Critical Regulatory and Compliance Issues with the US FDA in the 21st Century - PowerPoint PPT Presentation

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Critical Regulatory and Compliance Issues with the US FDA in the 21st Century


Recalls, Complaints, Field Alerts. Quality Systems ' ... Recalls. Biological Deviation Reports. What about a corporate perspective across various sites? ... – PowerPoint PPT presentation

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Title: Critical Regulatory and Compliance Issues with the US FDA in the 21st Century

Critical Regulatory and Compliance Issues with
the US FDA in the 21st Century
  • AOAC-SCS 2nd Annual
  • Regulatory and Compliance Conference
  • Co-Hosted by AAPS SCPDG
  • US FDA at Irvine
  • March 30-31, 2006
  • Jeff Yuen, MPH, MBA
  • Jeff Yuen and Associates

Quality SystemsRisk ManagementContinuous
Quality SystemsGMP Quality and Product Quality
QSIT Inspections
Quality Commitment, Attitude, Passion
  • Quality Systems
  • Minimum Standards
  • Commitment to Quality

Company Quality Life Cycle


Wisdom QA
The Quality Life Cycle Birth Adolescence
Maturity Wisdom
  • Quality Assurances influence early in
    development and technology transfer through
    commercialization of the drug product must be
    present, appropriately balanced with drug
    development objectives
  • Quality Assurances role and viability as a
    formal unit must become more predominant from the
    point of pivotal clinical trials through PAI.
  • FDA expects Quality Assurance to be completely
    responsible for commercially approved drug
  • Utilize outside objective assessments to prevent
    against tunnel vision and to keep your
    horizons fresh to new ideas and concepts
    were living in a dynamic world!

Quality SystemsTaking care of the Dirty
Laundry and taking out the Trash
  • Management and Tracking/Trending of OOS Results
  • Tracking and trending of initial OOS vs. initial,
    unconfirmed OOS vs. confirmed OOS
  • Management and Tracking/Trending of Deviations
  • Production/Manufacturing
  • Process Yields at Different Critical Phases of
    the Manufacturing Process
  • Reconciliation problems (brite, unlabeled stock
    and labeling)
  • Procedural (SOP) or Batch Record (BPR)
  • Documentation Errors
  • Unplanned Maintenance and/or Repairs
  • Out of Calibration Events

Quality SystemsProviding a Sound Foundation
for ensuring cGMP Compliance
  • Management and Tracking/Trending of Changes
  • Process, Methods, Specifications, Labeling,
    Facilities, Utilities, and Equipment
  • Management of Third Party Contractors and Service
  • Quality Agreements
  • Contract Manufacturers
  • Contract Test Laboratories
  • Management of qualified, experienced, and trained
  • What about changes in personnel (experience)
  • Are we using temporary employees or unionized
  • How do we qualify trainers?
  • Whats an adequate supervisor to employee ratios?
  • Do you have sufficient quality presence or
    influence in other departments?

Quality SystemsProviding a Sound Foundation
for ensuring cGMP Compliance
  • Management of Qualification
  • Facilities
  • Production
  • QC Laboratories
  • Utilities
  • Critical Product Contact
  • Equipment
  • Production
  • QC Laboratories
  • Hardware
  • Establishing an Environmental Monitoring Program
  • Establishing a Personnel Monitoring Program

Quality SystemsProviding a Sound Foundation
for ensuring cGMP Compliance
  • Management of Validation
  • Process
  • Safety
  • Viral Inactivation
  • Mycoplasma Removal
  • Aseptic Process Validation
  • Media Fills
  • Sterilization and SIP
  • Bioburden Control
  • Depyrogenation
  • Endotoxin Control
  • Cleaning and CIP
  • Manual, Semi-Automated, and Automated
  • Decontamination

Quality SystemsProviding a Sound Foundation
for ensuring cGMP Compliance
  • Management of Validation
  • Analytical Methods
  • Chemical and Microbiological
  • Software
  • Building Management Systems
  • Management of Investigations
  • Deviations
  • Biological Deviation Reports
  • Out of Specifications
  • Out of Trend
  • Failures (Non-Conformances)
  • Time Zero and On-Going Stability
  • Recalls, Complaints, Field Alerts

Quality SystemsProviding a Sound Foundation
for ensuring cGMP Compliance
  • Management of GXP Audit Programs
  • GLP, GCP, and GMP Audits
  • Internal
  • External
  • Document Control/Record Retention
  • Batch Production Record Issuance and Archives
  • Logbook and Controlled Forms Issuance and
  • SOP Issuance
  • Methods Issuance
  • Specifications
  • Master Labeling
  • Validation Documentation
  • Batch Release

Quality SystemsA Global or Corporate Perspective
  • Annual Product Reviews Annual Reports
  • Post Market Surveillance
  • () Rejected Batches
  • Complaints
  • Field Corrections
  • Field Alerts
  • Recalls
  • Biological Deviation Reports
  • What about a corporate perspective across
    various sites?

Top cGMP ViolationsWarning Letters (FY
  • 21CFR211.192
  • Deviation investigations
  • 21CFR211.22
  • Quality unit
  • 21CFR211.100
  • Written procedures (process and production
  • 21CFR211.160
  • Laboratory controls
  • 21CFR211.67
  • Equipment cleaning maintenance

Top cGMP ViolationsWarning Letters (FY
  • 21CFR211.113
  • Control of microbial contamination
  • 21CFR211.42
  • Design/construction of facilities
  • 21CFR211.165
  • Testing and release for distribution
  • 21CFR211.166
  • Stability testing
  • 21CFR211.25
  • Personnel qualifications and training

Evaluating Regulatory Risk
  • Ensure the product is well-characterized
  • Ensure there are adequate development reports and
    data to support the process
  • Ensure that contract manufacturers and test
    facilities operate in compliance with cGMPs
  • Ensure the manufacturing process and test methods
    are validated
  • Ensure that cleaning procedures have been
    validated including microbial assessments
  • Ensure the product meets all stability
  • Ensure all in-process assays are adequately

Evaluating Regulatory Risk
  • Ensure that risk assessments or a risk based
    approach to establishing process controls has
    been documented
  • Ensure A/NDA and BLA particularly the CMC Section
    is accurate and complete
  • Prepare and monitor contract manufacturing and
    laboratory test facilities for FDA PAI readiness
    and continued cGMP compliance
  • Ensure the manufacturing process is consistent
    with pre-established specifications
  • Ensure that release specifications are meaningful
  • Develop a system for evaluating cGMP compliance
    status on a routine basis (internal and external
    cGMP compliance)

Evaluating Regulatory Risk
  • Develop and establish quality systems to ensure
    processes are remain properly validated and
    equipment is maintained in a qualified state
  • Develop an adequate communication system between
    QA and all other departments
  • Ensure quality systems are integrated and
    centralized vs. decentralized
  • Develop an early warning system based on
    marketplace indicators and internal quality
    metrics complaints, adverse event reports,
    recalls, reject categories, rejected lots,
    stability failures, out-of-trend reports,
    deviation trend summaries, and out-of-specificatio
    n test results.
  • Ensure that the organizational structure is
    adequately designed to effectively support
    commercial cGMP compliance activities (e.g.
    management reviews)

Closing Comments
  • Quality Assurance is required to develop, manage,
    maintain, and monitor quality systems.
  • Quality Assurance is ultimately responsible for
    lot release including acceptance of errors,
    deviations, or out-of-specification test results
    are noted in the batch record.
  • Quality Assurance is responsible for the product
    even if errors are identified post-release.
  • Quality Assurance can not be unduly influenced or
    possess any perceived conflicts of interest.

Closing Comments
  • FDA initiates regulatory actions when concerns
    and evidence poor quality assurance oversight are
    identified, left uncorrected, and persistent.
  • Quality Assurance and Compliance must provide
    sufficient oversight and protection of public
  • Quality Assurance and Compliance is the first
    line of defense for virtual companys senior

Closing Comments
  • Senior Management must be appraised of potential
    significant quality issues and concerns.
  • Quality presence must be integrated into all
    departments not just thoughts or a sense of being
  • Quality must be designed into a product it can
    not be tested into a product.

Contact Information
CDR Jeffrey T. Yuen, MPH, MBA President
Principal Consultant Jeff Yuen and
Associates P.O. Box 6026 Orange, CA
92863-6026 Phone 714 282-1014 Fax 714
685-02!4 E-Fax 240 597-8351 E-mail
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