Beruflich Dokumente
Kultur Dokumente
MEDICAL DEVICE
GOOD MANUFACTURING PRACTICES MANUAL
5Th EDITION -
September 1991
PREPARED BY
DIVISION OF SMALL MANUFACTURERS ASSISTANCE
OFFICE OF TRAINING AND ASSISTANCE
PROJECT OFFICERS
ANDREW LOWERY
RICHARD J. RIVERA
FPA
FOREWORD
James S. Benson
Acting Director
Center for Devices and
Radiological Health
PREFACE
Joseph S. Arcarese
Director
Office of Training and Assistance
Center for Devices and
Radiological Health
Sincerely yours,
John F. Stigi
Director
Division of Small
Manufacturers
Assistance
CONTENTS
CONTENTS
FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ii
PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iii
OPEN LETTER TO MANUFACTURERS OF MEDICAL DEVICES . . . . . . . . . .
iv
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vi
3. PREPRODUCTION QUALITY . . . . . . . . . . . . . . . . . . . .
3-1
7. CHANGE CONTROL . . . . . . . . . . . . . . . . . . . . . . . .
7-1
9. PRODUCTION APPLICATIONS . . . . . . . . . . . . . . . . . . .
9-1
11. LABELING . . . . . . . . . . . . . . . . . . . . . . . . . . .
11-1
12. PACKAGING . . . . . . . . . . . . . . . . . . . . . . . . . .
12-1
13. DISTRIBUTION . . . . . . . . . . . . . . . . . . . . . . . . .
13-1
17. APPENDIX . . . . . . . . . . . . . . . . . . . . . . . . . . .
17-1
Good Manufacturing Practices Regulation . . . . . . . . . . .
17-2
Guideline List of Critical Medical Devices . . . . . . . . . .
17-12
Good Manufacturing Practices Preamble . . . . . . . . . . . .
17-21
Summary of Requirements Spreadsheet . . . . . . . . . . . . .
17-42
Preproduction Quality Assurance Planning: Recommendations
for Medical Device Manufacturers . . . . . . . . . . . . . .
17-43
Guideline on General Principles of Process Validation . . . .
17-61
Government-Wide Quality Assurance Program . . . . . . . . . .
17-73
ABSTRACT
INTRODUCTION
FLEXIBILITY OF THE GMP
MANUAL CONTENTS
GMP APPLICATIONS AND EXEMPTIONS
Exemptions
Component Manufacturers
Service Firms
Custom Device Manufacturers
Contract Manufacturers
Contract Testing Laboratories
Repackagers, Initial Distributors and Specification Developers
Repackers and Relabelers
Specification Developers
Initial Distributors of Imported Devices
INTRODUCTION
MANUAL CONTENTS
Component Manufacturers
Service Firms
Contract Manufacturers
Specification Developers
INTRODUCTION
QUALITY ASSURANCE SYSTEMS
QUALITY CONTROL
GOOD MANUFACTURING PRACTICES
Adequate Organization and QA Management
Formal and Documented QA Program
Approval of Materials, Components and Finished Devices
Adequate Quality Assurance Checks
Identify and Solve QA Problems
Periodic QA System Audits
Employee Training
INTERNATIONAL QA STANDARDS
TOTAL QUALITY ASSURANCE SYSTEM
Design Quality
Component Selection
Labeling Content
Process Quality
QA PROGRAM MAINTENANCE AND IMPROVEMENTS
SOME HIGHLIGHTS OF THE SAFE MEDICAL DEVICES ACT OF 1990
EXHIBIT
Example of a Standard Operating Procedure for Employee Training
INTRODUCTION
The written policies and objectives are set by management and are
influenced by outside factors such as customer requirements,
standards,
and regulations. For example, the customer requirements and needs
and
resulting device specifications should be known to be correct as
these
are based on market research, technical and medical considerations,
consensus standards, review of existing devices, environmental and
compatibility considerations, and design review. The objectives are
to
produce safe and effective (quality) devices at a profit. Ideally,
the
organization is everyone in the company as everyone is fully
committed
to the quality assurance program. In addition, however, organizations
such as design QA departments and production QA departments are
established to achieve specific objectives. Tasks to be performed to
meet the objectives are described in procedures and other documents.
QUALITY CONTROL
Employee Training
o GMP seminars;
o Individual consultations with managers, consultants, FDA
personnel, etc.;
o On-the-job training with an appropriate instructor;
o Video tapes and movies;
o Slide shows with an appropriate instructor;
o Reading GMP/QA manuals and textbooks; and
o Formal college QA courses.
INTERNATIONAL QA STANDARDS
The ISO 9000 series standards and ISO 8402 can be purchased
individually from the American National Standards Institute (ANSI)
1430 Broadway, New York, NY, 10018.
Two other reasons for having a total quality assurance system are
21
CFR Part 803, Medical Device Reporting (MDR), and product liability.
MDR requires manufacturers of medical devices to report to FDA
serious
complaints that they receive from any source. Product liability
actions
are the result of poor design, labeling, and manufacturing.
Reporting
and liability exposure are reduced by using a total quality assurance
system.
Design Quality
Component Selection
Labeling Content
Process Quality
We have reprinted below some key highlights from the Safe Medical
Devices Act of 1990 (Public Law 101-629) regarding device design and
problems with distributed devices:
Congress has amended the Federal Food, Drug, And Cosmetic (FD& C)
Act
to add new requirements and provisions concerning the regulation of
medical devices.
Device Tracking
Postmarket Surveillance
Effective: Immediately
Recall Authority
Effective: Immediately
Design Validation
EXHIBIT
C O M P A N Y L O G O
Employee Name:
Hire Date:
|Date
| Employee
| Present Job
| Type of Training
| Supervisor / Trainer
| Signature
| Signature
| Standard safety
| Defect awareness
CHAPTER 3
PREPRODUCTION QUALITY
INTRODUCTION
REGULATORY REQUIREMENTS
Medical Device Reporting
Application of the GMP Regulation
PRODUCT ASSURANCE
Device, Software, and Process Specifications
Design Evaluation versus Specifications
Software Validation
Labeling Evaluation
Design Reviews
ADEQUATE MASTER RECORD
ADEQUATE MANUFACTURING PROCESS
PROCESS VALIDATION
Validation Planning and Protocol
Equipment and Process Qualification
Validation Documentation
Revalidation
PERSONNEL TRAINING
DEVICE EVALUATION AND HISTORY RECORD
FINISHED DEVICE RELEASE
EXHIBITS
Design Transfer Checklists
INTRODUCTION
REGULATORY REQUIREMENTS
PRODUCT ASSURANCE
Product assurance is a quality assurance program that assures
quality is designed into a device. Under it, manufacturers determine
customer needs and expectations or specifications, if specifications
exists. These are documented by the manufacturer in device
specifications which, to the technical and economic extent feasible,
reflect the customer needs and expectations. In addition to device
specifications, a product assurance program encompasses employee
responsibility, safety standards, component selection, label content
and
physical characteristics, design evaluation, design analysis, design
review, adequate documentation, and correct transfer into production.
Meanwhile, under the GMP regulation, employees are being trained, and
manufacturing processes are being developed and validated for the new
product. During pilot production, the product assurance and GMP
programs
work together to make certain that design and production quality
goals
have been achieved.
o Misbranding
o Registration of the Establishment
o Premarket Notification [510(k)]
o FDA Performance Standards
o Premarket Approval
o Good Manufacturing Practices
o Color Additives
o Banned Devices
o Restricted Devices
Software Validation
o operator errors;
o induced failure of sensors;
o induced failure of output equipment;
o exposure to static electricity;
o power loss and restart;
o simultaneous inputs or interrupts; and,
o as appropriate, deliberate application of none, low, high,
positive, negative, and extremely high input values.
Labeling Evaluation
Design Reviews
PROCESS VALIDATION
o The finished device testing does not reveal all safety and
effectiveness related variations that may occur in the
device.
Validation Documentation
Revalidation
PERSONNEL TRAINING
The firm must assure that there are properly trained personnel or
programs to train personnel as needed to produce the new or modified
device. In one very valuable training technique, manufacturing
personnel
assist research and development personnel in assembling and
evaluating
engineering prototype devices. This technique:
EXHIBITS
Some of the items in the checklist such as human factors were not
discussed in detail in this manual because the intent here is to
describe a quality assurance system for controlling the listed items
or
activities rather than a text on how to design a product.
gmp1-5: 3/1/91
Sheet 1 of 3
ITEM COMMENTS*
(INSIDE THE DEVICE)
HARDWARE
1. Device Specification -
2. Connectors & Cables -
3. Connector Propriety -
4. Power Plug & Cord -
5. Cord Strain Relief -
6. General Construction -
7. Physical Stability -
8. Sharp; Hot; Moving;
Pinching Parts -
9. Liquid & Dirt Protect. -
10. Corrosion Resistance -
11. Maintainability -
Sheet 2 of 3
COMMENTS
LABELING
1. Specifications -
2. Annotated Code -
3. Flow Diagrams -
4. Displays -
5. Printouts -
7. Code Review -
8. Changeable -
9. Error Handling -
10. Operator Prompts -
11. Op. Error Prevent. -
Sheet 3 of 3
COMMENTS
HUMAN FACTORS
1. Hardware -
2. Software -
DOCUMENTATION
MANUFACTURING
1. Equipment Qualification -
2. Process Validation -
4. Pilot Production -
5. Pilot Release -
Sheet 1 of 1
TRANSFER CHECKLIST FOR IVDP
(For Non-Electromechanical IVDP)
Device Name: Catalog No.:
Vendor: Add:
ITEM COMMENTS*
1. Product Specification -
2. Verify Prod. Spec. -
3. Performance Factors -
-
4. Accuracy -
5. Precision -
6. Specificity -
7. Sensitivity -
8. Range -
9. Linearity -
10. Shelf-life Studies -
11. Preservative Performance -
12. Lyophilization Studies -
13. Reconstitution Studies -
14. Temp. Tolerance Test -
15. Humidity Tol. Test -
16. Shipping Test -
17. Verified Standards/Controls
Re Low, Normal & High Values -
18. Inner Containers -
19. Outer Packaging -
20. Packaging Labels -
21. Package Insert -
22. Aseptic Fill Validation -
23. Process Validation -
24. Environmental Controls -
25. Personnel Practices & Gowning -
26. Review Master Record & Index -
27. Processing Procedures -
28. Verified Test and Inspect. Proced. -
29. Data Forms -
30. Finished Dev. Storage -
31. Purchase Specifications -
32. Vendor Evaluation -
33. 510(k) or IDE/PMA Submission -
* The following abbreviations may be used in the comment column to
save
time.
U = Unsatisfactory NA = Not Applicable
GS = Generally Satisfactory NI = Needs Improvements
S = Satisfactory
Form ___________ Revised __________ Approved _________ Date ________
INTRODUCTION
BUILDINGS
Repackers and Rebuilders
Contamination Control
Orderly Operations
ENVIRONMENTAL CONTROL
General Controls
Analyze Operation
Specifications
Monitoring
CLEANING AND SANITATION
Personnel Sanitation Practices
Prevent Contamination by Hazardous Substances
Personnel Practices
EXHIBITS
Cleanroom and Station Procedure
Cleaning Procedure for the Aseptic Filling Room
INTRODUCTION
BUILDINGS
Contamination Control
Orderly Operations
General Controls
Analyze Operation
Specifications
Also see at the end of this chapter the procedure, "Cleanroom and
Work Station", which covers work practices, dress codes, and hygiene
for employees working in cleanrooms or at laminar-flow benches.
Monitoring
Personnel Practices
If eating, drinking, or smoking could have an adverse affect on
the
devices' fitness for use, manufacturing procedures must include
instructions on how to avoid such adverse effects. For example,
these
activities could be confined to specially designated areas.
Directions
and containers or equipment must be provided for timely and safe
disposal of trash, by-products, effluents and other refuse.
EXHIBITS
gmp1-18: 3/12/91
Sheet 1 of 2
11. Do not touch with gloves or finger cots any covered or uncovered
part of the body, or any item or surface that has not been
thoroughly cleaned.
2. Lint-free caps must be worn and must completely cover the head
and
hair except for the eyes, nose, mouth, and chin.
Sheet 2 of 2
1. Garments may vary with the operation being performed, but the
minimum garment shall be a pocketless, lint-free smock which
extends to within 15 inches below the work surface. The collar
and
cuffs shall have fasteners.
2. Head covering shall be worn, and shall completely cover the hair.
If the operation requires the wearer to lean over the work, or
move into the airstream between the filter bank and the work
piece, the front, sides, and rear neck areas of the head shall
also be covered.
5. Exercise extra care to rid the hands of normal residue from home
duties such as starching, baking, plastering, wallpapering,
painting, concrete work, carpentering or other particulate
generating activity.
Page 1 of 4
EQUIPMENT NEEDED:
A. Gowning Room:
Shoe and head covers are required in this area. Begin all
cleaning
at the top and finish at the bottom of any equipment or surface
to
be cleaned.
Page 2 of 4
B. Filling Room:
1. Move any remaining products (devices) to appropriate areas as
directed by your supervisor.
2. Empty all trash containers and replace liners.
3. Remove particulate matter from ledges, cabinets and external
surfaces of laminar-flow benches with a wiping cloth and
cleaning
solution.
4. Perform general straightening of shelves.
5. Remove debris and wet mop the floor with cleaning solution.
6. Spray the entire floor in the filling room with cleaning
solution,
using the provided sprayer. Allow the floor to air dry.
A. Gowning Room:
1. Use only one entrance and one exit when cleaning. The cleaning
direction will flow from entrance to exit.
2. Remove all non-essential equipment from the room and clean it.
Return he equipment after the entire area is cleaned.
3. Begin cleaning the room by wiping the entire ceiling area with
the
cleaning solution.
Frequent changes of the cleaning solution and the wiping cloths are
needed for effective cleaning of large areas such as the ceilings
and
walls. Make new solution and change wiping cloths when dirty.
7. Remove debris and wet mop the floor with cleaning solution.
8. Fill the sprayer with cleaning solution and wet the floor. Allow
to
air dry.
9. Gown according to procedure and go into the Filling room (SOP
G014).
B. Filling Room:
Page 3 of 4
4. Clean the walls next, starting at the top and cleaning toward
the
floor. Make new cleaning solution, and change wiping cloth when
dirty. 5. Empty all shelves and wipe with the cleaning solution.
Wipe
the
removed materials and put them back onto the cleaned shelf.
6. Wipe all cabinets and equipment with the cleaning solution from
top
to bottom.
7. Wipe all ledges and surfaces with the cleaning solution.
8. Pay particular attention to the laminar-flow workbenches because
the cleaning operation must end in the internal work surface of
the
hood.
Use a fresh wiping cloth and cleaning solution for the internal work
surfaces. Do not use the same cloth or solution which was used for
the
external cleaning. Discard solution and wiping cloths after cleaning
each hood.
8.1 First, switch off the laminar-flow hood, then clean all outside
surfaces from top of hood to bottom stand.
8.2 Second, clean all internal work surfaces such as:
a. Light covers
b. Air diffuser screen
c. Plexiglas sides
d. Workbench top.
10. Complete the documentation ledger and sign it. See Attachment A.
INTRODUCTION
MAINTENANCE
Records
Equipment Selection
MANUFACTURING MATERIALS
Analyze Use
Control Use
AUTOMATED PRODUCTION AND QA SYSTEMS
Software Validation Guidelines
Employee Responsibility and Training
Formal Development of Software
Commercial Software and Equipment
Validation of Equipment and Processes
Automated Data Collection and Processing
Equipment Controls and Audits
EQUIPMENT CALIBRATION
CALIBRATION REQUIREMENTS
Procedures
Personnel
Records
Schedules
Standards
EQUIPMENT ENVIRONMENT
AUDIT OF CALIBRATION SYSTEM
INTEGRATING MEASUREMENTS INTO THE QA SYSTEM
EXHIBITS
P.C. Board Cleaning
Calibration Procedures for Mechanical Measuring Tools
INTRODUCTION
MAINTENANCE
Records
Analyze Use
Control Use
There are also standards, books, and articles that can be used
for
guidance. Military Specification MIL-S-52779A and the Institute of
Electrical and Electronic Engineers (IEEE) "Standard for Software
Quality Assurance Plan" (IEEE Std 730-1984) are examples.
Manufacturers,
however, should not rely completely on such documents, but must
examine
their software needs and develop whatever controls are necessary to
assure software is adequate for its intended use [820.20(a)(4)].
EQUIPMENT CALIBRATION
CALIBRATION REQUIREMENTS
Procedures
Personnel
Managers and administrators must understand the scope,
significance
and complication of a metrology program in order to effectively
administer it.
Records
<Example Decals>
Schedules
Standards
EQUIPMENT ENVIRONMENT
gmp1-14: 3/7/91
EXHIBITS
DRAFT: ___________________________
APP: ____________
Date: __
[database1.0 PURPOSE: The purpose of this procedure is to document
production
operations performed on the XXXXXX printed circuit board washer.
2.0 This procedure sequentially identifies all operations necessary
to
properly operate and maintain this equipment.
3.0.2 Assure that the sump pump is on at the circuit breaker panel.
3.2 Push the main power "START" button (#21 on Control Panel
Diagram).
3.3 Visually inspect all pump compartment and screen filters for
debris
- make sure they are clean before continuing.
3.4 Push the fill buttons on the rear control panel to fill the wash
and rinse sections with water. Make sure all drain lines are closed.
The
incoming water will stop automatically when the tanks are filled to
the
correct levels.
3.6 Wait about 10 min. for water temperature to rise in the wash and
rinse tanks. Wait until the red lights on the temperature
controllers go off and the black needle aligns with the red
pointer.
3.7 Push the START-STOP button (#25 on diagram) on for the conveyer.
3.8 Push the "START" button (#28 on diagram) on for the Dryer cycle.
NOTE: conveyer belt MUST be moving when dryer section is on or the
equipment will be damaged.
4.1 Push the dryer cycle "STOP" button for the Wash and Rinse
sections
(#29 on control panel).
4.2 Turn Photocell Switch (on Rear Panel) to the "OFF" position.
4.3 Push the conveyer "START - STOP" button (#25 on diagram) to stop
the conveyer.)
4.4 Pull the DRAIN buttons on the control panel for the wash and
rinse
sections. Using litmus paper, take a reading on the wash tank
before
draining it. IF the wash water has a reading of "10" or less
drain
it; otherwise, do not drain the wash tank. Always drain the
rinse
tank.
4.5 Pull the FILL buttons on the control panel for the wash and
rinse
sections to let water flush the equipment for 5 minutes. Using a soft
cloth, wipe off any residue remaining on the equipment.
4.6 Pull the drain buttons on the control panel for the wash and
rinse
sections to let the water drain.
4.7 Remove the screen filter in the washer and remove any debris.
4.8 Wipe the exterior front section of the machine with a soft cloth.
4.9 Push the main power "STOP" button, (#33) to shut off the
equipment.
5.0 MAINTENANCE:
5.1 Monthly
5.1.2 Check the wear strips on the conveyer belt frame and replace
if
required. These are 2 white plastic strips located at the front of
the equipment.
5.1.3 Check conveyer belt tightness - using a wire cutter and needle
nose pliers, remove links to tighten if required.
5.2 Quarterly
Sheet 1 of 1
________________________________________________________________________
______ Drafted by App. Date
PROCEDURE:
5. After calibration, the date of calibration and the next due date
of
calibration shall be recorded on the Calibration Form No. .
Any
adjustments and/or repairs to the tool should be recorded. The form
is
placed in the tickler file according to the next calibration date.
gmp1-14: 3/8/91
INTRODUCTION
Document For Intended Employees
Adequate Information
Preparation and Signatures
Location of Records
Record Retention
DMR CONTENTS
DMR Index
General Documents
Specific Documents
Records for In Vitro Diagnostic Products
Device Specification
WRITTEN PROCEDURES
Developing Procedures
Content of Procedures
CHANGE CONTROL
EXHIBITS
Documents That May Appear in a Device Master Record
Device Master Record Index
Product Specification Portable Defibrillators
Zener Diode Specification
Label Example
Handle Assembly and Parts List
Cable Assembly and Parts List
Device Master Record Index for Amylase
Product Description
Amylase Diluent Solution
Filling Record Liquid, Non Freeze Dried
Finished Product Release Form
Production Sample Card
Shop Order Traveler
INTRODUCTION
o procurement,
o assembly,
o labeling,
o test and inspection, and
o packaging.
The most commonly used aids are models or samples. There are two
conditions that should be satisfied in order to use these aids.
First,
a written specification for the sample must be contained in the
device
master record. This specification, of course, may be the same as the
specification for the assembly or finished device to be manufactured.
This specification must be subject to a formal change-control
procedure.
Even though a model is available, the specification is needed for
present and future product development, and for production control
purposes. Second, the sample must:
Adequate Information
Although a firm tries to document for the intended employees,
there
is a need to audit periodically to see how well the goal is being
met.
There are various means of determining if information in the device
master record, production tools, and other production elements are
adequate for a given operation and associated employees. These
include
analyzing the amount of:
If any of these factors persist and if they are out of line with
industry norms or with the production of old designs, then the firm
should take corrective action. The corrective action may include
changes in supervision, documentation, adding new documentation,
modifying the design, using different tools, modifying the
environment,
etc. Corrective action, other than necessary "fire fighting" to
prevent
shipment of defective devices, should not be taken, however, until
the
real problem is identified.
Location of Records
Record Retention
file
ma
st
er
fi
le
DMR CONTENTS
General Documents
General documents are used for many activities that are essential
to
operating a manufacturing establishment -- these are not specific to
any
given product even if the company produces only one product. Thus,
the
DMR includes general documents such as standard operating procedures
(SOP's) and standard quality assurance procedures (QAP's). If the
company added another product line, the basic content of these
documents would undergo none or only minor changes.
li
br
at
io
po
li
cy
Specific Documents
Device Specification
1. Name of Product
2. Performance Characteristics
3. Classification
a. Regulatory c. Functional
b. Commercial d. Other
4. Physical Characteristics
a. Weight e. Consistency
b. Size f. Packaging
c. Color g. Power requirements
d. Form/Shape h. Other
5. Environmental Limitations
6. Important Components
WRITTEN PROCEDURES
Many sections of the GMP regulation require written procedures
for
guidance in performing various QA and manufacturing tasks. Certain
devices, such as in vitro products, because of the nature of the
manufacturing operations tend to have a relatively large number of
written procedures.
Developing Procedures
Content of Procedures
CHANGE CONTROL
EXHIBITS
Label Example
Product Description
3.1 Index
(Optional. See 1.0 above for total table of contents.)
1. Fabrication drawings
2. Surface finish procedures
3. Subassembly drawings
4. Wiring and piping diagrams
5. Assembly procedures
6. Assembly drawings
7. Reference documentation
1. Wiring and piping schematics
2. Test specifications
8. Sub-batch procedures
9. Blending or mixing procedures
10. Solution procedures
11. Final formulation procedures
12. Software packages
4.2 Labeling
1. Label drawings
2. Labeling drawings
3. Label/labeling review procedures and forms
4. Production control procedures and history record forms
5. Instruction manuals
6. Service manuals
7. Customer software
8. Customer feedback forms
4.3 Packaging
1. Package drawings
2. Closure drawings
3. Filling and/or packaging procedures
4. Packing procedures
5. Special shipment procedures
2.0 Policy: A DMR Index shall be prepared and maintained for all
devices being developed or manufactured.
4.0 Procedure:
CONTENTS
PRODUCT SPECIFICATION
3.0 Configurations
4.0 Functional Characteristics
TEST RECOMMENDATIONS
DEFINITIONS
1.8 Adult Anterior Paddles with Remote Charge 24990082-03 450 AAR
3.0 CONFIGURATIONS
Same as 4.1.3 except one paddle will have a charge button that
functions identically to MANUAL CHARGE button on the front panel (Ref.
1.8).
1. Slew Rate Limit - Limits the slew rate and, therefore, the
amplitude of the pacer pulses so that they can be seen on the display
and will not trigger the QRS detector in most lead configurations.
The heart rate meter displays heart rate as a bar at the screen
bottom. The heart rate is also compared to alarm limits that are
displayed on the same bar. When a limit is exceeded for longer than
three seconds, the red alarm led blinks, an audible alarm sounds, and
the writer runs (D320W/400W only). Alarms are disabled or reset by
putting the LOW LIMIT knob fully counter-clockwise and the HIGH LIMIT
fully clockwise. In this position the limit indications are not
displayed on the screen.
The synchronizer detects the peak of the R wave and, after the
discharge buttons on both defibrillator paddles have been pushed,
delivers the stored energy. The QRS amplitude must be set to at least
0.6 cm on the scope display using the SIZE control. QRS detection is
verified by an audible QRS beep and by a SYNC pulse displayed on the
scope at the time relative to each QRS complex that the energy would
have been delivered.
4.7.1 ON/OFF
A two pushbutton switch turns on the ECG amplifier and Solid Trace
Scope and puts the unit in the non-synchronous mode when ON is
depressed.
4.7.7 DISARM
A potentiometer used for setting the gain of the ECG amplifier. Gain
may be varied from X300 at fully CCW to X3000 at fully CW. At center
position, the gain is X1000.
4.7.9 FREEZE
4.7.10 1MV
A momentary pushbutton that injects a 1 mv +/- 2.5% signal
4.7.11 BEEP
A potentiometer used for setting the alarm high rate limit over a
range of at least 100 to 250 BPM. It is set to 120 BPM with knob
pointer is straight up.
A potentiometer used for setting the alarm low rate limit over a
range
of at least 0 to 150 BPM. It is set to 60 BPM with knob pointer is
straight up.
4.7.14 RECORD
*4.8 INDICATORS
A red lamp that begins flashing when the battery has a minimum of 1/2
hour of continuous monitoring capacity left or 2 charges to 320
joules
(1 charge to 400 joules). The lamp flashes to indicate circuit
operation when power is turned on.
4.8.2 SYNC
4.8.4 TEST
4.8.5 ALARM
A red light that flashed during an alarm.
4.8.6 LINE
Two red lights that illuminate when AC power is being received by the
unit.
4.8.8 Charging
A negative pulse displayed on the ECG trace with its center within 20
ms of where the energy should have been delivered if the DISCHARGE
BUTTON(S) had been pushed.
An illuminated bar graph showing Heart Rate and alarm limit settings.
*4.9 CONNECTORS
5.1.8 Charge Dump Time <25 volts left in 4 seconds and <2
joules in 3 minutes after activation
of
capacitor dump circuit.
Resolution: 8 bits
Phosphor: P31
Refresh Rate: 60 Hz
5.9 PADDLES
5.11.1 Temperature
5.11.2 Humidity
2. ELECTRONIC CHARACTERIISTICS
4. PHYSICAL CHARACTERISTICS
5. MARKING
7. APPROVED VENDORS
7.1 XXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXX
Phoenix, MD 21131
<Label Example>
2.2 Preparation
Cat. XXXXXXX
Cat. XXXXXXX
5. Final release
Example:
1.8 Units
Normal range for serum is 50 to 200 units at 37C. Infants below two
months have no measurable serum amylase. Adult level is reached by
the
age of one year. The above normal range includes an average serum
blank of 25 amylase units. Normal values for urine is less than 375
units per hour at 37C.
1.10 Precision
1.12 Cautions
Face masks and hair covering must be worn during solution and diluent
preparation, solution filling, tube racking and capping, and when
handling any raw material defined for use with this diagnostic test.
1.13 Manufacturing Flow Sheet. See Form No. 9926. [Not reprinted in
this Manual].
FOR USE IN CATALOG Numbers: XXXX-01 15 tests and XXXX-10 100 tests
Done by __________________
Checked by _________________
5. Add 125 mls of 1% _XXXXXX_ solution & mix well. Done by ______
6. Bring the volume to 50 liters with deionized water and mix well.
Re-check the pH. It should still be 7.00 0.05 @ 25C. Adjust, if
necessary, with 2N NaOH or 6N HCl.
DEIONIZED WATER:
9. Label the Diluent Solution with the Name, Batch Number, and Date of
manufacturing.
IODINE
Batch # __________________ Date Manuf. _________________
Date Received ____________ Time Received _______________
FILLING DATA
Machine(s) Before Filling - Signed _________________ Date _______
Cleaned:
After Filling - Signed _________________ Date _______
Fill Vol. _______ ml Limits ______ ml Filling
Batch Vol. ______ ml Leftover _______ml Method ________________
# Tubes or Vials Filled ______ #Bad Fills ______ [ ] Refilled
[ ] Not Refilled
APU ___________ ml TPU ___________ ml TPR ___________ ml
Dissapproved [ ] Approved [ ]
Comments: ___________________________________________________________
_____________________________________________________________________
_______________________________
Designee for Manufacturing
Comments: ___________________________________________________________
_____________________________________________________________________
_______________________________
Designee for Quality Control
INTRODUCTION
CHANGE CONTROL PROCEDURE
Identification
Effective Date
Responsibility
Revision Level
Evaluation
Communication
Updating Documentation
Documentation Distribution
Disposition of In-Process Items
Remedial Actions
Regulatory Submissions
Business Factors
QUALITY ASSURANCE REVIEW
CHANGES UNDER PREMARKET NOTIFICATION
Regulatory Background
Premarket Notification Decisions
GMP Control Always Required
EXHIBITS
Engineering Change Policy/Procedure
Change Control Forms
INTRODUCTION
o Draw a black line through but do not black out the old
information.
o See that the modified documents are placed into use and the
old documents are removed from production.
Identification
The written procedure must cover the identification of the
changed
device, assembly, component, labeling, software, process or
procedure,
and other related details. The change control form should have
blanks
for recording this data and other data discussed below.
Effective Date
The procedure must cover the effective date of the change which
is
usually a completion date, or action to be performed when a specific
event occurs, such as "implement the change when the new mixer is
installed and operational." The blank on the change control form for
recording the effective date should not be left empty.
Responsibility
The change control procedure should state which department or
designee is responsible for each function to be performed. One of
these
is the issuance, use, and control of blank and completed change
control
forms.
Revision Level
Evaluation
Communication
Updating Documentation
Documentation Distribution
Remedial Actions
Regulatory Submissions
The change procedure must cover these activities and must specify
that they be accomplished before the first lot of the changed devices
are released for distribution.
Regulatory Background
gmp2-7:8/11/87
EXHIBITS
An example of a detailed change control procedure and several
change
control forms are described below and exhibited.
The contents of any forms selected for use by a firm and how to
use
them should be discussed with all affected departments. Firms may
use
as is the example forms exhibited or modify them to meet their
specific
needs. In either case, after using an ECO procedure and forms for a
few
changes to products, processes, and associated documentation, needed
improvements to the form or procedure will become obvious.
gmp2-7:8/11/87
COMPANY LOGO
No: _____________
Rev: ____________
DATE: ___________
Sheet 1 of 7
---------------------------------------------------------------------
---
---SUBJECT: ENGINEERING CHANGE POLICY/PROCEDURE APPROVED:
President
1.0 PURPOSE: The intent of this policy is to assure that our
products
are safe, efficacious and reliable; meet the needs of the marketplace;
and are cost effective to manufacture and test on a continuing basis.
5.0 DEFINITIONS
5.3 Engineering Change Order (ECO): An ECO is an ECR (that is, the
completed ECO form and associated documents) which has been approved
by
the Engineering Change Board. An ECO must present a statement of the
problem, a solution, updated documentation, an effective date, and a
statement that the device and proposed changes meet regulatory
requirements.
5.4 Regulatory Compliance: The review by the Change Board includes
an
analysis of the change with respect to regulatory requirements. For
example, the following questions should be answered.
3. Does the change affect our GMP system? (A new use such as
infusion pumping by an existing precision metering pump means that a
switch to critical device GMP's is required.)
Sheet 2 of 7
6.0 RESPONSIBILITIES
Sheet 3 of 7
Sheet 4 of 7
After all Board Members in attendance have signed, the ECR becomes
an
engineering change order (ECO). Copies of the cover sheet may be
issued
by Technical Services upon request of the Board Members if the
effective
date is very near and the Change Board has not modified the ECR
before
approval. This action permits Manufacturing to use the previously
distributed marked-up sepias or "from-to" information on the ECR as
operating documentation until copies of the updated original
documents
are available for distribution.
Sheet 6 of 7
16. Disposition
1. Engineering Cost: List engineering cost of design and
documentation change.
The change notice is broken into Parts 1 and 2. Part 1 shows how
to
update the documentation. Part 2 is the special rework instructions
required by Manufacturing or Field Operations on how to update a
component or assembly that does not conform to the new revision.
(Note: The specific ECO form for this procedure is not included
in
this manual. However, several ECO forms follow. One of the example
forms, Engineering Change Package (ECP), is simply an ECO cover sheet
for a group of ECO's. An example of a filled-in group change is
included. It includes the completed ECP cover sheet and two
completed
ECO forms. The other three completed ECO forms noted on the example
ECP
are not reprinted.)
INTRODUCTION
COMPONENT QUALIFICATION
GMP CONTROLS
Specifications
Vendor Qualification
Acceptance Procedures
Acceptance Criteria
Testing and Inspection of Components
Acceptance and Rejection Records
Obsolete, Deteriorated, and Rejected Components
Component Storage
Critical Components
Supplier agreements
Rejected lots
Written test procedure
Sampling plans
Control numbers
EXHIBITS
Acceptance of Components
Material Receiving and Inspection Procedure
Identification Decals
Receiving Rejection Notice
INTRODUCTION
GMP CONTROLS
Specifications
Acceptance Procedures
In medium to large manufacturing operations, written instructions
are usually neces-sary to assure that components and manufacturing
materials are properly identified, pro-cessed and stored when
received.
Written inspection and test procedures are necessary to prescribe
the:
inspections and tests to be conducted; equipment to be used; test and
in-spection methods to be implemented; and data to be recorded. Prior
to
acceptance, all components must be either physically separated
(quarantined) or clearly identified as not yet accepted. The
decision
to separate or tag not-yet-accepted components should be made based
on
the characteristics of the device, the potential for mixups, plant
conditions, and manufacturing practices.
Acceptance Criteria
Critical Components
Supplier agreements
Rejected lots
Sampling plans
Control numbers
Control numbers for component traceability are mandatory for
critical components and "components" of in vitro diagnostic kits (21
CFR 809.10). Control numbers must be assigned to each lot or batch
of
critical components that were manufactured under similar condi-tions
over the same time period so that defects can be traced to the
component
manufactur-er and the cause of the defects determined and corrected.
If
a subassembly is regarded as a critical component by the
manufacturer,
a control number for that critical subassembly must be shown in the
device history record.
gmp .6
EXHIBITS
Acceptance of Components
________________________________________________________________________
___
Drafted by App. by Date
1.0 SCOPE
2.3 Enter the appropriate data into the Received Goods Log for
each
shipment received.
2.4 After completing the data entry, attach a yellow "HOLD" tag to
the
components, etc., and move the components, etc., immediately to the
receiving quarantine area. The pink copy of the purchase order must
accompany the material.
2.6 Quality control shall, after examining for damage and identity,
move the components, etc., to be inspected to the components, etc.,
to
the Receiving Inspection area.
3.0 INSPECTION
3.1 Pull the inspection history file for the components, etc., to
be
inspected. This file contains the Receiving History form and
inspection
procedure. Enter the appropriate data from the purchase order onto
the
Receiving History form and perform the inspection per the procedure.
Sheet 2 of 3
3.2 The QC manager shall assign a five digit lot number to each
vendor
lot received and enter the number on the Receiving History form.
4.0 DISPOSITION
4.1 Receiving and test data for each shipment are sent to the
designated individual for review and the decision regarding the
acceptability of the lot.
5.0 STOCKROOM
5.2 Components and other materials shall be stored and issued per
SOP
17320.
Note: Sheet 3 is the Receiving History log for this procedure. The
other
forms mentioned in this procedure are not reprinted. However,
similar
forms are in-cluded with another procedure located later in this
chapter.
INTRODUCTION
Is Master Record Adequate
Responsibility
What is Being Done
What Was Done
PRODUCTION AND PROCESS CONTROL
Specifications
Specification Changes
Processing Controls
Critical Devices
REPROCESSING
Retesting
Returned Devices
Critical Device Reprocessing
REPACKER/RELABELER PRODUCTION AND PROCESS CONTROLS
Operation Control
Reprocessing
CONTRACT STERILIZATION
Labeling Requirements
GMP Requirements for Contract Sterilization
INTRODUCTION
Responsibility
All employees must be made aware of device defects that may occur
from the improper performance of their specific jobs. Quality
assurance
personnel must be made aware of defects and errors likely to be
encountered as part of their quality assurance functions.
Finally, a broad view of what was done, what is being done, and
what
is likely to happen in the future is determined from a quality
assurance
systems audit. Audits are covered in chapter 15 of this manual. This
objective review of all quality assurance elements by individuals who
are not directly responsible for the operation being audited may
reveal
elements that need improvement. Management review and corrective
action
can change what is likely to happen to yield better quality products
and
higher profits.
Specifications
Specification Changes
Critical Devices
If YES, go to question 2.
REPROCESSING
Retesting
Returned Devices
Operation Control
4. Verify that the kit items are the desired items by checking
against
workorder, specifications, etc.
Record lot number of kit items where required. Lot numbers are
required for critical devices or when specified by the kit
manufacturer.
Lot numbers should be recorded in a manner that will facilitate ready
identification of all kits containing items with the same lot number.
CONTRACT STERILIZATION
Labeling Requirements
(i) Contains the names and post office addresses of the firms
involved
and is signed by the person authorizing such shipment and the
operator
or person in charge of the establishment receiving the devices for
sterilization.
Information transfer
Recordkeeping
Loading configuration
Preconditioning
Training
Nonconformance
gmp2-8:8/3/87
GMP - CHAPTER 10 - DEVICE EVALUATION
INTRODUCTION
Evaluation Specifications
FINISHED DEVICE EVALUATION
Simulated-use testing
Sampling Plans
Labeling and Packaging Inspection
Records
Product Release
Additional Requirements for Critical Devices
FAILURE INVESTIGATION
REPACKER/RELABELER DEVICE EVALUATION
EXHIBITS
Portable Defibrillator Test Procedure
Test DHR of a Printed Circuit Board Assembly
Device History Record (urine plate)
Batch Production Record (XLD)
Batch Production Record (Thayer Martin)
Batch Production Record (Blank form)
INTRODUCTION
Simulated-Use Testing
Sampling Plans
Records
Section 820.160 is not specific regarding finished device test
and
inspection records for noncritical devices; however, these records
must
be generated as they must be included as part of the device history
record (820.184). A device history record is a compilation of records
containing the complete production history of a finished device
[820.3(h)]. The term "complete" is interpreted for each family of
devices as allowed by 820.5. For many devices and manufacturing
operations, the major documents in the device history record are the
finished device inspection and test records. The history record must
be
reviewed because these records are used to show that finished devices
are manufactured in accordance with the device master record.
Product Release
FAILURE INVESTIGATION
GMP sections 820.162 and 820.198 require investigations after a
critical or non-critical finished device is released for distribution
and fails or allegedly fails to meet performance specifications.
Section
820.162 refers to analysis of actual failed devices, i.e., the
determination of the failure mechanism, and whether it is design or
manufacturing related. Section 820.198 is intended to apply to the
investigation of complaints involving possible failure of a device,
i.e., an investigation to determine if there actually is a failure.
EXHIBITS
This exhibit is a blank copy of the form used to record the batch
production record for the Thayer Martin component used in the urine
plate.
gmp2-2:8/3/87
CHAPTER 11 LABELING
LABELING REGULATIONS
Misbranding
False or Misleading Labeling
Adequate Directions for Use
Prescription Devices
Sterile Devices
CONTENT DEVELOPMENT AND APPROVAL
Write to Reader
Refer to Actual Device
Obvious Identification of Controls
Don't Distract Reader
Short and to the Point
Gobbledygook
Introduce Each Item
Accentuate Key Terms
Select Words Wisely
Try Labeling
Approval Policy and Procedure
GMP CONTROL OF LABELING
Label Integrity
Receipt and Inspection
Area Separation and Inspection
Storage
Label Check and Record
Critical Device Labeling
CHANGES
SHIPPING FOR PROCESSING
RELABELING AND OVER-LABELING
EXHIBITS
Drafting and Approval of Labeling
Approval Form for Labeling, Advertising, Literature, etc.
Administration Set Label
Labeling Control Record (1 Blank and 1 Completed)
Device History Record: OB/GYN (Plate)
User/Reader Comments
LABELING REGULATIONS
Section 201(k) of the FD& C Act defines the term "label" as "a
display of written, printed, or GRAPHIC matter upon the immediate
container of any article . . . ." The term "immediate container" does
not include a package liner. Any word, statement, or other
information
appearing on the immediate container must also appear on the outside
container or wrapper, if any, of the retail package or be easily
legible
through the outside container or wrapper. This labeling is not
required
on the shipping carton.
Section 502(f)(1) and (2) of the FD& C Act requires that device
labeling bear adequate directions for use, operating and servicing
instructions, and either adequate warnings against uses dangerous to
health, or information necessary for the protection of users. All
devices require directions for use unless specifically exempted by
regulation. Conditions for exemption from this requirement are in 21
CFR
801, Subpart D.
Misbranding
o its packaging does not bear a label containing the name and
place of business of the manufacturer, packer, or
distributor,
and an accurate statement of the quantity of contents;
o words, statements, or other required information are not
prominent on the labeling or are not stated clearly;
Title 21, CFR Part 801.5, defines "adequate directions for use"
as
"directions under which the layman can use a device safely and for
the
purpose for which it is intended." See Part 801.4 for a definition of
"intended use."
Prescription Devices
Sterile Devices
"Caution: Only the fluid path of the set is sterile and nonpyrogenic.
Do not use in a sterile or aseptic area without proper precautions."
There are some basic guidelines, rules, and practices that can be
used to immediately improve such writing. The following paragraphs
will
discuss them, with emphasis on how they can be used to make labeling
clear and comprehensible. Writers are also encouraged to obtain and
use
a standard college-level text on technical writing.
Write to Reader
The most serious problem is that writers tend to write to
themselves. Their material is clear to them -- and they mistakenly
think
it is as clear to others. For example, the sensitivity control on an
instrument is called: "gain" control on page one of the instruction
manual, "amplitude" control on page two, and "level" control in the
next
section. Further, the photograph in the Introduction shows the same
control with a call-out labeled "Signal Adjust". No wonder readers
are
confused! Yet the author of the example knew what he was trying to
write
about and, most certainly, he was writing to himself. When writing
labeling, especially for an OTC device, the author must know the
reading
level of the target audience. If data on reading levels is not
available, this may nessitate reader interviews to establish a
reading
level for the target audience.
With this correlation technique, the words "on" and "off" are
capitalized in the labeling only when they actually appear on the
instrument control panel. Note that "ON" is capitalized in "POWER
switch
to ON" as the actual switch has "POWER", "ON", and "OFF" printed by
it.
In contrast, note that "on" is not capitalized in the example "to
switch
the heater on" as it is not a label of a control on the device. Also,
be
careful to use a simple correlation system that is readily apparent
to
the intended audience.
Readers are very busy trying to learn how to use a new device.
They
should not be annoyed by any unnecessary distractions such as:
o changes in format,
o unusual typeface,
o incorrect page numbers, and
o incorrect figure numbers.
Gobbledygook
ORIGINAL EQUIVALENT
In most cases, the equivalent term in the list can replace the
original term. For the asterished items, the equivalent is simply a
direct statement of what is intended. Of the terms listed, the
combination most often used is "makes provision for". Simply
eliminating
"makes provision for" and "be provided for" from labeling will result
in
an immediate improvement for readers.
Introduce Each Item
Have you ever been run over by a pachysandra? If you can't fish
off
the bridge, does that mean you are allowed to fish only on or from
the
bridge? Better choices for the intended messages are: "Traffic
entering highway" or "No fishing from bridge".
Try Labeling
Finally, always have someone not familiar with the product
operate
it exactly according to the draft instructions and screen displays,
if
any. No coaching -- this is the "acid" test -- good luck! During the
trials, note any significant problems and make appropriate
corrections
to the instructions, prompts, or other labeling.
GMP
PHASE DEVICE TYPE SECTION CONTROL ACTIVITY
7. Separate
Operations NC C .120b Separate multiple
operations to
prevent
mixups.
8. Area
Inspection NC C .120c Before beginning
labeling
operations,
designee to
inspect area
and
remove
extraneous devices
and
labels.
Label Integrity
Many magazines use "wet" ink which smears when touched by sweaty
or
oily fingers. Obviously, this type ink will not meet the GMP design
requirements for package inserts, instruction manuals, and the like.
Labels may be mounted by adhesives, screws, rivets, drive screws,
etc., or printed or etched onto panels and/or onto controls. The
labels
should be located so that they will be seen but not be abraded during
use. (All of us have seen the unbelievable cases where safety labels
on
ladders and riding lawnmowers were placed in the foot rest areas. Of
course, they were scrubbed off after a few uses!)
Storage
Control number
Access restriction
EXHIBITS
Two copies of the same form are reproduced, one blank and the
other
showing what the form looks like when filled in. At the bottom of the
form, there is space to attach the actual labeling used so that a
comparison of the actual labeling used versus that required can be
made
during product release review.
User/Reader Comments
gmp3-9:8/7/87
Sheet 1
of 2
POLICY/PROCEDURE TITLE: Drafting and Approval of Labeling
ECN History
1.0 PURPOSE
2.0 SCOPE
4.0 FORMS
5.0 DEFINITIONS
6.0 PROCEDURE
article inspection.)
8.0 CHANGES
9.0 SCHEDULES
Comments, if any:
CHAPTER 12 PACKAGING
INTRODUCTION
PACKAGING DESIGN AND MATERIALS
User Preference
PROCUREMENT, ACCEPTANCE AND STORAGE
PACKAGING PROCESS
EXHIBITS
Product Specification: Pouch
Header Bag (Specification Form)
INTRODUCTION
As can be seen from the regulation, the primary package and the
secondary package or shipping container must adequately protect the
device under all reasonable conditions from packaging to ultimate use.
Failure to meet this requirement renders a device adulterated and has
resulted in recalls of sterile devices.
User Preference
The nurses believe that being able to see and clearly identify a
device is a "very important criterion of user preference". Also, as
stated above, double primary packaging is preferred for some sterile
devices.
PACKAGING PROCESS
The controls required will vary with the type of device packaged.
For example, when a sterile device is packaged, a manufacturer's
considerations must include:
gmp3-6:8/3/87
EXHIBITS
CHAPTER 13
DISTRIBUTION
INTRODUCTION
Holding and Distribution Procedures
Warehouse Storage
Distribution Records
DEVICE INSTALLATION
EXHIBITS
Finished Product Release Form
Release To Finished Goods/Shipping
Product Shipping Hold
Release From Product Shipping Hold
INTRODUCTION
Warehouse Storage
Distribution Records
o consignee name,
o consignee address,
o quantity shipped,
o date shipped, and
o control number.
DEVICE INSTALLATION
EXHIBITS
(Circle One)
Catalog No.
Packaging LOT # XXXX-01
XXXX-10
=========================================================================
====
==
The following device history documents were reviewed.
MFG QC
Disapproved [ ] Approved [ ]
Comments:
APPROVAL DATESHEET 1 0f 1
TYPE OF PRODUCT
PRODUCT DESCRIPTION
STATUS
CIRCLE EITHER YES OR NO
COMMENTS
___________________________ Date
INTRODUCTION
Complaint Handling System
Complaint Responsibility
Death and Injury Complaints
Complaint Records
Investigation Records
File Accessibility and Location
Non-medical Complaints
Trend Analysis
GMP SECTIONS RELATED TO COMPLAINTS
DEVICE FAILURE ANALYSIS
FEEDBACK FOR QA SYSTEM
COMPLAINT SOURCES
Service or Repair
Parts shipping trends
MEDICAL DEVICE REPORTING
Who Should Report
When To Report
EXHIBITS
Customer Feedback Cards
Complaint Processing Procedure
Complaint Data Forms
INTRODUCTION
Complaint Responsibility
Complaint Records
Investigation Records
Non-medical Complaints
Service or Repair
When to Report
There are specific time limits within which the MDR reports must
be
made. Any report of a death or serious injury must be made by phone
no
later than 5 calendar days from the initial receipt of the
information.
Malfunction reports must be made by phone or letter no later than 15
working days from the initial receipt of the information. In all
cases a
phone report must be followed by a written report within 15 working
days
from the initial receipt of the information by the firm. To meet
these
requirements, firms must have an information handling system to
assure
that data are screened to determine what must be reported to FDA.
This
system must also be able to follow up this information quickly and
accurately in order to comply with the MDR regulation. Firms which
have
a good system for processing complaint and failure investigations
such
as described in this chapter will have the organization and data
processing capabilities to meet the MDR requirements.
EXHIBITS
The first form titled "Customer Complaint" was developed and used
to
record routine complaints regarding complex electronic and
electromechanical devices.
POLICY:
SCOPE:
Sheet 2 of 4
FORMS USED
1. Customer Complaints
Sales Personnel
Service Personnel
One copy into a followup folder under the requested response date.
Sheet 3 of 4
The Assignee:
3. Make copies and retains a copy of the in-process form and any
attachments.
Quality Assurance:
The nature and date of any response made to the originator or the
customer. If this response is in writing, the communication is
appended
to the in-process form.
COMPLAINT LOG
Sheet 4 of 4
Month _______, 19_____
INTRODUCTION
AUDIT REQUIREMENTS
Procedure
Audit Schedule
Independent Auditor
Employee Training
Evaluation Criteria
Results and Corrective Actions
Audit Certification
EXHIBITS
Policy/Procedure for GMP Audit
Quality Assurance Audit Procedure
Vendor Survey Form
INTRODUCTION
AUDIT REQUIREMENTS
Procedure
o an objective,
o audit scope,
o an audit schedule,
o assignment of responsibilities, and
o evaluation criteria.
o Who? Designee
o What? QA system
o When? X months
o How? Per checklist
o Results? Report/review
o Actions? Corrective
Independent Auditor
Employee Training
Evaluation Criteria
Audit Certification
FDA has authority to review and copy all records required by the
GMP
regulation; however, FDA has elected not to routinely review audit
reports. The one exception to FDA's policy of not seeking access to
reports of audits of quality assurance programs is that FDA may seek
production of these reports in litigation under applicable procedural
rules, as for other otherwise confidential documents. Thus, a copy of
the current audit report should be maintained by the firm. FDA policy
was established because the agency does not wish to prejudice audits
by
having auditors concerned that their comments will be reviewed by FDA
investigators. Although FDA investigators do not have routine access
to
audit reports, they can request manufacturers to certify that audits
have been conducted and the results documented; however,
investigators
do not routinely request certification. If requested, a responsible
official of the firm must certify, in writing, that the firm has
complied with the audit requirements of the GMP regulation.
Investigators usually will ask questions regarding the audit report,
such as who prepared the report, when was the report written, who
reviewed the report, was corrective action taken based on the audit
result, etc. If investigators suspect audits are not being conducted,
questions to determine consistency in answers may be addressed to
those
individuals who should have reviewed these reports. FDA investigators
will routinely review audit procedures and audit checklists.
EXHIBITS
Two examples of audit procedures and three checklists, are
included
in this chapter. These may be modified to match individual operations
as
appropriate or used as guidelines.
No details are given for the format of the audit "report" because
the format generally is not important for the small firm -- employees
of
small firms communicate daily with each other. In fact, the "report"
may
be the list of findings neatly noted on the audit checklist. As noted
in
the procedure, however, summaries of the audit findings and
corrective
actions are recommended. The format Who, When, etc. discussed in the
text, was used to develop this example procedure. The first three
items
in this format are reflected in item 1 of the example and the
remaining
three are reflected in items 2, 3 and 4 of the example. The scope is
the
entire quality assurance system.
Page 15-7
Sheet 1 of 4
* * * * * * * * * *
Sheet 2 of 4
6. Etc.
7. Etc.
Sheet 3 of 4
a. clean?
b. healthy?
c. attired?
6. Etc.
Sheet 4 of 4
7. Etc.
________________________________________________________________________
___
POLICY: Periodic and planned audits of systems, processes, and
product
flow shall be performed to assure compliance with regulatory and
company requirements for current Good Manufacturing Practices (QA
system).
Sheet 2 of 2
REPORT OUTLINE
INTRODUCTION
AUTHORITY AND COVERAGE
Inspection Plan
Inspection Refusals
Inspection Preliminaries
Conduct During the Inspection
Close-out Meeting
After the Inspection
BASIC POINTS FOR AN INSPECTION PLAN
REGULATORY SANCTIONS
Adulteration
Misbranding
Management Letter
Warning Letter
Seizure
Detention
Restraining Orders and Injunctions
Citations
Recalls
Penalties
EXHIBITS
Notice of Inspection
Receipt for Samples
Affidavits
List of Observations
Establishment Inspection Report
Warning Letter
INTRODUCTION
Section 704(a) of the Food, Drug, and Cosmetic (FD& C) Act gives
FDA
the authority to conduct GMP inspections of medical device
manufacturers. During these inspections, facilities, manufacturing
processes records, and corrective action programs are examined by an
FDA investigator. The results provide information necessary to
evaluate
a firm's compliance with the device GMP regulation (21 CFR 820).
Inspection Plan
This chapter offers ideas on ways that a firm might prepare for,
undergo, and respond to an FDA inspection. First and foremost, it is
important to plan ahead! Before being visited by an FDA investigator,
a
firm should have in place an inspection procedure which takes into
account, and prepares a firm for, any eventuality. It should detail
company policy regarding such an inspection; and, very importantly,
designate those individual(s) who are to work with the FDA
investigator. Try to anticipate situations and have written
procedures
covering them. These procedures will provide continuity from one
inspection to another and help assure that corporate policies are
followed by employees receiving and accompanying the investigator.
Inspection Refusals
As noted above, Section 704(a) of the FD& C Act gives FDA clear
authority to conduct inspections. It is bad policy to refuse an
inspection because this sets up an adversarial situation and arouses
an
investigator's suspicions regarding the firm's compliance with the
GMP
regulation. If a firm refuses an inspection without a valid reason,
FDA
usually obtains a warrant which grants entry for an inspection.
Refusal
is noted in the firm's file maintained by FDA and may be interpreted
as
a lack of cooperation.
Inspection Preliminaries
Close-out Meeting
15. During the exit interview, make sure that all deviations are
adequately discussed. If there is disagreement, present all of
the
company information and any regulations and official
interpretations that support your viewpoint.
REGULATORY SANCTIONS
Misbranding
(f) Unless its labeling bears (1) adequate direction for use; and
(2)
such adequate warnings against use in those pathological
conditions or by children where its use may be dangerous to
health, or against unsafe dosage or methods of duration of
administration or application, in such manner and form, as are
necessary
for the protection of users ...
Management Letter
When top management is not present during the issuance of the
FDA-483 at the end of the inspection, FDA may send a Management
Letter
to top management such as the president, CEO, etc., of the firm to
assure that top management has a copy of the FDA-483. Because the
Management Letter is only a brief transmittal letter, it is not to be
considered or confused with the Warning Letter described below.
Warning Letter
Seizure
Detention
Citations
Recalls
Penalties
EXHIBITS
Notice of Inspection
Affidavits
The next four forms are used where interstate movement of devices
is
documented by collection of shipping records. The investigator
prepares
an affidavit (Forms FDA 463a, 1664a, or 1664b) referencing these
shipping records. A brief statement is included along with space for
a
description of the documents that relate to the interstate movement
of
the sample in question. Each form is to be signed by the investigator
and the person giving the information. On one of the sample forms
FDA
463a, the individual giving the information refused to sign the
affidavit; and in this case the investigator added a statement to
explain the lack of a signature.
List of Observations
Warning Letter
In this purged sample Warning Letter. blank lines replace
normally
blacked-out words.
WARNING LETTER
BOS-1-91W
_______________________________
_______________________________
_______________________________
We request that you come in to the District Office and meet with
Compliance Officer, __________. The purpose of the meeting is to
discuss the above findings and for you to present your corrective
actions to assure that your firm is now in compliance. A tentative
date for the meeting is ___________ at ____________.
Sincerely,
Edward J. McDonnell
District Director
Boston District Office
cc: ________________
GMP - CHAPTER 17 - APPENDIXES
TABLE OF CONTENTS
[Published in the Federal Register, Vol. 53, No. 52, March 17, 1988]
federal register
PART II
[4110-03]
The device GMP regulation has been developed in accordance with basic
principles of quality assurance. (See, for example, Juran, "Quality
Control Handbook," 3d ed., McGraw-Hill (1974).) These principles have
as their goal the production of articles that are fit for their
intended uses, and may be stated as follows: (1) Quality, safety,
and
effectiveness must be designed and built into the product; (2)
quality
cannot be inspected or tested into the finished product; and (3) each
step of the manufacturing process must be controlled to maximize the
probability that the finished product meets all quality and design
specifications.
The Commissioner agrees that the device GMP regulation should apply
to
the manufacture of any device to be imported or offered for import
into the United States. This was Congress' intent in amending
section
801(a) of the act (21 U.S.C. 381(a)) to allow the Commissioner to
prohibit the importation of a device that was not manufactured in
conformance with the good manufacturing practice requirements.
Devices that appear to be unsafe or ineffective, to have been
manufactured under conditions that were not in compliance with the
GMP
regulation, or to be otherwise adulterated or misbranded will be
detained when offered for import and will not be permitted to enter
the United States until FDA is satisfied that these devices, and
where
possible the conditions under which they were manufactured, are in
full compliance with the act and FDA regulations. FDA now inspects
some foreign device firms and has plans to increase the number of
foreign inspections. FDA is also exploring, with representatives of
foreign countries, the possible development of bilateral agreements
which will provide for the uniform application of GMP requirements
and
exchange of inspectional information on the manufacturing practices
of
domestic and foreign firms. These efforts recognize the importance
of international uniformity of requirements so that foreign and
domestic manufacturers both are treated fairly.
Factors which FDA hopes will reduce the regulation's costs include
the
flexibility provided in the document, the opportunity for
manufacturers to petition for an exemption or variance from one or
more requirements, the time given industry to comply with the
regulation, and FDA's education and training programs for industry.
The Committee and many comments recommended that the agency develop a
list of critical devices so that the industry and FDA field personnel
will know what devices are subject to critical device requirements.
The Commissioner agrees with the committee that a list of examples of
critical devices should be developed and made available. The process
used by FDA to develop this list and the involvement of the Device
GMP
Advisory Committee in this effort are described below.
The Commissioner agrees with these comments and has developed a list
of critical devices to serve as guidance to the industry. This list
is available and will be provided to all critical device
manufacturers
who are registered with FDA and, upon request, to any other
interested
person.
GENERAL PROVISIONS
The Commissioner agrees with the comments and has amended the final
regulation to apply to manufacture of finished devices only.
Although
the regulations do not apply to component suppliers, the Commissioner
has required manufacturers of finished devices to take the necessary
precautions to assure the quality of components. He also encourages
component manufacturers to use the regulations as a guide where
appropriate.
The Commissioner rejects these comments because FDA will continue its
longstanding practice of inspecting foreign plants and plans in the
future to conduct more inspections of foreign manufacturers of
devices
offered for importation into the United States. Such foreign
manufacturers, like domestic manufacturers, are required to comply
with the GMP requirements. Any imported device about which the
agency
has questions with respect to safety and effectiveness will be
detained upon importation until the agency is satisfied that it
complies with all applicable laws and regulations administered by FDA.
In addition, FDA will attempt to develop and implement bilateral
agreements with appropriate Government officials in other countries
to
provide greater assurance that foreign manufacturers of devices
offered for importation into the United States are adhering to the
GMP
regulation.
DEFINITIONS
The Commissioner is not persuaded that there is any need for the use
of symbols and other markings other than letters and/or numbers, and
he is not making the requested change.
17. Several comments said only class III devices (those requiring
premarket approval) should be declared "critical."
20. Several comments said the condition of the patient at the time a
device is used should be a factor in considering whether a device
should be considered as a "critical device."
34. Several comments said the quality control unit need not check
in-process production of noncritical devices because it has the
authority to reject the finished device if that should prove
necessary.
35. Several comments said the quality control personnel have no need
to review production records, as these records, have no bearing on
the
quality of the device.
The Commissioner shares the concerns of the comments and the Device
GMP Advisory Committee that general FDA access to audit reports would
tend to weaken the audit system. He believes that auditing of
quality
assurance programs is important, and he recognizes the need to
maintain a degree of confidentiality if audits are to be complete and
candid. Therefore, the Commissioner has decided that FDA must
require
each manufacturer to conduct periodic audits of its quality assurance
program and to prepare audit reports. The Commissioner has also
concluded that FDA must routinely inspect and copy manufacturers'
internal audit procedures. However, as a matter of administrative
policy, FDA will not request inspections and copying of the reports
of
audits of a manufacturer's quality assurance program when FDA
conducts
routine surveillance of a manufacturer's compliance with device GMP's.
When FDA needs to determine whether a manufacturer is conducting
audits in accordance with the regulation, a designated FDA employee
may request a responsible official of the manufacturer to certify in
writing that the manufacturer has complied with 820.20(b). Upon
receiving such a request, the official is required to submit, or to
have another responsible official of the manufacturer submit, the
certification of compliance. A person who submits a false
certification is liable to prosecution under 18 U.S.C. 1001 and 21
U.S.C. 331(q)(2).
41. Many comments said on-the-job training was more effective than a
documented training program and best served to provide the necessary
experience required by the regulation.
The Commissioner disagrees with the comment and has determined that
the Occupational Safety and Health Act (OSHA) regulations do not
include all of the personnel health and cleanliness requirements
needed in this regulation, which aims at protecting device users from
defective devices rather than protecting manufacturing employees from
job-related hazards. Although there are some areas of common
interest, the Commissioner believes that this regulation does not
conflict with OSHA regulations.
BUILDINGS
The Commissioner agrees with the suggestion and the final regulation
is changed accordingly.
The Commissioner rejects the comment because not all local laws
adequately address sewage and refuse disposal in device
establishments.
53. Many comments suggested that the requirement for written
procedures and schedules in proposed 820.56(e) be prefaced by "when
necessary" because not all cleaning procedures require written
procedures and schedules.
EQUIPMENT
The Commissioner rejects the comments and points out that the
manufacturer has flexibility in specifying levels of materials
allowed
on the device, provided the safety and effectiveness of the device
are
not compromised. The requirement directs the manufacturer to develop
and follow his own procedures for limiting amounts of manufacturing
materials. The Commissioner has revised this section to require that
the procedures for the removal of manufacturing materials be in
writing to assure that proper attention is directed to this activity.
CONTROL OF COMPONENTS
67. Several comments suggested that the requirement in proposed
820.80(a) for acceptance of components be limited to components
requiring testing.
The Commissioner agrees with the comments, and the requirement for a
designated individual to maintain rejection percentages for critical
components is deleted from 820.81(a). Additionally, the final
regulation clarifies that all lots of critical components shall be
representatively sampled for testing and examination. The
Commissioner believes this requirement is necessary to assure that
critical components are fit for their intended use.
The Commissioner agrees with the comments, but does not believe the
regulation should be changed because 820.81(a) does not impose a
general reserve-sampling requirement. For certain critical
components, such as the power source of a cardiac pacemaker, a
manufacturer should maintain a reserve sample of the component
because
experience has shown that, in a small number of instances. the
component may prematurely fail during its expected life. The
maintenance of a reserve sample provides the manufacturer with a
factual basis for determining the actual, as opposed to the expected,
life of the critical component and allows for the identification of
troublesome areas so that corrective action may be undertaken. In
developing procedures to implement 820.81(a) each manufacturer has
some flexibility to determine the quantity needed for analysis and
reserve, thus reducing the burden on manufacturers. If a
manufacturer
has good reasons to believe that it is not necessary to maintain a
reserve sample of a critical component, then the manufacturer need
not
do so. However, the manufacturer should be prepared to explain these
reasons to FDA.
77. Several comments on proposed 820.81(a) suggested that the
wording of the proposed requirement concerning identification of
critical components could be interpreted to mean that each critical
component must be identified with control numbers upon receipt.
The Commissioner points out that 820.81(a) requires only that each
lot of critical components be identified with a control number(s)
upon
receipt.
The Commissioner notes that the proposed regulations did not specify
that the written agreement must be contained in a separate document
and agrees that such agreement could be contained in a purchase order.
Therefore, he believes that no change in the regulation is necessary.
The Commissioner disagrees with the comment and notes that 820.5
states that the quality assurance program shall be appropriate to the
specific device manufactured. This flexible approach enables
manufacturer to exercise judgment in determining which specifications
and/or processing procedures for a particular device need to be
established, implemented, and controlled. The Commissioner is
revising the final rule for clarity.
85. Many comments suggested that the use of the term "statistical
control" in proposed 820.100(c), regarding ongoing trend analysis,
is
confusing and essentially duplicates the requirement in 820.100(b).
The Commissioner rejects the comments and points out that 820.130
on
device packaging in the final regulation applies to all packaging,
whether or not the immediate container or the shipping container, so
as to assure protection of the device during storage and shipment.
The Commissioner agrees with the comments, and the amendment is made.
Section 820.150 is also revised to clarify that the oldest approved
devices shall be distributed first where a device's quality or
fitness
for use deteriorates over time.
DEVICE EVALUATION
RECORDS
The Commissioner also notes that the principal reason for stipulating
that all records required by part 820 shall be maintained at the
manufacturing establishment or other reasonably accessible location
is
for the benefit of the manufacturer. By maintaining these records at
the manufacturing establishment or other reasonably accessible
location, responsible officials of a manufacturer can exercise
control
and accountability over the entire manufacturing process and thereby
maximize the probability that the finished device conforms to its
design specifications. The requirement helps assure that responsible
officials at the manufacturing establishment have ready access to
those documents essential for conducting self-inspections, complaint
investigations, failure analyses, and audits.
The Commissioner agrees with the comments, and 820.181 and 820.182
are revised in the final regulation to clarify the intent of the
requirements and to preserve the distinction between noncritical and
critical device requirements.
The Commissioner agrees with the comments, and the final regulation
is
revised to require that a device history record be maintained to
demonstrate that the device is manufactured in accordance with the
device master record. The device history record shall include or
refer to the location of the following information: The dates of
manufacture, the quantity manufactured, the quantity released for
distribution, and any control number used.
The Commissioner advises that he did not intend that each critical
component carry a control number. The final regulation is changed to
provide that critical components may be designated in the device
history record by a control number Identifying a particular lot of
critical components. The Commissioner has also revised 820.185 for
clarity and consistency of language.
135. Several comments said FDA should not cite section 519 of the
act
(21 U.S.C. 360i), regarding records and reports on devices, as part
of the authority for Part 820. It was argued that FDA had not met
the
specific requirements of section 519 of the act. One comment said
that findings must be made as to how each recordkeeping and reporting
requirement satisfies section 519 of the act and that FDA cannot
incorporate recordkeeping requirements under section 519 of the act
in
a GMP regulation but must issue a separate recordkeeping regulation.
The comment also asserted that FDA could require manufacturers to
maintain GMP records, but could not inspect them. The concern was
that if the GMP regulation' was promulgated under authority of
section
519 as well as section 520(f) of the act and other provisions, FDA
would have specific authority to inspect, copy, and verify required
records under section 704(e) of the act (21 U.S.C. 374(e)).
In three related cases, the U.S. District Court for the Northern
District of New York, in a written opinion dated April 6, 1978,
disagreed with FDA's determination that the term "restricted device"
includes preenactment prescription devices. Becton, Dickinson and
Company v. Food and Drug Administration et al. (Civ. Action No.
77-CV-181); United States v. Becton, Dickinson and Company (Civ.
Action No. 77-CV-337); In the matter of establishment inspection of
Bard-Parker Division of Becton, Dickinson and Company (Misc. 112)
(N.D. NY). These cases are under appeal to the U.S. Court of Appeals
for the Second Circuit. A contrary result was reached by the U.S.
District Court for the Central District of California in a decision
reinstating an inspection warrant, which was quashed by another judge
4 weeks earlier, that authorizes FDA to inspect records relating to
restricted devices (cardiac pacemakers). In the Matter of the
Establishment Inspection of American Technology, Inc., Civil Action
No. CV-1727-LEW (C.I). CA, decided June 5, 1978). The issue is also
pending in one other judicial district.
The GMP regulation, however, does not deal directly with the issues
in
these cases (the scope of section 704(a) authority and the meaning of
"restricted devices"). After Part 820 becomes effective, FDA will
have
clear authority under section 704(e) of the act to inspect and copy
required GMP records, including complaint files, for all devices,,
whether or not restricted devices, and regardless of the outcome of
the pending cases. After the effective date, a person who refuses to
allow FDA to inspect a required GMP record, or who causes such a
refusal, will have committed an act that is prohibited under section
301 (e) and (f) of the Act (21 U.S.C. 331 (e) and (f)) and will be
subject to regulatory action under section 302 or 303 (21 U.S.C. 332
or 333). In addition, under sections 501(h) and 502(t)(2) (21 U.S.C.
351(h), 352(t)(2)), devices are adulterated and misbranded if they
are
the subject of required GMP records to which FDA is refused access.
Such devices are subject to seizure.
IMPLEMENTATION
This regulation has been under development for a long time. The
device
industry has had an extraordinary involvement in its development.
Since 1973 the agency has encouraged device manufacturers to examine
their manufacturing practices in light of the draft and proposed
device GMP regulations. For several years FDA has engaged in
constructive dialog with representatives of the device industry to
foster a better understanding of the agency's overall approach to
device GMP's. Simply stated, this approach recognizes the need to
develop a regulation applicable to all device manufacturers. The
regulation should not be so specific as to specify for every type of
device manufacturer exactly what it must do and how its manufacturing
practices must be accomplished; but, rather the regulation should set
forth general requirements applicable to all manufacturers, with
additional requirements for manufacturers of critical devices. These
GMP requirements are designed to be flexible so that a device
manufacturer can develop a detailed set of procedures, as required by
820.5 and 820.20, which take into account a device's special
manufacturing needs without compromising strict adherence to quality
assurance requirements. FDA will look at these detailed procedures
and how they measure up to the requirements of Part 820 to determine
whether a manufacturer is complying with the regulation and is
operating in accordance with its own quality assurance program.
REFERENCES
Therefore, under the Federal Food, Drug, and Cosmetic Act (secs. 501,
502, 518, 519, 520(f), and 701(a) as amended, 52 Stat. 1049-1051 as
amended, 1055, 90 Stat. 562-569 (21 U.S.C. 351, 352, 360h, 360i,
360j(f), 371(a))) and under authority delegated to the Commissioner
(21 CFR 5.1), chapter I of title 21 of the Code of Federal
Regulations
is amended as follows:
* * * * *
May 1987
1.0 SCOPE
The design phase is the most important phase in the life cycle of a
device. The inherent safety, effectiveness, and reliability of a
device
are established during this phase. No matter how carefully a device
may
be manufactured or how perfect the GMP program, this inherent safety
and effectiveness cannot be improved except through design
enhancement.
Therefore, it is crucial that adequate controls be established and
implemented during the design phase to assure that the safety,
effectiveness and reliability of the device are optimally enhanced
prior to manufacturing to assure that an acceptable quality level can
be
achieved during production. It is only through careful planning and
management of the preproduction process that safety, effectiveness
and
reliability can be established in a device.
A design deficiency can be very costly once a device design has been
released to production and the device is manufactured and
distributed.
Costs may include not only replacement and redesign costs, with
resulting modifications to manufacturing, procedures, retraining, etc.
to enable manufacture of the modified device, but also liability
costs,
and loss of customer goodwill.
3.1 Organization
3.2 Specifications
\1\ For example, the pulse amplitude range for an external pacemaker
could be established as .5 to 28 mA at a lead of 1000 ohms, and
pulse
duration could be .1 to 9.9 ms.
Once these characteristics are agreed upon as those desired for the
proposed device (i.e. the design aim) they should be translated into
written design specifications. These preliminary specifications
provide
the details from which the design can be developed, and controlled,
as
well as the means by which the design can be evaluated.
Specifications
should address, as applicable, such performance characteristics as
durability/reliability, precision, stability, purity, and others
necessary to fulfill the product's intended purpose. Specifications
should be reviewed and evaluated by appropriate qualified personnel
from organization elements such as Marketing, R& D, Quality,
Reliability, and Manufacturing.
\2\ For example, a disposable blood tubing set was designed and
manufactured by Company A for use with Company B's dialysis machine.
The tubing was too rigid, such that when the air-embolism occlusion
safety system on the dialysis machine was at its lowest within-
specification force, the tubing would not necessarily occlude and air
could be passed to the patient. The tubing occluded fully under the
nominal occlusion force.
\4\ For example, one possible failure mode for an anesthesia machine
could be a sticking valve. If the valve's sticking could result in
over
or under-delivery of the desired anesthesia gas, a failsafe feature
should be incorporated into the design to prevent the wrong delivery,
or, if this is impractical, a suitable alarm system should be
included
to alert the user in time to take corrective action.
\7\ For example, the ITT Research Institute, Turin Road North, P.O.
Box 180, Rome N.Y., 13440, phone 315-336-2539 offers a Reliability
Design Training Course to manufacturers which includes Failure Mode
Effects Analysis and Fault Tree Analysis Techniques.
.4 Reliability Assessment
\11\ For example, the spring used to achieve proper spindle operation
in a volume ventilator experiences thousands of cycles of compression
and expansion. Failure of the spring could result in respiratory
arrest. Therefore, the spring's ability to perform reliably under
these
conditions must be assured through comprehensive qualification
testing.
Operator and service manuals should cover appropriate preventive
maintenance.
SQA should begin with a plan, which can be written using a guide such
as
ANSI/IEEE Standard 730-1984, Standard for Software Quality Assurance
Plans. Good SQA assures quality software from the beginning of the
development cycle by specifying up front the required quality
attributes of the completed software and the acceptance testing to be
performed. In addition, the software should be written in
conformance
with a company standard using structured programming. The SQA
representative or department should have the authority to enforce
implementation of SQA policies and recommendations.
3.7 Labeling
Clinical trials should not begin until the safety of the device has
been verified under simulated use conditions, particularly at the
expected performance limits. Simulated use testing should address use
with other applicable devices and possible misuse. Manufacturers of
devices that are likely to be used in a home environment and operated
by persons with a minimum of training and experience have an
obligation
to anticipate the types of operator errors most likely to occur.
These
manufacturers should design and label their products to encourage
proper use and minimize the frequency of misuse.\16\
Once the technical adequacy of the design has been verified through
applicable testing and the design has been approved, the approved
design including components, packaging and labeling is translated
into
approved, formal specifications. The device, however, is not yet
ready
to be released to manufacturing for routine production.
\17\ For example, a drainage catheter using a new Teflon material was
designed, fabricated and subsequently qualified in a laboratory
setting. Once the catheter was manufactured and distributed, however,
the manufacturer began receiving complaints that the bifurcated
sleeve
was separating from the catheter shrink base. Investigation found the
separation was due to dimensional shrinkage of the Teflon and
leeching
of the plasticizers from the sleeve due to exposure to Freon during
manufacturing. Had the device been exposed to actual production
conditions during fabrication of the prototypes, the problem may have
been detected before routine production and distribution.
3.10 Certification
3.11 Personnel
Once the design has been proven safe and effective and devices are
produced and distributed, the effort to assure that the device and
its
components have acceptable quality and are safe and effective is not
complete.
-THE END-
(Prepared by the Manufacturing Quality Assurance Branch, (HFZ-332),
Division of Compliance Programs)
APPENDIX I
DEFINITIONS
APPENDIX II
REFERENCES
MILITARY STANDARDS
VOLUNTARY STANDARDS
OTHER
gmP4-3
I. PURPOSE
II. SCOPE
This guideline is issued under Section 10.90 (21 CFR 10.90) and is
applicable to the manufacture of pharmaceuticals and medical devices.
It
states principles and practices of general applicability that are
not
legal requirements but are acceptable to the FDA. A person may rely
upon this guideline with the assurance of its acceptability to FDA,
or
may follow different procedures. When different procedures are used,
a
person may, but is not required to, discuss the matter in advance
with
the FDA to prevent the expenditure of money and effort on activities
that may later be determined to be unacceptable. In short, this
guideline lists principles and practices which are acceptable to the
FDA for the process validation of drug products and medical devices;
it
does not list the principles and practices that must, in all
instances,
be used to comply with law.
III. INTRODUCTION
Several firms have asked FDA for specific guidance on what FDA
expects
firms to do to assure compliance with the requirements for process
validation. This guideline discusses process validation elements and
concepts that are considered by FDA as acceptable parts of a
validation
program. The constituents of validation presented in this document
are
not intended to be all inclusive. FDA recognizes that, because of
the
great variety of medical products (drug products and medical
devices),
processes and manufacturing facilities, it is not possible to state
in
one document all of the specific validation elements that are
applicable. Several broad concepts, however, have general
applicability
which manufacturers can use successfully as a guide in validating a
manufacturing process. Although the particular process validation
will
vary according to such factors as the nature of the medical product
(e.g., sterile vs non-sterile) and the complexity of the process,
the
broad concepts stated in this document have general applicability
and
provide an acceptable framework for building a comprehensive approach
to
process validation.
DEFINITIONS
\1\ For example, USP XX states: "No sampling plan for applying
sterility tests to a specified proportion of discrete units selected
from a sterilization load is capable of demonstrating with complete
assurance that all of the untested units are in fact sterile."
A. Prospective Validation
\7\ For example, the AAMI Guideline for Industrial Ethylene Oxide
Sterilization of Medical Devices approved 2 December 1981, states:
"The performance qualification should include a minimum of 3
successful, planned qualification runs, in which all of the
acceptance
criteria are met.....(5.3.1.2.)."
Once the equipment configuration and performance characteristics are
established and qualified, they should be documented. The
installation
qualification should include a review of pertinent maintenance
procedures, repair parts lists, and calibration methods for each
piece
of equipment. The objective is to assure that all repairs can be
performed in such a way that will not affect the characteristics of
material processed after the repair. In addition, special post-
repair
cleaning and calibration requirements should be developed to prevent
the
inadvertent manufacture of nonconforming product. Planning during the
qualification phase can prevent confusion during emergency repairs
which could lead to use of the wrong replacement part.
The extent of revalidation will depend upon the nature of the changes
and how they impact upon different aspects of production that had
previously been validated. It may not be necessary to revalidate a
process from scratch merely because a given circumstance has changed.
However, it is important to carefully assess the nature of the change
to
determine potential ripple effects and what needs to be considered
as
part of revalidation.
3. Documentation
Test data may be useful only if the methods and results are
adequately
specific. As with prospective validation, it may be insufficient to
assess the process solely on the basis of lot by lot conformance to
specifications if test results are merely expressed in terms of
pass/fail. Specific results, on the other hand, can be statistically
analyzed and a determination can be made of what variance in data can
be expected. It is important to maintain records which describe the
operating characteristics of the process, e.g., time, temperature,
humidity, and equipment settings.\11\ Whenever test data are used to
demonstrate conformance to specifications, it is important that the
test methodology be qualified to assure that test results are
objective
and accurate.
Under the GWQAP program, FDA may advise the requesting agency
that a
firm has not met all the requirements of the device regulations. If,
for
instance, a firm is not registered, FDA will advise the requesting
agency. This agency then informs the manufacture which FDA
requirement
must be met before the evaluation can continue. After the
manufacturer
has complied
with the requirement, FDA review of available information will
continue
in order to determine if the firm is or is not acceptable.
Chief
Government Wide Quality Assurance Program, HFZ-331
Center for Devices and Radiological Health
1390 Piccard Drive
Rockville, Maryland 20850
301-427-1125
Department of Defense
Defense Personnel Support Center
Small Business Advisor
2800 South 20th Street
Philadelphia, Pennsylvania 19101
215-737-2321
Veterans Administration
Marketing Center
Small Business Center
Hines, Illinois 60141
708-216-2438