Single-Use Manufacturing Technologies - ISPE Th · Single-Use Manufacturing ... Bioreactors Connectivity Filtration Chromatography . 5 ReadyToRock Tour 2012 29/07/2013 Single Use

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

3 ReadyToRock Tour 2012

29/07/2013

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


System preparation

Classic NFF

ReadyToProcess™ NFF

System preparation including autoclaving and CIP

Controlled run

Post-CIP and -SIP/disposal

Controlled run


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

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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.

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www.gelifesciences.com/bioprocess

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Documents

Single-Use Manufacturing Technologies - ISPE Th · Single-Use Manufacturing ... Bioreactors Connectivity Filtration Chromatography . 5 ReadyToRock Tour 2012 29/07/2013 Single Use