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The amazing ability of continuous chromatography to adapt to a
moving environment. Roger-Marc Nicoud, Founder of Novasep
Barcelona, October 2013
Introduction
My thesis:
the environment pressure pushes Continuous Chromatography to evolve like animals evolved
according to Darwin’s law ….
and for that, I will use shortcuts , approximations and manipulations …
Improving what ?
System size Eluent consumption
Yield Operations
Comment Productivity kg/kg/day normally presented as the main objective function
Minimizing solvent consumption (prior to recycling) is a must in all large scale applications.
Can be a major cost contributor
Control / Process Stability / Cleaning can be critical costs contributors.
Mitigation large LP systems can be cheaper than smaller HP systems
Biopharma industry still a bit less concerned
Ancillary equipment is even more important than chromatography itself.
Life is often a matter of compromize
Continuous can helpCounter-current can help
Continuous is NOT synonymous with counter-current
A continuous but NOT counter-current animal
Be careful with comparisons
Batch My clever process
0
2
4
6
8
10
12
Productivity kg/kg/d
Optimum particle size, eluent composition … are different for Batch and continuous/CC processes.
S.M.B.: the key evolution …..
solid liquid
I
II
III
IVMinimizin
g E.C.
Evolution lead to the first continuous AND counter-current animal
Maximize productivity
Feed
Eluent
The first evidence of continuous chromatography
Environment pressure : Paraxylene• Scale (500,000 Mt/Y/Unit in 2010)
• Chromatographic conditions:– Selectivity about 2– Particle size about 1000 microns (inducing “poor” HETP ….)– Temperature about 180 °C (inducing low viscosity)
• Technical constraints– Target purity: > 99.8 %– “individual bed length” : limited to 1 m due to mechanical constraints
24 columns to reach total length
significant bed length of 24 m(no pb because of low viscosity)
Environment pressure : Fructose• Scale (50,000 Mt/Y/Unit in 2010): from Glucose-Fructose
mixtures• Chromatographic conditions:
– Selectivity about 1.5– Particle size about 300-500 microns (inducing “poor” HETP)– Temperature: 60 °C (thus viscosity about 10 cp )
• Technical constraints– Target purity: about 90 %– Minimize energy consumption for evaporating Water
total bed length of about 8-12 meters
Improving the classical SMB
• Add some degree of freedom by: – Connecting columns in different ways– Selecting different switching modes– Varying I/O lines composition and flows
• New processes are normally: – quasi-continuous instead of being truly continuous – taking advantage of «counter-current» contact
Fructose: further improvement
Commercial solutions implemented: • 4 or 6 columns• Eluent consumption decreased by about 10-15 % compared to SMB
Two sub periods
«Cousin animals»: • SSMB Novasep• ISMB Mitsubishi
A new animal
Environment pressure : optical isomers• Scale (1-100 Mt/Y/Unit in 2010)• Chromatographic conditions:
– Selectivity: typically between 1.2 and 2 – Little influence of particle size on packing cost– HETP depending on particle size …
• Technical constraints– Target purity: 95-99 % – Minimize system size / CSP inventory
Use small particle size
Total bed length about 0.5 m ….To be distributed between Ncol …At large scale L/D < 0.1 …..
The first SMB animal for separating optical isomers (1992):
Influence of petrochemical design is very visible ….
and the modern version ….
Optical isomers: further improvement
VariCol:• Truly continuous• Same hardware as SMB• Typically saves one
column out of 5-6.
VariCol
Key successes
For main successes, continuous chromatography is coupled with crystallization, isomerization and multiple effect evaporators
Very large scale does not mean « second-class » performance
In Line Dilution is key
Environment pressure : need for multicomponent (bio)separations.
Technically one can design a continuous three pure fractions TMB.
III
IIIIVV
VI
VIIVIII
Imposes to work with two suboptimal systems ?
The generic purification problem :
reduces to a binary separation if one wants the green or the red product.SMB is perfectly adapted to these situations(ex.: desalting, xylenes, capture …),
timeW P S
or change concept …
An animal with no progeny ?
Prefer two SMB in series :Paclitaxel, Cyclosporine, EPA …
Improving multicomponent separations
SW
P
S
W
P
I
II
III
IV
V
VI
P+S
P+W
A truly continuous gradient chromatographic process with 6-columns
MCSGP (Multicolumn Countercurrent Solvent Gradient Purification) from ETH.
Important features of the animal:• Opening liquid loop• Short-circuit• Gradient
Feed
S
W
P
I
II
III
IV
V
VI
I
II
III
IV
V
VI
P+S
P+W
I
II
III
IV
V
VI
P+S
P+W
Can be done with three columns
Not strictly continuous but counter current
Two sub periods
3-column MCSGP
“Cousin animal” from Novasep : GSSR Gradient (with) Steady-State Recycling
Environment pressure : need for capturing (biomolecules)
S Very strongly
retained
WNon retained
P
Selectivity is such that a solvent change is mandatory
Loading
Washing
Elution
t
RegenerationEquilibrationtcycle
Bioseparations: the BioSc concept
Use sequential feeding to reduce the number columns (as low as two).
Regenerate
Equilibrate
Target
Feed
Elute
Waste
S
W
PWash
WWash *
Two sub periods
Regenerate
Equilibrate
Target
Elute
Waste
S
W
PWash
W“Cousin animals” from : • Chromacon (Capture SMB)• GE (3C PCC)
Lysine production main steps
About 50,000 MT/year/unit
FERMENTATION
MEMBRANE FILTRATION
BIOMASS
ION EXCHANGEPURIFICATION
EVAPORATION
CRISTALLISATION
CRUDE L LYSINE HCl
ACIDIFICATION
Lysine purification: switch from batch to continous (a decade ago)
• First step: Strong Cation Exchange• Feed pH 3-4 so that Lys+ (maximizes loading and separation)• Then pH lowered to 1-2 so that Lys++ (maximizes capture of small
concentrations)• Wash • Elution by ammonia at pH 9 (Lys0)• Ammonia recycled through stripping
97% Lys with microbial byproducts and mineral cations
• Second step: Weak Cation Exchange• Feed at pH 9 (Lys0 goes through)• Regeneration at pH with diluted sulphuric acid• Wash
Gain continuous (about 10-column systems) vs Batch: resin inventory and effluent divided by about 3
Biopharma
Still looking for a first Biopharma industrial application of continuous chromatography ?
Many proof of concept published:• mAbs• pegylated proteins• peptides• fatty acids …..
Evolution ….
1960 1980 2000 2010 2020 ?
Num
ber o
f col
umns
Xylene
Sugars
I-SMBS-SMB
VariColMCSGP
MCSGPGSSRBioSc 3C PCC
12
6
4
24
2
Continuous character
100 %
50 %
Thank you !
Process integration may lead to non intuitive processes …
HFS 55 %
Glu 95 % Isomerization Glu-Fru 58-42SMB
Glu 90 %
HFS 55 %
Intuition
SMB
Glu 95 % Isomerization Glu-Fru 58-42
Glu 90 %
Fru 90 %
Optimized