crossing the threshold ( fda regulatory requirements for medical device manufacturers)
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Crossing the Threshold ( FDA Regulatory Requirements for Medical Device Manufacturers) DESIGN CONTROLS. FDA. Medical Device Design Controls. Introduction to the FDA Definitions Classes of devices Design control overview Risk assessment Verification and Validation testing - PowerPoint PPT PresentationTRANSCRIPT
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Crossing the Threshold( FDA Regulatory Requirements for Medical Device
Manufacturers)
DESIGN CONTROLS
FDA
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Medical Device Design Controls
Introduction to the FDA Definitions Classes of devices Design control overview Risk assessment Verification and Validation testing Software Quality Assurance Labeling Post design transfer issues
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Regulations
CBER CDRH CDER
Biologics
•21 CFR 600/601/610
Blood
•21CFR 606
21CFR 1270, 1271 (tissue)
21 CFR 58 (GLP)
21CFR 11 (electronic records)
Devices
•21 CFR 56 (IRB’s)
•21 CFR 58 (GLP)
•21CFR 11 (Electronic records)
•21 CFRR 800-1050 (devices)
•21 CFR 807 (510(k))
•21 CFR 812 (IDE)
•21 CFR 814 (PMA)
•21 CFR 21 CFR 820 QSR (GMP)
Drugs
• 21 CFR 56 (IRB’s)
• 21 CFR 58 (GLP)
• 21CFR 11 (Electronic records)
•21 CFR 210, 211 (Drug GMP’s)
• 21 CFR 312 (IND)
• 21 CFR 314 (NDA)
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What is a Medical Device?
Type of Product:An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar related article…
Intended use:…for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease . . . or intended to affect the structure or any function of the body…
Mode of action:… and which does not achieve any of its primary intended purposes through chemical action within or on the body or by being metabolized.
FD&C Act, §201(h)
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Research Design and Development
Manufacture and ServiceObsolescence
FDA review
Good Clinical PracticeClinical Trial ControlsGood Laboratory PracticeInvestigational Devices Exemptions (IDE’s)
Design ControlsGood Lab PracticesDocument ControlsElectronic Records
510(k) ClearancePMADocument Controls
Quality Systems RequirementsEstablishment RegistrationLabeling ControlsDesign controls
Record Retention
RecallsComplaints Medical Device Reporting
FDA Oversight in a Medical Device Life Cycle
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12 CFR 820.30 Requirements
All Class II and Class III devices, and some Class I devices require design controls.
Written procedures required. Procedures are controlled via document control.
Information about the design must be readily available to FDA – Design History Files.
Design controls can continue through the manufacturing and service phase.
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Intended use Product Class
Class I-Simple, Low risk. General controls needed (registration,
labeling, GMP) Class II- More complex, Medium risk.
Need 510(k) approval (some exemptions) Class III- Complex, High risk.
Generally life support, life sustaining, preventing impairment to human health or unreasonable risk to human life. Premarket Approval (PMA) needed prior to market.
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Examples
Class I Class II Class III Stethoscopes
Tung Depressors
Reagents used in Clinical Labs
Powered Tooth Brushes
Dental Chair
Catheters
Dental Implants
Biopsy Needles
Ultrasound Imaging System
Powered Wheelchair
Automatic Defibrillators
Artificial Hip Joints
Heart Valves
Extended Wear Contact Lenses
Left Ventricular Assist Devices
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Quality System
A Medical Device Quality System is designed to assure that products are Safe and Effective for their Intended Use
andConsistently meet the specifications as defined by results of clinical and/or detailed technical design and validation
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Design Control Elements21CFR 820.30
Design Planning Design Input (Requirements) Design Output (Specifications) Design Reviews (Technical) Design Verification (Meets
Specifications) Design Validation (Meets clinical needs) Design Transfer (Moves from Design to
Manufacturing) Design Changes (Formal Process) Design History File (DHF)
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Stage-Gate Method Defines phases of project. Uses design reviews and approvals as
gates between phases.
Feasibility and planning
Design ReviewDesign and
developmentDesign Review
Design history file
Verification and Validation
Transfer to manufacturing
Design ReviewOK OK OK OK OK OK
No
NoNo .no
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Design Controls General Stage-Gate Process
Phase I Feasibility and
Planning
Phase I Design Review
approved
Phase II, Design and Development
Phase II design review
approval
Phase III, Verification and
Validation
Phase III Design Review
Phase IV, Design documentation and transfer
Final design release
Document approval and
place deliverables in DHF
Document deliverables in the
DHF
Document approval and
place deliverables in the DHF
Document approval and
place deliverables in the DHF
Commercial manufacture
Feasibility assessment
Design input specifications
Regulatory/Clinical strategy
Initial Risk Assessment
Preliminary Project Plan
Initial Quality Plan
Design Review documentation
Final Design Specifications Design calculations, Summary of non-validation testing conducted, System Risk Assessment Final software code as intended to be released for
distribution Quality Plan Regulatory strategy Verification and validation test plan Labeling and user manuals Trace matrix between design specifications, risk
assessment and verification and validation test plan. Production prototype units for verification and
validation testing Bill of materials Quality documentation plan (inspection procedures,
Device Master Record, etc.) Design review
Hardware development
Software development
System integration
Design documentationFinal failure analysis/Risk ManagementLabels/labelingQuality Systems Testing planSystems verification test plan/Trace matrixDesign product brochures & literaturePilot build test protocol with approvalsReliability TestingMaterial requirementsManufacturing processesPackaging validationSterilization validationShelf life testingDesign and manufacturing V&V testing report Prior design review minutes reviewEssential Requirements ChecklistDesign History fileTechnical File or Design Dossier (If required per the Regulatory strategy)
System Verification testing
System Validation testing
Regulatory approvals
Design documentation
Labeling verification/validation
Initial manufacture of commercial
units
Feasibility/Technical
development
Design Input- customer input
documents
Project planning
Completed design of the product as manufacturedApproved vendors listComplete DMRManufacturing process validations as requiredFinal labeling/DFUsFinal marketing literatureDHF sign offDesign review and minutes
Yes
Yes
Yes Yes
Yes Yes
Yes Yes
Revise or Drop Project
Revise or Drop Project
Document in Design History
FileDrop DropRevise
Revise
Update or drop Document
rationale in DHFRedo testing
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Design Planning
Feasibility Studies Risk Assessments Project Plan Defines Interfaces with
Others Stage-Gate Methodology Constantly Changing
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Design Input-Feasibility Where
Customers Technical Papers Medical experts Service people
What Intended Use Technical Requirements Safety Issues
How Documented Approved Filed Formal Change Control System
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Risk Assessment
Clinical Risk Analysis
A compilation of the possible causes of death, serious injury or harm to either patient or user, from a procedural or medical basis, without regard to the specific device used for the procedure, based on actual clinical reference, prior art, published data, or documented experiences of knowledgeable clinical practitioners. These risks are associated with use of the device as detailed in its intended use statement and when used per the device’s instructions for use.
Manufacturing Risk Analysis
A compilation of the possible causes of death, serious injury or harm to anyone involved in the supply, testing, packaging, shipment, or disposal of a given device, as referenced by prior art, published data, or documented experiences or opinions of person(s) knowledgeable with the device and the methods of supply, testing, manufacture, packaging, shipment, and disposal of the device. Also, the manufacturing risk analysis contains the compilation of possible causes of a device to fail to perform to specifications in its intended use environment for the design life of the product which are caused by limitations or risks in the manufacturing process.
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Risk Assessment
Feasibility Clinical Risk
Summary
Design Input
Preliminary Design
Preliminary Risk Assessment:
Specification Trace Matrix: (links between) Specification Risk Analysis Fault Table Test PlanMitigations:
Final Risk Assessment:
Risk Management Document, Approvals
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ISO 14971 Risk Assessment
ExampleExample of a Hypothetical Risk
Assessment for a Electronic System to Monitor Patient Core
Body Temperatures
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Definitions
Harm: Physical injury or damage to the health of people, or damage to property or the environment
Hazard: Potential sources of harm Risk: Combination of the probability of Occurrence of
Harm and the Severity of the harm Risk Analysis: Systematic use of available information to
identify hazards and estimate the risk Residual Risk: Risk remaining after protective measures
and mitigations are taken Severity: A measure of the possible consequences of the
risk As Low As Reasonably Practicable (ALARP): The
residual risk is reduced to a level which is as low as can be reasonable implemented without sacrificing patient safety or clinical utility. The risk/benefit ratio is determined to be acceptable in light of technical feasibility and economic feasibility of implementing additional controls.
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Classification of Residual RiskSeverity Occurrence Detection Risk Quadrants Current Controls Corrective Actions
1 –10Scale
1- 10Scale
1-3 Scale 1- Risk, None to Little
None required None required
2- Risk, Minimal to Moderate
Recommended Recommended
3- Risk, Significant Required Required if no existing controls. (ALARP)
4- Risk, Serious Redesign * Redesign *
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SEVERITY TABLE Rating Effect Description of Rating Example
1 None No effect. Device operates as intended. Negligible
2 Very Minor Some customers notice defect. Device operates as intended. No effect on patient or clinician
3 Minor Device operates as intended. Slight effect on patient, clinician or user.
4 Very Low Patient comfort or convenience is slightlyReduced but with no patient, clinician or user injury.
5 Low Comfort or convenience is severely Reduced but with no patient, clinician or user injury.
6 Moderate Product is inoperable with no patient or user injury.
7 High Possible transient (reversible) minor injury to patient or user.
MarginalNeedle stick
8 Very High Transient minor injury to patient or user (possibility of further surgical procedures).
9 Hazardous - Possibly can contribute to death, severe injury,
permanent significant disability or severe occupational illness in patient or user.
Critical Exposure to blood borne pathogens
10 Hazardous – Irreversible
Can cause irreversible patient or clinician harm. (including for example organ failure, limb loss or death)
Catastrophic
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Occurrence
Rating Probability of Failure
Description of Rating Failure Rate
DFMEA PFMEA
1 Improbable Failure is unlikely. Failure unlikely. No failures ever associated with almost identical processes.
1 in 1,500,000(~ 0.000067%)
2 Remote Relatively few failures. Isolated failures associated with almost identical processes.
1 in 150,000(~ 0.00067%)
3 Isolated failures associated with similar processes.
1 in 15,000 (~ 0.0067%)
4 Occasional Occasional failures. Generally associated with processes similar to previous processes that have experienced occasional failures.
1 in 2000 (~ 0.05%)
5 1 in 400 (~ 0.25%)
6 Probable Repeated failures. Generally associated with processes similar to previous processes that have often failed.
1 in 80 (~1.25%)
7 1 in 20 (~ 5%)
8 Frequent Failure is almost inevitable. Failure is almost inevitable. 1 in 8 (~ 12.5%)
9 1 in 3 (~ 33 %)
10 1 in 2 ( 50%)
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Detection
Rating Probability of Detecti
on
Description of Rating
DFMEA PFMEA
1 Almost Certain
Design Control will almost certainly detect a potential Cause of Failure or subsequent Failure Mode.
Current Controls almost certain to detect failure mode or Cause.
Very High Very high chance Design Control will detect Cause of Failure or subsequent Failure Mode.
Very high likelihood that Current Controls will detect failure mode or Cause.
High High chance Design Control will detect Cause of Failure or subsequent Failure Mode.
High likelihood that Current Controls will detect failure mode or Cause.
2 Moderate Moderate chance Design Control will detect Cause of Failure or subsequent Failure Mode.
Moderate likelihood that Current Controls will detect failure mode or Cause.
3 Low Low chance Design Control will detect Cause of Failure or subsequent Failure Mode.
Low likelihood that Current Controls will detect failure mode or Cause.
Remote Remote chance Design Control will detect Cause of Failure or subsequent Failure Mode.
Remote likelihood that Current Controls will detect failure mode or Cause.
Absolute Uncertainty
Design Control will not detect a potential Cause of Failure or subsequent Failure Mode.
No known Controls available to detect Failure Mode or Cause.
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Quadrant MapOccurrence
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9Quad 4
8
7Quad 3
6
5Quad 2
4
3
2Quad 1
1
1 2 3 4 5 6 7 8 9 10Severity
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Risk Assessment TableClinical Risk AssessmentCause ID #Potential
Clinical RiskPossible effects
Potential causes
Initial State Controlling Action's)/ Design Mitigations
Post Mitigation State
. Spec Ref
SOf effect
OOf cause or
failure
Score SOf effect
OOf cause or
failure
DOf cause or
failure
Score (Quad)
CRA 01 Patient Core Temperature exceeds physiological limits
Severe Hyperthermia (Seizure, Death, Brain Damage)
Probe has a intermittent or “noisy” signal due to EMI in area
9 6 54 Audible and Visual Check Probe alarmEMC testing to UL/IEC 60601-1-2 Requirements
9 2 1 18Q3
CDS-015
CRA 02 Patient Core Temperature exceeds physiological limits
Severe Hyperthermia (Seizure, Death, Brain Damage)
Probe is loose or disconnected
9 6 54 Audible and Visual Check Probe alarm
9 2 1 18Q3
CDS-019
CRA 03 Patient Core Temperature exceeds physiological limits
Severe Hyperthermia (Seizure, Death, Brain Damage)
Probe not in calibration window Wrong Temp Probe used
9 7 63 Factory calibration window set for 400 Series thermistorSoftware Check for probe rangeAudible and Visual Check Probe alarm
9 2 1 18Q3
CDS-002
CRA 04 Patient Core Temperature exceeds physiological limits
Severe Hyperthermia (Seizure, Death, Brain Damage)
Infection, Drug reaction, disease state
9 4 36 Audible and Visual High Temp Alarm
9 2 1 18Q3
CDS-012
CRA 05 Patient Core temperature exceeds physiological limits
Severe Hyperthermia (Seizure, Death, Brain Damage)
Patient not being appropriately monitored
9 5 45 Audible and Visual High Temp AlarmLabeling and Training
9 2 1 18Q3
CDS-015
CRA 06 Patient Core temperature lower than physiological limits
Patient enters Hypothermia
Probe has a intermittent or “noisy” signal due to EMI in area
9 4 36 Audible and Visual Low Temp AlarmDesign for EMI immunity
9 2 1 18Q3
CDS-016
CRA 07 Patient Core temperature lower than physiological limits
Patient enters Hypothermia
Probe is loose or disconnected
9 6 54 Audible and Visual Low Temp AlarmAudible and Visual Check Probe alarmDesign fro interlocking connector
9 2 1 18Q3
CDS-018
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Design Output Final design specifications
Quantitative Documented Approved
Final specifications are contained in the design history file.
Final risk assessments completed. Clinical testing may be needed.
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Design Reviews
Formal Process Required for Phase Approval Checklists Minutes
Attendees- one not associated with items reviewed
Areas covered Action items/open issues
Open items closed for final release Formal design review prior to release for
manufacture and distribution
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Design Verification and Validation
Demonstrates that all the risks have been mitigated.
Demonstrates that specifications have been met.
Uses a trace matrix between risk assessment, specs and V&V plans.
Clinical trials may be needed to demonstrate safety and/or effectiveness.
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Design Verification And Validation
Verification - meets specification Validation - meets intended use Written procedure required. Testing must be documented,
reviewed and approved. Software must be verified and
validated. Manufacturing processes must be
verified and validated.
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System Verification and Validation
Product Requirements Specification complete
Software Validation and Verification Plan drafted
Software Requirements Specification generated
and approved
Software Development
Pilot Run completed
System Validation and Verification
Test Plan executed
System Validation Test Plan generated
Plan executed
Final Design Review
System integration completed
Detailed design
Plan approved ?
Plan approved ?
System V & V testing OK ?
Software V & V acceptable ?
System Validation and Verification Test Report generated
Software Validation and Verification Test
Report generated
Yes
No
Yes
Yes
Yes
No
No
No
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Software Quality-Design Controls
SRS
Software Verification Testing
System Design Specs and System V&V Activities
Unit level Risk and SRS trace
Unit verification activities
SDS
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Design Transfer Design moves from R&D to
manufacturing Manufacturing and production
specifications are documented Manufacturing risk assessment may
be needed Manufacturing IQ, OQ, PQ
IQ - Installation Qualification (Equipment) OQ - Operational Qualification( 1st ones meet specs) PQ - Performance Qualification (Consistently
repeatable)
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Design Changes All changes to the design after
release must be formally controlled (Change Control). Re-validation may be needed
Continues for the life of product. Documentation control system is
necessary.
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Labeling 21 CFR 801
Section 201(k) defines "label" as a:
"display of written, printed, or graphic matter upon the immediate container of any article..." The term "immediate container" does not include package liners. Any word, statement, or other information appearing on the immediate container must also appear "on the outside container or wrapper, if any there be, of the retain package of such article, or is easily legible through the outside container of wrapper."
Section 201(m) defines "labeling" as:
"all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article" at any time while a device is
held for sale after shipment or delivery for shipment in interstate commerce.
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Rx Medical Device Labeling
Intended Use Indications for Use Contraindications for Use Warnings, Cautions Description of the Device User Instructions Specifications Corrective Actions
(Troubleshooting)
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Labeling Controls
Need for a label or Labeling identified
Requirements determined
Translations needed?
Draft labeling created and
reviewed
Select qualified Supplier
Final labeling approval via
QSP0-0002 ECO process
Translations created
File and control per QSP0-0001Documentation
Control Process
Validation of labeling
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Labeling Verification
Labeling must be verified prior to FDA review and product release.
Users should also review labeling. Risk assessment “labeling”
mitigations must appear as warnings or cautions.
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Design History File
Record of the Development Process Plans Specifications V&V Test Results Design Reviews Changes to the Design
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Class Exercise-Design ControlsDr. Bright and Dr. Idea have found a novel way to produce a machine to determine if a heart attack patient has additional blockage in the coronary arteries that may be caused by the surgical bypass procedure (CABG). The machine non-invasively measures arterial flow by using Doppler sonar to determine if the arteries are blocked. It can be used in a patient’s home, by itself, on post heart attack patients who may be at risk for additional heart attacks. It transfers the data to a monitoring station at a EMS facility for 24/7 monitoring.
They have formed a company (The Bright-Idea Company), built a prototype and tested it in the lab on sheep and pigs. It worked great. Now they want to begin marketing it for use on humans.
1. Is the machine a medical device?2. What steps should Dr. Bright and Dr. Idea take before they
can begin marketing the machine? 3. What documents do they need to have on file?
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Questions