Table of Contents

Foreword to Second Edition xv

Foreword to First Edition xvi

Preface to Second Edition xvii

Preface to First Edition xviii

About the Companion Website xx

Part I Applied Preformulation 1

1 Mathematical Concepts 3

1.1 Introduction 3

1.2 Significant Figures and Rounding off Numbers 3

1.3 The Simple Linear Relationship 4

1.4 Exponential Rules 6

1.5 Logarithmic Rules 6

1.6 Differential Equations 7

1.7 Expanding and Reducing Formulas 9

1.8 Weights and Measures 9

References 10

Glossary 10

2 Thermodynamics 11

2.1 Introduction 11

2.2 The Zeroth Law of Thermodynamics 11

2.3 The First Law of Thermodynamics 11

2.4 The Second Law of Thermodynamics 12

2.5 The Third Law of Thermodynamics 13

2.6 Polymorphism 13

2.7 Physical Stability of Crystal Forms 14

2.8 Solubility 14

References 15

Glossary 16

3 Solubility and Dissolution 18

3.1 Introduction 18

3.2 Methods of API Solubility Enhancement 19

3.3 Nonionic, Ionic, and Acid–Base Concepts Related to Solubility and Dissolution 29

3.4 The Solubility of Gas in Liquid 29

3.5 The Solubility of Liquid in Liquid 30

3.6 The Solubility of Solid in Liquid 30

3.7 Disintegration and Dissolution 31

3.8 Concentration Units 34

3.9 The Partition Coefficient 39

3.10 Concluding Remarks 41

References 41

Glossary 44

Appendix 45

4 Biological Aspects of Formulations 46

4.1 Introduction 46

4.2 Bioavailability and Bioequivalence 46

4.3 Protocols for Determining Bioequivalence 48

4.4 Bioequivalence Procedure 49

4.5 FDA-Approved Methods for Bioequivalence Studies 49

4.6 Approaches to Improving Bioavailability 50

References 52

Glossary 53

5 Interfacial Properties 54

5.1 Introduction 54

5.2 Liquid–Solid Interface 54

5.3 Liquid–Liquid Interface 55

5.4 Dosage-Form Applications 55

5.5 Case Study: HLB Determination 58

5.6 Case Study: Determination of Required HLB (rHLB) 58

References 58

Glossary 59

6 Adsorption Phenomenon 60

6.1 Introduction 60

6.2 Adsorption on Filters 66

6.3 Adsorption of Proteins 66

References 66

Glossary 68

7 Rheological Principles 69

7.1 Introduction 69

7.2 Newtonian Systems 69

7.3 Non-Newtonian Systems 70

7.4 Viscoelasticity 72

7.5 Reynolds Number 74

7.6 Concluding Remarks 76

References 76

Glossary 77

8 Chemical Stability and Shelf-Life Determination 78

8.1 Introduction 78

8.2 Shelf-Life Determination 79

8.3 Stability of Biotechnology Products 84

8.4 Compounded Products and Their Beyond-Use Dates 86

References 102

Glossary 107

9 Particle Science 108

9.1 Introduction 108

9.2 Miromeritics 108

9.3 Micronization 113

9.4 Particle Size Preparation and Reduction for Pulmonary Delivery 114

9.5 Polymeric Particulate Matter 115

9.6 Nanoparticles 116

9.7 Segregation of Particles 121

9.8 Case Studies: Microscopic Particle Size Analysis, Determining Statistically Valid Sample Size, and Comparison of Sieve and Focused Beam Reflectance Measurement Chord Length Particle Size Distributions 122

References 126

Glossary 129

10 Basic Statistics and Design of Experimental Concepts 130

10.1 Descriptive Statistics 130

10.2 Inferential Statistics 131

10.3 Statistical Applications in Quality Control Testing 135

10.4 Design of Experiment 136

10.5 Multivariate Analysis (MVA) 140

10.6 Reliability and Validity Assessment 152

References 155

Glossary 155

11 Formulation Development Concepts 157

11.1 Preformulation 157

11.2 Scale-up Considerations 164

11.3 Combination Products 168

11.4 Rate-Controlled Drug Delivery 170

11.5 Drug Delivery Technologies for Improving Oral Delivery 172

11.6 Drug Delivery Technologies for Improving Transmucosal Delivery 173

11.7 Drug Delivery Technologies for Transdermal Delivery 173

11.8 Special Considerations for Biotechnology and Protein Delivery Systems 174

11.9 Drug–Excipient and Excipient–Excipient Interactions 177

11.10 The Presence of Contaminants in a Formulation 178

11.11 Other Considerations 179

References 179

Glossary 184

Part II Product Design 187

12 The Product Design Process 189

12.1 Introduction 189

12.2 Formulation Design 191

12.3 Process Design 194

12.4 Container Closure System Design 195

References 196

Glossary 198

12.A Appendix 199

13 Tablet Product Design 214

13.1 Introduction 214

13.2 Formulation Design 220

13.3 Process Design 225

13.4 Container Closure System Design 249

13.5 Risk Management 255

13.6 Attribute Tests 256

13.7 New Drug Application Stability Assessment 257

References 259

Glossary 264

13.A Appendix 265

14 Capsule Product Design 274

14.1 Introduction 274

14.2 Hard-Shell Capsules 274

14.3 Soft-Shell Capsules 288

14.4 Formulation and Process Optimization 291

14.5 Container Closure System Design 292

14.6 Risk Management 292

14.7 Attribute Tests 292

14.8 New Drug Application Stability Assessment 293

References 293

Glossary 295

14.A Appendix 296

15 Dispersed System Product Design 298

15.1 Introduction 298

15.2 Formulation Design 298

15.3 Process Design 322

15.4 Container Closure System Design 325

15.5 Risk Management 325

15.6 Attribute Tests 326

15.7 New Drug Application Stability Assessment 327

References 328

Glossary 330

Appendices 331

16 Aerosol Product Design 336

16.1 Introduction 336

16.2 Inhalation Formulation Design 338

16.3 Nasal, Buccal, Lingual, and Sublingual Aerosol Formulation Design 351

16.4 Container Closure System Design 354

16.5 Risk Management 356

16.6 Attribute Tests 356

16.7 New Drug Application Stability Assessment 359

References 363

Glossary 366

16.A Appendix 367

17 Sterile Injectable Product Design 369

17.1 Introduction 369

17.2 Formulation Design 370

17.3 Process Design 393

17.4 Container Closure System Design 404

17.5 Risk Management 407

17.6 Attribute Tests 407

17.7 New Drug Application Stability Assessment 408

References 409

Glossary 415

17.A Appendix 416

18 Ophthalmic Product Design 426

18.1 Introduction – Eye Anatomy and Physiology 426

18.2 Formulation Design 429

18.3 Process Design 436

18.4 Container Closure System Design 436

18.5 Attribute Tests 436

18.6 New Drug Application Stability Assessment 436

References 436

Glossary 438

18.A Appendix 438

19 Transdermal Product Design 442

19.1 Introduction – Skin Anatomy and Physiology 442

19.2 Formulation Design 444

19.3 Conclusions 457

References 457

Glossary 459

19.A Appendix 459

20 Oral Modified-Release Product Design 462

20.1 Introduction 462

20.2 FDA and U.S.P. Nomenclature 462

20.3 Modified-Release Mechanisms 464

20.4 In Vitro–In Vivo Correlations (IVIVC) 465

20.5 Coatings 466

20.6 Matrix Systems 467

20.7 Gastroretentive Devices 470

20.8 Osmotic-Controlled Release Systems 470

20.9 Conclusions 471

References 471

Glossary 472

20.A Appendix 473

Part III Regulatory Science 475

21 Regulatory Practices and Guidelines 477

21.1 Worldwide Regulatory Agencies 477

21.2 Good Manufacturing Practice (GMP) 484

21.3 FDA Inspection and Regulatory Actions (FDA 2020b, 2020d) 503

References 510

Glossary 511

21.A Appendix 519

22 Regulations for Compounding Pharmacies 525

22.1 Introduction 525

22.2 Sections 503A and 503B and Their Differences (FDA 2018a) 526

22.3 Compounding Guidelines 526

22.4 Good Compounding Practices (FDA 2007; Skoloff 2009; U.S.P 2020: U.S.P 2020); U.S.P. 2018; USP29 2006; USP29NF24 2006; OSBP 2017; NDBOPH 2020; NV 2020a; OR 2020; CPE 2017; OK 2020; KY 2016a; WA 2020a; FDA 2020a, 2020b) 527

22.5 Compounding Sterile Preparations (U.S.P. 2020; WA 2020b; CT 2020; OR 2020; NV 2020b; OK 2020; KY 2016b; NYBOP (n.d.); ASPH 2003, 2020; TU n.d.) 532

22.6 Stability Criteria and Beyond-Use Dating of Compounded Non-Sterile Preparations (U.S.P. 2020; WA 2020b; CT 2020; OR 2020; NV 2020b; OK 2020; KY 2016b; NYBOP (n.d.); ASPH 2003, 2020; TU n.d.) 536

22.7 Verification (U.S.P. 2020; U.S.P. 2020; WA 2020a, 2020b) 537

22.8 Patient Counseling (U.S.P. 2020; U.S.P. 2020; WA 2020a, 2020b) 537

22.9 Patient Monitoring and Adverse Events Reporting (U.S.P. 2020; WA 2020b) 537

22.10 Pharmacy Compounding Accreditation 537

22.11 Compounding: Inspections, Recalls, and Other Actions (FDA 2018b; FDA 2018c) 538

References 538

Glossary 540

22.A Appendix 541

23 IND and NDA Phase-Appropriate New Drug Development Process 554

23.1 Introduction 554

23.2 Preclinical Development Overview (FDA 1998) 555

23.3 Phase-Appropriate Clinical Trials Overview (FDA 1998) 556

23.4 Investigational New Drugs 558

23.5 Good Laboratory Practice for Nonclinical Laboratories Studies [21CFR58] (FDA 2020c) 564

23.6 CGMP for Phase 1 Investigational Drugs – Guidance for Industry (FDA 2008) 566

23.7 Good Clinical Practice [E6(R2)] Guidance for Industry (FDA 2016, 2018, 2019a) 568

23.8 NDA Review Process (FDA 1998) 570

References 574

Glossary 575

23.A Appendix 576

24 Biological, Biosimilar, Generic, and OTC Products 584

24.1 Biologicals (FDA 2015a, 2015b, 2016b 2018a, 2018b, 2019a, 2019b, 2019c, 2020a; EMA 2019) 584

24.2 Biosimilars (EMA n.d.-a, n.d.-b; FDA n.d.-a, n.d.-b; Christl n.d.; FDA n.d.-c; Lim n.d., 2013; FDA 2017a, 2017b, 2017c,

2018c, 2020b, 2020c; EMA 2019) 586

24.3 Generic Drugs (FDA 1998a, 2014b, 2017f, 2017g, 2018e, 2018g, 2019d) 588

24.4 Over-the-Counter Drugs (FDA 1998b, 2016a, 2018g, 2019f, 2020e, 2020f, 2020g) 593

References 598

Glossary 600

24.A Appendix 602

25 Accelerated New Drug Approval and Expedited Access of New Therapies 605

25.1 Introduction 605

25.2 Expedited Review and Approval of New Therapies (HIV n.d.; IOM 1991; FDA 2009a, 2010a, 2011b, 2014) 605

25.3 Expanded Access to New Therapies (HIV n.d.; FDA 2009a) 607

25.4 Orphan Drugs (EMA n.d.-a, n.d.-b; WebMD n.d.; FDA 1998a, 2005a, 2018, 2018b, 2020c; IOM 2010) 608

25.5 Pediatric Drugs (FDA 1998b, 2005b) 610

25.6 Pediatric Drug Development and the Orphan Drug Act Incentives (FDA 2010c) 612

25.7 Common EMEA/FDA Application for Orphan Medicinal Product Designation (EMA n.d.-a, n.d.-b;

FDA 2009b; FDA 2018) 612

References 613

Glossary 614

26 Post–Drug Approval Activities 617

26.1 Postmarket Requirements and Commitments (FDA 2016b, 2018f, 2020a, 2020e) 617

26.2 Postapproval Manufacturing Changes (FDA 2018d, 2020b) 618

26.3 Clinical Phase 4 Studies: Postmarketing Surveillance and Risk Assessment (FDA 2018d, 2019b) 619

26.4 Prescription Drug Advertising and Promotional Labeling Direct to Consumers (FDA 1998c) 622

References 623

Glossary 624

26.A Appendix 626

27 Drug Master Files, EU Dossiers, and API GMP Guidance 627

27.1 Drug Master Files (FDA 2001, 2011a, 2011b, 2011c, 2011d, 2011e) 627

27.2 European Marketing Authorization Dossiers 633

27.3 Good Manufactruing Practice (GMP) Guidance for Active Pharmaceutical Ingredients (Q7) (FDA 2016) 636

References 641

Glossary 643

28 Commissioning and Qualification 646

28.1 Regulatory Requirements (Health Canada 2009; EU 2015; FDA 2017, 2018a, 2020) 646

28.2 Preliminary C&Q Activities 647

28.3 Commissioning 649

28.4 Qualification and Validation 651

28.5 Qualification Protocols (ISPE 2001; Health Canada 2009; PIC/S 2018) 653

28.6 Process Validation (FDA 2014, 2019; PIC/S 2018) 657

28.7 Cleaning Validation (Health Canada 2008; FDA 2014, 2017; PIC/S 2018) 659

28.8 Computer Systems Validation (ISPE 2001; EU 2011) 660

28.9 Change Control (EU 2015; PIC/S 2018) 660

28.10 Revalidation (CDRH 1995; EU 2015; FDA 2015; PIC/S 2018) 661

References 661

Glossary 663

29 Quality Systems and Controls 666

29.1 Pharmaceutical Quality System (FDA 2019a) 666

29.2 Quality Systems Approach to CGMP Regulations 669

29.3 Inspection of Pharmaceutical Quality Control Laboratories (FDA 2014) 672

29.4 Pharmacopeias (U.S.P. 2014) 673

29.5 Analytical Instrument Qualification (U.S.P. 2019a; FDA 2010) 676

29.6 Validation of Analytical Procedures (U.S.P. 2019b; FDA 2000, 2015, 2019b) 679

29.7 Stability Testing of New Drug Substances and Products (U.S.P. 2006; ICH 1996; FDA 2018b, 2018c, 2018d) 680

29.8 Electronic Records; Electronic Signatures (Part 11) (FDA 2019) 682

References 684

Glossary 686

29.A Appendix 690

30 Safety, Toxicology, and Pharmacogenomics 696

30.1 Nonclinical Safety Studies (ICH 2009; FDA 2010) 696

30.2 Safety Pharmacology Studies (ICH 2000) 697

30.3 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals – (FDA 1997; EMA 2011a) 700

30.4 Carcinogenicity Studies of Pharmaceuticals (ICH 1995) 701

30.5 Genotoxicity Testing (ICH 1998, 2008) 702

30.6 Immunotoxicity Studies (ICH 2005b) 704

30.7 Safety Reporting Requirements 705

30.8 Pharmacogenomics (NIGMS 2005; ICH 2005b; ORNL 2010) 706

30.9 Pharmacovigilance (EMA 2011b, 2015, 2021; Eudro n.d.; FDA 2005c, 2005d) 709

30.10 FDA’s Predictive Toxicology Roadmap (FDA 2017, 2020) 711

References 711

Glossary 713

Appendix 716

31 Regulatory Science Initiatives for Advancing Public Health 719

31.1 Introduction 719

31.2 Advancing Regulatory Science for Public Health – A Framework for FDA’s Regulatory Science Initiatives (FDA 2010) 719

31.3 Advancing Regulatory Science at FDA – A Strategic Plan (FDA 2018b, 2018c, 2018d, 2018e, 2018f, 2018g, 2018h, 2018i, 2018j, 2018k, 2018l) 719

31.4 A Collaborative Implementation Framework (FDA 2010, 2011, 2018n) 723

References 724

32 Medical Devices 726

32.1 Introduction (FDA 2018a, 2019a, 2020a) 726

32.2 Device Determination Steps (FDA 2019a, 2020a) 726

32.3 Classification and Regulatory Requirements (FDA 2018b, 2020b) 727

32.4 Current Good Manufacturing Practices (CGMPs) and Quality System Regulation (QSR Regulation) Requirements 729

32.5 Medical Device Complaint Reporting and Recalls (FDA 2019h, 2019i) 731

References 731

Glossary 732

33 Combination Products 735

33.1 Introduction (FDA 2018, 2019e, 2020) 735

33.2 Product Jurisdiction/Assignment of Combination and Non-Combination Products (FDA 2019a, 2020) 736

33.3 Premarket and Marketing Applications (21 CFR Parts 312 and 812) (FDA 2019b, 2019c, 2020) 736

33.4 Current Good Manufacturing Practice – Subpart A (21CFR4) (FDA 2019d) 737

33.5 Postmarkeing Safety Reporting for Combination Products [21CFR4/Part 4 Regulation of Combination Products/Subpart B] (FDA 2019d) 737

References 738

33.A Appendix 739

34 Dietary Supplements 740

34.1 Introduction (FDA 2017a, 2019a, 2019b) 740

34.2 Dietary Ingredients (FDA 2019a, 2019b, 2019c) 740

34.3 Dietary Supplement Ingredient Advisory List (FDA 2019d) 741

34.4 DS Labeling: Claims Types and Requirements (FDA 2017b, 2018, 2019e) 741

34.5 Current Good Manufacturing Practice in Manufacturing, Packaging, Lableing, or Holding Operations for Dietary Supplements (21 CFR Part 111) (FDA 2019f) 741

34.6 FDA Inspection and Regulatory Actions (see – 21.3 FDA Inspection and Regulatory Actions – see Chapter 21 for details) 745

References 745

Glossary 745

34.A Appendix 746

35 Animal Drugs and Devices 751

35.1 FDA Center For Veterinary Medicine (CVM) (FDA 2019a) 751

35.2 Animal Drug Availability Act of 1996 (FDA 2019b) 751

35.3 Development and Approval Process (FDA 2017, 2020a) 752

35.4 CGMP and Others Compliance Requirements 756

35.5 Animal Drug Manufacturing Inspection – Pre-Approval (FDA 2006) 756

35.6 PostMarketing Survellance (FDA 2017, 2019d, 2020a) 756

References 757

Index 759