Lyophilization container

This application is filed on June 9, 2014, US Patent Provisional Application No. 62 / 009,629 (Title: Freeze-Dried), and US Patent Application No. 62 / 010,027 filed on June 10, 2014 (Title: Freeze-Dried). Title: Freeze-drying) and US Patent Provisional Application No. 62 / 142,146 (Title: Freeze-Drying Container) filed on April 2, 2015, claiming the priority of the US patent provisional application. The whole is explicitly incorporated into this application by the disclosure herein.

Freeze-drying is a process used to store and store substances such as biological substances, foods, and drugs to increase the shelf life of those substances. Freeze-drying is performed by first freezing the substance to solidify and then sublimating one component of the substance by placing the substance in a low pressure environment (below atmospheric pressure). Usually, the one component is a liquid at standard temperature and standard atmosphere, and water is an example.

<p>Depending on the type of substance and the volume to be lyophilized, the process may take several days to complete. There is a need to improve the efficiency of lyophilizing and shorten the lyophilization time without affecting the ability of the lyophilized material to be used later.</p><p>Embodiments of the present invention have been made in consideration of the above points and other points. However, the issues described herein do not limit the use of embodiments of the present invention.</p>

<p>This section is intended to illustrate some embodiments of the invention in a simple form and is not intended to identify the important or essential elements of the invention claimed. It is not intended to limit the scope of the claims.</p><p>Some embodiments relate to containers for lyophilizing, storing and infusion of blood components. In certain embodiments, the container comprises a first wall containing a flexible polymeric material and a second wall that is joined to the first wall to define the internal volume of the container. In certain embodiments, the second wall is made of a gas permeable material that allows gas to move from the inside to the outside of the container. In some embodiments, the container has a second chamber (or second portion) in which the lyophilized material is stored after treatment.</p><p>Another embodiment relates to a method of lyophilizing a multi-component liquid. In certain embodiments, the method comprises holding the multi-component liquid in a container and exposing the multi-component liquid to a first pressure below atmospheric pressure. Then, at least one component of the multi-component liquid is evaporated for a predetermined time. After evaporation, the multi-component liquid is frozen to form a solid. In some embodiments, the multi-component liquid is molded (eg, pressed by compressive force) during freezing. The solid is then exposed to a second pressure lower than the first pressure. Then, a part of the solid is sublimated. Then, one component in the solid is desorbed from the solid.</p><p>Yet another embodiment relates to a system for lyophilizing a multi-component liquid. An embodiment of the system comprises a first plate having a first surface and a second plate having a second surface facing the first surface. The second plate has a channel for circulating the fluid. The system further comprises a plate operating system that operates to increase and decrease the space between the first surface and the second surface. In some embodiments, the first plate has a second layer constituting the first surface. In some embodiments, the second layer is an infrared radiator for adding energy to the lyophilized material.</p><p>Non-restrictive and non-comprehensive embodiments are described with reference to the accompanying drawings.</p>

<figref num="1">FIG. 1 is a diagram of a first embodiment of an apparatus for freeze-drying a substance.</figref><figref num="2">FIG. 2 is a diagram of a second embodiment of an apparatus for freeze-drying a substance.</figref><figref num="3">FIG. 3 is a diagram of an embodiment of a shelf system.</figref><figref num="4">FIG. 4 is a diagram of the shelf system of FIG. 3 with the plate moved relative to the state of FIG.</figref><figref num="5">FIG. 5 is a diagram of a second embodiment of the shelf system.</figref><figref num="6">FIG. 6 is a diagram of the shelf system of FIG. 5 with the plate moved relative to the state of FIG.</figref><figref num="7">FIG. 7 is a diagram of an embodiment of a mechanism for moving two plates of a shelf system, which is part of the system shown in FIGS. 3-6.</figref><figref num="8">8A and 8B are diagrams of a first embodiment of the structure of two plates used as part of a shelf system.</figref><figref num="9">FIG. 9 is a diagram of a second embodiment of the structure of two plates used as part of a shelf system.</figref><figref num="10">FIG. 10 is a diagram of a third embodiment of the structure of two plates used as part of a shelf system.</figref><figref num="11">FIG. 11 is a diagram of a container used to contain a substance for lyophilization.</figref><figref num="12">FIG. 12 is an exploded view of a container similar to the container of FIG.</figref><figref num="13">FIG. 13 is a cross-sectional view of the container of FIG. 12 that holds the fluid.</figref><figref num="14">FIG. 14 is a cross-sectional view of a container composed of three walls according to an embodiment.</figref><figref num="15">FIG. 15 is a cross-sectional view of a container composed of three walls according to the second embodiment.</figref><figref num="16">FIG. 16 is a diagram of a container used for lyophilizing and after lyophilization, according to an embodiment, for containing a substance.</figref><figref num="17">17A to 17C are cross-sectional views of the container shown in FIG.</figref><figref num="18">18A and 18B are diagrams of containers used to contain material for and after lyophilization, according to other embodiments.</figref><figref num="19">19A-19C are diagrams of containers used for lyophilization and after lyophilization, according to other embodiments, for containing substances.</figref><figref num="20">20A-20C are views of containers used to contain material for and after lyophilization, according to yet another embodiment.</figref><figref num="21">FIG. 21 is a diagram of an embodiment of a system for storing biofluids and filling a plurality of containers for later freeze-drying.</figref><figref num="22">FIG. 22 is a diagram of an embodiment of a system for storing a biofluid, reducing the volume of the biofluid, and filling a plurality of containers with the biofluid for later freeze-drying.</figref><figref num="23">FIG. 23 is a diagram of an embodiment of a system for storing a biofluid, reducing pathogens in the fluid, and filling a plurality of containers with the biofluid for later freeze-drying.</figref><figref num="24">FIG. 24 shows that for later freeze-drying, the biofluid is stored, the volume of the biofluid is reduced, the pathogen of the reduced volume fluid is reduced, and multiple containers are filled with the biofluid. It is a figure of one Embodiment of the system for this.</figref><figref num="25">FIG. 25 is a diagram of a bag containing a fluid for processing and a vibration table for stirring the fluid while irradiating the fluid with light from a light source according to an embodiment.</figref><figref num="26">FIG. 26 is a diagram of an apparatus for reducing or inactivating pathogens and microorganisms according to an embodiment.</figref><figref num="27">FIG. 27 is a diagram of a process for lyophilizing, accommodating, reconstitution, storage and infusion of blood components according to an embodiment.</figref><figref num="28">FIG. 28 is a flowchart of a process for freeze-drying a substance according to an embodiment.</figref><figref num="29">FIG. 29 is a flow chart of a process for reducing the pathogens of a substance and lyophilizing the substance according to one embodiment.</figref><figref num="30">FIG. 30 is a diagram of an embodiment of a system for freeze-drying a substance using IR radiation.</figref><figref num="31">FIG. 31 is a diagram of another embodiment of the system for freeze-drying a substance using IR radiation.</figref><figref num="32">FIG. 32 is a flowchart of a process for freeze-drying a substance using IR radiation according to an embodiment.</figref><figref num="33">FIG. 33 is a diagram of an embodiment of a computer system used to implement an embodiment.</figref>

The principles of the invention will be further understood by reference to the following detailed description and embodiments shown in the accompanying drawings. Although specific features are shown and described in the detailed embodiments, it should be understood that the invention is not limited to the embodiments described below.

Hereinafter, embodiments shown in the accompanying drawings will be described in detail. Wherever possible, the same reference numerals are used in the drawings and description when referring to the same member.

FIG. 1 shows a first embodiment of an apparatus 100 for lyophilizing a substance (eg, in the form of a liquid, solid or a combination thereof) according to the present invention. As shown in FIG. 1, the device 100 has a chamber 104, a housing 108, a shelf system 112, and an interface 116. The housing 108 specifically houses a vacuum system, a temperature control system, and a control system. The vacuum system creates a low pressure environment in chamber 104 (eg, below atmospheric pressure). The temperature control system controls the temperature of the shelf system 112. The control system may have a computer system (with one or more processors) that controls various functions of the device 100. The operator can use the user interface 116 to enter data, parameters, and other information to control the functionality of the device 100. In one embodiment, the user interface 116 allows the operator to create and execute a custom process for lyophilization with a multi-step programmable cycle.

In embodiments, the lyophilized material is placed on a shelf system 112 in chamber 104. The vacuum system subsequently brings the environment in chamber 104 to a first pressure (lower than atmospheric pressure). In some embodiments, the first pressure is selected based on the evaporation of one component of the lyophilized material in the liquid state. After the chamber 104 reaches the first pressure, at least a portion of the first component evaporates from the material. Evaporation is carried out over the first period or until a predetermined amount of the first component evaporates from the substance.

After a portion of the first component evaporates, the remaining material is cooled and the residual liquid freezes to a solid. In embodiments, the evaporation described above is part of the freezing step. As can be seen, in some embodiments, the evaporation cools the remaining material to the extent that the liquid freezes to a solid. In another embodiment, in the above freezing, cooling may be performed by using another mechanism in addition to or instead of evaporation.

The vacuum system brings the environment in chamber 104 to a second pressure. In the embodiment, the second pressure is lower than the first pressure. Under the second pressure, the second part of the first component sublimates from the substance. In some embodiments, sublimation may include sublimation of other components of the substance.

In some embodiments, after sublimation, the substance is maintained at a second pressure for an additional period and one or more components are desorbed from the substance. The desorbed component is previously absorbed or adsorbed by the substance.

As described in detail below, in embodiments, the shelf system 112 is characterized by transporting / adding or removing energy to substances during lyophilization. The addition or removal of energy is performed in one or more of the above steps. For example, by using the shelf system 112, energy is added to the substance and the components from the substance are evaporated. Further, by using the shelf system 112, energy may be removed from the system, the substance may be cooled, and the liquid in the substance may be frozen and solidified. In embodiments, shelving system 112 may be used to add energy to the material during the sublimation step.

FIG. 2 shows a second embodiment of the apparatus 200 for freeze-drying a substance according to the present invention. The device 200 has the same characteristics as the device 100 and has a chamber 204 housed in a housing 208. The device 200 further comprises a shelf system 212 and a user interface 216. In an embodiment, the device 200 has the same functions as the device 100 and operates in the same manner. The apparatus 100 and the apparatus 200 are described only for the purpose of demonstrating that the present invention is feasible in any lyophilization apparatus or lyophilization system, and a particular design or a particular system configuration. Not limited to.

In the following, various configurations will be described as part of an embodiment of a lyophilizer (eg, apparatus 100 or apparatus 200) or lyophilization system. However, the present invention is not limited to this. The various steps of the lyophilization process may be carried out by different structures, appliances and systems. As a non-limiting example, in some embodiments, the evaporation step, the freezing step and the sublimation step (described above) are carried out by three separate devices. In other embodiments, one or more appliances may have various functions, allowing more than one step of the lyophilization process to be performed in one appliance.

As an example, the evaporation step may be performed in an apparatus that performs a freezing step. Evaporation provides cooling of the material during the freezing step, as described below for FIG. 29. After evaporation and freezing, the substance is transferred to a device that sublimates a component of the substance.

In some embodiments, the liquid component is evaporated from the substance in the first apparatus. Then, the substance is transferred to the second device and frozen. After freezing, the material is returned to the first device for lyophilization.

In other embodiments, the evaporation step is not performed as part of the process. In one device, the material is frozen and transferred to a second device for sublimation. As mentioned above, the invention is not limited to performing the process in any one device. It may include steps performed on multiple devices.

FIG. 3 shows an embodiment of a shelf system 300 used in a freeze-drying process / device such as, for example, the device 100 or device 200 described above. The shelf system 300 has plates 304 that make up the shelf 320. The plate 304 provides a surface for placing the freeze-dried material. Depending on the type of lyophilized substance, the substance is held in a container such as a tray, bag, bottle, etc., and the container is placed on the plate 304. FIG. 3 shows a container placed on the plate 304. The container contains the substance to be freeze-dried. The shelf system 300 also has an end plate 308. In embodiments, the end plate 308 is fixed as described in detail below.

In addition, the shelf system 300 has a motion control system 312 used to change the distance between the plates 304. As described in detail below, the distance between the plates 304 is variable, whereby the lyophilized material is formed by being pressed during the freezing step of the lyophilization process. In embodiments, the motion control system 312 is configured to move the plates 304 closer to and further from each other.

FIG. 4 shows a shelf system 300 in which the material is compressed by moving the plate 304, for example, to a fully compressed position, in the freeze-drying process, especially in the freezing step of the process. As shown in FIG. 4, the end plates 308 are maintained in the same position as shown in FIG. 3, but each plate 304 has the least amount of movement of the first plate (immediately below the end plate 308). , The movement amount of the 7th plate (farthest from the end plate 308) is increased so as to be the maximum. At the compression position shown in FIG. 4, pressure is applied to each container on the plate 304 and the container and material are pressed. That is, the compressive force is applied to the container and the substance in the container. As described in detail below, the application of pressure, such as pressing the container, has some effect on the lyophilization process and is used in some embodiments.

As will be appreciated, the motion control system 312 contains several different components used to move the plate 304. For example, the motion control system 312 includes a computer system including a processor, a memory, an input device, an output device, a communication device, and a combination thereof, such as a controller. The motion control system 312 further includes one or more motors, actuators, pumps, compressors, cylinders, pistons, pipes, valves, bladers, sensors, regulators, combinations thereof, hydraulic operation, pneumatic operation or mechanical operation. It may have other subsystems such as the system.

The system 300 further comprises a thermo-fluid system 316. The thermal fluid system 316 circulates the thermal fluid through at least a portion of the shelf 320 and controls the temperature of at least a portion of the plate 304 and thus the temperature of the material placed on the plate 304 for freeze-drying. The thermo-fluid system 316 is used to remove or add energy to the plate 304 of the shelf 320 during various steps of the freeze-drying process.

FIG. 5 is a diagram of another embodiment of the shelf system 500 used in a freeze-drying process / device such as, for example, the device 100 or device 200 described above. The shelf system 500 has a shelf 520 that provides a surface for placing freeze-dried material. The substance is held in a container such as a tray, bag, bottle, which is placed on the first plate 504 of the shelf 520. The shelf system 500 also has a second plate 508 that is part of the shelf 520. The second plate 508 is arranged above the first plate 504 so as to face the first plate 504. Further, the shelf system 500 has an operation control system 512. In an embodiment, the motion control system 512 is used to change the distance between the first plate 504 and the second plate 508 of the shelf. Pressure can be applied to the lyophilized material by varying the distance between the first plate 504 and the second plate 508, as detailed below. In one embodiment, the motion control system 512 is configured to move the first plate 504 closer to and further from the fixed second plate 508. In other embodiments, the second plate 508 may be moved closer to and further from the fixed first plate 504. In yet another embodiment, the motion control system 512 may be configured to bring the first plate 504 and the second plate 508 closer to and further from each other.

The motion control system 512 has any system suitable for moving the plate 504 and / or the plate 508 of the shelf 520. In one embodiment, it has components similar to a motion control system 312 (FIG. 3) having a computer system including a processor, memory, input device, output device, communication device, and a combination thereof, such as a controller. System 512 further includes one or more motors, actuators, pumps, compressors, cylinders, pistons, pipes, valves, air bags (bladders), sensors, regulators, combinations thereof, hydraulically operated, pneumatically operated or mechanically operated systems. It may have other subsystems such as.

FIG. 6 shows the shelf system 500 of FIG. 5 in which the material is pressed by moving the plates 504, 508 of the shelf 520 during the freeze-drying process, especially during the freezing step of the process. In FIG. 6, the second plate 508 is in a state of being moved downward toward the first plate 504. At the position shown in FIG. 6, pressure is applied to each container placed on the first plate 504 by applying pressure by the second plate 508. Such pressure application and / or molding of the frozen material is believed to improve the efficiency of the freeze-drying process and is used in some embodiments.

The system 500 further has a thermo-fluid system 516 similar to the thermo-fluid system 316. The thermal fluid system 516 circulates the thermal fluid within at least a portion of the shelf 520 and controls the temperature of at least a portion of the plates 504, 508 and thus the temperature of the material placed on the plates 504, 508 for freeze-drying. .. The thermo-fluid system 516 is used in performing energy removal or addition to shelves 520 during various steps of the freeze-drying process, as described in detail below.

The above description of the shelf systems 300, 500 is made for the purpose of exemplifying some features in certain embodiments of the present invention. Embodiments of the invention may include features not described above but within the scope of the invention. For example, the number of plates in the system may be changed. In some embodiments, the number of plates (eg, 304, 504) for holding the lyophilized material may be more than 2 or 3 or 4 or 5 or 6 or more. .. In other embodiments, the number of plates (eg, 304, 504) for holding the lyophilized material may be less than 12, or less than 11, or less than 10, or less than 9, or less than 8. .. In one embodiment, the number of plates (eg, 304, 504) for holding the lyophilized material is 7.

In other embodiments, the plate holding the lyophilized material (eg, 304, 504) has other characteristics. For example, a raised edge may be provided around the plate. As a result, the leaked substance is retained on the plate, and cleaning can be easily performed. The plate may also be connected to a motion control system (312, 512) and / or a thermo-fluid system (316, 516) using any suitable connector such as a connector, pipe, fitting, pipe, adapter, etc. .. In one working mode, the plates are connected for easy removal from the motion control system (312, 512) and / or the thermofluid system (316, 516) (eg, using a quick type pipe fitting). This makes cleaning easy.

FIG. 7 shows an embodiment of a system 700 having two plates and a mechanism for moving the plates, which is part of the shelf system 300 or 500 shown in FIGS. 3-6. The first plate 704 is positioned above the second plate 708 so that the surface 712 faces the surface 716 of the second plate. As shown in FIG. 7, a space 720 is formed between the two surfaces 712, 716 where the lyophilized material is placed, and as indicated by arrow 724, of one or more plates 704, 708. Depending on the operation, the space 720 can be increased or decreased. By reducing the space 720, the lyophilized material is pressed in one or more steps of the lyophilization process. Increase space 720 to relieve pressure. Alternatively, the space 720 is increased when the freeze-dried material is positioned on the plate 708.

In embodiments, any mechanism for moving one or more plates 704, 708 can be used. FIG. 7 shows an example of a mechanism for moving the plate 704 and / or the plate 708 to increase or decrease the size of space 720. In the embodiment shown in FIG. 7, the support member 728 is attached with the plates 704 and 708 so as to be able to approach and separate from each other.

The support member 728 has an outer support portion 732 and an inner support portion 736. For example, the outer support portion 732 is a hollow cylinder, and the inner support portion 736 is a shaft arranged in the hollow cylinder. In some embodiments, one of the plates 704 or 708 is attached to the outer support 732 and the other is attached to the inner support 736. The plates 704, 708 are attached to the support member 728 by any suitable mechanism. A non-limiting example of such a mechanism is the use of an L-shaped bracket, such as the L-shaped bracket 740. Further, in some embodiments, the plates 704, 708 are attached to each part of the support member 728 using fasteners such as screws, nuts, bolts, washers, or combinations thereof.

In the embodiment shown in FIG. 7, the outer support 732 has an opening 744, which allows the L-shaped bracket 740 to be attached to the inner support 736, allowing the L-shaped bracket 740 to move vertically. Become. One of the plates 704 and 708 is attached to the L-shaped bracket 740, and the space 720 can be increased or decreased by moving the L-shaped bracket 740.

In embodiments, at least a portion of the support member 728 is connected to a motion control system such as motion control system 312 (FIGS. 3 and 4) and motion control system 512 (FIGS. 5 and 6). As mentioned above, the motion control system is used to control the spacing of the space 720, increasing the space 720 and pressing the material during lyophilization in the placement of the material and in some steps in the lyophilization process. In some steps, reduce space 720.

The support member 728 and the bracket 740 are examples of mechanisms for moving the plates 704 and 708. In other embodiments, different components are used as part of different mechanisms for moving the plates 704, 708. Non-limiting examples include brackets, rails, fasteners, bearings, bushes, shafts, tubes, plates, welds, or combinations thereof.

Plates 704, 708 of FIG. 7 are merely exemplified as an embodiment of a plate structure that is part of a shelf system such as the shelf system 300 or shelf system 500 shown in FIGS. 3-6. In other embodiments, different structures or designs may be utilized. As mentioned above, other embodiments may have different mechanisms for varying the spacing of space 720 between plate 704 and plate 708. Other shelf systems may be provided with more support members than the two support members 728 shown in FIG. For example, four or more support members may be placed in the vicinity of the four corners of the plates 704 and 708. This is merely an example, and other embodiments are included within the scope of the present invention.

8A and 8B are diagrams of a first embodiment of a two-plate structure 800 used as part of a shelf system such as the system 300 shown in FIGS. 3 and 4. The structure 800 has a first plate 804 and a second plate 808. The first plate 804 has a surface 812 facing the surface 816 of the second plate 808. The two opposing surfaces 812, 816 form a space 820 between the surfaces.

In the embodiment, the plate 804 and the plate 808 have a similar structure. The plate 804 has a first layer 828, and in embodiments, the first layer 828 is made of a thermally conductive material. The first layer 828 has a channel 824 that serves as a flow path for the thermal fluid. The thermal fluid is used to control the temperature of the first layer 828 by heating or cooling the first layer 828.

Plate 804 further has a boundary 832 between the first layer 828 and the second layer 836. Boundary 832 contains an insulating material, which allows the temperature of the first layer 828 to differ from the temperature of the second layer 836. In other embodiments, the boundary 832 may have properties that aid in adhesion between the first layer 828 and the second layer 836, in place of or in addition to the above.

In one embodiment, the second layer 836 comprises an IR radiating material such as a ceramic material, a metal material, an intermetallic compound material and / or a composite material. In certain embodiments, the material is an infrared (IR) emitter that radiates infrared energy. In such an embodiment, the second layer 836 may have an embedded element for promoting IR radiation from the surface 812 by heating the layer 836. For example, layer 2 836 may have electrodes, heating elements, sensors (eg, thermocouples) and / or combinations thereof. As described in detail below, the IR energy radiated from surface 812 by layer 2 836 is used in performing several steps of the lyophilization process. As shown in the embodiments of FIGS. 8A and 8B, the plate 808 has a structure similar to the plate 804 such that it has a first layer 848, a second layer 856, a boundary 852, and a channel 844 for circulating thermal fluid. Have.

In embodiments, the plate structure 800 is part of a lyophilizer that includes other components such as a vacuum system that creates a low pressure environment around at least the shelves of the shelf system 300 (FIGS. 3 and 3). Used in 4). In these embodiments, the plates 804, 808 form part of the shelf 320 and are connected to the shelf operating system 312 and the thermofluid system 316.

In operation, the shelf system 300 (with plate structure 800) is a vacuum chamber (below atmospheric pressure) used to create a low pressure (below atmospheric pressure) environment around at least shelves 320 (eg, plates 804, 808) of system 300. For example, it is placed in 104 or 204). The shelf operation system 312 then increases the space 820 and places the container 840 (containing the substance 860 (a liquid such as a biological liquid in one embodiment)) on the surface 816 of the plate 808. The system 312 then moves one or more plates 804 and / or plate 808, reducing space 820 and slightly pressing vessel 840 (as shown in FIGS. 8A and 8B). The thermal fluid system 316 then circulates the thermal fluid through the channel 844 of the plate 808 to cool the first layer 848 of the plate 808 and thus the substance 860 in the container 840.

Without being constrained by theory, during the freezing step, the substance to be freeze-dried (eg, substance 860 in the container 840) may be pressed to form the substance into a more uniform cross section. Is thought to be possible. A more uniform cross section increases the efficiency of removing one component (eg, ice) from the material 860 in subsequent sublimation steps. That is, by reducing the variation in thickness, it is possible to make the rate at which the sublimation surface of the substance 860 progresses uniform in sublimation.

After the substance 860 freezes, the ambient environment of the shelf 320 is reduced to a low pressure to promote the sublimation of at least one component of the substance 860. The shelf operation system 312 then increases the space 820 in preparation for the sublimation step. In addition, thermal fluid is circulated through channel 844 to apply thermal energy to the material 860 in the container 840 (via the first layer 848 made of a heat conductive material), facilitating the sublimation of one component in the material 860. Let me.

As mentioned above, in some embodiments, the second layer 836 comprises an IR radiator. In these embodiments, the IR energy is directed to the substance 860 in the container 840 by activating the IR radiator. IR energy adds more energy to sublimate one component from substance 860. In these embodiments, the sublimation step is further enhanced by adding both thermal energy (from the thermal fluid circulating in channel 844) and IR energy (from the IR radiator in the second layer 836 of plate 804). It can be completed quickly.

In some embodiments, after sublimation, the material 860 is maintained at low pressure with the continuous addition of energy (heat and / or IR). In some embodiments, this is done to remove the component or any other component that is chemically bound to other components in the substance 860. As an example, this step removes hydrated water.

After the component is removed from the substance 860 by sublimation, the ambient environment of the shelf 320 is brought to atmospheric pressure and the substance 860 (and container 840) is removed from the plate 808 for storage or other processing.

As will be appreciated, the structure 800 allows a plate (eg, plate 804 or plate 808) to be used to process material placed both below and above the plate. For example, as described above, layer 2 836 has an IR radiator and adds energy to the material located below the IR radiator. However, the first layer 828 cools the material located above the first layer 828 and freezes the liquid in the material to a solid and also (eg, by circulating thermal fluid through the channel 824). It is used to add thermal energy to the substance. Similarly, the second layer 856 of the plate 808 is used as an IR radiator for the material placed below the second layer 856, and as mentioned above, the first layer 848 cools the material 860 and It is used to freeze the liquid in the material and to add thermal energy in the sublimation step.

FIG. 8B is a diagram of another embodiment of the plate structure 800. In this embodiment, the plate 808 has features shaped to hold the container and / or the substance to be lyophilized. As shown in FIG. 8B, the plate 808 has an edge 864 that corresponds to at least a portion of the shape of the container 840. The edge 864 defines where the container 840 is placed on the plate 808. Also, in some embodiments, the edge 864 is also useful when pressing the container 840 with the plate 804. The edge 864 allows the container 840 to be immobile when pressed by the plate 804. It is also used as a mold for lyophilized material in the freezing step.

In some embodiments, the edge 864 surrounds only part of the container. For example, the edges may be provided on two or three sides of the container. Alternatively, it may be provided discontinuously so as to enclose a part of the container and not to enclose the other part.

The above description of the use of the plate structure 800 in the shelf system 300 is for illustrative purposes only. The freeze-drying process utilizing the plate structure 800 and the shelf system 300 may further include steps not described above. The above description is not intended to explain everything completely, but merely to illustrate some features of the plate structure 800.

FIG. 9 shows a second embodiment of a two-plate structure 900 used as part of a shelf system, which is, for example, part of a shelf 320 (FIGS. 3 and 4) in system 300. Structure 900 has some features similar to structure 800 described above. The structure 900 has a first plate 904 and a second plate 908. The first plate 904 has a surface 912 facing the surface 916 of the second plate 908. The two opposing surfaces 912, 916 form a space 920 between the surfaces.

As shown in FIG. 9, the surface 916 has several shapes (eg, ridge portion 960). By providing these shapes, a surface having an improved heat transfer surface area and / or mass transfer surface area is formed. In embodiments, this is achieved by imparting a macro structure. For example, ridges 960, 964 impart a structure to the surface of the material during the freezing step of the freeze-drying process. Without being bound by theory, it is believed that improving the heat transfer surface area and / or mass transfer surface area of a substance promotes sublimation (a component of the lyophilized material) in the sublimation step. Be done. The case where the ridge portion 964 is provided on the surface 912 and the ridge portion 960 is provided on the surface 916 is shown, but the surfaces 912 and 916 provide a surface area with improved heat transfer characteristics and mass transfer characteristics. It may have other types of structures. As a non-limiting example of such a structure, the surface 916 may have a (random or constant) pattern of hemispherical recesses and / or hemispherical protrusions of the same size or different sizes.

In one embodiment, the size, shape or arrangement of the shape is determined by the points to be considered. For example, for a shape on surface 916, the shape is determined by factors that influence the transfer of thermal energy to the lyophilized material (eg, the stiffness of the container in which the material is housed). .. The rigidity of the vessel affects the contact between the lyophilized material and the surface 916, which affects the thermal energy transfer.

In the embodiment, each plate 904, 908 has a similar structure. In other embodiments, it may have a different structure. The plate 904 has a first layer 928, and in embodiments, the first layer 928 is made of a thermally conductive material. The first layer 928 has a channel 924 that serves as a flow path for the thermal fluid. The temperature of the first layer 928 is controlled by heating or cooling the first layer 928 using a thermal fluid.

Plate 904 further has a boundary 932 between the first layer 928 and the second layer 936. Boundary 932 contains an insulating material, which allows the temperature of the first layer 928 to differ from the temperature of the second layer 936. In other embodiments, the boundary 932 may have properties that aid in adhesion between the first layer 928 and the second layer 936, in place of or in addition to the above.

In one embodiment, layer 2 936 comprises an IR radiating material. In certain embodiments, the material is an infrared emitter that radiates infrared (IR) energy. In such an embodiment, the second layer 936 has an embedded electrode that heats the layer 936 and a surface 912 that radiates IR energy. IR energy is used in performing several steps of the freeze-drying process. As shown in the embodiment of FIG. 9, the plate 908 has a structure similar to the plate 904 such that it has a first layer 948, a second layer 956, a boundary 952, and a channel 944 that circulates the thermal fluid.

FIG. 10 shows a third embodiment of a two-plate structure 1000 used as part of a shelf system (eg, shelf 520) of system 500 shown in FIGS. 5 and 6. The structure 1000 has a first plate 1004 and a second plate 1008. The first plate 1004 has a surface 1012 facing the surface 1016 of the second plate 1008. The two opposing surfaces 1012 and 1016 form a space 1020 between the surfaces. A substance to be freeze-dried is arranged in the space 1020.

In embodiments, the plates 1004 and 1008 have different structures. Plate 1004 has a first layer 1028, and in embodiments, the first layer 1028 is made of a thermally conductive material. The first layer 1028 has a channel 1024 that circulates the thermal fluid. Plate 1004 further has a boundary 1032 between the first layer 1028 and the second layer 1036. Boundary 1032 contains an insulating material, which allows the temperature of the first layer 1028 to differ from the temperature of the second layer 1036. In other embodiments, the boundary 1032 may have properties that aid in adhesion between the first layer 1028 and the second layer 1036, in place of or in addition to the above.

In one embodiment, layer 2 1036 comprises an IR radiating material. In certain embodiments, the material is an infrared emitter that radiates infrared (IR) energy. In such an embodiment, the second layer 1036 may have an embedded element for generating and radiating IR energy. For example, layer 2 1036 comprises electrodes, heating elements, sensors (eg, thermocouples) and / or combinations thereof. The IR energy radiated by layer 2 1036 is used in several steps of the lyophilization process.

As shown in the embodiment of FIG. 10, plate 1008 has layer 1040. In embodiments, layer 1040 is made of a thermally conductive material. Layer 1040 has a channel 1044 that serves as a flow path for circulating the thermal fluid. The temperature of the lyophilized material placed on the layer 1040 and the surface 1016 is controlled by heating or cooling the first layer 1040 using a thermal fluid.

In embodiments, the plate structure 1000 is part of a lyophilizer that includes other components such as a vacuum system that creates a low pressure (below atmospheric pressure) environment around the shelf system 500 (Figure). Used in 5 and Figure 6). In these embodiments, the plates 1004, 1008 form part of the shelf 520 and are connected to the shelf operating system 512 and the thermofluid system 516.

In operation, the shelf system 500 with the plate structure 1000 (as part of the shelf 520) performs the same operation as the shelf system 300 with the plate structure 800 described above. The plate structure 1000 as part of the shelf 520 is placed in a vacuum chamber used to create a low pressure (eg, below atmospheric pressure) environment around at least the shelf 520 of the system 500. The shelf operating system 512 then increases space 1020 and places a container (containing a substance to be lyophilized (eg, bioliquid)) on surface 1016 of plate 1008. The system 512 then moves one or more plates 1004 and / or plates 1008 to reduce space 1020 and press the container containing the material to form a layer of material of substantially uniform thickness. The thermal fluid system 516 then circulates the thermal fluid through the channel 1044 of the plate 1008 to cool the layer 1044 of the plate 1008 and thus the material to be frozen.

As mentioned above, it is believed that by pressing the lyophilized material in the freezing step (though not constrained by theory), the cross section of the material can be made more uniform. A more uniform cross section is believed to increase the efficiency of removing one component (eg, ice) from the material in subsequent sublimation steps. That is, by reducing the variation in thickness, it is possible to make the rate of sublimation progressing in the substance uniform in sublimation, thereby making the sublimation step more efficient and in the shortest possible time. can do.

In another embodiment, during the freezing step, the lyophilized material is molded or shaped, for example, on the surface. For example, as described above, a structure is imprinted on the material and the surface area is increased (see, eg, Figure 9). In other embodiments, the substance is shaped based on the shape of the shelves or the shape of the container that houses the substance.

After the material placed on surface 1016 freezes, the ambient environment of the shelf 520 (with plate structure 1000) is reduced to low pressure to promote sublimation of at least one component of the material. Then, the shelf operation system 512 increases the space 1020 in preparation for the sublimation step. In addition, a thermal fluid is circulated through channel 1044 and heat energy is applied to the substance to promote the sublimation of one component in the substance.

As mentioned above, in some embodiments, layer 2 1036 is a layer comprising an IR radiator. In these embodiments, the IR energy is directed to the material on surface 1016 by activating the IR radiator. IR energy adds more energy to sublimate a component from a substance. In these embodiments, the sublimation step is further enhanced by adding both thermal energy (from the thermal fluid circulating in channel 1044) and IR energy (from the IR radiator in the second layer 1036 of plate 1004). It can be completed quickly.

In some embodiments, the sublimation step is performed using only IR energy. As mentioned above, the IR radiator of layer 2 1036 adds energy to the frozen material. In some of these embodiments, a thermal fluid circulating in channel 1044 is used to cool the lyophilized material. Without being bound by theory, it is believed that in the freeze-drying process, the sublimation of the material occurs on the surface of the material. Therefore, when thermal energy is applied to the bottom surface of the lyophilized material (eg, using the plate structure shown in FIG. 10), the energy must be transferred to the top surface where sublimation occurs. However, when heat is transferred through a substance, it raises the temperature of the substance at a certain point, and as a result, at that point, a component (eg, ice) melts, so that thermal energy is transferred to the top surface of the substance. That becomes even more difficult.

Therefore, in some embodiments, only IR energy is used to sublimate the material. Further, in order to avoid melting, heat energy is removed from the bottom surface of the substance to cool the substance and avoid melting. For example, referring to FIG. 10, the substance is placed in space 1020 for sublimation. The IR radiator of the second layer 1036 is used to apply IR energy to the material and sublimate one component of the material from the top surface of the material facing the second layer 1036. To avoid possible melting, the thermal fluid of channel 1044 is circulated at a temperature that removes energy (eg, acting as a heat sink) to keep the material cold and avoid melting. These are examples of processes performed using the plate structure shown in FIG. In other embodiments, the plate structure shown in FIG. 10 may be used to perform a process with different steps.

In some embodiments, after sublimation, the material is maintained at low pressure (eg, below atmospheric pressure) with the continuous addition of energy (heat and / or IR). In some embodiments, this is done to remove the component or any other component that is chemically bound to other components in the substance. As an example, this step removes hydrated water.

After the component (eg, the adsorbed component) has been removed from the material by sublimation, the ambient environment of shelf 520 is brought to atmospheric pressure and the material is removed from plate 1008 for storage or subsequent processing.

The above description of the plate structures 800, 900, 1000 has been made for embodiments in which the plate structure is incorporated into a lyophilizer or system (eg, device 100 or device 200), but the invention is not limited thereto. In other embodiments, the plate structures 800, 900, 1000 may be part of a different device used in some of the freeze-drying processes not performed in a single device. As a non-limiting example, the evaporation and freezing steps described above may be performed in an apparatus having one or more of the features of the plate structures 800, 900, 1000. Further, the sublimation step may be performed in other devices having the same or different features as described above in the plate structures 800, 900, 1000 or other devices not including those features of the plate structure.

As another example, the process may only have a freezing step and a sublimation step. The freezing step may be performed in an apparatus having one or more features of the plate structure 800, 900, 1000 or, for example, other features of molding material during freezing. The sublimation step may be performed on another device having the same or different features as the above features of the plate structures 800, 900, 1000, or another device not including the features of the plate structures 800, 900, 1000.

As yet another example, the freezing step may have a step of forming a surface on the material with improved heat transfer and mass transfer properties, such a step being performed in another device. You may. In these embodiments, the features of the plate structure 900 are used in the device. The previous step and the subsequent steps may be performed on one or more different devices.

Further, although the specific features have been described in the above description, other embodiments may include other structures, processes and steps as long as they are within the scope of the invention. As a non-limiting example, the lyophilization process involves sterile substances that need to be kept sterile. In these embodiments, the device is characterized by maintaining aseptic conditions for, for example, shelving systems, plates or other structures used in the freeze-drying process. Such aseptic conditions are maintained using various systems. Non-limiting examples of such systems include UV (ultraviolet) irradiation systems, microwave systems, cleaning systems, steam systems, pressure systems, additional vacuum systems, filtration systems, and / or combinations thereof. .. As an example, UV irradiation systems with UV lamps or UV-LEDs are used to sterilize freeze-drying equipment or system components to create a sterile environment for substances in freeze-drying that need to be kept sterile. maintain.

FIG. 11 shows an embodiment of containers 1100A, 1100B used to contain substances for lyophilization. As shown in FIG. 11, containers 1100A, 1100B are positioned on plates 1104, 1108 that are part of the shelf system of a lyophilizer such as appliance 100 or appliance 200.

FIG. 12 is an exploded view of the container 1200 having the same characteristics as the containers 1100A and 1100B. The container 1200 has a first wall 1204, a second wall 1208, and three port connectors 1212, 1216, 1220. As shown in FIG. 12, the three port connectors 1212, 1216, 1220 are located between the first wall 1204 and the second wall 1208. The port connector is used to fill the container 1200 with the substance to be frozen and dried, to add a liquid to the container 1200 to restore the substance that has been freeze-dried, and / or to remove the substance from the container 1200 (for example, the substance that has been freeze-dried). It is used when connecting to another container to take out the original). The port connectors 1212, 1216, 1220 need not be positioned between the first wall 1204 and the second wall 1208. For example, one or more ports of the port connectors 1212, 1216, 1220 may be integrated into one of the walls 1204, 1208.

In some embodiments, the first wall 1204 is made of a material that is permeable to at least some gases. For example, the first wall 1204 is made of a material that is highly permeable to water vapor and low permeable (ie, waterproof) to liquid water. Furthermore, in another embodiment, the first wall 1204 is made from a biocompatible material. Non-limiting examples of materials used for the first wall 1204 include flashspun high density polyethylene (HDPE) and polytetrafluoroethylene (PTFE). In one embodiment, first wall 1204 has a non-woven fabric containing fibers made from flashspun HDPE. In another embodiment, the first wall 1204 is based on a copolymer such as polyethylene copolymer, vinyl copolymer, acrylic copolymer, polypropylene copolymer, amide copolymer (eg, woven fabric or It is produced by forming (casting) on (non-woven fabric). In certain embodiments, the first wall 1204 is made by forming an acrylic copolymer on a nylon non-woven fabric.

First wall 1204 may be made from materials manufactured by a particular process. For example, as described above, the material is produced by a spinning process including, but not limited to, a flash span method, a spun bond method, a dry method, a wet method, a melt blow method, a spun lace method, and the like. These processes produce non-woven fabrics. Alternatively, the process is used to make fibers, which are further processed, for example, by stretching or weaving. Other examples of the material include polymers and copolymers formed on substrates such as woven fabrics and non-woven fabrics. When making the material for the first wall 1204, any of these processes can be used to make the material for the first wall 1204 with the desired properties, gas permeability, tensile strength, waterproofness, etc. can.

In one embodiment, the first wall 1204 is larger than about 15 metric perm (in the following, unless otherwise noted, perm is metric. Has a water vapor transmission rate greater than (perm), or about 20 perm, or greater than about 25 perm, or greater than about 30 perm, or greater than about 35 perm. In other embodiments, the water vapor transmission rate of the first wall 1204 is greater than about 50perm, or greater than about 75perm, or greater than about 100perm, or greater than about 150perm, or greater than about 200perm. In some embodiments, the first layer 1204 has a water vapor transmission rate in the range of about 10 perm to about 70 perm, eg, between about 15 perm and about 65 perm, or between about 20 perm and about 60 perm. In other embodiments, the first layer 1204 has a water vapor transmission rate in the range of about 50 perm to about 1000 perm, eg, between about 100 perm and about 750 perm, or between about 200 perm and about 500 perm. Also, in some embodiments, the first layer 1204 has a water resistance (ie, hydrostatic head) greater than about 100 cm, or greater than about 150 cm, or greater than about 200 cm, or greater than about 250 cm. In some embodiments, the first layer 1204 has a water resistance in the range of about 50 cm to about 400 cm, eg, between about 100 cm and about 350 cm, or between about 150 cm and about 300 cm. In some embodiments, the first layer 1204 has a combination of any of the above water vapor transmission rates and any of the above water resistance. In some embodiments, the first wall 1204 is made from a material containing a non-woven fabric formed from polymer fibers produced by a spinning process. In another embodiment, the first wall 1204 is made from a material containing a copolymer formed on a non-woven fabric. These materials are manufactured to have the above-mentioned water vapor transmission rate and water resistance.

In certain embodiments, wall 1208 is made from any suitable material, including polymers. In some embodiments, the wall 1208 is made from a transparent or translucent material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof. The transparent or translucent material is useful in embodiments in which a pathogen reduction process using a photosensitizer and lighting is performed on the material in the container 1200. In these embodiments, the container 1200 can be used as an irradiation container. In one embodiment, wall 1208 is biocompatible at the temperatures and pressures inherent in the lyophilization process. In one embodiment, wall 1208 comprises a polyolefin material.

In some embodiments, the wall 1208 is a single sheet if the container 1200 is a bag. In another embodiment, the wall 1208 provides depth for the material contained in the container 1200. In these embodiments, the wall 1208 takes the form of a tray.

FIG. 13 is a cross-sectional view of a container 1200 showing a volume of 1240. As shown in FIG. 13, wall 1204 is joined to wall 1208 at one or more joints 1224. Thus, in addition to the above-mentioned properties of walls 1204, 1208, the walls are made of mutually compatible materials such that they can be joined together to form the container 1200. The walls 1204, 1208 are joined together using one or more suitable techniques. Non-limiting examples of such techniques include heat sealing, ultrasonic welding, RF welding, solvent welding, laser welding, adhesive bonding, and / or combinations thereof.

In one embodiment, container 1200 is used to lyophilize biofluid (plasma 1244, eg, human plasma) held in volume 1240, as shown in FIG. In this embodiment, the wall 1204 is made of a material with a water vapor transmission rate greater than about 35 perm and a water resistance greater than about 100 cm. Thus, in the sublimation of ice, water vapor easily passes through layer 1204 while liquid plasma does not leak from volume 1240. Waterproofness is also useful when reconstitution of plasma with an aqueous solution.

In addition to the other features of the container 1200, the container can keep the lyophilized material sterile. That is, both wall 1204 and wall 1208 serve as barriers to pathogens, bacteria, or other microorganisms and prevent contamination of the material in container 1200. This feature is particularly useful when the lyophilized material is a biological liquid that is later injected into the patient. Since the inside of the container 1200 can be maintained in a closed aseptic environment, it is not necessary to ensure the aseptic state of the material environment during freeze-drying. That is, in the freeze-drying process, it is not necessary to sterilize the equipment to be used before performing various steps. This eliminates the need for expensive vacuum systems, filter systems, or other systems used in clean room environments. In these embodiments, the vessel 1200 is maintained closed for lyophilization and further treatment (eg, storage, rehydration (rehydration with water), utilization of rehydrated material). ..

FIG. 14 is a cross-sectional view of an embodiment of a container 1400 composed of three walls having a volume of 1440 containing a biological fluid such as plasma 1444 (eg, human plasma). As shown in FIG. 14, container 1400 has a third wall 1404, a first wall 1408, and a second wall 1412. As shown in FIG. 14, the third wall 1404 is located above and near the first wall 1408. In one embodiment, the third wall 1404 is used as a protective layer for the first wall 1408, in addition to other functions. The provision of the third wall 1404 prevents damage to the first wall 1408 that would occur when handling the container 1400. In addition, hands and other objects are prevented from coming into direct contact with the first wall 1408.

In certain embodiments, the third wall 1404 and the second wall 1412 are made of similar materials. In one embodiment, the material is the same as the material described for wall 1208. The third wall 1404 and the second wall 1412 may be made of any suitable material, including polymers. In some embodiments, the third wall 1404 and the second wall 1412 are made of a transparent or translucent material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof. The transparent or translucent material is useful in embodiments in which a pathogen reduction process using a photosensitizer and lighting is performed on the material in the container 1400. In these embodiments, the container 1400 can be used as an irradiation container. In one embodiment, wall 1404 is biocompatible at the temperatures and pressures inherent in the lyophilization process. In certain embodiments, the third wall 1404 and wall 1412 comprises a polyolefin material. In one embodiment, the walls 1404, 1408 are made of different materials.

In some embodiments, the first wall 1408 is made of a material that is permeable to at least some gas. For example, the first wall 1408 is made of a material that is highly permeable to water vapor and low permeable (ie, waterproof) to liquid water. Furthermore, in another embodiment, the first wall 1408 is made from a biocompatible material. Examples of materials used for the first wall 1408 include flashspun high density polyethylene (HDPE) and polytetrafluoroethylene (PTFE). In one embodiment, the first wall 1408 has a non-woven fabric containing fibers made from flashspun HDPE. In another embodiment, the first wall 1408 is based on a copolymer such as polyethylene copolymer, vinyl copolymer, acrylic copolymer, polypropylene copolymer, amide copolymer (eg, woven fabric or It is produced by forming it on a non-woven fabric). In one embodiment, the first wall 1408 is made by forming an acrylic copolymer on a nylon non-woven fabric.

In certain embodiments, the first wall 1408 has a water vapor transmission rate greater than about 15 perm, or greater than about 20 perm, or greater than about 25 perm, or greater than about 30 perm, or greater than about 35 perm. In some embodiments, the first wall 1408 has a water vapor transmission rate in the range of about 10 perm to about 700 perm, eg, between about 20 perm and about 650 perm, or between about 30 perm and about 600 perm. Also, in some embodiments, the first wall 1408 has a water resistance (ie, hydrostatic head) greater than about 100 cm, or greater than about 150 cm, or greater than about 200 cm, or greater than about 250 cm. In some embodiments, the first wall 1408 has a water resistance in the range of about 50 cm to about 400 cm, eg, between about 100 cm and about 350 cm, or between about 150 cm and about 300 cm. In some embodiments, the first wall 1408 has a combination of any of the above water vapor transmission rates and any of the above water resistance.

As shown in FIG. 14, the first wall 1408 is attached to both the wall 1404 and the wall 1412 at one or more joints 1424. Thus, in addition to other properties, the walls are made of mutually compatible materials such that they can be joined together to form the container 1400. The walls 1404, 1408, 1412 are joined together using one or more suitable techniques. Non-limiting examples of such techniques include heat sealing, ultrasonic welding, RF welding, solvent welding, laser welding, adhesive bonding and the like.

In one embodiment, container 1400 is used to lyophilize biofluids such as plasma 1444. In this embodiment, the wall 1408 is made of a material with a water vapor transmission rate greater than about 75 perm and a water resistance greater than about 100 cm. Thereby, in the sublimation step (eg, sublimation of ice), the water vapor passes through the wall 1408 and enters the volume 1448. Wall 1404 has one or more openings. This allows the gas (eg, water vapor) to escape from volume 1448 to the outside environment. The waterproofness of the wall 1408 prevents water vapor, which would condense at volume 1448, from leaking into volume 1440 and rehydrating the lyophilized plasma.

FIG. 15 is a cross-sectional view of a container 1500 composed of three walls having a volume of 1540 containing a biological fluid such as plasma 1544. As shown in FIG. 15, container 1500 has a third wall 1528, a first wall 1504, and a second wall 1508. As shown in FIG. 15, the third wall 1528 is located above and near the first wall 1504.

In certain embodiments, the second wall 1508 is made of a material similar to the material described for wall 1208 (FIGS. 12 and 13). The second wall 1508 may be made of any suitable material, including macromolecules. In some embodiments, the second wall 1508 is made of a transparent or translucent material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof. The transparent or translucent material is useful in embodiments where a pathogen reduction process using a photosensitizer and lighting is performed on the material in the container 1500. In these embodiments, the container 1500 can be used as an irradiation container. In one embodiment, the second wall 1508 is biocompatible at the temperatures and pressures inherent in the lyophilization process. In one embodiment, the third wall 1528 comprises a polyolefin material.

In some embodiments, the third wall 1528 and the first wall 1504 are made of a material that is permeable to at least some gases. For example, the third wall 1528 and the first wall 1504 are made of materials that are highly permeable to water vapor and low permeable (ie, waterproof) to liquid water. Furthermore, in other embodiments, the third wall 1528 and the first wall 1504 may be made from biocompatible materials. Examples of materials used for the third wall 1528 and the first wall 1504 include flashspun high density polyethylene (HDPE) and polytetrafluoroethylene (PTFE). In one embodiment, third wall 1528 and first wall 1504 have a non-woven fabric containing fibers made from flashspun HDPE. In another embodiment, the third wall 1528 has a polymer formed on a non-woven fabric.

In certain embodiments, the third wall 1528 and the first wall 1504 have a water vapor transmission rate greater than about 45 perm, or greater than about 60 perm, or greater than about 75 perm, or greater than about 90 perm, or greater than about 105 perm. In some embodiments, the third wall 1528 and the first wall 1504 have a water vapor transmission rate in the range of about 50 perm to about 900 perm, eg, between about 100 perm and about 850 perm, or between about 150 perm and about 800 perm. between. Also, in some embodiments, the third wall 1528 and the first wall 1504 have a water resistance greater than about 75 cm, or greater than about 125 cm, or greater than about 175 cm, or greater than about 225 cm (ie, hydrostatic head). Has. In some embodiments, the third wall 1528 and the first wall 1504 have water resistance in the range of about 25 cm to about 500 cm, eg, between about 50 cm and about 400 cm, or between about 100 cm and about 300 cm. It is between. In some embodiments, the third wall 1528 and the first wall 1504 have a combination of any of the above water vapor transmission rates and any of the above water resistance.

As shown in FIG. 15, the first wall 1504 (and, in some embodiments, the third wall 1528) is joined to the wall 1508 at one or more joints 1524. Thus, in addition to other properties, the first wall 1504 and the second wall 1508 are made of materials that are compatible with each other so that they can be joined together to form the container 1500. The walls 1528, 1504, 1508 are joined together in various combinations using one or more suitable techniques. Non-limiting examples of such techniques include heat sealing, ultrasonic welding, RF welding, solvent welding, laser welding, adhesive bonding and / or combinations thereof.

In some embodiments, the third wall 1528 and the first wall 1504 are made of the same or similar materials and / or materials with similar properties. Non-limiting examples of such properties include thickness, tear strength, toughness, water vapor transmission rate, water resistance and the like. However, in other embodiments, the third wall 1528 and the first wall 1504 may have different characteristics. For example, in some embodiments, the third wall 1528 may be thicker than the first wall 1504 in order to further add robustness to the container 1500. In other embodiments, the third wall 1528 may have a higher water vapor transmission rate. In this case, the water vapor that has passed through the first wall 1504 can more easily pass through the third wall 1528 and go out to the surrounding environment. In yet another example, the third wall 1528 may have higher waterproofness or may be a more effective barrier to microorganisms. In that case, water is prevented from seeping into the volume 1540, and the aseptic state of the volume 1540 is maintained.

Although not shown, in certain embodiments, the container 1500 may have a fourth wall above the third wall 1528. The fourth wall is provided as an additional protective layer. Similar to the 3rd layer 1404 of the container 1400, the 4th layer prevents damage to the 3rd wall 1528 that would occur when handling the container 1500, and in addition, a hand or other object is on the 3rd wall. Avoid direct contact with the 1528.

FIGS. 16-17C show embodiments of the container 1600 used to contain and store materials for freeze-drying and materials after freeze-drying. FIG. 16 is a front view of the container 1600. 17A-17C are various cross-sectional views of the container 1600 along the AA line (shown in FIG. 16). In some embodiments, the vessel 1600 is used to lyophilize a biological fluid such as whole blood or blood components. However, embodiments of the present invention are not limited to these. For any substance, liquid or solid, lyophilization and storage may be carried out using the embodiment of container 1600.

As shown in FIG. 16, the container 1600 has a first chamber 1604 and a second chamber 1608. As described below, in the embodiments shown in FIGS. 16-17C, Room 1 1604 is used for lyophilization of materials and Room 2 1608 is a lyophilized substance rehydrated. It is used to contain and store the substance until it is used. In other embodiments, it may be a different structure, design or component comprising a first chamber for accommodating material during lyophilization and a second chamber for accommodating material after lyophilization.

Room 1 1604 has port 1612. Substances such as blood or blood components (eg, human plasma) enter chamber 1 1604 via the port 1612. Room 2 1608 has port 1616. The hydrated water enters the second chamber 1608 via the port 1616. Room 2 1608 also has port 1620. The rehydrated substance exits chamber 2 1608 via port 1620 (eg, rehydrated blood components such as plasma exit chamber 2 via port 1620. Infused into the patient).

Referring to FIGS. 17A-17C, the first chamber 1604 has a first wall 1624 and a second wall 1628. The second wall is joined to the first wall to form the internal volume 1632 of the first chamber 1604. As mentioned above, Room 1 1604 is used to store material during lyophilization. The substance for lyophilization is housed in volume 1632.

In certain embodiments, the first wall 1624 is made of a flexible polymeric material. In some embodiments, the first wall 1624 is made of a transparent or translucent polymeric material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof.

As shown in FIG. 16, the second wall 1628 has a region 1656 having a gas permeability greater than that of the first wall 1624. Since the first chamber 1604 is used to store substances during lyophilization, a region 1656 is provided to allow gas (eg, water vapor) to escape from volume 1632 during lyophilization.

In certain embodiments, region 1656 is made from a material that is relatively permeable to gases such as water vapor and has sufficient strength to hold the material without leakage. In some embodiments, region 1656 is made from one or more of the following materials: That is, one or more of flashspun high density polyethylene (HDPE), polytetrafluoroethylene (PTFE), acrylics formed on woven or non-woven fabrics, amides formed on woven or non-woven fabrics, and / or combinations thereof. Made from.

In some embodiments, region 1656 may be larger than shown in FIG. 16 so as to occupy a portion larger than half of wall 1628, for example. In another embodiment, the entire wall 1628 is made of a material that is permeable to gases such as water vapor. In such an embodiment, there is no region 1656, instead the entire wall 1628 is the region for allowing gas (eg, water vapor) to escape from volume 1632. In yet another embodiment, multiple regions 1656 of the same size or different sizes may be provided as part of the wall 1628.

The rest of the wall 1628 (and, in certain embodiments, the wall 1624) is made from any suitable material. In certain embodiments, the wall 1628 and / or the wall 1624 is made of a flexible polymeric material. Examples of flexible polymeric materials used in parts of Wall 1628 and Wall 1624 are, but are not limited to, polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefin, polypropylene, polyvinyl chloride, or theirs. Combinations can be mentioned.

As mentioned above, the container 1600 has a second chamber 1608. The second chamber 1608 has a first wall 1636 joined to the second wall 1640 to define an internal volume 1644. In certain embodiments, Room 2 1608 is configured to store substances (eg, whole blood or blood components) after lyophilization. Therefore, the walls 1636, 1640 are made from a flexible polymeric material that is robust, can withstand long storage, and can withstand considerable handling. In some embodiments, walls 1636, 1640 are made from transparent or translucent polymeric materials. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof.

In addition to the first and second chambers 1604 and 1608, the container 1600 has a route 1648 as shown in FIGS. 17A, 17B and 17C as 1648A, 1648B and 1648C, respectively. Volume 1632 and volume 1644 are communicated (eg, fluid communication) by path 1648, but are also sealed by seal 1652 so that volume 1632 and volume 1644 are not communicated.

FIG. 17A shows path 1648A sealed by seal 1652. In this embodiment, there is no communication (eg, fluid communication) between volume 1632 and volume 1644. This embodiment is used when the material in chamber 1604 is being lyophilized. Seal 1652 keeps substances (eg, liquids or solids) out of volume 1644. Retaining the material in volume 1632 makes the lyophilization process more efficient. This is because the wall 1628 (which defines the volume 1632) is provided with a region 1656 for allowing gas (eg, water vapor) to escape.

The seal 1652 is formed using any suitable material, mechanism or process. Non-limiting examples of seals used as seals 1652 include welds, adhesives, breakable parts, clamps, joints, and / or combinations thereof. The formation of the seal 1652 includes mechanical tightening, welding (eg, radio frequency, ultrasonic waves, induction, welding of lasers, etc.), heat sealing, adhesive bonding, or other means. In one embodiment, the seal 1652 is opened to allow communication between volume 1632 and volume 1644.

FIG. 17B shows path 1648B opened to allow communication between volume 1632 and volume 1644. Similarly, FIG. 17C shows path 1648C in an open state to allow communication between volume 1632 and volume 1644. 17B and 17C show two different embodiments in which the amount of opening of path 1648 is different. In both embodiments, the material can flow from volume 1632 to volume 1644, although the amount of opening is different. Depending on the type of seal, path 1648 is opened with different opening amounts.

The embodiments shown in FIGS. 17B and 17C are used after the lyophilization process is complete. The lyophilized material in volume 1632 is transferred to volume 1644 via pathway 1648B or pathway 1648C. After transfer of material, Route 1648B or Route 1648C is resealed to prevent the material from returning to volume 1632. In some embodiments, chamber 1 1604 may be removed after the lyophilized material has been transferred to volume 1644 and route 1648B or route 1648C has been sealed. As an example, the seal 1652 is formed by welding and joining the wall 1636 and the wall 1640, and further, by cutting the wall 1624 and the wall 1628, the first chamber 1604 is separated from the second chamber 1608.

Hereinafter, a process according to an embodiment of the present invention for lyophilizing and storing whole blood or blood components (eg, plasma) will be described. However, the present invention is not limited thereto and may be used for lyophilizing and storing other substances. The following description refers to specific features of the container 1600 shown in FIGS. 16-17C, but the invention is not limited to being implemented by a particular structure. In other embodiments, different features may be utilized.

In certain embodiments, the liquid plasma fractionation product is placed in a container such as container 1600. Specifically, the plasma fractionation product is filled into chamber 1604 via port 1612. Chamber 1604 provides a sterile barrier and also allows lyophilization of plasma while allowing water vapor to escape through the wall (eg, region 1656).

After the chamber 1604 is filled with liquid plasma, the container 1600 is placed in an appliance for lyophilizing the substance, such as apparatus 100 (FIG. 1) or apparatus 200 (FIG. 2). Then, a freeze-drying process is performed on the liquid plasma.

During lyophilization of plasma, seals such as seal 1652 are present in pathway 1648, preventing communication between the volume of chamber 1604 and the volume of chamber 1608. That is, there is no fluid communication between volume 1632 and volume 1644.

After lyophilization of plasma, container 1600 is removed from the lyophilizer. By removing / opening the seal 1652, communication through route 1648 is allowed. The lyophilized plasma is transferred from volume 1632 to volume 1644. The seal 1652 is then closed or resealed. In some embodiments, chamber 1604 is removed from chamber 1608 after resealing of path 1648 or as part of the resealing step of path 1648.

In some embodiments, Room 1608 is robustly configured and also has considerable handling (eg, backpack transport in a military environment, mobile use such as a victim transport aircraft (helicopter or vehicle)). Made from materials that can withstand the rigors of handling). Thus, lyophilized plasma is stored in chamber 1608 for a relatively long period of time before it is put into use (eg, until it is rehydrated and infused into a patient).

In some embodiments, the rehydrated liquid is transferred to chamber 1608 through port 1616 before the lyophilized plasma is used. After some time has passed to hydrate the plasma (eg, less than 5 minutes), the rehydrated plasma is infused into the patient via port 1620.

For embodiments in which plasma is lyophilized, stored and infused using container 1600, the two chambers 1604, 1608 and the rest of the vessel are the processes of filling, lyophilization, inter-chamber transfer, storage and use. Throughout, it is maintained sterile and maintained as a closed system.

18A and 18B are front views of another container 1800 according to the embodiment of the present invention. In the embodiments shown in FIGS. 18A and 18B, the container 1800 has a single chamber 1804 with an internal volume of 1808. Container 1800 has a first portion 1804A (eg, top) and a second portion 1804B (eg, bottom).

Container 1800 has a first wall (not shown) and a second wall 1828. The second wall 1828 and the first wall are joined to form the internal volume 1808 of the chamber 1804. In certain embodiments, the first wall is made of a flexible polymeric material. In some embodiments, the first wall is made of a transparent or translucent polymer material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof.

As shown in FIG. 18A, the upper part of the wall 1828 has a gas permeable region 1856 that allows gas such as water vapor to escape from volume 1808. No gas permeation region is provided at the bottom of wall 1828.

Region 1856 has a gas permeability greater than the permeability of the first wall and the rest of the second wall 1828. Region 1856 is provided to allow gas (eg, water vapor) to escape from volume 1808 during lyophilization.

In certain embodiments, region 1856 is made from a material that is relatively permeable to gases such as water vapor and is strong enough to retain the lyophilized material without leaking. In some embodiments, region 1856 is made from one or more of the following materials: That is, one or more of flashspun high density polyethylene (HDPE), polytetrafluoroethylene (PTFE), acrylics formed on woven or non-woven fabrics, amides formed on woven or non-woven fabrics, and / or combinations thereof. Made from. The rest of the wall 1828 is made from any suitable material. In one embodiment, part of the second wall 1828 is made from a flexible polymeric material. Examples of flexible polymeric materials used as part of the wall 1828 include, but are not limited to, polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof. Be done.

For embodiments using container 1800, the lyophilized material is transferred into volume 1808 via one or more of ports 1816 and / or port 1820. After the lyophilized material is lyophilized, the lyophilized material is manually or automatically (eg, by a mechanical system) moved into the chamber 1804, so that most of the lyophilized material is at the bottom 1804B. Is placed in. After the lyophilized material is transferred to the bottom 1804B, the bottom 1804B is detached from the top 1804A as shown in FIG. 18B.

A seal 1860 is formed at the top of the bottom 1804B as part of or prior to the separation process between the top 1804A and the bottom 1804B. By Seal 1860, the lyophilized material is maintained in a sterile environment throughout the process of separating the bottom 1804B from the top 1804A. In certain embodiments, the seal 1860 is formed by any suitable sealing device. Non-limiting examples of equipment used to form the seal 1860 and separate the bottom 1804B from the top 1804A are, but not limited to, ultrasonic welding equipment, laser welding equipment, RF welding equipment, high frequency welding equipment, Examples thereof include an induction welding device, a hot bar welding device, a pulse welding device, a hot gas welding device, an infrared welding device, and / or a microwave welding device.

In some embodiments, the bottom 1804B is robustly configured and also has considerable handling (eg, backpack transport in a military environment, use on the move such as a victim transport aircraft (helicopter or vehicle)). It is configured to withstand the rigors of handling). Therefore, the lyophilized material is stored in the bottom 1804B until it is put into use.

In some embodiments, before the lyophilized material of bottom 1804B is used, the rehydrate liquid is transferred to bottom 1804B through one or more ports 1816 and / or port 1820. After some time has passed to hydrate the substance, the substance is transferred from the bottom 1804B and used via one or more ports 1816 and / or port 1820.

19A-19C are side views of another embodiment of the container 1900 used to contain the lyophilized material and to store the lyophilized material. The container 1900 has a first chamber 1904 and a second chamber 1908. As described below, in certain embodiments, the first chamber 1904 is used during lyophilization of the material and the second chamber 1908 is used to store the lyophilized material after lyophilization. ..

Room 1 1904 has port 1912. Substances (eg, plasma, whole blood, other blood components) are charged into chamber 1 1904 through the port 1912. Further, the first chamber 1904 has a first wall 1916 that defines the internal volume of the first chamber 1904 by being joined to the second wall 1920 via a side wall 1924. In some embodiments, the side wall 1924 or part thereof may be part of the first wall 1916 or the second wall 1920. For example, in certain embodiments, the first wall 1916 and / or the second wall 1920 may be formed from a single sheet sized to form a side wall 1924 or a portion thereof by bending. In other embodiments, the wall 1920 may be in the form of a tray with side walls 1924. In one embodiment, the side wall 1924 extends between the first wall 1916 and the second wall 1920 along the perimeter of the first wall 1916 and the second wall 1920.

As shown in FIGS. 19A and 19B, the side wall 1924 has creases 1928A, 1928B, 1928C. These creases allow the side wall 1924 to be folded and unfolded. FIG. 19A shows the side wall 1924 in a folded state where the internal volume of the chamber 1904 is reduced. FIG. 19B shows the side wall 1924 in the expanded state where the internal volume of the chamber 1904 is increased.

As shown in FIG. 19B, the chamber 1904 is connected to the chamber 1908 via route 1932. In FIG. 19A, clip 1936 is positioned to close and / or seal path 1932 to avoid communication between chambers 1904 and chamber 1908.

Returning to chamber 1904, walls 1920 and / or sidewalls 1924 are made from flexible polymeric materials. In some embodiments, the wall 1920 and / or the side wall 1924 is made of a transparent or translucent polymeric material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof.

Wall 1916 contains a gas permeable material. That is, the wall 1916 contains a material having a permeability greater than the permeability of the gas (eg, water vapor) of the wall 1920. Since the chamber 1904 is used to contain material during lyophilization, a permeable material is used to allow gas (eg, water vapor) to escape from the chamber 1904 during lyophilization. In certain embodiments, the entire wall 1916 may be made from a gas permeable material. In another embodiment, similar to wall 1828 of container 1800 (FIG. 18A), only a portion of the wall 1916 may contain a permeable material.

The permeable material used for the wall 1916 is made from a material that is relatively permeable to gases such as water vapor and has sufficient strength to hold the material without leakage. In some embodiments, the wall 1916 is made from one or more of the following materials: That is, one or more of flashspun high density polyethylene (HDPE), polytetrafluoroethylene (PTFE), acrylics formed on woven or non-woven fabrics, amides formed on woven or non-woven fabrics, and / or combinations thereof. Made from.

In certain embodiments, the wall 1916 has a water vapor transmission rate greater than about 65 perm, or greater than about 85 perm, or greater than about 105 perm, or greater than about 125 perm, or greater than about 145 perm. In some embodiments, the wall 1916 has a water vapor transmission rate in the range of about 70 perm to about 825 perm, eg, between about 95 perm and about 775 perm, or between about 120 perm and about 725 perm. Also, in some embodiments, the wall 1916 has a water resistance (ie, hydrostatic head) greater than about 70 cm, or greater than about 85 cm, or greater than about 100 cm, or greater than about 115 cm. In some embodiments, the wall 1916 has a water resistance in the range of about 20 cm to about 525 cm, eg, between about 25 cm and about 500 cm, or between about 30 cm and about 475 cm. In some embodiments, the wall 1916 has a combination of any of the above water vapor transmission rates and any of the above water resistance.

For embodiments where only part of the wall 1916 is a permeable material, the rest is made from any suitable material. Examples of flexible polymeric materials used in some of the walls 1916 include, but are not limited to, polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof. Be done.

As mentioned above, the container 1900 has a chamber 1908. The chamber 1908 has a first wall 1940. The first wall 1940 is joined to the second wall 1944 to define the internal volume of the chamber 1908 (see FIGS. 19B and 19C). In certain embodiments, the chamber 1908 is configured to store substances (eg, whole blood or blood components) after lyophilization. Therefore, the walls 1940, 1944 are made from flexible polymeric materials that are robust, withstand long storage, and withstand considerable handling. In some embodiments, the walls 1940, 1944 are made from a transparent or translucent polymeric material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof.

Room 1908 also has port 1948. In one embodiment, port 1948 is used to retrieve material from chamber 1908. In one embodiment, the lyophilized material in chamber 1908 is rehydrated in chamber 1908 and removed from chamber 1908 via port 1948. As an example, lyophilized plasma is stored in chamber 1908. After adding the rehydrated liquid to the lyophilized plasma, the rehydrated plasma is infused into the patient via port 1948. In another embodiment, the chamber 1908 has a number of ports greater than one. In such an embodiment, port 1948 is used to inject the rehydration fluid to rehydrate the lyophilized plasma and the other port is to rehydrate the patient with the plasma. Used to inject.

In FIG. 19A, the chamber 1908 is rolled up and therefore does not take up the same space as in the expanded state as shown in FIG. 19B. By being able to roll the chamber 1908 (FIG. 19A), for example, in a lyophilizer (eg 100 or 200), the space occupied by the container 1900 on the shelves can be reduced. If the chamber 1908 cannot be rolled up, the container 1900 will occupy additional shelf space that can be used to freeze-dry the material.

In addition to the chambers 1904, 1908, the container 1900 further has a route 1932. Path 1932 allows for communication between volume 1904 and volume 1908 (eg, fluid communication), while being sealed by a seal can also block communication between volume 1904 and volume 1908.

FIG. 19A shows path 1932 sealed by clip 1936. In this embodiment, there is no communication (eg, fluid communication) between volumes 1904 and volume 1908. This embodiment is used when the material in room 1904 is being lyophilized. Clip 1936 prevents substances in chamber 1904 (eg, liquids or solids) from entering the volume of chamber 1908. Retaining the material in volume 1904 makes the lyophilization process more efficient. This is because the wall 1916 contains a gas permeable material capable of allowing gas (eg, water vapor) to escape. If the transfer of material to chamber 1908 is possible, any gas must move to chamber 1904 and escape through wall 1916, which would prolong the freeze-drying process.

In other embodiments, instead of clip 1936, any suitable material, mechanism, or process may be used to form a seal between chambers 1904 and chamber 1908. Non-limiting examples of seals used in place of clip 1936 include welds, adhesives, breakable parts, joints, and / or combinations thereof. The formation of a seal between chambers 1904 and chamber 1908 includes mechanical tightening, welding (eg, radio frequency, ultrasonic, induction, laser welding, etc.), heat sealing, adhesive bonding, and / or other. Means can be mentioned.

FIG. 19B shows that clip 1936 has been removed, path 1932 has been opened, and communication between volumes 1904 and volume 1908 has become possible. After the material has been lyophilized in chamber 1904, the clip 1936 is removed and path 1932 is opened. With the route 1932 open, the lyophilized material is transferred from chamber 1904 to chamber 1908 for long-term storage.

After the lyophilized material is transferred to chamber 1908, chambers 1904 and 1908 are resealed and the communication between the two chambers is blocked. As shown in FIG. 19C, the chamber 1904 is separated from the chamber 1908 with the chamber 1908 sealed with a seal 1952. Room 1908 is then used to store the lyophilized material for a relatively long period of time (eg, about 2 years).

When using container 1900, the lyophilized substance (in one embodiment, the substance is plasma) is transferred to volume 1904 via port 1912. As a result of plasma infusion into chamber 1904, the side wall 1924 is expanded by creases 1928A-1928C to expand the volume of chamber 1904 (see chamber 1904 in Figure 19B). If the chamber 1908 is still rolled (see chamber 1908 in Figure 19A), the container 1900 is placed in a lyophilizer such as device 100 (Figure 1) or device (Figure 2) and plasma Freeze-dried. As mentioned above, the freeze-drying process comprises exposing the substance and container 1900 to a first pressure environment below atmospheric pressure, freezing, and sublimating one component of the substance. The gas generated during the sublimation process escapes from the chamber 1904 through the gas permeable material of the wall 1916.

After the material has been lyophilized, the lyophilized material is manually or automatically (eg, by a mechanical system) moved from chamber 1904 to chamber 1908. Specifically, first remove the clip 1936 to allow communication between chambers 1904 and 1908. The lyophilized material is then moved to room 1908. Room 1908 is sealed and room 1904 is separated from room 1908 as shown in FIG. 19C.

A seal 1952 is formed at the end of the chamber 1908 as part of or prior to the separation step between chambers 1904 and chamber 1908. By Seal 1952, the lyophilized material is maintained in a sterile environment throughout the process of separating chambers 1904 and 1908. In certain embodiments, the seal 1952 is formed by any suitable sealing device. Non-limiting examples of equipment used to form the seal 1952 and separate chambers 1904 from 1908 are, but not limited to, ultrasonic welding equipment, laser welding equipment, RF welding equipment, high frequency welding equipment. , Inductive welding device, hot bar welding device, pulse welding device, hot gas welding device, infrared welding device, and / or microwave welding device and the like.

20A-20C are side views of another embodiment of the container 2000 used to contain the lyophilized material and to store the lyophilized material. Container 2000 has a first chamber 2004 and a second chamber 2008. As described below, in certain embodiments, room 2004 is used during lyophilization of the substance and room 2008 is used until the lyophilized material is rehydrated and used. Used to store.

Room 1 2004 has port 2012. Substances (eg, plasma, whole blood, other blood components) are charged into chamber 1 2004 through the port 2012. Further, the first chamber 2004 has the first wall 2016 which constitutes the internal volume of the first chamber 2004 by being joined to the second wall 2020. In some embodiments, the wall 2020 may be depth relative to the material contained in the chamber 2004. In such an embodiment, the wall 2020 is in the shape of a tray.

As shown in FIG. 20B, room 2004 is connected to room 2008 via route 2032. In FIG. 20A, clip 2036 is positioned to close and / or seal path 2032 to avoid communication between chamber 2004 and chamber 2008.

Returning to chamber 2004, wall 2020 is made from flexible polymer material. In some embodiments, the wall 2020 is made from a transparent or translucent polymer material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof.

Wall 2016 contains gas permeable material. The wall 2016 contains a material having a permeability greater than the permeability of the gas (eg, water vapor) of the wall 2020. Since the chamber 2004 is used to contain material during lyophilization, a permeable material is used to allow gas (eg, water vapor) to escape from the chamber 2004 during lyophilization. In certain embodiments, the entire wall 2016 may be made from a gas permeable material. In another embodiment, similar to wall 1828 of container 1800 (FIG. 18A), only a portion of the area of wall 2016 may be formed of permeable material.

The permeable material used for Wall 2016 is made from a material that is relatively permeable to gases such as water vapor and is strong enough to hold the material without leaking. In some embodiments, the wall 2016 is made from one or more of the following materials: That is, one or more of flashspun high density polyethylene (HDPE), polytetrafluoroethylene (PTFE), acrylics formed on woven or non-woven fabrics, amides formed on woven or non-woven fabrics, and / or combinations thereof. Made from.

In certain embodiments, the wall 2016 has a water vapor transmission rate greater than about 135perm, or greater than about 150perm, or greater than about 165perm, or greater than about 180perm, or greater than about 195perm. In some embodiments, the wall 2016 has a water vapor transmission rate in the range of about 115 perm to about 725 perm, eg, between about 130 perm and about 700 perm, or between about 145 perm and about 675 perm. Also, in some embodiments, the wall 2016 has a water resistance (ie, hydrostatic head) greater than about 80 cm, or greater than about 90 cm, or greater than about 100 cm, or greater than about 110 cm. In some embodiments, the wall 2016 has a water resistance in the range of about 20 cm to about 500 cm, eg, between about 30 cm and about 450 cm, or between about 40 cm and about 400 cm. In some embodiments, the wall 2016 has a combination of any of the above water vapor transmission rates and any of the above water resistance.

For embodiments where only part of the wall 2016 is a permeable material, the rest is made from any suitable material. Examples of flexible polymeric materials used as part of Wall 2016 include, but are not limited to, polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof. Be done.

As mentioned above, the container 2000 has a chamber 2008. The chamber 2008 has a first wall 2040. The first wall 2040 is joined to the second wall 2044 to define the internal volume of the chamber 2008 (see Figure 20B). In certain embodiments, the chamber 2008 is configured to store substances (eg, whole blood or blood components) after lyophilization. Thus, the walls 2040, 2044 are made from a flexible polymeric material that is robust and can withstand long storage and considerable handling. In some embodiments, the walls 2040, 2044 are made from a transparent or translucent polymeric material. Non-limiting examples of such materials include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof.

Room 2008 also has port 2048. In certain embodiments, port 2048 is used to retrieve material from chamber 2008. In one embodiment, the lyophilized material in the chamber 2008 is rehydrated in the chamber 2008 and removed from the chamber 2008 via port 2048. As an example, lyophilized plasma is stored in room 2008. After adding the rehydrated liquid to the lyophilized plasma, the rehydrated plasma is infused into the patient via port 2048. In another embodiment, room 2008 has a number of ports greater than one. In such an embodiment, port 2048 is used to inject the rehydration fluid to rehydrate the lyophilized plasma, and the other port is to rehydrate the patient with the plasma. Used to inject.

In FIG. 20A, the chamber 2008 is rolled up and therefore does not take up the same space as in the expanded state as shown in FIG. 20B. By being able to roll the chamber 2008 (FIG. 20A), for example, in a lyophilizer (eg, FIG. 1 or FIG. 2), the space occupied by the container 2000 on the shelves can be reduced. If the chamber 2008 cannot be rolled up, the container 2000 will occupy additional shelf space that can be used to freeze-dry the material.

In addition to chambers 2004, 2008, container 2000 further has pathway 2032. Path 2032 allows communication between volume 2004 and volume 2008 (eg, fluid communication), while being sealed by a seal can also block communication between volume 2004 and volume 2008.

FIG. 20A shows path 2032 sealed by clip 2036. In this embodiment, there is no communication (eg, fluid communication) between volumes 2004 and 2008. This embodiment is used when the material in Room 2004 is lyophilized. Clip 2036 prevents substances in chamber 2004 (eg, liquids and solids) from entering the volume of chamber 2008. Retaining the material in volume 2004 makes the lyophilization process more efficient. This is because the wall 2016 contains a gas permeable material capable of allowing gas (eg, water vapor) to escape.

In other embodiments, instead of clip 2036, any suitable material, mechanism, or process may be used to form a seal between chambers 2004 and 2008. Non-limiting examples of seals used in place of clip 2036 include welds, adhesives, breakable parts, joints, and / or combinations thereof. The formation of the seal between chambers 2004 and 2008 includes mechanical tightening, welding (eg, welding of radio frequencies, ultrasonic waves, induction, lasers, etc.), heat sealing, adhesive bonding, or other means. Can be mentioned.

FIG. 20B shows a state in which clip 2036 has been removed, path 2032 has been opened, and communication between volumes 2004 and 2008 has become possible. After the material has been lyophilized in chamber 2004, the clip 2036 is removed and the pathway 2032 is opened. With route 2032 open, the lyophilized material is transferred from Room 2004 to Room 2008 for long-term storage.

After the lyophilized material is transferred to room 2008, room 2004 and room 2008 are resealed and the communication between the two rooms is blocked. As shown in FIG. 20C, the chamber 2004 is separated from the chamber 2008 with the chamber 2008 sealed with the seal 2052. Room 2008 is then used to store the lyophilized material for a relatively long period of time (eg, about 2 years).

FIG. 21 shows an embodiment of System 2100 for filling a container with biofluid. In one embodiment, the system 2100 is used to pool blood or blood components that will be lyophilized later. In one embodiment, the system 2100 is used to pool human plasma. Hereinafter, embodiments for pooling plasma will be described, but in other embodiments, other biofluids may be pooled.

The system 2100 has a plurality of ports 2104 to which a plurality of containers (eg, bags) containing plasma can be connected. In certain embodiments, the plasma is from various donors and each bag containing plasma is from a single donor. In some embodiments, plasma is selected based on the blood type of the donor. For example, plasma is from multiple donors of one blood group or matching blood group. In one embodiment, a plurality of specific blood types may be selected from a plurality of donors to generate a universal blood group. In certain embodiments, plasma from donors of blood types A, B, and AB may be used to create a versatile plasma that can be infused to a patient of any blood type.

After connecting to port 2104, plasma passes through a filter 2108 to remove some components or contaminants. In one embodiment, the filter 2108 is configured to remove cells such as white blood cells from plasma. In system 2100, only one filter 2108 is shown, but in other embodiments, system 2100 comprises a series of filters for filtering the above-mentioned components, or different components, or contaminants from plasma. You may have.

After filtration, the plasma is collected and pooled in container 2112. In one embodiment, the container 2112 is a bag that can hold a relatively large volume of plasma (eg, at least the volume of plasma in a plurality of containers connected to the plurality of ports 2104). Plasma is agitated and mixed while stored in container 2112. For such embodiments, the system 2100 further comprises the feature of performing agitation. Non-limiting examples of this feature include rollers, motors, ultrasonic transducers, power sources and the like.

In one embodiment, the system 2100 utilizes gravity to generate plasma flow from different parts of the system 2100 to different parts. In another embodiment, a pump is utilized to pump plasma from different parts of the system 2100 to different parts. In the embodiment shown in FIG. 21, pump 2116 is used to transfer plasma from container 2112 to container 2120. In other embodiments, the pump may be used in other parts of the system. For example, a pump may be used to move the plasma from the filter 2108 to the vessel 2112.

The container 2120 may be any container as long as it is suitable for holding plasma, but in one embodiment, the container is a container 1200 (FIGS. 12 and 13), a container 1600 (FIGS. 17A-18B), and a container 1800 (FIG. 17A-18B). 18A and 18B), container 1900 (FIGS. 19A-19C), and / or container 2000 (FIGS. 20A-20C). As described in detail below, the system 2100 pools a biofluid (eg, plasma), lyophilizes the fluid into a solid, stores the solid, and returns the solid to the original biofluid. Back and used with container 2120 in the process for using the biofluid to the patient.

FIG. 22 shows a second embodiment of system 2200 used to pool biofluids and fill containers. The system 2200 has the same characteristics as the system 2100, but with some other features. Similar to System 2100, System 2200 has multiple ports 2204 to which multiple containers (eg, bags) containing plasma can be connected. In certain embodiments, the plasma is from various donors and each bag containing plasma is from a single donor. As mentioned above, plasma is selected based on the blood type of the donor to produce plasma of one blood type or universal plasma that can be infused into patients of any blood type.

Plasma flows from port 2204 through filter 2208. The filter 2208 is similar to the filter 2108 and is used to remove some components (eg cells such as white blood cells) or contaminants from plasma. In other embodiments, the system 2200 may have a series of filters for filtering the above-mentioned components, or different components, or contaminants from plasma.

After filtration, the plasma is collected and pooled in container 2212. In one embodiment, the container 2212 is a bag. System 2200 further has components that perform plasma agitation. Non-limiting examples of this component include rollers, motors, ultrasonic transducers, power sources and the like.

The system 2200 also has a pump 2216. The pump is used to transfer plasma from vessel 2212 to filter 2220. In other embodiments, the pump may be used in other parts of the system. For example, a pump may be used to move the plasma from the filter 2208 to the vessel 2212.

Filter 2220 is used to concentrate plasma by removing water and salts from the plasma. In one embodiment, the filter 2220 is a hollow fiber membrane filter that removes water, salts, and small molecular weight molecules from plasma. Moisture, salts, and molecules from filter 2220 are collected in container 2228 and stored or discarded for later use. Although only one filter 2220 is shown in the system 2200, in other embodiments, the system 2200 may have a series of filters that remove at least water or other components from the plasma.

Pump 2232 is used to transfer plasma from filter 2220 to container 2236. Container 2236 may be any container as long as it is suitable for holding concentrated plasma, but in certain embodiments, the containers are container 1200 (FIGS. 12 and 13), vessel 1600 (FIGS. 16-17C). ), Container 1800 (FIGS. 18A and 18B), Container 1900 (FIGS. 19A-19C), and / or Container 2000 (FIGS. 20A-20C). System 2200 pools the biofluid (eg, plasma), lyophilizes the fluid into a solid, stores the solid, returns the solid to the original biofluid, and delivers the biofluid to the patient. Used with the container in the process for use.

FIG. 23 shows an embodiment of System 2300 for filling a container with biofluid. The system 2300 is similar to the system 2100 described above, but with the additional feature of reducing pathogens. In certain embodiments, the system 2300 is used to pool blood or blood components and reduce pathogens in the blood or blood components prior to lyophilization. In one embodiment, the system 2200 is used to pool human plasma and reduce pathogens. Hereinafter, embodiments of pooling plasma to reduce pathogens will be described, but in other embodiments, other biofluids may be pooled.

The system 2300 has a plurality of ports 2304 to which a plurality of containers (eg, bags) containing plasma can be connected. In certain embodiments, the plasma is from various donors and each bag containing plasma is from a single donor. In some embodiments, plasma is selected based on the blood type of the donor. For example, plasma is from multiple donors of one blood group or matching blood group. In one embodiment, a plurality of specific blood types may be selected from a plurality of donors to generate a universal blood group. In certain embodiments, plasma from donors of blood types A, B, and AB may be used to create a versatile plasma that can be infused to a patient of any blood type.

After connecting to port 2304, plasma passes through a filter 2308 to remove some components or contaminants. After filtration, the plasma is collected and pooled in container 2312. In one embodiment, the container 2312 is a bag that can hold a relatively large volume of plasma (eg, at least the volume of plasma in a plurality of containers connected to the plurality of ports 2304). Plasma is agitated and mixed while stored in container 2312. For such embodiments, the system 2300 further comprises the feature of performing agitation. Non-limiting examples of this feature include rollers, motors, ultrasonic transducers, power sources and the like.

In one embodiment, the system 2300 utilizes gravity to generate plasma flow from different parts of the system 2300 to different parts. In another embodiment, a pump is utilized to pump plasma from different parts of the system 2300 to different parts. For example, pump 2316 is used to transfer plasma from vessel 2324 to vessel 2320.

The system 2300 also has a container 2324 for storing the photosensitizer. Photosensitizers are used to reduce pathogens in plasma pooled in container 2312. In one embodiment, container 2324 contains an endogenous photosensitizer. Non-limiting examples of such sensitizers include flavins such as riboflavin.

Vessel 2312 is made from a material that is transparent or at least transparent to the wavelength of light used in the pathogen reduction process. In some embodiments, the vessel 2312 is made of a transparent or flexible polymeric material that is transparent to light of wavelengths ranging from at least about 250 nm to about 600 nm.

After the plasma is pooled in vessel 2312, the photosensitizer is mixed with plasma in vessel 2312. The system 2300 may further include a member that agitates the plasma and the photosensitizer. Non-limiting examples of such members include rollers, motors, ultrasonic transducers, power sources and the like.

After the photosensitizer is mixed with plasma in container 2312, the plasma is exposed to a light source such as light source 2328. In certain embodiments, the light source 2328 is a wavelength that interacts with the photosensitizer, which reduces pathogens in plasma. Examples and detailed description of pathogen reduction used in embodiments, including combinations of light wavelengths and photosensitizers, are described in US Pat. No. 6,548,241, US Pat. No. 6,258,577 and US Pat. No. 6,277,337. Provided in the specification. The entire US patent is expressly incorporated into this application by disclosure herein.

After irradiation with light source 2328, pathogen-reduced plasma is transferred to container 2320 (by pump 2316) for later freeze-drying. As the container 2320, any container may be used as long as it is suitable for retaining plasma with reduced pathogens. In certain embodiments, the containers are container 1200 (FIGS. 12 and 13), container 1600 (FIGS. 16C to 17C), container 1800 (FIGS. 18A and 18B), container 1900 (FIGS. 19A to 19C), and /. Alternatively, it may be the same as the container 2000 (FIGS. 20A to 20C).

FIG. 24 shows an embodiment of System 2400 for filling a container with biofluid. The system 2400 is similar to the system 2200 described above, but with the additional feature of reducing pathogens. In certain embodiments, the system 2400 is used to pool blood or blood components and reduce pathogens in the blood or blood components prior to lyophilization. In one embodiment, the system 2400 is used to pool human plasma and reduce pathogens.

Plasma flows from port 2404 through filter 2408. The filter 2408 is similar to the filter 2208 and is used to remove some components (eg cells such as white blood cells) or contaminants from plasma. In other embodiments, the system 2400 may have a series of filters for filtering the above-mentioned components, or different components, or contaminants from plasma.

After filtration, the plasma is collected and pooled in container 2412. In one embodiment, the container 2412 is a bag. System 2400 further comprises a member that performs plasma agitation. Non-limiting examples of this member include rollers, motors, ultrasonic transducers, power sources and the like.

The system 2400 also has a pump 2416. The pump is used to transfer plasma from the vessel 2412 to the filter 2420. In other embodiments, the pump may be used in other parts of the system. For example, a pump may be used to move the plasma from the filter 2408 to the vessel 2412.

Filter 2420 is used to concentrate plasma by removing water and salts from the plasma. In one embodiment, the filter 2420 is a hollow fiber membrane filter that removes water, salts, and small molecular weight molecules from plasma. Moisture, salts, and molecules from filter 2420 are collected in container 2428 and stored or discarded for later use. Although only one filter 2420 is shown in System 2400, in other embodiments, System 2400 may have a series of filters that remove at least water or other components from plasma.

Pump 2432 is used to transfer plasma from filter 2420 to container 2440. After the plasma has been transferred to container 2440, the photosensitizer contained in container 2244 is mixed with plasma in container 2440. The system 2400 may further include a member that agitates the plasma and the photosensitizer. Non-limiting examples of such members include rollers, motors, ultrasonic transducers, power sources and the like.

Vessel 2440 is made from a material that is transparent or at least transparent to the wavelength of light used in the pathogen reduction process. In some embodiments, the vessel 2440 is made of a transparent or flexible polymeric material that is transparent to light of wavelengths ranging from at least about 275 nm to about 625 nm.

After the photosensitizer is mixed with plasma in container 2440, the plasma is exposed to a light source such as light source 2448. In certain embodiments, the light source 2448 is a wavelength that interacts with the photosensitizer, which reduces pathogens in plasma. Examples and detailed description of pathogen reduction used in embodiments, including combinations of light wavelengths and photosensitizers, are described in US Pat. No. 6,548,241, US Pat. No. 6,258,577 and US Pat. No. 6,277,337. Provided in the specification. The entire US patent is expressly incorporated into this application by disclosure herein.

After irradiation with light source 2448, pathogen-reduced plasma is pumped into container 2436 by pump 2432 for later freeze-drying. As the container 2436, any container may be used as long as it is suitable for retaining plasma with reduced pathogens. In certain embodiments, the containers are container 1200 (FIGS. 12 and 13), container 1600 (FIGS. 16-17C), container 1800 (FIGS. 18A and 18B), container 1900 (FIGS. 19A-19C), and /. Alternatively, it may be the same as the container 2000 (FIGS. 20A to 20C).

In systems 2300, 2400, the light source (2328, 2448) may include other components and features in addition to the light source. For example, FIG. 25 shows a state in which the system 2500 is used as the light source 2328 (FIG. 23) and / or the light source 2448 (FIG. 24). As shown in FIG. 25, the system 2500 has a light source 2504 and a stirrer 2508 (eg, a vibration table). The stirrer 2508 stirs the fluid while irradiating the fluid in the container 2518 (in some embodiments, the container 2312 or the container 2440) with the light source 2504.

FIG. 26 shows another embodiment of device 2600, eg, a pathogen reduction device used as part of a light source (2328, 2448). As shown in FIG. 26, the device 2600 is provided with a light source 2608 on an openable door 2616. When the door 2616 is opened, a container with fluid is placed on the table 2612. In one embodiment, the table 2612 is provided with a window, which is positioned with a second light source 2604 for irradiating the fluid in the container. By closing the door 2616, the fluid in the container is radiated to both the light sources 2604 and 2608. In one embodiment, the table 2612 vibrates to agitate the fluid in the container before, after, or during irradiation with the light sources 2604, 2608.

In some embodiments, the system 2100, 2200, 2300, 2400 (or part of the system) may be provided as a disposable set that operates in conjunction with a permanent component of the system (eg, a light source). For example, in some embodiments, ports, filters, and containers may be manufactured in disposable sets with piping connected to various parts of the system. Permanent parts such as pumps and / or light sources operate in combination with disposable parts.

FIG. 27 shows the process 2700 of lyophilizing, storing, restoring, storing and infusing biofluid (plasma in FIG. 27). Process 2700 includes container 1200 (Fig. 12 and Fig. 13), container 1600 (Fig. 16 to Fig. 17C), container 1800 (Fig. 18A and Fig. 18B), container 1900 (Fig. 19A to Fig. 19C), container 2000 (Fig. 20A to Fig. 20A to). Performed using a suitable container such as a bag with the characteristics described above for FIG. 20C). In the following, the treatment for plasma performed using the container referred to as bag 1200 will be described, but other embodiments are not limited thereto.

In step 2704, the bag 1200 is filled with plasma. In certain embodiments, the bag 1200 is filled using a plasma pooling system such as the systems 2100, 2200, 2300 and / or 2400. In step 2708, plasma in bag 1200 is dispensed with one or more features of plate structure 800 (FIGS. 8A and 8B), plate structure 900 (FIG. 9), and / or plate structure 1000 (FIG. 10). , Freeze-dried in the bag 1200. The lyophilization process has the steps described below for Flowchart 2800. The steps include, for example, but not limited to, evaporating the liquid from the plasma while exposing the plasma to a first pressure (eg, below atmospheric pressure), freezing the remaining plasma while pressing to disperse the frozen plasma. There is a step of making, a step of sublimating a part of the frozen plasma while exposing the frozen plasma to a second pressure, and the like.

In FIG. 27, a container such as container 1200 is used, but in other embodiments, different containers may be used. Examples include containers such as container 1600 (FIGS. 16, 17C), container 1800 (FIGS. 18A and 18B), container 1900 (FIGS. 19A-19C), and / or container 2000 (FIGS. 20A-20C). used. For such embodiments, one chamber (or one portion) of the container is used for lyophilization of plasma. After lyophilization, the lyophilized plasma is transferred to the second or second chamber of the container and the first chamber (or first portion) is separated.

In step 2712, the bag 1200 containing the lyophilized plasma is packaged for storage. The packaging process has various steps and utilizes various packaging materials. In the process 2700, a sleeve 2740 is placed on the bag 1200 for added strength and is usually attached to the bag 1200 during subsequent process steps. Sleeve 2740 is made of any suitable material such as macromolecules. In certain embodiments, the sleeve 2740 is made of a flexible transparent or translucent polymer. Examples of such polymers include polycarbonate, acrylic, polystyrene, polysulfone, polyethylene, polyolefins, polypropylene, polyvinyl chloride, or combinations thereof.

The bag 1200 and sleeve 2740 are located within the foil bag 2744. The foil bag 2744 provides additional protection and prolongs the viability of lyophilized plasma in the bag 1200. The foil bag 2744 with a metallized layer is light-shielding, waterproof, has a desiccant, and is vacuum-packed. This prolongs the shelf life of lyophilized plasma. By using the flexible bag 1200, the flexible sleeve 2740, and the flexible foil bag 2744, the product becomes flexible and can be easily stored and transported by, for example, a backpack. In certain embodiments, lyophilization of plasma with a packaging step results in plasma having a shelf life of at least 2 years.

The bag 2748 containing the reconstitution fluid can be packaged with the bag 1200 in a foil bag 2744. If necessary, the lyophilized plasma of the bag 1200 is reconstituted with the fluid of the bag 2748 (see step 2716 in Figure 27). Bag 2748 is connected to bag 1200 to allow reconstitution fluid to flow into bag 1200. After a short period of time (eg, within 2 minutes), in some embodiments, after further agitation, the reconstituted plasma is ready for infusion to the patient in step 2720.

In another embodiment, in step 2724, the reconstituted plasma is transferred to bag 2748 for restorage in step 2728. In this embodiment, the bag 2748 has characteristics like a material that allows the liquid to be stored for a period of time. In some embodiments, plasma lyophilization and the use of bag 2748 allow the reconstituted plasma to be stored for at least one day prior to infusion from bag 2748 to the patient in step 2720.

A flowchart 2800 for a lyophilization process of a substance according to an embodiment is illustrated with reference to FIG. 28. In the following, specific devices for performing the steps of Flowchart 2800 are described, but the embodiments are not limited thereto. For example, some steps are described as being performed by a processor and others as being performed by one or more features of the lyophilizer. This is for illustrative purposes only, and Flowchart 2800 is not limited to being performed by a particular device, feature, or component. In certain embodiments, the flowchart 2800 is implemented by a lyophilizer such as the devices 100, 200 having one or more features of the plate structures 800, 900, 1000 described above in FIGS. 8A and 8B, 9 and 10. May be done.

In addition, any substance, including biological fluids such as blood, blood components, may be lyophilized by the process shown in Flowchart 2800. In certain embodiments, plasma is lyophilized by the process shown in FIG. 28, which is merely an example. The description of Flowchart 2800 is given for biological liquids (eg, plasma), but this is for illustrative purposes only and does not limit the scope of Flowchart 2800 to freeze-dry other substances.

Flowchart 2800 begins at step 2804. In certain embodiments, the flowchart 2800 optionally has a pathogen reduction step 2806. One embodiment of the pathogen reduction process is described below with reference to Flowchart 2900 of FIG.

After the optional pathogen reduction process (step 2806), in step 2808 the liquid (or other lyophilized material) is retained in the container. In certain embodiments, the container contains the lyophilized material before or during lyophilization, to store the lyophilized material for a relatively long period of time, and also to store the lyophilized material. Configured to be used for reconstruction. Also, in some embodiments, it is configured to be used to inject the reconstituted substance into a patient. In one embodiment, the container has one or more of the features described above for the container 1200. In other embodiments, if one chamber (or one portion) of the container is used for lyophilization and the other chamber (or other portion) is used for storage of lyophilized material, the containers 1600, 1800. , 1900, or 2000 is used. In certain embodiments, step 2808 has sub-steps such as placing the container on the shelves of a lyophilizer such as devices 100, 200.

Return to Flowchart 2800 and proceed from step 2808 to step 2812 to expose the container and liquid to the first pressure. In certain embodiments, the pressure is generated by a lyophilizer. The first pressure is lower than atmospheric pressure and depends on the substance to be lyophilized (eg, liquid). In embodiments where the plasma contains water, the first pressure is an absolute pressure of less than about 100 Torr, or less than about 75 Torr, or less than about 50 Torr, or less than about 25 Torr. In other embodiments, the first pressure is about 5x10.^-2Larger than Torr, or about 1x10^-1Larger than Torr, or about 5x10^-1Greater than Torr, or greater than about 1 Torr, or greater than about 1 Torr, greater than about 5 Torr, or greater than about 10 Torr. In yet another embodiment, the first pressure ranges from about 40 Torr to about 0 Torr, or from about 30 Torr to about 1 Torr, or from about 20 Torr to about 2 Torr, or from about 15 Torr to about 3 Torr. be. These are just a few examples of the first pressure range and in other embodiments different pressures may be used.

Proceed from step 2812 to optional step 2816 to evaporate the liquid from the lyophilized material. In embodiments where the substance is plasma, the liquid to be evaporated is water. Since the material is placed at a pressure below atmospheric pressure, only a relatively small amount of energy is required to evaporate the liquid from the material. Energy is supplied, for example, by a thermal fluid circulating in the plate of the shelf or by an IR radiator that is part of the shelf of the freeze-dryer.

In some embodiments, step 2816 is performed to reduce the volume of the lyophilized liquid. Without being bound by theory, it is believed that by performing step 2816 to reduce the volume of the liquid, subsequent sublimation steps can be performed more quickly and / or more efficiently.

Following step 2816, step 2820 is performed. In step 2820, the liquid is cooled and frozen to a solid, forming a frozen product. In one embodiment, the thermal fluid circulating in the plate of the shelf deprives energy, cools the liquid, and freezes it into a solid. In some embodiments, step 2820 optionally has a plurality of substeps. For example, substep 2824 is a step of evaporating a portion of the liquid. Evaporation cools the liquid to the extent that it freezes to a solid. In some embodiments, substep 2824 may be performed as part of step 2816 described above.

Further, in some embodiments, substep 2828 is performed for molding, for example, by pressing the container and the liquid in the container. Without being bound by theory, the pressing (or otherwise molding) of the container and the liquid (or other substance) in the container as part of freezing step 2820 is a liquid (or other substance). ) Is cooled and frozen, it is considered that a more uniform cross section can be formed. Therefore, it is believed that the more uniform cross-section will increase the efficiency of removing ice-like components from the frozen formulation during the subsequent sublimation step. That is, by reducing the variation in thickness, sublimation of the substance can occur at similar rates, improving process efficiency.

In some embodiments, pressure is applied using the shelf system 300 or shelf system 500 described with respect to FIGS. 3-6. In other embodiments, the pressure to press the material may be exerted by a different system such as a fluid-fillable flexible balloon or bladder. The balloon or air bag is positioned above the lyophilized material. The balloon or air bag is filled with a fluid (eg, gas or liquid) and the balloon or air bag inflates and presses against the frozen liquid. This is just an example of another embodiment, and in applying pressure to the container and the liquid, any method can be used to mold the container and / or the substance (eg, the liquid).

In step 2832, the container and the frozen product are exposed to the second pressure. In certain embodiments, the pressure is generated by a lyophilizer. The second pressure is lower than atmospheric pressure and lower than the first pressure. The pressure depends on the substance to be lyophilized. In embodiments where the substance contains water, the second pressure is about 5 × 10.^-1Less than Torr, or about 1x10^-1Less than Torr, or about 5x10^-2Less than Torr, or about 1x10^-2Less than Torr. In other embodiments, the second pressure is about 1x10.^-4Larger than Torr, or about 5x10^-4Larger than Torr, or about 1x10^-3Larger than Torr, or about 5x10^-3Larger than Torr, or about 1x10^-2Greater than Torr. These are just a few examples of the second pressure range, and in other embodiments different pressures may be used.

After step 2832, in step 2836, a portion of the frozen product (eg, in step 2820, the solid produced from the residual liquid) is sublimated. Energy is required to sublimate a substance from a frozen product. This energy is supplied, for example, by a thermal fluid circulating in the plate of the shelf. In some embodiments, step 2836 has sub-step 2840 that applies infrared energy by an IR radiator that is part of the lyophilizer shelf. In the embodiment where the shelves have a plate structure similar to the plate structures 800, 900, IR energy is applied from the top and heat energy from the thermal fluid is applied from the bottom. Then, the flowchart ends at step 2844.

Flowchart 2800 has been described by listing multiple steps in a particular order, but the invention is not limited thereto. In other embodiments, the steps may be performed in different orders, or in parallel, or different times (eg, before and after another step). Also, as mentioned above, Flowchart 2800 includes optional steps / substeps. However, the above steps not shown as options should not be considered essential to the present invention, and such steps may be performed in one embodiment and not in other embodiments.

In some embodiments, a portion of Flowchart 2800 may be performed as part of a customized lyophilization process performed by a lyophilizer or system. For example, an operator may utilize an application running on a computer system (eg, computer system 3300 described below) to create a custom process with one or more steps in Flowchart 2800. The material is then freeze-dried by performing the process in a freeze-drying device or system. In some embodiments, once created, the custom process can be run at the push of a button.

FIG. 29 shows a flowchart 2900 of a process of freeze-drying a substance according to another embodiment. In the following, specific devices for performing the steps of Flowchart 2900 are described, but the embodiments are not limited thereto. For example, some steps are described as being performed by a pathogen reduction device and other steps being performed by one or more features of the lyophilizer. This is for illustrative purposes only, and Flowchart 2900 is not limited to being performed by any particular device, feature, or component. In certain embodiments, flowchart 2900 may be implemented by a lyophilizer such as devices 100, 200.

In addition, any substance, including biological fluids such as blood, blood components, may be lyophilized by the process shown in Flowchart 2900. In certain embodiments, plasma is lyophilized by the process shown in FIG. 29, which is merely an example. The description of Flowchart 2900 is given for biological liquids (eg, plasma), but this is for illustrative purposes only and does not limit the scope of Flowchart 2900 to freeze-dry other substances.

Flowchart 2900 begins at step 2904 and proceeds to step 2908. In step 2908, the liquid is pooled in a container. In certain embodiments, systems such as systems 2400, 2500 are used to pool multiple units, eg plasma, in a larger container. In certain embodiments, step 2908 comprises stirring the liquid pooled in the container to mix the pooled liquid. The agitation uses a mechanism for agitating the liquid, and non-limiting examples of such a mechanism include pumps, vibrators, aerators, rollers, motors, ultrasonic transducers, power sources, and the like.

After step 2908, the process proceeds to step 2912 to add the pathogen reduction composition. In certain embodiments, the pathogen-reducing composition is an endogenous photosensitizer, such as flavin, which comprises riboflavin. In other embodiments, the pathogen-reducing composition may be another composition. For example, pathogen-reducing compositions include surfactants, buffers, salts, pH regulators, solvents and the like.

In step 2916, the liquid containing the pathogen reduction composition is exposed to light. Step 2916 involves the use of any suitable system with a light source. The light source irradiates the liquid containing the pathogen reduction composition at the wavelength required to reduce the pathogen in the liquid. In certain embodiments, a system such as System 2500 is used for both stirring the liquid and irradiating it with a light source. In another embodiment, a pathogen reduction device such as the device 2600 shown in FIG. 26 is used for both stirring the liquid and irradiating it with a light source. Stirring involves the use of a mechanism for stirring the liquid. Non-limiting examples of the mechanism include pumps, vibrators, aerators, rollers, motors, ultrasonic transducers, power sources and the like.

After step 2916, the liquid is lyophilized by any suitable lyophilization process 2920. For example, in some embodiments, flowchart 2900 proceeds to flowchart 2800 described above, where the pathogen-reduced liquid is lyophilized. In other embodiments, the lyophilization process may be accompanied by the flow chart 3200 described below with respect to FIG. Then, the flowchart 2900 ends at step 2936.

30 and 31 show embodiments of a system that freeze-drys a substance, primarily using IR (infrared) energy. As mentioned above for plate structures 800, 900, 1000, and Flowchart 2800 (FIG. 28), the present invention involves a freeze-drying process involving the use of IR energy in addition to or instead of thermal energy. offer. System 3000 (FIG. 30) and System 3100 (FIG. 31) are examples of systems used in embodiments that primarily utilize IR energy in the sublimation step of the lyophilization process. Thus, in the following, the material is frozen by system 3000 or other features of system 3100 or frozen in a different system or different device (eg, systems 100, 200 with plate structures 800, 900, and / or 1000). The explanation is given on the assumption that it has been done.

FIG. 30 shows a system 3000 that sublimates the material in the container 3004 as part of the freeze-drying process. In some embodiments, the container 3004 has two walls. The walls are joined together to define an internal volume in which the lyophilized material is placed. The material used for the walls of the container 3004 is made from a material that is relatively permeable to gases such as water vapor and has sufficient strength to hold the material without leakage. In some embodiments, the wall of the container 3004 is made from one or more of the following materials: That is, one or more of flashspun high density polyethylene (HDPE), polytetrafluoroethylene (PTFE), acrylics formed on woven or non-woven fabrics, amides formed on woven or non-woven fabrics, and / or combinations thereof. Made from.

The container 3004 with the frozen material inside is placed on a shelf 3008 configured to dissipate the gas moving through the container 3004. In one embodiment, the shelves 3008 are provided with a plurality of holes to allow gas to flow out of the container 3004. In another embodiment, the shelf 3008 is made from a screen structure or other porous structure capable of dissipating gas from the container 3004.

In addition, system 3000 has IR radiators 3012, 3016. As shown in FIG. 30, IR radiators 3012, 3016 are positioned to irradiate both sides of the vessel 3004 with IR energy. As mentioned above, sublimation occurs on the surface of matter. When using the structure shown in FIG. 30, sublimation occurs simultaneously in two planes, reducing the overall lyophilization time of the material.

FIG. 31 shows another embodiment of the system 3100 that sublimates the material in a container (3108, 3112, 3116, 3120) as part of the lyophilization process. Like container 3004, containers 3108, 3112, 3116, 3120 have two walls. The walls are joined together to define an internal volume in which the lyophilized material is placed. The materials used for the walls of containers 3108, 3112, 3116, 3120 are made from materials that are relatively permeable to gases such as water vapor and have sufficient strength to hold the material without leakage. Will be done. In some embodiments, the walls of the containers 3108, 3112, 3116, 3120 are made from one or more of the following materials: That is, one or more of flashspun high density polyethylene (HDPE), polytetrafluoroethylene (PTFE), acrylics formed on woven or non-woven fabrics, amides formed on woven or non-woven fabrics, and / or combinations thereof. Made from.

The system 3100 has a hanger section 3104 on which containers 3108, 3112, 3116, 3120 with frozen substances are hung. The hanger section 3104 is configured to have various hooks or other features for vertically holding the containers 3108, 3112, 3116, 3120.

System 3100 has IR radiators 3124, 3128, 3132, 3136, 3140. As shown in FIG. 31, the IR radiators 3124, 3128, 3132, 3136, 3140 are arranged to irradiate both sides of the container 3108, 3112, 3116, 3120 with IR energy. As mentioned above, sublimation occurs on the surface of matter. When the structure shown in FIG. 31 is used, sublimation occurs simultaneously on the two surfaces, reducing the overall lyophilization time of the material.

FIG. 32 shows a flowchart 3200 of a process of freeze-drying a substance according to an embodiment. In the following, specific devices will be described for performing the steps of Flowchart 3200, but embodiments are not limited to them.

Flowchart 3200 begins at step 3204 and proceeds to step 3208 for holding the substance in a container. In some embodiments, the substance is a liquid such as blood or blood components. In one embodiment, the substance is human plasma. In certain embodiments, the container for storing the material has a wall containing a material that is relatively permeable to a gas such as water vapor and has sufficient strength to hold the material during the process. Non-limiting examples of materials used include flashspun high density polyethylene (HDPE), polytetrafluoroethylene (PTFE), acrylics formed on woven or non-woven fabrics, amides formed on woven or non-woven fabrics, And / or made from one or more of their combinations.

In one embodiment, step 3208 involves moving the substance from one container to another. For example, in the case of human plasma embodiments, step 3208 involves pooling a plurality of units of plasma, transferring the plasma to a plurality of containers, and retaining the plasma in the plurality of containers.

After step 3208, flowchart 3200 proceeds to step 3212, where the substance is frozen. In some embodiments, step 3212 uses a shelf having a plate structure that includes the features of plate structure 800 (FIG. 8A and FIG. 8B), plate structure 900 (FIG. 9), or plate structure 1000 (FIG. 10). Accompany. For example, step 3208 involves placing the container on a shelf. The shelf has a path for circulating a thermal fluid to cool the substance and freeze the liquid in the substance in step 3212.

Step 3212 may include other substeps. For example, in one embodiment, step 3212 has a sub-step 3216 that forms a container and material (eg, presses during freezing). Molding is as in System 300 (Fig. 3) or System 500 (Fig. 5) using Plate Structure 800 (Fig. 8A and Fig. 8B), Plate Structure 900 (Fig. 9), and / or Plate Structure 1000 (Fig. 10). It is done using one or more shelving systems. In other embodiments, step 3212 may involve other steps or other structures (eg, formwork, woven fabric, stamps) that form the material during freezing.

Flowchart 3200 proceeds from step 3212 to step 3220, where the substance is exposed to a pressure below atmospheric pressure. The pressure is determined according to the substance to be freeze-dried. If the substance comprises water, the pressure is about 5 × 10.^-1Less than Torr, or about 1x10^-1Less than Torr, or about 5x10^-2Less than Torr, or about 1x10^-2Less than Torr. In other embodiments, the second pressure is about 1x10.^-4Larger than Torr, or about 5x10^-4Larger than Torr, or about 1x10^-3Larger than Torr, or about 5x10^-3Larger than Torr, or about 1x10^-2Greater than Torr. These are just a few examples of the second pressure range, and in other embodiments different pressure ranges may be used. In some embodiments, step 3220 is performed using a lyophilizer such as apparatus 100 (FIG. 1) and / or apparatus 200 (FIG. 2).

The flow chart proceeds from step 3220 to step 3224, where IR energy is applied to the substance. In certain embodiments, step 3224 may involve applying IR energy to only one side of the container. In other embodiments, step 3224 may involve applying IR energy to two or more sides of the container. Step 3224 takes place in a system that provides IR energy. Non-limiting examples of such systems include System 3000 (FIG. 30) and / or System 3100 (FIG. 31). Other examples of structures used to add IR energy include plate structure 800 (FIGS. 8A and 8B), plate structure 900 (FIG. 9), or plate structure 1000 (FIG. 10).

As part of step 3224, IR energy is applied to bring about a change in matter. For example, given IR energy, one component of a substance, 3228 (eg, ice), sublimates. Further, by applying IR energy, not only the component is sublimated, but also the component absorbed or adsorbed on the substance (for example, hydrated water) is removed (step 3232). Flowchart 3200 ends at step 3236.

FIG. 33 shows an example of components of a basic computer system 3300 in which an embodiment of the present invention is executed. For example, system 100 (FIG. 1) or system 200 (FIG. 2) may include some features of the basic computer system 3300 shown in FIG. 33. The computer system 3300 has an output device 3304 and an input device 3308. The output device 3304 may specifically include one or more displays such as CRTs, LCDs and / or plasma displays. The output device 3304 may also include a printer, a speaker, and the like. The input device 3308 may include, but is not limited to, a keyboard, a touch input device, a mouse, a voice input device, a scanner, and the like.

In an embodiment of the invention, the basic computer system 3300 may have one or more processors 3312 and memory 3316. In certain embodiments, the processor 3312 may be a general purpose processor capable of operating to execute processor executable instructions stored in memory 3316. Processor 3312 may include a single processor or a plurality of processors in the embodiment of the present invention. Further, in embodiments, each processor may be a single-core or multi-core processor having one or more cores for individually reading and executing instructions. Processors may include general purpose processors, application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), and other integrated circuits in embodiments.

Memory 3316 may include any storage medium for storing data and / or processor executable instructions in the short or long term. Memory 3316 includes, for example, random access memory (RAM), read-only memory (ROM), or electrically erasable, programmable read-only memory (EEPROM). Other storage media include, for example, CD-ROMs, tapes, digital versatile discs (DVDs), or other optical storage devices, tapes, magnetic disk devices, magnetic tapes, other magnetic storage devices, and the like.

The storage device 3328 may be any long-term data storage device or component. The storage device 3328 may include one or more of the devices described above in connection with the memory 3316. The storage device 3328 may be permanently installed or removable.

The computer system 3300 is also equipped with a communication device 3336. Communication device 3336 enables the system 3300 to communicate with a network (eg, wide area network, local area network, storage area network, etc.). The communication device 3336 may include a plurality of devices such as a modem, a hub, a network interface card, a wireless network interface card, a router, a switch, a bridge, a gateway, a wireless access point, and the like.

The components of the computer system 3300 are connected by the system bus 3340, as shown in FIG. However, in other embodiments, the components of the system 3300 may be connected by multiple buses.

Those skilled in the art will appreciate that various modifications and modifications can be made to the methods and structures of the invention without departing from the scope of the invention. Therefore, it should be understood that the invention is not limited to the particular embodiment described above. Rather, the invention is intended to include variants and modifications within the scope of the following claims and their equivalents.

Although embodiments and uses of the invention have been shown and described, it should be understood that the invention is not limited to the configurations and means described above. Various modifications, changes, etc. apparent to those skilled in the art can be made in the configuration, operation, and other details of the method and system of the present invention without departing from the scope of the present invention.