1st Edition

Biomaterials, Medical Devices, and Combination Products Biocompatibility Testing and Safety Assessment

    606 Pages 70 B/W Illustrations
    by CRC Press

    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.

    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

    Biography

    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