Preface xiii
1 US Regulations for the Pharmaceutical Industries 1
1.1 Introduction 1
1.2 The FDA: Formation of a Regulatory Agency 2
1.3 FDA's Seven Program Centers and Their Responsibility 6
1.3.1 Center for Biologics Evaluation and Research 6
1.3.2 Center for Drug Evaluation and Research 6
1.3.3 Center for Devices and Radiological Health 6
1.3.4 Center for Food Safety and Applied Nutrition 6
1.3.5 Center for Veterinary Medicine 6
1.3.6 Office of Combinational Products 6
1.3.7 Office of Regulatory Affairs 7
1.4 New Drug Development 7
1.4.1 Discovery 7
1.4.2 Investigational New Drug Application 8
1.4.3 Preclinical Studies (Animal) 9
1.4.4 Clinical Studies 10
1.5 Commercializing the New Drug 16
1.5.1 New Drug Application 17
1.6 Harmonization 23
1.6.1 Common Technical Document 23
1.7 Review Process of US NDA 25
1.8 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs 27
1.8.1 Organization and Personnel 27
1.8.2 Building and Facilities 28
1.8.3 Equipment 28
1.8.4 Control of Components and Drug Product Containers and Closures 29
1.8.5 Production and Process Controls 29
1.8.6 Packaging and Labeling Control 30
1.8.7 Holding and Distribution 31
1.8.8 Laboratory Controls 31
1.8.9 Records and Reports 32
1.8.10 Returned and Salvaged Drug Products 33
1.8.11 Other 33
1.9 Compliance 34
1.9.1 Quality System 35
1.9.2 Facilities and Equipment System 35
1.9.3 Materials System 36
1.9.4 Production System 36
1.9.5 Packaging and Labeling System 36
1.9.6 Laboratory Control System 36
1.10 Electronic Records and Electronic Signatures 37
1.10.1 Electronic Records 37
1.10.2 Electronic Signatures 38
1.11 Employee Safety 38
1.11.1 Process Safety Information 39
1.11.2 Process Hazard Analysis 40
1.11.3 Operating Procedures 41
1.11.4 Training 41
1.11.5 New Facility Startup 41
1.11.6 Mechanical Integrity 42
1.11.7 Hot Work Permit 42
1.11.8 Management of Change 42
1.11.9 Incident Investigation 43
1.11.10 Emergency Planning and Response 43
1.11.11 Compliance Audits 43
1.12 US EPA 43
1.12.1 Clean Air Act 44
1.12.2 Safe Drinking Water Act 45
1.12.3 Resource Conservation and Recovery Act 46
1.12.4 Emergency Planning and Community Right-to-Know Act 47
1.12.5 Clean Water Act 48
1.13 Process Analytical Technology 49
1.13.1 Process Understanding 49
1.13.2 Principles and Tools 50
1.13.3 Strategy for Implementation 51
1.14 Conclusion 51
References 51
Further Reading 52
2 Pharmaceutical Water Systems 53
2.1 Pharmaceutical Water Systems Basics 53
2.1.1 Fundamentals of Fluid Mechanics for Pharmaceutical Water Systems 58
2.2 Pharmaceutical Water Equipment 77
2.2.1 Centrifugal Pumps 77
2.2.2 Centrifugal Pump Installation Considerations 81
2.3 Thermodynamics Interlude 82
2.4 Heat Transfer for Pharmaceutical Water Production 90
2.5 Evaporation 109
2.6 Ion Exchange Systems 115
2.7 Reverse Osmosis 116
2.7.1 Principles of Reverse Osmosis 118
2.7.2 Reverse Osmosis Installation and Operational Costs 121
2.7.3 Reverse Osmosis Design Hint 122
2.8 cGMP Design and Facility Maintenance Considerations for Pharmaceutical Water Systems 122
References 128
Further Reading 129
3 Heating, Ventilating, and Air Conditioning 131
3.1 Fundamentals of HVAC Electrical Systems 132
3.1.1 Electric Motors 133
3.1.2 Motor Plate and Associated Data 134
3.2 Design Considerations 140
3.2.1 Weather Data 143
3.2.2 Temperature and Humidity 143
3.2.3 Ventilation 147
3.2.4 Air Filtration 149
3.2.5 Internal Loads 150
3.2.6 Air Distribution 150
3.2.7 Room Pressurization 151
3.2.8 Sound and Acoustic Criteria 152
3.2.9 Building Control Systems 158
3.3 Cleanrooms 158
3.3.1 Cleanroom Design Fundamentals 158
3.3.2 Cleanroom Monitoring, Maintenance, and Design Considerations for USP and USP Facilities 169
References 172
Further Reading 172
4 Pressure Vessels, Reactors, and Fermentors 175
4.1 Introduction 175
4.1.1 Pressure Vessels 175
4.1.2 Basics of Pressure Vessel Design and Specifications 178
4.1.3 Pharmaceutical Reactors 188
4.1.4 Kinetics and Reactor Fundamentals 188
4.1.5 Bioreactor Principles 197
4.1.6 Fermentor Principles 209
4.1.7 Heat Transfer Aspects of Fermentors 211
4.1.8 Bioreactor and Fermentor Design, Maintenance, Operating, and cGMP Considerations 214
4.2 Safety Relief Valves and Rupture Discs 219
4.2.1 Safety Relief Devices, Definition of Terms 219
4.2.2 Relief Valve Design and Specifications 223
4.2.3 Requirements and Capacity 223
References 237
Further Reading 238
5 Reliability, Availability, and Maintainability 239
5.1 Introduction to RAM 239
5.2 The Role of Reliability 240
5.3 The Role of Maintainability 247
5.4 The Preventive Maintenance Program 252
5.4.1 System Replacement Considerations 253
5.5 Human Factors 254
5.6 The Role of Availability 259
5.7 Basic Mathematics for Reliability, Availability, and Maintainability 259
5.8 Series and Parallel Configurations 271
5.9 Spares and Replacement Parts 271
References 276
Further Reading 277
6 Parenteral Operations 279
6.1 Introduction 279
6.2 Parenteral Definitions, Regulations, and Guidelines 280
6.2.1 Nomenclature and Definitions 280
6.3 Lyophilization 282
6.3.1 Background 282
6.3.2 Lyophilization Glossary 283
6.3.3 Lyophilizer Design and Operation 284
6.4 Lyophilizer Maintenance Issues 294
6.4.1 Maintenance Systems Analysis 294
References 296
Further Reading 296
7 Tableting Technology 299
7.1 Introduction 299
7.2 The Role of the FDA in the Manufacturing, Processing, Packing, and Holding of Drugs: The Relationship Between Regulations and Pharmaceutical Engineering 300
7.3 Tablet Blending Operations 304
7.3.1 Dry Granulation 305
7.3.2 Wet Granulation 320
7.4 Tableting Operations 322
7.4.1 Tablet Manufacturing 324
7.4.2 Tablet Press Maintenance 329
7.5 Coating 330
7.5.1 Tablet Coating 330
7.5.2 Tablet Coater Maintenance 331
7.6 Capsules 333
7.6.1 Capsule Fundamentals 334
7.6.2 Capsule Materials and Manufacturing 334
References 337
Further Reading 338
8 Corrosion and Passivation in Pharmaceutical Operations 339
8.1 Corrosion 339
8.2 Corrosion and Corrosion Protection in Pharmaceutical Operations 339
8.2.1 Definition of Corrosion 343
8.2.2 Corrosion Fundamentals 343
8.3 General Corrosion Protection in Pharmaceutical Operations 344
8.3.1 Electrochemical Action 344
8.3.2 Environmental Characteristics and Corrosion 349
8.3.3 Properties of Metals that Influence Corrosion 350
8.3.4 Effects of Fabrication and Assembly on Corrosion 350
8.3.5 Protective Films and Corrosion 352
8.3.6 Corrosion Activity in Solutions 352
8.3.7 Types of Corrosion 354
8.4 Corrosion- Resistant Metals and Alloys 365
8.4.1 Iron Alloys 366
8.4.2 Aluminum and Aluminum Alloys 367
8.5 Passivation and Rouging 368
8.5.1 Passivation 368
8.5.2 Rouging 369
8.6 General Corrosion Protective Measures 370
8.6.1 General Design Considerations for Corrosion Prevention 370
8.7 Pourbaix Diagrams 374
References 377
Further Reading 378
9 Pharmaceutical Materials of Construction 379
9.1 Introduction 379
9.2 Materials Selection and Performance Requirements 379
9.2.1 Introduction of Polymeric Materials for Single Use Systems 380
9.3 Advantages and Disadvantages of Stainless Steels and Polymers for cGMP and Non-cGMP Pharmaceutical Applications 381
9.4 Disposal of Single Use Components 382
9.5 Performance Considerations for Pharmaceutical Materials of Construction 392
9.5.1 Stainless Steels 392
9.5.2 Copper and Copper Alloys 394
9.5.3 Carbon Steels and Alloy Steels 396
9.5.4 Polymeric Materials: Overview 399
9.5.5 Preventing Pharmaceutical Materials Component Materials Failures 402
9.6 Practical Piping Calculations 403
References 408
Further Reading 409
10 Commissioning and Validation 411
10.1 Introduction to Commissioning and Validation 411
10.1.1 Introduction to Construction Specifications 411
10.2 Commissioning 416
10.2.1 Description of Tasks 419
10.2.2 Commissioning Costs 425
10.3 Validation 425
10.4 Process Validation 459
10.5 Electronic Records and Electronic Signatures 484
10.5.1 Application of Risk Assessment Methods to Outsourcing 491
10.5.2 Validation Costs 492
10.6 Comparison Between Commissioning and Validation 493
References 493
Further Reading 493
11 Topics and Concepts Relating to Pharmaceutical Engineering 495
11.1 Preliminary Concepts 495
11.1.1 Basic Statistical Concepts and Computational Techniques 495
11.2 Introduction to Six Sigma 508
11.2.1 Six Sigma Organization and Background 508
11.2.2 DMAIC: The Basic Six Sigma Acronym 514
11.2.3 Define 514
11.2.4 Measure 516
11.2.5 Analyze 519
11.2.6 Improve 520
11.2.7 Control 523
11.2.8 Lean Six Sigma 524
11.3 Process Analytical Technology 530
11.4 Quality by Design 537
References 540
Further Reading 540
Index 543
