ensuring an effective quality system m. kowolenko, ph.d. svp, biopharmaceutical operations &...
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Ensuring An Effective Quality System M. Kowolenko, Ph.D. SVP, Biopharmaceutical Operations & Technology. Role of the Quality Unit. Compliance with all relevant regulations and commitments made in license applications or supplements - PowerPoint PPT PresentationTRANSCRIPT
Ensuring An Effective Quality Ensuring An Effective Quality SystemSystem
M. Kowolenko, Ph.D.M. Kowolenko, Ph.D.SVP, Biopharmaceutical Operations & SVP, Biopharmaceutical Operations &
TechnologyTechnology
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Role of the Quality UnitRole 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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RequirementsRequirements
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.html
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Agency ExpectationsAgency 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 Inspection Guideline – QSIT QSIT
1. Verify that a quality policy, management review and quality audit procedures, quality plan, and quality system procedures and instructions have been defined & documented.
2. Verify that a quality policy and objectives have been implemented.
3. Review the firm’s established organizational structure to confirm that it includes provisions for responsibilities, authorities and necessary resources.
4. Confirm that a management representative has been appointed. Evaluate the purview of the management representative.
5. Verify that management reviews, including a review of the suitability and effectiveness of the quality system are being conducted.
6. Verify that quality audits, including re-audits of deficient matters, of the quality system are being conducted.http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htmhttp://www.fda.gov/cder/dmpq/7356_002M.pdf
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Form – 483
What’s Hot:
2004 2005
Quality Unit Investigations
Investigations Validation
Analytical Methods Record keeping (QU)
Validation Equipment and Facilities
Equipment and Facilities Analytical Methods
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Drug Quality System for the 21Drug Quality System for the 21stst Century 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 OpportunityQS: 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 SystemsQuality Systems
Quality Management System
Management Responsibilities
Product Realization
Measurement, Analysis and Improvement
Resource Management
Interested Parties
Interested Parties
Requirements
Satisfaction
input output
ISO 9004
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Quality SystemsQuality Systems
Process TransferProcess Transfer
MaterialMaterialControlsControls Records,Records,
Documents, & Documents, &Change ControlsChange Controls
Equipment & Equipment & Facility ControlsFacility Controls
Production & Production & Process ControlsProcess Controls
Corrective &Corrective &PreventivePreventive
ActionsActions
ManagementManagement
http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm
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Global Standards ProgramGlobal Standards Program
1. Train ing2. Perfo rm ance/cG M P3. Trend Analysis4. In tern al/E xtern al Aud its
M anagem entTools
1. Adverse E ven ts2. Com plain ts3. Deviations4. Investig atio ns
Corrective/Preventive
Action
1. F acility Ch anges2. Utilities3. M ain ten ance4. Reg . S ub m ission s/V al.
Facilities,Utilities &
Equipm ent
1. Process Valid atio n2. C lean in g V alid ation3. E M4. Batch Record s
5. Change Control6. Regu lato ryS ub m ission s
Production/P rocessControls
1. Hand ling o f R aw Data2. Assay Developm ent3. Stability Testing
LaboratoryControls
1. M aterial Sp ecificatio ns2. Accountab ility
M aterialControls
1. Do cum ent Con trol2. An nu al R eview of Docs3. E lectron ic Doc. M gm t.
Docum entationM anagem ent
M anagem ent Review
Q uality System
M anagem ent R esponsib ilities
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Global Standards Program Global Standards Program HierarchyHierarchy
Approves program approach, responsibility, resourcesQuality
Manual
Defines “must have”Global Standards
Lead Team/Steering Committee
Core Stakeholders
Answers “how to”SOP Work/Job Instructions
Working Groups
Other Supporting Documentation
Provides RecordsWorking Groups
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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
How do we make Quality How do we make Quality everyone's concern?everyone's concern?
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How do we gauge performance in a global How do we gauge performance in a global organization?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 21Pharmaceutical cGMPs for the 21stst Century Century A Risk-Based Approach (Final Report Fall 2004)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 customer’s needs
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Surveillance Leads to Proactive Management Surveillance Leads to Proactive Management of Operationsof Operations
Rejected/Discrepant material
Industry Surveillance/Compliance Updates
Annual Product review IssuesBPDRs/Withdrawals/Recalls
Maintenance RecordsLaboratory Testing Trend Reports
OOS Investigations
Customer Complaints Product Rework/Reprocessing
Statistical Analysis of Process Performance
Vendor Performance
Internal Audits
EM Reports
Management Review
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Management ReviewManagement Review
Recurring/Non-recurring Deviations
0
20
40
60
80
100
120
Mar-05 Apr-05 May-05 Jun-05 Jul-05
Recurring Non-Recurring Total Deviations
Month
19
Open RARs
0
10
20
30
40
50
60
70
80
90
February March April May June July
Total RARs Open
Total RARs Open > 30 Days
Total RARs Open > 120 Days
Management ReviewManagement Review
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Site Bulk ManufacturingSite Bulk ManufacturingProduct ScorecardProduct 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 $,000Cost per Gram $,000Batches 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 QualityBulk QualityGeneral Scorecard 1 of 2General Scorecard 1 of 2
General Metrics Scorecard Q1 Actual Q2 Target Apr Actual May Actual Jun Actual Q2 Actual
DEVIATIONSNumber of Batches Thawed * N/A 10 7 7 N/A
General Deviations per Batch * <5 5 9 13 9
Average Cycle Time * <30 38 44 38 40
Total Number of Deviations open >120 Days * 0 3 2 6 4
CAPAsTotal Number of Open CAPAs * N/A 248 220 215 N/A
Percent of Open Overdue CAPAs * 0% 56% 53% 50% 53%
OUT OF SPECIFICATIONNumber of OOS/AR generated * <4 3 6 9 6
Average Cycle Time * <30 125 108 12 82
Number of OOSs open >30 Days * <5 14 13 19 15
Number of OOSs open >120 Days * 0 3 4 7 5
REMEDIAL ACTION REPORTSTotal 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 <30 57 88 105 83
Number of RARs open >30 Days * <5 36 33 25 31
Number of RARs open >120 Days * 0 20 24 19 21
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Bulk Bulk QualityBulk Bulk QualityGeneral Scorecard 2 of 2General Scorecard 2 of 2
General Metrics Scorecard Q1 Actual
Q2 Target
Apr Actual
May Actual
Jun Actual
Q2 Actual
CRITICAL WORK ORDERSTotal Number of CWOs generated * N/A 41 63 63 167
Number of CWOs open >180 Days * 0 89 96 88 91
DOCUMENTATION METRICSNumber of Change Requests initiated * N/A 100 95 196 391
Average Change Request Cycle Time * <30 41 41 33 38
Number of Change Requests open >90 Days * <3 6 14 20 13
ASSAY FAILURESNumber of Assay Failures – Chemistry 111 <50 47 35 33 38
Number of Assay Failures – Bioanalytical 142 <50 58 46 27 44
ENVIRONMENTAL MONITORINGNumber of Action Alerts recorded 108 TBD 28 21 18 22
Percent of open Alert Actions >30 Days old * 0 19 12 6 12
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Management ReviewManagement Review
Action Item Responsible Due Date
Provide “Product Quality Overview” presentation to RTP-MR attendee list.
Prior to Next Meeting
Investigate/Evaluate configuration capability within TRACKWISE for sending notifications to TRN owners (or others as applicable) prior to the current 30-days notification.
Next Meeting
Include identification of corrective actions when presenting observable OOS/AR trends. Also to include: # related to OOSs, # related to ARs, # related to release testing for product mfg at RTP,# related to release testing for product mfg at other locations, # related to in-process testing, # related to stability testing, others as applicable.
Next Meeting
Understand the mechanism/process by which a given RAR could be left open for >120 days. What is the cause of the 21 RARs reported as open >120 days for the July-05 metrics.
Next Meeting
Further define scorecard metric definitions (e.g. CAPA, CWO, Validation)
September Meeting
Obtain assessment from CMC regarding the appropriate follow-up to the proposal of discontinuing the IMDM use testing.
September Meeting
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Guidance for IndustryGuidance for IndustryPAT – A Framework for Innovative Pharmaceutical Development, PAT – A Framework for Innovative Pharmaceutical Development,
Manufacturing, and Quality AssuranceManufacturing, 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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Amevive 2K Titer 2001-2002 Campaign and 2003 Campaign
0
50
100
150
200
250
300
350
GrA280 Average 2001-2002 UCL +3SD LCL -3SD Average 2003
MVA can identify key sources of variation in the process and provide models for enhanced control
Bat
ch 1
Bat
ch 1
4
Bat
ch 2
8
Bat
ch 4
2
Bat
ch 5
6
Bat
ch 7
0
Bat
ch 8
4
Bat
ch 9
8
Bat
ch
112
Bat
ch
126
Bat
ch
140
The end result is more consistent processes with lower failure rates
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On-line Batch MonitoringOn-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 Process Improvement and Problem SolvingProblem 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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Investigation ProcessD
ata
Gen
eral
Gen
eral
(1)Event Occurs
(2)Describe
Event Type
(3)Event
communicated
(4)Decision toInvestigate
(5)InvestigatorAssigned
Minimally include:1. Problem statement2. Data collection3. Root cause analysis4. Impact Statement5. CAPA6. Conclusion statement
(6)InvestigationConducted
1. Area manager assessment2. Quality assessment
(7)Investigation
Reviewed
(8)Investigation
Approved
Investigations Process FlowInvestigations Process Flow
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Investigation ApproachInvestigation 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 TechniquesInvestigation 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 Opportunities in Compliance and cGMPcGMP
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.