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

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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.