John Iannone, Technical Specialist/Program Manager, Toxikon Corporation

1. Material Characterization (ISO 10993-18)
When it is Needed
How to Satisfy the Requirements
John Iannone
Program Manager/ Technical Specialist

2. ISO 10993 – Biocompatibility & Characterization

3. ISO 10993
ISO 10993 consists of the following parts, under the general title
Biological evaluation of medical devices:
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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. 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. 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
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= Evaluation required by ISO, FDA and MHLW
= Evaluation required by ISO and FDA
=Evaluation required by FDA
=Evaluation required by ISO
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Biodegradation/
Biodegradable
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Reproductive/
Developmental
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Carcinogenicity
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Chronic Toxicity
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Hemocompatibility
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Implantation
Breached/Compromised
Surface
less than 24 hours
24 hours to 30 days
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Genetic
Toxicity/Genotoxicity
more than a 30 days
Mucous/Mucosal
Membrane
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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. 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. 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. 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
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9. Leachate Migration/ Extraction
Polymer
Migration
Extraction Solution
Environment of Concern
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10. So what are Extractables & Leachables?

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.
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12. Extractable/Leachable Relationship
Extractables/Leachables
» LEACHABLES are typically a SUBSET of EXTRACTABLES
» NOT ALL LEACHABLES are EXTRACTABLES
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13. When do I Need E&L Testing?

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.
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15. When do I perform an E&L Study?
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16. How do I satisfy the Requirements?

17. With so Many Devices… What is one to do?
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CONFIDENTIAL

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
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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!
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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
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21. Extractable/Leachable Sources
Potential
Inorganic
Compounds
of concerns
Metals
If you don’t look for it, you won’t find it!
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22. Leachable Sources
Volatile Organic Compounds:
»
»
»
»
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Monomer Residues
Solvent Residues from Production steps
residues from polymer treatments (e.g. washing)
Small Polymer Breakdown products

23. Leachable Sources
Semi-Volatile Organic Compounds:
»
»
»
»
»
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Lubricants
Plasticizers
Antioxidants
Polymer degradation products
Solvents with an elevated boiling point

24. Leachable Sources
Non-Volatile Organic Compounds:
»
»
»
»
»
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Fillers
Plasticizers
Antioxidants
Polymerization or Hydrogenation Catalysts
Anti-slip agents

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
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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. 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. 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
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Compound Toxicity Data?
Route of Administration?
How Much Delivered?
How Often?
How Long?
CONFIDENTIAL

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
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30. THANK YOU
John Iannone
Program Manager /Technical Specialist
john.iannone@toxikon.com
15 Wiggins Ave, Bedford, MA 01730
800-458-4141 x142
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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. 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.