Ensuring An Effective Quality System M. Kowolenko, Ph.D. SVP, Biopharmaceutical Operations

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Ensuring An Effective Quality SystemM.
Kowolenko, Ph.D.SVP, Biopharmaceutical
Operations Technology
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Role of the Quality Unit

• Compliance with all relevant regulations and
  commitments made in license applications or
  supplements
• Systems that assure control over the
  manufacturing and timely disposition process,
  regardless of location
• Assure that products meet all safety claims, have
  the identity and strength and meet all the
  quality and purity characteristics stated
• Provide leadership in the Continuous Improvement
  Process leading to risk reduction and improved
  customer satisfaction
• Probability and severity of harm.

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Requirements

• Internal
• Meet business objectives
• Produce product with all specified attributes
• Right the first time
• Efficient
• Value-added
• MAINTAIN CONTROL BE COMPLIANT

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GMPs in the 21st Century Objective Provide
high quality, cost-effective oversight of
industry manufacturing, processing and
distribution to reduce risk.
Apply the most current scientific knowledge
about risk management and quality assurance to
the FDA's requirements, including Current Good
Manufacturing Practice (CGMP) inspection,
compliance, and enforcement activities.
Develop new inspection approaches to more
effectively utilize new and existing resources.
Implement an efficient, risk-based system to
promote the wide availability of safe
FDA-regulated imports by increasing the
standards and improving the practices of source
countries and at points of entry into U.S.
commerce, improving detection of noncompliant
products, and developing standards and
procedures to maximize the cost- effectiveness of
agency oversight.
https//www.fda.gov/oc/mcclellan/strategic_risk.ht
ml
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Agency Expectations

• Systems that demonstrate Business in
  appropriate Control
• Management Oversight
• Proper delegation and administration
• Effective communication
• Audit, Monitor, Report
• Uniform enforcement, corrective actions
• Continuous improvement

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Inspection Guideline QSIT

• Verify that a quality policy, management review
  and quality audit procedures, quality plan, and
  quality system procedures and instructions have
  been defined documented.
• Verify that a quality policy and objectives have
  been implemented.
• Review the firms established organizational
  structure to confirm that it includes provisions
  for responsibilities, authorities and necessary
  resources.
• Confirm that a management representative has
  been appointed. Evaluate the purview of the
  management representative.
• Verify that management reviews, including a
  review of the suitability and effectiveness of
  the quality system are being conducted.
• Verify that quality audits, including re-audits
  of deficient matters, of the quality system are
  being conducted.http//www.fda.gov/ora/inspect_re
  f/igs/qsit/qsitguide.htm
• http//www.fda.gov/cder/dmpq/7356_002M.pdf

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Form 483
Whats Hot 2004 2005 Quality
Unit Investigations Investigations Validati
on Analytical Methods Record keeping
(QU) Validation Equipment and
Facilities Equipment and Facilities Analytical
Methods
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Drug Quality System for the 21st Century

• Science based Manufacturing Program
• Role of PAT
• Clear understanding of HACCP as it relates to
  process
• Risk based approach
• - Q9 Quality Risk Management
• Quality by design
• fitness for use
• life-cycle of specifications
• - Design Space
• Know thy Process and Product

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QS Business Opportunity

• Do Current Business Systems Practices meet
  worldwide requirements?
• Are the program documents too procedurally
  specific, inadequate, or absent to allow
  communication of requirements within a given
  system?
• Issues
• ownership avoidance
• dilute compliance
• stalemate issue resolution
• foster untimely response to changes
• lack of management oversight

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Quality Systems
ISO 9004
Quality Management System
Interested Parties
Interested Parties
Management Responsibilities
Measurement, Analysis and Improvement
Resource Management
Satisfaction
input
output
Product Realization
Requirements
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Quality Systems
Corrective Preventive Actions
Process Transfer
Production Process Controls
Management
Equipment Facility Controls
MaterialControls
Records, Documents, Change Controls
http//www.fda.gov/ora/inspect_ref/igs/qsit/qsitgu
ide.htm
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Global Standards Program
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Global Standards Program Hierarchy
Approves program approach, responsibility,
resources
Core Stakeholders
Quality Manual
Lead Team/Steering Committee
Defines must have
Global Standards
SOP Work/Job Instructions
Answers how to
Working Groups
Provides Records
Working Groups
Other Supporting Documentation
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How do we make Quality everyone's concern?

• Enhance metrics related to operational
  performance and add programs that incorporate
  increased awareness.
• operational performance metrics
• evolution of original supply chain cost of
  quality program
• increased interdepartmental involvement
• clear timelines, responsibility and
  accountability
• success measured as delivering on commitments

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How do we gauge performance in a global
organization?

• Management Review
• Objective is to assure we are operating in
  control and highlight issues before they become a
  crisis.
• Supplement daily and weekly meetings regarding
  production.
• Provide Sr. Management with a common tool for
  assessing global operations, determining resource
  allocations, and assuring operational activities
  are aligned.
• Meet compliance requirements of Quality Systems.

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Pharmaceutical cGMPs for the 21st Century A
Risk-Based Approach (Final Report Fall 2004)

• Under a quality system, the review should
  consider at least the following
• The results of audits and other assessments
• Customer feedback, including complaints
• The analysis of data trending results
• The status of actions to prevent a potential
  problem or a recurrence
• Any follow-up actions from previous management
  reviews
• Any changes in business practices or environment
  that may affect the quality system (such as the
  volume or type of operations)
• Product characteristics meet the customers needs

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Surveillance Leads to Proactive Management of
Operations
Rejected/Discrepant material
Statistical Analysis of Process Performance
Maintenance Records
Laboratory Testing Trend Reports
Industry Surveillance/ Compliance Updates
Vendor Performance
OOS Investigations
Internal Audits
Customer Complaints
Product Rework/Reprocessing
EM Reports
BPDRs/Withdrawals/Recalls
Annual Product review Issues
Management Review
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Management Review
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Management Review
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Site Bulk ManufacturingProduct Scorecard
Bulk Metrics Q1 Actual Q2 Target Apr Actual May Actual Jun Actual Q2 Actual
Delivery Index 100 100 100 100 100 100
Throughput Index 104 90 124 111 85 107
Average Yield 7.7 7.2 8.9 8.0 6.1 7.6
Cost per Batch ,000
Cost per Gram ,000
Batches Failed 0 0 0 0 0 0
Cost of Batches Lost 0 0 0 0 0 0
Grams Produced 61.8 100.8 36 40 31 106
Success Rate 100 90 100 100 100 100
Grams Planned 57.6 100.8 28.8 36.0 36.0 100.8
Thaw Rate 7 14 5 5 5.25 NA
Batches Completed 8 14 4 5 5 14
Batches Planned 8 14 4 5 5 14
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Bulk QualityGeneral Scorecard 1 of 2
General Metrics Scorecard Q1 Actual Q2 Target Apr Actual May Actual Jun Actual Q2 Actual
DEVIATIONS
Number of Batches Thawed N/A 10 7 7 N/A
General Deviations per Batch lt5 5 9 13 9
Average Cycle Time lt30 38 44 38 40
Total Number of Deviations open gt120 Days 0 3 2 6 4
CAPAs
Total Number of Open CAPAs N/A 248 220 215 N/A
Percent of Open Overdue CAPAs 0 56 53 50 53
OUT OF SPECIFICATION
Number of OOS/AR generated lt4 3 6 9 6
Average Cycle Time lt30 125 108 12 82
Number of OOSs open gt30 Days lt5 14 13 19 15
Number of OOSs open gt120 Days 0 3 4 7 5
REMEDIAL ACTION REPORTS
Total Number of instruments calibrated N/A 606 594 548 1,748
Percent of Out of Tolerance TBD 1.2 0.8 1.1 1.0
RAR Cycle Time Average 72 lt30 57 88 105 83
Number of RARs open gt30 Days lt5 36 33 25 31
Number of RARs open gt120 Days 0 20 24 19 21
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Bulk Bulk QualityGeneral Scorecard 2 of 2
General Metrics Scorecard Q1 Actual Q2 Target Apr Actual May Actual Jun Actual Q2 Actual
CRITICAL WORK ORDERS
Total Number of CWOs generated N/A 41 63 63 167
Number of CWOs open gt180 Days 0 89 96 88 91
DOCUMENTATION METRICS
Number of Change Requests initiated N/A 100 95 196 391
Average Change Request Cycle Time lt30 41 41 33 38
Number of Change Requests open gt90 Days lt3 6 14 20 13
ASSAY FAILURES
Number of Assay Failures Chemistry 111 lt50 47 35 33 38
Number of Assay Failures Bioanalytical 142 lt50 58 46 27 44
ENVIRONMENTAL MONITORING
Number of Action Alerts recorded 108 TBD 28 21 18 22
Percent of open Alert Actions gt30 Days old 0 19 12 6 12
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Management Review
 
 
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Guidance for IndustryPAT A Framework for
Innovative Pharmaceutical Development,
Manufacturing, and Quality Assurance

• Design and optimization of drug formulations and
  manufacturing processes within the PAT framework
  can include the following steps (the sequence of
  steps can vary)
• Identify and measure critical material and
  process attributes relating to product quality
• Design a process measurement system to allow
  real-time or near real-time (e.g. on-, in- or
  at-line) monitoring of all critical attributes
• Design process controls that provide adjustments
  to ensure control of all critical attributes
• Develop mathematical relationships between
  product quality attributes and measurements of
  critical material and process attributes

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Process Monitoring
Compare batch profile to average /- 3 standard
deviations
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MVA can identify key sources of variation in the
process and provide models for enhanced control
Batch 1 Batch 14 Batch 28 Batch 42 Batch
56 Batch 70 Batch 84 Batch 98 Batch
112 Batch 126 Batch 140
The end result is more consistent processes with
lower failure rates
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On-line Batch Monitoring
Combines and compares all the critical process
parameters to the average batch
Identifies process problems before they cause
failures
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Process Improvement and Problem Solving

• Process Improvement and Problem Solving
• Provide T/O with tools to do the appropriate
  root-cause analysis
• Identify the difference between Process
  Improvement and Problem Solving
• Is fundamental to how we approach Exceptions and
  CAPA
• MVA
• ASQ training

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Investigations Process Flow
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Investigation Approach

• QC Assay - investigation
• Methods Process
• Cell culture
• Downstream, including SLRs
• PVRs
• Deviations and CCRs
• Materials
• Cell banks
• Serum and Basal medium powder
• Resins
• Machines Equipment
• Equipment Facilities work orders (CWO)
• Bioreactor trains, columns, skids, storage areas,
  etc
• New equipment
• Organization Systems
• SOPs training
• Decision-making (ie., column repacking)
• Organization

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Investigation Techniques

• DataMining
• Statistical Tools
• Pattern-recognition analysis
• Gap Analysis
• Site current vs. historical
• Site vs. Site
• Analytical Testing Methods to diagnose/isolate by
  unit operation
• Experimental Design (scaled-down process), if
  needed

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Opportunities in Compliance and cGMP

• Compliance makes good business sense
• The intent of the regulatory agencies is to
  assure consistency in the product produced an
  understanding of the risk/benefit and design
  space of your process.
• Manufacturing organizations want consistency and
  predictability to maximize facility utilization.
• Both parties benefit from constant surveillance
  and feedback of the quality system process.