of 30
8/13/2019 Next Generation Biopharma Manufacturing Facilities
1/30
Next generation biopharma
manufacturing facilitiesTrends for biotherapeutics and their production
PABME, Dubai, April 29 2008Dr. Gnter Jagschies, Senior Director R&DStrategic Customer RelationsGE Healthcare Bio-Sciences ABUppsala, Sweden
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
2/30
8/13/2019 Next Generation Biopharma Manufacturing Facilities
3/30
3 / GE-Jagschies R&D / 2008-04-29
Overview
Pressure on pipeline efficiency and cost of treatment
Focus on manufacturing efficiency and costs
Varying API categories and production sources
Widely varying production scales
Switch from dedicated to multiproduct facilities
Flexibility, agility, cost efficiency
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
4/30
4 / GE-Jagschies R&D / 2008-04-29
Top selling biopharmaceuticals 2007
FVIII, F VIIYesNovo Nordisk, Wyeth, Bayer, Baxter 4,518Clotting factors
MabYesGenentech 5,527Rituxan / MabThera
VaccineNoMerck&Co 1,481Gardasil
MabYesMerck-Serono, BMS 1,439Erbitux
Mab fragmentNoGenentech, Novartis 1,386Lucentis
1,144
>1,200
2,439
2,762
3,000
3,605
4,114
4,277
4,862
4,948
5,275
8,223
10,926
11,101
US $ M
MabYesAbbott Laboratories Humira
Growth
No
Yes
No
No
No
Yes
Partly
Yes
Yes
Yes
Partly
No
Yes
Mammaliancells
ErythropoietinAmgen, Roche, J&JEPOs
MabJ&J, Schering-PloughRemicade
Fc fusion proteinAmgen, WyethEnbrel
rec hInsulinEli Lilly, Novo Nordisk, Sanofi-AventisInsulins
LMW HeparinSanofi-AventisLovenox
Glucocerebrosidase
Mab
Vaccine
rec hGH
Mab
G-CSF
Mab
alpha/beta-Interferon
Substance
GenzymeCerezyme
MedImmuneSynagis
WyethPrevnar / Prevenar
Pfizer, Novo Nordisk, Eli Lilly, SeronoGrowth hormones
GenentechAvastin
AmgenNeulasta / Neupogen
GenentechHerceptin
Schering-Plough, Roche, Biogen IdecBayer-Schering, Merck-Serono
Interferons
Companies countedBranded productProduct category
Biopharma blockbusters 2007: US $ 82,3 billionMab blockbusters 2007: US $ 26,5 billion
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
5/30
http://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
6/30
6 / GE-Jagschies R&D / 2008-04-29
Cost of treatment, example
0
5.000
10.000
15.000
20.000
25.000
Today -10% -20% -30% -40% -75%
Typical current level
Level of new or
established alternative
?
?
?
Future level?
Market forces:- Public health care systems- Shorter time to next innovation- Biosimilars
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
7/30
7 / GE-Jagschies R&D / 2008-04-29
New(?) Challenges
Flexibility
AgilitySpeed
Efficiency
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
8/30
8 / GE-Jagschies R&D / 2008-04-29
Source: Genetic Engineering News, 2002
20%
32%
6%
6%
3%
13%
20% Depreciation
Labour
Media
other Raw Materials
Protein A resin
other Consumables
Insurances, Taxes,
Maintenance
D
C
I,T,M
RML
M
Production EconomicsOperating Costs in Mab Production
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
9/30
9 / GE-Jagschies R&D / 2008-04-29
What is best-in-class performance?
Best in class performance isfoundation for the future
ac y u za on = -
Cost = 15% CoS (100 USD/g)
Process yield = 70-80%
Product titer = 5 g/LTime = 10 day upstream
2 days downstream
8/13/2019 Next Generation Biopharma Manufacturing Facilities
10/30
10 / GE-Jagschies R&D / 2008-04-29
Mabs, rProteins, Vaccines, Cells, Genes
2006 2004Pharmaceuticals Research & Manufacturing Association
(PhRMA) clinical trials summary (2004-2006):Mabs: 76 160
rProteins: 57 94
@ success rate: 20% > 50 approvals by2012
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
11/30
11 / GE-Jagschies R&D / 2008-04-29
Mabs and mammalian cells dominate(only products / API categories > US $ 1 billion included)
26.500
51.900
3.920
Mabs
rProteins
Vaccines
51.484
30.800
Mammalian cells
Other cells
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
12/30
12 / GE-Jagschies R&D / 2008-04-29
Biopharma production challenges(Production volume and revenue map, 2006 data)
Pharmacy list prices 2006, available packages:Arzneimittelkompendium (CH), MediMedia Gelbe ListePharmaindex (GER), RxUSA.com Pharmacy (USA)
Annual global sales 2006: Annual reports 2006 Plasma products: Marketing Research Bureau 2004
1
10
100
1.000
10.000
100.000
1.000.000
10.000.000
100.000.000
0,01 0,10 1,00 10,00 100,00 1.000,00 10.000,00 100.000,00 1.000.000,00
Annual production volume [kg]
Pharmacypricevalue[USD/g,2006]
HSA, plasma
Huminsulin
Rituxan/MabThera
HumalogAvastin
IVIG, plasma
EnbrelHumira
RemicadeHerceptin
SynagisPulmozyme
NeulastaReoPro
Aranesp
ReFacto
Neupogen
BeneFIX
KogenateAvonex
PegaSysRebif
NovoSeven
Humatrope
Xolair
Advate
Coagulation factor VIII EPO, Factor IX, VII, interferonsl HGH, low dose antibodiesn High dose antibodies, fusion proteins Insulinsr Plasma proteins
Most future Mabswill require annual
capacity of 100-500 kg
Some Mabswill require annual
capacity of 1-5 tons
Insulins
1-5 tons
Plasma proteins50-500 tons
Most rProteinswill require annualcapacity of 1-10 kg
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
13/30
13 / GE-Jagschies R&D / 2008-04-29
The challenge is the supply of vaccines
Capacity Time
0
500
1000
1500
2000
2500
milliondoses
2006 PandemicPlanning
There is a huge gap between the expecteddemand and the current capacity Most countries are looking for in-country
domestic solutions WHO is driving local capacity build up
20102004 WHO
Currently the manufacturing timeis ~6-9 months Need of faster supply less than 3 months
production time Difficult and time consuming to scale up with
old technology
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
14/30
14 / GE-Jagschies R&D / 2008-04-29
The vaccine landscape is changing and is
moving to new manufacturing methodsEgg-basedproductiontechnology
Cell Culture-basedproductiontechnology
Cell Freeproductiontechnology
System Eggs Mammalian Cells Insect and Bacterial Cells Recomb Cells
Lead Times 6-9 months ~6 months ~3 months Days?Maturity On the market New on the market In 2-4 years time -
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
15/30
15 / GE-Jagschies R&D / 2008-04-29
Many facilities have
brand new installations and up to 25year old installations, running with newand old processes.
dedicated one-product or multi-product setups.
a degree of mismatch betweencurrent bioreactor output and DSP line
dimensions chosen at the time of facilitydesign.
limited flexibility!
Large / modern biopharma facilities
Genentech, Oceanside, CA
Image: Boehringer Ingelheim GmbH
DocumentsPDFCompleteClick Here & Upgrade
Expanded FeaturesUnlimited Pages
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
16/30
16 / GE-Jagschies R&D / 2008-04-29
Production setup: 6 fermentors 1 DSP
Mab Cell Culture(6x 2.000 L, 5 g/L)
Cell Removal
Capture(1x 120 cm , 30 cm height)
Polishing 1(1x 80 cm , 25 cm height)
Polishing 2(1x 60 cm , 23 cm height)
UF/DFFormulation
Virus Removal
Virus Inactivation
Mab Cell Culture(6x 15.000 L, 5 g/L)
Cell Removal
Capture(1x 160 cm , 40 cm height)
Polishing 1(1x 160 cm , 42 cm height)
Polishing 2(1x 140 cm , 30 cm height)
UF/DFFormulation
Virus Removal
Virus Inactivation
- 313 L bed volume- 40 g/L capacity- one cycle
- 780 L bed volume- 40 g/L capacity- three cycles
10-ton/yr
scenario
1-ton/yr
scenario
- 125 L bed volume- 100 g/L capacity- one cycle
- 62 L bed volume- 200 g/L capacity- one cycle
- 850 L bed volume- 100 g/L capacity- one cycle
- 425 L bed volume- 200 g/L capacity- one cycle
10 kg/batch126 batches
80% yield
75 kg/batch168 batches
80% yield
DocumentsPDFCompleteC c e e & Upg ade
Expanded FeaturesUnlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
17/30
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
18/30
18 / GE-Jagschies R&D / 2008-04-29
Cell cultureDocumentsPDFComplete
Expanded FeaturesUnlimited Pages
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
19/30
19 / GE-Jagschies R&D / 2008-04-29
Chromatography
CD = 80cmCD = 100cmCD = 120cmCD = 140cmCD = 160cmCD = 180cm
DocumentsPDFCompleteExpanded Features
Unlimited Pages
Click Here & Upgrade
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
20/30
20 / GE-Jagschies R&D / 2008-04-29
Stainless steel space
Disposables space
Emerging production scenariosMore companies will have more than one product in production, many of them small in scale
Batches / product / year(scale: 1-170 with six-pack of bioreactors)
Bioreactorvolume
(scale:525000L)
Scale limit for many single-usecomponents: 1000 L
Large number of batchesfavors re-use strategies
10 100
10
100
1000
10000
cGMP fully dedicated facility(500-3.000 kg per product)
cGMP clinical manufacturing(2-30 kg per product)
cGMP multi-product facility(10-500 kg per product)cGMP multi-product facility
(10-500 kg per product)cGMP multi-product facility(10-500 kg per product)
Non-GMP pilot facility(10-500 g per product)
High product titers smaller installationsproduce largequantities
How much of GMP productionwill reach the disposable space?
Product ion sc enar ios n eed tocon sider higher degrees of f lexibi l i ty
High product titers fewer batches producelarge quantities
Lab bench designsused to be a
production transferissue.
Now the issue is
with stainless steel
engineer ing habi ts!
DocumentsPDFCompleteExpanded Features
Unlimited Pages
Click Here & Upgrade
E d d F t
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
21/30
21 / GE-Jagschies R&D / 2008-04-29
Reality checkHow many products are sharing facility capacity?
Products above one metric tonper year may still require oneor more dedicated facilities
Multiple product facilities willbe dominating the future
Flexibility in the design is bestprotection against uncertaintyin planning
Genentech manufacturing backgrounder (www.gene.com, 2006)
DocumentsPDFCompleteExpanded Features
Unlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
22/30
8/13/2019 Next Generation Biopharma Manufacturing Facilities
23/30
Click Here & Upgrade
Expanded Features
http://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
24/30
24 / GE-Jagschies R&D / 2008-04-29
LEAN chromatography - summaryClassic step (1st generation tools)
Improved step (use of up-to-date tools)
Value adding work
Non-value adding work
Required non-value adding work
Optional:Waste removed
Single-useoperation
Resin preparation*) Packing andre-packing*)
Excessive equilibration volume &)
Excessive elution volume &)
Excessive process time &) &) not optimized
Run
CIP and storage #)Equilibration Load Wash Elution Strip
Inefficientwash step &)
Resin Preparation*)
Run
CIP and storage #)Equilibration Load Wash Elution Strip
Packing andre-packing*)
Excessive equilibrationvolume &)
Excessive elutionvolume &)
&) not yet optimized
Inefficientwash step &)
ReadyToProcessTM
pre-packed
pre-qualifiedpre-sanitized
PreDictorTM plates(HTPD)
Fast,low cost
optimization(LEAN & SixSigma)
AxiChromTM
Faster procedureLess failure Modern resins
Higher capacityand flow, longer
lifetime
DocumentsPDFCompleteExpanded Features
Unlimited Pages
Click Here & Upgrade
Expanded Features
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
25/30
25 / GE-Jagschies R&D / 2008-04-29
Influenza vaccine production capacity buildup with disposables to save time
Traditional Flu Vaccine Production Facility Commissioning & Validation:
Build Facility
Validate Equipment
Commission Facility
Validate Process
Build Facility
Validate Equipment
Commission Facility
Validate Process
Time Saved
Saving ~60%
in time
Disposable Insect Cell Culture-Based Flu Vaccine Production:
DocumentsPDFCompleteExpanded Features
Unlimited Pages
Click Here & Upgrade
Expanded Features
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
26/30
26 / GE-Jagschies R&D / 2008-04-29
flexibel planning
flexible location
minimal capital investment
minimal process development
minimal distribution and storage local policies/relationships
local human capital
Our vision . . .the future is a modular, self-supporting, disposable production plant
Fast deployableproductioncapacity
DocumentsPDFCompleteExpanded Features
Unlimited Pages
Click Here & Upgrade
Expanded Features
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
27/30
27 / GE-Jagschies R&D / 2008-04-29
Process economy gains overall DSPUse of modern resins: combined effect of capacity, flow, and lifetime
10,911,8
19,2
37,4
0
5
10
15
20
25
30
35
40
Classic process Protein A update Protein A 3-step
model process
Protein A 2-step
model process
Downstream
costcontribution[USD/g]
0
20
40
60
80
100
120
DSPprocesstime[h]
Cost savings with modern resins up to 70%Process time down to 2 days from 5 days
2-step process: additional indirect gains fromspace and tankage requirements
Working volume 10,000 LTiter 5 g/LYield 79%
(Sepharose Fast Flowresins)
(MabSelect SuRe/CaptoS/ CaptoQ)
(MabSelect SuRe/Sepharose Fast Flow)
(MabSelect SuRe/Captoadhere)
DocumentsPDFCompleteExpanded Features
Unlimited Pages
Click Here & Upgrade
Expanded Features
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
28/30
28 / GE-Jagschies R&D / 2008-04-29
Process improvements
FacilityLow utilization Intense
Efficiency gains directly visible at management levelEfficiency gains hardly visible at management level
Investment in improvement pays off quicklyHesitant to invest in improvement
Equipment performance on critical pathExisting equipment, performance tolerance
Staff is a scarce resource, tough prioritizationStaff is available and has spare time
Intense facility utilizationLow facility utilization
Can be nothing Can be millions
Cost driven management Extra production time creates the opportunity to run more batches.
In a facility that produces several Mab products at a cost of $ 100M 70% of the costs may beconsidered fixed. At 5 days batch time up to 70 batches of 25 kg each could be run. One additionalbatch would reduce the cost per batch with $ ~15K. The savings amount to $ 1M / yr.
Revenue driven management At a commercial value of $ 2.000/gram, one extra batch of 25 kg of product would be
worth $ 50M of extra revenue.
DocumentsPDFCompleteExpanded Features
Unlimited Pages
Click Here & Upgrade
Expanded Features
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
29/30
29 / GE-Jagschies R&D / 2008-04-29
Conclusions
Monoclonal antibodies Improved processes with modern production tools and LEAN design are
requirements to remain competitive and meet treatment cost challenges
Insulin Diabetes is a growing challenge all over Asia. Local production will be a need
and a business opportunity
Plasma proteins Advanced healthcare is a growing need all over Asia. Again, local collection of
human plasma and fractionation is a business opportunity
Vaccines Vaccination carries the hope for cure instead of chronic treatment. Infectious
disease is a global threat (e.g., pandemic influenza). Short lead times of just afew months require fast deployment of production where the outbreak is.
DocumentsPDFCompletepUnlimited Pages
Click Here & Upgrade
Expanded Features
http://www.pdfcomplete.com/1002/2001/upgrade.htmhttp://www.pdfcomplete.com/1002/2001/upgrade.htm8/13/2019 Next Generation Biopharma Manufacturing Facilities
30/30
30 / GE-Jagschies R&D / 2008-04-29
Thank you
GE Healthcare Bio-Sciences AB, a General Electric company.
GE Healthcare Bio-Sciences AB
Bjrkgatan 30751 84 UppsalaSweden
Capto, MabSelect, and Sepharose are trademarks of GE Healthcare companies. Biacore is atrademark of Biacore AB.GE, imagination at work and GE monogram are trademarks of General Electric Company.
All goods and services are sold subject to the terms and conditions of sale of the company within GEHealthcare which supplies them. GE Healthcare reserves the right, subject to any regulatory andcontractual approval, if required, to make changes in specifications and features shown herein, ordiscontinue the product described at any time without notice or obligation. Contact your local GEHealthcare representative for the most current information.
2007 General Electric Company All rights reserved.
DocumentsPDFCompletepUnlimited Pages
http://www.pdfcomplete.com/1002/2001/upgrade.htm