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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



Arthur Brandwood 亚瑟博德博士

A Marriage of ISO 14971 & ISO 10993-1Biological Evaluation in a Risk Management Framework


ISO 14971 ISO 10993

Family of Three


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


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.


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


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


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”


Regulatory relevance

Essential Principle 2 (Risk Management)

Essential Principle 7.1 (Biological and Chemical Safety)

510(k) SubmisionSection 15 (Biocompatibility)


“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


The things that matter : determining which aspects of biological safety must be

considered for my device

Toxicity

Time

Location

Quantity (Dose)


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)


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


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


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


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…


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)


How? Apply Risk Management

ISO 14971



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


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



ISO 10993



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




management




Benefit

Risk

Safety is not Absolute


What’s the Acceptable Risk?


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




management



Quantity?


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




management




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




management




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




management




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


Are risks acceptable?Risk Analysis




management



Acceptance criteria met?

Risk Control Required

Biological Safety is

EstablishedYES

NO

Do this for each separate aspect

of biological safety under consideration


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




management




• 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




management




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


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


Biological Evaluation Process

Perform toxicological Risk Assessment


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



Questions?


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− and others including China

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ISO 10993 : A Risked Based Approach to Biological Safetybrandwoodbiomedical.com/wp-content/uploads/sites/11/2014/10/Arthur... · BRANDWOOD:BIOMEDICAL securing your compliance ISO