Managing Quality within a Network of Suppliers

Eda Ross Montgomery Melody Hebert April 6, 2011

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Managing Quality with a Network of Suppliers

• Defining the Process – Vertex’ Implementation of QbD – Governance Process • Commercial Manufacturing at contract manufacturing organizations – Interface with CMO quality systems – Implementation of QbD in batch records • Continuous Improvement – Ongoing Risk Management – Knowledge Management • Remaining challenges

3 QbD is Implemented in Stages Phase 1 Design Space Develop Product Understand product Develop specifications Perform risk Assessment Define design space Phase 2 Regulatory Filing Approach Phase 3 Implementation at Manufacturing Sites Phase 4 Continuous Improvement Develop matrix showing material attributes, IPCs, and process parameter control that ensures CQAs are met Develop real-time release strategy Agree on classifications of deviations Agree on change classifications Perform trending Interpret results across trending parameters Develop post-approval change strategy Develop “product and process description” strategy for marketing application Develop comparability protocol strategy Agree on process for including NORs and PARs in batch record Agree on overall control strategy Agree on trending protocol and process Identify opportunities for improvement; implement as appropriate Publish trends and metrics Set goals for continuous improvement

Governance Process is Critical for Successful Supplier Management • • • • Inter-Company Teams Agree on mutual expectations and deliverables for each team Agree on processes for escalation of issues and relationship management Agree on process for – Communication of unexpected results (OOS and OOT) – Conduct of investigations (OOS and OOT) – Degree of oversight expected and type of information to be exchanged – Evaluation metrics and frequency Steering Committee Cross-project team Project Team 4

QbD Governance Process is Compatible with Traditional Quality Systems

Control Strategy Document With Quality agreement, ensures cross-company alignment of quality systems Change Control and Other Quality Systems Criticality Analysis Trend Reports (Quarterly and Annual) Risk Assessment Master Batch Record 5 ©2009 Vertex Pharmaceuticals Incorporated

6 Commercial Manufacturing – Managing Quality under QbD at Suppliers with Traditional Quality Systems • • Vertex Quality systems completely embrace QbD CMO Quality systems should not be different for QbD and “traditional” products – Changes to CMO Quality systems should be minimized – Use change management procedures to drive implementation of changes – Use nonconformance and process monitoring to identify potential changes and drive continuous improvement • Vertex drives continuous process improvement with the support of and input from the CMO(s)

Implementation at Contract Manufacturing Organizations : Classifying Deviations relative to NORs and PARs

Deviation (Outside Design Space)

Predicted Output 7

Operating/Control Space

Parameter 1

Edge of Design Space Observation (Outside NOR but within Design Space)

8 A Single Approach to Assessing Criticality is Used for all Aspects of the Process Risk Assessment; e.g.

Amplitude of the Effect NOR vs design space Process Robustness Closeness of design space to edge of failure Yes Significant potential to impact a CQA?

No Non-critical High risk?

Yes Critical Key No

Implementation at Manufacturing Sites: Classification of Post Approval Changes is Consistent with SUPAC

Change Assessment Yes Change to specifications or change likely to impact safety, quality, or efficacy?

No Substantial impact on safety, quality, or efficacy?

Non-critical Minor Change Yes Critical Major Change 9 ©2009 Vertex Pharmaceuticals Incorporated No – Moderate Impact Key Moderate Change

10 Implementation of QbD at Contract Manufacturing Organizations: Implementation of QbD in Batch Records • Batch records are designed to ensure the process is operated where it performs best – NOR ranges are intended for routine commercial manufacturing • The batch record includes the NORs for critical and key process parameters and in process control (IPC) tests • Batch record can also include ranges for non-critical parameters • Tighter operating ranges or a mid-points may be implemented to avoid excursions outside the NOR or maximize product performance – PARs for critical and key process parameters and IPCs are included or referenced in the batch record • This makes the information readily available to manufacturing supervision

Risk Management and Continuous Improvement are Achieved Through a Coordinated Trending Process Product measurements data collection Deviation measurements data collection 11 Compliance measurements data collection Existing Systems – nothing new under QbD Trending All product performance and compliance data are evaluated together under QbD Change control

12 Continuous Improvement: Risk Management and Supplier Management • • • Coordinated approach to evaluation (trending) of – Product performance based on process parameters, IPCs, material attributes – Key performance indicators that may be indicative of product performance or could indicate a trend with Supplier’s systems, e.g. • Confirmed OOS • Deviations (Major and Minor) • Observations • Complaints Coordinated, periodic sharing of results with Suppliers – Each supplier reports product performance and key performance indicators to Vertex – Vertex’ conclusions on product performance and key performance indicators are shared with suppliers Coordinated approach to continuously improving product quality and performance

Trending Protocol

• Prospective, documented plan for monitoring during routine manufacturing – Critical and key process parameters – Critical and key material attributes – Activities where frequency of failure is above a threshold – Key performance indicators (see previous slide) • Predefined responsibility (Vertex or Supplier) for – monitoring – frequency of reporting – statistical tools to be used – thresholds for key performance indicators • Describes content of trending report and method for modifying trended parameters 13 ©2009 Vertex Pharmaceuticals Incorporated

Trending Report

• • • Comprehensive and cumulative – Quarterly reviews – Designed to meet annual product review requirements Trend reported for all product performance measurements and all key performance indicators – Evaluation of observed trend to predicted trend – Evaluation of discrete “events” that can signal other issues – Evaluation of actual vs. predicted frequency of “events” based on risk assessment – Evaluation of upstream material(s) for impact on product performance Conclusion about changes needed to the process, material attributes, operations, or key performance indicators 14 ©2009 Vertex Pharmaceuticals Incorporated

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Trending leads to Improvements in Process or Equipment

Batch 1 Batch 2 Batch 3 Batch 4 * Batch 5 Batch 6 PAR

Equipment malfunctioned Temperature lowered

Time •Temperature decreased to control at different target value •After equilibration, minor variations in temperature •Equipment malfunction resulted in addition of chiller capacity PAR

16 Knowledge Management: Correlating Drug Product Assay with Input Material DP No consistent bias

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Risk Management: Process Understanding Enables Prediction

Lots HQ00070 - HQ00072

140 130 120 110 100 90 80 70 60 50 40

• • Predictive model built from development runs Good agreement between actual and predicted value 

d50 PAR



d50 NOR d50 Predicted (



m) d50 OFFLINE (



m)

Risk Management: Trending Key Performance Indicators Allows Product Optimization Observations Minor Deviations Major Deviations 18 •Increased frequency of minor deviations •Minor deviations were for isolation time and temperature (non-critical parameter) •Filtration capacity increased

19 Knowledge Management Increases efficiency of resource utilization

Batch Release Time Batch Record Review 140 120 100 80 60 40 20 0 65 64 64 21 10 5 39 107 10 5 35 108 10 5 33 109 10 5 30 110 16 18 6 28 111 43 18 112 Batch 51 10 3 14 113 26 13 1 17 114 18 9 4 21 115 33 14 116 37 12 117

•Kaizen process to eliminate waste and focus on value-adding activities •Mechanism for data-based discussion of trends •Shared goal

Remediation and Disposition CMO Initial Response Vertex Review DOM and CMO Review

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Challenges – Data Management

• Need robust processes – To ensure data integrity from source at Supplier to finished report • Include error handling and updates/changes to data – To ensure timely availability of data for analysis and trending • Ensure scalability of the database(s) – Anticipate differences in terminology in the design phase – Anticipate changes to trending program • Build in flexibility – Anticipate commercial volume(s)

Challenges – Data Consistency

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6 4 2 0 20 18 16 14 12 10 8 10 2 0 8 6 4 18 16 14 12 Q4 2009 Root Cause Analysis - Q4 2009, Q1 2010, Q2 2010 and Q3 2010 (Stage 7, 10 & Stability) TBD Inconclusive Sam ple Reagents Failure to Follow SOP System Deficiency Maintenance Procedure / Instruction Q1 2010 Q2 2010 Q3 2010 Equipm ent Failure to Follow Procedure Hum an Error Quarter Root Cause Comparison Summary Maintenance Procedure / Instruction Sample TBD Shipping Inconclusive Human Error Equipment Q2 2010 Q3 2010 Quarter

Need Standardized Data and Definitions

•For Quality Metrics •Deviation root cause •Failure modes •At Vertex and Suppliers •For performance metrics

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Closing Thoughts

• • • • Focus on key and critical parameters and key performance indicators – Performance is built in Review the Process Regularly – Focus on knowledge improvements – Cover both corrective and preventative actions Plan for change – Programs, people, scale(s) of operation – Include changes to both process and tools Actively Manage Supplier Relationships – Think long-term – Develop and maintain common goals – Share conclusions and responsibility – Actively solicit feedback

23 Acknowledgements • • • • • • • • Carole Varanelli Geny Doss Trish Hurter Tom Gandek Kelly Tolton Antoinette Paone Drew Barlow Martin Warman