crelier dsp trends

832019 Crelier DSP Trends

httpslidepdfcomreaderfullcrelier-dsp-trends 148

Institut Life Technologies

Trends and trend setters in DownstreamProcessing

Simon Crelier

Life Technologies Institute

HES-SO Valais Wallis

CH-1950 Sion

5th International Summer Schoolon Advanced BiotechnologyAug 31 ndash Sep 4 2010Sta Margherita di Belice Sicily (I)

copy Fraunhofer ITEM 2010

copy Pall Life Sciences 2010




03092010 Trends and trend setters in DSP 2

Presentation outline

DSP past and present

Downstream bottleneck hype or reality

Trends

Is PAT (part of) the solution

Conclusion

A message from the tourist office

copy Glycotope Biotechnology 2010

Based in part on the following review article

Future of antibody purificationD Low et al J Chromatogr B 848 (2007) 48-63




18092008 Downstream processing for biotechnology 3

(itrsquos a long way) from DNA to product

New therapeutic

approach

Identification of gene Cloning of gene

transfection

Isolation of producing clones

Medium optimisationfermentation conditions

Scale-up process development

Commercial product

DSP




Downstream processing in short


PRODUCT HAS TO BE

Pure

ActiveSafe

Well-formulatedStable

SHOULD BE

Short

Efficientlaquo Gentle raquoCheap

STARTING MATERIAL

bull Complex heterogenous mixtures

bull Mostly aqueous

bull Low product concentrations

bull Large volumes to be handled

bull Molecules are sensitivelabile

bull High risk of contamination

Really




5

Common pathways for the isolation of products

FermentorLS

Separation

CellsBiomass

Supernatant Isolation

Isolation

Cell Disruption

Purification

PurificationExtracellular

Products

IntracellularProducts

Products

Cell debrisLS

Separation

03092010 Trends and trend setters in DSP





Capture

Purification

Polishing

Stage

Purity

Physical methods

SedimentationCentrifugation

FiltrationMicrofiltrationUltrafiltrationNanofiltration

Reverse osmosisElectrodialysis

Thermal methods

ExtractionATPS

PrecipitationAdsorptionChromatography

(IEX SEC ACHIC)

CrystallizationRefolding

A few basic considerations

Resolution

Capacity

Yield

Speed

Technical characteristicsof DSP unit operations

0

20

40

60

80

100

0 1 2 3 4 5 6 7

Nombre deacutetapes

R e n d e m e n t g l o b a l [ ]

Y=09

Y=08

Y=07

Y=06

Wanted few steps withhigh recovery yields




7

White biotech red biotech from low- to high-tech

Citric acid

Lactic acid

Antibiotics

Biopolymers

Ethanol biofuels

Industrial enzymes

Purification involves a large rangeof laquo standard raquo unit operationssuch as precipitation LL extrac-tion high pressure homogenization

Recombinant proteins

Monoclonal antibodies

Hormones

DSP using techniques more speci-fic to biotechnology membranefiltration affinity chromatography





8

Textbook DSP Cellmedium separation

Sedimentation

Filtration

Centrifugation

Cell lysis

Bead mill

HP homogenizer

Ultrasound

LL Extraction

Precipitation

Adsorption

Chromatography

Membrane filtration

etc hellip

Centrifugation

Micro- amp Ultrafiltration

Chromatography

DSP in the biopharma

Are we teaching the rightthings

Do we place our focus onthe correct topic(s)

An obsolete view of DSP





9

White biotech Citric acid production (gt 106 tonsyear)


Fermentedliquor

Calcium citrateprecipitation

Filtration andwashing

Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal

Decolourizingtreatment

Active carbonFiltration

ConcentrationCrystallizationCentrifugation

Mother liquor recycling

PackingSievingDrying




10

Production of a monoclonal antibody (a few tonsyear)

copy Pall Corporation 2007





11


J L DwyerBioTechnology 2 (11) pp 957 [1984]

5 gl1 gl

H W Blanch D S ClarkBiochemical Engineering Dekker 1997

Hepatitis BVaccine (1986)

Tissue PlasminogenActivator (1987)

Human GrowthHormone (1985)





12

Ainrsquot there a cure to the

downstream bottleneck blues

Dave Arcari





13

laquo DSP bottleneck raquo hellip Is it really there (Part I)


A reflectiondebate has been started on the ability of existing DSP technologies to keep up with theincreasing performance of biopharmaceutical processes




14

laquo DSP bottleneck raquo hellip Is it really there (Part II)

According to some theproblem is mostly one ofproper capacityestimation at the

development stage

However practicalconsiderations tend toshow that it is not thatsimple

Everyone agrees on onepoint improvements areneeded and alwayswelcome





Capacity of Protein A resins used to be sufficient


R L Fahrner et al Biotechnol Appl Biochem (1993) 30 121 ndash128

Load material was a cell culture mediumwith cells and cell debris removed bytangential flow filtration

It contained a recombinant humanizedmonoclonal antibody (IgG1) produced in

CHO cells at levels of ca 035 [gl]




16

The big picture has a name productivity

How to increase Productivity

Increase product titre

Upstream

Reduce run time Upstream

Downstream

Reduce down time

Fermentation Downstream

Increase recovery yield

Downstream

The search is more than everon for quick efficient androbust DSP unit operations ofhigh capacity

YDR

365CP

tt

odPr

P Productivity [g(lyear)]Cprod Product conc [gl]Rt Run time [d]Dt Down time [d]Y Recovery yield [-]





17

Single use bioreactors have paved the way

Suppliers Applikon GE Healthcare Kuumlhner MilliporeStedim Wave (and more)

Simple preparation sterile connections no CIP

Reduction of fermentation down time

10-100 L

100-500 L

BIOSTAT reg Cultibag RM

1000 Xcellerex





Single use filtration for clarification and virus removal


Mobius FlexReady for depth filtration

Mobius FlexReady for tangential flow filtration

I i




19

Chromatography of macromolecules the C-term rules

Macromolecules (proteins polymers

antibodiesDNA polysaccharides)

Small molecules (antibiotics peptidesamino acids hormones sugars)

s

s

uCu

BAH

In the van Deemter equation the C-termis directly related to the mass transferfrom the liquid to the solid phase

Improved mass transfer leads to higher

performance of the column in terms ofcapacity and resolution


I tit t




20

CIM product range

(BIA Separations)

Pall Mustangreg range

(Pall)Sartobindreg product range

(Sartorius Stedim)

Improved mass transfer dynamic binding capacity


Monoliths and membranesoffer chromatographicmedia with greatly improvedmass transfer characteris-

tics due to very low contri-bution of diffusion

I tit t




21

Monoliths Sponge Bob goes chromatographic


These matrices were introduced in 1990Theyare synthesized fom glycidyl methacrylate(GMA) and ethylene dimetha-crylate (EDMA)in the presence of porogens and an initiatorFunctional groups are then grafted on thesolid surface-

Separation of myoglobin (1) conalbumin (2) and soybean

trypsin inhibitor (3) at six different flow rates (40 80 120

160 200 and 240 mlmin

Applications separation of peptides proteinsoligonucleotides pDNA RNA and viruses Alsoused as catalytic bed for enzyme reactors

I tit t




Two other types of monoliths hellip

Silica gel based monoliths (Merck ldquoChromolithrdquo)

Polyacrylamide-based monolithic beds (Bio-Rad ldquoUnordquo)


Mostly used for analyticaland small-scale preparativeapplications

Chromatogram at 1st and

96th

injection

Mostly used for analyticaland small-scale preparativeapplications (up to 200 mgprotein)

I tit t




23

Membrane chromatography

Most usual chromatography laquo chemistries raquo (ion exchangeaffinity etc hellip) can be grafted on membranes which then playthe role of stationary phases

These modules are then used like a chromatographic column

They can be sanitized for multiple applications


Institut




Membrane chromatography most salliant features


Dynamic binding capactiy (DBC) is maintained over alarge range of flowrates

DBC and chromatogram are not much affected bymodule size (simplified scale-up)

Institut




25

For lab-scale evaluation Wedgereg radial

column from Sepragen Corporation

03092010 Trends and trend setters in DSPSepragen Superfloreg RFC Column

Improve mass transfer and productivity radial flowchromatography (RFC)

Principle of radial flow chromatography

Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d

Worth mentioning standardchromatography resins canbe used in the RFC columns

Institut




Proxcys CRIO-MD annular chromatography


Wedge-shaped column for small-scale developments

In situ capture of target molecule from broth

Institut





Shorter processing time Expanded Bed Adsorption

00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]

Fluid velocity [cmh]

Streamline

Amberlite IRA 410

Institut




HGMF (12) chromatography without column


HGMF High Gradient Magnetic Fishing

copy K E Ottow DTU PhD thesis 2009

The same chemistry as the one used for laquo classical raquochromatography resins can be applied to the magnetic particles

Institut





HGMF (22) design of a separation system


Implementation is simpleTechnology is easy to scale-upParticles can be very small efficient mass transfer

no pressure drop (no packed bed)

Institut




Make chromatography continuous (12) SMB(+)


BioSMBreg

SMB unit for the separation of a mixture into

three fractions (M Mazzottirsquos group ETHZ)

(+) Simulated Moving Bed chromatography

SMB installation connection diagram

SMB is not a new development

Despite a complex design it has found numerous applications in theoil industry sugar refining antibiotics purification racemateseparations etc hellip

Although best suited for two-component separations it hasinteresting potential for more complex mixtures such asencountered in biotechnological applications

Institut




In case you had a doubt on SMBrsquos up-scaleability hellip


Novasep Sequential Simulated Moving BedChromatography Applexion SSMB

Outotec SepTor SMB installationfor the purification of APIs

Institut




Make chromatography continuous (22) CAC(X)


(X) Continuous Annular Chromatography

Chromatography is by nature adiscontinuous process

Continous Annular Chromatography(CAC) offers the possibility ofcontinuously feeding the columnwith a mixture at a fixed point

The solutes migrate and separatewhile the solid phase rotates Thedifferent analytes will then exit thecolumn at a point that can bedetermined from their retention time

and the column rotation speed

Prior Engineering is one of the onlysuppliers for such systems

Institut




33

Integrated bioprocesses fermentation and DSP combined

in situ product recovery (ISPR)

D Stark et al Biotechnology and Bioengineering 83 (4) 376-385 (2003)

A toxic or inhibitory product isextracted into liquid-core microca-psules already during the produc-tion phase thereby improvingbiomass viability and increasingproductivity


Institut




One more example hellip


T Kaumlppler et al Biotechno0logy amp Bioengineering 102 (2) 535-545 2009

Institut




Radial chromatography with a twist for ISPR


Axcis columns combine 3 unit operations in one

bull Centrifugal forcesbull Microfiltrationbull Adsorptive chromatography

The mixture is then clarified and the targetmolecule concentrated and purified in one single

ldquochromatographicrdquo step

Further the Axcis columns are compatible with allstandard packed bed process-chromatographyresins

Institut




Process Analytical Technology applied to DSP

The PAT guidelines proposed by the FDA aim at a bettercontrol and understanding of biotechnology processes

In the case of DSP this can be achieved by on-line

monitoring of target substances and main contaminants Shorter analytical response times can certainly help

improve the productivity of purification trains be it onlyby a reduction of down times

Some examples have been found in the literature thatillustrate the above considerations drying of APIs real-time monitoring of crystallization breakthrough of targetmolecule out of a Protein A adsorption step


Institut




Spectroscopic monitoring of crystallization


Cornel J Lindenberg C Mazzotti M Ind Eng Chem Res 47 4870-4882 2008Cornel J Lindenberg C Mazzotti M Cryst Growth Des 9 (1) 243-252 2009

ATR-FTIR = Attenuated Total Reflectance Fourier Transform InfraRedFBRM = Focused Beam Reflectance Measurements Raman

Using such techniques as

ATR-FTIT and FBRM coupledwith chemometric datatreatment the onset of thecrystallization process as wellas the composition of thesolid and liquid phases can be

monitored in real-time

Institut



st tutLife Technologies

The ABC(1) approach The revenge of neglectedtechnologies


(1) Anything But Chromatography

Institut



Life Technologies

39

Protein extraction aqueous two-phase systems

GB Ferreira et al Braz Arch Biol

Technol 50 (3) 557-564 (2007)


bull Aqueous two-phase systems (ATPS) offer gentle conditions for the extraction of proteins

bull Their components are not expensive mass transfer is very rapid and scaling-up is easy

bull The partition of the molecule can be influenced by type of ATPS pH ionic strength hellip

bull Affinity ligands can be grafted on the ATPS constituents to improve selectivity and yields

Figure 2 - Response surface showing the influence ofpH and tie line length (TL) on part coefficient K

Institut



Life Technologies

Smart polymers and affinity precipitation

Precipitation is simple low-cost and easily scalable

Many precipitating agents are known and characterized

Precipitation selectivity is usually low but can beimproved by grafting affinity ligands on polymers

Smart (responsive) polymers undergo precipitation uponslight modifications of temperature or pH

Applications include biocatalysis isolation of proteins hellip


Institut



Life Technologies

Conclusion and outlook

DSP has to catch up with the dramatic increase inproductivity of modern biopharmaceutical processes

A lot can certainly be done by following a PAT approach toDSP (shorter response times optimal use of capacity)

Use of disposable separation components can probablyhelp reduce cycle time

New techniques such as improved stationary phasesmonolith amp membrane chromatography have potential

Revamping of neglected low-costhigh capacitytechniques such as precipitation look promising

The industry is very conservative and evolution is slow butunavoidable


Institut Lif T h l i



Life Technologies


grazie per la vostra attenzione




Life Technologies





Life Technologies

44

University of Applied Sciences Western Switzerland - Valais


Systems Engineering Life Technologies

Analytical chemistryFood technologyBiotechnology

InfotronicsPower amp Control

Materials amp Design

SierreEconomics amp Services

SionEngineering Sciences





Life Technologies

45

Chemistry Food Technology and Biotechnology22 years of co-existence under one single roof


httpwwwhevsch

httpitvhevsch




Life Technologies

46

Biotech at the HES-SO Valais (and in many other places)

Genetic engineering

Activity screening

from DNA to products

Downstreamprocessing

Bioprocessing

Enzymatic catalysis

Chemical amp Bioanalytics





Life Technologies

Meet the biotech crew

Dr Sergio Schmid head of biotech unit molecular biology Dr Kurt Eyer professor bioprocessing

Dr Fabian Fischer professor enzymatic catalysis

Dr Marc Pfeifer professor bioanalytics and diagnostics

Dr Simon Crelier professor downstream processing Dr Isabelle Krasniewski bioprocessing

Dr Sarah Wegmuumlller molecular biology

Christel Forreacute Ing HES molecular biology biochemistry

Julien Pott Ing HES bioprocessing downstream processing

Anne Walker dipl Natw ETH molecular biology cell culture

Gordana Pistoletti technician molecular biology up- amp downstream

Remy Dufresne Ing HES downstream processing

+ research assistants BScMSc students visiting students





Life Technologies

So if you want to reach new (academic) heights hellip





Presentation outline

DSP past and present

Downstream bottleneck hype or reality

Trends

Is PAT (part of) the solution

Conclusion

A message from the tourist office

copy Glycotope Biotechnology 2010

Based in part on the following review article

Future of antibody purificationD Low et al J Chromatogr B 848 (2007) 48-63






New therapeutic

approach


transfection




Commercial product

DSP






PRODUCT HAS TO BE

Pure

ActiveSafe


SHOULD BE

Short


STARTING MATERIAL


bull Mostly aqueous





Really




5


FermentorLS

Separation

CellsBiomass


Isolation

Cell Disruption

Purification


Products


Products

Cell debrisLS

Separation






Capture

Purification

Polishing

Stage

Purity

Physical methods




Thermal methods

ExtractionATPS


(IEX SEC ACHIC)



Resolution

Capacity

Yield

Speed


0

20

40

60

80

100

0 1 2 3 4 5 6 7

Nombre deacutetapes


Y=09

Y=08

Y=07

Y=06





7


Citric acid

Lactic acid

Antibiotics

Biopolymers

Ethanol biofuels

Industrial enzymes




Hormones






8


Sedimentation

Filtration

Centrifugation

Cell lysis

Bead mill

HP homogenizer

Ultrasound

LL Extraction

Precipitation

Adsorption

Chromatography

Membrane filtration

etc hellip

Centrifugation


Chromatography









9



Fermentedliquor



Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal









10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies







New therapeutic

approach


transfection




Commercial product

DSP






PRODUCT HAS TO BE

Pure

ActiveSafe


SHOULD BE

Short


STARTING MATERIAL


bull Mostly aqueous





Really




5


FermentorLS

Separation

CellsBiomass


Isolation

Cell Disruption

Purification


Products


Products

Cell debrisLS

Separation






Capture

Purification

Polishing

Stage

Purity

Physical methods




Thermal methods

ExtractionATPS


(IEX SEC ACHIC)



Resolution

Capacity

Yield

Speed


0

20

40

60

80

100

0 1 2 3 4 5 6 7

Nombre deacutetapes


Y=09

Y=08

Y=07

Y=06





7


Citric acid

Lactic acid

Antibiotics

Biopolymers

Ethanol biofuels

Industrial enzymes




Hormones






8


Sedimentation

Filtration

Centrifugation

Cell lysis

Bead mill

HP homogenizer

Ultrasound

LL Extraction

Precipitation

Adsorption

Chromatography

Membrane filtration

etc hellip

Centrifugation


Chromatography









9



Fermentedliquor



Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal









10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies







PRODUCT HAS TO BE

Pure

ActiveSafe


SHOULD BE

Short


STARTING MATERIAL


bull Mostly aqueous





Really




5


FermentorLS

Separation

CellsBiomass


Isolation

Cell Disruption

Purification


Products


Products

Cell debrisLS

Separation






Capture

Purification

Polishing

Stage

Purity

Physical methods




Thermal methods

ExtractionATPS


(IEX SEC ACHIC)



Resolution

Capacity

Yield

Speed


0

20

40

60

80

100

0 1 2 3 4 5 6 7

Nombre deacutetapes


Y=09

Y=08

Y=07

Y=06





7


Citric acid

Lactic acid

Antibiotics

Biopolymers

Ethanol biofuels

Industrial enzymes




Hormones






8


Sedimentation

Filtration

Centrifugation

Cell lysis

Bead mill

HP homogenizer

Ultrasound

LL Extraction

Precipitation

Adsorption

Chromatography

Membrane filtration

etc hellip

Centrifugation


Chromatography









9



Fermentedliquor



Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal









10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





5


FermentorLS

Separation

CellsBiomass


Isolation

Cell Disruption

Purification


Products


Products

Cell debrisLS

Separation






Capture

Purification

Polishing

Stage

Purity

Physical methods




Thermal methods

ExtractionATPS


(IEX SEC ACHIC)



Resolution

Capacity

Yield

Speed


0

20

40

60

80

100

0 1 2 3 4 5 6 7

Nombre deacutetapes


Y=09

Y=08

Y=07

Y=06





7


Citric acid

Lactic acid

Antibiotics

Biopolymers

Ethanol biofuels

Industrial enzymes




Hormones






8


Sedimentation

Filtration

Centrifugation

Cell lysis

Bead mill

HP homogenizer

Ultrasound

LL Extraction

Precipitation

Adsorption

Chromatography

Membrane filtration

etc hellip

Centrifugation


Chromatography









9



Fermentedliquor



Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal









10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies






Capture

Purification

Polishing

Stage

Purity

Physical methods




Thermal methods

ExtractionATPS


(IEX SEC ACHIC)



Resolution

Capacity

Yield

Speed


0

20

40

60

80

100

0 1 2 3 4 5 6 7

Nombre deacutetapes


Y=09

Y=08

Y=07

Y=06





7


Citric acid

Lactic acid

Antibiotics

Biopolymers

Ethanol biofuels

Industrial enzymes




Hormones






8


Sedimentation

Filtration

Centrifugation

Cell lysis

Bead mill

HP homogenizer

Ultrasound

LL Extraction

Precipitation

Adsorption

Chromatography

Membrane filtration

etc hellip

Centrifugation


Chromatography









9



Fermentedliquor



Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal









10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





7


Citric acid

Lactic acid

Antibiotics

Biopolymers

Ethanol biofuels

Industrial enzymes




Hormones






8


Sedimentation

Filtration

Centrifugation

Cell lysis

Bead mill

HP homogenizer

Ultrasound

LL Extraction

Precipitation

Adsorption

Chromatography

Membrane filtration

etc hellip

Centrifugation


Chromatography









9



Fermentedliquor



Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal









10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





8


Sedimentation

Filtration

Centrifugation

Cell lysis

Bead mill

HP homogenizer

Ultrasound

LL Extraction

Precipitation

Adsorption

Chromatography

Membrane filtration

etc hellip

Centrifugation


Chromatography









9



Fermentedliquor



Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal









10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





9



Fermentedliquor



Lime (CaO)

H2SO4

Filtrateto WWTP

Regeneration of

citric acid

Filtration

Gypsumfor disposal









10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





10







11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





11



5 gl1 gl









12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





12



Dave Arcari





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





13







14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





14



development stage
















16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies














16




Upstream


Downstream

Reduce down time



Downstream


YDR

365CP

tt

odPr






17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





17





10-100 L

100-500 L


1000 Xcellerex









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies









I i




19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





19





s

s

uCu

BAH





I tit t




20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





20

CIM product range

(BIA Separations)



(Sartorius Stedim)





I tit t




21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





21






160 200 and 240 mlmin


I tit t










96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies











96th

injection


I tit t




23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



Life Technologies








Institut



Life Technologies












Life Technologies






Life Technologies





Life Technologies

44













Life Technologies

45



httpwwwhevsch

httpitvhevsch




Life Technologies

46


Genetic engineering

Activity screening



Bioprocessing

Enzymatic catalysis






Life Technologies

















Life Technologies





23






Institut








Institut




25






Eluate

Separationlength

F e e d

F e e d

F e e d

F e e d

F e e d

F e e d


Institut








Institut






00

05

10

15

20

25

30

35

0 500 1000 1500

E x p a n s i o n

d e g r

e e

[ - ]


Streamline

Amberlite IRA 410

Institut









Institut









Institut






BioSMBreg








Institut








Institut












Institut




33






Institut







Institut











Institut











Institut











Institut







Institut



Life Technologies

39



Technol 50 (3) 557-564 (2007)







Institut



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25






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15

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Technol 50 (3) 557-564 (2007)







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Life Technologies

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Technol 50 (3) 557-564 (2007)







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Technol 50 (3) 557-564 (2007)







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39



Technol 50 (3) 557-564 (2007)







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44













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Technol 50 (3) 557-564 (2007)







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Life Technologies

46


Genetic engineering

Activity screening



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Life Technologies

















Life Technologies




Life Technologies

















Life Technologies




Life Technologies


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