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More About This Title Integrated Pharmaceutics: Applied Preformulation,Product Design, and Regulatory Science
English
English
ANTOINE AL-ACHI, PhD, CT (ASCP), is Associate Professor of Pharmaceutics in the College of Pharmacy & Health Sciences at Campbell University. He is also the former head of the Formulation Development Division of Campbell's Pharmaceutical Sciences Institute (CUPSI).
MALI RAM GUPTA, PhD, is Associate Professor of Pharmaceutical Sciences and Director of Pharmaceutical Education & Research Center (PERC) in the College of Pharmacy & Health Sciences. Prior to joining the faculty at Campbell University, he spent twenty-five years in various positions at Revlon, including director of quality control and assurance.
WILLIAM CRAIG STAGNER, PhD, RPh, is Professor of Pharmaceutical Sciences and Director of Campbell University's Center for Analysis of Pharmaceutical Biomaterials. Prior to joining the faculty at Campbell, he established the Pharmaceutics Department at Glaxo Research Institute.
English
FOREWORD xv
PREFACE xvii
PART IPREFORMULATION
CHAPTER 1MATHEMATICAL CONCEPTS3
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 2THERMODYNAMICS15
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 3SOLUBILITY AND DISSOLUTION25
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 4BIOLOGICAL ASPECTS OF FORMULATIONS45
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 5INTERFACIAL PROPERTIES57
5.1 Introduction 57
5.2 Liquid–Solid Interface 58
5.3 Dosage-Form Applications 58
References 63
Glossary 63
CHAPTER 6ADSORPTION PHENOMENON65
6.1 Introduction 65
6.2 Adsorption on Filters 68
6.3 Adsorption of Proteins 69
References 70
Glossary 71
CHAPTER 7RHEOLOGICAL PRINCIPLES73
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 8CHEMICAL STABILITY AND SHELF-LIFE DETERMINATION85
8.1 Introduction 85
8.2 Shelf-life Determination 86
8.3 Stability of Biotechnology Products 112
References 113
Glossary 117
CHAPTER 9PARTICLE SCIENCE119
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 10BASIC STATISTICS AND DESIGN OF EXPERIMENTAL CONCEPTS135
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 11FORMULATION DEVELOPMENT CONCEPTS157
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 IIPRODUCT DESIGN
CHAPTER 12THE PRODUCT DESIGN PROCESS181
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 13TABLET PRODUCT DESIGN215
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 14CAPSULE PRODUCT DESIGN319
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 15DISPERSED SYSTEM PRODUCT DESIGN359
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 16AEROSOL PRODUCT DESIGN415
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 17STERILE INJECTABLE PRODUCT DESIGN467
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 18OPHTHALMIC PRODUCT DESIGN561
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 19TRANSDERMAL PRODUCT DESIGN587
19.1 Introduction 587
19.2 Formulation Design 590
19.3 Conclusions 612
References 613
Glossary 615
Appendix 615
CHAPTER 20ORAL MODIFIED-RELEASE PRODUCT DESIGN619
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 IIIREGULATORY SCIENCE
CHAPTER 21REGULATORY PRACTICES AND GUIDELINES639
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 22REGULATIONS FOR COMPOUNDING PHARMACIES697
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 23IND AND NDA PHASE-APPROPRIATE NEW DRUG DEVELOPMENT PROCESS727
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 24GENERICS, BIOSIMILARS, AND OTCS753
24.1 Generic Drugs 753
24.2 Biosimilar Drugs 759
24.3 Over-the-Counter Drugs 760
References 767
Glossary 769
Appendix 769
CHAPTER 25ACCELERATED NEW DRUG APPROVAL AND EXPEDITED ACCESS OF NEW THERAPIES773
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 26POST–DRUG APPROVAL ACTIVITIES789
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 27DRUG MASTER FILES AND EU DOSSIERS805
27.1 Drug Master Files 805
27.2 European Marketing Authorization Dossiers 817
References 822
Glossary 824
CHAPTER 28COMMISSIONING AND QUALIFICATION829
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 29QUALITY SYSTEMS AND CONTROLS863
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 30SAFETY, TOXICOLOGY, AND PHARMACOGENOMICS911
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 31REGULATORY SCIENCE INITIATIVES FOR ADVANCING PUBLIC HEALTH939
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
