immortal facilities for diverse pipelines - ge...

Imagination at work.

Parrish M. Galliher

GE Healthcare January 2016

Immortal Facilities for Diverse Pipelines

Outline

2

1. Introduction – industry pressures and industry advances

2. Pipeline and scale diversity driving facility design diversity

3. Factors that drive facility obsolescence

4. A tale of 2 facilities: stainless steel and single usel and single use

5. How to avoid facility obsolesence

6. Facility futures – immortal possibilities via innovation 7. Conclusions

Outline

Biomanufacturing Facility Futures P. Galliher GEHC 2015


Pressure on biomanufacturing: • more diversity and more from less • smaller in market, for market mfg. • local, smaller facilities, smaller quotas • multi-product facilities • lower manufacturing cost • loss of economies of scale • higher mfg. quality standards

What can we do? • SU and higher productivity, titer/yield • higher facility utilization • multi-product, requiring flexible mfg. • less variability, fewer failures, less waste • higher efficiency operations • smarter facilities

Innovation drivers in Bioprocessing dominated by mAbs

Single use and high

titer is not enough!



Biotech pipelines - growing diversity…. Biotechnology has the potential to transform human health, saving even more millions: • biotherapeutics – mAbs dominate • biosimilars – global competition • biobetters – potent, lower dose and toxicity • orphan drugs – specialized treatments • vaccines – eggs to cells to rDNA vaccines • stem/T cell/organ gene therapies – game changer? • nutritional medicines – on the horizon

More diverse treatments need more diverse mfg.

Personalized precision medicines



More diverse pipelines, processes and scales M

an

ufa

ctu

rin

g S

cale

2,000L

20,000L

20L

2L

200L

rDN

A,

Ma

bs

bio

sim

ila

rs

va

cc

ine

s

bio

be

tte

rs

ce

ll t

he

rap

y

autologous

allogeneic

blockbusters

blockbusters blockbusters

blockbusters

intensified,

continuous,

local markets

intensified,

continuous,

microbial,

local markets

rDNA,

higher

potency,

local

markets

higher

potency,

continuous,

microbial,

local

market


Sin

gle

use

Sta

inle

ss s

tee

l

Imagination at work. Biomanufacturing Facility Futures P. Galliher 2015

Biotech curve balls – causing facility obsolescence

Radical process changes Titer change – more common today Clinical trial failure – 10% of drugs make it to the market Partnering - may shift mfg. elsewhere The drug is sold The company is sold Mfg. technology change Tax haven disappears


Speaker’s history with biomanufacturing facilities

location Facility type year obsolete reason

USA Stainless batch

1981 1985 Molecule change

EU Stainless batch

1986 1988 Titer change 10x

USA Stainless perfusion

1988 1992 Mfg. Technology change

USA Stainless fed-batch

1993 Still operational

Commercial licensed


1994 1999 Drug failed in Phase 3


1996 1999 Company closed

USA Single use batch, fed-batch,

perfusion

2003 Still operational

Clinical mfg. facility

2 out of 7 facilities operational today


Facility features that reduce long term utility

Insufficient capacity Overtaxed utilities Small suites, low ceiling heights

Fixed piping/tankage Corrosion and wear – sterilization and cleaning problems Outdated automation


Innovation toolbox – Process development

innovation cost quality speed

HT screening, QbD, DOE, scale down modeling, metabolomics optimization

impact?

Site directed gene integration, landing pad expression cassettes

Mfg. ready cell lines in R/D, microbial/yeast expression systems



Blockbusters to precision medicines A tale of 3 facilities….. World scale mfg.

Global supply mfg.

Large scale, single-product

Sized for blockbusters

Inflexible, fixed pipe SS

Slow to build/expensive

In market , for market mfg.

Local market production

Mid scale SU mfg.

Multi-product, flexible

Modular, fast, lower cost,

Blockbusters multi-ton/yr mid scale 100-1000 kg/yr mini-mfg. 1-10 kg/yr

At clinic, for clinic mfg.

Precision/personalized mfg.

Very small SU mfg.

Flexible, modular

Local to treatment ctrs.


11

Very large scale stainless steel facilities Global blockbuster/biosimilar mfg. – multi-ton/yr

Global scale stainless steel facilities

Benefits:

• Blockbuster/biosimilar world supply

• Suitable for multi-ton/yr capacity

• High economies of scale

• Closed systems, can be multi-product

Risks:

• $200M-$1B total installed capital cost

• 3-5 year timeline to GMP ready

• Risk of obsolescence before completed

• Expensive to operate and modify Biomanufacturing Facility Futures P. Galliher GEHC 2015

Production amts. for high dose mAb drugs/fusion proteins bulk drug total < 20 tons/year in 2013 (Mabs, Fc fusion) >>>$100B USD annual revenues worldwide

*) Enbrel is a Fc fusion protein: dosage, treatment cost, and production process is similar to monoclonal antibodies

Large scale stainless steel facilities - hugely successful




Insufficient capacity Complex utilities, overtaxed utilities High running costs

Small suites, low ceiling heights Fixed piping/tankage, connection to utilities Corrosion and wear Easy for Multi-product

√

√

√

√

Stainless steel facility

√


Blockbusters to precision medicines A tale of 3 facilities….. World scale mfg.

Global supply mfg.

Large scale, single-product

Sized for blockbusters

Inflexible, fixed pipe SS

Slow to build/expensive

In market , for market mfg.

Local market production

Mid scale SU mfg.

Multi-product, flexible

Modular, fast, lower cost

Blockbusters multi-ton/yr mid scale 100-1000 kg/yr mini-mfg. 1-10 kg/yr

At clinic, for clinic mfg.

Precision/personalized mfg.

Very small SU mfg.

Flexible, modular

Local to treatment ctrs.


15

Sources of Customer reports – last 5 years $ Savings with Single Use versus Stainless Steel


16

FlexFactory™ - GE’s single-use technology platform

• Extensive application of single-use technologies

• Capacity can be expanded or reduced based on demand

• Reconfigurable without major reconstruction or production delays

• Support multi-product processing

• Collaborative project management

• Comprehensive documentation

• Commissioning and qualification program

• Knowledge building with training, process support & on-going services

• Centralized process monitoring, control & data management

• Data trending for process optimization & improvement

Giving you flexibility

Understanding your needs

Centralized monitoring &

control

From cell culture to bulk product formulation


17

Customer reports – last 5 years Savings with Single Use versus Stainless Steel (12 users)

Company Increased

consumables

Facility

CAPITAL

Cost

Facility

footprint

Labor Time to

build

Turnover

time

Water

use

Energy

use

Carbon

footprint

Increased

capacity

Operating

COGs

Consulting

firm

+300% -25% -25% -30% -92% -50% -10%

Consulting

firm

+250% +10%

Large

pharma

+120% -50% -25% -48% -70% +30 -57%

Large

Pharma

-60% -50% -25%

Large

Pharma

-90%

Large

biotech

-75% -75% -50% -80% -80% -67%

Large

biotech

-55%

Large

Biotech

-25% -35% -25% -85% -25% -25%

Small

biotech

+250% -45% -25% -25%

Vaccine -75%

CMO +50% -50% -10% -50% -25% -30%

CMO -15%

average +194% -51% -30% -33% -37% -58% -85% -51% -40% +30% -32%

Cost of goods

includes cost of

consumables,

overwhelmed by

these savings

GEHC SU FlexFactory/Start 2 Finish BioProcess facilities Commercial licensed

Australia

(1 x 2000 L)

Germany (2 x 2000 L)

UK (1 x 1000 L)

China KUBio #1

(4 x 2000 L)

China KUBio #2

(4 x 2000L)

South Korea

(2 x 500 L, 2 x 2000 L)

Taiwan #1

(2 x 500 L)

Taiwan #2

1 x 2000L

Russia

(2 x 2000 L)

Massachusetts #1 (2 x 2000 L)

Massachusetts #2 (1 x 2000L, 1 x 500L)

St Louis (1 x 2000 L)

Maryland (1 x 1000 L)

Pennsylvania (1 x 2000L)

California (2 x 200L)

Completed

Ongoing

Singapore

AMGEN

(6 x 2000 L) Brazil

Unia Quimica

Bacterial

(2 x 50 L)

FioCruz 200L Vero

Florida

(2 x 500 L)

N. Carolina #1

1 x 2000L

N. Carolina

1 x 2000L

Japan (1 x 2000L)

Commercial licensed facility


India

(1 x 200L)

1 x 2000L

CHO cells are producing 3-6 g/L mAb but - diminishing returns above 5 g/L titer

Legacy processing technology

Diminishing returns

Data courtesy Guenter Jagschies, GEHC

Increasing titer/yield is not enough!

19 Biomanufacturing Facility Futures P. Galliher GEHC 2015

FlexFactory capacity output for a MAb production (kg/yr)

Assumptions:

70 % recovery through purification

20 batches per year, per reactor

Cell culture titer

1g/L 1.5g/L 2g/L 3g/L 4g/L 5 g/L 6 g/L

2 x 500 L 14 21 28 42 56 70 84

2 x 1000 L 28 42 56 84 112 140 168

2 x 2000 L 56 84 112 168 224 280 336

4 x 2000 L 108 168 228 336 448 540 648

6 x 2000L 168 252 336 504 672 840 1008

Scale




Insufficient capacity Complex utilities, overtaxed utilities High running costs

Small footprint suites, low ceiling heights Fixed piping/tankage, connection to utilities Corrosion and wear Single product

√

√

√

√

Stainless steel facility

√

Single use facility

√

√


Features of immortal facility designs keep it simple!

Minimal connectivity between equipment and utilities Portable equipment Large footprint suites High ceilings Large access panels/doors Minimal clean utilities Multiple HVAC zones Bi-directional flows


Possible future biologics facilities

through innovation and integration


Innovation Cost Quality Speed

Single use, increasingly closed, SU microbial

impact?

high cell density banks, perfusion N-1 or N stage

SU perfusion of cells, cells + product, SU sensors

Precipitation, flocculation, acoustic separations

Continuous DSP enables SU chromatography

Pre-packed columns and DSP membranes

Media or buffer concentrates, in-line dilution

Reducing raw material variability

At-line, On-line analytics, near real time QC

Multi-product mfg. – significant COGs reduction, facility utilization

Innovation toolbox – Manufacturing and Quality Control

Single use futures



Innovation toolbox – SU Facilities

Innovation Cost Quality Speed

SU futures – closed systems end to end ? ? ?

? ? ? impact? ? ? ?

SU friendly layouts for carry-in, carry-out SU ops

Modular buildings and pods

Liberal and aggressive ballroom facilities

Concurrent multi-product manufacturing


26

Traditional FlexFactory

Ballroom FlexFactory with containment

protection

Ballroom FlexFactory No containment

protection

3 versions of single use facilities

CEM containment

Gradient of Cross Contamination Risk

Gradient of Cost , Speed, Flexibility


Closed cell banking and N-1 stage inoculum process intensification though perfusion:

27

4.5 mL

50 to 100 x 106 cells/mL 1 to 10 L

3 to 4 weeks

< 2 weeks


N-1 stage perfusion - Biogen

N-1 stage XDR-200

N stage XDR-2000

Reference permission from Jonathan Romero, Biogen 2015

29

Closed plug and play pre-packed column and

membrane purification

GE Healthcare Ready to Process (RTP) LifeTech, Repligen Atoll GoPure /Opus/MaxiChrom

Natrix, Pall and Sartorius membranes


Continuous ÄKTA™ pcc system potential to make chromatography single use

ÄKTA™ pcc system

Systems can be delivered by GE Healthcare’s Life Sciences on demand for:

• Lab scale

• Pilot scale

• Manufacturing scale

BioProcess™ pcc system

30

0.5 mL/min to 4000 L/h

Impact of ILD at Customer site


Common mfg. space SU facilities – risk assessment

Advantages: - 30% less footprint

- Lower capital investment, faster buildout - Lower heat, light and power costs - Lower ISO-7 class 10,000 “C” HVAC costs - Lower class C gowning costs - Lower labor costs (one USP/DSP team) - Unparalleled flexibility - Much faster turnover time logistics for SU - Long term utility

Risks: - Not all SS or SU systems are fully “closed” - Validation of “functionally closed” systems - USP to DSP cross contamination risk - Batch loss risk upon rupture or breach - Regulatory risk

GE ballroom, Marlborough MA

Patheon ballroom, St. Louis MO



Enabling bioprocessing future...bringing it all together

Closed single use High density cell banks

N-1 high density perfusion Efficient, long life

facilities

Closed SU continuous DSP, buffer concentrates,

inline dilution/conditioning

+ +

Enables concurrent SU multi-product mfg.



Concurrent multi-product mfg. in common mfg. suite

Significant

reductions in COGS


Cell therapy manufacturing tumor infiltrating lymphocytes

Inoculum expansion

Culture perfusion

Cell washing

Cell concentration

Final formulation

Concentration and Harvest

Formulation buffer

Rocker bioreactor with integrated perfusion filter

expansion

perfusion

Wash buffer

Perfusion media

Fully closed aseptic processing


Very efficient cell therapy

facility

Very efficient cell therapy facilities

Conclusions

39

• Pipeline diversity increasing • More diverse facilities - no “panacea” design

• Very large stainless steel facilities needed (multi-ton blockbusters, biosimilars) • Mid-scale SU facilities will be needed up to 1000 kg/yr • Very small (precision cell therapy) facilities needed 1-10 kg/yr

• Immortal facilities - Keep it simple to avoid obsolescence

• Closed systems can enable concurrent multi-product mfg. – large COGS reduction

?

Can we get there safely with SU technology?



Thank you!

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