Integrated Pharmaceutics

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 <795> 2020: U.S.P <797> 2020); U.S.P. <1191> 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. <797> 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. <797> 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. <795> 2020; U.S.P. <797> 2020; WA 2020a, 2020b) 537 22.8 Patient Counseling (U.S.P. <795> 2020; U.S.P. <797> 2020; WA 2020a, 2020b) 537 22.9 Patient Monitoring and Adverse Events Reporting (U.S.P. <797> 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. <1058> 2019a; FDA 2010) 676 29.6 Validation of Analytical Procedures (U.S.P. <1225> 2019b; FDA 2000, 2015, 2019b) 679 29.7 Stability Testing of New Drug Substances and Products (U.S.P. <1150> 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