Packaging for preserving biological material

Abstract

A package for storing biological material, the package being filled with the biological material and placed in an apparatus for storing biological material such that, in use, the package is filled with the biological material and a heat exchange fluid flows around the package, the package including one or more package walls configured to define an interior compartment for receiving the biological material and one or more thermal contours defined across at least one of the package walls, and, in use, flow of the heat exchange fluid is directed at least in part by the one or more thermal contours to improve heat transfer between the heat exchange fluid and the biological material contained in the package.

Description

[Technical field]

[0001] The present invention relates to a package for storing biological material, particularly, but not exclusively, suitable for the freezing, cryopreservation and thawing of biological material such as whole blood. [Background technology]

[0002] The ability to store red blood cells (RBCs) outside the body has been considered a life-saving practice for many years. More recently, the use of cryopreserved RBCs in intravenous medicine has been extensively evaluated. RBCs undergo gradual deterioration during cryopreservation, and infusion of long-term stored RBCs has been associated with adverse clinical outcomes in terms of postoperative infections, length of hospital stay, and mortality.

[0003] Red blood cells are subject to international guidelines which require that hemolysis of red blood cell units be below acceptable levels (0.8% in Europe and 1% in the United States) and that the post-thaw recovery rate of red blood cells after deglycerolisation (i.e. freeze-thaw-wash recovery rate) be 80% or higher. Also, at least 75% of cryopreserved red blood cells should remain in circulation 24 hours after infusion.

[0004] Cryopreservation of large numbers of cells is necessary for therapeutic cell banking, which requires large or small amounts of highly concentrated cells. In addition, bioreactor systems often require seeding with large numbers of cells from running cell banks or starter cultures.

[0005] Medical device packaging is almost as important as the device itself. It plays a vital role in safely delivering specialized care to patients. Most single-use, sterile medical instruments can be opened with a high degree of confidence that sterility will be maintained during storage, handling, and transport.

[0006] Medical device packaging is doubly important because regulatory agencies recognize the critical nature of the sterile barrier or primary packaging and consider it a component or accessory of the medical device, meaning that the packaging is as important as the medical device itself.

[0007] The cooling rate of biological samples has been shown to have a dramatic effect on their long-term viability, influencing not only the rate and size of intracellular and extracellular ice crystal formation, but also solution effects that arise during the freezing process.

[0008] Crystallization occurs by the nucleation and growth of ice crystals in intracellular and extracellular regions as the temperature of the liquid approaches the crystallization temperature. Crystallization is a first-order phase transition that involves the release of energy through the latent heat of fusion. Many factors affect the liquid-to-solid phase transition, including cooling rate, homogeneity, and pressure.

[0009] The cooling rate is another parameter that has been used to optimize cell viability (Dumont, F., PA Marechai, 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 (CPAs) and cooling rate is also possible. In fact, the cooling rate determines the ice crystal size during freezing. As the solution begins to freeze, water in the extracellular fluid turns into ice, increasing the solute concentration in the extracellular fluid. The subsequent osmotic pressure causes the cells to dehydrate as water diffuses from the cytoplasm to the more concentrated external solution (Dumont, F., PA Marechai, and P. Gervais. 2004. Cell size and water permeability as determining factors for cell viability after freezing at different cooling rates. Appl. Environ. Microbiol. 70:268-272.). At low cooling rates, the volume is reduced by osmotic pressure, and all intracellular water escapes before intracellular crystallization. At intermediate cooling rates, the volume reduction leads to irreversible damage to the cells, and significant death is observed. At very high cooling rates, cells may not have time to reduce their volume due to the rapid heat flow, which may allow them to maintain a significant viability. Thus, the kinetics of freezing has a significant impact on cell viability, but in most cases the cooling rate cannot be well controlled. Summary of the Invention [Problem to be solved by the invention]

[0010] Cell death occurs due to massive water loss during slow cooling associated with increased extracellular osmolarity and a membrane-lipid phase transition, or due to crystallization during water loss from the cell with lethal membrane damage.

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

[0012] For solutions consisting primarily of water, the temperature range over which almost all crystallization occurs is reduced by a few degrees after the onset of freezing, 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 at a portion of the periphery and at a central region of the package. The central region, the area and thickness of the walls, and the periphery are configured to be sufficiently rigid to maintain the parallelism of the walls after the package is filled with the biological material. The package can be used for cryopreservation of the biological material.

[0014] The reference in this specification to any prior publication (or information derived therefrom) or known matter is not an acknowledgement or suggestion that the prior publication (or information derived therefrom) or known matter forms part of the general knowledge in the field of endeavor to which this specification pertains. [Means for solving the problem]

[0015] In one broad form, one aspect of the invention provides a package for storing biological material, wherein, in use, the package is filled with the biological material and placed in an apparatus for storing the biological material such that a heat exchange fluid flows around the package, the package including one or more package walls configured to define an interior compartment for receiving the biological material and one or more thermal contours defined across at least one of the package walls, and wherein, in use, flow of the heat exchange fluid is directed at least in part by the one or more thermal contours to improve heat transfer between the heat exchange fluid and the biological material contained within the package.

[0016] In one embodiment, the thermal contour is positioned to substantially match the flow of heat exchange fluid in use.

[0017] In one embodiment, the wrapper includes a plurality of thermal contours arranged parallel to one another.

[0018] In one embodiment, each of the thermal contours is defined across a respective one of the package walls as one of an elongated recess 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, the first and second walls connected together around a substantial portion of their respective peripheries to define an interior compartment.

[0020] In one embodiment, the one or more thermal contours are defined by the first and second walls being connected together along one or more connecting lines, the connecting lines being configured to divide the internal compartment into sub-compartments that enable fluid communication therebetween.

[0021] In one embodiment, in use, the package is filled with biological material such that the biological material is distributed among the sub-compartments, and the flow of heat exchange fluid is directed at least in part by one or more thermal contours to promote substantially even heat transfer between the heat exchange fluid and the biological material contained in each sub-compartment.

[0022] In one embodiment, the connecting lines are configured such that the biological material is substantially evenly distributed between each of the sub-compartments.

[0023] In one embodiment, the first and second walls are connected together along a plurality of edges including a leading edge facing the flow of heat transfer fluid in use and an opposing trailing edge, and a plurality of thermal contours extend between the leading edge and the trailing edge.

[0024] In one embodiment, the trailing edge is substantially parallel to the leading edge.

[0025] In one embodiment, at least some of the connecting lines interconnect with the leading edge.

[0026] In one embodiment, the thermal contour is disposed at an 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 the device for storing biological material.

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

[0029] In one embodiment, adjacent thermal contours are separated by a predetermined distance.

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

[0031] In one embodiment, the predetermined separation is selected to inhibit separation of the first and second walls.

[0032] In one embodiment, the predetermined distance is selected to limit the separation between the first wall and the second wall to a predetermined separation distance.

[0033] In one embodiment, the package depth 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 less than 4 mm, and less than 1 mm.

[0034] In one embodiment, the package is configured such that the first and second walls remain substantially parallel to one another when, in use, the package is filled with biological material.

[0035] In one embodiment, the first and second walls are formed from a sheet of wrapper material.

[0036] In one embodiment, the wrapper material is selected from one of the following: polymers, polypropylene, polyvinyl chloride, polyethylene terephthalate, ethylene vinyl acetate copolymers, copolymers, ethylene and vinyl acetate, metals, high alloys, and stainless steel.

[0037] In one embodiment, the package includes one or more openings to facilitate access to and from the package.

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

[0039] In one embodiment, the package is configured for storage of biological material selected from any of whole blood, platelets, red blood cells, white blood cells, plasma, blood products, sperm, cells, stem cells, organs or parts thereof, and tissue.

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

[0041] In one embodiment, the packager is configured for use in at least one of: cryopreservation of biological material, cryopreservation of biological material, and thawing of biological material.

[0042] In one embodiment, the packager is configured for use with a heat transfer rate selected from one of: 0°C to 10°C / min, 10°C to 50°C / min, 50°C to 100°C / min, and heat transfer rates greater than 100°C / min.

[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 invention provides a package for storing biological material, the package being characterized in that, in use, the package is filled with the biological material and placed in an apparatus for storing the biological material such that a heat exchange fluid flows around the package, the package including first and second walls coupled together around a substantial portion of their respective peripheries to define an internal compartment, and a plurality of thermal contours defined by the first and second walls coupled together along connecting lines configured to divide the internal compartment into sub-compartments enabling fluid communication therebetween, and in use, the biological material is distributed between the sub-compartments and the flow of the heat exchange fluid is directed at least in part 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, an aspect of the invention provides a method for use in designing a package for storing biological material, wherein in use the package is filled with the biological material and placed in an apparatus for storing the biological material such that a heat exchange fluid flows around the package, the method comprising the steps of: a) determining a package geometry including one or more package walls configured to define an interior compartment that enables the package to be filled with a desired volume of the biological material; b) determining thermal properties of the biological material, the package material for forming 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; and d) determining the method includes the steps of: performing an analysis of the flow of heat exchange fluid in the apparatus around the filled package in accordance with the determined package geometry, thermal properties, and operating conditions to determine an expected temperature gradient in the biological material in use; 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 a further analysis of the flow of heat exchange fluid in the apparatus around the filled package, including the one or more thermal contours, in accordance with the determined package geometry, selected configuration of the one or more thermal contours, thermal properties, and operating conditions to determine an expected temperature gradient in the biological material in use.

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

[0048] In one embodiment, the package shape includes opposing first and second walls connected together around a substantial portion of their respective peripheries to define an internal compartment, and a plurality of thermal contours defined by the first and second walls connected together along connecting lines configured to divide the internal compartment into sub-compartments allowing fluid communication therebetween, and the method includes performing an analysis of the flow of heat exchange fluid within the device around the filled package, and using the expected temperature gradients to select a configuration of the thermal contours to provide substantially equal heat transfer between the heat exchange fluid and the biological material contained in each of the sub-compartments.

[0049] It will be understood that the broad forms of the invention and their respective features can be used in combination, interchangeably, and / or independently, and reference to separate broad forms is not intended to be limiting.

[0050] Various examples and embodiments of the present invention will now be described with reference to the accompanying drawings. [Brief description of the drawings]

[0051] [Figure 1] FIG. 1 is a plan view of an example of a package for the storage of biological material. [Figure 2A] FIG. 2A is a schematic plan view of the packaging device of FIG. [Figure 2B] FIG. 2B is a schematic side view of the package of FIG. 2A. [Figure 2C] FIG. 2C is a schematic cross-sectional view of the package of FIG. 2A at section AA. [Figure 3A] FIG. 3A is a schematic plan view of a simplified analytical model of the package of FIG. 2A showing the analysis location of the entire package. [Figure 3B] FIG. 3B is a schematic cross-sectional view of a simplified analytical model of the package of FIG. 3A at section AA. [Figure 3C]FIG. 3C is a schematic detail of a cross-sectional view of the simplified analytical model of the package of FIG. 3B at Detail B, showing the analysis points within the package. [Figure 4A] FIG. 4A is a plot of the expected temperature gradient over time at analysis location P101 shown in FIG. 3A during cryopreservation of whole blood using a package. [Figure 4B] FIG. 4B is a plot of the expected temperature gradient over time at analysis location P103 shown in FIG. 3A during cryopreservation of whole blood using a package. [Figure 4C] FIG. 4C is a plot of the expected temperature gradient over time at analysis location P105 shown in FIG. 3A during cryopreservation of whole blood using a package. [Figure 5A] FIG. 5A shows temperature maps of the central layer of the package at subsequent time intervals during cryopreservation of whole blood using the package. [Figure 5B] FIG. 5B shows temperature maps of the central layer of the package at subsequent time intervals during cryopreservation of whole blood using the package. [Figure 5C] FIG. 5C shows temperature maps of the central layer of the package at subsequent time intervals during cryopreservation of whole blood using the package. [Figure 5D] FIG. 5D shows temperature maps of the central layer of the package at subsequent time intervals during cryopreservation of whole blood using the package. [Figure 6A] FIG. 6A shows temperature maps at subsequent time intervals during cryopreservation of whole blood using conventional blood bags. [Figure 6B] FIG. 6B shows temperature maps at subsequent time intervals during cryopreservation of whole blood using conventional blood bags. [Figure 6C] FIG. 6C shows temperature maps at subsequent time intervals during cryopreservation of whole blood using conventional blood bags. [Figure 6D] FIG. 6D shows temperature maps at subsequent time intervals during cryopreservation of whole blood using conventional blood bags. [Figure 7A]FIG. 7A shows top and side views of computational fluid dynamics (CFD) analysis results depicting the flow of heat transfer fluid within an apparatus for storage of biological material for use with a packager. [Figure 7B] FIG. 7B shows top and side views of computational fluid dynamics (CFD) analysis results depicting the flow of heat transfer fluid within an apparatus for storage of biological material for use with a packager. [Figure 8A] FIG. 8A shows a plot depicting the relationship between bag width, blood volume and red blood cell viability. [Figure 8B] FIG. 8B shows a plot depicting the relationship between bag width, blood volume and red blood cell viability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] An example of a package 100 for the storage of biological material will now be described with reference to Figures 1 and 2A-2C. The package 100 is provided such that, in use, the package 100 can be filled with biological material and placed in an apparatus for storing biological material such that a heat exchange fluid flows around the package 100.

[0053] As used herein, "biological material" includes a non-exhaustive list of the following materials: blood, plasma, platelets, white blood cells or other blood products, bacteria, viral 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.

[0054] Although the embodiments of package 100 described herein are particularly configured for the storage of whole blood as a biological material, it should be understood that package 100 may be configured for a wide range of biological materials, including other materials not explicitly described herein.

[0055] As used herein, "storage" of biological material refers to various processes that may be used in connection with the storage of biological material. In some instances, storage may include freezing or cooling the biological material, storing the frozen or cooled biological material, and thawing the biological material, or returning the biological material to a desired temperature for subsequent use as needed. Preferred embodiments of the packager may be specifically configured for at least one of cryopreservation of biological material, cryopreservation of biological material, and thawing of biological material.

[0056] An example of a suitable device for storing biological material is described in WO2020 / 102854A1, the entire disclosure of which is incorporated herein by reference. For example, as described in the aforementioned publication, the device may include an inner housing disposed within an outer insulated housing, the walls of the inner housing defining a compartment for receiving a biological product, the walls including an inlet wall for the inflow of heat exchange fluid into the compartment, an opposing outlet wall for the outflow of heat exchange fluid from the compartment, and a side wall and a base that adjoin the inlet wall to the outlet wall, the inlet wall and the outlet wall each including a series of openings for receiving a continuous flow of heat exchange fluid, such that during operation, items received in the compartment of the inner housing are immersed in the heat exchange fluid and exchange heat with the heat exchange fluid. In this context, a package 100 is filled with biological material and disposed within the compartment of the inner housing of the device such that the heat exchange fluid flows around the package 100.

[0057] Broadly speaking, the package 100 includes one or more package walls 111, 112 configured to define an interior compartment 101 for receiving biological material, and one or more thermal contours 120, 121 defined across at least one of the package walls 111. In use, the flow of a heat exchange fluid is directed at least in part 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.

[0058] For example, as the heat exchange fluid flows around the package 100 within the device, the thermal contours 120, 121 serve to direct the flow of the heat exchange fluid across the package walls to provide more uniform heat transfer between the heat exchange fluid and the biological material. This avoids areas of relatively high or low heat transfer that would result in the presence of "hot spots" or "cold spots" in the biological material during use. It will be appreciated that such hot or cold spots are generally undesirable as they represent variations in heat transfer rates that may adversely affect, for example, cell viability during or after storage of the biological material.

[0059] In contrast, it should be understood that the 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 biological material. For example, the thermal contours 120, 121 may be configured with respect to the package geometry, the thermal properties of the biological material, the package material and the heat exchange fluid, and the operating conditions of the apparatus, such that the heat transfer between the heat exchange fluid and the biological material is substantially evenly distributed with respect to the package geometry. In this regard, the configuration of the thermal contours 120, 121 may be selected based on a thermal analysis of the package in its intended use, suitable techniques for which are described in further detail below.

[0060] In any event, it will be appreciated that the use of a package 100 having thermal contours 120, 121 defined across at least one of the package walls 111 may facilitate improved cryopreservation, cryopreservation and / or thawing of biological material compared to the use of conventional packages lacking the thermal contours 120, 121.

[0061] Further details of preferred and / or optional features of a preferred embodiment of packager 100 will now be described with respect to Figures 1 and 2A-2C.

[0062] In a preferred embodiment, the thermal contours 120, 121 are positioned to substantially align with the flow of the heat exchange fluid during use. The expected flow direction of the heat exchange fluid through the device and relative to the package 100 during use can be determined experimentally or theoretically, for example, by performing a thermal analysis of the flow conditions, such as using computational fluid dynamics (CFD) analysis. The package can then be configured such that the thermal contours 120, 121 substantially align with the expected flow direction. This can include, for example, positioning the thermal contours 120, 121 at a predetermined angle relative to the package geometry, as described in more detail below.

[0063] In many embodiments, the wrapper 100 may include multiple thermal contours 120, 121, preferably arranged parallel to one another. It will be appreciated that such a parallel arrangement helps improve how the thermal contours 120, 121 direct the flow of heat exchange fluid to the wrapper 100 during use. However, it should be understood that providing multiple thermal contours is not required and that in some instances a single thermal contour may be provided. For example, in some wrapper geometries, such as straw or tube configurations, a single thermal contour may be arranged in a spiral across the cylindrical wall of the wrapper 100.

[0064] In the exemplary embodiment as shown in Figures 1 and 2A-2C, each of the thermal contours 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 best viewed in the cross-sectional profile shown in Figure 2C. In this example, each of the thermal contours 120, 121 is described as a groove, channel or recess in the respective package wall 111. However, in alternative embodiments, the thermal contours 120, 121 may be defined as an elongated protrusion in the respective package wall 111, for example in the form of a ridge in the respective package wall, etc. In either case, it will be appreciated that the thermal contours 120, 121 serve to direct the flow of a heat transfer fluid during use.

[0065] In some embodiments, such as shown in Figures 1 and 2A-2C, the package walls 111, 112 include opposing first and second walls, the first wall 111 and the second wall 112 connected together around a substantial portion of their respective perimeters to define the interior compartment 101. In this context, the thermal contours 120, 121 may be defined by the first wall 111 and the second wall 112 being connected together along one or more connecting lines 210. For example, as shown in Figure 2C, the thermal contours 120 may be formed as elongated recesses in the first wall 111, the first wall 111 being connected to the second wall 112 along respective connecting lines 210.

[0066] The connecting lines 210 can be configured to effectively divide the internal compartment 101 into sub-compartments 201 with fluid communication therebetween. In use, the package 100 can be filled with biological material such that the biological material is distributed among the sub-compartments 201, and the flow of heat exchange fluid is directed at least in part by the thermal contours 120, 121 to promote substantially even heat transfer between the heat exchange fluid and the biological material contained in each of the sub-compartments 201. In a preferred embodiment, the connecting lines 210 can be configured such that the biological material is substantially evenly distributed among each of the sub-compartments 201.

[0067] It will be appreciated that this even distribution of biological material between the sub-compartments 201, in combination with the thermal contours 120, 121 which direct the flow of the heat exchange fluid to promote substantially even heat transfer between the heat exchange fluid and the biological material contained in each sub-compartment 201, serves to minimize temperature variations throughout the biological material, thereby enabling consistent heat transfer during storage of the biological material.

[0068] In some embodiments, the first wall 111 and the second wall 112 may be connected together along multiple edges, including a leading edge 131 that faces the flow of heat transfer fluid in use, and an opposing trailing edge 132. The multiple thermal contours 120, 121 preferably extend between the leading edge 131 and the trailing edge 132. It will be appreciated that the thermal contours 120, 121 direct the flow of the heat exchange fluid as it reaches the leading edge 131 and subsequently traverses the respective walls of the packager 100 towards the trailing edge 132.

[0069] Typically, the trailing edge 132 is substantially parallel to the leading edge 131, such as in the configuration of the wrapper 100 shown in Figures 1 and 2A-2C, although this need not always be the case.

[0070] At least a portion of the connecting lines 210 that define the thermal contours 120, 121 may interconnect with the leading edge 131. Such an arrangement helps provide the wrapper with a more streamlined profile at the leading edge 131 to prevent disruption of the flow of the heat transfer fluid around the leading edge 131.

[0071] However, it should be understood that not all of the connecting lines 210 and associated thermal contours 120, 121 necessarily interconnect with the leading edge 131. In this regard, it should be noted that one thermal contour 121 in the embodiment of Figures 1 and 2A-2C is not interconnected with the leading edge 131. It will be understood that interconnecting this thermal contour 121 with the leading edge 131 would result in the formation of a small sub-compartment in which biological material may become trapped in the comer, which is undesirable for heat transfer and may inhibit filling or emptying of the package 100.

[0072] It should also be appreciated that the thermal contours 120, 121 can extend to the leading edge 131, similar to the arrangement described above, even in embodiments that do not include the connecting lines 210, 211.

[0073] The thermal contours 120, 121 may be disposed at a predetermined angle relative to a direction perpendicular to the leading edge 131. Preferably, the predetermined angle is selected according to a flow of heat exchange fluid in an apparatus for storing biological material. For example, the predetermined angle may be selected to substantially match the thermal contours 120, 121 relative to the flow of heat exchange fluid, as described above.

[0074] In some examples, the predetermined angle is between 0° and 30°. Preferably, the predetermined angle may be between 5° and 15°. In the particular embodiment of Figures 2A-2C, the predetermined angle may be about 10°. However, it should be understood that the predetermined angle may be selected outside of these ranges, for example, if the direction of flow of the heat exchange fluid is at a steeper angle than described above.

[0075] In the example of a package 100 including multiple thermal contours 120, 121, adjacent thermal contours 120, 121 are typically spaced apart by a predetermined distance. For example, in the embodiment of Figures 2A-2C, the predetermined distance may be between 15 mm and 20 mm. However, the particular distance will typically depend on the geometric configuration of the package 100 and may also depend on other factors, such as the particular biological material the package 100 is filled with.

[0076] As a general principle, the predetermined distance interval can be selected to inhibit separation of the first wall 111 and the second wall 112, particularly in use. It will be appreciated that in embodiments in which the thermal contours 120, 121 are defined to coincide with the connecting line 210, the first wall 111 and the second wall 112 are prevented from separating at the connecting line 210, and separation between the first wall 111 and the second wall 112, such as due to bulging when the package is filled with biological material, is inhibited according to the predetermined distance interval between adjacent thermal contours 120, 121.

[0077] In a preferred embodiment, the predetermined separation distance may be selected to limit the separation between the first wall 111 and the second wall 112 to a predetermined separation distance. It will be appreciated that a relatively small predetermined separation distance may be provided by decreasing the predetermined separation distance, and a relatively large predetermined separation distance may be possible by increasing the predetermined separation distance.

[0078] In some examples, the package depth, measured between the first wall 111 and the second wall 112, is preferably 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 generally depends on the overall package shape and thermal considerations.

[0079] Preferably, the package 100 is configured such that the first wall 111 and the second wall 112 remain substantially parallel to one another when the package 100 is filled with biological material in use. This may be achieved by a combination of the spacing between the connecting lines 210 and the associated thermal contours 120, 121.

[0080] As far as the structure of the wrapper 100 is concerned, the first wall 111 and the second wall 112 may be formed from a sheet of wrapper material. For example, the wrapper 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 wrapper materials can be used to create wrappers with different properties.

[0081] For example, if the first wall 111 and the second wall 112 are formed from sheets of flexible material such as a polymer, this may result in the package having a bulge when filled, which can be controlled, for example, by selecting an appropriate distance spacing between the heat contours 120, 121, as described above. The connection between the first wall 111 and the second wall 112 can be achieved by heat sealing or other suitable thermoforming techniques.

[0082] On the other hand, if the first wall 111 and the second wall 112 are formed from a sheet of rigid material such as metal, the thermal contours 120, 121 may be defined as deformations in the sheet without requiring a connection or a specific distance between the first wall 111 and the second wall 112. However, a connection between the first wall 111 and the second wall 112 may be provided by welding or the like to define sub-compartments for the reasons mentioned above.

[0083] The wrapper 100 can include one or more openings to facilitate filling and emptying the wrapper 100. These openings can include one or more ports 141, 142 extending through an edge 134 of the wrapper 100, as shown in Figures 2A and 2B. Preferably, the ports 141, 142 are provided on an edge 134 other than the leading edge 131 and the trailing edge 132. In this example, the ports 141, 142 can extend away from the first wall 111 and the second wall 112 of the wrapper 100. In one specific example, each port 141, 142 can include a luer lock connector to facilitate connection to tubing or the like to aid in filling or emptying the wrapper.

[0084] The packager can be configured to store a variety of biological materials, such as biological materials selected from any of whole blood, platelets, red blood cells, white blood cells, plasma, blood products, sperm, cells, stem cells, organs or parts thereof, and tissue.

[0085] As mentioned above, the embodiment of the packager 100 shown in Figures 1 and 2A-2C is particularly adapted for use in the cryopreservation of whole blood.

[0086] In other embodiments, the packager may be specifically configured for use in storing stem cells, 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 stem cells.

[0087] In still other embodiments, the packager may be configured for use in storing a variety of other types of biological material, such as chimeric antigen receptor T (CAR-T) cells, genetically modified cells, natural killer cells, blastocysts, embryos, eggs, zygotes, ovarian tissue, testicular tissue, sperm, and heart valves.

[0088] It should be understood that the examples of biological materials identified herein are not intended to be an exhaustive list and that the package may also be used for the storage of other biological materials.

[0089] In some examples, the packager 100 may be specifically configured for the storage of biological materials used in therapeutic treatments, such as CAR-T cell therapy.

[0090] The packager 100 can be configured to have a variety of different operating parameters for use with a variety of devices for storing biological material. For example, the packager 100 can be configured to accommodate heat transfer rates 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.

[0091] The package 100, while providing the functionality as described above, can also be provided in a variety of different package shapes and form factors. For example, the package 100 can be configured as a bag, as shown in Figures 1 and 2A-2C. However, the package may alternatively be configured as a straw or vial in other examples. It will also be appreciated that the features of the present invention can be applied to packages of various other form factors.

[0092] In one preferred embodiment, the package 100 may be specifically configured to include opposing first and second walls 111, 112 connected together around a substantial portion of their respective peripheries to define an internal compartment 101, and a plurality of thermal contours 120, 121 defined by the first and second walls 111, 112, connected together along connecting lines 210. The connecting lines 210 are configured to divide the internal compartment 101 into sub-compartments 201 that are capable of fluid communication therebetween. In use, the biological material is distributed between the sub-compartments 201, and the flow of the heat exchange fluid is at least partially directed by the thermal contours 120, 121 to improve heat transfer between the heat exchange fluid and the biological material contained in the sub-compartments 201 of the package.

[0093] Further detailed design considerations that may be applied in constructing preferred embodiments of the packager 100 will now be described.

[0094] In designing embodiments of the package 100, and as a result of validation testing of these embodiments, the applicant encountered issues related to uniformity of heat transfer throughout the package 100 during use. Studies were conducted which found a correlation between varying the package dimensions, configuration and materials and reduced cell viability. The studies focused specifically on the design and manufacture of packages for cryopreservation of blood and blood products. Validation testing confirmed that the more uniform the heat transfer throughout the bag, the more cell viability remained unchanged. Additionally, by performing thermal analysis and including a thermal contour as part of the package as described above, the heat transfer coefficient was improved for more controlled heat transfer as the volume of the package increased.

[0095] The specific configuration of the packager 100 shown in the embodiment of Figures 1A and 2A-2C was determined as a result of this research and thermal analysis, and details thereof are now outlined.

[0096] The package 100 is specifically provided in the form of a package configured for use in the cryopreservation of whole blood, having a volume of 15 mL and designed to have overall dimensions of approximately 150 mm x 120 mm.

[0097] In this embodiment, multiple thermal contours 120, 121 are included to direct the flow of heat exchange fluid around each sub-compartment defined therebetween to enable even heat transfer between the heat exchange fluids.

[0098] The spacing requirements between the thermal contours 120, 121 were determined by the overall minimum sample volume. The spacing between the thermal contours 120, 121 was used to create subcompartments that were substantially evenly distributed throughout the package to allow uniform heat transfer. The spacing between adjacent thermal contours 120, 121 is a minimum of 15 mm and a maximum of 20 mm. The same minimum and maximum spacing can be used as the package volume and dimensions increase.

[0099] The thermal contours 120, 121 are positioned to align with the direction of flow of heat exchange fluid within the cryopreservation device in use to allow for even and uniform heat transfer.

[0100] It was determined that the raised edges of the wrapper could disrupt the directional flow of the heat exchange fluid during use. To eliminate this problem and improve the consistency of heat transfer, the thermal contours 120, 121 were taken to the leading edge 131 of the wrapper to reduce the bulge of the wrapper in this area, and therefore reduce the disruption of the flow of the heat exchange fluid.

[0101] A total of seven thermal contours 120, 121 are included for this particular design. As sample and bag volumes increase, it is anticipated that additional thermal contours 120, 121 will be included to provide additional evenly distributed sub-compartments.

[0102] In the embodiment of Figures 1 and 2A-2C, packager 100 is constructed as a clamshell semi-rigid design using 250 micron food and medical grade glycol modified polyethylene terephthalate (PETG). Packager 100 includes a two-port design for filling / emptying and venting.

[0103] The standard method of filling IV bags in the medical industry is generally through the use of Luer locks, which may also be incorporated into port designs. These are standard in terms of threads, tapers, and seals to achieve a clean, safe, and sterile fill point. Additionally, ports may also use EVA tubing, which may be ultrasonically sealed.

[0104] The package 100 can be manufactured using a clamshell-type manufacturing method that forms two sheets of 250 micron PETG plastic to create a sealed container. Broadly speaking, the manufacturing process includes the steps of mold design and 3D printing, vacuum forming the 0.25mm PETG sheets, trimming the parts, welding the parts using a thermostatic sealer, and pressure testing / quality checking.

[0105] The packager 100 was designed using 3D design software. In this regard, 3D Computer Aided Design (CAD) models were developed in three different configurations to facilitate each step of the design process: Configuration 1: Mold shape for 3D printing, then used for the subsequent vacuum forming process. · Configuration 2: Simplified analytical model for computational fluid dynamics (CFD) analysis of heat transfer. · Configuration 3: 3D representation of the finished package.

[0106] The analytical model used for the CFD analysis is shown in Figures 3A-3C. Using this analytical model, the temperature gradient from the core to the package skin was analyzed at various locations as shown in Figures 3A-3C. Figure 3A shows the analysis locations throughout the package, and in particular, analysis locations P101, Pl02, Pl03, Pl04, and Pl05, which are spaced apart in the same subcompartment between thermal contours in the heat exchange fluid flow direction.

[0107] FIG. 3B is a cross-sectional view of the analytical model of FIG. 3A at section AA, and FIG. 3C is an enlarged detail of the analysis point in the package at location P101, ranging from the core to the package skin. In the analytical 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. Meanwhile, analysis point P101 represents the core of the biological material, and analysis points P101B through P101F represent various locations within the biological material from the core to just before the inner wall surface of the package skin. Similar analysis point nomenclature applies to the other analysis locations.

[0108] A CFD analysis was performed on the thermal properties of the biological material (whole blood), the package material (PETG), and the heat exchange fluid (hydrocarbon). The CFD analysis simulates 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 package was assumed to be floating freely within the device with its leading edge pointing in the direction of the heat exchange fluid flow, as shown in Figure 3A.

[0109] Examples of CFD analysis results are shown in Figures 4A-4C in the form of plots of temperature gradients over time at different analysis points P101, P103, and P105. As can be seen, these temperature gradients reflect similar cooling rates at the different analysis locations despite their relative distance from the leading edge of the wrapper, indicating that the wrapper design provides a more uniform heat transfer throughout the wrapper.

[0110] The results of this CFD analysis are also graphically represented in Figures 5A-5D, which show temperature maps of the central layer of the package at subsequent time intervals, specifically, at approximately 2 seconds, 17 seconds, 22 seconds, and 42 seconds after initiation of heat exchange fluid flow during operation of the cryopreservation device.

[0111] The temperature maps of Figures 5A-5D can be contrasted with the temperature maps shown in Figures 6A-6D generated for a similar CFD analysis performed using a model of a conventional IV blood bag for cryopreserving whole blood under similar operating conditions.

[0112] As seen in Figures 6A-6D, temperature maps of a conventional IV blood bag show significant temperature variations throughout the bag, with a substantial "hot spot" that persists near the center of the bag as the temperature of the outer regions of the bag decreases. Figures 5A-5D, on the other hand, show that the design of the package according to the present invention substantially reduces this problem by allowing for more even heat transfer within each sub-compartment defined between the thermal contours.

[0113] As mentioned above, the thermal contour is preferably provided at an angle relative to the leading edge of the wrapper, the angle being selected according to the direction of heat exchange fluid flow within the storage device, It will be appreciated that CFD analysis may also be used to determine the direction of heat exchange fluid flow for use in selecting the angle of the thermal contour.

[0114] In this regard, Figures 7A and 7B show examples of top and side views of the CFD analysis results depicting the flow of heat transfer fluid within a cryopreservation device in which a wrapper is configured. With reference to Figure 7A, the wrapper is positioned in the left chamber with the leading edge pointing downward relative to the flow, and it will be understood that in this context the angle of the thermal contours will be approximately aligned with the flow direction.

[0115] Thus, the thermal profile of the package may be substantially aligned with the direction of flow of the heat exchange fluid in use to further improve heat transfer between the heat exchange fluid and the biological material in use.

[0116] The specific configuration of the thermal contours can be selected with respect to a number of competing design considerations. As discussed above, the thermal contours improve heat transfer by directing the heat exchange fluid throughout the package. In a preferred embodiment where the thermal contours define subcompartments within the package, the thermal contours direct the fluid flow through each subcompartment, allowing for even heat transfer as demonstrated in the CFD results summary above.

[0117] To improve the consistency of heat removal, a thermal contour can be provided to the leading edge to allow the heat transfer fluid to overcome flow disturbances due to raised lips and boundaries, but in this embodiment, no thermal contour is provided to the opposing trailing edge of the wrapper to allow the contents to be evacuated from the bag.

[0118] It should be noted that while the thermal contours are included at angles to allow for directional heat exchange fluid flow, as discussed above, the angles of the thermal contours also facilitate the ejection of the contents from the package.

[0119] In designing embodiments of the package 100, and in validation testing of these embodiments, the applicant also encountered problems with increasing sample volumes. Studies were conducted that found a correlation between increasing sample volume and reduced cell viability. The studies were specifically focused on the design and manufacture of packages for the storage of blood and blood products. Validation testing confirmed that cell viability did not change with increasing volume if the bag depth did not change.

[0120] Table 1 below shows the red blood cell comparison test with increasing package measurements and the associated vitality changes.

[0121] [Table 1]

[0122] All blood tested in this study was undiluted whole blood with no added cryoprotectant, and all freezing and thawing followed standard laboratory procedures for the equipment provided for storing 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 trends were noted.

[0123] 8A and 8B are plots depicting the relationship between bag width, blood volume, and red blood cell viability. From the collected data, it is clear that there is a trend for red blood cell viability to decrease as blood bag width increases.

[0124] Based on this trend, Applicant has derived the following linear equation that describes the relationship between the average bag width of the package and the viability of red blood cells after cryopreservation: RBC% difference from baseline = -3.1484 x mean bag width (mm) + 5.054

[0125] This formula can be used to estimate the effect of increasing bag width on red blood cell viability, but it should be noted that it is not the only factor affecting the results.

[0126] In view of the above design considerations, it will be appreciated that another aspect of the present invention is a method for use in designing a package for the storage of biological material, which in use involves filling the package with the biological material and placing it in an apparatus for storing the biological material such that a heat exchange fluid flows around the package. Broadly, the method may include the steps of:

[0127] Typically, the method begins with determining a desired package shape including one or more package walls configured to define an interior compartment so that the package can be filled with a desired volume of biological material. The method also includes determining thermal properties of the biological material, the package material for forming the one or more package walls, and a heat exchange fluid, as well as 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.

[0128] With the package geometry, thermal properties and operating conditions determined, the next step of the method involves performing an analysis of the flow of heat exchange fluid within the apparatus around the filled package according to the determined package geometry, thermal properties and operating conditions to determine the expected temperature gradient in the biological material during use.

[0129] The expected temperature gradient is used 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. The method may then include performing a further analysis of the flow of the heat exchange fluid in the apparatus around the filled package, including the one or more thermal contours, according to the determined package shape, the selected configuration of the one or more thermal contours, the thermal properties and the operating conditions to determine an expected temperature gradient in the biological material during use.

[0130] The steps of constructing a thermal contour and performing further analysis thereon may be optionally repeated iteratively until a desired expected temperature gradient is determined.

[0131] In one example, this method may be advantageously applied to design a preferred embodiment of a packager, wherein the package shape includes opposing first and second walls, the first and second walls connected together around a substantial portion of their respective peripheries to define an interior compartment, and a plurality of thermal contours defined by the first and second walls connected together along connecting lines, the connecting lines configured to divide the interior compartment into sub-compartments enabling fluid communication therebetween.

[0132] In particular, the method may be extended to include performing an analysis of the flow of heat exchange fluid within the apparatus around the filled package and using the expected temperature gradients to select a thermal contour configuration to provide substantially equal heat transfer between the heat exchange fluid and the biological material contained in each sub-compartment.

[0133] In any event, it will be appreciated that the packages for storage of biological material described herein are provided with thermal contours to facilitate improved heat transfer between the heat exchange fluid and the biological material contained in the package, and in particular to avoid problems in conventional packages that experience inconsistent heat transfer resulting in persistent hot spots and the like.

[0134] The thermal contours are used to direct the flow of heat exchange fluid across the package in a more uniform manner, thus providing a more consistent heat transfer. Additionally, in preferred embodiments, the thermal contours match the connections between the walls of the package that effectively divide the package's interior compartment into sub-compartments, and the thermal contours can promote substantially equal heat transfer between the heat exchange fluid and the biological material contained in each of the sub-compartments. In preferred embodiments, the biological material can be substantially evenly distributed between each of the sub-compartments to further regulate the heat transfer and allow for more consistent results.

[0135] Throughout this specification and the claims which follow, unless the context dictates otherwise, the word "comprise" and variations such as "comprises" or "comprising" are understood to mean the inclusion of a stated integer or steps of integers, but not to the exclusion of other integers or steps. As used herein, unless otherwise specified, the term "about" means ±20%.

[0136] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "support" includes a plurality of supports. Throughout this specification and the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

[0137] Of course, while the foregoing has been given as illustrative examples of the present invention, it will be understood that all such and other modifications and variations therein, as will be apparent to those skilled in the art, are deemed to be within the broad scope and scope of the invention as defined herein. [Prior art documents] [Patent documents]

[0138] [Patent Document 1] Australian Patent Publication No. 2009258341 [Patent Document 2] International Publication No. 2020 / 102854 [Non-patent literature]

[0139] [Non-Patent Document 1] Dumont, F., P. A. Marechai, 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 [Non-Patent Document 2] Dumont, F., P. A. Marechai, and P. Gervais. 2004. Cell size and water permeability as determining factors for cell viability after freezing at different cooling rates. Appl. Environ. Microbiol. 70:268-272.

Claims

1. 1. A package for storing biological material, wherein, in use, the package is filled with biological material and placed in an apparatus for storing the biological material such 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 said biological material; b) one or more thermal contours defined across at least one of said package walls; Equipped with In use, the flow of the heat exchange fluid is directed at least in part by one or more of the thermal contours to improve heat transfer between the heat exchange fluid and the biological material contained in the package.

2. 2. The package of claim 1, wherein the package includes a plurality of thermal contours arranged parallel to one another, the thermal contours arranged to substantially align with the flow of the heat exchange fluid in use.

3. Each of the thermal contours extends across a respective one of the package walls, a) an elongated recess in each of said package walls; and b) an elongated protrusion on each of said package walls; The package of claim 1 defined as one of:

4. 10. The package of claim 1, wherein the package walls include opposing first and second walls joined together about a substantial portion of their respective peripheries to define the interior compartment.

5. 5. The package of claim 4, wherein the one or more thermal contours are defined by the first and second walls being connected together along one or more connecting lines, the connecting lines being configured to divide the interior compartment into sub-compartments that allow fluid communication therebetween.

6. 6. The package of claim 5, wherein, in use, the package is filled with biological material such that the biological material is distributed among the sub-compartments, and the flow of the heat exchange fluid is directed at least in part by one or more of the thermal contours to promote substantially uniform heat transfer between the heat exchange fluid and the biological material contained in each of the sub-compartments.

7. 5. The package of claim 4, wherein the first and second walls are connected to each other along a plurality of edges including a leading edge facing the flow of heat transfer fluid in use and an opposite trailing edge, and a plurality of the thermal contours extend between the leading and trailing edges.

8. 8. The package of claim 7, wherein at least some of the connecting lines interconnect with the leading edge.

9. the thermal contour is disposed at an angle relative to a direction normal to the leading edge; a) the predetermined angle is selected according to the flow of a heat exchange fluid in the device for storing biological material; and b) the predetermined angle is: i) Between 0° and 30° ii) between 5° and 15°, and iii) Approximately 10° At least one of The packaging device according to claim 7, wherein the packaging device is at least one of the following:

10. adjacent thermal contours are spaced apart by a predetermined distance; a) the predetermined distance is between 15 mm and 20 mm; b) the predetermined distance is selected to inhibit separation of the first and second walls; and c) the predetermined separation distance is selected to limit the separation of the first and second walls to a predetermined separation distance; The packaging device according to claim 4, wherein the packaging device is at least one of the following:

11. The depth of the package measured between the first and second walls is: a) less than 10 mm; b) less than 5 mm; c) 1 mm or more but less than 4 mm, and d) Less than 1 mm The packaging device according to claim 4, wherein the packaging device is at least one of the following:

12. 5. The package of claim 4, wherein the package is configured such that, in use, when the package is filled with the biological material, the first and second walls remain substantially parallel to one another.

13. The first and second walls are: a) a polymer, b) polypropylene, c) polyvinyl chloride, d) polyethylene terephthalate, e) ethylene vinyl acetate copolymer, f) copolymers, g) ethylene and vinyl acetate; h) metal; i) high alloys, and j) Stainless steel 5. The package of claim 4, formed from a sheet of package material selected from one of:

14. The packaging device a) Preservation of biological material, said biological material being i) whole blood; ii) platelets; iii) red blood cells; iv) white blood cells; v) plasma; vi) blood products; vii) sperm; viii) cells; ix) stem cells; x) organs or parts thereof, and xi) Organization Preservation of biological material, selected from one of b) Preservation of biological materials used in therapeutic treatments; c) cryopreservation of biological materials; d) cryopreservation of biological materials, and e) Thawing of biological material The package of claim 1 configured for at least one of:

15. The packaging device 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) More than 100°C per minute 10. The package of claim 1, configured for use with a heat transfer rate selected from one of:

16. The packaging device a) a bag; b) a straw, and c) Vial The packaging device according to claim 1 , wherein the packaging device is configured as one of the following:

17. 1. A package for storing biological material, wherein, in use, the package is filled with biological material and placed in an apparatus for storing the biological material such that a heat exchange fluid flows around the package, the package comprising: a) first and second opposing walls joined together about a substantial portion of their respective peripheries to define an interior compartment; b) a plurality of thermal contours defined by the first and second walls and connected together along connecting lines, the connecting lines configured to divide the interior compartment into sub-compartments that are capable of fluid communication therebetween; and Equipped with In use, the biological material is distributed between the subcompartments and the flow of heat exchange fluid is directed at least in part by the thermal contour to improve heat transfer between the heat exchange fluid and the biological material contained in the subcompartments of the package.

18. 1. A method for use in designing a package for storing biological material, the method comprising: in use, the package is filled with the biological material and placed in an apparatus for storing the biological material such that a heat exchange fluid flows around the package; the method comprising: a) determining a package shape including one or more package walls configured to define an interior compartment such that the package can be filled with a desired volume of the biological material; b) determining a thermal characteristic, said thermal characteristic comprising: i) biological material; ii) a package material for forming one or more of said package walls; and iii) the heat exchange fluid and c) determining operating conditions for the device, said operating conditions comprising: i) the velocity of the heat exchange fluid; ii) the temperature of the heat exchange fluid, and iii) the flow direction of the heat exchange fluid and d) performing an analysis of the flow of heat exchange fluid within the device around the filled package to determine the expected temperature gradient in the biological material during use according to the determined package geometry, the thermal properties and the operating conditions; e) using the predicted temperature gradient to select one or more thermal contour configurations 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; f) performing a further analysis of the flow of the heat exchange fluid in the device around the filled package, including one or more thermal contours, according to the determined package shape, the selected configuration of one or more thermal contours, the determined thermal properties, and the operating conditions to determine an expected temperature gradient in the biological material during use; A method for providing the above.

19. 20. The method of claim 18, comprising repeating steps e) and f) until a desired expected temperature gradient is determined.

20. 20. The method of claim 19, wherein the package shape includes opposing first and second walls coupled together around a substantial portion of their respective perimeters to define an interior compartment, and wherein a plurality of thermal contours defined by the first and second walls are connected together along connecting lines, the connecting lines configured to divide the interior compartment into sub-compartments that allow fluid communication therebetween, the method comprising: a) performing said analysis of the flow of said heat exchange fluid within said apparatus around said filled package; b) using the expected temperature gradient to select the configuration of the thermal contour to provide substantially uniform heat transfer between the heat exchange fluid and the biological material contained in each of the sub-compartments; A method comprising:

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