SMB RPI Lecture

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    Simulated Moving BedChromatography in thePharmaceutical Industry

    Ron Bates

    Bristol-Myers SquibbApril 19, 2004

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    Outline

    Short Biography

    What is Bristol-Myers Squibb

    Chromatography

    Batch vs continuous HPLC, LC, SMB, P-CAC

    Simulated Moving Bed Chromatography Introduction

    Theory (brief) Operation

    Applications in the Pharmaceutical Industry

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    B.S. Chemical Engineering, RPI, 1993

    Ph.D. Biochemical Engineering, University ofMaryland, Baltimore County, 1999 Focus: ion-exchange chromatography

    Pfizer, Groton, CT, 1999-2003 Focus: small molecule chromatography, HPLC, LC, SFC, SMB,

    FLASH, extraction, crystallization, precipitation

    Bristol-Myers Squibb, Syracuse, NY, 2003-present Focus: protein chromatography

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    Bristol-Myers Squibb

    Top-ten pharmaceutical company Products in numerous therapeutic areas

    Cardiovascular & Metabolic Diseases Mental HealthPravachol, Coumadin Abilify

    Headache and Migrane Infectious DiseasesExcedrin Reyataz, Sustiva

    OncologyErbitux, Taxol

    Strong pipeline focused in 10 therapeutic areas Oncology, Cardiovascular, Infectious Diseases, Inflammation, etc.

    Sites around the world U.S. Research/Manufacturing sites

    MA, NY, NJ, CT, IL, Puerto Rico

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    Bristol-Myers SquibbSyracuse, NY

    Clinical and Commercial Manufacturing Plant

    Small-molecule pilot plants Process development and optimization

    Clinical manufacturing Penicillin-based products

    Last US-based Penicillin manufacturer

    Bio-synthetic products

    Biotechnology Development, Manufacturing, Analytical Biosciences, Quality

    Control / Assurance

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    Bristol-Myers SquibbSyracuse, NY - Biotechnology

    Two lead protein therapeutics Abatacept: commericial in 2005

    Commercial-scale manufacturing

    Commercial launch out of Syracuse Facility BLA filing Dec. 2004

    LEA29Y: Phase III clinical trials in 2005 Development for next generation process

    Clinical production in 2004

    Expansion in analytical and quality groupsto support processes

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    Batch

    vs.

    Continuous Chromatography

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    Discrete starting and ending points

    Example: 10 minute HPLC cycle

    Types: GC, HPLC, FLASH, FPLC, LC, etc.

    Can be run in many modes: Linear, overloaded, frontal, etc.

    Batch Chromatography

    0 2 4 6 8 10 12time

    Concentration

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    Batch Chromatography

    (Raffinate)

    Feed

    Desorbent

    Desorbent

    Effluentto Waste

    Load

    Elution

    Elution

    Effluent

    to Waste

    Desorbent Elution

    (Extract)

    (To Waste)

    Strong

    Solvent

    Regeneration

    Reference: Linda Wang, Perdue University

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    Batch Chromatography

    Empty zone

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    Continuous Chromatography

    Feed is loaded onto column and product iscollected continuously

    Annular (P-CAC)

    Preparative continuous annular chromatography

    Countercurrent

    Simulated moving bed chromatography (SMB)

    Feed

    column

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    P-CAC

    Reference: Genetic Engineering News, Oct. 1, 1999

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    P-CAC

    Reference: Genetic Engineering News, Oct. 1, 1999

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    P-CAC

    Reference: Genetic Engineering News, Oct. 1, 1999

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    P-CAC

    Reference: Genetic Engineering News, Oct. 1, 1999

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    Simulated Moving Bed

    Chromatography (SMB)

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    What is SMB

    SMB is Simulated Moving Bed Chromatography.

    SMB is continuous countercurrent chromatography. The feed is pumpedinto the system and two (or more) product streams are continuouslycollected.

    SMB has been used for the production of millions of tons of bulkcommodities (p-xylene, high fructose corn syrup, etc...) for the past fourdecades.

    Due to improvements in column and equipment technology, SMB has

    recently been used in the pharmaceutical industry (Sandoz, SmithKline,UCB, Pfizer). HPLC costs: $100/kg to $5000/kg

    SMB costs: $50/kg to $200/kg

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    SMB versus HPLC

    Advantages of SMB: Lower solvent utilization (up to 10 times less than batch HPLC) Generally can use less expensive, larger stationary phases Able to get high recovery and high purity Sometimes better productivity Lower labor and QC costs Only partial separation of solutes is required to obtain high purity. Higher yield than batch 10% more than batch. High throughput 5 to 10 fold increase. Lower solvent consumption An order of magnitude lower. Continuous process.

    Disadvantage of SMB: Binary separation only Complexity

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    Commercial Applications of SMB Hydrocarbons

    Sugars

    Agrochemicals

    Antibiotics

    Peptides Chiral Drugs

    Gaining tremendous momentum FDA approves of the technology Chiral resin manufacturers sell resins specifically made for SMB

    Proteins? Useful as polishing step?

    SEC: remove aggregated form of product

    Multicomponent separations more difficult than traditional uses 8, 12, even 16 zone systems being examined

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    Basic Principle

    Mobile Phase

    Feed

    Continuous Countercurrent Chromatography

    stationary column

    A sample is injected in the centre of a stationary column

    The two components move at different speeds and are separated

    If we now move the column from right to left, at a speed halfway

    between that of the solutes, they now move in different directions ...

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    Basic Principle

    Mobile Phase

    Feedcolumn

    The two solutes now move in different directions relative to a stationaryobserver. If the column is very long, the bands will continue to separate.

    Continuous Countercurrent Chromatography

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    Basic Principle

    Mobile Phase

    Feedcolumn

    If we continue to add sample at the center, the components will continueto separate

    Continuous Countercurrent Chromatography

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    This is clearly a continuous system, but there are problems.

    The column needs to be of infinite length, the actual moving of solids isvery difficult and some way to introduce and remove the sample and theproducts are needed.

    We solve this by cutting the column into small segments and simulatingthe moving of them

    Basic Principle

    Mobile Phase

    Feedcolumn

    Continuous Countercurrent Chromatography

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    The feed and solvent inlets are now placed between the segments

    and are moved each time a segment is moved from one end to the other

    Basic Principle

    Mobile Phase

    Feedcolumn

    Continuous Countercurrent Chromatography

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    Products are removed by bleeding off a carefully calculated flow

    at suitable exit points. This changes the velocity of the bands in

    the column and forces the products to move toward the ports

    This ensures that the column segments are clean before they are moved

    and that the solvent can be recycled directly back through the system

    Mobile PhaseBasic Principle

    Mobile Phase

    Feedcolumn

    Continuous Countercurrent Chromatography

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    True Moving Bed

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    Binary Separation in a True Moving Bed

    Desorbent

    Desorbent

    Raffinate

    Extract

    Feed

    Feed

    Extract Raffinate

    Time : t

    Time : t + t

    Reference: Linda Wang, Perdue University

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    Binary Separation in a True Moving Bed

    Desorbent

    Raffinate

    Extract

    Feed

    ExtractRaffinate

    Time : t + 3t

    Feed

    Time : t + 2t

    Desorbent

    Reference: Linda Wang, Perdue University

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    Binary Separation in a True Moving Bed

    Desorbent

    Desorbent

    Raffinate

    Extract

    Feed

    Feed

    Extract Raffinate

    Time : t + 4t

    Time : t + 5t

    Reference: Linda Wang, Perdue University

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    TMB to SMB

    Since its very difficult to move solids, true

    countercurrent chromatography does notexist.

    Instead, the bed is broken into manyfractions and their movement is simulatedby changing the inlet and outlet ports

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    Simplified SMB - 1Feed

    Solvent

    Extract Raffinate

    FeedSolvent

    Extract Raffinate

    The system is started.....

    A frontal elution separation

    occurs in Section 3.

    1 2 3 4

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    Simplified SMB - 2FeedSolvent

    Extract Raffinate

    FeedSolvent

    Extract Raffinate

    The separation continues.....

    Eventually the front of

    pure product 1 reaches the

    outlet. It is distributed

    between the final Sectionand the product port

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    FeedSolvent

    Extract Raffinate

    Simplified SMB - 3

    FeedSolvent

    Extract Raffinate

    Finally, the mixed product

    reaches the outlet. To avoid

    collecting impure material, it

    is necessary to move the

    columns 1 position upstream.

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    FeedSolvent

    Extract Raffinate

    Simplified SMB - 4

    FeedSolvent

    Extract Raffinate

    The frontal separation

    continues; at the same time,

    the slow moving product starts

    to separate from the tail of the

    mixed product band in Section 2

    Eventually the fast moving

    product again reaches theoutlet and more pure product

    is collected.

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    FeedSolvent

    ExtractRaffinate

    Simplified SMB - 5When the mixed band reaches

    the end of Section 3 its tail has

    left Section 2 (if the separation

    has been correctly designed) and

    only pure product 2 remains inSection 2.

    FeedSolvent

    ExtractRaffinate

    To avoid collecting impure

    raffinate, the columns aremoved once more. Now, the

    pure component 2 is in Section 1.

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    FeedSolvent

    ExtractRaffinate

    Simplified SMB - 6

    FeedSolvent

    ExtractRaffinate

    The second component is now

    collected at the Extract port while

    the separation continues in Sections

    2 and 3.

    The faster component reaches the

    Raffinate port and is again collected;

    note that the outlet concentrations areneither constant nor concurrent.

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    FeedSolvent

    ExtractRaffinate

    Simplified SMB - 7

    FeedSolvent

    ExtractRaffinate

    Eventually, the mixed zone

    reaches the raffinate port and

    the columns are again switched.

    This simplified system is now

    in a steady state mode and will

    continue to cycle.

    Switch

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    The moving of the bed is simulated by moving the pointsof feed and mobile phase addition, as well as the points

    of raffinate and extract removal while keeping thecolumn positions fixed.

    Time = 0Extract

    Feed Raffinate

    Mobile

    Phase

    Feed

    Raffinate

    Time = 1

    Mobile

    Phase

    Extract

    Packed

    Column

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    The zones are made up of one or more columns

    Six-column SMB System

    Eight-column SMB system

    I II III IV I II III IV

    I II III IV I II III IV

    SMB Configurations

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    Li uid

    RAFFINATE

    ELUENT

    FEED

    EXTRACT

    t0

    Li uid

    RAFFINATE

    ELUENT

    FEED

    EXTRACT

    t0 + T / 2

    SMB Operation

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    Li uid

    t0 + 1 T

    EXTRACT

    FEED

    RAFFINATE

    ELUENT

    Li uid

    RAFFINATE

    FEED

    ELUENT

    EXTRACT

    t0 + 1 T + T / 2

    SMB Operation

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    Theory Governing Equations

    For another day

    Maybe

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    Theory Working Equations / Definitions

    k1 = capacity factor = (tr-t0) / t0

    = k2/ k1

    Rs = 2* (tr1-tr2) / (w1-w2)

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    SMB Method Development

    1. Start with linear batch experiments

    2. Increase either mass or volume of load to overload thecolumn

    3. Calculate isotherm

    4. Determine resistance to mass transfer (if important)

    5. Calculate necessary flow rates

    6. Optimize (either on-the-fly or with a proven model)

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    Linear Chromatography

    0 2 4 6 8 10 12time

    Concentration

    tr1

    tr2

    t0

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    Batch Chromatography Experiments

    Feed concentration As concentrated as possible to minimize disruption to

    Zone III velocity

    Need to run batch experiments at appropriate

    concentrations and solvents Desorbent composition

    Solubility of products

    Strength

    Trade-off between time and mobile phase utilization

    Sorbent Capacity, selectivity, resolving power

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    Feed Concentration

    Feed concentration: Consider two systems

    A: Concentrated feed

    B: Dilute feed

    Run batch experiments to examine effect ofconcentration

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    Desorbent composition

    Multiple trade-offs: Solubility of products and effectiveness of the

    solvent Not always complimentary

    Often solubility dictates solvent composition Speed

    Low k = high throughput More wear and tear on equipment Larger system needed

    Large k = low throughput Less wear and tear Smaller system acceptable

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    Choice of Sorbent

    Capacity: higher = better?

    Selectivity: higher = better?

    Resolving power: higher Rs

    = better?

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    Linear Chromatography

    0 2 4 6 8 10 12time

    Concentration

    tr1

    tr2

    t0

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    Volume Overloading

    time

    Absorbance

    B t h Ch t h t SMB

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    Batch Chromatography to SMBInitial Operating Conditions

    Determine optimal feed concentration,stationary phase and mobile phasecomposition (highest with lowest

    capacity factors)

    Calculate isotherm and mass transferresistances

    Either use software package or rules ofthumb to generate initial SMB flow rates

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    Zone velocities vI = vRecycle + vD vII = vI - vX vIII = vII + vF vRecycle = vIII - vRaff

    Solvent Mass Balances Flow Rates

    IIIIII IVvI vII vIII

    vRecycle

    vX vRaffvFvD

    Overall Mass Balance vD + vF = vX + vRaff

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    Flow rates Commercial SMB design models available

    Given batch results from 5-10 column experiments Flow rate, feed concentrations, retention times Solubility data

    Predict zone velocities, productivities Problems:

    Usually assumes simple adsorption model and lumped masstransfer coefficients

    Often difficult to interpret overloaded chromatograms

    Rules of Thumb

    Educated guesses based upon batch results fromlinear and overloaded experiments VII and VIII ratio (based upon retention times) VI to flush back-side of slowest component from zone I Feed concentration and flow rate based upon solubility data and

    solvent mass balance

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    Period

    The period is the time a column stays inone zone also called switching time.

    Changing the period has the effect of

    changing all 4 zones simultaneously, thuseither speeding up or slowing down thesolutes

    Example of switching time

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    Li uid

    RAFFINATE

    ELUENT

    FEED

    EXTRACT

    t0

    Example of switching time

    Liquid

    t0 + 1 T

    EXTRACT

    FEED

    RAFFINATE

    ELUENT

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    SMB Optimization

    Independent variables:

    Flow rates

    Recycle, Desorbent, Raffinate, Extract, Feed

    Period (switching time) Thats it.

    Procedure:

    Get the system bound, manipulate the flowrates to maximize throughput at requiredpurity

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    SMB Optimization

    IIIIII IVvI vII vIII

    vRecycle

    vX vRaffvFvD

    Questions:

    What is the effect of increasing the Zone I flow rate?

    How would one accomplish this?

    Zone II? Zone III?

    What if the system is underutilized (i.e., more feed canbe added to the system) how would one do this

    without affecting the other zone flow rates?

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    Two component SMB System

    FeedDesorbent

    Extract Raffinate

    Conc.

    I II III IV

    Bed Position

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    SMB Optimization

    IIIIII IVvI vII vIII

    vRecycle

    vX vRaffvFvD

    Questions:

    Extract contains too much of the weakly adsorbedspecies what do you do?

    If situation was reversed?

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    Two component SMB System

    FeedDesorbent

    Extract Raffinate

    Conc.

    I II III IV

    Bed Position

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    SMB Optimization

    IIIIII IVvI vII vIII

    vRecycle

    vX vRaffvFvD

    Questions:

    Extract contains too much of the weakly adsorbedspecies what do you do?

    If situation was reversed?

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    Two component SMB System

    FeedDesorbent

    Extract Raffinate

    Conc.

    I II III IV

    Bed Position

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    Examples of SMB

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    Two component SMB System

    M lti t S t

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    Multi-component System

    0 10 20 30 4000.10.20.30.40.50.60.70.8

    Time [min]

    Ci/CF,i

    Sulfuric AcidGlucoseXyloseAcetic Acid

    Single-component pulse data

    Reference: Linda Wang, Perdue University

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    Multi-Component SMB System

    Desorbent

    Extract(2, 3)

    Feed

    (1, 2, 3)

    Raffinate(1)

    I II III IV

    1 Fast Solute2 Intermediate Solute3 Slow Solute

    Concentration

    Bed Position

    Reference: Linda Wang, Perdue University

    Complete Separation in Tandem SMB

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    Complete Separation in Tandem SMB

    Column Number

    0 5 10 15 200

    0.5

    1

    Ci/CF,i

    Des. Ext. Feed Raf.Sulfuric AcidGlucose

    Acetic Acid

    0 5 10 15 200

    0.5

    1

    Ci/CF,i

    Des. Ext. Feed Raf.

    Reference: Linda Wang, Perdue University

    Profiles of a Parallel SMB

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    Profiles of a Parallel SMB

    Glucose yield: 94% Glucose purity: 99%

    0 5 10 15 200

    0.2

    0.4

    0.6

    0.8

    1

    1.2

    Column Number

    Ci/CF

    ,i

    E1D1

    B(o) F

    R1 D2

    E2 B(i)

    R2

    I

    *

    *

    II III IV V VI VII VIII IXSulfuric Acid

    Glucose

    Acetic Acid

    Reference: Linda Wang, Perdue University

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    Other Questions?