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

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Quality by Design is a paradigm shift in industry’s approach to new drug development

• A biotechnology industry leader, Amgen discovers, develops, and produces a variety of human therapeutics

• Most products in Amgen’s portfolio are biologics (greater complexity than “small molecules”)

• Typical for the industry, Amgen manages a long, complex, and highly regulated product lifecycle from drug discovery to market:

• Quality by Design (QbD) is a systematic and science-based approach to drug development (drug discovery through launch)

• 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

Drug Discovery

Clinical Trials Regulatory Filing Product Launch

10-12 Years

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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:

• Given time constraints, case study not exhaustive but example driven• An integrated approach is critical; to the extent possible, took

enterprise-wide perspective

Operational cycle times, including time to market and production cycle times

Economic impact; direct cost/savings and cost avoidance

Ability to meet demand while managing scrap and inventory

Extent of regulatory compliance and status of quality management systems

Cycle Time

Compliance & Quality

Cost

Supply Management

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Framework builds on the philosophy that QbD concepts are broadly applied and have impact to Operations objectives

Molecule Selection

Process Development & Characterization

Filing & Commercial Production

Technology Transfer

1 2 3 4

Cycle Times

Key Commercialization Elements

Investment Benefit

Compliance & Quality

QbD is an evolution of “Best Process Development Practices”; early investment yield benefits later in Commercialization as well as for subsequent pipeline molecules

Cycle Times Cycle Times Cycle Times

Compliance & Quality

Cost Cost

Supply Management

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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

• Invest in knowledge management• Modality-specific knowledge in

early development • Feedback from later-stage

development and commercial production

• Identify most promising candidates with innovative screening methods

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The Benefits of QbD in Molecule Selection

Identification of molecules with the optimal balance of bioactivity, stability, and manufacturability:

• Rapid advancement to commercialization

• Reduction in attrition

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The mAb Platform leverages prior development knowledge

Early development improvement since Platform Rev. 1

Average TiterConcentration of product in cell culture; a measure of cell culture productivity

> 2-fold increase

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 commercialization1.6-fold decrease

• The monoclonal antibody (mAb) platform is a library of knowledge for a common modality

• The platform has undergone several revisions since it was first implemented ~7 years ago

Example

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Implemented

mAb Platform

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QbD can speed commercialization and increase process understanding to meet regulatory expectations

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Ways to Apply QbD to Process Development & Characterization

• Invest in high throughput development tools

• 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

• Invest in knowledge management

The Benefits of QbD in Process Development & Characterization

• Optimal process conditions identified prior to commercial launch

• Clear definition of process boundaries

• Simplified comparability

• Readily accessible knowledge base for application across the pipeline

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Investment in the proper tools allows enhanced, accelerated development using QbD principles

Design of Experiments

Implemented

Lyo Cycle Development Without SFD

• Prior knowledge-based “guess and check”

• Conservative approach (longer cycles)

Lyo Cycle Development With SFD

• Cycle prediction in 1 or 2 runs

• Real-time temp measurement and adjustment (shorter cycles)

Process Characterization Without DOE

• Set acceptable ranges

• Less focus on parameter interactions

Process Characterization With DOE

• Focus on critical quality attributes (set design space)

• Fewer experiments

• Greater process knowledge

Example

QbD Tools

80% reduction in resource and time requirements for cycle development

30% reduction in resource and time requirements for process characterization

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In Progress

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QbD leverages knowledge gained during process development to simplify technology transfer

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Ways to Apply QbD to Technology Transfer

• Identify and close scale-to-scale and site-to-site gaps in:

• Equipment• Procedures

• Re-assess site-specific characterization and robustness needs

• Consider site selection in early development

The Benefits of QbD in Technology Transfer

• Reduction of risk: potential for less regulatory oversight

• Elimination of commercial-scale development work

• Reduction in FTE requirements

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Understanding equipment differences can minimize the need for commercial-scale development work

• 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 In Progress

StreamliningFill & Finish Tech

Transfer

Actual – Pilot-scale data reproduced at commercial scale

• Machinability Studies

• Validation Runs

• 5 Robustness Runs

• Engineering Run

Opportunity – Valid scale-down model eliminates need for much verification

• Machinability Studies

• Validation Runs

• 1 Robustness Run

• Engineering Run

Case Study: AMG-XYZ Fill/Finish Transfer

Savings: ~1 month in transfer timeline and hundreds of thousands of dollars in resources and raw materials

Example

3

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Integrating QbD principles within commercialization can yield a more robust and flexible process

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Ways to Apply QbD to Filing and Commercial Production

• Develop a CTD template incorporating QbD elements such as design space

• Apply Process Analytical Technology (PAT):

• Monitor critical process parameters (CPPs)

• Shift reactive, post-mortem analytics to pro-active, real-time control

The Benefits of QbD in Filing and Commercial Production

• In-control and capable processes

• Enhanced Operational Excellence:

• Greater opportunity and flexibility for process improvement

• Real-time product release

• Reduction in NCs and Scrap

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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

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

Example

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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 troubleshootingPotential 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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QbD yields additional operational benefits

Non-Conformances

Post-Marketing Regulatory Submissions

Complaints

Design space in marketing application: greater flexibility for process changes

Improved process control & greater flexibility from design space

• Evaluation based on complaints for one product delivery system since its launch

• Total cost of these complaints on the order of several million dollars – potentially avoided with QbD

• Based on review of all Class 2 and 3 NCs between April 2007 and March 2008

• QbD could prevent 7% of NCs

• Several hundred thousand dollars cost avoidance annually, not including:

• Cost of scrap• Cost of delayed disposition

• Based on review of all historic Post-Marketing Regulatory Submissions for one Amgen product

• 11% of US post-marketing submissions could be prevented with QbD

• Several hundred thousand dollars cost avoidance annually, not including:

• Cost of inventory accumulation• Cost of supporting studies (e.g., stability and comparability)

Improved product quality with a systematic approach to design

Example

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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

Molecule Selection

PD & Char.

Filing & MFG

Tech Transfer

QbD

1 2

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Current Approach to Commercialization Ideal State

• 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 SelectionProcess Development

& CharacterizationFiling & Commercial

ProductionTechnology Transfer

Knowledge Bank

• Each element of commercialization can input and access data

• Forms of waste that can be eliminated:• Searching for data• Translating data• Recreating existing knowledge

• Key Operational benefit: Rapid compilation of data for CTD construction

• 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

SystemsBusiness

ProcessesScience &

Technology

Process & Product Knowledge

DOE, PAT, Risk Analysis

Magnitude of investment is a strategic decision. Investment

should be on-going.

Knowledge Management

Leverage knowledge across lifecycle and pipeline

Potentially large financial investment for an IT solution

QbD Investment = f

Activity and Functional Alignment

Capture the right data at the right time

Minimal financial investment; requires shift in organizational momentum and significant time

to implement

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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

• Deborah Wong & Cathryn Shaw-Reid Amgen Advisors

• Charles Cooney & Roy WelschMIT Thesis Advisors

• Amgen Team and Mentors (among others!):• 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