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ISO 10993 :A Risked Based Approach to
Biological Safety
Dr Arthur Brandwood• Australian Delegation Leader to ISO TC 194 – Biocompatibility and
Clinical Trials• Previous Director Devices Registration and Assessment at TGA and
Director, TGA Biomaterials and Engineering Laboratories• Past President Australian Society for Biomaterials• Chair Regulatory Expert Panel AusMedtech• Member of AHWP SG1 and Leader of Combination Products Task group• Adviser and trainer to multiple Asia Pacific regional regulators• Visiting Professor in Biomedical Engineering, University of Sydney
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Arthur Brandwood 亚瑟博德 博士
A Marriage of ISO 14971 & ISO 10993-1Biological Evaluation in a Risk Management Framework
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ISO 14971 ISO 10993
Family of Three
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Agenda
Overview of ISO 10993 and its parts
ISO 14971 Risk Management Paradigm
Understanding Exposure and Risk Analysis
Understanding the Device/Materials
Testing as a supplement to knowledge
Reporting
Summary Overall Process
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ISO 10993High 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.Subsequent Parts are numbered ISO 10993-2 (Part 2) , ISO 10993-3 (Part 3) …
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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Biological Evaluation is both a Design Activity and part of Risk Management
ISO 13485 Biological Safety
requirements are a Design Input−What are the specific biological
hazards and risks in my application?
Compliance with biological safety is part of Design Verification−How do I show that my device
meets acceptable levels of biological safety?
ISO 14971 Biological Risks are dealt with
in conventional Risk Management framework:−Risk Analysis to identify hazards
and risks
−Risk Evaluation to determine level of risk
−Risk Control to mitigate risk
−Build on knowledge through post production monitoring
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Biological Evaluation is both a Design Activity and part of Risk Management
ISO 13485 Clause 7.3.1 Design and development
planning
ISO 14971, Clause 3.4 Risk Management Plan
PLANNING IS ESSENTIAL…
ISO 10993-1 Clause 4.1: “The biological evaluation shall be planned, carried out, and
documented by knowledgeable and experienced professionals”
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Regulatory relevance
Essential Principle 2 (Risk Management)
Essential Principle 7.1 (Biological and Chemical Safety)
510(k) SubmisionSection 15 (Biocompatibility)
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“Biocompatibility” is…
“the ability of a material to perform with an appropriate host response in a specific
application1”−Absence of unacceptable adverse effects (safety)−Presence of desired host responses (performance)
ISO 10993 mainly deals with safety, by consideration of the toxicity of biomaterials used in devices. But note: desired host responses (performance) must be considered as part of ISO 13485 design verification of device.
The Williams dictionary of Biomaterials, D.F. Williams, 1999
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The things that matter : determining which aspects of biological safety must be
considered for my device
Toxicity
Time
Location
Quantity (Dose)
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Durationof exposure
A – limited <24 hours
B – prolonged 24 hours – 30 days
C – permanent >30 days• (Note: These do NOT align with definitions used for
device classification purposes in the Medical Device Directives and in other GHTF based regulatory systems)
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Locationof Patient (or user) contact
•Intact Skin – compression bandage, E.C.G. electrodes
•Mucosa – intraoral devices, colonoscopes•Compromised Skin – Wounds
Surface
•Indirect blood path – blood/fluid sets•Tissue contacting – surgical instruments, •Circulating blood – dialysis equipment, intravenous catheters
External Communicating
•Tissue – orthopaedic implants•Blood – pacemaker leads, ventricular assistsImplant
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Device Categorization Biological Effect
Category Contact
DurationA – limited (<24h)B – prolonged (>24h, <30d)C‐ permanent
(>30d)
Cytotoxicity
Sensitizatio
n
Irrita
tion
System
ic Toxicity
(acute)
Subchron
ic Toxicity
Gen
otoxicity
Implan
tatio
n
Haemocom
patib
ility
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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Device Categorization Biological Effect
Category Contact
DurationA – limited (<24h)B – prolonged (>24h, <30d)C‐ permanent
(>30d)
Cytotoxicity
Sensitizatio
n
Irrita
tion
System
ic Toxicity
(acute)
Subchron
ic Toxicity
Gen
otoxicity
Implan
tatio
n
Haemocom
patib
ility
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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The Testing Trap
Simplistic 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 And tests are not foolproof…
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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)
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How? Apply Risk Management
ISO 14971
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ISO 14971 Risk Management Paradigm
Risk management
Risk assessment
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
Learn, iterate, develop
knowledge
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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
ISO 14971 Risk Management Paradigm
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Understand Your Device
How 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 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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Benefit
Risk
Safety is not Absolute
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What’s the Acceptable Risk?
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Understand Your Device Characterise the Materials− bulk material− additives − process aids − contaminants− degradation products
Manufacturer data Chemical & Physical Analysis− See Parts 18 & 19 for detailed guidance− See Parts 9, 13-17 for guidance on
degradation products Compliance with Materials
Standards
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
Quantity?
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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 Risks What 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
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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Do we know enough? 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
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Conduct of Testing
• Select protocols and controls as per applicable ISO 10993 Parts
• Consider Product Specific Standards and Regulatory Guidances
Test Selection
• Commercial Test houses offer GLP testing to ISO 17025 or to FDA 21CFR 58.
Conduct Final Testing under
Good Laboratory Practice (GLP)
Laboratory Quality Systems
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Are risks acceptable?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
Acceptance criteria met?
Risk Control Required
Biological Safety is
EstablishedYES
NO
Do this for each separate aspect
of biological safety under consideration
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Options, options, options…
•Reconfigure packaging to reduce levels of sterilant residues
•Reconfigure mould to avoid need for mould release agent
Change Design
•Substitute less toxic catalyst
Change Materials/additives
•Batch release pyrogen test• Inspection or testing of raw materials or of finished products
Manufacturing Controls
•Labelling cautions about known responses e.g. Contact dermatitis or anaphylaxis in natural latex products.
• (See Essential Requirement 2 in MDD)
Provide Warnings
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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• Trend analysis• Adverse events?
Monitor Device in clinical use
• If necessary change materials/design
Update risk assessments
• Can be restricted in scope to consider change only
Update Biological safety evaluation
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 SAFETY REPORTPlan
Description of device and applicationAcceptance criteria
Materials characterizationSpecific formulationManufacturing processesChemical characterizationPhysical characterisationDegradation products and leachables
Review of DataLiterature (include search strategy)In house dataMaterials manufacturer data
Supplementary testingDetails of protocols, acceptance criteriaResults and discussion
Risk Evaluation and Risk Controls AppliedResidual RisksConclusions – Biological Safety
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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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Biological Evaluation Process
Perform toxicological Risk Assessment
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Summary - Risk Management Approach:Efficient – Comprehensive – Robust
• 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 Analysis
• Review all information including test results – quantify risks
Risk Evaluation
• If required, take steps to reduce toxicity to acceptable levels• Consider further testing to verify effectiveness of controls
Risk Controls
• Document the entire process• Justify acceptability of risk in context of clinical application
Report
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