Antoine Al-Achi, PhD, is a Professor of Pharmaceutical Sciences at the College of Pharmacy & Health Sciences at Campbell University in North Carolina. He is also a former track head of the Industrial Pharmacy graduate major and former Head of the Formulation Development Division of Campbell’s Pharmaceutical Sciences Institute. Mali Ram Gupta, PhD, is an Associate Professor Emeritus of Pharmaceutical Sciences and Director of Pharmaceutical Education & Research (PERC) in the College of Pharmacy & Health Sciences Campbell University. Prior to joining Campbell in 2005, he spent over 25 years managing QA/QC departments of various pharma, cosmetic, and diagnostic companies. William Craig Stagner, PhD, is a Professor Emeritus of Pharmaceutical Sciences at the College of Pharmacy & Health Sciences Campbell University. In his time at Glaxo Research Institute (1987-95), he established the Pharmaceutics Department.

• Foreword to Second Edition xvForeword to First Edition xviPreface to Second Edition xviiPreface to First Edition xviiiAbout the Companion Website xxPart I Applied Preformulation 11 Mathematical Concepts 31.1 Introduction 31.2 Significant Figures and Rounding off Numbers 31.3 The Simple Linear Relationship 41.4 Exponential Rules 61.5 Logarithmic Rules 61.6 Differential Equations 71.7 Expanding and Reducing Formulas 91.8 Weights and Measures 92 Thermodynamics 112.1 Introduction 112.2 The Zeroth Law of Thermodynamics 112.3 The First Law of Thermodynamics 112.4 The Second Law of Thermodynamics 122.5 The Third Law of Thermodynamics 132.6 Polymorphism 132.7 Physical Stability of Crystal Forms 142.8 Solubility 143 Solubility and Dissolution 183.1 Introduction 183.2 Methods of API Solubility Enhancement 193.3 Nonionic, Ionic, and Acid–Base Concepts Related to Solubility and Dissolution 293.4 The Solubility of Gas in Liquid 293.5 The Solubility of Liquid in Liquid 303.6 The Solubility of Solid in Liquid 303.7 Disintegration and Dissolution 313.8 Concentration Units 343.9 The Partition Coefficient 393.10 Concluding Remarks 414 Biological Aspects of Formulations 464.1 Introduction 464.2 Bioavailability and Bioequivalence 464.3 Protocols for Determining Bioequivalence 484.4 Bioequivalence Procedure 494.5 FDA-Approved Methods for Bioequivalence Studies 494.6 Approaches to Improving Bioavailability 505 Interfacial Properties 545.1 Introduction 545.2 Liquid–Solid Interface 545.3 Liquid–Liquid Interface 555.4 Dosage-Form Applications 555.5 Case Study: HLB Determination 585.6 Case Study: Determination of Required HLB (rHLB) 586 Adsorption Phenomenon 606.1 Introduction 606.2 Adsorption on Filters 666.3 Adsorption of Proteins 667 Rheological Principles 697.1 Introduction 697.2 Newtonian Systems 697.3 Non-Newtonian Systems 707.4 Viscoelasticity 727.5 Reynolds Number 747.6 Concluding Remarks 768 Chemical Stability and Shelf-Life Determination 788.1 Introduction 788.2 Shelf-Life Determination 798.3 Stability of Biotechnology Products 848.4 Compounded Products and Their Beyond-Use Dates 869 Particle Science 1089.1 Introduction 1089.2 Miromeritics 108.3 Micronization 1139.4 Particle Size Preparation and Reduction for Pulmonary Delivery 1149.5 Polymeric Particulate Matter 1159.6 Nanoparticles 1169.7 Segregation of Particles 1219.8 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 12210 Basic Statistics and Design of Experimental Concepts 13010.1 Descriptive Statistics 13010.2 Inferential Statistics 13110.3 Statistical Applications in Quality Control Testing 13510.4 Design of Experiment 13610.5 Multivariate Analysis (MVA) 14010.6 Reliability and Validity Assessment 15211 Formulation Development Concepts 15711.1 Preformulation 15711.2 Scale-up Considerations 16411.3 Combination Products 16811.4 Rate-Controlled Drug Delivery 17011.5 Drug Delivery Technologies for Improving Oral Delivery 17211.6 Drug Delivery Technologies for Improving Transmucosal Delivery 17311.7 Drug Delivery Technologies for Transdermal Delivery 17311.8 Special Considerations for Biotechnology and Protein Delivery Systems 17411.9 Drug–Excipient and Excipient–Excipient Interactions 17711.10 The Presence of Contaminants in a Formulation 17811.11 Other Considerations 179Part II Product Design 18712 The Product Design Process 18912.1 Introduction 18912.2 Formulation Design 19112.3 Process Design 19412.4 Container Closure System Design 19513 Tablet Product Design 21413.1 Introduction 21413.2 Formulation Design 22013.3 Process Design 22513.4 Container Closure System Design 24913.5 Risk Management 25513.6 Attribute Tests 25613.7 New Drug Application Stability Assessment 25714 Capsule Product Design 27414.1 Introduction 27414.2 Hard-Shell Capsules 27414.3 Soft-Shell Capsules 28814.4 Formulation and Process Optimization 29114.5 Container Closure System Design 29214.6 Risk Management 29214.7 Attribute Tests 29214.8 New Drug Application Stability Assessment 29315 Dispersed System Product Design 29815.1 Introduction 29815.2 Formulation Design 29815.3 Process Design 32215.4 Container Closure System Design 32515.5 Risk Management 32515.6 Attribute Tests 32615.7 New Drug Application Stability Assessment 32716 Aerosol Product Design 33616.1 Introduction 33616.2 Inhalation Formulation Design 33816.3 Nasal, Buccal, Lingual, and Sublingual Aerosol Formulation Design 35116.4 Container Closure System Design 35416.5 Risk Management 35616.6 Attribute Tests 35616.7 New Drug Application Stability Assessment 35917 Sterile Injectable Product Design 36917.1 Introduction 36917.2 Formulation Design 37017.3 Process Design 39317.4 Container Closure System Design 40417.5 Risk Management 40717.6 Attribute Tests 40717.7 New Drug Application Stability Assessment 40818 Ophthalmic Product Design 42618.1 Introduction – Eye Anatomy and Physiology 42618.2 Formulation Design 42918.3 Process Design 43618.4 Container Closure System Design 43618.5 Attribute Tests 43618.6 New Drug Application Stability Assessment 43619 Transdermal Product Design 44219.1 Introduction – Skin Anatomy and Physiology 44219.2 Formulation Design 44419.3 Conclusions 45720 Oral Modified-Release Product Design 46220.1 Introduction 46220.2 FDA and U.S.P. Nomenclature 46220.3 Modified-Release Mechanisms 46420.4 In Vitro–In Vivo Correlations (IVIVC) 46520.5 Coatings 46620.6 Matrix Systems 46720.7 Gastroretentive Devices 47020.8 Osmotic-Controlled Release Systems 47020.9 Conclusions 471Part III Regulatory Science 47521 Regulatory Practices and Guidelines 47721.1 Worldwide Regulatory Agencies 47721.2 Good Manufacturing Practice (GMP) 48421.3 FDA Inspection and Regulatory Actions (FDA 2020b, 2020d) 50322 Regulations for Compounding Pharmacies 52522.1 Introduction 52522.2 Sections 503A and 503B and Their Differences (FDA 2018a) 52622.3 Compounding Guidelines 52622.4 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) 52722.5 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.) 53222.6 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.) 53622.7 Verification (U.S.P. 2020; U.S.P. 2020; WA 2020a, 2020b) 53722.8 Patient Counseling (U.S.P. 2020; U.S.P. 2020; WA 2020a, 2020b) 53722.9 Patient Monitoring and Adverse Events Reporting (U.S.P. 2020; WA 2020b) 53722.10 Pharmacy Compounding Accreditation 53722.11 Compounding: Inspections, Recalls, and Other Actions (FDA 2018b; FDA 2018c) 53823 IND and NDA Phase-Appropriate New Drug Development Process 55423.1 Introduction 55423.2 Preclinical Development Overview (FDA 1998) 55523.3 Phase-Appropriate Clinical Trials Overview (FDA 1998) 55623.4 Investigational New Drugs 55823.5 Good Laboratory Practice for Nonclinical Laboratories Studies [21CFR58] (FDA 2020c) 56423.6 CGMP for Phase 1 Investigational Drugs – Guidance for Industry (FDA 2008) 56623.7 Good Clinical Practice [E6(R2)] Guidance for Industry (FDA 2016, 2018, 2019a) 56823.8 NDA Review Process (FDA 1998) 57024 Biological, Biosimilar, Generic, and OTC Products 58424.1 Biologicals (FDA 2015a, 2015b, 2016b 2018a, 2018b, 2019a, 2019b, 2019c, 2020a; EMA 2019) 58424.2 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) 58624.3 Generic Drugs (FDA 1998a, 2014b, 2017f, 2017g, 2018e, 2018g, 2019d) 58824.4 Over-the-Counter Drugs (FDA 1998b, 2016a, 2018g, 2019f, 2020e, 2020f, 2020g) 59325 Accelerated New Drug Approval and Expedited Access of New Therapies 60525.1 Introduction 60525.2 Expedited Review and Approval of New Therapies (HIV n.d.; IOM 1991; FDA 2009a, 2010a, 2011b, 2014) 60525.3 Expanded Access to New Therapies (HIV n.d.; FDA 2009a) 60725.4 Orphan Drugs (EMA n.d.-a, n.d.-b; WebMD n.d.; FDA 1998a, 2005a, 2018, 2018b, 2020c; IOM 2010) 60825.5 Pediatric Drugs (FDA 1998b, 2005b) 61025.6 Pediatric Drug Development and the Orphan Drug Act Incentives (FDA 2010c) 61225.7 Common EMEA/FDA Application for Orphan Medicinal Product Designation (EMA n.d.-a, n.d.-b; FDA 2009b; FDA 2018) 61226 Post–Drug Approval Activities 61726.1 Postmarket Requirements and Commitments (FDA 2016b, 2018f, 2020a, 2020e) 61726.2 Postapproval Manufacturing Changes (FDA 2018d, 2020b) 61826.3 Clinical Phase 4 Studies: Postmarketing Surveillance and Risk Assessment (FDA 2018d, 2019b) 61926.4 Prescription Drug Advertising and Promotional Labeling Direct to Consumers (FDA 1998c) 62227 Drug Master Files, EU Dossiers, and API GMP Guidance 62727.1 Drug Master Files (FDA 2001, 2011a, 2011b, 2011c, 2011d, 2011e) 62727.2 European Marketing Authorization Dossiers 63327.3 Good Manufactruing Practice (GMP) Guidance for Active Pharmaceutical Ingredients (Q7) (FDA 2016) 63628 Commissioning and Qualification 64628.1 Regulatory Requirements (Health Canada 2009; EU 2015; FDA 2017, 2018a, 2020) 64628.2 Preliminary C&Q Activities 64728.3 Commissioning 64928.4 Qualification and Validation 65128.5 Qualification Protocols (ISPE 2001; Health Canada 2009; PIC/S 2018) 65328.6 Process Validation (FDA 2014, 2019; PIC/S 2018) 65728.7 Cleaning Validation (Health Canada 2008; FDA 2014, 2017; PIC/S 2018) 65928.8 Computer Systems Validation (ISPE 2001; EU 2011) 66028.9 Change Control (EU 2015; PIC/S 2018) 66028.10 Revalidation (CDRH 1995; EU 2015; FDA 2015; PIC/S 2018) 66129 Quality Systems and Controls 66629.1 Pharmaceutical Quality System (FDA 2019a) 66629.2 Quality Systems Approach to CGMP Regulations 66929.3 Inspection of Pharmaceutical Quality Control Laboratories (FDA 2014) 67229.4 Pharmacopeias (U.S.P. 2014) 67329.5 Analytical Instrument Qualification (U.S.P. 2019a; FDA 2010) 67629.6 Validation of Analytical Procedures (U.S.P. 2019b; FDA 2000, 2015, 2019b) 67929.7 Stability Testing of New Drug Substances and Products (U.S.P. 2006; ICH 1996; FDA 2018b, 2018c, 2018d) 68029.8 Electronic Records; Electronic Signatures (Part 11) (FDA 2019) 68230 Safety, Toxicology, and Pharmacogenomics 69630.1 Nonclinical Safety Studies (ICH 2009; FDA 2010) 69630.2 Safety Pharmacology Studies (ICH 2000) 69730.3 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals – (FDA 1997; EMA 2011a) 70030.4 Carcinogenicity Studies of Pharmaceuticals (ICH 1995) 70130.5 Genotoxicity Testing (ICH 1998, 2008) 70230.6 Immunotoxicity Studies (ICH 2005b) 70430.7 Safety Reporting Requirements 70530.8 Pharmacogenomics (NIGMS 2005; ICH 2005b; ORNL 2010) 70630.9 Pharmacovigilance (EMA 2011b, 2015, 2021; Eudro n.d.; FDA 2005c, 2005d) 70930.10 FDA's Predictive Toxicology Roadmap (FDA 2017, 2020) 71131 Regulatory Science Initiatives for Advancing Public Health 71931.1 Introduction 71931.2 Advancing Regulatory Science for Public Health – A Framework for FDA's Regulatory Science Initiatives (FDA 2010) 71931.3 Advancing Regulatory Science at FDA – A Strategic Plan (FDA 2018b, 2018c, 2018d, 2018e, 2018f, 2018g, 2018h, 2018i, 2018j, 2018k, 2018l) 71931.4 A Collaborative Implementation Framework (FDA 2010, 2011, 2018n) 72332 Medical Devices 72632.1 Introduction (FDA 2018a, 2019a, 2020a) 72632.2 Device Determination Steps (FDA 2019a, 2020a) 72632.3 Classification and Regulatory Requirements (FDA 2018b, 2020b) 72732.4 Current Good Manufacturing Practices (CGMPs) and Quality System Regulation (QSR Regulation) Requirements 72932.5 Medical Device Complaint Reporting and Recalls (FDA 2019h, 2019i) 73133 Combination Products 73533.1 Introduction (FDA 2018, 2019e, 2020) 73533.2 Product Jurisdiction/Assignment of Combination and Non-Combination Products (FDA 2019a, 2020) 73633.3 Premarket and Marketing Applications (21 CFR Parts 312 and 812) (FDA 2019b, 2019c, 2020) 73633.4 Current Good Manufacturing Practice – Subpart A (21CFR4) (FDA 2019d) 73733.5 Postmarkeing Safety Reporting for Combination Products [21CFR4/Part 4 Regulation of Combination Products/Subpart B] (FDA 2019d) 73734 Dietary Supplements 74034.1 Introduction (FDA 2017a, 2019a, 2019b) 74034.2 Dietary Ingredients (FDA 2019a, 2019b, 2019c) 74034.3 Dietary Supplement Ingredient Advisory List (FDA 2019d) 74134.4 DS Labeling: Claims Types and Requirements (FDA 2017b, 2018, 2019e) 74134.5 Current Good Manufacturing Practice in Manufacturing, Packaging, Lableing, or Holding Operations for Dietary Supplements (21 CFR Part 111) (FDA 2019f) 74134.6 FDA Inspection and Regulatory Actions (see – 21.3 FDA Inspection and Regulatory Actions – see Chapter 21 for details) 74535 Animal Drugs and Devices 75135.1 FDA Center For Veterinary Medicine (CVM) (FDA 2019a) 75135.2 Animal Drug Availability Act of 1996 (FDA 2019b) 75135.3 Development and Approval Process (FDA 2017, 2020a) 75235.4 CGMP and Others Compliance Requirements 75635.5 Animal Drug Manufacturing Inspection – Pre-Approval (FDA 2006) 75635.6 PostMarketing Survellance (FDA 2017, 2019d, 2020a) 756References 757Index 759

Antoine Al-Achi, PhD, is a Professor of Pharmaceutical Sciences at the College of Pharmacy & Health Sciences at Campbell University in North Carolina. He is also a former track head of the Industrial Pharmacy graduate major and former Head of the Formulation Development Division of Campbell’s Pharmaceutical Sciences Institute. Mali Ram Gupta, PhD, is an Associate Professor Emeritus of Pharmaceutical Sciences and Director of Pharmaceutical Education & Research (PERC) in the College of Pharmacy & Health Sciences Campbell University. Prior to joining Campbell in 2005, he spent over 25 years managing QA/QC departments of various pharma, cosmetic, and diagnostic companies. William Craig Stagner, PhD, is a Professor Emeritus of Pharmaceutical Sciences at the College of Pharmacy & Health Sciences Campbell University. In his time at Glaxo Research Institute (1987-95), he established the Pharmaceutics Department.

• Foreword to Second Edition xvForeword to First Edition xviPreface to Second Edition xviiPreface to First Edition xviiiAbout the Companion Website xxPart I Applied Preformulation 11 Mathematical Concepts 31.1 Introduction 31.2 Significant Figures and Rounding off Numbers 31.3 The Simple Linear Relationship 41.4 Exponential Rules 61.5 Logarithmic Rules 61.6 Differential Equations 71.7 Expanding and Reducing Formulas 91.8 Weights and Measures 92 Thermodynamics 112.1 Introduction 112.2 The Zeroth Law of Thermodynamics 112.3 The First Law of Thermodynamics 112.4 The Second Law of Thermodynamics 122.5 The Third Law of Thermodynamics 132.6 Polymorphism 132.7 Physical Stability of Crystal Forms 142.8 Solubility 143 Solubility and Dissolution 183.1 Introduction 183.2 Methods of API Solubility Enhancement 193.3 Nonionic, Ionic, and Acid–Base Concepts Related to Solubility and Dissolution 293.4 The Solubility of Gas in Liquid 293.5 The Solubility of Liquid in Liquid 303.6 The Solubility of Solid in Liquid 303.7 Disintegration and Dissolution 313.8 Concentration Units 343.9 The Partition Coefficient 393.10 Concluding Remarks 414 Biological Aspects of Formulations 464.1 Introduction 464.2 Bioavailability and Bioequivalence 464.3 Protocols for Determining Bioequivalence 484.4 Bioequivalence Procedure 494.5 FDA-Approved Methods for Bioequivalence Studies 494.6 Approaches to Improving Bioavailability 505 Interfacial Properties 545.1 Introduction 545.2 Liquid–Solid Interface 545.3 Liquid–Liquid Interface 555.4 Dosage-Form Applications 555.5 Case Study: HLB Determination 585.6 Case Study: Determination of Required HLB (rHLB) 586 Adsorption Phenomenon 606.1 Introduction 606.2 Adsorption on Filters 666.3 Adsorption of Proteins 667 Rheological Principles 697.1 Introduction 697.2 Newtonian Systems 697.3 Non-Newtonian Systems 707.4 Viscoelasticity 727.5 Reynolds Number 747.6 Concluding Remarks 768 Chemical Stability and Shelf-Life Determination 788.1 Introduction 788.2 Shelf-Life Determination 798.3 Stability of Biotechnology Products 848.4 Compounded Products and Their Beyond-Use Dates 869 Particle Science 1089.1 Introduction 1089.2 Miromeritics 108.3 Micronization 1139.4 Particle Size Preparation and Reduction for Pulmonary Delivery 1149.5 Polymeric Particulate Matter 1159.6 Nanoparticles 1169.7 Segregation of Particles 1219.8 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 12210 Basic Statistics and Design of Experimental Concepts 13010.1 Descriptive Statistics 13010.2 Inferential Statistics 13110.3 Statistical Applications in Quality Control Testing 13510.4 Design of Experiment 13610.5 Multivariate Analysis (MVA) 14010.6 Reliability and Validity Assessment 15211 Formulation Development Concepts 15711.1 Preformulation 15711.2 Scale-up Considerations 16411.3 Combination Products 16811.4 Rate-Controlled Drug Delivery 17011.5 Drug Delivery Technologies for Improving Oral Delivery 17211.6 Drug Delivery Technologies for Improving Transmucosal Delivery 17311.7 Drug Delivery Technologies for Transdermal Delivery 17311.8 Special Considerations for Biotechnology and Protein Delivery Systems 17411.9 Drug–Excipient and Excipient–Excipient Interactions 17711.10 The Presence of Contaminants in a Formulation 17811.11 Other Considerations 179Part II Product Design 18712 The Product Design Process 18912.1 Introduction 18912.2 Formulation Design 19112.3 Process Design 19412.4 Container Closure System Design 19513 Tablet Product Design 21413.1 Introduction 21413.2 Formulation Design 22013.3 Process Design 22513.4 Container Closure System Design 24913.5 Risk Management 25513.6 Attribute Tests 25613.7 New Drug Application Stability Assessment 25714 Capsule Product Design 27414.1 Introduction 27414.2 Hard-Shell Capsules 27414.3 Soft-Shell Capsules 28814.4 Formulation and Process Optimization 29114.5 Container Closure System Design 29214.6 Risk Management 29214.7 Attribute Tests 29214.8 New Drug Application Stability Assessment 29315 Dispersed System Product Design 29815.1 Introduction 29815.2 Formulation Design 29815.3 Process Design 32215.4 Container Closure System Design 32515.5 Risk Management 32515.6 Attribute Tests 32615.7 New Drug Application Stability Assessment 32716 Aerosol Product Design 33616.1 Introduction 33616.2 Inhalation Formulation Design 33816.3 Nasal, Buccal, Lingual, and Sublingual Aerosol Formulation Design 35116.4 Container Closure System Design 35416.5 Risk Management 35616.6 Attribute Tests 35616.7 New Drug Application Stability Assessment 35917 Sterile Injectable Product Design 36917.1 Introduction 36917.2 Formulation Design 37017.3 Process Design 39317.4 Container Closure System Design 40417.5 Risk Management 40717.6 Attribute Tests 40717.7 New Drug Application Stability Assessment 40818 Ophthalmic Product Design 42618.1 Introduction – Eye Anatomy and Physiology 42618.2 Formulation Design 42918.3 Process Design 43618.4 Container Closure System Design 43618.5 Attribute Tests 43618.6 New Drug Application Stability Assessment 43619 Transdermal Product Design 44219.1 Introduction – Skin Anatomy and Physiology 44219.2 Formulation Design 44419.3 Conclusions 45720 Oral Modified-Release Product Design 46220.1 Introduction 46220.2 FDA and U.S.P. Nomenclature 46220.3 Modified-Release Mechanisms 46420.4 In Vitro–In Vivo Correlations (IVIVC) 46520.5 Coatings 46620.6 Matrix Systems 46720.7 Gastroretentive Devices 47020.8 Osmotic-Controlled Release Systems 47020.9 Conclusions 471Part III Regulatory Science 47521 Regulatory Practices and Guidelines 47721.1 Worldwide Regulatory Agencies 47721.2 Good Manufacturing Practice (GMP) 48421.3 FDA Inspection and Regulatory Actions (FDA 2020b, 2020d) 50322 Regulations for Compounding Pharmacies 52522.1 Introduction 52522.2 Sections 503A and 503B and Their Differences (FDA 2018a) 52622.3 Compounding Guidelines 52622.4 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) 52722.5 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.) 53222.6 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.) 53622.7 Verification (U.S.P. 2020; U.S.P. 2020; WA 2020a, 2020b) 53722.8 Patient Counseling (U.S.P. 2020; U.S.P. 2020; WA 2020a, 2020b) 53722.9 Patient Monitoring and Adverse Events Reporting (U.S.P. 2020; WA 2020b) 53722.10 Pharmacy Compounding Accreditation 53722.11 Compounding: Inspections, Recalls, and Other Actions (FDA 2018b; FDA 2018c) 53823 IND and NDA Phase-Appropriate New Drug Development Process 55423.1 Introduction 55423.2 Preclinical Development Overview (FDA 1998) 55523.3 Phase-Appropriate Clinical Trials Overview (FDA 1998) 55623.4 Investigational New Drugs 55823.5 Good Laboratory Practice for Nonclinical Laboratories Studies [21CFR58] (FDA 2020c) 56423.6 CGMP for Phase 1 Investigational Drugs – Guidance for Industry (FDA 2008) 56623.7 Good Clinical Practice [E6(R2)] Guidance for Industry (FDA 2016, 2018, 2019a) 56823.8 NDA Review Process (FDA 1998) 57024 Biological, Biosimilar, Generic, and OTC Products 58424.1 Biologicals (FDA 2015a, 2015b, 2016b 2018a, 2018b, 2019a, 2019b, 2019c, 2020a; EMA 2019) 58424.2 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) 58624.3 Generic Drugs (FDA 1998a, 2014b, 2017f, 2017g, 2018e, 2018g, 2019d) 58824.4 Over-the-Counter Drugs (FDA 1998b, 2016a, 2018g, 2019f, 2020e, 2020f, 2020g) 59325 Accelerated New Drug Approval and Expedited Access of New Therapies 60525.1 Introduction 60525.2 Expedited Review and Approval of New Therapies (HIV n.d.; IOM 1991; FDA 2009a, 2010a, 2011b, 2014) 60525.3 Expanded Access to New Therapies (HIV n.d.; FDA 2009a) 60725.4 Orphan Drugs (EMA n.d.-a, n.d.-b; WebMD n.d.; FDA 1998a, 2005a, 2018, 2018b, 2020c; IOM 2010) 60825.5 Pediatric Drugs (FDA 1998b, 2005b) 61025.6 Pediatric Drug Development and the Orphan Drug Act Incentives (FDA 2010c) 61225.7 Common EMEA/FDA Application for Orphan Medicinal Product Designation (EMA n.d.-a, n.d.-b; FDA 2009b; FDA 2018) 61226 Post–Drug Approval Activities 61726.1 Postmarket Requirements and Commitments (FDA 2016b, 2018f, 2020a, 2020e) 61726.2 Postapproval Manufacturing Changes (FDA 2018d, 2020b) 61826.3 Clinical Phase 4 Studies: Postmarketing Surveillance and Risk Assessment (FDA 2018d, 2019b) 61926.4 Prescription Drug Advertising and Promotional Labeling Direct to Consumers (FDA 1998c) 62227 Drug Master Files, EU Dossiers, and API GMP Guidance 62727.1 Drug Master Files (FDA 2001, 2011a, 2011b, 2011c, 2011d, 2011e) 62727.2 European Marketing Authorization Dossiers 63327.3 Good Manufactruing Practice (GMP) Guidance for Active Pharmaceutical Ingredients (Q7) (FDA 2016) 63628 Commissioning and Qualification 64628.1 Regulatory Requirements (Health Canada 2009; EU 2015; FDA 2017, 2018a, 2020) 64628.2 Preliminary C&Q Activities 64728.3 Commissioning 64928.4 Qualification and Validation 65128.5 Qualification Protocols (ISPE 2001; Health Canada 2009; PIC/S 2018) 65328.6 Process Validation (FDA 2014, 2019; PIC/S 2018) 65728.7 Cleaning Validation (Health Canada 2008; FDA 2014, 2017; PIC/S 2018) 65928.8 Computer Systems Validation (ISPE 2001; EU 2011) 66028.9 Change Control (EU 2015; PIC/S 2018) 66028.10 Revalidation (CDRH 1995; EU 2015; FDA 2015; PIC/S 2018) 66129 Quality Systems and Controls 66629.1 Pharmaceutical Quality System (FDA 2019a) 66629.2 Quality Systems Approach to CGMP Regulations 66929.3 Inspection of Pharmaceutical Quality Control Laboratories (FDA 2014) 67229.4 Pharmacopeias (U.S.P. 2014) 67329.5 Analytical Instrument Qualification (U.S.P. 2019a; FDA 2010) 67629.6 Validation of Analytical Procedures (U.S.P. 2019b; FDA 2000, 2015, 2019b) 67929.7 Stability Testing of New Drug Substances and Products (U.S.P. 2006; ICH 1996; FDA 2018b, 2018c, 2018d) 68029.8 Electronic Records; Electronic Signatures (Part 11) (FDA 2019) 68230 Safety, Toxicology, and Pharmacogenomics 69630.1 Nonclinical Safety Studies (ICH 2009; FDA 2010) 69630.2 Safety Pharmacology Studies (ICH 2000) 69730.3 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals – (FDA 1997; EMA 2011a) 70030.4 Carcinogenicity Studies of Pharmaceuticals (ICH 1995) 70130.5 Genotoxicity Testing (ICH 1998, 2008) 70230.6 Immunotoxicity Studies (ICH 2005b) 70430.7 Safety Reporting Requirements 70530.8 Pharmacogenomics (NIGMS 2005; ICH 2005b; ORNL 2010) 70630.9 Pharmacovigilance (EMA 2011b, 2015, 2021; Eudro n.d.; FDA 2005c, 2005d) 70930.10 FDA's Predictive Toxicology Roadmap (FDA 2017, 2020) 71131 Regulatory Science Initiatives for Advancing Public Health 71931.1 Introduction 71931.2 Advancing Regulatory Science for Public Health – A Framework for FDA's Regulatory Science Initiatives (FDA 2010) 71931.3 Advancing Regulatory Science at FDA – A Strategic Plan (FDA 2018b, 2018c, 2018d, 2018e, 2018f, 2018g, 2018h, 2018i, 2018j, 2018k, 2018l) 71931.4 A Collaborative Implementation Framework (FDA 2010, 2011, 2018n) 72332 Medical Devices 72632.1 Introduction (FDA 2018a, 2019a, 2020a) 72632.2 Device Determination Steps (FDA 2019a, 2020a) 72632.3 Classification and Regulatory Requirements (FDA 2018b, 2020b) 72732.4 Current Good Manufacturing Practices (CGMPs) and Quality System Regulation (QSR Regulation) Requirements 72932.5 Medical Device Complaint Reporting and Recalls (FDA 2019h, 2019i) 73133 Combination Products 73533.1 Introduction (FDA 2018, 2019e, 2020) 73533.2 Product Jurisdiction/Assignment of Combination and Non-Combination Products (FDA 2019a, 2020) 73633.3 Premarket and Marketing Applications (21 CFR Parts 312 and 812) (FDA 2019b, 2019c, 2020) 73633.4 Current Good Manufacturing Practice – Subpart A (21CFR4) (FDA 2019d) 73733.5 Postmarkeing Safety Reporting for Combination Products [21CFR4/Part 4 Regulation of Combination Products/Subpart B] (FDA 2019d) 73734 Dietary Supplements 74034.1 Introduction (FDA 2017a, 2019a, 2019b) 74034.2 Dietary Ingredients (FDA 2019a, 2019b, 2019c) 74034.3 Dietary Supplement Ingredient Advisory List (FDA 2019d) 74134.4 DS Labeling: Claims Types and Requirements (FDA 2017b, 2018, 2019e) 74134.5 Current Good Manufacturing Practice in Manufacturing, Packaging, Lableing, or Holding Operations for Dietary Supplements (21 CFR Part 111) (FDA 2019f) 74134.6 FDA Inspection and Regulatory Actions (see – 21.3 FDA Inspection and Regulatory Actions – see Chapter 21 for details) 74535 Animal Drugs and Devices 75135.1 FDA Center For Veterinary Medicine (CVM) (FDA 2019a) 75135.2 Animal Drug Availability Act of 1996 (FDA 2019b) 75135.3 Development and Approval Process (FDA 2017, 2020a) 75235.4 CGMP and Others Compliance Requirements 75635.5 Animal Drug Manufacturing Inspection – Pre-Approval (FDA 2006) 75635.6 PostMarketing Survellance (FDA 2017, 2019d, 2020a) 756References 757Index 759

Antoine Al-Achi, PhD, is a Professor of Pharmaceutical Sciences at the College of Pharmacy & Health Sciences at Campbell University in North Carolina. He is also a former track head of the Industrial Pharmacy graduate major and former Head of the Formulation Development Division of Campbell’s Pharmaceutical Sciences Institute. Mali Ram Gupta, PhD, is an Associate Professor Emeritus of Pharmaceutical Sciences and Director of Pharmaceutical Education & Research (PERC) in the College of Pharmacy & Health Sciences Campbell University. Prior to joining Campbell in 2005, he spent over 25 years managing QA/QC departments of various pharma, cosmetic, and diagnostic companies. William Craig Stagner, PhD, is a Professor Emeritus of Pharmaceutical Sciences at the College of Pharmacy & Health Sciences Campbell University. In his time at Glaxo Research Institute (1987-95), he established the Pharmaceutics Department.

• Foreword to Second Edition xvForeword to First Edition xviPreface to Second Edition xviiPreface to First Edition xviiiAbout the Companion Website xxPart I Applied Preformulation 11 Mathematical Concepts 31.1 Introduction 31.2 Significant Figures and Rounding off Numbers 31.3 The Simple Linear Relationship 41.4 Exponential Rules 61.5 Logarithmic Rules 61.6 Differential Equations 71.7 Expanding and Reducing Formulas 91.8 Weights and Measures 92 Thermodynamics 112.1 Introduction 112.2 The Zeroth Law of Thermodynamics 112.3 The First Law of Thermodynamics 112.4 The Second Law of Thermodynamics 122.5 The Third Law of Thermodynamics 132.6 Polymorphism 132.7 Physical Stability of Crystal Forms 142.8 Solubility 143 Solubility and Dissolution 183.1 Introduction 183.2 Methods of API Solubility Enhancement 193.3 Nonionic, Ionic, and Acid–Base Concepts Related to Solubility and Dissolution 293.4 The Solubility of Gas in Liquid 293.5 The Solubility of Liquid in Liquid 303.6 The Solubility of Solid in Liquid 303.7 Disintegration and Dissolution 313.8 Concentration Units 343.9 The Partition Coefficient 393.10 Concluding Remarks 414 Biological Aspects of Formulations 464.1 Introduction 464.2 Bioavailability and Bioequivalence 464.3 Protocols for Determining Bioequivalence 484.4 Bioequivalence Procedure 494.5 FDA-Approved Methods for Bioequivalence Studies 494.6 Approaches to Improving Bioavailability 505 Interfacial Properties 545.1 Introduction 545.2 Liquid–Solid Interface 545.3 Liquid–Liquid Interface 555.4 Dosage-Form Applications 555.5 Case Study: HLB Determination 585.6 Case Study: Determination of Required HLB (rHLB) 586 Adsorption Phenomenon 606.1 Introduction 606.2 Adsorption on Filters 666.3 Adsorption of Proteins 667 Rheological Principles 697.1 Introduction 697.2 Newtonian Systems 697.3 Non-Newtonian Systems 707.4 Viscoelasticity 727.5 Reynolds Number 747.6 Concluding Remarks 768 Chemical Stability and Shelf-Life Determination 788.1 Introduction 788.2 Shelf-Life Determination 798.3 Stability of Biotechnology Products 848.4 Compounded Products and Their Beyond-Use Dates 869 Particle Science 1089.1 Introduction 1089.2 Miromeritics 108.3 Micronization 1139.4 Particle Size Preparation and Reduction for Pulmonary Delivery 1149.5 Polymeric Particulate Matter 1159.6 Nanoparticles 1169.7 Segregation of Particles 1219.8 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 12210 Basic Statistics and Design of Experimental Concepts 13010.1 Descriptive Statistics 13010.2 Inferential Statistics 13110.3 Statistical Applications in Quality Control Testing 13510.4 Design of Experiment 13610.5 Multivariate Analysis (MVA) 14010.6 Reliability and Validity Assessment 15211 Formulation Development Concepts 15711.1 Preformulation 15711.2 Scale-up Considerations 16411.3 Combination Products 16811.4 Rate-Controlled Drug Delivery 17011.5 Drug Delivery Technologies for Improving Oral Delivery 17211.6 Drug Delivery Technologies for Improving Transmucosal Delivery 17311.7 Drug Delivery Technologies for Transdermal Delivery 17311.8 Special Considerations for Biotechnology and Protein Delivery Systems 17411.9 Drug–Excipient and Excipient–Excipient Interactions 17711.10 The Presence of Contaminants in a Formulation 17811.11 Other Considerations 179Part II Product Design 18712 The Product Design Process 18912.1 Introduction 18912.2 Formulation Design 19112.3 Process Design 19412.4 Container Closure System Design 19513 Tablet Product Design 21413.1 Introduction 21413.2 Formulation Design 22013.3 Process Design 22513.4 Container Closure System Design 24913.5 Risk Management 25513.6 Attribute Tests 25613.7 New Drug Application Stability Assessment 25714 Capsule Product Design 27414.1 Introduction 27414.2 Hard-Shell Capsules 27414.3 Soft-Shell Capsules 28814.4 Formulation and Process Optimization 29114.5 Container Closure System Design 29214.6 Risk Management 29214.7 Attribute Tests 29214.8 New Drug Application Stability Assessment 29315 Dispersed System Product Design 29815.1 Introduction 29815.2 Formulation Design 29815.3 Process Design 32215.4 Container Closure System Design 32515.5 Risk Management 32515.6 Attribute Tests 32615.7 New Drug Application Stability Assessment 32716 Aerosol Product Design 33616.1 Introduction 33616.2 Inhalation Formulation Design 33816.3 Nasal, Buccal, Lingual, and Sublingual Aerosol Formulation Design 35116.4 Container Closure System Design 35416.5 Risk Management 35616.6 Attribute Tests 35616.7 New Drug Application Stability Assessment 35917 Sterile Injectable Product Design 36917.1 Introduction 36917.2 Formulation Design 37017.3 Process Design 39317.4 Container Closure System Design 40417.5 Risk Management 40717.6 Attribute Tests 40717.7 New Drug Application Stability Assessment 40818 Ophthalmic Product Design 42618.1 Introduction – Eye Anatomy and Physiology 42618.2 Formulation Design 42918.3 Process Design 43618.4 Container Closure System Design 43618.5 Attribute Tests 43618.6 New Drug Application Stability Assessment 43619 Transdermal Product Design 44219.1 Introduction – Skin Anatomy and Physiology 44219.2 Formulation Design 44419.3 Conclusions 45720 Oral Modified-Release Product Design 46220.1 Introduction 46220.2 FDA and U.S.P. Nomenclature 46220.3 Modified-Release Mechanisms 46420.4 In Vitro–In Vivo Correlations (IVIVC) 46520.5 Coatings 46620.6 Matrix Systems 46720.7 Gastroretentive Devices 47020.8 Osmotic-Controlled Release Systems 47020.9 Conclusions 471Part III Regulatory Science 47521 Regulatory Practices and Guidelines 47721.1 Worldwide Regulatory Agencies 47721.2 Good Manufacturing Practice (GMP) 48421.3 FDA Inspection and Regulatory Actions (FDA 2020b, 2020d) 50322 Regulations for Compounding Pharmacies 52522.1 Introduction 52522.2 Sections 503A and 503B and Their Differences (FDA 2018a) 52622.3 Compounding Guidelines 52622.4 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) 52722.5 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.) 53222.6 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.) 53622.7 Verification (U.S.P. 2020; U.S.P. 2020; WA 2020a, 2020b) 53722.8 Patient Counseling (U.S.P. 2020; U.S.P. 2020; WA 2020a, 2020b) 53722.9 Patient Monitoring and Adverse Events Reporting (U.S.P. 2020; WA 2020b) 53722.10 Pharmacy Compounding Accreditation 53722.11 Compounding: Inspections, Recalls, and Other Actions (FDA 2018b; FDA 2018c) 53823 IND and NDA Phase-Appropriate New Drug Development Process 55423.1 Introduction 55423.2 Preclinical Development Overview (FDA 1998) 55523.3 Phase-Appropriate Clinical Trials Overview (FDA 1998) 55623.4 Investigational New Drugs 55823.5 Good Laboratory Practice for Nonclinical Laboratories Studies [21CFR58] (FDA 2020c) 56423.6 CGMP for Phase 1 Investigational Drugs – Guidance for Industry (FDA 2008) 56623.7 Good Clinical Practice [E6(R2)] Guidance for Industry (FDA 2016, 2018, 2019a) 56823.8 NDA Review Process (FDA 1998) 57024 Biological, Biosimilar, Generic, and OTC Products 58424.1 Biologicals (FDA 2015a, 2015b, 2016b 2018a, 2018b, 2019a, 2019b, 2019c, 2020a; EMA 2019) 58424.2 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) 58624.3 Generic Drugs (FDA 1998a, 2014b, 2017f, 2017g, 2018e, 2018g, 2019d) 58824.4 Over-the-Counter Drugs (FDA 1998b, 2016a, 2018g, 2019f, 2020e, 2020f, 2020g) 59325 Accelerated New Drug Approval and Expedited Access of New Therapies 60525.1 Introduction 60525.2 Expedited Review and Approval of New Therapies (HIV n.d.; IOM 1991; FDA 2009a, 2010a, 2011b, 2014) 60525.3 Expanded Access to New Therapies (HIV n.d.; FDA 2009a) 60725.4 Orphan Drugs (EMA n.d.-a, n.d.-b; WebMD n.d.; FDA 1998a, 2005a, 2018, 2018b, 2020c; IOM 2010) 60825.5 Pediatric Drugs (FDA 1998b, 2005b) 61025.6 Pediatric Drug Development and the Orphan Drug Act Incentives (FDA 2010c) 61225.7 Common EMEA/FDA Application for Orphan Medicinal Product Designation (EMA n.d.-a, n.d.-b; FDA 2009b; FDA 2018) 61226 Post–Drug Approval Activities 61726.1 Postmarket Requirements and Commitments (FDA 2016b, 2018f, 2020a, 2020e) 61726.2 Postapproval Manufacturing Changes (FDA 2018d, 2020b) 61826.3 Clinical Phase 4 Studies: Postmarketing Surveillance and Risk Assessment (FDA 2018d, 2019b) 61926.4 Prescription Drug Advertising and Promotional Labeling Direct to Consumers (FDA 1998c) 62227 Drug Master Files, EU Dossiers, and API GMP Guidance 62727.1 Drug Master Files (FDA 2001, 2011a, 2011b, 2011c, 2011d, 2011e) 62727.2 European Marketing Authorization Dossiers 63327.3 Good Manufactruing Practice (GMP) Guidance for Active Pharmaceutical Ingredients (Q7) (FDA 2016) 63628 Commissioning and Qualification 64628.1 Regulatory Requirements (Health Canada 2009; EU 2015; FDA 2017, 2018a, 2020) 64628.2 Preliminary C&Q Activities 64728.3 Commissioning 64928.4 Qualification and Validation 65128.5 Qualification Protocols (ISPE 2001; Health Canada 2009; PIC/S 2018) 65328.6 Process Validation (FDA 2014, 2019; PIC/S 2018) 65728.7 Cleaning Validation (Health Canada 2008; FDA 2014, 2017; PIC/S 2018) 65928.8 Computer Systems Validation (ISPE 2001; EU 2011) 66028.9 Change Control (EU 2015; PIC/S 2018) 66028.10 Revalidation (CDRH 1995; EU 2015; FDA 2015; PIC/S 2018) 66129 Quality Systems and Controls 66629.1 Pharmaceutical Quality System (FDA 2019a) 66629.2 Quality Systems Approach to CGMP Regulations 66929.3 Inspection of Pharmaceutical Quality Control Laboratories (FDA 2014) 67229.4 Pharmacopeias (U.S.P. 2014) 67329.5 Analytical Instrument Qualification (U.S.P. 2019a; FDA 2010) 67629.6 Validation of Analytical Procedures (U.S.P. 2019b; FDA 2000, 2015, 2019b) 67929.7 Stability Testing of New Drug Substances and Products (U.S.P. 2006; ICH 1996; FDA 2018b, 2018c, 2018d) 68029.8 Electronic Records; Electronic Signatures (Part 11) (FDA 2019) 68230 Safety, Toxicology, and Pharmacogenomics 69630.1 Nonclinical Safety Studies (ICH 2009; FDA 2010) 69630.2 Safety Pharmacology Studies (ICH 2000) 69730.3 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals – (FDA 1997; EMA 2011a) 70030.4 Carcinogenicity Studies of Pharmaceuticals (ICH 1995) 70130.5 Genotoxicity Testing (ICH 1998, 2008) 70230.6 Immunotoxicity Studies (ICH 2005b) 70430.7 Safety Reporting Requirements 70530.8 Pharmacogenomics (NIGMS 2005; ICH 2005b; ORNL 2010) 70630.9 Pharmacovigilance (EMA 2011b, 2015, 2021; Eudro n.d.; FDA 2005c, 2005d) 70930.10 FDA's Predictive Toxicology Roadmap (FDA 2017, 2020) 71131 Regulatory Science Initiatives for Advancing Public Health 71931.1 Introduction 71931.2 Advancing Regulatory Science for Public Health – A Framework for FDA's Regulatory Science Initiatives (FDA 2010) 71931.3 Advancing Regulatory Science at FDA – A Strategic Plan (FDA 2018b, 2018c, 2018d, 2018e, 2018f, 2018g, 2018h, 2018i, 2018j, 2018k, 2018l) 71931.4 A Collaborative Implementation Framework (FDA 2010, 2011, 2018n) 72332 Medical Devices 72632.1 Introduction (FDA 2018a, 2019a, 2020a) 72632.2 Device Determination Steps (FDA 2019a, 2020a) 72632.3 Classification and Regulatory Requirements (FDA 2018b, 2020b) 72732.4 Current Good Manufacturing Practices (CGMPs) and Quality System Regulation (QSR Regulation) Requirements 72932.5 Medical Device Complaint Reporting and Recalls (FDA 2019h, 2019i) 73133 Combination Products 73533.1 Introduction (FDA 2018, 2019e, 2020) 73533.2 Product Jurisdiction/Assignment of Combination and Non-Combination Products (FDA 2019a, 2020) 73633.3 Premarket and Marketing Applications (21 CFR Parts 312 and 812) (FDA 2019b, 2019c, 2020) 73633.4 Current Good Manufacturing Practice – Subpart A (21CFR4) (FDA 2019d) 73733.5 Postmarkeing Safety Reporting for Combination Products [21CFR4/Part 4 Regulation of Combination Products/Subpart B] (FDA 2019d) 73734 Dietary Supplements 74034.1 Introduction (FDA 2017a, 2019a, 2019b) 74034.2 Dietary Ingredients (FDA 2019a, 2019b, 2019c) 74034.3 Dietary Supplement Ingredient Advisory List (FDA 2019d) 74134.4 DS Labeling: Claims Types and Requirements (FDA 2017b, 2018, 2019e) 74134.5 Current Good Manufacturing Practice in Manufacturing, Packaging, Lableing, or Holding Operations for Dietary Supplements (21 CFR Part 111) (FDA 2019f) 74134.6 FDA Inspection and Regulatory Actions (see – 21.3 FDA Inspection and Regulatory Actions – see Chapter 21 for details) 74535 Animal Drugs and Devices 75135.1 FDA Center For Veterinary Medicine (CVM) (FDA 2019a) 75135.2 Animal Drug Availability Act of 1996 (FDA 2019b) 75135.3 Development and Approval Process (FDA 2017, 2020a) 75235.4 CGMP and Others Compliance Requirements 75635.5 Animal Drug Manufacturing Inspection – Pre-Approval (FDA 2006) 75635.6 PostMarketing Survellance (FDA 2017, 2019d, 2020a) 756References 757Index 759