BR112020011717B1 - METHODS FOR PRELOADING AN EMPTY OR PARTIALLY EMPTY INSULATED CONTAINER WITH CO2 SNOW, TO CREATE A PRELOADED CONTAINER AT A FIRST LOCATION FOR TRANSPORTATION TO A SECOND LOCATION, TO SUPPLY A PERISHABLE ITEM TO ONE LOCATION, TO DELIVER THE PRELOADED CONTAINER WITH CO2 SNOW AT LEAST PARTIALLY DEPLETED AND TO CREATE AN INSULATED CONTAINER PRE-LOADED WITH CO2 SNOW IN A FIRST LOCATION TO TRANSPORT TO A SECOND LOCATION - Google Patents

Abstract

Automated and manual methods for pre-charging an empty or partially empty insulated container with CO2 snow are provided. A first location as a loading location loads liquid CO2 into a container to create a pre-charged container with CO2 snow. The loading location prepares the preloaded container for delivery to a second location, either by itself or through a third party. The second site may be a clinical site, which upon receipt of the pre-filled container, loads a perishable item such as a biological specimen into the pre-filled container. A user receives the pre-loaded container with perishable item and removes the perishable item from the pre-loaded container for testing (e.g., biological testing). Depending on the depletion level of the CO2 snow in the pre-charged container, the user returns the depleted container to the first location or the intermediate location.

Description

FIELD OF INVENTION

[0001] This invention relates to automated and manual methods for pre-loading CO2 snow into a container.

Background of the Invention

[0002] Drug development continues to be a major effort in the pharmaceutical industry. Drug development requires clinical trials to establish the safety and effectiveness of new treatments. Today, in the United States alone, there are a large number of clinical trials underway at various stages. Each clinical trial can involve hundreds to thousands of patients who volunteer to be administered certain experimental drugs. Generally, as part of clinical testing, biological samples (e.g., tissue samples, urine, blood) are collected from participants at a clinical site, such as a hospital, university, or doctor's office, and then transported to laboratories for analysis or to facilities where they can be stored frozen for analysis at a later time.

[0003] The ability to evaluate the safety and efficacy of an experimental drug requires obtaining reproducible and reliable results during clinical trials. Biological samples must be stabilized and preserved during storage and transport between, for example, the clinic and the laboratory. A common means of preserving biological samples today is to freeze them and store them in the presence of solid carbon dioxide (i.e., dry ice).

[0004] Dry ice systems typically involve manually loading samples and dry ice into an insulated box, such as a polystyrene box, at the clinical site where samples are acquired. The isolated box is typically provided to the clinical site by a pharmaceutical company or contract research organization administering the clinical trial. Insulated box components can be supplied in an assembled or disassembled state. Assembling the insulated box and loading the dry ice can be laborious. There may also be considerable cost and inconvenience associated with maintaining a sufficient supply of dry ice at the clinical site. Additionally, failure to use such dry ice within a certain duration may result in significant sublimation losses that cause the dry ice to lose its cooling effect. Additionally, the insulated box is typically not reusable and must be discarded, thus creating waste.

[0005] There are also other disadvantages in relation to transporting samples in conventional insulated boxes. The dry ice cools the inside of the insulated box as it sublimes into carbon dioxide vapor. There are a number of insulated boxes that can maintain a cool internal temperature for various durations up to four or five days. The internal space of the sample may be uniformly close to the dry ice temperature after initial dry ice loading, but as the dry ice sublimates, significant temperature gradients can emerge within the internal space of the sample, potentially compromising sample quality. . Insulated boxes are generally shipped via expedited delivery methods to ensure that a sufficiently cool temperature is maintained in the internal space of the sample. However, if delays or interruptions occur in transport routes, samples may degrade. As a result of these delays during transportation, it may be necessary to load additional dry ice into the bin during transit, which results in increased cost and logistical complexity for transportation.

[0006] An alternative to conventional dry ice carriers is a cryogenic liquid nitrogen-based vapor vessel. Cryogenic liquid nitrogen-based vapor vessels use an absorbent to retain the cold nitrogen in the vapor state and prevent the presence of nitrogen in its liquid form. However, these liquid nitrogen-based steam vessels have disadvantages. One disadvantage is the time and labor involved in preparing the vase. Specifically, users prime these vessels by pouring liquid nitrogen into the vessel; waiting several hours to allow sufficient absorption of the nitrogen onto the absorbent to occur; followed by decantation of excess liquid nitrogen before transport. Substantial handling of cryogenic liquid nitrogen is required, and significant time is required to prepare the liquid nitrogen carrier prior to use. Additionally, the costs associated with using liquid nitrogen-based steam vessels are significantly higher than alternative dry ice vessels.

[0007] In view of these disadvantages, there is an unmet need for an improved way to effectively provide containers designed to preserve samples in a container during storage and transportation.

SUMMARY OF THE INVENTION

[0008] In one aspect, the invention relates to a method for pre-charging an empty or partially empty insulated container with CO2 snow to create a pre-charged container at a first location for transport to a second location, comprising the steps of: receiving a source of liquid CO2 at the first location; operatively connecting a CO2 snow charger to the empty or partially empty container and the source of liquid CO2; generating the CO2 snow within the empty or partially empty container to create the pre-charged container; preparing the pre-charged container for delivery to the second location.

[0009] In a second aspect, the invention relates to a method for supplying a perishable item to a location, which comprises the steps of: receiving a pre-filled container at least partially filled with CO2 snow within the pre-filled container loaded; open the pre-filled container at least partially filled with CO2 snow; accessing an interior region of the pre-filled container at least partially filled with the CO2 snow; loading the perishable item into the pre-loaded container at least partially filled with the CO2 snow, with the perishable item being in sufficient proximity to the CO2 snow to maintain a temperature of the perishable item below an upper limit; reseal the pre-filled container at least partially filled with CO2 snow; Prepare the pre-loaded container at least partially filled with the CO2 snow with the perishable item in it for delivery to the site.

[0010] In a third aspect, the invention relates to a method of delivering the container pre-charged with at least partially exhausted CO2 snow, which comprises: receiving the container pre-charged with at least partially exhausted CO2 snow, being that said container pre-filled with at least partially exhausted CO2 snow further comprises one or more perishable items in sufficient proximity to the CO2 snow to maintain the temperature of the perishable item below an upper limit; opening the pre-filled container to access the interior of the pre-filled container; remove the one or more perishable items from the preloaded container; and delivering the pre-filled container to a location for loading, loading additional perishable items, or using at least a portion of the one or more perishable items that remain in the at least partially depleted container.

[0011] In a fourth aspect, the invention relates to a method of creating an insulated container pre-charged with CO2 snow at a first location for transport to a second location, comprising the steps of: providing a source of CO2 snow CO2 in a first location; introduce the CO2 snow into an empty or partially empty container at the first location; create the preloaded insulated container; and prepare the preloaded container for delivery to the second location. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1a illustrates a representative perspective view of a container and top plate with fill conduit attached to the top plate for producing carbon dioxide (CO2) snowpack within an automatic fill dispensing station. in accordance with the principles of the present invention; Figure 1b illustrates a cross-sectional view of Figure 1a, which shows in detail the flow of CO2 gas through the mesh sheet of the top plate; Figure 2a shows aspects of an automatic dispensing station for generating CO2 snowpack within containers of two different sizes, wherein each of the containers is shown in a respective inactive orientation, in accordance with the principles of the present invention; Figure 2b shows aspects of the automatic dispensing station of Figure 2a, wherein each of the two containers is shown in a respective filling orientation, in accordance with the principles of the present invention; Figure 3 shows an exemplary actuation mechanism used to dispense the CO2 snow block from one of the containers previously selected for filling and which is located in the automatic dispensing station; Figure 4 shows aspects of a conveyor belt system situated within the automatic dispensing station, wherein a box may be fed into the inlet of the conveyor system which is conveyed below the selected container filled with CO2 snow block and which is tilted into the dispensing orientation to transfer the CO2 snow pack from the container into the box as part of an automated vending system; Figure 5 shows a control methodology used to perform automatic dispensing in accordance with the principles of the present invention; Figure 6 shows a control methodology used to perform an automatic loading operation on a single container that is loaded within a charging station of Figure 8; Figure 7 shows a schematic process flow for introducing liquid CO2 from a CO2 supply pipeline that can be used in an automatic dispensing station that contains multiple containers; Figure 8 shows a charging station into which a container can be loaded to automatically charge the CO2 snow pack; Figure 9a shows an initial orientation of the selected container ready to dispense CO2 snow pack from within the container; Figure 9b shows an intermediate orientation created as a result of the selected container rotated 90° counterclockwise relative to the position of Figure 9a, as a result of the actuator assembly exerting an upward force along the sides of the container; Figure 9c shows a final tilted orientation of the selected container rotated an additional 45° counterclockwise relative to the position of Figure 9b, wherein the CO2 snow pack can be released from within the container into a box situated below the container. selected; Figure 10 illustrates a representative flow diagram for pre-charging CO2 snow in accordance with the principles of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0012] As will be described, in one aspect, the present invention provides a method for automatically generating blocks of CO2 snow of various sizes available from an automatic dispensing station. A user can readily access the generated CO2 snowpack from an inlet and outlet access window of a conveyor belt system situated within the dispensing station. The on-demand generation of the present invention eliminates the need for a user to maintain an inventory of CO2 snowpack or dry ice on site.

[0013] It should be understood that the terms "CO2 snow" and "dry ice" have the same meaning and may be used interchangeably in the present invention and throughout the application to mean particles of solidified CO2.

[0014] The "CO2 snow block" or "CO2 block", both of which can be used interchangeably in the present invention and throughout the application, means creating CO2 snow particles in a form substantially similar to a block of any shape consisting of tightly held particles.

[0015] "Fluid CO2" as used herein means any phase including a liquid phase, a gas phase, a vapor phase, a supercritical phase, or any combination thereof.

[0016] "CO2 source" or "liquid CO2 source" as used herein includes, but is not limited to, cylinders, dewars, bottles, and bulk or micro-bulk type tanks.

[0017] The term "conduit" or "conduit flow network", for use in the present invention, means tube, tubing, hose, distributor and any other suitable structure that is sufficient to create one or more flow paths and/or allow the passage of a fluid.

[0018] "Connected" or "operationally connected" as used herein means a direct or indirect connection between two or more components, such as piping and assembly, including, but not limited to, instrumentation, valves and conduit, except where otherwise specified , in order to allow fluid, mechanical, chemical and/or electrical communication between the two or more components.

[0019] "Item" as used herein means any temperature-sensitive goods, products or supplies that may be susceptible to deterioration, degradation and/or structural change or modification if not kept frozen or below a certain temperature, including, but not limited to, biological samples, such as blood, urine and tissue samples or their constituents; perishable foods such as meat, poultry, fish and dairy products; personal care items; and chemicals.

[0020] "Loading" as used herein means the process of introducing CO2 fluid from an external CO2 source into a container operatively connected to the external CO2 source.

[0021] "Container" as used herein means any storage, filling, delivery or transportable vessel capable of receiving CO2 fluid, including but not limited to, mold cavities, cylinders, dewars, bottles, tanks, barrels, bulk and microbulk type.

[0022] "Transportable" means a device that is capable of being moved, transported or shipped from a user location to another destination by any known means, including, but not limited to, air, land or water. Transportation or shipping may occur through various packaged delivery services, including, but not limited to, mail order, UPS® shipping services, FedEx® shipping services, and the like.

[0023] The embodiments as described below are by way of example only, and the invention is not limited to the embodiments illustrated in the drawings. It should also be understood that the drawings are not to scale and in certain cases details have been omitted which are not necessary for understanding the embodiments, such as conventional manufacturing and assembly details. It should also be understood that the exact configuration of conduit and valves is not drawn to scale, and certain features are intentionally omitted in each of the drawings to better illustrate various aspects of the automated loading and automated filling processes in accordance with the principles of the present invention. .

[0024] Embodiments are described with reference to drawings in which similar elements are referred to by similar numerals. The relationship and operation of the various elements of the embodiments will be better understood by the detailed description below. The detailed description contemplates the characteristics, aspects and modalities in various permutations and combinations, as being within the scope of the disclosure. The revelation may therefore be specified as comprising, consisting of or consisting essentially of, any of such combinations and permutations of these specific characteristics, aspects and modalities, or of one or more selected therefrom.

[0025] In one aspect of the present invention, a method for automatically filling carbon dioxide (CO2) snow pack into a selected container within an automatic dispensing station will be discussed with reference to Figures 1a, 1b, 2a, 2b, 3, 4, 5, 7, 9a, 9b and 9c. Figures 1a and 1b illustrate a first container 10 that is used with the automatic dispensing station 1 (Figures 2, 3, 4 and 5) to deliver CO2 snow pack 2 from the first container 10 into any suitable user box. The first container 10 includes a mold cavity 13 with a first top plate 15. The mold cavity 13 has a volume that is sized to receive the volume of the CO2 snow block 2. The desired volume of the CO2 snow block 2 is input into a programmable logic controller (PLC) 1085 of the automatic dispensing station 1. The PLC 1085 selects the mold cavity 13, which is situated within the automatic dispensing station 1, only when it determines that the mold cavity 13 has a volume equal to or greater than the input volume of the CO2 snow block 2 in the PLC 1085. The PLC 1085 orients the selected mold cavity 13 to a fill orientation (Figure 2b) and performs an automated fill process to fill the required amount of CO2 snow block 2 into the mold cavity 13. The filling process is preferably based on the filling time to obtain the desired volume of the CO2 snow block 2.

[0026] Upon completion of filling, the CO2 snow block 2 is transferred from the mold cavity 13 to a user box 22 (Figure 4) which is provided to a user for pickup.

[0027] Specifically, the user box 22 is fed to an input window 21 and subsequently transported along a conveyor belt 20 to a dispensing window 14 of the automatic dispensing station 1 for a user to access and pick up.

[0028] The structural details of the first container 10 are shown in Figures 1a and 1b. The mold cavity 13 generally includes a top plate 15, a bottom wall 16, and multiple vertically oriented side walls 17. The top plate 15 is characterized by a separation barrier support that is permeable only to gaseous CO2 and substantially impermeable. to the CO2 snow so that the gaseous CO2 can escape from the interior of the mold cavity 13 without significant loss of CO2 snow. Referring to Figure 1b, the separation barrier support includes a support structure 19 and a mesh sheet 18. It will be understood that any type of material can be used to define passages for the escape of gaseous CO2.

[0029] A fill conduit 23 has one end connected to the top plate 15 and another end connected to a CO2 supply pipe 1000. In a preferred embodiment, a total of four nozzles 12 are evenly distributed at one end of the conduit filler 23. Each nozzle 12 is separated from the other by approximately 90°, and each nozzle 12 has the same size opening and shape. The structure of the nozzles 12 creates a substantially uniform flow of CO2 fluid flow therethrough which allows for the creation of substantially uniform distribution and formation of the CO2 snowpack 2 within the mold cavity 13.

[0030] The nozzles 12 are oriented away from a vertical of the fill conduit 23 at an angle that is in the range of approximately 30° to 60° relative to the vertical of the fill conduit 23, so that the vertical extends perpendicular to a horizontal surface of the mold cavity 13. It should be understood that other nozzle designs and orientations are contemplated without departing from the scope of the present invention.

[0031] Figure 2a shows the automatic dispensing station 1 which is designed to contain multiple containers. The dotted line is representative of a structural shell of the automatic dispensing station 1 within which multiple containers of different volumes can be contained. Specifically, and for the purposes of simplicity to better explain the principles of the present invention, only two containers are shown, namely, the first container 10 of Figure 1a and a second container 26. The first container 10 has a smaller volume than the second container 26. The automatic dispensing station 1 is removably connected to the CO2 supply piping 1000, details of which are shown in Figure 7. The first container 10 is shown in an inactive orientation in which the first container 10 has the first dispensing plate. top 15 removed from the top of the first mold cavity 13. Similarly, the second container 26 is shown in an inactive orientation in which the second container 26 has the second top plate 28 removed from the top of the second mold cavity 25. Neither neither the first container 10 nor the second container 26 in the inactive orientation contains the CO2 snow block 2. Vertical actuators 29a and 29b are attached to the first top plate 15 and are configured to contract to lift the first top plate 15 away. of the first container 10 to create the inactive orientation. Vertical actuators 29a and 29b are configured to extend and cause the first top plate 15 to be lowered onto the first container 10 to create the filling orientation of Figure 2b. Similarly, vertical actuators 30a and 30b are attached to the second top plate 28 and are configured to lift the second top plate 28 away from the second container 26 to create the inactive orientation, and can be reconfigured to extend and make that the second top plate 28 lowers onto the second container 26 to create the fill orientation of Figure 2b.

[0032] The PLC 1085 is in electrical communication with the supply piping 1000 and the various components of the automatic dispensing station 1 and as a result can regulate the various actuators, valves, including automatic control valves and pressure regulating devices, transducers pressure and ventilation system as shown in Figure 7. The dotted lines in Figure 7 that extend between the PLC 1085 and the various components represent electrical communication. It should be further understood that the PLC 1085 communicates between the PLC 1085 and the various components, including the first container 10, the second container 26, and the various actuators 29a, 29b, 30a, 30b responsible for raising and lowering the top plate and the other actuator assemblies 91a, 91b responsible for rotating the mold cavities in a dispensing orientation (as will be explained with reference to Figures 9a, 9b and 9c).

[0033] Figure 2b shows the first container 10 and the second container 26 in a fill orientation in which the respective top plates 15 and 28 are lowered into their respective mold cavities 13 and 25 with sufficient pressure to form a seal to the along the periphery of their respective containers 10 and 26. The peripheral seal ensures that gaseous CO2 within the mold cavities 13/25 can escape only through the mesh sheet 18 and 31 of the first container 10 and the second container 26, respectively. Specifically, vertical actuators 29a and 29b are extended with respect to Figure 2a to cause the first top plate 15 to lower onto the first mold cavity 13 with sufficient pressure to form a seal along the periphery of the first mold cavity 13 Vertical actuators 30a and 30b are extended relative to Figure 2a to cause the second top plate 28 to lower onto the second mold cavity 25 with sufficient pressure to form a seal along the periphery of the second mold cavity 25. Figure 2b shows that the first fill conduit 23 and the second fill conduit 27 are removably connected to CO2 supply piping 1000 along which liquid CO2 may flow from a CO2 source 1090, which may comprise any container, including, but not limited to, cylinders, dewars, bottles, bulk or microbulk type tanks.

[0034] The automation process in connection with the automatic dispensing station 1 will now be described. In a preferred embodiment, the PLC 1085 is used to control the filling and sale of CO2 snow block 2 by the control methodology 5000 of Figure 5. The PLC 1085 may be situated in close proximity to the automatic dispensing station 1. In this example, and for simplicity purposes to better explain the principles of the present invention, the automatic dispensing station 1 contains a first container 10 and a second container 25. However, it should be understood that the automatic dispensing station 1 is, of preferably designed to accommodate a greater number of containers of different volumes. In one example, the PLC 1085 is situated as part of the CO2 supply piping 1000 shown in Figure 7. The PLC 1085 is preferably pre-programmed with a density of the CO2 snowpack to be produced. The CLP 1085 can use any density, but preferably uses 50 to 65 lb/ft3 and more preferably 55 to 60 lb/ft3. In step 501, the PLC 1085 can be activated. Next, a user inputs into the PLC 1085 a desired volume of the CO2 snow block to be generated (step 502). The user can also select on a Human Machine Interface (HMI) the size and/or shape of the specific CO2 snow block or 10/26 container. The PLC 1085, in response to the entered volume, selects and activates a suitable container within the automatic dispensing station 1 that has a volume capable of generating the entered volume of CO2 snow pack 2. The PLC 1085 determines that the cavity volume of mold 13 that corresponds to the first container 10 is smaller than the inserted volume. The PLC 1085 further determines that the volume of the mold cavity 25 corresponding to the second container 26 is equal to or greater than the inserted volume of the CO2 snow block 2. As a result, the PLC 1085 selects the second container 26 to be used for filling with CO2, and consequently transmits a signal to the second container 26.

[0035] A box 22 (e.g. cardboard box) is fed to an input window 21 of the conveyor belt system 4, which is situated within the automatic dispensing station 1 (step 503). Box 22 can be powered manually by a user or automatically. The box 22 has a volume that is sized to receive the inserted volume of the CO2 snow block 2 to be generated within a mold cavity.

[0036] Having selected the appropriate container for filling CO2 into it; and with the box 22 that has been placed along the inlet 21 of the conveyor belt 20 (step 503), the PLC 1085 is ready to perform pre-fill integrity checks (step 504). Several criteria need to be approved before the filling operation can begin. The PLC 1085 verifies that the ventilation system 1050 (Figure 7) is turned on via the "PS1000" pressure switch, shown in communication between the exhaust 1050 and the PLC 1085. Specifically, the PLC 1085 verifies that the exhaust system has been turned on and is functioning to allow CO2 gas and CO2 effluent gas to pass from the mold cavity 25 through the exhaust conduit 1050 and then to the exhaust system. The PLC 1085 also determines whether the pressure in the supply piping 1000 and second fill conduit 27 can be maintained without leaking. If any of these pre-population integrity criteria are not met, the 1085 PLC aborts the operation and sends a message and status to a human machine interface (HMI) for a user to take appropriate corrective action until all health checks have been completed. pre-filling form are approved (step 505).

[0037] If each of the prefill integrity checks is satisfied, then the PLC 1085 selects a suitable mold cavity and activates the selected suitable mold cavity from an inactive orientation to the fill orientation (step 506 ). The PLC 1085, in response to the input volume of the CO2 snowpack, selects a suitable container within the automatic dispensing station 1 that has a volume capable of generating the input volume of the CO2 snowpack 2. The PLC 1085 determines that the volume of the mold cavity 13 corresponding to the first container 10 is smaller than the inserted volume. The PLC 1085 further determines that the volume of the mold cavity 25 corresponding to the second container 26 is equal to or greater than the inserted volume of the CO2 snow block 2. As a result, the PLC 1085 selects the second container 26 to be used for filling CO2, and consequently transmits a signal to the second container 26 to activate the second container 26 from the inactive orientation (Figure 2a) to the filling orientation (Figure 2b) in connection with step 506. The second cavity of selected mold 25 in Figure 2a is shown in the inactive orientation with the second top plate 28 separated from the top of the second mold cavity 25. At this time, no CO2 snow blocks 2 are contained in the second mold cavity 25. The PLC 1085 transmits signals to the vertical actuators 30a and 30b to cause the vertical actuators 30a and 30b to extend downward in a longitudinal direction, as shown in Figure 2b, thereby causing the second top plate 28 to move downwardly toward the top of the second container 26. Vertical actuators 30a and 30b continue to move downward until they are uniformly positioned over the top of the second mold cavity 25, as shown in Figure 2b. Figure 2b shows that the second plate 28 has been lowered onto the top of the second container 26 with sufficient pressure to form a seal along the periphery of the second containers 26.

[0038] The PLC 1085 validates that the selected container 26 is in the fill orientation, and if not, the PLC 1085 will relay appropriate signals to orient the selected container 26 to the fill orientation. After verifying that the second container 26 is activated in the fill orientation, as shown in Figure 2b, the PLC 1085 may determine the predetermined or expected fill time of CO2 snow block 2 in the selected container 26 (step 507) as set forth below. The PLC 1085 receives a signal from the pressure transducer 1071 (Figure 7), which measures the pressure of the CO2 in the vapor headspace of the source 1090. The pressure transducer 1071 relays a signal corresponding to the pressure of the CO2 to the PLC 1085. Based on this pressure reading and the aggregate volume of the nozzles 12 in the second fill conduit 27 (a representative schematic of which is shown in Figure 1b), the PLC 1085 can determine the expected mass flow rate of the stream containing liquid CO2, which is determined empirically by a look-up table of pressure versus aggregate volume of the nozzles 12. Having determined the mass flow rate, the expected fill time (i.e., predetermined fill time) in the selected second container 26 is calculated by the PLC 1085 as the product of the inserted volume of the desired CO2 snow block and the preprogrammed density of the desired CO2 snow block to be filled. generated (e.g., 55 to 60 lb/ft3) divided by the empirically determined mass flow rate.

[0039] With the PLC 1085 calculating the predetermined fill time, the PLC 1085 requests a user message to activate a start button (step 508) to begin pressurizing the supply piping 1000 prior to the filling process. The valves, instrumentation and components of Figure 7 associated with the second fill conduit 27 are configured to be connected to the CO2 supply/source piping 1000 and receive CO2 gas and liquid CO2, as will now be explained. The gas conduit 1091 contains pressure transducers 1071 and 1070, and pressure indicator 1078. The pressure transducer 1071 measures the headspace pressure in the CO2 source 1090; the pressure indicator 1078 measures the pressure of the CO2 gas stream after being reduced by the pressure reducing valve 1080 (“PRV 1100”); and the pressure transducer 1070 measures the pressure of the stream containing liquid CO2 entering the second selected container 26. With the CO2 vapor valve 1094 set in the open position, the CO2 control valve 1100 set in the open position, the valve With the liquid CO2 withdrawal valve 1093 set in the closed position, and the CO2 control valve 1200 set in the closed position, CO2 gas is withdrawn from the vapor headspace of the CO2 source 1090 and flows into the gas conduit 1091. pressure regulator 1080 ("PRV 1100") reduces the pressure of the CO2 gas taken from the CO2 source 1090 from the CO2 pressure source (e.g., 350 to 400 psig) to about 150 psig, as measured by the pressure indicator. pressure 1078. The CO2 gas is preferably added in an amount to prevent the pressure of the liquid-containing CO2 from reducing below a certain pressure (e.g., about 150 psig) to ensure that the liquid does not decrease to a pressure that prematurely undergoes a phase change to a solid and/or gas within a portion of the supply piping conduit 1000 and the second fill conduit 27.

[0040] In addition to adequate pressurization of the pipeline conduit 1000, CO2 gas can optionally be added to flow and purge any residues and/or impurities for any amount of time. In one example, the purging process may continue for about 30 seconds to about 2 minutes. As the CO2 gas flows through the various portions of the gas conduit 1091, any residues and/or impurities may also be purged. The CO2 gas can be directed to the second container also 26 by configuring the valve 1301 open and configuring the valve 1302 closed. The container 26 at this stage of the filling process does not contain any substantial amount of CO2 snow particulates or CO2 snowpack 2. The CO2 gas flows in a downward direction through the filling conduit 27 and enters the mold cavity 25 The CO2 gas subsequently escapes from the container 26 through the mesh sheet 31 of the second top plate 28 (e.g., withdrawn in a substantially vertically oriented direction as shown in greater detail in Figure 1b by the upward arrows).

[0041] When the PLC 1085 determines that the pressure in the selected fill conduit 27 and the CO2 supply piping 1000 is at or above a lower pressure sufficient to prevent phase change of the liquid CO2 (e.g., preferably , equal to or greater than 150 psig, and more preferably from 150 psig to about 200 psig), filling of the CO2 snow block into the selected container 26 begins (step 509). The 1094 CO2 vapor valve can remain in the open position; and the control valve 1100 may remain in the open position thereby ensuring that adequate gas pressurization within the tubing 1000 is present before and during the filling of liquid CO2 into the container 26. To begin the flow of liquid CO2 from the CO2 source 1090 , the control valve 1302 is set in the closed position to ensure that the liquid-containing CO2 does not flow into the first container 10 (i.e., the non-selected container as determined by the PLC 1085); and the control valve 1301 is set in the open position to allow the liquid-containing CO2 to flow into the second container 26 (i.e., the selected container as determined by the PLC 1085). Referring to Figure 7, liquid-containing CO2 from the CO2 source 1090 flows along the liquid conduit 1092 through the control valve 1301 and then is introduced in a downward direction into the second fill conduit 27 of the second selected container 26 (as shown in Figure 1b). The check valve 1067 prevents the pressure of the liquid-containing CO2 from causing the CO2 gas to backflow within the conduit 1091 to the CO2 source 1090.

[0042] The CO2-containing liquid emerges from the nozzles 12 of the second fill conduit 27 to enter the selected mold cavity 25 of the second selected container 26. In a preferred embodiment, the end of the second fill conduit 27 has four nozzles 12, which are angled to direct or inject the CO2-containing liquid into the selected mold cavity 25, as shown in Figure 1b. A drop in pressure and temperature occurs as the liquid-containing CO2 passes through the nozzles 12 and into the selected mold cavity 25 to produce solid CO2 snow particles and CO2 effluent gas therein. The CO2 effluent gas passes through the mesh sheet 18 of the second top plate 28 while the solid particulates are too large to flow through the mesh sheet 18 and therefore remain trapped within the mold cavity 25. The particles and gas does not escape along the top edge of the container 26 as the periphery of the second container 26 is sealed as a result of actuators 30a and 30b which keep the second top plate 28 sufficiently pressed against the top of the mold cavity 25 during filling. As the CO2 effluent gas passes through the mesh sheet 31 as vented gas, it has the desirable effect of compacting the solid CO2 snow particles to form the CO2 snow block 2 within the mold cavity 25, starting thus the generation of the CO2 2 snowpack. The term "compaction", as used herein with reference to automated filling, refers to the compression of snow particles into a CO2 2 snowpack of suitable density. Compaction can affect the amount of CO2 snowpack that can be generated within the selected mold cavity 25. In this way, the present invention has the ability to use the formation of vented gas to improve the packing density of snow particles to form CO2 snow block 2. Vented CO2 gas flows through the openings of the mesh sheet 31 of the second top plate 28, as shown by the arrows in Figure 1b, thus preventing excess pressure from building up within the second mold cavity 25. It should be understood that gas can be withdrawn at any angle to a vertical of the second fill conduit 27 so that the vertical extends perpendicular to a horizontal surface of the selected mold cavity 25. The vented gas can then be directed to the exhaust conduit 1050 which is operatively connected to the second fill conduit 27.

[0043] CO2 snow particles continue to form within the selected mold cavity 25 in a block-like shape. A timer may continue to monitor an elapsed time and generate a signal corresponding to the elapsed time that is transmitted to the PLC 1085. The PLC 1085 continues to allow CO2-containing liquid to flow along the conduit 1092 as long as the elapsed time is less than the predetermined fill time (step 510).

[0044] When the PLC 1085 has determined that the elapsed time has reached the predetermined filling time, filling is stopped. Specifically, the PLC 1085 transmits a signal to the control valve 1301 to set it in the closed position, thereby preventing CO2-containing liquid from continuing to flow into the selected container 26. The main liquid withdrawal valve 1093 is also closed . The filling process is stopped (step 511) in this way. In response to the interruption of the flow of liquid CO2, the gaseous CO2 may return to flow along the gas conduit 1091 and into the fill conduit 807 and into the container, if desired, for a period of time as a means of purging any impurities or residues within the pipeline conduit 1000 and/or the selected container 26. As the CO2 gas flows into the selected container 26 and then drains away, the snow pack 2 may become more compacted.

[0045] Disconnection of piping 1000 may also occur as part of step 511.

[0046] Residual liquid CO2 may be trapped along the portion of the liquid conduit 1092 that extends from the control valve 1200 to the main liquid withdrawal valve 1093.

[0047] Safety relief valves 1086 and 1087 ("SRV 1102" and "SRV 1200") are designed to relieve residual pressure that may be trapped within the gas conduit 1091 and/or liquid conduit 1092. Custom Since the liquid CO2 trapped therein may eventually sublimate to CO2 gas, the pressure buildup may be relieved by the safety relief valve 1087, which in one example is set to actuate at 400 psig. The safety relief valve 1086 also serves to relieve pressure if and when the pressure buildup in the CO2 gas conduit 1091 reaches an upper limit (e.g., 400 psig).

[0048] Having finished the filling process, the PLC 1085 activates the selected mold cavity 25 from the filling orientation to a dispensing orientation (step 512). First, actuators 30a and 30b are contracted to cause the top plate 28 to be lifted away from the top of the mold cavity 25 in a similar manner as shown in Figure 2a. Figure 3 shows an enlarged view of the selected mold cavity 25 containing the desired volume of CO2 snow block 2 with the top plate 28 removed. The mold cavity 25 is ready to dispense the CO2 snow block 2 into a box 22, which is transported along the conveyor belt 20 to a position below the mold cavity 25 so that it can receive the snow block. of CO2 2 as it falls from within the mold cavity 25 into the box 22. Figure 4 shows the movement of the box 22 along the conveyor belt 20. Specifically, Figure 4 shows the conveyor belt system 4 with the box 22 moving from the inlet 21 of the conveyor belt window, to a position below the mold cavity 25 where it receives the CO2 block 2; and finally to a dispensing window of the conveyor belt system 4 ready to pick up with the desired CO2 block 2 loaded within the box. When it is determined that the box 22 is in the desired position (step 513), the mold cavity 25 is tilted to cause the CO2 snow block therein to be dispensed into the box 222, as will now be described in the sequence of Figures. 9a, 9b and 9c. Figure 3 and Figure 9a show the mold cavity 25 at the beginning of the dispensing process. Figure 3 shows that the actuator assembly 91a and the actuator assembly 91b are operatively connected to a first side 17a and a second side 17b of the selected mold cavity 25, respectively. For use in the present invention, and with reference to Figure 3, a part number followed by "a" is intended to refer to the first side of the mold cavity 25 and the same part number followed by "b" is intended to refer to the first side of the mold cavity 25. referring to the second side 17b of the mold cavity 25; and the same part number not followed by "a" or "b" is intended to refer generically to the structure associated with mold cavity 25 when mold cavity 25 is not shown in a perspective view (e.g., with reference to Figures 9a, 9b and 9c). By way of example, an actuator assembly 91 refers to the actuator assembly operatively connected to the first side 17a of the mold cavity 25 as shown in Figure 9a; actuator assembly 91b refers to the actuator assembly operatively connected to the second side 17b of the mold cavity 25; and the actuator assembly 91 generally refers to the mold cavity actuator assembly 25 as shown in the cross-sectional views of Figures 9a, 9b and 9c. Each of the actuator assemblies 91a and 91b remain engaged to the first side 17a and the second side 17b of the selected mold cavity 25 through respective pins 93a, 93b which are engaged in respective slots 92a and 92b. Actuator assemblies 91a and 91b cause the mold cavity 25 to rotate when the pin 93a, 93b slides along corresponding slots 92a, 92b (as will be explained below). The mold cavity 25 is capable of rotating about the pivot point 94a and 94b which is connected to the support leg structures 90a and 90b. Support leg structures 90a and 90b suspend the mold cavity 25 as shown in Figures 2a, 2b, 3 and 4. It should be understood that details of the actuator assemblies as shown in Figure 3 are omitted from the assembly system. conveyor belt of Figure 4 and the other figures showing the automatic dispensing station 1 for the purposes of clearly describing the salient aspects of the present invention in connection with those figures.

[0049] Starting from the orientation of Figure 3 and Figure 9a, actuator assembly 91a and actuator assembly 91b are each activated (e.g., programmed by PLC 1085) to exert an upward force that is transmitted to each of the pins 93a, 93b on the first side 17a and the second side 17b of the mold cavity 25, respectively. Pins 93a, 93b are deprived of upward movement within slots 92a, 92b. As a result, the pins 93a, 93b, each of which is spaced the same distance away from the pivot 94a, 94b, exert a torque that causes the mold cavity 25 to rotate counterclockwise. As the mold cavity 25 rotates counterclockwise, the slots 92a, 92b become vertically oriented thereby allowing the respective arms of the actuator assemblies 91a, 91b to extend upward along the slots 92a, 92b. Figure 9b shows an intermediate configuration of the rotated mold cavity 25 that has rotated 90 degrees counterclockwise about the pivot 94a, 94b in which the arms of the actuator assemblies 91a, 91b have partially expanded upwardly inward and along of slots 92a, 92b. The arms of the actuator assemblies 91a, 91b continue to exert an upward force through their respective pins 93a, 93b to create additional counterclockwise rotation of the mold cavity 25 until the arms and respective pins 93a, 93b have moved to the uppermost edge of slots 92a, 92b as shown in Figure 9c. Figure 9c represents an additional 45° counterclockwise rotation relative to Figure 9b. The inclined orientation of Figure 9c may allow the CO2 snow block 2 to be released from within the mold cavity 25 in the box 22 (step 515), which at this time is positioned below the mold cavity 25 as shown in Figure 4. Figure 4 shows the mold cavity 25 inverted to indicate that the CO2 snow block 2 has been released into the box 22. The designation "2" on the box 22 is intended to signify that the box 22 contains the CO2 snow block 2 .

[0050] With the CO2 snow block 2 released from the mold cavity 25 and dispensed into the box 22, the actuator arms are retracted, causing the pins 93a, 93b and the arms attached thereto to move downwardly along of the slots 92a, 92b to be reconfigured in the orientation of Figure 9a, which at this stage represents the inactive orientation of the mold cavity 25 (step 516). The box 22 with CO2 snow block 2 therein is transported along the conveyor belt 20 to the exit/dispensing window 14 of the conveyor belt system 4 ready for picking (step 517).

[0051] Although automated filling at an automatic dispensing station 1 has been carried out based on a predetermined filling time, automated filling can also occur based on other criteria. For example, the PLC 1085 may use another set point for padding, including, by way of example, a preset CO2 snowpack weight; a pressure in the selected mold cavity; a snowpack capacitance of CO2 2; a temperature in the container; or a deformation of a top plate of the selected mold cavity.

[0052] In another embodiment, as an alternative to using an automatic dispensing station 1, a method for automatically loading the CO2 snow block into a single container within a charging station can be realized. Figure 6 shows the associated control methodology 6000 and Figure 8 shows an example charging station 800.

[0053] The inlet of the charging station 800 is connected to the CO2 supply piping 1000 and the outlet of the charging station 800 is connected to the ventilation system 801. The CO2 supply piping 1000 is substantially identical, with the exception of that the automatic dispensing station 1 is now replaced by the charging station of Figure 8. The PLC 1085 is in electrical communication with the charging station 800, the CO2 supply piping 1000, the ventilation system 801 and associated components of the same. Having activated the PLC 1085 (step 600), a container is selected for filling (step 601). The container can be any suitable box in which the CO2 snow pack can be loaded. The container is placed within the charging station 800 (step 602). As described earlier in this document, prefill integrity checks (step 603) are performed by PLC 1085. As an additional prefill integrity check, a port sensor determines whether port 803 is locked. Failure to satisfy any of the pre-population integrity checks will prompt the PLC 1085 to generate a suitable HMI message for the user to take appropriate action (step 604).

[0054] When all prefill integrity checks are completed, the container is activated from the inactive orientation to the fill orientation (step 605). By way of example and not intended to be limiting, the fill orientation may include configuring a top plate over the top of the container by one or more vertical actuators that are placed over the top of the container to create a seal along the periphery. It should be understood that the container does not need to use a top plate and a mold cavity as described with reference to Figures 1a, 1b, 2a and 2b. Accordingly, if a top plate and mold cavity as described earlier in this document are not required, fill orientation may include introducing and orienting a suitable carrier that is operatively connected to the fill conduit and the top of the container.

[0055] The filling orientation also provides safety interlocks that are provided at the charging station 800 so that the door 803 remains locked during CO2 charging, and the container is safely loaded into the charging station 800 .

[0056] When the container is validated to be in a fill orientation, the user can enter the desired volume of CO2 snowpack desired to be generated within the container. In step 606, the PLC 1085 determines a predetermined fill time, as described earlier in this document, relative to step 507 in the example of Figure 5. The density of the CO2 snowpack (e.g., 55 to 60 lb/ft3) is pre-programmed in the PLC 1085; and the mass flow rate determined empirically from a look-up table of CO2 pressure versus aggregate volume of nozzles in the charger.

[0057] A user activates a start button (step 607) to begin the automated loading process. Filling begins as shown below (step 608). A sufficient amount of gaseous CO2 from the supply piping 1000 is introduced from the vapor headspace of the CO2 source 1090 into the fill conduit 807, which extends between the supply piping 1000 and the container. Supply piping 1000 is operatively connected to fill conduit 807.

[0058] CO2 gas is added into the conduit to pressurize the conduits of tubing 1000 to a level that is sufficient to prevent the pressure of the liquid CO2 from reducing below a certain pressure (e.g., below about 150 psig) in the conduit. which liquid CO2 may prematurely undergo a phase change to solid and/or gas within the piping conduit 1000 and fill conduit 807. The PLC 1085 continues to monitor the pressure in the supply piping 1000 from the supply transducer 1000. pressure 1070 (Figure 7), which measures the pressure of CO2 and the fill conduit 807. When it is determined that the pressure is at or above a certain pressure such that the liquid CO2 does not change phase, the PLC 1085 transmits a signal to a control valve 1200 to set it in the open position. With the control valve 1200 in the open position, liquid CO2 from the CO2 supply 1090 is withdrawn and flows along the conduit 1092. The pressure of the liquid CO2 is higher than that of the gaseous CO2 occupying the pipeline 1000; as a result, the flow of CO2 gas into the container stops as the liquid CO2 flows into the container from the charging station 800 along a first direction (e.g., substantially vertical and downward into the container). As liquid CO2 enters the container, it undergoes a phase change to transform into effluent gas and CO2 snowpack. The effluent gas escapes the container and flows through exhaust conduit 1050. Liquid CO2 continues to enter the container until the PLC 1085 determines that the elapsed fill time has reached the predetermined time. When the elapsed time has reached the predetermined time, the PLC 1085 relays a signal to the control valve 1200 to set it in the closed position, thereby stopping the withdrawal of liquid CO2 from the CO2 source 1090 (step 610). The main liquid withdrawal valve 1093 is also closed. In response to the interruption of the flow of liquid CO2, the gaseous CO2 may return to flow along the gas conduit 1091 and into the fill conduit 807 and into the container, if desired, for a period of time as a means of purging any impurities or residues within the conduit of piping 1000 and/or container. As the CO2 gas flows into the container and then flows into the exhaust conduit 1050, the snow pack may become more compacted. It should be understood that although valve 1093 and valve 1094 are shown as manual valves in Figure 7, automatic control valves can be used in place of each of the manual valves 1093 and 1094.

[0059] Shutdown can now be performed (step 611). Residual liquid CO2 may be trapped along the portion of the liquid conduit 1092 that extends from the control valve 1200 to the main liquid withdrawal valve 1093. Safety relief valves 1086 and 1087 ("SRV 1102" and " SRV 1200") are designed to relieve residual pressure that may be trapped in the gas conduit 1091 and/or liquid conduit 1092 when various components of the charging station system 800 and piping 1000 are disconnected. As the liquid CO2 trapped therein may eventually sublimate to CO2 gas, the pressure buildup may be relieved by the safety relief valve 1087, which in one example is set to actuate at 400 psig. The safety relief valve 1086 also serves to relieve pressure if and when the pressure buildup in the CO2 gas conduit 1091 reaches an upper limit (e.g., 400 psig).

[0060] After the shutdown has been completed in step 611, the PLC 1085 disables the safety interlocks of the charging station 800 so that the charging station door 803 can be opened to access and remove the container with the snow block of CO2 2 inserted in it.

[0061] It should be understood that automated loading into a container can also occur based on other criteria. For example, the PLC 1085 may use another set point for padding, including, by way of example, a preset CO2 snowpack weight; a pressure in the container; a snowpack capacitance of CO2 2; a temperature in the container; or a deformation of a top plate that can be used to seal the container.

[0062] Although the CO2 snow block container as described can be used with any "item" as defined below, in a preferred embodiment, the present invention is especially conducive to maintaining compliance with compaction protocols necessary to reproducibly preserve biological samples, thus preventing sample degradation and allowing samples to return to their functional state and be subjected to applicable tests upon arrival at their destination location. Additionally, the CO2 snow pack is preferably generated with better packing density that can maintain the required container temperature with prolonged cooling effect duration compared to transport containers containing CO2 dry ice produced by conventional techniques. . The prolonged duration of the cooling effect can reduce the risk of sample degradation in transportation and allow the user more flexibility to optimize cost and convenience regarding the preparation and assembly of the transportable containers of the present invention; when items (including samples such as biological samples) are captured; and the types of transport methods that can be used.

[0063] Numerous modifications to the present invention are contemplated without departing from the spirit of the present invention. For example, the sequence of steps in the control methodology for the automated filling station (Figure 5) can be changed so that the box 22 is positioned in place after passing pre-fill integrity checks. Regarding the charging station (Figure 6), the PLC can be activated after the container is loaded into the charging station. Additionally, the direction of injection of CO2 streams into the selected container may vary. For example, liquid containing CO2 can be injected upward; or sideways; or downward in various angle orientations, with the exact angle determined by the shape, design and geometry of the nozzle in the fill conduit.

[0064] Similarly, the effluent gas and CO2 gas within the selected container can be varied in order to flow in a downward direction or in a lateral direction or in an upward and angled direction.

[0065] Additionally, in relation to the automated loading station, the control methodology can be modified so that the user enters the volume of the snow block 2 and selects the container that is listed on the HMI of the automatic dispensing station 1.

[0066] The automated loading method described herein can be implemented as part of a method for pre-loading an empty or partially empty container with CO2 snow or CO2 snow block to create a pre-charged container. In one example, the charging station 800 of Figure 8 is used to create multiple containers pre-charged with CO2 snow on a batch, continuous or semi-continuous basis for shipping to other locations, such as a clinical site. The charging station 800 maintains an inventory of CO2 containers and supply. Figure 10 shows a representative schematic of the sequence of steps that the charging station 800 undergoes. Step 10000 requires the charging station to receive a CO2 supply source. Preferably, the CO2 supply is the CO2 supply 1090 that can be connected to the gas supply piping 1000. Step 10002 requires the CO2 supply piping 1000 to be operatively connected to the charging station 800 (Figure 8); and the container is loaded into the loading station 800. Any type of loading system can be used. For example, the charging system of order serial no. 15/645,152, details of which are incorporated herein by reference in its entirety for all purposes, may be operatively connected between a CO2 supply 1090 and the inlet of a container charged at charging station 800.

[0067] Step 10003 illustrates the generation of CO2 snow inside the container. The 6000 control methodology in Figure 6 can be used to generate the CO2 snow inside the container. After creating the preloaded container, step 10004 shows that the preloaded container is prepared for delivery to the second location. Preparation may include one or more steps. For example, the pre-charged container may be sealed (e.g., by a top cap) with a passage through which the CO2 effluent gas may escape, thereby substantially reducing or eliminating the build-up of CO2 gas pressure. which is formed during storage, preservation and/or transportation of items in the container. Additionally, return shipping instructions as well as usage instructions may be provided as part of the step to prepare the pre-filled container for delivery. Certain criteria can be used to determine whether a substantially depleted or partially depleted container should be returned to the loading location or, alternatively, be used for another shipment of perishable items. For example, and not intended to limit, the amount of CO2 snow that remains in the pre-filled container; the type of perishable items loaded in the container; the duration of shipping; and/or the required temperature that the perishable item needs not to exceed for a certain time during delivery, may determine that the pre-filled container needs to be refilled at the first location (e.g. loading location) to refill the container with CO2. Alternatively, the pre-filled container may be reusable in its partially depleted form without the need to refill the CO2 snow upon delivery to an intermediate location, thereby allowing an additional perishable item to be loaded into the partially depleted container for transportation. The extended cooling effect duration of pre-filled containers can reduce the risk of sample degradation in transit and allow for more flexibility to optimize cost and convenience across shipping method types.

[0068] Still further, preparing the preloaded container includes providing a label that can be affixed to the exterior of the preloaded container, which includes shipping information from the second location. The pre-filled container may be placed in a secondary container to require affixing the shipping label to the exterior of the secondary container. Additionally, if the specific type of perishable item is considered hazardous under certain regulations (e.g., Department of Transportation), labeling may need to identify such perishable contents as hazardous and may require custom packaging to ensure that the perishable items are properly contained. within the pre-filled container and any secondary container or optional packaging required for the pre-filled container to be inserted.

[0069] Upon preparation of the preloaded container for delivery, the preloaded container may be delivered to a second location via a designated commercial receiver or carrier for ground or air delivery. Alternatively, the person or entity responsible for creating the pre-loaded container at the loading location may itself deliver the pre-loaded container to the second location. In one example, the second location is a clinical site such as a hospital, pharmaceutical company, university or doctor's office or any other person or entity that carries one or more perishable items in the pre-loaded container. When the second location receives the preloaded container, the user at the second location accesses the preloaded container by removing, detaching, or opening a lid or other closing mechanism. The interior of the container preloaded in this way can be accessed. The second location may have an inventory of certain perishable items that require delivery to an end user.

[0070] The user at the second location places one or more perishable items directly or indirectly into the pre-loaded container so that at least a portion of the one or more perishable items is situated in sufficient proximity to the CO2 snow to maintain its temperature below of an upper limit. The perishable item is preferably placed on a product holder before loading into the pre-filled container. Instructions for return delivery may also be provided by the second location. For example, the second location may provide instructions to an end user for return shipping of the pre-filled container when the CO2 snow in the pre-filled container has been substantially depleted to a point where the temperature of the perishable item during delivery is not can no longer be kept below an upper limit. The preloaded container is resealed at the second location after the perishable item is loaded. Delivery to a third location may occur through a commercial carrier or designated receiver, or by the person or entity loading the perishable item into the pre-loaded container at the second location.

[0071] The third location is preferably an end user who opens the preloaded container and accesses the interior of the preloaded container to remove the perishable item for testing, use, or storage. The third party may perform the test or have the test conducted on your behalf. In one example, the third location is a contract research organization or a pharmaceutical company. The perishable item may be a biological sample, which has not degraded and is subject to applicable testing or use at the third party site. The user at the third location can determine whether the CO2 snow has sublimated to a point where the pre-filled container is substantially depleted such that it can no longer preserve the perishable items at the third location or during an additional delivery. Depending on several criteria, including, by way of example, the CO2 snow depletion level, along with the type of perishable item to be preserved and the desired duration for which the perishable items need to remain in the container, the user in the third location may notify a supply location (for example, the first location or another loading location) that the prefilled container is out of stock. The preloaded container in its substantially depleted state is returned to a loading location for possible refilling if determined upon inspection to be reusable. Alternatively, the pre-filled container in its partially depleted state can be returned to an intermediate location where new perishable items can be loaded into the container for additional use without replenishing the CO2 snow. It should be understood that the third party does not need to notify a specific location before returning a container. For example, the third-party location may send the container to a supply location or an intermediate location without notification. The third location can generate a return shipping label and/or use an existing return shipping label to ship to the desired location. Additionally, the third party does not need to inspect the container for reusability. The third site can subsequently deliver the container to any number of sites supporting the supply chain. The container does not need to be returned to the same intermediate location (e.g., the second location) where perishable items can be loaded or removed; or to the first location where CO2 snow can be carried. For example, the third party may leave perishable items inside the container or add additional perishable items to the container before sending the container to an additional site for testing, use or storage.

[0072] The following example illustrates a preferred embodiment of the present invention for preloading containers to be loaded when the perishable items to be loaded into them are biological samples. Company ABC has a charging station and an inventory of CO2 containers and supply sources. Company ABC creates multiple containers pre-filled with CO2 snow as described earlier in this document. Company ABC prepares multiple pre-filled containers for delivery to Company LMN. Company ABC has a 14-ton liquid CO2 storage tank located outside its facility. The liquid CO2 storage tank is connected to a dry ice charging system within the facility using insulated piping. The dry ice loading system is also connected to an empty cylindrical shaped vacuum insulated aluminum container with external dimensions of approximately 20 inches high by 12 inches in diameter and approximately 10 liters internal volume. Company ABC activates the dry ice loading system to flow liquid CO2 from the CO2 supply source into the container. Approximately 10 pounds of CO2 snow can be formed inside the container in less than 10 minutes. This amount of CO2 snow maintains the internal temperature of the container in the target zone below -70°C for 20 days. Company ABC places the pre-filled container with CO2 snow in a secondary container, such as a cardboard box. Company ABC labels the cardboard box for ground transportation to be picked up by a commercial carrier for delivery to Company LMN; and includes the LMN Company's intended address in the second location. The pre-charged container may be sealed (e.g., by a top cap that is mechanically secured to the container) with a passage through which CO2 effluent gas can escape, thereby substantially reducing or eliminating the build-up of pressure from the container. CO2 effluent gas that is formed during the storage, preservation and transportation of biological samples in the container. Instructions for use and return delivery instructions may be provided by Company ABC as part of the pre-filled container.

[0073] The pre-filled containers are shipped to LMN, which in this example is a clinical site. LMN receives the pre-filled containers with 15 or more days of CO2 snow remaining within each of the pre-filled containers. Upon receipt of the pre-filled containers, LMN opens the pre-filled containers and then places one or more vials into each pre-filled container so that they are at least partially embedded in the CO2 snow or surrounded by the CO2 snow. Alternatively, the one or more vials may be arranged to be in contact with the CO2 snow so that they are positioned on top of the CO2 snow or embedded, partially or completely, within it. Additionally, the CO2 snow may be in close proximity to the one or more vials within the container. The one or more vials are stored at LMN in an ultra-low temperature freezer at -70°C. Each vial contains a cell suspension. In one example, LMN Company loads a total of fifty (50) 2 milliliter vials with each vial containing 1.5 milliliters of the cell suspension. To preserve optimum cell quality, the vials are prepared for delivery to maintain a temperature below -70°C throughout the duration of shipment to the intended recipient at a third location. It is not necessary for additional CO2 snow or other refrigerant to be added to maintain such a temperature.

[0074] Company LMN loads a total of 50 vials into the pre-loaded containers and directly or indirectly ships the pre-loaded containers to Company XYZ located at the third location using ground transportation or other commercial delivery modes. Upon receipt of the pre-filled containers with samples in them, Company XYZ opens the pre-filled containers to access the vials for testing the cell suspensions. Pre-filled containers may be returned by Company XYZ to Company LMN or another intermediate location for loading more bottles if sufficient cooling capacity exists. Otherwise, pre-filled containers are considered substantially depleted and may be returned to Company ABC or another loading location for inspection to determine if they are reusable. If determined to be reusable, the loading location (e.g. Company ABC) may pre-charge the substantially depleted containers to create refilled pre-filled containers filled with the CO2 snow containers that can now be returned to Company LMN or another intermediate location for sample loading and to XYZ Company or another user location for sample testing.

[0075] Inspection preferably involves testing the rate of sublimation to ensure that the container can continue to provide sufficient refrigeration for the required duration. A typical inspection procedure consists of (1) introducing a measured weight of CO2 snow into the container; (2) measure the weight of remaining CO2 snow as it sublimates over a given amount of time; and (3) calculating the rate of sublimation to be the weight of the CO2 snow sublimated divided by the amount of time during which the weight of the CO2 snow in the container is lost. In this way, with knowledge of the sublimation rate and CO2 snow capacity of the container, the number of days that a fully charged container can supply is known. In a similar manner, the remaining life of a partially exhausted container or substantially exhausted container can be determined.

[0076] Variations to Figure 10 are contemplated. For example, CO2 snow can be created outside the container and then carried inside the container. For example, the automatic dispensing station 1 may be used to create and dispense pre-filled containers, which are then sent to a second location for loading perishable items therein. Alternatively, multiple locations can receive pre-filled containers. Still further, the automated control methodology of the present invention can be applied to any container and/or loading system. For example, the automated control methodology described herein may be used in connection with a container or loading system as described in Serial No. 15/645,152, details of which are incorporated herein by reference in their entirety for all the purposes. Specifically, the container may be used as part of the autofill dispensing station 1 or loading system 800 to carry out the preloading methods (Figure 10) of the present invention. Still further, the sequence of steps in Figure 10 can be carried out using any suitable container or loading system on a manual basis, including those described in serial application no. 15/645,152. For example, CO2 snow or CO2 snow block can be manually transferred from a CO2 source to an empty or partially empty container to create the pre-charged CO2 container that can be subsequently delivered to another location. Additionally, it should be understood that pre-charging methods as described herein may be used in connection with block CO2 snow, CO2 snow, and liquid CO2.

[0077] In another variation of Figure 10, the preloaded container can be used for multiple transport events after a single preload at the first location. For example, the preloaded container may be created at a first location and then delivered to a second location where the preloaded container is loaded with a first perishable item ("Material 1"). The container preloaded with Material 1 is then delivered to a third location where Material 1 is removed. The pre-loaded container still has sufficient cooling duration and is therefore returned to the second location where a second perishable item ("Material 2") is loaded into the pre-loaded container. The pre-loaded container with Material 2 loaded into the is delivered to the third or new fourth location where Material 2 is removed. At this point, the pre-loaded container is considered substantially exhausted (i.e., no longer showing sufficient cooling duration) and is therefore returned to the container. first location where the container is inspected to determine whether it is reusable. If it is determined to be reusable by the person or entity at the first location, the person or entity at the first location performs another pre-charge of CO2 snow to restore the cooling duration of the pre-charged container, which is ready for subsequent shipments in the manner described earlier in this document. It should be noted in this example that the CO2 snow does not need to be completely sublimated prior to the need for a subsequent pre-charge of CO2 snow into the container by the container. first location. In this way, greater utilization of the cooling duration can be realized.

[0078] The flow of pre-loaded containers in their various states (e.g., substantially depleted, partially depleted, perishable item loaded into them or removed from them) can occur in several ways. For example, the container preloaded with perishable material at the second location does not need to be shipped from the second location to a new third location, but could instead be shipped from the second location to the first location where the container it was pre-charged with CO2 snow. For example, an exhausted or partially exhausted pre-filled container may be returned by numerous locations involved in preparing or delivering the pre-filled containers or using and/or testing the perishable items therein. For example, the location, person, or entity that initiates the return of the substantially depleted or partially depleted preloaded container may also be the same location, person, or entity to load the perishable item into the preloaded container (e.g., the second location ) after the creation of the upstream preloaded container by the first location. In another example, the location, person, or entity that initiates the return of the substantially depleted or partially depleted preloaded container may be the same location, person, or entity that accesses the preloaded container to remove the perishable item therefrom at the destination. end-use after creating the preloaded container in the first location. In yet another example, the substantially depleted or partially depleted prefilled container may be requested for return by the same location, person, or entity that is creating the prefilled container (e.g., the first location). The actual act of transporting the pre-loaded container in a substantially depleted or partially depleted form after the perishable item has been removed therefrom from the place of use to the place where it is to be exchanged may be performed by the pre-loading place (e.g. example, the first location); by the carrier of perishable items (for example, the second location); or by the end user of the perishable item (e.g., final destination or third party location); or by any commercial carrier or receiver designated for ground or air delivery. Preferably, the actual act of exchanging a partially depleted or substantially depleted pre-filled container for a refilled pre-filled container or new pre-filled container filled with CO2 snow is performed by the first location performing the pre-loading operations. It should be understood that more than one location may perform preload operations on behalf of a given shipper of perishable items or end user of perishable items. It should further be understood that maintenance or repair of the substantially depleted or partially depleted container may be performed prior to performing a subsequent preloading operation at the first location, thereby ensuring adequate performance of the fleet of preloaded containers.

[0079] The present invention with regard to preloading is advantageous over conventional dry ice containers. The present invention offers ease of use throughout the supply chain; reproducibility of the amount of CO2 snow loaded into containers; and a fleet of longer-lasting containers. Pre-filled containers prepared, delivered and returned in accordance with the principles of the present invention generally retain about 10 to 15 or more days of CO2 snow remaining within each of the pre-filled containers, as opposed to five days or less with typical CO2 containers. The longer duration of CO2 snow within the pre-filled container allows the flexibility to use lower cost shipping (e.g. ground shipping) to the second location (e.g. clinical site such as a hospital, university or doctor's office or any other person or entity loading the perishable item into the pre-loaded container), as opposed to air or next-day shipping used for conventional containers. The second location has an ample amount of time to load the perishable item into the pre-loaded container without needing to refill the pre-loaded container with more CO2 snow. Consequently, the lowest cost (e.g. ground shipping) can be employed not only for shipping from the loading location to the second location, but also from the second location to the end user without risk of a substantial amount of CO2 snow. sublimate. The on-demand generation of CO2 snow of the present invention eliminates the need and associated challenges for an intermediate user or end user to acquire, maintain inventory, and handle CO2 snow.

[0080] Although what is considered to be certain embodiments of the invention has been shown and described, it will, of course, be understood that various modifications and changes in form or detail can readily be made without departing from the spirit and scope of the invention. It is therefore intended that this invention is not limited to the exact form and detail shown and described herein, nor to anything less than the whole of the invention herein disclosed and claimed hereinafter.

Claims (35)

1. Method for pre-loading an empty or partially empty insulated container (26) with CO2 snow to create a pre-charged container (26) at a first location for transport to a second location, characterized by comprising the steps of: receiving a source of liquid CO2 at the first location; operatively connecting a CO2 snow loader to the empty or partially empty container (26) and to the source of liquid CO2 at the first location; generating the CO2 snow within the empty or partially empty container (26) to create the pre-loaded container (26) at the first location, without carrying one or more perishable items; prepare the pre-loaded container (26) for delivery to the second location. 2. Method according to claim 1, characterized in that the step of preparing the pre-loaded container (26) for delivery to the second location further comprises: sealing the pre-loaded container (26); pack the pre-filled container (26); and providing the preloaded container (26) to a designated commercial carrier or receiver for ground or air delivery to the second location. 3. Method according to claim 1, characterized in that the step of preparing the pre-filled container (26) further comprises including a label with the pre-filled container (26), said label including shipping information for the second local. 4. Method according to claim 1, characterized in that the step of preparing the pre-filled container (26) includes packaging the pre-filled container (26) with instructions to an end user for returning the pre-filled container (26). loaded. 5. Method according to claim 1, characterized by further comprising the steps of: receiving an at least partially exhausted container (26) from the second location or other location of previous use; inspecting the at least partially depleted container (26), and in response thereto, generating CO2 snow in the at least partially depleted container (26) to create a refilled pre-charged container (26); preparing said refilled pre-filled container (26) for delivery to the second location, the location of previous use or another location. 6. Method according to claim 1, characterized in that the step of creating the container (26) preloaded in the first location is characterized by the absence of loading a perishable item. 7. Method according to claim 3, characterized in that the second site is a clinical site. 8. Method according to claim 1, characterized by further comprising: the first location receiving notification from the second location or a third location that the container (26) pre-filled with the CO2 snow is partially or substantially exhausted in order to of creating a partially or substantially depleted container (26). 9. Method according to claim 8, characterized in that it further comprises coordinating the return delivery of the substantially depleted container (26). 10. Method according to claim 8, characterized by creating a second pre-filled container (26) filled with CO2 snow pre-charged therein. 11. Method according to claim 1, characterized in that the generation of CO2 snow occurs in an automatic dispensing station (1) or in an automatic loading station (800). 12. Method according to claim 1, characterized in that it further comprises: the first location receiving an at least partially exhausted container (26) with no perishable item in it, said exhausted container (26) being defined as a pre-filled container (26). -charged with CO2 snow therein so that said CO2 snow has at least partially sublimated; inspect the container (26) at least partially exhausted; determining that the at least partially exhausted container (26) is reusable; filling the at least partially depleted container (26) with CO2 snow to create a pre-filled container (26) refilled with the CO2 snow; prepare the refilled and pre-filled container (26) for delivery. 13. Method for supplying a perishable item to a location characterized by the steps of: receiving a pre-loaded container (26) at least partially filled with CO2 snow inside the pre-loaded container (26) without one or more items perishables loaded in it; open the pre-filled container (26) at least partially filled with CO2 snow; accessing an interior region of the pre-charged container (26) at least partially filled with CO2 snow; loading the perishable item into the pre-loaded container (26) at least partially filled with the CO2 snow, the perishable item being in sufficient proximity to the CO2 snow to maintain a temperature of the perishable item below an upper limit; seal the pre-filled container (26) at least partially filled with CO2 snow; prepare the pre-loaded container (26) at least partially filled with the CO2 snow with the perishable item therein for delivery to the site. 14. The method of claim 13, wherein the step of preparing the container (26) pre-loaded with the perishable item therein for delivery further comprises the step of identifying the perishable item as a hazardous material. 15. Method according to claim 13, characterized in that it further comprises: receiving a partially exhausted container (26) from the location; accessing a partially exhausted interior of the container (26); and loading a second perishable item into the partially exhausted container (26) without introducing additional CO2 snow into the partially exhausted container (26). 16. The method of claim 13, further comprising placing the perishable item in a product holder followed by at least partially positioning the product holder with the perishable item therein in sufficient proximity to the CO2 snow to maintain the temperature of the perishable item below an upper limit. 17. Method according to claim 16, characterized in that the temperature of the product holder is maintained below -70 degrees Celsius during delivery to the final location. 18. The method of claim 13, further comprising providing instructions to an end user for return delivery of the pre-loaded container (26). 19. Method according to claim 13, characterized in that the step of preparing the pre-loaded container (26) with the perishable item loaded therein comprises configuring the pre-loaded container (26) ready for pickup by a commercial carrier or receiver designated. 20. Method for delivering the container (26) pre-charged with at least partially exhausted CO2 snow characterized by comprising: receiving the container (26) pre-charged with at least partially exhausted CO2 snow from a loading location at which a or more perishable items have been loaded into the pre-charged container (26), said container (26) pre-filled with at least partially depleted CO2 snow additionally comprising one or more perishable items in sufficient proximity to the CO2 snow to keep the temperature of the perishable item below an upper limit; opening the container (26) pre-charged with at least partially exhausted CO2 snow to access the interior of the pre-charged container (26); remove the one or more perishable items from the container (26) pre-loaded with at least partially exhausted CO2 snow; and delivering the pre-loaded container (26) with at least partially depleted CO2 snow to a location for loading, loading additional perishable items or using at least a portion of the one or more perishable items remaining in the pre-filled container (26). with CO2 snow at least partially depleted. 21. The method of claim 20, further comprising: notifying a supply location that the pre-loaded container (26) is substantially depleted, and responding thereto; return the container (26) pre-charged with at least partially exhausted CO2 snow to the supply location and, in response thereto, receive from the supply location (i) the container (26) pre-charged with CO2 snow at least partially depleted refilled and filled with CO2 snow and comprising the one or more perishable items; or (ii) a new pre-filled container (26) filled with CO2 snow and comprising the one or more perishable items. 22. Method for creating an insulated container (26) preloaded with CO2 snow at a first location for transportation to a second location, characterized by comprising the steps of: introducing the CO2 snow into an empty or partially empty container (26) empty at the first location from a CO2 source at the first location, without carrying one or more perishable items; creating the pre-loaded isolated container (26) at the first location; and preparing the pre-loaded container (26) for delivery from the first location to the second location. 23. Method according to claim 22, characterized in that the step of preparing the pre-loaded container (26) for delivery to the second location further comprises: sealing the pre-loaded container (26); and pack the pre-filled container (26). 24. The method of claim 22, further comprising the step of providing the pre-loaded container (26) to a designated commercial carrier or receiver for ground or air delivery to the second location. 25. Method according to claim 22, characterized in that the step of preparing the pre-filled container (26) further comprises including shipping information. 26. The method of claim 22, wherein the step of preparing the pre-filled container (26) includes packaging the pre-filled container (26) with instructions for an end user for returning a pre-filled container (26). -charged at least partially exhausted. 27. The method of claim 22, further comprising: receiving an at least partially depleted container (26) from the second location or another location of previous use; inspecting the at least partially depleted container (26), and in response thereto, introducing CO2 snow into the at least partially depleted container (26) to create a refilled, pre-charged container (26); preparing said refilled, pre-charged container (26) for delivery to the second location, the location of previous use, or another location. 28. Method according to claim 22, further comprising: the first location receiving notification from the second location or a third location that the container (26) pre-filled with the CO2 snow is at least partially or substantially exhausted . 29. Method according to claim 22, characterized in that the first location further comprises coordinating the return delivery of the container (26) pre-loaded with CO2 snow that is at least partially exhausted or substantially exhausted. 30. Method according to claim 22, characterized by creating a second pre-charged container (26) filled with CO2 snow pre-charged therein at the first location. 31. Method according to claim 22, characterized in that the step of introducing CO2 snow occurs manually or automatically. 32. Method according to claim 22, characterized in that it further comprises: the first location receiving an at least partially exhausted container (26) with no perishable item therein, said at least partially exhausted container (26) being defined as a container ( 26) pre-loaded with CO2 snow therein so that said CO2 snow has at least partially sublimated; inspect the container (26) at least partially exhausted; determining that the at least partially exhausted container (26) is reusable; introducing into the container (26) at least partially exhausted CO2 snow to create a pre-filled container (26) refilled with the CO2 snow; and preparing the refilled and pre-filled container (26) for delivery. 33. Method for creating a container (26) pre-loaded with CO2 snow at a first location for transport to a second location, characterized by comprising the steps of: introducing the CO2 snow into an empty or partially empty container (26) at the first location from a CO2 source at the first location; creating the preloaded container (26) at the first location; and preparing the preloaded container (26) for delivery from the first location to the second location; receiving an at least partially exhausted container (26) from the second location or other location of previous use; inspecting the at least partially depleted container (26), and in response thereto, introducing CO2 snow into the at least partially depleted container (26) to create a refilled, pre-filled container (26); preparing said refilled pre-filled container (26) for delivery to the second location, the location of previous use or another location. 34. Method for creating a container (26) pre-loaded with CO2 snow at a first location for transport to a second location, characterized by comprising the steps of: introducing the CO2 snow into an empty or partially empty container (26) at the first location from a CO2 source at the first location; creating the preloaded container (26) at the first location; preparing the preloaded container (26) for delivery from the first location to the second location; the first location subsequently receives notification from the second location or a third location that the container (26) pre-filled with CO2 snow is at least partially or substantially depleted. 35. Method for creating a container (26) pre-charged with CO2 snow at a first location for transporting to a second location and subsequently receiving the pre-charged container (26) in an exhausted state, characterized by comprising the steps of: introducing the CO2 snow into an empty or partially empty container (26) at the first location from a CO2 source at the first location; creating the preloaded container (26) at the first location; and preparing the preloaded container (26) for delivery from the first location to the second location; the first location subsequently receiving an at least partially depleted container (26) with one or more perishable items therein, said at least partially depleted container (26) defined as a container (26) pre-filled with CO2 snow in the same of so that said CO2 snow has at least partially sublimated; inspecting the at least partially exhausted container (26), determining that the at least partially exhausted container (26) is reusable; introducing into the container (26) at least partially exhausted CO2 snow to create a pre-filled container (26) refilled with the CO2 snow; and preparing the refilled and pre-filled container (26) for delivery.