Managing Quality within a Network of Suppliers

Eda Ross MontgomeryMelody HebertApril 6, 2011

2

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

Design Space Regulatory Filing Approach

Implementation at Manufacturing

Sites

Continuous Improvement

Phase 1 Phase 2 Phase 3 Phase 4

Develop Product Develop matrix showing material attributes, IPCs, and process parameter control that ensures CQAs are met

Agree on classifications of deviations

Perform trending

Understand product Develop real-time release strategy

Agree on change classifications

Interpret results across trending parameters

Develop specifications Develop post-approval change strategy

Agree on process for including NORs and PARs in batch record

Identify opportunities for improvement; implement as appropriate

Perform risk Assessment Develop “product and process description” strategy for marketing application

Agree on overall control strategy

Publish trends and metrics

Define design space Develop comparability protocol strategy

Agree on trending protocol and process

Set goals for continuous improvement

4

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 frequencyProject Team

Steering Committee

Cross-project team

5 ©2009 Vertex Pharmaceuticals Incorporated

QbD Governance Process is Compatible with Traditional Quality Systems

Control Strategy Document

Change Control and Other

Quality SystemsCriticality Analysis

Trend Reports (Quarterly and

Annual)

Risk Assessment Master BatchRecord

With Quality agreement, ensures cross-company alignment of quality systems

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)

7

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

Observation (Outside NOR but within Design Space)

Deviation (Outside Design Space)

Operating/Control SpaceEdge of Design Space

Parameter 1

Predicted Output

Par

amet

er 2

8

Significant potential to impact a CQA?

Critical Key

Yes No

Non-critical

Yes No

Risk Assessment; e.g.Amplitude of the EffectNOR vs design spaceProcess Robustness

Closeness of design space to edge of failure

High risk?

A Single Approach to Assessing Criticality is Used for all Aspects of the Process

9 ©2009 Vertex Pharmaceuticals Incorporated

Change to specifications or change likely to impact safety,

quality, or efficacy?

Critical Key

Yes No – Moderate Impact

Non-critical

Yes No

Change Assessment

Substantial impact on safety, quality, or

efficacy?

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

Major Change Moderate Change

Minor 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

11

Risk Management and Continuous Improvement are Achieved Through a Coordinated Trending Process

Product measurements data collection

Deviation measurements data collection

Compliance measurements data collection

Change controlTrending

Existing Systems – nothing new under QbD

All product performance and compliance data

are evaluated together under

QbD

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

13 ©2009 Vertex Pharmaceuticals Incorporated

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

14 ©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

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Trending leads to Improvements in Process or Equipment

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Spray Drying Time

Temperature lowered

*

Equipment malfunctioned

PAR

PAR

Batch 5

Time

Batch 1 Batch 2 Batch 3 Batch 4 Batch 6

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

16

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SDD USL: NMT 105

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04SDD Batch #

Q4 2009 Q2 2010 Q3 2010

Y Weighted Average API Assay as-is (% w/w) SDD Assay (% l.c.)DP

Knowledge Management: Correlating Drug Product Assay with Input Material

No consistent bias

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In-Process Wet SDD D50 Data:Lots HQ00070 - HQ00072

40

50

60

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110

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130

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d50 PAR

d50 Predicted (m)

d50 NOR

d50 OFFLINE (m)

D5

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et

( m)

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

Risk Management: Process Understanding Enables Prediction of Product Performance

Measured

Res

pons

e

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Risk Management: Trending Key Performance Indicators Allows Product Optimization

Tota

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(%

w/w

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LOQ 0.03%

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API Batch #

Legend

Total Organic Impurity (NMT 1.5% w/w)

Process Observation

Analytical Event

Process Event

Minor Deviations

Observations

Major Deviations

• Increased frequency of minor deviations• Minor deviations were for isolation time and temperature (non-critical parameter)• Filtration capacity increased

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Knowledge Management Increases efficiency of resource utilization

Batch Release Time Batch Record Review

39 35 33 30 2818 14 17 21 14 12

5 5 5 5 6

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1 1

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107 108 109 110 111 112 113 114 115 116 117

Batch

# o

f D

ay

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Remediation andDisposition

CMO InitialResponse

Vertex Review

DOM and CMOReview

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

20

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)

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Challenges – Data Consistency

Root Cause Analysis - Q4 2009, Q1 2010, Q2 2010 and Q3 2010 (Stage 7, 10 & Stability)

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4

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Q4 2009 Q1 2010 Q2 2010 Q3 2010

Quarter

# o

f E

ven

ts

TBD

Inconclusive

Sample

Reagents

Failure to Follow SOP

System Deficiency

Maintenance

Procedure / Instruction

Equipment

Failure to FollowProcedure

Human Error

Root Cause Comparison Summary

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Q2 2010 Q3 2010

Quarter

# o

f Eve

nts

Maintenance

Procedure / Instruction

Sample

TBD

Shipping

Inconclusive

Human Error

Equipment

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