ANALYTICAL TECHNIQUES FOR CLINICAL CHEMISTRY ANALYTICAL TECHNIQUES FOR CLINICAL CHEMISTRY METHODS AND APPLICATIONS Edited by Sergio Caroli National Institute of Health, Viale Regina Elena, Rome, Italy Gyula Zaray Eoătvoăs Lorand University, Budapest, Hungary Copyright Ó 2012 by John Wiley & Sons, Inc All rights reserved Published by John Wiley & Sons, Inc., Hoboken, NJ Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com Requests to the Publisher for 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forever in our hearts Sergio Caroli and Gyula Z aray CONTENTS FOREWORD xxiii PREFACE xxv CONTRIBUTORS xxvii PART I Exploring Fundamentals Good Clinical Practice Principles: Legal Background and Applicability Umberto Filibeck, Angela Del Vecchio, and Fabrizio Galliccia Summary 3 1.1 Introduction 1.2 Good Clinical Practice 1.2.1 ICH E6: Guidelines for Good Clinical Practice 1.2.2 WHO Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products 1.2.3 WHO Handbook for Good Clinical Research Practice Guidance for Implementation 1.2.4 WHO Good Clinical Laboratory Practice 4 7 1.3 Good Clinical Practice: Legal Background in the European Union 1.4 Good Clinical Practice: Applicability in the European Union 1.4.1 EU 2007 Conference on the Implementation and Applicability in the European Union of Legislation on Clinical Trials of Medical Products 1.4.2 Directives 2001/20/EC, 2005/28/EC, and Good Clinical Practice in Case of Noncommercial Clinical Trials 10 1.5 Good Clinical Practice and Bioequivalence Trials: GCP Inspections and Laboratories 1.5.1 General Aspects 1.5.2 EMA Guidelines on Bioequivalence Studies 1.5.3 EMA Reflection Paper for Applicants Who Want to Submit Bioequivalence Performed Outside the European Union 10 11 13 13 14 15 viii CONTENTS 1.5.4 Good Clinical Practice Bioequivalence Inspections 1.5.5 Good Clinical Practice Clinical Laboratory Inspections 1.5.6 Good Clinical Practice Inspections on Phase I Units 1.6 Good Clinical Practice for Clinical Trials with Advanced Therapy Medicinal Product 1.7 Good Clinical Practice and Clinical Trials in Developing Countries 1.7.1 The Increase of Clinical Trials in Developing Countries 1.7.2 European Union Legislation and Clinical Trials in Developing Countries References Clinical Chemistry and the Quest for Quality Sergio Caroli Summary 16 19 20 20 22 22 23 25 29 29 2.1 Introduction 30 2.2 Quality Today 2.2.1 General Aspects 2.2.2 Major Quality Systems and Their Scope 31 31 32 2.3 Conclusions 55 References Uncertainty in Clinical Chemistry Measurements Including Preanalytical Variables Marit Sverresdotter Sylte, Tore Wentzel-Larsen, and Bjørn J Bolann Summary 55 59 59 3.1 Introduction 60 3.2 Analytical Uncertainty in Laboratory Results 3.2.1 General Aspects 3.2.2 Control Materials 3.2.3 Estimating Analytical Precision 3.2.4 Within-Run Precision (Repeatability) 3.2.5 Total Analytical Precision (Reproducibility) 3.2.6 Estimating Precision Using Duplicates 62 62 62 64 65 66 66 3.3 Trueness and Traceability 3.3.1 Basic Concepts 67 67 CONTENTS 3.3.2 3.3.3 3.3.4 3.3.5 3.3.6 3.3.7 Reference Methods and Materials Estimating the Trueness Factorizing the Patients’ Results Changing Reagent Lot Analytical Specificity Method Validation ix 69 70 70 71 72 73 3.4 Proficiency Testing 3.4.1 Background Information 3.4.2 Choice of EQA Schemes 3.4.3 Interpretation and Actions 74 74 75 76 3.5 Biological Variations and Quality Goals 77 3.6 Reference Intervals 3.6.1 Establishing Reference Intervals 3.6.2 Transferring Reference Intervals 80 80 83 3.7 Estimating Preanalytical Uncertainty 3.7.1 Setting the Stage 3.7.2 Preanalytical Variables 3.7.3 The Model for an Uncertainty Budget 3.7.4 Statistical Analysis 3.7.5 Assumptions and Modeling Details 83 83 86 88 89 90 3.8 Conclusions 92 References The Role and Significance of Reference Values in the Identification and Evaluation of Trace Elements from Diet Pietro Apostoli and Maria Cristina Ricossa Summary 4.1 Reference Values 93 97 97 97 4.2 Reference Values in Specific Groups of Population: The Children Case 100 4.3 Trace Elements and Diet 106 4.4 Arsenic 108 4.5 Mercury 110 4.6 Lead 112 4.7 Chromium 114 x CONTENTS 4.8 Cadmium 115 4.9 Conclusions 116 References 117 Sample Collection, Storage, and Pretreatment in Clinical Chemistry 127 Andrew Taylor Summary 127 5.1 Introduction 128 5.2 Collection Procedures 5.2.1 Sample Types 5.2.2 Practical Issues 129 129 130 5.3 Storage 132 5.4 Pretreatment 133 5.5 Conclusions References Metal Toxicology in Clinical, Forensic, and Chemical Pathology Jose A Centeno, Todor I Todorov, Gijsbert B van der Voet, and Florabel G Mullick Summary 136 137 139 139 6.1 Introduction 140 6.2 Biological Markers 140 6.3 Methodology for Trace Metal Ion Analysis in Clinical, Forensic, and Chemical Pathology 6.3.1 Clinical Chemistry Implications 6.3.2 Forensic Toxicology Implications 6.3.3 Chemical Pathology Implications 141 141 143 143 6.4 Case Studies of Relevance to Research and Diagnosis on Clinical Chemistry, Forensic Toxicology, and Chemical Pathology 6.4.1 Case Study No 1: Copper Levels in Placental Tissues as a Biomarker for Menkes Disease 6.4.2 Case Study No 2: Cd, Fe, Se, and Zn in Prostate Tissue as Biomarkers for Prostate Disease 6.4.3 Case Study No 3: Measurement of Dental Implant Corrosion Products and Histological Correlation in Periimplant Tissues 144 144 145 146 CONTENTS 6.4.4 Case Study No 4: Skin Pigmentation after Exposure to Topical Hg from Skin Ointment 6.4.5 Case Study No 5: Analysis of U Isotope Ratios by using ICP-MS for the Assessment of Natural U or DU Exposures xi 148 149 Disclaimer 152 References 152 PART II Selected Applications 157 Elemental Speciation in Clinical Sciences Douglas M Templeton Summary 159 159 7.1 Introduction 7.1.1 General Aspects 7.1.2 Definitions 7.1.3 Levels of Speciation 159 159 160 161 7.2 Selected 7.2.1 7.2.2 7.2.3 167 167 167 170 Elements Background Concepts Biological Speciation of Essential Elements Biological Speciation of Toxic Elements 7.3 Conclusions References The Role of Analytical Chemistry in the Safety of Drug Therapy Sa´ndor Goăroăg Summary 172 173 179 179 8.1 Drug Quality and Analysis: Their Role in Drug Safety 8.1.1 Introductory Remarks 8.1.2 The Role of Pharmacopoeias in Assuring Drug Quality 180 180 181 8.2 Methodological Aspects 8.2.1 Historical Overview 8.2.2 Spectroscopic Techniques 8.2.3 Chromatography and Related Techniques 8.2.4 Hyphenated Techniques 8.2.5 Miscellaneous Methods 189 189 190 192 195 198 8.3 The Role of Analytical Chemistry in Drug Research, Development, and Production 200 xii CONTENTS 8.3.1 8.3.2 8.3.3 8.3.4 QC of Drugs Drug Impurity Profiling Drug Stability Issues Contribution of Analytical Chemistry to Drug Research 8.3.5 Chiral Issues 8.4 Future Trends References Analytical Techniques and Quality Control of Pharmaceuticals Fedele Manna, Francesca Rossi, and Rossella Fioravanti Summary 200 202 214 215 223 227 227 245 245 9.1 Introduction 245 9.2 Sources of Impurities in Medicines 246 9.3 Validation of Analytical Methods 9.3.1 Specificity 9.3.2 Linearity 9.3.3 Precision 9.3.4 Trueness 9.3.5 Accuracy 9.3.6 Dosing Range 9.3.7 Quantification Limit 247 248 248 248 249 249 249 250 9.4 Analytical Approaches 9.4.1 General 9.4.2 TLC 9.4.3 HPLC 9.4.4 CE 250 250 251 251 253 9.5 Conclusions 253 References 10 Detection of Drugs in Biological Fluids for Antidoping Control Sabina Strano Rossi and Marcello Chiarotti Summary 253 257 257 10.1 Introduction 257 10.2 Doping Control and Analytical Requirements 258 REFERENCES 785 [18] Ma, M K., Woo, M, and McLeod, H L (2002) Genetic basis of drug metabolism, Am J Health-System Pharm 59, 2061–2069 [19] Trenti, T., Canali, C., and Scognamiglio, A (2006) Clinical governance and evidencebased laboratory medicine, Clin Chem Lab Med 44, 724–732 [20] Ramsay, A., Magnusson, C., and Fulop, N (2010) The relationship between external and local governance systems: the case of health care associated infections and medication errors in one NHS trust, Qual Saf Health Care, doi:10.1136/qshc.2009.037473 or http:// qualitysafety.bmj.com/content/early/2010/06/26/qshc.2009.037473.full.pdf Accessed March 2012 INDEX AAS, see Atomic Absorption Spectrometry Absorption, Distribution, Metabolism, Excretion, 217, 218 Absorption Photometry, 67 Accelerated Solvent Extraction, 350 Accreditation, 29, 59 Accuracy, 17, 57, 201, 249, 732 Acrolein, 576 Acylcarnitines, 520–522 Active Pharmaceutical Ingredients, 246 Acyl-Coenzyme A, Thioesters, 538–540 ADME, see Absorption, Distribution, Metabolism, Excretion Advanced therapy, 18 ADR, see Adverse Drug Reaction Advanced Therapy Medicinal Product, 18, 19 Adverse Drug Reaction, 48, 49 AEC, see Anion Exchange Chromatography AES, see Atomic Emission Spectrometry AFS, see Atomic Fluorescence Spectrometry Agenzia Italiana per il Farmaco, 22 AIFA, see Agenzia Italiana per il Farmaco Air pollution, 279 Allergens, see also Immunological products Aluminum, 139 chemical speciation, 170 Alveolar air, 654 Alzheimer’s disease, 480 Amino acids, 520–522, 540–542 Amniotic fluid, 614 Ampicillin, analysis, 200 Anabolic steroids, analysis, 258, 260 Analysis, statistical, 87–90 Animals, studies on, 287–290 Anion Exchange Chromatography, 415, 421, 422, 645 Antibody microarray, 734 Antibody-based multiplexing platform, 695 AP, see Absorption Photometry APCI, see Atmospheric Pressure Chemical Ionization API, see Active Pharmaceutical Ingredients Archive, 34, 35, 50 Arsenic, 103, 108–110, 139, 140, 143, 410–422 biotransformation, 410, 411 chemical speciation, 171, 409, 410 in drinking water, 160 in fingernail, 414 in fish, 95 in seafood, 95 in toenail, 414 in urine, 111 in water, 95 metabolism, 410, 411 organometallic compounds, 166 Arsenobetaine, 109, 165, 411, 414, 416, 422 Arsenocholine, 109, 165, 411, 414, 416, 422 Arsenolipids, 109 Arsenosugars, 109, 165, 417 Arsine oxide, trimethyl-, 415, 417, 422 Arsine, trimethyl-, 414, 417 Arsinic acid, dimethyl-, 109–110, 140, 143, 165, 171, 411, 414–419, 422 Arsonic acid, monomethyl-, 109–110, 140, 143, 165, 171, 411, 414–419 Arsenicals, clinical applications, 411, 412 Arsinoylethanol, Dimethyl-, 422 ASE, see Accelerated Solvent Extraction Analytical Techniques for Clinical Chemistry: Methods and Applications, First Edition Edited by Sergio Caroli and Gyula Za´ray Ó 2012 John Wiley & Sons, Inc Published 2012 by John Wiley & Sons, Inc 787 788 INDEX Association of Official Analytical Chemists, 248 Atmospheric Pressure Chemical Ionization, 196, 507, 513, 515, 519, 535 APPI, see Atmospheric Pressure Photo Ionization ATMP, see Advanced Therapy Medicinal Product Atmospheric Pressure Chemical Ionization, 709, 722 Atmospheric Pressure Photoionization, 513 Atomic Absorption Spectrometry, 69, 139, 141, 192, 270, 277, 281, 282, 286, 287, 341, 342, 346, 352, 354, 358, 368, 374, 412, 413, 416–418, 421, 423, 424, 426–429, 431, 432, 435, 439 Atomic Emission Spectrometry, 269, 271, 272, 276, 293, 336, 367 emission sources, 269, 270 Atomic Fluorescence Spectrometry, 281, 319, 341, 342, 346, 353, 412–414, 416, 417, 424, 426, 427–429, 431, 438, Authority monitoring, 22, 36 regulatory, 2, 22, 30, 36, 40, 53 Automated Mass Spectral Deconvolution and Identification System, 720 BE, see Bioequivalence Beta-agonists, 258, 260, 261 Beta blockers, 260, 261 Betamethasone, analysis, 200 Bile acids, 544, 545 Biochemical profiling, 691, 694, 700, 719 Bioequivalence, 1, 12, 13, 221 inspections, 11, 14 Bioimaging of metals, 479, 781, 782, 785, 787, 791, 793–795 Biological monitoring, 269, 367 Biomarkers, 139–141, 143–146, 555–584, 690, 699, 703, 706–708, 710, 716–718, 732, 737, 738, 743, 747, 750, 752 levels of trace metals, 140 Biosensors, 455 electrochemically mediated, 460 enzymatic direct electron transfer, 461 surface plasmon resonance, 462 Biotechnology products, Blood, analysis, 6, 76, 86, 127, 139, 258, 282–285, 287, 367, 368, 370–372, 374–380, 384–387, 429 Body fluids analysis 128–130, 282–285 Bones analysis, 139, 282 Breath analysis, 651, 652, 655, 658, 662, 664–675, 669, 671, 675–677 markers, 656, 671 Bromine in biological fluids, 376, 377 C, see Coulometry Cadmium, 103, 115, 116, 139 chemical speciation, 171 in biological fluids, 374, 375 in rice, 95, 116 in prostate, 145, 146 in vegetables, 95 in water, 95, 116 Capacitively Coupled Microwave Plasma, 270 Capillary Electrochromatography, 180, 195, 202–205, 224, 253, 542 Capillary Electrophoresis, 180, 194, 195, 204–226, 245, 251, 253, 263, 278, 288, 291, 319, 353, 354, 416, 422 Capillary Zone Electrophoresis, 253, 355, 416, 422 Capnography, 666 Carbohydrates, 548 Cardiovascular diseases, 128 Carnitine, biosynthesis, 538 Cation Exchange Chromatography, 414, 419, 421, 422 Cavity Ring-Down Spectroscopy, 662 CC, see Collision Cell CCD, see Charge-Coupled Device CD, see Circular Dichroism CDC, see Center for Disease Control CE, see Capillary Electrophoresis CEC, see Capillary Electrochromatography or Cation Exchange Chromatography Cefpodoxime proxetil, degradation, 216 Cell lines, 615 Cell therapy products, Center for Disease Control, 97 Central Nervous System, 102 INDEX Cerebrospinal fluid, 129, 613 Certification, 29 Certified Reference Materials, 59, 67, 68, 278, 281, 290, 291, 353, 355–359, 384–387, 399, 419, 483, 486 Charge-Coupled Device, 340 Chemical entities, Chemiluminesce, 252, 262 Chiral compounds, 223 Chromium, 114, 115, 140 chemical speciation, 170 in A553 human lung adenocarcinoma epithelial cells, 616 in fish, 95, 115 in food, 115 in meat, 95 in seafood, 95, 115 in soil, 115 in urine, 115 in vegetables, 115 in water, 95, 115 Circular Dichroism, 192 CL, see Chemiluminescence Clean room, 44 CLIA, see Clinical Laboratory Improvement Act Clinical Laboratory Improvement Act, 76 Clinical Laboratory Standards Institute, 61, 62, 64, 65, 70–73, 78, 85, 86, 348, 359, 776 Clinical Research Associate, 5, 38 Clinical samples, analysis, 319 Clinical Trial, 1–4, 7, 8, 11, 18, 21, 22 authorization, subjects, CLSI, see Clinical Laboratory Standards Institute CM, see Control Materials CMP, see Capacitively Coupled Microwave Plasma CNS, see Central Nervous System Codex Alimentarius, 248 Cold Vapor, 288, 292, 319, 322, 334, 342, 346, 353, 367, 374, 429, 432 Collection procedures, 129–132 Collision Cell, 630 Committee for Proprietary Medicinal Products, 6, 10 Community Reference Laboratories, 50 789 Complexes, formation, 164 Contract Research Organization, 6, 13, 14 Control charts, Levey-Jennings, 62 Control Materials, 60–63, 74, 75 Copper, 129, 139, 144 chemical speciation, 168, 169 in biological fluids, 133, 375, 376 in blood, 611 in brain tissue, 487 in colorectal cancer cell lines, 616 in placental tissues, 144–146 in plasma, 612 in serum, 133, 612 in rat heart muscle cells, 616 in urine, 613 Coulometry, 67 CPMP, see Committee for Proprietary Medicinal Products CRA, see Clinical Research Associate CRDS, see Cavity Ring-Down Spectroscopy CRM, see Certified Reference Materials CRO, see Contract Research Organization Cryo-trapping, 278 CT, see Clinical Trial or Cryo-trapping CTA, see Clinical Trial Authorization CV, see Cold Vapor CZE, see Capillary Zone Electrophoresis DAD, see Diode-Array Detector DCP, see Direct Current Plasma Dental implants, corrosion, 146–148 Deramciclan biotransformation, 222 analysis, 219 Detection limits, 17, 72, 201, 429, 439, 440, 467, 482, 515, 518, 575 Developing countries, 20, 21 Dexamethasone, analysis, 200 Diabetes mellitus, 651, 671–673 Difference Gel Electrophoresis, 725 Differential Scanning Calorimetry, 199 Differential Thermogravimetry, 199 Diffuse Reflectance Infrared Fourier Transform, 197 DIGE, see Difference Gel Electrophoresis Diode-Array Detector, 251, 438 Direct analysis in real time, 723 Direct Current Plasma, 270, 336, 343 790 INDEX Directives, European Union 98/79/EC, 57, 67, 779 2001/20/EC, 1, 2, 6, 9–12 2001/83/EC, 1, 2003/94/EC, 2005/28/EC, 1, 2, 6, 9–11 Diuretics, 260 DMA, see Arsinic acid, dimethylDMAE, see Arsinoylethanol, DimethylDNA damage, 212 Doping control, 257, 258 Double focusing mass analyzers, 630, Dosing range, 249, 250 DRC, see Dynamic Reaction Cell DRIFT, see Diffuse Reflectance Infrared Fourier Transform Drugs, 129 analysis, 180, 181, 184–187, 246, 291, 455–471, 482, 488, 499, 506, 508, 509, 523, 526 development, 690–699, 737–743 identification, 182, 187 content uniformity, 188 dissolution, 188 formulation, 221 impurity profiling, 202 impurity profiling strategies, 203 quality, 180, 181 physical constants, 182 purity, 182, 188, 189, 246, 247 safety, 179–181 side effects, 179 stability, 214, 215, 221 DSC, see Differential Scanning Calorimetry DTG, see Differential Thermogravimetry Dynamic Reaction Cell, 420 EC, see European Commission ECD, see Electron Capture Detection ED-XRF, see Energy Dispersive X-ray Fluorescence EDL, see Electrodeless Discharge Lamps EESI, see Extractive Electrospray Ionization E-health records, 776, 782 EI, see Electrospray Ionization EII, see Electron Impact Ionization Electroanalysis, 198, 199 Electrodeless Discharge Lamps, 320, 321 Electron Capture Detection, 193, 426, 427, 431 Electron Impact Ionization, 191, 252 Electron Paramagnetic Resonance, 281 Electrospray Ionization, 196, 198, 223, 252, 507, 513, 514, 574, 722, 723, 728 Electronic state, 161–163 Electrothermal Atomization Atomic Absorption Spectrometry, 134, 139, 142, 147, 270, 277, 278, 283, 284, 289–291, 319, 322, 328, 331, 339, 346, 350, 351, 358, 367–369, 376, 398, 412, 413, 418, 427, 611 Electrophoresis, 136 Elements, trace, 95, 140, 276–292, 319–321, 324, 325, 327, 345–348, 350, 351, 353, 354, 367–369, 374–383 ELISA, see Enzyme-Linked Immunosorbent Assay ELSD, see Evaporative Light-Scattering Detection EMA, see European Medicines Agency EMEA, see European Medicines Agency EN 45001 norms, 51 Enalapril maleate, analysis, 200 End-tidal air, 653, 655–657 Endogenous selenium, 636 Energy Dispersive X-ray Fluorescence, 604 Enzyme-linked Immunosorbent Assay, 466, 558, 559, 564, 565, 573, 576, 628, 658–660, 734, 735, 744, 778 Ephedrines, 258 EPO, see Erythropoietins EPR, see Electron Paramagnetic Resonance EPTA, see EQA, see External Quality Assurance Error random, 60 systematic, 60, 76, 77 total analytical, 76, 77 Erythropoietins, 258, 259, 261, 262 ESI, see EI ESMS, see Mass Spectrometry, Electron Spray ETA-AAS, see Electrothermal Atomization Atomic Absorption Spectrometry Ethics Committee, 7, 8, 22 European Commission, 11, 36 European Medicines Agency, 1, 2, 6, 12, 13, 17, 22, 41, 738 INDEX European Parliamentary Technology Assessment, European Pharmacopoeia, 17 European Union, 1–3, 6–8, 13, 14, 21 European Union Regulation 732/2004, 21 EU, see European Union Evaporative Light-Scattering Detection, 193 Exhaled air, 651–652, 654–656, 666, 675 Exhaled breath condensate, 571, 677 Exogenous selenium, 636 Extractive electrospray ionization, 723 Extractive products, FAB, see Fast Atom Bombardment FAES, see Flame Atomic Emission Spectrometry Fast Atom Bombardment, 191, 196, 630 FBE, see Flat-Bed Electrophoresis FDA, see Food and Drug Administration Feces, 129 Ferric Reducing Ability of Plasma, 559, 560 FI, see Flow Injection FID, see Flame Ionization Detection Final Report, 34–36, 38 FAAS, see Flame Atomic Absorption Spectrometry FL, see Fluorescence Flame Atomic Absorption Spectrometry, 134, 192, 277, 284, 292, 319, 355, 367, 368, 375, 376 Flame Atomic Emission Spectrometry, 270 Flame Ionization Detection, 193, 212 Flame Photometric Detection, 435, 438, 439 Flame Photometric Detection, Pulsed, 435, 439 Flame photometry, 67 Flat-Bed Electrophoresis, 353, 354 Flow Injection, 277, 412, 419 Fluorescence, 252 Fluid, spinal, 76 Food, analysis, 206, 291, 292 Food and Drug Administration, 30, 32, 180, 246, 249, 738 Fourier Transform Cyclotron Resonance Mass Spectrometry, 482, 729 791 FP, see Flame Photometry Fourier Transform Infrared Spectroscopy, 205, 215 FPD, see Flame Photometric Detection FR, see Final Report FRAP, see Ferric Reducing Ability of Plasma FTI, see Fourier Transform Infrared Spectroscopy Fundamental parameter method, 608 GAMP, see Good Automated Manufacturing Practice GC, see Gas Chromatography Gas Chromatography, 67, 134, 182, 190, 193, 197, 202–206, 212, 221, 245, 251, 257, 260, 261, 263, 289, 291, 368, 415, 416, 425–432, 435–440, 507, 508, 519, 542, 558, 559, 561, 565, 566, 570–572, 574–576, 628, 658–660, 720 Gas Chromatography Tandem-Mass Spectrometry, 575, 658, 704, 720 GC, see Gas Chromatography GC-MS/MS, see Gas Chromatography Tandem-Mass Spectrometry GCP, see Good Clinical Practice GCLP, see Good Clinical Laboratory Practice GD, see Glow Discharge GDP, see Good Distribution Practice GE, see Gel Electrophoresis Gel Chromatography, 479, 508 Gel Electrophoresis, 277, 725 Gene therapy products, GH, see Growth Hormones, 258 Glow Discharge, 343 Glucocorticoids, 261 Growth hormones, analysis, 258 Glucose, 64, 66, 70, 77, 83, 84 Glucuro-conjugation, 260 Gold in biological fluids, 377, 378 Good Automated Manufacturing Practice, 45 Good Clinical Laboratory Practice, 6, 18, 27, 30, 37, 38, 40 inspections, 17, 18 Good Clinical Practice, 1–3, 8, 27, 30, 36–38, 40, 47, 245 inspections, 11, 15, 22 Good Distribution Practice, 27, 30, 45–47 792 INDEX Good Laboratory Practice, 17, 27, 28, 30, 32, 34–37, 40, 47, 50–53, 245 inspections, 37 GLP, see Good Laboratory Practice Good Manufacturing Practice, 2, 14, 17, 30, 40–47, 245 Good Pharmacovigilance Practice, 28, 30, 47–49 Good Storage Practice, 45 GPvP, see Good Pharmacovigilance Practice Growth Hormones, analysis, 258, 262 GSP, see Good Storage Practice Guideline, European Union, E6/CPMP/ICH/ 137/95 GCP, 1–3 HACCP, see Hazard Analysis and Critical Control Point Hair analysis, 129, 281, 367, 373, 374, 378, 384–387, 420 Hazard Analysis and Critical Control Point, 44 HCL, see Hollow Cathode Head Space Extraction, 425, 426 Helsinki, declaration, 3, 21 Hemochromatosis, 129 Heartsbreath test, 669 Herbal products, HG, see Hydride Generation High Performance Liquid Chromatography, 67, 134, 135, 139, 143, 180, 182–184, 186, 187, 189, 190, 192, 194, 195, 199, 200, 202, 204–206, 208, 210, 212, 215, 217, 219, 224, 225, 227, 245, 251, 257, 263, 276, 285, 289, 319, 342, 352, 353, 359, 368, 382–384, 387, 414, 417–422, 425, 430–432, 437, 439, 440, 466, 535, 549, 558, 559, 562, 563, 565, 569–571, 575, 633, 638, 641, 646 High-Throughput Screening, 215 HIS, see Hospital Information Systems Hollow Cathode, 320, 321, 417 Homeopathic products, Hospital Information Systems, 775, 777 HPLC, see High Performance Liquid Chromatography HSE, see Head Space Extraction HTS, see High-Throughput Screening Human Metabolome Data Base, 721 Hydride Generation, 278, 292, 319, 322, 331–334, 338, 342, 346, 353, 367, 413, 414, 417, 418, 426, 435, 438, 439 Hyphenated techniques, 195, 227, 409, 410, 417–422, 512, 545, 564, 642 based on Atomic Absorption Spectrometry, 417 based on Atomic Fluorescence Spectrometry, 417 based on Capillary Electrophoresis, 197 based on Electrothermal Atomization Atomic Absorption Spectrometry, 418 based on Gas Chromatography, 197 based on High Performance Liquid Chromatography, 195, 417, 535, 542, 549 based on Inductively Coupled Plasma Mass Spectrometry, 197, 417, 418–422 based on Infrared Spectrometry, 197 based on Liquid Chromatography, 417, 418 based on Mass Spectrometry, 195–197, 421 based on Nuclear Magnetic Resonance, 196 based on Solid-Phase Extraction, 196 based on Thin Layer Chromatography, 197 based on Ultra-Performance Liquid Chromatography, 196, 535, 542, 549 based on Ultraviolet Spectrometry, 196 IC, see Ion Exchange Chromatography ICH, see International Conference on Harmonization ICP-AES, see Inductively Coupled Plasma Atomic Emission Spectrometry ICP-MS, see Inductively Coupled Plasma Mass Spectrometry IDA, see Isotope Dilution Analysis ID-MS, see Mass spectrometry, isotope dilution IEC, see Ion Exchange Chromatography IEF, see Isoelectric Focusing IFCC, see International Federation of Clinical Chemistry and Laboratory Medicine IGFs, see Insulin-like Grow Factors IMEP, see International Measurement Evaluation Programme INDEX Immune sera, see also Immunological products Immunoaffinity Chromatography, 575 Immunoelectrophoresis, 353 Immunological products, Immunometric assays, 199, 257, 264 IMP, see Investigational medicinal product Impurities determination, 207, 208 genotoxic, 180, 212 in cimetidine, 212 in ethinylestradiol, 209 in pipecuronium bromide, 208 synthesis, 206, 207 IMS, see Ion Mobility Spectrometry INAA, see Instrumental Neutron Activation Analysis Inductively Coupled Plasma Atomic Emission Spectrometry, 139, 142, 143, 147, 161, 192, 270–277, 280–292, 319, 337, 339–342, 344, 349, 350, 352, 358, 368, 376, 412, 421, 435 Inductively Coupled Plasma Mass Spectrometry, 134, 139, 140, 142, 192, 277, 278–292, 319, 342–344, 346–350, 352–355, 357–359, 368, 369, 371–380, 382–384, 387, 398–400, 402–404, 406, 413, 414, 416–423, 426–428, 430, 432, 437–440, 479, 481, 482, 485, 489, 625, 628, 633, 634, 636, 637, 640, 643, 644–646 Information Technology, 29, 777, 778 Infrared spectroscopy, 134, 180, 187, 190, 197, 199, 204, 221, 250 Inhaled air, 654, 675 Inherited Metabolic Diseases, 520–522, 535, 536 Institute for Reference Materials and Measurements, 356 Instrumental Neutron Activation Analysis, 280, 281, 414 Insulin-like Grow Factors, 262 Interferences gaseous phase, 334 hydroxide, 344, 345 isobaric, 344 liquid phase, 333, 334 793 matrix, 345 non-spectral, 331 oxide, 344, 345 polyatomic ions, 344 spectral, 328, 330, 369 International Conference on Harmonization, 1, 11, 179, 182, 183, 201, 217, 246, 247, 249 International Federation of Clinical Chemistry and Laboratory Medicine, 776 International Measurement Evaluation Programme, 67 International Standardization Organization, 29, 39, 59, 249 IEC Guide 25, 51, 780 IEC 17025 norm, 28, 50–53, 258, 259, 780 13528, 127, 128, 132 15189, 59, 73, 128 9000 series, 49 standards, 17, 30, 49, 50 International Union of Pure and Applied Chemistry, 28, 161, 248, 351 Investigational medicinal product, 2, 8, 10, 14 In vitro diagnostics, 776 Iodine in biological fluids, 376, 377 Ion Exchange Chromatography, 414, 418 Ion Mobility Spectrometry, 657, 662 Ion Pair Chromatography, 415 IPC, see Ion Pair Chromatography IPD, see Isotope Pattern Deconvolution IPD-ICP-MS, see Isotope Pattern Deconvolution-Inductively Coupled Plasma-Mass Spectrometry IRMM, see Institute for Reference Materials and Measurements Iron, 129, 139, 144 chemical speciation, 167 in amniotic fluid, 614 in brain tissue, 487 in colorectal cancer cell lines, 616 in plasma, 612 in prostrate, 145, 146 in rat heart muscle cells, 616 in serum, 612 in urine, 613 ISO, see International Standardization Organization 794 INDEX Isoelectric Focusing, 261, 353, 354 Isoprostanes, 572 Isotope Dilution Analysis, 631 Isotope analysis, 142, 149–152, 384 IRMS, see Mass Spectrometry, Isotopic Ratio ISMS, see Mass Spectrometry, Ion Spray Isoprenoid biosynthesis, 547 Isotope Pattern Deconvolution, 631, 643 Isotope Pattern Deconvolution-Inductively Coupled Plasma-Mass Spectrometry, 627, 634, 637 IT, see Information Technology IUPAC, see International Union of Pure and Applied Chemistry IVD, see In vitro diagnostics Keshan disease, 282 LA, see Laser Ablation Labelling technologies, 730 Laboratory Information and Management System, 775, 777 Laboratory Information System, 39, 40 Laboratory Medicine, 775–784 LAMMA, see Laser-Activated Microprobe Mass Analysis Laser Ablation, 143, 278, 281, 286, 289, 290, 479, 485–501 Laser-Activated Microprobe Mass Analysis, 287 Laser Microprobe, 343 Laser Spectroscopy, 658, 661 LC-MS, see Liquid Chromatography Mass Spectrometry LC-MS/MS, see Liquid ChromatographyTandem Mass Spectrometry Lead, 112–114, 139 chemical speciation, 172 in biological fluids, 113, 114, 130, 374, 375 in beverages, 95 in food, 113 in soil, 113 in vegetables, 95 in water, 95, 113 isotopic composition, 161 organometallic compounds, 166 LC, see Liquid Chromatography Levonorgestrel, analysis, 186 Linearity, 70, 201, 248 Lipid hydroperoxides, 568 Lipid oxidation, 566–569 Lipidomics, 545 Liquid Chromatography, 196–198, 206, 217, 219, 221, 222, 252, 261, 263, 291, 382–384, 387, 415, 418, 421, 422, 425, 434, 438, 439, 440 Liquid Chromatography Mass Spectrometry, 575, 722–724 Liquid Chromatography-Tandem Mass Spectrometry, 507, 510, 511, 518–520, 523, 535, 536, 564, 575, 722–724 Liquid-Liquid Extraction, 424–425, 511, 525 LIS, see Laboratory Information System Lithium, isotopic composition, 161 Liver, 139 LLE, see Liquid-Liquid Extraction LM, see Laser Microprobe LS, see Laser Spectroscopy MA, see Marketing authorization Macromolecular complexes, 166, 167 MAD, see Mutual Acceptance of Data MALDI, see Matrix-Assisted Laser Desorption Ionization Manganese, 144 chemical speciation, 170, 171 Marketing authorization, 2, 13 application, 13 Mass Spectrometry, 67, 136, 189–191, 196, 197, 199, 200, 204, 205, 208, 210, 212, 215, 219, 221, 223, 227, 245, 250, 252, 253, 257, 259–261, 263, 269, 293, 508, 510, 513–516, 518, 520, 526, 535, 536, 542, 549, 565, 628, 657, 695, 720, 728, 729 electron spray, 421 ion spray, 421 isotope dilution, 67, 140, 277 isotopic ratio, 257, 263 plasma-based, 269 Matrix-Assisted Laser Desorption Ionization, 191, 196, 478–486, 494–497, 513, 545, 725, 731 MEEKC, see Microemulsion Electrokinetic Chromatography, MEKC, see Micellar Electrokinetic Chromatography INDEX Member States, 7, Menkes’ disease, 144, 376 Mercury, 103, 110–112, 139, 140, 422–432 chemical speciation, 172, 409, 410 in biological fluids, 112, 374, 375 in fish, 95, 111, 112 in seafood, 95 in skin ointments, 148, 149 in urine, 112 in water, 95, 111 organometallic compounds, 166 Metabolic finger printing, 700 Metabolomics, 382–384, 507, 535, 537, 545, 549, 691, 693, 696, 700–701, 718–720, 722–724, 731–733, 737, 746–748 Micellar Electrokinetic Chromatography, 180, 195, 198, 253 Microemulsion Electrokinetic Chromatography, 180, 195, 198 Microwave-Assisted Digestion, 278, 319, 490, 609 Microwave-Assisted Extraction, 424 Microwave-Induced Plasma, 270, 336, 343 Milk analysis, 282–285, 327 Minimum Required Performance Levels, 259 MIP, see Microwave-Induced Plasma MMA, see Arsonic acid, monomethylMolecular markers, 691–695, 697–703, 706–708, 710, 716–718, 731, 733, 734, 736–738, 742, 744–752 Molybdenum in artificial joints, 405 in biological fluids, 397 in biological tissues, 397 in blood, 403 in cereals, 398 in food, 398, 400, 401 in liver, 398 in milk, 398, 403, 404 in pulse, 398 intake in human population, 401, 402, 404, 405 in serum, 398 in urine, 399, 401, 402 liver dysfunction, 405, 406 occupational exposure, 405 renal failure, 406 795 MS, see Mass Spectrometry or Member States Multidimensional protein identification technology, 728 Multiple Reaction Monitoring, 196, 219 Mutual Acceptance of Data, 27, 32 MRM, see Multiple Reaction Monitoring MRPL, see Minimum Required Performance Levels MW, see Microwaves MWAE, see Microwave-Assisted Extraction NAA, see Neutron Activation Analysis Nails, analysis, 129, 367, 373, 378, 386, 420 Narcotics, 261 National Health and Nutrition Examination Survey, 98 National Institute for Environmental Studies, 356 National Institute of Standards and Technology, 356 National Reference Laboratories, 50 National Research Centre for Certified Reference Materials, 356 National Testing Authority, 257 Natural Resources Defense Council, 31 Neuron transmitters, 548, 549 Neutron Activation Analysis, 278, 279, 281, 284, 286, 398, 403, 404, 414, 630 NHNES, see National Health and Nutrition Examination Survey Nickel, chemical speciation, 171 in blood, 611 NIES, see National Institute for Environmental Studies NIST, see National Institute of Standards and Technology Nitrogen Phosphorous Detection, 257, 261 NMR, see Nuclear Magnetic Resonance NPD, see Nitrogen Phosphorous Detection NRCCRM, see National Research Centre for Certified Reference Materials NRDF, see Natural Resources Defense Council 796 INDEX Nuclear Magnetic Resonance, 180, 189–192, 196, 199, 202, 204–206, 208–210, 212, 215, 217, 221, 227, 245, 250, 441, 694, 700, 705, 721, 722, 737 H-NMR, 700–702, 709, 721, 747, 749 13 C-NMR, 721, 749 Occupational Safety and Health Administration, 39 OECD, see Organisation for Economic Cooperation and Development OFRR, see Opto-Fluidic Ring Resonator OLC, see Overpressured-Layer Chromatography Optical Rotatory Power Dispersion, 192 Opto-Fluidic Ring Resonator, 664 ORAC, see Oxygen Radical Absorbance Capacity Oral fluids, 263 Organic chemistry, synthetic, 215 Organisation for Economic Cooperation and Development, 27, 32, 36 Principles of Good Laboratory Practice, 33 Organometallic species, 164–166, 409, 410 ORD, see Optical Rotatory Power Dispersion Organic acids, 542 Organs analysis, 285, 286 OSCS, see Oversulfated Chondroitin Sulfate OSHA, see Occupational Safety and Health Administration Overpressured-Layer Chromatography, 194 Oversulfated Chondroitin Sulfate, analysis, 212 Oxcarbazepine, analysis, 200 Oxidation state, 161–163 Oxidative stress, 595 Oxidized low density lipoprotein assay, 576 Oxygen Radical Absorbance Capacity, 559, 560 PAGE, see Polyacrylamide Gel Electrophoresis Palladium in biological fluids, 377, 378 Pantoprazole, synthesis, 213 Parkinson’s disease, 480 PAT, see Process Analytical Technology Patients, results, factorizing, 68, 69 Pathology chemical, 141, 143 clinical, 141 forensic, 141, 143 PCA, see Principal Components Analysis PDA, see Photodiode Array Peptide hormones, 257, 262 Personalized medicine, 782 PET, see Positron Emission Tomography Pharmaceutical Inspections Convention, 41 Pharmacopoeia, 182, 200, 201, 225, 227 Europe, 181, 184, 185, 225 France, 181 Germany, 181 Italy, 181 Japan, 181 United Kingdom, 181 United States, 181, 184, 187, 225 Pharmacovigilance, 47–49 Phase 1, 18 Phospholipids, 547, 548 Photoacoustic spectroscopy, 662 Photodiode Array, 190, 195, 200, 204, 205, 208–210, 340 Photoelectric effect, 596, 597 PI, see Principal Investigator PIC, see Pharmaceutical Inspections Convention PIN diode, 604 PIXE, see Proton Induced X-Ray Emission Placebo, Plants analysis, 281 Plasma, analysis, 76, 127, 139, 282–285, 612, 613 derived products, Platinum in biological fluids, 377, 378 in Cisplatin-resistent cancer cells, 616 in serum, 612 PLE, see Pressurized Liquid Extraction Pleural fluid, 129 Polyacrylamide Gel Electrophoresis, 353, 354, 478, 479, 485, 486, 495, 497 Precision, 17, 57, 62–64, 201, 248, 249 Pressurized Liquid Extraction, 350, 435 Pridinol mesylate, analysis, 200 Principal Components Analysis, 287 Principal Investigator, 34–36 Process Analytical Technology, 202, 227 Proficiency testing, 28, 40, 59, 68, 72–75, 319, 356–359 INDEX Protein carbonyls, 562–563 Protein precipitation, 510 Protein profiling, 724–725 Proteomics, 479, 691, 693, 696, 699, 701, 709, 715, 718–720, 724–726, 728, 731, 733, 747 Proton Induced X-Ray Emission, 481 Proton Transfer Reaction Mass Spectrometry, 657, 660 PTR-MS, see Proton Transfer Reaction Mass Spectrometry Purines, 542–544 PFPD, see Flame Photometric Detection, Pulsed Pv, see Pharmacovigilance Pyrimidines, 542–544 QA, see Quality Assurance QAP, see Quality Assurance Program QAU, see Quality Assurance Unit QbD, see Quality by Design QC, see Quality Control QM, see Quality Management QP, see Qualified Person Qualified Person, 14, 41, 42, 49 Quality management, 29, 40 Quality Assurance, 4, 17, 18, 58, 67, 359, 385–387, 777 Program, 34, 35, 38, 42 Unit, 34–36, 41, 42, 45, 50 Quality by Design, 202, 227 Quality Control, 4, 17, 38, 42, 45, 63, 77, 179, 187, 189, 190, 193, 200, 227, 355–359 Quantification limits, 18, 201, 250, 575 RA, see Authority, regulatory Radiopharmaceutical products, Raman spectroscopy, 190, 191, 199 Range, analytical, 201 REACH, see Registration, Evaluation, Authorisation and Restriction of Chemicals Reactive Oxygen Species, 555, 670 Reagent lot, changing, 69 Receiver operating characteristic curve, 706 Recovery, analytical, 72 Reference Materials, 59, 67, 68, 278, 319, 355, 356, 384–387, 482, 490, 498, 513 797 Reference Methods, 67 Reference Person, 58 Reference Range, 58, 78–81 Reference Values aluminum, 97, 102 antimony, 97, 99 arsenic, 97, 102, 103 barium, 97, 99, 102 beryllium, 97, 99, 102 bismuth, 97 biomarkers, 540 boron, 102 cadmium, 97, 99–103 cesium, 99, 102 chemical elements, 95, 97 in adults, 107 in children, 105 in food, 104, 106 chromium, 97, 102 cobalt, 97, 99, 102 copper, 97, 102 fluorine, 97 gallium, 97 germanium, 97 gold, 97 indium, 97 iron, 97 lead, 97, 99, 103 lithium, 97 magnesium, 97 manganese, 97, 102 mercury, 97, 99–103 molybdenum, 97, 99, 102 nickel, 97, 102 platinum, 97, 99, 102 selenium, 97, 102 silver, 97 strontium, 97 tellurium, 97 thallium, 97, 99, 102 tin, 97 titanium, 97 tungsten, 99, 102 uranium, 97, 99 vanadium, 97, 102 zinc, 97, 102 Registration, Evaluation, Authorisation and Restriction of Chemicals, 53 Repeatability, 63, 201 798 INDEX Reproducibility, analytical, 63, 64 Responsible Person, 45 Reversed-Phase Chromatography, 352, 415, 568, 569 Reversed-Phase High Performance Liquid Chromatography, 193, 215 RGH-192, analysis, 219, 220 RM, see Reference Materials Robustness, 201 ROS, see Reactive Oxygen Species RP, see Responsible Person RP-HPLC, see Reversed-Phase High Performance Liquid Chromatography RV, see Reference Values Saliva, analysis, 129, 367, 373 Salicylic acid, acetyl-, analysis, 186 Sample collection, 127, 129, 347, 348, 370, 371 Sample storage, 127, 131, 132, 348, 349, 370, 371 Sample pretreatment, 127, 133–136, 260, 319, 371–374, 398–399, 423–426, 434, 435, 609 Scanning Electron Microscopy, 481 SCE, see Scanning Electron Microscopy SD, see Study Director SEC, see Size-Exclusion Chromatography Secondary Ion Mass Spectrometry, 343 SELDI, see Surface Enhanced Laser Desorption Ionization Selected Ion Flow Tube Mass Spectrometry, 657, 660 Selenium, 139, 140, 627, 631, 634, 637 chemical speciation, 169, 170, 626, 627, 632–634, 637 in biological fluids, 375, 376 in erythrocytes, 634, 637 in feces, 634 in plasma, 612 in prostrate, 145, 146 Selenocysteine, 628, 640, 642 Selenomethionine, 635, 641, 643 Selenoproteins, 627, 628, 636, 640–643 Selenospecies, 637 in erythrocytes, 640 in serum, 642 in urine, 637 Selenosugars, 637, 640 Sensor-based system, 658, 663 Serum, analysis 64, 76, 127, 131, 139, 282–285, 287, 367–372, 374–378, 384–387 SFC, see Supercritical Fluid Chromatography Si(Li) detector, 597, 604, 605, SIFT-MS, see Selected Ion Flow Tube Mass Spectrometry Single Nucleotide Polymorphism, 696, 724 Silver in biological fluids, 377, 378 SIMS, see Secondary Ion Mass Spectrometry Single Photon Emission Computerized Tomography, 218 Size-Exclusion Chromatography, 282, 284–286, 288, 290, 352, 641, 736 Skin pigmentation, 148, 149 SNP, see Single Nucleotide Polymorphism Solid Phase Extraction, 511, 512, 518, 523, 524, 564, 573 Soils analysis, 280 Solids, direct analysis, 352 Solid-Phase Extraction, 196, 424, 434 Solid-Phase Microextraction, 212, 214, 215, 261, 416, 424, 425, 426, 429, 434, 435, 437, 439, 440 Sonication, 319, 414 SOP, see Standard Operating Procedure Spark Source, 343 SPE, see Solid-Phase Extraction SPECT, see Single Photon Emission Computerized Tomography SPME, see Solid-Phase Microextraction Speciation analysis, 139, 140, 142, 159, 163, 164, 351, 352, 382–384, 409 Specificity, 70, 248 SPC, see Summary of Product Characteristics Spectrophotometry, 190 Sponsor, 4, 34 SPR, see Surface Plasmon Resonance SR-TXRF, see Syncrotron Radiation induced Total Reflection X-ray Fluorescence SS, see Spark Source Stabilized Temperature Platform Furnace, 331 Standard Operating Procedure, 4, 17, 18, 34–36, 38, 39, 41, 42, 46, 48, 50 Steroid hormones, 129, 260, 261 Sterols, 549 INDEX Sterol lipids, 524 Stimulants, 261 STPF, see Stabilized Temperature Platform Furnace Study Director, 34–35, 50 Sulfacetamide, analysis, 185 Summary of Product Characteristics, Supercritical Fluid Chromatography, 202, 204, 206, 224 Surface Enhanced Laser Desorption Ionization, 731 Surface Plasmon Resonance, 465 Syncrotron Radiation induced Total Reflection X-ray Fluorescence, 595 TAT, see Turn-Around Time TEAC, see Trolox Equivalent Antioxidant Capacity TCH350, degradation 3, 21 Telemedicine, 777 Test Facility, 29 Management, 34–36 TF, see Test Facility TFM, see Test Facility Management Therapeutic drug monitoring, 507–509, 523 Thermal Analysis, 199 Thermal Ionization Mass Spectrometry, 142, 287, 343, 630 Thin Layer Chromatography, 182–184, 189, 194, 202–206, 217, 218, 221, 224, 245, 251, 573, 574 Thorium in biological fluids, 378 Threshold of Toxicological Concern, 212 TIC, see Total Ion Current Time of Flight Spectrometry, 198, 261, 355, 441, 481, 482, 484, 489, 496, 513, 518, 519, 637, 720, 723, 728, 729, 731 Tin, 432–441 organometallic compounds, 166, 409, 410 Tissues analysis, 285, 286, 614, 615 Titrimetry, 198 TLC, see Thin Layer Chromatography TMA, Arsine, trimethyl-, 414 TMAO, see Arsine oxide, trimethylTMF, see Trial Master File TMS, see Thermal Ionization Mass Spectrometry TOC, see Total Organic Carbon 799 Total Organic Carbon, 609 Toxicodynamic Molecular Mechanisms, 738, 747–748 TOF, see Time of Flight Spectrometry TOSCA, see Total Oxyradical Scavenging Capacity Assay Total Ion Current, 196 Total Oxyradical Scavenging Capacity Assay, 559, 560 Total Radical Trapping Antioxidant Parameter, 559, 560 Total Reflection X-Ray Fluorescence, 192, 285, 286, 595, 605 Traceability, 65, 66 Transcriptomics, 691, 694, 696, 718–720, 733, 738, 751 TRAP, see Total Radical Trapping Antioxidant Parameter Trial Master File, 10 Trimetazidine in plasma, analysis, 223 Trolox Equivalent Antioxidant Capacity, 559, 560 Trueness, 59, 65, 66, 68, 69, 90, 249 TTC, see Threshold of Toxicological Concern Turn-around time, 775 patients, 775 laboratory, 775 Two-dimensional gel proteomics, 725 TXRF, see Total Reflection X-Ray Fluorescence Ultra-Performance Liquid Chromatography, 193, 196, 215, 518, 519, 535, 549, 700 Ultraviolet-Visible spectroscopy, 179, 182, 185, 187, 189, 190, 196, 200, 204–206, 209, 215, 250, 251, 257 Uncertainty, 57–60, 81–83 budget, 86, 90 UPLC, see Ultra-Performance Liquid Chromatography Uranium, 140, 149–152 depleted, 149–152 in biological fluids, 378 isotopic composition, 161 Urine, analysis 76, 131, 139, 258, 284, 367, 368, 370, 371, 373–378, 382–387, 613, 695, 697, 706, 709, 719, 744, 746, 747, 752 800 INDEX U-Vis spectroscopy, see Ultraviolet-Visible spectroscopy Vaccines, see also Immunological products Validation of methods, 12, 14–17, 51, 52, 71, 201, 247, 248, 250, 385–387, 399, 780, 781 Variables, preanalytical, 84 Variation, biological, 75, 76 WADA, see World Antidoping Agency Water analysis, 279 Wavelength Dispersive X-ray Fluorescence, 604 WBA, see Whole-Body Autoradiography WD-XRF, see Wavelength Dispersive X-ray Fluorescence WHO, see World Health Organization Wilson’s disease, 129, 375, 481 Whole-Body Autoradiography, 218 World Antidoping Agency, 257–259, 263 World Health Organization, 2, 5, 22, 38, 41, 48, 65 Xenobiotics in biological fluids, analysis, 257, 263, 264 X-ray detectors, 603 X-ray diffraction, 190, 199, 221 X-ray fluorescence, 350 X-ray Fluorescence Microtomography, 606 X-ray optics, 600 X-ray spectrometry, 441, 481 X-ray sources, 597 XRF-mT, see X-ray Fluorescence Microtomography Zinc chemical speciation, 169 in amniotic fluid, 614 in biological fluids, 375, 376 in blood, 611 in brain tissue, 487, 614 in colorectal cancer cell lines, 616 in plasma, 612 in prostrate, 145, 146 in rat heart muscle cells, 616 in serum, 612 in urine, 613 ... Cataloging-in-Publication Data: Analytical techniques for clinical chemistry : methods and applications / edited by Sergio Caroli, Gyula Za´ray p cm Includes index ISBN 978-0-470-44527-3 (cloth) Clinical chemistry Analysis... Air inlets; 2, decontaminated air; and 3, exhausts Analytical Techniques for Clinical Chemistry: Methods and Applications, First Edition Edited by Sergio Caroli and Gyula Za´ray Ó 2012 John Wiley... Biotransformation and Metabolism Clinical Application of Arsenicals Analytical Techniques and Clinical Applications xvi CONTENTS 15.2.5 Arsenic Speciation 15.2.6 Application of Arsenic Speciation Techniques