Single-Use Manufacturing Technologies - ISPE Th · Single-Use Manufacturing ... Bioreactors...

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

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Unit Operations

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The development of disposables for biopharmaceutical manufacture

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

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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

• 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

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

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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

Monomer yield > 75% 81% 81%

Aggregate <1% 0.6% 0.6%

Host cell protein < 10 ppm 1.0 1.0

Leached protein A < 10

< 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

Extractables

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Environmental Impact Life Cycle Assessment Study

29/07/2013

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

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