Classifications

• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D3/00—Devices using other cold materials; Devices using cold-storage bodies
  • F25D3/12—Devices using other cold materials; Devices using cold-storage bodies using solidified gases, e.g. carbon-dioxide snow
  • F25D3/14—Devices using other cold materials; Devices using cold-storage bodies using solidified gases, e.g. carbon-dioxide snow portable, i.e. adapted to be carried personally
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
  • B65D81/38—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents with thermal insulation
  • B65D81/3825—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents with thermal insulation rigid container being in the form of a box, tray or like container with one or more containers located inside the external container
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D17/00—Arrangements for circulating cooling fluids; Arrangements for circulating gas, e.g. air, within refrigerated spaces
  • F25D17/04—Arrangements for circulating cooling fluids; Arrangements for circulating gas, e.g. air, within refrigerated spaces for circulating air, e.g. by convection
  • F25D17/042—Air treating means within refrigerated spaces
  • F25D17/047—Pressure equalising devices
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D3/00—Devices using other cold materials; Devices using cold-storage bodies
  • F25D3/12—Devices using other cold materials; Devices using cold-storage bodies using solidified gases, e.g. carbon-dioxide snow
  • F25D3/125—Movable containers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D2205/00—Venting means
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D2205/00—Venting means
  • B65D2205/02—Venting holes
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25B—REFRIGERATION MACHINES, PLANTS OR SYSTEMS; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS
  • F25B2600/00—Control issues
  • F25B2600/25—Control of valves
  • F25B2600/2525—Pressure relief valves
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D2303/00—Details of devices using other cold materials; Details of devices using cold-storage bodies
  • F25D2303/08—Devices using cold storage material, i.e. ice or other freezable liquid
  • F25D2303/082—Devices using cold storage material, i.e. ice or other freezable liquid disposed in a cold storage element not forming part of a container for products to be cooled, e.g. ice pack or gel accumulator
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D2303/00—Details of devices using other cold materials; Details of devices using cold-storage bodies
  • F25D2303/08—Devices using cold storage material, i.e. ice or other freezable liquid
  • F25D2303/082—Devices using cold storage material, i.e. ice or other freezable liquid disposed in a cold storage element not forming part of a container for products to be cooled, e.g. ice pack or gel accumulator
  • F25D2303/0821—Devices using cold storage material, i.e. ice or other freezable liquid disposed in a cold storage element not forming part of a container for products to be cooled, e.g. ice pack or gel accumulator the element placed in a compartment which can be opened without the need of opening the container itself
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D2303/00—Details of devices using other cold materials; Details of devices using cold-storage bodies
  • F25D2303/08—Devices using cold storage material, i.e. ice or other freezable liquid
  • F25D2303/084—Position of the cold storage material in relationship to a product to be cooled
  • F25D2303/0843—Position of the cold storage material in relationship to a product to be cooled on the side of the product
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D2303/00—Details of devices using other cold materials; Details of devices using cold-storage bodies
  • F25D2303/08—Devices using cold storage material, i.e. ice or other freezable liquid
  • F25D2303/084—Position of the cold storage material in relationship to a product to be cooled
  • F25D2303/0844—Position of the cold storage material in relationship to a product to be cooled above the product
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D2303/00—Details of devices using other cold materials; Details of devices using cold-storage bodies
  • F25D2303/08—Devices using cold storage material, i.e. ice or other freezable liquid
  • F25D2303/084—Position of the cold storage material in relationship to a product to be cooled
  • F25D2303/0845—Position of the cold storage material in relationship to a product to be cooled below the product
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
  • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
  • F25D3/00—Devices using other cold materials; Devices using cold-storage bodies
  • F25D3/02—Devices using other cold materials; Devices using cold-storage bodies using ice, e.g. ice-boxes
  • F25D3/06—Movable containers

Definitions

• COOLING ELEMENT SHIPPING BOX WITH A COOLING ELEMENT, METHOD FOR TEMPERATURE STABILISATION, AND USE OF A COOLING ELEMENT
• the present invention relates to a cooling element according to the preamble of claim 1. Additionally, the invention relates to a shipping box comprising one or more cooling elements. Moreover, the invention relates to a method for temperature stabilization. Also, the invention relates to a use of such a method or cooling element or shipping box.
• Low-temperature product shipments are often done using dry ice (frozen or solid carbon dioxide) as a refrigerant. In equilibrium, under atmospheric conditions, the sublimation temperature of dry ice is around -78.5°C. These shipments consist of a thermally insulated shipping box containing dry ice pellets, the product to be shipped and a temperature logger. The product and logger are fully covered by dry ice on all sides.
• dry ice frozen or solid carbon dioxide
• shipments are sometimes done at higher temperatures, such as -20°C.
• Such shipments require the use of packs of selected phase-change material(s) as a refrigerant material.
• this approach is more complex and costly than the use of dry ice as refrigerant. Additionally, not all products are compatible with shipments at these elevated temperatures.
• a cooling element comprising a container, the container defining a volume within one or more walls of the container; the volume being airtight sealed, wherein the container contains dry ice (solid carbon dioxide) and is configured for releasing carbon dioxide gas from the volume and blocking ingress of ambient gas into the volume.
• the cooling element as defined above overcomes the temperature excursion issue by providing that in the container filled with dry ice the gas volume is consisting of carbon dioxide is maintained at a constant composition without disturbance from ambient gases, i.e., by mixing with variable amounts of ambient gases. Additionally, the provision for the release of carbon dioxide gas allows the internal pressure to remain constant and equal or near ambient pressure. As a result, the equilibrium between the solid phase and the gas phase of carbon dioxide (CO2) remains constant by maintaining the CO2 partial pressure at a constant level. A constant CO2 partial pressure prevents excessive sublimation of carbon dioxide relative to the ‘normal’ sublimation required for remaining at the sublimation point. Since the sublimation reaction is endothermic, excessive sublimation would be accompanied by strong cooling below the equilibrium temperature, which is -78.5°C at atmospheric pressure (1 atm, -1013 hPa).
• the invention provides a cooling element as described above wherein the material of the container walls is selectively permeable for carbon dioxide gas.
• carbon dioxide can be released from the container by diffusion through the wall(s) of the container.
• the container material allows that the internal pressure can be regulated in this manner, while preventing entry of ambient gas into the internal volume, which would alter the equilibrium conditions between CO2 gas and dry ice.
• the invention provides a cooling element as described above wherein the container comprises a one-way valve for releasing gas from the internal volume.
• the one-way valve allows the release of carbon dioxide gas from the container, while preventing entry of ambient gas into the internal volume.
• the invention provides a cooling element as described above wherein the one-way valve is an overpressure release valve.
• the release pressure can be predetermined which allows to control the pressure of CO2 in contact with the dry ice and thus the sublimation temperature.
• the one-way valve is configured to release carbon dioxide gas from the internal volume at an internal overpressure relative to ambient pressure.
• the invention provides a cooling element as described above wherein the material of the container is a flexible material.
• a receptacle an object with an internal volume for holding a product can be surrounded by/wrapped in the cooling element, improving the thermal contact such that better cooling of the product can be obtained.
• the invention provides a cooling element as described above wherein the volume of the container is configured for containing between about 50 grams and about 20 kilograms of carbon dioxide dry ice.
• the invention provides a cooling element as described above wherein the carbon dioxide dry ice is provided in the form of dry ice pellets.
• the dry ice has a relative large surface which allows that an equilibrium between gas and solid carbon dioxide can be obtained at relatively high rate.
• the present invention relates to a shipping box comprising a thermally insulated volume therein, and configured for holding a product or a receptacle holding a product and one or more cooling elements as described above, wherein the one or more cooling elements are arranged to enclose the product or the receptacle holding the product.
• the invention relates to a shipping box comprising a thermally insulated volume therein, and configured for holding at least one receptacle and one or more cooling elements as described above, wherein the one or more cooling elements are arranged to enclose the receptacle.
• the shipping box is configured to maintain its temperature at carbon dioxide sublimation temperature (-78.5°C at 1 atm) without the risk of temperature changes to lower temperatures of about -85°C.
• the invention provides a shipping box as described above wherein the shipping box is configured with thermally insulating walls and cover surrounding the thermally insulated volume.
• the invention provides a shipping box as described above wherein the thermally insulated volume is configured to have an internal pressure equal to external air pressure.
• the shipping box is arranged to have a same internal pressure as the ambient which is useful in environments where expected pressure changes are relatively small.
• the invention provides a shipping box as described above wherein the thermally insulated volume is an air-tight volume and the shipping box comprises a pressure relief valve for releasing gas from the thermally insulated volume.
• the release pressure for carbon dioxide from the cooling element and the internal pressure of the cooling element can be pre-set which provides that a better control of the temperature in the cooling element.
• the invention provides a shipping box as described above wherein a temperature logger is placed in the thermally insulated volume adjoining the receptacle for holding a product, and the one or more cooling elements are arranged to enclose both the receptacle and the temperature logger.
• the invention provides a shipping box as described above, wherein the receptacle comprises a vial containing a (bio)pharmaceutical substance or advanced therapy medicinal product, and the vial is provided with a rubber stopper.
• the invention provides a shipping box as described above, wherein the (bio)pharmaceutical substance or advanced therapy medicinal product comprise one or more substances selected from a group comprising small molecules, oligonucleotides, nucleic acids, peptides, proteins, antibodies, protein or antibody-drug conjugates, gene therapy, cell therapy, vaccines, blood or blood-derived components and microbiota derived products.
• the (bio)pharmaceutical substance or advanced therapy medicinal product comprise one or more substances selected from a group comprising small molecules, oligonucleotides, nucleic acids, peptides, proteins, antibodies, protein or antibody-drug conjugates, gene therapy, cell therapy, vaccines, blood or blood-derived components and microbiota derived products.
• the present invention also relates to a method for temperature stabilisation of a product contained in one or more receptacles, during shipment in dry ice, comprising: providing a shipping box comprising a thermally insulated volume therein; placing one or more cooling elements and a receptacle holding a product in the thermally insulated volume, while arranging the one or more cooling elements to enclose the one or more receptacles, in which each cooling element comprises a container, the container defining an internal volume within one or more walls of the container; the internal volume being air-tight sealed and filled with dry ice, wherein the container is configured for releasing carbon dioxide gas from the volume and for blocking ingress of ambient gas into the volume; the method further comprising: releasing carbon dioxide gas from the internal volume of the container at a predetermined overpressure of the carbon dioxide gas relative to ambient pressure.
• the present invention also relates to a method for temperature stabilisation of one or more receptacles during shipment in dry ice, comprising: providing a shipping box comprising a thermally insulated volume therein; placing one or more cooling elements and a receptacle holding a product in the thermally insulated volume, while arranging the one or more cooling elements to enclose the one or more receptacles, in which each cooling element comprises a container, the container defining an internal volume within one or more walls of the container; the internal volume being air-tight sealed and filled with dry ice, wherein the container is configured for releasing carbon dioxide gas from the volume and for blocking ingress of ambient gas into the volume; the method further comprising: releasing carbon dioxide gas from the internal volume of the container at a predetermined overpressure of the carbon dioxide gas relative to ambient pressure.
• the invention provides a method as described above wherein the material of the container walls is selectively permeable for carbon dioxide gas.
• the invention provides a method as described above wherein the method comprises providing the container with a one-way valve for releasing carbon dioxide gas from the internal volume.
• the invention provides a method as described above wherein the one-way valve is configured as an overpressure valve. According to an aspect, the invention provides a method as described above wherein the method comprises maintaining a pressure in the thermally insulated volume at ambient pressure.
• the invention provides a method as described above wherein the method comprises: providing the thermally insulated volume as an air-tight volume and providing the shipping box with a pressure relief valve for releasing gas from the thermally insulated volume for maintaining a constant pressure in the thermally insulated volume.
• the invention provides a method as described above wherein the method comprises: arranging a temperature logger in the thermally insulated volume adjoining the receptacle for holding the product, and the temperature logger is also enclosed by the one or more cooling elements.
• the invention provides a method as described above wherein the method further comprises: maintaining a temperature in the thermally insulated volume at the sublimation temperature of carbon dioxide, while dry ice is present in the one or more cooling elements.
• the invention provides a method as described above wherein the method comprises: preceding the placement of one or more cooling elements and a product in the thermally insulated volume of the shipping box: providing the container of the cooling elements with an opening to access the internal volume of the cooling elements; filling the internal volume of the cooling elements with dry ice through the opening; air-tight sealing the opening after filling the internal volume with dry ice; and providing the container of the cooling elements with a pressure regulation means.
• the invention provides a method as described above wherein the method comprises: preceding the placement of one or more cooling elements and one or more receptacles in the thermally insulated volume of the shipping box: providing the container of the cooling elements with an opening to access the internal volume of the cooling elements; filling the internal volume of the cooling elements with dry ice through the opening; air-tight sealing the opening after filling the internal volume with dry ice; and providing the container of the cooling elements with a pressure regulation means.
• the invention provides a method as described above wherein the method comprises: preceding the placement of one or more cooling elements and a product in the thermally insulated volume of the shipping box: providing the container of the cooling elements with an opening to access the internal volume of the cooling elements; filling the internal volume of the cooling elements with dry ice through the opening; air-tight sealing the opening after filling the internal volume with dry ice; and maintaining a small opening in the air-tight sealing for releasing carbon dioxide gas from the internal volume and for blocking ingress of ambient gas into the volume.
• the invention provides a method as described above wherein the method comprises: preceding the placement of one or more cooling elements and one or more receptacles in the thermally insulated volume of the shipping box: providing the container of the cooling elements with an opening to access the internal volume of the cooling elements; filling the internal volume of the cooling elements with dry ice through the opening; air-tight sealing the opening after filling the internal volume with dry ice; and maintaining a small opening in the air-tight sealing for releasing carbon dioxide gas from the internal volume and for blocking ingress of ambient gas into the volume.
• the invention provides for the use of a cooling element as defined above for the shipment in dry ice of at least one receptacle holding a product comprising a (bio)pharmaceutical substance or advanced therapy medicinal product.
• the invention also provides for the use of a cooling element as defined above for the shipment in dry ice of at least one receptacle holding a product comprising a (bio)pharmaceutical substance or advanced therapy medicinal product, wherein during the shipment in dry ice there is a temperature stabilization of the product contained in said at least one receptacle; wherein there is a shipping box comprising a thermally insulated volume therein; wherein there is one or more cooling elements as defined above and at least one receptacle in the thermally insulated volume; and wherein the one or more cooling elements are arranged to enclose the one or more receptacles.
• the invention provides for the use of a shipping box as defined above for the shipment of at least one receptacle holding a product comprising a (bio)pharmaceutical substance or advanced therapy medicinal product. Additionally or alternatively, the invention provides for the use of a method for temperature stabilisation as defined above for the shipment of at least one receptacle holding a product comprising a (bio)pharmaceutical substance or advanced therapy medicinal product(s).
• Figure 1 schematically shows a cooling element according to an embodiment of the invention.
• FIGS. 2 and 3 schematically show a cooling element according to an embodiment of the invention.
• Figure 4 schematically shows a shipping box according to an embodiment of the invention.
• Figure 5 shows the carbon dioxide phase diagram.
• Figure 7 Representation of a standard CB-EPS-24 transportation box.
• FIG. 8 Schematic representation of the conventional approach (Fig. 8 A) and new approach tested in the exploratory study described in the example (Fig. 8B).
• FIG. 9 Sealed CO2 valve bag for packing entire dry-ice content during shipment. One-way valve let CO2 gas out and prevents temperature drop in the box.
• Figure 10 A Two pouches filled with dry ice and the thermocouples in a CBS-EPS-24 box.
• B Full 6 pouches filled with dry ice placed in a CBS-EPS-24 box.
• C CB-EPS-24 box filled directly with dry-ice with thermocouple placement.
• FIG. A The freezer bags used for the experiment. Note the partially closed sealing zipper for CO2 venting.
• Figure 12 This experiment compared the temperature in a shipping box filled with dry ice (Fig. 12A) to the temperature in a box filled with dry ice-containing sealed “coffee bean” bags (Fig. 12B). During the first two hours of the experiment the shipping box was closed. After two hours, two air holes (15mm diameter) were punched diagonally across from each other in the sides (walls) of each of the boxes, allowing an airflow to circulate through the boxes.
• Figure 13 This experiment compared the temperature in a shipping box filled with dry ice (Fig. 13 A) to the temperature in a box filled with dry ice-containing sealable freezer bags (Fig. 13B). During the first hour and 20 minutes of the experiment the shipping box was closed. After approx, one hour and 20 minutes, two air holes (15mm diameter) were punched diagonally across from each other in the sides (walls) of each of the boxes, allowing an airflow to circulate through the boxes.
• FIG. 1 schematically shows a cooling element 10 according to an embodiment of the invention.
• the cooling element 10 of the invention comprises a container 20 which is configured to hold carbon dioxide in an internal volume 30 of the container.
• the internal volume is defined by the walls of the container and is configured to be air-tight sealable.
• the container is provided with a pressure regulation means 25 to provide that an internal pressure in the internal volume 30 can be regulated, i.e., kept substantially constant.
• the internal volume can be filled with solid carbon dioxide (dry ice) as refrigerant.
• dry ice solid carbon dioxide
• the pressure regulation 25 of the cooling element provides that the pressure of the carbon dioxide gas is maintained at a substantially constant pressure to avoid an overpressure that can deform or damage the container of the cooling element.
• the walls 20 of the container are or comprise selectively permeable membranes 25 for carbon dioxide gas which allow that carbon dioxide gas can diffuse from the internal volume to the outside of the container (for example the ambient).
• a one-way gas release valve 25 can be arranged in a wall of the container to release gas from the internal volume at a predetermined internal pressure.
• the one-way valve can be an overpressure release valve.
• FIG. 2 schematically show a cooling element 10 according to an embodiment of the invention.
• the container is a pouch made from flexible material such as a plastic that is filled with dry ice and carbon dioxide gas.
• the pouch comprises a one-way gas release valve 25 as described above.
• Such a pouch is a member of a plurality of similar or identical pouches that are designed to be placed adjacent to a receptacle for a product (not shown) such as a vial, bottle or box. To obtain cooling, the receptacle is surrounded by a plurality of the pouches which thermally isolate the receptacle and its contents from the environment.
• FIG. 3 schematically shows a cooling element 12 according to an embodiment of the invention.
• the cooling element comprises a flexible or deformable pouch capable of containing dry ice and carbon dioxide gas and which is designed to be wrapped or folded around a receptacle 40. In this manner cooling of the receptacle can be done by means of a single cooling element.
• the cooling element is designed as a sleeve in which the product can be inserted.
• the internal volume 30 of the cooling element 12 is formed in between the inner and outer walls 22, 24 of the sleeve.
• the cooling element can have various sizes and shapes depending on the application: the internal volume can be configured to contain between about 50 grams and about 20 kilograms of dry ice.
• the dry ice is provided in the form of dry ice pellets.
• the internal volume 30 of the cooling element 10; 12 is filled with dry ice and subsequently air-tight sealed.
• FIG. 4 schematically shows a shipping box 50 according to an embodiment of the invention.
• the shipping box is arranged for transport of receptacle(s) (40) for holding product(s) that require cooling to avoid exposure to varying and/or relatively high temperature.
• the shipping box comprises bottom, top and side walls 52, 54, 56 that form an enclosure which defines a shipping volume 58 for holding the receptacle(s) 40.
• the top wall of the shipping box is a removable cover to provide access to a top opening of the shipping volume.
• the walls 52, 54, 56 are constructed from or comprise thermal insulating material to provide thermal insulation of the shipping volume.
• one or more cooling elements 10; 12 as described above can be arranged within the shipping volume.
• the receptacle(s) 40 is (are) placed in the shipping volume 58 in a manner that the receptacle is enveloped or surrounded by the one or more cooling elements.
• the receptacle can be wrapped in a foldable cooling element and then placed in the shipping box.
• the receptacle and cooling elements are stacked in the shipping volume in a manner that the receptacle is surrounded on substantially all sides by the cooling elements.
• a temperature logging device 60 may be included with the receptacle(s) 40.
• the receptacle(s) and the logger device are in a package that is surrounded by the cooling element(s) 10; 12.
• the shipping box 50 as shown in Figure 4 is oriented in upright position.
• the dry ice absorbs heat, sublimation of CO2 takes place within the internal volume of the cooling element(s) 10; 12 and the amount of carbon dioxide gas in the internal volume 30 increases.
• the pressure in the internal volume 30 is regulated and excess carbon dioxide gas is released into the shipping volume 58 which is separated from the internal volume 30 of the cooling element(s). Most of the released carbon dioxide gas is accumulating in the shipping volume. However due to the separation the carbon dioxide gas in the shipping volume is not included in the equilibrium reaction of the carbon dioxide gas and the dry ice in the cooling elements. The reaction between the carbon dioxide gas and the dry ice is contained in the cooling elements and isolated from the ambient.
• the shipping box 50 may be an air-tight sealable box.
• the shipping box In order to prevent overpressure in the shipping volume, the shipping box is provided with an overpressure valve (not shown) to release carbon dioxide gas from the shipping volume.
• the shipping box may comprise one or more through-holes (not shown) in the walls to reduce the overpressure relative to the ambient pressure.
• the top opening of the shipping box is not horizontally levelled, and in this orientation, carbon dioxide gas can flow out from the shipping box into the ambient. At the same time, ambient gas can enter the shipping volume. However, due to the confinement of the dry ice and carbon dioxide gas in the internal volume 30 of the cooling element(s) 10; 12, the ambient gas will not enter the internal volume 30.
• the shipping box is used for transport or shipment of receptacles 40 such as vials 42 containing a (bio)pharmaceutical substance that requires cooling to prevent deterioration.
• receptacles 40 such as vials 42 containing a (bio)pharmaceutical substance that requires cooling to prevent deterioration.
• Such (bio)pharmaceuticals may comprise one or more substances selected from a group comprising small molecules, oligonucleotides, nucleic acids, peptides, proteins, antibodies, protein or antibody-drug conjugates, gene therapy, cell therapy, vaccines, blood or blood-derived components and microbiota derived products.
• ATMPs advanced therapy medicinal products
• the invention relates to a method for temperature stabilisation of one or more receptacles 40 during shipment in dry ice, which comprises
• each cooling element comprises a container 20, the container defining an internal volume 30 within one or more walls of the container; the internal volume 30 is airtight sealed and filled with dry ice, and the container is configured for releasing carbon dioxide gas from the volume and for blocking ingress of ambient gas into the volume.
• the method further comprises releasing carbon dioxide gas from the internal volume of the container at a predetermined overpressure of the carbon dioxide gas relative to ambient pressure.
• the method above can be used for the transportation or shipment of receptacles such as vials containing (bio)pharmaceuticals as described above.
• FIG. 5 shows the carbon dioxide phase diagram.
• the phase diagram shows the phases (solid 100, liquid 105, gas 110) of carbon dioxide as a function of temperature and pressure.
• the phases are separated by binary phase lines: carbon dioxide gas and solid are separated by a sublimation line 120, gas and liquid by a saturation line 130 and solid and liquid by a melting line 140.
• the sublimation line, saturation line and melting line meet at a triple point 150.
• the sublimation temperature of dry ice at 1 atm is only -78.5°C when considering a 100% CO2 atmosphere in equilibrium with dry ice.
• the temperature of a gaseous/solid CO2 system can drop below -78.5°C in two situations: when the absolute pressure drops below 1 atm, while maintaining a 100% CO2 concentration (i.e. during air transport), or when the relative concentration of CO2 drops below 100% while maintaining an absolute pressure of 1 atm (i.e. during mixing with other gases).
• the present invention prevents relatively large temperature excursions below the atmospheric sublimation point of carbon dioxide at -78.5°C by application of the cooling element as described above.
• the temperature of a receptacle and product i.e., a rubber stopped vial 42, 44 and substance in the vial
• the risk of an impaired sealing integrity of rubber stopped 44 vials 42 is reduced.
• the invention also provides for the use of a cooling element as defined above for the shipment in dry ice of at least one receptacle holding a product comprising a (bio)pharmaceutical substance or advanced therapy medicinal product, wherein during the shipment in dry ice there is a temperature stabilization of the product contained in said at least one receptacle (40); wherein there is a shipping box (50) comprising a thermally insulated volume (58) therein; wherein there is one or more cooling elements (10, 12) as defined above and at least one receptacle (40) in the thermally insulated volume (58); and wherein the one or more cooling elements (10, 12) are arranged to enclose the at least one receptacle (40).
• Dry ice solid carbon dioxide, CO2
• CO2 solid carbon dioxide
• a shipment box dry ice is usually surrounded by 100% gaseous CO2, at an ambient pressure of 1 bar.
• the partial pressure drops ( Figure 6) and therefore also the temperature of the cooling agent.
• an imperfect sealing of a shipment box can causeCO2 gas from dry ice to escape from the box and to be substituted by air which comes in contact with dry ice inside the box.
• the experiment consisted of two parts. In the first part the conventional shipment approach was tested. An inner insulating Styrofoam box (Figure 7) with two holes (radius of each hole was 15mm, see Figure 8 for more details) was used as a transportation box. The holes enabled cross-airflow within the box and were made for mimicking imperfections of the sealing in standard transportation boxes that can occur before or during a shipment.
• the boxes were closed and first allowed to equilibrate in the absence of any air leaks for a period of one to two hours, with the thermocouple datalogger running. After that initial period, two air holes (15mm diameter) were punched diagonally across from each other in the sides (walls) of each of the boxes, allowing an airflow to circulate through the boxes. The boxes were left in this state overnight.
• the one-way vented (coffee bean) bags were relatively large in view of the interior of the shipping box, making it difficult to completely fill the box with these bags. Gaps between the bags were large so the box with bags contained significantly less dry ice than the box that was filled with dry ice directly (estimated to be less than half the amount of dry ice, by weight). Also, some areas of the box (upper edges) did not fit an additional bag and thus contained air gaps (FIG. 10). Because of this sub-optimal configuration, the experiment was repeated using standard sealable 1.5L plastic freezer bags (Fig. 11). These bags were smaller and made of a thinner, more flexible material (e.g. low density Polyethylene (LDPE)), allowing a better filling of the box. 16 of the plastic freezer bags were used to fill a shipping box. The required venting of the bags was achieved by only partially closing the seal strip, leaving an opening of 2 cm in length.
• LDPE low density Polyethylene
• the box containing unprotected dry ice After introducing an artificial air leak, after approx. 2 hours, the box containing unprotected dry ice, showed a temperature drop, slowly reaching equilibrium temperatures that were between 7-14 degrees lower. The lowest temperature that was reached was -92 °C, which would qualify as a “low-temperature excursion” (Fig. 12 A). The box with dry icecontaining coffee bean bags also showed a slight drop in temperature, but only about 3 deg C. The minimum temperature that was reached in that experiment was -78 °C, which would not be classified as a temperature excursion (Fig. 12B). Interestingly, the observed temperature drop appeared to occur much faster in the box containing coffee bean bags than in the box containing unprotected dry ice.
• thermocouple The temperature change in the box containing partly sealed dry ice bags was smaller, showing a very low temperature drop measured by the thermocouple at 8cm, while the thermocouples at 2cm and 14 cm measured a small rise in temperature (Fig. 13B).
• the temperature profile looked slightly more stable for the freezer bags than for the coffee pouches.
• the top thermocouple (20cm) in both boxes showed a much higher temperature because it was located above the level of the dry ice. The warming of the temperature due to the incoming air caused by the leak can clearly be seen in the upper thermocouple.
• the second type of pouch was tested after encountering several practical issues with the available coffee bean bags (size, seal, surface area, material thickness, thermal conductance, packing efficiency). Indeed, a slightly more stable interior temperature was achieved using the smaller and thinner freezer bags.

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• 2021
  • 2021-10-19 EP EP21794817.3A patent/EP4232375A1/de active Pending
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