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WO2008077155A1 - Stérilisation d'objets contenant des molécules biologiques - Google Patents

Stérilisation d'objets contenant des molécules biologiques Download PDF

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Publication number
WO2008077155A1
WO2008077155A1 PCT/US2007/088728 US2007088728W WO2008077155A1 WO 2008077155 A1 WO2008077155 A1 WO 2008077155A1 US 2007088728 W US2007088728 W US 2007088728W WO 2008077155 A1 WO2008077155 A1 WO 2008077155A1
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Prior art keywords
antibody
eto
antibodies
temperature
polypeptide
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PCT/US2007/088728
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English (en)
Inventor
Xanthe M. Lam
Tue Nguyen
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Genentech, Inc.
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Publication of WO2008077155A1 publication Critical patent/WO2008077155A1/fr

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    • 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
    • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20—Gaseous substances, e.g. vapours
    • A61L2/206—Ethylene oxide
    • 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
    • A61L2/0082—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 chemical substances
    • A61L2/0094—Gaseous substances

Definitions

  • the invention relates to methods for surface-sterilizing objects containing ethylene- oxide-sensitive, temperature-sensitive compounds, including biological molecules.
  • Objects used in medical applications are generally sterilized before use. Sterilization can be accomplished by a variety of methods including, e.g., steam sterilization, radiation sterilization, gas sterilization (e.g. with ethylene oxide), and chemical sterilization.
  • these treatments cannot be used for objects containing pharmaceutical compositions because their active ingredients are typically sensitive to them.
  • steam and gas sterilization are generally performed at high temperatures (approx. 45 0 C to 55 0 C or higher) that damage certain active ingredients in pharmaceutical compositions.
  • the agents used for radiation or chemical sterilization generally cause chemical damage to the active ingredients. Consequently, pharmaceutical compositions are generally sterilized by an alternative method, e.g. by filtration, and then packaged into separately sterilized objects. Because of the complexity of this process, it is difficult to also ensure the sterility of the surfaces of the objects.
  • the invention relates to methods for surface-sterilizing objects containing ethylene- oxide-sensitive, temperature-sensitive compounds, such as biological molecules.
  • the invention is based, in part, on the surprising discovery of ethylene-oxide -based sterilization conditions that will effectively sterilize the surface of an object but which do not significantly damage ethylene-oxide-sensitive, temperature-sensitive compounds contained inside.
  • the invention provides a method for surface-sterilizing an object having an ethylene-oxide(EtO)-impermeable interior space containing a compound with a temperature-sensitive and EtO-sensitive activity by exposing the object to EtO under conditions such that the object is surface-sterilized and the compound retains at least 50% of said activity.
  • the conditions comprise: a) temperature between 25 0 C and 35 0 C; b) EtO concentration of between 300 mg/L and 800 mg/L; and c) relative humidity between 45% and 60%; for between 1 and 6 hours.
  • the conditions comprise: a) temperature between 27 0 C and 33 0 C; b) EtO concentration of between 300 mg/L and 600 mg/L; and c) relative humidity between 48% and 52%; for between 1 and 6 hours. In some embodiments, the conditions comprise: a) temperature of 3O 0 C; b) EtO concentration of 600 mg/L; and c) relative humidity of 50%; for 1, 1.5 or 2 hours.
  • the compound retains at least 90% of said activity.
  • the compound is a polypeptide, e.g. an antibody, which includes monoclonal antibodies, chimeric antibodies, humanized antibodies or human antibodies.
  • the percent alkylation of the polypeptide is not statistically different from a control polypeptide not exposed to EtO.
  • the antibody is an antigen-binding fragment, e.g. a Fab fragment.
  • the Fab fragment binds VEGF, e.g. ranibizumab (LUCENTIS®).
  • the compound is present in an aqueous pharmaceutical composition, e.g. a composition comprising at least one of: an amino acid, a disaccharide and a non-ionic surfactant.
  • the pharmaceutical composition comprises histidine, trehalose and polysorbate 20.
  • the object is a syringe.
  • the syringe comprises glass and comprises a stopper comprising OlIl -1 laminated with FluroTec®; and a tip cap comprising OlIl -1 laminated with FluroTec® or D21-7H laminated with FluroTec®.
  • the object is contained within a package comprising an EtO-permeable material, e.g. TYVEK®.
  • the invention provides an object produced by a method of the invention.
  • a "compound” is any molecule that has an activity which can be measured.
  • Compounds according to the present invention generally have a pharmacological activity.
  • the activity of a compound may include the ability to bind to a particular molecule, to inhibit (or enhance) an enzymatic activity, induce a particular physiological response, etc.
  • an "ethylene-oxide-impermeable” or “EtO-impermeable” object is one in which no more than 0.5 ppm EtO is present inside the object after EtO sterilization.
  • EtO-impermable object my comprise, e.g., glass and/or certain plastics.
  • an activity is "ethylene-oxide-sensitive" or “EtO-sensitive” when the activity is reduced following exposure to ethylene oxide (EtO). In some embodiments, the exposure is to 10 ppm EtO at 3O 0 C for 3 days. In some embodiments, the activity is reduced by at least 90% following EtO exposure. In some embodiments, the activity is reduced by less that 90%, e.g.
  • percent alkylation in the context of a polypeptide is the percentage of polypeptide that is in the basic peak relative to polypeptide that is in the acidic or main peaks as measured by IEC.
  • an activity is "temperature-sensitive" when the activity is reduced following exposure to a high temperature, e.g. above room temperature. In some embodiments, the exposure is for 2 hours. In some embodiments, the activity is reduced following exposure to temperatures of at least 3O 0 C, e.g. at least 35 0 C, 4O 0 C, 45 0 C, 5O 0 C, 55 0 C or 6O 0 C. In some embodiments, the activity is reduced by at least 90% following exposure to a high temperature. In some embodiments, the activity is reduced by less that 90%, e.g. at least 80%, 70%, 60% or 50%. In some embodiments, the activity is reduced by at least 5% or at least 1%.
  • the surfact of an object is "sterilized" when the amount of at least one biological contaminant present on the surface of the object being treated according to the present invention is reduced following the treatment.
  • the amount is reduced by at least one log (i.e. by at least 10-fold). In some embodiments of the invention, the amount is reduced by 2 logs, 3 logs, 4 logs, 5 logs, or 6 logs.
  • a biological contaminant is a contaminant that, upon direct or indirect contact with a biological material, may have a deleterious effect on the biological material.
  • biological contaminants include viruses; bacteria or bacterial spores; parasites; yeasts; molds; mycoplasmas; and prions.
  • a biological contaminant need not be naturally or accidentally present.
  • a biological contaminant may be Bacillus subtilis spores deliberately placed on the surface of an obj ect to be sterilized in order to monitor the success of the sterilization.
  • a "subject” is a human subject or patient.
  • polypeptide is broadly defined and includes both short polypeptides as well as longer polypeptides such as proteins and protein fragments.
  • polypeptide may include from dipeptides, tripeptides, and the like to enzymes, hormones, antibodies or any fragments of these that has an activity.
  • antibody is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity.
  • monoclonal antibody refers to an antibody from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope(s), except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts.
  • Such monoclonal antibody typically includes an antibody comprising a polypeptide sequence that binds a target, wherein the target-binding polypeptide sequence was obtained by a process that includes the selection of a single target binding polypeptide sequence from a plurality of polypeptide sequences.
  • the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones or recombinant DNA clones.
  • the selected target binding sequence can be further altered, for example, to improve affinity for the target, to humanize the target binding sequence, to improve its production in cell culture, to reduce its immunogenicity in vivo, to create a multispecific antibody, etc., and that an antibody comprising the altered target binding sequence is also a monoclonal antibody of this invention.
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • monoclonal antibody preparations are advantageous in that they are typically uncontaminated by other immunoglobulins.
  • the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including, for example, the hybridoma method (e.g., Kohler et ah, Nature, 256:495 (1975); Harlow et ah, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et ah, in: Monoclonal Antibodies and T-CeIl Hybridomas 563-681, (Elsevier, N.Y., 1981)), recombinant DNA methods (see, e.g., U.S. Patent No.
  • phage display technologies see, e.g., Clackson et ah, Nature, 352:624-628 (1991); Marks et ah, J. MoI. Bioh, 222:581-597 (1991); Sidhu et ah, J. MoI. Biol. 338(2):299-310 (2004); Lee et ah, J.Mol.Bioh 340(5): 1073-1093 (2004); Fellouse, Proc. Nat. Acad. ScL USA 101(34): 12467- 12472 (2004); and Lee et a J. Immunol.
  • Methods 284(1-2): 119-132 (2004), and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences see, e.g., WO 1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits et ah, Proc. Natl. Acad. ScL USA, 90:2551 (1993); Jakobovits et ah, Nature, 362:255-258 (1993); Bruggemann et ah, Year in Immuno., 7:33 (1993); U.S. Patent Nos.
  • the monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; and Morrison et al, Proc. Natl. Acad. ScL USA, 81 :6851-6855 (1984)).
  • Chimeric antibodies of interest herein include “primatized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey, Ape etc) and human constant region sequences, as well as “humanized” antibodies.
  • "Humanized” forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or nonhuman primate having the desired specificity, affinity, and capacity.
  • humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Antibody fragments comprise a portion of an intact antibody, preferably comprising the antigen binding region thereof ("an antigen-binding fragment").
  • an antigen-binding fragment examples include Fab, Fab', F(ab') 2 , and Fv fragments; diabodies; linear antibodies; single- chain antibody molecules; and multispecific antibodies formed from antibody fragment(s).
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual "Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab') 2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.
  • Fv is the minimum antibody fragment which contains a complete antigen- recognition and antigen-binding site. This region consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. It is in this configuration that the three hypervariable regions of each variable domain interact to define an antigen- binding site on the surface of the VH-VL dimer. Collectively, the six hypervariable regions confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three hypervariable regions specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain (CHl) of the heavy chain.
  • Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHl domain including one or more cysteines from the antibody hinge region.
  • Fab' -SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear at least one free thiol group.
  • F(ab') 2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • exemplary antibodies include HER2 antibodies including trastuzumab (HERCEPTIN®) (Carter et al, Proc. Natl. Acad. ScL USA, 89:4285-4289 (1992), U.S. Patent No. 5,725,856) and pertuzumab (OMNITARGTM) (WO01/00245); CD20 antibodies (see below); IL- 8 antibodies (St John et al, Chest, 103:932 (1993), and International Publication No.
  • HERCEPTIN® trastuzumab
  • OMNITARGTM pertuzumab
  • CD20 antibodies see below
  • IL- 8 antibodies St John et al, Chest, 103:932 (1993), and International Publication No.
  • VEGF or VEGF receptor antibodies including humanized and/or affinity matured VEGF antibodies such as the humanized VEGF antibody huA4.6.1 bevacizumab (AVASTIN®) and ranibizumab (LUCENTIS®) (Kim et al., Growth Factors, 7:53-64 (1992), International Publication Nos. WO 96/30046 and WO 98/45331); PSCA antibodies (WOO 1/40309); CD40 antibodies, including S2C6 and humanized variants thereof (WO00/75348) and TNX 100 (Chiron/Tanox); CDl Ia antibodies including efalizumab (RAPTIVA®) (US Patent No.
  • TNF- ⁇ antibodies including cA2 or infliximab (REMICADE®), CDP571, MAK-195, adalimumab (HUMIRATM), CDP-870 (Celltech), anti-TNF- ⁇ polyclonal antibody (e.g. PASSTNF-aTM; Verigen); Tissue Factor (TF) antibodies (European Patent No.
  • ⁇ 4- ⁇ 7 integrin antibodies WO 98/06248
  • EGFR antibodies chimerized or humanized 225 antibody, cetuximab (ERBUTIX®; ImClone; WO 96/40210) or panitumumab (VECTIBIXTM; Amgen)
  • CD3 antibodies such as OKT3 (US Patent No. 4,515,893)
  • CD25 or Tac antibodies such as CHI-621 (SIMULECT®) and ZENAP AX® (US Patent No.
  • CD4 antibodies such as the cM-7412 antibody (Choy et al , Arthritis Rheum 39(l):52-56 (1996)); CD52 antibodies such as CAMPATH-IH (ILEX/Berlex) (Riechmann et al, Nature 332:323- 337 (1988)); Fc receptor antibodies such as the M22 antibody directed against FcRI as in Graziano et al, J.
  • ANTEGREN® natalizumab
  • CEA carcinoembryonic antigen
  • CD33 antibodies such as Hu M195 (Jurcic et al, Cancer Res 55(23 Suppl):5908s-5910s (1995) and CMA-676 or CDP771; CD22 antibodies such as LL2 or epratuzumab (LYMPHOCIDE®; Immunomedics), including epratuzumab Y- 90 (Juweid et al, Cancer Res 55(23 Suppl):5899s-5907s (1995)), CD22 antibody (Abiogen, Italy), CMC 544 (Wyeth/Celltech), combotox (UT Southwestern), BL22 (NIH), and
  • LympoScan Tc99 Immunomedics
  • EpCAM antibodies such as 17- IA (P ANOREX ®); GpIIb/IIIa antibodies such as abciximab or c7E3 Fab (REOPRO®); RSV antibodies such as MEDI-493 (SYNAGIS®); CMV antibodies such as PROTOVIR®; HIV antibodies such as PRO542; hepatitis antibodies such as the Hep B antibody OSTA VIR®; CA 125 antibody OvaRex; idiotypic GD3 epitope antibody BEC2; v3 antibody (e.g. VITAXIN®;
  • human renal cell carcinoma antibody such as ch-G250; ING-I; anti-human 17- IA antibody (3622W94); anti-human colorectal tumor antibody (A33); anti-human melanoma antibody R24 directed against GD3 ganglioside; anti-human squamous-cell carcinoma (SF-25); human leukocyte antigen (HLA) antibody such as Smart IDlO and the anti-HLA DR antibody Oncolym (Lym-1); CD37 antibody such as TRU 016 (Trubion); IL- 21 antibody (Zymogenetics/Novo Nordisk); anti-B cell antibody (Impheron); B cell targeting MAb (Immunogen/Aventis); 1D09C3 (Morphosys/GPC); LymphoRad 131 (HGS); Lym-1 antibody Y-90 (USC); LIF 226 (Enhanced Lifesci.); BAFF antibody (e.g., WO 03/33658); BAFF receptor antibody (e.
  • anti-complement antibody such as C5 antibody (e.g. eculizumab, 5Gl.1; Alexion); oral formulation of human immunoglobulin (e.g. IgPO; Protein Therapeutics); IL- 12 antibody such as ABT-874 (CAT/Abbott); and Teneliximab (BMS-224818).
  • C5 antibody e.g. eculizumab, 5Gl.1; Alexion
  • oral formulation of human immunoglobulin e.g. IgPO; Protein Therapeutics
  • IL- 12 antibody such as ABT-874 (CAT/Abbott)
  • Teneliximab BMS-224818.
  • the antibody herein is ranibizumab.
  • CD20 antibodies include: “C2B8,” which is now called “rituximab"
  • CD20 binding molecules such as the AME series of antibodies, e.g., AME 33 antibodies as set forth in WO 2004/103404 and US2005/0025764 (Watkins et al, Eli Lilly/Applied Molecular Evolution, AME); CD20 binding molecules such as those described in US 2005/0025764 (Watkins et al); A20 antibody or variants thereof such as chimeric or humanized A20 antibody (cA20, hA20, respectively) or IMMU-106 (US 2003/0219433, Immunomedics); CD20-binding antibodies, including epitope-depleted Leu- 16, 1H4, or 2B8, optionally conjugated with IL-2, as in US 2005/0069545A1 and WO 2005/16969 (Carr et al); bispecific antibody that binds CD22 and CD20, for example, hLL2xh
  • the preferred CD20 antibodies herein are chimeric, humanized, or human CD20 antibodies, more preferably rituximab, humanized 2H7, 2F2 (Hu-Max-CD20) human CD20 antibody (Genmab), and humanized A20 antibody (Immunomedics).
  • a "hormone” is used in the methods of the invention.
  • This generally refers to polypeptide hormones, which are generally secreted by glandular organs with ducts. Included among the hormones are, for example, growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; estradiol; hormone-replacement therapy; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, or testolactone; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); prolactin, placental lactogen, mouse gonadotropin-associated peptide, gonadotropin-releasing hormone; inhibin; activin; mullerian-inhibiting substance; and thrombopoietin
  • a "growth factor” is used in the methods of the invention.
  • This generally refers to proteins that promote growth, and include, for example, hepatic growth factor; fibroblast growth factor; vascular endothelial growth factor; nerve growth factors such as NGF- ⁇ ; platelet-derived growth factor; transforming growth factors (TGFs) such as TGF- ⁇ and TGF- ⁇ ; insulin-like growth factor-I and -II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon- ⁇ , - ⁇ , and - ⁇ ; and colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (G-CSF).
  • growth factor includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native-sequence growth factor, including synthetically produced small-molecule entities and
  • non-polypeptide compounds are used in the methods of the invention. These include, e.g., pegaptanib (MACUGEN®; Eyetech Pharmaceuticals), steroids, and compounds used for RNA-interference mediated therapy.
  • pegaptanib MACUGEN®; Eyetech Pharmaceuticals
  • steroids and compounds used for RNA-interference mediated therapy.
  • a "pharmaceutical composition” is a solution comprising a compound which is suitable for administration to a subject.
  • Pharmaceutical compositions according to the invention may be obtained by mixing the compound with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of aqueous solutions, lyophilized or other dried formulations.
  • Acceptable carriers, excipients, or stabilizers are nontoxic to subjects at the dosages and concentrations employed, and may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine,
  • the formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.
  • Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
  • the active ingredients may also be entrapped in microcapsule prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsule and poly-(methylmethacylate) microcapsule, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • macroemulsions for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • the formulations placed inside the object are also sterile. This is readily accomplished, e.g. by filtration through sterile filtration membranes.
  • Sustained-release preparations may be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the fusion polypeptide, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No.
  • copolymers of L-glutamic acid and ⁇ ethyl-L-glutamate non-degradable ethylene -vinyl acetate
  • degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)
  • poly-D-(-)-3-hydroxybutyric acid While polymers such as ethylene - vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.
  • encapsulated antibodies When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37°C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.
  • the methods of the invention are typically used to sterilize objects containing pharmaceutical formulations.
  • the methods of the invention may be used with syringes, vials or cartridges (such as are used in devices designed for multiple injections).
  • the method of the invention may be used with a syringe with or without a needle. In the latter case, some sort of cap or needle shield is generally positioned where the needle will subsequently be attached.
  • EtO sterilization runs on syringes containing a ranibizumab solution at a protein concentration indicated in Table 2 in a solution with 10 mM histidine HCl, 10% ⁇ , ⁇ - trehalose dehydrate, 0.01% polysorbate 20, pH 5.5
  • each run also included a paper strip with approximately 1.9 x 10 6 Bacillus subtilis spores, which was used to monitor the sterilization as follows: the strip was soaked in media, vortexed vigorously and then serial dilutions were plated and grown for one week. We then varied the following sterilization-critical factors as indicated in Table 1 : temperature, relative humidity, time of exposure (gas dwell), and EtO concentration. Table 1. Test runs for EtO Sterilization
  • the ranibizumab in the syringe was tested in a variety of ways to measure its activity.
  • the physical integrity of the molecule was analyzed by size- exclusion chromatography (SEC), ion-exchange chromatography (IEC), reverse-phase high- performance liquid chromatography (rp-HPLC) and capillary electrophoresis-SDS (CE-SDS).
  • SEC size- exclusion chromatography
  • IEC ion-exchange chromatography
  • rp-HPLC reverse-phase high- performance liquid chromatography
  • CE-SDS capillary electrophoresis-SDS
  • ranibizumab in the treated syringes for function by testing both its ability to bind VEGF by ELISA and its ability to antagonize VEGF induction of human umbilical vein endothelial cell (HUVEC) growth.
  • HUVEC human umbilical vein endothelial cell
  • each run also included a paper strip with approximately 1.9 x 10 6 Bacillus subtilis spores, which was used to monitor the sterilization as follows: the strip was soaked in media, vortexed vigorously and then serial dilutions were plated and grown for one week.

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Abstract

L'invention concerne un procédé pour stériliser en surface des objets contenant des composés sensibles à l'oxyde d'éthylène et sensibles à la température, y compris des molécules biologiques.
PCT/US2007/088728 2006-12-21 2007-12-21 Stérilisation d'objets contenant des molécules biologiques WO2008077155A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
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WO2014187779A1 (fr) * 2013-05-24 2014-11-27 Bayer Pharma Aktiengesellschaft Procédé de stérilisation superficielle d'une seringue prête à l'emploi
US20150197359A1 (en) * 2012-07-06 2015-07-16 3-D Matrix, Inc. Fill-finish proces for peptide solutions
JPWO2013147299A1 (ja) * 2012-03-31 2015-12-14 学校法人早稲田大学 生体組織の処理方法及び生体組織
WO2017209998A1 (fr) * 2016-06-01 2017-12-07 Centurion Medical Products Corporation Procédés de fabrication de récipients préremplis sans verre
WO2018215580A1 (fr) 2017-05-24 2018-11-29 Formycon Ag Procédé de stérilisation de seringues en plastique pré-remplies contenant un antagoniste du vegf
WO2018217995A1 (fr) 2017-05-24 2018-11-29 Formycon Ag Conditionnements pharmaceutiques pré-remplis stérilisables comprenant une formulation liquide d'un antagoniste du vegf
WO2018218013A2 (fr) 2017-05-24 2018-11-29 Sio2 Medical Products, Inc. Conditionnement pharmaceutique stérilisable pour formulations ophtalmiques
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EP3685826B1 (fr) 2012-07-03 2021-11-03 Novartis AG Seringue
US11519020B2 (en) 2018-05-25 2022-12-06 Regeneron Pharmaceuticals, Inc. Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF
US11769597B2 (en) 2015-12-03 2023-09-26 Regeneron Pharmaceuticals, Inc. Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF
WO2024197344A1 (fr) * 2023-03-27 2024-10-03 Phebra Pty Ltd Procédé de stérilisation

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Publication number Priority date Publication date Assignee Title
WO2011006877A1 (fr) * 2009-07-14 2011-01-20 Novartis Ag Décontamination de surface de récipients pré-remplis dans leur suremballage
JPWO2013147299A1 (ja) * 2012-03-31 2015-12-14 学校法人早稲田大学 生体組織の処理方法及び生体組織
US11786664B2 (en) 2012-05-07 2023-10-17 Medline Industries, Lp Prefilled container systems
US10780228B2 (en) 2012-05-07 2020-09-22 Medline Industries, Inc. Prefilled container systems
US12048837B2 (en) 2012-06-01 2024-07-30 Novartis Ag Syringe
EP3777834B1 (fr) 2012-06-01 2022-02-16 Novartis AG Seringue
US11103644B2 (en) 2012-06-01 2021-08-31 Novartis Ag Syringe
US11110226B2 (en) 2012-06-01 2021-09-07 Novartis Ag Syringe
US11147925B2 (en) 2012-06-01 2021-10-19 Novartis Ag Syringe
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US11185635B2 (en) 2012-06-01 2021-11-30 Novartis Ag Syringe
EP3685826B1 (fr) 2012-07-03 2021-11-03 Novartis AG Seringue
US12006085B2 (en) 2012-07-06 2024-06-11 3-D Matrix, Ltd. Fill-finish process for peptide solutions
US20150197359A1 (en) * 2012-07-06 2015-07-16 3-D Matrix, Inc. Fill-finish proces for peptide solutions
US10793307B2 (en) * 2012-07-06 2020-10-06 3-D Matrix, Ltd. Fill-finish process for peptide solutions
WO2014187779A1 (fr) * 2013-05-24 2014-11-27 Bayer Pharma Aktiengesellschaft Procédé de stérilisation superficielle d'une seringue prête à l'emploi
US11769597B2 (en) 2015-12-03 2023-09-26 Regeneron Pharmaceuticals, Inc. Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF
WO2017209998A1 (fr) * 2016-06-01 2017-12-07 Centurion Medical Products Corporation Procédés de fabrication de récipients préremplis sans verre
WO2018218013A2 (fr) 2017-05-24 2018-11-29 Sio2 Medical Products, Inc. Conditionnement pharmaceutique stérilisable pour formulations ophtalmiques
WO2018217995A1 (fr) 2017-05-24 2018-11-29 Formycon Ag Conditionnements pharmaceutiques pré-remplis stérilisables comprenant une formulation liquide d'un antagoniste du vegf
WO2018215580A1 (fr) 2017-05-24 2018-11-29 Formycon Ag Procédé de stérilisation de seringues en plastique pré-remplies contenant un antagoniste du vegf
US11519020B2 (en) 2018-05-25 2022-12-06 Regeneron Pharmaceuticals, Inc. Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF
US12116622B2 (en) 2018-05-25 2024-10-15 Regeneron Pharmaceuticals, Inc. Methods of associating genetic variants with a clinical outcome in patients suffering from age-related macular degeneration treated with anti-VEGF
WO2024197344A1 (fr) * 2023-03-27 2024-10-03 Phebra Pty Ltd Procédé de stérilisation

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