METHODS FOR THE INACTIVATION OF MICROORGANISMS IN BIOLOGICAL FLUIDS, FLOW THROUGH REACTORS AND METHODS OF CONTROLLING THE LIGHT SUM DOSE TO EFFECTIVELY INACTIVATE MICROORGANISMS IN BATCH REACTORS

• US 20110206554A1
• Filed: 05/04/2011
• Published: 08/25/2011
• Est. Priority Date: 08/24/2004
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Inventors: Turecek, Peter, Schwarz, Hans-Peter, Anderle, Heinz, Kreil, Thomas, Matthiessen, Peter, Boggs, Daniel R.
• Granted Patent: US 8,377,375 B2
• Time in Patent Office: Days
• US Class Current: 422/3
• CPC Class Codes: A23L 3/26 by irradiation without heating
• CPC Class Codes: A23L 3/28 with ultraviolet light
• CPC Class Codes: A61L 2/0011 using physical methods
• CPC Class Codes: A61L 2/10 Ultraviolet radiation
• CPC Class Codes: A61L 2/28 Devices for testing the effectiveness or completeness of sterilisation, e.g. indicators which change colour apparatus involving enzymes or microorganisms C12M1/34; methods involving enzymes or microorganisms C12Q1/00
• CPC Class Codes: G01N 21/33 using ultraviolet light G01N21/39 takes precedence
• CPC Class Codes: H05B 3/0052 for fluid treatments

Abstract

The present invention relates to a method for determining an effective dose of monochromatic or polychromatic light from one or more light sources to inactivate microorganisms present in a biological fluid, preferably a non-transparent fluid. Moreover, there is provided a method for the inactivation of microorganism in a biological fluid in a flow-through-reactor. Moreover, the invention advantageously provides a flow-through-reactor with one or more thermostated light sources. The invention further provides a method of controlling the light sum dose of monochromatic or polychromatic light emitted from one or more light sources to effectively inactivate microorganisms present in a biological fluid in a batch reactor.

Claims

1. A method for determining an effective dose of monochromatic or polychromatic light from one or more light sources to inactivate microorganisms present in a non-transparent biological fluid comprising measuring the effect of the monochromatic or polychromatic light on a dosimetric solution matching the turbidity of the biological fluid at the photoinactivating wavelengths used, the turbidity and absorbance of the biological fluid, the turbidity and the viscosity of the biological fluid, the turbidity and the absorbance and the viscosity of the biological fluid, the absorbance of the biological fluid, or the viscosity and absorbance of the biological fluid, based on a light dose calibration by i) irradiating the dosimetric solution in a layer of an optical path-length sufficiently thin to absorb only a fraction of the incident light at a predetermined defined irradiance for a defined time to apply a defined fluence (light dose) resulting in a change of a measurable physical or chemical magnitude, and ii) by reading out the dose corresponding to the change in the magnitude measured during or after the light irradiation of the dosimetric solution in the light irradiation reactor, wherein step i) is executed before step ii) or vice versa.

2. The method according to claim 1, wherein along the optical path length 100% or less of the incident irradiance is absorbed.

3. The method according to claim 1, wherein along the optical path length 50% or less of the incident irradiance is absorbed.

4. The method according to claim 1, wherein the biological fluid is inactivated in a flow-through-reactor and wherein the defined fluence can be modified by changing the defined irradiance and/or by changing the defined time determined by the flow rate of the biological fluid in the flow-through-reactor.

5. The method according to claim 1, further comprising determining the dose-distribution by titration of the number of viable microorganisms before and after, or before, during and after irradiating the biological fluid spiked before or during, or before and during the irradiation with the viable microorganisms.

6. The method according to claim 1, further comprising monitoring the intensity of the one or more light sources during the irradiation in order to determine an irradiating dose.

7. The method according to claim 1, wherein the light is in the UV range.

8. The method according to claim 1, wherein the dosimetric solution comprises an agent or a combination of agents selected from the group consisting of alkali metal iodide, alkaline earth metal iodide, ammonium iodide, aqueous uridine phosphate, alkali metal benzoate, alkaline earth metal benzoate, ammonium benzoate, alkali metal peroxodisulfate, alkaline earth metal peroxodisulfate, ammonium peroxodisulfate, tert-butanol, polyvinylpyrrolidone, bentonite, mica, montmorillonite, nontronite, hectorite, kaolinite, halloysite, dickite, a clay mineral, chalk, silica, fumed silica, baryte, gypsum, talcum, magnesia, alumina, bismuth oxychloride, zinc oxide, an alkaline earth sulphate, an alkaline earth carbonate, an alkaline earth phosphate, an alkaline earth hydroxyphosphate, an alkaline earth halogen phosphate, an insoluble silicate, an insoluble alumosilicate, an insoluble carbonate, an insoluble sulphate, an insoluble phosphate, an insoluble hydroxyl phosphate, a halogen phosphate, a perfluorinated hydrocarbon or a derivative thereof, a perfluorinated carboxylic acid or a salt thereof, and polyvinylpolypyrrolidone.

9. The method according to claim 1, wherein the dosimetric solution comprises a diluted potassium iodide-potassium iodate actinometer.

10. The method according to claim 1, wherein the dosimetric solution comprises a diluted potassium iodide-potassium iodate/polyvinylpyrrolidone actinometer.

11. The method according to claim 1, wherein the dosimetric solution comprises a diluted sodium benzoate actinometer.

12. The method according to claim 1, wherein the dosimetric solution comprises a diluted potassium peroxodisulfate/tert-butanol actinometer.

13. The method according to claim 1, wherein the dosimetric solution comprises a turbidity-causing agent.

14. The method according to claim 1, wherein the microorganisms are selected from the group consisting of species of the monera kingdom, spores of the species of the monera kingdom, species of the fungi kingdom, spores of the species of the fungi kingdom, prokaryotes, eukaryotes, and viruses.

15. The method according to claim 1, wherein the viruses are selected from the group consisting of Parvoviridae viruses, Minute Murine Virus, Canine Parvovirus, Bovine Parvovirus, Porcine Parvovirus, Feline Parvovirus, Circoviridae viruses, Circinoviridae viruses, Picornaviridae viruses, Hepatitis A Virus, and Encephalomyocarditis Virus, Anelloviridae viruses, Encephalomyocarditis Virus, Enteroviridae RNA viruses, Microviridae DNA bacteriophages, and Leviviridae RNA bacteriophages.

16. The method according to claim 1, wherein the method is performed in conjunction with at least one other sterilization or microorganism inactivation method.

17. The method according to claim 1, wherein the biological fluid comprises at least one additive to reduce damage and loss of biological activity of the fluid.

18. The method according to claim 1, wherein the method is performed with a solvent detergent treatment.

19. The method according to claim 5, wherein the effective dose of light to inactivate microorganisms present in a biological fluid is a dose which inactivates at least about 99.9% of the viable microorganisms in the biological fluid.

20. The method according to claim 1, wherein the biological fluid is inactivated in a flow-through-reactor.

21. The method according to claim 1, wherein the biological fluid is a fluid selected from the group consisting of milk, whey, milk products, products derived from milk, fruit juices, products derived from fruit, vegetable juices, products derived from vegetable, native plant sap, transgenic plant sap, synthetic beverages, processed beverages, fermented beverages, alcoholic beverages, blood, plasma, plasma fractions, serum, fluids derived from blood, fluids derived from plasma, fluids derived from serum, fluids containing protein fractions, spinal fluid, cerebral fluid, lymph, saliva, semen, urine, prokaryotic cell culture supernatant, eukaryotic cell culture supernatant, prokaryotic cell lysate, eukaryotic cell lysate, a fluid intended for external therapeutical use, a fluid intended for enteral therapeutical use, a fluid intended for parenteral therapeutical use, a fluid intended for external cosmetic use, and a fluid intended for diagnostic use.

22. A UV-photoinactivation flow-through-reactor, in which one or more light sources are encased by an envelope thermostat, through which envelope thermostat a thermostated and essentially light-transparent liquid is flowing to remove heat from the lamp, thereby ensuring an essentially constant lamp intensity.

23. A flow-through-reactor according to claim 22, wherein the flow-through-reactor is a reactor type selected from the group consisting of a gravity-driven thin-film-generating type, a turbulent actively mixed flow type, a centrifugally driven thin-film-generating type, a coiled tube type, a baffled tube type, a motionless mixer tube type, a turbulent statically mixed flow-tube type, a laminar-tube type, and a turbulent flow-tube type.

24. A method of controlling the light sum dose of monochromatic or polychromatic light emitted from one or more light sources to effectively inactivate microorganisms present in a biological fluid in a batch reactor, comprising the steps of:

a) determining the absorption-dependent irradiation source target light sum dose based on the effective dose of monochromatic or polychromatic light to inactivate microorganisms present in the biological fluid, the irradiation light dose rate and the irradiation time necessary to effectively inactivate the microorganisms in the batch reactor;

b) recording the irradiation light dose rate and the irradiation time during inactivation of the microorganisms present in the biological fluid in the batch reactor;

c) calculating the absorption-dependent irradiation source light sum dose based on the measurements in step b);

d) comparing the absorption-dependent irradiation source light sum dose determined in step c) with the absorption-dependent irradiation source target light sum dose determined in step a); and

e) discontinuing light exposure of the biological fluid once the absorption-dependent irradiation source light sum dose is equal to or greater than the absorption-dependent irradiation source target light sum dose.

25. The method of controlling the absorption-dependent irradiation source light sum dose according to claim 24, wherein the method is continued until the absorption-dependent irradiation source light sum dose is essentially equal to the absorption-dependent irradiation source target light sum dose despite irradiation light dose rate variations and/or intermediate switching off of at least one of the one or more light sources.

26. The method according to claim 24, wherein the effective dose is determined by measuring the effect of the monochromatic or polychromatic light on a dosimetric solution, comprising measuring the effect of the monochromatic or polychromatic light on a dosimetric solution matching the turbidity of the biological fluid at the photoinactivating wavelengths used, the turbidity and absorbance of the biological fluid, the turbidity and the viscosity of the biological fluid, the turbidity and the absorbance and the viscosity of the biological fluid, the absorbance of the biological fluid, or the absorbance and viscosity of the biological fluid, based on a light dose calibration by i) irradiating the dosimetric solution in a layer of an optical path-length sufficiently thin to absorb only a fraction of the incident light at a predetermined defined irradiance for a defined time to apply a defined fluence (light dose) resulting in a change of a measurable physical or chemical magnitude, and ii) by reading out the dose corresponding to the change in the magnitude measured during or after the light irradiation of the dosimetric solution in the light irradiation reactor, wherein step i) is executed before step ii) or vice versa.

27. The method according to claim 24, wherein the recording of the irradiation light dose rate and the irradiation time is carried out using at least one electronic radiometer, at least one chart recorder, and/or at least one sum counter.