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WHEN, WHY AND HOW TO OUTSOURCE BIOMANUFACTURING: THE ROLE OF SINGLE USE TECHNOLOGIES
John CoyneSr. Manager: Bioprocessing Research and Development Manufacturing Pfizer, Inc.23 Years Industry Experience, 8 Years with Pfizer
01Nov16
Innovating to bring
therapies to patients that
significantly improve their
lives.
We make medicines and vaccines
that help people when they are
sick and prevent them from
getting sick in the first place.
Silk Stockings and Biopharmaceuticals
Ludwig VonMises….the queen of England and silk stockings.
Drivers (1 of 2)
Economic
1.3 billion people in 2011. 1.4 billion in 2015. USA 312/321
GDP per capita $5575 PP 2011. $7808 in 2015 (40% increase). USA $49k/$55k – 12% increase
$7.3T GDP – second largest. (2011) $10.7 T in 2015 USA $15.5 / $17.9T
5.1% of GDP healthcare spending 2010
2012 – third largest pharma market in the world
Global: Pharmaceutical Market Growth, 2012 Global: Pharmaceutical Market Size, 2012
-8
-5
-2
-1
-1
-1
0
0
2
2
4
4
13
18
19
21
24
45
-10 0 10 20 30 40 50
Spain
Italy
United Kingdom
Canada
France
Europe (Top 5)
United States
North America
Germany
Japan (including Hospitals)
Mexico
Australia / New Zealand
India (Retail)
Brazil
Latin America
China (Hospital)
Argentina
Venezuela
(% Change)
Source: Decision Resources. Based on data released December 2012 from IMS Health.
© 2013 DR / Decision Resources, LLC.
5.5
6.8
8.2
10.2
11.9
12.3
13.8
14.4
19.5
21.8
26.9
36.5
42.3
48.4
101.6
103.8
238.1
257.6
0 100 200 300
Argentina
Venezuela
Mexico
India (Retail)
Australia / New Zealand
Spain
United Kingdom
Italy
Canada
Brazil
France
Germany
Latin America
China (Hospital)
Japan (including Hospitals)
Europe (Top 5)
United States
North America
($B)
5
Note: Percent change in retail drug sales for the 12 months to October 2012. Note: Market sizes are from retail drug sales for the 12 months to October 2012.
Pharma Revenue by Country 2012
Drivers (2 of 2)
Regulatory
Chinese specific Clinical Trials
Long review times (Changing) 4-6 years.
Ongoing reforms
Clinical reviews / data integrity
13th 5 year plan – focus on technology, including biotech.
Ongoing smaller reforms.
Unwritten expectations.
Why does it take so long?
7
2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026
Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3
GMP InspectionNDA ReviewPV StabilityManufacture PV
Pilot LotsTT to new facilityDP facility Stick Build
Clinical Phase 3 (+report)
Mfg Clinical Lots
Clinical Phase 1 (+report)Clinical Lot release
Training
Site Selection
TT to China
Facility InfrastructureDS FacilityCTA Review
Mfg IND lots
Small Scale POC
CTA Submission
StabilityAnalytical Characterization
Reg / Tox Study
Regulatory Engagement – De Risk
CFDA Approval
Funding Approval
GE Value – Direct Benefits…..Process Development
GE Marlboro Scale down and Disposables
conversion
GE ShanghaiMfg Reg/Tox/ lots for CTA
application to take off critical path
Tech Transfer
GE Marlboro Support 200L xfer to Shanghai
Support 2000L xfer to Greenfield site
GE ShanghaiSupport startup in Greenfield site
DS Facility Build
KuBio Greenfield• 18 months from PO to OQ
complete
• Provides equipment SOPs
• Allows new team to focus on
DP facility startup
GE ShanghaiOperator training in parallel to
construction on exact equipment
and procedures
China Knowledge
100 years in China“Long Term View”
GE Govt/Reg AffairsSophisticated / Experienced
strategists
GE Finance Experienced with tax and financing
IP ProtectionEstablished controls and firewalls in
place already
Facility ImplicationsLower cost – become cost effective at making small batches.
Biggest impact when looking at whole operation
Multiproduct Design = Volume
• Family Approach
• Contamination control
In an integrated development process, less TT time
• No CIP / SIP
• More replication
Footnotes:
2. BioPharm International, Rita Peters, Jan 2014
3. Aspen Brook survey, 90 respondents - 2016
Low Cost Cheap (Opportunity)
• Technology progression drives improvement AND cost reduction.
• Hotel phone call…… cell phone……Face Time
• Platforms easier to support
• Continuous Manufacturing – “out not up”
• PAT and continuous verification
Single use – Many examples one can Google
• 38.1% single-use products offer a cost savings2
• 55.6% indicate the high cost was a challenge to using single-use products2
• Time savings and flexibility key in decision process2
Problem statement:high level
n
NPV = t=0
Where: t = time of cash flow
i = discount rate, opp cost
Rt = net cash flow at time (t)
Year 1 Year 3 Year 4 Year 5 Year 6 Year 7Year 2
Rt
(1+i)t
Faster to MarketRealize revenue stream earlier
While standard construction benefits exist….
• Construction times shorter – Modular approach (building and unit op)…lots of already installed capacity.
• Reduce need for facility controls through engineering
…other areas offer larger opportunity
• Integrated Development
• Transportability of data
• Common platform – easier support (more next page)
• Move the facility
• Development work before construction
Yes
No
Q4 2015 Ian Read Review_vF.pptx 13
Process transfer to Fast Trak Team in China
GE’s Fast Trak Asia and US teams collaborating/training during the 200 L single-use production batches
Marlborough, MA, U.S.A. Shanghai, China
Currently working with GE Fast Trak team MBO for further batches to buy down
regulatory risk
Pfizer Confidential. For Internal Use Only.
Design scope of work Convert from conventional to single-use
technologies Scale-up from 10 L to 200 L, with ultimate
target of 2000 L, bioreactor for two biosimilar mAb molecules
Deploy a global, flexible, scalable, cost-effective biosimilar manufacturing platform under aggressive timelines
Be first to market in emerging regions Process transfer to customer’s site in
emerging region
Aggressive timelines: completion of work in less than six months
Molecule biosimilarity comparison after process transfer to single-use technology
Process and equipment design Protection of customers intellectual
property (IP) Communication with and alignment of
global teams Real-time scope/process changes and
definition phase progressed
Outsourcing Process developmentGE’s Fast Trak ServicesPROJECT NEEDS PROJECT DELIVERABLES
Q4 2015 Ian Read Review_vF.pptx 15
Outsourcing Process DevelopmentGE’s Fast Trak Services
Technology
Transfer
Pfizer Confidential. For Internal Use Only.
4 × 10 L single-use runs
Process transfer
Generation of
protocols
solution records
bill of materials
Initial scopeAnother set of 10 L single-use runs were performed
Process transfer
Generation of
protocols
solution records
bill of materials
Process confirmation
Scale-up
4 × 200 L single-use runs
Generation of
protocols
solution records
bill of materials
Proof of concept
Process scaled from a vial to complete purification of two biosimilar mAb
molecules with the goal to manufacture at 2000 L scale
Q4 2015 Ian Read Review_vF.pptx 16
Conversion to Single-useGE’s Fast Trak Services
Upstream process Downstream process
Critical parameters:
Seed train, agitation rates,
pH, dissolved O2 , sparge
pore size, feed, gassing,
and bioreactor control
strategies.
Critical parameters:
Velocities, resin binding
capacities, collection criteria,
flux rates, temperatures,
pressures, pH, conductivity,
hold times, storage conditions.
Q4 2015 Ian Read Review_vF.pptx 17
Product A & B: upstream process results
Product A 10 L confirmation run 200 L run 1 200 L run 2
Maximum cell density 17× 106 M cells/mL 24 × 106 M Cells/mL 20 × 106 M Cells/mL
Product titer 2.4 mg/mL 3.3 mg/mL 3.2 mg/mL
Comparable to client data
Low but acceptable Yes Yes
Product biosimilarityconfirmation
Confirmed Confirmed Confirmed
Product B 10 L confirmation run 200 L run 1 200 L run 2
Maximum cell density 11 ×106 M cells/mL 10 × 106 M cells/mL 11 × 106 M cells/mL
Product titer 3.4 mg/mL 3.4 mg/mL 3.9 mg/mL
Comparable to client data
Yes Yes Yes
Product biosimilarityconfirmation
Confirmed Confirmed Confirmed
Q4 2015 Ian Read Review_vF.pptx 18
Product A: downstream process results
Product A 10 L confirmation runStep recovery
200 L run 1Step recovery
200 L run 2Step recovery
Clarification 86% 88% 88%
Protein A +VI 93% 102% 91%
Anion exchange 89% 86% 99%
UFDF 95% 98% 97%
Total process recovery 68% 76% 73%
Comparable to client data
Yes Yes Yes
Product biosimilaritycomparison
Confirmed Confirmed Confirmed
Q4 2015 Ian Read Review_vF.pptx 19
Product B: downstream process results
Product B 10 L confirmation runStep recovery
200 L run 1Step recovery
200 L run 2Step recovery
Clarification 84% 85% 93%
Protein A +VI 114% 98% 95%
Anion exchange 93% 86% 93%
Cation exchange 73% 78% 79%
UFDF 95% 94% 96%
Total process recovery 62% 53% 65%
Comparable to client data
Yes Yes Yes
Product biosimilaritycomparison
Confirmed Confirmed Confirmed
UFDF = ultrafiltration/diafiltration
Fast Trak Project outcomes More products addresses probability nature of revenue stream
to some degree
Conversion from conventional to single-use technology and scale-up from 10 L to 200 L
Project completed in 5 months (incl. completion of 6 × 10 L batches, 4 × 200 L batches, generation of > 50 process documents, and 4 complete bills of materials.
Customer internal timeline for similar scope of work was estimated to 18 months.
Black box approach to protect customer’s intellectual property (IP) (initially, culture media and feeds, several process solutions, and biosimilarity analytics were unknown).
Succeeded in titer requirement of 3–4 g/L.
Product met biosimilarity requirements.
Process transfer to ChinaGE’s Local Fast Trak services teams support process transfer to emerging regions, sourcing of local raw materials, and understand local government and regulatory requirements
Single-use FlexFactory™ platformKUBio™ facility
At GE
FAST TRAK MANUFACTURING SERVICES
Process developmentAnalytical developmentScale-up
Documentation preparationcGMP manufacturingTrain/educate customer team
TransPlant
PROCESS DOCUMENTATION TRAINING START-UPANALYTICAL
21cGMP = current good manufacturing practices
ReplicationAbility to ensure consistent supply
Quality implications (positive) – counter to distributed control
Regulatory?
Aspiration Copy Exactly & Leverage
Typically based on physical location now.
Stability for filing
Center support for remotely run plants?
Q4 2015 Ian Read Review_vF.pptx 23
Innovation anticipating market changes
Process development
Technology
Transfer
Global Support,
Troubleshooting, Data
Acquisition and Analysis
Pfizer Confidential. For Internal Use Only.
28Jun16 Hangzhou SiteGroundbreaking Ceremony
Parcel 1 Block and Stack (Phase 1)
1)中国杭州辉瑞生物科技工业中心
Site Rendering – Dragon Well
26
KUBio™ manufacturing facility
The KUBio facility is GE’s cGMP-compliant process solution for mAb
production. The modular units are factory-built, final assembly on customer site. Because different parts are developed concurrently, your KUBio facility is fully operational in just 18 to 24 months.
Assembled on brown or greenfield site
Built, assembled, qualified, and ready-to-
run within 18 to 24 months
Includes FlexFactory™ single-use platform
2 × 500 L to 4 × 2000 L facilities
Segregated up- and downstream
operations, including gowning
Multiproduct facilities
More products addresses probability nature of revenue stream to some degree
Flexible for future needs that are unknown today
As volume of finished goods per plant gets smaller – what is our role as manufacturers?
Approaches on Modular addresses all above
Bios DS - several options• mAbs have a fairly common platform
• Cell Lines and development work to switch
• No “platform” for vaccines
Aseptic• Reduce clean room size / number
• Why Grade C outside of an isolator?
• Why isolator – engineering solutions in development
• Drug development – why vials or syringes?
o Other delivery methods that don’t require sterile dosage forms.
Conclusion –China is pulling us into the Future
The role of pharmaceutical manufacturing will change to reflect business & technical drivers
Facilities will evolve accordingly
Our role today is to anticipate those needs
