21 CFR 820 QSR - Training - 1

Quality System Regulation (QSR)
Training
Or How to Ensure Development, Production

and Sale of Safe, Effective, Consistent Product
FDLI – February 2003
February 03 Alquest – Linda Alexander

Overview
z QSR History, Purpose and Scope
z Changes from Prior GMPs
z Regulatory Requirements
z FDA Inspectional Focus – QSIT
– Management Responsibility
– Design Controls
– Production and Process Controls
– Corrective and Preventative Action
z Integration of all QSR systems

Quality System
z U.S. FDA Quality System Regulation
(QSR) - 21 CFR Part 820
z Harmonized with European Requirements
– ISO 9001
– EN 46001
– Medical Devices Directive (MDD)
– ISO 13485

Regulation Evolution
z Current regulation covers design
through commercialization of product
QSR Regulation
1997 (SMDA 1990) Controls for
ISO Regulation 1990 Tracking Design
GMP Regulation
1978, 1982, 1990 Ensure Consistency Ensure Consistency
ISO Regulation 1990 of Manufacturing of Manufacturing
Medical Device Approval for Approval for Approval for
Amendments Commercialization Commercialization Commercialization
1976 (Law)
PAST CURRENT

Quality System Elements
z Management Responsibility z Acceptance Activities
z Quality Audit z Acceptance Status
z Personnel z Nonconforming Product
z Design Controls z Corrective and Preventive
z Document Controls Action
z Purchasing Controls z Labeling and Packaging
z Identification and Traceability Control
z Production and Process Control z Handling, Storage,
Distribution and Installation
z Inspection, Measuring and Test
Equipment z Records
z Servicing
z Process Validation
z Statistical Techniques
Quality System
• Final Release
Design Inspection Criteria
• Segregation and
Storage • Device
Manufacture • Product Shipment tracking/
• Specification • Tracking of Product handling of
Development complaints
• Testing • Establishing Production • Corrective
• Prototyping Processes Distribute Action as
• Selection of • Testing needed
Suppliers • Developing Acceptance • Servicing
• Transfer to Criteria
Production • Equipment Calibration
• Tracking of and Maintenance Monitor
Design Changes • Labeling Performance
• Tracking Changes
Quality System Elements
Management Responsibility:
z Establish policy and objectives for, and
commitment to, quality
z Establish Organizational Structure
z Designate a Management Representative
z Conduct Management Reviews

Management Responsibility (Cont.)
z Organizational Chart - Example
President and CEO
Research and
Operations Sales and Marketing
Development
Manufacturing Sales Engineering
QA/QC
Regulatory Research Lab
(Management Rep)

Management Responsibility (Cont.)
z Establish a Quality Plan
z Additional Management Considerations
– Define appropriate responsibility, authority, and
interrelationships of all personnel who manage, perform,
and assess work affecting quality
– Provide adequate resources for management,
performance of work and assessment activities (including
internal audits)
– Display management commitment in decision-making
and involvement in management reviews

Quality System Element
Internal Quality Audits
z Audits of all QS elements shall be periodically
conducted to:
– Demonstrate compliance of the quality system to
regulations, and/or
– Identify nonconformities and areas for improvement
in processes
z Reports of audits must be documented and
reviewed by management of the areas that were
audited
Personnel and Training
z Employees, who’s work affects quality, must
have appropriate education, background,
training and experience to do their jobs
z Records of education, training, background
and experience must be maintained

Design Controls
z Procedures to control and verify design of
all products to ensure design requirements
are met
z Develop a design/development plan
z Develop and document design input
– Design input = Design requirements or specs

Design Controls (cont.)
z Develop and document design output
– Design output = Finished product and DMR
(i.e., finished product specification)
z Plan formal reviews of the design
throughout the development process
z Develop procedures for ensuring correct
translation into routine production

z Document changes implemented in the

design during development phase, and test
as needed
– Include “regression analysis”
z Maintain records of design process
z Conduct validation and verification testing

Design
User Needs Reviews
Design Inputs
Design
Process
Design
Verification
Outputs
Is it Done
Validation Right? Final Device
Does it Work?
Document Controls
z Establish and maintain a Quality System that is
appropriate for devices designed and manufactured and
meets regulatory requirements.
z Ensure documentation developed is adequate for its
intended purpose or requirement
z Make documents accessible to those who need them
z Ensure control of the accuracy and usage of current
versions of documents
z Maintain records of document changes

Purchasing
z Document requirements, including quality
requirements that suppliers must meet
z Evaluate Suppliers, Contractors and
Consultants on ability to meet requirements
z Define type and extent of controls over
products, services and suppliers
z Maintain records for each supplier

Identification & Traceability
z Maintain procedures to identify product during
all stages of receipt, production, distribution,
and installation to prevent mix-ups
z Each unit or lot of finished device has a lot
number
z Systems can be complex or simple
– FDA judges this system to be a measure of your
control over your production system
Production and Process Controls
z Production processes must be developed,
conducted, controlled and monitored to ensure
the device conforms to its specs
z Process control procedures are necessary where
deviations from the device specification could
result from the production process
z Significant changes to these procedures must be
verified or validated prior to implementation
Production /Process Control (cont.)
z Control environment when it can adversely
affect product
z Ensure equipment meets specified
requirements and is adequately maintained
z Process validation is required when results of
process cannot be fully verified by
inspection/test
z Document validation activities and results
Inspection and Testing
z Maintain procedures for acceptance activities
z Upon receipt, incoming material is inspected,
tested or otherwise verified to demonstrate that
it meets specified requirements
z In-process material must:
– meet specified requirements, where appropriate
– be controlled until inspection and test is completed
z Each production run or lot of finished devices
must meet the stated acceptance criteria
Inspection, Measuring and Test Equipment
z Ensure that equipment is suitable for use and
capable of producing valid results
z Specific and detailed calibration procedures
z Calibration standards must be traceable to
national or international standards, if possible

Inspection, Test and Acceptance Status
z Identification of acceptance status is required
throughout manufacturing, packaging,
labeling, installation and service
z Product must be clearly identified as
conforming or nonconforming to the
acceptance criteria

Nonconforming Product
z Maintain procedures for control of product
that does not conform to specifications
z Disposition of non-conforming product must
be documented

Corrective and Preventive Action (CAPA)
z Maintain procedures for implementing
corrective and preventive action
z Analyze data to identify and investigate areas
requiring action - get to the root cause
z process analysis
z quality audits
z service and complaint record analysis
z management reviews
z non-conformities

Corrective and Preventive Action (cont.)
z Identify the action(s) needed to address the root

cause of nonconformities in the Quality System
z VERIFY or VALIDATE the action to ensure it
is effective & does not adversely affect product
– Confirm changes to documentation
– Follow up audit
– Review of production or field reports

Corrective and Preventive Action
(cont.)
z Documentation shall include identified
problem, investigation, root cause, action
plan and verification results
z Report CAPA information relating to
quality problems:
– To those directly responsible for assuring the
quality of such product
– As part of Management Review meetings
Labeling and Packaging Control
z Maintain procedures for:
z Label integrity: legibility and adhesive adequacy
z Labeling inspection: accuracy of information
z Labeling storage: identification and accessibility
z Labeling operations: track label and labeling used for each

lot/batch of product
z Control number: must accompany the unit through
manufacturing and distribution
z Packaging/shipping containers: ensure proper construction
to protect device during processing and distribution
Handling, Storage, Installation and Delivery
z Maintain procedures to minimize mix-ups,
damage, deterioration, contamination or
other adverse effects during handling
z Maintain distribution records
z Maintain installation and servicing
procedures and records

Quality Records
z Maintain all records required by the Quality
System in an area reasonably accessible to
the manufacturer and auditors
z Records must be legible and stored to
minimize deterioration and to prevent loss
z Records stored electronically are backed up

Complaint Handling
z Maintain procedures for receiving, reviewing,
investigating, and responding to complaints
z Records shall be maintained for each complaint
– Document details of event, investigation, corrective
action, and response to complainant
– Must be reasonably accessible to the manufacturing
facility

Statistical Techniques
z Establish, where appropriate, procedures for
using valid statistical techniques for
establishing, controlling and verifying the
acceptability of process capability and product
characteristics
z Inspection samples
z Test quantities
– Sampling plans must be based on valid statistical

rationale (e.g., ANSI/ASQC Z1.4, 1993, LTPD)
FDA Inspection Process - QSIT
z FDA is responsible for inspecting firms who
manufacture devices cleared for use in
humans
– PMA Approval process
– 510(k) Clearance Notices
– Registration and Listing Requirements
z FDA targets firms who have had previously
violative inspections and firms with whom
they have no history
FDA Inspection Process
z FDA has modified their inspection processes -
became more interactive
– Pre-announcements: 3-5 days prior to beginning
their inspection
– New techniques: QSIT/HACCP
z QSIT: Quality System Inspection Technique
z HACCP: Hazard Analysis and Critical Control Points
– Discussion of their findings during the inspection

process so there should be NO surprises

Quality System Inspection
Technique
z More similar to the ISO inspectional method
z Evaluates seven main subsystems by
focusing on four inspectional areas
z Significantly more interaction between the
Investigator and all levels of the company to
determine objective compliance

Technique
z Four Inspectional Areas
– Management Responsibility
– Design Controls
– Production and Process Controls
– Corrective and Preventive Action
z Secondary Areas
– Facility and Equipment Control
– Material Controls
– Records/Document Controls
Reports of
Corrections and
Removals
Medical Medical
Device Device
Reporting Corrective Tracking
&
Preventive
Action
Facility
& Design
Equipment Controls
Controls
Management
Production
Material &
Controls Process
Records/ Controls
Documents/
Change Sterilization
Controls Process
Control
Technique
z Based on “Top Down” Approach
z Inspector reviews a sampling of records
– statistically determined number
z Follows record trail to conclusion
z Monitors strict compliance to procedural
tasks
z Evaluates raw data to confirm conclusions

Technique
z Typical Inspection Process
– Opening Meeting 15-20 minutes
– Plant Tour 30-45 minutes
– Overview of Product 60-90 minutes
– Meeting with Top Management: 1/2 day
– Design Controls: 1 day
– Corrective and Preventive Action: 1-11/2 days
– Document and Data Control 11/2 - 2 days
– Closeout Meeting
Top Ten FDA 483 Items
Records (20%)
CAPA (50%)
PAPC (30%)
Non-QSIT Inspections
Top Ten FDA 483 Items
Records (10%)
CAPA (30%)
PAPC (20%)
Mgmt (40%)
QSIT Inspections
Confirm that quality audit
Verify existence of quality
procedures ensure that
policy, management review Confirm that management audits and reaudits of
and quality audit review procedures ensure deficient matters are
procedures. that executive management conducted.
reviews the suitability and
effectiveness with
Confirm implementation of
sufficient frequency Suspend inspection of
quality policy and
objectives. Management Controls -
Return to Management
Confirm that Management Controls Subsystem after
Confirm establishment of completing inspection of
Rep has been appointed?
org structure. other subsystems.
Does this person have
Does it have provisions for:
authority over and
- responsibility and
responsibility for:
authority?
- ensuring QS is effectively
- resources? Evaluate whether
established and
maintained? management with
- reporting on the executive responsibility
performance of the QS to ensures that an adequate
Management management with and effect QS has been
executive responsibility? established.
Controls
For a selected design
Confirm that risk
project, confirm that
Confirm that device analysis was performed
procedures have been
defined and documented software was validated?
Confirm that design
Determine if any
Review the design plan changes were controlled
unresolved discrepancies
and assess the firm’s - including validation or
remain from design
conduct of risk analysis verification, where
validation
appropriate
Confirm that the design
Confirm that validation
inputs were established Confirm that design
demonstrated the
approved design met reviews were conducted
Confirm that design user needs and intended
outputs essential to the uses - and that activities
proper function of the Confirm that design was
were conducted on
device were identified correctly transferred to
production devices or
production
equivalent
Confirm that acceptance
criteria were established Confirm that verification Design
prior to test activities demonstrated that
outputs met inputs Controls
Confirm that procedures
have been defined and Confirm that if process
documented cannot be fully verified,
it was validated
Confirm that if process
is software controlled,
Select a process and the software was
Confirm that:
confirm that process is validated
-nonconformances were
controlled and monitored handled appropriately
- equipment was
adjusted, calibrated and Confirm that personnel
maintained are qualified or trained
Confirm that process is to implement processes
-process was adequately
operating within
validated
specified limits
- per review of DHR or
other records
Production and
Process Controls
Confirm that procedures Confirm that failure
have been defined and investigation procedures Confirm that appropriate
documented are followed action has been taken for
-is investigation level identified problems
commensurate with risk?
Confirm that quality data
- is investigation Confirm that action
sources have been
conducted to root cause? taken is:
identified and analyzed
- is product controlled to - effective
to identify existing
prevent distribution until - verified or validated
product and quality
resolution? prior to implementation
problems that require
corrective action - not detrimental to the
Confirm that data finished device
received by the CAPA - implemented and
Confirm that sources of
system are complete, documented
product and quality
information that may accurate and timely
show unfavorable trends -appropriate statistical Confirm that information
have been identified and methods used? has been properly
analyzed to identify - results compared across disseminated, including
issues that may require different data sources reports at management
preventive action review
CAPA Controls
Audit Conduct
z Assign escort for Inspector(s)
– Typically QA personnel (Quality Management Rep)
– Capture questions, comments from Inspector and any
documents reviewed
– Intervene/clarify for “auditee”
z Seek department head for initial questions
z Prepare and coach department heads to
understand audit process
– Be truthful, but not volunteering
– Convince FDA that operation meets QS requirements
At the Conclusion of the
Inspection ...
“Evaluate whether management with
executive responsibility ensures that
an adequate and effective quality
system has been established and
maintained.”

Integration of all QSR Systems
z Comprehensive coverage of all essential
functions of a manufacturing facility
– Design
– Development
– Manufacture
– Distribution
– Post-market monitoring
z Intended to ensure “Continuous Improvement”

Continuous Improvement
Design
Develop
Improve/
Innovate
Monitor Manufacture
Distribute
Quality System Regulation
z Develop a system that is appropriate for YOU
– Lots of flexibility in requirements for how the
system can be configured
– Don’t be afraid to make changes if something is
not working
z Can’t implement the changes until the documentation
is done
z Most of these requirements make good
business sense - use it to your advantage!
Who Should Care?
z FDA expects that a company producing
product for use in humans is meeting the
Quality System Regulation
– Non-compliance may result in Warning Letter,
negative publicity, submission hold, civil penalties
z FDA holds Company Management responsible
for function of the Quality System
z FDA specifically meets with the “most
responsible” person in the company to discuss
the commitment to quality
Questions??

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Quality System Regulation (QSR)

Or How to Ensure Development, Production

FDLI – February 2003

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

President and CEO

Manufacturing Sales Engineering

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

z Document changes implemented in the

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

z service and complaint record analysis

February 03 Alquest – Linda Alexander

z Identify the action(s) needed to address the root

February 03 Alquest – Linda Alexander

z Labeling storage: identification and accessibility

z Labeling operations: track label and labeling used for each

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

– Sampling plans must be based on valid statistical

– Discussion of their findings during the inspection

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

February 03 Alquest – Linda Alexander

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