Package for preservation of biological material

Abstract

A package for preservation of biological material wherein, in use, the package is filled with biological material and placed in an apparatus for preservation of biological material such that a heat exchange fluid flows around the package, the package comprising: one or more package walls configured to define an internal compartment for receiving biological material; and one or more thermal profiles defined on the at least one packaging wall wherein, in use, a flow of the heat exchange fluid is at least partially directed by the one or more thermal profiles to improve heat transfer between the heat exchange fluid and the biological material contained in the packaging.

Description

Background of the Invention

[0001] The present invention relates to a package for the preservation of biological materials, and is particularly, but not limited to, suitable for cryopreservation, frozen storage and thawing of biological materials such as whole blood. Description of the prior art

[0002] For many years, the ability to store red blood cells (RBCs) outside the body has been recognized as a life-saving practice. Recently, the use of refrigerated RBCs in transfusion medicine has been extensively evaluated. During refrigerated storage, RBCs gradually deteriorate, and transfusion of long-term stored RBCs has been associated with adverse clinical outcomes in terms of postoperative infection, length of hospital stay, and mortality.

[0003] RBCs are subject to international guidelines that require that hemolysis in an RBC unit must remain below permissible levels (i.e., 0.8% in Europe and 1% in the United States) and that the post-thaw recovery rate of deglycerolated RBCs (i.e., freeze-thaw-wash recovery) must exceed 80%. In addition, at least 75% of cryopreserved RBCs must still be circulating 24 hours after transfusion.

[0004] Freezing large numbers of cells is a prerequisite for therapeutic cell banks. This requires high concentrations of cells in large or small quantities. In addition, bioreactor systems usually need to be inoculated with large numbers of cells from working cell banks or starter cultures.

[0005] Medical device packaging is almost as important as the device itself. The packaging used for medical devices plays a critical role in safely delivering specialized treatments to patients. Most single-use sterile medical devices can be opened with a high degree of confidence because it remains sterile throughout storage, handling, and transportation.

[0006] The reason why medical device packaging is so important is that regulatory agencies recognize its importance by considering the sterile barrier or primary packaging as a component or accessory of the medical device. This means that the packaging is almost as important as the device itself.

[0007] The cooling rate of biological specimens has been shown to have a significant impact on their long-term viability. The cooling rate not only affects the rate and size of both intracellular and extracellular ice crystals; it also affects the thawing effects that occur during the freezing process.

[0008] When the temperature of the liquid approaches its crystallization temperature, crystallization occurs by nucleation and growth of ice crystals in both the intracellular and extracellular regions. Crystallization is a first order phase transition that includes energy released due to latent heat of fusion. Many factors such as cooling rate, uniformity, and pressure affect the phase transition from liquid to solid.

[0009] The cooling rate is another parameter used to optimize cell viability (Dumont, F., P. A. Marechal and P. Gervais, 2003. Influence of cooling rate on Saccharomyces cerevisiae destruction during freezing: unexpected viability at ultra-rapid cooling rates, Cryobiology 46: 33-42). Simultaneous management of cryoprotectants (CPA) and cooling rate can be used. In fact, the cooling rate determines the size of ice crystals during freezing. When the solution begins to freeze, the water in the extracellular fluid turns into ice, thereby increasing the solute concentration in the extracellular fluid. Subsequent osmosis dehydrates the cells as water diffuses from the cytoplasm into the more concentrated external solution (Dumont, F., P. A. Marechal, and P. Gervais, 2004, Cell size and water permeability as determining factors for cell viability after freezing at different cooling rates, Applied Environmental Microbiology 70: 268-272). When the cooling rate is low, osmotic flow causes volume reduction, and all intracellular water flows out before crystallization occurs within the cell. When the cooling rate is in the medium range, the volume reduction causes irreversible damage to the cells, and significant mortality is observed. When the cooling rate is very high, the cells may not have time to reduce their volume due to the rapid heat flow, which may allow significant viability to be maintained. Therefore, freezing dynamics have a great influence on cell viability; however, most of the time the cooling rate cannot be well controlled.

[0010] Cell death results from either massive water efflux during slow cooling, which is associated with an increase in extracellular osmotic pressure and membrane lipid phase transitions, or from crystallization during efflux, which results in lethal membrane damage.

[0011] According to this hypothesis, cell death occurs during a lag time determined by matrix crystallization. Cell death corresponds to temperatures between 0°C and -5°C. However, there is a second stage of cell death at lower temperatures.

[0012] For solutions composed primarily of water, the temperature range over which almost all crystallization occurs drops to a few degrees after freezing begins, and the crystallization temperature depends on the concentration of the solute.

[0013] AU2009258341B2 discloses a package for biological material, comprising two substantially parallel walls connected to each other along a portion of their perimeter and a central region of the package. The central region, wall area and thickness, and perimeter are configured to ensure that the walls have sufficient rigidity to remain parallel after the package is filled with biological material. The package can be used for cryopreservation of biological material.

[0014] Reference in this specification to any prior publication (or information obtained therefrom) or any known matter is not and should not be taken as an acknowledgement or acknowledgment or in any form of implication that the prior publication (or information obtained therefrom) or known matter forms part of the common general knowledge in the field to which this specification relates. SUMMARY OF THE INVENTION

[0015] In one broad form, one aspect of the present invention is directed to providing a package for preserving biological material, wherein, in use, the package is filled with the biological material and placed in an apparatus for preserving the biological material such that a heat exchange fluid flows around the package, the package comprising: one or more package walls configured to define an internal compartment for receiving the biological material; and one or more thermal contours defined on at least one of the package walls, wherein, in use, the flow of the heat exchange fluid is at least partially guided by the one or more thermal contours to improve heat transfer between the heat exchange fluid and the biological material contained in the package.

[0016] In an embodiment, the thermal contour is arranged to be substantially aligned with the flow of the heat exchange fluid in use.

[0017] In an embodiment, the package includes a plurality of thermal profiles arranged parallel to each other.

[0018] In an embodiment, each thermal contour is defined across a respective one of the package walls as one of: an elongated depression in the respective package wall; and an elongated protrusion in the respective package wall.

[0019] In one embodiment, the package wall includes opposing first and second walls connected together around a majority of their respective perimeters to define an interior compartment.

[0020] In an embodiment, the one or more thermal contours are defined by the first wall and the second wall connected together along one or more connection lines, the connection lines being configured to divide the interior compartment into sub-compartments, wherein fluid communication between the sub-compartments is allowed.

[0021] In one embodiment, in use, the package is filled with biomaterial such that the biomaterial is distributed between the subcompartments, and the flow of the heat exchange fluid is at least partially directed by one or more thermal contours to facilitate substantially uniform heat transfer between the heat exchange fluid and the biomaterial contained in each subcompartment.

[0022] In an embodiment, the connecting lines are configured to ensure that the biological material is substantially evenly distributed between the various sub-compartments.

[0023] In an embodiment, the first wall and the second wall are connected together along a plurality of edges including a front edge facing the heat transfer fluid in use and an opposite rear edge, the plurality of thermal contours extending between the front edge and the rear edge.

[0024] In an embodiment, the rear edge is substantially parallel to the front edge.

[0025] In an embodiment, at least some of the connection lines are interconnected with the front edge.

[0026] In an embodiment, the thermal profile is arranged at a predetermined angle relative to a direction perpendicular to the leading edge.

[0027] In one embodiment, the predetermined angle is selected according to the flow of a heat exchange fluid in an apparatus for preserving biological material.

[0028] In one embodiment, the predetermined angle is at least one of: between 0° and 30°; between 5° and 15°; and about 10°.

[0029] In an embodiment, adjacent thermal contours are spaced apart by a predetermined spacing distance.

[0030] In one embodiment, the predetermined spacing is between 15 mm and 20 mm.

[0031] In one embodiment, the predetermined separation distance is selected to limit the separation of the first wall and the second wall.

[0032] In an embodiment, the predetermined separation distance is selected to limit the separation of the first wall and the second wall to the predetermined separation distance.

[0033] In an embodiment, a depth of the package measured between the first wall and the second wall is at least one of: less than 10 mm; less than 5 mm; between 1 mm and 4 mm; and less than 1 mm.

[0034] In an embodiment, the package is configured such that, in use, the first wall and the second wall remain substantially parallel to each other when the package is filled with the biological material.

[0035] In an embodiment, the first wall and the second wall are formed from a sheet of packaging material.

[0036] In one embodiment, the packaging material is selected from one of the following: polymer; polypropylene; polyvinyl chloride; polyethylene terephthalate; ethylene-vinyl acetate copolymer; copolymer; ethylene and vinyl acetate; metal; high alloy; and stainless steel.

[0037] In an embodiment, the package comprises one or more openings to facilitate filling and emptying of the package.

[0038] In an embodiment, the one or more openings include one or more ports extending through an edge of the package.

[0039] In one embodiment, the package is configured to store a biological material selected from one of the following: whole blood; platelets; red blood cells; white blood cells; plasma; blood cells; sperm; cells; stem cells; organs or parts thereof; and tissues.

[0040] In one embodiment, the package is configured for storing biological material to be used in therapeutic treatment.

[0041] In an embodiment, the package is configured for at least one of: cryopreservation of the biological material; cryogenic storage of the biological material; and thawing of the biological material.

[0042] In an embodiment, the package is configured for a heat transfer rate selected from one of: between 0°C and 10°C per minute; between 10°C and 50°C per minute; between 50°C and 100°C per minute; and greater than 100°C per minute.

[0043] In one embodiment, the package is configured as a bag.

[0044] In one embodiment, the package is configured as one of: a straw; and a vial.

[0045] In another broad form, one aspect of the present invention is directed to providing a package for preserving biological material, wherein, in use, the package is filled with the biological material and placed in an apparatus for preserving the biological material so that a heat exchange fluid flows around the package, the package comprising: opposing first and second walls, the first and second walls being connected together around a majority of their respective perimeters to define an internal compartment; and a plurality of thermal contours defined by the first and second walls, the thermal contours being connected together along connecting lines, the connecting lines being configured to divide the internal compartment into sub-compartments, wherein fluid communication between the sub-compartments is allowed, wherein, in use, the biological material is distributed between the sub-compartments, and the flow of the heat exchange fluid is at least partially guided by the thermal contours to improve heat transfer between the heat exchange fluid and the biological material contained in the sub-compartments of the package.

[0046] In another broad form, one aspect of the invention is directed to a method for designing a package for the preservation of a biological material, wherein, in use, the package is filled with the biological material and placed in an apparatus for preserving the biological material such that a heat exchange fluid flows around the package, the method comprising: a) determining a package geometry comprising one or more package walls, the package walls being configured to define an internal compartment to allow the package to be filled with a desired volume of biological material; b) determining the thermal properties of the biological material; the packaging material used to form the one or more package walls; and the heat exchange fluid; c) determining operating conditions of the apparatus, including: a velocity of the heat exchange fluid; a temperature of the heat exchange fluid; and a flow direction of the heat exchange fluid. d) performing an analysis of the flow of a heat exchange fluid within an apparatus surrounding a filled package based on the determined package geometry, thermal characteristics, and operating conditions to determine an expected temperature gradient in the biomaterial in use; e) using the expected temperature gradient to select a configuration of one or more thermal contours defined across at least one package wall to improve heat transfer between the heat exchange fluid and the biomaterial contained in the package; and f) performing a further analysis of the flow of a heat exchange fluid within an apparatus surrounding a filled package including the one or more thermal contours based on the determined package geometry, the selected configuration of the one or more thermal contours, the thermal characteristics, and operating conditions to determine an expected temperature gradient in the biomaterial in use;

[0047] In an embodiment, the method comprises repeating steps e) and f) until the desired expected temperature gradient is determined.

[0048] In one embodiment, the packaging geometry includes opposing first and second walls, the first and second walls being connected together around a majority of their respective perimeters to define an internal compartment, and a plurality of thermal contours defined by the first and second walls being connected together along connecting lines, the connecting lines being configured to divide the internal compartment into sub-compartments, wherein fluid communication between the sub-compartments is allowed, the method comprising: performing an analysis of the flow of a heat exchange fluid within an apparatus surrounding a filled package; and selecting a configuration of the thermal contours using an expected temperature gradient to provide substantially uniform heat transfer between the heat exchange fluid and the biological material contained in each sub-compartment.

[0049] It will be understood that the broad forms of the invention and their respective features may be used in combination, interchangeably and / or independently and that reference to a single broad form is not intended to be limiting. Brief introduction of the attached figure

[0050] Various examples and embodiments of the present invention will now be described with reference to the accompanying drawings, in which:-

[0051] Figure 1 is a plan view of an example of a package for storage of biological material;

[0052] Figure 2A yes Figure 1 A schematic plan view of the packaging;

[0053] Figure 2B yes Figure 2A A schematic side view of a package of;

[0054] Figure 2C yes Figure 2A A schematic cross-sectional view of a package at section AA;

[0055] Figure 3A yes Figure 2A A schematic plan view of a simplified analysis model of a package showing analysis locations across the package;

[0056] Figure 3B yes Figure 3A A schematic cross-sectional view of a simplified analytical model of a package at section AA;

[0057] Figure 3C yes Figure 3B A schematic detail view of a cross-sectional view of a simplified analysis model of a package at detail B, showing the analysis points within the package;

[0058] Figure 4A Is this packaging used for whole blood during cryopreservation? Figure 3A A graph of the expected temperature gradient at analysis position P101 versus time is shown;

[0059] Figure 4B Is this packaging used for whole blood during cryopreservation? Figure 3A A graph of the expected temperature gradient at analysis position P103 versus time is shown;

[0060] Figure 4C Is this packaging used for whole blood during cryopreservation? Figure 3A The expected temperature gradient at the analysis position P105 is shown as a function of time;

[0061] Figures 5A to 5D shows a temperature profile of the center layer of the package at subsequent time intervals during cryopreservation of whole blood using the package;

[0062] Figures 6A to 6D shows a temperature profile at subsequent time intervals during cryopreservation of whole blood using conventional blood bags;

[0063] Fig. 7A and 7B A top view and a side view showing the results of a computational fluid dynamics (CFD) analysis depicting the flow of a heat transfer fluid in an apparatus for holding biological material for use with packaging; and

[0064] Fig. 8A and 8B A graph depicting the relationship between bag width, blood volume, and RBC viability is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0065] Now refer to Figure 1 and Figures 2A to 2C An example of a package 100 for preservation of biological material is described. The package 100 is provided such that, in use, the package 100 can be filled with biological material and placed in an apparatus for preserving biological material such that a heat exchange fluid flows around the package 100 .

[0066] As used herein, "biological material" includes the following non-exhaustive list of materials: blood, plasma, platelets, leukocytes or other blood products; bacteria, viruses, bacteria, fungi or other microorganisms; organs or parts thereof, semen, eggs, colostrum, skin, serum, vaccines, stem cells (e.g., from bone marrow, umbilical cord blood, amniotic fluid, etc.), umbilical cord, bone marrow, germ cells, tumor cells, colostrum and plant cells.

[0067] The embodiment of the package 100 described herein is particularly configured for storing whole blood as the biological material, but it should be understood that the package 100 can be configured for a wide range of biological materials, including other materials not expressly mentioned herein.

[0068] As used herein, "preservation" of a biological material refers to a variety of processes that can be used to store a biological material. In some examples, preservation can involve freezing or cooling the biological material, storing the frozen or cooled biological material, and thawing the biological material or otherwise returning the biological material to a desired temperature for subsequent use. Preferred embodiments of the packaging can be specifically configured for at least one of cryopreservation of the biological material, cryogenic storage of the biological material, and thawing of the biological material.

[0069] An example of a suitable device for preserving biological material is described in WO2020 / 102854A1, the entire disclosure of which is incorporated herein by reference. For example, as described in the above disclosure, the device may include an inner shell arranged in an outer insulating shell, wherein the walls of the inner shell define a compartment for receiving a biological product, the walls including an inlet wall for allowing a heat exchange fluid to flow into the compartment, an opposite outlet wall for allowing the heat exchange fluid to flow out of the compartment, a side wall and a base, the side wall and the base connecting the inlet wall to the outlet wall, wherein the inlet wall and the outlet wall each include a series of holes to accommodate a continuous heat exchange fluid flowing through the device, so that in operation, the items received in the compartment of the inner shell are immersed in the heat exchange fluid to exchange heat with the heat exchange fluid. In this case, the package 100 is filled with biological material and placed in the compartment of the inner shell of the device so that the heat exchange fluid flows around the package 100.

[0070] Broadly speaking, the package 100 includes one or more package walls 111, 112 configured to define an interior compartment 101 for receiving a biological material, and one or more thermal contours 120, 121 defined on at least one of the package walls 111. In use, the flow of a heat exchange fluid is at least partially directed by the one or more thermal contours 120, 121 to improve heat transfer between the heat exchange fluid and the biological material contained in the package 100.

[0071] For example, as the heat exchange fluid flows around the package 100 within the device, the thermal contours 120, 121 can help guide the heat exchange fluid through the respective package walls, thereby facilitating more uniform heat transfer between the heat exchange fluid and the biological material. This can help avoid relatively high or low heat transfer areas that may otherwise result in "hot spots" or "cold spots" in the biological material in use. It will be appreciated that such hot spots or cold spots are generally undesirable because they represent variations in the rate of heat transfer that may adversely affect cell viability, etc., during or after storage of the biological material.

[0072] Rather, it should be appreciated that thermal contours 120, 121 may be provided to at least partially control or optimize the rate of heat transfer between the heat exchange fluid and the biomaterial. For example, thermal contours 120, 121 may be configured for the packaging geometry, the biomaterial, the thermal characteristics of the packaging material and the heat exchange fluid, and the operating conditions of the apparatus to ensure that the heat transfer between the heat exchange fluid and the biomaterial is substantially evenly distributed relative to the packaging geometry. In this regard, the configuration of thermal contours 120, 121 may be selected based on thermal analysis of the packaging in its intended use, and suitable techniques for doing so will be discussed in further detail when appropriate.

[0073] Regardless, it will be appreciated that use of a package 100 defining thermal contours 120 , 121 across at least one package wall 111 may help improve cryopreservation, frozen storage, and / or thawing of biological material as compared to use of conventional packages without any thermal contours 120 , 121 .

[0074] Now refer to Figure 1 and Figures 2A to 2C Further details of preferred and / or optional features of suitable embodiments of the package 100 are described.

[0075] In a preferred example, the thermal contours 120, 121 may be arranged to be substantially aligned with the flow of the heat exchange fluid in use. For example, the expected flow direction of the heat exchange fluid within the device and the flow direction relative to the package 100 in use can be determined experimentally or theoretically, for example, by performing thermal analysis on the flow conditions, such as by using computational fluid dynamics (CFD) analysis, etc. Therefore, the package can be configured so that the thermal contours 120, 121 are substantially aligned with the expected flow direction. This may involve, for example, arranging the thermal contours 120, 121 at a predetermined angle relative to the package geometry, as will be discussed in further detail below.

[0076] In many embodiments, the package 100 may include multiple thermal profiles 120, 121, which are preferably arranged parallel to each other. It will be appreciated that this parallel arrangement can help improve the way in which the thermal profiles 120, 121 guide the flow of the heat exchange fluid relative to the package 100 in use. However, it should be understood that it is not necessary to provide multiple thermal profiles, and in some examples, a single thermal profile can be provided. For example, in some packaging geometries such as straws or tube configurations, a single thermal profile can be provided on the cylindrical wall of the package 100 in a spiral arrangement.

[0077] exist Figure 1 and Figures 2A to 2C In the example embodiment shown, each thermal contour 120, 121 may be defined across a respective one of the package walls 111 as an elongated depression in the respective package wall 111, as shown in FIG. Figure 2C 1. The thermal contours 120, 121 are best viewed in the cross-sectional profile shown. In this example, each thermal contour 120, 121 may be described as a groove, channel or recess in the corresponding package wall 111. However, in alternative embodiments, the thermal contours 120, 121 may be defined as elongated protrusions in the corresponding package wall 111, such as in the form of ridges or the like in the corresponding package wall. In either case, it will be appreciated that the thermal contours 120, 121 will assist in directing the flow of the heat transfer fluid in use.

[0078] In some embodiments, such as Figure 1 and Figures 2A to 2C In the embodiment shown in , the package walls 111, 112 include opposing first and second walls that are connected together around a majority of their respective perimeters to define the interior compartment 101. In this case, the thermal contours 120, 121 can be defined by the first and second walls 111, 112 being connected together along one or more connection lines 210. For example, as Figure 2C As shown, the thermal contour 120 may be formed as an elongated recess in the first wall 111 , where the first wall 111 is connected to the second wall 112 along a corresponding connection line 210 .

[0079] The connection line 210 can be configured to effectively divide the internal compartment 101 into sub-compartments 201, wherein fluid communication between the sub-compartments is allowed. In use, the package 100 can be filled with biological material so that the biological material is distributed between the sub-compartments 201, and the flow of the heat exchange fluid will be at least partially guided by the thermal contours 120, 121 to facilitate substantially uniform heat transfer between the heat exchange fluid and the biological material contained in each sub-compartment 201. In a preferred example, the connection line 210 can be configured to ensure that the biological material is substantially evenly distributed between the various sub-compartments 201.

[0080] It will be appreciated that the uniform distribution of the biomaterial between the subcompartments 201, together with the thermal profiles 120, 121 directing the flow of the heat exchange fluid to promote substantially uniform heat transfer between the heat exchange fluid and the biomaterial contained in each subcompartment 201, can help minimize temperature variations throughout the biomaterial, thereby allowing consistent heat transfer during storage of the biomaterial.

[0081] In some embodiments, the first wall 111 and the second wall 112 may be connected together along a plurality of edges including a front edge 131 facing the flow of the heat transfer fluid in use and an opposite rear edge 132. A plurality of thermal contours 120, 121 will preferably extend between the front edge 131 and the rear edge 132. It will be appreciated that when the heat exchange fluid reaches the front edge 131 and then traverses the corresponding wall of the package 100, the thermal contours 120, 121 will direct the heat exchange fluid to flow toward the rear edge 132.

[0082] Typically, the rear edge 132 is substantially parallel to the front edge 131, such as in Figure 1 and Figures 2A to 2C The package 100 is shown in this configuration, but this need not always be the case.

[0083] At least some of the connection lines 210 defining the thermal contours 120, 121 may interconnect the front edge 131. This arrangement may assist in providing a more streamlined profile for the package at the front edge 131, thereby preventing interruption of heat transfer fluid flow around the front edge 131.

[0084] However, it should be understood that not all connection lines 210 and associated thermal profiles 120, 121 are necessarily interconnected with the front edge 131. In this regard, it should be noted that Figure 1 and Figures 2A to 2C One of the thermal contours 121 in the example of FIG. 1 is not interconnected with the front edge 131. It will be appreciated that interconnecting the thermal contour 121 to the front edge 131 would create a small sub-compartment that could trap biological material in its corners, which may be undesirable for heat transfer and may also hinder filling or emptying of the package 100.

[0085] It should also be appreciated that even in embodiments that do not include connection lines 210 , 211 , the thermal contours 120 , 121 may extend all the way to the front edge 131 in a manner similar to the above-described arrangement.

[0086] The thermal profiles 120, 121 may be arranged at a predetermined angle relative to a direction perpendicular to the front edge 131. Preferably, the predetermined angle is selected according to the flow of the heat exchange fluid in the apparatus for preserving biological material. For example, the predetermined angle may be selected so that the thermal profiles 120, 121 are substantially aligned with the flow of the heat exchange fluid as described above.

[0087] In some examples, the predetermined angle may be between 0° and 30°. Preferably, the predetermined angle may be between 5° and 15°. Figures 2A to 2C In a specific embodiment of the invention, the predetermined angle may be about 10°. However, it should be understood that the predetermined angle may be selected outside these ranges, for example, if the flow direction of the heat exchange fluid is steeper than the angle mentioned above.

[0088] In examples of packages 100 that include multiple thermal contours 120, 121, adjacent thermal contours 120, 121 will generally be spaced apart by a predetermined spacing distance. Figures 2A to 2C In an embodiment of the present invention, the predetermined spacing distance may be between 15 mm and 20 mm. However, the specific spacing distance generally depends on the geometric configuration of the package 100 and may also depend on other factors, such as the specific biological material that the package 100 will be filled with.

[0089] As a general principle, particularly in use, the predetermined separation distance may be selected to limit separation of the first wall 111 and the second wall 112. It will be appreciated that in embodiments where the thermal contours 120, 121 are defined to coincide with the connection line 210, the first wall 111 and the second wall 112 will be prevented from separating at the connection line 210, and separation between the first wall 111 and the second wall 112, such as separation due to bulging when the package is filled with biomaterial, will be limited according to the predetermined separation distance between adjacent thermal contours 120, 121.

[0090] In a preferred embodiment, the predetermined separation distance may be selected to limit the separation of the first wall 111 and the second wall 112 to a predetermined separation distance. It will be understood that a relatively smaller predetermined separation distance may be provided by reducing the predetermined separation distance, and a relatively larger predetermined separation distance may be provided by increasing the predetermined separation distance.

[0091] In some examples, the package depth measured between the first wall 111 and the second wall 112 will preferably be less than 10 mm. The package depth may be less than 5 mm, and in some embodiments, the package depth may be between 1 mm and 4 mm. However, in some applications, it may be desirable to provide a smaller package depth, such as less than 1 mm. It should be understood that the optimal package depth will generally depend on the overall package geometry and thermal considerations, some of which will be described in further detail when appropriate.

[0092] Preferably, the package 100 will be configured such that in use when the package 100 is filled with biological material, the first wall 111 and the second wall 112 remain substantially parallel to each other. This can be achieved by a combination of the spacing between the connection lines 210 and the associated thermal profiles 120,121.

[0093] In terms of the configuration of the package 100, the first wall 111 and the second wall 112 may be formed from a sheet of packaging material. For example, the packaging material may be selected from a polymer (such as polypropylene, polyvinyl chloride, polyethylene terephthalate, or ethylene vinyl acetate copolymer), a copolymer (such as ethylene and vinyl acetate), or a metal (such as a high alloy metal or stainless steel). It will be appreciated that different packaging materials may allow for packaging with different properties.

[0094] For example, if the first wall 111 and the second wall 112 are made of sheets of flexible material such as a polymer, this may result in the package being susceptible to bulging when filled, but this can be controlled as described above by selecting an appropriate spacing between the thermal profiles 120, 121. The connection between the first wall 111 and the second wall 112 may be achieved by heat sealing or other suitable thermoforming techniques.

[0095] On the other hand, if the first wall 111 and the second wall 112 are made of a sheet of a rigid material such as metal, the thermal profiles 120, 121 may be defined as deformations of the sheet without requiring a connection between the first wall 111 and the second wall 112 or a specific spacing therebetween. However, a connection between the first wall 111 and the second wall 112 may still be provided, such as by welding, to define the sub-compartments for the reasons described above.

[0096] The package 100 may include one or more openings to facilitate filling and emptying the package 100. The openings may include one or more ports 141, 142 extending through the edge 134 of the package 100, such as Figure 2A and 2BPreferably, the ports 141, 142 will be disposed on the edge 134 other than the front edge 131 and the rear edge 132. In this example, the ports 141, 142 may extend away from the first wall 111 and the second wall 112 of the package 100. In a particular example, each port 141, 142 may include a Luer lock connector to facilitate connection to tubing or the like to assist in filling or emptying the package.

[0097] The package can be configured to store a range of different biological materials, such as a biological material selected from one of the following: whole blood; platelets; red blood cells; white blood cells; plasma; blood cells; sperm; cells; stem cells; organs or parts thereof; and tissues.

[0098] As mentioned above, Figure 1 and Figures 2A to 2C The illustrated example embodiment of the package 100 has been specifically configured for cryopreservation of whole blood.

[0099] In other embodiments, the package may be specifically configured for storing stem cells or the like, such as: adult stem cells such as hematopoietic stem cells, mesenchymal stem cells, neural stem cells, epithelial stem cells, skin stem cells; embryonic / pluripotent stem cells; induced pluripotent stem cells; bone marrow-derived stem cells; or umbilical cord blood.

[0100] In other embodiments, the packaging can be configured to store a range of other types of biological materials, such as: chimeric antigen receptor T (CAR-T) cells, transgenic cells, natural killer cells, blastocysts, embryos, oocytes, fertilized eggs, ovarian tissue, testicular tissue, sperm, and heart valves.

[0101] It should be understood that the examples of biological materials listed herein are not an exhaustive list and that the packaging may also be used to store other biological materials.

[0102] In some examples, package 100 may be specifically configured for preserving biological material for therapeutic treatments such as CAR-T cell therapy.

[0103] The package 100 can be configured for use with a range of different biomaterial storage devices having a range of different operating parameters. For example, the package 100 can be configured to be compatible with a heat transfer rate selected from: between 0°C and 10°C per minute; between 10°C and 50°C per minute; between 50°C and 100°C per minute; and greater than 100°C per minute.

[0104] The package 100 can also provide a range of different package geometries and form factors while providing the functionality described above. For example, the package 100 can be configured as a bag, such as Figure 1 and Figures 2A to 2CHowever, in other examples, the package can also be configured as a straw or a vial. It will also be understood that the features of the present invention can be applied to packages of various other form factors.

[0105] In a preferred form, the package 100 can be specifically configured to include: a first wall 111 and a second wall 112 opposite each other, the first wall 111 and the second wall 112 are connected together around most of their respective perimeters to define the internal compartment 101; and a plurality of thermal contours 120, 121 defined by the first wall 111 and the second wall 112, which are connected together along a connecting line 210. The connecting line 210 is configured to divide the internal compartment 101 into sub-compartments 201, wherein fluid communication between the sub-compartments is allowed. In use, the biological material is distributed between the sub-compartments 201, and the flow of the heat exchange fluid is at least partially guided by the thermal contours 120, 121 to improve the heat transfer between the heat exchange fluid and the biological material contained in the sub-compartments 201 of the package.

[0106] Further detailed design considerations applicable in constructing a preferred embodiment of the package 100 will now be described.

[0107] While designing embodiments of the package 100, and while performing validation testing on these embodiments, applicants encountered issues associated with uniformity of heat transfer across the package 100 in use. It was found that there was a correlation between different package sizes, configurations, and materials and reduced cell viability. This research specifically focused on the design and manufacture of packaging bags used to cryopreserve blood and blood products. Validation testing confirmed that the more uniform the heat transfer was maintained along the entire bag, the more cell viability would remain the same. In addition, by performing thermal analysis and using thermal profiling as part of the package (as described above), the heat transfer coefficient was improved as the package volume increased for more controlled heat transfer.

[0108] Based on the results of this study and thermal analysis, it was determined Figure 1 A and Figures 2A to 2C The specific construction of the package 100 shown in the embodiment of FIG. 1 will now be outlined in further detail.

[0109] The package 100 is particularly provided in the form of a packaging bag for whole blood cryopreservation, and is designed to have a volume of 15 mL and an overall size of approximately 150 mm×120 mm.

[0110] In this embodiment, a plurality of thermal contours 120, 121 are included to direct the flow of heat exchange fluid around each sub-compartment defined therebetween, thereby allowing for uniform heat transfer between the heat exchange fluids.

[0111] The spacing requirement between the thermal contours 120, 121 is determined by the overall minimum sample volume. The spacing between the thermal contours 120, 121 is used to create substantially evenly distributed sub-compartments across the entire package to allow for even heat transfer. The spacing between adjacent thermal contours 120, 121 is a minimum of 15 mm and a maximum of 20 mm. As the volume and size of the package increases, the same minimum and maximum spacing can still be used.

[0112] The thermal contours 120, 121 have been arranged to align with the directional flow of heat exchange fluid within the cryogenic storage device in use to allow for even and consistent heat transfer.

[0113] It has been determined that the raised edge of the package interferes with the directional flow of the heat exchange fluid during use. In order to eliminate this problem and improve the consistency of heat transfer, the thermal contours 120, 121 are brought to the leading edge 131 of the package bag to seek to reduce the package protrusion in this area, thereby seeking to reduce the interference with the flow of the heat exchange fluid.

[0114] For this particular design, a total of seven thermal contours 120, 121 are included. As sample and bag volumes increase, it is contemplated that additional thermal contours 120, 121 may be included to provide additional, evenly distributed sub-compartments.

[0115] exist Figure 1 and Figures 2A to 2C In the embodiment of the present invention, the package 100 is constructed as a clamshell semi-rigid design using 250 micron, food and medical grade glycol-modified polyethylene terephthalate glycol (PETG), which is selected because it is suitable for low temperature thermoforming and low temperature sealing (approximately 140° C.). The package 100 includes a molded 2-port design for filling / emptying and venting.

[0116] The standard method of filling IV bags in the medical industry is usually to use a Luer lock, which can also be used in the port design. These are standard in terms of threads, tapers and seals to achieve a clean, safe and sterile fill point. In addition, the port can use EVA tubing, which is suitable for sealing using various ultrasonics.

[0117] The package 100 can be manufactured using a clamshell manufacturing method that involves forming two 250 micron PETG plastic sheets to create a closed volume container. Broadly speaking, the manufacturing method includes the following steps: mold design and 3D printing, vacuum forming 0.25 mm PETG sheets; trimming parts; welding parts using a constant temperature heat sealer; and performing pressure testing / quality inspection.

[0118] The package 100 is designed using 3D design software. In this regard, three different 3D computer-aided design (CAD) models were developed to simplify each step of the design process, as shown below: Configuration 1: The mold shape for 3D printing, which is then used for the subsequent vacuum forming process; Configuration 2: A simplified analytical model for computational fluid dynamics (CFD) analysis of heat transfer; · Build 3: Finished partial 3D representation of the package.

[0119] exist Figures 3A to 3C The analytical model used for CFD analysis is shown in Figure 2. Using this analytical model, the temperature gradient at various locations from the core to the package skin is analyzed, such as Figures 3A to 3C shown. Figure 3A The analysis positions of the entire package are shown, and specifically analysis positions P101, P102, P103, P104 and P105, which are spaced apart in the flow direction of the heat exchange fluid in the same sub-compartment between the thermal profiles as shown.

[0120] Figure 3B Shows Figure 3A A cross-sectional view of the analytical model at section AA, and Figure 3C An enlarged detail of the analysis point within the package at position P101 is shown, ranging from the core to the package skin. In the analysis model, analysis point P101X represents the outer wall surface of the package skin, and analysis point P101Y represents the inner wall surface of the package skin. On the other hand, analysis point P101 represents the core of the biomaterial, and analysis points P101B to P101F represent various positions within the biomaterial ranging from the core to the inner wall surface of the package skin. Similar analysis point nomenclature is applied to other analysis positions.

[0121] A CFD analysis was performed on the thermal properties of the biological material (whole blood), the packaging material (PETG), and the heat exchange fluid (hydrocarbon). The CFD analysis simulated the operating conditions of the cryopreservation device, including the velocity of the heat exchange fluid, the temperature of the heat exchange fluid, and the flow direction of the heat exchange fluid within the device. In this example, the packaging was assumed to be freely suspended within the device with its leading edge facing the flow direction of the heat exchange fluid, as shown in Figure 2. Figure 3A shown.

[0122] Figures 4A to 4C An example of CFD analysis results is shown in the form of a graph of temperature gradients versus time at different analysis points at analysis positions P101, P103, and P105. From the results, it can be seen that although these temperature gradients are at different relative distances from the front edge of the package, they reflect similar cooling rates at different analysis positions, which proves that the package design provides more uniform heat transfer throughout the package.

[0123] The CFD analysis results are also presented graphically in Figures 5A to 5D, these figures show respectively the temperature profile of the central layer of the package at subsequent time intervals, and specifically at approximately 2 seconds, 17 seconds, 22 seconds and 42 seconds from the start of the flow of the heat exchange fluid during operation of the cryogenic storage device.

[0124] Figures 5A to 5D The temperature diagram can be compared with Figures 6A to 6D For comparison with the temperature graph shown, Figures 6A to 6D The temperature map shown was generated from a similar CFD analysis performed using a model of a conventional IV blood bag for cryopreservation of whole blood under similar operating conditions.

[0125] As in Figures 6A to 6D As can be seen in FIG. 1 , the temperature plot of a conventional IV blood bag shows significant temperature variation across the bag, with a sizable "hot spot" persisting near the center of the bag as the temperature of the outer regions of the bag decreases. Figures 5A to 5D It has been demonstrated that the packaging design according to the present invention significantly reduces this problem by allowing for a more uniform heat transfer within each sub-compartment defined between the thermal contours.

[0126] As described above, the thermal profile is preferably arranged at an angle relative to the front edge of the package, wherein the angle is selected according to the flow direction of the heat exchange fluid in the holding device. It will be appreciated that CFD analysis may also be used to determine the flow direction of the heat exchange fluid for selecting the angle of the thermal profile.

[0127] in this regard, Fig. 7A and 7B Examples of top and side views of CFD analysis results depicting the flow of a heat transfer fluid in a cryogenic storage device constructed from packaging are shown. Fig. 7A , the package is positioned in the left chamber with the leading edge facing downwards into the flow, and it will be appreciated that in this case the angle of the thermal profile will be generally aligned with the flow direction.

[0128] Thus, the thermal profile of the package may be substantially aligned with the directional flow of the heat exchange fluid in use to further improve heat transfer between the heat exchange fluid and the biological material in use.

[0129] The specific configuration of the thermal contour may be selected based on a number of competing design considerations. As described above, the thermal contour provides improved heat transfer by directing a heat exchange fluid through the package. In a preferred embodiment where the thermal contour defines sub-compartments in the package, the thermal contour directs the flow of the fluid through each sub-compartment to allow uniform heat transfer, as demonstrated by the CFD results outlined above.

[0130] To improve the uniformity of heat dissipation, the thermal contour may be brought to the leading edge to allow the heat transfer fluid to overcome any disturbances to flow from the raised edges and borders. However, in this embodiment, the thermal contour is not brought to the opposite rear edge of the package to allow the contents to drain from the bag.

[0131] The thermal profile has been included at an angle to allow for directional heat exchange fluid flow as described above, but it is worth noting that the angle of the thermal profile also facilitates the discharge of the contents from the package.

[0132] In designing embodiments of the package 100, and in performing validation testing on these embodiments, applicants also encountered the problem of increasing sample volume. Studies have found that there is a correlation between increased sample volume and decreased cell viability. This study specifically focused on the design and manufacture of packaging bags for the storage of blood and blood products. Validation testing confirmed that as the volume increases and the bag depth remains the same, the cell viability will remain the same.

[0133] Table 1 below shows the red blood cell comparison test and its associated viability changes for increasing bag measurements. Table 1: Comparative testing of red blood cells with increasing bag measurements and their associated viability changes

[0134] All blood tested during this experiment was undiluted whole blood to which no cryoprotectants were added, and all cryopreservation and thawing followed standard laboratory procedures for equipment used to preserve biological materials. The bags were filled and the thickest and thinnest parts of the bags were measured using digital calipers. The average cross-sectional width of the bags was estimated and examined for trends.

[0135] Fig. 8A and 8B A graph depicting the relationship between bag width, blood volume and RBC viability is shown. From the data collected, it is clear that there is a trend that an increase in blood bag width leads to a decrease in RBC viability.

[0136] Based on this trend, the applicant derived the following linear equation, which describes the relationship between the average packaging equipment bag width and the RBC viability after cryopreservation: Percent difference of RBC from baseline = -3.1484 x average pocket width (mm) + 5.054.

[0137] Using this equation, one can estimate the effect of increasing bag width on RBC viability, but it is important to note that it is not the only factor affecting the results.

[0138] In view of the above design considerations, it can be appreciated that another aspect of the present invention is a method for designing a package for the preservation of biological material, wherein, in use, the package is filled with biological material and placed in an apparatus for preserving biological material such that a heat exchange fluid flows around the package. Broadly speaking, the method may include the following steps.

[0139] Typically, the method will first determine a desired package geometry including one or more package walls configured to define an internal compartment to allow the package to be filled with a desired volume of biological material. The method will also involve determining thermal properties of the biological material, the packaging material used to form the one or more package walls, and the heat exchange fluid; and determining operating conditions of the apparatus, including: the velocity of the heat exchange fluid, the temperature of the heat exchange fluid, and the flow direction of the heat exchange fluid.

[0140] With the package geometry, thermal characteristics, and operating conditions determined, the next step of the method would include performing an analysis of the flow of a heat exchange fluid within the device surrounding the filled package to determine expected temperature gradients in the biomaterial in use based on the determined package geometry, thermal characteristics, and operating conditions.

[0141] The expected temperature gradient is used to select a configuration of one or more thermal contours defined across at least one package wall to improve heat transfer between a heat exchange fluid and the biomaterial contained in the package. The method may then include performing further analysis of the flow of the heat exchange fluid within the apparatus surrounding the filled package including the one or more thermal contours based on the determined package geometry, the selected configuration of the one or more thermal contours, the thermal characteristics, and the operating conditions to determine the expected temperature gradient in the biomaterial in use.

[0142] The steps of constructing a thermal profile and performing further analysis thereon can optionally be repeated in an iterative manner until the desired expected temperature gradient is determined.

[0143] In one example, the method can be advantageously applied to design a preferred embodiment of a package wherein the package geometry includes opposing first and second walls, the first and second walls being connected together around a majority of their respective perimeters to define an internal compartment, and a plurality of thermal contours defined by the first and second walls being connected together along connection lines configured to divide the internal compartment into sub-compartments, wherein fluid communication between the sub-compartments is allowed.

[0144] Specifically, the method can be extended to include analyzing the flow of a heat exchange fluid within the device surrounding the fill package; and using the expected temperature gradient to select the configuration of the thermal profile to provide substantially uniform heat transfer between the heat exchange fluid and the biological material contained in each subcompartment.

[0145] Regardless, it will be appreciated that the packaging described herein for preservation of biological material can be provided with thermal contours to help improve heat transfer between the heat exchange fluid and the biological material contained in the packaging, and in particular to avoid problems such as experiencing inconsistent heat transfer in conventional packaging resulting in persistent hot spots.

[0146] The thermal contours are used to direct the flow of the heat exchange fluid through the package in a more uniform manner, thereby providing a more consistent heat transfer. In addition, in a preferred embodiment, the thermal contours coincide with the connections between the walls of the package, thereby effectively dividing the internal compartment of the package into sub-compartments, so that the thermal contours can facilitate a substantially uniform heat transfer between the heat exchange fluid and the biomaterial contained in each sub-compartment. In a preferred example, the biomaterial can be substantially evenly distributed between each sub-compartment to further regulate the heat transfer and allow for more consistent results.

[0147] In this specification and the claims that follow, unless the context requires otherwise, the word "comprise" and variations such as "include" or "comprising" will be understood to imply the inclusion of the stated integer, or group of integers, or steps, but not the exclusion of any other integer, or group of integers. As used herein, the term "about" means ±20%, unless otherwise indicated.

[0148] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise. Thus, for example, reference to "a support" includes a plurality of supports. In this specification and the following claims, reference will be made to a number of terms, which, unless otherwise intended, shall be defined to have the following meanings.

[0149] Of course, it will be appreciated that while the foregoing is presented by way of illustrative examples of the present invention, it will be apparent to those skilled in the art that all such and other modifications and variations are considered to fall within the broad purview and scope of the present invention as described herein.

Claims

1. A package for the preservation of biological materials, wherein: In use, the package is filled with biological material and placed in a device for holding the biological material so that a heat exchange fluid flows around the package, the package comprising: a) one or more package walls configured to define an interior compartment for receiving the biological material; and b) one or more thermal contours defined on at least one of the package walls, wherein, in use, the flow of a heat exchange fluid is at least partially directed by the one or more thermal contours to improve heat transfer between the heat exchange fluid and the biological material contained in the package.

2. The packaging according to claim 1, characterized in that The thermal contour is arranged to be substantially aligned with the flow of the heat exchange fluid in use.

3. The package according to claim 1 or claim 2, characterized in that: The package includes a plurality of thermal profiles arranged parallel to each other.

4. The package according to any one of claims 1 to 3, characterized in that Each of the thermal profiles is defined on a respective one of the package walls as one of: a) an elongated depression in a corresponding package wall; and b) Elongated protrusions in the corresponding packaging wall.

5. The package according to any one of claims 1 to 4, characterized in that The package wall includes opposing first and second walls connected together around a majority of their respective perimeters to define the interior compartment.

6. The package according to claim 5, characterized in that The one or more thermal contours are defined by the first and second walls connected together along one or more connection lines configured to divide the interior compartment into sub-compartments wherein fluid communication between the sub-compartments is permitted.

7. The package according to claim 6, characterized in that In use, the package is filled with biological material so that the biological material is distributed between the sub-compartments, and the flow of the heat exchange fluid is at least partially guided by the one or more thermal contours to facilitate substantially uniform heat transfer between the heat exchange fluid and the biological material contained in each of the sub-compartments.

8. The package according to claim 6 or claim 7, characterized in that The connecting lines are configured to ensure that the biological material is substantially evenly distributed between each of the sub-compartments.

9. The package according to any one of claims 5 to 8, characterized in that The first and second walls are connected together along a plurality of edges including a front edge facing a heat transfer fluid in use and an opposing rear edge, the plurality of thermal contours extending between the front edge and the rear edge.

10. The package according to claim 9, characterized in that The rear edge is substantially parallel to the front edge.

11. A package according to claim 9 or claim 10, characterized in that At least some of the connection lines are interconnected with the front edge.

12. The package according to any one of claims 9 to 11, characterized in that The thermal profile is arranged at a predetermined angle relative to a direction perpendicular to the leading edge.

13. The package according to claim 12, characterized in that The predetermined angle is selected according to the flow of a heat exchange fluid in the apparatus for preserving the biological material.

14. A package according to claim 12 or claim 13, characterized in that The predetermined angle is at least one of the following: a) between 0° and 30°; b) between 5° and 15°; and c) About 10°.

15. A package according to any one of claims 5 to 14, characterized in that Adjacent thermal contours are spaced apart by a predetermined spacing distance.

16. The package according to claim 15, characterized in that The predetermined spacing distance is between 15 mm and 20 mm.

17. A package according to claim 15 or claim 16, characterised in that The predetermined separation distance is selected to limit separation of the first wall and the second wall.

18. The package according to claim 17, characterized in that The predetermined separation distance is selected to limit the separation of the first wall and the second wall to a predetermined separation distance.

19. A package according to any one of claims 5 to 18, characterised in that The depth of the package measured between the first wall and the second wall is at least one of: a) Less than 10 mm; b) less than 5 mm; c) between 1 mm and 4 mm; and d) Less than 1 mm.

20. A package as claimed in any one of claims 5 to 19, characterised in that The package is configured such that, in use, when the package is filled with the biological material, the first wall and the second wall remain substantially parallel to each other.

21. A package as claimed in any one of claims 5 to 20, characterised in that The first and second walls are formed from a sheet of packaging material.

22. The package according to claim 21, characterized in that The packaging material is selected from the following: a) polymers; b) polypropylene; c) polyvinyl chloride; d) Poly(terephthalic acid); e) ethylene-vinyl acetate copolymer; f) copolymers; g) ethylene and vinyl acetate; h) metals; i) high alloys; and j) Stainless steel.

23. A package as claimed in any one of claims 1 to 22, characterised in that The package includes one or more openings to facilitate filling and emptying of the package.

24. The package according to claim 23, characterized in that The one or more openings include one or more ports extending through an edge of the package.

25. A package as claimed in any one of claims 1 to 24, characterised in that The package is configured to store a biological material selected from: a) whole blood; b) Platelets; c) red blood cells; d) white blood cells; e) plasma; f) blood cells; g) sperm; h) cells; i) stem cells; j) organs or parts thereof; and k) Organization.

26. A package as claimed in any one of claims 1 to 25, characterised in that The package is configured for storing biological material for therapeutic treatment.

27. A package according to any one of claims 1 to 26, characterized in that The packaging is configured for at least one of the following: a) Cryopreservation of biological materials; b) frozen storage of biological materials; and c) Thawing of biological material.

28. A package according to any one of claims 1 to 27, characterised in that The package is configured for use at a heat transfer rate selected from one of: a) between 0°C and 10°C per minute; b) between 10°C and 50°C per minute; c) between 50°C and 100°C per minute; and d) Exceeding 100°C per minute.

29. A package according to any one of claims 1 to 28, characterized in that The package is configured as a bag.

30. A package as claimed in any one of claims 1 to 28, characterised in that The packaging structure is one of the following: a) straws; and b) vial.

31. A package for the preservation of biological material, wherein: In use, the package is filled with biological material and placed in a device for holding the biological material so that a heat exchange fluid flows around the package, the package comprising: a) opposing first and second walls connected together around a majority of their respective perimeters to define an interior compartment; and b) a plurality of thermal contours defined by the first wall and the second wall, the thermal contours being connected together along connection lines, the connection lines being configured to divide the internal compartment into sub-compartments, wherein fluid communication between the sub-compartments is permitted, wherein, in use, the biomaterial is distributed between the sub-compartments and the flow of the heat exchange fluid is at least partially guided by the thermal contours to improve heat transfer between the heat exchange fluid and the biomaterial contained in the sub-compartments of the package.

32. A method for designing a package for the preservation of biological material, wherein: In use, the package is filled with biological material and placed in a device for holding the biological material so that a heat exchange fluid flows around the package, the method comprising: a) determining a package geometry comprising one or more package walls configured to define an interior compartment to allow the package to be filled with a desired volume of biological material; b) Determine the thermal properties of: i) the biological material; ii) packaging material for forming said one or more packaging walls; and iii) the heat exchange fluid; c) determining the operating conditions of the device, including: i) velocity of the heat exchange fluid; ii) the temperature of the heat exchange fluid; and iii) the flow direction of the heat exchange fluid; d) performing an analysis of the flow of said heat exchange fluid within said device surrounding a fill package to determine expected temperature gradients in said biomaterial in use based on the determined package geometry, thermal characteristics and operating conditions; e) using the expected temperature gradient to select a configuration of one or more thermal contours defined across at least one of the package walls to improve heat transfer between the heat exchange fluid and the biological material contained in the package; and f) performing further analysis of the flow of the heat exchange fluid within the device surrounding the filled package including the one or more thermal contours based on the determined package geometry, the selected configuration of the one or more thermal contours, thermal characteristics and operating conditions to determine expected temperature gradients in the biomaterial in use.

33. The method of claim 32, wherein: The method comprises repeating steps e) and f) until the desired expected temperature gradient is determined.

34. The method of claim 33, wherein: The package geometry includes opposing first and second walls, the first and second walls connected together around a majority of their respective perimeters to define an interior compartment, and a plurality of thermal contours defined by the first and second walls connected together along connection lines, the connection lines configured to divide the interior compartment into sub-compartments, wherein fluid communication between the sub-compartments is permitted, the method comprising: a) performing an analysis of the flow of the heat exchange fluid within the device surrounding the fill package; and b) selecting a configuration of said thermal profile using expected temperature gradients to provide substantially uniform heat transfer between said heat exchange fluid and said biological material contained in each of said subcompartments.

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