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Material characterization per ISO 10993-18: When is it needed & how do I satisfy the requirements?

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Material characterization per ISO 10993-18: When is it needed & how do I satisfy the requirements?

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John Iannone, Technical Specialist/Program Manager, Toxikon Corporation

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  1. 1. Material Characterization (ISO 10993-18) When it is Needed How to Satisfy the Requirements John Iannone Program Manager/ Technical Specialist
  2. 2. ISO 10993 – Biocompatibility & Characterization
  3. 3. ISO 10993 ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – – – – – – – – Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity & reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification & quantification of potential degradation products – Part 10: Tests for irritation & skin sensitization – Part 11: Tests for systemic toxicity – Part 12: Sample preparation & reference materials 2
  4. 4. ISO 10993 ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – – – – – – – – Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity & reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification & quantification of potential degradation products – Part 10: Tests for irritation & skin sensitization – Part 11: Tests for systemic toxicity – Part 12: Sample preparation & reference materials 3
  5. 5. Biocompatibility Testing Matrix Devices connecting the internal to the external/External communicating device Blood Vessels/Blood Path Indirect more than a 30 days less than 24 hours 24 hours to 30 days more than a 30 days less than 24 hours 24 hours to 30 days more than a 30 days less than 24 hours Tissue/Bone/Dentin 24 hours to 30 days more than a 30 days less than 24 hours Circulating Blood 24 hours to 30 days more than a 30 days less than 24 hours Internally implanted devices/Implant device Tissue/Bone 24 hours to 30 days more than a 30 days less than 24 hours Blood 24 hours to 30 days more than a 30 days     4                                             = Evaluation required by ISO, FDA and MHLW = Evaluation required by ISO and FDA =Evaluation required by FDA =Evaluation required by ISO                Biodegradation/ Biodegradable  Reproductive/ Developmental   Carcinogenicity                     Chronic Toxicity                     Hemocompatibility                         Implantation Breached/Compromised Surface less than 24 hours 24 hours to 30 days                         Genetic Toxicity/Genotoxicity more than a 30 days Mucous/Mucosal Membrane                         Supplemental Sub acute and/or Sub chronic toxicity Body Surface Contact Device/Surface Device 24 hours to 30 days Pyrogenicity less than 24 hours Skin Systemic Toxicity (Acute) Contact duration Irritation/Intracutaneous Reactivity Body Contact Contact Sensitivity/Sensitization Category Initial Evaluation Cytotoxicity Device Categories
  6. 6. ISO 10993 ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – – – – – – – – Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity & reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification & quantification of potential degradation products – Part 10: Tests for irritation & skin sensitization – Part 11: Tests for systemic toxicity – Part 12: Sample preparation & reference materials 5
  7. 7. ISO 10993 ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – – – – – – – – Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity & reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification & quantification of potential degradation products – Part 10: Tests for irritation & skin sensitization – Part 11: Tests for systemic toxicity – Part 12: Sample preparation & reference materials 6
  8. 8. ISO 10993 (continued) ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – Part 13: Identification & quantification of degradation products from polymeric medical devices – Part 14: Identification quantification of degradation products from ceramics – Part 15: Identification & quantification of degradation products from metals & alloys – Part 16: Toxicokinetic study design for degradation products & leachables – Part 17: Establishment of allowable limits for leachable substances – Part 18: Chemical characterization of materials – Part 19: Physico-chemical, morphological & topographical characterization of materials – Part 20: Principles & methods for immunotoxicology testing of medical devices 7
  9. 9. Leachate Migration/ Extraction Polymer Migration Extraction Solution Environment of Concern 8
  10. 10. So what are Extractables & Leachables?
  11. 11. EXTRACTABLES & LEACHABLES » Extractables: Extractables are compounds that migrate from the contact surface under more aggressive conditions such as elevated temperature, extended contact time, or aggressive solvent system. Any component that is added to or pulled from the device or the materials used to make the device, including degradants and residuals. What CAN come out. » Leachables: Leachables are compounds that migrate from the contact surface under normal conditions of exposure. Leachables are usually subset of extractables. What DOES come out. 10
  12. 12. Extractable/Leachable Relationship Extractables/Leachables » LEACHABLES are typically a SUBSET of EXTRACTABLES » NOT ALL LEACHABLES are EXTRACTABLES 11
  13. 13. When do I Need E&L Testing?
  14. 14. When Do I Need or Want E&L Testing? » Failed or Interesting Biocompatibility Results – Determine source – Examine applicability » Evaluate Changes in Mfg Processes/ Material Supplier – Compare Extraction Profiles pre & post change (profile MUST be sufficiently comprehensive!) » Novel Device (i.e. combination products) – Is standard Biocompatibility sufficient testing? » Obtain Well Understood Extraction Profile – May reduce testing needs & risk  Colorants, Implants, etc. 13
  15. 15. When do I perform an E&L Study? 14
  16. 16. How do I satisfy the Requirements?
  17. 17. With so Many Devices… What is one to do? 16 CONFIDENTIAL
  18. 18. Understand what is happening Extractable Testing » Identify the potential compounds extracted into model solvents under aggressive conditions » Determine which, if any, compounds may affect patient or product Leachable Testing » Measure actual amount of leached compounds as a function of time » Determine How Much of What is present and: Does exposure to the patient affect safety?  Tox Assessment 17
  19. 19. How do I perform an E&L Study? » Extraction Ratios • Sensitive enough to evaluate relevant exposure • ISO 10993-12 • Lifetime exposure » Extraction Solutions • Consider the environment of concern • Body Contact (ISO 10993-12: polar & apolar) • Drug product formulation » Extraction Temperature • Simulated (Leachables) or Aggressive (Extractables) • Body Contact, Storage Conditions » Extraction Duration • Exhaustive, Simulated, Accelerated, Asymptotic Behavior » Sufficiently Comprehensive Trace Analysis • If you don’t look for it, you won’t find it! 18
  20. 20. But my material is used to make devices all the time! SOURCES OF LEACHATES » Polymer Additives  Antioxidants, Slip Agents, UV Stabilizers, Plasticizers, Colorants » Polymer Degradation Products  Sterilization, Storage, Processing » Residues  Monomers, Catalyst, Solvents » Manufacturing Impurities  Cleaners, Lubricants » Migration from Secondary Contacting Material  Adhesive, Ink, Multi-film, Nonhomogeneous Material, Packaging 19
  21. 21. Extractable/Leachable Sources Potential Inorganic Compounds of concerns Metals If you don’t look for it, you won’t find it! 20
  22. 22. Leachable Sources Volatile Organic Compounds: » » » » 21 Monomer Residues Solvent Residues from Production steps residues from polymer treatments (e.g. washing) Small Polymer Breakdown products
  23. 23. Leachable Sources Semi-Volatile Organic Compounds: » » » » » 22 Lubricants Plasticizers Antioxidants Polymer degradation products Solvents with an elevated boiling point
  24. 24. Leachable Sources Non-Volatile Organic Compounds: » » » » » 23 Fillers Plasticizers Antioxidants Polymerization or Hydrogenation Catalysts Anti-slip agents
  25. 25. Leachable Sources Inorganic Metal base complexes or compounds with metals in their molecular structure » » » Fillers Pigments Catalyst Residues Potential Inorganic Compounds of concerns Metals ICP 24
  26. 26. Analytical Methods for E&L Determination “FIRST PASS” Testing for Extractable Studies Try to Fully Characterize the Extraction Profile of material, using: Standard Analytical Equipment, e.g. 1. Headspace GC/MS 2. GC/MS 3. LC/MS 4. ICP 5. FTIR Optimized Procedures & Procotols » Leverage Compound Database (ie:TOX-RAY) for First Pass Analytical Techniques built on years of expertise & high volume of studies  high probability of ID in First Pass
  27. 27. Analytical Methods for E&L Determination LEACHABLES testing Select Targets, based upon » Extraction Studies » TOX-RITE information or other Toxicological Assessment information Ensure Adequate Quantitation of Relevant Compounds! Adequate Quantitation Impacted by: » The dosing regimen (frequency, volume) » The complexity of the Matrix » The toxicity of compounds
  28. 28. Risk Assessment of Medical Devices ISO 10993-17 Used as a follow-up to extractables and/or leachables testing (ISO 10993-18) » Review safety information for all identified compounds » Set limits of safe exposure » Compare limits to amounts seen in E&L data Anything can be poison/safe... It just depends on the dose • • • • • 27 Compound Toxicity Data? Route of Administration? How Much Delivered? How Often? How Long? CONFIDENTIAL
  29. 29. Conclusion Materials used in device design are utilized in more sensitive and unique configurations Biocompatibility Assays assess various mechanisms that may produce a reaction in the patient Chemical Characterization provides Key Information » Required to better design complicated/integrated systems » Understand how various interactions will ultimately affect the patient » Conduct a proper risk assessment of the total system Ensuring the product will do what it was set out to do: IMPROVE PATIENT CARE 28
  30. 30. THANK YOU John Iannone Program Manager /Technical Specialist john.iannone@toxikon.com 15 Wiggins Ave, Bedford, MA 01730 800-458-4141 x142 29
  31. 31. Analytical Methods for E&L Determination “SECOND PASS” Testing Utilize Specialized Analytical Equipment for further identification of any unknown compounds High End Analytical Equipment, e.g. 1. 2. 3. 4. 5. LC/MS Orbitrap GC-ToF (often in combination with derivatization) FT-MS NMR SEM-EDXA Project Related Second Pass Testing » » Evaluate the need to identify unknowns on a case by case basis Is it Toxicologically & Physiologically Relevant? Note: Be sure to collect data and further develop database from 2nd Pass testing to improve subsequent 1st Pass testing
  32. 32. Analytical Methods for E&L Determination ACCELERATED LEACHABLES testing In some cases: a SIMULATION study » As a step in between an Extraction Study & a “Formal Leachable” Study » Understanding the real risk of which extractable compounds may become leachable » Account for unexpected leachables and for secondary leachables » Using screening methodologies, not optimized for the specific matrix.

Description

John Iannone, Technical Specialist/Program Manager, Toxikon Corporation

Transcription

  1. 1. Material Characterization (ISO 10993-18) When it is Needed How to Satisfy the Requirements John Iannone Program Manager/ Technical Specialist
  2. 2. ISO 10993 – Biocompatibility & Characterization
  3. 3. ISO 10993 ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – – – – – – – – Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity & reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification & quantification of potential degradation products – Part 10: Tests for irritation & skin sensitization – Part 11: Tests for systemic toxicity – Part 12: Sample preparation & reference materials 2
  4. 4. ISO 10993 ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – – – – – – – – Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity & reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification & quantification of potential degradation products – Part 10: Tests for irritation & skin sensitization – Part 11: Tests for systemic toxicity – Part 12: Sample preparation & reference materials 3
  5. 5. Biocompatibility Testing Matrix Devices connecting the internal to the external/External communicating device Blood Vessels/Blood Path Indirect more than a 30 days less than 24 hours 24 hours to 30 days more than a 30 days less than 24 hours 24 hours to 30 days more than a 30 days less than 24 hours Tissue/Bone/Dentin 24 hours to 30 days more than a 30 days less than 24 hours Circulating Blood 24 hours to 30 days more than a 30 days less than 24 hours Internally implanted devices/Implant device Tissue/Bone 24 hours to 30 days more than a 30 days less than 24 hours Blood 24 hours to 30 days more than a 30 days     4                                             = Evaluation required by ISO, FDA and MHLW = Evaluation required by ISO and FDA =Evaluation required by FDA =Evaluation required by ISO                Biodegradation/ Biodegradable  Reproductive/ Developmental   Carcinogenicity                     Chronic Toxicity                     Hemocompatibility                         Implantation Breached/Compromised Surface less than 24 hours 24 hours to 30 days                         Genetic Toxicity/Genotoxicity more than a 30 days Mucous/Mucosal Membrane                         Supplemental Sub acute and/or Sub chronic toxicity Body Surface Contact Device/Surface Device 24 hours to 30 days Pyrogenicity less than 24 hours Skin Systemic Toxicity (Acute) Contact duration Irritation/Intracutaneous Reactivity Body Contact Contact Sensitivity/Sensitization Category Initial Evaluation Cytotoxicity Device Categories
  6. 6. ISO 10993 ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – – – – – – – – Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity & reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification & quantification of potential degradation products – Part 10: Tests for irritation & skin sensitization – Part 11: Tests for systemic toxicity – Part 12: Sample preparation & reference materials 5
  7. 7. ISO 10993 ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – – – – – – – – Part 1: Evaluation and testing within a risk management process Part 2: Animal welfare requirements Part 3: Tests for genotoxicity, carcinogenicity & reproductive toxicity Part 4: Selection of tests for interactions with blood Part 5: Tests for in vitro cytotoxicity Part 6: Tests for local effects after implantation Part 7: Ethylene oxide sterilization residuals Part 9: Framework for identification & quantification of potential degradation products – Part 10: Tests for irritation & skin sensitization – Part 11: Tests for systemic toxicity – Part 12: Sample preparation & reference materials 6
  8. 8. ISO 10993 (continued) ISO 10993 consists of the following parts, under the general title Biological evaluation of medical devices: – Part 13: Identification & quantification of degradation products from polymeric medical devices – Part 14: Identification quantification of degradation products from ceramics – Part 15: Identification & quantification of degradation products from metals & alloys – Part 16: Toxicokinetic study design for degradation products & leachables – Part 17: Establishment of allowable limits for leachable substances – Part 18: Chemical characterization of materials – Part 19: Physico-chemical, morphological & topographical characterization of materials – Part 20: Principles & methods for immunotoxicology testing of medical devices 7
  9. 9. Leachate Migration/ Extraction Polymer Migration Extraction Solution Environment of Concern 8
  10. 10. So what are Extractables & Leachables?
  11. 11. EXTRACTABLES & LEACHABLES » Extractables: Extractables are compounds that migrate from the contact surface under more aggressive conditions such as elevated temperature, extended contact time, or aggressive solvent system. Any component that is added to or pulled from the device or the materials used to make the device, including degradants and residuals. What CAN come out. » Leachables: Leachables are compounds that migrate from the contact surface under normal conditions of exposure. Leachables are usually subset of extractables. What DOES come out. 10
  12. 12. Extractable/Leachable Relationship Extractables/Leachables » LEACHABLES are typically a SUBSET of EXTRACTABLES » NOT ALL LEACHABLES are EXTRACTABLES 11
  13. 13. When do I Need E&L Testing?
  14. 14. When Do I Need or Want E&L Testing? » Failed or Interesting Biocompatibility Results – Determine source – Examine applicability » Evaluate Changes in Mfg Processes/ Material Supplier – Compare Extraction Profiles pre & post change (profile MUST be sufficiently comprehensive!) » Novel Device (i.e. combination products) – Is standard Biocompatibility sufficient testing? » Obtain Well Understood Extraction Profile – May reduce testing needs & risk  Colorants, Implants, etc. 13
  15. 15. When do I perform an E&L Study? 14
  16. 16. How do I satisfy the Requirements?
  17. 17. With so Many Devices… What is one to do? 16 CONFIDENTIAL
  18. 18. Understand what is happening Extractable Testing » Identify the potential compounds extracted into model solvents under aggressive conditions » Determine which, if any, compounds may affect patient or product Leachable Testing » Measure actual amount of leached compounds as a function of time » Determine How Much of What is present and: Does exposure to the patient affect safety?  Tox Assessment 17
  19. 19. How do I perform an E&L Study? » Extraction Ratios • Sensitive enough to evaluate relevant exposure • ISO 10993-12 • Lifetime exposure » Extraction Solutions • Consider the environment of concern • Body Contact (ISO 10993-12: polar & apolar) • Drug product formulation » Extraction Temperature • Simulated (Leachables) or Aggressive (Extractables) • Body Contact, Storage Conditions » Extraction Duration • Exhaustive, Simulated, Accelerated, Asymptotic Behavior » Sufficiently Comprehensive Trace Analysis • If you don’t look for it, you won’t find it! 18
  20. 20. But my material is used to make devices all the time! SOURCES OF LEACHATES » Polymer Additives  Antioxidants, Slip Agents, UV Stabilizers, Plasticizers, Colorants » Polymer Degradation Products  Sterilization, Storage, Processing » Residues  Monomers, Catalyst, Solvents » Manufacturing Impurities  Cleaners, Lubricants » Migration from Secondary Contacting Material  Adhesive, Ink, Multi-film, Nonhomogeneous Material, Packaging 19
  21. 21. Extractable/Leachable Sources Potential Inorganic Compounds of concerns Metals If you don’t look for it, you won’t find it! 20
  22. 22. Leachable Sources Volatile Organic Compounds: » » » » 21 Monomer Residues Solvent Residues from Production steps residues from polymer treatments (e.g. washing) Small Polymer Breakdown products
  23. 23. Leachable Sources Semi-Volatile Organic Compounds: » » » » » 22 Lubricants Plasticizers Antioxidants Polymer degradation products Solvents with an elevated boiling point
  24. 24. Leachable Sources Non-Volatile Organic Compounds: » » » » » 23 Fillers Plasticizers Antioxidants Polymerization or Hydrogenation Catalysts Anti-slip agents
  25. 25. Leachable Sources Inorganic Metal base complexes or compounds with metals in their molecular structure » » » Fillers Pigments Catalyst Residues Potential Inorganic Compounds of concerns Metals ICP 24
  26. 26. Analytical Methods for E&L Determination “FIRST PASS” Testing for Extractable Studies Try to Fully Characterize the Extraction Profile of material, using: Standard Analytical Equipment, e.g. 1. Headspace GC/MS 2. GC/MS 3. LC/MS 4. ICP 5. FTIR Optimized Procedures & Procotols » Leverage Compound Database (ie:TOX-RAY) for First Pass Analytical Techniques built on years of expertise & high volume of studies  high probability of ID in First Pass
  27. 27. Analytical Methods for E&L Determination LEACHABLES testing Select Targets, based upon » Extraction Studies » TOX-RITE information or other Toxicological Assessment information Ensure Adequate Quantitation of Relevant Compounds! Adequate Quantitation Impacted by: » The dosing regimen (frequency, volume) » The complexity of the Matrix » The toxicity of compounds
  28. 28. Risk Assessment of Medical Devices ISO 10993-17 Used as a follow-up to extractables and/or leachables testing (ISO 10993-18) » Review safety information for all identified compounds » Set limits of safe exposure » Compare limits to amounts seen in E&L data Anything can be poison/safe... It just depends on the dose • • • • • 27 Compound Toxicity Data? Route of Administration? How Much Delivered? How Often? How Long? CONFIDENTIAL
  29. 29. Conclusion Materials used in device design are utilized in more sensitive and unique configurations Biocompatibility Assays assess various mechanisms that may produce a reaction in the patient Chemical Characterization provides Key Information » Required to better design complicated/integrated systems » Understand how various interactions will ultimately affect the patient » Conduct a proper risk assessment of the total system Ensuring the product will do what it was set out to do: IMPROVE PATIENT CARE 28
  30. 30. THANK YOU John Iannone Program Manager /Technical Specialist john.iannone@toxikon.com 15 Wiggins Ave, Bedford, MA 01730 800-458-4141 x142 29
  31. 31. Analytical Methods for E&L Determination “SECOND PASS” Testing Utilize Specialized Analytical Equipment for further identification of any unknown compounds High End Analytical Equipment, e.g. 1. 2. 3. 4. 5. LC/MS Orbitrap GC-ToF (often in combination with derivatization) FT-MS NMR SEM-EDXA Project Related Second Pass Testing » » Evaluate the need to identify unknowns on a case by case basis Is it Toxicologically & Physiologically Relevant? Note: Be sure to collect data and further develop database from 2nd Pass testing to improve subsequent 1st Pass testing
  32. 32. Analytical Methods for E&L Determination ACCELERATED LEACHABLES testing In some cases: a SIMULATION study » As a step in between an Extraction Study & a “Formal Leachable” Study » Understanding the real risk of which extractable compounds may become leachable » Account for unexpected leachables and for secondary leachables » Using screening methodologies, not optimized for the specific matrix.

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