ISO : A Risked Based Approach to Biological Safety

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1 ISO : 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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3 A Marriage of ISO & ISO Biological Evaluation in a Risk Management Framework Arthur Brandwood 亚瑟 博德博士

4 Family of Three ISO ISO 10993

5 Agenda Overview of ISO and its parts ISO Risk Management Paradigm Understanding Exposure and Risk Analysis Understanding the Device/Materials Testing as a supplement to knowledge Reporting Summary Overall Process

6 ISO 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.

7 Evaluation Strategy ISO :2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process. Subsequent Parts are numbered ISO (Part 2), ISO (Part 3) Test Methods Part 5: Cytotoxicity Part 10: Irritation & hypersensitivity Part 11: Systemic toxicity Part 3: Genotoxicity, carcinogenicity and reproductive toxicity Part 6: Implantation and local effects Part 4: Blood compatibility Part 16: Toxicokinetic study design for leachables and degradation products Part 20: Principles and methods for immunotoxicology testing Sterilization Residuals Part 7: Ethylene oxide sterilization residuals Animal Welfare Part 2: Animal welfare requirements Reference Materials Part 8: Selection of reference materials Part 12: Sample preparation and reference materials Degradation Products Part 9: Framework for Identification and quantification of degradation products Part 13: Identification and quantification of polymeric degradation products Part 14: Identification and quantification of ceramic degradation products Part 15: Identification and quantification of metallic degradation products Part 17: Establishment of allowable limits for leachables Materials Characterization Part 18: Chemical characterization of materials Part 19: Physico-chemical, morphological and topographical characterization

8 Biological Evaluation is both a Design Activity and part of Risk Management ISO 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 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

9 Biological Evaluation is both a Design Activity and part of Risk Management PLANNING IS ESSENTIAL ISO Clause Design and development planning ISO 14971, Clause 3.4 Risk Management Plan ISO Clause 4.1: The biological evaluation shall be planned, carried out, and documented by knowledgeable and experienced professionals

10 Regulatory relevance Essential Principle 2 (Risk Management) Essential Principle 7.1 (Biological and Chemical Safety) 510(k) Submision Section 15 (Biocompatibility)

11 Biocompatibility is the ability of a material to perform with an appropriate host response in a specific application 1 Absence of unacceptable adverse effects (safety) Presence of desired host responses (performance) ISO 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 design verification of device. The Williams dictionary of Biomaterials, D.F. Williams, 1999

12 The things that matter : determining which aspects of biological safety must be considered for my device Location Time Quantity (Dose) Toxicity

13 Duration of exposure A limited B prolonged C permanent <24 hours 24 hours 30 days >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)

14 Location of Patient (or user) contact Surface Intact Skin compression bandage, E.C.G. electrodes Mucosa intraoral devices, colonoscopes Compromised Skin Wounds External Communicating Indirect blood path blood/fluid sets Tissue contacting surgical instruments, Circulating blood dialysis equipment, intravenous catheters Implant Tissue orthopaedic implants Blood pacemaker leads, ventricular assists

15 Device Categorization Biological Effect ISO :2009 Table A.1 Category Contact Duration A limited (<24h) B prolonged (>24h, <30d) C permanent (>30d) Cytotoxicity Sensitization Irritation Systemic Toxicity (acute) Subchronic Toxicity Genotoxicity Implantation Haemocompatibility Surface device External communicating device Implant device Mucosal Membrane Breached or compromised surface Blood Path, indirect Tissue/bone/ dentin Circulating blood Tissue/bone Blood A X X X B X X X C X X X A X X X B X X X C X X X X X A X X X B X X X C X X X X X A X X X X X B X X X X X C X X X X X X A X X X B X X X X X X X C X X X X X X X A X X X X X B X X X X X X X X C X X X X X X X X A X X X B X X X X X X X C X X X X X X X A X X X X X X X B X X X X X X X X C X X X X X X X X

16 Device Categorization Biological Effect FDA General Program Memorandum G 95 #1 (1995) Table 1 Category Surface device External communicating device Implant device Contact Mucosal Membrane Breached or compromised surface Blood Path, indirect Tissue/bone/ dentin Circulating blood Tissue/bone Blood Duration A limited (<24h) B prolonged (>24h, <30d) C permanent (>30d) Cytotoxicity Sensitization Irritation A X X X B X X X C X X X Systemic Toxicity (acute) Subchronic Toxicity Genotoxicity Implantation A X X X B X X X O O O C X X X O X X O A X X X O B X X X O O O C X X X O X X O Haemocompatibility A X X X X X B X X X X O X C X X O X X X O X A X X X O B X X O O O X X C X X O O O X X 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 A X X X O B X X O O O X X C X X O O O X X 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

17 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

18 Don t Do Unnecessary Testing testing shall not be carried out where: 1) results are available from relevant [previous] studies or 2) existing pre-clinical and clinical data, including history of safe use, meet the requirements of biological [evaluation]... (ISO Clause 6.2.1)

19 How? Apply Risk Management ISO 14971

20 ISO Risk Management Paradigm Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk assessment Learn, iterate, develop knowledge Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Risk management Post-production information Post production experience Review of risk management

21 ISO Risk Management Paradigm Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation ISO Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Post-production information Post production experience Review of risk management So How do I apply this to Biological Risk Management?

22 Understand Your Device Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Post-production information Post production experience Review of risk management 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.

23 Safety is not Absolute Risk Benefit

24 What s the Acceptable Risk?

25 Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Post-production information Post production experience Review of risk management 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, for guidance on degradation products Compliance with Materials Standards Quantity?

26 Identify Hazards Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Post-production information Post production experience Review of risk management 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

27 Estimate Risks Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Post-production information Post production experience Review of risk management 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 ( Routes of administration NOAEL, LOAEL compare these to known quantities and release profiles in your device

28 Do we know enough? Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Post-production information Post production experience Review of risk management 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 Compare test results to acceptability criteria

29 Conduct of Testing Test Selection Select protocols and controls as per applicable ISO 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 or to FDA 21CFR 58.

30 Are risks acceptable? Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk Evaluation Risk acceptability decisions YES Biological Safety is Established Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Acceptance criteria met? Do this for each separate aspect of biological safety under consideration Post-production information Post production experience Review of risk management NO Risk Control Required

31 Options, options, options Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance 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 Post-production information Post production experience Review of risk management Labelling cautions about known responses e.g. Contact dermatitis or anaphylaxis in natural latex products. (See Essential Requirement 2 in MDD)

32 Learn, Iterate and Develop Knowledge Risk Analysis Intended use/intended purpose identification Hazard identification Risk estimation Risk Evaluation Risk acceptability decisions Risk Control Option analysis Implementation Residual risk evaluation Overall risk acceptance Monitor Device in clinical use Trend analysis Adverse events? Update risk assessments If necessary change materials/design Update Biological safety evaluation Post-production information Post production experience Review of risk management Can be restricted in scope to consider change only

33 BIOLOGICAL SAFETY REPORT Plan Description of device and application Acceptance criteria Materials characterization Specific formulation Manufacturing processes Chemical characterization Physical characterisation Degradation products and leachables Review of Data Literature (include search strategy) In house data Materials manufacturer data Supplementary testing Details of protocols, acceptance criteria Results and discussion Risk Evaluation and Risk Controls Applied Residual Risks Conclusions Biological Safety

34 Biological Evaluation Process Consider Clinical Application and Biological Risks Materials Characterization Consider Existing Data Do Testing to Fill Gaps in Knowledge NO Existing Knowledge Sufficient to Evaluate? Evaluate Risks YES Apply Required Risk Controls Prepare Biological Evaluation Report

35 Biological Evaluation Process Perform toxicological Risk Assessment

36 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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38 Questions?

39 TGA Submissions Australian Sponsor Service and others including China Regulatory Strategy Risk Analysis and Standards Compliance Quality Systems Clinical Trials Postmarket Compliance Reimbursement Regulatory Intelligence Training Let s talk! Contact us for a free noobligation initial consultation and quote help@brandwoodbiomedical.com Brandwood Biomedical has offices in Sydney and Beijing and offers specialist expertise throughout the Asia Pacific