• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    BULK LIOPHILIZATION USING FREEZING BY SPRAYING AND SHAKING DRYING. A freeze dryer processes bulk powder products. The freeze dryer freezes the product by mixing an atomized spray of the product with sterile liquid nitrogen. The resulting powder is lyophilized in a container, and the contents of the container are agitated to maintain contact of the product with the heated container wall to prevent agglomeration.
    公开号:BR112013002675B1
    申请号:R112013002675-8
    申请日:2010-08-04
    公开日:2020-11-24
    发明作者:Francis W. Demarco；Ernesto Renzi
    申请人:Ima Life North America Inc.；
    IPC主号:
    专利说明:

    [0001] The present invention relates generally to freeze-drying processes and equipment for removing moisture from a product using vacuum and low temperature. More specifically, the invention relates to the freeze-drying of bulk powder and especially pharmaceutical products and other bulk powder products, including those requiring aseptic handling. Background
    [0002] Freeze drying is a process that removes a suspension medium or solvent, typically water from a product. Although the present disclosure uses water as the exemplary solvent, other solvents, such as alcohol, can also be removed in lyophilization processes and can be removed with the apparatus and methods currently disclosed.
    [0003] In a freeze-drying process to remove water, the water in the product is frozen to form ice and, in a vacuum, the ice is sublimated and the steam flows towards a condenser. The water vapor is condensed in the condenser like ice and is subsequently removed from the condenser. Lyophilization is particularly useful in the pharmaceutical industry, since the integrity of the product is preserved during the lyophilization process and product stability can be ensured for relatively long periods of time. The lyophilized product is commonly, but not necessarily, a biological substance.
    [0004] Pharmaceutical freeze-drying is often an aseptic process that requires sterile conditions in the freeze-drying chamber. It is critical to ensure that all components of the lyophilization system coming into contact with the product are sterile.
    [0005] Most bulk freeze drying in aseptic conditions is done in a freeze dryer designed for bottles, in which the qranel product is placed in trays designed to contain bottles. In an example of a prior art lyophilization system 100 shown in figure 1, a batch of product 112 is placed in freeze drying trays 121 in a freeze drying chamber 110. Freeze drying shelves 123 are used to support trays 121 and transfer heat to and from the trays and the product as required by the process. A heat transfer fluid flowing through conduits in the shelves 123 is used to remove or add heat.
    [0006] Under vacuum, the frozen product 112 is heated slightly to cause sublimation of the ice in the product. Water vapor resulting from sublimation of the ice flows through a passage 115 into a condensation chamber 120 containing condensation coils or other surfaces 122 kept below the condensation temperature of the water vapor. A coolant is passed through coils 122 to remove heat, causing water vapor to condense like ice in the coils.
    [0007] Both the lyophilization chamber 110 and the condensation chamber 120 are held in vacuum during the process by a vacuum pump 150 connected to the discharge from the condensation chamber 120. Non-condensable gases contained in chambers 110, 120 are removed by the vacuum pump 150 and discharged at a higher pressure outlet 152.
    [0008] Tray dryers are designed for aseptic bottle drying and are not optimized for handling bulk product. The product must be manually loaded into the trays, lyophilized, and then manually removed from the trays. Handling the trays is difficult, and creates the risk of spilling liquid. Heat transfer resistances between the product and the trays, and between the trays and the shelves, sometimes cause uneven heat transfer. The dry product must be removed from the trays after processing, resulting in loss of product handling.
    [0009] As the process is carried out on a large mass of product, agglomeration into a "mass" often occurs, and lamination is necessary to obtain a suitable powder and uniform particle size. Cycle times can be longer than necessary due to the resistance of the large mass of product to heat up and the poor heat transfer characteristics between the trays, the product and the shelves.
    [0010] Spray lyophilization has been suggested, in which a liquid substance is sprayed in an environment of low pressure, low temperature, and water in the resulting frozen particles is sublimated by exposing the falling particles to radiant heat (see, for example, US patent no. 3,300,868). This process is limited to materials from which water can be removed quickly, while the particles are carried by air, and requires radiant heaters in a low temperature environment, reducing efficiency.
    [0011] Spray freezing of a product by atomizing the product together with liquid nitrogen (LN2) or a cold gas has been suggested in combination with atmospheric lyophilization using a desiccant gas such as nitrogen. An example is shown in US patent no. 7,363,726. Frozen particles are collected in a drying container having a bottom with a porous metal filter plate. The desiccant gas is passed through the product, creating a partial pressure of water vapor from the product on the dry desiccant gas, causing sublimation and / or evaporation of the water contained in the product. Such a process is not easily adapted for aseptic processing, because both cold freezing gas and desiccant gas must be sterile. The process can potentially consume large amounts of nitrogen. Atmospheric drying is typically slower than vacuum drying of equivalent powder.
    [0012] Agitated lyophilizers perform both the freezing step and the vacuum sublimation step under agitated conditions. Heat is introduced through the container jacket during the sublimation stage. A stirred freeze dryer was marketed, for example, by Hosokawa Micron Powder Systems of Summit, NJ.
    [0013] An improved technique is needed to process bulk quantities of aseptic materials that are not contained in bottles. The technique must maintain an aseptic environment for the process, and minimize handling of the product in trays, with the potential for spills. The process must avoid secondary operations such as lamination to produce uniform particle sizes. The process should avoid the heat transfer problems associated with drying bulk product in trays. The process should be as continuous as possible, avoiding product transfer between equipment whenever possible. summary
    [0014] The present disclosure addresses the needs described above for providing a lyophilization system to lyophilize bulk product by removing a liquid. The system includes a lyophilization chamber for containing product during the lyophilization process, and at least one bulk product spray nozzle connected to a bulk product source. At least one bulk product spray nozzle is directed into an interior of the freeze-drying chamber to spray the bulk product into the freeze-drying chamber.
    [0015] The system additionally includes at least one aseptic freezing spray nozzle connected to a freezing agent source. At least one freezing agent spray nozzle is directed into the freeze-drying chamber to spray the freezing agent into the freeze-drying chamber. At least one bulk product spray nozzle and at least one lyophilizing agent spray nozzle are additionally directed to mix respective sprays inside the lyophilization chamber to create a spray frozen product.
    [0016] The system also includes a stirring mechanism in a lower portion of the freeze-drying chamber to stir frozen product by spray accumulated in the lower portion of the chamber, a heater to heat at least the lower walls of the freeze-drying chamber, a condensation chamber in communication with the lyophilization chamber and comprising surfaces for condensing an exhaust gas vapor received from the freezer drying chamber, and a vacuum pump in communication with the condensation chamber.
    [0017] The system may also include a sterilizer introduction means for introducing a sterilizer into the lyophilization chamber. The sterilizer can be selected from the group consisting of vapor and vaporized hydrogen peroxide.
    [0018] The stirring mechanism may include a rotationally driven stirrer to move the frozen product particles by spraying to the walls of the chamber for heating. The rotationally driven stirrer can be driven by a drive shaft that passes through the chamber wall, or can be magnetically driven from outside the chamber wall. The stirring mechanism may alternatively be a vibration mechanism externally mounted on the chamber wall.
    [0019] The freezing agent can be sterile liquid nitrogen. A lower portion of the lyophilization chamber may be of a conical shape. The heater can be an electric heater, or it can be a jacket to circulate a heated fluid. The heated fluid can be heated at least in part from the heat extracted from the freezing agent.
    [0020] Another lyophilization system for lyophilizing bulk product by removing a liquid, comprises a freezing chamber to contain product during the freezing process, and a plurality of spray nozzles configured to mix sprays of the bulk product and a freezing agent within the freezing chamber to produce a spray frozen product powder.
    [0021] The system also includes a plurality of drying chambers, each drying chamber being connected to the freezing chamber by a respective selectively lockable duct. Each drying chamber comprises a stirring mechanism in a lower portion of the drying chamber for stirring powder of frozen product by spraying in the lower portion of the chamber, and a heater for heating at least lower walls of the drying chamber.
    [0022] The system additionally includes at least one condensing chamber, each of the plurality of drying chambers being in communication with at least one of the condensing chambers, the condensing chambers comprising surfaces for condensing a vapor from the exhaust gas received from the drying chambers. A vacuum pump is in selective communication with the drying chambers and the condensing chamber.
    [0023] The system can additionally include a control means for operating selectively closable ducts to guide the frozen product powder by spraying in a first chamber of the plurality of drying chambers while simultaneously operating a second chamber of the drying chambers by evacuating the second chamber with the vacuum pump and heat the lower walls of the second chamber with the heater.
    [0024] A first drying chamber can be in selective communication with first and second condensing chambers, whereby one of the first and second condensing chambers is operated to condense the solvent vapor while the condensed solvent is removed from another of the chambers.
    [0025] The system may include a sterilizer introduction means for introducing a sterilizer at least into the freezing chamber and drying chambers. The sterilizer can be selected from the group consisting of vapor and vaporized hydrogen peroxide. The freezing agent can be sterile liquid nitrogen. Lower portions of the drying chambers can be tapered.
    [0026] Another embodiment of the invention is a method for lyophilizing a bulk product containing a liquid. The bulk product is sprayed into a freezing container, and a freezing agent is sprayed into the freezing container, the freezing agent intermixing with the sprayed bulk product to freeze the liquid contained in the bulk product to form a frozen powder before of the product falls into a lower portion of the freezing container.
    [0027] The frozen powder is subjected to vacuum, is stirred and is heated to cause sublimation of frozen liquid in the bulk product to form a lyophilized product. The lyophilized product is then returned to atmospheric pressure.
    [0028] Submitting the frozen powder to vacuum, stirring the frozen powder and heating the frozen powder can be carried out in the freezing container, or can be carried out in a drying container separate from the freezing container.
    [0029] The method may additionally include transferring a first portion of frozen powder from the freezing container to a first drying container, performing in the first drying container the steps of submitting the frozen powder to vacuum, stirring the frozen powder and heating the frozen powder, transferring a second portion of the frozen powder from the freezing container to a second drying container, and performing in the second drying container the steps of submitting the frozen powder to vacuum, stirring the frozen powder and heating the frozen powder.
    [0030] The freezing agent can be sterile liquid nitrogen. The bulk product and the freezing agent can be sprayed from separate nozzles into the freezing container. Bulk product spraying and freezing agent spraying can be carried out simultaneously. Heating the frozen powder can include transferring heat from the walls of a container.
    [0031] The method may additionally include condensing vapor from the sublimation of the frozen liquid in a condensation container. Brief description of the drawings
    [0032] Figure 1 is a schematic drawing of a prior art lyophilization system. Figure 2 is a schematic drawing of a lyophilization system according to a developmental mode. Figure 3 is a cut-away view of a freeze dryer according to an embodiment of the development. Figure 4 is a schematic drawing of a lyophilization system according to a developmental mode. Figure 5 is a flow chart showing an action method with an aspect of the disclosure. description
    [0033] The present disclosure describes systems and methods for freeze-drying bulk materials in an efficient manner. In cases where aseptic bulk materials are processed, these materials can be processed without compromising the product's aseptic qualities. More specifically, the systems and methods of the present disclosure are directed to a bulk powder dryer that is optimized for freezing and drying product in powder form.
    [0034] The processes and devices can be advantageously used in drying pharmaceutical products that require aseptic or sterile processing, such as injectables. The methods and devices can also be used, however, in the processing of materials that do not require aseptic processing, but require removal of moisture while preserving the structure and require that the resulting dry product be in powder form. For example, metal / ceramic products used as superconductors or to form nanoparticles or microcircuit heat sinks can be produced using the techniques disclosed.
    [0035] The systems and methods described here can be carried out in part by an industrial controller and / or computer used in combination with the processing equipment described below. The equipment is controlled by a plant logic controller (PLC) that has operational logic for valves, motors, etc. an interface with the PLC is provided via a PC. The PC loads a recipe or user-defined program on the PLC to run. The PLC will upload historical course data to the PC for storage. The PC can also be used to manually control the devices, operating specific steps such as freezing, thawing, steam in place, etc.
    [0036] The PLC and PC include central processing units (CPU) and memory, as well as input / output interfaces connected to the CPU via a bus. The PLC is connected to the processing equipment through the input / output interfaces to receive data from sensors monitoring various conditions of the equipment such as temperature, position, speed, flow, etc. the PLC is also connected to operate devices that are part of the equipment.
    [0037] The memory can include random access memory (RAM) and read-only memory (ROM). The memory can also include removable media such as a disk drive, tape drive, etc., or a combination of them. RAM can function as a data memory that stores data used when running programs on the CPU, and is used as a workspace. The ROM can function as a program memory to store a program including steps performed on the CPU. The program can reside in the ROM, and can be stored on removable media or any other media usable on a non-volatile computer on the PLC or the PC, as computer-readable instructions stored on it for execution by the CPU or other processor to execute the revealed methods on here.
    [0038] The methods and apparatus currently described use spray freezing by combining the atomized liquid product (through spray nozzles) with atomized liquid nitrogen (LN2). In cases where the systems and methods currently described are used in processing products that require sterile or aseptic processing, sterile LN2 is used. A technique for the production of sterile liquid nitrogen is described in the international publication PCT no. WO 2009 / 029749A1, assigned to Linde, Inc. of Murray Hill, New Jersey, USA.
    [0039] An exemplary system 200 according to a revealed embodiment is shown in figure 2. Spray nozzles 212 are connected to a source 211 of the liquid product. The nozzles are arranged to atomize the product in a 210 lyophilization container. The liquid product can be a solution or a suspension of a biological solid in water or another liquid. Atomization of the product results in a dispersion of fine particles in the lyophilization container 210.
    [0040] Both particle size and particle size distribution are dependent on spray technology. For example, nozzle geometry, product flow rate and nozzle placement in the chamber can influence these process outputs. Particle size and size distribution are important for product application. For example, for powder handling, it is preferable to have particle sizes above 100 microns, while for pulmonary applications, the particle size should be around 6 microns.
    [0041] Another set of spray nozzles 214 is arranged to mix a spray of an aseptic freezing agent such as sterile LN2 with the atomized liquid product. The atomized liquid product freezes as the sterile LN2 vaporizes and absorbs heat from the liquid product in the lyophilization container 210. The spray nozzles 214 are connected to a source 213 of the aseptic freezing agent. In the example shown, sterile LN2 is used. The use of sterile LN2 as the cold source makes it possible for direct contact of aseptic atomized product with the cold source or freezing agent, without contamination. In another embodiment, cold sterile gaseous nitrogen is used instead of LN2.
    [0042] The dimensions of the freezing chamber are such that a sufficient amount of time is left for the product to be in contact with the freezing agent to allow freezing of the product before reaching the bottom of the chamber. The spray-frozen liquid product collects at the bottom of the lyophilization container 210 as a frozen powder, while the gaseous freezing agent is bled from the container. Deflectors can be used in the lyophilization container to allow the particles to settle to the bottom without becoming trapped in the bled gas. The spray freezing process produces small particles of product that are quickly frozen because the smaller particles have a much larger surface area to mass ratio and therefore minimal resistance to heat input. This property also speeds up the drying process.
    [0043] The lyophilization container 210 can be pre-cooled to prevent frozen particles from thawing after contact with container walls or auxiliary parts. The lyophilization container 210 can also be cooled during spraying and subsequent steps to keep the powder frozen as the additional product is sprayed and frozen in the container. The container can be cooled, at least partly, by passing a cooled heat exchange fluid 219 like oil through heat exchangers 230 positioned to heat or cool the drying container 210. The heat exchange fluid is cooled in the heat exchanger. heat 218 by cold N2 discharge from condenser 216. The container may also have a tapered bottom section to facilitate handling of the product. The freezing step is completed when a sufficient amount of liquid product is spray-frozen and collected at the bottom of container 210. A vacuum is then pulled into lyophilisation container 210. A vacuum pump 260 may be in communication with a condenser 250 which, in turn, can be connected to the freeze-drying container 210 by opening a valve 256. In this case, the freeze-drying container 210 is subjected to vacuum pressure by operating the vacuum pump 260 and opening the valve 256 between the condenser 250 and the lyophilization container 210.
    [0044] After the chamber is evacuated, heat is introduced into the vessel walls. The same heat exchangers 230 or different heat exchangers can be positioned at the bottom of the container to apply heat through the walls of the container to the frozen powder. In the embodiment shown, the heat transfer fluid 219 passing through the heat exchangers 230 is heated by an oil heater 271. Alternatively, the container can be directly heated using electrical resistance or other techniques.
    [0045] To move the frozen product particles to the drum walls for heating, while preventing agglomeration of the product from occurring, the frozen powder is stirred. In one embodiment, a slow speed stirring mechanism includes a stirrer 235 at the bottom of the container. The slow speed stirring mechanism also includes a motor 236 and a drive shaft 237. The drive shaft passes through a sealed opening in the container 210, allowing the motor to be installed outside the container, maintaining the aseptic environment inside . In another embodiment, the agitation mechanism is magnetically coupled to an external drive motor, avoiding the use of seals.
    [0046] Alternatively, a vibration mechanism 339 (figure 3) externally mounted to the container wall 300 induces vibrations on the container wall, causing frozen powder to circulate towards and away from the container wall. The vibration mechanism may, for example, be a pneumatic piston impact vibrator or it may be a displaced mass driven by an electric motor. The vibration can alternatively be mounted on a support leg (not shown) of the lyophilization container. In another mode, the container is tipped over, causing the powder to circulate.
    [0047] Returning to figure 2, as the liquid frozen in the sublimation product, steam is carried through valve 256 into the condensation container 250. Cooled condensation surfaces 257 in the condensation container collect the condensed vapor. In the case of water vapor, the vapor condenses like ice. Condensed ice must be periodically removed from the condensation container.
    [0048] Upon completion of the drying step, the freezing container 210 is returned to atmospheric pressure and a valve 245 at the bottom of the drying chamber opens to allow the dry product to move through a collection valve or plate to a removable collection vessel 240 Unlike a traditional freeze-dried tray system, handling of the freeze-dried product is minimized, and transfer from the container to the collection vessel can take place in an aseptic, controlled environment.
    [0049] The freeze drying system 200 provides a bulk freeze dryer having a higher yield and easier product collection than previous freeze drying solutions such as tray dryers. The technique allows freezing by spraying the product in a sterile freeze-drying operation. No prior sterile freeze-drying method known uses spray freezing.
    [0050] A freeze-drying container 300, shown in figure 3, includes several exemplary aspects discussed above. The container includes an upper container wall 302 having a cylindrical shape and a lower container wall 301 having, in the embodiment shown, a tapered shape. An upper plate 303 is sealed to the upper container wall and is removed only for assembly and repair procedures, not during normal processing or maintenance.
    [0051] In the embodiment where the product is stirred by mixing, the top plate 303 can support a motor 336 and drive train 337 to drive an agitator comprising a spiral paddle 335. The paddle 335 is shaped to move the product that is so close to the wall upper container 302 as lower container wall 301. The blade rotates in close proximity to the walls, minimizing dead space between the blade and the walls. The agitator is supported from above, avoiding the need for a bearing assembly at the bottom of the container where the lyophilized product is discharged at the end of a cycle.
    [0052] A rotational washing nozzle 340 guides a liquid sanitizer on the inner container walls and top plate as the nozzle rotates. The complete assembly can be sterilized using steam, vaporized hydrogen peroxide (VHP) or another sterilizer. Since all components that contact the product are enclosed in the lyophilization container, and the container does not need to be opened after each cycle, sterilization may not be necessary after each cycle.
    [0053] 303 nozzles 212 (figure 2) for spraying the liquid product and nozzles 214 for spraying the sterile freezing agent are also mounted on the top plate. The nozzles 212, 214 can be mounted flush with, or slightly recessed on the inner surface of the top plate 303, to leave an upper portion of the spiral paddle 335 free when that paddle is rotating. Alternatively, nozzles 212, 214 can extend into the container 300, and the spiral paddle 335 can be configured to provide clearance for the nozzles. In yet another embodiment, the spray freezing process takes place in a separate container, and the frozen powder is transferred to container 300.
    [0054] A valve or discharge plate 345 at the lower end of the container is opened after each cycle to discharge the lyophilized product. When closed, the valve or discharge plate is in close proximity to the rotational path of the spiral blade 335 to eliminate any dead space that would otherwise be created. Similarly, an inspection door (not shown) can be provided in an opening of the upper container wall 302 and can be configured to provide an inner surface that is flush with the inner surface of the upper container wall, also reducing dead space.
    [0055] Another embodiment 400 of the disclosed freeze dryer, shown in Figure 4, includes a separate freezing container 410 that feeds several drying containers 480a, 480b, 480c arranged in parallel. The freezing container 410 operates in a similar manner to that described above with reference to figure 2. The spray nozzles 412 are connected to a source 411 of liquid product. The nozzles 412 are arranged to atomize the product in the freezing container 410. Another set of spray nozzles 414 is arranged to mix an aseptic spray such as sterile LN2 with an atomized liquid product. Liquid in the atomized product freezes as the sterile LN2 vaporizes and absorbs heat from the product, before the product reaches the bottom of the lyophilization container 410. The spray nozzles 412 are connected to a source 413 of the aseptic freezing agent.
    [0056] Each drying container 480a, 480b, 480c is selectively interconnected to the freezing container 410 by respective passages 481a, 481b, 481c. The drying containers can be selected to receive frozen product from the freezing container 410 by opening valves at each end of the corresponding passages. For example, drying container 480a is selected by opening valves 482, 483 at each end of passage 841a. The valves in the remaining passages 481b, 481c remain closed as drying container 480a receives product from freezing container 410. The other drying containers 480b, 480c are selected to receive product in a similar manner to that described for drying container 480a .
    [0057] Drying containers 480a, 480b, 480c functional as described above with reference to figure 2. For example, in relation to drying container 480a, one or more heating liners 430 are positioned at the bottom of the container to apply heat through the walls from container to frozen powder. A heat transfer fluid 419 is pumped through the heating jackets 430 to provide heat energy. A slow speed stirring mechanism including a 435 agitator at the bottom of the container moves particles of the frozen product to the drum walls for heating, while preventing product agglomeration from occurring. The slow speed stirring mechanism further includes a 436 motor and a 437 drive shaft.
    [0058] Upon completion of the drying cycle, the product can be released via passages 484a, 484b, 484c to a common collection container 440. Each passage has valves 485, 486 at the ends to selectively connect the collection container 440 with a drying container specific. Alternatively, each drying container 480a, 480b, 480c can have a dedicated collection container (not shown).
    [0059] As drying is a more time-consuming step than freezing, individual batches being processed by the freeze-drying system 400 would be at different drying stages. For example, as a batch of frozen product is being transferred from freezing container 410 to drying container 480a, another batch of product that had previously been transferred to drying container 480b could be undergoing heating / sublimation in the drying container, while yet another batch that had been transferred even earlier to the drying container 480c could have completed drying and repressurization, and be in the process of transferring to the 440 collection container. freezing is processed in scattered batches, allowing full utilization of both the freezing container and the drying container.
    [0060] One or more condensing containers 490 are in communication with the drying containers via conduits 491a, 491b, 491c. A vacuum pump (not shown) is connected to the condensation vessel and maintains the freeze-dried system under vacuum pressure during processing. In a preferred embodiment of the disclosed system, at least two parallel condensing containers 490 are used in the system, with each drying container 480a, 480b, 480c being alternatively connectable to more than one condensing container. This arrangement allows a condensate container to be removed from the line for defrosting while continuing to direct effluent from the drying containers to an alternating condensation container.
    [0061] The lyophilization system 400 allows the lyophilization process to run semi-continuously, with the spray freezing process operating continuously and the drying process being divided into parallel containers that process successive scattered batches, resulting in continuous filling of the collection container. Condensation containers can be removed from the line and defrosted without interrupting the continuous process.
    [0062] A unique lyophilization method 500 for use in drying a bulk product containing a liquid solvent is also currently shown and shown schematically in figure 5 under aseptic conditions. The liquid solvent can be water, alcohol or another solvent. The bulk product is sprayed, in step 510, into an aseptic freezing container. Simultaneously, an aseptic freezing agent, such as sterile LN2, is sprayed in step 520, into the aseptic freezing container and intermixed with the sprayed bulk product. The liquid freezing agent quickly evaporates, absorbing the heat of the powdered bulk product and causing the solvent in the bulk product to freeze. A frozen powder is formed before the bulk product reaches a lower portion of the lyophilization container.
    [0063] The frozen powder can be transferred to a separate drying container to perform the subsequent steps, or it can remain in the freezing container. In any case, the frozen powder is subjected, in step 530, to vacuum, and is stirred, in step 540, with an aseptic low-speed stirring mechanism, a vibrator or other stirring mechanism. At the same time, the frozen powder is heated slightly, in step 550, to cause sublimation of the frozen solvent in the bulk product to form a lyophilized product. Heat can be transferred to the frozen powder from the walls of the container.
    [0064] Steam from the sublimation of the product's solvent can be collected by condensing the value onto a cooled surface in a condensation container. The condensed solvent must be removed periodically from the cooled surface. In the case where water is used as the solvent, solid ice is collected in the condensation container, which must be periodically defrosted.
    [0065] The lyophilized product is then returned, in step 560, to atmospheric pressure and transferred to a vessel.
    [0066] In the case where the frozen powder is transferred to a separate drying container, several drying containers can be used to serve a single freezing container, thereby creating a semi-continuous process. A batch of frozen powder batch is produced and transferred from the aseptic freezing container to a first aseptic drying container, and in the first aseptic drying container, the frozen powder is vacuumed, stirred and heated. A second batch of frozen powder is produced and transferred from the aseptic freezing container to a second aseptic drying container, and in the second aseptic drying container, it is vacuumed, stirred and heated. Processing in the first and second drying containers is spread to sequentially remove from the freezing container. A sufficient number of additional drying containers can be used to keep the freezing container operating continuously.
    [0067] The Detailed Description above is to be understood to be in every respect illustrative and exemplary, but not restrictive, and the scope of the invention disclosed here should not be determined from the Description of the Invention, but rather from the Claims as interpreted according to the full breadth permitted by patent laws. It should be understood that the modalities shown and described here are only illustrative of the principles of the present invention and that various modifications can be implemented by those skilled in the art without departing from the scope and spirit of the invention.
    权利要求:
    Claims (30)
    [0001]
    Freeze-drying system for freeze-drying bulk product by removing a liquid characterized by the fact that it comprises: a freeze-drying chamber to contain product during the freeze-drying process, at least one bulk product spray nozzle connected to a bulk product source, the at least one bulk product spray nozzle being directed into an interior of the freeze-drying chamber to spray the bulk product in the freeze-drying chamber; at least one freezing agent spray nozzle connected to a freezing agent source, the at least one freezing agent spray nozzle being directed into the freeze-drying chamber to spray the freezing agent into the freezing chamber lyophilization, the at least one bulk spray nozzle and the at least one freezing agent spray nozzle being additionally directed to mix respective sprays inside the lyophilization chamber to create a spray frozen product; a mechanical stirring mechanism in a lower portion of the freeze-drying chamber to stir frozen product by spraying accumulated in the lower portion of the chamber to move particles of the product into contact with walls of the freeze-drying chamber; a heater to heat at least the bottom walls of the freeze-drying chamber, a condensing chamber in communication with the freeze-drying chamber and comprising surfaces for condensing a discharge gas vapor received from the freeze-drying chamber, a vacuum pump in communication with the condensation chamber; and a controller comprising memory that stores a program that, when executed by the controller, causes the lyophilization system to execute: an aseptic spray freeze cycle in which the bulk product is sprayed from at least one bulk product nozzle in the freeze-drying chamber and a freezing agent is sprayed from at least one freezing agent spray nozzle in the chamber lyophilization, to produce a powder frozen by spraying in the lyophilization chamber; and an aseptic vacuum freeze-drying cycle in which the vacuum pump evacuates the condensation chamber and the freeze-drying chamber, the heater heats the lower walls of the freeze-drying chamber and the rotating mechanical stirring mechanism is rotated to dry the frozen powder by spraying .
    [0002]
    System, according to claim 1, characterized by the fact that it also comprises: a sterilizer introduction means for introducing a sterilizer into the lyophilization chamber.
    [0003]
    System according to claim 2, characterized by the fact that the sterilizer is selected from the group consisting of vapor and vaporized hydrogen peroxide.
    [0004]
    System according to claim 1, characterized by the fact that the stirring mechanism comprises a rotationally driven stirrer.
    [0005]
    System, according to claim 1, characterized by the fact that the rotationally driven agitator is driven by a drive shaft that passes through the chamber wall.
    [0006]
    System according to claim 1, characterized by the fact that the rotationally driven agitator is magnetically driven from the outside of the chamber wall.
    [0007]
    System according to claim 1, characterized by the fact that the agitation mechanism is a vibration mechanism externally mounted on the chamber wall.
    [0008]
    System according to claim 1, characterized by the fact that the agitation mechanism is a vibration mechanism mounted on a support leg of the lyophilization chamber.
    [0009]
    System according to claim 1, characterized by the fact that the freezing agent is sterile liquid nitrogen.
    [0010]
    System according to claim 1, characterized by the fact that a lower portion of the lyophilization chamber is conical in shape.
    [0011]
    System according to claim 1, characterized by the fact that the heater is an electric heater.
    [0012]
    System according to claim 1, characterized by the fact that the heater is a jacket to circulate a heated fluid.
    [0013]
    System, according to claim 1, characterized by the fact that it also comprises: a jacket attached to the lyophilization chamber to circulate a cooled fluid to cool the chamber during spraying; and a heat exchanger to cool the cooled fluid using bleed gas from the freezing agent source.
    [0014]
    Freeze-drying system to freeze bulk product by removing a liquid characterized by the fact that it comprises: a freezing chamber for containing product during the freezing process; a plurality of spray nozzles configured to mix sprays of the bulk product and a freezing agent within the freezing chamber to produce a spray frozen product powder; a plurality of drying chambers, a plurality of selectively closable ducts connecting the freezing chamber with the drying chambers, the ducts being configured to transfer the frozen product powder by spraying in bulk without using trays and shelves; each drying chamber comprising: a stirring mechanism in a lower portion of the drying chamber for stirring powder of frozen product by spraying in the lower portion of the chamber, and a heater to heat at least lower walls of the drying chamber; at least one condensing chamber, each of the plurality of drying chambers being in communication with at least one of the condensing chambers, the condensing chambers comprising surfaces for condensing a discharge gas vapor received from the drying chambers; and a vacuum pump in selective communication with the drying chambers and the condensing chamber.
    [0015]
    System, according to claim 14, characterized by the fact that it also comprises: a control means for operating the selectively closable ducts to guide the frozen product powder by spraying in a first chamber of the plurality of drying chambers while simultaneously operating a second chamber of the drying chambers by evacuating the second chamber with the vacuum pump and heat the lower walls of the second chamber with the heater.
    [0016]
    System according to claim 14, characterized by the fact that a first drying chamber is in selective communication with first and second condensing chambers, whereby one of the first and second condensing chambers is operated to condense the solvent vapor while condensed solvent is removed from another of the chambers.
    [0017]
    System, according to claim 14, characterized by the fact that it also comprises: a sterilizer introduction means for introducing a sterilizer at least into the freezing chamber and drying chambers.
    [0018]
    System, according to claim 17, characterized by the fact that the sterilizer is selected from the group consisting of vapor and vaporized hydrogen peroxide.
    [0019]
    System according to claim 14, characterized by the fact that the freezing agent is sterile liquid nitrogen.
    [0020]
    System according to claim 14, characterized by the fact that lower portions of the drying chambers are conical.
    [0021]
    Method for lyophilizing a bulk product containing a liquid characterized by the fact that it comprises: spray the bulk product in a freezing container; spraying a freezing agent into a freezing container, the freezing container being at first pressure, the freezing agent intermixing with the sprayed bulk product to freeze the liquid contained in the bulk product to form a frozen powder before the product falls to a lower portion of the freezing container; without transferring the frozen powder, subject the freezer to a vacuum pressure less than the first pressure, stir the vacuum frozen powder using the mechanical stirring mechanism; after subjecting the freezing container to vacuum pressure, heat the frozen powder to cause sublimation of frozen liquid in the bulk product to form a lyophilized product; and return the lyophilized product to atmospheric pressure.
    [0022]
    Method according to claim 21, characterized in that stirring the frozen powder in a vacuum and heating the frozen powder are carried out in the freezing container.
    [0023]
    Method according to claim 21, characterized by the fact that the freezing agent is sterile liquid nitrogen.
    [0024]
    Method according to claim 21, characterized in that the bulk product and the freezing agent are sprayed from separate nozzles in the freezing container.
    [0025]
    Method according to claim 21, characterized in that the spraying of the bulk product and spraying of the freezing agent are carried out simultaneously.
    [0026]
    Method according to claim 21, characterized in that the heating of the frozen powder comprises transferring heat to the walls of a container using a heat transfer fluid.
    [0027]
    Method, according to claim 28, characterized by the fact that it also comprises: removing heat from the walls of the lyophilization container during spraying using a cooled heat transfer fluid using bleed gas from the production of the freezing agent.
    [0028]
    Method, according to claim 21, characterized by the fact that it also comprises: condensing sublimation vapor from the frozen liquid in a condensation container.
    [0029]
    System according to claim 1, characterized in that at least one bulk product spray nozzle and at least one freezing agent spray nozzle are recessed into a wall of the freeze-drying chamber to clean the stirring mechanism mechanics.
    [0030]
    System according to claim 1, characterized in that the mechanical stirring mechanism is configured to provide clearance for at least one bulk spray nozzle and at least one freezing agent spray nozzle.
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    同族专利:
    公开号 | 公开日
    JP2013538327A|2013-10-10|
    US20130118026A1|2013-05-16|
    EP2601466A4|2015-05-27|
    EP2601466B1|2017-10-04|
    ES2649045T3|2018-01-09|
    CN103069240B|2015-06-17|
    DK2601466T3|2018-01-02|
    US9052138B2|2015-06-09|
    JP5680199B2|2015-03-04|
    WO2012018320A1|2012-02-09|
    EP2601466A1|2013-06-12|
    BR112013002675A2|2016-05-31|
    CN103069240A|2013-04-24|
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    法律状态:
    2019-01-15| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2019-08-20| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|
    2020-09-08| B09A| Decision: intention to grant|
    2020-11-24| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 24/11/2020, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/US2010/002167|WO2012018320A1|2010-08-04|2010-08-04|Bulk freeze drying using spray freezing and stirred drying|
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