Freeze drying using a combination of a freezing chamber and a condenser

Abstract

The miniature freeze dryer (200) removes liquid from the raw powder product. The freeze dryer uses a single cryogenic vessel (210) to both (1) freeze the liquid contained in the raw product and (2) condense the vapor produced by sublimating the frozen liquid. A vacuum pump (212) is connected to the cryogenic vessel (210) and creates a vacuum within the cryogenic vessel (210) and within the drying vessel (260). The vapor produced by sublimating the frozen liquid in the drying vessel (260) is drawn into the cryogenic vessel (210) and condensed.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit under 35 U.S.C. § 119(e) of co-pending U.S. Provisional Application No. 63 / 033,049, entitled "FREEZE DRYING WITH COBINED FREEZING CHAMBER AND CONDENSER," filed June 1, 2020 (Attorney Reference No. EDW.13A.WO), which is incorporated herein by reference in its entirety and claims priority thereto.

[0002] The present invention relates generally to a freeze-drying process and apparatus that uses sublimation under vacuum and low temperatures to remove moisture from products. [Background technology]

[0003] Freeze-drying is the process of removing a solvent or suspension medium from a product. In this disclosure, water is used as an exemplary solvent, but other media, such as alcohol, can also be removed in the freeze-drying process and can be removed with the methods and apparatus of this disclosure.

[0004] The freeze-drying process for removing water involves freezing the water in a product to form ice. Under vacuum, the ice sublimes, and the resulting water vapor flows to a condenser, where it condenses as ice and is then removed. Freeze-drying is particularly useful in the pharmaceutical industry because the freeze-drying process preserves product integrity, ensuring product stability over relatively long periods of time. Freeze-dried products are typically, but not necessarily, biological materials.

[0005] The freeze-drying of pharmaceuticals is often an aseptic process that requires sterile conditions within the freeze-drying system. It is important to ensure that all components of the freeze-drying system that come into contact with the product are sterile.

[0006] Freeze-drying of raw product under sterile conditions can be performed in a freeze-dryer having shelves for supporting trays of product. In one example of a prior art freeze-drying system 100 shown in FIG. 1, batches of product 112 are loaded onto freeze-drying trays 121 in a freeze-drying chamber 110. Freeze-dryer shelves 123 are used to support the trays 121 and transfer heat between the trays and the product as required by the process. A heat-transfer fluid flowing through conduits within the shelves 123 is used to dissipate heat or heat up.

[0007] Under vacuum, frozen product 112 is heated slightly to cause sublimation of ice within the product. Water vapor resulting from the sublimation of the ice flows through passageway 115 into condensing chamber 120, which contains a condensing coil or other surface 122 maintained below the condensation temperature of the water vapor. Refrigerant is passed through coil 122 to remove heat, causing the water vapor to condense as ice on the coil.

[0008] Both the freeze-drying chamber 110 and the condensation chamber 120 are maintained at a vacuum during the drying process by a vacuum pump 150 connected to the exhaust of the condensation chamber 120. Non-condensable gases within the chambers 110, 120 are removed by the vacuum pump 150 and exhausted through an outlet 152 on the high pressure side.

[0009] One technique for preparing a product suspension or solution for the freeze-drying process is spray freezing. In spray freezing, the product is atomized in a spray-freezing vessel and exposed to a freezing medium, such as cryogenic nitrogen gas. Controlling the particle size of the atomized product can result in a frozen powder with a high surface area to mass ratio, increasing the efficiency of the subsequent drying process.

[0010] In certain applications, a batch throughput process such as that described above may be used in which the frozen product is dried in a drying chamber after the freezing process is completed for the batch of product. Such innovations in pilot processes and product development equipment allow for greater flexibility in experimentation and the use of simpler, less expensive equipment.

[0011] There is a need for improved equipment and technology for use in low volume applications such as pilot processes and product development. Equipment needs to have a minimal footprint for use in a laboratory environment. Equipment needs to be capable of producing sterile products for use in product testing. Equipment needs to be simple, low cost, and energy efficient. Summary of the Invention

[0012] The present disclosure addresses the aforementioned needs by providing a freeze-drying system for freeze-drying an original product by removing liquid. The system includes a cryocontainer having a cooling element, a product introduction inlet communicating with the interior of the cryocontainer and connected to a source of original product, and a drying chamber having a heating element. A selectively openable product transfer conduit connects the cryocontainer to the drying chamber, and at least one selectively openable bypass conduit connects the cryocontainer to the drying chamber via at least one vapor inlet of the cryocontainer. A selectively operable vacuum pump communicates with the interior of the cryocontainer via a vacuum outlet of the cryocontainer, the vacuum outlet of the cryocontainer being isolated from the at least one vapor inlet of the cryocontainer.

[0013] Another embodiment includes a freeze-drying system for freeze-drying an original product by removing liquid, the freeze-drying system including a cryocontainer having a cooling element, a product introduction inlet communicating with the interior of the cryocontainer and connected to a source of the original product, and a drying chamber having a heating element. A selectively openable product transfer conduit connects the cryocontainer and the drying chamber through at least one vapor inlet of the cryocontainer. A selectively operable vacuum pump communicates with the interior of the cryocontainer through a vacuum outlet of the cryocontainer, the vacuum outlet of the cryocontainer being separated from the at least one vapor inlet of the cryocontainer.

[0014] Another embodiment of the present invention is a method for freeze-drying a liquid-containing raw product, the method comprising: providing a cryocontainer having a cooling element; providing a drying chamber having a warming element; the cryocontainer and the drying chamber being in fluid communication via a transfer conduit blocked by a selector valve; isolating the cryocontainer from the drying chamber by closing the selector valve; introducing the liquid-containing raw product into the cryocontainer containing a gas having a first pressure and a temperature below the freezing point of the liquid, whereby the liquid is frozen in the cryocontainer to form a frozen liquid-containing raw product; removing isolation of the cryocontainer from the drying chamber by opening the selector valve; transferring the frozen liquid-containing raw product from the cryocontainer to the drying chamber via the transfer conduit; subjecting the cryocontainer and the drying chamber to a vacuum pressure lower than the first pressure while the cryocontainer and the drying chamber are in fluid communication, whereby the frozen liquid in the drying chamber sublimes to form a vapor; drawing the vapor from the drying chamber into the cryocontainer; and condensing the vapor in the cryocontainer. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 is a schematic diagram of a prior art freeze-drying system. [Figure 2A] FIG. 1 is a schematic perspective, partially cut-away view of a freeze-drying system according to one embodiment of the present disclosure. [Figure 2B] FIG. 2B is a schematic perspective view of the freeze-drying system of FIG. 2A taken along line 2B-2B. [Figure 3] 1 is a flowchart illustrating a method according to one aspect of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present disclosure describes a system and method for freeze-drying raw materials in an efficient manner using a compact, low-cost system. The disclosed system and method relates to a raw powder freeze dryer optimized for freezing and drying products to produce powder forms.

[0017] The present process and apparatus can be used to dry pharmaceuticals that require aseptic or sterilized processing, such as injectables. However, the method and apparatus can also be used to process materials that do not require aseptic processing but require moisture removal while maintaining structure. For example, ceramic / metal products used as superconductors or to form nanoparticle or microcircuit heat sinks can be manufactured using the disclosed technology.

[0018] The system disclosed herein effectively utilizes a single cryogenic vessel as both (1) a freezing chamber for freezing a medium containing the raw product during the freezing stage of the process and (2) a condenser for condensing the sublimated medium during the drying stage. In embodiments, the cryogenic vessel is a spray-freezing tower with cooled walls. During the freezing stage of certain embodiments, a solution or suspension containing the raw product and medium is sprayed from one of one or more nozzles at the top of the cryogenic vessel, and the medium freezes as it falls through the tower, creating a powdered frozen product. A product transfer conduit between the spray-freezing tower and the drying chamber is opened at intervals to allow the powdered frozen product to fall from the cryogenic vessel into the drying chamber.

[0019] During the drying phase of certain embodiments, a vacuum pump in communication with the cryocontainer is activated to evacuate the cryocontainer. One or more bypass conduits between the cryocontainer and the drying chamber can bypass the product transfer conduit and provide fluid communication between the cryocontainer and the drying chamber during the drying phase.

[0020] The drying chamber is then also evacuated by a vacuum pump via the cryostat and the bypass conduit, and the medium containing the raw product sublimes in the drying chamber. The sublimated medium passes as vapor through the bypass conduit into the cryostat, which is maintained at a low temperature during the drying phase by continuously cooling its walls after the freezing phase. The vapor condenses in the cryostat. The resulting condensate is periodically removed.

[0021] By using the same vessel to freeze the medium during the freezing stage and condense the evaporated medium during the drying stage, the system disclosed herein eliminates the need for a separate condensing chamber, reducing the size and bulk of the system. Additionally, by cooling only a single chamber instead of both a freezing chamber and a condenser, the system is more energy efficient. Fewer components result in lower initial system costs.

[0022] An exemplary system 200 according to one disclosed embodiment is shown in Figures 2A and 2B. Cryogenic vessel 210 functions as both a freezing chamber for freezing the product and a condenser for removing condensable gases from the effluent produced during drying of the product. System 200 can be used to perform a batch freeze-drying process, including a freezing step and a drying step. In one example, the maximum batch volume can be approximately 5 liters of product / medium suspension or solution.

[0023] In the illustrated embodiment, the interior of container 210 is cooled by circulating a cryogenic fluid, such as liquid nitrogen, through inlet 220, through the double wall of container 210, and through outlet 230. In other embodiments, cooling elements other than the wall can be used to cool the contents of container 210. The container may be cylindrical with curved vertical sidewalls. The container may include a conical bottom to direct the frozen product to isolation valve 268. During the freezing phase, the interior of container 210 may be filled with sterile gaseous nitrogen, which may be filtered using sterile filter 232. The sterile nitrogen gas may also be used to regulate other pressures within the system.

[0024] The spray nozzle 240 is connected to a liquid product reservoir 266 that contains the raw product suspended or dissolved in a liquid medium, such as a suspension or solution of biosolids in water or other liquid. The liquid product reservoir includes a cooling system, such as a Peltier plate, to keep the product refrigerated if necessary for product preservation. The amount of suspension or solution in the liquid product reservoir 266 can be monitored by a scale 267 that measures the weight of the reservoir system containing the product.

[0025] A suspension or solution from a liquid product reservoir 266 is flowed to the atomizing nozzle 240 using pressurized nitrogen gas. The nitrogen gas may be passed through a sterile filter 232. The nozzle 240 is positioned to atomize the product within the cryogenic vessel 210. Atomization of the product results in a dispersion of fine particles within the cryogenic vessel 210. Both the particle size and particle size distribution depend on the atomization technology. For example, the nozzle geometry, product flow rate, and nozzle placement within the chamber can affect the process output. The particle size and particle size distribution are important to the application of the product. For example, for powder processing, a particle size of 100 microns or greater is preferred, while for pulmonary applications, the particle size should be approximately 6 microns.

[0026] In an embodiment, the frozen product can fall through an atmosphere of nitrogen gas cooled by the walls of the cryocontainer 210. The dimensions of the container are such that the product is allowed sufficient time to come into contact with the nitrogen gas atmosphere to allow the product to freeze before reaching the bottom of the chamber. The spray-frozen liquid product collects at the bottom of the cryocontainer 210 as a frozen powder. The spray-freezing process produces small particles of product, which freeze quickly because they have a large surface area to mass ratio and therefore minimal resistance to heat input. This characteristic also speeds the drying process.

[0027] Isolation valve 268 separates cryocontainer 210 from drying chamber 260 and can be activated during either or both of the freezing and drying stages. The isolation valve may remain closed during spray freezing in the cryocontainer to maintain sufficiently low temperatures within the container without the need to cool the drying chamber. In certain embodiments, after a sufficient amount of liquid product has been spray frozen and collected at the bottom of cryocontainer 210, isolation valve 268 is opened to allow the frozen product to drop from cryocontainer 210 through product transfer conduit 269 into drying chamber 260. Isolation valve 268 may be opened only once at the end of the freezing stage of the process, or it may be opened periodically during the freezing stage to prevent excessive accumulation of frozen product at the bottom of cryocontainer 210. For example, isolation valve 268 may be opened after freezing each 0.5 liter of product / media suspension or solution to transfer the frozen product, after which the isolation valve may be closed to continue freezing more product until the entire batch (e.g., 5 liters) has accumulated in drying chamber 260. This procedure avoids warming of the frozen product caused by excess frozen product accumulation in the isolation valve 268. The isolation valve is in direct communication with the drying chamber and is not temperature controlled.

[0028] In another example, the isolation valve is opened every 15 minutes to discharge the frozen product into the drying chamber. In other examples, the isolation valve is opened every hour or every 30 minutes.

[0029] Temperature-controlled shelves 250 in the drying chamber 260 hold the frozen product as it enters the chamber. A circulating heat transfer fluid, along with the shelves 250, is used to maintain the process temperature of the frozen product. For example, the product in the drying chamber 260 may be maintained in its frozen state as additional product is frozen in the cryogenic vessel 210, or the product in the drying chamber 260 may be slightly heated during the drying phase to induce sublimation of the medium.

[0030] A vibrating unit 251 is connected to the shelf 250 to vibrate the shelf and impart a vibrating motion to the frozen products. The shelf 250 is vibrated after the completion of the freezing step or after each transfer of the frozen products. The vibrating shelf spreads and levels the collected frozen products on the shelf, forming or maintaining a product layer of uniform thickness and improving drying efficiency.

[0031] After the freezing step is completed, a drying step is performed in which the now frozen medium is removed from the product using a sublimation process. During the drying step of the disclosed freeze-drying process, the cryocontainer 210 is maintained at a low temperature, for example, by continuously circulating a cryogenic fluid in the double wall of the container. A vacuum pump 212 connected to the cryocontainer 210 is activated to evacuate the system. The cryocontainer 210 is directly evacuated by the vacuum pump 212. The vacuum pump 212 may be an independent, free-standing vacuum pump, as shown in FIG. 2A, or it may be part of a vacuum pump bank 270 that also includes a liquid ring pump.

[0032] During the drying phase, product transfer conduit 269 may be closed using valve 268, and one or more bypass conduits 214 are valved to connect cryocontainer 210 to drying chamber 260 via cryocontainer steam inlet 215. To avoid blocking vacuum pump 212, which could occur due to the small size of product transfer conduit 269, bypass conduit 214 allows evacuation of drying chamber 260 via cryocontainer 210, bypassing product transfer conduit 269 and valve 268. Furthermore, if the product transfer conduit remains open during the drying phase, ice or condensate may accumulate and block the area where the product transfer conduit enters the cryocontainer. In embodiments, the shape of that area is designed to direct frozen product into the drying chamber during the freezing phase, but is not designed to prevent ice accumulation during the drying phase. In other embodiments, both the bypass conduit and the product transfer conduit may be open and used as a steam inlet during the drying phase. In yet another embodiment, no bypass conduit is provided and the product transfer conduit is used both for product transfer from the cryogenic vessel to the drying chamber and as a vapor inlet for flowing vapor from the drying chamber to the cryogenic vessel.

[0033] During the drying stage of the process, the freezing media in drying chamber 260 is exposed to vacuum and slightly heated by shelf 250, causing the media to sublimate and generate vapor. The vapor is drawn from the drying chamber through bypass conduit 214 and / or product transfer conduit 269 into one or more vapor inlets of cryocontainer 210. The vapor condenses as ice on the interior walls of the cryocontainer or other cooling elements of the vessel. The condensed vapor is removed from the cryocontainer periodically or before the vessel begins a subsequent batch freeze-drying operation in which the vessel is used to freeze a product / media suspension.

[0034] Vacuum pump 212 is connected to cryocontainer 210 via cryocontainer vacuum outlet 213. Vacuum outlet 213 is separate from vapor inlet 215 of cryocontainer 210 so that condensable vapor flowing from the drying chamber flows through cryocontainer 210 and condenses on the walls of the cryocontainer or other cooling elements. "Separate," as used herein, means that the vacuum outlet and vapor inlet are different openings that access the interior of the cryocontainer. Advantageously, the two openings are spaced apart and not adjacent to each other. In one embodiment, if substantially the entire length of the cryocontainer is used to condense vapor from the drying chamber, vacuum outlet 213 of cryocontainer 210 may be near the top of the vessel, while vapor inlet 215 may be near the bottom of vessel 210.

[0035] After the drying stage is complete, both the drying chamber 260 and the cryocontainer 210 are returned to atmospheric pressure. The shelves 250 may be tilted and / or vibrated to move the dried product from the shelves to the dried product collection container 262. The sight glass 264 may be used for in-line NIR moisture measurement after the batch is completed. The cryocontainer may again be isolated from the drying chamber to begin freezing a new batch of product.

[0036] A method for freeze-drying a liquid-containing raw product according to an embodiment of the present invention is illustrated by the flowchart 300 shown in FIG. 3. As shown in block 310, the system is first calibrated. The cryocontainer 210 is cooled by circulating liquid nitrogen through the double wall or using other cooling elements. The cryocontainer is purged with atmospheric air, such as sterile nitrogen gas. Then, in block 320, the liquid product is pumped from the liquid product reservoir 266 into the nozzle feed system adjacent to the nozzle 240 using pressurized nitrogen gas.

[0037] The freezing stage of the freeze-drying process then begins, as indicated in block 330. The liquid product is dispensed through a nozzle and frozen within the cryogenic container 210. The isolation valve 268 is periodically opened to allow batches of frozen product to fall onto the refrigerated shelves 250 in the drying chamber 260. In the example referenced above, the valve is opened after freezing every 0.5 liters of product / media suspension.

[0038] After opening the isolation valve one or more times to transfer the product to the drying chamber, the freezing stage of the freeze-drying process ends at block 340. In an exemplary embodiment, the maximum batch size is 5 liters of product / media suspension, resulting in a layer depth of 8-11 mm on the shelf 250. Each time the isolation valve 268 is opened to discharge frozen product onto the shelf 250, the product on the shelf is leveled using a vibratory drive, as shown in block 350.

[0039] Once the shelf 250 is full, as shown in block 360, the isolation valve 268 is closed and the valve in the bypass conduit is opened. The vacuum pump 212 is activated to evacuate the drying chamber 260 using the bypass conduit 214 connecting the drying chamber to the cryocontainer 210. A predetermined temperature and pressure sequence is then executed to dry the batch of product, as shown in block 370. This sequence may be stored as part of the programmable logic controller program that controls the various components of the system. Upon completion of the drying operation, the drying chamber and cryocontainer are returned to atmospheric pressure, the shelf 250 is tilted to collect the dried product, and the sight glass 264 may be used to measure residual moisture with in-line NIR.

[0040] The systems and methods described herein may be implemented in part by an industrial controller and / or computer used in combination with the processing equipment described below. The equipment is controlled by a programmable logic controller (PLC) with operational logic for valves, motors, etc. Interface to the PLC is provided via a PC. The PC loads operator-defined recipes or programs into the PLC for execution. The PLC uploads historical data from runs to the PC for storage. The PC can also be used to manually control the equipment or to perform specific steps, such as freezing, thawing, or evaporation, in place.

[0041] PLCs and PCs include a central processing unit (CPU), memory, and an input / output interface connected to the CPU via a bus. The PLC is connected to the processing unit via the input / output interface to receive data from sensors that monitor various conditions of the device, such as temperature, position, speed, and flow rate. The PLC is also connected to operate devices that are part of the device.

[0042] The memory may include random access memory (RAM) and read-only memory (ROM). The memory may also include removable media such as a disk drive, a tape drive, or a combination thereof. The RAM may function as a data memory for storing data used during execution of a program in the CPU and may be used as a working area. The ROM may function as a program memory for storing a program including steps to be executed by the CPU. The program may reside in the ROM or may be stored on other non-volatile computer-usable media or removable media in a PLC or PC as computer-readable instructions stored therein for execution by the CPU or other processor to perform the methods disclosed herein.

[0043] The foregoing detailed description is understood in all respects to be illustrative and representative, but not restrictive, and the scope of the invention disclosed herein is to be determined not from the detailed description of the invention, but from the claims which are to be interpreted in accordance with the full scope allowed by patent law. It will be understood that the embodiments shown and described herein are merely illustrative of the principles of the invention, and that various modifications can be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims

1. A freeze-drying system (200) for freeze-drying an original product by removing liquid, comprising: a cryogenic vessel (210) having a cooling element; a product introduction inlet (240) communicating with the interior of the cryogenic vessel (210) and connected to a source (266) of the raw product; a drying chamber (260) having a heating element; a selectively openable product transfer conduit (269) connecting the cryogenic vessel (210) and the drying chamber (260); at least one selectively openable bypass conduit (214) connecting the cryocontainer (210) to a drying chamber (260) via at least one vapor inlet (215) of the cryocontainer (210); a selectively operable vacuum pump (212) in communication with the interior of the cryocontainer (210) via a vacuum outlet (213) of the cryocontainer (210); a controller including a memory for storing a program; Equipped with The program, when executed by the controller, causes the freeze-drying system (200) to: a freezing step in which the raw product is introduced through the product introduction inlet (240) to produce a frozen powder in the cryogenic vessel (210) at a first pressure, and the frozen powder is transferred to the drying chamber (260) via the product transfer conduit (269); a drying stage in which the vacuum pump (212) evacuates the cryogenic vessel (210) and the drying chamber (260) to a vacuum pressure lower than the first pressure, and sublimated and frozen liquid is drawn from the drying chamber (260) through the at least one bypass conduit (214) into the cryogenic vessel (210) and condenses on the cooling element; Execute A freeze-drying system, wherein the vacuum outlet (213) of the cryocontainer (210) is separated from the at least one vapor inlet (215) of the cryocontainer (210).

2. 2. The freeze-drying system of claim 1, wherein the product introduction inlet (240) further comprises at least one spray nozzle (240) connected to spray the raw product into the cryogenic vessel (210).

3. 3. The freeze-drying system of claim 2, wherein the cryogenic container (210) further comprises a cylindrical container having a curved vertical wall, the at least one spray nozzle (240) is connected at a top of the cylindrical container, and the cooling element consists of the curved vertical wall.

4. 2. The freeze-drying system of claim 1, wherein the cryogenic container (210) is above the drying chamber (260), and the product transfer conduit (269) connects a bottom of the cryogenic container (210) to the drying chamber (260).

5. 2. The freeze-drying system of claim 1, wherein the drying chamber further comprises a shelf positioned to receive product from the product transfer conduit.

6. The freeze-drying system of claim 5 , wherein the warming element comprises a heat transfer fluid circulation system within the shelf (250).

7. The freeze-drying system of claim 5, further comprising a vibration unit (251) connected to vibrate the shelf (250).

8. The freeze-drying system of claim 5, further comprising a tilt unit connected to tilt the shelf (250).

9. 1. A method for freeze-drying a liquid-containing raw product, comprising: Providing a cryocontainer (210) having a cooling element; providing a drying chamber (260) having a heating element; The cryogenic vessel (210) and the drying chamber (260) are in fluid communication via a transfer conduit (269) that is blocked by an isolation valve (268); isolating the cryocontainer (210) from the drying chamber (260) by closing the isolation valve (268); introducing the raw product comprising the liquid into the cryogenic vessel (210) containing a gas having a first pressure and a temperature below the freezing point of the liquid, whereby the liquid is frozen in the cryogenic vessel (210) to form an raw product comprising a frozen liquid; removing isolation of the cryocontainer (210) from the drying chamber (260) by opening the isolation valve (268); transferring the raw product comprising frozen liquid from the cryogenic vessel (210) to the drying chamber (260) via the transfer conduit (269); after transferring the raw product, closing the isolation valve (268) and opening a selectively closable bypass conduit (214) that bypasses the selectively closable product transfer conduit (269); subjecting the cryogenic vessel (210) and the drying chamber (260) to a vacuum pressure lower than the first pressure while the cryogenic vessel (210) and the drying chamber (260) are in fluid communication, whereby the frozen liquid in the drying chamber (260) sublimes to form a vapor; drawing the vapor from the drying chamber (260) into the cryogenic vessel (210); condensing the vapor in the cryogenic vessel (210).

10. The method of claim 9, wherein introducing the raw product containing the liquid into the cryogenic vessel (210) comprises atomizing the raw product.

11. 10. The method of claim 9, wherein opening the isolation valve (268) to remove isolation of the cryogenic vessel (210) from the drying chamber (260) further comprises opening the isolation valve (268) in a selectively closable product transfer conduit (269).

12. Transferring the raw product including frozen liquid from the cryogenic vessel (210) to the drying chamber (260) includes: opening the isolation valve (268) in the selectively closable product transfer conduit (269); transferring a portion of the batch of raw product containing frozen liquid onto a temperature-controlled shelf (250) in said drying chamber (260); closing the isolation valve (268); Repeating the introduction of the raw product containing the liquid into the cryogenic vessel (210); 10. The method of claim 9, further comprising periodically

13. transferring the raw product including the frozen liquid from the cryogenic container (210) to the drying chamber (260) further comprises transferring the raw product onto a shelf (250) in the drying chamber (260); 10. The method of claim 9, further comprising vibrating the shelf (250) to form a substantially uniform depth of the raw product including frozen liquid on the shelf (250).

14. 10. The method of claim 9, further comprising circulating a cryogenic fluid through the cooling element of the cryogenic vessel (210) during the introducing of the raw product including the liquid into the cryogenic vessel (210) containing the gas having the first pressure and during the subjecting of the cryogenic vessel (210) and the drying chamber (260) to a vacuum pressure lower than the first pressure.

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