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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