Next Generation Biopharma Manufacturing Facilities

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Next generation biopharma manufacturing facilities

Trends for biotherapeutics and their production PABME, Dubai, April 29 2008
Dr. Gnter Jagschies, Senior Director R&D Strategic Customer Relations GE Healthcare Bio-Sciences AB Uppsala, Sweden
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Acknowledgments
Gail Sofer Lars Hagel Brian Kelley Karol cki Greg Blank Wolfgang Berthold Joachim K Walter Kjell Eriksson Hans J Johansson Eggert Brekkan
2 / GE-Jagschies R&D / 2008-04-29
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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
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Top selling biopharmaceuticals 2007

Branded product Product category EPOs Insulins Interferons Rituxan / MabThera Enbrel Remicade Herceptin Clotting factors Neulasta / Neupogen Avastin Lovenox Humira Growth hormones Prevnar / Prevenar Gardasil Erbitux Lucentis Synagis Cerezyme US $ M 11,101 10,926 8,223 5,527 5,275 4,948 4,862 4,518 4,277 4,114 3,605 3,000 2,762 2,439 1,481 1,439 1,386 >1,200 1,144 Growth Companies counted Amgen, Roche, J&J Eli Lilly, Novo Nordisk, Sanofi-Aventis Schering-Plough, Roche, Biogen Idec Bayer-Schering, Merck-Serono Genentech Amgen, Wyeth J&J, Schering-Plough Genentech Novo Nordisk, Wyeth, Bayer, Baxter Amgen Genentech Sanofi-Aventis Abbott Laboratories Pfizer, Novo Nordisk, Eli Lilly, Serono Wyeth Merck&Co Merck-Serono, BMS Genentech, Novartis MedImmune Genzyme Mammalian cells Yes No Partly Yes Yes Yes Yes Yes Partly Yes No Yes No No No Yes No Yes No Substance Erythropoietin rec hInsulin alpha/beta-Interferon Mab Fc fusion protein Mab Mab FVIII, F VII G-CSF Mab LMW Heparin Mab rec hGH Vaccine Vaccine Mab Mab fragment Mab Glucocerebrosidase
Biopharma blockbusters 2007: US $482,3 billion / GE-Jagschies R&D / 2008-04-29 Mab blockbusters 2007: US $ 26,5 billion
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Need for efficiency improvement
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Cost of treatment, example

Typical current level
25.000
? ?
Market forces: - Public health care systems - Shorter time to next innovation - Biosimilars
20.000
Level of new or established alternative
15.000
10.000
Future level?
5.000
0 Today -10% -20% -30% -40% -75%
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New(?) Challenges
Flexibility Agility Speed Efficiency
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Production Economics
Operating Costs in Mab Production
20% 20%
Depreciation Labour
I,T,M
D
Media other Raw Materials
13%
C
Protein A resin
L
3% 6% 6%
RM M
32%
other Consumables Insurances, T axes, Maintenance

Source: Genetic Engineering News, 2002
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What is best-in-class performance?

Facility utilization Cost Process yield Product titer Time = = = = = 80-100% 15% CoS (100 USD/g) 70-80% 5 g/L 10 day upstream 2 days downstream <7 days change over
Best in class performance is foundation for the future

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Mabs, rProteins, Vaccines, Cells, Genes
2006
Pharmaceuticals Research & Manufacturing Association (PhRMA) clinical trials summary (2004-2006): Mabs: rProteins: 76 57 20% 160 94 > 50 approvals by
2004
@ success rate: 2012
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Mabs and mammalian cells dominate

(only products / API categories > US $ 1 billion included)
3.920
26.500
30.800
Mabs rProteins Vaccines
51.484
51.900
Mammalian cells Other cells
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Biopharma production challenges

(Production volume and revenue map, 2006 data)
Most rProteins will require annual capacity of 1-10 kg
100.000.000
10.000.000 Pharmacy price value [USD/g, 2006]
ReFacto Kogenate Avonex Advate
1.000.000
100.000
Aranesp Rebif PegaSys Neupogen NovoSeven Neulasta BeneFIX ReoPro Humatrope Humira Pulmozyme
Coagulation factor VIII EPO, Factor IX, VII, interferons l HGH, low dose antibodies n High dose antibodies, fusion proteins Insulins Some Mabs r Plasma proteins
10.000
Herceptin
1.000
100
Most future Mabs will require annual capacity of 100-500 kg
Enbrel Remicade Rituxan/MabThera Xolair Avastin Humalog Huminsulin
Synagis
will require annual capacity of 1-5 tons
10
Insulins 1-5 tons
IVIG, plasma
Plasma proteins 50-500 tons
HSA, plasma
1 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]

Pharmacy list prices 2006, available packages: Arzneimittelkompendium (CH), MediMedia Gelbe Liste Pharmaindex (GER), RxUSA.com Pharmacy (USA) Annual global sales 2006: Annual reports 2006 Plasma products: Marketing Research Bureau 2004
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The challenge is the supply of vaccines

Capacity
2500 2000 million doses 1500 1000 500 0
Time
2004
2006
2010
WHO
Pandemic Planning
There is a huge gap between the expected demand and the current capacity Most countries are looking for in-country domestic solutions WHO is driving local capacity build up
Currently the manufacturing time is ~6-9 months Need of faster supply less than 3 months production time Difficult and time consuming to scale up with old technology
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The vaccine landscape is changing and is moving to new manufacturing methods

Egg-based production technology Cell Culture-based production technology Cell Free production technology
System
Eggs
Mammalian Cells ~6 months New on the market
Insect and Bacterial Cells Recomb Cells ~3 months In 2-4 years time Days? -
Lead Times 6-9 months Maturity On the market
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Many facilities have

Large / modern biopharma facilities
brand new installations and up to 25 year old installations, running with new and old processes.
Genentech, Oceanside, CA
dedicated one-product or multiproduct setups. a degree of mismatch between current bioreactor output and DSP line dimensions chosen at the time of facility design.
Image: Boehringer Ingelheim GmbH
limited flexibility!
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Production setup: 6 fermentors 1 DSP

1-ton/yr scenario
10 kg/batch 126 batches 80% yield
Mab Cell Culture

(6x 2.000 L, 5 g/L)
10-ton/yr scenario
75 kg/batch 168 batches 80% yield - 313 L bed volume - 40 g/L capacity - one cycle
Mab Cell Culture

(6x 15.000 L, 5 g/L)
Cell Removal
Cell Removal
Capture
(1x 120 cm , 30 cm height)
Capture
- 780 L bed volume - 40 g/L capacity - three cycles
Virus Inactivation
Virus Inactivation
- 125 L bed volume - 100 g/L capacity - one cycle
Polishing 1
Polishing 1
Virus Removal
Virus Removal
Polishing 2
Polishing 2
UF/DF Formulation
UF/DF Formulation
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Scale up issues
Quick educational excurse: What happens if technology progress is not anticipated or underestimated?
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Cell culture
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Chromatography
CD= =180cm 80cm CD 120cm 140cm 160cm 100cm

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Emerging production scenarios

More companies will have more than one product in production, many of them small in scale Bioreactor volume
Stainless steel space Lab bench designs used to be a production transfer issue. Now the issue is with stainless steel engineering habits! High product titers fewer batches produce large quantities
Large number of batches cGMP fully dedicated facility favors re-use strategies (500-3.000 kg per product)
(scale: 5 25 000 L)
cGMP multi-product facility (10-500 kg per product) facility cGMP multi-product (10-500 kg per product) cGMP multi-product facility
(10-500 kg per product)
High product titers smaller installations produce large quantities
10000
1000
cGMP clinical manufacturing

Scale limit for many single-use (2-30 kg per product) components: 1000 L
100
How much of GMP production will reach the disposable space? Production scenarios need to consider higher degrees of flexibility
Non-GMP pilot facility

10
(10-500 g per product)
Disposables space
10 100
Batches / product / year

(scale: 1-170 with six-pack of bioreactors) 20 / GE-Jagschies R&D / 2008-04-29
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Reality check
How many products are sharing facility capacity? Products above one metric ton per year may still require one or more dedicated facilities Multiple product facilities will be dominating the future Flexibility in the design is best protection against uncertainty in planning
Genentech manufacturing backgrounder (www.gene.com, 2006)
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A paradigm shift is coming up
Homemade, custom engineering with lack of global standards and no holistic view on economic efficiency (re-inventing of wheels!) Fixed systems with complex piping and automation requirements (likely site specific) Laborious design, commissioning and qualification DQ, IQ, OQ, PQ, etc., (very formal, not very smart) Change-over between campaign too laborious and time consuming (the iron age)
The change
"Got aa few problems going from lab "Got few problems with getting scale to full-scale commercial." enough value out of this facility."
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Ten Commandments
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Use technology platforms Optimize facility utilization Create flexibility in manufacturing Use LEAN tools Address process yield Eliminate batch failures Use advanced selectivities Use most recent technology Minimize buffer related costs Bundle incremental improvements
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LEAN chromatography - summary

Classic step (1st generation tools)
Excessive elution volume &) Excessive equilibration volume &) Excessive process time &)
&)
not optimized
Resin preparation*)
Packing and re-packing*) Run TM ReadyToProcess

Equilibration Load
Inefficient wash step &)
AxiChromTM Faster procedure Less failure

Resin Preparation*)
Wash
Elution
Strip
CIP and storage #)
pre-packed pre-qualified pre-sanitized

Packing and re-packing*) Run
Equilibration Load Wash Elution Strip
Modern resins
Optional: Waste removed Single-use operation
Higher capacity and flow, longer lifetime

CIP and storage #)
Inefficient wash step &) Excessive equilibration volume &)

&)
elution PreDictorTM Excessive plates volume (HTPD) not yet optimized

&)
Value adding work Non-value adding work Required non-value adding work
Fast, tools) Improved step (use of up-to-date low cost optimization (LEAN & SixSigma)
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Influenza vaccine production capacity build up with disposables to save time

Traditional Flu Vaccine Production Facility Commissioning & Validation:
Build Facility Commission Facility Validate Equipment Validate Process
Disposable Insect Cell Culture-Based Flu Vaccine Production:

Build Facility Commission Facility Validate Equipment Validate Process Time Saved
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Saving ~60% in time
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Our vision . . .the future is a modular, selfsupporting, disposable production plant

flexibel planning flexible location minimal capital investment minimal process development minimal distribution and storage local policies/relationships local human capital
Fast deployable production capacity

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Process economy gains overall DSP

Use of modern resins: combined effect of capacity, flow, and lifetime
Cost savings with modern resins up to 70% Process time down to 2 days from 5 days 2-step process: additional indirect gains from space and tankage requirements
37,4
40
Downstream cost contribution [USD/g]
120
35 30 25 20 15 10 5 0
100
Working volume 10,000 L Titer 5 g/L Yield 79%

19,2
80
60
40 11,8 10,9 20
Classic process
(Sepharose Fast Flow resins)
Protein A update
(MabSelect SuRe / Sepharose Fast Flow)
Protein A 3-step model process

(MabSelect SuRe / Capto S/ Capto Q)
Protein A 2-step model process

(MabSelect SuRe / Capto adhere)
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DSP process time [h]
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Process improvements
Can be nothing Can be millions
Low
Low facility utilization Staff is available and has spare time Existing equipment, performance tolerance Hesitant to invest in improvement
Facility utilization
Intense
Intense facility utilization Staff is a scarce resource, tough prioritization Equipment performance on critical path Investment in improvement pays off quickly
Efficiency gains hardly visible at management level
Efficiency gains directly visible at management level
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 be considered fixed. At 5 days batch time up to 70 batches of 25 kg each could be run. One additional batch 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.
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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 a few months require fast deployment of production where the outbreak is.
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Thank you
GE Healthcare Bio-Sciences AB, a General Electric company. GE Healthcare Bio-Sciences AB Bjrkgatan 30 751 84 Uppsala Sweden Capto, MabSelect, and Sepharose are trademarks of GE Healthcare companies. Biacore is a trademark 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 GE Healthcare which supplies them. GE Healthcare reserves the right, subject to any regulatory and contractual approval, if required, to make changes in specifications and features shown herein, or discontinue the product described at any time without notice or obligation. Contact your local GE Healthcare representative for the most current information. 2007 General Electric Company All rights reserved.
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