Main description:

An examination of all aspects of the science and art of dosage form development

Integrating physical pharmacy, drug design, and drug regulation, this book examines all the key elements needed to produce effective dosage forms for drug delivery. It begins by setting a solid foundation of physical pharmacy principles such as drug stability estimation, rheology, and interfacial properties. Next, the authors explain how to incorporate these principles into product design. Lastly, the book integrates harmonized pharmaceutical development regulatory guidelines and requirements with the science and technology of pharmaceutical product design in the United States, European Union, and Japan.

Integrated Pharmaceutics offers a comprehensive portrait of pharmaceutical product design, fully describing the science and art of dosage form development. Readers will find clear and thorough coverage of:

• Fundamental physical pharmacy principles and their role in drug product design


• Regulatory science section covering drug regulation, pharmacy compounding practices, manufacturing validation, and quality systems and controls


• Recent regulatory guidelines for quality by design, design space analysis, process analytical technology, polymorphism characterization, blend sample uniformity, stability protocols, and biopharmaceutical classification systems

Each chapter includes a glossary defining key terms and a list of references leading to the primary literature in the field. Many of the chapters also feature case studies, reference appendices, and practical problems, enabling readers to apply the principles set forth in the book to solve common problems in drug product design.

With its comprehensive, multidisciplinary approach, Integrated Pharmaceutics is recommended for graduate–level courses in pharmacy, the pharmaceutical sciences, pharmaceutics, physical pharmacy, drug formulation and design, and biomedicine. The book will also enable professionals in the pharmaceutical industry to apply an effective integrated approach to drug product design.

Back cover:

An examination of all aspects of the science and art of dosage form development

Integrating physical pharmacy, drug design, and drug regulation, this book examines all the key elements needed to produce effective dosage forms for drug delivery. It begins by setting a solid foundation of physical pharmacy principles such as drug stability estimation, rheology, and interfacial properties. Next, the authors explain how to incorporate these principles into product design. Lastly, the book integrates harmonized pharmaceutical development regulatory guidelines and requirements with the science and technology of pharmaceutical product design in the United States, European Union, and Japan.

Integrated Pharmaceutics offers a comprehensive portrait of pharmaceutical product design, fully describing the science and art of dosage form development. Readers will find clear and thorough coverage of:

• Fundamental physical pharmacy principles and their role in drug product design


• Regulatory science section covering drug regulation, pharmacy compounding practices, manufacturing validation, and quality systems and controls


• Recent regulatory guidelines for quality by design, design space analysis, process analytical technology, polymorphism characterization, blend sample uniformity, stability protocols, and biopharmaceutical classification systems

Each chapter includes a glossary defining key terms and a list of references leading to the primary literature in the field. Many of the chapters also feature case studies, reference appendices, and practical problems, enabling readers to apply the principles set forth in the book to solve common problems in drug product design.

With its comprehensive, multidisciplinary approach, Integrated Pharmaceutics is recommended for graduate–level courses in pharmacy, the pharmaceutical sciences, pharmaceutics, physical pharmacy, drug formulation and design, and biomedicine. The book will also enable professionals in the pharmaceutical industry to apply an effective integrated approach to drug product design.

Contents:

FOREWORD xv

PREFACE xvii

PART I PREFORMULATION

CHAPTER 1 MATHEMATICAL CONCEPTS 3

1.1 Introduction 3

1.2 The Simple Linear Relationship 4

1.3 Exponential Rules 7

1.4 Logarithmic Rules 8

1.5 Differential Equations 10

1.6 Expanding and Reducing Formulas 12

References 13

Glossary 14

CHAPTER 2 THERMODYNAMICS 15

2.1 Introduction 15

2.2 The Zeroth Law of Thermodynamics 15

2.3 The First Law of Thermodynamics 16

2.4 The Second Law of Thermodynamics 17

2.5 The Third Law of Thermodynamics 18

2.6 Polymorphism 18

2.7 Physical Stability of Crystal Forms 20

2.8 Solubility 21

References 22

Glossary 23

CHAPTER 3 SOLUBILITY AND DISSOLUTION 25

3.1 Introduction 25

3.2 Concentration Units 26

3.3 What Should be Done When Alcohol is Prescribed in a Formulation 35

3.4 The Partition Coefficient 36

3.5 Disintegration and Dissolution 38

3.6 Concluding Remarks 43

References 43

Glossary 44

CHAPTER 4 BIOLOGICAL ASPECTS OF FORMULATIONS 45

4.1 Introduction 45

4.2 Bioavailability and Bioequivalence 45

4.3 Protocols for Determining Bioequivalence 49

4.4 Bioequivalence Procedure 49

4.5 FDA–Approved Methods for Bioequivalence Studies 50

4.6 Approaches to Improving Bioavailability 52

References 54

Glossary 54

CHAPTER 5 INTERFACIAL PROPERTIES 57

5.1 Introduction 57

5.2 Liquid Solid Interface 58

5.3 Dosage–Form Applications 58

References 63

Glossary 63

CHAPTER 6 ADSORPTION PHENOMENON 65

6.1 Introduction 65

6.2 Adsorption on Filters 68

6.3 Adsorption of Proteins 69

References 70

Glossary 71

CHAPTER 7 RHEOLOGICAL PRINCIPLES 73

7.1 Introduction 73

7.2 Newtonian Systems 74

7.3 Non–Newtonian Systems 75

7.4 Viscoelasticity 78

7.5 Reynolds Number 81

7.6 Concluding Remarks 81

References 82

Glossary 82

CHAPTER 8 CHEMICAL STABILITY AND SHELF–LIFE DETERMINATION 85

8.1 Introduction 85

8.2 Shelf–life Determination 86

8.3 Stability of Biotechnology Products 112

References 113

Glossary 117

CHAPTER 9 PARTICLE SCIENCE 119

9.1 Introduction 119

9.2 Particle Size Estimation and Distribution 120

9.3 Micronization 125

9.4 Particle Size Preparation and Reduction for Pulmonary Delivery 126

9.5 Polymeric Particulate Matter 128

9.6 Nanoparticles 128

9.7 Segregation of Particles 131

References 132

Glossary 133

CHAPTER 10 BASIC STATISTICS AND DESIGN OF EXPERIMENTAL CONCEPTS 135

10.1 Descriptive Statistics 135

10.2 Inferential Statistics 137

10.3 Statistical Applications in Quality Control Testing 146

10.4 Design of Experiment 148

References 154

Glossary 154

CHAPTER 11 FORMULATION DEVELOPMENT CONCEPTS 157

11.1 Preformulation 157

11.2 Scale–up Considerations 158

11.3 Combination Products 159

11.4 Rate–Controlled Drug Delivery 160

11.5 Drug Delivery Technologies for Improving Oral Delivery 163

11.6 Drug Delivery Technologies for Improving Transmucosal Delivery 165

11.7 Drug Delivery Technologies for Transdermal Delivery 166

11.8 Special Considerations for Biotechnology and Protein Delivery Systems 166

11.9 Drug Excipient and Excipient Excipient Interactions 170

11.10 The Presence of Contaminants in a Formulation 172

11.11 Other Considerations 173

References 174

Glossary 176

PART II PRODUCT DESIGN

CHAPTER 12 THE PRODUCT DESIGN PROCESS 181

12.1 Introduction 181

12.2 Formulation Design 183

12.3 Process Design 188

12.4 Container Closure System Design 190

References 192

Glossary 193

Appendixes 194

CHAPTER 13 TABLET PRODUCT DESIGN 215

13.1 Introduction 215

13.2 Formulation Design 222

13.3 Process Design 243

13.4 Container Closure System Design 283

13.5 Risk Management 292

13.6 Attribute Tests 293

13.7 New Drug Application Stability Assessment 296

References 298

Glossary 304

Appendixes 306

CHAPTER 14 CAPSULE PRODUCT DESIGN 319

14.1 Introduction 319

14.2 Hard–Shell Capsules 320

14.3 Soft–Shell Capsules 343

14.4 Formulation and Process Optimization 348

14.5 Container Closure System 350

14.6 Risk Management 350

14.7 Attribute Tests 350

14.8 New Drug Application Stability Assessment 352

References 353

Glossary 355

Appendixes 356

CHAPTER 15 DISPERSED SYSTEM PRODUCT DESIGN 359

15.1 Introduction 359

15.2 Formulation Design 360

15.3 Process Design 399

15.4 Container Closure System Design 401

15.5 Risk Management 402

15.6 Attribute Tests 402

15.7 New Drug Application Stability Assessment 405

References 406

Glossary 408

Appendixes 409

CHAPTER 16 AEROSOL PRODUCT DESIGN 415

16.1 Introduction 415

16.2 Formulation Design 416

16.3 Container Closure System Design 443

16.4 Risk Management 446

16.5 Attribute Tests 450

16.6 New Drug Application Stability Assessment 455

References 458

Glossary 462

Appendix 463

CHAPTER 17 STERILE INJECTABLE PRODUCT DESIGN 467

17.1 Introduction 467

17.2 Formulation Design 468

17.3 Process Design 511

17.4 Container Closure System Design 530

17.5 Risk Management 535

17.6 Attribute Tests 535

17.7 New Drug Application Stability Assessment 536

References 539

Glossary 546

Appendixes 548

CHAPTER 18 OPHTHALMIC PRODUCT DESIGN 561

18.1 Introduction 561

18.2 Formulation Design 565

18.3 Process Design 577

18.4 Container Closure System Design 577

18.5 Attribute Tests 577

18.6 New Drug Application Stabilty Assessment 578

References 578

Glossary 580

Appendix 581

CHAPTER 19 TRANSDERMAL PRODUCT DESIGN 587

19.1 Introduction 587

19.2 Formulation Design 590

19.3 Conclusions 612

References 613

Glossary 615

Appendix 615

CHAPTER 20 ORAL MODIFIED–RELEASE PRODUCT DESIGN 619

20.1 Introduction 619

20.2 Coatings 625

20.3 Matrix Systems 628

20.4 Gastroretentive Devices 631

20.5 Osmotic Controlled Release Systems 632

20.6 Conclusions 633

References 634

Glossary 635

Appendix 636

PART III REGULATORY SCIENCE

CHAPTER 21 REGULATORY PRACTICES AND GUIDELINES 639

21.1 Worldwide Regulatory Agencies 639

21.2 Good Manufacturing Practice 651

21.3 FDA Inspection and Regulatory Actions 685

References 687

Glossary 689

CHAPTER 22 REGULATIONS FOR COMPOUNDING PHARMACIES 697

22.1 Introduction 697

22.2 Compounding Guidelines 698

22.3 FDA Compliance Policy Guides 699

22.4 Good Compounding Practices 705

22.5 Stability Criteria and Beyond–Use Dating of Compounded Preparations 717

22.6 Verification 719

22.7 Patient Counseling 719

22.8 Pharmacy Compounding Accreditation 720

References 720

Glossary 721

Appendixes 722

CHAPTER 23 IND AND NDA PHASE–APPROPRIATE NEW DRUG DEVELOPMENT PROCESS 727

23.1 Introduction 727

23.2 Preclinical Development Overview 728

23.3 Phase–Appropriate Clinical Trials Overview 730

23.4 Investigational New Drugs 734

23.5 NDA Review Process 744

References 750

Glossary 751

CHAPTER 24 GENERICS, BIOSIMILARS, AND OTCS 753

24.1 Generic Drugs 753

24.2 Biosimilar Drugs 759

24.3 Over–the–Counter Drugs 760

References 767

Glossary 769

Appendix 769

CHAPTER 25 ACCELERATED NEW DRUG APPROVAL AND EXPEDITED ACCESS OF NEW THERAPIES 773

25.1 Introduction 773

25.2 Expedited Review and Approval of New Therapies 774

25.3 Expanded Access to New Therapies 776

25.4 Orphan Drugs 778

25.5 Pediatric Drugs 780

25.6 Pediatric Drug Development and the Orphan Drug Act Incentives 783

25.7 Common EMEA/FDA Application for Orphan Medicinal Product Designation 784

References 784

Glossary 785

CHAPTER 26 POST DRUG APPROVAL ACTIVITIES 789

26.1 Postmarket Requirements and Commitments 789

26.2 Postapproval Manufacturing Changes 790

26.3 Clinical Phase 4 Studies: Postmarketing Surveillance and Risk Assessment 792

26.4 Prescription Drug Advertising and Promotional Labeling Direct to Consumers 798

References 799

Glossary 801

Appendix 804

CHAPTER 27 DRUG MASTER FILES AND EU DOSSIERS 805

27.1 Drug Master Files 805

27.2 European Marketing Authorization Dossiers 817

References 822

Glossary 824

CHAPTER 28 COMMISSIONING AND QUALIFICATION 829

28.1 Regulatory Requirements 829

28.2 Preliminary C&Q Activities 832

28.3 Commissioning 834

28.4 Qualification and Validation 838

28.5 Qualification Protocols 842

28.6 Process Validation 849

28.7 Cleaning Validation 854

28.8 Computer Systems Validation 856

28.9 Change Control 856

28.10 Revalidation 857

References 857

Glossary 859

CHAPTER 29 QUALITY SYSTEMS AND CONTROLS 863

29.1 Pharmaceutical Quality System 863

29.2 Quality Systems Approach to CGMP Regulations 868

29.3 Inspection of Pharmaceutical Quality Control Laboratories 875

29.4 Pharmacopeias 877

29.5 Analytical Instrument Qualification 881

29.6 Validation of Analytical Procedures 886

29.7 Stability Testing of New Drug Substances and Products 889

References 893

Glossary 895

Appendixes 900

CHAPTER 30 SAFETY, TOXICOLOGY, AND PHARMACOGENOMICS 911

30.1 Nonclinical Safety Studies 911

30.2 Safety Pharmacology Studies 914

30.3 Carcinogenicity Studies of Pharmaceuticals 918

30.4 Genotoxicity Testing 920

30.5 Immunotoxicity Studies 923

30.6 Safety Reporting Requirements 926

30.7 Pharmacogenomics 927

References 930

Glossary 932

Appendixes 935

CHAPTER 31 REGULATORY SCIENCE INITIATIVES FOR ADVANCING PUBLIC HEALTH 939

31.1 Introduction 939

31.2 Advancing Regulatory Science for Public Health: The Promise of Regulatory

Science 940

31.3 Advancing Regulatory Science at FDA: Strategic Plan for Regulatory

Science 940

31.4 Collaborative Implementation Framework 943

References 944

Glossary 945

INDEX 947