FDA Medical Device Quality Systems Compliance

1
FDA Medical Device Quality Systems Compliance
2
Agenda

• Introductions, Attendance Sign in
• Domestic and International Quality Systems
• Food and Drug Law
• Organization of the FDA
• Break ( 15 min)
• Procedures
• FDA Quality Systems Regulations ( 21 CFR 820)
• Lunch
• Labeling
• Complaint Handling
• Record Keeping
• Break (15 Min)
• FDA Quality Systems Audits
• Exam
• Course Evaluations

3
US and European Regulatory Systems
US
European System
Congress Passes Laws
European Commission Issues Directives
FDA Writes Regulations
Harmonized Standards adopted by the Member
Countries
Companies Develop Quality Systems Procedures
Member Countries identify independent Notified
Bodies
Notified Bodies Audit for Compliance to the
Directive and Harmonized Standards
FDA Audits for Compliance to Regulations
4
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

5
US vs. European Quality System Requirements

• US
• 21 CFR 820
• (Also known as the QSR)
• Guidance Documents

• Europe
• Essential Requirements
• Harmonized Standards
• ISO 13485

6
Background of the FDA

• Biologics Control Act. 1902
• The Pure Food and Drug Act-1906
• Food Drugs and Cosmetics Act -1938
• Medical Device Amendments to the FDCA 1976
• Safe Medical Devices Act- 1990
• FDAMA- 1997

7
Offices of Medical Product Regulation within
the U.S. Food and Drug Administration (FDA)
CBER Center for Biologics Evaluation and Research
CDRH Center for Devices and Radiological Health
CDER Center for Drug Evaluation and Research
8
Definitions
9
FDA Center Responsibilities
CDRH
CDER
CBER
Zocor Viagra Tylenol Celebrex Penicillin
Stethoscopes MRI Scanners Hemodialysis
Machines Surgical Instruments Microwave ovens
Blood Products Vaccines Gene/Cell Therapy Stem
Cell Research
10
Regulations
CDRH
CDER
CBER

• 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)

• Devices
• 21 CFR 21 CFR 820 QSR (GMP)
• 21 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)

• Biologics
• 21 CFR 600/601/610
• Blood
• 21CFR 606
• CLIA
• 21CFR 1270, 1271 (tissue)
• 21 CFR 58 (GLP)
• 21CFR 11 (electronic records)

11
Class Exercise - FDA Organization

• Which division of the FDA has authority over the
  following products?
• Blood banks
• Bandages
• Computer terminals
• Bone graft material
• Pre-filled antibiotic syringes
• Lasers for eye surgery
• Artificial skin graft materials
• Contact Lenses
• Dog and Cat Food

12
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

13
Quality Control
14
Quality Assurance
15
Quality System Basics (ctd)

• Quality is everyones responsibility
• Quality has measurable attributes
• Specifications are the ? of a Quality System
• Documented policy and procedures contribute to
  consistency
• Quality planning is essential

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Quality Systems Basics (ctd)

• Clinical evaluation is the basis for safety and
  effectiveness
• Design Controls and validation assure that
  designs meet clinical expectations and
  specifications
• Process validation assures consistency
• Identification, segregation and control of
  materials and products prevents mix-ups
• Documentation control is essential

17
Quality System Basics (ctd)

• Corrective and preventative action systems
  foster continual improvement
• Labeling is important
• Internal and external (FDA) auditing keeps
  quality systems up to date

18
The Documentation Pyramid
Quality Manual
Procedures
Work Instructions
Records (forms, notebooks, travelers)
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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
• Medical Device Directive (MDD)
• Essential Requirements
• Notified Body

20
Procedures

• FDA 21 CFR 820 requires following written
  procedures

21
Group Exercise Draw a House
22

• Draw A House
• Read all instructions before beginning to draw
  the house
• Draw your house in the lower ½ of the page
• Begin by drawing a rectangle approximately 4
  inches wide by 3 inches tall, with the long side
  parallel to the bottom edge of the paper. The
  bottom of the rectangle should be 1 inch from the
  bottom of the paper.
• Locate the center of the top edge of the
  rectangle. Put a small dot at that point.
• Put a small dot 1 ½ inches above the dot you
  just made. This dot will be above the rectangle.
• Draw a line from the new dot to each edge of the
  top of the rectangle.
• Draw a door in the center of the rectangle. The
  door should be 3/4 inch wide by 2 inches tall.
  The bottom of the door should touch the bottom of
  the rectangle.
• Draw a window, approximately 1 inch square on
  each side of the door, 1 inch from the bottom of
  the rectangle. Hint A average thumb is about 1
  inch wide at the knuckle. The edge of each
  window should be ¼ inch from the nearest edge of
  the door.
• Draw 4 panes of glass in each window by making a
  cross in each window. Each pane should be the
  same size.
• Draw a chimney on the left side of the roof of
  the house. The chimney should be parallel to the
  left wall of the rectangle, touching the roof.
  The chimney should be ½ inch wide by 1 inch tall
  and go straight up.
• Draw some smoke coming from the chimney. A
  squiggly line will represent smoke.
• Put your pencil down when you are finished.

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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

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Management Controls

• Possible careers
• Internal Auditor
• External Auditor
• Quality Specialist
• Quality Systems Trainer

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Who is an Auditor?
An Auditor is someone who comes in after the war
is lost to bayonet the wounded Anon.
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Management Controls21CFR 820 Subpart B

• Quality Policy Defined
• Management Representative
• Management Review
• Quality Systems Procedures
• Quality Systems Audits
• Trained Personnel

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Design Controls

• Possible Careers
• Design Engineer or Technicians
• Quality Test Technicians
• Clinical Specialists
• Documentation Specialists

28
Design Controls

• 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

29
Design Controls

• A Design Control System is intended to design
  products which
• provide safe and effective medical devices,
• meet the clinical needs of the intended patient
  population,
• provide outstanding value to the user,
• satisfy the needs and expectations of our
  customers.
• Phased approach to product development
• Each phase has deliverables
• Design reviews are the checkpoints

30
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)

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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

• 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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Design Output

• Final Design Specifications
• Quantitative
• Documented
• Approved
• Final Risk Assessments
• Clinical Testing May Be Needed

34
Design Reviews

• Planned Formal Technical Reviews
• Independent Member of Review Team
• Documented

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Design Verification And Validation

• Verification - Meets Specification
• Validations - Meets Intended Clinical Use
• Written Procedure Required
• Testing Must be Documented, Reviewed and Approved
• Software Must be Validated
• Manufacturing Processes Must be Validated

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Design Transfer

• Design moves from RD to Manufacturing
• Manufacturing and Production Specifications are
  Documented
• 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
  controlled (Engineering Change Control)
• Re-validation may be needed
• Continues for the Life of Product

38
Design History File

• Record of the Development Process
• Plans
• Specifications
• VV Test Results
• Design Reviews
• Changes to the Design

39
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 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?

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Manufacturing and Servicing the Product
41
Manufacturing and Service

• 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

42
Documents Controls

• Career Opportunities
• Documentation Control Specialist
• Change Order Coordinator
• Drafter

43
Documents 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

44
Purchasing Controls

• Career Opportunities
• Purchasing Agent
• Buyer
• Supplier Auditor

45
Purchasing Controls

• Written Procedures Required
• Supplier Selection Process
• Approved Supplier List
• Purchase Orders
• Detailed Specifications Needed
• Supplier is Required to Have Current
  Specifications
• Supplier Auditing

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Identification and Traceability

• Career Opportunities
• Receiving and Inspection Coordinators
• Shipping Coordinators
• Quality Technicians

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Identification and Traceability

• Unique Identification of Product Through All
  stages of Receiving, Production, Installation,
  and Service
• Separate Accepted (Good) from Non- Conforming
  (Bad)
• Implants or Life Sustaining Product Requires
  Traceability to the User

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Production and Process Controls

• Career Opportunities
• Calibration Technician
• Maintenance Technicians
• Change Coordinators
• Trainers
• Process Validation Technicians

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Production and Process Controls

• Written Instructions (SOPs) Required
• Environmental Controls
• Clean Rooms
• Personnel
• Health, Cleanliness, etc.
• Contamination Control
• Equipment
• Maintenance Schedules
• Software Validation Required in Process Equipment

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Inspection, Measurement and Test Equipment

• Routine Calibration of Measurement Equipment
• Reference Standards Must Be Maintained
• Records Must Be Kept In Secure Areas

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Acceptance Activities

• Career Opportunities
• Inspection Technician
• Test Technicians
• Non-conforming product coordinator

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Acceptance Activities

• Written Procedures are Required for all
  Inspection and Test Activities
• Receiving Inspection
• In-Process Inspection and Test
• Final Inspection and Test
• Records

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Non-Conforming Product

• Non-conforming- Def Does not meet
  Specifications
• Segregation, Identification and Status of
  Nonconforming Product is Required
• Material Review Board (MRB)
• Rework, Retest and Disposition

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Typical Inspection, NCMR, and Rework
Process (The Happy Path)
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Corrective and Preventative Actions (CAPA)

• Career Opportunities
• Quality Analyst
• Quality Engineer
• Complaint Coordinator

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Corrective and Preventative Actions (CAPA)

• Includes Internal and External Actions
  (Complaints to be covered after lunch)
• Corrective Actions- Actions Taken After
  Occurrence of the Event to Prevent Reoccurrence
• Process Analysis
• Failure Analysis
• Procedure Review

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Corrective and Preventative Actions (CAPA)

• Examples of Corrective Actions
• Review of Field Failures
• Review of NCMR
• Procedure Reviews
• Corrective Actions Should be Validated to
  Assure They Work

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Corrective and Preventative Actions (CAPA)

• Preventative Action- Actions Taken to Prevent a
  Problem from Occurring
• Process Validations (IQ,OQ,PQ)
• Trend Analysis of Complaints, Repairs
• Internal Production Rework Trend Analysis
• (NCMR DATA)
• Supplier Audits and Reviews
• Highly Accelerated Stress Screening Testing
  (HASS)
• Highly Accelerated Life Testing (HALT)
• Market Information Review from Competitors

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Corrective and Preventative Actions (CAPA)

• Communicate the Results of Analysis
• Management Reviews must Include CAPA Information
• Documentation of Actions is REQUIRED
• Indication of the effectiveness of the Quality
  System

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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

61
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

62
Handling, Storage, Distribution and Installation

• Career Opportunities
• Material Handlers
• Stockroom Personnel
• Shipping Personnel
• Field Installation
• Traffic Managers

63
Handling, Storage, Distribution and Installation

• Official Release (QA) from Production to Storage
  (Stockroom) Required
• Mix-Ups Must be Prevented
• Prevention from Damage or Deterioration
• Shelf Life
• Stock Control-FIFO

64
Handling, Storage, Distribution and Installation

• Procedures Required to Assure that Only GOOD
  Product is Released for Distribution
• Records of Following must be Kept by Manufacturer
• Name and Address of Consignee (Company or Person
  who Receives Product)
• Quantity shipped
• Date Shipped
• Serial, Lot Numbers Shipped

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Handling, Storage, Distribution and Installation

• Installation Instructions Required (IQ)
• Installation of Equipment Must Be Verified
• Records Kept (if done by Mfgr.)

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Records

• General
• Records Must be Legible
• Security maintained
• Available for Life of Product
• (min) 2 years past shipping date

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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,
  SOPs, Generic Training Procedures, Other
  Non-device Specific Quality Procedures

68
Service

• Career Opportunities
• Service Technicians

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Service

• Written Procedure For Service Required
• Testing Post Servicing Required
• Record is part of the DHR
• Records Must Contain
• Name and SN of Device
• Date and Person Servicing Device
• Service preformed and Test Results
• Service Information Must Reviewed for Complaints

70
Statistical Techniques

• Valid Statistical Plans must be used for all
  sampling and testing to verify conformance to
  specifications

71
Class Exercise Manufacturing and Service

• The Bright-Idea Company received approval to
  market the machine . They have produced
  approximately 1000 of the machines, shipped 700
  to their customers.
• One afternoon, the final tester began to notice
  that the machines did not always work the way
  they were supposed to at the final test station.
  He was rejecting about 50 of them.
• The design engineer in charge found that there
  was a sticky valve in about 50 of one of the
  lots of valves they received two months ago. It
  was hard to tell if the valves would always fail
  or not, because the problem was intermittent.
• 350 machines had been made using the lot with
  the defective valves.
• You are the Quality Engineer responsible for
  Corrective Actions. What steps should you take
  next?

72
Labeling

• Career Opportunities
• Label Designer
• Graphic Artist
• Technical Writer

73
Labeling21 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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Over The Counter (OTC)Device Labeling

• Principal Display Panel 21 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 801.61
• 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 801.62
• 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.

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Prescription Device Labeling

• Prescription Device 21 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.

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Rx 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)

77
FDA Actions for Mislabeling

• Warning Letters
• Mandatory Recall
• Injunctions to Stop Shipment
• Seizure
• Fines and Imprisonment

78
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 representatives 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.

79
Class Exercise- Labeling

• Review of Respironics REMStar Heated Humidifier
  labeling for
• Indications for use
• Contraindications
• Prescription Statement
• Description
• Corrective Actions

80
Complaints
81
Complaint Definitions

• Any written, electronic, or oral communication
  that alleges deficiencies related to the
• Identity
• quality
• durability
• reliability
• safety
• effectiveness
• or performance
• of a device after it is released for
  distribution."

82
(No Transcript)
83
Sources of Complaints

• Complaints that shall be processed according to
  the GMP requirements may be received from
• Customers by letter, credit memo, returned goods
  form, or phone
• A manufacturer's representative, or other
  employees
• The MedWatch voluntary reporting program
• A service or repair request
• Journal articles or
• The FDA

84
What to do
85
Complaints-MDR

• Medical Device Report (MDR)-The MDR regulation
  requires that all manufacturers of medical
  devices notify FDA when they become aware of a
  death or serious injury that may have been caused
  or contributed to by one of their marketed
  devices and/or any malfunction of one of their
  devices which, if it were to recur, would be
  likely to cause or contribute to a death or
  serious injury.

86
Class Exercise

• Sandy Bright is Dr. Brights daughter. One
  day she was at a neighbors house (Ms. Consumer)
  when the machine Dr. Brights company made
  stopped working while Ms. Consumer was using it
  and Ms. Consumer had to go to the hospital. Ms.
  Consumer told Sandy to tell her Dad about the
  problem. Sandy told her Dad the next morning.
• What Should Dr. Bright do and when?

87
FDA Audits
88
FDA Audits

• Career Opportunities
• FDA Compliance Officer
• FDA Consumer Safety Officer
• Internal Auditor

FDA
89
FDA Audits of a Device Manufacturer

• Types
• QSR-Risk Based Approach
• Targeted- Based on a Complaint/Recall
• Establishment must be registered
• May Be Unannounced
• FDA issues a Form 482-Notice of Inspection
• If problems- FDA issues a form 483-Notice of
  Observations
• Possible Warning Letter if not corrected.

90
Manufacturers 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
• Dont offer any bribes
• Lunch
• Trips to Hawaii
• Baseball Game Tickets
• Company Party

91
Employee Responsibility

• Remain Calm
• Answer Questions Truthfully
• Dont Volunteer Information
• Refer to Procedures
• If in Doubt, Refer to Supervisor/Escort

92
Questions
93
Test