Brandwood cimdr 2015 biological safety risk management en

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Risk Management of Biological Evaluation – What’s the Future for ISO

10993?


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.


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


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


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


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


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


ISO 14971

ISO/TR 15499

ISO 10993


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


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







decisions



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







decisions


Understand Your Device


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







decisions



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







decisions


http://toxnet.nlm.nih.gov/


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







decisions


Do we know enough?


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.


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







decisions



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



Post-production information • Post production experience• Review of risk management

Risk Evaluation • Risk acceptability decisions



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



Post-production information • Post production experience• Review of risk management

Risk Evaluation • Risk acceptability decisions



Biological Evaluation Process


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


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


Major review of 10993 parts















leachables

















leachables

















leachables




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


Arthur Brandwood 亚瑟博德博士

A Marriage of US FDA & ISO


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


Thank You

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Brandwood cimdr 2015 biological safety risk management en