Chemical Analysis of Antibiotic Residues in Food

JIAN WANG is currently a research scientist leading a research and development unit for the Canadian Food Inspection Agency in Calgary, Alberta. His responsibilities include planning and conducting research projects in method development for antibiotic and pesticide residues in foods using advanced mass spectral analysis techniques such as UPLC/Q-TOF and LC/ESI-MS/MS. He has written over thirty publications for various journals and books. He was most recently awarded the CFIA Science Branch Recognition Award for leading method development on melamine investigation in 2007. JAMES D. MacNEIL retired as head of the Centre for Veterinary Drug Residues of the Canadian Food Inspection Agency in 2007. His recent achievements include receiving the Joint FAO/WHO Expert Committee on Food Additives 50th Anniversary commemorative silver medal awarded in 2006 for services to JECFA; the Public Service of Canada Award of Excellence, a career achievement in 2007; and appointment as scientist emeritus by CFIA in 2008. He is the former scientific editor for "Drugs, Cosmetics, and Forensics" of the Journal of AOAC International and the author of numerous publications on veterinary drug residue analysis. He is currently an adjunct professor in the Department of Chemistry, Saint Mary's University, Halifax, Canada.JACK F. KAY works in the UK Department for Environment, Food and Rural Affairs. He helped draft European Commission Decision 2002/657/EC and, in 2008, introduced joint auditing to this and ISO 17025 standards into a major UK laboratory. He has actively participated in the Codex Committee on Residues of Veterinary Drugs in Food for more than ten years and was appointed an expert advisor on honey to the Food and Agriculture Organization of the United Nations in 2008. Since 2005, he has held an Honorary Senior Research Fellowship in the Department of Mathematics and Statistics at the University of Strathclyde, Scotland.

• Preface xv Acknowledgment xviiEditors xixContributors xxi1 Antibiotics: Groups and Properties 1Philip Thomas Reeves1.1 Introduction, 11.1.1 Identification, 11.1.2 Chemical Structure, 21.1.3 Molecular Formula, 21.1.4 Composition of the Substance, 21.1.5 pKa, 21.1.6 UV Absorbance, 31.1.7 Solubility, 31.1.8 Stability, 31.2 Antibiotic Groups and Properties, 31.2.1 Terminology, 31.2.2 Fundamental Concepts, 41.2.3 Pharmacokinetics of Antimicrobial Drugs, 41.2.4 Pharmacodynamics of Antimicrobial Drugs, 51.2.4.1 Spectrum of Activity, 51.2.4.2 Bactericidal and Bacteriostatic Activity, 61.2.4.3 Type of Killing Action, 61.2.4.4 Minimum Inhibitory Concentration and Minimum Bactericidal Concentration, 71.2.4.5 Mechanisms of Action, 71.2.5 Antimicrobial Drug Combinations, 71.2.6 Clinical Toxicities, 71.2.7 Dosage Forms, 81.2.8 Occupational Health and Safety Issues, 81.2.9 Environmental Issues, 81.3 Major Groups of Antibiotics, 81.3.1 Aminoglycosides, 81.3.2 ß-Lactams, 101.3.3 Quinoxalines, 181.3.4 Lincosamides, 201.3.5 Macrolides and Pleuromutilins, 211.3.6 Nitrofurans, 271.3.7 Nitroimidazoles, 281.3.8 Phenicols, 301.3.9 Polyether Antibiotics (Ionophores), 311.3.10 Polypeptides, Glycopeptides, and Streptogramins, 351.3.11 Phosphoglycolipids, 361.3.12 Quinolones, 361.3.13 Sulfonamides, 441.3.14 Tetracyclines, 451.4 Restricted and Prohibited Uses of Antimicrobial Agents in Food Animals, 521.5 Conclusions, 52Acknowledgments, 53References, 532 Pharmacokinetics, Distribution, Bioavailability, and Relationship to Antibiotic Residues 61Peter Lees and Pierre-Louis Toutain2.1 Introduction, 612.2 Principles of Pharmacokinetics, 612.2.1 Pharmacokinetic Parameters, 612.2.2 Regulatory Guidelines on Dosage Selection for Efficacy, 642.2.3 Residue Concentrations in Relation to Administered Dose, 642.2.4 Dosage and Residue Concentrations in Relation to Target Clinical Populations, 662.2.5 Single-Animal versus Herd Treatment and Establishment of Withholding Time (WhT), 662.2.6 Influence of Antimicrobial Drug (AMD) Physicochemical Properties on Residues and WhT, 672.3 Administration, Distribution, and Metabolism of Drug Classes, 672.3.1 Aminoglycosides and Aminocyclitols, 672.3.2 ß-Lactams: Penicillins and Cephalosporins, 692.3.3 Quinoxalines: Carbadox and Olaquindox, 712.3.4 Lincosamides and Pleuromutilins, 712.3.5 Macrolides, Triamilides, and Azalides, 722.3.6 Nitrofurans, 732.3.7 Nitroimidazoles, 732.3.8 Phenicols, 732.3.9 Polyether Antibiotic Ionophores, 742.3.10 Polypeptides, 752.3.11 Quinolones, 752.3.12 Sulfonamides and Diaminopyrimidines, 772.3.13 Polymyxins, 792.3.14 Tetracyclines, 792.4 Setting Guidelines for Residues by Regulatory Authorities, 812.5 Definition, Assessment, Characterization, Management, and Communication of Risk, 822.5.1 Introduction and Summary of Regulatory Requirements, 822.5.2 Risk Assessment, 842.5.2.1 Hazard Assessment, 882.5.2.2 Exposure Assessment, 892.5.3 Risk Characterization, 902.5.4 Risk Management, 912.5.4.1 Withholding Times, 912.5.4.2 Prediction of Withdholding Times from Plasma Pharmacokinetic Data, 932.5.4.3 International Trade, 932.5.5 Risk Communication, 942.6 Residue Violations: Their Significance and Prevention, 942.6.1 Roles of Regulatory and Non-regulatory Bodies, 942.6.2 Residue Detection Programs, 952.6.2.1 Monitoring Program, 962.6.2.2 Enforcement Programs, 962.6.2.3 Surveillance Programs, 972.6.2.4 Exploratory Programs, 972.6.2.5 Imported Food Animal Products, 972.6.2.6 Residue Testing in Milk, 972.7 Further Considerations, 982.7.1 Injection Site Residues and Flip-Flop Pharmacokinetics, 982.7.2 Bioequivalence and Residue Depletion Profiles, 1002.7.3 Sales and Usage Data, 1012.7.3.1 Sales of AMDs in the United Kingdom, 2003–2008, 1012.7.3.2 Comparison of AMD Usage in Human and Veterinary Medicine in France, 1999–2005, 1022.7.3.3 Global Animal Health Sales and Sales of AMDs for Bovine Respiratory Disease, 103References, 1043 Antibiotic Residues in Food and Drinking Water, and Food Safety Regulations 111Kevin J. Greenlees, Lynn G. Friedlander, and Alistair Boxall3.1 Introduction, 1113.2 Residues in Food—Where is the Smoking Gun?, 1113.3 How Allowable Residue Concentrations Are Determined, 1133.3.1 Toxicology—Setting Concentrations Allowed in the Human Diet, 1133.3.2 Setting Residue Concentrations for Substances Not Allowed in Food, 1143.3.3 Setting Residue Concentrations Allowed in Food, 1143.3.3.1 Tolerances, 1153.3.3.2 Maximum Residue Limits, 1163.3.4 International Harmonization, 1173.4 Indirect Consumer Exposure to Antibiotics in the Natural Environment, 1173.4.1 Transport to and Occurrence in Surface Waters and Groundwaters, 1193.4.2 Uptake of Antibiotics into Crops, 1193.4.3 Risks of Antibiotics in the Environment to Human Health, 1203.5 Summary, 120References, 1214 Sample Preparation: Extraction and Clean-up 125Alida A. M. (Linda) Stolker and Martin Danaher4.1 Introduction, 1254.2 Sample Selection and Pre-treatment, 1264.3 Sample Extraction, 1274.3.1 Target Marker Residue, 1274.3.2 Stability of Biological Samples, 1274.4 Extraction Techniques, 1284.4.1 Liquid–Liquid Extraction, 1284.4.2 Dilute and Shoot, 1284.4.3 Liquid–Liquid Based Extraction Procedures, 1294.4.3.1 QuEChERS, 1294.4.3.2 Bipolarity Extraction, 1294.4.4 Pressurized Liquid Extraction (Including Supercritical Fluid Extraction), 1304.4.5 Solid Phase Extraction (SPE), 1314.4.5.1 Conventional SPE, 1314.4.5.2 Automated SPE, 1324.4.6 Solid Phase Extraction-Based Techniques, 1334.4.6.1 Dispersive SPE, 1334.4.6.2 Matrix Solid Phase Dispersion, 1344.4.6.3 Solid Phase Micro-extraction, 1354.4.6.4 Micro-extraction by Packed Sorbent, 1374.4.6.5 Stir-bar Sorptive Extraction, 1374.4.6.6 Restricted-Access Materials, 1384.4.7 Solid Phase Extraction-Based Selective Approaches, 1384.4.7.1 Immunoaffinity Chromatography, 1384.4.7.2 Molecularly Imprinted Polymers, 1394.4.7.3 Aptamers, 1404.4.8 Turbulent-Flow Chromatography, 1404.4.9 Miscellaneous, 1424.4.9.1 Ultrafiltration, 1424.4.9.2 Microwave-Assisted Extraction, 1424.4.9.3 Ultrasound-Assisted Extraction, 1444.5 Final Remarks and Conclusions, 144References, 1465 Bioanalytical Screening Methods 153Sara Stead and Jacques Stark5.1 Introduction, 1535.2 Microbial Inhibition Assays, 1545.2.1 The History and Basic Principles of Microbial Inhibition Assays, 1545.2.2 The Four-Plate Test and the New Dutch Kidney Test, 1565.2.3 Commercial Microbial Inhibition Assays for Milk, 1565.2.4 Commercial Microbial Inhibition Assays for Meat-, Egg-, and Honey-Based Foods, 1595.2.5 Further Developments of Microbial Inhibition Assays and Future Prospects, 1605.2.5.1 Sensitivity, 1605.2.5.2 Test Duration, 1615.2.5.3 Ease of Use, 1615.2.5.4 Automation, 1615.2.5.5 Pre-treatment of Samples, 1625.2.5.6 Confirmation/Class-Specific Identification, 1635.2.6 Conclusions Regarding Microbial Inhibition Assays, 1645.3 Rapid Test Kits, 1645.3.1 Basic Principles of Immunoassay Format Rapid Tests, 1645.3.2 Lateral-Flow Immunoassays, 1655.3.2.1 Sandwich Format, 1665.3.2.2 Competitive Format, 1665.3.3 Commercial Lateral-Flow Immunoassays for Milk, Animal Tissues, and Honey, 1685.3.4 Receptor-Based Radioimmunoassay: Charm II System, 1705.3.5 Basic Principles of Enzymatic Tests, 1715.3.5.1 The Penzyme Milk Test, 1715.3.5.2 The Delvo-X-PRESS, 1725.3.6 Conclusions Regarding Rapid Test Kits, 1745.4 Surface Plasmon Resonance (SPR) Biosensor Technology, 1745.4.1 Basic Principles of SPR Biosensor, 1745.4.2 Commercially Available SPR Biosensor Applications for Milk, Animal Tissues, Feed, and Honey, 1755.4.3 Conclusions Regarding Surface Plasmon Resonance (SPR) Technology, 1765.5 Enzyme-Linked Immunosorbent Assay (ELISA), 1785.5.1 Basic Principles of ELISA, 1785.5.2 Automated ELISA Systems, 1785.5.3 Alternative Immunoassay Formats, 1795.5.4 Commercially Available ELISA Kits for Antibiotic Residues, 1795.5.5 Conclusions Regarding ELISA, 1805.6 General Considerations Concerning the Performance Criteria for Screening Assays, 1815.7 Overall Conclusions on Bioanalytical Screening Assays, 181Abbreviations, 182References, 1826 Chemical Analysis: Quantitative and Confirmatory Methods 187Jian Wang and Sherri B. Turnipseed6.1 Introduction, 1876.2 Single-Class and Multi-class Methods, 1876.3 Chromatographic Separation, 1956.3.1 Chromatographic Parameters, 1956.3.2 Mobile Phase, 1956.3.3 Conventional Liquid Chromatography, 1966.3.3.1 Reversed Phase Chromatography, 1966.3.3.2 Ion-Pairing Chromatography, 1966.3.3.3 Hydrophilic Interaction Liquid Chromatography, 1976.3.4 Ultra-High-Performance or Ultra-High-Pressure Liquid Chromatography, 1986.4 Mass Spectrometry, 2006.4.1 Ionization and Interfaces, 2006.4.2 Matrix Effects, 2026.4.3 Mass Spectrometers, 2056.4.3.1 Single Quadrupole, 2056.4.3.2 Triple Quadrupole, 2066.4.3.3 Quadrupole Ion Trap, 2086.4.3.4 Linear Ion Trap, 2096.4.3.5 Time-of-Flight, 2106.4.3.6 Orbitrap, 2126.4.4 Other Advanced Mass Spectrometric Techniques, 2146.4.4.1 Ion Mobility Spectrometry, 2146.4.4.2 Ambient Mass Spectrometry, 2146.4.4.3 Other Recently Developed Desorption Ionization Techniques, 2166.4.5 Fragmentation, 2166.4.6 Mass Spectral Library, 216Acknowledgment, 219Abbreviations, 220References, 2207 Single-Residue Quantitative and Confirmatory Methods 227Jonathan A. Tarbin, Ross A. Potter, Alida A. M. (Linda) Stolker, and Bjorn Berendsen7.1 Introduction, 2277.2 Carbadox and Olaquindox, 2277.2.1 Background, 2277.2.2 Analysis, 2297.2.3 Conclusions, 2307.3 Ceftiofur and Desfuroylceftiofur, 2307.3.1 Background, 2307.3.2 Analysis Using Deconjugation, 2317.3.3 Analysis of Individual Metabolites, 2327.3.4 Analysis after Alkaline Hydrolysis, 2327.3.5 Conclusions, 2337.4 Chloramphenicol, 2337.4.1 Background, 2337.4.2 Analysis by GC-MS and LC-MS, 2337.4.3 An Investigation into the Possible Natural Occurrence of CAP, 2357.4.4 Analysis of CAP in Herbs and Grass (Feed) Using LC-MS, 2367.4.5 Conclusions, 2367.5 Nitrofurans, 2367.5.1 Background, 2367.5.2 Analysis of Nitrofurans, 2367.5.3 Identification of Nitrofuran Metabolites, 2377.5.4 Conclusions, 2397.6 Nitroimidazoles and Their Metabolites, 2397.6.1 Background, 2397.6.2 Analysis, 2407.6.3 Conclusions, 2417.7 Sulfonamides and Their N4-Acetyl Metabolites, 2417.7.1 Background, 2417.7.2 N4-Acetyl Metabolites, 2427.7.3 Analysis, 2437.7.4 Conclusions, 2447.8 Tetracyclines and Their 4-Epimers, 2447.8.1 Background, 2447.8.2 Analysis, 2457.8.3 Conclusions, 2467.9 Miscellaneous, 2467.9.1 Aminoglycosides, 2467.9.2 Compounds with Marker Residues Requiring Chemical Conversion, 2477.9.2.1 Florfenicol, 2477.9.3 Miscellaneous Analytical Issues, 2507.9.3.1 Lincosamides, 2507.9.3.2 Enrofloxacin, 2517.9.4 Gaps in Analytical Coverage, 2517.10 Summary, 252Abbreviations, 253References, 2548 Method Development and Method Validation 263Jack F. Kay and James D. MacNeil8.1 Introduction, 2638.2 Sources of Guidance on Method Validation, 2638.2.1 Organizations that Are Sources of Guidance on Method Validation, 2648.2.1.1 International Union of Pure and Applied Chemistry (IUPAC), 2648.2.1.2 AOAC International, 2648.2.1.3 International Standards Organization (ISO), 2648.2.1.4 Eurachem, 2658.2.1.5 VICH, 2658.2.1.6 Codex Alimentarius Commission (CAC), 2658.2.1.7 Joint FAO/WHO Expert Committee on Food Additives (JECFA), 2658.2.1.8 European Commission, 2668.2.1.9 US Food and Drug Administration (USFDA), 2668.3 The Evolution of Approaches to Method Validation for Veterinary Drug Residues in Foods, 2668.3.1 Evolution of “Single-Laboratory Validation” and the “Criteria Approach,” 2668.3.2 The Vienna Consultation, 2678.3.3 The Budapest Workshop and the Miskolc Consultation, 2678.3.4 Codex Alimentarius Commission Guidelines, 2678.4 Method Performance Characteristics, 2688.5 Components of Method Development, 2688.5.1 Identification of “Fitness for Purpose” of an Analytical Method, 2698.5.2 Screening versus Confirmation, 2708.5.3 Purity of Analytical Standards, 2708.5.4 Analyte Stability in Solution, 2718.5.5 Planning the Method Development, 2718.5.6 Analyte Stability during Sample Processing (Analysis), 2728.5.7 Analyte Stability during Sample Storage, 2728.5.8 Ruggedness Testing (Robustness), 2738.5.9 Critical Control Points, 2748.6 Components of Method Validation, 2748.6.1 Understanding the Requirements, 2748.6.2 Management of the Method Validation Process, 2748.6.3 Experimental Design, 2758.7 Performance Characteristics Assessed during Method Development and Confirmed during Method Validation for Quantitative Methods, 2758.7.1 Calibration Curve and Analytical Range, 2758.7.2 Sensitivity, 2778.7.3 Selectivity, 2778.7.3.1 Definitions, 2778.7.3.2 Suggested Selectivity Experiments, 2788.7.3.3 Additional Selectivity Considerations for Mass Spectral Detection, 2798.7.4 Accuracy, 2818.7.5 Recovery, 2828.7.6 Precision, 2838.7.7 Experimental Determination of Recovery and Precision, 2838.7.7.1 Choice of Experimental Design, 2838.7.7.2 Matrix Issues in Calibration, 2868.7.8 Measurement Uncertainty (MU), 2878.7.9 Limits of Detection and Limits of Quantification, 2878.7.10 Decision Limit (CCa) and Detection Capability (CCß), 2898.8 Significant Figures, 2898.9 Final Thoughts, 289References, 2899 Measurement Uncertainty 295Jian Wang, Andrew Cannavan, Leslie Dickson, and Rick Fedeniuk9.1 Introduction, 2959.2 General Principles and Approaches, 2959.3 Worked Examples, 2979.3.1 EURACHEM/CITAC Approach, 2979.3.2 Measurement Uncertainty Based on the Barwick–Ellison Approach Using In-House Validation Data, 3029.3.3 Measurement Uncertainty Based on Nested Experimental Design Using In-House Validation Data, 3059.3.3.1 Recovery (R) and Its Uncertainty [u(R)], 3069.3.3.2 Precision and Its Uncertainty [u(P )], 3129.3.3.3 Combined Standard Uncertainty and Expanded Uncertainty, 3129.3.4 Measurement Uncertainty Based on Inter-laboratory Study Data, 3129.3.5 Measurement Uncertainty Based on Proficiency Test Data, 3179.3.6 Measurement Uncertainty Based on Quality Control Data and Certified Reference Materials, 3199.3.6.1 Scenario A: Use of Certified Reference Material for Estimation of Uncertainty, 3209.3.6.2 Scenario B. Use of Incurred Residue Samples and Fortified Blank Samples for Estimation of Uncertainty, 324References, 32510 Quality Assurance and Quality Control 327Andrew Cannavan, Jack F. Kay, and Bruno Le Bizec10.1 Introduction, 32710.1.1 Quality—What Is It?, 32710.1.2 Why Implement a Quality System?, 32810.1.3 Quality System Requirements for the Laboratory, 32810.2 Quality Management, 32910.2.1 Total Quality Management, 32910.2.2 Organizational Elements of a Quality System, 33010.2.2.1 Process Management, 33010.2.2.2 The Quality Manual, 33010.2.2.3 Documentation, 33010.2.3 Technical Elements of a Quality System, 33110.3 Conformity Assessment, 33110.3.1 Audits and Inspections, 33110.3.2 Certification and Accreditation, 33210.3.3 Advantages of Accreditation, 33210.3.4 Requirements under Codex Guidelines and EU Legislation, 33210.4 Guidelines and Standards, 33310.4.1 Codex Alimentarius, 33310.4.2 Guidelines for the Design and Implementation of a National Regulatory Food Safety Assurance Program Associated with the Use of Veterinary Drugs in Food-Producing Animals, 33410.4.3 ISO/IEC 17025:2005, 33410.4.4 Method Validation and Quality Control Procedures for Pesticide Residue Analysis in Food and Feed (Document SANCO/10684/2009), 33510.4.5 EURACHEM/CITAC Guide to Quality in Analytical Chemistry, 33510.4.6 OECD Good Laboratory Practice, 33610.5 Quality Control in the Laboratory, 33610.5.1 Sample Reception, Storage, and Traceability throughout the Analytical Process, 33610.5.1.1 Sample Reception, 33610.5.1.2 Sample Acceptance, 33710.5.1.3 Sample Identification, 33710.5.1.4 Sample Storage (Pre-analysis), 33710.5.1.5 Reporting, 33810.5.1.6 Sample Documentation, 33810.5.1.7 Sample Storage (Post-reporting), 33810.5.2 Analytical Method Requirements, 33810.5.2.1 Introduction, 33810.5.2.2 Screening Methods, 33810.5.2.3 Confirmatory Methods, 33910.5.2.4 Decision Limit, Detection Capability, Performance Limit, and Sample Compliance, 33910.5.3 Analytical Standards and Certified Reference Materials, 33910.5.3.1 Introduction, 33910.5.3.2 Certified Reference Materials (CRMs), 34010.5.3.3 Blank Samples, 34110.5.3.4 Utilization of CRMs and Control Samples, 34110.5.4 Proficiency Testing (PT), 34110.5.5 Control of Instruments and Methods in the Laboratory, 34210.6 Conclusion, 344References, 344Index 347