Characterization of Impurities and Degradants Using Mass Spectrometry E-Book

Guodong Chen

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Veröffentlichungsjahr: 2011

Beschreibung

The book highlights the current practices and future trends in structural characterization of impurities and degradants. It begins with an overview of mass spectrometry techniques as related to the analysis of impurities and degradants, followed by studies involving characterization of process related impurities (including potential genotoxic impurities), and excipient related impurities in formulated products.  Both general practitioners in pharmaceutical research and specialists in analytical chemistry field will benefit from this book that will detail step-by-step approaches and new strategies to solve challenging problems related to pharmaceutical research.

Leseprobe

Contents

Cover

Wiley Series on Pharmaceutical Science and Biotechnology: Practices, Applications, and Methods

Title Page

Copyright

Preface

Contributors

Acronyms

Part I: Methodology

Chapter 1: Introduction to Mass Spectrometry

1.1 History

1.2 Ionization Methods

1.3 Mass Spectrometer Types

1.4 Tandem Mass Spectrometry

1.5 Separation Techniques Coupled to Mass Spectrometry

1.6 Prospects for Mass Spectrometry

References

Chapter 2: LC Method Development and Strategies

2.1 Introduction

2.2 Column, pH, and Solvent Screening

2.3 Gradient and Temperature Optimization

2.4 Orthogonal Screening

2.5 High-Efficiency Separation

2.6 Conclusions

References

Chapter 3: Rapid Analysis of Drug-Related Substances using Desorption Electrospray Ionization and Direct Analysis in Real Time Ionization Mass Spectrometry

3.1 Introduction

3.2 Ionization Apparatus, Mechanisms, and General Performance

3.3 Drug Analysis in Biological Matrices Using DESI and DART

3.4 High-Throughput Analysis

3.5 Chemical Imaging and Profiling

3.6 Future Perspectives

References

Chapter 4: Orbitrap High-Resolution Applications

4.1 Historical Anecdote

4.2 General Description of Orbitrap Operating Principles

4.3 The Orbitrap is a “Fourier Transform” Device

4.4 Performing Experiments in Trapping Devices

4.5 Determining Elemental Compositions Of “Unknowns” Using an Orbitrap

4.6 Orbitrap Figures of Merit in Mass Measurement

4.7 HPLC Orbitrap MS: Accurate Mass Demonstration and Differentiation of Small Molecule Formulas Very Proximate in Mass/Charge Ratio Space

4.8 Determination of Trace Contaminant Compositions by Simple Screening HPLC-MS and Infusion Orbitrap MS

4.9 Determining Substructures: Orbitrap Tandem Mass Spectrometry (MSn)

4.10 Multianalyzer (Hybridized) System: the Linear Ion Trap/Orbitrap for MS/MS and Higher-Order MSn, n > 2

4.11 Mass Mapping to Discover Impurities

4.12 The Current Practice of Orbitrap Mass Spectrometry

4.13 Conclusion

References

Chapter 5: Structural Characterization of Impurities and Degradation Products in Pharmaceuticals Using High-Resolution LC-MS and Online Hydrogen/Deuterium Exchange Mass Spectrometry

5.1 Introduction

5.2 Characterization of Impurities

5.3 Characterization of Degradation Products

5.4 Conclusions

References

Chapter 6: Isotope Patten Recognition on Molecular Formula Determination for Structural Identification of Impurities

6.1 Introduction

6.2 Three Basic Approaches to Isotope Pattern Recognition

6.3 The Importance of Lineshape Calibration

6.4 Spectral Accuracy

6.5 Formula Determination with Quadrupole MS

6.6 Formula Determination with High-Resolution MS

6.7 Conclusions and Future Directions

References

Part II: Application

Chapter 7: Practical Application of Very High-Pressure Liquid Chromatography Across the Pharmaceutical Development–Manufacturing Continuum

7.1 Introduction

7.2 Theory and Benefits Of VHPLC

7.3 VHPLC Method Development

7.4 Other Practical Considerations

7.5 VHPLC Method Validation

7.6 Summary

References

Chapter 8: Impurity Identification for Drug Substances

8.1 Introduction

8.2 Case Studies

8.3 Conclusions

References

Chapter 9: Impurity Identification in Process Chemistry by Mass Spectrometry

9.1 Introduction

9.2 Experimentation

9.3 Applications

9.4 Concluding Remarks

Acknowledgments

References

Chapter 10: Structure Elucidation of Pharmaceutical Impurities and Degradants in Drug Formulation Development

10.1 Importance of Drug Degradation Studies in Drug Development

10.2 Drug Degradation Studies in Formulation Development

10.3 Complexity of Impurity Identification in Drug Development

10.4 Strategy for Structure Elucidation of Unknowns

10.5 Hyphenated Analytical Techniques Used in Drug Development

10.6 Case Studies

Acknowledgment

References

Chapter 11: Investigation of Degradation Products and Extractables in Developing Topical OTC (Over the Counter) and NCE (New Chemical Entity) Consumer Healthcare Medication Products

11.1 Introduction

11.2 Oxidatively Induced Coupling of Miconazole Nitrate with Butylated Hydroxytoluene in a Topical Ointment

11.3 Extractables from Rubber Closures of a Prefilled Semisolid Drug Applicator

11.4 New Degradation Products and Pathways of Vitamin D and Its Analogs

11.5 Reductive Degradation of a 1,2,4-Thiadiazolium Derivative

11.6 Conclusions

References

Chapter 12: Characterization of Impurities and Degradants in Protein Therapeutics by Mass Spectrometry

12.1 Introduction to Therapeutic Proteins

12.2 Recent Advances in Mass Spectrometry

12.3 Impurities

12.4 Degradation Products

12.5 Conclusions

References

Chapter 13: Identification and Quantification of Degradants and Impurities in Antibodies

13.1 Introduction to Antibodies and Protein Drugs

13.2 Overview of Degradations and Impurities in Protein Drugs and Antibodies

13.3 Methods Used to Identify and Quantitate Degradations and Impurities

13.4 Conclusions

Appendix

References

Index

Wiley Series on Pharmaceutical Science and Biotechnology: Practices, Applications, and Methods

Series Editor:

Mike S. Lee

Milestone Development Services

Mike S. Lee • Integrated Strategies for Drug Discovery Using Mass Spectrometry

Birendra Pramanik, Mike S. Lee, and Guodong Chen • Characterization of Impurities and Degradants Using Mass Spectrometry

Mike S. Lee and Mingshe Zhu • Mass Spectrometry in Drug Metabolism and Disposition: Basic Principles and Applications

Copyright © 2011 by John Wiley & Sons. 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:

Characterization of impurities and degradants using mass spectrometry /edited by Birendra N. Pramanik, Mike S. Lee, Guodong Chen.

p. cm.

Includes index.

ISBN 978-0-470-38618-7 (cloth)

1. Drugs–Analysis. 2. Drugs–Spectra. 3. Mass spectrometry. 4. Contamination (Technology) I. Pramanik, Birendra N., 1944- II. Lee, Mike S., 1960- III. Chen, Guodong.

RS189.5.S65C53 2010

615'.l–dc22

2010023283

Printed in the United States of America

eBook ISBN: 978-0-470-92136-4

oBook ISBN: 978-0-470-92137-1

ePub ISBN: 978-0-470-92297-2

Preface

During the past decade, new formats for automated, high-throughput sample generation combined with a faster pace of drug development led to a shift in sample analysis requirements from a relatively pure sample type to a trace mixture. Mass spectrometry–based technologies played a significant role in this transition and assumed a critical role in pharmaceutical analysis throughout each stage of drug development ranging from drug discovery to manufacturing. A critical part of the development and support of a marketed product is the analysis of impurities and degradation products. Structural information on drug impurities can serve to accelerate the drug discovery–development cycle. The use of chromatographic methods such as high-performance liquid chromatography (HPLC) has long been a hallmark of impurity and degradant analysis. HPLC is often used to profile and classify molecules and work in concert with mass spectrometry to assist with the elucidation of structure. Identification of resulting impurities is based on direct comparison of the mass spectrometric fragmentation of the impurity with the parent drug tandem mass spectrometry (MS/MS) fragmentation patterns. The use of rapid and systematic strategies based on hyphenated analytical techniques such as liquid chromatography–mass spectrometry (LC-MS) profiling and liquid chromatography–tandem mass spectrometry (LC-MS/MS) substructural techniques has become a standard analytical platform for impurity identification activities. We are delighted to highlight current analytical approaches, industry practices, and modern strategies for the identification of impurities and degradants in drug development of both small-molecule pharmaceuticals and protein therapeutics. We provide an ensemble of analytical applications that require the combination of separation techniques and mass spectrometry methods that reflect achievements in impurity and degradant analysis.

We would like to acknowledge the special efforts of all the authors who have made significant contributions to this book. Special thanks go to the acquisitions and production editors at John Wiley & Sons, Inc. for their assistance.

Birendra N. Pramanik Mike S. Lee Guodong Chen

Contributors

Michael Ackerman, Bristol-Myers Squibb Company, Pennington, NJ

David W. Berberich, Covidien, St. Louis, MO

Guodong Chen, Bristol-Myers Squibb Company, Princeton, NJ

Hao Chen, Department of Chemistry and Biochemistry, Ohio University, Athens, OH

Himanshu S. Gadgil, Amgen Inc., Seattle, WA

Ming Gu, Cerno Bioscience, Danbury, CT

David M. Hambly, Amgen Inc., Seattle, WA

Tao Jiang, Covidien, St. Louis, MO

Brent Kleintop, Bristol-Myers Squibb Company, New Brunswick, NJ

Mike S. Lee, Milestone Development Services, Newtown, PA

Jiwen Li, Department of Chemistry and Biochemistry, Ohio University, Athens, OH

David Q. Liu, GlaxoSmithKline, King of Prussia, PA

Frances Liu, Novartis, East Hanover, NJ

Peiran Liu, Bristol-Myers Squibb Company, Pennington, NJ

Joseph McClurg, Covidien, St. Louis, MO

Frank Moser, Covidien, St. Louis, MO

Michael Motto, Novartis, East Hanover, NJ

Zheng Ouyang, Department of Biomedical Engineering, Purdue University, West Lafayette, IN

Changkang Pan, Novartis, East Hanover, NJ

Birendra N. Pramanik, Merck and Co., Kenilworth, NJ

Reb Russell, Bristol-Myers Squibb Company, Pennington, NJ

Ruth Waddell Smith, Department of Chemistry, Michigan State University, East Lansing, MI

Scott A. Smith, Department of Chemistry, Michigan State University, East Lansing, MI

Robert J. Strife, Procter & Gamble, Mason, OH

Mingjiang Sun, GlaxoSmithKline, King of Prussia, PA

Li Tao, Bristol-Myers Squibb Company, Pennington, NJ

Qinggang Wang, Bristol-Myers Squibb Company, New Brunswick, NJ

R. Randy Wilhelm, Covidien, St. Louis, MO

Lianming Wu, GlaxoSmithKline, King of Prussia, PA

Wei Wu, Bristol-Myers Squibb Company, Pennington, NJ

Yu Xia, Department of Chemistry, Purdue University, West Lafayette, IN

Gang Xue, Pfizer Inc., Groton, CT

Fa Zhang, Johnson & Johnson, Skillman, NJ

Yining Zhao, Pfizer Inc., Groton, CT

Acronyms1

ADCCantibody-dependent cell-mediated cytotoxicityADMEadsorption, distribution, metabolism, excretionAGCautomatic gain controlAGEadvanced glycation endproductAHOTaxial harmonic orbital trappingANDAabbreviated new-drug applicationAPCIatmospheric-pressure chemical ionization (DAPCI—desorption APCI)APIatmospheric-pressure ionizationAPTDIatmospheric-pressure thermal desorption/ionizationASAPatmospheric solid analysis probeAUCanalytical ultracentrifugationCDCcomplement-dependent cytotoxicityCDRcomplementarity-determining regionCEcapillary electrophoresisCfcontinuous flowCHOChinese hamster ovaryCIchemical ionization; chemical impactCIDcollision-induced dissociationCITcylindrical ion trapCLNDchemiluminescent nitrogen detectorCOMcenter of massCOSYcorrelation spectroscopyCVcoefficient of variationCZEcapillary-zone electrophoresisDADdiode array detectionDAPPIdesorption atmospheric-pressure photoionizationDARTdirect analysis in real timeDBDIdielectric barrier discharge ionizationDEdelayed extractionDECdetermination of elemental (de)compositionDEPTdistortionless enhancement by polarization transferDESIdesorption electrospray ionization (FD-DESI—fused-droplet DESI; MALDESI—matrix-assisted laser DESI)DeSSIdesorption sonic spray ionizationDLIdirect liquid introductionDOEdesign of experiment(s)DSdrug substanceECDelectron capture dissociationEESIextractive electrospray ionization (ND-EESI—neutral desorption EESI)EIelectron impactEICelectrospray ionization chromatographyELDIelectrospray-assisted desorption/ionizationESSIelectrosonic spray ionizationETDelectron transfer dissociationEUenzyme unitFABfast-atom bombardmentFFFfield flow fractionationFIDIfield-induced droplet ionizationHAPGDIhelium atmospheric-pressure glow discharge ionizationHC/LCheavy chain/light chainHCDhigher-energy C-trap (or collision-induced) dissociationHCPhost cell proteinHCVhepatitis C virusHF/LFhigh field/low fieldHIChydrophobic interaction chromatographyHMBCheteronuclear multibond coherenceHTShigh-throughput screeningIAAisotope abundance analysisICPinductively coupled plasmaICRion cyclotron resonanceIE/KEinternal energy/kinetic energyIECion exchange chromatographyIEFisoelectric focusingILAimmunoligand assayIMSion mobility spectrometryJeDIjet desorption ionizationLAESIlaser ablation electrospray ionizationLALlimulus amebocyte lysateLMCliquid microjunction chromatographyLODlimit of detectionLSIMSliquid secondary ionization mass spectrometryLTPlow-temperature plasmaLTQlinear trap quadrupolemAbmonoclonal antibodyMAGICmonodisperse aerosol generation interface for chromatographyMALDImatrix-assisted laser desorption/ionizationMCPmicrochannel plateMDDmaximum daily doseMPmodel proteinMPDmultiphoton dissociationMPPSIRDmass peak profiling from selected ion recording dataMSDmass spectrometry detectorNCEnew chemical entityNDAnew-drug applicationNI/PInegative ion/positive ionNMPnext maximum projectionNOEnuclear Overhauser effectNOESYnuclear Overhauser enhancement spectroscopyOTopen tubularOVATone variable at a timePADIplasma-assisted desorption/ionizationPAGEpolyacrylamide gel electrophoresisPBparticle beamPCAprincipal-components analysisPDADphotodiode array detectionPDMpharmaceutical development–manufacturingPDMSplasma desorption mass spectrometryPETpositron emission tomographyPGMprofile generation modelPPCpractical peak capacityPPIPPNpulsed positive ion–pulsed negative ionPTMposttranslational modificationQITquadrupole ion trapQMFquadrupole mass filterrFCrecombinant factor CRICreconstructed ion chromatogramRITrectilinear ion trapRPreversed phaseRRTrelative retention timeRSDrelative standard deviationRTretention timeSAspectral accuracySECsize exclusion chromatographySFCsupercritical fluid chromatographySIDsurface-induced dissociationSIMSsecondary-ion mass spectrometrySMBsupersonic molecular beamSPEsolid-phase extractionSSPsurface sampling probeSWIFTstored waveform inverse Fourier transformTDCtime-to-digital converterTGAthermogravimetric analysisTICtotal-ion chromatogramTOFtime of flight (oaTOF—orthogonal acceleration TOF; reTOF—reflectron TOF)VOCvolatile organic compoundWBAwhole-body autoradiography

Note

1. Partial list only; common terms (IR, HLC, GC, NMR, RF, etc.), proper names (FDA, NIST, etc.), and chemical compounds (SDS, TCA, etc.) omitted here.

Phase I

Methodology