WO2004087220A1 - Isolation d'un proteine d'une source naturelle sous forme sterile - Google Patents

Isolation d'un proteine d'une source naturelle sous forme sterile Download PDF

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Publication number
WO2004087220A1
WO2004087220A1 PCT/AU2004/000423 AU2004000423W WO2004087220A1 WO 2004087220 A1 WO2004087220 A1 WO 2004087220A1 AU 2004000423 W AU2004000423 W AU 2004000423W WO 2004087220 A1 WO2004087220 A1 WO 2004087220A1
Authority
WO
WIPO (PCT)
Prior art keywords
sterile
protein
natural source
membrane
sterilised
Prior art date
Application number
PCT/AU2004/000423
Other languages
English (en)
Inventor
Bhanu Manickavasagam
Original Assignee
Norika Holdings Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Norika Holdings Pty Ltd filed Critical Norika Holdings Pty Ltd
Priority to JP2006503993A priority Critical patent/JP2006522024A/ja
Priority to AU2004226875A priority patent/AU2004226875A1/en
Publication of WO2004087220A1 publication Critical patent/WO2004087220A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/08—Radiation
    • A61L2/10—Ultraviolet radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0017—Filtration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
    • A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
    • A61L2/0029—Radiation
    • A61L2/0035—Gamma radiation
    • 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

Definitions

  • the present invention is concerned with a process for the isolation of a protein from a natural source in sterile form, more particularly, a process in which a protein solution derived from the natural source is filtered under sterile conditions to provide a sterile pharmaceutical product.
  • filtration membranes contain pores , and the smaller the pore size the smaller the particles retained on the filter.
  • the process of ultrafiltration can be used to filter viruses from a solution where a membrane with a pore size to exclude particles from lOOkD to 500kD is chosen .
  • United States Patent No. 5,736,051 describes the filtration of pharmacological liquids to exclude viruses and, indeed, the polyvinylidene fluoride membrane of the invention appears principally designed for that purpose.
  • the patent does not teach or suggest maintenance of a sterile environment during the filtration, or sterilisation of the filtration membrane . Filtration under these conditions is nevertheless capable of removing the specific viruses identified such as Tl bacteriophage , PR772 coliphage and PP7 bacteroiophage from both the test solutions (containing only virus) and the immunoglobulin solutions filtered, but the product cannot be considered entirely sterile .
  • United States Patent No. 6,365,395 describes removing virus from an immunoglobulin solution following a first filtration step in which protein aggregates comprising protein trimers and higher protein polymers are removed.
  • the filtration is conducted under conditions to retain the virus on the membrane while permitting passage of the protein, without seemingly performing the filtration under sterile conditions . Accordingly, specific virus contaminants are removed without seemingly achieving full sterility.
  • a further disclosure in similar vein is European Patent Application No. 0219295, in which a solution of human growth hormone obtained from the pituitary gland is filtered to exclude the Creutzfeldt-Jacob virus, which can be present in pituitary gland extracts if a donor was infected.
  • the filtration step undertaken to remove CJD virus is done in a sterile environment. Therefore, while the process will remove the specific contaminant that may be present (CJD virus) it will not necessarily achieve a fully sterile product. Accordingly, there remains a need for a process in which a protein from a natural source can be isolated in sterile form for use as a pharmaceutical product, and not merely with selected pathogens removed.
  • a process for the isolation of a protein from a natural source in sterile form for use as a pharmaceutical product comprising the steps of:
  • a sterile solution comprising a protein from a natural source and a solvent therefor when prepared by the process of the first aspect of the invention .
  • the solution of the isolated protein and a solvent therefor may further comprise additional substances .
  • it may further comprise salts and/or acid and base combinations so as to constitute a buffer.
  • the preparation and constitution of such solutions is well known to the person skilled in the art.
  • the protein may be any protein from any natural source, and may have been isolated in an extraction process from a solid material or, conveniently, be contained in a liquid fraction such as blood serum.
  • the solution may be provided as a direct result of a purification process, for example, as a solution of the material isolated in a chromatographic separation procedure. However, the solution may also be subjected to additional purification steps such as a subsequent diafiltration step. Still further, solvent exchange may take place without collecting the protein in solid form through a diafiltration process involving buffer exchange.
  • the pore size is selected to be sufficiently small to exclude pathogens. Preferably, the pore size is as large as possible beneath this limit in order to enhance the flow characteristics of the membrane, and generally in the range of lOOkD to 0.2 ⁇ m. In a particularly preferred embodiment of the invention the pore size is 0.2 ⁇ m.
  • the membrane is sterilised using gamma radiation but any convenient sterilisation method may be used provided the membrane is not degraded. It is convenient to obtain a filter capsule which has been pre- sterilised in this fashion.
  • the filtration process is carried out in a sealed container which has been sterilised, for example through exposure to UV light, although any suitable method of sterilisation may be employed.
  • a suitable period of exposure to UV light is 30 minutes or more. It is convenient for small scale work to use a glovebox which allows for manipulation of the apparatus within the sterile area.
  • the sterile filtrate may be collected and stored in solution for subsequent use in this form. Alternatively, steps may be taken to precipitate the protein from the sterile solution if so desired, for example, by freeze drying.
  • Step 1 Whole live abalone are obtained and may be processed immediately or stored in an appropriate tank until required.
  • Step 2 Rinse abalone under running water prior to shucking. Working on a chopping board, shuck the animal and remove the body from the shell .
  • Step 3 Carefully cut around the top of the foot to remove the guts .
  • Step 4 Rinse the foot under running water prior to bleeding. Working in a clean container to collect any blood, cut away the mouth area and store for later use. Make several deep incisions across the front of the foot. Store the initial blood collection in a coldroom.
  • Step 5 Quickly transfer the foot to a draining tray above a collection vessel. Stand the abalone upright in the tray and cover . Allow the blood to drain overnight in a coldroom.
  • Step 6 Remove any solid material from the blood by centrifugation at 12000 x g. Store the supernatant in a coldroom until required.
  • Step 7 Prepare 12 column volumes + 8 supernatant volumes of equilibration buffer .
  • the equilibration buffer consists of 18 mM acetic acid + 1 mM MgCl 2 + 1 mM CaCl 2 at pH 5.5.
  • Step 8 Prepare 5 column volumes of elution buffer per column run.
  • the elution buffer consists of 18 mM acetic acid + 1 M NaCl + 1 mM MgCl 2 + 1 mM CaCl 2 at pH 5.5.
  • Step 9 Pack a suitably sized column (Pharmacia Index 140-500) with 5L of Bio-Rad Macro-Prep High S resin and equilibrate with equilibration buffer for at least 7 column volumes and until the pH and conductivity of the column outflow are within 0.05 pH units and 0.5 mS of the buffer .
  • the maximum running flow rate was 500ml/min.
  • Step 10 Buffer exchange of the supernatant against the equilibrium buffer is performed with a 100 kD NMWCO ultrafiltration cartridge .
  • Step 11 Diafilter the supernatant for at least 6 supernatant volumes and until the supernatant conductivity is within 0.5 mS of the equilibrium buffer. Collect the diafiltration permeate.
  • Step 12 Concentrate the diafiltered supernatant down to 3 system hold-up volumes less than the original supernatant volume . Drain the system hold-up and add to the retentate . Rinse the cartridge by recirculating 1.5 hold-up volumes of equilibration buffer at the operating flowrate for 10 minutes. Drain the system holdup and add to the retentate .
  • Step 13 Prepare 2L of ultrafiltration cartridge cleaning solution per m 2 of membrane area .
  • the storage solution consists of 1 M NaOH at 40° C. Clean the cartridge by recirculating the cleaning solution for at least 30 minutes. Rinse the cartridge with deionised water until the pH of the retentate and permeate are ⁇ 7.
  • Step 14 Prepare 2L of ultrafiltration cartridge storage solution per m 2 of membrane area.
  • the storage solution consists of 0.1 M NaOH or 20% ethanol . Rinse the cartridge with storage solution then seal and store the cartridge in a coldroom.
  • Step 15 Begin loading the column at the running flowrate. Measure the absorbance at 280 nm of the column outflow and collect the UV absorbing flow through fractions . Plot the UV absorbance of the fractions against the cumulative volume collected.
  • Step 16 Wash the column with at least 3 column volumes of equilibration buffer and until the absorbance at 280 nm of the column outflow has reached baseline.
  • Step 17 Elute the column with at least 3 column volumes of elution buffer and until the absorbance at 280 nm of the column outflow has reached baseline.
  • Step 18 Repeat from the equilibrium step (step 9) for up to 2 additional column runs. Further runs will require column cleaning (steps 19 and 20) every 3 runs.
  • Step 19 Prepare 2 column volumes of cleaning in place solution.
  • the CIP solution consists of 1 M NaOH. Clean the column at the running pressure. Collect the UV absorbing CIP fractions and plot on the chromatogram.
  • Step 20 Wash the column with at least 2 column volumes of equilibration buffer and until the absorbance at 280 nm of the column outflow has reached baseline and the pH of the column out low ⁇ 7. Continue to collect the UV absorbing fractions and plot on the chromatogram.
  • Step 21 Prepare 1 column volume of storage solution.
  • the storage solution consists of 20% ethanol . Rinse the column at the running flowrate . Seal , label , and store the packed column.
  • Step 22 Conduct a protein assay on the chromatography samples and pool the elutions . Calculate the volume required for a 20 mg/ml solution of final product .
  • Step 23 Prepare 8 product volumes of diafiltration buffer.
  • the diafiltration buffer consists of 53 mM Na 2 HP0 4 + 30 mM NaH 2 P0 4 + 150 mM NaCl at pH 7.2.
  • Step 24 Final concentration and buffer exchange of the product is performed with a 100 kD NMWCO ultrafiltration cartridge.
  • Step 25 Concentrate the pooled column elutions down to the volume calculated in step 22. Collect the ultra iltration permeate .
  • Step 26 Diafilter the ultrafiltration retentate for at least 6 retentate volumes and until the retentate pH is within 0.03 pH units of the diafiltration buffer . Collect the diafiltration permeate .
  • Step 27 Concentrate the diafiltered product down to 3 system hold-up volumes less than the required final product volume . Drain the system hold-up and add to the retentate . Rinse the cartridge by recirculating 1.5 hold-up volumes of diafiltration buffer at the operating flowrate for 10 minutes. Drain the system hold-up and add to the retentate.
  • Concentrated diafiltration retentate was sterilised in a filtration apparatus comprising a filter capsule pre-sterilised with gamma radiation set up in a sterile glovebox. Filtrate tubing and receiving bottles were sterilised by autoclaving. The process involved the following steps :
  • the concentrated diafiltration retentate is sterilised by filtration through the membrane, which in this case is a 0.2 ⁇ m membrane, into a sterile container with the necessary manipulations of the apparatus being made by the operator by way of the glove extending into the glovebox .
  • the final, sterile filtered serum product showed no growth on LB agar plates , aerobic count plates , coliform count plates, or yeast and mould count plates.
  • the plate counts of the pre- and post-filtration samples show that the reduction in the total microbial count to be of the order of 10 4 .
  • the absence of colonies on the post-filtration plates indicate that the filtration step has met the criteria for acceptable sterility.
  • the process of the present invention is useful in the preparation of sterile solutions of proteins from natural sources for pharmaceutical use .

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Water Supply & Treatment (AREA)
  • Peptides Or Proteins (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)
  • Apparatus For Disinfection Or Sterilisation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé qui permet d'isoler une protéine d'une source naturelle, en vue de l'utiliser comme produit pharmaceutique. Le procédé consiste à: 1) mettre en oeuvre une membrane stérilisée dont les pores sont suffisamment petites pour exclure des agents pathogènes; 2) faire passer une solution de protéines dérivée d'une source naturelle au travers de la membrane, dans un environnement stérile; et 3) recueillir le filtrat stérile.
PCT/AU2004/000423 2003-04-02 2004-04-01 Isolation d'un proteine d'une source naturelle sous forme sterile WO2004087220A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2006503993A JP2006522024A (ja) 2003-04-02 2004-04-01 無菌様式での自然源からのタンパク質の単離
AU2004226875A AU2004226875A1 (en) 2003-04-02 2004-04-01 Isolation of a protein from a natural source in sterile form

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2003901515A AU2003901515A0 (en) 2003-04-02 2003-04-02 Sterilisation process for pharmaceutical product
AU2003901515 2003-04-02

Publications (1)

Publication Number Publication Date
WO2004087220A1 true WO2004087220A1 (fr) 2004-10-14

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PCT/AU2004/000423 WO2004087220A1 (fr) 2003-04-02 2004-04-01 Isolation d'un proteine d'une source naturelle sous forme sterile

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AU (1) AU2003901515A0 (fr)
WO (1) WO2004087220A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008011136A2 (fr) * 2006-07-20 2008-01-24 Sicor Inc. Procédé de préparation d'un ingrédient pharmaceutique actif stérile solide

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105550A (en) * 1972-12-23 1978-08-08 Mueller Hans Preparation of sterile products
US4360435A (en) * 1979-11-01 1982-11-23 Baxter Travenol Laboratories, Inc. Process for sterilizing and transferring a solution
EP0219295A2 (fr) * 1985-10-07 1987-04-22 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JCR PHARMACEUTICALS CO., LTD Procédé de production de l'hormone de croissance humaine
US5211950A (en) * 1989-05-23 1993-05-18 Teijin Limited Stabilized calcitonin pharmaceutical composition
EP0610729A1 (fr) * 1993-01-27 1994-08-17 Dr. Karl Thomae GmbH Procédé pour la purification des protéines et peptides à partir des solutions contenant des lipides
US5641483A (en) * 1995-06-07 1997-06-24 Beaulieu; Andre Wound healing formulations containing human plasma fibronectin
US5736051A (en) * 1993-12-22 1998-04-07 Pall Corporation Polyvinylidene fluoride membrane and method for removing viruses from solutions
US5780037A (en) * 1995-04-14 1998-07-14 Pharmaprint, Inc. Mistletoe extract and method
RU2122864C1 (ru) * 1996-12-26 1998-12-10 Московский научно-исследовательский институт эпидемиологии и микробиологии им.Г.Н.Габричевского Препарат иммуноглобулина для внутривенного введения и способ его получения
EP0776212B1 (fr) * 1994-08-19 1999-06-02 SANORELL PHARMA GmbH & CO. Procede de production de preparations pharmaceutiques et/ou de produits alimentaires exempts d'infection a partir d'un materiau infectieux contenant notamment des prions
US6004025A (en) * 1997-05-16 1999-12-21 Life Technologies, Inc. Automated liquid manufacturing system
US6024938A (en) * 1994-07-07 2000-02-15 Ortho Pharmaceutical Corporation Lyophilized imaging agent formulation comprising a chemotactic peptide
CA2256246A1 (fr) * 1998-12-18 2000-06-18 Alan M. Jones Procede de filtration sur membrane de solutions de proteines
US6303113B1 (en) * 1991-08-15 2001-10-16 Roche Diagnostics Gmbh Process for the production of pharmaceutical preparations containing human protein for infusion or injection purposes
US6365395B1 (en) * 2000-11-03 2002-04-02 Millipore Corporation Process for removing protein aggregates and virus from a protein solution
EP1250929A1 (fr) * 1999-12-20 2002-10-23 Mitsubishi Pharma Corporation Compositions a base de proteines de plasma exemptes de virus traitees a l'aide d'une membrane poreuse et procede de production
US6518406B1 (en) * 1999-06-23 2003-02-11 Octapharma Ag Method for purification of proteins

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4105550A (en) * 1972-12-23 1978-08-08 Mueller Hans Preparation of sterile products
US4360435A (en) * 1979-11-01 1982-11-23 Baxter Travenol Laboratories, Inc. Process for sterilizing and transferring a solution
EP0219295A2 (fr) * 1985-10-07 1987-04-22 NIHON CHEMICAL RESEARCH KABUSHIKI KAISHA also known as JCR PHARMACEUTICALS CO., LTD Procédé de production de l'hormone de croissance humaine
US5211950A (en) * 1989-05-23 1993-05-18 Teijin Limited Stabilized calcitonin pharmaceutical composition
US6303113B1 (en) * 1991-08-15 2001-10-16 Roche Diagnostics Gmbh Process for the production of pharmaceutical preparations containing human protein for infusion or injection purposes
EP0610729A1 (fr) * 1993-01-27 1994-08-17 Dr. Karl Thomae GmbH Procédé pour la purification des protéines et peptides à partir des solutions contenant des lipides
US5736051A (en) * 1993-12-22 1998-04-07 Pall Corporation Polyvinylidene fluoride membrane and method for removing viruses from solutions
US6024938A (en) * 1994-07-07 2000-02-15 Ortho Pharmaceutical Corporation Lyophilized imaging agent formulation comprising a chemotactic peptide
EP0776212B1 (fr) * 1994-08-19 1999-06-02 SANORELL PHARMA GmbH & CO. Procede de production de preparations pharmaceutiques et/ou de produits alimentaires exempts d'infection a partir d'un materiau infectieux contenant notamment des prions
US5780037A (en) * 1995-04-14 1998-07-14 Pharmaprint, Inc. Mistletoe extract and method
US5641483A (en) * 1995-06-07 1997-06-24 Beaulieu; Andre Wound healing formulations containing human plasma fibronectin
RU2122864C1 (ru) * 1996-12-26 1998-12-10 Московский научно-исследовательский институт эпидемиологии и микробиологии им.Г.Н.Габричевского Препарат иммуноглобулина для внутривенного введения и способ его получения
US6004025A (en) * 1997-05-16 1999-12-21 Life Technologies, Inc. Automated liquid manufacturing system
CA2256246A1 (fr) * 1998-12-18 2000-06-18 Alan M. Jones Procede de filtration sur membrane de solutions de proteines
US6518406B1 (en) * 1999-06-23 2003-02-11 Octapharma Ag Method for purification of proteins
EP1250929A1 (fr) * 1999-12-20 2002-10-23 Mitsubishi Pharma Corporation Compositions a base de proteines de plasma exemptes de virus traitees a l'aide d'une membrane poreuse et procede de production
US6365395B1 (en) * 2000-11-03 2002-04-02 Millipore Corporation Process for removing protein aggregates and virus from a protein solution

Non-Patent Citations (4)

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Title
DATABASE WPI Derwent World Patents Index; Class B04, AN 2000-204044/18 *
GENNARO ALFONSO R.: "The science and practice of pharmacy", part CH40 2000, LIPPINCOTT WILLIAMS & WILKINS, BALTIMORE MARYLAND USA, article REMINGTON: "Sterilization", pages: 753 - 778 *
MILLIPORE CATALOGUE - VIRESOLVE PROCESS AREA MODULES, MILLIDISK CARTRIDGE FILTERS AND 33 MM MILLEX FILTER UNITS, Retrieved from the Internet <URL:http://www.millipore.com/catalogue.nsf/docs/C605,www.millipore.com/catalogue.nsf/docs/C525,www.millipore.com/catalogue.nsf/docs/C7610> *
SIGMA CHEMICAL COMPANY: "Organic compounds and diagnostic reagents", CATALOGUE OF BIOCHEMICALS, 1993, pages - 1893, 1894, 1897 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008011136A2 (fr) * 2006-07-20 2008-01-24 Sicor Inc. Procédé de préparation d'un ingrédient pharmaceutique actif stérile solide
WO2008011136A3 (fr) * 2006-07-20 2008-04-17 Sicor Inc Procédé de préparation d'un ingrédient pharmaceutique actif stérile solide

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JP2006522024A (ja) 2006-09-28

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