bioanalysis

3.1 INTRODUCTION

3.2 GLOBAL BIOANALYTICAL GUIDANCE

3.3 BIOANALYTICAL QUALITY

3.4 SCIENCE, QUALITY, AND REGULATION

ACKNOWLEDGMENTS

REFERENCES

Part II: Current Understanding of LC-MS Bioanalysis-Related Regulations

Chapter 4: Current Regulations for Bioanalytical Method Validations

4.1 INTRODUCTION

4.2 CONTEXT OF THE REGULATORY ENVIRONMENT

4.3 VALIDATIONS OF METHODS

4.4 CONCLUSION

REFERENCES

Chapter 5: Current Understanding of Bioanalytical Assay Reproducibility: Incurred Sample Reanalysis, Incurred Sample Stability, and Incurred Sample Accuracy

5.1 INTRODUCTION

5.2 INCURRED SAMPLE REANALYSIS

5.3 INCURRED SAMPLE STABILITY

5.4 INCURRED SAMPLE ACCURACY

5.5 SUMMARY

REFERENCES

Chapter 6: Lc-Ms Bioanalytical Method Transfer

6.1 INTRODUCTION

6.2 PREPARATION FOR METHOD TRANSFER

6.3 CURRENT UNDERSTANDING ON REGULATORY REQUIREMENTS FOR BIOANALYTICAL METHOD TRANSFER

6.4 METHOD TRANSFER

6.5 COMMON CAUSES OF BIOANALYTICAL METHOD TRANSFER FAILURE

6.6 INVESTIGATION OF A METHOD TRANSFER FAILURE

6.7 SUMMARY

REFERENCES

Chapter 7: Metabolites in Safety Testing

7.1 INTRODUCTION

7.2 TIMING OF ADME STUDIES WITH RADIOLABELED MATERIALS

7.3 FIH STUDIES

7.4 STANDARD FREE QUANTIFICATION AND ITS LIMITATIONS

7.5 TIERED OPTIONS FOR DETERMINATION OF HUMAN METABOLITE EXPOSURES AND RESPECTIVE LIMITATIONS

7.6 SUMMARY

REFERENCES

Chapter 8: A Comparison of FDA, EMA, ANVISA, and Others on Bioanalysis in Support of Bioequivalence/ Bioavailability Studies

8.1 INTRODUCTION TO BIOAVAILABILITY/BIOEQUIVALENCY STUDIES

8.2 REGULATIONS FROM THE US FDA

8.3 REGULATIONS FROM THE EUROPEAN MEDICINES AGENCY

8.4 REGULATIONS FROM THE BRAZILIAN SANITARY SURVEILLANCE AGENCY (ANVISA)

8.5 OTHER INTERNATIONAL GUIDELINES

8.6 CONCLUSION

REFERENCES

Chapter 9: A Comparison of the Guidance of FDA, OECD, EPA, and Others on Good Laboratory Practice

9.1 INTRODUCTION

9.2 FDA VERSUS EPA ON GLP

9.3 FDA GLP VERSUS OECD GLP PRINCIPLES

9.4 SOME COUNTRY SPECIFIC REQUIREMENTS ON GLP

9.5 GLP INSPECTION

9.6 SUMMARY

REFERENCES

Chapter 10: Current Understanding of Bioanalysis Data Management and Trend of Regulations on Data Management

10.1 INTRODUCTION

10.2 BIOANALYTICAL WORKFLOW AND DATA MANAGEMENT

10.3 COMPUTER SYSTEMS VALIDATION

10.4 CHALLENGES FOR BIOANALYTICAL DATA INTEGRITY AND SECURITY

10.5 FUTURE PERSPECTIVES

10.6 CONCLUSIONS

REFERENCES

Chapter 11: Regulatory Inspection Trends and Findings of Bioanalytical Laboratories

11.1 INTRODUCTION

11.2 CURRENT REGULATORY INSPECTION TRENDS

11.3 INADEQUATE INVESTIGATION—THE MDS CASE

11.4 DATA INTEGRITY CONCERN—THE CETERO CASE

11.5 DISCUSSION AND ANALYSIS OF SPECIFIC REGULATORY INSPECTION FINDINGS

11.6 RECOMMENDATIONS TO SUPPORT AN EFFECTIVE FDA INSPECTION—READINESS PREPARATION

REFERENCES

Part III: Best Practice in LC-MS Bioanalysis

Chapter 12: Assessment of Whole Blood Stability and Blood/Plasma Distribution of Drugs

12.1 ASSESSMENT OF WHOLE BLOOD STABILITY OF DRUGS

12.2 BLOOD/PLASMA DISTRIBUTION OF DRUGS

12.3 SUMMARY

ACKNOWLEDGMENT

REFERENCES

Chapter 13: Best Practice in Biological Sample Collection, Processing, and Storage for LC-MS in Bioanalysis of Drugs

13.1 INTRODUCTION

13.2 SAMPLE COLLECTION

13.3 DOCUMENTATION

13.4 REDUCING ADSORPTION OF ANALYTE TO CONTAINERS

13.5 SAMPLE COLLECTION FOR PEPTIDES AND PROTEINS

13.6 STABILIZING SAMPLES

13.7 BIOLOGICALLY HAZARDOUS SAMPLES

13.8 SAMPLE STORAGE

13.9 TRANSPORT AND SHIPPING OF SAMPLES

13.10 COMPLIANCE CHECKLIST

13.11 SUMMARY

ACKNOWLEDGMENT

REFERENCES

Chapter 14: Best Practices in Biological Sample Preparation for LC-MS Bioanalysis

14.1 WHY DO SAMPLE PREPARATION?

14.2 WHAT SHOULD YOU KNOW ABOUT THE SAMPLE?

14.3 KNOW YOUR TOOLS

14.4 KNOW YOUR NEEDS

14.5 CONCLUSION AND PERSPECTIVES

REFERENCES

Chapter 15: Best Practice in Liquid Chromatography for LC-MS Bioanalysis

15.1 INTRODUCTION

15.2 THEORETICAL CONSIDERATIONS

15.3 PRACTICAL CONSIDERATIONS FOR METHOD DEVELOPMENT

15.4 SAMPLE ANALYSIS

15.5 MAKING RUGGED METHODS

15.6 LESS IS MORE

15.7 HIGH-RESOLUTION AND HIGH-SPEED ANALYSIS

15.8 SPECIAL CHALLENGES AND OPPORTUNITIES

15.9 CONCLUSIONS

REFERENCES

Chapter 16: Best Practice in Mass Spectrometry for LC-MS

16.1 INTRODUCTION

16.2 ANALYZERS MOST OFTEN USED FOR LC-MS AND LC-MS/MS BIOANALYSIS

16.3 IONIZATION TECHNIQUES FOR UHPLC-MS

16.4 LC-MS IN QUANTITATIVE ANALYSIS

16.5 PERSPECTIVES

REFERENCES

Chapter 17: Use of Internal Standards in LC-MS Bioanalysis

17.1 INTRODUCTION

17.2 SELECTION AND USE OF IS

17.3 PERFORMANCE OF IS

17.4 CONCLUSION

ACKNOWLEDGMENT

REFERENCES

Chapter 18: System Suitability in LC-MS Bioanalysis

18.1 OVERVIEW

18.2 REGULATORY REQUIREMENTS FOR SYSTEM SUITABILITY

18.3 MONITORING INSTRUMENT PERFORMANCE

18.4 CONCLUSIONS

REFERENCES

Chapter 19: Derivatization in LC-MS Bioanalysis

19.1 INTRODUCTION

19.2 DERIVATIZATION REAGENTS ENHANCING IONIZATION EFFICIENCY IN LC/ESI-MS

19.3 DERIVATIZATION REAGENTS IN LC/ESI-MS/MS

19.4 CONCLUSION

REFERENCES

Chapter 20: Evaluation and Elimination of Matrix Effects in LC-MS Bioanalysis

20.1 INTRODUCTION

20.2 POTENTIAL IMPACT OF MATRIX EFFECTS

20.3 COMMON CAUSES OF MATRIX EFFECTS

20.4 MECHANISM OF MATRIX EFFECTS

20.5 METHODS TO IDENTIFY AND EVALUATE MATRIX EFFECTS

20.6 REGULATORY GUIDANCE ON EVALUATION AND AVOIDANCE OF MATRIX EFFECTS

20.7 METHODS TO AVOID OR ELIMINATE MATRIX EFFECTS

20.8 FUTURE PROSPECTS

ACKNOWLEDGMENTS

REFERENCES

Chapter 21: Evaluation and Elimination of Carryover and/or Contamination in LC-MS Bioanalysis

21.1 OVERVIEW

21.2 CURRENT UNDERSTANDING OF REGULATORY PERSPECTIVES ON CARRYOVER AND CONTAMINATION

21.3 CARRYOVER—WHAT IS IT?

21.4 CONTAMINATION—WHAT IS IT?

21.5 WHAT DO THE MANUFACTURERS SAY?

21.6 MANAGING CARRYOVER AND CONTAMINATION IN LC-MS BIOANALYSIS

21.7 SUMMARY

ACKNOWLEDGMENTS

REFERENCES

Chapter 22: Automation in LC-MS Bioanalysis

22.1 INTRODUCTION

22.2 AN OVERVIEW OF AUTOMATED SAMPLE PREPARATION IN LC-MS BIOANALYSIS

22.3 ROBOTIC LIQUID HANDLING PIPETTING MODES AND ASSOCIATED TECHNOLOGY

22.4 OPTIMIZING ROBOTIC LIQUID HANDLING PERFORMANCE

22.5 SOLID PHASE EXTRACTION

22.6 PROTEIN PRECIPITATION

22.7 LIQUID–LIQUID EXTRACTION

22.8 PRACTICAL CONSIDERATIONS: STRATEGY, QUALITY, AND COMPLIANCE

22.9 CONCLUDING REMARKS

REFERENCES

Chapter 23: LC-MS Bioanalysis of Drugs in Tissue Samples

23.1 INTRODUCTION

23.2 CLASSIFICATION OF TISSUES

23.3 WORKFLOW

23.4 TISSUE SAMPLE COLLECTION

23.5 TISSUE SAMPLE PREPARATION

23.6 CALIBRATION STANDARD AND QC SAMPLE PREPARATION

23.7 ANALYTE EXTRACTION

23.8 LC-MS/MS ANALYSIS

23.9 FIT-FOR-PURPOSE LC-MS/MS METHOD QUALIFICATION

23.10 DATA ANALYSIS AND REPORTING

23.11 SUMMARY

ACKNOWLEDGMENT

REFERENCES

Chapter 24: LC-MS Bioanalysis of Drugs in Urine

24.1 INTRODUCTION

24.2 BEST PRACTICE IN DEVELOPING A ROBUST URINE LC-MS QUANTITATION METHOD

24.3 SUMMARY

REFERENCES

Chapter 25: LC-MS Bioanalysis of Unbound Drugs in Plasma and Serum

25.1 INTRODUCTION

25.2 PROTEIN BINDING

25.3 REGULATORY REQUIREMENTS REGARDING UNBOUND DRUG CONCENTRATIONS IN SPECIAL POPULATIONS

25.4 TECHNIQUES FOR THE BIOANALYSIS OF UNBOUND DRUGS IN PLASMA AND SERUM

25.5 EXAMPLES

REFERENCES

Chapter 26: LC-MS Bioanalysis of Drugs in Bile

26.1 BILE AND BILIARY EXCRETION

26.2 BILE SAMPLE COLLECTION

26.3 BILE SAMPLE PREPARATION

26.4 BILE SAMPLE LC-MS BIOANALYSIS

26.5 SUMMARY

REFERENCES

Chapter 27: LC-MS Bioanalysis of Intracellular Drugs

27.1 INTRODUCTION

27.2 SAMPLE PREPARATION

27.3 LC-MS INTRACELLULAR DRUG BIOANALYSIS

27.4 APPLICATION

27.5 CONCLUSIONS

REFERENCES

Chapter 28: LC-MS Bioanalysis of Endogenous Compounds as Biomarkers

28.1 INTRODUCTION

28.2 APPROACHES FOR BIOMARKER QUANTITATION

28.3 BIOMARKER ASSAY VALIDATION AND STUDY CONDUCT

28.4 SUMMARY AND PROSPECTIVE

REFERENCES

Chapter 29: LC-MS Bioanalysis of Drugs in Hemolyzed and Lipemic Samples

29.1 INTRODUCTION

29.2 HEMOLYSIS

29.3 LIPEMIA

29.4 CONCLUSION

ACKNOWLEDGMENT

REFERENCES

Chapter 30: Best Practices in LC-MS Method Development and Validation for Dried Blood Spots

30.1 INTRODUCTION

30.2 METHOD DEVELOPMENT

30.3 METHOD VALIDATION

30.4 CONCLUSIONS

REFERENCES

Chapter 31: LC-MS Method Development Strategies for Enhancing Mass Spectrometric Detection

31.1 INTRODUCTION

31.2 DIFFERENTIAL MOBILITY SPECTROMETRY

31.3 MULTIPLE REACTION MONITORING CUBED

31.4 ATMOSPHERIC PRESSURE PHOTOIONIZATION

31.5 MS SIGNAL ENHANCEMENT VIA MOBILE PHASE ADDITIVES AND ANIONIC AND CATIONIC ADDUCTS PRECURSOR IONS

31.6 CONCLUSIONS

REFERENCES

Chapter 32: LC-MS Bioanalysis-Related Statistics

32.1 INTRODUCTION

32.2 BASIC STATISTICS

32.3 CALIBRATION

32.4 BIAS AND PRECISION

32.5 STABILITY

32.6 INCURRED SAMPLE REPRODUCIBILITY

REFERENCES

Chapter 33: Simultaneous LC-MS Quantitation and Metabolite Identification in Drug Metabolism and Pharmacokinetics

33.1 INTRODUCTION

33.2 UNIT RESOLUTION MASS SPECTROMETERS IN DRUG METABOLISM AND PHARMACOKINETICS

33.3 HIGH-RESOLUTION MASS SPECTROMETRY IN DRUG METABOLISM AND PHARMACOKINETICS

33.4 MASS DEFECT FILTER IN LC-MS

33.5 SIMULTANEOUS LC-MS QUANTITATION/ METABOLITE IDENTIFICATION

LC-MS WORKFLOW: QqQLIT

33.7 LC-MS WORKFLOW: HIGH-RESOLUTION MASS SPECTROMETRY

33.8 CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

Part IV: Representative Guidelines and/or Experimental Protocols of LC-MS Bioanalysis

Chapter 34: LC-MS Bioanalysis of Ester Prodrugs and Other Esterase Labile Molecules

34.1 INTRODUCTION

34.2 COMMON ESTERASES THAT CATALYZE HYDROLYSIS OF ESTER PRODRUGS AND OTHER MOLECULES

34.3 METHODOLOGY AND APPROACHES

34.4 SUMMARY

34.5 A REPRESENTATIVE PROTOCOL-LC-MS BIOANALYSIS OF BMS-068645 AND ITS ACID METABOLITE IN HUMAN PLASMA

REFERENCES

Chapter 35: LC-MS Bioanalysis of ACYL Glucuronides

35.1 INTRODUCTION

35.2 CHEMICAL REACTIVITY AND BIOANALYTICAL IMPLICATIONS

35.3 SAMPLE COLLECTION AND STORAGE

35.4 SAMPLE PREPARATION

35.5 LC-MS/MS QUANTIFICATION

35.6 INCURRED SAMPLE REANALYSIS OF AGs

35.7 SUMMARY

35.8 REPRESENTATIVE PROTOCOLS

REFERENCES

Chapter 36: Regulated Bioassay Of N-Oxide Metabolites Using LC-MS: Dealing with Potential Instability Issues

36.1 INTRODUCTION

36.2 FORMATION OF N-OXIDE METABOLITES

36.3 DISTRIBUTION AND EXCRETION OF N-OXIDES

36.4 METABOLISM OF N-OXIDES

36.5 BIOLOGICAL ACTIVITIES OF N-OXIDES

36.6 EXPERIMENTAL PROTOCOL

36.7 REGULATORY CONSIDERATIONS

36.8 EXAMPLES

36.9 CONCLUSIONS

REFERENCES

Chapter 37: Hydrolysis of Phase II Conjugates for LC-MS Bioanalysis of Total Parent Drugs

37.1 INTRODUCTION

37.2 METHODS AND APPROACHES

37.5 EXAMPLE PROTOCOL

REFERENCES

Chapter 38: LC-MS Bioanalysis of Reactive Compounds

38.1 INTRODUCTION

38.2 DETERMINATION OF REACTIVE COMPOUND EXPOSURE IN VIVO

38.3 MEASUREMENT OF SULFHYDRYL- CONTAINING COMPOUNDS

38.4 CONCLUSION

38.5 REPRESENTATIVE PROTOCOLS

REFERENCES

Chapter 39: LC-MS Bioanalysis of Photosensitive and Oxidatively Labile Compounds

39.1 INTRODUCTION

39.2 PHOTOSENSITIVE COMPOUNDS

39.3 OXIDATION OF COMPOUNDS

39.4 SUMMARY

39.5 PROTOCOL FOR DEVELOPING LC-MS/MS METHOD FOR BIOANALYSIS OF PHOTOSENSITIVE AND OXIDATIVELY LABILE COMPOUNDS

REFERENCES

Chapter 40: LC-MS Bioanalysis of Interconvertible Compounds

40.1 INTRODUCTION

40.2 INTERCONVERSION OF LACTONES AND HYDROXY ACIDS

40.3 STEREOISOMERIC INTERCONVERSION

40.4 CONSIDERATIONS FOR DEVELOPING BIOANALYTICAL METHODS FOR INTERCONVERTIBLE COMPOUNDS

40.5 VALIDATION AND QUALITY CONTROL OF METHODS FOR INTERCONVERTIBLE COMPOUNDS

40.6 SUMMARY

40.7 REPRESENTATIVE PROTOCOL FOR LC-MS/MS METHOD DEVELOPMENT FOR BIOANALYSIS OF INTERCONVERTIBLE COMPOUNDS

REFERENCES

Chapter 41: LC-MS Bioanalysis of Chiral Compounds

41.1 INTRODUCTION

41.2 APPLICATIONS

41.3 CURRENT CONSIDERATIONS AND PROTOCOLS IN DEVELOPING A ROBUST CHIRAL LC-MS/MS BIOANALYTICAL METHOD

41.4 CURRENT METHOD VALIDATION CONSIDERATIONS AND PROTOCOLS FOR CHIRAL BIOANALYTICAL LC-MS/MS

41.5 CONCLUSION

REFERENCES

Chapter 42: LC-MS Bioanalysis of Peptides and Polypeptides

42.1 INTRODUCTION

42.2 METHODS AND APPROACHES

42.3 EXAMPLE EXPERIMENTAL PROTOCOLS

42.4 CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

Chapter 43: LC-MS Bioanalysis of Nucleosides

43.1 INTRODUCTION

43.2 METHODS AND APPROACHES

REFERENCES

Chapter 44: LC-MS Bioanalysis of Nucleotides

44.1 INTRODUCTION

44.2 PREANALYTICAL METHODS AND APPROACHES

44.3 TROUBLESHOOTING

REFERENCES

Chapter 45: LC-MS Bioanalysis of Steroids

45.1 INTRODUCTION

45.2 METHODS AND APPROACHES

45.3 REPRESENTATIVE PROTOCOLS OF LC-MS BIOANALYSIS OF STEROID HORMONES

ACKNOWLEDGMENTS

REFERENCES

Chapter 46: LC-MS Bioanalysis of Liposomal Drugs and Lipids

46.1 INTRODUCTION

46.2 METHODS AND APPROACHES

46.3 PROTOCOLS

REFERENCES

Chapter 47: LC-MS Bioanalysis of Proteins

47.1 INTRODUCTION

47.2 METHODS

47.3 SUMMARY

REFERENCES

Chapter 48: LC-MS Bioanalysis of Oligonucleotides

48.1 INTRODUCTION

48.2 PHYSIOCHEMICAL PROPERTIES AND MODIFICATIONS OF OLIGONUCLEOTIDES

48.3 METHODS AND APPROACHES

48.4 PROTOCOLS

48.5 TROUBLESHOOTING OLIGONUCLEOTIDE LC-MS BIOANALYSIS

48.6 SUMMARY

REFERENCES

Chapter 49: LC-MS Bioanalysis of Platinum Drugs

49.1 INTRODUCTION

49.2 METHODS AND APPROACHES

49.3 TROUBLESHOOTING

REFERENCES

Chapter 50: Microflow LC-MS for Quantitative Analysis of Drugs in Support of Microsampling

50.1 INTRODUCTION

50.2 METHODS AND APPROACHES

50.3 PROTOCOLS

50.4 TROUBLESHOOTING

ACKNOWLEDGMENTS

REFERENCES

Chapter 51: Quantification of Endogenous Analytes in Biofluids by a Combination of LC-MS and Construction of Calibration Curves Using Stable-Isotopes as Surrogate Analytes with True Biological Control Matrices

51.1 INTRODUCTION

51.2 METHODS AND APPROACHES

REFERENCES

Appendix 1: Body and Organ Weights and Physiological Parameters in Laboratory Animals and Humans

Appendix 2: Anticoagulants Commonly Used in Blood Sample Collection

Appendix 3: Solvents and Reagents Commonly Used in LC-MS Bioanalysis

Appendix 4: Glossary of terms used in LC-MS Bioanalysis

Index

Copyright © 2013 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.
Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Handbook of LC-MS bioanalysis : best practices, experimental protocols, and regulations / edited by Wenkui Li, Ph.D., Novartis Institutes for BioMedical Research, Jie Zhang, Ph.D., Novartis Institutes for BioMedical Research, Francis L.S. Tse, Ph.D., Novartis Institutes for BioMedical Research.

pages cm
Includes bibliographical references and index.
ISBN 978-1-118-15924-8 (cloth)
1. Drugs--Spectra--Handbooks, manuals, etc. 2. Drugs--Analysis--Handbooks, manuals, etc. 3. Mass spectrometry--Handbooks, manuals, etc.
4. Liquid chromatography--Handbooks, manuals, etc. I. Li, Wenkui, 1964- editor of compilation. II. Zhang, Jie, 1962- editor of compilation.
III. Tse, Francis L. S., editor of compilation. IV. Title: Handbook of liquid chromatography-mass spectrometry bioanalysis.
RS189.5.S65H36 2013
615.1′901--dc23
2013004581

ISBN: 9781118159248

PREFACE

Bioanalysis is the most heavily regulated area within the discipline of drug metabolism and pharmacokinetics, which supports a large sector of drug development. The health authorities have very specific requirements regarding quality and integrity of bioanalytical results, and different customers usually have additional expectations on the performance of bioanalytical assays.

Much has happened in recent years toward faster, cheaper, and better ways of providing quality bioanalytical results. Both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) have renewed or are renewing their guidances on bioanalytical method validation (e.g., 21July2011/EMEA/CHMP/EWP/192217/2009) with the ultimate goal of improving the quality of bioanalytical results. Novel approaches to bioanalytical method development as well as advents of new liquid chromatographic (LC) techniques and mass spectrometric (MS) instruments have been reported. Various automatic laboratory procedures, electronic laboratory notebooks, and data management systems are now available. All of these culminate in a remarkable improvement in the quality, speed, and cost-effectiveness of bioanalytical work and contribute to the value we deliver to the patient.

Given the rapid changes within the field of bioanalysis and also in the larger area of drug development in which we operate, it is timely to conduct a broad overview of our discipline. This book is the first comprehensive handbook for LC-MS bioanalysis and provides an update on all important aspects of LC-MS bioanalysis of both small molecules and macromolecules. It not only addresses the needs of the bioanalytical scientists on the pivotal projects but also features perspectives on some advanced and emerging technologies including high-resolution mass spectrometry and dried blood spot (DBS) microsampling.

The 51 chapters of the book are divided into four parts. Part I provides a comprehensive overview on the role of LC-MS bioanalysis in drug discovery and development and therapeutic drug monitoring (Chapter 1), the key elements of a regulated bioanalytical laboratory (Chapter 2), and the current international regulations and quality standards of bioanalysis (Chapter 3).

In Part II, the global regulations and quality standards related to LC-MS bioanalysis are reviewed and compared. Chapter 4 highlights the current regulations governing bioanalytical method validations from a number of countries and regions including Brazil (ANVISA), Canada, China, the European Union (EMA), India, Japan, and the United States (FDA). This is followed by two in-depth reviews on the topics of assay reproducibility (Chapter 5) and method transfer (Chapter 6). Chapter 7 presents the current practices and regulatory requirements on Metabolites in Safety Testing (MIST). The guidances of regulatory bodies worldwide on bioanalysis for bioequivalence (BE)/bioavailability (BA) studies are compared in Chapter 8, whereas Chapter 9 concerns the specific topic of good laboratory practice (GLP) and its interpretation and application by different agencies, countries, and regions. Of special interest is the rapid evolvement of regulations on bioanalytical data management, which is discussed in Chapter 10. Chapter 11 concludes Part II by giving a detailed analysis of regulatory inspections including health authority expectation, reported inspectional trends, citations, and regulatory followup letters. Recent FDA 483 observations as well as other “hot topics” in bioanalysis compliance that have raised concerns about data integrity are reviewed. Applicable best practices in LC-MS bioanalysis are portrayed in Part III. From this section of the book, the reader will find sound scientific rationale and helpful practical instructions on the assessment of whole blood stability and blood/plasma distribution (Chapter 12), and on biological sample collection, processing and storage (Chapter 13). Chapter 14 introduces various sample preparation techniques for LC-MS bioanalysis, while the best practices in LC separation and MS detection are discussed in Chapters 15 and 16, respectively. A good bioanalytical method must be sensitive, specific, selective, reproducible, high-throughput, and fundamentally robust. Many factors that can contribute to the success of an assay are reviewed including the choice of internal standard (Chapter 17), evaluation of system suitability (Chapter 18), sensitivity enhancement via derivatization of analyte(s) of interest (Chapter 19), evaluation and elimination of matrix effect (Chapter 20), evaluation and elimination of carryover and/or contamination (Chapter 21), and robotic automation (Chapter 22). Chapters 23–29 describe the bioanalysis of drugs, biomarkers, and other analytes of interest in various body fluids and tissues, and Chapter 30 is devoted to DBS sampling and related bioanalytical issues. Chapter 31 offers some useful strategies for enhancing MS detection, and Chapter 32 shows the proper use of statistics as a tool for ensuring adequate method performance in LC-MS bioanalysis. The simultaneous quantitative and qualitative LC-MS bioanalysis of drugs and metabolites are discussed in Chapter 33.

Part IV aims to provide detailed instructions with representative experimental protocols for the LC-MS bioanalysis of various types of drug molecules commonly encountered in the bioanalytical laboratory today (Chapters 34–49). Chapter 50 describes a typical procedure using microflow LC-MS for the quantitative analysis of drugs in support of microsampling. Finally, a protocol on the quantification of endogenous analytes in biofluids without a true blank matrix is given in Chapter 51.

Our purpose in committing to this project was to provide scientists in industry, academia, and regulatory agencies with not only all the “important points to consider” but also all “practical tricks to implement” in LC-MS bioanalysis of various molecules according to current health authority regulations and industry practices. In this book, we are confident that we have accomplished our goal. The book represents a major undertaking, which would not have been possible without the contributions of all the authors and the patience of their families. We also thank the terrific editorial staff at John Wiley & Sons and give a special acknowledgment to Michael Leventhal, Associate Editor, and Robert Esposito, Associate Publisher, at John Wiley & Sons for their premier support of this project.

WENKUI LI, PhD
JIE ZHANG, PhD
FRANCIS L.S. TSE, PhD

CONTRIBUTORS

Arnold, Mark E., Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, USA

Aubry, Anne-Françoise, Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, USA

Awaiye, Kayode, Bioanalytical, BioPharma Services Inc., Toronto, ON, Canada

Bansal, Surendra K., Bioanalytical Research & Development, Non-Clinical Safety, Hoffmann-La Roche Inc., Nutley, NJ, USA

Barrientos-Astigarraga, Rafael E., Magabi Pesquisas Clínicas e Farmacêuticas Ltda, Itaqui Itapevi, Sao Paulo, Brazil

Bartels, Michael J., Toxicology and Environmental Research & Consulting, The Dow Chemical Company, Midland, MI, USA

Bartlett, Michael G., Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA

Bennett, Patrick, Thermo Fisher Scientific, San Jose, CA, USA

Briscoe, Chad, US Bioanalysis, PRA International, Lenexa, KS, USA

Bruenner, Bernd A. Bioanalytical Sciences, Pharmacokinetics & Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA

Carter, Spencer, Tandem Labs, a Labcorp Company, Salt Lake City, UT, USA

Chen, Buyun, Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA

Chow, Frank, Lachman Consultant Services Inc., Westbury, NY, USA

Cohen, Lucinda, NJ Discovery Bioanalytical Group, Merck, Rahway, NJ, USA

Cohen, Sabine, Hospices Civils de Lyon, Laboratoire de biochimie-toxicologie, Centre Hospitalier Lyon-Sud, Pierre Bénite, Cedex, France

de Boer, Theo, Analytical Biochemical Laboratory (ABL) B.V., W.A. Scholtenstraat 7, Assen, The Netherlands

Demers, Roger, Tandem Labs, a Labcorp Company, West Trenton, NJ, USA

Duggan, Jeffrey X., Bioanalysis & Metabolic Profiling, DMPK, Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA

Edom, Richard, Bioanalysis, Janssen Research & Development, Global Development Operations, Raritan, NJ, USA

Evans, Christopher A., PTS-DMPK Bioanalytical Science & Toxicokinetics (BST), GlaxoSmithKline, King of Prussia, PA, USA

Flarakos, Jimmy, Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

Fu, Yunlin, Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

Gagnieu, Marie-Claude, Hospices Civils de Lyon, Laboratoire de pharmacologie, Hôpital E. Herriot, Lyon, France

Gao, Hong, Drug Metabolism & Pharmacokinetics, Vertex Pharmaceuticals Inc., Cambridge, MA, USA

Garofolo, Fabio, Bioanalytical, Algorithme Pharma Inc., Laval (Montreal), Quebec, Canada

Guitton, Jérôme, Hospices Civils de Lyon, Laboratoire de ciblage thérapeutique en cancérologie, Centre Hospitalier Lyon-Sud, Pierre Bénite, Cedex, France; Université Claude Bernard Lyon I, Laboratoire de Toxicologie, ISPBL, Lyon, France

Hawthorne, Glen, Department of Bioanalysis, Huntingdon Life Sciences, Alconbury, Cambridgeshire, UK

Hayes, Michael, Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

Hill, Howard M., Pharmaceutical Development, Huntingdon Life Sciences, Alconbury, Cambridgeshire, UK

Ho, Stacy, Drug Metabolism & Pharmacokinetics, Preclinical Biosciences, Sanofi, Waltham, MA, USA

Hoffman, David, Early Development Biostatistics, Sanofi, Bridgewater, NJ, USA

Huang, Qingtao (Mike), Bioanalysis, Janssen Research & Development, Global Development Operations, Raritan, NJ, USA

James, Christopher A., Bioanalytical Sciences, Pharmacokinetics & Drug Metabolism, Amgen Inc., Thousand Oaks, CA, USA

Ji, Allena J., Clinical Specialty Lab, Genzyme, A Sanofi Company, Framingham, MA, USA

Jian, Wenying, Bioanalysis, Janssen Research & Development, Global Development Operations, Raritan, NJ, USA

Kindt, Erick, Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc., San Diego, CA, USA

Kudoh, Shinobu, Pharmaceuticals & Life-sciences Division, Shimadzu Techno-Research, Inc., Nakagyo-ku, Kyoto-shi, Kyoto-fu, Japan

Lachman, Leon, Lachman Consultant Services, Inc., Westbury, NY, USA

Lefebvre, Isabelle, Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-UM1-UM2, Université Montpellier 2, Montpellier, Cedex, France

Li, Feng (Frank), Alliance Pharma Inc., Malvern, PA, USA

Li, Hongyan, Bioanalytical Sciences, Pharmacokinetics & Drug Metabolism, Amgen Inc, Thousand Oaks, CA, USA

Li, Wenkui, Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

Li, Wenlin (Wendy), Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc., San Diego, CA, USA

Licea-Perez, Hermes, PTS-DMPK Bioanalytical Science & Toxicokinetics (BST), GlaxoSmithKline, King of Prussia, PA, USA

Lin, Zhongping (John), Bioanalytical Services, Frontage Laboratories Inc., Malvern, PA, USA

Liu, Guowen, Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, USA

Love, Iain, Department of Bioanalysis, Huntingdon Life Sciences, Alconbury, Cambridgeshire, UK

Majumdar, Tapan K., Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

Martinez, Elizabeth M., Department of Medicinal Chemistry & Pharmacognosy, University of Illinois College of Pharmacy, Chicago, IL, USA

McGinnis, A. Cary, Department of Pharmaceutical & Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA

Meng, Min, Tandem Labs, a Labcorp Company, Salt Lake City, UT, USA

Miller, Jeffrey D., Product Applications, AB Sciex, Framingham, MA, USA

Moyer, Michael, Bioanalytical Services, Frontage Laboratories Inc., Malvern, PA, USA

Nash, Bradley, Global Quality & Compliance, PPD, Richmond, VA, USA

Ohnmacht, Corey M., US Bioanalysis, PRA International, Lenexa, KS, USA

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Yang, Ziping, Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

Yau, Martin, Lachman Consultant Services, Inc., Westbury, NY, USA

Yuan, Weiwei, QPS LLC, Newark, DE, USA

Zeng, Jianing, Bioanalytical Sciences, Bristol-Myers Squibb Co., Princeton, NJ, USA

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Zhang, Fagen, Toxicology & Environmental Research & Consulting, The Dow Chemical Company, Midland, MI, USA

Zhang, Jie, Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

Zhou, Jin, Drug Metabolism & Pharmacokinetics, Boehringer-Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA

ABBREVIATIONS

AAPS | American association of pharmaceutical scientists
AAS | Atomic absorption spectroscopy
AC | Absolute carryover
Ach | Acetylcholine
ACUP | Animal care and use protocol
ADC | Antibody–drug conjugate
ADME | Absorption, distribution, metabolism, and excretion
AFA | Adaptive focused acoustics
ALQ/AULOQ | Above the upper limit of quantification
ANDA | Abbreviated new drug application
ANVISA | National health surveillance agency (in Portuguese, Agência Nacional de Vigilância Sanitária)
AP | Analytical procedure
APCI | Atmospheric pressure chemical ionization
API | Atmospheric pressure ionization
APPI | Atmospheric pressure photoionization
ASE | Accelerated solvent extraction
ASEAN | Association of southeast asian nations
AUC | Area under the curve
BA | Bioavailability
BDMA | Butyldimethylamine
BDMAB | Butyldimethylammonium bicarbonate
BE | Bioequivalence
BIMO | Bioresearch monitoring
BLQ/BLLOQ | Below the lower limit of quantification

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