EP0960311B1 - Einfrier- und auftaubehälter mit thermischen brücken - Google Patents

Einfrier- und auftaubehälter mit thermischen brücken Download PDF

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Publication number
EP0960311B1
EP0960311B1 EP98906117A EP98906117A EP0960311B1 EP 0960311 B1 EP0960311 B1 EP 0960311B1 EP 98906117 A EP98906117 A EP 98906117A EP 98906117 A EP98906117 A EP 98906117A EP 0960311 B1 EP0960311 B1 EP 0960311B1
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EP
European Patent Office
Prior art keywords
container
thermal transfer
heat
transfer system
medium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP98906117A
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English (en)
French (fr)
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EP0960311A1 (de
Inventor
Richard Wisniewski
Leonidas Cartwright Leonard
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Sartorius Stedim North America Inc
Original Assignee
Integrated Biosystems Inc
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Publication date
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27488434&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP0960311(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US08/895,782 external-priority patent/US6196296B1/en
Application filed by Integrated Biosystems Inc filed Critical Integrated Biosystems Inc
Priority to EP05009933A priority Critical patent/EP1580505A1/de
Publication of EP0960311A1 publication Critical patent/EP0960311A1/de
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Classifications

    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F28—HEAT EXCHANGE IN GENERAL
    • F28D—HEAT-EXCHANGE APPARATUS, NOT PROVIDED FOR IN ANOTHER SUBCLASS, IN WHICH THE HEAT-EXCHANGE MEDIA DO NOT COME INTO DIRECT CONTACT
    • F28D7/00—Heat-exchange apparatus having stationary tubular conduit assemblies for both heat-exchange media, the media being in contact with different sides of a conduit wall
    • F28D7/02—Heat-exchange apparatus having stationary tubular conduit assemblies for both heat-exchange media, the media being in contact with different sides of a conduit wall the conduits being helically coiled
    • F28D7/024—Heat-exchange apparatus having stationary tubular conduit assemblies for both heat-exchange media, the media being in contact with different sides of a conduit wall the conduits being helically coiled the conduits of only one medium being helically coiled tubes, the coils having a cylindrical configuration
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F25—REFRIGERATION OR COOLING; COMBINED HEATING AND REFRIGERATION SYSTEMS; HEAT PUMP SYSTEMS; MANUFACTURE OR STORAGE OF ICE; LIQUEFACTION SOLIDIFICATION OF GASES
    • F25D—REFRIGERATORS; COLD ROOMS; ICE-BOXES; COOLING OR FREEZING APPARATUS NOT OTHERWISE PROVIDED FOR
    • F25D31/00—Other cooling or freezing apparatus
    • F25D31/006—Other cooling or freezing apparatus specially adapted for cooling receptacles, e.g. tanks
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F28—HEAT EXCHANGE IN GENERAL
    • F28D—HEAT-EXCHANGE APPARATUS, NOT PROVIDED FOR IN ANOTHER SUBCLASS, IN WHICH THE HEAT-EXCHANGE MEDIA DO NOT COME INTO DIRECT CONTACT
    • F28D1/00—Heat-exchange apparatus having stationary conduit assemblies for one heat-exchange medium only, the media being in contact with different sides of the conduit wall, in which the other heat-exchange medium is a large body of fluid, e.g. domestic or motor car radiators
    • F28D1/06—Heat-exchange apparatus having stationary conduit assemblies for one heat-exchange medium only, the media being in contact with different sides of the conduit wall, in which the other heat-exchange medium is a large body of fluid, e.g. domestic or motor car radiators with the heat-exchange conduits forming part of, or being attached to, the tank containing the body of fluid
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F28—HEAT EXCHANGE IN GENERAL
    • F28D—HEAT-EXCHANGE APPARATUS, NOT PROVIDED FOR IN ANOTHER SUBCLASS, IN WHICH THE HEAT-EXCHANGE MEDIA DO NOT COME INTO DIRECT CONTACT
    • F28D7/00—Heat-exchange apparatus having stationary tubular conduit assemblies for both heat-exchange media, the media being in contact with different sides of a conduit wall
    • F28D7/10—Heat-exchange apparatus having stationary tubular conduit assemblies for both heat-exchange media, the media being in contact with different sides of a conduit wall the conduits being arranged one within the other, e.g. concentrically
    • F28D7/12—Heat-exchange apparatus having stationary tubular conduit assemblies for both heat-exchange media, the media being in contact with different sides of a conduit wall the conduits being arranged one within the other, e.g. concentrically the surrounding tube being closed at one end, e.g. return type
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F28—HEAT EXCHANGE IN GENERAL
    • F28F—DETAILS OF HEAT-EXCHANGE AND HEAT-TRANSFER APPARATUS, OF GENERAL APPLICATION
    • F28F1/00—Tubular elements; Assemblies of tubular elements
    • F28F1/02—Tubular elements of cross-section which is non-circular
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F28—HEAT EXCHANGE IN GENERAL
    • F28F—DETAILS OF HEAT-EXCHANGE AND HEAT-TRANSFER APPARATUS, OF GENERAL APPLICATION
    • F28F1/00—Tubular elements; Assemblies of tubular elements
    • F28F1/10—Tubular elements and assemblies thereof with means for increasing heat-transfer area, e.g. with fins, with projections, with recesses
    • F28F1/12—Tubular elements and assemblies thereof with means for increasing heat-transfer area, e.g. with fins, with projections, with recesses the means being only outside the tubular element
    • F28F1/14—Tubular elements and assemblies thereof with means for increasing heat-transfer area, e.g. with fins, with projections, with recesses the means being only outside the tubular element and extending longitudinally
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F28—HEAT EXCHANGE IN GENERAL
    • F28D—HEAT-EXCHANGE APPARATUS, NOT PROVIDED FOR IN ANOTHER SUBCLASS, IN WHICH THE HEAT-EXCHANGE MEDIA DO NOT COME INTO DIRECT CONTACT
    • F28D21/00—Heat-exchange apparatus not covered by any of the groups F28D1/00 - F28D20/00
    • F28D2021/0019—Other heat exchangers for particular applications; Heat exchange systems not otherwise provided for
    • F28D2021/0077—Other heat exchangers for particular applications; Heat exchange systems not otherwise provided for for tempering, e.g. with cooling or heating circuits for temperature control of elements

Definitions

  • the present invention relates generally to systems containing structures such as fins to aid in the transfer of heat into or out of a medium. More particularly, the present invention relates to heating and cooling structures which are suited for use in heat, cooling, thawing, and freezing biopharmaceutical products.
  • a container used to heat or cool a medium will have a heat exchange fluid circulated in tubes placed in or around the exterior of the container.
  • a heat exchange fluid circulated in tubes placed in or around the exterior of the container.
  • one or more extensions of the container or any structures in the container may be used to increase the surface area of the system that is in contact with the medium.
  • fins will be attached by one end to a portion of the container or some other structure in the container, and the fins will conduct heat to or from that portion of the container.
  • a fin is typically attached to the container or an internal structure at only one point, all of the heat transferred to or from the fin to the container or an internal structure must enter or leave the fin through the one connection that the fin has with the rest of the system.
  • One configuration that has been used to solve this problem is to build a system in which one or more of the fins are rigidly attached to both the container and an internal structure within the container. This allows heat to be transferred to or from a fin through two portions of the fin, increasing the rate at which heat is put into or withdrawn from a medium placed in the container.
  • What is needed is a system in which heat can be put into or withdrawn from a fin through more than one portion of the fin while the system is operating while enabling structures within the container to be removed to allow for cleaning and decontaminating of the system. Furthermore, what is needed is a system in which it is not required to physically connect or weld the fin to a portion of the container in order for heat to be transferred into or out of a portion of the fin.
  • a structure within the container e.g. a fin
  • fin will be used generically to mean any heat exchange member of the system that extends into the medium, including but not limited to a coil, a flattened protrusion, a tube, or any other structure extending into the container.
  • a particular type of extension of the container is being discussed, such as a coil, the name of the particular type of extension may be used to help clarify the configuration of the system.
  • a biopharmaceutical product thermal transfer system comprising:
  • the structure includes a fin.
  • a distal end of the fin is placed in close proximity to a portion of the container. Since the fin, and the container are not rigidly attached the structure, including the fin, can be removed from the container.
  • a bridge made of the frozen medium will form between the distal end of the fin and the portion of the container close to the distal end of the fin. This bridge will allow heat to be conducted to or from the fin across the bridge speeding the removal of heat form the medium.
  • the fin is at least partially attached to a structure within the container allowing heat to be transferred out of the fin through the attachment point and the thermal bridge when it is formed.
  • the distal end of the fin is placed close enough to another surface of the container, for example, another fin or structure in the container, such that when the medium is cooled, the thermal transport bridge is formed between the fin and the other structure in the container - which may of course be a fin.
  • a first heat exchange member is at least partially coupled to an interior surface of the container.
  • a second heat exchange member at least partially coupled to the structure wherein a portion of the first heat exchange member is placed in close proximity to a portion of the second heat exchange member to aid formation of a thermal transfer bridge that improves conduction of heat into or out of the medium.
  • the structure and the second heat exchange member can be removed from the system to aid in cleaning since they are not rigidly attached to the container or the first heat exchange member.
  • Yet another embodiment of the invention comprises a heat exchange member which is at least partially coupled to an interior surface of the container wherein a distal end of the heat exchange member is placed in close proximity to the structure to allow formation of a thermal transfer bridge that conducts heat out of the medium.
  • the structure can be removed from the container.
  • the present invention is useful for the cooling of a medium.
  • the thermal bridges help transfer heat out of the medium.
  • the medium can also be a gas being converted to a liquid or a liquid being converted to a gas. In these cases the liquid phase of the medium that collects between the fin and the structure will act as the thermal bridge to enhance the conduction of heat between the fin and the structure.
  • the fin can have structures on it which will enhance the formation of solid or liquid thermal bridges and/or enhance the heat conduction through such bridges. For example, a portion of the fin may be enlarged to provide more surface area for conduction and contact with a thermal bridge or the fin may be tailored to enhance nucleation of the solid or condensation of the liquid. Also, a fin may have a non-uniform cross-section to enhance thermal transport to achieve desired thermal transport characteristics. This may be desirable to help achieve cryobiology protocols. Furthermore, the fin can have interior channels that allow a heat exchange medium to flow within at least a portion of the fin. Other variations are possible without departing from the scope of the invention.
  • the system may be configured so that a cooling device is coupled to any portion of the container.
  • a cooling device could be attached to an exterior portion of the container (e.g. a wall of the container), to an internal structure of the container, or directly to one or more of the fins.
  • the system should be constructed such that the distance to be bridged by the thermal transport bridge will be a function of the thermal properties of the medium and the system, manufacturing requirements and construction processes used to build the system, and other relevant paramenters of the system and components used.
  • the size of the gap to be filled by the bridge can be determined through simple trial and error.
  • the fins may be structures of any shape which are placed against or wedged between surfaces in the container. Thermal bridges will then form between the fins and the adjacent surface or surfaces of the container.
  • the fins can have ends adapted to fit in preconfigured slots in surfaces of the container. In this way the fins can be reconfigurable attached to portions of the container so that the number, configuration, and type of the fins used can be easily changed to meet changing manufacturing, process, or protocol needs.
  • the optimum gap is proportional to the thickness of the fin. In another aspect of the present invention, the optimum gap is less than 0.0508m (2 inches), preferably less than 0.0254m (1 inch), more preferably less than 0.0127m (1/2 inch), even more preferably less than 0.00635m (1/4 inch), and most preferably less than 0.00318m than (1/8 inch).
  • the container can be porous and need not have a top or a bottom.
  • the medium can be cooled as it passes through the container.
  • the container used in the present invention is not limited in shape, size or material from which it is constructed. In one aspect of the present invention, the container may have a volume of 1 liter to 5 liters, 1 liter to 250 liters, or 250 to 10,000 liters.
  • the present invention can be usefully applied in many fields.
  • the present invention can be used to freeze and preserve a variety of biopharmaceutical products, including but not limited to proteins, cells, antibodies, medicines, plasma, blood, buffer solutions, viruses, serum, cell fragments, cellular components, and any other biopharmaceutical product.
  • the present invention allows processing of such biopharmaceutical products consistent with generally accepted manufacturing procedures.
  • the present invention promotes uniform freezing at a rapid pace which allows the product in the container to be frozen in as close to its native state as possible. Additionally, the present invention allows the freezing process to be done in a repeatable fashion so that a user can be assured that the freezing process is not causing batch to batch variations in the product. This allows the end use of the product to be decoupled from the manufacturing steps needed to create the product since the product can be stored in the frozen state after it is manufactured, and thawed when and where it is needed.
  • the present invention can also be used during any stage of a purification process. For example, after products are processed using size separation or affinity separation, fermentation, licing, concentration filtration, selective affinity chromatography, removal of micro contaminants or low level impurities through ion exchange, viral filtration, chromatography, putting the product in a buffered solution delivery system, or after any other processing step the resulting product can be stored using the present invention. This allows a hold to be put on the manufacturing process without degrading the intermediate product.
  • the present invention can be used to freeze the intermediate product quickly and uniformly enough so that the product remains close to its native state.
  • the molecules in the product are not brought significantly closer together--freeze concentration is reduced, and unwanted reactions can be slowed or stopped.
  • the present invention can be used to increase the flexibility of a manufacturing process, making planning and scheduling of the process easier. Intermediate products can be frozen for later processing or shipping. Additionally, since the present invention can be scaled to any size desired, large batches of products can be prepared all at once, preserved using the present invention, and used as needed at a later time.
  • Heating and cooling system 2 is comprised of container 4, fins 6 and structure 8. Fins 6 are configured such that they are placed in close proximity to interior surface 10 of container 4. Generally, a small gap between fin 6 and interior surface 10 is preferable. However, the size of this gap may be dictated by manufacturing tolerances, material parameters, or other practical considerations.
  • Figure 2 shows a cutaway top view of container 4, fins 6 and structure 8.
  • Any arrangement design, configuration, or number of fins could be used without departing from the present invention.
  • the fins need not be symmetrically positioned within the container, they need not be the same shape and they need not be made of the same material.
  • structure 8 is heated or cooled by flowing a heat exchange fluid down interior passage 12 towards end piece 14.
  • the heat exchange fluid then flows up through the outer passage 16 of structure 8.
  • This flow pattern of the heat exchange fluid and the symmetric configuration of the fins about structure 8 aids system 2 to begin cooling the medium in the container from the bottom up. This is so because the heat exchange fluid is first closely coupled to the medium in the container and the fins at the bottom of the container.
  • Cooling the medium from the bottom up is particularly advantageous when a liquid medium is being frozen and, as is true for water, the density of the frozen medium is less than that if the liquid phase. Freezing from the bottom up prevents pressure from building up as might be the case if the liquid phase was constrained by the solid phase.
  • End piece 14 has bottom fin 30 attached to it.
  • Bottom fin 30 functions the same as fins 6.
  • a thermal transport bridge is formed between bottom fin 30 and a portion of interior surface 10.
  • taper 19 on fin 6 helps to slow the formation of a thermal bridge on the upper portion of fin 6. This will slightly slow the heat transfer out of the upper portion of the container, allowing the system to freeze the medium from the bottom up.
  • a taper can be used on any portion of the fin to help create a preferred direction for removal of heat from the container.
  • Container 4 has jacket 20 surrounding its circumference. Between exterior surface 18 of container 4 and jacket 20 is fluid flow path 22. Spiral baffle 24 corkscrews around container 4 between exterior surface 18 and jacket 20 forcing heat exchange fluid in fluid flow path 22 to flow in a spiraling path around the exterior surface 18 of container 4. Heat exchange fluid flows into fluid flow path 22 through port 26 and out through port 28 resulting in the heat exchange fluid flowing around container 4 from the bottom to the top. This flow pattern for the heat exchange fluid aids system 2 in cooling the medium in the container from the bottom up.
  • the heat exchange fluid can be flowed through the system at other points and in a time or process varying manner in order to tailor the timing, direction, and rate of heat flow into or out of the system.
  • materials used in, or the shape, or configuration of the system, including the fins can be used to control parameters of the heating or cooling process such as rate, timing or directionality.
  • the medium in the container begins to cool.
  • the medium is sufficiently cooled, a portion of the medium between the distal end of fins 6 and interior surface 10 will freeze. This frozen bridge will allow heat to be conducted between fins 6 and container 4 through the frozen bridge. This will enable heat to be taken out of the medium at a higher rate, speeding the freezing of the medium in the container.
  • the present invention will work with any type of medium including but not limited to biopharmaceutical products.
  • Figure 3 illustrates the formation of thermal bridges in accordance with one aspect of the present invention.
  • Figure 3a is a top view of one embodiment of the present invention in which structure 31 has 8 fins 32 attached to it. Each fin 32 extends close to interior surface 33 of container 34.
  • Figure 3b illustrates a simulation for the system shortly after thermal bridges 35 have begun to form.
  • the material properties of 315 stainless steel were used for the container and the fins, and the coolant temperature was -45 °C.
  • the temperature of the liquid was -0.2 °C
  • the temperature of the fin in contact with the liquid was close to -0.2 °C
  • the temperature of the portion of the fin in contact with the frozen product was declining toward the temperature of the wall.
  • the temperature of the wall was within 2-5 °C of the temperature of the coolant.
  • FIG. 3b depicts the temperature profile of the medium within the compartments 36 formed by fins 32. As shown in the graphs in figure 3c, heat is withdrawn from the medium within the cavity through interior container wall 33, structure 31 and fins 32.
  • the relative uniformity with which the present invention allows heat to be removed from the medium promotes the growth of dendritic structures during the freezing process.
  • the present invention by allowing heat to be removed from both ends of a fin, helps to create a uniform temperature profile within the container.
  • the fins can be positioned to effectively segment the container into a plurality of smaller volumes, so that heat can be more uniformly removed from each segmented section.
  • figure 2 shows container 4 segmented into 6 section by the fins.
  • the present invention can be used to achieve dendritic ice growth even if fins are rigidly attached at more than one point to the system. Fins can be used to segment the container into small regions which can be more uniformly heated and cooled.
  • Dendritic ice growth is particularly useful many areas, including but not limited to the cryopreservation of biopharmaceutical products.
  • surface 501 which could be any surface of the present invention
  • dendrites 502 will form and grow moving away form surface 501.
  • the substance 503 in the medium being frozen and will eventually become surrounded by dendrites 502.
  • substance 503 will eventually become trapped in the frozen medium 504.
  • the growth rate of dendrites 502 can be controlled. Controlling the growth rate of dendrites 502 allows the present invention to be used to control the amount of liquid removed from substance 503 as it enters and becomes trapped by growing dendritic front 505.
  • substance 503 can be any substance one desires to preserve.
  • coolant can be circulated through any part of the system, only one part of the system, or coolant need not be used and the system could be cooled by other means or indirectly or passively.
  • removable liners can be placed over the distal ends of fins 6 to prevent them from contacting interior surface 10 when structure 8 and fins 6 are inserted or removed from container 4. This may be desired, for example, to avoid scratching interior surface 10 with fins 6 during assembly and disassembly.
  • fins 39 may be partially coupled to interior container wall 41 and the distal end of each fin can be place in close proximity to structure 37 such that the thermal bridge is formed between a distal end of each of fins 39 and structure 37.
  • fins 40 are attached to interior surface 42. Fins 44 are attached to structure 46.
  • System 38 is constructed such that portions of fins 40 and fins 44 are in contact, nearly in contact or can be rotated such that this is the case. Then, when the medium in the container freezes, thermal transport bridges will form between portions of fins 40 and fins 44.
  • fins 40 and 44 need not be parallel. Fins 40 and 44 can be angled with respect to each other such that gap 45 varies along the length of fins 40 and 44.
  • FIG. 6 depicts a number of possible arrangements of fins.
  • fin 48A may be partially coupled to structure 50A and a distal end placed in close proximity to another structure, 50B, such that the thermal bridge is formed between the distal end of fin 48A and structure 50B
  • Fins 54 are coupled to interior wall 56.
  • a distal end of fin 54A is placed near distal ends of fins 58, and fins 58 are coupled to structures 50.
  • a thermal bridge will form between the distal ends of fins 54A, 58A and 58B.
  • a thermal bridge can be formed between more than two fins. Forming a thermal bridge between two or more fins may be desirable if, for example, design constraints or other constraints require portions of the container to be held a distance from an actively cooled surface.
  • a fin and thermal bridge can be used to help extract heat from the isolated structure.
  • FIG. 7 depicts a number of other possible arrangements of fins.
  • a fin can be configured so that the thermal bridge is formed not between the distal ends of two fins but between the distal end of one fin and some other portion of another fin.
  • fin 60 will form a thermal bridge with fin 62 at a central portion of fin 60
  • fin 64 will form a thermal bridge with fin 66 at a central portion of fin 64.
  • a fin need not be initially coupled to anything and thermal transport bridges may be formed between portions of the fin and other portion of the system.
  • fin 68 is not rigidly attached to any structure within the container, but it will form a thermal bridge with fins 64 and 70 and structures 72.
  • fins may have structures on them to aid in the formation of thermal transport bridges or to enhance the thermal transport capabilities of the bridges.
  • Fins 62 have extended surfaces 76 on their distal ends. Extended surface 76 will allow a wider thermal bridge to be formed, improving the heat transfer rate of the bridge. This may be desirable in certain circumstances. For example, the thermal transport properties of the fin material may be superior to those of the frozen material that forms the thermal bridge. Increasing the area of the thermal bridge will improve its total heat transfer properties.
  • extended surface 78 may be used to enhance the formation of a thermal bridge with fin 62 whether or not extended surface 76 is attached to fin 62.
  • FIG 8 shows another embodiment of the present invention. This embodiment details another configuration of fins in accordance with the present invention.
  • fins 80 are connected to structure 81 and will form thermal bridges with structures 82.
  • Fins 83 are connected to structures 82 and will form thermal bridges with interior container wall 84.
  • Fins 85 will form thermal bridges with each other, and fins 86 will form thermal bridges with interior container wall 84
  • FIG. 9 shows yet another embodiment of the present invention.
  • Fin 87 has a non-uniform cross section along its length. Fin 87 is thicker at end 88 where it connects to structure 89 and thinner in its central portion. The fin then widens out at its distal end 90 where it is in close proximity to interior surface 91 A thermal bridge will form between distal end 90 and interior surface 91. The thicker base of the fin will allow more heat flux to be withdrawn from the fin at end 88 and distal end 90.
  • FIG. 10 shows still another embodiment of the present invention.
  • Fins 92 are attached to structure 93 and will form thermal bridges with container wall 94.
  • Fins 92 are curved to form compartments 95. Compartmentalization of the container allows more uniform cooling to be achieved since the distance from any point in the medium to a cooled surface is reduced. Also, the reduction in distance between cooled surfaces can be used to decrease the time required to freeze a medium.
  • Other fins such as fins 96 may be added to further compartmentalize compartments 95.
  • Fins 97 can also be used to form thermal bridges with another structure 98.
  • FIG 11 shows another embodiment of the present invention.
  • fins 102 have interior passageways 104. Heat exchange fluid flows into interior passageways 104 through openings 106 in structure 108.
  • Fins 102 may have dimples 110 or spacers 114 or turbulizers to help optimize the flow pattern 118 of the heat exchange fluid. Dimples or spacers help optimize the flow pattern 118 of the heat exchange fluid for reasons including, increasing the interior surface area of the fin which comes in contact with the heat exchange fluid, and giving the heat exchange fluid more time to absorb heat from the fins. This speeds the freezing process and allows converging of the dendrites more quickly.
  • fins 102 may have extensions 120 on them. As shown in Figure 12a, heat exchange fluid does not flow within extensions 120. Extensions 120 are connected to fins 102 and extend close to interior surface 122 of container 124. Figure 12b shows a detail view of fin 102, extension 120 and interior surface 122. Figure 12c shows a detail view of another embodiment of the present invention in which there is no extension placed on the end of fin 102.
  • thermal transfer bridge 126 will begin to form between interior surface 122 and extension 120.
  • thermal transfer bridge will begin to form between fin 102 and interior surface 122.
  • FIG. 13 shows yet another embodiment of the present invention.
  • the heat exchange fluid flows into and out of fins 202 through tubes 204 connected to the top 206 of fins 202.
  • the fins are not connected to a central structure.
  • thermal transfer bridges 208 will form between the fins 202 and the interior surface 210 and between interior portions 212 of fins 202.
  • Figure 14a depicts yet another embodiment of the present invention.
  • system 300 has internal fins 304 which are attached to structure 306.
  • Heat exchange fluid flows through structure 306.
  • the flow of the heat exchange fluid can be configured to be similar to the flow described for structure 8 in figure 1. Any other flow configuration can be used to achieve a desired cooling or heating rate. Additionally, heat exchange fluid may be flowed through interior fins 304 if desired.
  • Coil 308 is placed in a surrounding relationship to interior fins 304. Heat exchange fluid flows into coil 308 through input 310 and flows out through output 312. Exterior fins 314 are placed between coil 308 and interior surface 316 of container 302. In one aspect of this embodiment, exterior fins can be free standing, attached to coil 308 or attached to interior surface 316. In another aspect of this embodiment, heat exchange fluid can be flowed through exterior fins 314 through coil 308, interior surface 316, external inputs, or any other supply.
  • thermal transport bridges are formed between interior fins 304 and coil 308, coil 308 and external fins 314, external fins 314 and interior surface 316, and the coils of coil 308.
  • FIG 14b show a top view of system 300.
  • fins 314 are depicted as not being attached to coil 308. Fins 314 could be suspended by supports from the top or bottom of container 302 or fins 314 could be free standing.
  • Figure 15 depicts still another embodiment of the present invention.
  • system 400 has internal fins 402 attached to structure 404 and first coil 406 surrounding internal fins 402.
  • Middle fins 408 are placed around first coil 406 and second coil 410 surrounds middle fins 408.
  • Exterior fins 412 are placed between second coil 410 and interior surface 414.
  • First and second coils 406 and 410 receive heat exchange fluid through input 416 and 418 respectively and the heat exchange fluid flows out through outputs 420 and 422 respectively.
  • Figure 15b shows a top view of this embodiment.
  • fins 408 and 412 are depicted as freely suspended.
  • Thermal transport bridges will form between internal fins 402 and first coil 406, the coils of first coil 406, first coil 406 and middle fins 408, middle fins 408 and second coil 410, the coils of second coil 410, second coil 410 and exterior fins 412, and exterior fins 412 and interior surface 414.
  • Figure 15c shows a detail side view of the formation of the thermal transport bridges 424 between the coils of one of first coil 406 or second coil 410, and the thermal transport bridges 426 formed between the coils and fins, interior fins middle fins or exterior fins.
  • Distances X 1 and X2 can be optimized as desired as a function of the properties of the fins the coil the medium and the container.
  • the Figure 15d shows a top view of the formation of the thermal bridges depicted in figure 15c.
  • FIGs 16 show other possible configurations of coils consistent with the present invention.
  • central pipe 602 has a round cross section. Cooling fluid flows through the interior of pipe 602. Central pipe 602 is adjacent to and will form a thermal bridge with fin 604. Pipe 606 also has cooling fluid flowing through it, and it is adjacent to the other end of fin 604. Pipe 606 has a non-circular cross-section. Any cross-section pipe can be used consistent with the present invention.
  • a non-circular cross-section pipe 608 is show in a different orientation with respect to the adjacent fins.
  • Figure 17 shows non-circular cross-section pipes used in a system.
  • the angle formed between two adjacent fins is small and therefore the non-circular cross section pipes 610 are oriented so that they can be placed closer together.
  • One advantage of using non-circular cross-section pipes is that the elongated surface area of non-circular pipes 610 allows for a longer portion of the interface between compartments 612 to be cooled by a pipe with a cooling medium flowing through it.
  • Figure 17b shows non-circular cross-section pipe 614 used in a different orientation from that in Figure 17a.
  • the angle formed by adjacent fins is larger and therefore non-circular cross-section pipes 614 can be used in the orientation shown.
  • non-circular cross-section pipes 614 protrude into the adjacent compartments and advantageously help to more uniformly cool the medium within the compartments.
  • Figure 18 shows another configuration of pipes and fins that is consistent with the present invention.
  • the non-circular cross-section pipes 702 have fins 704 welded onto them.
  • Figures 19 show yet another example of the use of non-circular cross-section fins consistent with the present invention.
  • a non-circular cross-section pipe 802 is wound into a coil, similar to coil 308 of figure 14a.
  • Non-circular cross-section pipe 802 has extended flat side 804 adjacent to fins 806.
  • Extended flat side 804 makes it easier for thermal bridges to form between coil 808 formed by pipes 802 and fins 806, and between pipes 802 of coil 808.
  • Figure 19b shows pipes 810 of a different cross-section which also advantageously aid in the formation of thermal bridges.
  • Non-circular cross-section pipes 802 or 810 allow fins 806 or fins 812 to be closer together for a given internal pipe cross-sectional area when compared to a circular pipe. Since the fins are closer together, thermal bridges will form more quickly, speeding up the freezing process and keeping it more uniform.
  • Figure 20 details yet another possible configuration of non-circular cross-section pipes 902 and fins 904.
  • the geometry shown can be used to compartmentalize large volume tanks.
  • the compartments thus formed can be made as small as is needed in order to achieve a desired level of uniformity.
  • the present invention can be usefully applied in many fields.
  • the present invention can be used to freeze and preserve a variety of biopharmaceutical products, including but not limited to proteins, cells, antibodies, medicines, plasma, blood, buffer solutions, viruses, serum, cell fragments, cellular components, and any other biopharmaceutical product.
  • the present invention allows processing of such biopharmaceutical products consistent with generally accepted manufacturing procedures.
  • the present invention promotes uniform freezing at a rapid pace which allows the product in the container to be frozen in as close to its native state as possible. Additionally, the present invention allows the freezing process to be done in a repeatable fashion so that a user can be assured that the freezing process is not causing batch to batch variations in the product. This allows the end use of the product to be decoupled from the manufacturing steps needed to create the product since the product can be stored in the frozen state after it is manufactured, and thawed when and where it is needed.
  • the present invention can also be used during any stage of a purification process. For example, after products are processed using size separation or affinity separation, fermentation, licing, concentration filtration, selective affinity chromatography, removal of micro contaminants or low level impurities through ion exchange, viral filtration, chromatography, putting the product in a buffered solution delivery system, or after any other processing step the resulting product can be stored using the present invention. This allows a hold to be put on the manufacturing process without degrading the intermediate product.
  • the present invention can be used to freeze the intermediate product quickly and uniformly enough so that the product remains close to its native state.
  • the molecules in the product are not brought significantly closer together--freeze concentration is reduced, and unwanted reactions can be slowed or stopped.

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  • Physical Or Chemical Processes And Apparatus (AREA)

Claims (52)

  1. System zur Temperaturübertragung für ein biopharmazeutisches Produkt mit
       einem Behälter (4, 34, 302), der dazu geeignet ist, ein Medium aufzunehmen, das ein biopharmazeutisches Produkt enthält,
       einer Wärmeaustauscherstruktur (6, 8; 31, 33; 37, 39; 40, 44, 46; 50A, 50B, 50C, 58A, 54A, 54B, 54C; 60, 62, 64, 66, 68, 70, 72; 82, 83; 87, 89; 92, 93; 102, 120; 314; 412), die in dem Behälter so angeordnet ist, daß die Struktur einen von dem Behälter begrenzten Raum in eine Vielzahl von Kompartimenten unterteilt, wobei der Behälter und die Struktur so angeordnet sind, daß ein distales Ende der Struktur in unmittelbarer Nähe einer inneren Oberfläche des Behälters (33; 41; 42; 84; 91; 94; 122; 316; 414) ist, so daß bei der Verwendung in einem Zwischenraum zwischen dem distalen Ende der Struktur und der inneren Oberfläche des Behälters durch das Medium eine gefrorene und/oder flüssige Temperaturübertragungsbrücke ausgebildet wird, wobei als Reaktion darauf, daß die innere Oberfläche aktiv gekühlt wird, über die Temperaturübertragungsbrücke Wärme von dem distalen Ende der Struktur zu der inneren Oberfläche übertragen wird.
  2. System zur Temperaturübertragung nach Anspruch 1 mit
    einer Vielzahl von Wärmeaustauscherstrukturen in dem Behälter.
  3. System zur Temperaturübertragung nach Anspruch 1 oder Anspruch 2, wobei
       ein Abstand zwischen dem distalen Ende der Wärmeaustauscherstruktur und der inneren Oberfläche des Behälters nicht größer als 0,0254 m (ein Inch) ist.
  4. System zur Temperaturübertragung nach einem der Ansprüche 1 bis 3, wobei
       die Wärmeaustauscherstruktur so aufgebaut ist, daß sie einen Bereich einer Oberfläche der Struktur, der in Kontakt mit dem Medium steht, maximiert.
  5. System zur Temperaturübertragung nach Anspruch 1, wobei
       die Wärmeaustauscherstruktur ein oder mehrere Wärmeaustauscherelemente aufweist und wobei ein distales Ende des Wärmeaustauscherelements in unmittelbarer Nähe zu der inneren Oberfläche des Behälters angeordnet ist, so daß in einem Zwischenraum zwischen dem Wärmeübertragungselement und der inneren Oberfläche des Behälters durch das Medium eine Temperaturübertragungsbrücke ausgebildet wird und Wärme aus dem Medium durch die Temperaturbrücke übertragen wird.
  6. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei
       eine Kühlvorrichtung mit der in dem Behälter angeordneten Wärmeaustauscherstruktur verbunden ist und für deren Kühlung sorgt.
  7. System zur Temperaturübertragung nach Anspruch 6, wobei
       die Kühlvorrichtung Gänge in der Struktur umfaßt, durch welche während der Anwendung Wärmeaustauscherfluid fließt, um eine Kühlung des Mediums zu bewirken.
  8. System zur Temperaturübertragung nach einem der Ansprüche 5 bis 7, wobei
       eine Wärmeaustauscherfluid durch einen äußeren Durchgang in der Struktur aus der Struktur heraus fließt, wobei ein Teil des äußeren Durchgangs eine äußere Wand der Struktur umfaßt.
  9. System zur Temperaturübertragung nach einem der Ansprüche 5 bis 8, wobei
       ein innerer Teil der Struktur, der in den Behälter hineinragt, Ablenkmittel aufweist.
  10. System zur Temperaturübertragung nach einem der Ansprüche 5 bis 9, wobei
       eine Wärmeaustauscherfluid aus der Struktur in das Wärmeaustauscherelement fließt.
  11. System zur Temperaturübertragung nach einem der Ansprüche 5 bis 10, wobei
       eine Wärmeaustauscherfluid aus einer Wärmeaustauscherzuleitung in das Wärmeaustauscherlement fließt.
  12. System zur Temperaturübertragung nach einem der Ansprüche 5 bis 11, wobei
       ein Wärmeaustauscherfluidsfluß nicht durch das distale Ende des Wärmeübertragungselements fließt.
  13. System zur Temperaturübertragung nach einem der Ansprüche 5 bis 12, wobei
       das Medium gekühlt ist, so daß in dem Medium ein thermischer Gradient in einer vorbestimmten Richtung ausgebildet wird.
  14. System zur Temperaturübertragung nach Anspruch 1, wobei
       ein Wärmeübertragungselement wenigstens teilweise mit einer inneren Oberfläche eines Behälters verbunden ist, und wobei ein distales Ende des Wärmeübertragungselements in unmittelbarer Nähe zu der Struktur angeordnet ist, so daß eine von dem Medium in einem Zwischenraum zwischen dem distalen Ende des Wärmeübertragungselements und der Struktur ausgebildete Temperaturübertragungsbrücke Wärme aus dem Medium leitet.
  15. System zur Temperaturübertragung nach Anspruch 14 mit
       einer mit dem Wärmeübertragungselement verbundenen und bei der Verwendung für deren Kühlung sorgenden Kühlvorrichtung.
  16. System zur Temperaturübertragung nach Anspruch 14 oder Anspruch 15, wobei
       das Wärmeübertragungselement so aufgebaut ist, daß es einen Bereich einer Oberfläche des Wärmeübertragungselements, der mit dem Medium in Kontakt tritt, maximiert.
  17. System zur Temperaturübertragung nach einem der Ansprüche 14 bis 16, wobei
       das Wärmeübertragungselement wenigstens teilweise mit einem Boden des Behälters verbunden ist.
  18. System zur Temperaturübertragung nach Anspruch 1, wobei
       ein erstes Wärmeübertragungselement wenigstens teilweise mit einer inneren Oberfläche eines Behälters verbunden ist und
       ein zweites Wärmeübertragungselement wenigstens teilweise mit einer Struktur verbunden ist und wobei ein Teil des ersten Wärmeübertragungselements in unmittelbarer Nähe zu einem Teil des zweiten Wärmeübertragungselements angeordnet ist, so daß eine in einem Zwischenraum zwischen dem ersten Wärmeübertragungselement und dem zweiten Wärmeübertragungselement durch das Medium ausgebildete Temperaturübertragungsbrücke die Wärmeleitung in das oder aus dem Medium heraus verbessert.
  19. System zur Temperaturübertragung nach Anspruch 18, wobei
       eine Kühlvorrichtung mit der in dem Behälter angeordneten Struktur verbunden ist und für deren Kühlung sorgt.
  20. System zur Temperaturübertragung nach Anspruch 18 oder Anspruch 19 zusätzlich mit
       einer entfernbaren Zwischenlage, die so aufgebaut ist, daß sie wenigstens einen Teil des ersten Wärmeübertragungselements abdeckt.
  21. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 20 zusätzlich mit
       einer entfernbaren Zwischenlage, die so konfiguriert ist, daß sie wenigstens einen Teil des zweiten Wärmeübertragungselements abdeckt.
  22. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 21 zusätzlich mit
       einer entfernbaren Zwischenlage, die so konfiguriert ist, daß sie wenigstens einen Teil des ersten Wärmeübertragungselements und des zweiten Wärmeübertragungselements abdeckt.
  23. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 22, wobei
       ein Abstand zwischen dem distalen Ende des ersten Wärmeübertragungselements und einem distalen Ende des zweiten Wärmeübertragungselements nicht größer als 0,0254 m (ein Inch) ist.
  24. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 23, wobei
       der Behälter eine Hülle umfaßt, der einen zwischen der Hülle und einer Wand des Behälters angeordneten Zwischenbereich zur Aufnahme eines Kühlfluidflusses begrenzt, wobei die Hülle des weiteren eine Vielzahl von spiralförmigen Ablenkmitteln für die Verbesserung des thermischen Austauschs zwischen dem Fluid und dem Behälter aufweist.
  25. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 24, wobei
       das zweite Wärmeübertragungselement an einem Ende der Struktur angeordnet ist.
  26. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 25, wobei
       eine Wärmeaustauscherfluid in dem ersten Wärmeübertragungselement fließt.
  27. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 26, wobei
       ein innerer Teil des ersten Wärmeübertragungselements Ablenkmittel aufweist.
  28. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 27, wobei
       das erste Wärmeübertragungselement so konfiguriert ist, daß es einen Bereich einer Oberfläche des Wärmeübertragungselements, der mit dem Medium in Kontakt steht, maximiert.
  29. System zur Temperaturübertragung nach einem der Ansprüche 18 bis 28, wobei
       eine Wänneaustauscherverlängerung wenigstens teilweise mit dem ersten Wärmeübertragungselement verbunden ist.
  30. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche mit
       einer Kühlvorrichtung, die mit dem Behälter verbunden ist und für dessen Kühlung sorgt.
  31. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche mit
    einer Kühlvorrichtung, die mit der Struktur verbunden ist und für deren Kühlung sorgt.
  32. System zur Temperaturübertragung nach Anspruch 31 mit
    einer Kühlvorrichtung, die mit dem Behälter und der Struktur verbunden ist und für deren Kühlung sorgt.
  33. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche mit
    einer entfernbaren Zwischenlage, die so aufgebaut ist, daß sie wenigstens einen Teil der Struktur abdeckt.
  34. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei
    ein Volumen des Behälters in dem Bereich von im wesentlichen 1 Liter bis 250 Liter liegt.
  35. System zur Temperaturübertragung nach einem der Ansprüche 1 - 33, wobei
    ein Volumen des Behälters in dem Bereich von im wesentlichen 250 Liter bis 10.000 Liter liegt.
  36. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei
       der Behälter eine Hülle umfaßt, die einen zwischen der Hülle und einer Wand des Behälters angeordneten Zwischenbereich zur Aufnahme eines Wärmeaustauscherfluidflusses begrenzt, wobei die Hülle des weiteren eine Vielzahl von spiralförmigen Ablenkmitteln zur Verbesserung des thermischen Austauschs zwischen dem Wärmeaustauscherfluid und dem Behälter umfaßt.
  37. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei
       eine Wärmeaustauscherfluid in der Struktur fließt.
  38. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei
       ein innerer Teil der Struktur Ablenkmittel aufweist.
  39. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wo bei
    das Medium so gekühlt wird, daß ein thermischer Gradient in einer vorbestimmten Richtung ausgebildet wird.
  40. System zur Temperaturübertragung nach Anspruch 39, wobei
       das Medium so gekühlt wird, daß ein thermischer Gradient in einer vorbestimmten Richtung ausgebildet wird und die Kühlung in einer vorbestimmten Rate erfolgt.
  41. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei
       das Medium Proteine umfaßt.
  42. System zur Temperaturübertragung nach einem der Ansprüche 5, 14 oder 18, wobei
    eine Wärmeaustauscherfluid in dem Wärmeübertragungselement fließt.
  43. System zur Temperaturübertragung nach einem der Ansprüche 5, 14 oder 18, wobei
    ein innerer Teil des Wärmeübertragungselements Ablenkmittel aufweist.
  44. System zur Temperaturübertragung nach einem der Ansprüche 5, 14 oder 18, wobei
    es eine Vielzahl von Wärmeübertragungselementen aufweist.
  45. System zur Temperaturübertragung nach einem der Ansprüche 5, 14 oder 18, wobei
       ein Abstand zwischen dem distalen Ende des Wärmeübertragungselements und der inneren Oberfläche des Behälters nicht größer als 0,0254 m (ein Inch) ist.
  46. System zur Temperaturübertragung nach einem der Ansprüche 5, 14 oder 18 mit
       einer entfernbaren Zwischenlage, die so aufgebaut ist, daß sie wenigstens einen Teil des Wärmeübertragungselements abdeckt.
  47. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei
       das System ein Gefriersystem ist, um das Einfrieren des Mediums zu bewirken.
  48. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei
    die Struktur von dem Behälter abtrennbar ist.
  49. System zur Temperaturübertragung nach einem der vorangegangenen Ansprüche, wobei die Wärme durch einen oder mehrere Teile der Struktur in das oder aus dem Medium übertragen werden kann.
  50. Verfahren zur Kühlung eines biopharmazeutischen Produkts, wobei man bei dem Verfahren
       einen Behälter mit einer Wärmeaustauscherstruktur bereitstellt, die darin so angeordnet ist, däß die Struktur einen von dem Behälter begrenzten Raum in eine Vielzahl von Kompartimenten unterteilt, wobei der Behälter und die Struktur so angeordnet sind, daß ein distales Ende der Struktur in unmittelbarer Nähe zu einer inneren Oberfläche des Behälters liegt,
    ein Medium in dem Behälter bereitstellt, das ein biopharmazeutisches Produkt umfaßt,    und
    die innere Oberfläche aktiv kühlt, so daß in einem Zwischenraum zwischen dem distalen Ende der Struktur und der inneren Oberfläche des Behälters durch das Medium eine gefrorene und/oder eine flüssige Temperaturübertragungsbrücke ausgebildet wird, wobei über die Temperaturübertragungsbrücke Wärme von dem distalen Ende der Struktur auf die innere Wand übertragen wird.
  51. Verfahren nach Anspruch 50, wobei die Wärmeaustauscherstruktur ein oder mehrere Wärmeübertragungselemente aufweist, und wobei ein distales Ende des Wärmeübertragungselements in unmittelbarer Nähe zu einer inneren Oberfläche des Behälters so angeordnet ist, daß in einem Zwischenraum zwischen dem Wärmeübertragungselement und der inneren Oberfläche des Behälters durch das Medium eine Temperaturübertragungsbrücke ausgebildet wird und Wärme über die Temperaturübertragungsbrücke aus dem Medium übertragen wird.
  52. Verfahren nach Anspruch 50, wobei das Wärmeübertragungselement wenigstens teilweise mit einer inneren Oberfläche des Behälters verbunden ist und wobei ein distales Ende des Wärmeübertragungselements in unmittelbarer Nähe zu der Struktur angeordnet ist, so daß eine in einem Zwischenraum zwischen dem distalen Ende des Wärmeübertragungselements und der Struktur durch das Medium ausgebildete Temperaturübertragungsbrücke Wärme aus dem Medium heraus leitet.
EP98906117A 1997-02-04 1998-02-04 Einfrier- und auftaubehälter mit thermischen brücken Expired - Lifetime EP0960311B1 (de)

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US895782 1992-06-09
US3728397P 1997-02-04 1997-02-04
US37283P 1997-02-04
US89593697A 1997-07-17 1997-07-17
US89577797A 1997-07-17 1997-07-17
US895936 1997-07-17
US895777 1997-07-17
US08/895,782 US6196296B1 (en) 1997-02-04 1997-07-17 Freezing and thawing vessel with thermal bridge formed between container and heat exchange member
PCT/US1998/002065 WO1998034078A1 (en) 1997-02-04 1998-02-04 Freezing and thawing vessel with thermal bridges

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DK0960311T3 (da) 2006-02-20
DE69832261D1 (de) 2005-12-15
JP2002513459A (ja) 2002-05-08
ES2251071T3 (es) 2006-04-16
EP1580505A1 (de) 2005-09-28
DE69832261T2 (de) 2006-08-03
CA2279958A1 (en) 1998-08-06
ATE309512T1 (de) 2005-11-15
JP2007240145A (ja) 2007-09-20
WO1998034078A1 (en) 1998-08-06

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