DE69832261T2 - FREEZERS AND TANKS WITH THERMAL BRIDGES - Google Patents

Abstract

The present invention relates to a thermal transfer system for heating or cooling a medium. A structure (8, 37, 46, 50, 72, 81, 82, 89, 93, 98, 108, 306, 404) positioned inside a container (4, 34, 124 302). The structure (8, 37, 46, 50, 72, 81, 82, 89, 93, 108, 306, 404) segments the container (4, 34, 124 302) into a plurality of compartments (36, 95) wherein a distal end of the structure (8, 37, 46, 50, 72, 81, 82, 89, 93, 108, 306, 404) is in close proximity to an interior surface of the container (10, 33, 42, 91, 122, 210, 316, 414) to allow formation of a thermal transfer bridge (35, 208, 424, 426) that conducts heat into or out of the medium.

Description

Note on related applications

The The present application is based on the provisional application with the Serial No. 60 / 037,283, filed February 4, 1997 and incorporated herein by reference. The present invention refers to U.S. Patent Application Serial No. 08 / 895,782 (Attorney Docket No. 17882705) filed on July 17, 1997 with the Title "Freezing and thawing containers with between container and heat exchange part formed thermal bridge ", with the same named inventors Richard Wisniewski, Leonidas Cartwright Leonard, and incorporated herein by reference, and to US patent application Ser Serial No. 08 / 895,936 (Attorney Docket No. 17882706) on 17 July 1997 entitled 'Freezing and thawing containers with between heat exchange parts formed thermal bridge "with the same named Inventors Richard Wisniewski, Leonidas Cartwright Leonard, and the incorporated herein by reference, and the US patent application Serial No. 08 / 895,777 (Attorney Docket No. 17882702) on 17 July 1997 entitled 'Freezing and defrosting formed with between inner structure and heat exchanger part thermal bridge "with the same named Invent Richard Wisniewski, Leonidas Cartwright Leonard, who passed through here the reference is incorporated.

1st area the invention

The The present invention relates generally to systems which Structures, such. B. ribs, included in the transfer from heat in to help a medium into or out of this. More precisely The present invention relates to heating and cooling down structures suitable for use in heating, Cool, Thawing and freezing of biopharmaceutical products.

typically, has a container, used to heat or cool a medium Heat exchange fluid, which circulates in pipes in or around the outside of the container are arranged. To the transfer of heat to improve the medium or from the medium to the heat exchange fluid, can one or more extensions of the container or any other Structures in the container used to the surface of the system in contact with the medium.

Usually be ribs with one end to a section of the container or any other structure mounted in the container, and the ribs conduct heat to this section or away from this section of the container. There a rib, however, typically on the container or an internal structure only attached at one point, the entire heat, the transferred to or from the rib on the container or an internal structure through which enter or leave a connection has the rib with the rest of the system.

A Embodiment that has been used to solve this problem exists in building a system in which one or more of the ribs rigid both on the container as well as an internal structure inside the container are. This makes possible, that heat to or from a rib is transmitted through two sections of the rib, indicating the speed elevated, with what heat in one in the container arranged medium introduced or subtracted from this.

By rigidly attaching a rib between the container and a structure within of the container however, the structure inside the container itself becomes stuck to the container appropriate. The fixed attachment of the structure within the container can make the cleaning and decontamination of the container more difficult. In addition, can it may be harder to make the system, for example tighter tolerances are required so that the rib is attached to two surfaces within of the container can be attached, and each rib requires two or more Welded joints. Furthermore, it can be uncomfortable, expensive or impossible for ribs made of certain materials that are to be welded to a container or can.

What needed is a system into which heat is introduced or from which heat is dissipated may be from a rib through more than one section of the rib while the System is operating, removing structures inside the container can be to allow cleaning and decontamination of the system. Furthermore, a system is needed which does not require the rib with a section of the container physically connect or weld to this, so Heat in or transmitted from a portion of the rib.

SUMMARY THE INVENTION

It is an object of an embodiment of the present invention to provide a system in which heat can be transferred from a system through heat-conducting paths consisting in part of the medium which is cooled so that heat flows between different portions of the system by passing through the medium flows through.

It is an object of an embodiment of the present invention to provide a system in which heat out a structure inside the container (eg, a rib) through more than one portion of the structure (the term "rib" is used more generally) Way used to any heat exchange part of the system that extends into the medium, what a coil, a flattened tab, a pipe or any includes other structure which is in the container extends without being limited to such a structure. As far as a certain type of extension or extension of the container is discussed, such. B. a coil, the name of the relevant Type of extension used to help shape the figure to clarify the system or clearer).

It Another object of an embodiment of the present invention Invention to provide a system in which structures within of the container can be removed to allow cleaning and decontamination of the system.

A Another object of an embodiment of the present invention is to have ribs containing passageways, which make it possible the existence cooling fluid flows inside the ribs.

A Another object of an embodiment of the present invention is to have ribs which the lead away of heat improve from a medium, which, however, not rigid at one attached to the other part of the system.

A Another object of an embodiment of the present invention is to have ribs that no uniform Have cross-section to a faster dissipation of heat from a medium in the System to enable.

Yet another object of an embodiment The present invention is to have a system which controlled freezing rates for a medium, such as. B. a pharmaceutical product, achieved in the cryopreservation to help.

Yet another object of an embodiment The present invention is to have a system which Promotes a controlled freezing process to a dendritic To support ice growth, to help with the cryopreservation of media, including Proteins, cells, blood, plasma, other biopharmaceutical products or food, without, however, being limited thereto.

A Another object of an embodiment of the The present invention is to have a system which quickly cool a medium can.

According to a first aspect of the present invention there is provided a biopharmaceutical product thermal transfer system comprising:
a container adapted to receive a medium comprising a biopharmaceutical product, a heat exchanger structure disposed in the container so that the structure divides a cavity defined by the container into a plurality of compartments or compartments, the container and the structure being arranged such that the distal end of the structure is in close proximity to an inner surface of the container such that in use a frozen and / or liquid heat transfer bridge through the medium in the gap between the remote end of the structure and the inner surface of the container is formed, wherein heat from the distal end of the structure through the thermal transfer bridge in response to the fact that the inner surface is actively cooled, is transferred to the inner surface.

In an embodiment of the present invention the structure a rib or a rib or lamella. A remote one The end of the rib or fin is placed near a portion of the container. Because the fin or the container and not rigidly together attached, the structure including the rib can be removed from the container become.

If a medium frozen within the container becomes, a bridge forms, which consists of the frozen medium, between the remote one End of the rib and the section of the container, which is the remote Near the end of the rib. This bridge allows heat to or from the rib over the bridge is directed what the discharge of heat accelerated from the medium.

In an embodiment According to the present invention, the rib is at least partially attached a structure inside the container attached what makes it possible that heat out the rib transmitted through the attachment point and the thermal bridge if this is formed.

In another embodiment of the present invention, the distal end of the rib is located close enough to another surface of the container, such as another rib or structure within the container, so that when the medium is cooled, the heat transfer bridge between the rib and the on whose structure is formed in the container, which of course can also be a rib.

In a further embodiment The invention is a heat exchanger part at least partially connected to an inner surface of the container. A second heat exchanger part is at least associated with the structure, with a portion of the first heat exchanger at a close distance to a portion of the second heat exchanger part is arranged to help in the formation of the thermal transfer bridge, what the heat conduction into or out of the medium. In a embodiment of the present invention the structure and the second heat exchanger part be removed from the system to aid cleaning since Do not stare at the container or the first heat exchanger part are attached.

A another embodiment The invention has a heat exchanger part on, which at least partially with an inner surface of the container is connected, with a remote end of the heat exchanger part at a close distance is arranged to the structure to allow the formation of a thermal transfer bridge, the heat dissipates from the medium. In a further embodiment of the can present invention, since the rib and the container not rigidly attached to each other, the structure removed from the container become.

The The present invention is useful for cooling a Medium. When a medium is frozen, the thermal bridges help dissipate heat to transfer to the medium.

The Medium can also be a gas, which is in a liquid is converted, or a liquid, which is converted into a gas. In these cases, the liquid phase acts of the medium that accumulates between the rib and the structure, as the thermal bridge, around the heat conduction between the rib and the structure increase.

In addition, can the rib or fin carry structures on which they training of solid or liquid thermal bridges reinforced and / or the heat conduction reinforced by such bridges. For example For example, a section of the rib may be enlarged to accommodate a larger area for the pipe and to provide contact with a thermal bridge, or the rib may be specially designed to have a Germination for the solid body or the condensation of the liquid strengthened. Furthermore For example, a rib may have a non-uniform cross section to the heat transport to reinforce desired to achieve thermal transport properties. This may be desirable to help win cryobiological protocols.

Farther The rib can have inner channels have that make it possible the existence heat exchange medium flows within at least a portion of the rib. Other Variations are possible without departing from the scope of the invention.

The System may be configured so that a cooling device with any Section of the container connected is. For example, without deviate from the present invention, a cooler an outer section of the container (for example on a wall of the container), on an internal structure of the container or directly on one or more of the ribs attached.

in the In general, the system should be constructed so that the distance, which are bridged by the heat transfer bridges must, a function the thermal properties of the medium and the system, the manufacturing requirements and the design processes which is used to build the system as well as other relevant ones Parameters of the system and the components that are used. The size of the gap, the one by the bridge filled out can, must be determined by simple experiments.

According to one Aspect of the present invention may be the rib structures be with any shape that is placed on or between the surfaces surfaces in the container be trapped. Form thermal bridges then between the ribs and the adjacent surface or the surfaces of the container out. For example, you can the ribs have ends that are designed for that are in previously formed slots in the surfaces of the container to fit. That way you can the ribs are reconfigurably attached to sections of the container so that the Number, the configuration and the type of ribs used in changed in a simple way can be to adapt to a modified manufacturing, another Procedure or protocol requirement.

According to one Aspect of the present invention is the optimal gap (gap to be bridged) proportional to the thickness of the rib. According to another aspect of the present invention the gap or gap is less than 0.0508 m (2 inches), preferably less than 0.0254 m (1 inch), and more preferably less than 0.0127 m (1/2 inch) and even more preferably less than 0.00635 m (1/4 Inch), and most preferably less than 1/8 inch (0.00318 m).

Without departing from the present invention soft, the container can be porous and must have no top and also no bottom. The medium may be cooled as it passes through the container. In addition, the container used in the present invention is not limited in shape, size or material of which it is constructed. According to one aspect of the present invention, the container may have a volume of 1 to 5 liters, 1 to 250 liters or 250 to 10,000 liters.

The The present invention can be usefully applied in many fields become. For example, the present invention may be useful in the biopharmaceutical Industry used to be a variety of biopharmaceutical To freeze and preserve product, including Proteins, cells, antibodies, Medicine, plasma, blood, buffer solutions, Viruses, serums, cell fragments, cell components and any other biopharmaceutical products, but is not limited thereto.

In addition, the present invention, the processing of such biopharmaceutical Products in accordance with generally accepted manufacturing process.

you could use the present invention to form a biopharmaceutical Freeze product by sterilizing the container, the product to be frozen is pumped through a sterile filter into the container and then the product heat is removed using the present invention to the Product inside the container freeze.

The present invention promotes a uniform freezing at high speed, allowing the product in the container to be so close as possible on his or in his natural Condition is frozen. additionally allows the present invention that the Freezing process is done in a repeatable manner so that a user can be sure that the Freezing process no product changes the individual games causes. This allows the final use of the Product from the manufacturing steps needed to the product to produce, decouple, as the product is in the frozen state can be saved after it has been established, and can be thawed when and where it is needed.

The The present invention may also be practiced during any stage of a Cleaning process can be used. For example, after products was processed using a size separation or affinity separation, Fermentation, licing, concentration filtration, selective affinity chromatography, Removal of micro-components or impurities on lower Level by ion exchange, virus filtration, chromatography, introduction of the product into a dispensing system with buffered solution or after any other processing step, the resulting Product stored using the present invention. this makes possible it, that one Interruption in the manufacturing process can be made, without that Intermediate thereby impaired or deteriorates.

If for example during a manufacturing process in which various components be disconnected, make an interruption of the processing would like to, so can contaminating proteases are present in the intermediate, the Over time, some of the proteins of interest in the Remove product. The present invention can be used to freeze the intermediate quickly and evenly enough, so that this Product stays very close to its original state. The molecules in the product are not brought closer together - the freezing concentration is diminished and unwanted Reactions can slowed or stopped.

The The present invention can therefore be used to provide the flexibility of a Increase the manufacturing process, what the designing and planning makes the process easier. Intermediates can be frozen be for a later processing or for the Transport. additionally can, since the present invention will be adapted to any desired size can, big games or quantities of the products processed at once and using preserved at the present invention and at a later date Need to be used.

SHORT DESCRIPTION THE FIGURES

1 is a side view of the finned heating and cooling device.

2 FIG. 12 is a top view of the ribs and structure within the container shown in FIG.

3a . 3b and 3c show the formation of thermal bridges and curves showing the temperature profile of different cross-sections of the container and the medium.

3d Figure 10 shows dendritic ice growth and inclusion of units, such as cells, in the egg.

4 is another possible arrangement of the ribs.

5 is yet another possible arrangement of the ribs.

6 shows a number of possible rib geometries and combinations.

7 shows even more possible rib geometries and combinations.

8th shows yet another possible configuration of rib geometries and combinations.

9 shows a cross-sectional view of a rib, which has a non-uniform thickness.

10 shows a rib geometry that allows a compartmentalization of the container by using alternate rib geometries.

11 is a cutaway view showing a container and inner flaps of two ribs.

12a is a top view of the container and the ribs behind 11 ,

12b is a detail view of the distal end of a rib with an extension that extends close to the inner wall of the container.

12c Figure 11 is a detail view showing another embodiment of a rib without an extension in which the hollow rib structure extends close to the inner wall of the container.

13 is a cutaway view showing a container, the inner flaps of two ribs and no central structure. The heat exchange fluid is introduced into the ribs through tubes in the tops of the ribs.

14a is a cutaway view showing a container, a set of inner ribs, a set of outer ribs, and a coil.

14b is a top view of the system 14a ,

15a Figure 11 is a cutaway view showing a container, a set of inner ribs, a set of middle ribs, a set of outer ribs, a first coil, and a second coil.

15b is a top view of the system 15a ,

15c Figure 11 is a side view of details of the thermal bridges that form between the respective turns of the coils and between the ribs and the turns of the coil.

15d Figure 11 is a top view of details of the thermal bridges that form between the coils and the ribs.

16a and 16b show tubes with non-circular cross section.

17a and 17b show tubes of non-circular cross section in use in a system.

18 show non-circular cross-section tubes attached to ribs in various configurations.

19a and 19b show tubes of non-circular cross-section in use in a coil assembly within a system.

20 shows a configuration of non-circular cross-section tubes and ribs useful for compartmentalizing in a system.

PRECISE DESCRIPTION

An embodiment of the present invention is in 1 shown. The heating and cooling system 2 consists of the container 4 , the ribs 6 and the structure 8th , Ribs 6 are designed so that they are in close proximity or in close proximity to the inner surface 10 of the container 4 are arranged. Generally there is a small gap between the rib 6 and the inner surface 10 to prefer. However, the size of this gap can be determined by manufacturing tolerances, material parameters or other practical considerations.

2 shows a cutaway view from above of the container 4 , Ribs 6 and the structure 8th , There are in the present embodiment 6 Ribs symmetrical around the structure 8th are arranged around. Any arrangement, configuration or number of ribs could be used without departing from the present invention. For example, the ribs inside the container need not be symmetrical. They do not have to be the same shape and they do not have to be made of the same material.

According to 1 becomes the structure 8th heated or cooled by passing a heat exchange fluid through the internal passageway 12 down towards the tail 14 flows or flows. The heat exchange fluid then flows up through the outer passage 16 the structure 8th , This flow pattern of the heat exchange fluid and the symmetrical configuration of the ribs with respect to the structure 8th helps the system 2 to start the cooling of the medium in the container from bottom to top. This is because the heat exchange fluid first bonds very well to the medium in the container and to the ribs at the bottom of the container.

The Cool The medium from bottom to top is particularly advantageous when a liquid medium is frozen and, as z. B. for water, the density of frozen medium is lower than that of the liquid phase. Freezing from the bottom up prevents pressure building up, as it does the case could be if the liquid Phase is restricted or included by the solid phase.

It It is understood that professionals in the field other flow patterns, Rib shapes and rib arrangements could be used to cause the Medium in any preferred direction heated or cooled, evenly, and / or at a specified speed without departing from the present Deviate from the invention. additionally can Parameter of the heat exchange fluid, such as B. the flow rate and / or temperature can be used to influence the speed with which the medium cooled becomes.

At the tail 14 is a lower rib 30 appropriate. The lower rib 30 works in the same way as the ribs 6 , A heat transfer bridge is placed between the lower rib 30 and a section of the inner surface 10 educated.

According to one aspect of the present invention, the rejuvenation helps 19 the rib 6 thereby, forming a thermal bridge at the upper portion of the rib 6 to slow down. This somewhat slows the transfer of heat from the upper portion of the container, allowing the system to freeze the medium from bottom to top. Such a taper or taper can be used on any part of the rib to help create a preferred direction for the removal of heat from the container.

The container 4 has a sleeve or a jacket 20 that surrounds its circumference. Between the outer surface 18 of the container 4 and the coat 20 there is a fluid flow path 22 , A spiral baffle 24 runs helically between the outer surface 18 and the coat 20 around the container 4 and forces the heat exchange fluid in the fluid flow path 22 that it is in a spiraling path around the outside surface 18 of the container 4 flows around. The heat exchange fluid flows through the port 26 in the fluid flow path 22 and from the connection 28 out, which causes the heat exchange fluid from bottom to top around the container 4 flows around. This flow pattern of the heat exchange fluid helps the system 2 cools the medium in the container from bottom to top.

It it goes without saying that too other fluid flow patterns and baffles may be used to cause the medium in any preferred direction, evenly and / or with a specified one Speed or rate heats or cools without being present Deviate from the invention. additionally can Parameter of the heat exchange fluid, such as B. the flow velocity or flow rate and / or the temperature used to speed or rate at which the medium is cooled. Furthermore, you can the heat exchange fluid at other points and in a temporal or procedural manner flow through the system in varying ways to the direction and the rate of heat flow into or out of the system. Additionally, materials, that are used in the system, or the shape or configuration of the system, including the ribs, used to parameters of the heating or cooling process to control, such. As the speed, the time or the Direction.

When the container 4 , the structure 8th and the ribs 6 cooled by the coolant, the medium begins to cool in the container. When the medium is sufficiently cooled, a portion of the medium becomes between the distal and distal ends of the ribs 6 and the inner surface 10 freeze or freeze. This frozen bridge allows heat to pass between the ribs 6 and the container 4 passed over the frozen bridge. This allows heat to be removed from the medium at a higher rate which accelerates the freezing of the medium in the container. The present invention works with, but is not limited to, any type of medium including biopharmaceutical products.

3 illustrates the formation of thermal bridges according to one aspect of the present invention. 3a is a top view of an embodiment of the present invention, in which the structure 31 8 ribs attached 32 Has. Every rib 32 extends close to the inner surface 33 of the container 34 ,

3b illustrates a simulation of the system shortly after thermal bridges 35 have started to train. In this simulation, 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, and the temperature of the fin in contact with the liquid was close to -0.2 ° C, and the temperature of the portion of the fin which was in contact with the frozen product lowered depending on the temperature of the wall. The temperature of the wall was within a range of 2 to 5 ° C of the temperature of the coolant.

How to use the curves in 3b Heat can be detected from the ribs 32 discharged through both ends. Compared to a finned structure in which heat is removed only from one end of the fin, the medium is cooled at a higher rate. 3c shows the temperature profile of the medium within the compartments or compartments 36 passing through the ribs 32 be formed. As it is in the curves in 3c is shown, heat from the medium in the cavity through the inner container wall 33 , the structure 31 and the ribs 32 subtracted or removed.

The relative uniformity with which the present invention enables the removal of heat from the medium promotes the growth of dendritic structures during the freezing process. By allowing heat to be dissipated from both sides of a fin, the present invention helps create a uniform temperature profile within the container. In addition, the ribs may be arranged to effectively divide the container into a plurality of smaller volumes so that heat may be dissipated more uniformly from each partitioned portion. For example, shows 2 the container 4 divided into 6 sections by the ribs.

It It should be noted that the The present invention can be used to promote dendritic ice growth even if the ribs are rigid at more than one point connected to the system or attached to this. The ribs can be used be to the container into small areas that can be heated and cooled more evenly.

Dendritic ice growth is particularly useful in many areas, including, but not limited to, the cryopreservation of biopharmaceutical products. As in 3d is shown, when heat from the surface 501 (which could be any surface of the present invention), dendrites 502 and grow, moving away from the surface 501 move on. While the dendrites 502 grow, the substance becomes 503 Frozen in the medium and finally dendrites 502 surround. While the dendrites 502 grow, the substance becomes 503 finally in the frozen medium 504 captured. By removing the heat dissipation from the surface 501 controls or controls the growth rate of dendrites 502 be controlled or controlled. Controlling the growth rate of dendrites 502 allows the present invention to be used to measure the amount of liquid which is derived from the substance 503 is removed as she enters and through the growing, dendritic front 505 is included to control. It should be noted that the substance 503 can be any substance that you want to conserve.

It understands that no active cooling both the structure as well as the container must be done to apply the present invention. Without from the present Can deviate a coolant by any Part of the system, or only part of it of the system, or coolant does not need at all to be used, and the system could be replaced by any other Device or cooled indirectly or passively.

In another embodiment of the invention, removable panels or coatings may be applied over the distal ends of the ribs 6 be arranged to prevent it from interfering with the inner surface 10 contact if the structure 8th and the ribs 6 in the container 4 be inserted or removed from this. This may be desirable, for example, to scratch the inner surface 10 with ribs 6 during assembly and disassembly.

Other rib configurations are possible without departing from the present invention. For example, in 4 Ribs 39 partly with the inner container wall 41 be connected and the distal or remote end of each rib may be close to the structure 37 be arranged so that the thermal bridge between a distal (remote) end of each of the ribs 39 and the structure 37 is formed.

In 5 are ribs 40 on the inner surface 42 appropriate. ribs 44 are at the structure 46 appropriate. The system 38 is constructed so that sections of the ribs 40 and the ribs 44 be in contact with each other, almost in contact or can be rotated so that this is the case. Then, when the medium freezes in the container, heat transfer bridges form between sections of ribs 40 and ribs 44 , According to another aspect of the present invention, the ribs 40 and 44 not parallel. Ribs 40 and 44 may be angled relative to each other so that the gap 45 along the length of the ribs 40 and 44 varied.

6 shows a number of possible arrangements of ribs. For example, the rib 48A partly on the structure 50A be coupled and a remote end may be in close proximity to another structure 50B be arranged so that the thermal bridge between the distal end of the rib 48A and the structure 50B is formed. Ribs 54 are with the inner wall 56 connected. A distal end of the rib 54A is near distal ends of the ribs 58 arranged, and the ribs 58 are with structures 50 connected. A thermal bridge forms between the distal ends of the ribs 54A . 58A and 58B , Thus, a thermal bridge can be formed between more than two ribs. Forming a thermal bridge between two or more ribs may be desirable if, for example, model constraints or other limitations require portions of the container to be spaced from an actively cooled surface. A fin and thermal bridge can be used to help extract heat from the isolated structure.

7 shows a number of other possible arrangements of ribs. A rib may be configured so that the thermal bridge is not formed between the distal end of two ribs but between the distal end of one rib and any other part of another rib. For example, the rib forms 60 a thermal bridge with the rib 62 at a central portion of the rib 60 , and the rib 64 forms a thermal bridge with the rib 66 at a central portion of the rib 64 , Furthermore, a rib need not be connected to anything from the beginning, and heat transfer bridges may be formed between portions of the rib and other portions of the system. For example, the rib is 68 not rigidly connected to any structure within the container, but forms a thermal bridge with ribs 64 and 70 and the structures 72 ,

In addition, ribs may have structures that assist in the formation of heat transfer bridges to enhance the heat transfer properties of the bridges. Ribs 62 have extended surfaces 76 at their distal ends. The extended surface 76 allows a wider thermal bridge to be formed, which improves the heat transfer rate of the bridge. This may be desirable under some circumstances. For example, the thermal transport properties of the fin material may be superior to those of the frozen material forming the thermal bridge. Increasing the area of the thermal bridge improves its overall heat transfer properties.

In addition, other types of extended surfaces may be attached to the ribs, structures, or inner surface of the container to assist in the formation of heat transfer bridges having the desired characteristics. For example, the advanced interface 78 used to form a thermal bridge with or on the rib 62 regardless of whether the expanded area 76 at the rib 62 is appropriate.

8th shows a further embodiment of the present invention. This embodiment shows details of another configuration of ribs according to the present invention. In this embodiment, the ribs are 80 with the structure 81 connected and form thermal bridges with the structures 82 , Ribs 83 are with structures 82 connected and form thermal bridges with the inner container wall 84 , Ribs 85 form thermal bridges with each other, and the ribs 8th form thermal bridges with the inner vessel wall 84 ,

9 shows still another embodiment of the present invention. The rib 87 has a non-uniform cross-section along its length. The rib 8th is at the end 88 thicker, where they attach to the structure 89 connects and is thinner in its central section. The rib then widens at its distal end 90 where they are in close proximity to the inner surface 91 located. A thermal bridge forms between the distal end 90 and the inner surface 91 , The thicker base portion of the rib allows for a greater heat flow at the end 88 and at the distal end 90 is deducted from the rib.

10 shows still another embodiment of the present invention. ribs 92 are at the structure 93 attached and form thermal bridges with the container wall 94 , Ribs 92 are so curved that they compartments or compartments 95 form. The compartmentalization of the container allows more uniform cooling to be achieved because the distance from any point in the medium to a cooled surface is reduced. Also, the reduction in the distance between cooled surfaces can be used to shorten the time required to freeze a medium. Other ribs, such. B. the ribs 96 , can be added to the compartments or compartments 95 to divide even further. Ribs 97 can also be used to heat bridges with egg another structure 98 to build. Those skilled in the art will recognize that other shapes and configurations of ribs may be used to create more or fewer compartments of any desired size, and that this scheme may be scaled up to any desired container volume without departing from the present invention ,

11 shows a further embodiment of the present invention. In this embodiment, the ribs have 102 internal passages 104 , Heat exchange fluid flows into the internal passages 104 through openings 106 in the structure 108 , Ribs 102 have impressions 110 or spacers 114 or swirler to help with the flow pattern 118 to optimize the heat exchange fluid. Indentations or spacers help with the flow pattern 118 of heat exchange fluid, for reasons including increasing the inner surface of the fin which contacts the heat exchange fluid and allowing more time for the heat exchange fluid to absorb heat from the fins. This speeds up the freezing process and allows the dendrites to converge faster.

According to one aspect of the present invention, the ribs 102 extensions 120 wear. As in 12a shown, the heat exchange fluid does not show flow within the extensions 120 , The extensions 120 are with the ribs 102 connected and extend into the vicinity of the inner surface 122 of the container 124 , 12b shows a detailed view of a rib 102 , the extension 120 and the inner surface 122 , 12c shows a detailed view of another embodiment of the present invention, wherein no extension at the end of the rib 102 is arranged.

As in 12b As shown, when the present invention is used, it begins to contain a medium within the container 124 Freeze, a heat transfer bridge 126 itself between the inner surface 122 and the extension 120 train. In 12c The heat transfer bridge starts between the rib 102 and the inner surface 122 train.

13 shows still another embodiment of the present invention. In this embodiment, the heat exchange fluid flows into the fins 202 and from the ribs 202 out through pipes 204 with the upper end 206 the ribs are connected. In this embodiment, the ribs are not connected to a central structure. When this embodiment is used to freeze a medium, thermal transport bridges form 208 between the ribs 202 and the inner surface 210 and between inner surfaces 212 the ribs 202 ,

14a shows still another embodiment of the present invention. In this embodiment, the system has 300 inner ribs 304 attached to the structure 306 are attached. Heat exchange fluid flows through the structure 306 , The flow of heat exchange fluid can be made to be similar to the flow as it is to the structure 8th in 1 has been described. Another flow configuration may be used to achieve a desired rate of cooling or heating. In addition, one can heat exchange fluid through the inner ribs 304 let flow, if desired.

A coil 308 becomes in the way to the inner ribs 304 arranged that it surrounds these. Heat exchange fluid flows into the coil 308 through the entrance 310 and flows through the exit 312 out. Outer ribs 314 are between the coil 308 and the inner surface 316 of the container 302 arranged. In one aspect of this invention, outer ribs may be freestanding on the spool 308 attached or on the inner surface 316 to be appropriate. According to another aspect of the present invention, one may heat exchange fluid through outer ribs 314 , through the coil 308 , the inner surface 316 Allow external inputs or any other input to flow.

In this embodiment, heat transfer bridges between the inner ribs 304 and the coil 308 , the coil 308 and outer ribs 314 , the outer ribs 314 and the inner surface 316 and the turns of the coil 308 educated.

14b shows a top view of the system 300 , In this embodiment, ribs 314 so shown that they are not attached to the coil 308 are attached. Ribs 314 could be attached to brackets from the top or bottom 302 be hung or ribs 314 could be freestanding.

15 shows a further embodiment of the present invention. In this embodiment, the system has 400 inner ribs 402 attached to the structure 404 attached, and the first coil 406 which the inner ribs 402 surrounds. Medium ribs 408 are around the first coil 406 arranged around, and a second coil 410 surrounds the middle ribs 408 , Outer ribs 412 are between the second coil 410 and the inner surface 414 arranged. First and second coils 406 respectively. 410 take heat exchange fluid through the entrance 416 respectively. 418 on, and the heat exchange fluid flows through exits 420 respectively. 422 out.

15b shows a view from above of this embodiment. In this embodiment, the ribs are 408 and 412 shown as freely hung. Heat transfer bridges form between the internal ribs 402 and the first coil 406 , the turns of the first coil 406 , the first coil 406 and the middle ribs 408 , the middle ribs 408 and the second coil 410 , the turns of the second coil 410 , the second coil 410 and outer ribs 412 and outer ribs 412 and the inner surface 414 ,

15c shows details of a side view of the formation of the heat transfer bridges 424 between the turns of either the first coil 406 or the second coil 410 , and the heat transfer bridges 426 formed between the coils and the ribs, inner ribs, middle ribs or outer ribs. Distances X1 and X2 can be optimized as desired as a function of the properties of the ribs, coil, media and container. 15d shows a top view of the training of in 15c illustrated thermal bridges.

16 shows still further possible configurations of coils that are in accordance with the present invention. In 16a has a pipe 602 a round cross section. A coolant fluid flows through the inner surface 602 , The central tube 602 runs next to the rib 604 and forms a thermal bridge with this. Through the pipe 606 Also flows a coolant fluid, and it is located near the other end of the rib 604 , The pipe 606 has a non-circular cross-section. A tube of any cross-section may be used as long as it is consistent with the present invention. In 16b is a pipe 608 shown with a non-circular cross-section in a different orientation with respect to the adjacent ribs.

17 shows tubes of non-circular cross-section as used in a system. In 17a For example, the angle formed between two adjacent ribs is small, and therefore, the non-circular cross-sectional tubes 610 aligned so that they can be placed closer to each other. An advantage of using tubes of non-circular cross-section is that the elongate surface of non-circular tubes 610 It allows a greater part of the interface between the compartments 612 is cooled by a tube with a flowing cooling medium.

17b shows a pipe 614 of non-circular cross-section, in a different orientation to that in 17a is used. In 17b For example, the angle formed between adjacent ribs is larger, and therefore tubes can 614 be used with non-circular cross-section in the illustrated orientation. In the illustrated orientation are the tubes 614 with non-circular cross-section in the adjacent compartments and contribute advantageously to the medium in the compartments to cool more uniformly.

18 shows yet another embodiment of tubes and fins consistent with the present invention. In 18 have the pipes 702 with non-circular cross-section ribs 704 that are welded to it.

19 shows yet another embodiment of the use or use of ribs of non-circular cross-section, which is consistent with the present invention. In 19a is a pipe 802 wound with a non-circular cross section to a coil and is similar to a coil 308 according to 14a , The pipe 802 with non-circular cross-section has an extended, flat side 804 next to the ribs 806 is arranged. The extended flat side 804 makes it easier for there to be thermal bridges between the coil 808 passing through pipes 802 is formed, and the ribs 806 , as well as between the pipes 802 the coil 808 form. 19b shows pipes 810 with a different cross section, which also advantageously support the formation of thermal bridges.

Tube 802 or 810 with non-circular cross-section allow ribs 806 or ribs 812 for a given inner cross-sectional area of the tube are closer together compared to a circular tube. As the ribs are closer together, thermal bridges will form faster, speeding up the freezing process and making it more uniform.

20 shows yet another possible configuration of pipes 902 with non-circular cross-section and ribs 904 , The illustrated geometry can be used to divide large volume tanks into compartments. The compartments formed in this way can be made as small as necessary to achieve a desired level of uniformity.

The The present invention can be usefully applied in many fields become. For example, the present invention may be useful in the biopharmaceutical Industry used to be a variety of biopharmaceutical To freeze and store products such as proteins, cells, antibodies, medicines, Plasma, blood, buffer solutions, Viruses, serums, cell fragments, cellular components and either includes, but is not limited to, other biopharmaceutical product.

Additionally allowed the present invention, the processing of such biopgarmazeutischer Prdukte in accordance with generally accepted manufacturing procedures.

you could use the present invention to form a biopharmaceutical Freeze product by sterilizing the container, the product to be frozen is pumped through a sterile filter into the container and then heat is removed from the product using the present invention, around the product inside the container to freeze.

The present invention promotes a uniform freezing at a high speed, allowing the product to soak in the container far in its original Condition as possible is frozen. additionally allows the present invention that the Freezing process happens in a repeatable manner so that a user can be sure that the Freezing process no variations of the product from batch to batch caused. this makes possible it that the final Use of the product from the required manufacturing steps is separated to produce the product, since the product in the frozen state can be stored or stored after it has been manufactured, and then, when and where it is needed, can be thawed.

The The present invention may also be during any stage a cleaning process can be used. For example, after products using size distribution or Affinity separation, Fermentation, licing, concentration filtration, selective affinity chromatography, the removal of microcontaminants or impurities at a low level by ion exchange, virus filtration, chromatography, placement of the product in a dispensing system for the buffered solution or was processed after some other processing step, may be the resulting product using the present Be stored invention. This allows the manufacturing process to be stopped can, without the intermediate or intervening Deteriorate product.

If for example during a manufacturing process in which various components disconnected, stopping or interrupting processing would like to make so can contaminating proteases are present in the intermediate which over time some of the proteins of interest in the product could worsen or degrade. The present invention can be used to intervene Product fast and uniform freeze enough so that the Product stays very close to its original state. The molecules in the Product are not brought together significantly closer, which becomes freeze concentration diminished and unwanted Reactions can slowed or stopped.

The restrict the above examples The invention in no way, but are only examples potential embodiments of the present invention. Other embodiments are possible without to deviate from the present invention.

Claims (52)

Temperature transfer system for a biopharmaceutical product with a container ( 4 . 34 . 302 ) adapted to receive a medium containing a biopharmaceutical product, a heat exchanger structure ( 6 . 8th ; 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 ) disposed in the container such that the structure divides a space bounded by the container into a plurality of compartments, the container and the structure being arranged such that a distal end of the structure is proximate an inner surface of the container ( 33 ; 41 ; 42 ; 84 ; 91 ; 94 ; 122 ; 316 ; 414 ), so that when used in a space between the distal end of the structure and the inner surface of the container through the medium, a frozen and / or liquid temperature transfer bridge is formed, wherein in response to the fact that the inner surface is actively cooled over the thermal transfer bridge is transferred heat from the distal end of the structure to the inner surface. Temperature transfer system according to claim 1 with a variety of heat exchanger structures in the container. Temperature transfer system according to claim 1 or claim 2, wherein a distance between the distal end of heat exchanger structure and the inner surface not the container greater than 0.0254 m (one inch). System for temperature transfer according to one of claims 1 to 3, wherein the heat exchanger structure is constructed so that they an area of a surface the structure in contact with the medium is maximized. The thermal transfer system of claim 1, wherein the heat exchanger structure comprises one or more heat exchange elements and wherein a distal end of the heat exchanger element is disposed in close proximity to the inner surface of the container so that a temperature transfer bridge is formed in the space between the heat transfer element and the inner surface of the container through the medium and heat is transferred from the medium through the temperature bridge , Temperature transfer system according to one of the preceding Claims, being a cooling device with the in the container arranged heat exchanger structure is connected and for whose cooling provides. A temperature transfer system according to claim 6, the cooling device Gears in the structure comprises through which during the application heat exchange fluid flows, to a cooling of the To effect the medium. Temperature transfer system according to one of claims 5 to 7, wherein a heat exchange fluid through an external passage flowing out of the structure in the structure, being part of the outer passageway an outer wall of the structure. Temperature transfer system according to one of claims 5 to 8, wherein an inner part of the structure which projects into the container, Has deflection means or diaphragms. Temperature transfer system according to one of claims 5 to 9, wherein a heat exchange fluid from the structure into the heat exchanger element flows. Temperature transfer system according to one of claims 5 to 10, wherein a heat exchange fluid from a heat exchanger inlet in the heat exchanger element flows. Temperature transfer system according to one of claims 5 to 11, wherein a Wärmeaustauschauscherfluidsfluß not through the distal end of the heat transfer element flows. Temperature transfer system according to one of claims 5 to 12, the medium cooled is, so that in the medium a thermal gradient in a predetermined direction is trained. A temperature transfer system according to claim 1, wherein a heat transfer element at least partially connected to an inner surface of a container is, and wherein a distal end of the heat transfer element in close proximity to the Structure is arranged so that a from the medium in a space between the distal end the heat transfer element and the structure formed temperature transfer bridge heat directs the medium. Temperature transfer system according to claim 14 with one with the heat transfer element connected and in use for their cooling caring cooling device. Temperature transfer system according to claim 14 or claim 15, wherein the heat transfer element is constructed so that it an area of a surface the heat transfer element, which comes in contact with the medium, maximizes. System for temperature transfer according to one of claims 14 to 16, wherein the heat transfer element at least partially connected to a bottom of the container. A temperature transfer system according to claim 1, in which a first heat transfer element at least partially connected to an inner surface of a container is and a second heat transfer element is at least partially connected to a structure and wherein a Part of the first heat transfer element close to a part of the second heat transfer member is arranged so that a in a space between the first heat transfer member and the second heat transfer element formed by the medium temperature transfer bridge the heat conduction improved in or out of the medium. A temperature transfer system according to claim 18, being a cooling device with the in the container arranged structure is connected and provides for their cooling. Temperature transfer system according to claim 18 or claim 19 in addition with a removable liner or cover layer, which is constructed so is, that you covers at least a portion of the first heat transfer element. A temperature transfer system according to any one of claims 18 to 20 additional with a removable liner or topcoat so configured is, that you covers at least a part of the second heat transfer element. A thermal transfer system according to any one of claims 18 to 21, further comprising a removable liner or cover layer configured to at least part of the ers th heat transfer element and the second heat transfer element covers. A temperature transfer system according to any one of claims 18 to 22, wherein a distance between the distal end of the first heat transfer element and a distal end of the second heat transfer member not larger than 0.0254 m (one inch) is. A temperature transfer system according to any one of claims 18 to 23, wherein the container a Covered casing that one between the shell and a wall of the container arranged intermediate region for receiving a cooling fluid flow limited, the shell Furthermore, a plurality of spiral deflection means or diaphragms for the Improvement of the thermal exchange between the fluid and the container having. A temperature transfer system according to any one of claims 18 to 24, wherein the second heat transfer element is arranged at one end of the structure. A temperature transfer system according to any one of claims 18 to 25, wherein a heat exchange fluid in the first heat transfer element flows. A temperature transfer system according to any one of claims 18 to 26, wherein an inner part of the first heat transfer element deflecting means having. A temperature transfer system according to any one of claims 18 to 27, wherein the first heat transfer element is configured to have a Area of a surface the heat transfer element, which is in contact with the medium, maximizes. A temperature transfer system according to any one of claims 18 to 28, wherein a heat exchanger extension at least partially connected to the first heat transfer element. Temperature transfer system according to one of the preceding claims with a cooling device, the one with the container is connected and for its cooling provides. Temperature transfer system according to one of the preceding claims with a cooling device, which is connected to the structure and provides for its cooling. A temperature transfer system according to claim 31 with a cooling device, the one with the container and the structure is connected and provides for its cooling. Temperature transfer system according to one of the preceding claims with a removable liner constructed to at least covering part of the structure. Temperature transfer system according to one of the preceding Claims, being a volume of the container is in the range of substantially 1 liter to 250 liters. A thermal transfer system according to any one of claims 1 - 33, wherein a volume of the container is in the range of substantially 250 liters to 10,000 liters. Temperature transfer system according to one of the preceding Claims, the container a case comprises the one between the shell and a wall of the container arranged intermediate region for receiving a heat exchange fluid flow limited, the shell Further, a plurality of spiral deflection means for improvement the thermal exchange between the heat exchange fluid and the container includes. Temperature transfer system according to one of the preceding Claims, wherein a heat exchange fluid flowing in the structure. Temperature transfer system according to one of the preceding Claims, wherein an inner part of the structure comprises deflection means. Temperature transfer system according to one of the preceding Claims, the medium being so cooled will that one thermal gradient is formed in a predetermined direction. A temperature transfer system according to claim 39, the medium being so cooled will that one thermal gradient formed in a predetermined direction will and the cooling at a predetermined rate. Temperature transfer system according to one of the preceding Claims, wherein the medium comprises proteins. Temperature transfer system according to one of Claims 5, 14 or 18, wherein a heat exchange fluid in the heat transfer element flows. A thermal transfer system according to any one of claims 5, 14 or 18, wherein an inner Part of the heat transfer element has deflection. Temperature transfer system according to one of Claims 5, 14 or 18, wherein it has a plurality of heat transfer elements. Temperature transfer system according to one of Claims 5, 14 or 18, wherein a distance between the distal end of the heat transfer element and the inner surface of the container not bigger than 0.0254 m (one inch). Temperature transfer system according to one of Claims 5, 14 or 18 with a removable liner that is constructed that she at least a part of the heat transfer element covers. Temperature transfer system according to one of the preceding Claims, the system being a freezer system to freeze the medium to effect. Temperature transfer system according to one of the preceding Claims, the structure of the container is separable. Temperature transfer system according to one of the preceding Claims, being the heat by one or more parts of the structure in or out of the Transfer medium can be. Method of cooling of a biopharmaceutical product, wherein the method one container with a heat exchanger structure provides which is arranged therein so that the Structure one of the container limited space divided into a variety of compartments, the container and the structure are arranged so that a distal end of the structure close to an inner surface of the container lies, provides a medium in the container, the biopharmaceutical product, and the inner surface is active cools, so that in a space between the distal end of the structure and the inner surface of the container the medium is formed a frozen and / or a liquid temperature transfer bridge, being over the temperature transfer bridge heat from transferred to the distal end of the structure on the inner wall becomes. The method of claim 50, wherein the heat exchanger structure one or more heat transfer elements and wherein a distal end of the heat transfer element in the immediate Close to an inner surface of the container is arranged so that in a gap between the heat transfer element and the inner surface of the container a temperature transfer bridge is formed by the medium and heat over the Temperature transfer bridge off transferred to the medium becomes. The method of claim 50, wherein the heat transfer element at least partially connected to an inner surface of the container, and wherein a distal end of the heat transfer element close is arranged to the structure, so that in a space between the distal end of the heat transfer element and the structure formed by the medium temperature transfer bridge heat out of the medium.