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This document provides an outline of a presentation and is incomplete without the accompanying oral commentary and discussion. Conclusions and/ or potential strategies contained herein are NOT necessarily endorsed by Pfizer
management. Any implied strategy herein would be subject to management, regulatory and legal review and approval before implementation.
Accelerating clinical evaluation of
biotherapeutics: can cost, speed and
throughput be improved without
compromising quality?
Tanya Shang, Jeff Salm, Anthony Barry, Tom
Porter, Tim Charlebois
CMC Strategy Forum Europe
May 7, 2014
Outline
• Decline in R&D Productivity and Unsustainable Cost of BioTx
Development
• Innovation as Evolution
• Case Study: Low Cost Low Volume Development Option
• Next Steps
The Decline in R&D Productivity:
Increased Spending, Lower Output
3
0
20
40
60
80
100
120
140
160
Worldwide Total Pharmaceutical R&D Spend
WW
Ph
arm
a R
&D
Sp
en
d (
$b
n)
+10.6% CAGR 2002-08
+2.3% CAGR 2009-16
0
10
20
30
40
50
60
70
FDA Approval Count (NMEs & Biologics)
Total mol. NMEs Biologics
No
. of
Mo
lecu
les
Ap
pro
ved
Source: EvaluatePharma April 30, 2010
CGAR: Compound Growth Annual Rate
Development Costs Impact Patients
• Why Should we care about Cost?
• Current cost of developing drugs is unsustainable
• Inhibitory to bringing innovation in biomedical research to patients
• Direct influence on drug costs
• Huge investment required drives focus on few “safe”
targets
• Innovative solutions need to be developed from every front
• Innovations in CMC development (speed, cost, flexibility) can
enable innovations in many areas
Pfizer Approach for CMC Innovations
•Foundation of Innovation: Existing Systems based on
internal and industry-wide mAb Platform knowledge
•Understanding stage-specific innovation drivers
Molecular Stability •Platform formulations
•Formulation selection
•Pre-screen for stability in discovery
•Confirmatory GMP stability studies
Foundation: How We Do Things Now
(Examples)
Standardized,
Robust
Analytics
Platform
Processes
GxP Systems
Clone Selection
Screening (e.g. Sequence
Variants)
Molecular Assessment
new mAbs assessed based on
platform knowledge
Product Quality •Cell bank testing
•In-process testing
•Release testing
•Representativeness of non-clinical materials
pI, Mw,
sequence
liabilities,
modeling
Titer Platform
Process
performance, in-
process stability
Stability,
viscosity, F/T,
handling
Structure, PTM
heterogeneity,
method
suitability
Assessment of “Platform Fit” of Pre-
development Candidates
Material Production
(Exploratory Toxicology, Non-clincal
PK/PD) Candidate
Selection
•Designed to maximize alignment with platform
process, formulation, and methodologies used for
clinical materials
•Not just Manufacturability, but increased probability
of consistent quality!
Molecular Assessment
mAb Platform Knowledge
•Platform process, formulation, and methods have evolved
over the last decade
– Platform expression systems e. g. CHO
– Upstream and downstream process standardization
– Same raw materials, media, filters, buffers and resins
– Platform formulations e.g. histidine/sucrose and standardized DP
configurations
– Standardized analytical methods and specifications
• Many companies have arrived at similar platform
processes and methods
Platform Evolution: Current Best Practices to Ensure
Consistent Quality
Platform: Streamlined
Body Shape
Common Selection Pressure: Sustained Rapid Swimming
in Marine Environment
Common Selection Pressure: Achieving Consistent
Process Performance, Product Quality, Meeting Clinical
Demand and Regulatory Requirements
Platform process,
formulation and
analytics
What Will Drive the Next Evolution?
What drives the need to innovate in biologics
development & manufacturing?
Pfizer Confidential │ 10
• R&D Productivity (ROI)- driven by clinical costs
• High cost to reach futility
• Breakthrough therapy designation- critical path issues
• Proof of mechanism trials, biomarkers, precision medicine
R&D
Drivers
• Enterprise costs: capital, operating expenses, compliance
• Product costs: response to price, reimbursement pressure
• Market access, regionalization
• Cycle times, inflexible capacity, tech transfer, comparability
Manuf.
Drivers
LOW COST LOW VOLUME (LCLV) DEVELOPMENT OPTION
Case Study
Design of LCLV
Implementation of First LCLV Project
Pre-IND and IND Experience
What is LCLV, and Why Did We Build it?
• Developed to provide appropriate amount of material to project
teams for toxicology and early phase clinical studies in a cost
and resource-sparing manner
• Built to enable fast progression of mAb programs to clinical
evaluation with targeted, efficient investment
– Ideal for novel mechanisms, small mechanistic clinical evaluations
12
Key Elements of LCLV
• Limited quantities of toxicology and clinical materials
manufactured
– All DS converted to DP
• Minimal process, product, and analytical development
– “Plug and Play” standardized process, formulation and analytics
• Molecular Assessment to Identify mAbs that fit the platform
13
LCLV Relies Upon Molecular Assessment
• To leverage LCLV process/strategy, mAb must meet pre-defined
criteria – established based on relevance to process and product
performance
– Sequence Analyses—no obvious “red flags”
– Productivity in CHO-SSI (clonal pools titer)
– Fit with purification platform (impurity, HMW removal, compatibility)
– Analytical methods suitable without development
– Stability and concentration/viscosity suitable in fixed formulation
• All criteria evaluated prior to selection of final candidate
– Enables development criteria to be used as screening tool
– Provides requisite data to minimize process, formulation and analytical
development
14
How Does LCLV Compare?
15
*Cost includes Transferrables, overhead and FTE
Std mAb Option LCLV Option
Toxicology Material >200 g in ~8 months
• From non-GMP batch
250 g in ~6 months • From non-GMP batch
Drug Substance >2 Kg >400 g
Drug Product >10,000 vials
• Configuration adaptable
~2,500 vials • Fixed config
IND
~15 months ~14 months • US currently
Cost 100% ~50%
1 SSI Implementation (reduced cell line dev)
2 Streamlined Process Development
3 Modified Cell Bank method
4 Combined RegTox FIH
5 Modular Virus Clearance
6 Smaller Scale Process
7 Bioassay as characterization only
8 Reduced development stability testing
9 Reduced assay development and verification
10 All DS filled into DP (No GMP DS Stability)
11 No Reference Material
12 Reduced release and stability testing
13 Platform CMC package
14 Molecular Assessment
15 Streamlined formulation development
16 Streamlined DP tech transfer and manufacture
…And how did we do it?
16
Standing Offer Updates - Summary 10.28.13 updated summary 12-5-13.pptx
Extensive review of standard
mAb offer Identifies key
opportunity “buckets”
Risk analysis, time and cost
implications and
understanding
interdependencies
Opportunity Bucket #5: Modular Viral Clearance
• Description
– Modular viral clearance package to support regulatory
requirements; product specific studies in late stage
– Cost, material, and FTE savings
• Justification
– proven viral clearance capabilities of unit operations
• Risks
– Regulatory acceptance of strategy
Decision: opportunity pursued in LCLV Option (US)
Opportunity Bucket #10: NO DS Formal Stability
• Description
– There will be no DS stability program
– Cost, material, and FTE savings
– Reduce complexity by eliminating activity that adds no value
• Justification
– All DS will be filled into DP, no long-term storage
– Molecular assessment includes stability in formulation, to provide confidence for
short term storage/temp excursions
– Product quality controlled at DP release and stability testing
• Risks
– Business risk: molecular assessment not predictive, GMP DS is unstable over a
few months at -20 oC and fails DP release
– Regulatory Acceptance
Decision: opportunity pursued in LCLV Option
Opportunity Bucket #7: No Bioassay
Development
• Description
– Bioassay will be transferred from Discovery, performed on Toxicology material and DP
as characterization assay only; full development/incorporation in specs in later stage
– Activities eliminated: method development and qualification; bioassay in release and
stability testing
• Justification
– Discovery bioassay (with proper guidance in Molecular Assessment) is scientifically
appropriate to demonstrate biological activity
– Bioassays typically less stability-indicating than biochemical assays
• Risks
– Regulatory acceptance
Decision: opportunity not pursued in LCLV Option
Apr May Jun Jul Aug Sep Oct Nov Dec
2012 Q3 Q4
Candidate
Selection Molecular Assessment
Implementation of First LCLV Project
1.32
1.27
1.34
1.31 > 5%
HMW mA
U
time
SSI 12 day
culture
ProA
60min pH 3.5
Hold
TMAE
Viral filtration
UF/DF
Analytical
SEC
>
LCLV Criterion: < 5% HMW in ProA Pool
< Go
No-Go
Production in CHO SSI
0
5
10
15
20
25
30
35
40
45
50
0 50 100 150 200
Vis
cosi
ty (c
P)
Concentration (mg/mL)
1.27 1.31 1.32
1.33 1.34
Viscosity
0
10
20
30
40
50
1.27 1.28 1.29 1.30 1.31 1.32 1.33 1.34
% a
gg
reg
ate
115-157mg/ml aggregation in
His-Sucrose platform buffer
Tech Transfer
Start
Oct Nov Dec Jan Feb Mar Apr May Jun
2012 2014 Q4 Q1 Q2
Jul Aug Sep
Q3
GMP DS
Mfg
GMP
DP
Mfg
Tox Manufacture Tox
Material
Available
Candidate
Selection
Tech Transfer to New CMO
Oct Nov Dec
Q4
IND
Submission
(Nov 8)
Pre-IND
Telecon
FIH
(Dec 17)
Pre-IND
Briefing Doc
Implementation of First LCLV Project
Pre-IND and IND Experience
Modular Viral Clearance
• In Pre-IND briefing document, proposed filing modular retroviral
clearance data in a DMF for use across Pfizer phase I/II mAbs
• Viral clearance data using bracketed approach (8 mAbs)
– Overall clearance of > 16.4 LRV demonstrated for MuLV
• FDA agreed that DMF is appropriate approach
No formal DS stability when all DS is converted to DP
• IND included 3 month hold data only
Reduced DS Testing
• 5 assays removed from standard DS spec (redundant to DP testing)
• FDA agreed that proposed limited assays were reasonable (Concentration,
SE-HPLC, identity, bioburden, endotoxin), recommended bioassay
Overall positive FDA feedback on LCLV elements
• No CMC questions on the IND
Next Steps
• Implement and improve LCLV on additional programs
• Explore LCLV implementation ex-US
– Modular viral clearance approach
– Release and stability strategies
• Integrate some of the LCLV elements into standard mAb
development paradigm
• Beyond LCLV—speed, throughput, flexibility and cost
• Molecular Design and Molecular Assessment
– Design and Select for stable, well-behaved mAbs in addition to
biological activity
– Development of predictive tools
Summary
• CMC Development has a significant role in changing current
BioTx clinical development model
• Platform knowledge in mAb development can be leveraged to
improve efficiency without compromising quality
• Partnerships with project teams, CMOs, and regulatory
agencies are necessary to affect positive change
Acknowledgments
Marta Czupryn
Steffanie Pluschkell
Robert Repetto
Sa Ho
Kristin Murray
Tom Crowley
Tom Greenwood
Maeve Donegan
Bernie Huyghe
Bob Faneuff
Monica Purcell
Ling Gu
Concepcion Kafka
Bob Kitchen
Janelle Lavoie
Lisa Marzilli
Jim Mercer
Joe McLaughlin Gerry Boushelle
Karen Cook
Jon Coffman
Paula Miller
Martin Allen
Rob Dufield
Freddie Fowlkes
Derek Gates
Jackie Moxham
Nick Warne
Laura Lin
Tao He
Mark Krebs
Backup Slides
Cost of Development for ‘Standard’ mAb Adjusted for
Attrition
$-
$50,000,000
$100,000,000
$150,000,000
$200,000,000
$250,000,000
$300,000,000
$-
$2,000,000
$4,000,000
$6,000,000
$8,000,000
$10,000,000
$12,000,000
$14,000,000
$16,000,000
0 1 2 3 4 5 6 7 8 9
Inte
grated P
roje
ct Co
stDe
velo
mp
en
t F
TE C
ost
Years
FTE Cost
FTE cost (Adjusted for attrition)
Total Cost
Total Cost (Adjusted for attrition)
FIH -Start Candidate
Selection
Ph. IIb
start Ph. III
start
BLA
sub. Launch