Development of Biopharmaceutical Drug-Device Products (AAPS Advances in the Pharmaceutical Sciences Series, 35)

Preface
Contents
Contributors
Part I: Drug Product Development
	Chapter 1: Monoclonal Antibodies: Structure, Physicochemical Stability, and Protein Engineering
		1 Structure of Monoclonal Antibodies
			1.1 General Structure
			1.2 Crystallizable Fragment (Fc)
			1.3 Hinge Region
			1.4 Antigen-Binding Fragment
		2 Chemical and Physical Degradation of Monoclonal Antibodies
			2.1 Physical Degradation
				Aggregation
				Opalescence and LLPS
			2.2 Chemical Degradation
				Deamidation
				Oxidation
				N-Terminal Pyroglutamate
				Fragmentation
		3 Advances in Protein Engineering to Improve Stability and Efficacy
			3.1 Modification to Improve Stability
			3.2 Improving Efficacy and Half-Life Through Engineering
		References
	Chapter 2: Challenges and Considerations in the Design of Antibody-Drug Conjugates
		1 Introduction
		2 Mechanism of Action (MOA)
		3 Target Antigen Selection
		4 Selection of the Monoclonal Antibody
		5 Selection of Linkers
			5.1 Cleavable Linkers
			5.2 Non-cleavable Linkers
			5.3 Bystander Effect
		6 Selection of Cytotoxin
		7 Conjugation Process
		8 Drug-to-Antibody Ratio (DAR)
		9 Pharmaceutical Stability Considerations
			9.1 Stability Implications Due to Lysine Conjugation
			9.2 Effect of Disulfide-Bond Elimination During Cysteine Conjugation
			9.3 Linker-Drug Hydrophobicity and DAR
		10 Formulation Considerations
		References
	Chapter 3: Enabling Biologics Combination Products: Device Ability in Protein Therapeutics
		1 Introduction
		2 The Patient-Centric Approach and Drug-Device Integration
		3 Device Ability Begins in Discovery Research
			3.1 Device Ability Tools for Predicting Solution Behavior
		4 Combination Products: Matrices and Scaffolds
			4.1 Protein “Aggregation” and Association upon Interaction with Drug Delivery Matrices
				Delivery System Saturation: The rhBMP-2 Example
				Extracting Thermodynamic Data from Equilibrium Binding Analysis
			4.2 Silk Protein Scaffolds for Biomedical Applications: Sustain Release of Monoclonal Antibodies
				Silk Lyogels
		5 Summary
		References
	Chapter 4: Production Strategies and Challenges with IgG-Based Bispecific Ab Formats
		1 Introduction
		2 Overview of General Strategies to Produce IgG-Like Bispecific Antibodies
		3 Bispecific Ab Formats Composed of One HC and One LC
			3.1 Mab2™
		4 Bispecific Ab Formats Composed of Three Chains
			4.1 κλ Body
			4.2 BEAT® and Regeneron’s Platform
				BEAT® (Bispecific Engagement by Antibodies Based on the T-Cell Receptor)
				Regeneron’s Platform
			4.3 XmAb® Platform
			4.4 ART-Ig
		5 Bispecific Ab Formats Composed of Four Chains
			5.1 Ab Formats Requiring Expression in Two Cells
			5.2 Ab Formats Composed of Four Chains Enabling Expression in a Single Cell
				Ab Formats with Engineered HC-LC Interfaces
		6 Conclusion
		References
	Chapter 5: Lessons Learned in Understanding Dual Variable Domain-Ig (DVD-Ig) Structural Complexity to Select DVD-Ig Lead and Therapeutic Candidates
		1 Introduction
		2 DVD-Ig Format
			2.1 Aspects Considered in Developing the DVD-Ig Format: Utilize Existing Platforms and Expertise
				Manufacturing Platforms
				Expression Platforms
				Purification Platforms
			2.2 Understanding the Biology of the DVD-Ig Architecture to Select DVD-Ig Lead Candidates
				Structure-Function Relationship
				Expression Levels: The Impact of VD Combinations, Orientation, and Linkers
				Inner and Outer VD Function
				Drug-Like Properties
		3 Analytical Methods to Interrogate Drug-Like Properties
			3.1 Solubility Assessment
			3.2 Size Homogeneity
			3.3 Monomer Stability and Aggregate Levels
			3.4 Purity Assessment
			3.5 Hydrophobicity, Charge, and Serum Stability Relationship with Domain Orientation
			3.6 Methods to Interrogate Primary, Secondary, and Tertiary Structure
			3.7 Impact of Biophysical and Biochemical Attributes on DVD-Ig Colloidal Stability and Formulation Development
				High-Concentration Stability
				Freeze/Thaw Stability
				Forced Degradation Studies
		4 Concluding Remarks
		References
	Chapter 6: High-Throughput Conformational and Colloidal Stability Screening of Biologic Molecules
		1 Introduction
			1.1 Background and Purpose of Investigation
			1.2 Introduction to Simultaneous Differential Scanning Fluorimetry and Light Scattering
		2 Methods and Experimental Design
			2.1 Materials
			2.2 Size-Exclusion Chromatography
			2.3 Simultaneous Differential Scanning Fluorimetry and Static Light Scattering
			2.4 Statistical Analysis
		3 Results and Discussion
			3.1 Differential Fluorescent Emission and Static Light Scattering Profiles as a Function of Concentration
				Monoclonal Antibodies
				Dual-Variable Domain Immunoglobulins
			3.2 Relation of mAb and DVD-Ig Aggregation to Thermal Fluorescent and Light Scattering Parameters
		4 Summary and Conclusion
		Bibliography
	Chapter 7: An Empirical Phase Diagram: High-Throughput Screening Approach to the Characterization and Formulation of Biopharmaceuticals
		1 Introduction
		2 Biophysical Characterization of Biopharmaceuticals
		3 Empirical Phase Diagrams
			3.1 Construction of Empirical Phase Diagrams (EPDs)
			3.2 EPDs Using a pH/Temperature Phase Space
				Employing a Single Technique
				Employing Multiple Techniques
			3.3 EPDs Using Other Environmental Variables
				Temperature Versus Concentration
				Ionic Strength Versus pH
		4 New Approaches to EPDs
		5 Extending the EPD Paradigm Using Data Science and Machine Learning
		6 Development and Optimization of High-Throughput Stabilizer Screening Assays
		7 Conclusion
		References
	Chapter 8: Biophysical Characterization and the Development of Therapeutic Proteins
		1 Primary Structure
		2 Secondary Structure
		3 Tertiary Structure-Sensitive Methods
		4 Quaternary Structure and Protein Aggregation
		References
	Chapter 9: Leveraging the Multi-attribute Method (MAM) to Improve Biotherapeutic Development
		1 Introduction
		2 Biotherapeutic Design
		3 Upstream Development
		4 Downstream Process Development
		5 Formulation
		6 Conclusion
		References
	Chapter 10: Analytical Methods for Antibody Drug Conjugate Characterization
		1 Introduction
		2 Protein Content
		3 Biological Potency
		4 Purity and Impurities
			4.1 Characterization and Control of Size Variants
				Control and Characterization of Low Molecular Weight Species (LMW Species)
				Characterization and Control of Submicron Aggregates (HMW Species)
				Characterization and Control of Particulates >1 μm
			4.2 Characterization and Control of Charge Variants
				icIEF
				CZE
				Monitoring Posttranslational Modifications Using Charge Variant Analysis
			4.3 Characterization and Control of Conjugation Variants
				Separation of DAR Heterogeneity
				Structural Elucidation of DAR Peaks by Mass Spectrometry (MS)
		5 Process-Related Impurities
			5.1 Small Molecule Impurities
			5.2 Residual Solvents
			5.3 Elemental Impurities
		6 Physicochemical Characterization
			6.1 Sequence, Chemical Modification, and Disulfide Bonding Characterization by LC-MS
			6.2 Characterization of Higher-Order Structure
				Circular Dichroism (CD)
				Differential Scanning Calorimetry
				Hydrogen/Deuterium Exchange-MS
		7 Surfactant Characterization
		References
	Chapter 11: Particles in Biopharmaceuticals: Causes, Characterization, and Strategy
		1 Overview
		2 Causes
			2.1 Drug Product (DP) Degradation
			2.2 Interfacial Stress
			2.3 Polysorbate Degradation
		3 Characterization
			3.1 Subvisible Particles
			3.2 Visible Particles
		4 Strategy
			4.1 Regulatory Expectations and Current Landscape
			4.2 Strategy: Control and Mitigation
			4.3 Control Strategy at Development Phase
			4.4 Control Strategy After Filling Phase
			4.5 Control Strategy at Stability Studies
			4.6 Control Strategy at Post Marketing
			4.7 Mitigation Strategies
		References
	Chapter 12: Strategies in the Development of Formulations for Antibody-Based Therapeutics
		1 Introduction
		2 Pre-formulation Development: Moving the Right Molecule Forward
			2.1 Overview of the Analytical Methods and Stress Conditions Used in Pre-formulation Development
				Plasma Stability
				Conformational Stability
				Colloidal Stability
				pI and Posttranslational Modifications
			2.2 Developability and Candidate Selection of Antibodies
			2.3 Novel Antibody-Based Formats
		3 Formulation Development Strategies for Early and Late Stages
			3.1 Strategy for Early-Stage Formulation Development
				Frozen Liquid Drug Product
				Lyophilized Drug Product
				Shipping Simulation Study
			3.2 Strategy for Late-Stage (Commercial) Formulation Development
				Step 1: Analytical Characterization and Degradation Pathways Elucidation
				Step 2: FIH Formulation Assessment
				Step 3: pH and Buffer Screening Study
				Step 4: Agitation Study
				Step 5: Selection of Stabilizer
				Step 6: Extended Formulation Studies
					Viscosity Study
					Oxidation
					Deamidation
					Aggregation
					Preservatives
				Step 7: Upfront Manufacturability Assessment
				Step 8: Formulation Robustness
		References
	Chapter 13: Formulation Development for Biologics Utilizing Lab Automation and In Vivo Performance Models
		1 Introduction
			1.1 QbD in Formulation Development for Biologics
		2 Enabling QbD in Formulation Development by High-Throughput Screening
			2.1 Overview of Elements Required for an Automated High-Throughput Formulation Screening
				Workflow Standardization
					Screening Design
					Standardization of Methods and Assays
				Miniaturization
				Automation and Software Integration Strategy
					Liquid Handling (as a Starting Point for Partial Automation)
					Workflow Requirements and QbD Defining Automation Strategy
					High Throughput of Formulation Conditions and Design Space
					Automation Strategy: Fully Integrated Versus Decentralized Islands
					Implementation Challenges
					Intelligent Automation as a Paradigm Shift
				Data Management
					High-Throughput Data Handling Following QbD
					Area of Conflict: Manual Data Handling for Automated Workflows
					Evolution of Data Handling Strategies: From eLN to Hadoop
					Data Integrity in Automated Data Handling
					A Data Framework for Standardization and Flexibility
				Data Evaluation
					Compiling of a Summary Report
				Data Science
					Usage of Process Data, Log Files, and Analytical Data for Advanced Analytics/Data Science and Intelligent Automation
					Data FAIRization and Sharing Data in an Enterprise Data Platform
					Vision for In Silico Supported Formulation Screenings
		3 Enabling QbD in Formulation Development by Predictive In Vivo Performance Models
			3.1 Introduction: Predictive In Vivo Performance Models to Understand the (Bio)-Relevance of Critical Quality Attributes (CQAs)
				Characterizing Protein Metabolism as a Tool for De-Risking CQAs
				Bioavailability
		4 Concluding Remarks
		References
	Chapter 14: Practical Considerations in High Concentration Formulation Development for Monoclonal Antibody Drug Products
		1 Introduction
		2 Considerations on HCPF Properties
			2.1 Solubility
				Solubility Limit
				Solubility Enhancement Strategy
			2.2 Increased Aggregation
				Concentration-Dependent Aggregation
				Minimizing Aggregation in Liquid Formulation
				Stress Condition Selection for Formulation Screening
				Aggregation During Drug Substance Frozen Storage
			2.3 Increased Viscosity
				Viscosity-Reducing Strategy
					Buffer and pH
					Thermal Stabilizer
					Viscosity Reducer
				Alternative Strategy to Overcome High Viscosity Challenge
			2.4 Increased Impurity Concentrations
		3 Analytical Considerations
			3.1 Protein Concentration Determination
			3.2 Subvisible Particulate Analysis
		4 Primary Container Considerations
		5 Summary
		References
	Chapter 15: Drug Product Formulation Development and Formulation Robustness Criteria for a mAb in a Pre-filled Syringe
		1 Introduction
		2 Formulation Considerations for a mAb in PFS
			2.1 Pre-robustness Study Design and Raw Data Management for mAbs in a PFS
				Design
				Raw Data
			2.2 Selecting Worst-Case Formulations for a Final Robustness Study
		3 Stability and Compatibility with Pre-filled Syringe Container Closure System
			3.1 Drug Product Stability
			3.2 Syringe Components
				Plunger Stopper
				Rigid Needle Shield
				Tungsten
				Silicone Oil
		4 Drug Product Processing Conditions
			4.1 Ambient Light
			4.2 Hydrogen Peroxide
		5 Conclusions
		References
	Chapter 16: Development of Robust Lyophilization Process for Therapeutic Proteins: A Case Study
		1 Introduction
		2 Formulation Development
			2.1 Sucrose-Mannitol Formulation System
			2.2 Formulation Selection
			2.3 Liquid Stability in the Liquid and Characterization
				Conformational Stability
				Chemical and Physical Stability
			2.4 Lyophilization Process Development
				Glass Transition Temperature of the Maximally Freeze Concentrate
				Lyophilization Process Parameters
				Lyophilization Design Space
				Lyophilization Process Robustness
				Physical Properties and Stability of the Lyophilizate
					Crystallinity and Glass Transition of the Lyophilizate of the Sucrose-Mannitol Formulation
					Sub-visible Particle Analysis
					Stability in the Drug Product at Accelerated Stress Conditions
		3 Conclusion
		References
	Chapter 17: Scale-Down Models for Robust Biologics Drug Product Process Development
		1 Introduction
		2 Process Development Using QbD Approach
			2.1 Process Risk Description for Drug Product Manufacturing
		3 Small-Scale/Minipiloting Tools
			3.1 Shear Stress Minipiloting Tool
			3.2 Interfacial Stress Minipiloting Tool
			3.3 Light Stress Study
			3.4 Metal-Induced Degradation Study
		4 Scale-Down Models for Each Unit Operations
			4.1 Scale-Down Freeze–Thaw Study
			4.2 Scale-Down Mixing Model
			4.3 Scale-Down Filtration Study
			4.4 Scale-Down Pumping and Filling Study
		5 Robust Tech Transfer to Manufacturing Site
		References
	Chapter 18: Design of Clinical In-Use Studies
		1 Introduction
		2 Design of Clinical In-Use Studies: Technical and Practical Considerations
			2.1 Diluent Compatibility
			2.2 Dose Preparation Accuracy
			2.3 Material Compatibility
			2.4 Air-Liquid Interfacial Stress
			2.5 Allowable In-Use Storage Conditions and Durations: Physicochemical and Microbiological Considerations
			2.6 Analytical Challenges
			2.7 Mock Infusion Setup
			2.8 Clinical In-Use Study Approach
		3 Clinical In-Use Case Studies for Varied Biological Modalities
			3.1 Case Study 1: Analytical Challenges
			3.2 Case Study 2: Protein Adsorption to In-Line Filters
			3.3 Case Study 3: Excipient Dilution
			3.4 Case Study 4: Interfacial Stress
			3.5 Case Study 5: Syringe Pump Administration
			3.6 Case Study 6: Ultra-Low Dose Administration
		4 Conclusion
		References
	Chapter 19: Design of a Bulk Freeze-Thaw Process for Biologics
		1 Introduction
		2 Physics of the Freezing and Crystallization Process
			2.1 Recrystallization of Ice/Ostwald Ripening
			2.2 Formation of the Glassy Phase in Frozen Systems
		3 Bulk Storage Options
		4 Cryopreservation: Impact of Freezing Process on Protein Solutions and Modes of Denaturation
			4.1 Cryoconcentration
				Mitigation Strategies for Cryoconcentration Effects
			4.2 Ice-Liquid Surface Denaturation
				Strategies to Minimize Ice-Liquid Interface
			4.3 Cold Denaturation
				Strategies to Minimize Cold Denaturation
		5 Freeze-Thaw Technologies
			5.1 Uncontrolled Rate Freeze-Thaw Technology
				Process Development
					For Freezing Process
					For Thawing Process
					Mixing Time
				Process Characterization, Robustness Studies, and Design Space Considerations for Uncontrolled Rate Freeze-Thaw
			5.2 Controlled Rate Freeze-Thaw Technology
				Process Development
				Process Characterization, Robustness Studies, and Design Space: Controlled Rate Freeze-Thaw
					CryoWedge®
					Celsius Bag: S3 System
		6 Case Study
			6.1 Case Study 1 (Fusion Protein)
			6.2 Case Study 2 (Peptibody)
		7 Practical Considerations
			7.1 Formulation Considerations
			7.2 Physical Properties and Storage Temperature Considerations
			7.3 Heat Flow
		References
	Chapter 20: Freeze-Thaw Process Data Analysis and Mechanistic Modeling: Simplified Lumped Capacitance Analysis for Small Fill Volumes
		1 Background and Motivation
		2 Problem Statement
		3 Applicability of Lumped Capacitance Model for Heat Transfer
		4 Lumped Capacitance Model for Freezing and Thawing Time of Solution in a Primary Package
			4.1 Solidification/Melting Phase Change Process
		5 Experimental Data Analysis and Comparison with the Model
		6 Application of the Model for Freeze-Thaw Process Design
		7 Future Directions for High-Fidelity Mechanistic Modeling of Freeze-Thaw Process
			7.1 Secondary and Tertiary Packaging
			7.2 Higher-Fidelity Modeling for Bi>0.1
		References
	Chapter 21: Rational Design of a Freeze-Drying Process for Protein Products
		1 Introduction
		2 Thermal Properties of the Formulation
		3 The Freezing Phase
			3.1 Freezing
			3.2 Annealing
		4 The Primary Drying Phase
			4.1 Primary Drying Phase Design
			4.2 A Novel Fast Analytical Design Space (fast-DS)
				Verification of the Analytical Product Temperature Isotherm (Tcrit-isotherm)
				Creating the “Fast Design Spaces” (fast-DS) Using the Analytical Product Temperature Isotherm (Tcrit-isotherm)
				The Effect of Tcrit, Kv, and Rp on the Fast Design Space (fast-DS)
					Part 1: Effect of Tcrit
					Part 2: Effect of Kv
					Part 3: Effect of Rp
				Example Use of the fast-DS: A Practical Guide
					For Estimating Kv = f(Pch)
					For Estimating Rp,max
					Comments on the Benefit of the New “fast-DS” Tool in the Initial Design
			4.3 Determination of the Endpoint of Primary Drying
				Single Vial Methods
				Batch PAT Methods
					Capacitance Manometer and Pirani Gauge
					Dew Point Monitor
					The Residual Gas Analyzer Mass Spectrometer (LYOPLUS™)
					Pressure Rise Techniques
					Gas Plasma Spectroscopy (Lyotrack)
					Tunable Diode Laser Absorption Spectroscopy (TDLAS)
		5 Secondary Drying
		6 Considerations for Scale-Up and Manufacturing Challenges
		7 Case Study
		References
	Chapter 22: Development and Scale-Up of the Mixing Process for Biopharmaceuticals
		1 Introduction
		2 Mixing Fundamentals and Basic Scale-Up Considerations
			2.1 Turbulence
			2.2 Basic Impeller Design
			2.3 Platform Approaches and Empirical Correlation-Based Scale-Up
				Platform Approach to Determining Agitation Rate and Mixing Time for Shear-Insensitive Systems
				Empirical Correlation-Based Scale-Up
				Average Shear Rate Calculations
		3 Computational and Experimental Assessment of Mixing and Shear
			3.1 Small-Scale Shear and Gas Entrapment Assessment
			3.2 Methodology for Small-Scale Assessment
			3.3 Use of Models and Experiments to Guide Shear-Sensitive Process Scale-Up and Scale-Down
				Assess Mixing Parameters and Batch Size for the Compounding Process
				Assessment of Shear Exposure
				Dissolution of Excipients
			3.4 Use of Models and Experiments to Guide Oxygen-Sensitive Process Scale-Up and Scale-Down
				CFD Approaches to Understand Oxygen Impact
				Experimental Approach to Understand Oxygen Impact
		4 Concluding Remarks
		References
	Chapter 23: Case Study for the Implementation and Utilization of a Technology Platform for Sterile-Grade Filtration
		1 Introduction
		2 Identification of Process Parameter
			2.1 Initial Risk Analysis
		3 Available Prior Knowledge from Guidelines and Regulatory Requirements
		4 Exploring the Knowledge Space and Establishing a Sterile Filtration Technology Platform
		5 Overall Available Knowledge Space and Evaluation of a Reduced Product-Specific Filter Evaluation
		6 Conclusion
		References
	Chapter 24: Considerations and Challenges When Filling High-Concentration Monoclonal Antibody Formulations into Prefilled Syringes
		1 Introduction
		2 Development and Use of a Bench-Top Filling Setup for PFS Process Design and Optimization
		3 Optimization of Filling Profiles
		4 Mitigation of Formulation Drying at Filling Nozzle Tip during Prolonged Interruptions
			4.1 Effect of SB Settings
			4.2 Effect of Filling Nozzle Characteristics
				Effect of Filling Nozzle Characteristics: ID
				Effect of Filling Nozzle Characteristics: Materials of Construction
		5 Optimizing Filling Precision with Different Filling Systems
			5.1 Comparison of Filling Technologies: Piston Pump, Time-Pressure Filler, and Peristaltic Pump
				Piston Pumps
				Time-Pressure Filler
				Peristaltic Pump
			5.2 Utilizing a Bench-Top Setup to Perform Filling Precision Studies
				Surrogate or Product?
				Experimental Setup Design
				Example of Filling Precision Data Analysis with the Peristaltic Pump
		6 Plunger Stopper Insertion
			6.1 Comparison of Stopper Insertion Technologies: Vent Tube (Mechanical) Versus Vacuum (Pressure)
			6.2 Utilizing a Bench-Top Setup for Stoppering Studies
		7 Conclusion
		References
	Chapter 25: Peptide Drug/Device Combinations
		1 Overview of Peptide Therapeutics
			1.1 History of Peptides as Drugs
			1.2 Limiting Factors When Using Peptides in the Clinic
			1.3 Advances in the Use of Peptides as Drugs
		2 Formulation of Peptides
			2.1 Pre-formulation Studies
			2.2 Formulation Development
			2.3 Pharmaceutical Excipients
			2.4 Aggregation in Protein Formulations
			2.5 Peptide Bond Formation (Coupling Methods)
			2.6 Synthesis Approaches
			2.7 Separation and Purification (Chromatography)
			2.8 Characterisation with Mass Spectrometry
			2.9 Stability Testing
		3 Delivery System Considerations for Peptide Therapeutics
			3.1 Pharmacokinetics of Peptides
			3.2 Delivery Approaches
			3.3 Parenteral Peptide Drugs
			3.4 Intranasal and Enteral Delivery
			3.5 Challenges in Delivery of Peptides
		4 Conclusion
		References
Part II: Drug-Device Combination Products
	Chapter 26: Development Challenges and Opportunities for Drug/Device Combination Products
		1 History
		2 Power of Global Guidance
		3 Drug Delivery Systems (Drug-Device Combination Products)
			3.1 Multiple-Dose Reusable Devices
			3.2 Multiple-Dose Prefilled Devices
			3.3 Single-Dose Auto-injectors (AI) and Prefilled Syringes (PFS)
			3.4 Platform Designs
		4 Organizational Challenges
			4.1 Drug and Device Organization Integration
			4.2 Project Management/Technical Leadership
			4.3 Regulatory Challenges
			4.4 Human Factors Challenges
			4.5 Needed Improvements in Regulatory Interactions
			4.6 Future Opportunities and Challenges
		5 Conclusion
	Chapter 27: Evolving Regulatory Landscape for Combination Products: US Perspective
		1 Combination Products Defined
		2 Combination Product Regulations and Key Policy Events
			2.1 Historical Overview
			2.2 FDA’s Focus on Combination Products Leading Up to the Enactment of the Cures Act
				Lean Management Process Mapping
				Combination Products Policy Council
				Improved Intercenter Consult Request (“ICCR”) Process Pilot
				Pre-RFD Process
			2.3 Impact of the Cures Act on Combination Product Regulation
			2.4 Changing Regulatory Landscape for Combination Products Post-Cures
				PDUFA VI Commitments
				Post-Cures Combination Product Guidance
		3 Increasing Technical and Submission Expectations for Combination Products
			3.1 Expanding Combination Product Industry
			3.2 Combination Product cGMPs
				Key Terminology Clarifications
				Design Controls for Combination Product
				Remediation for Products Not Developed Under Design Controls
				Purchasing Controls for Combination Products
			3.3 Impact of Technical Guidance on Combination Product Regulatory Expectations
				Container Closure Systems
				Inhalation Products
				Injection Products
				Human Factors Guidance
				Essential Performance Requirements and Control Strategies
				Delivery System Bridging
			3.4 Submission Expectations Related to Part 4
				Declaration of Quality System
				Structure and Content Placement Expectations
				Master Files and Referenced Submissions
		4 Life Cycle Management Considerations
			4.1 Postapproval Modifications to Combination Products
			4.2 Postmarket Safety Reporting (PMSR)
		5 Perspectives for the Future
	Chapter 28: Evolving Regulatory Landscape for Drug-Device Combination Products: Europe and Other Major Market Perspectives
		1 Introduction
		2 Inconsistency: It Starts with Terminology
		3 Challenges
		4 Global Harmonization Opportunities
			4.1 International Medical Device Regulators Forum (IMDRF)
			4.2 International Coalition of Medicines Regulatory Authorities (ICMRA)
			4.3 Importance of Innovation in Medical Product Regulation
			4.4 EMA Regulatory Science Strategy to 2025
		5 Focus on the Current European Regulatory Framework
			5.1 European Medical Device Directive and Times of Change
			5.2 Notified Body Opinion
		6 Outside the USA and Europe
			6.1 Country and Specific Regional Overview
			6.2 Industry Perspective and Seeking Global Harmonization
			6.3 Role of the Manufacturer Role in Regulation of Combination Products
			6.4 LifeCycle Management
	Chapter 29: Importance of Design Control and Risk Management Processes in Combination Product Development
		1 Introduction
		2 Design Controls
			2.1 Design Verification and Validation
			2.2 Phase Appropriate Design and Testing
		3 Risk Management
			3.1 Governance
			3.2 Risk Management Plans
		4 Monitoring Processes
			4.1 Clinical Evaluation Reports
			4.2 Details for Device Vigilance System
			4.3 Case Management and Expedited Reporting
			4.4 Device Safety Surveillance
			4.5 Other Issues Impacting Device Safety
		5 Conclusion
	Chapter 30: Standards for Injectable Delivery Devices: ISO 11608 Series and Others
		1 Introduction
		2 The ISO 11608 Family of Standards – Needle-Based Injection Systems
			2.1 ISO 11608 Parts 1, 2 and 3
			2.2 ISO 11608 Part 4 (2006)
			2.3 ISO 11608 Part 5 (2012)
			2.4 ISO 11608 Part 7 (2016)
			2.5 ISO 11608 Part 6 (Planned for 2020–2021)
			2.6 ISO 23908 – Post-Use Needle Stick Protection (2012)
		3 Non-needle-Based Medication Delivery Systems
			3.1 ISO 21649 – Needle-Free Delivery Systems (2006)
			3.2 ISO 20072 – Aerosol Drug Delivery Devices (2009)
		4 Other Important ISO and IEC Standards Which a Medication Delivery System Developer Needs
		5 Conclusion
	Chapter 31: Human Factors Regulations and Standards in Combination Product Development: IEC 62366 and FDA Guidance Documents
		1 Introduction to Human Factors
			1.1 Scope of Application
		2 Key US and International Guidance
			2.1 US Guidance
				CDER’s Definition of Critical Tasks
			2.2 International Guidance
		3 Expectations for Human Factors Data in Submissions
		4 Overview of Human Factors Process
			4.1 Identify Users and Use Environments
			4.2 Identify User Interface Components
				Drug/Device/Biologic Components
				Training
				Instructional Materials (IFU and Packaging)
			4.3 Develop and Leverage a Use-Related Risk Analysis (URRA)
			4.4 Apply Human Factors Guidance for Biosimilar Products for the US Market as Needed
		5 Best Practices for Incorporating Human Factors Strategies
			5.1 Start the HF Process Early
			5.2 Leverage Applicable Prior Work
			5.3 Keep the Global Market in Mind
			5.4 Collect Labeling-Focused Data
		6 Common Human Factors Challenges During Validation Testing
			6.1 Account for Negative Transfer
			6.2 Cautiously Rely on Training as a Mitigation
			6.3 Cautiously Rely on the IFU as a Mitigation
			6.4 Provide Data-Driven Design Justifications
			6.5 Carefully Consider When to Use Quick Reference Guides
			6.6 Determine How to Enable Users to Confirm Delivery of Dose
		References
	Chapter 32: A Science and Risk-Based Approach to Bridging Drug-Device Combination Products
		1 Introduction
			1.1 What Is Bridging?
			1.2 Scope
			1.3 Constituent Parts of the Combination Products
			1.4 The Bridging Exercise
			1.5 Base Device Versus to-Be-Marketed Presentation
		2 General Principles
		3 Considerations for Bridging
			3.1 New Device Platforms
			3.2 Timing for Introducing Device Component into CTs
			3.3 Holistic Approach for Biopharmaceutical with Multiple Programs
			3.4 PK Study Criteria
			3.5 Leveraging Prior Device Platform Experience
			3.6 Real-Life Patient Handling
			3.7 Changes in Device Design Within Platform
		4 Global Considerations
		5 Device Component Quality Attributes
			5.1 Release Specifications
			5.2 Essential Performance Requirements
			5.3 Stability Testing
			5.4 Device Reliability
		6 Bridging Studies
			6.1 Stepwise Progression of Bridging Studies
			6.2 A Word on Human Factors Testing
		7 Conclusions and Future Guidance
		References
	Chapter 33: Design and Development Considerations for Autoinjector Delivery Systems: Technology Developer and Industry Perspectives
		1 Introduction
		2 Autoinjector Definition
		3 Autoinjector Examples
		4 Design Considerations: How Do You Know What to Design?
		5 Developing an Autoinjector Combination Product: Pharma/Device Partnership
		6 Technology Landscaping and Partner Selection
		7 Team Formation
		8 Landscaping and Partner Assessment
		9 Business Agreements
		10 Feasibility Assessment
		11 Platform Technology Approach
		12 Trade-Offs of Platform Devices Versus Bespoke Device
		13 Future Challenges
		14 Future Opportunities: Connected Devices
		15 Conclusion
		References
	Chapter 34: A Case Study of Bridging from a Lyophilizate Formulation to an Autoinjector for Patient Self-Administration
		1 From Intravenous Injection in First-in-Human to Autoinjector on the Market: A Long Journey
		2 The Technical Development Challenges for a New Device in a New Indication
		3 Leveraging to New Indications
		4 Conclusions
		References
	Chapter 35: On-Market Prefilled Syringe and Autoinjector Studies
		1 Introduction
			1.1 Insight into On-Market Support
				On-Market Support
				Commodity Variability
				Post-approval Changes
				Reliability and Scalability of Processes
				Summary
		2 Autoinjector: A Combination Product
			2.1 Primary Container
			2.2 Drug Product
			2.3 Subassembly
		3 PFS Characterization and Interaction with Biologic Formulations
			3.1 Syringe
			3.2 Stopper
			3.3 Needle
			3.4 Siliconization
			3.5 Summary
		4 Product Enhancements: Approach to Making Changes to a High-Volume Product
		5 Design Improvements
			5.1 Actuation Force Improvements
			5.2 Assembly Improvements
		6 Conclusion
		References
	Chapter 36: Considerations in the Development, Approval, and Commercialization of On-Body Delivery Devices Used in Combination with a Biologic
		1 Introduction
		2 Requirements Development
		3 Risk Management
			3.1 Use of Consensus Standards
		4 Human Factors Usability
		5 System Considerations
			5.1 Integration and Interface of System Components
			5.2 Extractables and Leachables
			5.3 Biologic Stability and Device Shelf Life
			5.4 Software Classification
			5.5 Software Privacy Concerns
			5.6 Consensus Standards
			5.7 Transfer to Manufacturing
		6 Regulatory Considerations
		7 Sustaining Engineering
		8 Device Development Partnership
			8.1 Leverage Internal Experts
		9 Conclusion
Index