1. Version 2 1 FDA Medical Device Quality System Introduction

2. Version 2 2 Agenda Overview of FDA, Domestic and International Quality Systems FDA Quality System Regulations (21 CFR 820) Documentation and Records Labeling FDA Quality Systems Audits

3. Version 2 3 Introduction This is an awareness level course designed to provide a background of the Quality System Regulation with a focus on documentation, labeling, and audits.

4. Version 2 4 CBER Center for Biologics Evaluation and Research CDRH Center for Devices and Radiological Health CDER Center for Drug Evaluation and Research Offices of Medical Product Regulation within the U.S. Food and Drug Administration (FDA)

5. Version 2 5 US vs. European Laws US Food, Drug and Cosmetics Act Medical Device Amendments (1976) Safe Medical Devices Amendments (1990) FDAMA (1997) Europe Medical Device Directive (MDD) 1993 Active Implantable Medical Device Directive (AIMD) 1990

6. Version 2 6 US vs. European Quality System Requirements US 21 CFR 820 (Also known as the QSR) Guidance Documents Europe Essential Requirements Harmonized Standards ISO 13485

7. Version 2 7 Regulations 21 CFR 800-1050 (devices) 21 CFR 820 Quality System Regulation (GMP—Good Manufacturing Process) 21 CFR 807 (510K) 21 CFR 812 (IDE—Investigational Device Exemption) 21 CFR 814 (PMA—Premarket Approval) 21 CFR 11 (ERES—Electronic Records and Electronic Signatures) 21 CFR 50 (Informed Consent) 21 CFR 56 (IRB—Institutional Review Boards) 21 CFR 58 (GLP—Good Laboratory Practices)

8. Version 2 8 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

9. Version 2 9 Quality Control

10. Version 2 10 Written Procedures FDA 21 CFR 820 requires following written procedures Remember…… If you didn’t document it, you didn’t do it! If you didn’t do it, DON’T document it!

11. Version 2 11 The Documentation Pyramid Quality Manual Procedures Work Instructions Records (forms, notebooks, travelers)

12. Version 2 12 Quality System Processes Management Controls Design Controls Materials Controls Document Controls Purchasing Controls Production and Process Controls Facilities and Equipment Controls Document, Record and Change Controls Corrective and Preventative Action Labeling Controls Handling, Storage, and Distribution controls Servicing Controls Statistical Techniques

13. Version 2 13 Important Terms Device Master Record (DMR)- Device History Record (DHR) Design History File (DHF) Technical File Complaint Corrective Action Controlled Document Engineering Change Order (ECO) Labeling Verification Validation Traceability

14. Version 2 14 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)

15. Version 2 15 Document Controls Controlled System Review and Approval Required – Signature, Date – Authorized Personnel Listed in a Procedure Engineering Change Order Process (ECO) Electronic Records Require Special Security

16. Version 2 16 Production and Process Controls Written Instructions (SOP’s) Required Environmental Controls –Clean Rooms Personnel –Health, Cleanliness, etc. Contamination Control Equipment –Maintenance Schedules –Software Validation Required in Process Equipment

17. Version 2 17 Records General –Records Must be Legible –Security maintained –Available for Life of Product (min) 2 years past shipping date –Should be an ongoing process in real time

18. Version 2 18 Records Device Master Record (DMR)( Recipe) –Design Specifications –Process Specifications –QA Procedures –Packaging Info Records –Labeling Info –Installation and Maintenance Info Device History Record (DHR)(As really Built) –Date of Manufacture –Quantity Manufactured –Quantity Released for Distribution –Acceptance ( Test) Records –Primary Labeling Information Quality System Record (QSR) – Quality Manual, Management Review Procedures, SOP’s, Generic Training Procedures, Other Non-device Specific Quality Procedures

19. Version 2 19 Labeling We will focus on labeling for commercial devices. Labeling is different for a commercial device versus an investigational device. Follow all policies and procedures regarding labeling requirements. Ensure that the label on the device matches the label on the outer packaging. –Follow specific work instructions for labeling

20. Version 2 20 Labeling and Packaging Written Procedures Required Label Integrity- –Does the label remain legible for product life Label Inspection –Control of labels required Label Storage –Secure area –QA release Labeling Operations –Assure that labels are not mixed up –Recalls of FDA regulated product can be initiated by mis- labeling Serial Numbers

21. Version 2 21 Labeling and Packaging Packaging must be Designed to Assure That Products Are Protected During Transit and Storage –Shipping testing –Environmental testing ( Temperature, Humidity ) –Specialized labeling of the package may be needed Sterile Packaging has Special Considerations

22. Version 2 22 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.

23. Version 2 23 Over The Counter (OTC) Device Labeling Principal Display Panel 21 CFR 801.6021 CFR 801.60 The principal display panel is that portion of the label which is intended to be displayed, presented, shown, or examined under customary conditions for retail sales. Statement of Identity 21 CFR 801.6121 CFR 801.61 The statement of identity of the device must be listed on the principal display panel. –It must list the common name –Indications for use –Bold type, –Reasonably sized generally parallel to the base of the package Net Quantity of Contents Statement 21 CFR 801.6221 CFR 801.62 The label of an over-the-counter (OTC) device in package form must contain a statement of net quantity of contents in terms of weight, measure, numerical count; or a combination of numerical count and weight, measure.

24. Version 2 24 Prescription Medical Device Labeling- General Requirements Intended Use Indications for Use Contraindications for Use Warnings, Cautions Description of the Device User Instructions Specifications Corrective Actions (Troubleshooting)

25. Version 2 25 Prescription Device Labeling Prescription Device 21 CFR 801.10921 CFR 801.109 A device which, because of any potentiality for harmful effect, or the supervision of the method of its use, or the collateral measures necessary to its use is not safe unless under a practitioner licensed by law to direct use this device, and hence for which "adequate directions for use" cannot be written, is exempt from such provided: –- It is in the possession of either a licensed practitioner or persons lawfully engaged in the manufacture of distribution of the product; –- Its labeling bears an Rx statement, i.e., "Caution: Federal law restricts this device to sale by or on the order of a (Insert name of physician, dentist or other licensed practitioner;" –- Its labeling bears information for use including, indications, effects, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which the device can safely be used; and –- All labeling other than labels and carton bears the date of issuance or date of the latest revision.

26. Version 2 26 Labeling for Investigational Devices Current Good Manufacturing Practice (cGMP—21 CFR 820) –Or waiver Good Clinical Practices (GCP) Label Requirements – 21 CFR 812.5 –Caution—Investigational device. Limited by Federal or U.S. law to investigational use. –Describe all relevant contraindications, hazards, adverse effects, interfering substances or devices, warnings, and precautions. –No false or misleading information. –Cannot represent device as safe or effective for purpose for which it is being investigated.

27. Version 2 27 FDA Actions for Mislabeling Warning Letters Mandatory Recall Injunctions to Stop Shipment Seizure Fines and Imprisonment

28. Version 2 28 FDA Legal Actions SEC. 303. [21 U.S.C. 333] (a)(1) Any person who violates a provision of section 301 shall be imprisoned for not more than one year or fined not more than $1,000, or both. Notwithstanding the provisions of paragraph (1) of this section, if any person commits such a violation after a conviction of him under this section has become final, or commits such a violation with the intent to defraud or mislead, such person shall be imprisoned for not more than three years or fined not more than $10,000 or both. Knowingly distributing drugs/devices in violation of section 503(e)(2)(A), shall be imprisoned for not more than 10 years or fined not more than $250,000, or both. Any manufacturer or distributor who distributes drug/device samples by means other than the mail or common carrier whose representative, during the course of the representative’s employment or association with that manufacturer or distributor, violated section 301(t) because of a violation of section 503(c)(1) or violated any State law prohibiting the sale, purchase, or trade of a drug sample subject to section 503(b) or the offer to sell, purchase, or trade such a drug sample shall, upon conviction of the representative for such violation, be subject to the following civil penalties: (A) A civil penalty of not more than $50,000 for each of the first two such violations resulting in a conviction of any representative of the manufacturer or distributor in any 10-year period. (B) A civil penalty of not more than $1,000,000 for each violation resulting in a conviction of any representative after the second conviction in any 10-year period.

29. Version 2 29 FDA Audits/Inspections Types –QSR-Risk Based Approach –Targeted- Based on a Complaint/Recall Establishment must be registered May Be Unannounced Inspector presents Form 482-Notice of Inspection and badge Sponsor must give access to the records and allow copying of records FDA

30. Version 2 30 Things not to do when FDA audits… Run away and hide until they leave. Tell them you don’t really work here, you are just visiting and point to your co-worker to handle it. Refuse to let them in, noting your policy of not seeing anyone without an appointment. Tell them the building is infested with bees and it would be too risky for them to enter. Tell them there must be some mistake, they have the wrong business and give them the address of a competitor. Tell them you are under a doctor’s care for amnesia.

31. Version 2 31 What should you do when FDA audits? FDA audits are generally unannounced. Be prepared for unannounced audits by knowing the company policy for FDA audits. Ensure that you are always complying with regulations and specific policies and procedures so that you are prepared in the event of an audit.

32. Version 2 32 Employee Responsibility Remain Calm Answer Questions Truthfully Don’t Volunteer Information Refer to Policies and Procedures If in Doubt, Refer to Supervisor/Escort

33. Version 2 33 Manufacturer’s Responsibilities Have Written Policy for FDA or other External Audits Have Records Organized Have an Escort at all Times Have a Separate Room for the Auditor Bring Information to Auditor Be Courteous Don’t offer any “bribes” –Lunch –Trips to Hawaii –Baseball Game Tickets –Company Party

34. Version 2 34 FDA Inspection If problems- FDA issues a form 483-Notice of Observations Deviations from guidance documents noted in Establishment Inspection Report (EIR) Possible Warning Letter if not corrected

35. Version 2 35 Summary FDA regulations must be followed in the device manufacturing process. Proper labeling is required; follow all company policies and procedures –Read instructions carefully –Do not make unauthorized changes in processes Document all required information in appropriate places. Store records in the required manner, for the required time period, and in an appropriate area.

36. Version 2 36 Questions

37. Version 2 37 References FDA Website, www.fda.gov/cdrhwww.fda.gov/cdrh 21 CFR 820 FDA Publication, Device Advice