Title: Critical Regulatory and Compliance Issues with the US FDA in the 21st Century
1Critical 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
2Quality SystemsRisk ManagementContinuous
Improvement
3Quality SystemsGMP Quality and Product Quality
4QSIT Inspections
5Quality Commitment, Attitude, Passion
- Quality Systems
- Minimum Standards
- Commitment to Quality
6Company Quality Life Cycle
Birth
Wisdom QA
Adolescence
Maturity
7The 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
products. - 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!
8Quality 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
9Quality 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
Providers - Quality Agreements
- Contract Manufacturers
- Contract Test Laboratories
- Management of qualified, experienced, and trained
personnel - What about changes in personnel (experience)
levels? - Are we using temporary employees or unionized
personnel? - How do we qualify trainers?
- Whats an adequate supervisor to employee ratios?
- Do you have sufficient quality presence or
influence in other departments?
10Quality 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
11Quality 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
12Quality 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
13Quality 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
Archives - SOP Issuance
- Methods Issuance
- Specifications
- Master Labeling
- Validation Documentation
- Batch Release
14Quality 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?
15Top cGMP ViolationsWarning Letters (FY
2004-2005)
- 21CFR211.192
- Deviation investigations
- 21CFR211.22
- Quality unit
- 21CFR211.100
- Written procedures (process and production
controls) - 21CFR211.160
- Laboratory controls
- 21CFR211.67
- Equipment cleaning maintenance
16Top cGMP ViolationsWarning Letters (FY
2004-2005)
- 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
17 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
requirements - Ensure all in-process assays are adequately
validated
18Evaluating 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)
19Evaluating 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)
20Closing 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.
21Closing 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
health. - Quality Assurance and Compliance is the first
line of defense for virtual companys senior
management.
22Closing 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-minded. - Quality must be designed into a product it can
not be tested into a product.
23Contact 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
jtyassociates_at_prodigy.net