Transcript Developing the Business - LGO

A 2009 MIT LGO Thesis:
Developing the Business Case for Quality by
Design in the Biopharmaceutical Industry
Julie Matthew
January 22, 2010
MIT LGO Alumni Web Seminar
Quality by Design is a paradigm shift in industry’s
approach to new drug development
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A biotechnology industry leader, Amgen discovers, develops, and produces
a variety of human therapeutics
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Most products in Amgen’s portfolio are biologics (greater complexity than “small
molecules”)
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Typical for the industry, Amgen manages a long, complex, and highly regulated
product lifecycle from drug discovery to market:
10-12 Years
Drug
Discovery
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Clinical
Trials
Regulatory
Filing
Product
Launch
Quality by Design (QbD) is a systematic and science-based approach to
drug development (drug discovery through launch)
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Not a new concept for most manufacturing industries
Defined in a new pharma/biotech industry standard (ICH Q8) in 2005
Gaining momentum among innovators and regulators – a QbD strategy is
imperative for biotechnology
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Both internal and external drivers have required industry to
define the value of Quality by Design
• External Drivers:
• QbD is gaining momentum among innovators and regulators: a
QbD strategy is imperative for biotechnology
• Regulatory expectations are increasing; QbD may become “the
cost of doing business”
• Internal Drivers:
• Need to prioritize and/or integrate ongoing QbD efforts
• Need to understand the “who, what, and where” in terms of
focus and level of investment
• Need a collective understanding of major impact areas within
the business; determine an appropriate level of investment
(enterprise perspective)
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Business Case is intended to provide a holistic
understanding of the value of QbD
• Methodology:
• Primary interviews of 40+ SMEs within R&D and Operations at Amgen
• Collection and analysis of relevant historical data
• Deep-dive project within Drug Product & Device Development
• Assumptions
• Assess business impact in four key areas of Operations:
Cycle Time
Cost
Operational cycle times, including time to market and
production cycle times
Economic impact; direct cost/savings and cost avoidance
Supply
Management
Ability to meet demand while managing scrap and inventory
Compliance &
Quality
Extent of regulatory compliance and status of quality
management systems
• Given time constraints, case study not exhaustive but example driven
• An integrated approach is critical; to the extent possible, took
enterprise-wide perspective
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Framework builds on the philosophy that QbD concepts are
broadly applied and have impact to Operations objectives
Key Commercialization Elements
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Molecule
Selection
Process
Development &
Characterization
Technology
Transfer
Filing &
Commercial
Production
Cycle Times
Cycle Times
Cycle Times
Cycle Times
Compliance &
Quality
Cost
Cost
Supply
Management
Compliance &
Quality
Investment
Benefit
QbD is an evolution of “Best Process Development Practices”; early investment yield benefits
later in Commercialization as well as for subsequent pipeline molecules
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QbD can enhance molecule selection by harnessing the
organization’s collective product and process knowledge
Ways to Apply QbD to
Molecule Selection
The Benefits of QbD in
Molecule Selection
• Invest in knowledge management
• Modality-specific knowledge in
early development
• Feedback from later-stage
development and commercial
production
Identification of molecules with the
optimal balance of bioactivity, stability,
and manufacturability:
• Rapid advancement to
commercialization
• Reduction in attrition
• Identify most promising candidates
with innovative screening methods
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Example
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The mAb Platform leverages prior development knowledge
mAb
Platform
 Implemented 
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The monoclonal antibody (mAb) platform is a library of
knowledge for a common modality
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The platform has undergone several revisions since it was
first implemented ~7 years ago
Early development improvement since Platform Rev. 1
Average Titer
Concentration of product in cell culture;
> 2-fold increase
a measure of cell culture productivity
Cycle Time to Tox
Release
Time from selection of molecule to first
toxicity studies with animal models;
includes early process development
1.4-fold decrease
FTE
Requirements
Number of resources required to
advance a molecule to the next stage
in commercialization
1.6-fold decrease
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QbD can speed commercialization and increase process
understanding to meet regulatory expectations
Ways to Apply QbD to Process
Development & Characterization
The Benefits of QbD in Process
Development & Characterization
• Invest in high throughput
development tools
• Optimal process conditions
identified prior to commercial launch
• Use DOE, PAT, and risk analysis to
• Verify relationships between
critical process parameters
(CPPs) and critical quality
attributes (CQAs)
• Identify optimal process
conditions and process
boundaries
• Clear definition of process
boundaries
• Simplified comparability
• Readily accessible knowledge base
for application across the pipeline
• Invest in knowledge management
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Example
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Investment in the proper tools allows enhanced,
accelerated development using QbD principles
QbD Tools
 In Progress 
Lyo Cycle Development Without SFD
Lyo Cycle Development With SFD
• Prior knowledge-based “guess and
check”
• Cycle prediction in 1 or 2 runs
• Conservative approach (longer
cycles)
• Real-time temp measurement
and adjustment (shorter
cycles)
80% reduction in resource and time requirements for
cycle development
Process Characterization Without DOE
Design of
Experiments • Set acceptable ranges
 Implemented 
Process Characterization With DOE
• Focus on critical quality
attributes (set design space)
• Less focus on parameter
interactions
• Fewer experiments
• Greater process knowledge
30% reduction in resource and time requirements for
process characterization
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QbD leverages knowledge gained during process
development to simplify technology transfer
The Benefits of QbD in
Technology Transfer
Ways to Apply QbD to
Technology Transfer
• Identify and close scale-to-scale and
site-to-site gaps in:
• Equipment
• Procedures
• Reduction of risk: potential for less
regulatory oversight
• Re-assess site-specific
characterization and robustness
needs
• Reduction in FTE requirements
• Elimination of commercial-scale
development work
• Consider site selection in early
development
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Example
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Understanding equipment differences can minimize
the need for commercial-scale development work
Streamlining
Fill & Finish Tech
Transfer
 In Progress 
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Equipment and method differences are being identified
across sites
Knowledge of differences can be used to strengthen
validity of scale-down models
Strong scale-down models reduce risk in tech transfer,
requiring fewer verification runs at the commercial site
Case Study: AMG-XYZ Fill/Finish Transfer
Actual – Pilot-scale data
reproduced at commercial scale
Opportunity – Valid scale-down model
eliminates need for much verification
• Machinability Studies
• Machinability Studies
• Validation Runs
• Validation Runs
• 5 Robustness Runs
• 1 Robustness Run
• Engineering Run
• Engineering Run
Savings: ~1 month in transfer timeline and hundreds of
thousands of dollars in resources and raw materials
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Integrating QbD principles within commercialization
can yield a more robust and flexible process
Ways to Apply QbD to Filing and
Commercial Production
The Benefits of QbD in Filing and
Commercial Production
• Develop a CTD template
incorporating QbD elements such as
design space
• In-control and capable processes
• Enhanced Operational Excellence:
• Greater opportunity and flexibility
for process improvement
• Apply Process Analytical Technology
(PAT):
• Monitor critical process
parameters (CPPs)
• Shift reactive, post-mortem
analytics to pro-active, real-time
control
• Real-time product release
• Reduction in NCs and Scrap
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Example
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Statistical methods enable real-time control of critical
quality attributes, increasing process robustness
Real-Time Multivariate Statistical Process Monitoring (MSPM)
 Implemented 
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Example
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Statistical methods enable real-time control of critical
quality attributes, increasing process robustness
Real-Time Multivariate Statistical Process Monitoring (MSPM)
 Implemented 
Benefits of Real-Time Monitoring
Example (observed at one Amgen site)
Real-time prediction of process
performance
Predicted product titers within 10% of actual
Earlier identification of process
deviations
Contamination event identified 3 hours earlier
than by operators
Rapid troubleshooting
Potential for multi-million dollar savings in lost
product for identifying root cause of a series of
low-yield batches (historical example)
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Example
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QbD yields additional operational benefits
Non-Conformances
Improved process control & greater
flexibility from design space
Post-Marketing Regulatory
Submissions
Design space in marketing
application: greater flexibility for
process changes
Complaints
Improved product quality with a
systematic approach to design
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Based on review of all Class 2 and 3 NCs between
April 2007 and March 2008
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QbD could prevent 7% of NCs
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Several hundred thousand dollars cost avoidance
annually, not including:
• Cost of scrap
• Cost of delayed disposition
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Based on review of all historic Post-Marketing
Regulatory Submissions for one Amgen product
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11% of US post-marketing submissions could be
prevented with QbD
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Several hundred thousand dollars cost avoidance
annually, not including:
• Cost of inventory accumulation
• Cost of supporting studies (e.g., stability and
comparability)
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Evaluation based on complaints for one product
delivery system since its launch
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Total cost of these complaints on the order of several
million dollars – potentially avoided with QbD
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Cumulative benefits from these examples represent only a
portion of potential savings
$ = up to $100K; $$ = $100K to $1M; $$$ = $1M to $10M
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The greatest challenge under QbD is alignment
Current Approach to Commercialization
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Molecule
Selection
Ideal State
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PD & Char.
QbD
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Filing &
MFG
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Tech
Transfer
QbD emphasizes a strong link between the product and the process;
this link should be reflected in commercialization practice
Amgen can maximize the benefits of QbD by integrating processes
through:
• Knowledge management systems
• Business Processes
• Communication between elements throughout commercialization
• Design for manufacturability
• Feedback loops
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A knowledge management system could integrate
processes and cut waste across the product lifecycle
Molecule Selection
Process Development
& Characterization
Technology Transfer
Filing & Commercial
Production
Knowledge Bank
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Each element of commercialization can input and access data
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Forms of waste that can be eliminated:
• Searching for data
• Translating data
• Recreating existing knowledge
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Key Operational benefit: Rapid compilation of data for CTD construction
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Majority of the investment will be in data capture prior to TT, filing, and
launch
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Focused investment in three areas will maximize the
benefit of QbD
QbD Investment =
f
Science &
Technology
Systems
Business
Processes
Process & Product
Knowledge
Knowledge Management
Activity and Functional
Alignment
DOE, PAT, Risk Analysis
Leverage knowledge across
lifecycle and pipeline
Capture the right data at the
right time
Potentially large financial
investment for an IT solution
Minimal financial investment;
requires shift in organizational
momentum and significant time
to implement
Magnitude of investment is a
strategic decision. Investment
should be on-going.
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Business Case: QbD implementation requires investment
across commercialization, but economic and operational
benefits would be significant
• Internal drivers do exist for QbD in a large biopharmaceutical
company
• Benefits are operational as well as economic; they are likely
underestimated in the business case
• Greatest challenges are in alignment of business process,
organizational structure, and culture under QbD paradigm
• Recommendations:
• Promote knowledge sharing across functions and sites
• Identify leadership/champions to sustain QbD momentum
• Create a cross-functional team to develop a comprehensive internal
QbD roadmap
• Align internal and external efforts
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Acknowledgements
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Deborah Wong & Cathryn Shaw-Reid
Amgen Advisors
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Charles Cooney & Roy Welsch
MIT Thesis Advisors
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Amgen Team and Mentors (among others!):
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Joe Halcomb
Bob Maroney
Ed Walls
Erwin Freund
Feroz Jameel
Chakradhar Padala
Christian Ruitberg
Wei Liu
Cenk Undey
Joseph Phillips
Karen Parker
Ricardo Diaz
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Questions?
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Back-up
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Product vs. Process Complexity
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Biotechnology industry is more than 10 years behind other
industries in applying Quality by Design principles
Quality cannot be ensured through inspection and rework, but
must be built in through the appropriate design of the process
and product
http://www.wtec.org/loyola/polymers/c7_s6.htm
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