US20120231506A1 - Multistep final filtration - Google Patents

Multistep final filtration Download PDF

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Publication number
US20120231506A1
US20120231506A1 US13/394,766 US201013394766A US2012231506A1 US 20120231506 A1 US20120231506 A1 US 20120231506A1 US 201013394766 A US201013394766 A US 201013394766A US 2012231506 A1 US2012231506 A1 US 2012231506A1
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Prior art keywords
filter
pore size
immunoglobulin
solution
combination
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Abandoned
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US13/394,766
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English (en)
Inventor
Roberto Falkenstein
Klaus Schwendner
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Hoffmann La Roche Inc
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Hoffmann La Roche Inc
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Assigned to F. HOFFMANN-LA ROCHE AG, A SWISS COMPANY reassignment F. HOFFMANN-LA ROCHE AG, A SWISS COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FALKENSTEIN, ROBERTO, SCHWENDNER, KLAUS
Assigned to HOFFMANN-LA ROCHE INC. reassignment HOFFMANN-LA ROCHE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG, A SWISS COMPANY
Publication of US20120231506A1 publication Critical patent/US20120231506A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/34—Extraction; Separation; Purification by filtration, ultrafiltration or reverse osmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • a first filtration step with a pre-filtration with a filter with a pore size of 3.0 ⁇ m and a main-filtration with a filter with a pore size of 0.8 ⁇ m and a second filtration with a pre-filtration with a filter with a pore size of 0.45 ⁇ m and with a main-filtration with a filter with a pore size of 0.22 ⁇ m.
  • Protein solutions with a concentration of more than 100 g/l are prone to difficulties during the final filtration step, e.g. by having only low transmembrane fluxes or blocking of the employed filter by aggregates or particles formed during the formulation or concentration process or due to added excipients resulting in an increased viscosity of the concentrated solution.
  • a two-stage filter constructed using a membrane with a smooth interior underlaid with a thin, flexible porous membrane supported by a rigid screen support with a ridged expander tube is reported in EP 0 204 836.
  • a combination of at least two membrane filter units of different membrane material and different filter pore size and filter pore geometries is reported in DE 3 818 860.
  • One aspect as reported herein is a method for the preparation of an immunoglobulin solution comprising the following steps
  • Another aspect as reported herein is the use of a filter combination as reported herein of a combination of a first and second filter, whereby the first filter comprises a pre-filter with a pore size of 3.0 ⁇ m and a main-filter with a pore size of 0.8 ⁇ m and the second filter comprises a pre-filter with a pore size of 0.45 ⁇ m and a main-filter with a pore size of 0.22 ⁇ m, for the final filtration of an immunoglobulin solution prior to active pharmaceutical ingredient preparation.
  • Another aspect as reported herein is a method for producing an immunoglobulin comprising the following steps
  • a further aspect as reported herein is a kit comprising a first filter comprising a pre-filter with a pore size of 3.0 ⁇ m and a main-filter with a pore size of 0.8 ⁇ m and the second filter comprising a pre-filter with a pore size of 0.45 ⁇ m and a main-filter with a pore size of 0.22 ⁇ m.
  • the first filter has an area that is at most twice the area of the second filter. In another embodiment the first and second filter have about the same total filter area.
  • the immunoglobulin solution comprises a sugar, and/or an amino acid, and/or a surfactant, and/or a salt. In a further embodiment the immunoglobulin solution has a concentration of from 100 g/l to 300 g/l. In still another embodiment the immunoglobulin solution has a volume of from 3 liter to 100 liter. In a further embodiment the filtrating is with an applied pressure of from 0.1 bar to 4.0 bar. In one embodiment the immunoglobulin solution has a concentration of 160 g/l or more and the filtrating is with an applied pressure of 1.45 bar or more.
  • the immunoglobulin solution comprises a sugar and a surfactant and has a concentration of 125 mg/ml or more and the filtrating is with an applied pressure of 0.75 bar or less. In a further embodiment of 0.7 bar or less.
  • the immunoglobulin is an anti-IL13 receptor alpha antibody or an anti-HER2 antibody.
  • the purifying is with a protein A affinity chromatography step and at least one step selected from cation exchange chromatography, anion exchange chromatography, and hydrophobic interaction chromatography.
  • a combination of two filters or filter units each comprising a pre-filter and a main-filter and each with a specifically selected pore size can be used to filter highly concentrated and viscous, as well as formulated immunoglobulin solutions, i.e. comprising a sugar and a surfactant, during the final packaging step.
  • a first filter comprising a pre-filter an a main-filter with a pore size of 3.0 ⁇ m and 0.8 ⁇ m, respectively, and a second filter comprising a pre-filter and a main-filter with a pore size of 0.45 ⁇ m and 0.22 ⁇ m, respectively is highly advantageous.
  • the immunoglobulin solution comprises the immunoglobulin and an excipient.
  • the excipient comprises one or more substances selected from sugars, such as glucose, galactose, maltose, sucrose, trehalose and raffinose, amino acids, such as arginine, lysine, histidine, ornithine, isoleucine, leucine, alanine, glutamic acid, aspartic acid, glycine, and methionine, salts, such as sodium chloride, potassium chloride, sodium citrate, potassium citrate, sodium phosphate, potassium phosphate, and surfactants, such as polysorbates, and poly(oxyethylene-polyoxypropylene) polymers.
  • the filtrating as reported herein is used as the final filtration step in the production of a therapeutic antibody. It can be carried out after the required excipients, stabilizer and/or anti-oxidants have been added to the highly concentrated antibody solution.
  • the ratio of amount of antibody in kg to total area of the filter is of from 1000 g/m 2 to 10,000 g/m 2 . In another embodiment the ratio is of from 1000 g/m 2 to 6000 g/m 2 . In still another embodiment the ratio is from 4000 g/m 2 to 6000 g/m 2 .
  • polypeptide is a polymer consisting of amino acids joined by peptide bonds, whether produced naturally or synthetically. Polypeptides of less than about 20 amino acid residues may be referred to as “peptides”, whereas molecules consisting of two or more polypeptides or comprising one polypeptide of more than 100 amino acid residues may be referred to as “proteins”.
  • a polypeptide may also comprise non-amino acid components, such as carbohydrate groups, metal ions, or carboxylic acid esters. The non-amino acid components may be added by the cell, in which the polypeptide is expressed, and may vary with the type of cell.
  • Polypeptides are defined herein in terms of their amino acid backbone structure or the nucleic acid encoding the same. Additions such as carbohydrate groups are generally not specified, but may be present nonetheless.
  • immunoglobulin refers to a protein consisting of one or more polypeptide(s) substantially encoded by immunoglobulin genes.
  • the recognized immunoglobulin genes include the different constant region genes as well as the myriad immunoglobulin variable region genes. Immunoglobulins may exist in a variety of formats, including, for example, Fv, Fab, and F(ab) 2 as well as single chains (scFv) or diabodies.
  • complete immunoglobulin denotes an immunoglobulin which comprises two so called light immunoglobulin chain polypeptides (light chain) and two so called heavy immunoglobulin chain polypeptides (heavy chain).
  • Each of the heavy and light immunoglobulin chain polypeptides of a complete immunoglobulin contains a variable domain (variable region) (generally the amino terminal portion of the polypeptide chain) comprising binding regions that are able to interact with an antigen.
  • variable domain variable region
  • Each of the heavy and light immunoglobulin chain polypeptides of a complete immunoglobulin also comprises a constant region (generally the carboxyl terminal portion).
  • the constant region of the heavy chain mediates the binding of the antibody i) to cells bearing a Fc gamma receptor (Fc ⁇ R), such as phagocytic cells, or ii) to cells bearing the neonatal Fc receptor (FcRn) also known as Brambell receptor. It also mediates the binding to some factors including factors of the classical complement system such as component (C1q).
  • Fc ⁇ R Fc gamma receptor
  • FcRn neonatal Fc receptor
  • C1q component
  • the variable domain of an immunoglobulin's light or heavy chain in turn comprises different segments, i.e. four framework regions (FR) and three hypervariable regions (CDR).
  • immunoglobulin fragment denotes a polypeptide comprising at least one domain of the variable domain of a heavy chain, the C H 1 domain, the hinge-region, the C H 2 domain, the C H 3 domain, the C H 4 domain of a heavy chain, the variable domain of a light chain and/or the C L domain of a light chain. Also comprised are derivatives and variants thereof. For example, a variable domain, in which one or more amino acids or amino acid regions are deleted, may be present.
  • immunoglobulin conjugate denotes a polypeptide comprising at least one domain of an immunoglobulin heavy or light chain conjugated via a peptide bond to a further polypeptide.
  • the further polypeptide is a non-immunoglobulin peptide, such as a hormone, or growth receptor, or antifusogenic peptide, or complement factor, or the like.
  • the term “filter” denotes both a microporous or macroporous filter.
  • the filter comprises a filter membrane which itself is composed of a polymeric material such as, e.g. polyethylene, polypropylene, ethylene vinyl acetate copolymers, polytetrafluoroethylene, polycarbonate, poly vinyl chloride, polyamides (nylon, e.g. ZetaporeTM, N 66 PosidyneTM), polyesters, cellulose acetate, regenerated cellulose, cellulose composites, polysulphones, polyethersulfones, polyarylsulphones, polyphenylsulphones, polyacrylonitrile, polyvinylidene fluoride, non-woven and woven fabrics (e.g.
  • the filter membrane of the first and second filter is made of cellulose acetate.
  • the final purification step is a so called “polishing step” for the removal of trace impurities and contaminants like aggregated immunoglobulins, residual HCP (host cell protein), DNA (host cell nucleic acid), viruses, or endotoxins.
  • polishing step often an anion exchange material in a flow-through mode is used.
  • affinity chromatography with microbial proteins e.g. protein A or protein G affinity chromatography
  • ion exchange chromatography e.g. cation exchange (carboxymethyl resins), anion exchange (amino ethyl resins) and mixed-mode exchange
  • thiophilic adsorption e.g. with beta-mercaptoethanol and other SH ligands
  • hydrophobic interaction or aromatic adsorption chromatography e.g. with phenyl-sepharose, aza-arenophilic resins, or m-aminophenylboronic acid
  • metal chelate affinity chromatography e.g.
  • Ni(II)- and Cu(II)-affinity material size exclusion chromatography
  • electrophoretical methods such as gel electrophoresis, capillary electrophoresis
  • Gel electrophoresis capillary electrophoresis
  • a first aspect as reported herein is a method for the preparation of an immunoglobulin solution comprising
  • the protein concentration is of from 100 g/l to 300 g/l. In another embodiment the protein concentration is of from 100 g/l up to 200 g/l. In a further embodiment the protein concentration is of from 120 g/l to 165 g/l. In another embodiment the immunoglobulin solution has a volume of from 3 liter to 100 liter. This solution volume is equivalent to a total mass of the immunoglobulin of from 300 g to 50,000 g. In one embodiment the volume is of from 3.1 liter to 80 liter. At a protein concentration of from 120 g/l to 165 g/l this solution volume is equivalent to a total mass of the immunoglobulin of from 370 g to 13,200 g. In one embodiment the immunoglobulin is an anti-IL 13 receptor alpha antibody. In another embodiment the immunoglobulin is an anti-HER2 antibody.
  • Another aspect as reported herein is a method for producing an immunoglobulin comprises the following steps
  • the cell is a prokaryotic cell or a eukaryotic cell. In one embodiment in which the cell is a prokaryotic cell the cell is selected from E. coli cells, or bacillus cells. In one embodiment in which the cell is a eukaryotic cell the cell is selected from mammalian cells, in a special embodiment from CHO cells, BHK cells, HEK cells, Per.C6® cells and hybridoma cells. In one embodiment the cell is a mammalian cell selected from CHO-K1 and CHO DG44. In one embodiment the cultivating is at a temperature of from 20° C. to 40° C., and for a period of from 4 to 28 days. In one embodiment the purifying is with a protein A affinity chromatography step and at least one step selected from cation exchange chromatography, anion exchange chromatography, and hydrophobic interaction chromatography.
  • a combination of a first filter unit comprising a pre-filter an a main-filter with a pore size of 3.0 ⁇ m and 0.8 ⁇ m, respectively, and a second filter unit comprising a pre-filter and a main-filter with a pore size of 0.45 ⁇ m and 0.22 ⁇ m, respectively, is advantageous for processing (filtrating) highly concentrated immunoglobulin solution by allowing the filtration of a complete batch of a concentrated immunoglobulin solution without the need to replace the filter.
  • each of the two filters employed in the units as well as the filter combination has approximately the same filter area, i.e. within two times the area of the smallest filter.
  • the method is operated in one embodiment with an applied pressure of 1.45 bar or more, in another of 1.5 bar or more. If the solution is a concentrated immunoglobulin solution with a concentration of 125 g/l or more, i.e. 130 g/l or 135 g/l, to which at least a sugar and a surfactant have been added then the method is operated in an embodiment with an applied pressure of 0.75 bar or less, in another embodiment of 0.7 bar or less.
  • kits comprising a first filter unit comprising a pre-filter and a main-filter with a pore size of 3.0 ⁇ m and 0.8 ⁇ m, respectively, and a second filter unit comprising a pre-filter and a main-filter with a pore size of 0.45 ⁇ m and 0.22 ⁇ m, respectively.
  • a filter comprising a first filter unit comprising a pre-filter and a main-filter with a pore size of 3.0 ⁇ m and 0.8 ⁇ m, respectively, and a second filter unit comprising a pre-filter and a main-filter with a pore size of 0.45 ⁇ m and 0.22 ⁇ m, respectively for the filtration of a concentrated immunoglobulin solution with a protein concentration of at least 100 g/l.
  • An exemplary antibody is an immunoglobulin against the IL13 receptor al protein (anti-IL13R ⁇ 1 antibody) e.g. as reported in SEQ ID NO: 01 to 12 of WO 2006/072564 (incorporated herein by reference).
  • Another exemplary immunoglobulin is an anti-HER2 antibody reported in WO 92/022653, WO 99/057134, WO 97/04801, U.S. Pat. No. 5,677,171 and U.S. Pat. No. 5,821,337 (incorporated herein by reference).
  • a highly concentrated immunoglobulin solution cannot be filtered with a single sterile filter with a pore size of 0.45 ⁇ m (pre-filter) and 0.22 ⁇ m (main-filter) without blocking of the pores of the filter with a loading of more than 2,460 g protein per square meter of filter area.
  • the concentrated immunoglobulin solutions were filtered through the single filter with the parameters as shown in Table 2.
  • a highly concentrated immunoglobulin solution can be filtered with a combination of two filters with a pore size of 3.0 ⁇ m (pre-filter) and 0.8 ⁇ m (main-filter) and of 0.45 ⁇ m (pre-filter) and 0.22 ⁇ m (main-filter) without blocking of the pores of the filter independent from the loading of protein per square meter of total filter area.
  • a combined filter with a first filter unit with a pore size of 3.0 ⁇ m and 0.8 ⁇ m, respectively, and a second filter unit with a pore size of 0.45 ⁇ m and 0.22 ⁇ m, respectively, and a filter area each of 0.6 square meters has been employed.
  • the concentrated immunoglobulin solutions were filtered through the combination of the two filters with the parameters as shown in Table 5.
  • a conditioned protein A eluate can be filtered with a combination of two filters but the flow has to be reduced if the filter area does not match between the two filters.
  • a filter unit with a pore size of 3.0 ⁇ m (pre-filter) and 0.8 ⁇ m (main-filter) with a filter area of 1.8 square meters and a filter unit with a pore size of 0.45 ⁇ m (pre-filter) and 0.22 ⁇ m (main-filter) with a filter area of 0.6 square meters has been employed.
  • the concentrated immunoglobulin solutions were filtered through the combined filter with the parameters as shown in Table 8.
  • a conditioned protein A eluate can be filtered with a combination of two filters without a reduction of the flow if the filter area does match between the two filters.
  • the filter unit with a pore size of 3.0 ⁇ m and 0.8 ⁇ m has a filter area of 0.2 square meters and the filter unit with a pore size of 0.45 ⁇ m and 0.22 ⁇ m has a filter area of 0.2 square meters.
  • Solutions comprising either an anti-IL13R ⁇ antibody or an anti-HER2 antibody were filtered with a filter combination employing different filter area and filter pore size as well as different excipients and applied pressure.
US13/394,766 2009-10-01 2010-09-29 Multistep final filtration Abandoned US20120231506A1 (en)

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EP09012460.3 2009-10-01
EP09012460 2009-10-01
PCT/EP2010/064487 WO2011039274A1 (en) 2009-10-01 2010-09-29 Multistep final filtration

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US15/444,018 Abandoned US20180009878A1 (en) 2009-10-01 2017-02-27 Multistep final filtration
US16/660,635 Active 2033-04-21 US11891430B2 (en) 2009-10-01 2019-10-22 Multistep final filtration

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US (3) US20120231506A1 (lt)
EP (3) EP3133083B1 (lt)
JP (1) JP5458183B2 (lt)
KR (3) KR101653471B1 (lt)
CN (3) CN103980346A (lt)
AU (1) AU2010302662B2 (lt)
BR (1) BR112012004054B1 (lt)
CA (1) CA2773674C (lt)
CY (1) CY1118577T1 (lt)
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HK (2) HK1200178A1 (lt)
HR (2) HRP20161693T1 (lt)
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CN104610447A (zh) 2015-05-13
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JP2013505733A (ja) 2013-02-21
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