About the Editor xvi
List of Contributors xviii
Preface xxi
Acknowledgment xxv
1 Drug Approval Process and Regulatory Requirements 1
1.1 Introduction 1
1.2 The Regulatory Process for New Drug Entity 2
1.2.1 Preclinical Studies 2
1.2.2 Investigational New Drug Application (INDA) 2
1.2.2.1 Phase 1 Clinical 2
1.2.2.2 Phase 2 Clinical 3
1.2.2.3 Phase 3 Clinical 3
1.2.3 New Drug Application (NDA) 3
1.2.3.1 NDA Review by FDA 3
1.2.3.2 NDA Review Process 4
1.3 Good Laboratory Practice for Nonclinical Laboratory Studies 5
1.4 Validation of Analytical Procedures: Methodology 6
1.5 FDA Role in the Discovery and Development of New Drug Entities 7
1.5.1 INDA Analytical Requirements 7
1.5.2 NDA Analytical Requirements 8
1.5.3 Biotechnology?]Derived Products - Small Molecules 8
1.6 FDA Inspectors' Role in Analytics Relative to Products in the Marketplace 9
1.6.1 FDA Compliance Program Guidance Manual (Implemented on 09/11/2015 with a Completion Date of 09/11/2016 - Program 7356.002) 9
1.6.2 Guide for Inspection of Microbiological Pharmaceutical Quality Control Laboratories 10
1.6.3 Biotechnology Inspection Guide 11
1.7 Conclusions 12
References 12
2 Pharmacopeias and Compendial Approval Process 14
2.1 Introduction 14
2.2USP History 14
2.3 Evolution of the Mission of the USP 15
2.4 The USP Organization 16
2.4.1 The USP Convention 16
2.4.2 The Board of Trustees 16
2.4.3 The Council of Experts 16
2.4.4 Expert Panels to the Council of Experts 16
2.4.5 Stakeholder Forums and Project Teams 17
2.4.6 USP Staff 17
2.5 The USP-NF Revision Process 17
2.6 Publications of USP 18
2.6.1 USP?]NF 18
2.6.2 Pharmacopeial Forum 18
2.6.3 Supplements 18
2.6.4 USP Spanish Edition 18
2.6.5 USP Reference Standards 18
2.6.6 Chromatographic Columns 18
2.6.7 USP Dictionary 18
2.6.8 USP Dietary Supplements Compendium 19
2.6.9 Food Chemical Codex 19
2.6.10 USP Medicines Compendium 19
2.7 Relationship between USP and FDA 19
2.8 USP and the Pharmacopoeias of Europe and Japan 20
2.8.1 The European Pharmacopoeia 20
2.8.2 The Pharmacopeia of Japan 21
2.9 Harmonization of Pharmacopeial Monographs and General Chapters 21
2.9.1 PDG Working Procedures 22
2.9.2 Status of the Pharmacopeial Harmonization Initiative 25
2.9.3 Roles and Responsibilities of Major Stakeholders in Pharmacopeial Harmonization 28
2.9.4 The Roles and Responsibilities of Industry in Pharmacopeial Harmonization 29
2.9.5 The Roles and Responsibilities of the Regulatory Agencies in Pharmacopeial Harmonization 30
2.9.6 The Roles and Responsibilities of the International Conference on Harmonization (ICH) in Pharmacopeial Harmonization 30
2.9.7 Advantages of Pharmacopeial Harmonization 31
2.9.8 Disadvantages of Pharmacopeial Harmonization 31
2.10 Comparisons between the PDG Process and the ICH Process in Harmonization 32
2.11 The Special Case of Pharmacopeial Harmonization of Excipients 33
2.12 Retrospective versus Forward Pharmacopeial Harmonization 33
2.13 Conclusions and Recommendations 34
2.14 Final Thoughts 35
List of Abbreviations 35
References 36
3 Common Methods in Pharmaceutical Analysis 37
3.1 Scope 37
3.2 Analytical Methods 37
3.2.1 Separation Methods 37
3.2.1.1 High?]Performance Liquid Chromatography 37
3.2.1.2 Gas Chromatography 39
3.2.1.3 Thin?]Layer Chromatography 39
3.2.1.4 Supercritical Fluid Chromatography 39
3.2.1.5 Capillary Electrophoresis 40
3.3 Spectroscopy Methods 40
3.3.1 Ultraviolet 40
3.3.2 Infrared 40
3.3.3 Raman Spectroscopy 40
3.3.4 Nuclear Magnetic Resonance 41
3.3.5 Mass Spectrometry 41
3.4 Other Spectroscopy Methods 41
3.4.1 Atomic Absorption Spectroscopy and Inductively Coupled Plasma Spectroscopy 41
3.5 Wet Chemistry Methods 42
3.5.1 Titration 42
3.5.2 Loss on Drying (LOD) 42
3.5.3 Loss on Ignition (LOI) 43
3.5.4 Residue on Ignition (ROI) or Sulfated Ash 43
3.5.5 Water Determination 43
3.6 Performance Methods (Contributed by Oscar Liu) 43
3.6.1 Disintegration 43
3.6.2 Dissolution 44
3.6.3 Uniformity of Dosage Units 45
3.6.4 Aerodynamic Particle Size Distribution Analysis 46
3.7 Microbiological Methods (Contributed by Roger Dabbah) 47
3.7.1 Introduction 47
3.7.2 Microbial Limit Tests 48
3.7.2.1 Microbial Limit Tests - Enumeration via a Plate Count 48
3.7.2.2 Membrane Filtration Method 49
3.7.2.3 Most Probable Number (MPN) Procedure 49
3.7.3 Tests for Specified Microorganisms 49
3.7.4 Sterility Test 50
3.8 Critical Factors Involved in Microbial Limit Tests and in Sterility Tests 51
3.9 Harmonization of Pharmacopeial Procedures and Requirement 52
3.10 Bacterial Endotoxins Test 52
3.11 Summary 53
References 54
4 Common Calculations 58
4.1 Scope 58
4.2 Calculations (Quantitative Analysis) 58
4.2.1 Percent Loss on Drying (LOD) 58
4.2.2 Percent Loss on Ignition (LOI) 59
4.2.3 Percent Residue on Ignition (ROI) 59
4.2.4 Assay 59
4.2.4.1 Chromatography (HPLC, GC) 59
4.2.4.2 Spectroscopy (UV, IR, etc.) 61
4.2.4.3 Titration 62
4.2.4.3.1 Direct 62
4.2.4.3.2 Residual or Back Titration 62
4.2.5 Organic Impurities 63
4.2.5.1 Chromatography (HPLC, GC) 63
4.3 Calculations (System Suitability Parameters) 64
4.3.1 Resolution (R) 64
4.3.2 Tailing Factor (T) or Asymmetry Factor (As) 65
4.3.3 Number of Theoretical Plates (N) 66
4.3.4 Capacity Factor (k') or Retention Factor (k) 67
4.4 Summary 67
References 67
5 Analytical Method Validation, Verification, and Transfer 69
5.1 Introduction 69
5.2 Scope 69
5.3 Typical Validation Characteristics 70
5.4 Definition and Determination of Analytical Characteristics 70
5.4.1 Accuracy 70
5.4.2 Precision 71
5.4.2.1 Repeatability 71
5.4.2.2 Intermediate Precision (Ruggedness) 71
5.4.2.3 Reproducibility 72
5.4.3 Specificity 72
5.4.4 Detection Limit (DL) 73
5.4.5 Quantitation Limit (QL) 74
5.4.6 Linearity 75
5.4.7 Range 75
5.5 Types of Analytical Procedures 76
5.6 Typical Validation Requirement 76
5.7 Revalidation 77
5.8 System Suitability 77
5.9 Forced Degradation (Stressed) Studies 78
5.10 Analytical Method Verification 79
5.11 Analytical Method Transfer 81
5.11.1 Comparative Testing 81
5.11.2 Co?]Validation between Labs 81
5.11.3 Revalidation 81
5.11.4 Transfer Waiver 81
5.12 Summary and Conclusion 82
References 82
6 Specifications 84
6.1 Scope 84
6.2 Introduction 84
6.3 Types of Tests 86
6.4 Types of Specifications 87
6.5 Selection of Tests and Procedures 89
6.5.1 Universal Tests 89
6.5.1.1 Drug Substances 90
6.5.1.2 New Drug Products 92
6.5.2 Specific Tests 94
6.5.2.1 Drug Substances 94
6.5.2.2 Drug Products 95
6.6 Establishing Acceptance Criteria 97
6.6.1 Rounding Rules 97
6.6.2 Statistical Estimation 98
6.6.2.1 Confidence Interval 100
6.6.2.2 Prediction Interval 100
6.6.2.3 Tolerance Interval 101
6.6.2.4 Monte Carlo Simulation of Quality Attributes 102
6.6.3 Establishing Acceptance Criteria Limits 102
6.6.3.1 Acceptance Criteria for Attributes that Do Not Change with Time 103
6.6.3.2 Acceptance Criteria for Attributes that Change with Time-Trend Analysis 104
6.7 Release Specifications 106
6.7.1 Using the Process Capability Index to Estimate Attribute Acceptance Criteria 107
6.8 Relationship between Release and Shelf-Life Specifications 108
6.9 Using a Control Chart for Trend Analysis 110
6.10 Life Cycle Management of Specifications 111
6.10.1 Approach to Life Cycle Management 111
6.10.2 Impact of the Investigation of Out?]Of?]Specification (OOS) and Out?]Of?]Trend (OOT) Results on Test Methods and Specifications 111
6.11 Summary 112
Acknowledgments 113
References 113
7 Impurities 116
7.1 Scope 116
7.2 Definitions 116
7.3 Classification of Impurities 117
7.4 Qualification of Impurities 118
7.5 Other Specific Types of Impurities 121
7.6 Non?]Drug?]Related Impurities 123
7.7 Other Sources of Impurities 123
7.8 Degradation/Stability Studies 124
7.9 Summary 124
References 124
8 Good Documentation Practices 127
8.1 Scope 127
8.2 Definition, Purpose, and Importance 128
8.2.1 Definition 128
8.2.1.1 ISO Definition and Benefits 128
8.2.1.2 Definition of Document 129
8.2.1.3 Definition of Record 129
8.2.1.4 Definition of Documentation 129
8.2.2 Purpose of GDocP 131
8.2.3 Importance of GDocP 131
8.3 General Rules and Principles of GDocP 132
8.3.1 Requirements of Records 132
8.3.2 General Tips in GDocP 134
8.3.2.1 Time Recording 135
8.3.2.2 Date Recording 135
8.3.2.3 Backdating 135
8.3.2.4 Signature and Initial 135
8.3.2.5 Rounding Rules for Numbers 136
8.3.2.6 Corrections 136
8.3.2.7 Missing Data 137
8.3.2.8 Voiding Records 137
8.3.2.9 Recreating and Rewriting of the Records 137
8.3.2.10 Deviations 138
8.4 General Tips for Laboratory Notebook Documentation 139
8.4.1 Assignment 139
8.4.2 Documentation 140
8.4.3 Storage 142
8.5 Electronic Documents and Electronic Signatures (21 CFR, Part 11) 142
8.5.1 Definition of 21 CFR 142
8.5.2 21 CFR - Subchapter A - General 143
8.5.2.1 Part 11 - Electronic Records and Electronic Signatures 143
8.5.2.1.1 Subpart A - General Provisions 143
8.5.2.1.2 Subpart B - Electronic Records 145
8.5.2.1.3 Subpart C - Electronic Signatures 147
8.6 US Pharmacopeia General Chapter <1029> 148
8.6.1 Background 148
8.6.2 Purpose 148
8.6.3 Outline of the Chapter 148
8.7 Rules Governing Medicinal Products in the European Union (Vol. 4: Documentation) 149
8.7.1 What is New in the Latest Version? 149
8.7.2 Outline of EU GDocP Regulations 150
8.7.2.1 Principle 150
8.7.2.2 Required GMP Documentation (by Type) 150
8.7.2.3 Generation and Control of Documentation 151
8.7.2.4 Good Documentation Practices 152
8.7.2.5 Retention of Documents 153
8.7.2.6 Specifications 153
8.7.2.7 Manufacturing Formula and Processing Instructions 154
8.7.2.8 Procedures and Records 157
8.8 GDocP Enforcement 158
8.8.1 Regulatory Bodies in Charge 159
8.8.2 FDA GDocP Compliance Observations 159
8.8.3 FDA GDocP Fraud Observations 160
8.8.4 Excerpts of 483 GDocP Observations 160
8.9 Summary 161
Abbreviations 161
References 162
9 The Management of Analytical Laboratories 165
9.1 Introduction 165
9.2 Principles of Management Applicable to the Laboratory Function 166
9.2.1 System Thinking 166
9.2.2 Organizational Structure 166
9.2.3 Accountability and Responsibility 167
9.2.4 Management of Personnel 167
9.2.5 Allocation and Utilization of Resources 167
9.2.6 Internal Interactions 168
9.2.7 External Interactions 168
9.2.8 Ethical Behavior 169
9.3 Management of Analytical Scientists 169
9.3.1 Technical Issues Impacting the Management of an Analytical Laboratory 169
9.3.1.1 Selection of Analytical Methods 169
9.3.1.2 All Selected Methods Should Be Validated for Their Intended Purposes 169
9.3.1.3 The International Congress on Harmonization (ICH) Factor 170
9.3.1.4 Management of Analytical Laboratory and cGMPs and GLPs 170
9.3.1.5 Management under International Standardization Organization Certification 170
9.3.2 Administrative Issues 170
9.3.2.1 Performance Plans and Appraisals 170
9.3.2.2 Training of Personnel and Promotional Opportunities 171
9.3.2.3 Hiring and Firing of Personnel 171
9.3.3 Managerial Issues in an Analytical Laboratory 172
9.3.3.1 Planning 172
9.3.3.2 Organizing 172
9.3.3.3 Monitoring and Control 173
9.3.3.4 Resolution of Conflicts 173
9.4 Conclusions and Recommendations 174
Abbreviations 174
References 175
10 Analytical Instrument Qualification 176
10.1 Introduction 176
10.2 Definitions 177
10.3 Qualification: General Flow 179
10.4 Qualification Strategy: V Model 179
10.5 Qualification 180
10.5.1 Qualification Scheme for New Equipment 180
10.6 Qualification Phases 183
10.6.1 User Requirement Specification 183
10.6.2 Impact Assessment 183
10.6.3 Design Qualification 184
10.6.4 Factory Acceptance Test (FAT) 185
10.6.5 Site Acceptance Test (SAT) 185
10.6.6 Installation Qualification (IQ) 186
10.6.7 Operational Qualification (OQ) 187
10.6.8 Performance Qualification (PQ) 187
10.6.9 Performance Verification (PV) 188
10.6.10 Requalification 188
10.7 Qualification Issues 188
10.8 Combined Qualification Approach/Commissioning 189
10.9 Risk?]Based Approach 189
10.10 Calibration/Verification 189
10.11 Track Performance Verification/Calibration Due Date 190
10.12 Warning Letters Related to Laboratory Equipment 190
10.13 Equipment Qualification/Validation and Its Importance 190
10.14 Examples 192
10.14.1 HPLC (High?]Performance Liquid Chromatography) 192
10.14.2 UV/Visible Spectrophotometer 192
10.14.3 Autotitrator 201
10.14.4 Karl Fischer Titrators 201
10.14.5 Weighing Balance 201
10.14.6 Auto Pipettes 201
10.14.7 Gas Chromatography 209
10.14.8 Analytical Column Qualification 209
10.14.9 Melting Point 209
10.15 Qualification Status of Existing Equipment/Instrument 212
10.16 Summary 212
Acknowledgments 215
References 215
List of Abbreviations 217
Index 221
