FDA Quality System Regulations ISO 13485 Regulatory Inspections

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FDA Quality System RegulationsISO
13485Regulatory Inspections

• Copenhagen, Denmark
• November 4, 2009
• John Wilson, Jr., PhD, MPH
• Senior Vice President, Clinical Trial Monitoring
  Services

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First Principles

• Several full-length seminar topics
• Quality System Regulations (QSR)/ISO 13485
• Quality System Inspection Technique (QSIT)
• FDA Inspection Preparation
• Necessarily brief and introductory version

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Overview

• Overview of the FDA QSR/GMPs
• ISO 13485 as point of reference
• FDA QSIT Guide
• General Pointers for Managing FDA Inspections

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Not Starting from Scratch

• European community has a good understanding of
  ISO requirements, including ISO 13485
• Many requirements of ISO 13485 and QSR are
  similar.

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What is ISO 13485?

• A standard, published in 2003, that represents
  the requirements for a comprehensive management
  system for the design and manufacture of medical
  devices.
• Stand-alone document, harmonized with ISO 9001. A
  fundamental difference, however, is that ISO 9001
  requires the organization to demonstrate
  continuous improvement, whereas ISO 13485
  requires only that they demonstrate the quality
  system is implemented and maintained.

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ISO 13485

• Other specific differences include
• Promotion and awareness of regulatory
  requirements as a management responsibility.
  Example of a market specific regulatory
  requirement is 21 CFR 820 Quality System
  Regulation for Medical Devices sold in the United
  States.
• Focus on risk management activities
• Specific requirements for inspection and
  traceability for implantable devices
• Specific requirements for documentation and
  validation of processes for sterile medical
  devices
• Specific requirements for verification of the
  effectiveness of corrective and preventive
  actions

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What is QSR?

• Quality System requirements for medical devices
  have been internationally recognized as a way to
  assure product safety and efficacy and customer
  satisfaction since at least 1983, and were
  instituted as requirements in a final rule
  published in 1996. The rule is promulgated at 21
  CFR 820.

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QSR

• The FDA has identified in the QS regulation the
  essential elements that a quality system shall
  embody for design, production and distribution,
  without prescribing specific ways to establish
  these elements. These elements include, but are
  not limited to
• Quality System
• personnel training and qualification
• product design
• documentation
• purchasing
• product identification and traceability at all
  stages of production
• controlling and defining production and process

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QSR (continued)

• Quality System (continued)
• defining and controlling inspection, measuring
  and test equipment
• validating processes
• product acceptance
• controlling nonconforming product
• instituting corrective and preventive action when
  errors occur
• labeling and packaging controls
• handling, storage, distribution and installation
  
• records
• statistical techniques
• all overseen by Management Responsibility and
  Quality Audits.

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QSR (continued)

• QSR allows some leeway in the details of quality
  system elements.
• It is left to manufacturers to determine the
  necessity for, or extent of, some quality
  elements and to develop and implement procedures
  tailored to their particular processes and
  devices.
• For example, if it is impossible to mix up labels
  at a manufacturer because there is only one label
  to each product, then there is no necessity for
  the manufacturer to comply with all of the GMP
  requirements under device labeling.

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21 CFR 820Applicability

• Any finished device that is
• Intended for human use
• Manufactured
• Imported
• Or offered for import in all states and
  territories of the United States, D.C. and Puerto
  Rico.

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Key Areas of Difference (QSR/ISO13485)

• Customer Focus
• Complaint Handling
• CAPA
• Records
• Documentation
• Labeling

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Management Responsibility
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Management Responsibility
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Management Responsibility
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Management Responsibility
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Management Responsibility
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A Look at Two Specific Areas

• Individual approvals
• Change procedures

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Individual Approvals

• There are numerous activities described in the
  QSR that require an approval by a designated
  individual, including
• Design Master Records
• Design Control Activities
• Maintenance, Inspection, Validation and
  Calibration of Equipment
• Process Validation and Performance
• Acceptance Activities
• Authorization for Non-conforming product
• Decisions not to Investigate Complaints
• Certification made by Management for records
  exempt from FDA inspection.
• Labeling

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Change Procedures

• FDA places major emphasis on change management
• Specs, method, process, procedural
• Changes must be verified or validated as
  appropriate, and adequately documented
• Frequent nonconformity if only following ISO
  13485

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A Word about FDA Inspections

• If I dont bring it up now
• Plus, its important!

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Consequences of Noncompliance

• Product can be considered adulterated or
  misbranded
• Various administrative and enforcement actions
• CAPA
• Warning Letter for serious violations
• Failure to obtain approval to import into USA
• Market withdrawal/recall

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QSIT

• Quality System Inspection Technique (QSIT)
• Top Down versus Bottom Up
• Top Down
• Are procedures that address the QSR defined and
  documented?
• Are the procedures being followed?
• Bottom Up
• Examine quality problems
• Determine if deviations from QSR exist

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QSIT
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Systems Based Inspection

• Four major subsystems
• Management
• Design Controls
• CAPA
• Production and Process Controls
• Three other sub-systems are linked through review
  of the major ones listed above
• Facility and Equipment Controls
• Material Controls
• Records/Documents/Change Controls

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Management

• Documented of the Quality Plan/Policy
• Procedures for Quality System and Quality audits
• Management Representative identified
• Confirmation of Management Review
• Confirmation that Quality audits are conducted as
  required

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Design Control

• Documented Design procedures and plans
• Documentation of Design inputs or requirements
• Documentation of Design outputs or specifications
• Documentation of Design verification
• Documentation of Design validation
• Validation of software
• Documentation of Risk Analysis at appropriate
  intervals
• Documentation of Design Reviews
• Documentation and verification of Design Transfer

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Corrective and Preventive Action

• Written CAPA Procedure
• Investigation of root causes
• Review of appropriate sources of data
• Application of statistical analysis
• Control of Non-conforming product
• Documentation of CAPA
• Communication with individuals involved in CAPA
• Management review of CAPA

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Production and Process Control

• Control and monitoring of Processes
• Handling of rejected or non-conforming products
• Documentation that equipment is adjusted,
  calibrated and maintained appropriately.
• Documented verification/validated of
  manufacturing processes.
• Documented verification/ validation of Software
  (product and non-product).
• Documentation that employees are qualified and
  trained.

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FDA Inspections

• Focus on
• Class III devices
• Implantable/ life supporting/ life sustaining
  devices
• New device
• History of significant violations in the past
• Foreign manufacturers are typically contacted 2 -
  3 months in advance to schedule an inspection.
• Its recommended that the Manufacturer forward
  the Quality System Manual for pre-inspection
  review.

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Focus of Inspection Readiness

• Inspection Team Established and Documented
• Logistics Established
• Program (Opening Meeting, Overview of Quality
  System, Key Issues)
• Training
• Mock Inspection (Facility Tour, Audit, etc.)
• Review of Facilities

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Maintaining Inspection Readiness

• Conduct periodic facility inspections
• Perform Mock Reviews, as appropriate
• Maintain current documentation/ data/ information
  related to past inspections.

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Inspection Readiness

• Know how to interpret the regulations and apply
  them.
• Conduct training for personnel.
• Conduct regular mock inspections.
• Review logistics
• Identify and Coordinate Team
• Perform Mock Interviews
• Review Quality Policy and Supporting
  Documentation

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John R. Wilson, Ph.D. Senior Vice
President jwlison_at_beaufortadvisors.com
Beaufort, LLC 500 East Main Street Suite
1301 Norfolk, Virginia 23510 1 (757)
383-6000 www.beaufortCRO.com