Drying chamber for bulk freeze drying system

Abstract

The freeze-drying vessel (302) having a drying chamber (304) and a movable transfer belt (360, 362, 364, 366) is moved by a driven drum (370, 388), respectively. Each transfer belt includes a transfer surface (402, 404, 408, 410) that transfers the frozen particles (282). Each transfer surface is vertically disposed within the chamber and moves in a direction opposite to the lower transfer surface (400, 406). A removal device (416, 418) is located adjacent to each driven drum and removes frozen particles from the end (371, 373, 375, 377) of each transfer surface, respectively, and allows the removed frozen particles to flow downward to the lower transfer surface. A heating element (363, 361) is located adjacent to each transfer belt and sublimes the frozen particles to form the freeze-dried product (284).

Description

[Technical field]

[0001] 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 / 140,451, filed January 22, 2021, and entitled "BULK FREEZE DRYING SYSTEM," (Attorney Docket No. EDW.14A2.US), which is incorporated by reference in its entirety and to which this application claims the benefit of priority. FIELD OF THEINVENTION

[0002] The present disclosure relates generally to bulk freeze-drying systems and methods, and more particularly to a freeze-drying chamber having a plurality of movable product transport belts, each belt moved by a rotating driven drum spaced horizontally from an idler drum to form a plurality of horizontal product transport surfaces transporting frozen particles in alternating directions, and at least one product removal device removing frozen particles from an end of each product transport surface to allow the removed frozen particles to flow downwardly to a lower product transport surface for eventual discharge through a drying chamber outlet. [Background technology]

[0003] background Freeze-drying is the process of removing a solvent or suspending medium, typically water, from a product. The present disclosure uses water as an exemplary solvent, but other solvents, such as alcohol, can also be removed in the freeze-drying process and can be removed using the methods and apparatus of the present disclosure.

[0004] The freeze-drying process for removing water involves freezing the water in the product to form ice, sublimating the ice under vacuum, and allowing the vapor to flow to a condenser. The water vapor is condensed as ice on the condenser and is later removed from the condenser. Freeze-drying is particularly useful in the pharmaceutical industry because the integrity of the product is maintained during the freeze-drying process and the stability of the product can be guaranteed for relatively long periods of time. The freeze-dried product is usually, but not necessarily, a biological material. Summary of the Invention [Problem to be solved by the invention]

[0005] Pharmaceutical lyophilization is often an aseptic process that requires sterile conditions in the freezing and drying chamber. It is important to ensure that all components of the lyophilization system that come into contact with the product are sterile.

[0006] Sterile freeze-drying of bulk products can be performed in a freeze-dryer where the bulk product is placed in trays. In one example of a conventional freeze-drying system 100 shown in Figure 1, batches of product 112 are placed in freeze-dryer trays 121 in a freeze-drying chamber 110. A freeze-drying shelf 123 is used to support the trays 121 and transfer heat between the trays and the product depending on the process. A heat transfer fluid flowing through conduits in the shelf 123 can be used to remove or add heat.

[0007] Under vacuum, the frozen product 112 heats slightly, causing ice to sublime within the product. Water vapor resulting from the sublimation of the ice flows through passages 115 into a condensing chamber 120 that contains a condensing coil or other surface 122 maintained below the condensation temperature of the water vapor. A coolant passes through the coil 122 to remove the heat, and the water vapor condenses as ice on the coil.

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

[0009] Tray dryers are typically designed for sterile vial drying and are not optimized to handle bulk products. Bulk products must be manually loaded into trays, lyophilized, and then manually removed from the trays. Handling the trays is difficult and creates the risk of liquid spillage. Heat transfer resistance between the product and the trays and between the trays and shelves sometimes causes irregular heat transfer. Dried products must be removed from the trays after processing, resulting in handling losses of product.

[0010] Because the process is performed on large quantities of product, agglomeration into a "cake" often occurs and grinding is required to obtain the proper powder and uniform particle size. Cycle times can be longer than necessary due to the resistance of the bulk product to heating and the poor heat transfer characteristics between the trays, product, and shelves.

[0011] Spray freezing has been used as a technique to create particulate frozen bulk products. Problems with current systems include control of particle size in the frozen bulk product and efficient removal of heat from the sprayed droplets. [Means for solving the problem]

[0012] overview A freeze-drying vessel for a freeze-drying system having a freezing vessel that produces frozen product particles by freezing droplets of a fluid product is disclosed. The vessel includes a freeze-drying chamber having a drying chamber inlet for receiving frozen particles, a vacuum port for evacuating the drying chamber to a first vacuum pressure, and a drying chamber outlet. The vessel also includes a plurality of movable product transport belts, each of which is moved by a rotating driven drum horizontally spaced apart from an idler drum to form a plurality of horizontal product transport surfaces for transporting frozen particles. Each product transport surface is vertically disposed within the drying chamber and moves in a horizontal direction opposite to the lower product transport surface. The product transport surfaces include an upper product transport surface and a bottom product transport surface, the upper product transport surface receiving frozen particles from the drying chamber inlet.

[0013] The vessel also includes at least one product removal device disposed adjacent each driven drum for removing frozen particles from an end of each product transport surface to allow the removed frozen particles to flow downwardly to the lower product transport surface.

[0014] The vessel further includes at least one heating element disposed adjacent each product transport surface for heating the frozen particles to promote sublimation of the frozen particles to form a freeze-dried product in powder form that flows downwardly from the bottom product transport surface and is discharged through the drying chamber outlet.

[0015] A person skilled in the art can apply each of the features of the present invention together or severally in any combination or subcombination. Exemplary embodiments of the present invention are further described in the following detailed description in conjunction with the accompanying drawings, in which: [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 illustrates a conventional freeze-drying system. [Diagram 2] FIG. 1 is a schematic diagram of a bulk freeze-drying system according to one embodiment of the present invention. [Figure 3A] 1A-1D are side and top views of the interior of an exemplary freezing container according to one aspect of the present invention. [Figure 3B] 1A-1D are side and top views of the interior of an exemplary freezing container according to one aspect of the present invention. [Figure 4] FIG. 2 is a perspective view of the interior of a freeze-drying vessel and drying chamber according to one embodiment of the present invention. [Diagram 5] FIG. 13 is a front view of an alternative embodiment of the drying chamber. [Figure 6A] FIG. 1 illustrates a method of forming a lyophilized product according to one embodiment of the present invention. [Figure 6B] FIG. 1 illustrates a method of forming a lyophilized product according to one embodiment of the present invention. [Figure 7A]FIG. 13 is a perspective view of an alternative embodiment of a freeze column. [Figure 7B] FIG. 7B shows a nozzle assembly for mounting to the upper end of each tube of the freeze column shown in FIG. 7A. [Figure 8A] FIG. 13 is a cross-sectional view of a further alternative embodiment of a freeze column. [Figure 8B] FIG. 8B is a perspective view of the freezing column shown in FIG. 8A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Detailed Description Although various embodiments incorporating the teachings of the present disclosure have been shown and described in detail herein, those skilled in the art can easily devise many other various embodiments that still incorporate these teachings. The scope of the present disclosure is not limited in its application to the details of the exemplary embodiments of the configuration and arrangement of components described herein or illustrated in the drawings. The present disclosure encompasses other embodiments and can be implemented or carried out in various ways. It should also be understood that the phraseology and terminology used herein is for the purpose of description and should not be considered limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Unless otherwise specified or limited, the terms "mounted," "connected," "supported," and "coupled," and variations thereof, are used broadly and encompass direct and indirect mounting, connecting, supporting, and coupling. Moreover, "connected" and "coupled" are not limited to physical or mechanical connections or couplings.

[0018] In certain aspects of the present disclosure, systems and methods are described for lyophilizing a sterile bulk fluid product in an efficient manner without compromising the sterile quality of the product and without increasing the product yield. Additionally, the systems and methods of the present disclosure are directed to optimized bulk lyophilization that provides a dry product in powder form.

[0019] The process and apparatus can be advantageously used for drying bulk fluid pharmaceuticals that require sterile or aseptic processing, such as injectables. In this regard, it is important that all components of the freeze-drying system that come into contact with the product are sterile. However, the method and apparatus may also be used in processing materials that do not require aseptic processing, but require moisture removal while preserving structure and that require the resulting dried product to be in powder form. For example, ceramic / metal products used as superconductors or to form nanoparticles or microcircuit heat sinks can be produced using the disclosed technology.

[0020] The methods described herein may be performed, in part, by at least one industrial controller and / or computer used in conjunction with the processing equipment described below. In one embodiment, bulk freeze-drying system 200 (FIG. 2) includes controllers 205A and 205B that control the opening and closing of valves 222, 236, 270, 336, 338 and 210, 310, 312, 314, 316, respectively. The equipment is controlled by a programmable logic controller (PLC) that has the operating logic for valves, motors, etc. An interface to the PLC is provided via a personal computer (PC). The PC loads user-defined recipes or programs into the PLC for execution. The PLC uploads historical data from its execution to the PC for storage. The PC may also be used to manually control the device and operate specific steps such as freezing, defrosting, steaming appropriately, etc.

[0021] PLCs and PCs have a central processing unit (CPU), memory, and an input / output interface connected to the CPU via a bus. A PLC is connected to processing equipment through the input / output interface to receive data from sensors that monitor various conditions of the equipment, such as temperature, position, speed, flow rate, etc. A PLC is also connected to operate devices that are part of the equipment.

[0022] The memory may include random access memory (RAM) and read only memory (ROM). The memory may also include removable media such as disk drives, tape drives, or combinations thereof. The RAM functions as a data memory that stores data used during execution of the program in the CPU and is used as a work area. The ROM functions as a program memory that stores the program including the steps executed by the CPU. The program may reside on the ROM, on a removable medium, or on any other non-volatile computer usable medium in the PLC or PC as computer readable instructions stored therein for execution by the CPU or other processor to perform the methods disclosed herein.

[0023] A bulk freeze-drying system 200 according to one aspect of the invention is shown in FIG. 2. The system 200 includes a source 202 of a bulk fluid product, such as a liquid product, and a product container 204 having a product reservoir 206. The product source 202 and the product reservoir 206 are connected by a fluid passageway or conduit 208 that provides fluid communication between the product source 202 and the product reservoir 206. The conduit 208 includes a valve 210 that controls the flow of a fluid product 212, such as a liquid product, to the product reservoir 206. The product container 204 also includes a first pressure sensor 214 that measures a static pressure head of the product 212 that is formed when the product 212 is introduced into the product reservoir 206. In an embodiment, the first pressure sensor 214 may be a differential pressure transducer (DPT) that provides a liquid level measurement of the product 212 in the product reservoir 206 based on a change in reservoir pressure in the product reservoir 206. The product reservoir 206 may be partially or completely filled with the product 212 until a predetermined liquid level of the product 212 suitable for operating the nozzle 230 is detected by the first pressure sensor 214. It should be understood that other devices or sensors may be used to determine the amount or level of the product 212 in the product reservoir 206. The product reservoir 206 is also in fluid communication with a sterile conditioning fluid source 216, such as a nitrogen gas (N2) source, through a fluid conduit 218 connected between the fluid source 216 and the product reservoir 206 to allow injection of a fluid, such as a sterilizing gas 220, into the product reservoir 206. The fluid conduit 218 includes a valve 222 that controls the flow of gas into the product reservoir 206. In an embodiment, an outlet 224 of the fluid conduit 218 is positioned such that the gas 220 is injected into an empty portion 226 of the partially filled product reservoir 206.

[0024] The system 200 also includes a freezing vessel 228 having at least one substantially vertical nozzle 230 (see FIG. 3A) extending through a top wall 232 of the freezing vessel 228. The freezing vessel 228 and the nozzle 230 are located below the product reservoir 206. A fluid conduit 234 including a valve 236 is connected between the product reservoir 206 and an inlet end 238 of the nozzle 230. When the valve 236 is opened, the product 212 flows downward by gravity from the product reservoir 206 through the valve 236 to the nozzle inlet end 238. The product 212 is then sprayed from the outlet end 240 of the nozzle 230 in the form of uniform continuous droplets 242 that flow downward into a freezing chamber 244 (see FIG. 3A) of the freezing vessel 228 as described below. In an embodiment, the nozzle may be made of sapphire and includes a piezoelectric actuator 235 configured to generate droplets, such as nozzles available from Nisco Engineering AG of Zurich, Switzerland.

[0025] When spraying the product 212, it is important to control the size of the droplets 242, e.g., the diameter of the droplets 242. According to one aspect of the present invention, the size of the droplets depends on at least three operating parameters of the nozzle 230. The parameters include the pressure at which the product 212 is supplied to the nozzle 230 (i.e., the nozzle pressure), and the frequency and amplitude of the signal used to energize the piezoelectric actuator of the nozzle 230. It has been determined herein by the inventors that a predetermined constant nozzle pressure (i.e., the set point pressure) should be maintained for the nozzle 230 to generate a plurality of consecutive droplets 242 having a desired substantially uniform size. In one embodiment, the diameter of each droplet is about 1 mm. The nozzle pressure is detected by a second pressure sensor 246 disposed between the product reservoir 206 and the nozzle 230.

[0026] During the spraying of the product 212, the product 212 in the product reservoir 206 is consumed, the liquid level of the product 212 in the product reservoir 206 decreases, and thus the nozzle pressure decreases below the set pressure. According to one embodiment of the present invention, the sterilizing gas 220 from the fluid source 216 is then injected into the product reservoir 206 at an appropriate gas flow rate. The gas 220 biases against the product 212, thus increasing the pressure in the product reservoir 206 and providing a back pressure. The increase in pressure compensates for the decrease in the liquid level of the product 212, and thus maintains the set pressure of the nozzle 230. The gas flow rate of the gas 220 injected into the product reservoir 206 is controlled or modulated by the valve 222 to provide a suitable pressure increase in the product reservoir 206 that achieves the set pressure. The gas flow rate can be increased as necessary to compensate for further decrease in the liquid level of the product 212 and maintain the set pressure of the nozzle 230. Alternatively, the gas flow rate may be decreased as necessary to maintain the set point pressure to compensate for an increase in the liquid level of product 212 that may occur as product 212 is added to product reservoir 206. Thus, pressure sensor 246 provides feedback information used to increase or decrease the gas flow rate of gas 220 injected into product reservoir 206. Additionally, vibration damping material 237 may be used to isolate nozzle 230 from ambient vibrations so that the desired droplet uniformity is maintained. In an embodiment, vibration damping material 237 may be a known vibration damping material, or a flexible arrangement such as a flexible sanitary flange may be used.

[0027] 3A and 3B, side and top views, respectively, of the interior of the freezing vessel 228 are shown. The freezing vessel 228 includes a tube having an inner peripheral wall 250 that defines a freezing chamber 244. The nozzle outlet end 240 is located at the top of the freezing chamber 244 and sprays the product 212 in the form of uniform continuous droplets 242 that flow downward into the freezing chamber 244. The freezing vessel 228 also includes an outer peripheral wall 252 that is spaced from the inner wall 250 and has a substantially annular shape, forming an empty cavity 254 between the inner wall 250 and the outer wall 252. It is understood that the inner and outer walls 250 and the cavity 254 may have other shapes, such as elliptical, arcuate, etc. The freezing vessel 228 further includes cavity inlet 260 and outlet 262 conduits that extend from a bottom 264 and a top 266, respectively, of the outer wall 252 of the freezing vessel 228. The cavity inlet 260 connects a source 268 of cooling fluid, such as liquid nitrogen (LN2), to the cavity 254 to provide fluid communication between the LN2 source 268 and the cavity 254. The cavity inlet 260 includes a valve 270 (FIG. 2) that controls the flow of LN2 272 to the cavity 254. The cavity outlet 262 is also in fluid communication with the cavity 254. As will be described, the LN2 272 is used to remove heat from a freezing zone 280 within the freezing chamber 274 to reduce the temperature. In this embodiment, the LN2 272 is in direct contact with the interior wall 250 as the LN2 272 flows through the cavity 254 to remove heat. The heat is absorbed by the LN2 272, causing evaporation of a portion of the LN2 flowing through the cavity 254, resulting in the emission of a two-phase flow 285 comprising N2 and LN2 (i.e., mixed N2 / LN2 flow 285) from the cavity 254 via the cavity outlet 262. In an embodiment, the cavity inlet 260 is positioned such that the LN2 enters the cavity 254 at a lower location than the location at which the mixed N2 / LN2 flow 285 is emitted from the cavity 254 through the cavity outlet 262.

[0028] In use, LN2 272 flows from LN2 source 268 through cavity inlet 260, valve 270, enters the lower portion of cavity 254, rises upward through cavity 254, and a mixed N2 / LN2 stream 285 exits the upper portion of cavity 254 through cavity outlet 262. Thus, LN2 272 rises to a height H within cavity 254 corresponding to the vertical distance between inlet bottom 274 of cavity inlet 260 and outlet bottom 276 of cavity outlet 262. This forms a freeze column having an LN2 jacket 278 surrounding a portion of freeze chamber 244. LN2 272 within cavity 254 reduces the temperature of the corresponding portion of freeze chamber 244 to form freeze zone 280 having a freeze zone temperature and a freeze zone height equal to height H (i.e., height H of freeze zone 280). As previously discussed, the product 212 is sprayed from the nozzle exit end 240 in the form of uniform continuous droplets 242 that flow downward into the freezing chamber 244. According to one aspect of the invention, the distance (i.e., height H) that the droplets 242 travel downward through the freezing zone 280 provides sufficient time for the droplets 242 to freeze to form particles of the frozen product 282 (i.e., frozen particles 282) when exposed to a freezing zone temperature. In one embodiment, the temperature of the freezing zone 280 is about -150 to -185°C. In this embodiment, a freezing zone 280 is formed having a freezing zone temperature sufficient to form frozen particles 282.

[0029] A temperature sensor 283, such as a resistance temperature detector (RTD), is located at the cavity outlet 262 to monitor the temperature of the combined N2 / LN2 flow 285 exiting the cavity outlet 262 (i.e., N2 / LN2 flow exit temperature). The N2 / LN2 flow exit temperature is indicative of the freeze zone temperature of the freeze zone 280. According to one aspect of the invention, a set point temperature for the N2 / LN2 flow exit temperature is determined that is indicative of the freeze zone temperature. The freeze zone temperature may be adjusted or regulated by increasing or decreasing the flow of LN2 272 through the cavity 254. In particular, increasing the LN2 flow removes additional heat from the freeze zone 280, thus decreasing the freeze zone temperature. Conversely, decreasing the LN2 flow through the cavity 254 increases the freeze zone temperature since less heat is removed from the freeze zone 280. The LN2 flow rate through the cavity 254 may be adjusted by controlling the valve 270. Nozzle outlet end 240 is positioned a sufficient distance from freeze zone 280 to ensure that operation of nozzle 230 is not affected by the low temperatures of freeze zone 280. In certain embodiments, nozzle 230 may also include a nozzle heating element 286, such as an electric heater, to heat nozzle 230 and maintain nozzle 230 at a suitable operating temperature.

[0030] The height H of the freezing zone 280 is selected based on the freezing temperature and droplet volume of the product being sprayed. To accommodate products 212 having different freezing temperatures and droplet volumes, the height H of the freezing zone 280 may be increased or decreased by moving either the cavity inlet 260 or the cavity outlet 262, or by moving both the cavity inlet 260 and the cavity outlet 262, relative to the outer wall 252. In some embodiments, the cavity inlet 260 may be moved vertically upward relative to the outer wall 252 to decrease the height H of the freezing zone 280. In particular, moving the cavity inlet 260 upward to decrease the height H allows the freezing of the droplets 242 to occur closer to the nozzle outlet end 240 than would occur by moving the cavity outlet 262 downward to decrease the height H. The outer wall 252 may include multiple attachment points for mounting the cavity inlet 260 and / or cavity outlet 262 at different vertical locations on the outer wall 252 in order to move the cavity inlet 260 and / or cavity outlet 262 to change the height H. Alternatively, vertically movable attachment points may be used to connect to either the cavity inlet 260 and / or cavity outlet 262 to change the height H.

[0031] After the frozen particles 282 pass through the freezing zone 280, the frozen particles 282 flow downwardly through a freezing chamber outlet 288 defined by the interior wall 250. A funnel element 290 is attached to the freezing vessel 228. The funnel element 290 includes an internal passageway 292 that reduces in size from a funnel inlet 294 to a funnel outlet 296 forming a tapered passageway 292. The frozen particles 282 from the freezing chamber outlet 288 enter the funnel inlet 294 and are guided downwardly by the tapered passageway 292 and exit through the funnel outlet 296.

[0032] The system 200 further includes an upper intermediate container 298 having an upper intermediate chamber 300, a freeze-drying container 302 having a freeze-drying chamber 304 (see FIG. 4), and a lower intermediate container 306 having a lower intermediate chamber 308. The freeze-drying container 302 is located below the upper intermediate container 298, and the lower intermediate container 306 is located below the freeze-drying container 302. Valves 310 and 312 are connected between the funnel element 290 and the upper intermediate container 298, and between the upper intermediate container 298 and the freeze-drying container 302, respectively. Valves 314 and 316 are connected between the freeze-drying container 302 and the lower intermediate chamber 308, and between the lower intermediate chamber 308 and a dried product collection canister 318, respectively. In an embodiment, the valves 310, 312, 314, and 316 may be split butterfly valves.

[0033] The system 200 further includes a first vacuum pump 320 in fluid communication with the known first condensing unit 322 and second condensing unit 324 via a first vacuum line 326 and a second vacuum line 328 connected between the first condensing unit 322 and the second condensing unit 324, respectively. A drying chamber vacuum line 330 extending from the drying chamber 304 is connected between a first condensing vacuum line 332 and a second condensing vacuum line 334 extending from the first condensing unit 322 and the second condensing unit 324, respectively. The first condensing vacuum line 332 and the second condensing vacuum line 334 include valves 336 and 338, respectively. The drying chamber 304 is in fluid communication with the first vacuum pump 320 and the first condensing unit 322 when the valve 336 is open. Alternatively, the drying chamber 304 is in fluid communication with the first vacuum pump 320 and the second condensing unit 324 when valve 338 is open. The drying chamber 304 is evacuated to the first vacuum pressure by the first vacuum pump 320 when valve 336 is open and valves 338, 312, 314 are closed. Alternatively, the drying chamber 304 is evacuated to the first vacuum pressure when valve 338 is open and valves 336, 312, 314 are closed. The upper intermediate chamber 300 is in fluid communication with the second vacuum pump 340 via a second vacuum line 342 connected between the upper intermediate chamber 300 and the second vacuum pump 340.

[0034] During operation of the system 200, the freezing chamber 244 and the tapered passage 292 are maintained at approximately atmospheric pressure. The valve 310 is closed during the generation of a batch of frozen particles 282 in the freezing vessel 228. Once the batch is completed, the valve 310 is opened, thus allowing the frozen particles 282 to flow downward by gravity from the funnel outlet 296 through the valve 310 into the upper intermediate chamber 300. Once the frozen particles 282 from the funnel element 290 have been transferred into the upper intermediate chamber 300, the valve 310 is closed. With the valve 312 also closed, the upper intermediate chamber 300 is then evacuated by the second vacuum pump 340 to a vacuum pressure substantially similar to the vacuum pressure in the drying chamber 304 (i.e., the first vacuum pressure). Once the first vacuum pressure is reached, the valve 312 is opened, allowing the frozen particles 282 to flow downward by gravity from the upper intermediate chamber 300 through the valve 312 into the drying chamber 304. Once the frozen particles 282 from the upper intermediate chamber 300 have been transferred to the drying chamber 304, the valve 312 is closed. The upper intermediate chamber 300 is then returned to near atmospheric pressure in preparation for the next batch of frozen particles 282. The funnel element 290, the valve 310, the upper intermediate vessel 298, and the valve 312 may include at least one cooling element, such as a silicone oil cooling jacket, that cools the funnel element 290, the valve 310, the upper intermediate vessel 298, and the valve 312 to a temperature that prevents thawing of the frozen particles 282 in contact with the walls and other surfaces of the funnel element 290, the valve 310, the upper intermediate vessel 298, and the valve 312.

[0035] 4, a perspective view of the interior of freeze-drying vessel 302 and drying chamber 304 is shown in accordance with one embodiment of the present invention. Drying chamber 304 includes first and second side walls 344 and 346, a bottom wall 345, and a top wall 357 that includes a drying chamber inlet 348 that receives frozen particles 282 from valve 312 as previously described. Drying chamber 304 also includes a vacuum port 350 in top wall 357 that is in fluid communication with drying chamber vacuum line 330. During operation of system 200, drying chamber 304 is evacuated to a first vacuum pressure through vacuum port 350 by first vacuum pump 320.

[0036] The drying chamber 304 further includes a plurality of movable product transport elements 352 that each move the frozen particles 282 in a substantially horizontal direction. Each of the product transport elements 352 is horizontally oriented and vertically spaced apart within the drying chamber 304. Each product transport element 352 may be configured as a movable continuous product transport belt. In an embodiment, the drying chamber 304 may include a first continuous product transport belt 360, a second continuous product transport belt 362, a third continuous product transport belt 364, and a fourth continuous product transport belt 366 that are vertically spaced apart within the drying chamber 304. The belts 360, 362, 364, 366 may be fabricated from a material suitable for contact with the frozen particles 282, such as stainless steel or a polymer. It is understood that additional or fewer belts may be used.

[0037] The inner surface 368 of the first belt 360 and the third belt 364 respectively contact a first driven pulley or drum 370 located on a first side 372 of the drying chamber 304 and a first idler drum 374 disposed on a second side 376 opposite the first side 372 of the drying chamber 304, and the first belt 360 and the third belt 364 form a first horizontal belt section 378 and a third horizontal belt section 380 between the first driven drum 370 and the second idler drum 374, respectively. The inner surface 368 of the first belt 360 and the third belt 364 also contact a first movable belt tensioner device 382 and a third movable belt tensioner device 384 spaced vertically downward from the first horizontal belt section 378 and the third horizontal belt section 380, respectively.

[0038] The inner surfaces 386 of the second and fourth belts 362, 366 are in contact with respective second driven drums 388, 390 located on the second side 376 and the first idler drums 390 located on the first side 372 of the drying chamber 304, such that the second and fourth belts 362, 366 form second and fourth horizontal belt sections 392, 394 between the second driven drums 388, 390. The inner surfaces 386 of the second and fourth belts 362, 366 are also in contact with second and fourth movable belt tensioner devices 396, 398 spaced vertically downward from the second and fourth horizontal belt sections 392, 394, respectively. The positions of the first tensioner device 382, ​​the third tensioner device 384, the second tensioner device 396 and the fourth tensioner device 398 are vertically adjustable to maintain a desired tension in the first belt 360, the third belt 364, the second belt 362 and the fourth belt 366 to ensure a desired horizontal movement of the first horizontal belt section 378, the third horizontal belt section 380, the second horizontal belt section 392 and the fourth horizontal belt section 394, respectively. Each of the belt tensioners 382, ​​396, 384, 398 may be a pulley whose position is vertically adjustable to maintain a desired tension in the respective belt 360, 362, 364, 366.

[0039] The first driven drum 370, which drives the first and third belts 360 and 364, and the second driven drum 388, which drives the second and fourth belts 362 and 366, may be magnetically coupled to a chamber drive system located outside the drying chamber 304 to rotate the first and second driven drums 370 and 388 to provide a sterile environment. Alternatively, the first and second driven drums 370 and 388 may be attached to an external drive system via associated drive shafts that extend through the wall of the drying chamber 304. An axial seal system may be used to seal each drive shaft to maintain a sterile environment within the drying chamber 304.

[0040] In operation, a first driven drum 370 associated with the first belt 360 and the third belt 364, respectively, is driven to rotate in a clockwise direction to continuously move the first belt 360 and the third belt 364, respectively, between the first driven drum 370 and the second idler drum 374 to form continuous first and third horizontal belt sections 378 and 380 that move horizontally in a first direction 400 (see arrows) from the second side 376 to the first side 372 of the drying chamber 304. The outer surfaces of the first and third horizontal belt sections 378 and 380 form first or top transfer surfaces 402 and third product transfer surfaces 404, respectively, that receive and transport the frozen particles 282 in the first direction 400.

[0041] A second driven drum 388 associated with the second belt 362 and the fourth belt 366, respectively, is driven to rotate in a counterclockwise direction, causing continuous movement of the second belt 362 and the fourth belt 366 between the second driven drum 388 and a first idler drum 390 to form continuous second horizontal belt sections 392 and fourth horizontal belt sections 394 moving horizontally in a second direction 406 (see arrows) opposite the first direction 400 from the first side 372 to the second side 376. Outer surfaces of the second horizontal belt sections 392 and fourth horizontal belt sections 394 form second product transport surfaces 408 and fourth product transport surfaces 410, respectively, that receive and transport the frozen particles 282 in the second direction 406. Thus, the first product transport surface 402, the second product transport surface 408, the third product transport surface 404, and the fourth product transport surface 410 move alternately in a horizontal direction.

[0042] During operation, the frozen particles 282 from the drying chamber inlet 348 flow or fall downward by gravity onto an inlet product distribution device 412 located between the drying chamber inlet 348 and the first product transport surface 402 of the first belt 360. The inlet product distribution device 412 serves to arrange the frozen particles 282 in a substantially flat layer or distribution on the first product transport surface 402. In an embodiment, the inlet product distribution device 412 may include an array of vertical plate elements 414 having increasing lengths and arranged to form a substantially flat layer of frozen particles 282 on the first product transport surface 402. Alternatively, the inlet product distribution device 412 may include a vibration element that vibrates the frozen particles 282 to provide a substantially flat layer of frozen particles 282 on the first product transport surface 402.

[0043] The frozen particles 282 on the first product transport surface 402 are then moved in a first direction 400 by the first belt 360 toward a first product removal device 416 disposed adjacent to a first driven drum 370 associated with the first belt 360. In an embodiment, the first product removal device 416 may include a scraper blade element configured to remove the frozen particles 282, along with a second product removal device 418, a third product removal device 422, and a fourth product removal device 426, as described below. The product removal device 416 may be disposed adjacent to an idler drum. The first product removal device 416 serves to remove the frozen particles 282 from the first product transport surface 402. The removed frozen particles 282 then flow downward from the first end 371 of the first belt 360 or cascade onto the first belt product distribution device 418 downwardly adjacent to the first product removal device 416, providing a substantially flat layer of frozen particles 282 on the second product transport surface 408 of the second belt 362 located below the first belt 360.

[0044] The frozen particles 282 on the second product transport surface 408 are then moved in a second direction 406 by the second belt 362 towards a second product removal device 418 located adjacent to a second driven drum 388 associated with the second belt 362. The second product removal device 418 then removes the frozen particles 282 from the second product transport surface 408. The removed frozen particles 282 then flow downwardly from a second end 373 of the second belt 362 or cascade onto a second belt product distribution device 420 downwardly adjacent to the second product removal device 418 to provide a substantially flat layer of frozen particles 282 on the third product transport surface 404 of the third belt 364 located below the second belt 362.

[0045] The movement of the frozen particles 282 relative to the remaining third belt 364 and fourth belt 366 corresponds to the movement described with respect to the first belt 360 and second belt 362, respectively. In particular, the frozen particles 282 on the third product transport surface 404 are then moved in a first direction 400 by the third belt 364 towards a third product removal device 422 located adjacent to the first driven drum 370 associated with the third belt 364. The third product removal device 422 then removes the frozen particles 282 from the third product transport surface 404. The removed frozen particles 282 then flow downward from the third end 375 of the third belt 364, or cascade onto the third belt product distribution device 424 downwardly adjacent to the third product removal device 422, providing a substantially flat layer of frozen particles 282 on the fourth product transport surface 410 of the fourth belt 366 located below the third belt 364.

[0046] The frozen particles 282 on the fourth product transport surface 410 are then moved in the second direction 406 by the fourth belt 366 towards a fourth product removal device 426 located adjacent to a second driven drum 388 associated with the fourth belt 366. The fourth product removal device 426 then removes the frozen particles 282 or the freeze-dried product 284 from the fourth product transport surface 410, as described.

[0047] While the drying chamber 304 is under vacuum as described above, the frozen particles 282 located on the first product transport surface 402, the second product transport surface 408, the third product transport surface 404, and the fourth product transport surface 410 are heated simultaneously to heat the frozen particles 282 and promote sublimation of the frozen particles 282. In one aspect of the invention, the drying chamber 304 further includes a heating element that provides radiant heat to heat the frozen particles 282 and promote sublimation of the frozen particles 282 as the particles move over the first belt, the second belt, the third belt, and the fourth belt. In one embodiment, the lower heating element 361 can be positioned below the first horizontal belt section 378 of the first belt 360. Additionally, the second horizontal belt section 392, the third horizontal belt section 380, and the fourth horizontal belt section 394 of the second belt 362, the third belt 364, and the fourth belt 366, respectively, may be disposed between the associated upper heating element 363 and the lower heating element 361. The upper heating element 363 and the lower heating element 361 are spaced apart from the corresponding first horizontal belt section 378, the second horizontal belt section 392, the third horizontal belt section 380, and the fourth horizontal belt section 394 to provide sufficient heat to promote sublimation of the frozen particles 282. The temperature of each heating element 363, 361 is independently adjustable to provide a desired amount of heat. The upper heating element 363 and the lower heating element 361 may include an electromagnetic energy source, an electric heater, a heat transfer fluid source, or other source. In a further embodiment, microwave energy is utilized to deliver the sublimation energy to the frozen particles 282. In this embodiment, the upper heating element 363 and the lower heating element 361 are replaced with equipment for microwave heating, which may include a microwave antenna or microwave generator, a microwave cage (a type of Faraday cage), and a microwave agitator that provides an even distribution of microwaves across the frozen particles 282. Alternative materials of construction for the components of the drying chamber 304 may be utilized when using microwave energy.

[0048] As the frozen particles 282 are moved by the first belt 360, the second belt 362, the third belt 364, and the fourth belt 366, the upper heating element 363 and the lower heating element 361 are used to heat the frozen particles 282 to promote sublimation of the frozen particles 282, ultimately forming a freeze-dried product 284 in powder form. The frozen product 284 is then removed from the fourth product or bottom transport surface 410 by the fourth product removal device 426. The frozen product 284 then falls by gravity from the fourth end 377 of the fourth belt 366, through the bottom wall 345 of the drying chamber 304, and through a drying chamber outlet 428 that extends onto the valve 314 (see FIG. 2).

[0049] As the frozen liquid in the product 212 sublimes, vapor is drawn from the drying chamber 304 by a first vacuum pump 320 through a drying chamber vacuum line 330 and collected in a first condensing unit 322 when a valve 336 is opened (see FIG. 2). Cooled condensing surfaces in the first condensing unit 322 and the second condensing unit 324 collect the vapor. In the case of water vapor, the vapor condenses as ice on the condensing surface. For example, the condensing surface may include a condensing coil that is maintained below the condensation temperature of the water vapor. A coolant passes through the coil 122 to remove heat and cause the water vapor to condense as ice on the coil.

[0050] Once the ice capacity of the first condensing unit 322 is reached, valve 336 is closed and valve 338 is opened to allow steam to be collected in the second condensing unit 324. The condensed ice is then simultaneously removed from the first condensing unit 322 so that the first condensing unit 322 may be utilized again to collect steam when the second condensing unit 324 reaches its ice capacity. When the first condensing unit 322 again reaches its capacity, the aforementioned process of simultaneously removing ice from the first condensing unit 322 and switching to the second condensing unit 324 to collect steam is repeated. According to one aspect of the invention, either the first condensing unit 322 or the second condensing unit 324 may be used to collect steam while ice is being removed from the condensing unit that is not being used (i.e., for example, collecting steam in the first condensing unit 322 while simultaneously removing ice from the second condensing unit 324, or using the second condensing unit 324 to collect steam while simultaneously removing ice from the first condensing unit 322) to allow for continuous operation of the system 200. In one embodiment, more than two condensing units may be used to collect steam.

[0051] 5 shows a front view of an alternative embodiment of the drying chamber 304. In this embodiment, the drying chamber 304 includes a first belt 360, a second belt 362, a third belt 364, a fourth belt 366, and a fifth belt 430 arranged in a staggered configuration. For example, the first ends 432 of the first belt 360, the third belt 364, and the fifth belt 430 are located closer to the first side 372 of the drying chamber 304 than the first ends 431 of the second belt 362 and the fourth belt 366. Thus, the first ends 432 of the third belt 364 and the fifth belt 430 extend horizontally beyond the first ends 431 of the second belt 362 and the fourth belt 366, respectively. In addition, the second ends 433 of the second belt 362 and the fourth belt 366 are located closer to the second side 376 of the drying chamber 304 than the second ends 435 of the first belt 360, the third belt 364, and the fifth belt 430, respectively. Thus, the second ends 433 of the second belt 362 and the fourth belt 366 extend horizontally beyond the second ends 435 of the first belt 360 and the second belt 364. According to one aspect of the invention, the first ends 432 of the third belt 364 and the fifth belt 430, and the second ends 433 of the second belt 362 and the fourth belt 366 provide additional surface area for receiving the frozen particles 282 from the preceding shelf. In one embodiment, the separate belts 360, 362, 364, 366 can be replaced with a single continuous belt. In addition, a belt tensioner is not used in the embodiment shown in FIG. 5. Additionally, the product transport surfaces 402 , 408 , 404 , 410 may be angled as desired to aid in the movement of the frozen particles 282 .

[0052] During operation, the first belt 360, the second belt 362, the third belt 364, the fourth belt 366, and the fifth belt 430 are moved at a sufficiently slow speed such that the frozen particles 282 are transferred in a cascading manner from one belt surface to an adjacent belt located below the first belt. The slow movement of each belt 360, 362, 364, 366, 430 may be paused to increase residence time within the drying chamber 304. The belts 360, 362, 364, 366, 430 may be considered product contacting parts that may require that a belt or belts can be replaced in a manner that does not require excessive disassembly of the drying chamber 304. To facilitate changing of the belts 360, 362, 364, 366, 430, the upper heating element 363 and the lower heating element 361 may be attached to the wall of the freeze-drying vessel 302 to form a cantilever configuration that releases belt tension and allows clear access for changing the belts 360, 362, 364, 366, 430.

[0053] Referring again to FIG. 2 , the lower intermediate chamber 308 is in fluid communication with the second vacuum pump 340 via a third vacuum line 434 connected between the lower intermediate chamber 308 and the second vacuum pump 340. When the valves 314 and 316 are closed, the lower intermediate chamber 308 is evacuated to a first vacuum pressure by the second vacuum pump 340. When a batch of lyophilized product 284 is received from the eighth shelf 372 as described above, the valve 314 is opened, thus allowing the lyophilized product 284 to flow downward into the lower intermediate chamber 308 by gravity. When the batch of lyophilized product 284 is transferred to the lower intermediate chamber 308, the valve 314 is closed, and the lower intermediate chamber 308 is returned to approximately atmospheric pressure. The valve 316 is then opened to allow the lyophilized product 284 to be discharged by gravity into a dry product collection canister 318, such as a sterile stainless steel container. The lyophilized product 284 may then be used to fill containers such as vials, syringes, etc. for shipping. Alternatively, the lyophilized product 284 may be deposited into a hopper feeder, which serves as a feeder for directly filling the lyophilized product 284 into vials, syringes, etc., without the use of a collection canister 318. Additionally, the lower intermediate chamber 308 is evacuated to a first vacuum pressure in preparation for receiving the next batch of lyophilized product 284.

[0054] 6A and 6B, a method 436 of forming a freeze-dried product 284 according to one embodiment of the present invention is shown. In step 438, the fluid product 212 is sprayed into the freezing chamber 244, which is at approximately atmospheric pressure, to form frozen particles 282. In step 440, the frozen particles 282 are then transferred to the upper intermediate chamber 300, which is at approximately atmospheric pressure. In step 442, the upper intermediate chamber 300 is evacuated to a first vacuum pressure. In step 444, the frozen particles 282 are transferred from the upper intermediate chamber 300 to the drying chamber 304, which is also evacuated to a first vacuum pressure. Once the frozen particles 282 have been transferred to the drying chamber 304, the upper intermediate chamber 300 is returned to approximately atmospheric pressure in step 446 in preparation for receiving the next batch of frozen particles 282. The method 436 also includes providing a plurality of horizontal product transfer belts 360, 362, 364, 366 vertically arranged in the drying chamber 304, which alternately move the frozen particles 282 in a horizontal direction in step 448. In step 450, the frozen particles 282 flow downward from the ends 371, 373, 375, 377 of each product transfer belt 360, 362, 364, 366 to the lower product transfer belt, respectively. The frozen particles 282 are simultaneously heated in step 452 to cause sublimation of the frozen liquid, generating vapor and forming a freeze-dried product 284 in powder form. In step 454, at least two condensation units 322, 324 are provided, where a condensation unit is used to collect vapor while ice is removed from another condensation unit that has reached ice capacity to allow for continuous operation of the system 200. The lyophilized product 284 is then transferred from the drying chamber 304 to the lower intermediate chamber 308, which is evacuated to a first vacuum pressure, in step 456. The lower intermediate chamber 308 is returned to near atmospheric pressure, in step 458. The lyophilized product 284 is then transferred from the lower intermediate chamber 308 to a dried product collection canister or hopper feeder 318, in step 460. In step 462, the lower intermediate chamber 308 is evacuated to a first vacuum pressure in preparation for receiving the next batch of lyophilized product 284.

[0055] Referring to FIG. 7A, a perspective view of an alternative embodiment of a freeze column 464 is shown. In this embodiment, the freeze column 464 may include a plurality of vertical tubes, each defining an associated freeze chamber 244 (see FIG. 3A). In FIG. 7A, an exemplary freeze column 464 is shown including a first hollow tube 466, a second hollow tube 468, a third hollow tube 470, and a fourth hollow tube 472, each disposed within a cryogenically cooled freeze vessel 474 having a substantially rectangular shape. An upper portion 476 of each tube 466, 468, 470, 472 may extend above the freeze vessel 474. Referring to FIG. 7B, a nozzle assembly 478 for mounting to an upper end 480 of each tube 466, 468, 470, 472 is shown. Nozzle assembly 478 includes a mounting wall 480 having at least one substantially vertical nozzle 230 (see FIG. 3A ) extending therethrough to form nozzle assembly 478. Nozzle 230 is connected to fluid conduit 234 as previously described in connection with FIG. 3A . In some embodiments, each nozzle assembly 478 may include up to four nozzles 230.

[0056] According to an embodiment of the invention, other shapes such as square, circular, etc. can be used for the freezing vessel 474. The freezing vessel 474 may be cooled by a flow of LN2 or LN2 maintained at a set point temperature indicative of the freezing zone temperature in each tube 466, 468, 470, 472. As described above in connection with Figures 3A and 3B, the product 212 is sprayed from the nozzle outlet end 240 in the form of uniform continuous droplets 242 that flow downward into the freezing chamber 244. The distance that the droplets 242 travel downward through the freezing zone 280 in each tube provides sufficient time for the droplets 242 to freeze to form frozen particles 282 when exposed to the freezing zone temperature. The frozen particles 282 from the tubes then flow downward through the valve 310 into the single funnel element 290 and into the upper intermediate chamber 300.

[0057] Referring to FIG. 8A, a cross-sectional view of a further alternative embodiment of a freeze column 474 is shown. In this embodiment, the freeze column 474 includes spaced apart inner and outer walls 482 and 484 that form a wall chamber 486. The inner wall 482 is also spaced apart from the tubes 466, 468, 470, 472 to form a column space 485 between each tube 466, 468, 470, 472 and the inner wall 482. The tubes 466, 468, 470, 472 extend through a plurality of vertically spaced apart baffles 487 that are oriented horizontally within the freeze column 474. Referring to FIG. 8B, a perspective view of the freeze column 474 is shown. The freeze column 474 includes an inlet device 488 that extends through the outer and inner walls 484 and 482. The inlet device 488 functions to deliver sterile LN2 at atmospheric pressure in the form of a spray that is sprayed onto the outside of the tubes 466, 468, 470, 472. The wall chamber 486 between the walls 482, 484 is filled with LN2 to form an LN2 jacket. The LN2 jacket is configured to operate at a pressure above atmospheric pressure to generate a wall temperature below the liquefaction point of the atmospheric spray LN2. The spray LN2 vaporizes upon contact with the outside of the tubes 466, 468, 470, 472 to form sterile LN2 vapor 490 that cools the tubes 466, 468, 470, 472.

[0058] According to one aspect of the invention, a first gap 492 is formed between a first set of alternating baffles 494 and each tube 466, 468, 470, 472. A second set of alternating baffles 495 (i.e., the remaining baffles) is configured such that a second gap 496 is formed between each remaining alternating baffle 495 and the interior wall 482. The first gap 492 and the second gap 496 form a steam passageway that directs sterilizing LN2 steam in a substantially serpentine downward path 498 along the vertical length of the tubes 466, 468, 470, 472 to maintain the cooled gas cooling of the tubes 466, 468, 470, 472. It is understood that other path shapes may be used. The sterile LN2 vapor then impinges on frozen particles 282 (see also FIG. 3A) located within the funnel 290, either maintaining the frozen particles 282 in a frozen state or freezing droplets 242 of the liquid product or frozen particles 282 that are semi-frozen after exiting the tubes 466, 468, 470, 472. In an alternative embodiment, the outer wall 484 and the inner wall 482 may extend beyond the ends 500 of the tubes 466, 468, 470, 472 to allow for impingement of the sterile LN2 on the frozen particles before entering the funnel 290.

[0059] Thus, the freeze-drying system 200 according to embodiments of the present invention allows for a continuous freeze-drying process. In addition, the freeze-dried product 284 produced according to embodiments of the present invention is produced without the use of a tray dryer in which the bulk product is manually loaded into a tray, freeze-dried, and then manually removed from the tray. The freeze-dried product 284 produced according to embodiments of the present invention does not require grinding to achieve proper powder size and uniformity. Furthermore, embodiments of the present invention provide improved techniques for processing bulk quantities of sterile materials in a controlled, aseptic environment.

[0060] While particular embodiments of the present disclosure have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended in the appended claims to cover all such changes and modifications that are within the scope of this disclosure.

Claims

1. 1. A freeze-drying vessel (302) for a freeze-drying system (200) having a freezing vessel (228) for producing frozen product particles (282) by freezing droplets (242) of a fluid product (212), comprising: a freeze-drying chamber (304) having a drying chamber inlet (348) for receiving the frozen product particles (282), a vacuum port (350) for evacuating to a first vacuum pressure, and a drying chamber outlet (428); a plurality of movable transfer belts (360, 362, 364, 366), each of said plurality of movable transfer belts moved by a rotating driven drum (370, 388) horizontally spaced from an idler drum (374, 390) to form a plurality of horizontal product transport surfaces (402, 404, 408, 410) for transporting said frozen product particles (282), each of said plurality of horizontal product transport surfaces (402, 404, 408, 410) being connected to said freeze-drying channel; a plurality of movable product transport belts (360, 362, 364, 366) vertically disposed within the drying chamber (304) and moving in a horizontal direction (400, 406) opposite the lower product transport surface, said plurality of horizontal product transport surfaces (402, 404, 408, 410) including a top product transport surface (402) and a bottom product transport surface (410), said top product transport surface (402) receiving said frozen product particles (282) from said drying chamber inlet (348); at least one product removal device (416, 418) disposed adjacent each of the rotating driven drums (370, 388) and configured to remove the frozen product particles (282) from an end (371, 373, 375, 377) of each of the plurality of horizontal product transport surfaces (402, 404, 408, 410) and to allow the removed frozen product particles (282) to flow downwardly to a lower product transport surface; at least one heating element (363, 361) disposed adjacent each of the plurality of horizontal product transport surfaces (402, 404, 408, 410) for heating the frozen product particles (282) to promote sublimation of the frozen product particles (282) and form a freeze-dried product (284) in powder form that flows downwardly from the bottom product transport surface (410) and is discharged through the drying chamber outlet (428); A freeze-drying container (302) comprising:

2. A freeze-drying container (302) as described in claim 1, further comprising a belt tensioner (382, 396, 384, 398) spaced vertically downward from each of the plurality of horizontal product transfer surfaces (402, 404, 408, 410).

3. A freeze-drying container (302) as described in claim 1, characterized in that at least one of the plurality of horizontal product transfer surfaces (402, 404, 408, 410) is located between an upper heating element (363) and a lower heating element (361).

4. The freeze-drying container (302) of claim 1, wherein each driven drum (370, 388) is magnetically coupled to a chamber drive system located outside the freeze-drying chamber (304) for rotating the associated rotating driven drum (370, 388).

5. The freeze-drying container (302) of claim 1, characterized in that each of the rotating driven drums (370, 388) is attached to an external drive system via an associated drive shaft extending through a wall of the freeze-drying chamber (304), and further includes an axial sealing system for sealing each drive shaft to maintain a sterile environment within the freeze-drying chamber (304).

6. The freeze-drying container (302) of claim 1, wherein the at least one product removal device (416, 418) comprises a scraper blade element.

7. 2. The freeze-drying container (302) of claim 1, wherein the freezing container (228) includes at least one tube (466, 468, 470, 472), the at least one tube (466, 468, 470, 472) defining a freezing chamber (244) for forming the frozen product particles (282), and wherein sterile liquid nitrogen vapor contacts an exterior of each of the at least one tube (466, 468, 470, 472) to cool each of the at least one tube (466, 468, 470, 472), and the sterile liquid nitrogen vapor also contacts liquid product or semi-frozen particle droplets (242) as they exit each of the at least one tube (466, 468, 470, 472).

8. 2. The freeze-drying container of claim 1, wherein an intermediate chamber (300) is located between the freezing container (228) and the freeze-drying container (302), the intermediate chamber (300) including a first valve (310) and a second valve (312), the first valve (310) being opened to receive the frozen product particles (282) from the freezing container (228) into the intermediate chamber (300), the first valve (310) being subsequently closed to evacuate the intermediate chamber (300) to a first vacuum pressure, and thereafter the second valve (312) being opened to allow the frozen product particles (282) to fall by gravity from the intermediate chamber (300) through the drying chamber inlet (348) into the freeze-drying chamber (304).

9. 1. A freeze-drying vessel (302) for a freeze-drying system (200) having a freezing vessel (228) for producing frozen product particles (282) by freezing droplets (242) of a fluid product (212), comprising: a freeze-drying chamber (304) having a drying chamber inlet (348) for receiving the frozen product particles (282), a vacuum port (350) evacuated to a first vacuum pressure, and a drying chamber outlet (428); a plurality of moving product transport belts (360, 362, 364, 366), each of said plurality of moving product transport belts (360, 362, 364, 366) moved by a rotating driven drum (370, 388) spaced horizontally from an idler drum (374, 390) to form a plurality of horizontal product transport surfaces (402, 404, 408, 410) transporting said frozen product particles (282); a plurality of moving product transport belts (360, 362, 364, 366), each of which is vertically disposed within said freeze-drying chamber (304) and moves in a horizontal direction (400, 406) opposite a lower product transport surface, said plurality of horizontal product transport surfaces (402, 404, 408, 410) including a top product transport surface (402) and a bottom product transport surface (410); an inlet product distribution device (412) disposed between the drying chamber inlet (348) and the top product transport surface (402) to receive the frozen product particles (282) from the drying chamber inlet (348) and to place the frozen product particles (282) in a substantially even layer on the top product transport surface (402); at least one product removal device (416, 418) located adjacent each of the rotating driven drums (370, 388) for removing the frozen product particles (282) from an end (371, 373, 375, 377) of each of the plurality of horizontal product transport surfaces (402, 404, 408, 410), respectively, and allowing the removed frozen product particles (282) to flow downwardly to a lower product transport surface; a belt product distribution apparatus associated with said at least one product removal device (416, 418) for disposing said frozen product particles (282) in a substantially flat layer on a lower product transport surface; at least one heating element (363, 361) disposed adjacent each of the plurality of horizontal product transport surfaces (402, 404, 408, 410) for heating the frozen product particles (282) to promote sublimation of the frozen product particles (282) to form a freeze-dried product in powder form that flows downwardly from the bottom product transport surface (410) and is discharged through the drying chamber outlet (428); A freeze-drying container (302) comprising:

10. A freeze-drying container (302) as described in claim 9, further comprising a belt tensioner (382, 396, 384, 398) spaced vertically downward from each of the plurality of horizontal product transport surfaces (402, 404, 408, 410).

11. A freeze-drying container (302) as described in claim 9, characterized in that at least one of the plurality of horizontal product transfer surfaces (402, 404, 408, 410) is located between an upper heating element (363) and a lower heating element (361).

12. A freeze-drying container (302) as described in claim 9, characterized in that each of the rotating driven drums (370, 388) is magnetically coupled to a chamber drive system located outside the freeze-drying chamber (304) for rotating the associated rotating driven drum (370, 388).

13. A freeze-drying container (302) as described in claim 9, characterized in that each of the rotating driven drums (370, 388) is attached to an external drive system via an associated drive shaft extending through a wall of the freeze-drying chamber (304), and further includes an axial sealing system for sealing each drive shaft to maintain a sterile environment within the freeze-drying chamber (304).

14. The freeze-drying container (302) of claim 9, wherein the at least one product removal device (416, 418) comprises a scraper blade element.

15. 10. The freeze-drying container of claim 9, wherein the freezing container includes at least one tube defining a freezing chamber for forming the frozen product particles, and wherein sterile liquid nitrogen vapor contacts an exterior of each of the at least one tube to cool each of the at least one tube, and wherein the sterile liquid nitrogen vapor also contacts droplets of liquid product or semi-frozen particles as they exit each of the at least one tube.

16. 10. The freeze-drying container of claim 9, wherein the intermediate chamber is located between the freezing container and the freeze-drying container, the intermediate chamber including a first valve and a second valve, the first valve being opened to receive the frozen product particles from the freezing container into the intermediate chamber, the first valve being subsequently closed to evacuate the intermediate chamber to the first vacuum pressure, and thereafter the second valve being opened to allow the frozen product particles to fall by gravity from the intermediate chamber through the drying chamber inlet and into the drying chamber.

17. The freeze-drying vessel of claim 9, wherein the inlet product distribution device (412) comprises an array of vertical plate elements (414) arranged to form a substantially flat layer of the frozen product particles (282) on the top product transport surface (402).

18. The freeze-drying container (302) of claim 9, wherein the inlet product distribution device (412) includes a vibration element that vibrates the frozen product particles (282) to provide a substantially flat layer of the frozen product particles (282) on the top product transport surface (402).

19. 1. A method of moving and heating a freeze-dried product within a freeze-drying vessel (302) for a freeze-drying system (200) having a freezing vessel (228) for producing frozen product particles by freezing droplets (242) of a fluid product (212), comprising: providing a freeze-drying chamber (304) having a drying chamber inlet (348) for receiving the frozen product particles (282), a vacuum port (350) through which the freeze-drying chamber (304) is evacuated to a first vacuum pressure, and a drying chamber outlet (428); moving a plurality of moving product transport belts (360, 362, 364, 366) having a plurality of horizontal product transport surfaces (402, 404, 408, 410) that transport the frozen product particles (282), each of the plurality of horizontal product transport surfaces (402, 404, 408, 410) being vertically disposed within the freeze-drying chamber (304) and moving in an opposite horizontal direction (400, 406) to a lower product transport surface, the plurality of horizontal product transport surfaces (402, 404, 408, 410) including a top product transport surface (402) and a bottom product transport surface (410), the top product transport surface (402) receiving the frozen product particles (282) from the drying chamber inlet (348); removing the frozen product particles (282) from an end (371, 373, 375, 377) of each of the plurality of horizontal product transport surfaces (402, 404, 408, 410) allowing the removed frozen product particles (282) to flow downwardly to a lower product transport surface; heating the frozen product particles (282) to promote sublimation of the frozen product particles (282) and form a freeze-dried product in powder form that flows downward from the bottom product transport surface (410) and is discharged through the drying chamber outlet (428); The method according to claim 1, further comprising:

20. 20. The method of claim 19, further comprising providing an inlet product distribution device (412) positioned between the drying chamber inlet (348) and the top product transport surface (402) to receive the frozen product particles (282) from the drying chamber inlet (348) and to arrange the frozen product particles (282) in a substantially flat layer on the top product transport surface (402).

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