BioProcess Technology Consultantswww.bptc.com
Rick Stock2012 BIO International ConventionBioProcess Theater PresentationUpstream ProcessingBoston, MAJune 19th, 2012
Economic Impact of Single-Use Bioreactors
Current Facility Designs
Large hard-piped, stainless steel based facilities with stainless steel bioreactors
Very expensive to build and validate Construction costs ≥$300 Million Construction timelines 2-5 years or more
Controlled environment, highly classified suites Tightly controlled flow of people, materials, and
equipment Huge utilities for WFI, HVAC, clean steam, CIP Extensive piping, transfer panels, complex operations
From Clone to Commercial®Photos courtesy of Lonza Biologics
Today’s Biopharmaceutical Facility
Most facilities today were built for low titer (<1 g/L) processes Multiple 20,000 L bioreactors each with inoculum
bioreactors up to 4,000 L
Photos courtesy of Lonza Biologics
Current facilities struggle to match downstream capacity with bioreactor output due to large process volumes Technologies that enable higher bioreactor titers
will exasperate the DSP bottleneck
From Clone to Commercial®
1978 Recombinant insulin produced
2015-2020
Industry Standard:
1-3 g/L2010
Industry Leaders:3-8 g/L
Future Leaders:>10 g/L
Improved strains
Innovation has Increased Titers and Yields
From Clone to Commercial®Ref: T. Charlebois, BIOMAN 2006 Conference, (2006); M. Smith, BPI
Europe Conference (2005); F. Wurm, Nature Biotechnology, (2004)
Commercial products have expressionlevels in the range of 0.2 – 3.0 g/L with thehighest titers seen for monoclonal antibody products
New technologies to improve cell line development and expression levels coupled with improved and optimized media, supplements, and bioreactor conditions have increased titers
A Brief History of Single-Use Bioreactors
1970sUse of flasks,pipettes, filters,blood bags
1980sBags formedia,harvest,buffer prep
1996Introduction ofWaveBioreactor
2004First 250 Ldisposablebioreactor
2009First 2,000 Ldisposablebioreactor
From Clone to Commercial®
Single Use Bioreactors
XcellerexXDRTM Bioreactor
Sartorius StedimBiostat® Culti-bag
Thermo Fisher (Hyclone)Single-use Bioreactor
ATMINucleoTM Bioreactor
GE HealthcareWave Bioreactor
From Clone to Commercial®
Stainless Steel vs. Single-use Bioreactors
From Clone to Commercial®
0
25
50
75
100
Acidic Isoforms Main Peak
(%)
1000L SUB BR 100L SS BR 3L BR
0
25
50
75
100
Monomer Total Agg
Agg
rega
te (%
)
1000L SUB BR 100L SS BR 3L BR
Comparable cell growth and productivity Product yield and quality similar in both systems
Ref: Noe, W, Antibody Development and Production (2011)
Environmental Impact of DisposablesEnergy Consumption Water Usage
Reduced water usage of up to 183,000 L/batch at 1,000 L scale Compared to cleanable stainless steel systems, single use systems use:
• 8 – 20X less water and cleaning chemicals• Approximately 50% less energy consumption
Ref: Sinclair A, et al. BioPharm Int. (2008), Rawlings B, Pora H. BioProcess Int. (2009), Noe, W, Antibody Development and Production (2011) From Clone to Commercial®
Driving Forces for Single-Use Technologies Improved return on capital
• Reduced and deferred capital investment• Increased speed of deployment• Cost structure shifted to variable costs (reduction in capital equipment costs)
Greater flexibility to match bioreactor size with titers and needs• Reduced process equipment complexity• Process and product flexibility• Improved process control and portability
Reduced facility complexity and cost• Faster construction, commissioning, and launch• No change-over cleaning/validation between strains/products• Significant reduction in facility/equipment validation
From Clone to Commercial®
Modeled Monoclonal Antibody Process
10 From Clone to Clinic®
Seed 1
Seed 2
Seed 3
Production
Centrifugation
Depth Filtration
UF/DF 1
Protein A
Viral Inactivation
Cation Exchange
Anion Exchange
Viral Filtration
UF/DF 2
Final Filtration
Fill/Finish
Process Case #1 – Monoclonal Antibody Production Designed for monoclonal antibody product with expression levels
of 2 g/L and 5g/L with a 66% overall purification yield (filled vial) 2,000L Scale Disposables used for media & buffer prep and product holds (<2,000L) Single product facility Single reactor Single purification line Batch duration: ~8 weeks including change over times
• ~4 weeks inoculum train (3 seed steps)• ~2 weeks bioreactor (bottle neck)• ~1 week purification• ~0.5 week final purification and bulk filling
150 mg dose (liquid fill) in a 25 mL vial
From Clone to Commercial®
Process Case #1A 2,000L Case, 2 g/LTraditional SS Single-Use % Difference
# of Batches/year 19 23 +21%Throughput (kg/year) 50 60 +21%Total Capital 39.0 36.7 -6%Total Annual Costs $20,670,000 $20,800,000 +1%
Capital Charge $6,460,000 $6,080,000 -6%Materials $740,000 $870,000 +18%Consumables $2,470,000 $3,510,000 +42%Labor (Direct/Indirect) $9,090,000 $8,560,000 -6%Maintenance/Utilities $1,930,000 $1,810,000 -6%
COGS ($/g) $414 $344 -17%
12 From Clone to Clinic®
Process Case #1B 2,000L Case, 5 g/LTraditional SS Single-Use % Difference
# of Batches/year 19 23 +21%Throughput (kg/year) 125 151 +21%Total Capital 49.1 46.6 -5%Total Annual Costs $25,140,000 $25,690,000 +2%
Capital Charge $8,130,000 $7,730,000 -5%Materials $820,000 $970,000 +18%Consumables $4,230,000 $5,590,000 +32%Labor (Direct/Indirect) $9,550,000 $9,100,000 -5%Maintenance/Utilities $2,440,000 $2,320,000 -5%
COGS ($/g) $201 $170 -16%
13 From Clone to Clinic®
Process Case #2 – Monoclonal Antibody Production Designed for monoclonal antibody product with expression levels
of 2 g/L and 5g/L with a 66% overall purification yield (filled vial) 10,000L Scale: 5 x 2000L Disposable vs 2 x 5,000L Traditional SS Disposables used for media & buffer prep and product holds (<2,000L) Single product facility Single purification line Pool 2 of the disposable runs Batch duration: ~8 weeks including change over times
• ~4 weeks inoculum train (3 seed steps)• ~2 weeks bioreactor (bottle neck)• ~1 week purification• ~0.5 week final purification and bulk filling
150 mg dose (liquid fill) in a 25 mL vial
From Clone to Commercial®
Process Case #2A 10,000L Case, 2 g/L, Single ProductTraditional SS Single-Use % Difference
# Equiv. of Batches/year 20 24 +20%Throughput (kg/year) 256 305 +19%Total Capital 103.1 80.2 -22%Total Annual Costs $53,150,000 $55,690,000 +5%
Capital Charge $17,080,000 $13,290,000 -22%Materials $2,780,000 $3,380,000 +22%Consumables $8,470,000 $12,350,000 +46%Labor (Direct/Indirect) $19,660,000 $22,640,000 +15%Maintenance/Utilities $5,190,000 $4,060,000 -22%
COGS ($/g) $207 $183 -12%
15 From Clone to Clinic®
Process Case #2B 10,000L Case, 5 g/L, Single ProductTraditional SS Single-Use % Difference
# Equiv. of Batches/year 20 24 +20%Throughput (kg/year) 641 762 +19%Total Capital 114.5 86.9 -24%Total Annual Costs $62,280,000 $67,310,000 +8%
Capital Charge $18,970,000 $14,400,000 -24%Materials $3,040,000 $3,760,000 +24%Consumables $12,010,000 $18,470,000 +54%Labor (Direct/Indirect) $22,470,000 $26,200,000 +17%Maintenance/Utilities $5,820,000 $4,500,000 -23%
COGS ($/g) $97 $88 -9%
16 From Clone to Clinic®
Process Case #3 – Monoclonal Antibody Production Designed for monoclonal antibody product with expression levels
of 2 g/L and 5g/L with a 66% overall purification yield (filled vial) 10,000L Scale: 5 x 2000L Disposable vs 2 x 5,000L Traditional SS Disposables used for media & buffer prep and product holds (<2,000L) Multi-product product facility, 4 products/year, 2 campaigns each Two purification lines Batch duration: ~8 weeks including change over times
• ~4 weeks inoculum train (3 seed steps)• ~2 weeks bioreactor (bottle neck)• ~1 week purification• ~0.5 week final purification and bulk filling
150 mg dose (liquid fill) in a 25 mL vial
From Clone to Commercial®
Process Case #3A 10,000L Case, 2 g/L, Multi-ProductTraditional SS Single-Use % Difference
# Equiv. of Batches/year 15 22 +60%Throughput (kg/year) 204 294 +44%Total Capital ($M) $103.1 $80.2 -22%Total Annual Costs $46,680,000 $53,050,000 +16%
Capital Charge $17,080,000 $13,290,000 -22%Materials $2,180,000 $3,220,000 +48%Consumables $6,660,000 $11,750,000 +76%Labor (Direct/Indirect) $15,640,000 $21,650,000 +38%Maintenance/Utilities $5,150,000 $4,050,000 -21%
COGS ($/g) $229 $183 -20%
18 From Clone to Clinic®
Process Case #3B 10,000L Case, 5 g/L, Multi-ProductTraditional SS Single-Use % Difference
# Equiv. of Batches/year 15 22 +49%Throughput (kg/year) 509 736 +28%Total Capital 114.5 86.9 -24%Total Annual Costs $54,270,000 $65,140,000 +20%
Capital Charge $18,970,000 $14,400,000 -24%Materials $2,390,000 $3,580,000 +50%Consumables $9,430,000 $17,580,000 +86%Labor (Direct/Indirect) $17,740,000 $25,120,000 +42%Maintenance/Utilities $5,760,000 $4,490,000 -22%
COGS ($/g) $107 $89 -17%
19 From Clone to Clinic®
Summary/Conclusions Greatest impact is on efficiency and flexibility Allows for greater throughput (more batches) which lowers cost of goods Single-use bioreactors can have higher operating costs on a yearly basis Higher operating costs are due to increase in batch capacity (consumables, labor,
materials) Higher operating costs are somewhat balanced by lower capital and
maintenance/utilities costs
20 From Clone to Clinic®
Thank You!
BioProcess Technology Consultants, Inc.12 Gill Street, Suite 5450Woburn, MA 01801
508-344-2810
Rick Stock
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