Risk Management of Biological Evaluation What s the Future for ISO 10993?

Transcription

1 Risk Management of Biological Evaluation What s the Future for ISO 10993?

2 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.

3 Evaluation Strategy ISO :2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process. Test Methods Part 5: Cytotoxicity Part 10: Irritation & hypersensitivity Part 11: Systemic toxicity Part 3: Part 6: Part 4: Genotoxicity, carcinogenicity and reproductive toxicity Implantation and local effects 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

4 Cytotoxicity Sensitization Irritation Systemic Toxicity (acute) Subchronic Toxicity Genotoxicity Implantation Haemocompatibility ISO :2009 Table A.1 Device Categorization Biological Effect Category Contact Duration A limited (<24h) B prolonged (>24h, <30d) C- permanent (>30d) 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

5 The Testing Trap Simple 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

6 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) ISO 14971

7 A Marriage of ISO & ISO Biological Evaluation in a Risk Management Framework

8 ISO ISO 10993

9 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?

10 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 misuse? This will allow definition of acceptability criteria.

11 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 Characterise the Materials bulk material additives process aids contaminants degradation products Manufacturer data Chemical & Physical Analysis See Parts 18 & 19 for detailed guidance Quantity? (Dose) See Parts 9, for guidance on degradation products Compliance with Materials Standards

12 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

13 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 (ISO )

14 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

15 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.

16 Risk Analysis Are risks acceptable? 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

17 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.

18 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

19 Biological Evaluation Process

20 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

21 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

22 Major review of parts

23 Evaluation Strategy ISO :2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process. Test Methods Part 5: Cytotoxicity Part 10: Irritation & hypersensitivity Part 11: Systemic toxicity Part 3: Part 6: Part 4: Genotoxicity, carcinogenicity and reproductive toxicity Implantation and local effects 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

24 Evaluation Strategy ISO :2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process. Test Methods Part 5: Cytotoxicity Part 10: Irritation & hypersensitivity Part 11: Systemic toxicity Part 3: Part 6: Part 4: Genotoxicity, carcinogenicity and reproductive toxicity Implantation and local effects 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

25 Evaluation Strategy ISO :2009 Biological Evaluation of Medical Devices: Part 1: Evaluation and testing within a risk management process. Test Methods Part 5: Cytotoxicity Part 10: Irritation & hypersensitivity Part 11: Systemic toxicity Part 3: Part 6: Part 4: Genotoxicity, carcinogenicity and reproductive toxicity Implantation and local effects 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

26 Cytotoxicity Sensitization Irritation Systemic Toxicity (acute) Subchronic Toxicity Genotoxicity Implantation Haemocompatibility 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) A X X X B X X X C X X X 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 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

27 A Marriage of US FDA & ISO Arthur Brandwood 亚瑟 博德博士

28 What s Changing? Part 1 Strong emphasis on risk management Incorporate TR 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

29 Thank You