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Single-Use Manufacturing Technologies
Debbie Cohen Bioprocess Engineer Asia Technical & Applications Sales Bangkok July 2013
2 GE ISPE Bangkok
18JUL2013
Agenda
Unit Operations
Conventional versus Single-Use
Validation
Environmental Impact
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Unit Operations
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The development of disposables for biopharmaceutical manufacture
Media
preparation
Filtration
& filling
Harvest
collection
Cell culture
bioreactor
incl. perfusion
Purification Finishing Bulk
storage
Filling Separation
& filtration
Downstream Upstream
Bioreactors Connectivity Filtration Chromatography
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Single Use Bioreactor Systems
• Ready-to-use reactor chamber
• Full automation control
• Comparability to SST systems
Online measurement
and control
gases
CO2
Air
O2
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Cell culture clarification examples
Using standard off-the-shelf assemblies, trials
can be performed rapidly and in a completely
aseptic, ready-to-use format.
• Custom assemblies
• pre-assembled to exact specifications
• No pre-flushing required.
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Using ReadyToProcess™ crossflow assemblies significantly reduces the
risk of contamination as the process is entirely self-contained, pre-
flushed, and sterile.
Single-use cell culture, cell
concentration and media exchange
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Normal flow filtration applications Reduces non-value adding steps
System preparation
Classic NFF
ReadyToProcess™ NFF
System preparation including autoclaving and CIP
Controlled run
Post-CIP and -
SIP/disposal
Controlled run
Circuit disassembly/disposal
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Hybrid operations
ReadyToProcess™ solutions can be
integrated into existing processes or
combined with traditional filtration
operations when scale is an issue.
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Single-use/Campaign-use chromatography • The ÄKTA™ ready system handles 2 sizes of
disposable, exchangable flow paths (low flow, high
flow)
• No cleaning or cleaning validation needed
• Prepacked, presanitized, prequalified columns
available with a range of BioProcess™ media
• System also operates with other bioprocess
columns
Image shown is an isocratic system.
Gradient system is an option
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6-fold reduction in setup time with Single-use chromatography
2 hour set-up time
instead of 11 hours
Conventional chromatography
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Influenza Harvest Application Influenza vaccine process
Cell culture and infection
Cell culture using microcarriers
Normal flow filtration
Removal of cell debris
Cross flow filtration
Concentration of influenza and
removal of DNA and Host cell
impurities
Chromatography
Bind/elute or flow through mode
removal of DNA and Host cell
impurities
Cross flow filtration
Formulation - concentration and buffer
exchange
Normal flow filtration
Sterile filtration
Harvest
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Influenza Harvest Application Waste time reduction
System preparation
Classic
CFF
ReadyToProcess™ CFF
System preparation including CIP
Controlled run
Post-CIP and -SIP/disposal
Controlled run
Circuit disassembly/disposal
System preparation
Classic NFF
ReadyToProcess™ NFF
System preparation including autoclaving and CIP
Controlled run
Post-CIP and -SIP/disposal
Controlled run
Circuit disassembly/disposal
NFF
CFF
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Removing time-consuming steps with single-use products
provides an opportunity to increase production capacity by 30%.
Poster presented at ASME: 2nd Annual Bioprocess Technology Seminars & Exhibition — Europe
Stockholm, Sweden, 23–25 June, 2008
CMC Biologics, Denmark
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Conventional versus Single-Use
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Single-use systems cannot compromise product quality
”You are responsible for assessing…the effect of any CMC changes on the identity, strength, quality, purity, and potency of the product as they may relate to the safety or efficacy of the product.”
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Establishing product comparability in a single-use process: a case study
Complete MAb process
CHO cell line expressing MAb at 1 g/L
All but one step performed with ReadyToProcess™. Traditional centrifugation is used in step 2
Product quality and purity measured at each step
Time measured for each unit operation
Cell culture
Harvest (centrifugation & filtration)
Capture (MabSelect Sure™)
Virus inactivation
Buffer exchange (UF/DF)
Polishing (Capto™ adhere)
Formulation (UF/DF) & sterile filtration
Final product
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Case study objectives
• Process targets – Monomer yield ≥ 75%
– Aggregate level < 1%
– Host Cell Proteins (HCP) ≤ 10 ppm
– Leached Protein A ligand ≤ 10 ppm
Purification challenge: High aggregate content in feed (9-14%)
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Analytical results versus study objectives
Process objective Traditional
process
ReadyToProcess™
platform
Target
achievemen
t
Monomer yield > 75% 81% 81%
Aggregate <1% 0.6% 0.6%
Host cell protein < 10 ppm 1.0 1.0
Leached protein A < 10
ppm
< LOQ 0.1
All process objectives achieved using
ReadyToProcess platform
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Same process output, substantial reduction in process time Process step ReadyToProcess
™ Traditional
process
Harvest 2 h 2 h
MabSelect SuRe™*
8 h 17 h
Buffer exchange 3.5 h 6 h
Capto™ adhere** 5 h 14 h
Formulation 4.5 h 6.5 h
Total time 23 h 45.5 h * Two cycles including preparations
** One cycle including preparations A 50% reduction in process time
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Validation
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Supplier vs. manufacturer responsibilities • Manufacturer is responsible for product quality
• Suppliers often have the needed knowledge for single-use products
• Manufacturer:
– can contract out testing
– must perform supplier audits and verify Certificates of Analysis
• Manufacturer must have data ready for regulatory review or referenced in Master File (for U.S.)
• Data include manufacturing of single-use products
– Raw materials (sources, quality, duplicate supply)
– Validated process
– In-process testing
– Final product testing
– Stability/shelf-life
– Notification of changes in manufacturing
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Supplier qualification Important considerations
• Quality Management System
• When auditing, determine that consistently reliable disposable products will be delivered batch-to-batch
• Traceability of raw materials should be assessed
• Assess data on removal or absence of any harmful materials used in manufacturing
• If products are sterile, review sterility validation documentation
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Extractables and leachables
EXTRACTABLES: What CAN come out, tested at
exaggerated conditions
LEACHABLES: What WILL come out under actual process
conditions and be present in the drug
Leachable
s
Extractables
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Environmental Impact Life Cycle Assessment Study
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Life Cycle Assessment (LCA)
Assess overall environmental impact
throughout a product’s life cycle: Climate change
Ozone depletion
Human toxicity
Photochemical smog
Particulate matter
Ionising radiation
Terrestrial acidification
Eutrophication
Ecotoxicity
Land occupation
Land transformation
Water depletion
Metal depletion
Fossil fuel depletion
Carbon footprint is
a subset of LCA
• A structured process and methodology
• Various impact assessment methods available
• Software tools and databases available
• ISO 14040-44 guidelines
Multiple
impact
categories
Material
extraction Use
Material
processing
Manufacturing
Waste
management
Recycle
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Comparison: Full Process Train
• Detailed comprehensive LCA
study following ISO* Standards
• 3rd-party critical review panel
• Comparison of complete process
train
• Traditional durable vs. single-use
• Multiple scales: 100L, 500L,
2000L
• Monoclonal antibody production
• 10-batch campaign
• 6 g/L titre
Diagram Courtesy of BioPharm Services, Ltd.
*ISO 14040: Environmental management – Life cycle assessment – Principles and framework ISO 14044: Environmental management – Life cycle assessment – Requirements and guidance
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Key participants
Interpretation
Goal & Scope
Definition
Inventory
Analysis
Impact
Assessment
Classification
Characterization
Weighting
Inputs & Outputs:
Net Energy use, type
of energy used, Net
GHG generated, etc
Potential
environmental impact::
•resource depletion
•global warming
•land use
•eutrophication
•acidification
• etc
Interpretation
Goal & Scope
Definition
Inventory
Analysis
Impact
Assessment
Classification
Characterization
Weighting
Inputs & Outputs:
Net Energy use, type
of energy used, Net
GHG generated, etc
Potential
environmental impact::
•resource depletion
•global warming
•land use
•eutrophication
•acidification
• etc
Using Biopharm’s
proprietary software:
LCA modeling
3rd-party review
Data generation
Sponsorship
ecoassessment center of excellence
GE Global Research
GE Healthcare
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Goals of this study
Estimate shifts in environmental impacts when transitioning from
traditional durable to single-use process technology 1
2 Elucidate any shift that occurs in distribution of environmental burden
between the distributor and consumer of biopharmaceutical
components
3 Identify product or process stages that contribute the most to
environmental burden
4 Explore opportunities for “greening” disposables through product design,
implementation, and waste management
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Process Train for Production of mAbs
1 N-2 Seed 2 N-1 Seed 3 Bioreactor 4 Depth Filtration Clarification 5 Bioburden Reduction I 6 Protein A 7 Virus Inactivation 8 Bioburden Reduction II 9 No Tank Bioburden Reduction 10 Capture IEX 11 Flow Through IEX 12 Viral Filtration 13 UF/DF 14 Sterile Filtration II Support CIP/SIP System
KEY
Vent Filter
Cell Growth
Media Prep Cell Growth
Media Sterilization
Cell Culture
Air Filtration
Clarification
Blending /
Storage
NFF
Pleated
Capture Virus
Inactivation
pH
Adjustment
Clarification
Pool Mixing
Sterile
Filtration
Blending /
Storage
Removal Polishing
Blending /
Storage
Virus Filtration
Diafiltration /
Concentration Sterile
Filtration
Storage
Product
Fill Storage
Adjustment /
Holding
3
14 13
12 11 10
9 8 7 6
5
4
2
1
N-1 Seed N-2 Seed
Support CIP/SIP System
(not shown)
Diagram Courtesy of BioPharm Services, Ltd.
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Cumulative Energy Demand and Global Warming Potential
WFI, process water, and steam drive greenhouse gas emissions
and cumulative energy demand
Supply Chain Use Phase End of Life Supply Chain Use Phase End of Life
2000L scale
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Cumulative Energy Demand and Global Warming Potential
38-40% of CED and GWP impacts are
related to Support CIP/SIP System
2000L scale
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Water Usage
Use Phase water savings due to reduction or elimination of cleaning
and sterilization between batches
2000L scale
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Water Usage
Water usage dominated by Support CIP/SIP System
2000L scale
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Environmental impact assessment
Midpoint impact category Unit
Climate change kg CO2 eq
Ozone depletion kg CFC-11 eq
Human toxicity kg 1,4-DB eq
Photochemical oxidant formation kg NMVOC
Particulate matter formation kg PM10 eq
Ionising radiation kg U235 eq
Terrestrial acidification kg SO2 eq
Freshwater eutrophication kg P eq
Marine eutrophication kg N eq
Terrestrial ecotoxicity kg 1,4-DB eq
Freshwater ecotoxicity kg 1,4-DB eq
Marine ecotoxicity kg 1,4-DB eq
Agricultural land occupation m2a
Urban land occupation m2a
Natural land transformation m2
Water depletion m3
Metal depletion kg Fe eq
Fossil depletion kg oil eq
ReCiPe Midpoint (H) V1.04 / World ReCiPe H
Single Use approach exhibits lower environmental impact
in all 18 categories studied
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End of Life Comparison: 2000L Scale
Conservative Assumptions Considered All single use components are incinerated Not Considered Waste heat recovery
Fossil depletion
Metals depletion
Climate change
Human toxicity
Particulate matter
Climate change
Ag land occupation
Urban land occupation
Land transformation
impact benefit
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Key takeaways
More and more single use technology is transitioning into the industry
It is important to objectively understand the environmental burden shifts associated with these technology transitions
Environmental LCA methodology provides detailed insight about the net environmental performance of complex product systems
1
2
3
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Key takeaways
Single Use technology exhibits lower environmental impact across the full life cycle reduction of WFI, process water, steam
less requirement for CIP/SIP
Single Use technology does show larger environmental burdens at end of life, but these impacts are minor relative to use phase energy and water savings
4
5
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Thank you
WAVE Bioreactor is a trademark of GE Healthcare companies. GE, imagination at work, and GE monogram are trademarks of
General Electric Company.
© 2012 General Electric Company – All rights reserved.
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.
GE Healthcare Bio-Sciences AB, a General Electric Company.
www.gelifesciences.com/bioprocess
GE Healthcare Bio-Sciences AB
Björkgatan 30
751 84 Uppsala
Sweden