economic impact of single-use bioreactors. - bptc · 2012 bio international convention bioprocess...

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


Single Use Bioreactors

XcellerexXDRTM Bioreactor

Sartorius StedimBiostat® Culti-bag

Thermo Fisher (Hyclone)Single-use Bioreactor

ATMINucleoTM Bioreactor

GE HealthcareWave Bioreactor


Stainless Steel vs. Single-use Bioreactors


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


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


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%


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%



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




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%


Process Case #2B 10,000L Case, 5 g/L, Single ProductTraditional SS Single-Use % Difference



COGS ($/g) $97 $88 -9%



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




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%


COGS ($/g) $229 $183 -20%


Process Case #3B 10,000L Case, 5 g/L, Multi-ProductTraditional SS Single-Use % Difference



COGS ($/g) $107 $89 -17%


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


Thank You!

BioProcess Technology Consultants, Inc.12 Gill Street, Suite 5450Woburn, MA 01801

508-344-2810

[email protected]

Rick Stock

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economic impact of single-use bioreactors. - bptc · 2012 bio international convention bioprocess...

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