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

1. Crossing the Threshold ( FDA Regulatory Requirements for Medical Device Manufacturers) DESIGN CONTROLS FDA

2. 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

3. Regulations CDRH CDER CBER • 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) • 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) • Biologics • 21 CFR 600/601/610 • Blood • 21CFR 606 • 21CFR 1270, 1271 (tissue) • 21 CFR 58 (GLP) • 21CFR 11 (electronic records)

4. 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)

5. FDA Oversight in a Medical Device Life Cycle FDA review Research Design and Development • Good Clinical Practice • Clinical Trial Controls • Good Laboratory Practice • Investigational Devices Exemptions (IDE’s) • 510(k) Clearance • PMA • Document Controls • Design Controls • Good Lab Practices • Document Controls • Electronic Records Manufacture and Service Obsolescence • Recalls • Complaints • Medical Device Reporting • Quality Systems Requirements • Establishment Registration • Labeling Controls • Design controls Record Retention

6. 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.

7. 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.

8. Examples

9. Quality System A Medical Device Quality System is designed to assure that products areSafe and Effectivefor their Intended Use and Consistently meet the specifications as defined by results of clinical and/or detailed technical design and validation

10. 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)

11. Defines phases of project. Uses design reviews and approvals as gates between phases. Stage-Gate Method

12. Design Controls General Stage-Gate Process

13. Design Planning • Feasibility Studies • Risk Assessments • Project Plan Defines Interfaces with Others • Stage-Gate Methodology • Constantly Changing

14. 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

15. Risk Assessment

16. Feasibility Clinical Risk Summary Design Input Preliminary Design Preliminary Risk Assessment: Specification Trace Matrix: (links between) Specification Risk Analysis Fault Table Test Plan Mitigations: Final Risk Assessment: Risk Management Document, Approvals Risk Assessment

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

18. 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.

19. Classification of Residual Risk

20. SEVERITY TABLE

21. Occurrence

22. Detection

23. Quadrant Map

24. Risk Assessment Table

25. 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.

26. 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

27. 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.

28. 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.

29. System Verification and Validation

30. System Design Specs and System V&V Activities SRS SDS Software Verification Testing Unit level Risk and SRS trace Unit verification activities Software Quality-Design Controls

31. 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)

32. 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.

33. 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.

34. Rx Medical Device Labeling • Intended Use • Indications for Use • Contraindications for Use • Warnings, Cautions • Description of the Device • User Instructions • Specifications • Corrective Actions (Troubleshooting)

35. Labeling Controls

36. 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.

37. Design History File • Record of the Development Process • Plans • Specifications • V&V Test Results • Design Reviews • Changes to the Design

38. Class Exercise-Design Controls Dr. 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. • 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?

39. Questions