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

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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


place deliverables in the DHF


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



Probe is loose or disconnected

9 6 54 Audible and Visual Check Probe alarm

9 2 1 18Q3

CDS-019



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



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


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

Documents

Crossing the Threshold ( FDA Regulatory Requirements for Medical Device Manufacturers)