1. Development and Regulation of Medical Products (MEDR-101)
Prof. Moustafa M. Mohamed
Vice dean
Faculty of Allied Medical Science
Pharos University in Alexandria

2. Medical Device Design Controls
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Medical Device Design Controls
Introduction to the Food and Drug Administration (FDA)
Definitions
Classes of devices
Design control overview
Risk assessment
Verification and Validation testing
Software Quality Assurance
Labeling
Post design transfer issues
C. Richard G.Confer, PE, Inc

3. FDA Oversight in a Medical Device Life Cycle
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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
Produce Marketing Association (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
C. Richard G.Confer, PE, Inc

4. Intended use Product Class
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Intended use Product Class
Class I-Simple, Low risk.
General controls needed (registration, labeling, GMP)
Class II- More complex, Medium risk.
Need 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.
C. Richard G.Confer, PE, Inc

5. 2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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 Food and Drug Administration FDA – Design History Files.
Design controls can continue through the manufacturing and service phase.
C. Richard G.Confer, PE, Inc

6. 2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Examples
C. Richard G.Confer, PE, Inc

7. 2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Quality System
A Medical Device Quality System is designed to assure that products are Safe and Effective for their Intended Use and Consistently meet the specifications as defined by results of clinical and/or detailed technical design and validation
C. Richard G.Confer, PE, Inc

8. Design Process of Medical Equipment

9. Design Control Elements
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Design Control Elements
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)
C. Richard G.Confer, PE, Inc

10. Design Planning Feasibility Studies Risk Assessments
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Design Planning
Feasibility Studies
Risk Assessments
Project Plan Defines Interfaces with Others
Stage-Gate Methodology
Constantly Changing
C. Richard G.Confer, PE, Inc

11. Design Input-Feasibility
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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
C. Richard G.Confer, PE, Inc

12. 2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Risk Assessment
C. Richard G.Confer, PE, Inc

13. 2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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.
C. Richard G.Confer, PE, Inc

14. Design Output Final design specifications
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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.
C. Richard G.Confer, PE, Inc

15. Design Reviews Formal Process Required for Phase Approval Checklists
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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
C. Richard G.Confer, PE, Inc

16. Design Verification and Validation
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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.
C. Richard G.Confer, PE, Inc

17. Design Verification And Validation
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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.
C. Richard G.Confer, PE, Inc

18. Design Transfer Design moves from R&D to manufacturing
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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)
C. Richard G.Confer, PE, Inc

19. 2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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.
C. Richard G.Confer, PE, Inc

20. Labeling 21 CFR 801 Section 201(k) defines "label" as a:
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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.
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 (b) requires the inspection and testing of incoming materials including labeling; and 21 CFR (f) requires buildings to be of suitable design and have sufficient space for packaging and labeling operations. 21 CFR 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 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

21. Rx Medical Device Labeling
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Rx Medical Device Labeling
Intended Use
Indications for Use
Contraindications for Use
Warnings, Cautions
Description of the Device
User Instructions
Specifications
Corrective Actions (Troubleshooting)
C. Richard G.Confer, PE, Inc

22. Labeling Verification
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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.
C. Richard G.Confer, PE, Inc

23. Design History File Record of the Development Process Plans
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Design History File
Record of the Development Process
Plans
Specifications
V&V Test Results
Design Reviews
Changes to the Design
C. Richard G.Confer, PE, Inc

24. Class Exercise-Design Controls
2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
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?
C. Richard G.Confer, PE, Inc

25. 2/7/2007
Crossing the Threshold - ( FDA Regulatory Requirements for Medical Device Manufacturers)
Questions
C. Richard G.Confer, PE, Inc