Handbook of LC-MS Bioanalysis Best Practices, Experimental Protocols, and Regulations

Consolidates the information LC-MS bioanalytical scientists need to analyze small molecules and macromolecules

The field of bioanalysis has advanced rapidly, propelled by new approaches for developing bioanalytical methods, new liquid chromatographic (LC) techniques, and new mass spectrometric (MS) instruments. Moreover, there are a host of guidelines and regulations designed to ensure the quality of bioanalytical results.

Presenting the best practices, experimental protocols, and the latest understanding of regulations, this book offers a comprehensive review of LC-MS bioanalysis of small molecules and macromolecules. It not only addresses the needs of bioanalytical scientists working on routine projects, but also explores advanced and emerging technologies such as high-resolution mass spectrometry and dried blood spot microsampling.

Handbook of LC-MS Bioanalysis features contributions from an international team of leading bioanalytical scientists. Their contributions reflect a review of the latest findings, practices, and regulations as well as their own firsthand analytical laboratory experience. The book thoroughly examines:

• Fundamentals of LC-MS bioanalysis in drug discovery, drug development, and therapeutic drug monitoring
• The current understanding of regulations governing LC-MS bioanalysis
• Best practices and detailed technical instructions for LC-MS bioanalysis method development, validation, and stability assessment of analyte(s) of interest
• Experimental guidelines and protocols for quantitative LC-MS bioanalysis of challenging molecules, including pro-drugs, acyl glucuronides, N-oxides, reactive compounds, and photosensitive and autooxidative compounds

With its focus on current bioanalytical practice, Handbook of LC-MS Bioanalysis enables bioanalytical scientists to develop and validate robust LC-MS assay methods, all in compliance with current regulations and standards.

WENKUI LI, PhD, is Senior Fellow in the Department of Drug Metabolism & Pharmacokinetics at Novartis Institutes for BioMedical Research, where he focuses on regulated LC-MS/MS bioanalysis for the toxicokinetic and pharmacokinetic assessment of drug candidates. Dr. Li is a member of the editorial board of Biomedical Chromatography.

JIE ZHANG, PhD, is Senior Fellow in the Department of Drug Metabolism & Pharmacokinetics at Novartis Institutes for BioMedical Research, where he focuses on regulated LC-MS bioanalysis for the toxicokinetic and pharmacokinetic assessment of drug candidates. In addition, Dr. Zhang evaluates and implements novel technologies and processes in regulated LC-MS bioanalysis.

FRANCIS L. S. TSE, PhD, is Vice President of Drug Metabolism & Bioanalytics at Novartis Institutes for BioMedical Research, overseeing the unit's strategy and operations in North America and Asia. Dr. Tse is a Fellow of the American Association of Pharmaceutical Scientists, APhA Academy of Pharmaceutical Research and Science, and American College of Clinical Pharmacology.

Editors’ Preface
Wenkui Li, Jie Zhang and Francis LS Tse

Part I: Overview of LC-MS Bioanalysis

1. Roles of LC-MS Bioanalysis in Drug Discovery, Development and Therapeutic Drug Monitoring
Steve Unger, Wenkui Li, Jimmy Flarakos and Francis L.S. Tse

2. Overview: Fundamentals of a Bioanalytical Laboratory
Naidong Weng, Shefali Patel, Qiangtao (Mike) Huang, Wenying Jian, and Richard Edom

3. International Regulations and Quality Standards of Bioanalysis
Surendra Bansal

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

4. Current Regulations for Bioanalytical Method Validations
Mark E. Arnold, Rafael E. Barrientos-Astigarraga, Fabio Garofolo, Shinobu Kudoh, Shrinivas S. Savale, Shinobu Kudoh, Daniel Tang, Philip Timmerman and Peter van Amsterdam

5. Current Understanding of Bioanalytical Assay Reproducibility – Incurred Sample Reanalysis (ISR), Incurred Sample Stability (ISS) and Incurred Sample Accuracy (ISA)
Manish Yadav, Pranav S. Shrivastav, Theo de Boer, Jaap Wieling, and Puran Singhal

6. LC-MS Bioanalytical Method Transfer
Zhongping (John) Lin, Wenkui Li and Naidong Weng,

7. Metabolites in Safety Testing (MIST)
Ragu Ramanathan and Dil M. Ramanathan

8. A Comparison of FDA, EMA, ANVISA, and Others on Bioanalysis in Support of Bioequivalence / Bioavailability Studies
Bradley Nash

9. Comparison of the Guidance of FDA, OECD, EPA and Others on Good Laboratory Practice
J. Kirk Smith

10. Current Understanding of Bioanalysis Data Management and Trend of Regulations on Data Management
Zhongping (John) Lin, Jianing Zeng, Joe Rajarao, Michael Moyer and Michael Hayes

11. Regulatory Inspections Trends and Findings of Bioanalytical Laboratory
Frank Chow, Martin Yau, and Leon Lachman,

Part III: Best Practice in LC-MS Bioanalysis

12. Assessment of Whole Blood Stability and Blood/Plasma Distribution of Drugs
Iain Love, Graeme T. Smith and Howard M. Hill

13. Best Practice in Biological Sample Collection, Processing and Storage for LC-MS Bioanalysis of Drugs
Maria Pawula, Glen Hawthorne, Graeme T. Smith and Howard M. Hill

14. Best Practice in Biological Sample Preparation for LC-MS Bioanalysis
Guowen Liu and Anne-Francoise Aubry

15. Best Practice in Liquid Chromatography for LC-MS Bioanalysis
Steve Unger and Naidong Weng

16. Best Practice in Mass Spectrometry for LC-MS
Richard van Breemen and Elizabeth M. Martinez

17. Use of Internal Standard in LC-MS Bioanalysis
Aimin Tan and Kayode Awaiye

18. System Suitability in LC-MS Bioanalysis
Chad Briscoe

19. Derivatization in LC-MS Bioanalysis

Tomofumi Santa

20. Evaluation and Elimination of Matrix Effect in LC-MS Bioanalysis
Christopher A. James and Bernd Bruenner

21. Evaluation and Elimination of Carryover and/or Contamination in LC-MS Bioanalysis
Howard M. Hill and Graeme T. Smith

22. Automation in LC-MS Bioanalysis
Joseph Tweed

23. LC-MS/MS Bioanalysis of Drugs in Tissue Samples
Hong Gao, Stacy Ho and John Williams

24. LC-MS Bioanalysis of Drugs in Urine
Allena J. Ji

25. LC-MS Bioanalysis of Unbound Drugs in Plasma and Serum
Theo de Boer and Jaap Wieling

26. LC-MS Bioanalysis of Drugs in Biles
Hong Gao and John Williams

27. LC-MS Bioanalysis of Intracellular Drugs
Fagen (Frank) Zhang and Michael Bartels

28. LC-MS LC-MS Bioanalysis of Endogenous Compounds as Biomarkers
Wenying Jian, Richard Edom and Naidong Weng

29. LC-MS Bioanalysis of Drugs in Hemolyzed and Lipemic Samples
Min Meng, Spencer Carter and Patrick Bennett

30. Best Practice in LC-MS Method Development and Validation for Dried Blood Spots (DBS)
Jie Zhang, Tapan K. Majumdar, Jimmy Flarakos and Francis Tse

31. LC-MS Method Development Strategies for Enhancing Mass Spectrometric Detection
Yuan-Qing Xia and Jeffrey D. Miller

32. LC-MS Bioanalysis-related Statistics
David Hoffman

33. Simultaneous LC-MS Quantitation and Metabolite Identification in Drug Metabolism and Pharmacokinetics
Patrick Rudewicz

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

34. LC-MS/MS Bioanalysis of Ester Prodrugs and Other Esterase Labile Molecules
Wenkui Li, Yunlin Fu, Jimmy Flarakos and Duxi Zhang

35. LC-MS Bioanalysis of Acyl Glucurorides
Jin Zhou and Jeffery X. Duggan and Feng (Frank) Li

36. Regulated bioassay of N-oxide metabolites using LC-MS: Dealing with potential instability issues
Tapan K. Majumdar

37. Hydrolysis (Acidic or Enzymatic) of Phase II Conjugates for LC-MS Bioanalysis of Total Parent Drugs
Laixin Wang, Weiwei Yuan, Scott Reuschel and Min Meng

38. LC-MS Bioanalysis of Reactive Compounds
Hermes Licea-Perez, Christopher Evans and Yi (Eric) Yang

39. LC-MS Bioanalysis of Photosensitive and Autooxidative Compounds
Corey Ohnmacht

40. LC-MS Bioanalysis of Interconvertible Compounds
Nico van de Merbel

41. LC-MS Bioanalysis of Chiral Compounds
Naidong Weng

42. LC-MS Bioanalysis of Peptides and Polypeptides
Christopher A. James and Hongyan Li

43. LC-MS Bioanalysis of Nucleosides
Laixin Wang and Min Meng

44. LC-MS Bioanalysis of Nucleotides
Sabine Cohen, Marie-Claude Gagnieu, Isabelle Lefebvre and Jérôme Guitton

45. LC-MS Bioanalysis of Steroids
Jie Zhang and Frank Stanczyk

46. LC-MS/MS Bioanalysis of Bioanalysis of Liposomal Drugs and Lipids
Troy Voelker and Roger Demers

47. LC-MS Bioanalysis of Proteins
Ziping Yang, Wenkui Li, Harold T. Smith and Francis L.S. Tse, Novartis

48. Liquid Chromatography-Mass Spectrometric Bioanalysis of Oligonucleotides
Michael G. Bartlett, Buyun Chen and A. Cary McGinnis

49. LC-MS Bioanalysis of Platinum Drugs
Troy Voelker and Min Meng

50. Micro-flow LC-MS for Quantitative Analysis of Drugs in Support of Microsampling
Heather Skor and Sadayappan V. Rahavendran

51. Quantification of Endogenous Analytes in Biofluids by a Combination of Liquid Chromatography-Mass Spectrometry and Construction of Calibration Curves Using Stable-Isotopes as Surrogate Analytes with True Biological Control Matrices
Wenlin (Wendy) Li, Lucinda Cohen and Erick Kindt

Appendix:

1. Common Biological Matrices and Respective Physiological Properties

2. Anticoagulants and Other Addictives Commonly Used in Biological Sample Collection

3. Buffers, Reagents and Mobile Phase Additives Commonly Used in LC-MS Bioanalysis

4. Common Terms and Instrument Parameters of LC-MS Bioanalysis

5. Abbreviation

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