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SPreclinical Testing for the Medical Device Industry –
Material Properties, Leachables/Extractables, and Surface Cleanliness
Jonas Weissenrieder, Ph.D.
Pace Analytical Life Sciences
Oakdale, Minnesota
Life Sciences
Effects of Material and Chemical properties on the biological profile
Chemical and Material Analysis
Why do chemical characterization?
Equivalence studies?
Economy?
Leachables/Extractables
How to design an extraction study?
Surface cleanliness
What to look for?
Outline
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What is influencing the biocompatibility?
Materials directly influence biocompatibility
High or low leachables/extractables
Surface/interfacial properties
particulates chemical compounds
biomolecules
surface topography and chemistry (device)
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Why Chemical Characterization?
Stronger signals than in animal studies
Bisphenol A (BPA)
Validated LC/MS/MS method
Health Canada requires information of
devices made from or containing BPA
Polycarbonate and Epoxy
Once you know what is dangerous,
chemical characterization is to prefer.
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ISO 14971: Medical Device –Risk Management
The toxicological risk assessment should take into account the chemical nature of the material; therefore it is necessary to determine the chemical composition of processing additives, residues, potential extractables and leachables.
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05Why Chemical Characterization?
Why Chemical Characterization?
Safety and Regulatory requirements
Part of 10993-1, perform chemical
characterization prior to animal studies
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ISO 10993-1 Evaluation and Testing
Biological Evaluation
Biological Testing Testing Administrative
Material Characterization
Chemical Characterization / Toxicological Evaluation
ISO 10993-18Chemical characterization of materials
ISO 10993-9ID and Quant. of deg. products
ISO 10993-13Polymers
ISO 10993-14Ceramics
ISO 10993-13Metals and Alloys
ISO 10993-16Toxicokinetic degradation and leachables
ISO 10993-17Est. allowable limits for leachables
ISO 10993-7Ethylene Oxide
ISO 10993-19Phys. Chem. materials
ISO 10993-6local effects after implantation
ISO 10993-5vitro cytotoxicity
ISO 10993-4interactions with blood
ISO 10993-3Genotoxicity, carcinogenicity,
and reproductive toxicity
ISO 10993-8Metals and Alloys
ISO 10993-2Metals and Alloys
ISO 10993-10irritation and delayed-type
hypersensitivity
ISO 10993-11systemic toxicity
ISO 10993-20immunotoxicology
ISO 10993-12Sample Preparation
ISO 10993-12Metals and Alloys
ISO 10993-12Sample Preparation
Life Sciences
ISO 10993-18
Identify chemical nature of materials
Composition (additives, residues, cleaning, processing etc.)
Predict biological response
Evaluating the potential of device to release substances or breakdown products due to manufacturing process
Changes in the material construction that are due to the manufacturing process or insufficient control of process
Potential reduction of animal testing
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ISO 10993-18
To demonstrate equivalence of a proposed material to a clinically established material
Screening for suitability of new materials
Judging equivalence of prototype to final device
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Decision Flow Chart from ISO 10993-18
STOP Extract Estimate clinical exposure
Composition
IdentifyMaterials, Components,
residue
Equivalent?
NoNo
Concerns?Yes
Yes
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Preliminary Evaluation
Supplier Data:• Technical data: known additives, residues, impurities, composition,
biological safety data, etc.
• Product literature: material specifications, MSDS
• Details of material composition and formulation
Device Manufacturer Data:• Internal specification and processing
• Material characterization data
• Biological safety data
• Clinical data
• Medical device reports
Other Pertinent data:• Literature Search: Journals, databases, etc.
• Known material interactions
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Decision Flow Chart from ISO 10993-18
STOP Extract Estimate clinical exposure
Composition
IdentifyMaterials, Components,
residue
Equivalent?
NoNo
Concerns?Yes
Yes
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Select the appropriate analytical method to provide the requiredinformation for toxicological evaluation – qualitative or quantitative
Material Composition
- base material
- additives and processing aids
Polymerization / crosslinking / curing processes
Fabrication process and additives used to assist fabrication
Cleaning & washing processes
Packaging & storage processes
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13Composition
Composition
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Evaluation using e.g.TOC, NVR and RoI
DI-GC-MS
ICP
FTIR
LC-MS
SHS-GCMS, DHS-GC-MS, SHS-FTIR
Polymer molecular weight
GPC or Viscosity
Surface AnalysisXPS, SEM-EDX, etc.
Material Equivalence
Perform an assessment of the data gathered:
• Is the proposed material equivalent to existing clinically established material including clinical exposure and processing?
• Does the proposed material meet an existing standard for intended use duration of contact and invasiveness?
• Is the proposed material already established in a more invasive exposure?
• Does the proposed material contain a chemical component or residue which has equal toxicological safety the component it replaces in a clinically established material (assuming similar exposure)?
• Is the only difference between the proposed material and clinically established material the elimination or reduction of an additive/contaminant/residue etc.?
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Decision Flow Chart from ISO 10993-18
STOP Extract Estimate clinical exposure
Composition
IdentifyMaterials, Components,
residue
Equivalent?
NoNo
Concerns?Yes
Yes
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Sources of Extractables/Leachables
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Additives – Stabilizers, Plasticizers, Modifiers, Catalysts
Process Impurities – Mould Release Agents, Anti-static and Anti-slip agents
Lubricants – Oils and Degreasing Agents
Monomers and Higher MW Oligomers from incomplete polymerization
Residual Solvents
Degradation Products
Exaggerated extraction
any extraction designed to get a greater extraction result than
simulated use
Simulated use extraction
extraction of sample with a medium and under conditions that
simulate product use, for the purpose of evaluating its potential
hazard to the patient during routine clinical use
exhaustive extraction
extraction until the amount of residues in a subsequent extraction is
less than 10% of that detected in the first extraction, or until there is
no significant increase in the cumulative residues detected.
Sample Preparation
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Life Sciences
19ISO 10993-12 : Extraction ratios
Extract in both polar and non-polar medium
ISO 10993-12 : Extraction conditions
Extract under agitation
(121 ± 2)°C for (1 ± 0.1) h
(70 ± 1)°C for (24 ± 2) h
(50 ± 2)°C for (72 ± 2) h
(37 ± 1)°C for (72 ± 2) h
(37 ± 1)°C for (24 ± 2) h
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Accuracy and precision
Specificity
LOD and LOQ
Linearity and Range
Ruggedness
Robustness
Validation
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Chemical Equivalence Example
Exhaustive extraction in polar and non-polar liquid
Exaggerated (70°°°°C in Water and IPA)
SHS-GC-MS and DHS-GC-MS
Samples from Conditions
Before Change
Process change of a device with metal and polymers
Samples from Conditions After
Change
ICP, DI-GC-MS, TOC, and NVR
Compare ResultsLife Sciences
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SHS-GC-MS and DHS-GC-MS
Biological Evaluation Testing
If equivalence is demonstrated, it may be possible to reduce the degree of biocompatibility testing.
If equivalence cannot be demonstrated through
material characterization, it may be necessary to
perform the full battery of biocompatibility tests.
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Approximate Price comparison
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Chemical Characterization
$4,0005-10 days12 devices
Biological Evaluation
$20,000 60 days
28 devices
(less than 24 h, blood contact)
Tool to tighten up process control
Assist in in future generations and product families
Chemical Characterization
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Additional benefits:
Surface Cleanliness
Recovery, etc
Extraction → Analysis for Unknown and known contaminants
Complicated geometry -> swabbing, rinsing
Method Feasibility
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Method Validation
Surface Analysis
Direct evaluation,
particulates, etc.
Choose Analytical Techniques
Method Development
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Thank you for your attention!
Jonas Weissenrieder, Ph.D.Pace Analytical Life Sciences
Oakdale, [email protected]
www.pacelifesciences.com
Life Sciences