Medical Device Risk Management James Pink Requirements The medical device industry is highly regulated and based upon a device specific risk rating for dealing.
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Medical Device Risk Management James Pink Requirements The medical device industry is highly regulated and based upon a device specific risk rating for dealing with the level of regulation to be applied prior to market acceptance All modern medical device regulations cite ISO14971:2007 as being the standard to apply for medical devices Global Harmonisation requirements GHTF safety and performance requirements require risk management to be used as a basis of identifying, evaluating, controlling and continuously monitoring the effectiveness of risk controls. The need for risk management Source GHTF Study Group 1 4 The need for risk management Source GHTF Study Group 1 5 The need for risk management 6 Does it mean anything to me as adrug manufacturer If you have a drug delivered by means of a combination product then you are required to ensure that the device meets all safety and performance criteria of medical device regulations. As a result you are required to ensure that devices for drug-device combinations are being designed, manufactured, supplied and used in a way that all risks are controlled and the risks are outweighed by the clinical benefit. The need for risk management 8 Risk management process ISO14971:2007 requirements 9 Risk Management Organisation •Failures in Test •Technology limitations •User feedback including failures and hazards •Summarise knowledge with respect to risks Proof of concept 10 Design Planning •Clinical literature Review •Standards •Competitor products • Create Risk Management Plan •Simulations and Validations •Testing results •Supplier Part approvals •Bench Testing •Clinical investigations •Risk Management Reviews Designing Design Transfer •Process Validation data •Supplier qualification data •Manufactured variance analysis •Process FMEA •Risk Controls and Transfer to Validation, Complaints, Vigilance, Change control and Supply chain •Clinical follow-up trends •Published articles •Complaints investigations •Usability trends •Survivorship •Other PMS analysis •New Risks, Frequencies and severities Clinical Validation Risk management process Input Output New Product development New Process introduction Change to Product Change to process Significant Change Adverse Incident trends Adverse Manufacture trends New markets / users PMS Trends CAPA Trends Risk Management controls Management Review analysis Adverse trends awareness Manufacturing limits & Controls Supplier limits & Controls Surgeon Training points Post Market Clinical Follow-up Complaints investigator training Change control team awareness CAPA investigator awareness Resources Meetings, Measures and actions Risk Management Team Risk Management experts Risk Management database Customers and Clinical leads PMS Meetings Product Review meetings Supplier Meetings Change control meetings Intra project Risk Analysis meetings Risk Management review meetings Management Review meeting Surgeon / User feedback Clinical Evaluation updates New Standards, risks and controls Records Risk Management Plans Risk Management FMEA’s Risk Management Reports 11 Activity Risk management process Example Complaints Analysis New Product Development Change Control Risk Management Clinical Evaluation Validation CAPA A new product development project is initiated. The process requires a plan, defines the information sources and identifies how clinical benefit will be derived from customers. Risk reviews, tools and methods are all defined including the forms, procedures and records required A Final report is written defining residual risks, controls and clinical benefit 12 Risk management process Example Complaints Analysis New Product Development Change Control Risk Management Clinical Evaluation Validation CAPA 13 A change in Valve supplier is proposed for the MDI. The process defines what will happen, how the change is categorised based upon importance and defines the level of process risk management, controls and reviews necessary. Risk reviews, tools and methods are all defined including the forms, procedures and records required Risk Management - Acceptability ISO14971:2007 requirements THIS HAS TO COME FROM A JOINT REVIEW WITH YOU AND YOUR SUPPLIER 14 Probability 5 4 3 2 1 = = = = = <1 in 100 1 in 100 1 in 1000 1 in 10,000 >1 in 100,000 Based upon Surgical procedures 15 Increasing probability of occurrence of Harm Risk management acceptability Severity 5 4 3 2 1 Increasing severity of Harm = = = = = Death Revision / irreversible Reversible injury Minor Injury Inconvenience Probability 5 4 3 2 1 = = = = = <1 in 100 1 in 100 1 in 1000 1 in 10,000 >1 in 100,000 Based upon Surgical procedures 16 Increasing probability of occurrence of Harm Risk management acceptability Severity 5 4 3 2 1 Increasing severity of Harm Device fails to deliver appropriate uniform dose over time = = = = = Critical to safety Critical to function Customer Image Upset the customer Inconvenience Risk management acceptability 17 Risk management acceptability 18 Risk management acceptability 19 Risk management acceptability 20 Risk management acceptability 21 Risk management acceptability 22 Risk management acceptability Tips Ensure that you are focussed on the current state of the art with relation to drug - device performance Ensure that you are able to define hazardous situations based upon the major associated failures Be aware that the level of acceptability will be based around your critical to safety and quality requirements. The final clinical harm will be required so that contract design suppliers and manufacturers are aware of the severity of failure. 23 Risk management plans ISO14971:2007 requirements 24 Risk management plans Lifecycle phases Design and Development Concept and Definition Transfer to Manufacture and limited market placement Post Market If a drug manufacturer uses a device they must develop risk management plans that will ensure all elements of risk are covered from design through to manufacture 25 Risk management plans Step Step Step Step Step Step Hazardous Situation Valve affects Dose plume 26 Hazard Mechanical fatigue Harm Too much drug 1 2 3 4 5 6 - Undertake literature review Review previous designs Undertake Design Verification Undertake Design Validation Assign probability value Include in Clinical Evaluation Design Feature Probability Severity Valve and Actuator Fatigue ? 3 5 Risk management plans Risk Verification Report Risk Management Meeting date 21/12/2009 1 2 3 4 Summary Verified information source from Clinical evaluation report C01989 issue 2 Design FMEA conducted 21/12/2008 verified Test report T18786 revision 1 verified Reviewed Test report and confirmed risk control acceptable Conclusion Risks identified in the risk analysis coincide with the original information sources and risk management activities defined within the RM Plan document D001 revision 3 Controls within Design have been reviewed and reduction of probability is consistent with the control Signed ____________Date 21/12/2009 Hazardous Situation Valve affects Dose plume1 27 Hazard Mechanical fatigue Harm Too much drug Design Feature Probability Severity Valve and Actuator Fatigue2 ? 33 5 Risk management file ISO14971:2007 requirements 28 Risk management file Requirement Risk Management Plan Clinical Evaluation – PHA* Identification of Characteristics Design FMEA Application FMEA Process / Supplier FMEA Risk Management Report 29 Risk Analysis ISO14971:2007 30 Risk analysis • Failures in Test • Technology limitations • User feedback including failures and hazards • Summarise knowledge with respect to risks Design Planning • Clinical / Scientific literature Review • Standards • Competitor products • Create Risk Management Plan • Draw up Hazards Proof of concept • Simulations and Validations • Testing results • Supplier Part approvals • Bench Testing • Clinical investigations • Risk Management Reviews Design Transfer • Process Validation data • Supplier qualification data • Manufactured variance analysis • Process FMEA • Risk Controls and Transfer to Validation, Complaints, Vigilance, Change control and Supply chain • Clinical follow-up trends • Customer Performance evaluation • Published articles • Complaints investigations • Usability trends • Other PMS analysis • New Risks, Frequencies and severities Clinical Validation Designing Annex G activities MDI MDI Preliminary Hazard Analysis 31 Clinical / Scientific evaluation Preliminary report MDI MDI MDI MDI DFMEA Revision 1 DFMEA Revision 3 PFMEA Revision 1 PMCF Revision 1 Risk analysis 32 Preliminary Hazard Analysis Review of FDA Guidance provides the following summary of requirements.... Characteristic Hazardous Situation Potential Harm Severity Dose content uniformity Insufficient Dose uniformity - Design characteristic failure / Actuator / Valve insufficient dose delivered too high dose delivered depends on customer / drug depends on customer / drug Dose content uniformity Degradation of Dose uniformity over time – Design characteristic failure of actuator / valve over the lifetime of uses As above As Above Aerodynamic particle size Particle size is > 5Microns - Design characteristic failure of the MDI (Size and shape of expansion chamber / stem insufficient dose delivered As above Spray Pattern and Plum geometry Inappropriate spray pattern and or plume geometry – Design characteristic failure / Actuator / Valve As above As above Leaching Drug chamber / contact materials leaching polynuclear aromatics (PNAs), nitrosamines, monomers, plasticizers, accelerators etc. Toxicological effects depends on customer / drug and patient contact 33 The preliminary clinical / Scientific report Description of the intended performance Describe reasonable performance expectations Describe indications and claims if known Standards and Regulatory guidance review Literature review based upon common features / exclusion and inclusion criteria Summary of current methods and their limitations including current techniques, instrumentation and surgical technique, current outcomes and expected clinical benefit Evaluation of your experiences from similar devices Confirmation from your customer relating to some of the most important aspects for their Drug Master file. = Compilation of Hazards / Hazardous situations to be included in future risk analysis = Consideration relating to risk acceptability 34 The preliminary clinical report Ensure that previous risk analysis are reviewed. Review of Design failures (Where output could not be achieved) Review of failed validations Review of limitations – Technology, Process, Supply chain or Drug delivery Review of customer complaints relating to similar designs or similar intended use 35 Risk analysis – PHA for MDI. Hazard Forseeable sequence of events Hazardous situation Information Source Harm Mechanical Dose content uniformity After several actuations the dose content uniformity is compromised Design FDA Guidance Design and Test data on file Insufficient dose Overdose No dose FDA Guidance Design Data on file Toxicological / Poisoning [See Design FMEA for Valve and actuator design] Process See Process FMEA Use [See usability / AFMEA] Chemical Leaching Unintended leaching of toxic compounds from the container / plastic components enter into the drug and are delivered to the patient Design [Selection of the material and manufacturing method – See DFMEA] Process [See PFMEA – Inappropriate moulding parameters – incorrect material spec] Use [See usability / AFMEA] 36 Risk management in Design Tip Ensure that there are regular reports relating to the design progress but ensure that risks identified and their references are reported within the phase as this concentrates the minds of the people undertaking the design project 37 Risk management documentation in design 38 Risk Management Plan Clinical / Scientific Reports R&D Reports Process Validation reports Supplier qualification reports Design Validation reports Usability reports Identification of characteristics affecting safety Design FMEA Process FMEA Application FMEA Risk management summary Post market clinical follow up and risk reviews Transfer to manufacture risk management control plans Risk management in design • Failures in Test • Technology limitations • User feedback including failures and hazards • Summarise knowledge with respect to risks Design Planning • Simulations and Validations • Testing results • Supplier Part approvals • Bench Testing • Clinical investigations • Risk Management Reviews • Clinical / Scientific literature Review • Standards • Competitor products • Create Risk Management Plan • Draw up Hazards Proof of concept • Process Validation data • Supplier qualification data • Manufactured variance analysis • Process FMEA • Risk Controls and Transfer to Validation, Complaints, Vigilance, Change control and Supply chain • Clinical follow-up trends • Customer Performance evaluation • Published articles • Complaints investigations • Usability trends • Other PMS analysis • New Risks, Frequencies and severities Designing Clinical literature Design Standards Competitor products Recalls and advisory Previous RA Prelim Hazard Analysis Intended Use Characteristics Hazard identification Risk Mgt Plan 39 Design Transfer Clinical Validation Outcomes Risk Analysis Reliability data Customer feedback Manufacturing data Risk Report Typical Controls in Design. 40 Functional Testing / Bench Testing Testing against a Standard – Validation i.e. ISO11137, ISO11607, ISO7206-4, IEC 60601-1 – FDA Guidance Simulation – Finite Element – Wear performance Hand Calculation Prototype study Choice of Materials Choice of processes and Technology Focus Group (Human Factor Analysis) Clinical Literature Searches Concept Reviews (Focus Group) – Surgeon / Clinical / User opinion CAD Assembly / Tolerance Study Design of Experiments Tolerance Stack Analysis Assembly Testing Scientific / Engineering Constant Review of Similar Designs Measurement Systems analysis Clinical Investigations Validations MTBF – Stability testing REMEMBER The control will be used in order to give you assurance when you are doing a test that you have covered a risk........ Typical controls in Design ISO Standards FDA Guidance Customer Testing methods Bespak Testing methods 41 Risk Management in process Moulding Material processing Machining Storage Assembly Risks Distribution Cleaning Sterilisation Labelling Packaging 42 Risk Management in process Validation activities should be initiated with risk management Process hazards should derive from the DFMEA Moulding Material processing Machining Storage Assembly Risks Distribution Cleaning Sterilisation Labelling Packaging 43 Risk Management in process Hazards How Moulding can initiate the hazard Moulding Material processing Machining Leaching Storage Assembly Inappropriate material Incorrect Heat and pressure Incorrect additives Inappropriate mould time ????? Risks Sequence of events inappropriate cross linking of polymer leads to plasticiser free radical inappropriate material formulation / ingredient selected 44 Moulding controls Distribution Cleaning Sterilisation Labelling Packaging Material verification Process Validation of Moulding parameters Goods inwards Verification of raw materials QC Sampling for Leaching Typical Controls in Process. 45 Testing Points Trained in a SOP Gauge R&R Process Validation Monitoring and Measurement (SPC Process or product parameters) Poke Yoke Settings Checkmate Verifications / Closed Loop Systems Software validation 5S / Line Clearances Identification and Traceability Physical Location controls Start up verifications In process verifications Routine Maintenance Calibration ISO13485:2003 / Ordinance or FDA Control requirements. Supplier Evaluation – First Article / PPAP Routine Audits Risk Controls – Risk benefit ISO14971:2007 requirements 46 Risk controls – risk benefit ISO14971:2007 requirements 47 Risk Management Report 48 Typical Risk Management Report Summarises the Way you did risk management Summarises that the risk controls have been implemented (And verified) Summarises where you got the information Provides a succinct summary of the results of the activities and how controls will be reviewed on an ongoing basis 49 Keeping risk management alive Concept diagram - MDI Define Define the the need need What the clinical benefit would be Reasonable expected performance Hazards relating to the current use, Technology Database 51 Define the Scope Project Define the Scope ofof the Project Area MDI Operator / User COPD Patient Delivery method Valve / Actuator Intended Use Particle Size Number of uses Drug type Indications for use Critical to quality requirements Technology Moulding / Machining Develop the Product Develop the Product Risk control Verification Risk Manage Report Design Validation DFMEA Lifecycle Develop the Product Place on Market PHA PHA Select the Risk Management Plan to use Generic RM Plan Dev Develop the Product Implement Process Customer Acceptability Process Validation Clinical Benefit V Risk Risk controls effective? Custom RM Plan Dev change to risk? Lifecycle NO PFMEA YES On Market RM Plan Lifecycle Change RM Plan Lifecycle