Quality System Regulation QSR Training

1
Quality System Regulation (QSR)Training
Or How to Ensure Development, Production and Sale
of Safe, Effective, Consistent Product

• FDLI February 2003

2
Overview

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

3
Quality System

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

4
Regulation Evolution

• Current regulation covers design through
  commercialization of product

QSR Regulation 1997 (SMDA 1990) ISO Regulation
1990
Controls for Tracking Design
GMP Regulation 1978, 1982, 1990 ISO Regulation
1990
Ensure Consistency of Manufacturing
Ensure Consistency of Manufacturing
Approval for Commercialization
Approval for Commercialization
Approval for Commercialization
Medical Device Amendments 1976 (Law)
CURRENT
PAST
5
Quality System Elements

• Management Responsibility
• Quality Audit
• Personnel
• Design Controls
• Document Controls
• Purchasing Controls
• Identification and Traceability
• Production and Process Control
• Inspection, Measuring and Test Equipment
• Process Validation

• Acceptance Activities
• Acceptance Status
• Nonconforming Product
• Corrective and Preventive Action
• Labeling and Packaging Control
• Handling, Storage, Distribution and Installation
• Records
• Servicing
• Statistical Techniques

6
Quality System

• Final Release Inspection Criteria
• Segregation and Storage
• Product Shipment
• Tracking of Product

Design

• Device tracking/ handling of complaints
• Corrective Action as needed
• Servicing

Manufacture

• Specification Development
• Testing
• Prototyping
• Selection of Suppliers
• Transfer to Production
• Tracking of Design Changes

• Establishing Production Processes
• Testing
• Developing Acceptance Criteria
• Equipment Calibration and Maintenance
• Labeling
• Tracking Changes

Distribute
Monitor Performance
7
Quality System Elements

• Management Responsibility
• Establish policy and objectives for, and
  commitment to, quality
• Establish Organizational Structure
• Designate a Management Representative
• Conduct Management Reviews

8
Management Responsibility (Cont.)

• Organizational Chart - Example

President and CEO
Research and Development
Operations
Sales and Marketing
Manufacturing
Sales
Engineering
QA/QC (Management Rep)
Regulatory
Research Lab
9
Management Responsibility (Cont.)

• Establish a Quality Plan
• 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

10
Quality System Element

• Internal Quality Audits
• 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
• Reports of audits must be documented and reviewed
  by management of the areas that were audited

11
Quality System Element

• Personnel and Training
• Employees, whos work affects quality, must have
  appropriate education, background, training and
  experience to do their jobs
• Records of education, training, background and
  experience must be maintained

12
Quality System Element

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

13
Design Controls (cont.)

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

14
Design Controls (cont.)

• Document changes implemented in the design during
  development phase, and test as needed
• Include regression analysis
• Maintain records of design process
• Conduct validation and verification testing

15
Design Controls (cont.)
Design Reviews
User Needs
Design Inputs
Design Process
Design Outputs
Verification
Is it Done Right?
Final Device
Validation
Does it Work?
16
Quality System Element

• Document Controls
• Establish and maintain a Quality System that is
  appropriate for devices designed and manufactured
  and meets regulatory requirements.
• Ensure documentation developed is adequate for
  its intended purpose or requirement
• Make documents accessible to those who need them
• Ensure control of the accuracy and usage of
  current versions of documents
• Maintain records of document changes

17
Quality System Element

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

18
Quality System Element

• Identification Traceability
• Maintain procedures to identify product during
  all stages of receipt, production, distribution,
  and installation to prevent mix-ups
• Each unit or lot of finished device has a lot
  number
• Systems can be complex or simple
• FDA judges this system to be a measure of your
  control over your production system

19
Quality System Element

• Production and Process Controls
• Production processes must be developed,
  conducted, controlled and monitored to ensure the
  device conforms to its specs
• Process control procedures are necessary where
  deviations from the device specification could
  result from the production process
• Significant changes to these procedures must be
  verified or validated prior to implementation

20
Production /Process Control (cont.)

• Control environment when it can adversely affect
  product
• Ensure equipment meets specified requirements and
  is adequately maintained
• Process validation is required when results of
  process cannot be fully verified by
  inspection/test
• Document validation activities and results

21
Quality System Element

• Inspection and Testing
• Maintain procedures for acceptance activities
• Upon receipt, incoming material is inspected,
  tested or otherwise verified to demonstrate that
  it meets specified requirements
• In-process material must
• meet specified requirements, where appropriate
• be controlled until inspection and test is
  completed
• Each production run or lot of finished devices
  must meet the stated acceptance criteria

22
Quality System Element

• Inspection, Measuring and Test Equipment
• Ensure that equipment is suitable for use and
  capable of producing valid results
• Specific and detailed calibration procedures
• Calibration standards must be traceable to
  national or international standards, if possible

23
Quality System Element

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

24
Quality System Element

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

25
Quality System Element

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

26
Corrective and Preventive Action (cont.)

• Identify the action(s) needed to address the root
  cause of nonconformities in the Quality System
• 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

27
Corrective and Preventive Action (cont.)

• Documentation shall include identified problem,
  investigation, root cause, action plan and
  verification results
• Report CAPA information relating to quality
  problems
• To those directly responsible for assuring the
  quality of such product
• As part of Management Review meetings

28
Quality System Element

• Labeling and Packaging Control
• Maintain procedures for
• Label integrity legibility and adhesive
  adequacy
• Labeling inspection accuracy of information
• Labeling storage identification and
  accessibility
• Labeling operations track label and labeling
  used for each lot/batch of product
• Control number must accompany the unit through
  manufacturing and distribution
• Packaging/shipping containers ensure proper
  construction to protect device during processing
  and distribution

29
Quality System Element

• Handling, Storage, Installation and Delivery
• Maintain procedures to minimize mix-ups, damage,
  deterioration, contamination or other adverse
  effects during handling
• Maintain distribution records
• Maintain installation and servicing procedures
  and records

30
Quality System Element

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

31
Quality System Element

• Complaint Handling
• Maintain procedures for receiving, reviewing,
  investigating, and responding to complaints
• 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

32
Quality System Element

• Statistical Techniques
• Establish, where appropriate, procedures for
  using valid statistical techniques for
  establishing, controlling and verifying the
  acceptability of process capability and product
  characteristics
• Inspection samples
• Test quantities
• Sampling plans must be based on valid statistical
  rationale (e.g., ANSI/ASQC Z1.4, 1993, LTPD)

33
FDA Inspection Process - QSIT

• 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
• FDA targets firms who have had previously
  violative inspections and firms with whom they
  have no history

34
FDA Inspection Process

• FDA has modified their inspection processes -
  became more interactive
• Pre-announcements 3-5 days prior to beginning
  their inspection
• New techniques QSIT/HACCP
• QSIT Quality System Inspection Technique
• HACCP Hazard Analysis and Critical Control
  Points
• Discussion of their findings during the
  inspection process so there should be NO
  surprises

35
Quality System Inspection Technique

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

36
Quality System Inspection Technique

• Four Inspectional Areas
• Management Responsibility
• Design Controls
• Production and Process Controls
• Corrective and Preventive Action
• Secondary Areas
• Facility and Equipment Control
• Material Controls
• Records/Document Controls

37
Reports of Corrections and Removals
Medical Device Tracking
Medical Device Reporting
Corrective Preventive Action
Design Controls
Facility Equipment Controls
Management
Material Controls
Production Process Controls
Records/ Documents/ Change Controls
Sterilization Process Control
38
Quality System Inspection Technique

• Based on Top Down Approach
• Inspector reviews a sampling of records
• statistically determined number
• Follows record trail to conclusion
• Monitors strict compliance to procedural tasks
• Evaluates raw data to confirm conclusions

39
Quality System Inspection Technique

• 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

40
Top Ten FDA 483 Items
Records (20)
CAPA (50)
PAPC (30)
Non-QSIT Inspections
41
Top Ten FDA 483 Items
Records (10)
CAPA (30)
PAPC (20)
Mgmt (40)
QSIT Inspections
42
Confirm that quality audit procedures ensure that
audits and reaudits of deficient matters are
conducted.
Verify existence of quality policy, management
review and quality audit procedures.
Confirm that management review procedures ensure
that executive management reviews the suitability
and effectiveness with sufficient frequency
Confirm implementation of quality policy and
objectives.
Suspend inspection of Management Controls -
Return to Management Controls Subsystem after
completing inspection of other subsystems.
Confirm that Management Rep has been
appointed? Does this person have authority over
and responsibility for - ensuring QS is
effectively established and maintained? -
reporting on the performance of the QS to
management with executive responsibility?
Confirm establishment of org structure. Does it
have provisions for - responsibility and
authority? - resources?
Evaluate whether management with executive
responsibility ensures that an adequate and
effect QS has been established.
Management Controls
43
For a selected design project, confirm that
procedures have been defined and documented
Confirm that risk analysis was performed
Confirm that device software was validated?
Confirm that design changes were controlled -
including validation or verification, where
appropriate
Determine if any unresolved discrepancies remain
from design validation
Review the design plan and assess the firms
conduct of risk analysis
Confirm that the design inputs were established
Confirm that validation demonstrated the approved
design met user needs and intended uses - and
that activities were conducted on production
devices or equivalent
Confirm that design reviews were conducted
Confirm that design outputs essential to the
proper function of the device were identified
Confirm that design was correctly transferred to
production
Confirm that acceptance criteria were established
prior to test activities
Design Controls
Confirm that verification demonstrated that
outputs met inputs
44
Confirm that procedures have been defined and
documented
Confirm that if process cannot be fully verified,
it was validated
Confirm that if process is software controlled,
the software was validated
Select a process and confirm that process is
controlled and monitored
Confirm that -nonconformances were handled
appropriately - equipment was adjusted,
calibrated and maintained -process was adequately
validated
Confirm that personnel are qualified or trained
to implement processes
Confirm that process is operating within
specified limits - per review of DHR or other
records
Production and Process Controls
45
Confirm that procedures have been defined and
documented
Confirm that failure investigation procedures are
followed -is investigation level commensurate
with risk? - is investigation conducted to root
cause? - is product controlled to prevent
distribution until resolution?
Confirm that appropriate action has been taken
for identified problems
Confirm that quality data sources have been
identified and analyzed to identify existing
product and quality problems that require
corrective action
Confirm that action taken is - effective -
verified or validated prior to implementation -
not detrimental to the finished device -
implemented and documented
Confirm that data received by the CAPA system are
complete, accurate and timely -appropriate
statistical methods used? - results compared
across different data sources
Confirm that sources of product and quality
information that may show unfavorable trends have
been identified and analyzed to identify issues
that may require preventive action
Confirm that information has been properly
disseminated, including reports at management
review
CAPA Controls
46
Audit Conduct

• Assign escort for Inspector(s)
• Typically QA personnel (Quality Management Rep)
• Capture questions, comments from Inspector and
  any documents reviewed
• Intervene/clarify for auditee
• Seek department head for initial questions
• Prepare and coach department heads to understand
  audit process
• Be truthful, but not volunteering
• Convince FDA that operation meets QS requirements

47
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.

48
Integration of all QSR Systems

• Comprehensive coverage of all essential functions
  of a manufacturing facility
• Design
• Development
• Manufacture
• Distribution
• Post-market monitoring
• Intended to ensure Continuous Improvement

49
Continuous Improvement
Design
Develop
Improve/Innovate
Monitor
Manufacture
Distribute
50
Quality System Regulation

• Develop a system that is appropriate for YOU
• Lots of flexibility in requirements for how the
  system can be configured
• Dont be afraid to make changes if something is
  not working
• Cant implement the changes until the
  documentation is done
• Most of these requirements make good business
  sense - use it to your advantage!

51
Who Should Care?

• 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
• FDA holds Company Management responsible for
  function of the Quality System
• FDA specifically meets with the most
  responsible person in the company to discuss the
  commitment to quality

52
Questions??