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

DESIGN CONTROLS FDA

Medical Device Design ControlsIntroduction to the FDADefinitions Classes of devicesDesign control overviewRisk assessmentVerification and Validation testingSoftware Quality AssuranceLabeling Post design transfer issues

RegulationsCBERCDRHCDERBiologics21 CFR 600/601/610Blood21CFR 60621CFR 1270, 1271 (tissue)21 CFR 58 (GLP)21CFR 11 (electronic records)

Devices21 CFR 56 (IRBs)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 (IRBs)

21 CFR 58 (GLP)

21CFR 11 (Electronic records)21 CFR 210, 211 (Drug GMPs) 21 CFR 312 (IND) 21 CFR 314 (NDA)

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)

FDA Oversight in a Medical Device Life CycleResearchDesign and DevelopmentManufacture and ServiceObsolescenceFDA reviewGood Clinical PracticeClinical Trial ControlsGood Laboratory PracticeInvestigational Devices Exemptions (IDEs)Design ControlsGood Lab PracticesDocument ControlsElectronic Records510(k) ClearancePMADocument Controls

Quality Systems RequirementsEstablishment RegistrationLabeling ControlsDesign controls

Record RetentionRecallsComplaints Medical Device Reporting

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.

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.

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

Quality SystemA Medical Device Quality System is designed to assure that products are Safe and Effective for their Intended UseandConsistently meet the specifications as defined by results of clinical and/or detailed technical design and validation

Design Control Elements21CFR 820.30Design PlanningDesign 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)

Stage-Gate MethodDefines phases of project.Uses design reviews and approvals as gates between phases.

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 assessmentDesign input specificationsRegulatory/Clinical strategyInitial Risk AssessmentPreliminary Project PlanInitial Quality Plan Design Review documentation

Final Design SpecificationsDesign calculations, Summary of non-validation testing conducted, System Risk AssessmentFinal software code as intended to be released for distributionQuality Plan Regulatory strategyVerification and validation test planLabeling and user manualsTrace matrix between design specifications, risk assessment and verification and validation test plan.Production prototype units for verification and validation testingBill 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 File

Drop

Drop

Revise

Revise

Update or drop

Document rationale in DHF

Redo testing

Design PlanningFeasibility StudiesRisk AssessmentsProject Plan Defines Interfaces with OthersStage-Gate MethodologyConstantly Changing

Design Input-FeasibilityWhereCustomersTechnical PapersMedical expertsService peopleWhatIntended UseTechnical RequirementsSafety IssuesHowDocumentedApprovedFiledFormal Change Control System

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 devices 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.

Risk Assessment

ISO 14971 Risk Assessment ExampleExample of a Hypothetical Risk Assessment for a Electronic System to Monitor Patient Core Body Temperatures

Definitions

Harm: Physical injury or damage to the health of people, or damage to property or the environment Hazard: Potential sources of harmRisk: Combination of the probability of Occurrence of Harm and the Severity of the harmRisk Analysis: Systematic use of available information to identify hazards and estimate the risk Residual Risk: Risk remaining after protective measures and mitigations are takenSeverity: A measure of the possible consequences of the riskAs 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.

Classification of Residual Risk

SEVERITY TABLE

Occurrence

Detection

Quadrant Map

Occurrence109Quad 487Quad 365Quad 2432Quad 1112345678910Severity

Risk Assessment Table

Clinical Risk AssessmentCause ID #Potential Clinical RiskPossible effectsPotential causesInitial StateControlling Action's)/ Design MitigationsPost Mitigation State.Spec Ref SOf effectOOf cause or failureScore SOf effectOOf cause or failureDOf cause or failureScore (Quad) CRA 01Patient Core Temperature exceeds physiological limits Severe Hyperthermia (Seizure, Death, Brain Damage)Probe has a intermittent or noisy signal due to EMI in area9654Audible and Visual Check Probe alarmEMC testing to UL/IEC 60601-1-2 Requirements92118Q3CDS-015CRA 02Patient Core Temperature exceeds physiological limitsSevere Hyperthermia (Seizure, Death, Brain Damage)Probe is loose or disconnected9654Audible and Visual Check Probe alarm92118Q3CDS-019CRA 03Patient Core Temperature exceeds physiological limitsSevere Hyperthermia (Seizure, Death, Brain Damage)Probe not in calibration window Wrong Temp Probe used9763Factory calibration window set for 400 Series thermistorSoftware Check for probe rangeAudible and Visual Check Probe alarm92118Q3CDS-002CRA 04 Patient Core Temperature exceeds physiological limitsSevere Hyperthermia (Seizure, Death, Brain Damage)Infection, Drug reaction, disease state9436Audible and Visual High Temp Alarm92118Q3CDS-012CRA 05Patient Core temperature exceeds physiological limitsSevere Hyperthermia (Seizure, Death, Brain Damage)Patient not being appropriately monitored 9545Audible and Visual High Temp AlarmLabeling and Training 92118Q3CDS-015CRA 06Patient Core temperature lower than physiological limitsPatient enters HypothermiaProbe has a intermittent or noisy signal due to EMI in area9436Audible and Visual Low Temp AlarmDesign for EMI immunity92118Q3CDS-016CRA 07Patient Core temperature lower than physiological limitsPatient enters Hypothermia Probe is loose or disconnected9654Audible and Visual Low Temp AlarmAudible and Visual Check Probe alarmDesign fro interlocking connector92118Q3CDS-018

Design OutputFinal design specificationsQuantitative DocumentedApprovedFinal specifications are contained in the design history file.Final risk assessments completed.Clinical testing may be needed.

Design ReviewsFormal ProcessRequired for Phase ApprovalChecklists MinutesAttendees- one not associated with items reviewedAreas coveredAction items/open issuesOpen items closed for final releaseFormal design review prior to release for manufacture and distribution

Design Verification and ValidationDemonstrates 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.

Design Verification And ValidationVerification - meets specificationValidation - meets intended useWritten procedure required.Testing must be documented, reviewed and approved.Software must be verified and validated.Manufacturing processes must be verified and validated.

System Verification and Validation

Software Quality-Design Controls

Design TransferDesign moves from R&D to manufacturingManufacturing and production specifications are documented Manufacturing risk assessment may be neededManufacturing IQ, OQ, PQIQ - Installation Qualification (Equipment)OQ - Operational Qualification( 1st ones meet specs)PQ - Performance Qualification (Consistently repeatable)

Design ChangesAll changes to the design after release must be formally controlled (Change Control).Re-validation may be neededContinues for the life of product.Documentation control system is necessary.

Labeling 21 CFR 801Section 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.

Rx Medical Device Labeling

Intended UseIndications for UseContraindications for UseWarnings, CautionsDescription of the DeviceUser InstructionsSpecificationsCorrective Actions (Troubleshooting)

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

Labeling VerificationLabeling 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.

Design History FileRecord of the Development ProcessPlansSpecificationsV&V Test ResultsDesign ReviewsChanges to the Design

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 patients 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.

Is the machine a medical device?What steps should Dr. Bright and Dr. Idea take before they can begin marketing the machine? What documents do they need to have on file?

Questions

Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)The term "accompanying" is interpreted liberally to mean more than physical association with the product. It extends to posters, tags, pamphlets, circulars, booklets, brochures, instruction books, direction sheets, fillers, etc. "Accompanying" also includes labeling that is brought together with the device after shipment or delivery for shipment in interstate commerce. Advertising According to an appellate court decision: "Most, if not all advertising, is labeling. The term 'labeling' is defined in the FFDCA as including all printed matter accompanying any article. Congress did not, and we cannot, exclude from the definition printed matter which constitutes advertising.

Medical device manufacturers must incorporate in their quality assurance (QA) program several elements that relate to labeling in order to meet the Good Manufacturing Practice (GMP) requirements of the Quality System regulation. The QA program must be adequate to ensure that labeling meets the GMP device master record requirements with respect to legibility, adhesion, etc., and ensure that labeling operations are controlled so that correct labeling is always issued and used.Labeling includes equipment labels, control labels, package labels, directions for use, maintenance manuals, etc. The displays on CRT's and other electronic message panels are considered labeling if instructions, prompts, cautions, and parameter identification information are given.Various sections of the QS regulation have an impact on labeling: Section 21 CFR 820.80(b) requires the inspection and testing of incoming materials including labeling; and 21 CFR 820.70(f) requires buildings to be of suitable design and have sufficient space for packaging and labeling operations. 21 CFR 820.120 deals with specific requirements for the control of labeling. It applies to the application of labeling to ensure legibility under normal conditions of use over the expected life of the device; and also applies to inspection, handling, storage, and distribution of labeling. FDA considers a device to be adulterated if these requirements are not met. These requirements do not apply to the adequacy of labeling content, except to make sure the content meets labeling specifications contained in the device master record. However, failure to comply with GMP requirements, such as proofreading and change control, could result in labeling content errors. In such cases, the device is misbranded and adulterated. Specifications are required in the design history file (DHF) 21 CFR 820.30 for the content and physical design parameters of labels. Labeling specifications are: engineering drawing and/or artwork for each label, appropriate inspection or control procedures, and appropriate procedures for attaching the labels. All procedures, drawings, and artwork must have the name of the preparer, an approval signature, and a date. The approval signature, date, etc., may be on the backside of artwork or on a label approval form. Further, artwork may contain only an identification code or title if the "content" of the artwork is duplicated on approved engineering drawings or adequately identified (cross-referenced) with respect to the label approval form.Hard copy labels, package inserts, and similar labeling are specified and purchased as components. For correct purchase and use of labeling, specifications are usually stated on engineering drawings and/or purchase specifications. Thus, artwork or "copy" alone will not fulfill the device master record requirements for labeling except for the most simplistic labeling such as brief errata sheets.The engineering drawings or purchase specifications and mounting procedure must specify, as appropriate, the label substrate, dimensions, ink, finish, mounting method, etc., so that the purchased label will remain attached and legible during the customary conditions of processing, storage, handling, distribution, and use.Front panels, other instrument panels, meters, fuses, pushbuttons, and the like often are labels or contain labels and must, as appropriate, meet device master record and control requirements. Component specifications, assembly drawings, and test/inspection procedures may be appropriate controls to prevent mixup of meters, pushbuttons, and other labeled instrument controls. Controls to prevent mixups are generally not needed for front and other instrument panels.Whether a firm considers a software driven display to be labeling or data makes little difference under the Quality System regulation, because either way, the finished device labeling or data must meet the device master record specifications. When firms develop and validate software, they should also review these electronic displays to see that the "labeling" meets all applicable requirements, such as adherence to specifications in the device master record, correct parameter identification, agreement with the instruction manual, and of course, correct display of performance data.When reviewing or auditing labeling operations, it is wise to keep in mind that the Quality System regulation contains flexible requirements and thus allows flexibility in a quality assurance program. The degree of labeling control needed to satisfy the Quality System regulation varies considerably for different devices and operations. In order to avoid wasting money and increasing the cost of health care, manufacturers need to give considerable and prudent thought to the appropriate level of control needed for their operations. Information and guidelines presented in this chapter should aid manufacturers in making these decisions. The level of control needed should be reconsidered when products are added or changed. Likewise, the controls needed and success of the existing control program must be reviewed during QA system audits.C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net; Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)C. Richard G.Confer, PE, Inc. 2007 rconfer@comcast.net;