US20030095890A1 - Methods for sterilizing biological materials containing non-aqueous solvents - Google Patents
Methods for sterilizing biological materials containing non-aqueous solvents Download PDFInfo
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- US20030095890A1 US20030095890A1 US09/960,703 US96070301A US2003095890A1 US 20030095890 A1 US20030095890 A1 US 20030095890A1 US 96070301 A US96070301 A US 96070301A US 2003095890 A1 US2003095890 A1 US 2003095890A1
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- biological material
- radiation
- aqueous solvent
- residual solvent
- solvent content
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Classifications
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- 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
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- 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
- C07K16/26—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against hormones ; against hormone releasing or inhibiting factors
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- 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
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- A—HUMAN NECESSITIES
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- 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
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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
- A61L2/0005—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
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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
- A61L2/02—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
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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
Definitions
- the present invention relates to methods for sterilizing biological materials to reduce the level of one or more active biological contaminants or pathogens therein, such as viruses, bacteria (including inter- and intracellular bacteria, such as mycoplasmas, ureaplasmas, nanobacteria, chlamydia, rickettsias), yeasts, molds, fungi, prions or similar agents responsible, alone or in combination, for TSEs and/or single or multicellular parasites.
- the present invention particularly relates to methods of sterilizing biological materials containing one or more non-aqueous solvents with irradiation.
- Many biological materials that are prepared for human, veterinary, diagnostic and/or experimental use may contain unwanted and potentially dangerous biological contaminants or pathogens, such as viruses, bacteria (including inter- and intracellular bacteria, such as mycoplasmas, ureaplasmas, nanobacteria, chlamydia, rickettsias), yeasts, molds, fungi, prions or similar agents responsible, alone or in combination, for TSEs and/or single or multicellular parasites. Consequently, it is of utmost importance that any biological contaminant or pathogen in the biological material be inactivated before the product is used.
- viruses such as viruses, bacteria (including inter- and intracellular bacteria, such as mycoplasmas, ureaplasmas, nanobacteria, chlamydia, rickettsias), yeasts, molds, fungi, prions or similar agents responsible, alone or in combination, for TSEs and/or single or multicellular parasites. Consequently, it is of utmost importance that
- the viruses of concern for both human and animal-derived biological materials the smallest, and thus most difficult to inactivate, belong to the family of Parvoviruses and the slightly larger protein-coated Hepatitis virus.
- the Parvovirus B19, and Hepatitis A are the agents of concern.
- porcine-derived materials the smallest corresponding virus is Porcine Parvovirus. Since this virus is harmless to humans, it is frequently chosen as a model virus for the human B19 Parvovirus. The demonstration of inactivation of this model parvovirus is considered adequate proof that the method employed will kill human B19 virus and Hepatitis A, and by extension, that it will also kill the larger and less hardy viruses such as HIV, CMV, Hepatitis B and C and others.
- heat treatment of biological materials may require heating to approximately 60° C. for a minimum of 10 hours, which can be damaging to sensitive biological materials. Indeed, heat inactivation can destroy 50% or more of the biological activity of certain biological materials.
- Filtration involves filtering the product in order to physically remove contaminants. Unfortunately, this method may also remove products that have a high molecular weight. Further, in certain cases, small viruses may not be removed by the filter.
- the procedure of chemical sensitization involves the addition of noxious agents which bind to the DNA/RNA of the virus and which are activated either by UV or other radiation.
- This radiation produces reactive intermediates and/or free radicals which bind to the DNA/RNA of the virus, break the chemical bonds in the backbone of the DNA/RNA, and/or cross-link or complex it in such a way that the virus can no longer replicate.
- This procedure requires that unbound sensitizer is washed from products since the sensitizers are toxic, if not mutagenic or carcinogenic, and cannot be administered to a patient.
- Irradiating a product with gamma radiation is another method of sterilizing a product.
- Gamma radiation is effective in destroying viruses and bacteria when given in high total doses (Keathly et al., “Is There Life After Irradiation? Part 2 ,” BioPharm July-August, 1993, and Leitman, Use of Blood Cell Irradiation in the Prevention of Post Transfusion Graft-vs-HostDisease,” Transfusion Science 10:219-239 (1989)).
- the published literature in this area however, teaches that gamma radiation can be damaging to radiation sensitive products, such as blood, blood products, protein and protein-containing products.
- An object of the invention is to solve at least the above problems and/or disadvantages and to provide at least the advantages described hereinafter.
- a first embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising irradiating the biological material with radiation for a time effective to sterilize the material at a rate effective to sterilize the material and to protect the material from radiation.
- Another embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) adding to a biological material at least one stabilizer in an amount effective to protect the biological material from radiation; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the material.
- Another embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) reducing the residual solvent content of a biological material to a level effective to protect the biological material from radiation; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material.
- Another embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) reducing the temperature of a biological material to a level effective to protect the biological material from radiation; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material.
- Another embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) applying to the biological material a stabilizing process selected from the group consisting of: (a) reducing the residual solvent content of a biological material, (b) adding to the biological material at least one stabilizer, and (c) reducing the temperature of the biological material; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material, wherein the stabilizing process and the rate of irradiation are together effective to protect the biological material from radiation.
- a stabilizing process selected from the group consisting of: (a) reducing the residual solvent content of a biological material, (b) adding to the biological material at least one stabilizer, and (c) reducing the temperature of the biological material; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material, wherein the stabilizing process and the rate
- Another embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) applying to the biological material at least two stabilizing processes selected from the group consisting of: (a) reducing the residual solvent content of a biological material, (b) adding to the biological material at least one stabilizer, and (c) reducing the temperature of the biological material; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material, wherein the stabilizing processes may be performed in any order and are together effective to protect the biological material from radiation.
- the invention also provides a composition comprising a biological material and a non-aqueous solvent in an amount effective to preserve the preparation for its intended use following sterilization with radiation.
- the invention also provides a composition comprising at least one biological material, a least one non-aqueous solvent and at least one stabilizer, wherein the non-aqueous solvent and stabilizer are together present in an amount effective to preserve the material for its intended use following sterilization with radiation.
- FIG. 1 is a graph showing the effect of gamma radiation on dried urokinase suspended in polypropylene glycol (PPG) 400 or phosphate buffered saline (PBS).
- PPG polypropylene glycol
- PBS phosphate buffered saline
- FIG. 2 is a graph showing the activity of immobilized anti-insulin monoclonal antibody after irradiation in the presence of various forms of polypropylene glycol.
- FIG. 3 is a graph showing the effect of gamma radiation on trypsin suspended in polypropylene glycol at varying levels of residual solvent (water) content.
- FIGS. 4 ( a )- 4 ( d ) show the effects of porcine heart valves gamma irradiated in the presence of polypropylene glycol 400 (PPG400) and, optionally, a scavenger.
- PPG400 polypropylene glycol 400
- FIGS. 5 ( a )- 5 ( e ) show the effects of gamma irradiation on porcine heart valve cusps in the presence of 50% DMSO and, optionally, a stabilizer, and in the presence of polypropylene glycol 400 (PPG400).
- PPG400 polypropylene glycol 400
- FIGS. 6 ( a )- 6 ( e ) show the effects of gamma irradiation on frozen porcine AV heart valves soaked in various solvents and irradiated to a total dose of 30 kGy at 1.584 kGy/hr at ⁇ 20° C.
- FIGS. 7 ( a )- 7 ( h ) show the effects of gamma irradiation on frozen porcine AV heart valves soaked in various solvents and irradiated to a total dose of 45 kGy at approximately 6 kGy/hr at ⁇ 70° C.
- the term “sterilize” is intended to mean a reduction in the level of at least one active biological contaminant or pathogen found in the biological material being treated according to the present invention.
- biological material is intended to mean any substance derived or obtained from a living organism.
- biological materials include, but are not limited to, the following: cells; tissues; blood or blood components; proteins, including recombinant and transgenic proteins, and proteinaceous materials; enzymes, including digestive enzymes, such as trypsin, chymotrypsin, alpha-galactosidase and iduronodate-2-sulfatase; immunoglobulins, including mono and polyimmunoglobulins; botanicals; food and the like.
- biological materials include, but are not limited to, the following: ligaments; tendons; nerves; bone, including demineralized bone matrix, grafts, joints, femurs, femoral heads, etc.; teeth; skin grafts; bone marrow, including bone marrow cell suspensions, whole or processed; heart valves; cartilage; corneas; arteries and veins; organs, including organs for transplantation, such as hearts, livers, lungs, kidneys, intestines, pancreas, limbs and digits; lipids; carbohydrates; collagen, including native, afibrillar, atelomeric, soluble and insoluble, recombinant and transgenic, both native sequence and modified; chitin and its derivatives, including NO-carboxy chitosan (NOCC); stem cells, islet of Langerhans cells and other cells for transplantation, including genetically altered cells; red blood cells; white blood cells, including monocytes; and platelets.
- NOCC NO-
- non-aqueous solvent is intended to mean any liquid other than water in which a biological material may be dissolved or suspended and includes both inorganic solvents and, more preferably, organic solvents.
- suitable non-aqueous solvents include, but are not limited to, the following: alkanes and cycloalkanes, such as pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane; alcohols, such as methanol, ethanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, and octanol; esters, such as ethyl acetate, 2-methoxyethyl acetate, butyl acetate and benzyl benzoate; aromatics, such as benzene, toluene, pyridine,
- biological contaminant or pathogen is intended to mean a biological contaminant or pathogen that, upon direct or indirect contact with a biological material, may have a deleterious effect on the biological material or upon a recipient thereof.
- biological contaminants or pathogens include the various viruses, bacteria (including inter- and intracellular bacteria, such as mycoplasmas, ureaplasmas, nanobacteria, chlamydia, rickettsias), yeasts, molds, fungi, prions or similar agents responsible, alone or in combination, for TSEs and/or single or multicellular parasites known to those of skill in the art to generally be found in or infect biological materials.
- viruses such as human immunodeficiency viruses and other retroviruses, herpes viruses, filoviruses, circoviruses, paramyxoviruses, cytomegaloviruses, hepatitis viruses (including hepatitis A, B and C and variants thereof), pox viruses, toga viruses, Ebstein-Barr viruses and parvoviruses; bacteria, such as Escherichia, Bacillus, Campylobacter, Streptococcus and Staphalococcus; nanobacteria; parasites, such as Trypanosoma and malarial parasites, including Plasmodium species; yeasts; molds; fungi; mycoplasmas and ureaplasmas; chlamydia; rickettsias, such as Coxiella burnetti ; and prions and similar agents responsible, alone or in combination, for one or more of the disease states known as transmiss, viruses, such as human immunodeficiency viruses and other retroviruses,
- active biological contaminant or pathogen is intended to mean a biological contaminant or pathogen that is capable of causing a deleterious effect, either alone or in combination with another factor, such as a second biological contaminant or pathogen or a native protein (wild-type or mutant) or antibody, in the biological material and/or a recipient thereof.
- blood components is intended to mean one or more of the components that may be separated from whole blood and include, but are not limited to, the following: cellular blood components, such as red blood cells, white blood cells and platelets; blood proteins, such as blood clotting factors, enzymes, albumin, plasminogen, fibrinogen and immunoglobulins; and liquid blood components, such as plasma, plasma protein fraction (PPF), cryoprecipitate, plasma fractions and plasma-containing compositions.
- cellular blood components such as red blood cells, white blood cells and platelets
- blood proteins such as blood clotting factors, enzymes, albumin, plasminogen, fibrinogen and immunoglobulins
- liquid blood components such as plasma, plasma protein fraction (PPF), cryoprecipitate, plasma fractions and plasma-containing compositions.
- cellular blood component is intended to mean one or more of the components of whole blood that comprises cells, such as red blood cells, white blood cells, stem cells and platelets.
- blood protein is intended to mean one or more of the proteins that are normally found in whole blood.
- blood proteins found in mammals, including humans include, but are not limited to, the following: coagulation proteins, both vitamin K-dependent, such as Factor VII and Factor IX, and non-vitamin K-dependent, such as Factor VIII and von Willebrands factor; albumin; lipoproteins, including high density lipoproteins and low density lipoproteins; complement proteins; globulins, such as immunoglobulins IgA, IgM, IgG and IgE; and the like.
- a preferred group of blood proteins includes Factor I (fibrinogen), Factor II (prothrombin), Factor III (tissue factor), Factor V (proaccelerin), Factor VI (accelerin), Factor VII (proconvertin, serum prothrombin conversion), Factor VIII (antihemophiliac factor A), Factor IX (antihemophiliac factor B), Factor X (Stuart-Prower factor), Factor XI (plasma thromboplastin antecedent), Factor XII (Hageman factor), Factor XIII (protransglutamidase), von Willebrands factor (vWF), Factor Ia, Factor Ia, Factor IIIa, Factor Va, Factor VIa, Factor VIIa, Factor VIIIa, Factor IXa, Factor Xa, Factor XIa, Factor XIIa and Factor XIIIa.
- blood proteins includes proteins found inside red blood cells, such as hemoglobin and various growth factors, and derivatives of these proteins.
- proteins found in commercially available plasma protein fraction products such as Plasma-Plex® (Centeon/Aventis Behring), Protenate® (Baxter Laboratories), Plasmanate® (Bayer Biological) and Plasmatein® (Alpha Therapeutic).
- liquid blood component is intended to mean one or more of the fluid, non-cellular components of whole blood, such as plasma (the fluid, non-cellular portion of the whole blood of humans or animals as found prior to coagulation) and serum (the fluid, non-cellular portion of the whole blood of humans or animals as found after coagulation).
- a biologically compatible solution is intended to mean a solution to which a biological material may be exposed, such as by being suspended or dissolved therein, and remain viable, i.e., retain its essential biological and physiological characteristics.
- a biologically compatible buffered solution is intended to mean a biologically compatible solution having a pH and osmotic properties (e.g., tonicity, osmolality and/or oncotic pressure) suitable for maintaining the integrity of the material(s) therein.
- Suitable biologically compatible buffered solutions typically have a pH between 4 and 8.5 and are isotonic or only moderately hypotonic or hypertonic.
- Biologically compatible buffered solutions are known and readily available to those of skill in the art.
- stabilizer is intended to mean a compound or material that reduces damage to the biological material being irradiated to a level that is insufficient to preclude the safe and effective use of the material.
- Illustrative examples of stabilizers include, but are not limited to, the following: antioxidants; free radical scavengers, including spin traps, such as tert-butyl-nitrosobutane (tNB), ⁇ -phenyl-tert-butylnitrone (PBN), 5,5-dimethylpyrroline-N-oxide (DMPO), tert-butylnitrosobenzene (BNB), ⁇ -(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) and 3,5-dibromo-4-nitroso-benzenesulphonic acid (DBNBS); combination stabilizers, i.e., stabilizers which are effective at quenching both Type I and Type
- stabilizers include, but are not limited to, the following: ethanol; acetone; fatty acids, including 6,8-dimercapto-octanoic acid (lipoic acid) and its derivatives and analogues (alpha, beta, dihydro, bisno and tetranor lipoic acid), thioctic acid, 6,8-dimercapto-octanoic acid, dihydrolopoate (DL-6,8-dithioloctanoic acid methyl ester), lipoamide, bisonor methyl ester and tatranor-dihydrolipoic acid, furan fatty acids, oleic and linoleic and palmitic acids and their salts and derivatives; flavonoids, phenylpropanoids, and flavenols, such as quercetin, rutin and its derivatives, apigenin, aminoflavone, catechin, hesperidin and, naringin; ca
- Particularly preferred examples include single stabilizers or combinations of stabilizers that are effective at quenching both Type I and Type 1I photodynamic reactions and volatile stabilizers, which can be applied as a gas and/or easily removed by evaporation, low pressure and similar methods. Such individual or combinations of stabilizers are referred to herein as “combination stabilizers”.
- residual solvent content is intended to mean the amount or proportion of freely-available liquid in the biological material.
- Freely-available liquid means the liquid, such as water or an organic solvent (e.g., ethanol, isopropanol, acetone, polyethylene glycol, etc.), present in the biological material being sterilized that is not bound to or complexed with one or more of the non-liquid components of the material.
- Freely-available liquid includes intracellular water.
- the residual solvent contents related as water referenced herein refer to levels determined by the FDA approved, modified Karl Fischer method (Meyer and Boyd, Analytical Chem., 31:215-219, 1959; May, et al., J. Biol.
- Quantitation of the residual levels of other solvents may be determined by means well known in the art, depending upon which solvent is employed.
- the proportion of residual solvent to solute may also be considered to be a reflection of the concentration of the solute within the solvent. When so considered, the greater the concentration of the solute, the lower the amount of residual solvent.
- the term “sensitizer” is intended to mean a substance that selectively targets viral, bacterial, prion and/or parasitic contaminants, rendering them more sensitive to inactivation by radiation, therefore permitting the use of a lower rate or dose of radiation and/or a shorter time of irradiation than in the absence of the sensitizer.
- sensitizers include, but are not limited to, the following: psoralen and its derivatives and analogs (including 3-carboethoxy psoralens); inactines and their derivatives and analogs; angelicins, khellins and coumarins which contain a halogen substituent and a water solubilization moiety, such as quaternary ammonium ion or phosphonium ion; nucleic acid binding compounds; brominated hematoporphyrin; phthalocyanines; purpurins; porphorins; halogenated or metal atom-substituted derivatives of dihematoporphyrin esters, hemaloporphyrin derivatives, benzoporphyrin derivatives, hydrodibenzoporphyrin dimaleimade, hydrodibenzoporphyrin, dicyano disulfone, tetracarbethoxy hydrodibenzoporphyrin,
- atoms which bind to prions, and thereby increase their sensitivity to inactivation by radiation may also be used.
- An illustrative example of such an atom would be the Copper ion, which binds to the prior protein and, with a Z number higher than the other atoms in the protein, increases the probability that the prion protein will absorb energy during irradiation, particularly gamma irradiation.
- proteinaceous material is intended to mean any material derived or obtained from a living organism that comprises at least one protein or peptide.
- a proteinaceous material may be a naturally occurring material, either in its native state or following processing/purification and/or derivatization, or an artificially produced material, produced by chemical synthesis or recombinant/transgenic technology and, optionally, process/purified and/or derivatized.
- proteinaceous materials include, but are not limited to, the following: proteins and peptides produced from cell culture; milk and other dairy products; ascites; hormones; growth factors; materials, including pharmaceuticals, extracted or isolated from animal tissue, such as heparin and insulin, or plant matter; plasma, including fresh, frozen and freeze-dried, and plasma protein fraction; fibrinogen and derivatives thereof, fibrin, fibrin I, fibrin II, soluble fibrin and fibrin monomer, and/or fibrin sealant products; whole blood; protein C; protein S; alpha-1 anti-trypsin (alpha-1 protease inhibitor); butyl-cholinesterase; anticoagulants, such as coumarin drugs (warfarin); streptokinase; tissue plasminogen activator (tPA); erythropoietin (EPO); urokinase; neupogen; anti-thrombin-3; alpha-glucosidase; (fetal) bovine serum/horse serum
- the term “radiation” is intended to mean radiation of sufficient energy to sterilize at least some component of the irradiated biological material.
- Types of radiation include, but are not limited to, the following: (i) corpuscular (streams of subatomic particles such as neutrons, electrons, and/or protons); (ii) electromagnetic (originating in a varying electromagnetic field, such as radio waves, visible (both mono and polychromatic) and invisible light, infrared, ultraviolet radiation, x-radiation, and gamma rays and mixtures thereof); and (iii) sound and pressure waves.
- Such radiation is often described as either ionizing (capable of producing ions in irradiated materials) radiation, such as gamma rays, and non-ionizing radiation, such as visible light.
- the sources of such radiation may vary and, in general, the selection of a specific source of radiation is not critical provided that sufficient radiation is given in an appropriate time and at an appropriate rate to effect sterilization.
- gamma radiation is usually produced by isotopes of Cobalt or Cesium
- UV and X-rays are produced by machines that emit UV and X-radiation, respectively, and electrons are often used to sterilize materials in a method known as “E-beam” irradiation that involves their production via a machine.
- Visible light both mono- and polychromatic, is produced by machines and may, in practice, be combined with invisible light, such as infrared and UV, that is produced by the same machine or a different machine.
- the term “to protect” is intended to mean to reduce any damage to the biological material being irradiated, that would otherwise result from the irradiation of that material, to a level that is insufficient to preclude the safe and effective use of the material following irradiation.
- a substance or process “protects” a biological material from radiation if the presence of that substance or carrying out that process results in less damage to the material from irradiation than in the absence of that substance or process.
- biological material may be used safely and effectively after irradiation in the presence of a substance or following performance of a process that “protects” the material, but could not be used safely and effectively after irradiation under identical conditions but in the absence of that substance or the performance of that process.
- an “acceptable level” of damage may vary depending upon certain features of the particular method(s) of the present invention being employed, such as the nature and characteristics of the particular biological material and/or non-aqueous solvent(s) being used, and/or the intended use of the biological material being irradiated, and can be determined empirically by one skilled in the art.
- An “unacceptable level” of damage would therefore be a level of damage that would preclude the safe and effective use of the biological material being sterilized.
- the particular level of damage in a given biological material may be determined using any of the methods and techniques known to one skilled in the art.
- a first preferred embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising irradiating the biological material with radiation for a time effective to sterilize the material at a rate effective to sterilize the material and to protect the material from radiation.
- Another preferred embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) adding to a biological material at least one stabilizer in an amount effective to protect the biological material from radiation; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the material.
- Another preferred embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) reducing the residual solvent content of a biological material to a level effective to protect the biological material from radiation; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material.
- Another preferred embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) reducing the temperature of a biological material to a level effective to protect the biological material from radiation; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material.
- Another preferred embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) applying to the biological material a stabilizing process selected from the group consisting of: (a) reducing the residual solvent content of a biological material, (b) adding to the biological material at least one stabilizer, and (c) reducing the temperature of the biological material; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material, wherein the stabilizing process and the rate of irradiation are together effective to protect the biological material from radiation.
- a stabilizing process selected from the group consisting of: (a) reducing the residual solvent content of a biological material, (b) adding to the biological material at least one stabilizer, and (c) reducing the temperature of the biological material; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material, wherein the stabilizing process and the
- Another preferred embodiment of the present invention is directed to a method for sterilizing a biological material that is sensitive to radiation and contains a non-aqueous solvent comprising: (i) applying to the biological material at least two stabilizing processes selected from the group consisting of: (a) reducing the residual solvent content of a biological material, (b) adding to the biological material at least one stabilizer, and (c) reducing the temperature of the biological material; and (ii) irradiating the biological material with radiation at an effective rate for a time effective to sterilize the biological material, wherein the stabilizing processes may be performed in any order and are together effective to protect the biological material from radiation.
- Another preferred embodiment of the present invention is directed to a composition
- a composition comprising a biological material and a non-aqueous solvent in an amount effective to preserve the preparation during sterilization with radiation, such that it remains suitable nad effective for its intended use.
- Another preferred embodiment of the present invention is directed to a composition
- a composition comprising at least one biological material, a least one non-aqueous solvent and at least one stabilizer, wherein the non-aqueous solvent and stabilizer are together present in an amount effective to preserve the material for its intended use following sterilization with radiation.
- the non-aqueous solvent is preferably a non-aqueous solvent that is not prone to the formation of free-radicals upon irradiation, and more preferably a non-aqueous solvent that is not prone to the formation of free-radicals upon irradiation and that has little or no dissolved oxygen or other gas(es) that is (are) prone to the formation of free-radicals upon irradiation.
- Volatile non-aqueous solvents are particularly preferred, even more particularly preferred are non-aqueous solvents that are stabilizers, such as ethanol and acetone.
- the biological material may contain a mixture of water and a non-aqueous solvent, such as ethanol and/or acetone.
- the non-aqueous solvent(s) is preferably a non-aqueous solvent that is not prone to the formation of free-radicals upon irradiation, and most preferably a non-aqueous solvent that is not prone to the formation of free-radicals upon irradiation and that has little or no dissolved oxygen or other gas(es) that is (are) prone to the formation of free-radicals upon irradiation.
- Volatile non-aqueous solvents are particularly preferred, even more particularly preferred are non-aqueous solvents that are stabilizers, such as ethanol and acetone.
- a stabilizer is added prior to irradiation of the biological material which contains a non-aqueous solvent with radiation.
- This stabilizer is preferably added to the biological material which contains a non-aqueous solvent in an amount that is effective to protect the biological material from the radiation.
- the stabilizer is added to the biological material which contains a non-aqueous solvent in an amount that, together with the non-aqueous solvent, is effective to protect the biological material from the radiation.
- Suitable amounts of stabilizer may vary depending upon certain features of the particular method(s) of the present invention being employed, such as the particular stabilizer being used and/or the nature and characteristics of the particular biological material which contains a non-aqueous solvent being irradiated and/or its intended use, and can be determined empirically by one skilled in the art.
- the residual solvent content of the biological material which contains a non-aqueous solvent is reduced prior to irradiation of the biological material with radiation.
- the residual solvent content is preferably reduced to a level that is effective to protect the biological material from the radiation.
- Suitable levels of residual solvent content may vary depending upon certain features of the particular method(s) of the present invention being employed, such as the nature and characteristics of the particular biological material which contains a non-aqueous solvent being irradiated and/or its intended use, and can be determined empirically by one skilled in the art. There may be biological materials for which it is desirable to maintain the residual solvent content to within a particular range, rather than a specific value.
- the residual solvent (water) content of a biological material may be reduced by dissolving or suspending the biological material which contains a non-aqueous solvent in a non-aqueous solvent that is capable of dissolving water.
- the biological material is in liquid phase, the same result may also be achieved by the dilution of the residual solvent (water) by the addition of liquid non-aqueous solvent.
- such a second non-aqueous solvent is not prone to the formation of free-radicals upon irradiation and has little or no dissolved oxygen or other gas(es) that is (are) prone to the formation of free-radicals upon irradiation.
- reducing the residual solvent content may be accomplished by any of a number of means, such as by increasing the solute concentration.
- concentration of protein in the biological material which contains a non-aqueous solvent dissolved within the solvent may be increased to generally at least about 0.5%, typically at least about 1%, usually at least about 5%, preferably at least about 10%, more preferably at least about 15%, even more preferably at least about 20%, still even more preferably at least about 25%, and most preferably at least about 50%.
- the residual solvent content of a particular biological material which contains a non-aqueous solvent may be found to lie within a range, rather than at a specific point.
- a range for the preferred residual solvent content of a particular biological material which contains a non-aqueous solvent may be determined empirically by one skilled in the art.
- the methods described herein may be performed at any temperature that doesn't result in unacceptable damage to the biological material which contains a non-aqueous solvent, i.e., damage that would preclude the safe and effective use of the biological material.
- the methods described herein are performed at ambient temperature or below ambient temperature, such as below the eutectic point or freezing point of the biological material which contains a non-aqueous solvent being irradiated.
- the residual solvent content of the biological material which contains a non-aqueous solvent may be reduced by any of the methods and techniques known to those skilled in the art for reducing solvent from a biological material which contains a non-aqueous solvent without producing an unacceptable level of damage to the biological material.
- Such methods include, but are not limited to, addition of solute, evaporation, concentration, centrifugal concentration, vitrification and spray-drying.
- a particularly preferred method for reducing the residual solvent content of a biological material which contains a non-aqueous solvent is lyophilization.
- Another particularly preferred method for reducing the residual solvent content of a biological material which contains a non-aqueous solvent is the addition of solute.
- Another particularly preferred method for reducing the residual solvent content of a biological material which contains a non-aqueous solvent is spray-drying.
- Another particularly preferred method for reducing the residual solvent content of a biological material which contains a non-aqueous solvent is vitrification, which may be accomplished by any of the methods and techniques known to those skilled in the art, including the addition of solute and or additional solutes, such as sucrose, to raise the eutectic point of the biological material which contains a non-aqueous solvent, followed by a gradual application of reduced pressure to the biological material which contains a non-aqueous solvent in order to remove the residual solvent.
- the resulting glassy material will then have a reduced residual solvent content.
- the biological material which contains a non-aqueous solvent to be sterilized may be immobilized upon a solid surface by any means known and available to one skilled in the art.
- the biological material which contains a non-aqueous solvent to be sterilized may be present as a coating or surface on a biological or non-biological substrate.
- the radiation employed in the methods of the present invention may be any radiation effective for the sterilization of the biological material which contains a non-aqueous solvent being treated.
- the radiation may be corpuscular, including E-beam radiation.
- the radiation is electromagnetic radiation, including x-rays, infrared, visible light, UV light and mixtures of various wavelengths of electromagnetic radiation.
- a particularly preferred form of radiation is gamma radiation.
- the biological material which contains a non-aqueous solvent is irradiated with the radiation at a rate effective for the sterilization of the biological material, while not producing an unacceptable level of damage to that material.
- Suitable rates of irradiation may vary depending upon certain features of the methods of the present invention being employed, such as the nature and characteristics of the particular biological material, which may contain a non-aqueous solvent, being irradiated, the particular form of radiation involved and/or the particular biological contaminants or pathogens being inactivated. Suitable rates of irradiation can be determined empirically by one skilled in the art. Preferably, the rate of irradiation is constant for the duration of the sterilization procedure. When this is impractical or otherwise not desired, a variable or discontinuous irradiation may be utilized.
- the rate of irradiation may be optimized to produce the most advantageous combination of product recovery and time required to complete the operation. Both low ( ⁇ 3 kGy/hour) and high (>3 kGy/hour) rates may be utilized in the methods described herein to achieve such results.
- the rate of irradiation is preferably selected to optimize the recovery of the biological material which contains a non-aqueous solvent while still sterilizing the biological material which contains a non-aqueous solvent. Although reducing the rate of irradiation may serve to decrease damage to the biological material which contains a non-aqueous solvent, it will also result in longer irradiation times being required to achieve a particular desired total dose. A higher dose rate may therefore be preferred in certain circumstances, such as to minimize logistical issues and costs, and may be possible when used in accordance with the methods described herein for protecting a biological material which contains a non-aqueous solvent from irradiation.
- the rate of irradiation is not more than about 3.0 kGy/hour, more preferably between about 0.1 kGy/hr and 3.0 kGy/hr, even more preferably between about 0.25 kGy/hr and 2.0 kGy/hour, still even more preferably between about 0.5 kGy/hr and 15 kGy/hr and most preferably between about 0.5 kGy/hr and 1.0 kGy/hr.
- the rate of irradiation is at least about 3.0 kGy/hr, more preferably at least about 6 kGy/hr, even more preferably at least about 16 kGy/hr, and even more preferably at least about 30 kGy/hr and most preferably at least about 45 kGy/hr or greater.
- the biological material which contains a non-aqueous solvent to be sterilized is irradiated with the radiation for a time effective for the sterilization of the biological material.
- the appropriate irradiation time results in the appropriate dose of irradiation being applied to the biological material which contains a non-aqueous solvent.
- Suitable irradiation times may vary depending upon the particular form and rate of radiation involved and/or the nature and characteristics of the particular biological material which contains a non-aqueous solvent being irradiated. Suitable irradiation times can be determined empirically by one skilled in the art.
- the biological material which contains a non-aqueous solvent to be sterilized is irradiated with radiation up to a total dose effective for the sterilization of the biological material, while not producing an unacceptable level of damage to that material.
- Suitable total doses of radiation may vary depending upon certain features of the methods of the present invention being employed, such as the nature and characteristics of the particular biological material which contains a non-aqueous solvent being irradiated, the particular form of radiation involved and/or the particular biological contaminants or pathogens being inactivated. Suitable total doses of radiation can be determined empirically by one skilled in the art.
- the total dose of radiation is at least 25 kGy, more preferably at least 45 kGy, even more preferably at least 75 kGy, and still more preferably at least 100 kGy or greater, such as 150 kGy or 200 kGy or greater.
- the particular geometry of the biological material which contains a non-aqueous solvent being irradiated may be determined empirically by one skilled in the art.
- a preferred embodiment is a geometry that provides for an even rate of irradiation throughout the preparation.
- a particularly preferred embodiment is a geometry that results in a short path length for the radiation through the preparation, thus minimizing the differences in radiation dose between the front and back of the preparation. This may be further minimized in some preferred geometries, particularly those wherein the preparation has a constant radius about its axis that is perpendicular to the radiation source, by the utilization of a means of rotating the preparation about said axis.
- an effective package for containing the preparation during irradiation is one which combines stability under the influence of irradiation, and which minimizes the interactions between the package and the radiation.
- Preferred packages maintain a seal against the external environment before, during and post-irradiation, and are not reactive with the preparation within, nor do they produce chemicals that may interact with the preparation within.
- Particularly preferred examples include but are not limited to containers that comprise glasses stable when irradiated, stoppered with stoppers made of rubber that is relatively stable during radiation and liberates a minimal amount of compounds from within, and sealed with metal crimp seals of aluminum or other suitable materials with relatively low Z numbers. Suitable materials can be determined by measuring their physical performance, and the amount and type of reactive leachable compounds post-irradiation and by examining other characteristics known to be important to the containment of biological materials empirically by one skilled in the art.
- an effective amount of at least one sensitizing compound may optionally be added to the biological material which contains a non-aqueous solvent prior to irradiation, for example to enhance the effect of the irradiation on the biological contaminant(s) or pathogen(s) therein, while employing the methods described herein to minimize the deleterious effects of irradiation upon the biological material.
- Suitable sensitizers are known to those skilled in the art, and include psoralens and their derivatives and inactines and their derivatives.
- the irradiation of the biological material which contains a non-aqueous solvent may occur at any temperature that is not deleterious to the biological material being sterilized.
- the biological material which contains a non-aqueous solvent is irradiated at ambient temperature.
- the biological material which contains a non-aqueous solvent is irradiated at reduced temperature, i.e., a temperature below ambient temperature, such as 0° C., ⁇ 20° C., ⁇ 40° C., ⁇ 60° C., ⁇ 78° C. or ⁇ 196° C.
- the biological material which contains a non-aqueous solvent is preferably irradiated at or below the freezing or eutectic point of the biological material.
- the biological material which contains a non-aqueous solvent is irradiated at elevated temperature, i.e., a temperature above ambient temperature, such as 37° C., 60° C., 72° C. or 80° C. While not wishing to be bound by any theory, the use of elevated temperature may enhance the effect of irradiation on the biological contaminant(s) or pathogen(s) and therefore allow the use of a lower total dose of radiation.
- the irradiation of the biological material which contains a non-aqueous solvent occurs at a temperature that protects the preparation from radiation. Suitable temperatures can be determined empirically by one skilled in the art.
- the temperature at which irradiation is performed may be found to lie within a range, rather than at a specific point.
- a range for the preferred temperature for the irradiation of a particular biological material which contains a non-aqueous solvent may be determined empirically by one skilled in the art.
- the irradiation of the biological material which contains a non-aqueous solvent may occur at any pressure which is not deleterious to the biological material which contains a non-aqueous solvent being sterilized.
- the biological material which contains a non-aqueous solvent is irradiated at elevated pressure. More preferably, the biological material which contains a non-aqueous solvent is irradiated at elevated pressure due to the application of sound waves or the use of a volatile.
- elevated pressure may enhance the effect of irradiation on the biological contaminant(s) or pathogen(s) and/or enhance the protection afforded by one or more stabilizers, and therefore allow the use of a lower total dose of radiation.
- Suitable pressures can be determined empirically by one skilled in the art.
- the pH of the biological material which contains a non-aqueous solvent undergoing sterilization is about 7.
- the biological material which contains a non-aqueous solvent may have a pH of less than 7, preferably less than or equal to 6, more preferably less than or equal to 5, even more preferably less than or equal to 4, and most preferably less than or equal to 3.
- the biological material which contains a non-aqueous solvent may have a pH of greater than 7, preferably greater than or equal to 8, more preferably greater than or equal to 9, even more preferably greater than or equal to 10, and most preferably greater than or equal to 11.
- the pH of the preparation undergoing sterilization is at or near the isoelectric point of one of the components of the biological material. Suitable pH levels can be determined empirically by one skilled in the art.
- the irradiation of the biological material which contains a non-aqueous solvent may occur under any atmosphere that is not deleterious to the biological material being treated.
- the biological material which contains a non-aqueous solvent is held in a low oxygen atmosphere or an inert atmosphere.
- the atmosphere is preferably composed of a noble gas, such as helium or argon, more preferably a higher molecular weight noble gas, and most preferably argon.
- the biological material which contains a non-aqueous solvent is held under vacuum while being irradiated.
- a biological material which contains a non-aqueous solvent is stored under vacuum or an inert atmosphere (preferably a noble gas, such as helium or argon, more preferably a higher molecular weight noble gas, and most preferably argon) prior to irradiation.
- a liquid biological material which contains a non-aqueous solvent is held under low pressure, to decrease the amount of gas, particularly oxygen, dissolved in the liquid, prior to irradiation, either with or without a prior step of solvent reduction, such as lyophilization.
- degassing may be performed using any of the methods known to one skilled in the art.
- the amount of these gases within or associated with the preparation may be reduced by any of the methods and techniques known and available to those skilled in the art, such as the controlled reduction of pressure within a container (rigid or flexible) holding the preparation to be treated or by placing the preparation in a container of approximately equal volume.
- the biological material which contains a non-aqueous solvent to be treated is a tissue
- at least one stabilizer is introduced according to any of the methods and techniques known and available to one skilled in the art, including soaking the tissue in a solution containing the stabilizer(s), preferably under pressure, at elevated temperature and/or in the presence of a penetration enhancer, such as dimethylsulfoxide.
- introducing at least one stabilizer into a tissue include, but are not limited to, applying a gas containing the stabilizer(s), preferably under pressure and/or at elevated temperature, injection of the stabilizer(s) or a solution containing the stabilizer(s) directly into the tissue, placing the tissue under reduced pressure and then introducing a gas or solution containing the stabilizer(s) and combinations of two or more of these methods.
- One or more sensitizers may also be introduced into a tissue according to such methods.
- a particular biological material which contains a non-aqueous solvent may also be lyophilized, held at a reduced temperature and kept under vacuum prior to irradiation to further minimize undesirable effects.
- the sensitivity of a particular biological contaminant or pathogen to radiation is commonly calculated by determining the dose necessary to inactivate or kill all but 37% of the agent in a sample, which is known as the D 37 value.
- the desirable components of a biological material may also be considered to have a D 37 value equal to the dose of radiation required to eliminate all but 37% of their desirable biological and physiological characteristics.
- the sterilization of a biological material which contains a non-aqueous solvent is conducted under conditions that result in a decrease in the D 37 value of the biological contaminant or pathogen without a concomitant decrease in the D 37 value of the biological material.
- the sterilization of a biological material which contains a non-aqueous solvent is conducted under conditions that result in an increase in the D 37 value of the material.
- the sterilization of a biological material which contains a non-aqueous solvent is conducted under conditions that result in a decrease in the D 37 value of the biological contaminant or pathogen and a concomitant increase in the D 37 value of the biological material.
- Tubes 4-6 were gamma irradiated at 45 kGy (1.9 kGy/hr) at 4° C. Tubes 1-3 were controls (4° C.).
- PPG400 Fluka cat. #81350.
- Substrate urokinase substrate 1
- colormetric Calbiochem. cat. #672157, lot B23901, 5 mg vials, final concentration 1.5 mM.
- Urokinase suspended in PPG400 and then gamma irradiated to a total dose of 45 kGy maintained the same percent activity as gamma irradiated dry powder urokinase (80%).
- urokinase suspended in PBS subjected to the same gamma irradiation maintained only 6% activity. The results of this experiment are presented in FIG. 1.
- the plates were covered with a plate sealer and incubated at 37° C. for one hour with shaking. The plates were then washed four times with TBST and 100 ⁇ l of 1 mg/ml phosphatase substrate in DEA buffer were added to each well and the plates were incubated at 37° C. with shaking. Absorption was read at both 405 and 620 nm at 5 minute intervals as needed. The absorption at 630 nm (background) was subtracted from the value at 405 nm to obtain a corrected absorption value.
- Blocking buffer 2% BSA/PBS (pH 7.4).
- TBST Tris Buffered Saline (pH 7.4) with 0.05% Tween 20.
- Biotin-Labelled Insulin from bovine pancreas—Sigma 1-2258 lot 110H8065, 5 mg insulin, 1.2 mol. FITC per mol. insulin, reconstituted in 5 ml sterile water at 1.0 mg/ml stored at 4° C.
- Binding Buffer 0.25% BSA/PBS (pH 7.4).
- DEA Buffer per 1 L—97 ml diethanolamine (Sigma D-8885), 0.1 g MgCl 2 .6H 2 O, 0.02% sodium azide, stored at 4° C.
- Phosphatase Substrate p-nitrophenyl phosphate—Sigma 104-105, 5 mg/tablet.
- the phosphatase substrate was prepared fresh as a 1 mg/ml solution in phosphatase substrate buffer, i.e., DEA buffer.
- the solution is light sensitive so it had to be stored in the dark until ready to dispense.
- liquid thrombin containing 50% glycerol and spiked with porcine parvovirus (PPV) was irradiated to varying total doses of radiation.
- [0132] Add 100 ⁇ l 100% glycerol, 20 ⁇ l thrombin (100 U/ml thrombin) spiked with 50 ⁇ l PPV and optionally 20 ⁇ l (200 mM) sodium ascorbate as a stabilizer (adjusted to a total volume of 1 ml with H 2 O) to Wheaton 3 ml tubes (in duplicate), and irradiate to a total dose of 10, 30 or 45 kGy at 1.8 kGy/hr at 4° C.
- [0133] Label and seed 96-well cell culture plates to allow at least 4 well per dilution (seeding to be done one day before inoculation). Add 200 ⁇ l of cell suspension per well at a concentration of 4 ⁇ 10 4 /ml. The same cell culture medium is used for cell growth and maintenance after virus inoculation.
- TCID 50 is calculated from CPE reading according to the method of Kärber.
- Wheaton tubes glass serum vials, Wheaton #223684, lot #1154132-02.
- Thrombin bovine origin, 5000 US Units (5000 U/ml stock).
- PPV titer of porcine parvovirus was determined by TCID 50 and was about 9.0 log/ml (032301 stock).
- PPV spike ratio was 1:4 (50 ⁇ l PPV stock mixed with 150 ⁇ l protein solution) into liquid thrombin.
- PEG Buffer 0.1 M NaCl, 0.01 M Tris (pH 7.4), 1 mM EDTA.
- Siliconized stoppers were used in the experiment obtained from American Stemli (Princeton, N.J.), 6720GC rubber formulation, lot #G009/7202.
- PK-13 ATCC #CRL-6489
- passage # 14 Cells are maintained in PK-13 growth medium (Dulbecco's modified Eagle medium supplemented with 10% FBS and IX pencillin/streptomycin/L-glutamine).
- Trypsin was suspended in polypropylene glycol 400 at a concentration of about 20,000 U/ml and divided into multiple samples. A fixed amount of water (0%, 1%, 2.4%, 4.8%, 7%, 9%, 10%, 20%,33%) was added to each sample; a 100% water sample was also prepared which contained no PPG 400.
- Samples were irradiated to a total dose of 45 kGy at a rate of 1.9 kGy/hr and a temperature of 4° C. Following irradiation, each sample was centrifuged to pellet the undissolved trypsin. The PPG/water soluble fraction was removed and the pellets resuspended in water alone for activity testing.
- Assay conditions 5 U/well trypsin (50 U/ml)+BAPNA substrate (0.5 mg/ml) was serially diluted 3-fold down a 96-well plate. The assay was set up in two 96-well plates and absorption read at both 405 and 620 nm at 5 and 20 minutes. The absorption at 630 nm (background) was subtracted from the value at 405 nm to obtain a corrected absorption value. The change in this value over time between 5 and 15 minutes of reaction time was plotted and Vmax and Km determined in Sigma Plot using the hyperbolic rectangular equation).
- porcine heart valves were gamma irradiated in the presence of polypropylene glycol 400 (PPG400) and, optionally, a scavenger, to a total dose of 30 kGy (1.584 kGy/hr at ⁇ 20° C.).
- PPG400 polypropylene glycol 400
- a scavenger a scavenger
- Heating module Pulierce, Reacti-therm. Model #18870, S/N 1125000320176
- MW 250; therefore, want 250 mg/ml for 1M or 125 mg/ml for 0.5 M
- PV heart valves were thawed on wet ice.
- SCb stabilizer mixture comprising of 1.5 ml 125 mM Trolox C, 300 ⁇ l 1 M Lipoic Acid, 600 ⁇ l 0.5 M Coumaric Acid and 600 ⁇ l 0.5 M n-Propyl Gallate. (Final concentrations: 62.5 mM, 100 mM, 100 mM and 100 mM respectively.)
- Samples were irradiated at a rate of 1.584 kGy/hr at ⁇ 20° C. to a total dose of 30 kGy.
- FIGS. 4 A- 4 C The HPLC results are shown in FIGS. 4 A- 4 C. In the presence of PPG 400, the results were nearly identical whether the heart valve had been irradiated or not. The addition of a single stabilizer (trolox C) or a stabilizer mixture produced even more effective results. The gel analysis, shown in FIG. 4D, confirmed the effectiveness of the protection provided by these conditions.
- Spectrofluorometer is set for excitation at 295 nm and emission at 395 nm.
- FIGS. 5 A-D The HPLC results are shown in FIGS. 5 A-D.
- the major peak represents the Internal-Pyridinoline (int-Pyd) peak.
- Irradiation in an aqueous environment (PBS) produced pronounced decreases in the smaller peaks (FIG. 5A).
- Reduction of the water content by the addition of a non-aqueous solvent (PPG 400) produced a nearly superimposable curve (FIG. 5B).
- DMSO was less effective (FIG. 5C), while DMSO plus a mixture of stabilizers (FIG. 5D) was more effective at preserving the major peak although some minor peaks increased somewhat.
- the area under the pyd peak for each sample was calculated as shown in the table below.
- Porcine heart valve cusps were obtained and stored at ⁇ 80° C. in a cryopreservative solution (Containing Fetal calf serum, Penicillin-Streptomycin, M199 media, and approximately 20% DMSO).
- DMSO JT Baker cat#9224-01 lot#H406307.
- Sodium ascorbate Aldrich cat#26,855-0 lot 10801HU; prepared as a 2M stock in Nerl water.
- FCS Fetal calf serum
- Freeze Medium QS 100 ml
- FIGS. 6 A- 6 D The results of the HPLC analysis are shown in FIGS. 6 A- 6 D. Irradiation in an aqueous environment (PBS) produced decreases in the smaller peaks (FIG. 6A). Reduction of the water content by the addition of a non-aqueous solvent (20% DMSO) reproduced these peaks more faithfully (FIG. 6B). Increasing the DMSO concentration to 50% was slightly more effective (FIG. 6C), while DMSO plus a mixture of stabilizers (FIG. 6D) was very effective at preserving both the major and minor peaks (the additional new peaks are due to the stabilizers themselves). Gel analysis is shown in FIG. 6E and reflects the major conclusions from the HPLC analysis, with significant loss of bands seen in PBS and retention of the major bands in the presence of non-aqueous solvents with and without stabilizers.
- FIGS. 7 A- 7 F The results of the HPLC analysis are shown in FIGS. 7 A- 7 F. Irradiation in an aqueous environment (PBS) resulted in changes in the minor peaks and a right shift in the major peak. The inclusion of various non-aqueous solvents, reduction in residual water, and the addition of stabilizers produced profiles that more closely matched those of the corresponding controls.
- the gel analysis is shown in FIGS. 7 G- 7 H and shows a significant loss of bands in PBS, while the other groups demonstrated a. significant retention of these lost bands.
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AU2002326816A AU2002326816B2 (en) | 2001-09-24 | 2002-09-24 | Methods of sterilizing biological materials containing non-aqueous solvents |
KR1020047004290A KR100909068B1 (ko) | 2001-09-24 | 2002-09-24 | 비수용성 용매를 함유하는 생물학적 물질을 살균하기 위한방법 |
JP2003530337A JP4213587B2 (ja) | 2001-09-24 | 2002-09-24 | 非水性溶媒を含む生物学的材料を殺菌する方法 |
PCT/US2002/028134 WO2003026703A1 (en) | 2001-09-24 | 2002-09-24 | Methods of sterilizing biological materials containing non-aqueous solvents |
CA002460644A CA2460644A1 (en) | 2001-09-24 | 2002-09-24 | Methods of sterilizing biological materials containing non-aqueous solvents |
CNA028208617A CN1585651A (zh) | 2001-09-24 | 2002-09-24 | 将含有非水性溶剂的生物材料灭菌的方法 |
MXPA04002720A MXPA04002720A (es) | 2001-09-24 | 2002-09-24 | Metodos para esterilizar materiales biologicos que contienen solventes no acuosos. |
PL02368308A PL368308A1 (en) | 2001-09-24 | 2002-09-24 | Methods of sterilizing biological materials containing non-aqueous solvents |
IL16084002A IL160840A0 (en) | 2001-09-24 | 2002-09-24 | Method of sterilizing biological materials containing non-aqueous solvents |
EA200400473A EA200400473A1 (ru) | 2001-09-24 | 2002-09-24 | Способы стерилизации биологических материалов, содержащих неводные растворители |
EP02761560A EP1438077A4 (de) | 2001-09-24 | 2002-09-24 | Verfahren zur sterilisation biologischer materialien mit nicht-wässrigen lösungsmitteln |
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US12/264,106 US7848487B2 (en) | 2001-09-24 | 2008-11-03 | Methods for sterilizing biological materials containing non-aqueous solvents |
US12/959,106 US20110091353A1 (en) | 2001-09-24 | 2010-12-02 | Methods for Sterilizing Tissue |
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US20110091353A1 (en) * | 2001-09-24 | 2011-04-21 | Wilson Burgess | Methods for Sterilizing Tissue |
US20030180181A1 (en) * | 2002-02-01 | 2003-09-25 | Teri Greib | Methods for sterilizing tissue |
US20060270571A1 (en) * | 2005-05-26 | 2006-11-30 | Burke Peter A | Deactivation of mineral encapsulated nanobacteria |
US20090130739A1 (en) * | 2005-05-26 | 2009-05-21 | American Sterilizer Company | Deactivation of mineral encapsulated nanobacteria |
US20070134814A1 (en) * | 2005-12-09 | 2007-06-14 | Kajander E O | Methods and compositions for the detection of calcifying nano-particles, identification and quantification of associated proteins thereon, and correlation to disease |
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Also Published As
Publication number | Publication date |
---|---|
CN1585651A (zh) | 2005-02-23 |
EA200400473A1 (ru) | 2004-10-28 |
ZA200401975B (en) | 2006-06-28 |
PL368308A1 (en) | 2005-03-21 |
IL160840A0 (en) | 2004-08-31 |
JP4213587B2 (ja) | 2009-01-21 |
WO2003026703A1 (en) | 2003-04-03 |
EP1438077A1 (de) | 2004-07-21 |
US7848487B2 (en) | 2010-12-07 |
AU2002326816B2 (en) | 2008-02-21 |
JP2005503239A (ja) | 2005-02-03 |
MXPA04002720A (es) | 2005-11-08 |
EP1438077A4 (de) | 2005-08-31 |
KR20040044984A (ko) | 2004-05-31 |
KR100909068B1 (ko) | 2009-07-23 |
CA2460644A1 (en) | 2003-04-03 |
US20090202039A1 (en) | 2009-08-13 |
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