BIOMATERIALS, MEDICAL DEVICES, AND COMBINATION PRODUCTS. BIOCOMPATIBILITY TESTING AND SAFETY ASSESSMENT

• Safety Evaluation of Medical Devices
Introduction
Biocompatibility
Fundamentals of Biocompatibility Tests
Scope of Devices and the Medical Device Market
History
Nonspecific Regulatory Considerations
References
• Regulatory Aspects and Strategy in Medical Device and Biomaterials Safety Evaluation
Regulatory Basis
Toxicity Testing: Medical Devices
References
• Road Map to Test Selections
Key Concepts
References
• Materials in Medical Device Design
Introduction
Metals
Ceramics and Glasses
Polymers
Textiles
Biologically Sourced Materials
Surface-Modifying Materials
Tissue Engineering Scaffolds
Nanomaterials
References
• What to Test: Sampling and Sample Preparation
Sampling
Randomization
Sample Preparation
Reference Materials
Conclusion
References
• Cytotoxicity Testing
Introduction
Background
Crystal Violet Staining
Silicone Microphysiometer
Microtox Test
Neutral Red Uptake (NRU) Assay
MTT
Agar Diffusion Test
Direct Contact Test
Elution Test
Colony-Forming Assay (CFA)
Correlation With In Vivo Results
Conclusion
References
• Hemocompatibility (ISO 10993-4)
Noncontact Devices
External Communicating Devices
Implant Devices
Hemolysis Tests
The Osmotic Fragility Test
Erythrocyte Stability
Whole Blood Clotting Time
Thrombogenicity
Complement Activation
Protein Adsorption
Coagulation
Platelets
Conclusion
References
• Local Tissue Tolerance
Dermal Irritation
Ocular Irritation Testing
Other Nonparenteral Route Irritation Tests
Parenteral Irritation/Tolerance
Parenteral Routes
Intracutaneous Irritation
Factors Affecting Irritation Responses and Test Outcome
References
• Immunotoxicology (ISO 10993-20)
Overview of the Immune System
Immunotoxic Effects
Immunosuppression
Immunostimulation
Evaluation of the Immune System
Immunopathologic Assessments
Humoral Immunity
Cell-Mediated Immunity
Nonspecific Immunity
Host-Resistance Assays
Hypersensitivity
Local Lymph Node Assay (LLNA)
Approaches
Problems and Future Directions
References
• Implantation Biology and Studies
Usp Implantation Test
ISO 10993 Implantation Test
Preparation of Specimens for Implantation
Test Method for Implantation in Subcutaneous Tissue
References
• Acute Systemic Toxicity Testing and Device Safety Evaluation
Introduction
Acute Systemic Toxicity Characterization
References
• Genotoxicity
Introduction
DNA Structure
Cytogenetics
References
• Subchronic and Chronic Toxicity and Reproductive and Developmental Toxicity
Introduction
Objectives
Regulatory Considerations
Study Design and Conduct
Parameters to Measure
Histopathology
Study Interpretation and Reporting
Reproductive and Developmental Toxicity
Introduction
ICH Study Designs
Methodological Issues
Data Interpretation
References
• Carcinogenicity
Animal Model
Dose Selection
Interpretation of Results
References
• Degradation Products and Impurities Processes in Medical Devices
Introduction
Metals
Ceramics and Glasses
Degradation Processes
Effects of Sterilization
Interpretation of Sterility Test Results
Heavy Metals
Acknowledgment
References
• Special Case Devices
Introduction
Respiratory and Inhalation Devices
Ophthalmic Devices
Cardiovascular Devices and Prostheses
Tampons
Devices for Dentistry
References
• Combination Products
Device/Drug Combination Products
Historical Background
References
• Clinical Studies for Medical Devices
Design Considerations
Epidemiology
Conclusion
References
• Leachables and Extractables from Medical Devices
Introduction
Sample Preparation
General Principles of Leachables and Extractables under ISO 10993
Analytical Methods
Risk Assessment of Extracted Moieties
Introduction to (Q)SAR for Leachable and Extractable Evaluation
Risk Assessment for Leachables and Extractables
References
• Toxicokinetics in Biomaterial and Device Safety Evaluation
Introduction
Regulations
Principles
Laboratory Methods
Physiologically Based Pharmacokinetic (PBPK) Modeling
Biologically Derived Materials
References

• Special Studies
Anti-Infective Materials
Specific Tests
21-Day Eye Irritation Study in Rabbits
Systemic Injection Test
Production of Toxic Shock Syndrome Toxin-1 (TSST-1)
Inflammatory Responses to Biomaterials
References
• Case Histories and Problem Resolution
Phthalates Leaching From Polymer Devices
BPA: Bisphenol A
Talc on Gloves and Condoms
Latex Allergy
Silicones in Devices (Historical)
Intrauterine Devices
Toxic Shock Syndrome (Historical)
Conclusion
References

Appendix A: Selected Regulatory and Toxicological Acronyms
Appendix B: Contract Testing Laboratories
Appendix C: Notable Regulatory Internet Addresses
Appendix D: Non-U.S. Medical Device Regulators

• Provides a clear presentation of the global regulatory requirements and challenges in evaluating the biocompatibility and clinical safety of the materials used in producing medical devices and in the devices themselves
• Includes concerns arising from packaging, material processing, and contact with production machinery
• Presents the most current approaches for isolating and assessing the risk arising from chemical entities released from market-ready devices

Biomaterials, Medical Devices, and Combination Products is a single-volume guide for those responsible for—or concerned with—developing and ensuring patient safety in the use and manufacture of medical devices.
The book provides a clear presentation of the global regulatory requirements and challenges in evaluating the biocompatibility and clinical safety of the materials used in producing medical devices as well as the devices themselves.
Starting with material characterization and selection, considerations of concerns arising from packaging and contact with production machinery, and extensive coverage of combination products, the book also provides the latest approaches to isolating, quantitating, identifying and assessing the risk arising from chemical entities released from market-ready devices.
Also incorporated are new case examples and citations with the means of access to Internet-based regulatory and scientific sites, reflecting the universal adoption of this technology into our world.
The book takes into consideration the fact that device markets are global, the continual advancement of technology, and the increasing global harmonization of safety regulations. Each aspect of device safety evaluation is reviewed in terms of the International Organization for Standardization (ISO), US Food and Drug Administration (FDA), European Union (EU), and Japanese Ministry of Health, Labour, and Welfare (MHLW) perspectives.

Authors
• Shayne Cox Gad, PhD, DABT, Gad Consulting Services, Raleigh, North Carolina, USA
• Samantha Gad-McDonald, B.S.ENGR, Gad Consulting Services, Raleigh, North Carolina, USA

Contents
• Safety Evaluation of Medical Devices
• Regulatory Aspects and Strategy in Medical Device and Biomaterials Safety Evaluation
• Road Map to Test Selections
• Materials in Medical Device Design
• What to Test: Sampling and Sample Preparation
• Cytotoxicity Testing
• Hemocompatibility (ISO 10993-4)
• Local Tissue Tolerance
• Immunotoxicology (ISO 10993-20)
• Implantation Biology and Studies
• Acute Systemic Toxicity Testing and Device Safety Evaluation
• Genotoxicity
• Subchronic and Chronic Toxicity and Reproductive and Developmental Toxicity
• Carcinogenicity
• Degradation Products and Impurities Processes in Medical Devices
• Special Case Devices
• Combination Products
• Clinical Studies for Medical Devices
• Leachables and Extractables from Medical Devices
• Toxicokinetics in Biomaterial and Device Safety Evaluation
• Special Studies
• Case Histories and Problem Resolution
Appendix A: Selected Regulatory and Toxicological Acronyms
Appendix B: Contract Testing Laboratories
Appendix C: Notable Regulatory Internet Addresses
Appendix D: Non-U.S. Medical Device Regulators