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Risk Management of Biological Evaluation – What’s the Future for ISO
10993?
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ISO 10993
High level guidance on how to conduct a biological evaluation
Detailed test methods for investigation of different aspects of biological safety
Supporting guidance on materials characterisation, use of reference materials, animal welfare, and more.
Reference to other test methods and guidances in Pharmacopoeia and national standards.
This body of guidance has taken almost 25 years to develop.
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Evaluation Strategy ISO 10993–1:2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process.
Test MethodsPart 5: CytotoxicityPart 10: Irritation & hypersensitivityPart 11: Systemic toxicityPart 3: Genotoxicity, carcinogenicity and
reproductive toxicityPart 6: Implantation and local effectsPart 4: Blood compatibilityPart 16: Toxicokinetic study design for
leachables and degradation productsPart 20: Principles and methods for
immunotoxicology testing
Reference MaterialsPart 8: Selection of reference materialsPart 12: Sample preparation and reference materials
Animal WelfarePart 2: Animal welfare requirements
Sterilization ResidualsPart 7: Ethylene oxide sterilization residuals
Degradation ProductsPart 9: Framework for Identification and
quantification of degradation productsPart 13: Identification and quantification of polymeric
degradation productsPart 14: Identification and quantification of ceramic
degradation productsPart 15: Identification and quantification of metallic
degradation productsPart 17: Establishment of allowable limits for
leachables
Materials CharacterizationPart 18: Chemical characterization of materialsPart 19: Physico-chemical, morphological and
topographical characterization
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Device Categorization Biological Effect
Category Contact
DurationA – limited (<24h)
B – prolonged (>24h, <30d)
C- permanent (>30d)
Cytotoxicity
Sensitization
Irritation
Systemic Toxicity (acute)
Subchronic Toxicity
Genotoxicity
Implantation
Haemocompatibility
Surface device
A X X X
B X X X
C X X X
Mucosal Membrane
A X X X
B X X X
C X X X X X
Breached or compromised surface
A X X X
B X X X
C X X X X X
Externalcommunicating
device
Blood Path, indirect
A X X X X X
B X X X X X
C X X X X X X
Tissue/bone/ dentin
A X X X
B X X X X X X X
C X X X X X X X
Circulating blood
A X X X X X
B X X X X X X X X
C X X X X X X X X
Implant device
Tissue/bone
A X X X
B X X X X X X X
C X X X X X X X
BloodA X X X X X X X
B X X X X X X X XC X X X X X X X X
ISO 10993-1:2009Table A.1
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The Testing TrapSimple approach
− just read the Table(s) and carry out tests. BUT, this is:
− expensive− wasteful− slow− unethical – using unnecessary animal experiments,
and− may miss some specific aspects relevant to your
device
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Don’t Do Unnecessary Testing
… testing shall not be carried out where:1) results are available from
relevant [previous] studies … or2) … existing pre-clinical and
clinical data, including history of safe use, meet the requirements of biological [evaluation]...
(ISO 10993-1 Clause 6.2.1)
ISO 14971
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A Marriage of ISO 14971 & ISO 10993-1Biological Evaluation in a Risk Management Framework
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ISO 14971
ISO/TR 15499
ISO 10993
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ISO 14971 Risk Management Paradigm
So How do I apply this to Biological Risk Management?
Risk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information
• Post production experience
• Review of risk management
Risk Evaluation • Risk acceptability
decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
ISO 10993
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Understand Your DeviceHow is it used
− duration and location of contact− consult Table A1 (and don’t forget
FDA G95-1)− consult regulatory guidances and
product standards− special factors – e.g. dental mucosa− misuse?
This will allow definition of acceptability criteria.
Risk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information
• Post production experience
• Review of risk management
Risk Evaluation • Risk acceptability
decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
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Characterise the Materials− bulk material− additives − process aids − contaminants− degradation products
Manufacturer dataChemical & Physical Analysis
− See Parts 18 & 19 for detailed guidance
− See Parts 9, 13-17 for guidance on degradation products
Compliance with Materials Standards
Quantity?(Dose)
Risk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information
• Post production experience
• Review of risk management
Risk Evaluation • Risk acceptability
decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
Understand Your Device
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Identify Hazards
What is the known toxicity of each material component?
What kind of toxic effects are known, are they relevant?
What is the dose-response relationship?−Availability – rate and pattern of
release−Total Patient Exposure
Risk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information
• Post production experience
• Review of risk management
Risk Evaluation • Risk acceptability
decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
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Estimate RisksWhat do we already know?
−Data on earlier generation devices−Other similar uses of the materials and
additives−In house testing data−Materials Manufacturer data−Literature
Understand the toxicology−Toxicology Databases
E.g. TOXNET (http://toxnet.nlm.nih.gov)−Routes of administration−NOAEL, LOAEL – compare these to known
quantities and release profiles in your device (ISO 10993-17)
Risk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information
• Post production experience
• Review of risk management
Risk Evaluation • Risk acceptability
decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
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Is existing knowledge enough to understand the biological risks applicable to the device use?
If not – carry out testing to fill the gaps in knowledge−Do testing according to
appropriate Parts of ISO 10993
−Compare test results to acceptability criteria
Risk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information
• Post production experience
• Review of risk management
Risk Evaluation • Risk acceptability
decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
Do we know enough?
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Conduct of TestingTest Selection
−Select protocols and controls as per applicable ISO 10993 Parts
−Consider Product Specific Standards and Regulatory Guidances
Conduct Final Testing under Good Laboratory Practice (GLP) Laboratory Quality Systems−Commercial Test houses offer GLP testing to ISO
17025 or to FDA 21CFR 58.
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Are risks acceptable?
Acceptance criteria met?
Risk Control Required
Biological Safety is
EstablishedYES
NO
Do this for each separate aspect of biological
safety under consideration
Risk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information
• Post production experience
• Review of risk management
Risk Evaluation • Risk acceptability
decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
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Options, options, options…Change Design
• Reconfigure packaging to reduce levels of sterilant residues• Reconfigure mould to avoid need for mould release agent
Change Materials/additives
• Substitute less toxic catalyst
Manufacturing Controls
• Batch release pyrogen test• Inspection or testing of raw materials or of finished products
Provide Warnings
• Labelling cautions about known responses e.g. Contact dermatitis or anaphylaxis in natural latex products.
Risk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information • Post production experience• Review of risk management
Risk Evaluation • Risk acceptability decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
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Monitor Device in clinical use
• Trend analysis• Adverse events?
Update risk assessments
• If necessary change materials/design
Update Biological safety evaluation
• Can be restricted in scope to consider change only
Learn, Iterate and Develop KnowledgeRisk Analysis
• Intended use/intended purpose identification
• Hazard identification • Risk estimation
Post-production information • Post production experience• Review of risk management
Risk Evaluation • Risk acceptability decisions
Risk Control• Option analysis • Implementation • Residual risk evaluation • Overall risk acceptance
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Biological Evaluation Process
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Existing Knowledge Sufficient to Evaluate?
Consider Clinical Application and Biological Risks
Materials Characterization
Do Testing to Fill Gaps in Knowledge
Evaluate Risks
Prepare Biological Evaluation
Report
Consider Existing Data
Apply Required Risk Controls
NO
YES
Biological Evaluation Process
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Summary - Risk Management Approach: Efficient – Comprehensive – Robust
Risk Analysis• Know your materials and their interactions• Draw on published literature, materials supplier’s data, comparative device experience• Then decide what you don’t know – identify testing needed• Do testing to fill in any gaps in knowledge• Justify not conducting testing when there is sufficient relevant pre-existing knowledge
Risk Evaluation
• Review all information including test results – quantify risks
Risk Controls• If required, take steps to reduce toxicity to acceptable levels• Consider further testing to verify effectiveness of controls
Report• Document the entire process• Justify acceptability of risk in context of clinical application
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Major review of 10993 parts
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Evaluation Strategy ISO 10993–1:2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process.
Test MethodsPart 5: CytotoxicityPart 10: Irritation & hypersensitivityPart 11: Systemic toxicityPart 3: Genotoxicity, carcinogenicity and
reproductive toxicityPart 6: Implantation and local effectsPart 4: Blood compatibilityPart 16: Toxicokinetic study design for
leachables and degradation productsPart 20: Principles and methods for
immunotoxicology testing
Reference MaterialsPart 8: Selection of reference materialsPart 12: Sample preparation and reference materials
Animal WelfarePart 2: Animal welfare requirements
Sterilization ResidualsPart 7: Ethylene oxide sterilization residuals
Degradation ProductsPart 9: Framework for Identification and
quantification of degradation productsPart 13: Identification and quantification of polymeric
degradation productsPart 14: Identification and quantification of ceramic
degradation productsPart 15: Identification and quantification of metallic
degradation productsPart 17: Establishment of allowable limits for
leachables
Materials CharacterizationPart 18: Chemical characterization of materialsPart 19: Physico-chemical, morphological and
topographical characterization
BRANDWOODBIOMEDICALsecuring your compliancewww.brandwoodbiomedical.com© Brandwood Biomedical
Evaluation Strategy ISO 10993–1:2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process.
Test MethodsPart 5: CytotoxicityPart 10: Irritation & hypersensitivityPart 11: Systemic toxicityPart 3: Genotoxicity, carcinogenicity and
reproductive toxicityPart 6: Implantation and local effectsPart 4: Blood compatibilityPart 16: Toxicokinetic study design for
leachables and degradation productsPart 20: Principles and methods for
immunotoxicology testing
Reference MaterialsPart 8: Selection of reference materialsPart 12: Sample preparation and reference materials
Animal WelfarePart 2: Animal welfare requirements
Sterilization ResidualsPart 7: Ethylene oxide sterilization residuals
Degradation ProductsPart 9: Framework for Identification and
quantification of degradation productsPart 13: Identification and quantification of polymeric
degradation productsPart 14: Identification and quantification of ceramic
degradation productsPart 15: Identification and quantification of metallic
degradation productsPart 17: Establishment of allowable limits for
leachables
Materials CharacterizationPart 18: Chemical characterization of materialsPart 19: Physico-chemical, morphological and
topographical characterization
BRANDWOODBIOMEDICALsecuring your compliancewww.brandwoodbiomedical.com© Brandwood Biomedical
Evaluation Strategy ISO 10993–1:2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process.
Test MethodsPart 5: CytotoxicityPart 10: Irritation & hypersensitivityPart 11: Systemic toxicityPart 3: Genotoxicity, carcinogenicity and
reproductive toxicityPart 6: Implantation and local effectsPart 4: Blood compatibilityPart 16: Toxicokinetic study design for
leachables and degradation productsPart 20: Principles and methods for
immunotoxicology testing
Reference MaterialsPart 8: Selection of reference materialsPart 12: Sample preparation and reference materials
Animal WelfarePart 2: Animal welfare requirements
Sterilization ResidualsPart 7: Ethylene oxide sterilization residuals
Degradation ProductsPart 9: Framework for Identification and
quantification of degradation productsPart 13: Identification and quantification of polymeric
degradation productsPart 14: Identification and quantification of ceramic
degradation productsPart 15: Identification and quantification of metallic
degradation productsPart 17: Establishment of allowable limits for
leachables
Materials CharacterizationPart 18: Chemical characterization of materialsPart 19: Physico-chemical, morphological and
topographical characterization
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Device Categorization Biological Effect
Category Contact
DurationA – limited (<24h)
B – prolonged (>24h, <30d)
C- permanent (>30d)
Cytotoxicity
Sensitization
Irritation
Systemic Toxicity (acute)
Subchronic Toxicity
Genotoxicity
Implantation
Haemocompatibility
Surface device
A X X X
B X X X
C X X X
Mucosal Membrane
A X X X
B X X X O O O
C X X X O X X O
Breached or compromised surface
A X X X O
B X X X O O O
C X X X O X X O
Externalcommunicating
device
Blood Path, indirect
A X X X X X
B X X X X O X
C X X O X X X O X
Tissue/bone/ dentin
A X X X O
B X X O O O X X
C X X O O O X X
Circulating blood
A X X X X O X
B X X X X O X O X
C X X X X X X O X
Implant device
Tissue/bone
A X X X O
B X X O O O X X
C X X O O O X X
Blood
A X X X X X X
B X X X X O X X X
C X X X X X X X X
FDA General Program Memorandum G–95 #1 (1995)Table 1
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Arthur Brandwood 亚瑟博德 博士
A Marriage of US FDA & ISO
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What’s Changing? Part 1
−Strong emphasis on risk management− Incorporate TR 15499 as Annex−Testing as a last step
Part 17−Refine the model, extra guidance on complex mixtures
Part 18−Where can Chemistry substitute for biology?
Parts 5, 10 and others− In vitro alternatives to animal models−Substantial technical updates
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Thank You