materials characterization

8/10/2019 Materials Characterization

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Material

Characterization


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OverviewOverviewISO10993ISO10993--1:2003(E) Section 3.31:2003(E) Section 3.3 The following should be considered for their The following should be considered for theirrelevance to the overall biological evaluation ofrelevance to the overall biological evaluation ofthe devicethe deviceMaterial(s) of Manufacturer,Material(s) of Manufacturer,

Intended additives, process contaminants, &Intended additives, process contaminants, &and residues, Leachable substances,and residues, Leachable substances,Degradation products, other components andDegradation products, other components andtheir interactions in the final product and thetheir interactions in the final product and theproperties and characteristics of the finalproperties and characteristics of the finalproductproduct


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Our GoalsOur GoalsTo assist in establishing biocompatibility of aTo assist in establishing biocompatibility of a

Medical Device by identifying and quantifyingMedical Device by identifying and quantifyingthe chemical constituents of the materialsthe chemical constituents of the materials

Develop compliant & cost effective One ShotDevelop compliant & cost effective One Shot

Analyses meeting multiple requirementsAnalyses meeting multiple requirementsoutlined in the ISO10993 Standardsoutlined in the ISO10993 Standards

Minimize the number of devices for testingMinimize the number of devices for testing

Support process control in manufacturingSupport process control in manufacturing


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Importance of TestingImportance of TestingDemonstrate equivalency of proposed materialsDemonstrate equivalency of proposed materialsto a clinically established materialto a clinically established material

Demonstrate equivalency of device to aDemonstrate equivalency of device to aprototypeprototype

Material selectionMaterial selection

Material degradationMaterial degradationAssessment of overall biological safety of aAssessment of overall biological safety of amedical device (ISO10993medical device (ISO10993--1 & 14971)1 & 14971)

Vendor changesVendor changesQuality control on incoming raw materialsQuality control on incoming raw materials

Chemical correlation to physical testingChemical correlation to physical testing

Process validationsProcess validations


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DefinitionsDefinitionsExhaustive ExtractionExhaustive ExtractionExtraction until theExtraction until theamount of the residues in a subsequentamount of the residues in a subsequentextraction is less than 10% of that detected inextraction is less than 10% of that detected inthe first extractionthe first extraction

SimulatedSimulated--use Extractionuse ExtractionExtraction forExtraction forevaluating the potential risk to the patient or userevaluating the potential risk to the patient or userduring routine use of a device using andduring routine use of a device using andextraction method with an appropriate mediumextraction method with an appropriate medium

that simulates product usethat simulates product use

Definitions from ANSI/AAMI BE83:2006 Biological Evaluation of MeDefinitions from ANSI/AAMI BE83:2006 Biological Evaluation of Medical Devicesdical Devices

Part 18 Chemical Characterization of MaterialsPart 18 Chemical Characterization of Materials


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DefinitionsDefinitionsExtractableExtractableSoluble substances removed fromSoluble substances removed from

material when treated with solventmaterial when treated with solvent

LeachableLeachableChemical removed from a medicalChemical removed from a medical

device by the action of water and other liquidsdevice by the action of water and other liquidsrelated to the use of the devicerelated to the use of the device

Definitions from ANSI/AAMI BE83:2006 Biological Evaluation of MeDefinitions from ANSI/AAMI BE83:2006 Biological Evaluation of Medical Devicesdical Devices

Part 18 Chemical Characterization of MaterialsPart 18 Chemical Characterization of Materials


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Information to Collect BeforeInformation to Collect Before

TestingTesting

Select the appropriate analytical method to provideSelect the appropriate analytical method to provide

the required information for toxicological evaluationthe required information for toxicological evaluationqualitative or quantitativequalitative or quantitative

Material CompositionMaterial Composition

-- base materialbase material-- additives and processing aidsadditives and processing aids

Polymerization / crosslinking / curing processesPolymerization / crosslinking / curing processes

Fabrication process and additives used to assistFabrication process and additives used to assistfabricationfabrication

Cleaning & washing processesCleaning & washing processes

Packaging & storage processesPackaging & storage processes


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Potential Sources ofPotential Sources of

Extractables/LeachablesExtractables/LeachablesAdditivesAdditivesStabilizers, Plasticizers, ModifiersStabilizers, Plasticizers, Modifiers

ProcessProcessMould Release Agents, AntiMould Release Agents, Anti--staticstaticand Antiand Anti--slip agentsslip agents

LubricantsLubricantsOils and Degreasing AgentsOils and Degreasing Agents

AcceleratorsAccelerators

Monomers and Higher MW Oligomers fromMonomers and Higher MW Oligomers fromincomplete polymerizationincomplete polymerization

Residual SolventsResidual Solvents

Degradation ProductsDegradation ProductsTemperature,Temperature,Absorption, Hydrolysis, Oxidation, Corrosion orAbsorption, Hydrolysis, Oxidation, Corrosion orDissolutionDissolution


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Examples of Qualitative &Examples of Qualitative &

Quantitative ParametersQuantitative Parameters


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Qualitative Test MethodsQualitative Test MethodsIf extractables / leachables are not known,If extractables / leachables are not known,

perform screening methods to assessperform screening methods to assessmaterialsmaterials

-- USP Physicochemical TestUSP Physicochemical Test (NVR, Residue on(NVR, Residue onIgnition, Heavy Metals, Metals , and Buffering Capacity)Ignition, Heavy Metals, Metals , and Buffering Capacity)

-- GCMSGCMSSearchable LibrariesSearchable Libraries

-- FTIRFTIRLow ResolutionLow Resolution

-- Headspace TechnologyHeadspace Technology

GCMSGCMS

FTIRFTIRHigh ResolutionHigh Resolution


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Physicochemical TestPhysicochemical TestGood Starting PointGood Starting Point

A group of tests to characterize plasticA group of tests to characterize plasticcomponents of pharmaceutical containerscomponents of pharmaceutical containersand medical devicesand medical devices

Perform extractions with polar and nonPerform extractions with polar and non--polar solvents (e.g. H2O, IPA, & heptane)polar solvents (e.g. H2O, IPA, & heptane)

Determines presence of solubleDetermines presence of solublesubstances without regard to the identitysubstances without regard to the identity

Volatiles are not detectedVolatiles are not detected


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FTIRFTIRLow ResolutionLow Resolution

Fingerprints MaterialsFingerprints Materials

When compared to aWhen compared to a

known standard canknown standard can

be used to identify abe used to identify a

materialmaterial

Provides QualitativeProvides Qualitative

not Quantitativenot Quantitative


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FTIR Static Headspace (SHS):

Outgassing ProfileFTIR Static HS Gas Cell

Total Cumulative

Outgassing vs Time

FITR Spectra

Concentratio

n

A

bsorbanceUnits

Time

SAMPLE

IR Source

IR Detector


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Dynamic HeadspaceDynamic HeadspaceOven (25 oC to 250 oC)

Sample is placed inside

the oven manifold

N2 Flow

Semi-VOCs

VOCs VOCs

TD Tube

is Analyzed

Thermal Desorption

(TD)

Trapping Tube

Resulting

Chromatogram

Semi-

VOCs

Volatile and SemiVolatile and Semi--Volatile CompoundsVolatile Compounds

ContaminantsContaminants

Sample is sealed in a leak free

Teflon Sample Chamber

ResidualsResiduals


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Advantages of HeadspaceAdvantages of HeadspaceAnalytes are concentratedAnalytes are concentratedNo SolventsNo Solvents

Ability to analyze Volatiles and nonAbility to analyze Volatiles and non--VolatilesVolatiles(including acid and bases)(including acid and bases)

--Residuals SolventsResiduals Solvents

--PlasticizersPlasticizers--AdditivesAdditives

--PhthalatesPhthalates

Shorter testing times than solvent extractionShorter testing times than solvent extractionGood Searchable LibrariesGood Searchable Libraries

Methods can be validated for quantificationMethods can be validated for quantification


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Quantitative Test MethodsQuantitative Test Methods

If extractables / leachables areIf extractables / leachables are

known, quantitative methods provideknown, quantitative methods provideactual concentrationsactual concentrations

Methods must be validatedMethods must be validated-- ICH Q2(R1)ICH Q2(R1)

-- USP USP

Search literature for publishedSearch literature for publishedmethodsmethods


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Example of Extractable AnalysisExample of Extractable Analysis

Polymer A + Chemical B YieldsPolymer A + Chemical B Yields

Finished Product CFinished Product C

Need to quantify the residuals fromNeed to quantify the residuals from

polymer A and Chemical B topolymer A and Chemical B todemonstrate purity.demonstrate purity.


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ApproachApproachSearch literature, which reveals that aldehydes, organicSearch literature, which reveals that aldehydes, organicacids, oligomers, and polymer may be present asacids, oligomers, and polymer may be present as

residualsresidualsScreened samples using FTIR (high resolution)Screened samples using FTIR (high resolution)

Extract finished product at 37Extract finished product at 37ooC for 24 Hours in Water,C for 24 Hours in Water,IPA, and Heptane (ISO10993IPA, and Heptane (ISO10993--12)12)

Develop GCDevelop GC--ECD method for residual aldehydesECD method for residual aldehydesDeveloped Static GCMS method for residual organicDeveloped Static GCMS method for residual organicacidacid

Run GelRun Gel--permeation chromatography GPC to look forpermeation chromatography GPC to look for

MW distribution of residual polymerMW distribution of residual polymerRun LCMS to look for high MW oligomersRun LCMS to look for high MW oligomers

Total time ~2 to 3 weeksTotal time ~2 to 3 weeks


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Database of MaterialsDatabase of Materials


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Example of Leachable AnalysisExample of Leachable AnalysisA proposal to reduce the allowable limit ofA proposal to reduce the allowable limit of

ethylene oxide residuals by a factor of 5ethylene oxide residuals by a factor of 5was made to the ISO community.was made to the ISO community.

Current analytical challenge: The currentCurrent analytical challenge: The current

analytical technology is not sensitive toanalytical technology is not sensitive tosupport the limit changesupport the limit change

Current technology will increase theCurrent technology will increase the

analysis cost to manufacturer by up to 5Xanalysis cost to manufacturer by up to 5Xfor devices alone.for devices alone.


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ApproachApproachEvaluated sensitivity Static of FTIREvaluated sensitivity Static of FTIR

Demonstrated equivalency of GCDemonstrated equivalency of GC--FIDFID

SPEMI and FTIR (SS,SPEMI and FTIR (SS, PeBaxPeBax,,

PolyproplyenePolyproplyene

,,

multicomponentmulticomponent

polymer)polymer)

Performed exhaustive and simulated usePerformed exhaustive and simulated use

comparisoncomparison

Presented to AAMI for approvalPresented to AAMI for approvalCurrently validating the methodCurrently validating the method


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FTIR AdvantagesFTIR AdvantagesFTIR Provides simultaneous analysis EO,ECH, EG (ISOFTIR Provides simultaneous analysis EO,ECH, EG (ISO1099310993--018)018)

Increased sensitivityIncreased sensitivity EO sensitivity to ~3ugEO sensitivity to ~3ug

ECH sensitivity to ~8ugECH sensitivity to ~8ug

Reduced testing time for exhaustive analysisReduced testing time for exhaustive analysisRate of release can be measured, calculatedRate of release can be measured, calculated

Other leachables are quantifiable in gas phaseOther leachables are quantifiable in gas phase

NonNon--destructive, vapor can be purged from system fordestructive, vapor can be purged from system for

further analysis, and Device may be used for additionalfurther analysis, and Device may be used for additionalextractions.extractions.

Minimal handling and the entire device is sampledMinimal handling and the entire device is sampled


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Analytical CapabilitiesAnalytical CapabilitiesGCMS, GCFID, GCECD, GCTCDGCMS, GCFID, GCECD, GCTCD

HPLCHPLC--UV,UV,--RI,RI,--DAD, LCMS, LCMSMSDAD, LCMS, LCMSMSFTIRFTIRLiquid and Gas PhaseLiquid and Gas Phase

HeadspaceHeadspaceDynamic and StaticDynamic and Static

Ion ChromatographyIon ChromatographyInherent ViscosityInherent Viscosity

GPCGPC

Permeability TestingPermeability TestingDissolutionDissolution

materials characterization

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