Systems and methods for freezing and storing biopharmacuetical material

ES 2 265 057 T3

DESCRIPTION

Systems and procedures for freezing, storing and thawing biopharmaceutical material.

Technical field

The invention relates generally to biopharmaceutical materials, methods and preservation systems, and more particularly to systems and methods for transporting, freezing, storing and thawing biopharmaceutical materials. Background of the technique

Preservation of biopharmaceutical materials is important in the manufacture, storage, sale, and use of such materials. For example, biopharmaceutical materials are often preserved by freezing between processing steps and during storage. Similarly, biopharmaceutical materials are often frozen during transportation between manufacturing sites.

Preservation of biopharmaceutical materials today often involves placing a container containing liquid biopharmaceutical material in a freezer cabinet, chest freezer or chamber freezer and allowing the biopharmaceutical material to be frozen. Specifically , the container is often placed on a shelf in the freezer cabinet, chest freezer or chamber freezer, and the biopharmaceutical material is allowed to freeze. These containers can be stainless steel jars, plastic bottles or jugs, or plastic bags. They are typically filled to a specified volume to allow for freezing and expansion and then transferred to freezers at temperatures typically ranging from -20 ° C to -70 ° C or lower.

To ensure efficient use of the available space within the freezer, the containers are placed side-by-side and are sometimes stacked in an arrangement with varying spatial regularity. Under these conditions, the cooling of the biopharmaceutical solution occurs at different rates depending on the exposure of each container to the surrounding cooling air and to the extent that the container is shielded by neighboring containers. For example, containers located near the cooling source or those outside a container arrangement will cool faster than those further away from the cooling source and / or located inside the arrangement. From containers.

In general, the adjacent placement of multiple containers in a freezer creates thermal gradients from container to container. The speed of freezing and the quality of the product then depend on the actual freezer load, the space between the containers and the movement of air within the freezer. This results in a different thermal history for the contents of the containers depending on their position within a freezer, for example. Also, using different containers for independent parts of a single batch of biopharmaceutical may cause different results for parts of the same batch due to different thermal histories resulting from freezing in a multi-container freezer, particularly if the storage arrangement it is fortuitous and random. Another consequence of obtaining a range of freezing times is that certain containers can freeze so slowly that the target solute cannot be captured further into the ice phase, but remains progressively in a smaller liquid phase. This phenomenon is referred to as "cryoconcentration". In some cases, such cryoconcentration could result in precipitation of the biopharmaceutical resulting in loss of product.

Disposable containers such as plastic bags or other flexible containers are often damaged, resulting in the loss of biopharmaceutical material. In particular, the volumetric expansion of biopharmaceutical materials during freezing could generate excessive pressure in an overfilled bag or in an occluded liquid pocket adjacent to the plastic bags, possibly leading to rupture or damage to the integrity. out of the bag. Furthermore, the handling of such disposable containers, such as plastic bags, during freezing, thawing or shipping of these containers often results in damage to the same, due, for example, to bumps, abrasions, impacts or other resulting events. mishandling that is the result of operator errors or inadequate protection of the bags being used.

Thus, there is a need for systems and procedures to freeze, store and thaw biopharmaceutical materials that are controlled, and that do not result in the loss of biopharmaceutical material, but instead create conductive conditions to preserve the biopharmaceutical material from a uniform, repeatable, in a protected environment.

United States document US-A-4 107 397, which is considered the closest document of the prior art, describes a bioreceptacle and support system for deep freezing of biological substances, which also comprises a sensor to measure and control cooling applied to the receptacle by means of the bath of a liquefied refrigerant.

Summary of the invention

The present invention relates to a container for freezing, storing and thawing a biopharmaceutical material as well as a system and a method for freezing, storing and thawing a biopharmaceutical material as claimed in claims 1, 9 and 28, respectively.

The present invention provides, in a first aspect, a container for freezing, storing and thawing a biopharmaceutical material, which is received in a frame to support and protect said container. The container includes a material adapted to receive the biopharmaceutical material inside for freezing, storage and thawing in a liquid or frozen state, and the container includes a flange that can be connected to the support frame to hold the flexible container in the frame. of support.

The present invention provides, in a second aspect, a system for freezing, storing and thawing a biopharmaceutical material that includes a container and a frame. The container is adapted to receive the biopharmaceutical material therein and the container includes a flange. Armor

ES 2 265 057 T3 is adapted to receive the container and fits mechanically with the flange.

The present invention provides, in a third aspect, a method for freezing, storing and thawing a biopharmaceutical material. The method includes providing a container adapted to contain the biopharmaceutical material for freezing, storage and thawing, and to place the container in a frame to support and protect the container.

The present invention provides, in a fourth aspect, a system for freezing, storing and thawing a biopharmaceutical material that includes a container adapted to receive the biopharmaceutical material therein for freezing, storing and thawing. The container is adapted to receive a support member to support the container.

The present invention provides, in a fifth aspect, a method for freezing, storing and thawing a biopharmaceutical material. The method includes providing a container adapted to contain the biopharmaceutical material for freezing, storage and thawing and connecting a sleeve of the container to the support member.

The present invention provides, in a sixth aspect, a system for freezing, storing and thawing a biopharmaceutical material that includes a container adapted to receive the biopharmaceutical material therein for freezing and later thawing. The container is configured to conform to the shape of an interior of a temperature control unit, when substantially filled with the biopharmaceutical material, and / or to the shape of a protective structure adapted to receive the container.

The present invention provides, in a seventh aspect, a system for freezing, storing and thawing a biopharmaceutical material that includes a flexible container adapted to contain the biopharmaceutical material. The flexible container is adapted to substantially conform to the shape of a first interior of a temperature control unit and is adapted to substantially conform to a second interior of a storage vessel.

The present invention provides, in an eighth aspect, a method for freezing, storing and thawing a biopharmaceutical material that includes providing a sterile container adapted to contain the biopharmaceutical material for freezing and configuring the sterile container to conform to the shape of an interior. of a temperature control unit.

The present invention provides, in a ninth aspect, a system for storing a biopharmaceutical material that includes a flexible container configured to contain the biopharmaceutical material for freezing, wherein the flexible container further includes a means for mechanically accommodating with at least one unit. temperature control and a storage vessel to support the flexible container.

The present invention provides, in a tenth aspect, a system for freezing, storing and thawing biopharmaceutical material, which includes a flexible container, a conduit and a temperature control unit. The flexible container is adapted to receive a liquid biopharmaceutical material therein for freezing, storage and thawing, wherein the container completely encloses an inner part to receive the biopharmaceutical material. Also, the container is configured to form a three-dimensional shape when filled with the biopharmaceutical material wherein the three-dimensional shape has a first side and a second side opposite the first side. The conduit is connected to the flexible container to allow the container outlet to be in fluid communication with the interior through the conduit. The temperature control unit includes a first surface and a second surface facing the first surface. Also, the temperature control unit is configured to receive the flexible container therein, when the container is filled with the biopharmaceutical material. The container conforms to the shape of the inside of the temperature control unit and the first side and the second side of the container make contact with the first surface and the second surface of the temperature control unit, when the container is substantially filled with the biopharmaceutical material. The first and / or second surfaces of the temperature control unit include a heat transfer surface.

Brief description of the drawings

The subject matter to which the invention refers is clearly stated and claimed in the claims at the end of the specification. The foregoing and other features, as well as the advantages of the invention, will be readily understood from the following detailed description of the preferred embodiments taken in conjunction with the accompanying drawings in which:

Figure 1 is a perspective view of a flexible container in accordance with the present invention;

Figure 2 is a perspective view of the flexible container of Figure 1 received in a frame;

Figure 3 is a perspective view of another example of a flexible container with a smaller capacity than that shown in Figure 2, being received in a frame, according to the present invention;

Figure 4 is a perspective view of another example of a frame supporting the flexible container of Figure 2, in which the frame includes foot members;

Figure 5 is a perspective view of a temperature control unit that receives the frame and the flexible container of Figure 2 inside it.

Figure 6 is a cross-sectional view of the temperature control unit of Figure 5;

Figure 7 is a perspective view of the frame and the flexible container of Figure 2 that can be received in a protective cover;

Figure 8 is a perspective view of the frame and the flexible container of Figure 4 that can be received in a protective cover;

Figure 9 is a perspective view of a plurality of flexible containers and frames received in protective covers of Figure 8, being stacked one on top of the other;

Figure 10 is a perspective view of the frame and flexible container of Figure 2 showing a channel for receiving the drainage pipe that can be connected to the flexible container;

ES 2 265 057 T3

Figure 11 is a perspective view of the flexible container of Figure 2 connected to the drain tube receivable in the channels of Figure 10;

Figure 12 is a perspective view of the frame and flexible container of Figure 2 including the drain tube that can be received in the cavity located between the flexible container and the top of the frame;

Figure 13 is a perspective view of a trolley device for transporting one or more frames and flexible containers of Figure 2;

Figure 14 is a perspective view of the carriage of Figure 13 adjacent to the temperature control unit of Figure 5 for transporting the frame of Figure 2 between them;

Figure 15 is an exploded view of another embodiment of a flexible container for carrying biopharmaceutical materials, receivable in a modular frame, in accordance with the present invention;

Figure 16 is a perspective view of the flexible container of Figure 15;

Figure 17 is a perspective view of the flexible container of Figure 15 connected to the upper handle of the frame of Figure 15;

Figure 18 is a perspective view of the flexible container received in the frame of Figure 15;

Figure 19 is a perspective view of a portion of the frame of Figure 15 illustrating a mooring loop of the flexible container being connected to a mooring shoulder of the frame;

Figure 20 is a perspective view of yet another embodiment of a flexible container for storing and freezing biopharmaceutical materials, being received in a clamp armature, in accordance with the present invention;

Figure 21 is a perspective view of the flexible container and frame of Figure 20 in an open position illustrating the flexible container placed in the frame;

Figure 22 is a perspective view of the flexible container and frame of Figure 20 showing a rotatable side that is closed;

Fig. 23 is a perspective view of yet another embodiment of a flexible container for storing and freezing biopharmaceutical materials in which the flexible container receives a support rod in accordance with the present invention;

Figure 24 are perspective views of various support rods for receiving flexible containers of different capacities;

Figure 25 is a perspective view of one of the support rods of Figure 24 received in the sleeves of a plurality of flexible containers for storing and freezing biopharmaceutical materials;

Figure 26 is a perspective view of the flexible container of Figure 23 being received in a protective cover, in accordance with the present invention;

Figure 27 is a perspective view of the flexible container and support rod of Figure 24, received in a cart device for transporting one or more flexible containers;

Figure 28 is an enlarged perspective view of a portion of Figure 27 illustrating the flexible container and support rod of Figure 23, received in the carriage of Figure 27;

Figure 29 is a perspective view of yet another embodiment of a support rod received in a sleeve of a flexible container and the support rod being received on support members of a cart for transporting the flexible container, in accordance with the present invention;

Figure 30 is a side elevation view of a frame and flexible container of Figure 20 configured to fill the container;

Figure 31 is a side elevation view of a frame and flexible container of Figure 20 configured to drain the container;

Figure 32 is a side elevation view of a flexible container and frame of Figure 20 configured to drain the container;

Figure 33 is a block diagram of another embodiment of a system for freezing, storing and thawing biopharmaceutical material in accordance with the present invention;

Figure 34 is a perspective view of parts of a container for storing and freezing biopharmaceutical materials in the form of a flexible container usable in the system of Figure 33 before assembly thereof;

Figure 35 is a perspective view of parts of the flexible container of Figure 34 after they have been welded;

Figure 36 is a perspective view of the flexible container of Figure 35 after it has been assembled;

Figure 37 is a perspective view of another embodiment of a container for storing and freezing biopharmaceutical materials including a flexible, sterile container and a rigid support usable in connection with the present invention;

Figure 38 is a side elevation view of a storage structure usable in the system depicted in Figure 33 to receive a flexible container for containing biopharmaceutical material;

Figure 39 is an end elevation view of the storage structure of Figure 38;

Figure 40 is a cross-sectional view of the storage structure of Figure 38;

Figure 41 is a cross-sectional view of the end elevation view of Figure 39;

Figure 42 is a side elevation view of the storage structure of Figure 38 further including a conduit;

Figure 43 is a side elevation view of two copies of another embodiment of a storage structure usable in the system depicted in Figure 33 for holding a flexible container for containing biopharmaceutical material;

Figure 44 is an elevation view of the storage structure of Figure 43;

Figure 45 is a cross-sectional view of the storage structure of Figure 44;

Figure 46 is a side elevation view of the storage structure of Figure 44, including the flexible container of Figure 33 therein;

Figure 47 is a perspective view of the storage structure of Figure 44 being folded;

ES 2 265 057 T3

Figure 48 is a block diagram of a system for regulating the temperature of a plurality of flexible containers for containing biopharmaceutical material, in accordance with the present invention;

Figure 49 is a cross-sectional view of a portion of the system of Figure 48 having pointed interior portions including a plurality of flexible containers inserted therein;

Figure 50 represents a cross-sectional view of the system of Figure 48, in which the flexible container is integrally formed with a top plate within a temperature control unit;

Figure 51 is a cross-sectional view of a portion of a flexible container integrally formed with a top plate, in accordance with the present invention;

Figure 52 is a cross-sectional view of another embodiment of a flexible container for containing biopharmaceutical material received in a temperature control unit, in accordance with the present invention;

Figure 53 is a top elevation view of the flexible container and the temperature control unit of Figure 52;

Figure 54 is a cross-sectional side view of a portion of the flexible container of Figure 52 further depicting a weld of an upper portion to a continuous wall of the flexible container; Y

Figure 55 is a cross-sectional side view of another embodiment of a system for storing biopharmaceutical material, including a plurality of flexible containers that are received in a temperature control unit, in accordance with the present invention.

Detailed description

In accordance with the principles of the present invention, systems and procedures are provided for freezing, storing, and thawing biopharmaceutical materials.

When processing biopharmaceutical materials such as cells for cryopreservation, for example, if the cells are frozen too fast, with too high a water content, the cells can develop intracellular ice crystals. As a result of this, cells can break down and / or become unviable. On the other hand, if cells are frozen too slowly, they are exposed to overly concentrated solutes for a longer period of time, which can also lead to cell damage.

The rate of freezing can affect the distribution of biopharmaceutical material within a frozen volume with a non-uniform distribution of biopharmaceutical materials, leading to deleterious effects. In one embodiment, freeze rate control can be represented as dendrite freeze forward rate control, with the dendrite freeze front moving from a cold wall within a block region of the biopharmaceutical material. The rate of freezing also affects the final frozen matrix, which may have characteristics that are protective of the biopharmaceutical material or harmful to the biopharmaceutical material. For example, a frozen matrix with biopharmaceutical material embedded within a vitrified part between dendritic ice crystals can be of the biopharmaceutical material protective type. Matrices harmful to biopharmaceutical material take different forms; for example, (1) a very tight cellular ice crystal matrix or (2) a montage of a large number of fine ice crystals with product layered very thinly along the crystal edges. The characteristics of the frozen matrix depend on the ice crystal structure, with the preferred structure being the dendritic ice crystal structure. Said desirable matrix structure depends mainly on the freezing front velocity with other important factors second, such as the temperature gradient, the composition and concentration of solutes and the geometry of the freezing container.

In accordance with the present invention, maintaining the speed of a dendritic ice crystal freezing front (hereinafter referred to as "dendritic freezing front") in a range from about 5mm per hour to about 250mm per hour, or more preferably, in a range from about 8mm per hour to about 180mm per hour, or most preferably, In the range of about 10mm per hour to about 125mm per hour, advantageous cryoprocessing conditions are provided in a wide range of feasible operating ranges and systems so that damage to biopharmaceutical materials can be minimized or avoided.

As an example, the following discussion illustrates the relationship between dendritic freezing front velocity and the size and spacing of frozen dendrites in the context of freezing biopharmaceutical materials.

If the velocity of the dendritic freeze front is much lower than about 5 mm per hour, the dendrites may be small and densely packed within the dendritic freeze front. Consequently, the dendritic freezing front behaves as a solid interface with solutes and biopharmaceutical materials not being integrated within the solid mass, but instead being rejected and pushed towards the center of a flexible sterile container thus causing severe cryogenization. in the liquid phase of biopharmaceutical materials.

As the rate of the dendritic freezing front increases to, but remains still less than about 5 mm per hour, the growth of the dendrites becomes somewhat larger in size and further apart, developing in cell or columnar patterns. In this case, still only a small percentage of the solutes or biopharmaceutical materials become embedded within the solid mass. Instead, most solutes and biopharmaceutical materials are driven forward by the advancing dendritic freezing front and their concentration increases in the liquid phase of biopharmaceutical material 110. This situation can result in damage to biopharmaceutical materials .

As the velocity of the dendritic freezing front increases up to, but remains still less than about 5 mm per hour, the growth of the dendrites becomes somewhat larger in size and further apart, developing in pa5

ES 2 265 057 T3 cell or column trones. In this case, still only a small percentage of the solutes or biopharmaceutical materials can become embedded within the solid mass. Instead, most solutes and biopharmaceutical materials are driven forward by the advancing dendritic freezing front and their concentration increases in the liquid phase of biopharmaceutical material 110. This situation can result in damage to biopharmaceutical materials.

If the velocity of the dendritic freezing front increases above approximately 250 mm per hour, the dendrites begin to decrease in size and become more compactly packed, thereby losing the ability to properly embed solutes and particles comprised on biopharmaceutical materials within the freeze front.

If the velocity of the dendritic freezing front is much higher than about 250 mm per hour, the resulting solid mass comprises a random, unbalanced structure of fine ice crystals. Such rapid cryocooling could be achieved, for example, by supercooling small volumes of biopharmaceutical materials, by freezing biopharmaceutical materials in thin layers, or by immersing small volumes of biopharmaceutical materials into liquid nitrogen or other cryogenic fluids.

For example, in biopharmaceutical materials subjected to super cooling in a liquid phase followed by rapid ice crystal growth, the velocity of the dendritic freezing front exceeds 1000 mm / s. Such rapid dendritic front velocities can create solid masses comprising biopharmaceutical materials, where the solid masses are not made up of balanced ice crystals. These unbalanced solid masses are prone to ice recrystallization when the dissolution of smaller ice crystals and the growth of larger crystals can impose excessive mechanical forces on biopharmaceutical materials. In addition, biopharmaceutical materials in unbalanced solid masses can be distributed between ice crystals in very thin layers over the granulate boundaries. This produces a large ice product contact interface area, due to the very large number of small ice crystals, which is detrimental to biopharmaceutical materials.

The spacing between dendrites can be regulated by increasing or decreasing the heat flux out of the system (thereby influencing thermal effects and the resulting velocities of the dendritic freezing front), and through the selection and concentration of solutes.

The length of the free dendrites may depend in part on the velocity of the front and the temperature gradient along the dendrites. Free dendrite can refer to the length of the dendrite that sticks into the liquid phase or, alternatively, the thickness of a "watery zone" or "phase two zone", for example, a mixture of glass needles. of dendritic ice and the liquid phase between them. At the tips of the dendrites, the temperature is close to 0 ° C, and gradually decreases to adjust the wall temperature along the length of the dendrite and the solidified mass away from the front. The temperature of the liquid between the dendrites also decreases with proximity to the cold wall. As cryocooling continues, with certain solutes such as salt, the solute concentration reaches a eutectic concentration and temperature.

The solution between the dendrites then solidifies, reaching the complete or substantially complete solid or dendritic state. This state is a matrix of dendritic ice crystals and solidified solutes in a eutectic state between those dendritic ice crystals. Some solutes (for example, bicarbonate) do not form eutectics. Instead, they can form a glassy state or crystallize between dendritic ice crystals. The glassy state can protect a biopharmaceutical, while a crystalline state can have a detrimental effect on a biopharmaceutical. Dendritic ice crystals are further described in "Developing Large-Scale Cryopreservation Systems for Biopharmaceutical Systems", written by R. Wisniewski, of BioPharm 11 (6): 50-56 of 1998, and in "Large Scale Cryopreservation of Cells Components and Biological Solutions ”, written by R. Wisniewski, BioPharm 11 (9): 42-61 of 1998, which are incorporated herein by reference.

In an exemplary embodiment illustrated in Figures 1 through 6, the parts of a system for refrigerating, freezing, preserving, processing, transporting, thawing, and storing biopharmaceutical materials are shown. The system may include a sterile container, such as a flexible container 10, adapted to contain the biopharmaceutical materials and adapted to be supported by means of a support structure, such as a frame 15. The flexible container 10 and armature 15 can also be adapted to be received in a temperature control unit 20, a transport device 290 (Figures 13 and 14), and / or a storage unit.

Flexible container 10 may be formed of a laminated film that includes a plurality of layers and may have an interior volume ranging from 0.01 to 100 liters, for example. In addition, the flexible container 10 could be available in various sizes to accommodate different uses, for example, flexible 5, 10 and 20 liter containers can be used. It is also possible to form a contact layer with the biocompatible product inside the flexible container 10 of a low density polyethylene, ethylene polyethylene very low density vinyl acetate copolymer, polyester, polyamide, poly (vinyl chloride), polypropylene, polyfluoroethylene, polyvinylidene fluoride, polyurethane or fluoroethylenepropylene, for example. A gas and water vapor barrier layer can also be formed of an ethylene / vinyl alcohol copolymer blend within a polyamide or ethylene vinyl acetate copolymer. In addition, the flexible container 10 can include a layer with high mechanical forces (for example, a polyamide), and an outer layer with insulating effect to heat welding, for example, polyester. The layers can be compatible with hot and cold conditions and can be able to resist ionizing radiation for sterilization purposes. Also, the flexible container 10 may have a large surface area to volume ratio, and a relatively thin wall thereby stimulating heat transfer through it when received at the temperature control unit 20. An example of useful materials for

ES 2 265 057 T3 formulation of flexible container 10 is described in United States Patent No. 5,988,422 to Vallot, the object of which is incorporated herein by reference in its entirety. Also, the flexible container 10 may be disposable, thus promoting ease of use and the prevention of cross contamination within the flexible container 10 which could occur when other types of containers are reused.

The sterile, flexible containers 10 can be adapted to be received in a truss 15 to support the flexible container 10. For example, the flexible container 10 may include an outwardly extending flange 100 adapted to be received in a truss channel 200. 15, as depicted in Figures 1 through 3. For example, flange 100 could be a reinforced plastic rod sized to be received in channel 200. In this way, the flange 100 and therefore the flexible container 10, can be inserted vertically downwards or can be withdrawn vertically upwards, but cannot be moved laterally or in other directions than up and down due to to the mechanical coupling of flange 100 with channel 200. In this way, the flange 100 serves as a support for the flexible container 10 on the side, preserves a shape of the flexible container 10 during filling thereof, reduces the deformation of the container 10 and ensures the dimensional stability of the flexible container 10 by expanding a load. placed thereon along three different sides of the flexible container 10, that is, both sides and the bottom thereof.

In addition, the flexible container 10 may include a vertically extending flange or rod (not shown) projecting from an upper side 11 of the flexible container 10. The vertically extending flange may be configured to be received in the channel. 200 and may be substantially perpendicular to flange 100. The vertically extending flange may also be configured to connect to an upper portion of the frame 15 to reduce deformation of the flexible container 10 when the flexible container 10 is received in the frame 15.

The flexible container 10 may also include a tab 110 or other means for receiving a tag to provide an indication to a user of the contents of the flexible container 10. Such tag may include written information, a built-in microchip, an RF transmitter, and / or an electronic or magnetic barcode for the indication of the content of the flexible container 10 to facilitate the identification, monitoring and / or characterization of the content thereof. The use of the tag can thus simplify the management of materials stored in a flexible container 10, received in a frame 15, when stored in a large freezer containing other frames and flexible containers that may appear similar to this one.

As shown in Figure 2, the flexible container 10 may include one or more ports or conduits 120 to allow the filling or draining of biopharmaceutical materials or other solids, liquids, or gases into and / or out of the interior (not shown ) of the flexible container 10. Lines 120 can also be used to insert a measurement probe (not shown) into flexible container 10 (e.g., pH electrode, conductivity sensor, temperature probe, ion sensitive electrode, probe spectrophotometric, an ultrasonic sensor, an optical fiber). The conduits 120 may be located at the top of the container and / or at the bottom of the flexible container 10. The position of the conduits can facilitate the filling and / or drainage of the containers. Conduit 120 can be integrated into flexible container 10 or can be connected to a receiving port (not shown) thereof. For example, conduit 120 could be connected to a receiving port using a fitting located within the inlet port. Assemblies such as those described in US Patent No. 6,186,932 can be used to connect such conduits. Also, assemblies that can maintain the sterility of the contents of the container or the flexible container can be preferably used. The mounts can be configured in different shapes, such as straight mounts and / or curved mounts including ninety (90) degree elbows, if desired. In another example, conduit 120 may include a filter (not shown) to filter out any impurities or other unwanted materials from the biopharmaceutical material.

The temperature control unit 20 is configured to control the temperature of an interior 25 thereof, as shown in Figures 5 and 6. Also, the temperature control unit 20 may include within, or may be coupled to, a controller (not shown) to allow a user to control the heating, cooling, freezing or thawing, for example, of biopharmaceutical materials. in the flexible container 10, when inserted into the interior 25 of the temperature control unit 20. The heating, cooling, freezing or thawing of the contents of the flexible containers 10 located within the temperature control unit 20 can be controlled by blowing a continuous flow of hot or cold air, through direct contact of the containers. with hot and cold surfaces, or by spraying a cooling fluid (eg liquid nitrogen), for example.

In a preferred embodiment, the temperature control unit 20 is a heat exchanger that has one or more conduction plates for heating and / or cooling the flexible container 10 and the biopharmaceutical material contained therein, as represented in FIGS. Figures 5 and 6. For example, the temperature control unit 20 may include plates 28 for contacting the flexible container 10 to cool the contents thereof. Also, one or more of the mentioned plates 28 are movable to allow compression of the flexible container 10 when the flexible container 10 is received inside the frame 15 and the frame 15 is received inside 25 of the temperature control unit. 10. In addition, the temperature control unit 20 may include one or more non-temperature controlled walls (not shown) separated from the plates 28 that may be configured to compress the flexible container 10, when the flexible container 10 is received. in the armature 15 and armature 15 it is received inside 25 of the temperature control unit 20, as shown in figure 6.

ES 2 265 057 T3

For example, the temperature control unit 20 may control a rate of the rate of the dendritic freeze front (not shown) within the biopharmaceutical materials through feedback temperature information relative to the biopharmaceutical materials from one or more temperature sensors (not shown) that can be inserted into container 10 through ports 120 or that can be connected to or integrated into plates 28. This feedback loop allows more precise control of heat removal from biopharmaceutical materials and makes it easier to control the speed of the dendritic freeze front to be within the indicated ranges. Variables such as the thickness of the flexible sterile container 10, the thickness of the armature 15, the thermal resistance between the flexible sterile container 10 and the plates 28. etc., are automatically taken into account through the feedback loop.

The dendritic freezing front separates the biopharmaceutical materials presented as a solid mass from the liquid form of the biopharmaceutical materials, thereby producing a solid-liquid interface at which dendrites are formed. As heat removal from the biopharmaceuticals continues, the dendritic freeze front advances away from the interior surface of the flexible sterile container 10, as additional liquid biopharmaceuticals frozen within a solid mass. In one embodiment of the present invention, the speed of the dendritic freezing front is the speed with which the dendritic freezing front advances.

In one embodiment, the rate at which heat is removed (ie, heat flux) from the biopharmaceutical materials determines the rate of the dendritic freeze front. Since the temperature gradient between the biopharmaceutical materials and the plates 28 is correlated with the rate at which heat is removed from the biopharmaceutical materials, the rate of the dendritic freeze front can be controlled by controlling the temperature of the plates. 28.

In a preferred embodiment, heat is removed from the biopharmaceutical materials at a rate that promotes substantially uniform advancement of the dendritic freezing front within substantially the entire volume of the biopharmaceutical materials or a substantially constant rate of the dendritic freezing front. Maintaining a substantially constant velocity of the dendritic freezing front within the flexible sterile container 10 in accordance with one embodiment of this invention is desirable because it provides substantially steady-state conditions for uninterrupted dendritic ice crystal growth, regardless of dendritic ice crystal growth. distance to the chilled heat transfer source within freezing volume.

The frame 15 may be formed to receive and hold a flexible container 10 to provide additional rigidity and supports to the flexible container 10, thereby facilitating handling, storage and / or temperature control thereof. Armature 15 may include a first aperture 210 and a second aperture 211 (Figure 6) on an opposite side of armature 15 from aperture 210. These openings expose a large surface area of ​​the flexible container 10 to the interior 25 of the temperature control unit 20. Through these openings, the flexible container 10 can come into contact with heat transfer surfaces such as plates. 28 (from Figure 6), the air at a controlled temperature, or the liquid cooling spray inside the temperature control unit 20. For example, a first side 12 of the flexible container 10 may come into contact with a heat transfer surface (for example, one of the plates 28) inside 25 of the temperature control unit 20 (Figure 5) through of the opening 210 to control the temperature of the biopharmaceutical material in the flexible container 10. Alternatively, side 12 of flexible container 10 may be exposed to static or circulating air within temperature control unit 20. For example, biopharmaceutical material may be frozen or thawed while in flexible container 10, when the flexible container 10 is received within the armature 15 and the armature 15 is received within the temperature control unit 20.

Also, the flexible container 10 can be adapted to be compressed by means of plates 28 (figure 6), when substantially filled with the biopharmaceutical material, and the flexible container 10 and the armature 15 are received inside 25 of the control unit. temperature 20. Furthermore, the contents of the flexible container 10 can freeze or solidify while the plates 28 compress it in the temperature control unit 20 to cause the flexible container 10 to have a dimension or width 115 in a direction between the first opening 210 and the second opening 211 (Figure 6) of the frame 15, which is less than or equal to the dimension or width 230 of an interior 240 of the frame 15 in the same direction as the dimension 115. In this way, the flexible container 10 that has the biopharmaceutical material frozen in its interior can be confined within an envelope or thickness defined by the armor 15. By means of the compression of the flexible container 10 in the armor 15, a profile is created of substantially rectangular cross-section of the flexible container 10 that has the biopharmaceutical material therein. Such a cross-sectional profile encourages contact between the flexible container 10 and the heat transfer plates 28. This is particularly true at the corners of the flexible container 10, thus allowing freezing to take place in a uniform manner in one direction. normal to plates 28. Furthermore, compression of the flexible container 10 can force the biopharmaceutical material in the flexible container 10 to occupy any void or space between the plate 28 and the flexible container 10. By reducing or minimizing said voids or spaces, the contact of the plate 28 with the flexible container 10 can be more uniform and in this way can cause a more uniform cooling of the biopharmaceutical material contained in the flexible container 10.

Frame 15 may further include upwardly extending sides 260, bottom 270, and top 280 to protect and support flexible container 10. Top 280 may be hinged to frame 15 to allow top 280 to open and allow flexible container 10 to be inserted into interior 240, and top 280 to be closed to protect

ES 2 265 057 T3 the flexible container 10. Also, the upper part 280 may include a handle 285, as best shown in Figure 4, and the upper part 280 may be attachable so that it can be removed to the sides 260 In this way, a user can connect the top 280 to the sides 260 to allow the handle 285 to be grasped to carry the frame 15 with or without the flexible container 10 received therein, which may contain biopharmaceutical material. The armature 15 may preferably be formed of materials that remain stable and retain their structural properties. Specifically, such materials should retain their load bearing capacity and exhibit glass transition temperatures of no more than -80 ° C while being resistant to cleaning agents and procedures commonly used in biopharmaceutical manufacturing, for example, hydroxide. sodium, sodium hypochloride (ChlorOX), peracetic acid, etc.

For example, the sides 260 can be formed of fluoropolymer resin (ie, TEFLON) at the top 280, and the bottom can be formed of stainless steel. Also, the sides 260, bottom 270, and / or top 280 can be made from any number of other materials including aluminum, polyethylene, polypropylene, polycarbonate, and polysulfone, for example. Additional materials may include composite materials such as glass reinforced plastic, carbon fiber reinforced resins, or other engineering plastic materials known to offer high strength to weight ratios and serving various temperatures of interest. Those skilled in the art will understand that the sides 260, bottom 270, and / or top 280 may be monolithic and integrally formed as one piece or suitably connected together. Also, the sides 260, bottom 270, and / or top 280 could be formed from the same material (eg, stainless steel) or could be formed from different materials and connected together. The frame 15 may also include one or more foot members 14 to hold the frame 15 in a vertical position, as depicted in Figure 5. As will be understood by those skilled in the art, the foot members 14 may be integrated or connectable. to one or more sides 260 of the truss 15.

In addition, the armor 15 can be adapted to be received within a protective structure or cover 250 to protect the flexible container 10, as shown in Figures 7 and 8. The protective cover 250 can cover the opening 210 and / or the second opening 211 to protect the flexible container 10, when the flexible container 10 is received inside the frame 15, to prevent it from receiving a puncture or in any case damaged. In addition, protective cover 250 may also include a plurality of openings 255 to facilitate heat transfer therethrough, when flexible container 10, armature 15, and cover 250 are received within the temperature control unit. 20 (Figure 5) or another temperature controlled environment, such as a chamber freezer.

The openings 255 also allow a visual control of the interior of the flexible container 10, when the protective cover 250 covers the frame 15. Two or more frames 15 enclosed in the protective cover 250 are stacked horizontally or vertically, as shown in the figure 9, for example. In both situations, intimate contact between the adjacent faces of the stacked boxes can be avoided by wedges (not shown) to allow unobstructed air passage. This arrangement is favorable for rapid and uniform temperature control when the interior 25 of the temperature control unit 20 is cooled or heated through the effect of air convection. Protective cover 250 also allows flexible liquid-filled containers to be smoothed down to a thickness defined by the inner surface of protective cover 250 for more efficient storage and handling. In addition, the cover 250 may be configured to receive the flexible container 10 from the top thereof or from the bottom thereof, as is apparent from Figures 7 and 8, respectively.

The armature 15 can also support the auxiliary equipment and tubes. For example, as depicted in Figure 10, truss 15 may be equipped with a channel 16 along one or more sides 260 and / or bottom 270 to route drain tubes 282 (Figures 10 to 12) . The flexible container 10 may be connected to an integrated or drainage tube 282 that may be configured to be received in the channel 16, that is, it may include a horizontally extending portion 286 and a vertically extending portion 287 to conform to the horizontal and vertical portions of channel 16, as depicted in Figure 11. A compartment or cavity 19 may be located between the top 11 of the flexible container 10 and the top 280 of the armature 15, as shown in Figure 12. The cavity 19 can receive the drain tube 282 for storage prior to storage. use drain tube 282 to drain inside flexible container 10. In addition, cavity 19 may include capstans 284 around which drain tubes 282 may be wrapped for storage thereof. Cavity 19 can also be used to hold flexible container accessories such as wind filters, line filters, connectors, and sampling ports (not shown). The cavity 19 can provide protection for accessories during storage and transportation. Accessories are often made of plastic that can become brittle at low temperatures. The cavity 19 can secure the accessories in a secure position thereby preventing the accessories from slipping out of the frame 15 and the flexible container 10 and from being damaged or broken.

Furthermore, the frame 15 can be adapted to be received in a storage unit or a transport device, such as a carriage 290, as shown in Figures 13 and 14. For example, the width 230 of the frame 15 may be less than or equal to the dimension or width 295 of a channel 297 of carriage 190 to allow frame 15 to be received on carriage 290. Also, a bottom side 298 of the channel 297 may be at the same or similar height as the height of the bottom side of the interior 25 of the temperature control unit 20, as shown in Figure 5 and Figures 13 and 14 to allow frame 15 to be easily slidable from carriage 290 into interior 25 of temperature control unit 20. In addition, temperature control unit 20 may also include

ES 2 265 057 T3 a movable support 22 to hold the frame 15 inside 25 of the temperature control unit 20. The movable support member 22 can also be advanced outside the interior 25 with the frame 15 supported thereon . In this way, movable support member 22 can be advanced to a point where armature 15 can be slid out of movable support member 22 into channel 297 of carriage 290. Also, channel 297 may include one or more channel supports 292 to hold armature 15 in channel 297.

The temperature control unit 20 can also include an armature advance mechanism 15 outside the interior 25 of the temperature control unit 20, which can be activated by means of a lever 23, as shown in the figure. 5. For example, the frame advancement mechanism may include a movable support member 22 that is advanced in response to activation of lever 23. In this way, the frame 15 can be easily moved from inside 25 of the temperature control unit 20 to the carriage 290 through the movement of the movable support member 22 that holds the frame 15, when the temperature control unit temperature 20 and carriage 290 are located adjacent to each other. The cart 290 may have insulating walls to reduce heat losses during storage or transportation of the frame 15 that supports one or more flexible containers 10. In addition, for long-term storage of the biopharmaceutical product contained in the flexible container 10, in the liquid state or in the frozen state, a chamber freezer, chest freezer or refrigerator cabinet (not shown) can be equipped with rails or supports. channel (not shown) adapted to receive trusses 15.

The armature 15 can secure the flexible container 10 in a defined position. Said arrangement facilitates the handling and transportation of the flexible liquid-filled container 10. In particular, the filling and draining operations are facilitated by means of a self-holding position of the flexible container 10 held by the frame 15, when it is held by members standing 14. Alternatively, the flexible container 10 can be filled and / or drained while the armature 15 that has a flexible container 10 inside it is located within the carriage 290. Classically, flexible liquid-filled containers are drained by means of gravity. . Flexible containers are generally hung upside down or at least tilted to allow for complete drainage. This operation can be unsafe and / or bulky due to weight restrictions, for example for flexible containers with volumes greater than 10 liters. Thus, it may be desirable to secure large volume containers in self-supporting frames to facilitate drainage of the containers.

In another embodiment of the present invention, a flexible container 350 may be adapted to carry biopharmaceutical material therein to be received in a frame 360 ​​to support the flexible container 350, as shown in Figures 15 through 19. The frame 360 It may include a left side 370, a right side 380, a lower portion 390, and an upper portion 400 that can be connected to each other. Flexible container 350 may include a flange 405 and armature 360 ​​may include one or more projections or posts 420 projecting outwardly from the top 400 of armature 360 ​​in a direction substantially perpendicular to the left side 370 and the right side 380. Flange 405 may include one or more openings 410 sized to receive one or more posts 420. Specifically, the post (s) 420 can be inserted through the opening (s) 410 and the post (s) can thus hold the flange 405, and thus, the flexible container 350 and any contents thereof. One or more flanges or catch members 430 may be connected in addition to the upper part 400, they may be rotatable via hinges towards the flexible container 350, and they may be adapted to receive one or more posts 420. In this manner, when the capture member 430 is rotated towards the flexible container 350 and the posts 420 are received therein, the posts 420 can provide the hold for the flexible container 350 in a vertical position while the capture member 430 it can inhibit or prevent movement of the flange 405 of the flexible container 350 in a direction parallel to the posts 420 and away from the top 400 (eg, a horizontal direction). For example, said support in the vertical direction can inhibit the deformation of the container 350 and said support in the horizontal direction can inhibit the movement of the container 350 away from the frame 360 ​​and that it can be damaged by a foreign object, for example.

Flexible container 350 may also include one or more tie-down loops 450 that can be connected to armature 15 through tie-off projections (Figure 19), on an outer surface 385 of the right side 380, and on an outer surface (which not shown) on the left side 370, for example. The left side 370 and / or the right side 380 may also include openings 470 (Figures 15 and 19) to allow tie loops 450 to pass through to join tie pins 460. By connecting lashing loops 450 to lashing lugs 460, flexible container 350 can be secured on its bottom portions, thereby inhibiting movement of flexible container 350 away from frame 360 ​​and preventing damage. or break due to a foreign object, for example.

Also, flexible container 350 may include one or more ports or conduits 355 to allow insertion or removal of biopharmaceutical liquids or other liquids or gases into and / or outside of an interior (not shown) of flexible container 350. Referring to Figure 15, the armor 360 may include a translucent or transparent portion 480 to allow a user to view a label (not shown) or other indication to a user such as the contents of the flexible container 350, when said label or said indicator are attached to the flexible container 350. The tag could include written information, a built-in microchip, an RF transmitter and / or an electronic or magnetic barcode, for example. Furthermore, the transparent portion 480 could further include a fiber optic guide or reader or a wave guide, for example. Left side 370 and / or right side 380 may also be formed to include one or more foot members 490 to maintain frame 360 ​​in a vertical position. How will those understand

As those skilled in the art, foot members 490 may be integrated or connectable to the left side 370 and / or the right side 380.

The top 400 may include a handle 402 to allow a user to carry a flexible container 350, when the flexible container 350 is received in the frame 360, with or without the flexible container 350 being substantially filled with biopharmaceutical material. The upper part 400 may also be adapted to be connected to the flexible container 350 to allow the upper part 400 to support the flexible container, without the flexible container 350 being connected to the left side 370, the right side 380 or the lower part 390, such as it is shown in Figure 11. In this way, a user can carry the flexible container 350 connected only to the upper part 400.

In another embodiment of the present invention, an armature 600 may include a first part 610 and a second part 620 adapted to be connected or clamped to each other, as shown in Figures 20 through 22. By connecting one to the other. the other, the first part 610 and the second part 620 can also secure the flexible container 630 to carry biopharmaceutical materials between them. Specifically, the flexible container 630 may include one or more flanges 660 that can be connected between an inner surface 615 of a first part 610 and an inner surface 625 of a second part 620. The flanges 660 may include one or more openings 665 to receive posts 670 projecting from the inner surface 625 of the second part 620. The inner surface 615 of the first part 610 may also include one or more openings corresponding to the posts 670. The reception of the posts 670 in the openings 615 inhibits the movement of the flange 660, and thus the movement of the flexible container 630 when the flange 660 is received between the first part 610 and the second part 620. In this way, the flexible container 630 can be supported between a first part 610 and a second part 620 so that lateral and / or vertical support is provided to the flexible container 630 by means of a first part 610 and a second part 620 together. with posts 670. In this way, the flexible container 630 can retain its shape during filling thereof, reduced deformation of the flexible container can be achieved, and the flexible container 630 can be contained within an envelope of space defined by the armature 600.

Flexible container 630 may include one or more ports or conduits 635 to allow filling or drainage of biopharmaceutical liquids or other liquids or gases into and / or outside of an interior (not shown) of flexible container 630. Flexible container 630 may also include a label or indicator 680 protruding from frame 600 to indicate to a user the contents of flexible container 10, when said label or indicator is attached to flexible container 630. Also, a rotatable side 612 of a first part 610 can be opened to allow the flexible container 630 to protrude a lower side 614 of the first part 610, when the flexible container 630 is not substantially filled with biopharmaceutical material. This allows flexible container 630 to be extended to minimize creasing in flexible container 630 during filling thereof. After the flexible container 630 is substantially filled with biopharmaceutical material, any slack in the flexible container 630 can be tensioned and the flexible container 630 cannot protrude from the underside 614. In this way, the rotating side 612 can be closed, when the flexible container 630 is substantially filled with the biopharmaceutical material, to protect a lower part of the flexible container 630 from coming into contact with any external object.

In a further embodiment of the present invention, a flexible container 700 for containing biopharmaceutical materials may include one or more sleeves 710 to receive a support member 720 to support flexible container 700, as depicted in Figures 23 through 25. Specifically, the sleeves 710 may be dimensioned to allow the member 720 to be supported to pass coaxially therethrough, and the support member 720 may include a support rod or lancet portion 725 and a handle portion 730. Also, the Handle portion 730 may be formed so that it is positioned over the center of gravity of flexible container 700, when flexible container 700 is substantially filled with biopharmaceutical materials. The flexible container 700 may be carried by a user holding handle portion 730, for example, when the flexible container 700 is substantially filled with liquid biopharmaceutical materials. In addition, the support member 720 can be adapted to support more than one flexible container 700, as shown in FIG. 25. Also, the flexible container 700 can be received in a protective cover 750, as shown in FIG. 26. . The protective cover 750 may include an interior foam liner to inhibit or prevent shock or rupture of the flexible container 700. Also, the protective cover 750 may be insulated to maintain the flexible container 700 at a desired temperature. In addition, flexible container 700 may include a label 760 similar to label 110, to designate the contents of flexible container 700, which may protrude above an upper surface 755 of protective cover 750. Flexible container 700 may also include one or more ports or conduits 705 to allow the biopharmaceutical or other materials to be inserted into or removed from therein.

As shown in Figures 27 and 28, the support member 720 can be received in a storage unit 800, while the support member 720 supports the flexible container 700, which is substantially filled with biopharmaceutical material, for example. Specifically, a first end 722 of the support member 720 can be positioned on top of a support frame 810 of the storage unit 800 and a bottom side 732 of a handle portion 730 of the support member 720 can be place on top of a second support frame 820 of storage unit 800. Support frame 810 and second support frame 820 may include hollow portions 812 and 822, respectively, to receive support member 720. In this way, as is evident in Figure 28, support member 720 with container The flexible hose 700 attached thereto can be easily slid into the storage unit 800. Also, the sides of the recessed portions 812 and 822 can inhibit mo11

ES 2 265 057 T3 movement of the support member 720 along the support frame 810 and the second support frame 820 in a direction substantially perpendicular to a longitudinal direction of the support member 720, while contained in the unit storage 800. Furthermore, the storage unit 800 may also include dividers 840 between adjacent flexible containers 700 to inhibit contact between adjacent flexible containers which could result in damage to the flexible containers, either to the containers themselves or their contents. In another example, a support member 900 (FIG. 29) similar to support member 720, includes a toe member 910 connected thereto, which is adapted to be received and to rest on a second support frame 820 so that the support member 900 can be inserted vertically on top of support frame 810 and second support frame 820, rather than being slidable on support frame 810 and second support frame 820, as for support member 720.

Although the containers have been described herein as flexible containers, the containers can be made of a semi-rigid material such as polyethylene or the like. Such semi-rigid material can retain its shape and / or stand upright on its own when empty and when filled with a biopharmaceutical material. An example of such a container could include a container similar to a standard plastic milk jug. Containers made from such similar semi-rigid materials can benefit from the additional stiffness provided by bonding to a truss, for example. Furthermore, the containers, if formed of a flexible material or a semi-rigid material, contain outer surfaces that make contact with the inner surfaces (for example, heat transfer plates) of a temperature control unit 20 such that there is a direct contact between cooled interior surfaces (for example, at a subzero temperature) or heated from the temperature control unit 20 and the external surfaces of the container containing biopharmaceutical materials. Alternatively, the external surfaces of the containers for containing the biopharmaceutical materials may be in contact with the air flow inside the temperature control unit 20 to cause cooling and / or heating of the containers that they have the biopharmaceutical materials inside to cause the temperature control of the biopharmaceutical materials.

The biopharmaceutical material found within the flexible containers described above could in this way be cooled or otherwise thermoregulated in the temperature control unit 20 (for example, at a subzero temperature). When the aforementioned operation is completed, the flexible containers can be removed from the temperature control unit 20 by removing the flexible containers and the trusses or other support structures in which the flexible containers are received or connected thereto, for example . The trusses of other support structures that hold the flexible containers can be stored in a large refrigerator or freezer with an indoor air temperature of about minus 20 degrees Celsius, for example.

Also, the biopharmaceutical material found in the flexible containers described above can be removed from and / or inserted therein by rotating the position of the flexible containers. For example, as shown in FIG. 30, flexible container 630 received in armature 600 can be filled with liquid biopharmaceutical material through line 635 via rotating armature 600 so that line 635 is above the tube. underside of armature 600. Also, the flexible container 630 can be emptied by rotating the armature so that the conduit 635 is slightly below the bottom of the armature 600, as shown in Figure 31, or by rotating the armature 600. upside down and allowing the contents to drain, as illustrated in Figure 32. The other flexible containers described above can be filled and / or drained through in a similar manner by manipulating the trusses or support structures to which they can be attached.

A typical process for processing and / or preserving biopharmaceutical material is described as follows. The flexible container 10 is inserted into the armature 15 and the upper part 280 is closed, as shown in Figures 2 and 3. The biopharmaceutical material, eg liquid biopharmaceutical material, is inserted through the conduit 120 into the container. flexible 10. The flexible container 10 while being held on the frame 15, is then inserted into the temperature control unit 20, as shown in Figures 5 and 6, where the biopharmaceutical content is frozen in a controlled manner (for example, at -20 ° C or less), for example, so that the rate of freezing (including the rate of the dendritic freezing front from the sides of the container to the center) is controlled within the upper and lower limits, as described in US Patent Application Serial Number 09 / 905,488, thus avoiding or inhibiting the cryoconcentration of the biopharmaceutical material, thereby avoiding the undesirable degradation of the biopharmaceutical material. After the biopharmaceutical material has been frozen in the flexible container 10, the flexible container 10 can be removed from the temperature control unit 20 and placed in a large freezer, for example, a chamber freezer that has inside an air temperature of about -20 ° C, as is typically present in large medical institutions (eg hospitals).

It will be apparent to those skilled in the art from the foregoing description that the flexible container 350 (FIG. 15) may have its contents frozen or its temperature regulated and stored and stored in the same manner as a flexible container 10.

Specifically, the flexible container 350 can be received in the frame 360 ​​and the frame 360 ​​can be inserted within the temperature control unit 20 or in a different refrigerator, freezer or heater. The flexible container 630 (Figure 20) can be received in the frame 600, and can have its contents frozen in the temperature control unit 20, and the flexible container 630 can also be stored in a freezer.

ES 2 265 057 T3 camera. Similarly, flexible container 700 (FIG. 23) can receive support member 710 and can be inserted into temperature control unit 20 or other means to heat or cool its contents. Also, the flexible container 700 can be stored in a chamber freezer. From the present description it will be understood by those skilled in the art that modifications can be made to the specific examples described herein and the steps to perform the procedure to preserve, freeze and / or process the biopharmaceutical material.

Furthermore, the flexible containers described above can be removed from a freezer or other system for storing the flexible containers and the contents thereof at a controlled temperature. These flexible containers that have biopharmaceutical material inside can be received in a controlled temperature control unit to heat, melt and / or thaw the biopharmaceutical material contained in the flexible containers.

In another embodiment of the present invention, depicted in Figure 33, a system for cooling, preserving, and storing biopharmaceutical materials is shown. This system may include a flexible container such as a flexible container 1010 adapted to contain the biopharmaceutical materials, configured to conform to a shape of an interior of a temperature control unit 1020 (eg, a heat exchanger) and / or be shaped into a shape of an interior of a support structure 1032 for storing the biopharmaceutical materials.

The temperature control unit 1020 is configured to be operatively coupled to a temperature control unit 1027 to control the flow of fluid through a conductive medium, such as heat transfer plates 1040 of the unit. temperature control 1020 to control the temperature of an interior 1025 thereof. A controller 1050 allows a user to control the temperature regulation unit 1027 to control the heating and / or cooling of conductive medium, such as plates 1040, to cause freezing or thawing, for example, of biopharmaceutical materials. in a container such as a flexible container 1010, when inserted into the interior 1025 of the temperature control unit 1020. Controller 1050 may also be coupled to a temperature sensor (not shown) located within 1025 of temperature control unit 1020. The temperature sensor may be located on one or more plates 1040, for example, and can provide temperature feedback to controller 1050 to facilitate control of temperature regulating unit 1027. In United States patent application number 09 / 905,488 of July 13, 2001 and in United States patent application number 09 / 863,126 of May 22, 2001, all of these patents incorporated herein by For reference, an example of a 1020 temperature control unit is described. The cooling systems described in the aforementioned applications, and the freezing and / or thawing techniques described herein, can be used in conjunction with the systems and processes for freezing, storing, and thawing biopharmaceutical materials of the present invention. . Specifically, the cryogenic coolers or heat exchangers described in these applications can be configured to incorporate and / or receive the containers for the storage of biopharmaceutical materials described herein and their associated structures.

The flexible container 1010 may be configured to conform to the shape of the interior 1025 of the temperature control unit 1020. Specifically, the flexible container 1010 may be conformed to the interior 1025 so that any space or void can be reduced or avoided. between flexible container 1010 and heat transfer plates 1040. For example, flexible container 1010 when substantially filled may take a parallelepiped shape. In addition, the flexible container 1010 may be configured so that it can take the shapes of interiors other than that interior 1025 so that the spaces or voids between the flexible container 1010 and the heat transfer plates therein can be reduced or avoided. containers with other shapes. Although the containers are described herein as flexible containers, the containers can be made of a semi-rigid material. Such material can be used to construct a container that is shaped to conform to the interior of the temperature control unit 1020. Preferably, the container if it is formed of a flexible material or a semi-rigid material, contains surfaces that are in contact with the interior surfaces (for example, heat transfer plates) of the 1020 temperature control unit so that there is direct contact between the cooled (or heated in the defrosting process) surfaces of the temperature control unit and the outer surfaces of the container that contain biopharmaceutical materials.

In one example, flexible container 1010 when substantially filled, can form a parallelepiped shape. Flexible container 1010 can be formed by welding multiple sheets of material to form the shape of the parallelepiped, as depicted in Figures 36 and 37, among others. An example of a method for forming flexible container 1010 is depicted in Figures 34 through 36. A top film 1105 and a bottom film 1110, used to form the flexible container are placed on top of each other, and an additional film 1115 and a film 1120 are folded, for example, as bellows and inserted between the film 1105 and film 1110. Four longitudinal welds are executed to seal the four longitudinal corners of the flexible container using a hot weld on the floor. For example, 45 degree welds are made between the inner bellows and the top film 1105 and the bottom film 1110 and transverse welds are made to seal the top and bottom faces of the flexible container 1010. Flaps 1150 can be created (Figure 37) leaving a film layer on the welds at 45 degrees. Also, holes 1151 (FIG. 37) are made by punching the flaps by means of circular film welding, as is known to those skilled in the art.

ES 2 265 057 T3

In another example, a flexible container 1015 used as a container for freezing, storing, and thawing biopharmaceutical materials is depicted in FIG. 37. An inlet port 1035 allows the biopharmaceutical materials to be inserted into an interior (not shown) of the flexible container 1015 and to be removed therefrom. A tube (not shown in Figure 37) similar to that shown in Figure 42 can be connected to inlet port 1035 using a fitting located within the inlet port. Accessories such as those described in US Patent No. 6,186,932 can be used for connection of said tubes. Also, accessories that can maintain the sterility of the contents of the container or the flexible container can be preferably used. The fittings can be configured in different ways, such as straight fittings and / or angled fittings including ninety (90) degree elbows if desired. A rigid or semi-rigid bracket 1200 having holes 1151 can be inserted through slots 1210 in bracket 1200. One or more terminals 1153 can be inserted through holes 1151. In this way, a user can hold and carry a flexible container 1015 and holder 1200 by means of a handle 1250 of holder 1200. For example, each of the four flaps 1150 may contain a hole 1151. The four flaps can be inserted into each of the four slots 1210 on bracket 1200. A terminal may be inserted through each of the two holes on opposing slots. For example, long terminals (not shown) can be inserted through a pair of holes in the flaps so that two terminals can be used to attach bracket 1200 to flexible container 1015.

Although terminals are specifically mentioned herein, those skilled in the art will understand that the flexible container 1010 or other container can be used with or without the bracket 1200, and that other means of securing the flexible container can be used. 1010 to bracket 1200 such as clamps or other fastening means. Furthermore, although the container is described herein as a flexible container, the container may be made of a semi-rigid material. Such material can be used to construct a container that is shaped in accordance with the interior of the temperature control unit 1020. Preferably, the container if it is formed of a semi-rigid material or a flexible material, contains surfaces that make contact with the interior surfaces (for example, heat transfer plates) of the 1020 temperature control unit so that there is direct contact between the cooled (or heated in the defrosting process) surfaces of the temperature control unit and the external surfaces of the container containing biopharmaceutical materials.

Referring to Figures 38 through 42, a support structure such as a vessel 1060 may have an interior portion 1300 adapted to receive a container such as a flexible container 1010 and an upper portion 1310 to cover the interior 1300. The inner portion 1300 is formed in a shape substantially similar to a container containing biopharmaceutical materials, such as a flexible, sterile container 1010, when filled or when it contains the biopharmaceutical material. In this way, the walls and / or the bottom surface of the inner portion 1300 can serve to hold the flexible container 1010, when the flexible container 1010 containing biopharmaceutical material is inserted therein. The top 1310 may also include an opening 1320 to receive a conduit or tube 1330 to fill and / or empty the flexible container 1010 through, and through an inlet port of the flexible container 1010 (not shown) as is depicted in Figures 41 and 42. Opening 1320 may include a filter (not shown) to filter out any biopharmaceutical material. The flexible container 1010 in the vessel 1060 can also be emptied by turning the vessel 1060 upside down and allowing the contents to drain.

The vessel 1060 can thus receive an empty, sterile and flexible container 1010. The flexible container 1010 can be filled through a tube 1330 with the biopharmaceutical material before the flexible container 1010 is transferred to the control unit of temperature 1020 (figure 33). The flexible container can then be removed from the vessel 1060 and placed within the temperature control unit 1020 as shown in FIG. 33, where cooling and freezing occurs. After the biopharmaceutical material is frozen (for example, at -20 ° C or less) or its temperature is regulated (for example, thawing) in the flexible container 1010 in the temperature control unit 1020, the flexible container 1010 can be returned to vessel 1060, for example. Vessel 1060 may be insulated to allow transportation of flexible container 1010 to a location for use of the biopharmaceutical material. Thus, in one embodiment of the system depicted in Figure 33, the support structure 1032 for receiving, transporting, and storing a container such as a sterile flexible container 1010 comprises the insulated vessel depicted in Figures 38 through 42. However , if desired, vessel 1060 may not be insulated. Vessel 1060 can be constructed to be efficiently placed in a chamber freezer or other structure to maintain the biopharmaceutical material and flexible container 1010 in a frozen state at a desirable temperature. Furthermore, the vessel 1060 may be adapted to receive a label 1340 that can include written information and / or an electronic or magnetic barcode to indicate the contents thereof to facilitate the identification, tracking and characterization of the contents thereof. The use of the label 1340 can thus simplify the management of materials stored in the container 1060 when stored in a large freezer that contains other containers that may appear similar to it. for example, the freezer may be a chamber freezer that has an indoor air temperature of -20 ° C. In another example, the flexible container 1010 can be placed in a separate rigid container (not shown) for example, a pointed anodized aluminum container to receive the flexible container 1010 and configured to be placed within the vessel 1060 and of the temperature control unit 1020 (FIG. 33) to freeze and / or thaw the contents of the flexible container 1010. The rigid container may be made of thermally conductive material and may be constructed to

ES 2 265 057 T3 be stored in a large freezer when filled with a biopharmaceutical material.

The bottom of the vessel 1060 may contain one or more notches 1324 as shown in Figures 38 through 42. The notches 1324 are configured to receive projections 1310 that are located on the top cover of the vessel 1060. When a top 1312 placed on vessel 1060, the projections allow one or more vessels to be stacked on top of another vessel. The projections 1310 of a lower pot may fit within the notches 1324 located in the bottom of a pot stacked on top of the pot. The top cover of each vessel 1060 may also contain a hole 1320 or other passage to allow a tube 1330 connected to the container to be placed therethrough over the flexible container 1060. Such a configuration is shown in Figure 42.

In another embodiment of the invention, the support structure 1032 of Figure 33 may be in the form of a collapsible container such as a cage 1400 that is also adapted to receive the flexible container 1010 such as the one depicted in Figure 33 within inside 1410, as shown in Figures 43 through 46. Also, the cage 1400 may be adapted to be stacked with the vessel 1060 of Figures 33 and 38 through 42, or additional cages 1400 such as those shown in Figures 43 through 47, in which the top 1310 and a top 1420 of vessel 1400 include projections 1422 and projections 1310, respectively. Vessel 1060 and cage 1400 include receiving ports 1424 and 1314 respectively to receive the projections, thereby allowing stacking of cage 1400 and / or vessel 1060. The cage 1400 (Figures 43 to 47) and / or the vessel 1060 (Figures 38 to 42) could be formed of an expanded polystyrene, for example, a STYROFOAM type material, a rigid polyurethane (closed cell), polyethylene or other suitable engineering material, including composite materials, for example. Additionally, cage 1400 and vessel 1060 may be formed through injection molding, extrusion blow molding, or injection blow molding, for example. As shown in FIG. 47, the cage 1400 can be folded or folded to allow storage of the same in a less bulky manner. As such, a collapsible cage 1400 and / or vessel 1060 may be formed, for example, of polycarbonate, polysulfone, polyethylene, or other suitable engineering materials, including composite materials, for example. Such a collapsible and bendable cage 1400 can also be formed through injection molding, or the machining and assembly of the component parts thereof.

In a further embodiment of the present invention, a temperature control unit 1500 may include a plurality of receiving interior parts 1510 to receive a plurality of flexible containers 1515 adapted to contain biopharmaceutical material, as depicted in Figure 48. Each Receiving inner portion 1510 may include a plurality of heat transfer plates 1520 for regulating a temperature of one of the flexible containers 1515. The temperature control unit 1500 is coupled to a temperature control unit 1530 to regulate the temperatures of the plates 1520 in which the temperature control unit 1530 is controlled by means of a controller 1540, programmable by the Username. Controller 1540 may also be coupled to one or more temperature sensors (not shown) located on one or more interior portions 1510 (eg, on one or more plates 1520). Feedback from the temperature sensors relative to the temperature of the interior parts 1510 can allow the controller 1540 to more precisely control the temperature of the interior parts 1510 and thus the biopharmaceutical material, when the flexible containers 1515 are received. in the interior parts 1510 that contain the biopharmaceutical material.

A temperature control unit 1501 similar to that shown in Figure 48, may be adapted to receive or may include a rigid support plate 1550 that may be oriented to form a spike-shaped interior 1511, as shown. in Figure 49. Support plate 1550 may be configured to receive one or more top plates 1200 connected to flexible container 1516. Heat transfer plates 1521 within temperature control unit 1501 may be oriented to form a pointed groove. Backer plate 1550 can be formed of polycarbonate, polysulfone, or polyethylene through injection molding or machining, for example, as will be apparent to those skilled in the art. Also, the top plate 1200 may have slots 1518 adapted to mechanically engage with the receiving slots 1562 of a receiving portion 1560 of the rigid support plate 1550. In this way, flexible containers 1516 can be inserted into one of the interior parts 1511 of the temperature control unit 1501 thereby mechanically engaging the top plate 1200 with the rigid support plate 1550. The flexible container 1516 can therefore be supported on the temperature control unit 1501 to heat or cool the biopharmaceutical material contained therein, as shown in FIG. 50. It may be possible, as shown in Figure 51, to construct a container for containing the biopharmaceutical material as the combination of a flexible container 1570 integrally formed with a rigid or semi-rigid plate 1571 so that the flexible container 1570 and the upper plate 1571 are formed as a single unit.

Figures 52 through 54 depict another example of a flexible container 1600 mechanically engaged with a cell or interior 1612 of a temperature control unit 1610. Flexible container 1600 includes a flexible top 1630 that includes holes 1640 adapted for receiving the projections 1650 connected to a top 1660 of the temperature control unit 1610. Holes 1640 may be aligned with projections 1650 when flexible container 600 is inserted into temperature control unit 1610 to secure flexible container 1600 to top 1660. This support of the top 1630 of the flexible container 1600 is especially useful when the flexible container 1600 is being filled through an opening 1605 located in the top 1630 of the flexible container 1600, because in this case, the flexible container 1600 does not contain even biopharmaceutical material in the form

ES 2 265 057 T3 that the side walls or side plates 1615 of the temperature control unit 1610 can support the flexible container 1600 and the contents thereof. Also, a vessel (not shown) for storing flexible container 1600 during transport or temperature controlled storage thereof may include projections similar to projections 1650 to mechanically engage holes 1640 to support a top 1630 of the container. flexible 1600. The top 1630 may be welded to the side walls 1635 of the flexible container 1600, as shown in FIG. 55, as will be understood by those skilled in the art.

Another example of a system for freezing, thawing, storing and preserving biopharmaceutical material is depicted in Figure 55. Containers 1700, with biopharmaceutical materials inside with an integrated or removable top plate attached thereto, as described above, are adapted to mechanically couple parts 1710 of a flexible container support structure 1720. Specifically, containers 1700 include tops 1705 having notches 1707 that can be vertically inserted into notches 1712 of receiving portions 1710 thereby supporting containers 1700. Container 1700 can be filled with biopharmaceutical material through of openings 1709 while mechanically coupled with support structure 1720. When filled, the containers 1700 and support structures 1720 can be positioned so that the containers 1700 are inserted into the temperature control units 1800, as shown in Figure 55. The biopharmaceutical material of one or more More containers 1700 can in this way be cooled or regulated in the temperature control unit 1800 (for example, frozen at -20 ° C or less). When said operation is complete, the containers 1700 can be removed from the temperature control unit 1800 by removing the support structure 1720, for example, to a vessel (not shown). The vessel (not shown) or other container that is large enough to receive the support frame 1720 can be stored in a larger freezer with an indoor air temperature of -20 ° C, for example.

Another example of a procedure for freezing, thawing, storing and preserving biopharmaceutical material is described as follows. The flexible container 1010 is inserted into the support structure 1032 (figure 33) so that the vessel 1060 (figures 38 to 42) and the upper part 1310 are placed inside it, as shown in figures 41 and 42 . The biopharmaceutical material is inserted through an opening 1320 and through a conduit 1330 into the flexible container 1010. The flexible container 1010 is then removed from the vessel 1060 and is inserted into the temperature control unit 1020, as shown. shown in figure 33. The content of the biopharmaceutical material is frozen in the temperature control unit 1020 in a controlled manner, for example, so that the rate of freezing is controlled within upper and lower limits, as described in the patent application of the United States with serial number 09 / 905,488, thus avoiding or inhibiting the cryoconcentration of the biopharmaceutical material, thus avoiding the undesirable degradation of the biopharmaceutical material. After the biopharmaceutical material in flexible container 1010 is frozen, flexible container 1010 can be removed from temperature control unit 1020 and reinserted into vessel 1060 which can then be placed in a large freezer, for example, a cold room freezer with an indoor air temperature of about -20 ° C, as typically found in large medical institutions (eg hospitals). It will be apparent to those skilled in the art from the foregoing description that the contents of the flexible container 1516 (Figure 49) can be frozen or its temperature can be regulated in the temperature control unit 1500 and stored in Vessel 1060 (Figures 38 to 42). In addition, the contents of the flexible container 1600 (Figure 52) can be frozen in a temperature control unit 1610 using a plate 1615 and a support from the flexible container 1720, and the flexible container 1615 can be stored in a vessel adapted to receive the 1720 flexible container support. Furthermore, those skilled in the art will understand that modifications can be made to the specific examples described herein and to the steps to perform the biopharmaceutical material preservation procedure.

From the above description, one skilled in the art will understand that the flexible containers described herein can be adapted for use in containers, trusses, storage units, support structures, transport devices, control units. of temperature, heat exchangers, vessels and / or processors of various shapes and / or sizes. In addition, trusses, containers, support structures, heat exchangers, temperature control units, vessels and / or processors can be adapted to receive flexible containers of various shapes and sizes. These frames, vessels or support structures can be adapted for the long or short term storage of flexible containers containing the biopharmaceutical materials in liquid or frozen state, or can be adapted to transport the flexible containers containing biopharmaceutical materials in liquid or frozen state. For example, storage units, vessels, or transport devices may be insulated to allow the material to remain at a given temperature for an extended period of time. Furthermore, these flexible containers, trusses, containers, support structures, temperature control units, heat exchangers and / or processors can be adapted for use with materials other than biopharmaceutical materials. Finally, storage containers, support structures, vessels or frames can be equipped with various transport mechanisms, such as wheels, sliders, slides, dry ice storage compartments or other devices to facilitate transport and organization. thereof.

While the invention has been represented and described in detail herein, it is

ES 2 265 057 T3 It will be obvious to those skilled in the relevant art that various modifications, additions, substitutions and the like can be made without departing from the scope of the invention, and that these are therefore considered within the scope of the invention. application of the invention as defined in the following claims.