WO1997017132A1 - Procede d'adsorption et milieu de separation - Google Patents

Procede d'adsorption et milieu de separation Download PDF

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Publication number
WO1997017132A1
WO1997017132A1 PCT/SE1996/001431 SE9601431W WO9717132A1 WO 1997017132 A1 WO1997017132 A1 WO 1997017132A1 SE 9601431 W SE9601431 W SE 9601431W WO 9717132 A1 WO9717132 A1 WO 9717132A1
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WIPO (PCT)
Prior art keywords
beads
population
gel
filler
density
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PCT/SE1996/001431
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English (en)
Inventor
Hans Berg
Mats Carlsson
Dag LINDSTRÖM
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Pharmacia Biotech Ab
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Publication date
Application filed by Pharmacia Biotech Ab filed Critical Pharmacia Biotech Ab
Priority to AU75931/96A priority Critical patent/AU719422B2/en
Priority to EP96938590A priority patent/EP0861119A1/fr
Priority to JP9518129A priority patent/JP2000500063A/ja
Publication of WO1997017132A1 publication Critical patent/WO1997017132A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
    • B01D15/18—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns
    • B01D15/1807—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns using counter-currents, e.g. fluidised beds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28004—Sorbent size or size distribution, e.g. particle size
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28011—Other properties, e.g. density, crush strength
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28016—Particle form
    • B01J20/28019—Spherical, ellipsoidal or cylindrical
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28026—Particles within, immobilised, dispersed, entrapped in or on a matrix, e.g. a resin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/2803—Sorbents comprising a binder, e.g. for forming aggregated, agglomerated or granulated products
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2215/00—Separating processes involving the treatment of liquids with adsorbents
    • B01D2215/02—Separating processes involving the treatment of liquids with adsorbents with moving adsorbents
    • B01D2215/021—Physically moving or fluidising the adsorbent beads or particles or slurry, excluding the movement of the entire columns

Definitions

  • the invention relates to adsorption processes, particularly chromatography, on expanded/fluidized beds.
  • the most advanta ⁇ geous bed is generated by expanding/fluidizing a bed consisting of sedimented beads by directing a flow of fluid against the force causing sedimentation.
  • a sample is introduced into the fluidizing flow.
  • the sample-carried substance or substances to be separated out are therewith adsorbed on the beads so as to be delayed in relation to the sample in its passage through the bed.
  • Adsorption is achieved by virtue of the ability of the matrix/beads to bind to the substance or substances to be separated out.
  • a less effective bed can be generated by agitating suspendible beads with the aid of a turbulent flow or by mechanical agitation.
  • This latter type of bed does not, of course, refer to chroma ⁇ tography, but to a batch-wise adsorption process.
  • the term "bead” refers to the population of particles making up the the bed. Beads may be more or less spherical and encompasses thus also irregular forms, such as granules, crush-like forms etc, although in connection with the invention spherical or otherwise rounded forms are preferred.
  • back-mixing is kept to a minimum, in order to achieve an effective chromatographic process.
  • Back-mixing in a bed is often measured as axial dispersion, often expressed by
  • the vessel dispersion number will preferably be ⁇ 75xl0 "3 , more preferably ⁇ 20xl0" 3 .
  • Back- mixing in the bed can be illustrated with the vessels-in- series model, where each vessel, or tank, represents a theoretical plate (see Levenspiel) , "Chemical Reaction
  • the number of plates of a bed is related directly to the vessel dispersion number.
  • the number of plates for an expanded bed intended for chromatography is preferably > 5, more preferably > 30.
  • the number of plates is 1, i.e. complete agitation.
  • Expansion/fluidization of the bed is normally effected in a column having provided at its ends a net structure which covers the cross-sectional area of the column, or with some other perforated device which will not generate turbulence in the flow. See, for instance, WO-A-9218237 (Pharmacia Biotech AB, Uppsala, Sweden) in this regard.
  • elution can be effected directly from the expanded bed.
  • the bed may be allowed to settle and adsorbed material eluated from the bed with the aid of a fluid flow normally delivered in a direction opposite to that in which the bed is expanded.
  • H/H 0 the degree of expansion H/H 0
  • H the height of the expanded bed
  • H 0 the height of the sedimented bed.
  • the degree of expansion will normally lie in the range of 2-10, preferably 2.4-3.2, with a priority that the bed will, at the same time, be stable and achieve the number of bottoms necessary in context.
  • Stream ⁇ line® which utilizes beads of cross-linked polysaccharide (agarose) with quartz particles (similar to glass crush with sharp edges) as filler.
  • the beads have a density of about 1.2 with sizes lying in the range of 125-315 ⁇ .
  • Streamline® has been used primarily for ion exchange chromatography. See also WO-A-9218237 (Pharmacia Biotech AB) in which there is given a description of suitable column constructions.
  • the other main supplier is Bioprocessing Ltd.
  • a concentration gradient is generated by virtue of allowing a series of batch adsorptions to be carried out with more or less heavily pronounced back-mixing in each segment.
  • WO-A-9200799 KEM-EN-TEK; Upfront Chromatography teaches the use of a fluidized bed in which it is endeavoured to generate homogenous intermixing and distribution of flow by agitating the inlet flow to create a mixing zone that is followed by a non-turbulent zone.
  • the non-turbulent zone has later been claimed to behave as a stable expanded bed.
  • the direction of flow may be either upward or downward utilizing beads that are heavier or lighter, respectively, than the fluid utilized.
  • This latter publication discloses a large number of fillers and polymeric materials that can be combined to produce beads usable for adsorption in fluidized beds.
  • PROBLEMS RELATED TO EARLIER FLUIDISED BED SYSTEM In the case of adsorption processes on expanded and/or fluidized beds, there is an expressed desire to use beads that have an improved total capacity and/or breakthrough capacity.
  • the desire for improved breakthrough capacity becomes particularly manifest when wishing to use rates of flow above those that can be achieved with current tech ⁇ niques, for instance rates of flow of 1,000 cm/h and prefera ⁇ bly still higher, such as flow rates up to 1,500 cm/h.
  • the requirement of stable expanded beds and low degrees of expansion described above also requires access to beads which are able to form sediments more readily.
  • Beads of higher density are also desirable in batch adsorptions in fluidized beds having a high degree of back-mixing (unstable) , since beds of this nature will sediment more rapidly at the end of the adsorption process.
  • bead populations whose beads have a higher density or are larger than is the case in earlier known techniques.
  • an increase in flow rate will in most cases result in a decrease in the breakthrough capacity, which in turn counter ⁇ acts high productivity in the processes concerned.
  • Parallel herewith is the need for beads that have an improved break- through capacity.
  • a first objective of the invention is to provide more rapid methods for adsorption/desorption processes that involve fluidized beds. Of particular importance in this regard is chromatography on expanded beds.
  • a second objective is to provide filler matrices that have improved breakthrough capacity and are particularly adapted for chromatography on a stable expanded bed.
  • a third objective is to make possible high yields in chromatography on stable expanded beds.
  • a main aspect of the invention resides in an adsorption method as defined in the introduction.
  • This aspect of the invention is characterized in that the beads used contain filler in the form of granules or particles having a density > 3 g/cm 3 , preferably > 4 g/cm 3 , and thereabove.
  • Those fillers that have been studied hitherto have all had a density ⁇ 20 g/cm 3 . This does not exclude the possibility of utilizing other potential fillers with still higher densities, e.g. up to 25 g/cm 3 . It is important that the filler particles are inert and undissolvable in those conditions applied to the use of the beads.
  • the material in suitable filler particles is often a heavy metal, either in the form of an alloy such as steel (e.g.
  • the filler may also comprise metal spheres (e.g. tantalum) .
  • the filler particles may vary in size and the size of said particles will always be much smaller than the size of the beads used. Typical sizes are 1-70 ⁇ , with a preference to a range of 15-50 ⁇ m.
  • the geometric shape of the filler is highly significant when wishing to retain a high breakthrough capacity in relation to corresponding beads which lack filler.
  • preferred filler shapes are spheres, ellipsoids, droplets, noodle shapes, bean shapes and other rounded shapes including aggregates/agglomerates and irregular shapes thereof. A particular preference is given to rounded shapes which are continuously rounded.
  • the filler content of the beads is determined by the density to be achieved, i.e. the rates of flow that are conceivable for use.
  • the beads When a stable expanded bed is used, the beads should preferably vary in size and/or in density so that they are able to more easily position themselves stably, with lighter and/or smaller beads above heavier and/or larger beads . No association in the form of column segmentation i ⁇ necessary. Neither is it necessary to use magnetic filler in combination with external magnetic fields. Thus, there can be used a bead fraction having sizes within a given range where the proportion of beads in the lower part of the range will be larger than the beads in the upper part thereof.
  • Typical particle size distributions for a bead population used to create a stable expanded bed are normally such that 95% of the beads fall within a range whose width is 0.1 to 10 times the mean bead diameter, preferrably 0.3 to 3 times the mean bead diameter.
  • the exact particle size distribution to be selected will depend on factors, such as flow rate, mean bead diameter, density of beads, density of fluid etc.
  • a too wide particle size distribution will result in elutriation and/or sedimenting of large proportions of beads.
  • a too narrow particle size distribution will counteract stabilization of the expanded bed. This implies that the population of beads can only be monodisperse in case the individual beads of a population have density distribution within a given density interval.
  • the ratio between total surface area the beads (outer pus inner surface) and the total bead volume is highly signifi ⁇ cant to breakthrough capacity. Larger relative contact surface areas (small beads) lead to a higher breakthrough capacity.
  • the total capacity is only marginally affected.
  • the mean particle size of the beads should generally lie in the range of 10-1,000 ⁇ m, with preference to a range of 50-700 ⁇ m. The lower limit is determined with a view to the fact that the beads shall not be able to escape from the column in which the expanded bed has been created. Other factors which influence the choice of range limits for bead sizes and distribution within said range include the desired capacity and the substance or substances to be separated from the sample. Although less preferred, another alternative is to vary the density of the beads used in one and the same bed. Bead fractions in which both the size and the density of the individual beads vary can also be used.
  • the density (mean density) of the beads will always be > 1 g/cm 3 , for instance > 1.1 g/cm 3 , such as > 1.2 g/cm 3 , and upwards (measured in the buffer used to maintain the bed in a fluidized state) .
  • Beads that are used in one and the same bed will preferably have generally the same density.
  • the amount of filler required can be readily determined from a given polymer base matrix and from the density desired. It is preferred that the beads are porous with open pores. Optimal porosity can be determined on the basis of the substance or substances to be adsorbed among other things, and can be calculated conventionally.
  • Kav should lie in the range of 0.40-0.95 for the substance or substances to be adsorbed.
  • Kav see L. Hagel in "Protein Purification, Principles, High Resolution, and Applications", J-C Janson and L Ryden (Eds), VCH Publishers Inc. New York, 1989, p. 99.
  • the beads are normally comprised of a polymer base matrix in which the filler is enclosed.
  • the polymer in the base matrix may be hydrophobic, for instance a bead which is comprised of styrene-divinyl benzene copolymer and which is hydrophilized on the surface by coating it with an appropri ⁇ ate hydrophilic polymer (preferably a polymer having hydroxy or amino groups), for instance.
  • the base matrix may be comprised of an insoluble or soluble hydrophil ⁇ ic polymer, for instance agarose, cellulose, dextran starch, etc., which has been cross-linked to the degree of porosity and stability desired in a known manner, when necessary.
  • agarose was the polymer preferred, preferably in a cross-linked form.
  • the beads often have some form of affinity to the substance or substances to be separated out. This normally means that the base matrix is substituted with one or more groups that have affinity to the substance/substances concerned. Typical groups are:
  • Groups having a specific affinity for instance bio- affinity groups, such as between IgG-binding protein
  • the matrix itself may also have an affinity to the substance or substances to be adsorbed, this affinity being expressed by virtue of the substance concerned being delayed when it shall pass a bed of non-substituted beads.
  • affinity chromatography such as ion-exchange chromatography, biospecific affinity chromatography, hydrophobic chromatogra ⁇ phy, "Reverse Phase Chromatography", chelate chromatography, covalent chromatography, etc.
  • beads according to the above substituted with IgG-binding protein such as Protein A, G, H or L, preferably produced by recombinant techniques and optionally containing cysteine (for instance rProtein A-cys) was particularly preferred to affinity-purify IgG, particularly monoclonal antibodies.
  • adsorption can be effected batch-wise in a vessel in which the particles are fluidized by subjecting them to a flow of liquid or by agitation.
  • the samples to be purified may be of the same type as those earlier used in chromatographic processes on packed or expanded beds, or in batch adsorption processes on fluidized beds.
  • the invention can be applied to great benefit in the direct treatmen of supernatants/culture media from fermenta- tors and other cell culture vessels, particularly in chro ⁇ matographic processes on expanded beds.
  • the invention will function for the separation of compounds of various molecular weights and types. Examples are polysaccharides, proteins/polypeptides and nucleic acids and synthetic water-soluble polymers, e.g. with molecular weights > 5,000 dalton. Typically preferred molecular weights with regard to substances to be adsorbed on the beads in accordance with the invention are > 50,000, preferably > 100,000.
  • the affinity group concerned may be introduced on a bead by activating an appropriate hydrophilic group, such as carboxy, amino, hydroxy, etc., with a suitable bifunctional reagent, such as CNBr, bisepoxide or corresponding epihalohydrin, etc., which in is turn reacted with a compound that exhibits the affinity group concerned.
  • an appropriate hydrophilic group such as carboxy, amino, hydroxy, etc.
  • a suitable bifunctional reagent such as CNBr, bisepoxide or corresponding epihalohydrin, etc.
  • a second aspect of the invention is a bead population (bead fraction) according to the above, which is suitable for use as a matrix in adsorption processes, particularly chromatographic processes, effected on expanded/fluidized beds in accordance with the aforegoing.
  • This aspect of the invention also includes the population in the form of a stable expanded bed according to the above, placed in a chromatographic column.
  • the aspect also includes bead populations which lack affinity groups, including preactiva- ted forms. In this latter case, the customer/user can himself introduce a desired group.
  • a particularly important embodiment of this second aspect of the 4 invention includes beads which are substituted with IgG-binding protein, particularly an IgG-binding protein containing the amino acid cystein for mediating binding to the beads.
  • Proteins of this type have earlier been produced by recombinant techniques, e.g. cysteine-variants of Protein A (Ljungquist, et al, (Eur. J. Biochem. 186 (1989) 557-561) and Profy (EP 284,368), and cysteine-variants of Protein G (Fahnestock, et al (U.S. 4,977,247)). It is known to bind cysteine-containing proteins covalently to solid phases via thiol groups.
  • IgG-binding protein particularly recombinant Protein A-cys
  • the base matrix comprised cross-linked agarose.
  • the filler had the aforesaid particle form. See also the experimental part of this document.
  • the alloy has a density of 8.4 g/cm 3 .
  • the particles have a spherical shape and preparations with two diameters were used (16-44 ⁇ & ⁇ 16 ⁇ m) .
  • Tantalum (Ta) (Novakemi AB, Enskede, Sweden) , having a density of 16.5 g/cm 3 and consisting of sintered spheri ⁇ cal particles. Diameter 5-44 ⁇ m. o Tungsten carbide (WC) (AB Sandvik Coro ant, Sweden) having a density of 15.6 g/cm 3 and consisting of small (in relation to tantalum) sintered spherical particles. Two preparations were used (diameter 10-50 ⁇ m and ⁇ 15 ⁇ m) .
  • Zirconium oxide (ZrQ ) (MEL Chemicals, Manchester, England) having a density of 5.6 g/cm 3 and consisting of small (in relation to tantalum) sintered spherical particles. There was used a preparation having a diameter of 5-30 ⁇ m.
  • Emulsion Step 1.1 Dissolution of ethyl cellulose in the emulsi ⁇ fying reactor.
  • Step 1.2 Preparing a solution containing agarose and filler.
  • Method 900 ml of distilled water were charged to the reactor. The agitator was then activated and 36 g of agarose were delivered. The mixture was heated to 95°C until the agarose had dissolved (about one hour) . 378 g Anval® were then added to the mixture and the mixture was agitated for a further fifteen minutes, after which the temperature was lowered to 70°C.
  • Step 1.3 Transferring the solution containing agarose and filler to the emulsifying vessel.
  • Step 1.4 Adjusting particle size.
  • Target values When desiring a gel in which the beads of the main bead fraction have a diameter of 80-160 ⁇ , the emulsifying process is interrupted when 95% (volume) of the beads have a diameter ⁇ 200 ⁇ m (standard gel) . When desiring bead diameters of 80-200 ⁇ m in the main bead fraction, the emulsifying process is interrupted when 95% of the beads have a diameter ⁇ 250 ⁇ m.
  • Step 1.5 Cooling. Cooling: Heating of the water bath was stopped. With the equipment used (laboratory scale) , the temperature of the bath was lowered from 60 to 30°C in about seven hours.
  • Step 1.6 Working up. Method: The beads were washed by agitation and thereaf ⁇ ter decantered (3x) with 3 1 of 99.5% ethanol. Washing of the beads was continued on nutsch with 4 x 2 1 of ethanol with self-draining. The beads were finally transferred to distilled water, via agitation and decantering.
  • rProtein A-cys Recombinant Protein A-cys (rProtein A-cys) contained the four IgG-binding domains (E, D, A, B and C) of the native form, followed by the first eight amino acids of the X-domain, followed by a non-Protein A sequence of five amino acids and cysteine in the C-terminal (the Protein A sequence corresponded to alanine in position 18 up to and including proline in position 316 in accordance with EP 284,368. The process was analogous with the process earlier described by Profy T (EP 284,268) and Lungquist, et al (Eur. J. Biochem. 186 (1989) 557-561) . Solutions of rProtein A-cys were stored in a reduction buffer.
  • N-hvdrolxysuccinimide 30 ml of standard gel were washed with distilled water, mixed with 3.67 g NaOH dissolved in 18 ml distilled water while stirring, and the temperature was adjusted to 24°C. After some minutes, 7.2 ml of epichlorohydrin were added while vigorously stirring the mixture. After two hours, the gel was washed on a glass filter with 300 ml of distilled water. The washed gel was then mixed with 6-aminocapronic acid (6-ACS; 30 ml solution 1 M 6-ACS, 1 M NaCl pH 11.5) and the mixture stirred for 17-24 hours and then finally washed with 200 ml 0.5 M NaCl.
  • 6-aminocapronic acid 6-ACS; 30 ml solution 1 M 6-ACS, 1 M NaCl pH 11.5
  • the gel was then again washed, now with 2 x 30 ml acetone, whereafter the gel was mixed with 15 ml acetone and activated with 559 mg NHS and 1007 mg of dicyclohexylcarbodiimide while stirring the system. After 4-17 hours at 31°C, the gel was washed with 2 x 30 ml acetone + 450 ml isopropanol and cooled with 210 ml of ice-cold 1 mM HCl.
  • the dry-sucked gel was mixed with 100 ml glycerol dissolved in 900 ml 0.2 M sodium bicarbonate, 0.5 M NaCl, 1 mM EDTA, pH 10, while stirring the system. The system was stirred overnight at 37°C, whereafter the gel ⁇ was pH-washed on nutsch with 0.1 M Tris, 0.15 M NaCl, pH 8, and 0.05 M acetic acid in three cycles with a 3 x 1 gel volume in each cycle. The gel was finally washed with water.
  • Breakthrough capacity Q B binding of IgG
  • c/c 0 0.01
  • Buffer A 20 mM sodium phosphate, pH 7.0.
  • Buffer B 0.1 M glycine, pH 3.0.
  • Protein hlgG (Pharmacia Biotech AB) . / Flow: 10 ml/min. —> 300 cm/h.
  • Buffer A 20 mM sodium phosphate, pH 7.0.
  • Buffer B 0.1 M glycine, pH 3.0.
  • Protein 0.5 mg/ml hlgG (Pharmacia Biotech AB) in buffer A.
  • Buffer A 10 mM sodium dihydrophosphate, 0.15 M sodium chloride and 10 mm EDTA, pH 7.0.
  • Buffer B 0.5 M acetic acid (gives a pH of about 2.7).
  • IgG solution 150 mg hlgG in 10 ml of buffer A.
  • a 280 was read-off after diluting to 1:10 and the total IgG capacity (mg (IgG/ml gel) was determined as the eluate volume (ml) x A. 280 (diluted eluate) x 7.244.
  • the density varies between 1.6-1.8.
  • a column (200 mm, 100 cm height) containing a distributor whose hole area was 0.3% of the total area, was filled with 15 cm (4.7 1 rProtein A-cys gel) having a particle size distribution in the range of 80-160 ⁇ m.
  • the gel was expanded to 38 cm at a linear flow rate of 300 cm/h (20 mM Na phosphate, pH 7.0).
  • the pressure drop across the distributor was 100 Pa.
  • a positive step-response injection with 0.25% acetone solution was introduced into the column as a stimulus experiment. When 100% of the acetone solution could be detected at the column outlet, the flow was switched back to buffer solution for a negative step response.
  • the plate number for the column and system was calculated on the basis of the negative step response in accordance with the same principle as that applied with pulse injection (Chemical Reaction Engineering, 2nd Edition, John Wiley & Sons (1971) ) .
  • the number of plates for the column plus system was 40. Compensation was then made for the number of plates for the system contribution, resulting in 34 plates for the column. In turn, this corresponded to a vessel dispersion number of 17 x IO '3 .
  • the breakthrough capacity is significantly influenced by the type of filler used and its diameter and shape. Studied fillers can be divided into groups: o Group 1 - Approximate breakthrough capacity (IgG) for gel with and without filler.
  • Anval® Diameter 16-20 ⁇ m spherical particles.
  • Anval® Diameter 16-44 ⁇ m spherical particles. Tantalum: Diameter 5-44 ⁇ m sintered spherical parti ⁇ cles.
  • o Group 2 About 25% lower breakthrough capacity (IgG) than Group 1.
  • Anval® Diameter ⁇ 16 ⁇ m spherical particles.
  • Tungsten carbide Diameter 10-50 ⁇ m sintered small 11 spherical particles.
  • Zirconium oxide Diameter 5-30 ⁇ m sintered small 11 spherical particles.
  • o Group 3 Roughly a 70% lower breakthrough capacity
  • Tungsten carbide Diameter ⁇ 15 ⁇ m sintered small 11 spherical particles.
  • Quartz Diameter ⁇ 25 ⁇ m "crush-like particles”. 11 In relation to tantalum.
  • IgG which is about 30% lower than Anval® (16-44 ⁇ m) .
  • o Tungsten carbide ( ⁇ 15 ⁇ m) gives a breakthrough capacity (IgG) which is about 50% lower than Anval® ( ⁇ 16 ⁇ m) .
  • o Quartz ( ⁇ 25 ⁇ m) gives a breakthrough capacity (IgG) which is about 75% lower than Anval® ( ⁇ 16 ⁇ m) and about 40% lower than tungsten carbide ( ⁇ 15 ⁇ m) .
  • Anval® tantalum > tungsten carbide > quartz. If it is assumed that the breakthrough capacity is influenced solely by shape, a smooth, spherical surface (Anval®) is better than the surface of small, spherical sintered particles (tungsten carbide). Worst of all are the irregular particles ("crush " (quartz)) . It can be seen from the study that quartz included in existing matrices for Streamline® is least suited as a filler.
  • a preferred mode employs, bead diameters ⁇ 80 ⁇ m, when not taking the entire system solution into account.
  • a net which functions to retain the bed while allowing fermentor solution to pass through (including particulate impurities) .
  • the upper bead diameter should preferably lie as close as possible to the lower bead diameter, if optimal capacity is to be obtained.

Abstract

La présente invention concerne une population de perles d'une densité supérieure à 1 g/cm3 et comportant une matrice base polymère dans laquelle est incorporé une charge particulaire. La caractéristique des perles est que la densité des particules de charge est supérieure ou égale à 3 g/cm3 et que la densité et/ou la taille des perles se distribuent dans des plages prédéterminées de densité et de taille. Les particules de charge présentant le plus d'intérêt sont celles qui présentent des formes arrondies, telles que des sphères, des ellipsoïdes ou des agrégats/agglomérats de celles-ci. Cette population de perles convient particulièrement aux processus d'adsorption en lits fluidisés, et de préférence aux lits élargis stables.
PCT/SE1996/001431 1995-11-07 1996-11-06 Procede d'adsorption et milieu de separation WO1997017132A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU75931/96A AU719422B2 (en) 1995-11-07 1996-11-06 Adsorption method and separation medium
EP96938590A EP0861119A1 (fr) 1995-11-07 1996-11-06 Procede d'adsorption et milieu de separation
JP9518129A JP2000500063A (ja) 1995-11-07 1996-11-06 吸着法および分離媒体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9503926-9 1995-11-07
SE9503926A SE9503926D0 (sv) 1995-11-07 1995-11-07 Adsorptionsförfarande och separationsmedium

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WO1997017132A1 true WO1997017132A1 (fr) 1997-05-15

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EP (1) EP0861119A1 (fr)
JP (1) JP2000500063A (fr)
AU (1) AU719422B2 (fr)
CA (1) CA2236875A1 (fr)
SE (1) SE9503926D0 (fr)
WO (1) WO1997017132A1 (fr)

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WO2002005922A1 (fr) * 2000-07-18 2002-01-24 Mpb Cologne Gmbh, Molecular Plant & Protein Biotechnology Procede pour extraire des proteines sous une forme pure a partir de plantes
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WO2016053563A1 (fr) 2014-10-01 2016-04-07 Mjn U.S. Holdings Llc Composition nutritionnelle pour le milieu gastro-intestinal permettant d'obtenir un microbiome et un profil métabolique améliorés
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WO2018210807A1 (fr) 2017-05-17 2018-11-22 Mead Johnson Nutrition Company Composition nutritionnelle comprenant des oligosaccharides de lait humain et ses utilisations
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US6783962B1 (en) 1999-03-26 2004-08-31 Upfront Chromatography Particulate material for purification of bio-macromolecules
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SE9503926D0 (sv) 1995-11-07
AU719422B2 (en) 2000-05-11
EP0861119A1 (fr) 1998-09-02
JP2000500063A (ja) 2000-01-11
AU7593196A (en) 1997-05-29
CA2236875A1 (fr) 1997-05-15

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