Ophthalmic Product Development: From Bench to Bedside (AAPS Advances in the Pharmaceutical Sciences Series, 37)

✍ Scribed by Seshadri Neervannan (editor), Uday B. Kompella (editor)

• Publisher: Springer
• Year: 2022
• Tongue: English
• Leaves: 643
• Category: Library

✦ Synopsis

This is a comprehensive textbook addressing the unique aspects of drug development for ophthalmic use. Beginning with a perspective on anatomy and physiology of the eye, the book provides a critical appraisal of principles that underlie ocular drug product development. The coverage encompasses topical and intraocular formulations, small molecules and biologics (including protein and gene therapies), conventional formulations (including solutions, suspensions, and emulsions), novel formulations (including nanoparticles, microparticles, and hydrogels), devices, and specialty products. Critical elements such as pharmacokinetics, influence of formulation technologies and ingredients, as well as impact of disease conditions on products development are addressed. Products intended for both the front and the back of the eye are discussed with an eye towards future advances.

✦ Table of Contents

Preface
Contents
Part I: Introduction and Background
Introduction and History of Ophthalmic Product Development
Challenges and Uniqueness for Ocular Product Development
Ophthalmic Products and Their Progressive Complexity
Conventional Topical Products
Posterior Segment Drug Products
Other Key Components of an Ophthalmic Product
Artificial Tears Are a Key Segment in Ophthalmic World
Repurposing Has Been a Key Stratagem in Ophthalmology
Regulations Are Still Evolving, Especially for Complex Products
Conclusion
References
Ocular Surface Anatomy and Physiology: Impact on Product Development
Introduction
Lids and Blinking
Tears and Nasolacrimal Drainage
Conjunctiva
Cornea
Aqueous Humor
Formulation Approaches
Species Difference and Impact on Product Development
Conclusion
References
Anatomy and Physiology of the Anterior Chamber: Impact on Product Development
Introduction
Relevant Anatomy of the Anterior Segment
Ciliary Body
Iris
Ciliary Epithelium
Aqueous Humor
Secretion by Active Solute Transport
Pharmacology of Secretion
Measurement of Secretion Rate
Circadian Rhythm in Aqueous Secretion
Convective Mixing and Turnover in the Anterior Chamber
Aqueous Flare
Aqueous Humor Outflow Pathways
Trabecular Meshwork Outflow
Uveoscleral Outflow
Outflow Facility
Further Considerations on the Balance Between Aqueous Inflow and Outflow
Summary
References
Part II: Fundamental Approach to Ophthalmic Product Development
Back of the Eye Anatomy and Physiology: Impact on Product Development
Introduction
General Anatomy and Major Compartments
The Lymphatic Pathways
Convective and Advective Flow
The Sclera
The Suprachoroidal Space (SCS)
Effects of Raised Intraocular Pressure
Vitreous Humour
Flow Processes in the Vitreous
Pressure Effect
Removal of the Lens or Vitreous
The Ageing Eye
Access to the Retina
The Inner Limiting Membrane
Blood Flow
Outer Blood-Brain Barrier
Melanin
Concluding Remarks
References
Physicochemical and Biological Fundamentals for Drug Delivery to the Eye
Introduction
Drug Delivery to the Eye: Biological Fundamentals
Relevant Ocular Anatomy and Physiology
Orbit
Tissues of the Ocular Coat
Tissues of the Inner Eye
Biological Barriers to Ocular Drug Penetration
Static Barriers
Dynamic Barriers
Metabolic Barriers
Drug Delivery to the Eye: Physicochemical Fundamentals
Candidate Selection
Druggability Assessment
Ocular Bioavailability
Developability Assessment (DAS)
Technology Selection
Concluding Remarks
References
Transcorneal Kinetics of Topical Drugs and Nanoparticles
Introduction
Ophthalmic Drug Products and Precorneal Drug Dynamics
Transcorneal Penetration
Ocular Fluorometry for Assessment of Topical Drug Kinetics
Spot Fluorometer
Confocal Scanning Microfluorometer
Penetration of Rhodamine B (as a Lipophilic Fluorescent Drug Surrogate)
Penetration of Sulforhodamine B and Fluorescein (as a Hydrophilic Fluorescent Drug Surrogates)
Penetration of Nanoparticles
Modeling of Pharmacokinetics of Topical Lipophilic Drugs
Summary
References
Topical Ophthalmic Dosage Form Development: Key Components and Critical Quality Attributes
Introduction
Ophthalmic Drug Delivery Route Considerations
Structure of the Eye
Routes of Drug Delivery to Ocular Tissues
Complexity in Drug Delivery to Target Tissues
General Considerations for Ophthalmic Dosage Form Development
Dosage Form Selection
Phase/Stage of Development
Physicochemical Properties of the Drug
Dose Strength
Selection of Components
Drug
Preservative
Excipients
Container Closure System
Sterilization Method Selection
Formulation Development Strategy
QbD Approach to Formulation Development
Quality Target Product Profile
Critical Quality Attributes (CQAs) for Ophthalmic Dosage Forms
Critical Process Parameters (CPPs)
Relating Component CQAs and Manufacturing Process CPPs with CQAs of Dosage Form
Control Strategy
Case Example: Sterile Ophthalmic Solution
Step 1: Define Desired Dosage Form and Performance Attributes through the Quality Target Product Profile (QTPP) as it Relates to Quality, Safety, and Efficacy
Step 2: Identify Approach to Formulation and Manufacturing Process Development of the Drug Product Using Domain Expertise/Prior Knowledge and Drug Substance Information
Step 3: Identify Potential Critical Quality Attributes (CQAs) of Drug Substance, Excipients, Process Intermediates, and Drug Product
Step 4: Identify Potential Critical Process Parameters (CPPs), i.e., Process Parameters that May Impact CQA, of All Unit Operations in the Manufacturing Process
Step 5: Using Risk Assessment and Experimental Approaches, Determine the Functional Relationships That Link Raw Material CQAs and Unit Operation CPPs to Drug Product CQA
Step 6: Refine Formulation and Manufacturing Process, if Necessary, and Repeat Steps 3–5 to Meet the QTPP Defined in Step 1
Step 7: Use the Enhanced Product and Process Understanding in Combination with Quality Risk Management to Establish Design Space (Includes Raw Material Properties and Process Variables) and Control Strategy
Conclusion
References
Intraocular Injectable Dosage Form Development: Key Components and Critical Quality Attributes
Introduction and Background
Overview
Intraocular Administration
Intravitreal Administration of VEGF Inhibitors
Alternate Modes of Administration
Drug Development Process
Linkage of Product Characteristics Throughout Development
Submission Components
Identification and Characterization of Drug Substance
Analytical Methods
Identification and Rationale of Product Composition
Selection and Rationale of Container Closure System
Definition of Well-Controlled Manufacturing Process
Stability Studies
Critical Quality Attributes and Specifications
References
Microbiological Considerations for Ophthalmic Products: Sterility, Endotoxin Limits, and Preservatives
Introduction
Sterility Requirement for Ophthalmic Products
Sterility Test Consideration
Challenges with Sterility Tests
Terminal Sterilization Versus Aseptic Manufacturing Process
Control Strategy for Assurance of Ophthalmic Product Sterility
Sterile Endophthalmitis Linked to Endotoxin Contamination
Animal Studies to Assess the Inflammatory Potential of Endotoxin in Ophthalmic Products
Compendial and International Guidance for Endotoxin Limits
Compendial Endotoxin Testing Methods
Low Endotoxin Recovery
Endotoxin Control Strategy
Preservatives’ Role and Function
Formulation Development with Preservative
Preservative Effectiveness Chapters and International Guidelines
Shelf Stability Testing
In-Use and Discard Date Studies
Forward Thinking and Design Space for New Preservatives
Conclusions
References
Packaging Development: Multi-Dose Container Closure for Preservative Free Products, Extractable/Leachables from Packaging, New Technologies
Introduction
CCS Development Strategy
Drug in Eye Drop Bottle Development According to QbD
Qualification of Eye Drop Bottle
Safety
Compatibility
Protection
Performance
Quality Control
Device in Eye Drop Bottle Development According to Design Control
Drug in Multidose Preservative-Free (MDPF) Eye Drop Bottle
Device Verification and Validation
CCS for Ophthalmic Products
Unit-Dose Vial
Multidose Bottle
Multidose Preservative-Free (MDPF) System
Novel Dispensing Systems to Aid Instillation to the Eye
Conclusion
References
Part III: Pharmaceutical Product Development
Liquid Ophthalmic Drug Products: Physicochemical Properties, Formulations, and Manufacturing Considerations
Preface
Considerations for Drug Substance
Physical and Chemical Considerations
Chemical Characteristics
Physical Characteristics
Drug Product Considerations
pH, Buffers, and Buffering Capacity
Osmolarity and Osmolality
Inactive Ingredients Found in Liquid Ophthalmic Products
Manufacturing Considerations
References
Ocular Suspension and Nanosuspension Products: Formulation Development Considerations
Introduction
Routes of Ocular Drug Administration and the Associated Barriers to Consider for Developing Ophthalmic Products
Ophthalmic Suspension Formulation
Target Product Profile (TPP) and Desirable Attributes
Key Considerations in the Development of Ophthalmic Suspension and Nanosuspension Formulations
Physical Properties of the Active Pharmaceutical Ingredient (API)
Particle Size of the API
Role of Excipients
Viscosity-Modifying (Enhancing) Agents
Wetting and Solubilizing Agents
Suspending Agents
pH Buffering Agents
Tonicity Agents
Clarifying Agents
Preservatives
Preservative’s Safety and Efficacy Assessment in Ocular Formulation
Sterility
Container/Closure System
Nanosuspensions
Manufacturing Process of Nanosuspension Formulations
Application of Nanosuspension Formulations in Ocular Drug Delivery
Manufacturing Consideration in Scale-Up Development of Ocular Suspension Dosage Form
Stability Consideration of the Suspension and Nanosuspension Dosage Forms
Physical Stability
Chemical Stability
References
Emulsions for Topical Eye Delivery: State of the Art and Future Perspectives
Introduction
Products on the Market and Being Developed for Topical Delivery
Emulsions Used as Artificial Tears
Introduction
Anionic Emulsions
Cationic Emulsions
Conclusion
Emulsions Used as Active Ingredient Vehicle
Marketed Products
Restasis
Durezol®
Ikervis®
Lacrinmune®
Xelpros®
Products Under Development
PADciclo™
Catioprost®
Tacrolimus
Dexamethasone
Indomethacin
Self-Emulsifying Drug Delivery Systems (SEDDSs)
Discussion and Conclusion
Size
Drug Distribution into the Complex Emulsion System
Mechanism of Penetration
Fate of the Emulsion on the Ocular Surface
Possible Improvements Would Contribute to Extending the Use of Emulsions
Other Routes of Administration
Process of Manufacture
To Conclude
References
Microparticle Products for the Eye: Preformulation, Formulation, and Manufacturing Considerations
Introduction
Components of Microparticles
Active Substances
Biomaterials Employed in Microencapsulation
Other Components of Microparticulate Formulations
Solvents
Microencapsulation Techniques
Physical Microencapsulation Techniques
Spray-Drying
Supercritical Fluid Precipitation
Emulsion Solvent Evaporation/Extraction
Fluid-Bed Microencapsulation
Physicochemical Microencapsulation Techniques
Coacervation
Ionic Gelation
Chemical Microencapsulation Techniques
Interfacial Polymerization
Others
Microfluidics
Sterilization
Characterization of Microparticles
Morphological Studies
Particle Size Analysis and Distribution
Infrared Absorption Spectrophotometry
Differential Scanning Calorimetry (DSC)
X-Ray Diffraction (XRD)
Gel Permeation Chromatography (GPC)
Determination of Drug Loading Efficiency
In Vitro Release Studies
Administration of Microparticles: Efficacy Studies
Topical Administration
Intraocular Administration
Periocular Route
Conclusions
References
Nanoparticle Products for the Eye: Preformulation, Formulation, and Manufacturing Considerations
Introduction
Overcoming Ocular Barriers
Overcoming the Tear Film
Overcoming the Corneal Barrier
Overcoming the Blood-Retinal Barrier
Development of Nanoparticles as Ocular Drug Delivery Systems
Preformulation
Active Compounds
Biomaterials
Excipients
Optimization Studies
Nanoparticles for Ocular Drug Delivery
Polymeric Nanoparticles
Lipid Nanoparticles
Nanoparticle Preparation Methods
Polymeric Nanoparticles
Emulsification-Solvent evaporation
Emulsification-Solvent Displacement Method or Nanoprecipitation
Emulsification-Reverse Salting-Out
Dialysis Technique
Supercritical Fluid Technology
In Situ Polymerization
Lipid Nanoparticles
Low Energy Methods
Solvent Emulsification-Evaporation Method
Microemulsion-Based Method
Lipid Film Dispersion Method
High Energy Methods
High-Shear Homogenization
High-Pressure Homogenization (HPH)
Ultrasonication Technique
Characterization Parameters
Freeze-drying of Nanoparticles
Administration Routes and Applications of Nanoparticles for Ocular Drug Delivery
Anterior Eye Segment
Topical Administration: Eye Drops
Topical Administration: Gels and In Situ Gelling Systems
Intracameral Administration
Embedment into Contact Lenses
Posterior Eye Segment
Subconjunctival Administration
Intravitreal Administration
Subretinal Administration
Microneedles
Functionalization of Nanoparticles
Conclusions
References
Advanced Hydrogel Formulations for the Eye
Introduction
Supramolecular Hydrogels
Dendrimer Hydrogels
Conclusions
References
Ophthalmic Product Development for Biologics
Introduction
Need for Development of Ophthalmic Biologic Agents
Current Landscape for Ophthalmic Biologics
EYLEA® (Aflibercept)
AVASTIN® (Bevacizumab)
BEOVU® (Brolucizumab-dbll)
XEOMIN® (IncobotulinumtoxinA)
MACUGEN® (Pegaptanib Sodium)
JETREA® (Ocriplasmin)
LUCENTIS® (Ranibizumab)
Challenges Associated with the Development of Ophthalmic Biologics
Biological Challenges
Challenges Associated with Formulation Development
Clinical Development Challenges
Risks Associated with Repeated Intravitreal Injections
Determination of Pharmacokinetics (PK) After Intravitreal Injection
Translation of Results from Clinical Trials to Real-World Outcomes
Challenges Associated with Masking Treatment Arms in a Clinical Study
Need for Suitable Animal Models
Formulation and Drug Product Development Considerations For Ophthalmic Biologics
Pragmatic Considerations for Formulation Development of Biologics
Effect of pH and Buffer Type on Protein Stability
Role of Excipients in Improving Protein Stability
Salt
Sugars
Surfactant
Amino Acids and Polymers
Container Closure Considerations
Manufacturing Considerations
Drug Product Development
Sterilization Considerations
Regulatory Expectations
Future Outlook
References
Part IV: Specialty Products and Generic Development
Implantable Devices to Treat Ophthalmic Conditions: Drug Delivery Systems
Introduction
Ocular Drug Delivery Systems
Alternatives to Typical Ophthalmic Drug Administration Routes
Biodegradable Ocular Drug Delivery Systems
Biodegradable Implants in Clinical Use
Ozurdex/Posurdex
DEXYCU
Bimatoprost Implant
Investigational Biodegradable Implants
Brimonidine DDS
GB-102
OTX-TKI
OTX-TIC
AR-13503
AR-1105
PA5108
Discontinued Biodegradable Implants
Surodex
ENV515
IBI 20089
Nonbiodegradable Ocular Drug Delivery Systems
Nonbiodegradable Intravitreal Implants in Clinical Use
Retisert
Iluvien
YUTIQ
Investigational Nonbiodegradable Implants
Travoprost Intraocular Implant
Targeted Episcleral Delivery System (Episcleral Implant/Reservoir)
Discontinued Nonbiodegradable Implants
Vitrasert
I-Vation
Lumitect
NT-503
Implantable Drug Pumps
Replenish MicroPump
Port Delivery System
Ocular Inserts
Insoluble Ocular Inserts in Clinical Use or In Development
Mydriasert
Punctal Plugs
Bimatoprost Ring
OphthaCoil
TODDD
Soluble Ocular Inserts
Lacrisert
OTX-TP
Bioerodible/Biodegradable Ocular Inserts
NODS
Investigational Ocular Inserts
Brimonidine-Based Insert
Discontinued Ocular Inserts
Dextenza
Gelfoam
Ocusert Pilo
Conclusion
References
Development of Artificial Tears Products for Ocular Conditions
Introduction
Dry Eye Disease
Post-Operative Care
Contact Lens Comfort
Concomitant Use
Specialized Uses of Artificial Tears
Development Process
Product Requirements
Ingredients
Excipients
Preservatives
Raw Material Procurement
Process Development
Sterilization Methods and Strategies
Container-Closure Issues
Stability Issues
Clinical Validation
Final Steps for Commercialization
Regulatory Submissions
Product Launch Activities
Conclusions
References
Approval of Topical Ophthalmic Generic Products in the USA: Simple to Complex Dosage Forms and Establishing Equivalency
Therapeutic Equivalents and Generic Products
Inactive Ingredient Changes
The ANDA Regulatory Pathway
Offices Involved in Review of Ophthalmic Drug Applications
Bioequivalence Standards for Generic Drug Approval
Solution Products
Suspension and Emulsion Products
Ophthalmic Ointments
Research to Advance Equivalency Standards
Conclusion
References
The Development and Commercialization of Sustained-Release Ocular Drug Delivery Technologies
Introduction
Early Developments in Extraocular Sustained-Release Drug Delivery Products
Later Approved Extraocular Release Products
Intraocular Sustained Delivery
Later Intraocular Sustained-Release Drug Delivery Products
Intravitreal Injection (Non-Sustained Release) Drug Delivery Products
Developing New Sustained-Release Technologies
Drug Delivery Development: If a Drug Delivery Technology (DDT) Platform Only Approach Is the Primary Strategy
Challenges to a DDT-Focused Strategy
Opportunities for DDT-Focused Strategy
Drug Delivery Development: If a New Drug Is the Primary Strategy
Existing Drug-Existing Delivery System
Existing Drug: New Delivery System
New Drug: Existing Delivery System
New Drug: New Delivery System
Product Development
The “Ideal” DDT System
Target Release Profile
Commercialization: New Sustained-Release Drug Delivery Product
Stage 1: Clinical and Regulatory Program Management
Stage 2: Execution of Drug Delivery Development Program
Intellectual Property (IP)
Funding
Technology Pipeline
Summary: The Future
References
Trademarks
Manufacturing Considerations and Challenges for AAV Ocular Gene Therapy
Adeno-Associated Virus Vectors
Manufacture and Purification of AAV
Formulation Strategies
Aggregation of Vectors
Conclusions and Outlook
References
Correction to: Physicochemical and Biological Fundamentals for Drug Delivery to the Eye
Index