Freeze-drying method of freeze-drying apparatus

Abstract

To provide a freeze-drying method of a freeze-drying apparatus, where: a material to be dried can be nucleated in a short time and uniformly; a container accommodating the material to be dried is not overturned during nucleation; and sterility can be ensured.SOLUTION: In a nucleation step performed before a pre-freezing step, ice particles R are formed in a main tube 2, and since the step is performed under control at a nucleation temperature, nucleation rapidly proceeds in a container 5 from an upper part of the container to a lower part thereof, large ice crystals are formed, and as a result, water vapor transfer resistance of an already-dried layer is reduced and a primary drying time is shortened. Further, since the ice particles R do not generate a large blowing force when flowing from the main tube 2 into a drying chamber 1, the containers 5 in the drying chamber 1 are not overturned. Furthermore, since the ice particles R formed on an inner wall of the main tube under aseptic control flow into the drying chamber 1, a material to be dried M is not contaminated.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a freeze-drying method for improving nucleation and crystal growth of a liquid material to be dried, such as food or medicine, in a freeze-drying apparatus for freeze-drying the liquid material to be dried.

Background Art

[0002] As a freeze-drying method for this type of freeze-drying apparatus, a preliminary freezing step of freezing and solidifying a liquid material to be dried (for example, a liquid medicine filled in a vial) stored in a drying chamber, and a primary drying step of removing moisture from the material to be dried frozen in this preliminary freezing step And a secondary drying step of removing trace amounts of unfrozen water contained in the material to be dried that has become a dry solid through the primary drying step and drying the material to be dried until it reaches a predetermined moisture content.

[0003] In such a freeze-drying process of the material to be dried, the preliminary freezing step is an important step. That is, in the material to be dried in each vial during the preliminary freezing step, uniform ice crystals are formed in a shallower supercooled state, thereby reducing the dried layer water vapor transfer resistance of the material to be dried during the heating step (the transfer resistance of water vapor passing through the layer that has already been dried in the material to be dried). This is a technical problem in the preliminary freezing system of the freeze-drying apparatus.

[0004] The various purposes of preliminary freezing are complete solidification of the material to be dried that fixes internal moisture, adjustment of the microstructure of the material to be dried, which is mainly an ice crystal structure, adjustment of the physicochemical state of the solute, and adjustment of the micro shape of the material to be dried. And if the freeze-drying process of the freeze-drying apparatus is summarized and explained, it is to remove only the moisture by vaporization without changing the micro shape and microstructure of the material to be dried formed during preliminary freezing and leaving the state and position of the various components fixed during preliminary freezing.

[0005] Therefore, a considerable part of the quality of freeze-dried products is determined by the suitability of pre-freezing. To load the material to be dried into the drying chamber of a freeze-drying device via vials and dry the material to be dried to a predetermined moisture content, it is necessary to make the material to be dried in all vials uniform and reduce the water vapor transfer resistance of the already dried layer during pre-freezing. To achieve this, it is necessary to control ice crystal nucleation.

[0006] The normal pre-freezing process is carried out on the freezing shelf (which also doubles as a drying and heating shelf) in the drying chamber. However, not only the shelf temperature (the temperature of the shelf), but also as shown in Fig. 14, the location where the vial 5 is placed on the shelf 4, specifically whether it is placed closer to the center of the shelf 4 or closer to the wall 1a of the drying chamber 1, and also the convection of the air in the drying chamber affect the freezing process.

[0007] In addition, the pre-freezing program includes not only the reaching temperature of the shelf, but also the cooling rate of the shelf and sometimes heat treatment with a constant intermediate temperature during the warming process. The accurate reproducibility of this shelf temperature control is a necessary condition for uniform quality. However, since freezing involves a stochastic process, the equality and reproducibility of the micro-mixed structure of the frozen body and its physicochemical state are not always guaranteed only by the accuracy and uniformity of the freezing temperature program. In the pre-freezing process, the material to be dried in all vials does not freeze evenly, and there is randomness. Therefore, it is necessary to ensure that the width of the variation in the freezing state, which is inevitable in a stochastic process, is sufficiently narrow. The precipitation of ice crystals is accompanied by supercooling, and the precipitation of solute crystals is accompanied by supercooling and supersaturation. The probability of nucleation is involved in the phenomenon of when and where supercooling is broken, when solute crystals precipitate, or whether they solidify in an amorphous state. To keep this stochastic process within the allowable variation range required for the product, it is necessary to find the optimal temperature conditions, and sometimes it cannot be completely controlled. From this, the control of the ice crystal nucleation temperature in the freezing process is required.

[0008]

[0009] ​When the material to be dried in its initial state is cooled in terms of concentration and temperature, even if it intersects with the freezing point - melting point curve, if the solution is not in contact with ice crystals, it remains supercooled. When the solution temperature in contact with the cooling surface (bottom surface) of the vial reaches the intersection point (ice nucleation temperature) with the ice nucleation curve, ice nuclei are formed in that part, and fine dendritic crystals are instantaneously formed throughout the solution part cooled below the freezing point. The latent heat of ice crystal precipitation consumes the cold storage, and the temperature rises to the freezing point curve. The supercooling degree of a homogeneous solution without suspended foreign substances is affected by the contact angle (hydrophilicity) of the inner surface of the vial, but it ranges from about 20°C to 30°C.

[0010] The size and arrangement of ice crystals formed in the first stage of the preliminary freezing process have a strong influence on the behavior of the solute side and its microstructure during the subsequent freezing process, and also affect the behavior during the drying process and the rehydration dissolution process. In the case of needle-shaped ice crystals as shown in Fig. 15(a), capillary-like pores form channels for sublimation, dehumidification (and rehydration penetration) in the deep part, but in the case of an isolated ice crystal layer as shown in Fig. 15(b), sublimation, dehumidification, and rehydration penetration become difficult.

[0011] During the primary drying process, the increase and decrease of the water vapor transfer resistance in the already dried layer are affected by the degree of supercooling during the preliminary freezing process, that is, the nucleation temperature affects the size and arrangement of ice crystals, and thereby has a great influence on the drying time during the primary drying process. That is, when the bottom surface of the vial in contact with the shelf reaches the nucleation temperature of the material to be dried, all parts of the material to be dried are sufficiently cooled below the freezing point. When the degree of supercooling is high (deep), as shown in Fig. 15(b), the material to be dried has an independent pore type (isolated ice crystal) arrangement. As a result, the water vapor transfer resistance in the already dried layer increases, and the primary drying time becomes longer. On the other hand, if most of the material to be dried is still above the freezing point and the degree of supercooling is low (shallow), and the bottom surface of the vial reaches the nucleation temperature of the material to be dried, except for the vicinity of the bottom surface of the vial, it has a capillary type (needle-shaped ice crystal) arrangement. As a result, the water vapor transfer resistance in the already dried layer is reduced, and the primary drying time becomes shorter. It should be noted that experimental research results have been reported that for every 1°C increase in the nucleation temperature, the drying time is shortened by about 3%.

[0012] ​The pre-freezing program for the crystalline material to be dried is selected from three perspectives: the ice crystal arrangement and dimensions that are advantageous for drying and dissolution during use, maintaining the final freezing temperature below the complete solidification temperature, and the uniformity of the frozen state of all vials. Also, the shelf temperature control program realizes predetermined ice nucleation after supercooling and programs (annealing treatment) to obtain a uniform ice crystal structure in the subsequent cooling process by selecting the initial cooling rate of the material to be dried, such as placing the vial on a deeply pre-cooled shelf or cooling the shelf after placing the vial, and keeping the variation in the initial ice crystal arrangement within an acceptable range. However, when it is difficult to achieve even with this control program, although it is an existing technique, a program (annealing treatment) may be adopted in which the once-frozen vial is heated, a considerable portion of the uneven ice crystals is melted, and then a uniform ice crystal structure is obtained in the subsequent cooling process. In recent years, various nucleation control techniques have been developed to overcome the non-uniform ice nucleation and crystal growth of the material to be dried in the pre-freezing process. The concept of controlling the nucleation temperature was first introduced by T.W. Rowe in 1990 and developed by Rambhatla et al. for both crystalline and amorphous materials. In these experiments, after controlling the product temperature to below 0°C, nitrogen gas cooled in a drying chamber at normal pressure was introduced to form an ice fog that promotes the nucleation of the solution.

[0013] Regarding this ice fog method, Petal et al. reported an improvement measure of reducing the pressure in the drying chamber during the nucleation stage. When the pressure in the chamber is reduced to about 50 Torr, a high-density and uniform ice fog is formed, and rapid ice nuclei are formed in all vials.

[0014] In such a known ice fog method (conventional method), a method of forming an ice fog by introducing a low-temperature gas (nitrogen) into a high-humidity drying chamber and a method of providing an internal convection device in the drying chamber to disperse it have also been proposed as a method of combining with the above method. However, the conventional ice fog method requires a cooling device for producing a low-temperature gas, raising concerns about increased costs and device complexity. Also, there is a problem that the nucleation time and temperature of all materials to be dried cannot be perfectly controlled. Specifically explained To clarify, when introducing a low-temperature gas into the drying chamber, the time for ice fog to enter each vial varies depending on the vial placement position in the drying chamber. Therefore, the problem is that nucleation cannot occur simultaneously or instantaneously in all vials.

[0015] As described above, the conventional ice fog method had the problems that the nucleation time increased and there was variation in nucleation among the materials to be dried in each vial, making it impossible to achieve uniform quality.

[0016] To solve such problems, as a freeze-drying method for a freeze-drying apparatus also adopting the ice fog method, the invention described in Japanese Patent No. 5847919 has been proposed.

[0017] The invention described in this publication forms ice particles (ice fog) in a cold trap (a device for frosting the water vapor flowing in from the drying chamber 1) outside the drying chamber 1, and as shown in Fig. 14, rapidly introduces these ice particles R into the drying chamber 1. Thereby, the ice particles R are introduced into the vials 5 in the drying chamber 1, causing uniform nucleation in the materials to be dried in all the vials 5 on the shelf board 4 in the drying chamber 1. Specifically, a gas is introduced into the cold trap to form ice particles R in the cold trap under atmospheric pressure. Next, the inside of the drying chamber 1 is depressurized to a pressure lower than atmospheric pressure (about 50 Torr). Thereafter, the ice particles R in the cold trap are rapidly discharged into the drying chamber 1 through a main pipe equipped with a main valve. Thereby, the ice particles R enter the drying chamber 1, are uniformly dispersed in all the vials 5, and nucleation occurs instantaneously.

Prior Art Documents

Patent Documents

[0018]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0019] However, in the freeze-drying method of the freeze-drying apparatus described in the above publication, when rapidly transporting ice particles from the cold trap into the drying chamber, since they pass through the main pipe and main valve parts that are not temperature-controlled at low temperatures, the ice particles may decrease or disappear due to the heat influence from the outside, and thus stable nucleation may not be achieved. In addition, the cold trap is located on the downstream side of the drying chamber, and depending on the device specifications and the operation of the user, aseptic management may not be sufficient, and there is a high possibility that the material to be dried will be contaminated by the inflow of ice particles that are not aseptically managed.

[0020] The present invention has been made to solve such problems, and its object is to form ice particles (ice mist) on the inner wall of the main pipe portion under aseptic management in the same space as the inside of the drying chamber, thereby eliminating the heat influence from the outside and using the ice particles maintained in an aseptic state to provide a freeze-drying method for a freeze-drying apparatus that does not cause contamination of the material to be dried.

Means for Solving the Problems

[0021] In order to solve the above problems, the present invention according to claim 1 is a freeze-drying method of a freeze-drying apparatus having a drying chamber for storing a large number of containers filled with a liquid material to be dried, a main pipe communicating with the drying chamber and passing water vapor generated from the material to be dried, and a cooling device for condensing and collecting water vapor on the inner wall of the main pipe, the method having a preliminary freezing step of previously freezing the material to be dried in the drying chamber and a drying step of heating the material after the preliminary freezing step to dry the material to be dried. In the freeze-drying method, there is a nucleation step of nucleating the material to be dried before the preliminary freezing step. The nucleation step includes a step of cooling the drying chamber and the cold trap and maintaining the temperature in the drying chamber at a temperature for nucleation of the material to be dried, a frosting step of introducing a gas containing moisture such as nitrogen or air into the cold trap simultaneously with or after the step of cooling and maintaining the material to be dried, to attach ice particles to the cold trap plate in the cold trap, a depressurization step of depressurizing the cold trap, the drying chamber and the main pipe after the frosting step, and an ice particle production and conveyance step of rapidly introducing a gas into the main pipe after the depressurization step to roll up the ice particles adhering to the inner wall of the main pipe and convey the rolled-up ice particles into the drying chamber. The invention according to claim 3 is to depressurize the drying chamber and the main pipe in the depressurization step, and other configurations are the same as those of the invention according to claim 1.

[0022] According to the inventions of claim 1 and claim 3, in the nucleation step performed before the preliminary freezing step, ice particles are formed on the inner wall of the main pipe, and the ice particles are conveyed into the drying chamber through the main pipe.

[0023] Here, since the inside of the drying chamber is cooled to maintain the nucleation temperature of the material to be dried, nucleation rapidly proceeds from the upper part to the bottom part of the container, and large ice crystals are formed. Therefore, the water vapor transfer resistance of the already dried layer is reduced, and the primary drying time is shortened.

[0024] Also, when transporting ice particles from the main pipe inner wall into the drying chamber, since the pressures inside the main pipe and in the drying chamber are equal, although the gas introduced into the main pipe rolls up the ice particles on the inner wall of the main pipe due to its blowing force, the blowing force is not very large when flowing from the main pipe into the drying chamber. As a result, the ice particles are evenly transported into the drying chamber without tipping over the containers inside the drying chamber. Note that the main pipe has a main valve for opening and closing it (Claims 2 and 4), and a vacuum pump is connected to the cold trap or the main pipe, and a pressure reduction process is carried out by driving this vacuum pump (Claim 5 or Claim 6). Further, in this pressure reduction process, the pressures inside the main pipe and in the drying chamber may be 50 to 10 Torr (Claim 7).

[0025] As in the invention of Claim 8, in the ice particle production and transportation process, the temperature of the inner wall of the main pipe may be set to about -15°C or lower. Also, as in the invention of Claim 9, the gas introduced into the main pipe in the frosting process is a gas containing moisture such as sterile steam, nitrogen, air, etc. Moreover, it is better to have a higher humidity in manufacturing ice particles. Therefore, it is desirable that the gas introduced into the main pipe has a humidity of 50% or more.

[0026] In the invention of Claim 10, the means for introducing gas into the main pipe and the drying chamber has a gas introduction passage communicating with the outside of the freeze-drying apparatus and a gas introduction valve for opening and closing the gas introduction passage. According to the invention of Claim 10, the air outside the freeze-drying apparatus flows into the main pipe through the gas introduction passage to produce ice particles.

Advantages of the Invention

[0027] According to the present invention, by controlling the temperature in the drying chamber to be maintained at the nucleation temperature, the material to be dried becomes needle-shaped ice crystals. As a result, the water vapor transfer resistance of the already dried layer is reduced, and the primary drying time is shortened. Also, when transporting ice particles into the drying chamber, since the pressure in the main pipe and the drying chamber is the same, although the ice particles are evenly transported into the drying chamber, the gas flow is not so strong, so there is an advantage that the container in the drying chamber is not overturned. Further, since the ice particles formed on the inner wall of the aseptically managed main pipe flow into the drying chamber, there is an advantage that the material to be dried is not contaminated.

Brief Description of the Drawings

[0028]

Figure 1

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Figure 15

Mode for Carrying Out the Invention

[0029] An embodiment of the freeze-drying method of the freeze-drying apparatus according to the present invention will be described with reference to the drawings. First, the schematic configuration of an embodiment of the freeze-drying apparatus will be described with reference to FIG. 1.

[0030] As shown in FIG. 1, the freeze-drying apparatus W includes a drying chamber 1 for freeze-drying a material to be dried (for example, a chemical solution M), a product loading door 13 installed in the drying chamber 1, a main pipe 2 communicating with the drying chamber 1 and passing water vapor generated from the chemical solution M, and a cold trap 3 communicating with the main pipe 2 and condensing and collecting the water vapor flowing in from the main pipe 2.

[0031] Here, the chemical solution M loaded into the drying chamber 1 is placed on the shelf plates 4 arranged in a plurality of upper and lower stages, and is in a state of being filled in a container (for example, a vial 5 or a tray not shown). In addition, a vacuum gauge 6 is installed in the drying chamber 1 to detect the pressure inside the drying chamber 1. Although three shelf levels are shown, the present invention is not limited thereto.

[0032] The main pipe 2 has a main valve 2a for controlling the opening and closing of the gas flow. The communication state between the drying chamber 1 and the cold trap 3 is controlled by opening and closing the main valve 2a.

[0033] The cold trap 3 is connected to the vacuum pump 8 via the inlet valve 7. When the inlet valve 7 is opened and the vacuum pump 8 is driven, the gas in the drying chamber 1 is sucked through the main pipe 2 and the cold trap 3, and the inside of the drying chamber 1 including the main pipe 2 and the cold trap 3 can be evacuated. Incidentally, this vacuum exhaust system may also be connected to the vacuum pump 8' via the inlet valve 7' connected to the main pipe 2. Also, a cold trap plate (hereinafter referred to as a CT plate) 3a is disposed in the cold trap 3, and the CT plate 3a has a structure for condensing and collecting the water vapor flowing into the cold trap 3.

[0034] The freeze-drying apparatus W also has a heat medium circulation apparatus 9 and a cooling apparatus 12. The heat medium circulation apparatus 9 has a heat medium pump 9a, a heater 9b, a cooler 9c, and a medium switching valve 9d. When the medium switching valve 9d is switched to one side, the heating medium of the heater 9b and the cooling medium of the cooler 9c are circulated to each shelf 4 by the driving of the heat medium pump 9a. When the medium switching valve 9d is switched to the other side, the cooling medium of the cooler 9c is circulated to the main pipe cooler 10 that cools the main pipe 2 by the driving of the heat medium pump 9a. By such circulation of the medium, each shelf 4 is heated or cooled, and the main pipe 2 is cooled. On the other hand, the cooling apparatus 12 has a refrigerator 12a, a water-cooled condenser 12b, expansion valves 12c, 12d, a circulation pump 12e, and a cooling tower 12f. The water cooled by the cooling tower 12f is circulated to the water-cooled condenser 12b by the driving of the circulation pump 12d. The refrigerant cooled by the water-cooled condenser 12b is circulated to the cooler 9c through the expansion valve 12c by the driving of the refrigerator 12a, and is also circulated to the CT plate 3a through the expansion valve 12d. By such circulation of water and refrigerant, the CT plate 3a is cooled, and the medium of the cooler 9c is cooled. The water-cooled condenser 12b is connected to the cooling tower 12f via the circulation pump 12e, but this water-cooling system may be replaced with an air-cooling system (not shown). Further, the main pipe cooler 10 is configured with a general-purpose cooling structure using a jacket, a cooling coil, and a cooling plate, but instead of this cooling structure, a cooling system (not shown) configured with an independent chiller unit or the like may be adopted.

[0035] In the freeze-drying apparatus W configured as described above, a gas introduction passage 11 is connected to the main pipe 2, and air (ambient air or nitrogen gas and dry air) outside the freeze-drying apparatus W can be introduced into the main pipe 2. Further, a gas introduction valve 11a is provided in the middle of the gas introduction passage 11 to open and close the gas introduction passage 11, and a sterile filter 11b is attached to the tip of the gas introduction passage 11 to prevent foreign substances from entering the drying chamber 1 and the main pipe 2. Further, a steam introduction valve 11c for introducing sterile steam or sterile humidified air is provided on one side of the gas introduction passage 11, and moisture for forming ice particles may be introduced.

[0036] Subsequently, the drive control circuit of the freeze-drying apparatus W will be described with reference to the block diagram of FIG. 2.

[0037] As shown in FIG. 2, the freeze-drying apparatus W has a control panel 20 as control means, and a sequencer 21 is mounted on the control panel 20.

[0038] The sequencer 21 is programmed to drive and control the main valve 2a, the suction port valve 7, the vacuum pump 8, the heat medium circulation device 9, the cooling device 12, the gas introduction valve 11a, and the steam introduction valve 11c based on the output signals from the vacuum gauge 6, the operation switch 14, and the temperature sensor 15. Here, the temperature sensor 15 is composed of various temperature sensors, specifically, a sensor for detecting the temperature of the shelf board 4, a sensor for detecting the temperature of the main pipe, and a sensor for detecting the temperature of the cold trap 3.

[0039] The freeze-drying apparatus configured as described above performs freeze-drying operation control as shown in the flowchart of FIG. 3. That is, when the operation switch 14 is turned on (S1), a nucleation step (S2) for nucleating the chemical solution M, a preliminary freezing step (S3) for freezing the chemical solution M, a primary drying step (S4) for removing the moisture of the chemical solution M frozen in this preliminary freezing step, and a secondary drying step (S5) for removing trace amounts of unfrozen water contained in the chemical solution M that has become a dry solid through the primary drying step and drying the chemical solution M until it reaches a predetermined moisture content proceed sequentially, and the freeze-drying operation is terminated.

[0040] That is, the characteristic configuration of the present invention lies in the nucleation step executed at the stage prior to this preliminary freezing step. Hereinafter, this characteristic configuration will be described in detail.

[0041] As shown in FIG. 4, the nucleation step includes a chemical solution cooling and temperature maintenance step (S21), a frosting step (S22), a depressurization step (S23), and an ice particle production and transport step (S24). Hereinafter, each step will be described in order.

[0042] First, in the chemical solution cooling and temperature maintenance step (S21), as shown in FIG. 5, the heat medium circulation device 9 and the cooling device 12 are driven and controlled (S21a) so as to maintain the chemical solution M in the vial 5 at the nucleation temperature (for example, any temperature within the range of -3°C to -12°C), and this is executed for, for example, 60 minutes (S21b). Thereby, the chemical solution M in each vial 5 arranged on the upper surface of the shelf plate 4 is uniformly cooled.

[0043] Simultaneously with or subsequent to this chemical solution cooling and temperature maintaining step (S21), a frosting step (S22) shown in FIG. 6 is started. In this frosting step, the heat medium circulation device 9 and the cooling device 12 are driven to circulate a low-temperature heat medium through the main pipe cooler 10, and the inside of the main pipe 2 is cooled and maintained at -15°C or lower (S22a). As a result, the pressure inside the drying chamber 1 and the main pipe 2 becomes slightly negative pressure. When the gas introduction valve 10a is opened in this state, since the pressure inside the drying chamber 1 and the main pipe 2 is lower than the external pressure, external gas passes through the sterile filter 11b and further flows into the drying chamber 1 and the main pipe 2 through the gas introduction passage 11 (shown by the broken-line arrow in FIG. 1). As the external gas, for example, the outside air of the freeze-drying apparatus W can be cited, and it is desirable that the humidity of this outside air is high, for example, 50% or more. On the other hand, considering the state where the humidity of the outside air is not high, for example, a pure steam generation device (not shown) or the like may be installed, and the water vapor generated by this device may be guided to the gas introduction passage 11 by opening the steam introduction valve 11c. Further, the external gas is not limited to air, and may be, for example, nitrogen containing moisture. In this way, the gas introduced into the gas introduction passage 11 flows into the main pipe 2, and the moisture S of the gas adheres to the inner wall of the main pipe as frost F (aggregation of ice particles R). In addition, the moisture contained in the air inside the chamber and the moisture S in the air flowing in from the product loading door 13, which is opened when the vial is inserted, also adhere as frost F (aggregation of ice particles R).

[0044] After the chemical solution cooling and temperature maintaining step (S21) and the frosting step (S22), the depressurization step (S23) shown in FIG. 7 is started. In this depressurization step, the main valve 2a of the main pipe 2 is opened (S23a). As a result, the drying chamber 1 and the cold trap 3 communicate with each other through the main pipe 2, and the internal air pressures become equal to each other. After opening the main valve 2a, the vacuum pump 8 is started (S23b), and the inlet valve 7 is opened (S23c). Thereby, the gas in the drying chamber 1, the main pipe 2, and the cold trap 3 is sucked into the vacuum pump 8 (indicated by the thick arrow in FIG. 1), and the pressures in the drying chamber 1 and the main pipe 2 decrease. This evacuation operation is continued until the pressures in the drying chamber 1 and the main pipe 2 reach any pressure between, for example, 50 and 10 Torr (S23d). When the pressures in the drying chamber 1 and the main pipe 2 reach the set pressure, the main valve 2a is closed (S23e), the inlet valve 7 is closed (S23f), and the vacuum pump 8 is stopped (S23g). Thereby, the depressurization step is completed. In the depressurization step, the gas introduction valve 11a and the vapor introduction valve 11c are in a closed state.

[0045] When the depressurization step is completed, the process proceeds to the ice particle production and transfer step shown in FIG. 8. In this ice particle production and transfer step, first, the gas introduction valve 11a is opened (S24a). Here, since the pressures in the drying chamber 1 and the main pipe 2 are lower than the outside, the outside gas passes through the sterile filter 11b and flows into the gas introduction passage 11. This air becomes air free of foreign substances by the sterile filter 11b, and further flows into the main pipe 2 through the gas introduction passage 11 (indicated by the broken-line arrow in FIG. 1). Here, since the pressure in the main pipe 2 is between 50 and 10 Torr, the flow rate of the gas flowing into the main pipe 2 is rapid and it enters, and the frost adhering to the inner wall of the main pipe is lifted off and separated from the inner wall of the main pipe. This separated frost (ice particles R) is conveyed into the drying chamber 1 through the main pipe 2 and flows toward each vial 5 in the drying chamber 1 (indicated by the broken-line arrow in FIG. 1). Such a situation is continued until the inside of the drying chamber 1 and the main pipe 2 return to the atmospheric pressure (S24b).

[0046] By continuing such an ice particle production and conveyance process, the ice particles R are surely supplied to each vial 5 arranged in the drying chamber 1, and the chemical solution M in all the vials 5 is instantaneously nucleated. Specifically, nucleation proceeds sequentially from the top to the bottom of the vial 5 and is completed within several seconds. Also, since the pressure difference between the drying chamber 1 and the main pipe 2 is small, the flow velocity of the gas flowing from the main pipe 2 toward the drying chamber 1 is not so strong, and the vials 5 arranged on the shelf plate 4 do not fall over or move.

[0047] When the ice particle production and conveyance process continues and the drying chamber 1 and the main pipe 2 return to atmospheric pressure, the gas introduction valve 11a is closed (S24c). Thereby, the ice particle production and conveyance process ends. Thus, according to the present embodiment, there is an advantage that the material to be dried is not contaminated by flowing the ice particles formed on the inner wall of the aseptically managed main pipe 2 into the drying chamber 1.

[0048] When the nucleation process (S2) as described above is completed, similar to a conventional freeze-drying apparatus, it sequentially shifts to a preliminary freezing process → a primary drying process → a secondary drying process.

[0049] Hereinafter, an experiment was conducted to determine whether or not nucleation in the nucleation process (S2) was performed well by a testing machine of the freeze-drying apparatus W.

[0050] <Embodiment of the testing machine> As a testing machine for the freeze-drying apparatus according to the present invention, a pre-production machine model RL-301BS was used. In addition, parts corresponding to those in the testing machine are described using the same reference numerals at the parts described in FIGS. 1 and 2.

[0051] The area of the shelf board 4 in the drying chamber 1 is 1.09 m². The shelf board 4 has dimensions of 440W×620L×21t and the effective number of stages is 4. On each tray, 448 vials 5 with a diameter of φ24.5 are installed. 3 mL of a 10% aqueous solution of sucrose (C₁₂H₂₂O₁₁) is dispensed into each vial 5 and loaded onto the first-stage shelf board 4 in the drying chamber 1. On another tray, 448 vials 5 with a diameter of φ24.5 are installed. 3 mL of a 10% aqueous solution of a mixture of mannitol (C₆H₁₄O₆) and sucrose in a ratio of 5:5 is dispensed into each vial 5 and loaded onto the second-stage shelf board 4 in the drying chamber 1 to conduct the experiment.

[0052] Note that the chemical solution M is a sterile injection preparation. In the production machine, since gas passing through the sterile filter 11b is introduced into the drying chamber 1 and the main pipe 2, it is assumed that there is less moisture in the system and it is difficult for frost to form on the inner wall of the main pipe 2. Therefore, in the experiment using the testing machine, the inside of the drying chamber 1 and the main pipe 2 were replaced with nitrogen, and in a dry state equivalent to that of the production machine, it was confirmed whether nucleation occurred simultaneously or instantaneously in all the vials 5.

[0053] <Example 1 by the testing machine> In Example 1, the shelf plate 4 was cooled and maintained at the nucleation temperature of -6°C, and the time for this cooling and temperature maintenance process was set to about 60 minutes. At this time, the temperatures of the chemical liquid M in the three vials 5 arranged at different locations were -4.9°C, -5.7°C, and -4.9°C respectively. Also, since the main pipe 2 was cooled to -20°C or lower, the pressures in the drying chamber 1 and the main pipe 2 became slightly negative pressures. Then, the gas introduction valve 11a was opened, and air with a humidity of 50% or more was introduced into the main pipe 2, and the pressure in the main pipe 2 was restored to atmospheric pressure. In this state, frost adhered to the inner wall of the main pipe 2. After closing the gas introduction valve 11a, the main valve 2a was opened, the vacuum pump 8 was started, the draw valve 7 was opened, and the pressures in the drying chamber 1, the main pipe 2, and the cold trap 3 were reduced to 10 Torr. Next, the main valve 2a was closed, the draw valve 7 was closed, and the vacuum pump 8 was stopped. Then, the gas introduction valve 11a was opened, and gas was rapidly introduced into the drying chamber 1 and the main pipe 2. The introduced gas lifted the frost F adhering to the inner wall of the main pipe 2, and the lifted frost (ice particles R) was rapidly transported into the drying chamber 1 and simultaneously transferred to all the vials 5 in the drying chamber 1 and evenly dispersed. As a result, nucleation occurred simultaneously in all the vials 5 over several seconds.

[0054] <Example 2 by the testing machine> In Example 2, the shelf plate 4 was cooled and maintained at -6°C in the same manner as in Example 1, and the time for this cooling and temperature maintenance process was set to about 60 minutes. In the frosting process, the gas introduction valve 10a was opened, humidified nitrogen (air containing moisture) was introduced into the cold trap 3, and the pressure was restored to atmospheric pressure. In this state, frost adhered to the CT plate 3a. Other operations were the same as in Experimental Example 1, and nucleation occurred simultaneously in all the vials 5 over several seconds.

[0055] Also, experiments were conducted with the shelf plate 4 set at -3°C and -9°C to cool and maintain the chemical liquid M in the vial 5. As a result, it was confirmed that for all 440 vials loaded in the second stage of the shelf plate 4, nucleation proceeded simultaneously from the upper part to the bottom of the chemical liquid in the vial and was completed within several seconds. Thereby, it was verified that it is also feasible when set at -3°C and -9°C.

[0056] <Demonstration of the Effects of the Invention> Next, the effects of nucleation temperature control will be described by presenting three types of experimental examples below.

[0057] Vials 5 with a diameter of φ24.5 were used, and 448 vials per tray × 3 trays, for a total of 1,344 vials were prepared. Each vial 5 contained a dried material dispensed with a 10% aqueous sucrose solution. These vials 5 were loaded into the drying chamber 1, and a freeze-drying process was carried out. A product temperature sensor was inserted into one vial at the end of the shelf 4 and two vials 5 at the center of the shelf 4, respectively, to measure and record the product temperature (product temperature 1, product temperature 2, and product temperature 3) of the dried material. <Experimental Example Without Controlling the Nucleation Temperature> Figure 9 is a graph showing a normal freeze-drying process without a nucleation step. During normal pre-freezing, the supercooling temperature of the solution was product temperature 1: -9.2°C, product temperature 2: -8.2°C, and product temperature 3: -12.6°C. When measuring the time it took for the product temperature of vial 5 to catch up with the shelf temperature during the primary drying process, product temperature 2 reached it 40 hours after the start of primary drying, and product temperature 3 reached it 34.5 hours after the start of primary drying. From the recording curve of the sublimation rate, between 18 hours from the start of primary drying, the sublimation rate decreased almost linearly from a maximum value of 0.087 kg / hr to 0.063 kg / hr. <Experimental Example with Controlled Nucleation Temperature> Figure 10 shows an example in the freeze-drying apparatus W according to the present invention having a nucleation step, where the nucleation temperature was controlled to -6°C. First, 1,344 vial solutions were loaded into the drying chamber 1, and before the pre-freezing step, the nucleation temperature of the nucleation step according to the present invention was controlled to -6°C. During the primary drying process, the product temperatures 2 and 3 of the vials at the center of the shelf were the same, and sublimation ended almost simultaneously. Also, the time it took for product temperatures 2 and 3 to catch up with the shelf temperature was both 35 hours, which was 5 hours shorter than the drying time of 40 hours in normal freezing. From the recording curve of the sublimation rate, between 18 hours from the start of primary drying, the sublimation rate only decreased from a maximum of 0.085 kg / hr to 0.078 kg / hr, and since the sublimation rate at the initial stage of the primary drying process was almost constant, it became clear that the water vapor transfer resistance of the already dried layer was reduced by the present invention compared to normal freezing.

[0058] Figure 11 shows an example in the freeze-drying apparatus W according to the present invention having a nucleation step, where the nucleation temperature is controlled to -3°C. First, 1,344 vial solutions were loaded into the drying chamber 1, and before the pre-freezing step, the nucleation temperature in the nucleation step according to the present invention was controlled to -3°C. During the primary drying step, the product temperatures 2 and 3 of the vials at the center of the shelf were the same, and sublimation ended almost simultaneously. Also, the time when the product temperature caught up with the shelf temperature was both 34.5 hours, which was shortened by 5.5 hours compared to the drying time of 40 hours in normal freezing. From the recording curve of the sublimation rate, between 18 hours from the start of the first drying, the sublimation rate only decreased from a maximum of 0.086 kg / hr to 0.080 kg / hr, and since the sublimation rate at the initial stage of the primary drying step was almost constant, it became clear that the water vapor transfer resistance of the already dried layer was reduced compared to normal freezing.

[0059] As described above, in the freeze-drying method of the freeze-drying apparatus W, when controlling the nucleation temperature, uniform ice crystals are deposited between the vials, and since the nucleation temperature is controlled to a higher temperature (-6°C, -3°C, etc.), the ice crystals have a structure that reduces the water vapor transfer resistance of the already dried layer. With the increase in the sublimation rate, the primary drying time is shortened, and at the same time, the sublimation rates between the vials become equal.

[0060] In this way, the freeze-drying method of the freeze-drying apparatus was experimentally tested with a testing machine, and it was demonstrated that by having a nucleation step (a step of controlling the nucleation temperature), extremely advantageous effects can be exerted. Needless to say, this demonstration can also be similarly applied to a production machine for freeze-drying a large number of vials.

[0061] Note that since the production machine is large and has a steam sterilization SIP process to ensure sterility, the inside of the drying chamber 1 and the cold trap 3 is in a dry state. Therefore, to some extent, in the process of ice particle formation in the cold trap 3 and the conveyance process of ice particles to the drying chamber 1, it is disadvantageous compared to the testing machine and the pre-production machine. However, to solve these problems, pure steam (not shown) may be used to supplement the humidity in the frosting process, or the pressure of the cold trap may be set lower in the depressurization process.

[0062] FIG. 12 shows another embodiment of the freeze-drying method of the freeze-drying apparatus according to the present invention. In the above embodiment, the inlet valve and the vacuum pump were provided to communicate with the cold trap, but in this embodiment, the inlet valve 7' and the vacuum pump 8' are provided to communicate with the main pipe 2. Note that since the other configurations are the same as those in the above embodiment, the same reference numerals are used and the description thereof is omitted.

[0063] FIG. 13 is a flowchart showing the depressurization process according to another embodiment. That is, after the chemical solution cooling / temperature maintenance process (S21) and the frosting process (S22), the depressurization process shown in FIG. 13 is started. In this depressurization process, the main valve 2a of the main pipe 2 is closed (S23a'). As a result, the drying chamber 1, the main pipe 2, and the cold trap 3 are in a non-communicating state. Then, the vacuum pump 8' is started (S23b'), and the inlet valve 7' is opened (S23c'). As a result, the gas in the drying chamber 1 and the main pipe 2 is sucked into the vacuum pump 8' (indicated by the thick arrow in FIG. 12), and the pressure in the drying chamber 1 and the main pipe 2 decreases. This evacuation operation is continued until the pressure in the drying chamber 1 and the main pipe 2 reaches any pressure between, for example, 50 and 10 Torr (S23d'). When the pressure in the drying chamber 1 and the main pipe 2 reaches the set pressure, the inlet valve 7' is closed (S23e'), and the vacuum pump 8' is stopped (S23f'). Thereby, the depressurization process is terminated.

[0064] According to this embodiment, since the inside of the main pipe 2 and the drying chamber 1 can be depressurized without putting the cold trap 3 in a vacuum state, the depressurization region becomes smaller, and accordingly, the vacuum pump 8' can be miniaturized.

Explanation of Reference Numerals

[0065] W... freeze-drying apparatus, 1... drying chamber, 2... main pipe, 2a... main valve, 3... cold trap, 4... shelf plate, 5... vial, 7 and 7’... stopper valve, 8 and 8’... vacuum pump, 9... heat medium circulation device, 10... main pipe cooler, 11... gas introduction passage, 12... cooling device, 13... product loading door, M... chemical solution (material to be dried), R... ice particles, S... moisture.

Claims

1. In a freeze-drying method of a freeze-drying apparatus comprising a drying chamber for storing a large number of containers filled with a liquid material to be dried, a main pipe communicating with the drying chamber and allowing the water vapor generated from the material to be dried to pass through, and a cold trap communicating with the main pipe and condensing and collecting the water vapor flowing out from the main pipe, having a preliminary freezing step of freezing the material to be dried in the drying chamber and a drying step of heating the material to be dried after the preliminary freezing step to dry the material to be dried, it has a nucleation step of nucleating the material to be dried before the preliminary freezing step. The nucleation step includes a step of cooling the drying chamber, the main pipe, and the cold trap and maintaining the inside of the drying chamber at a temperature for nucleation of the material to be dried, and a frosting step of attaching ice particles to the inner wall of the main pipe by a gas containing moisture such as nitrogen, air, or sterile steam introduced into the main pipe or the moisture in the air in the chamber simultaneously with or after the step of cooling and maintaining the temperature of the material to be dried, after the frosting step, a depressurization step of depressurizing the inside of the cold trap, the main pipe, and the drying chamber, and after the depressurization step, a step of rapidly introducing a gas into the main pipe to lift the ice particles attached to the inner wall of the main pipe and transporting the lifted ice particles into the drying chamber. A freeze-drying method of a freeze-drying apparatus, characterized by the above.

2. The freeze-drying method of the freeze-drying apparatus according to Claim 1, characterized in that the main pipe is provided with a main valve for opening and closing the gas flow path between the drying chamber and the cold trap.

3. In a freeze-drying method of a freeze-drying apparatus comprising a drying chamber for storing a large number of containers filled with a liquid material to be dried, a main pipe communicating with the drying chamber and allowing the water vapor generated from the material to be dried to pass through, and a cold trap communicating with the main pipe and condensing and collecting the water vapor flowing out from the main pipe, having a preliminary freezing step of freezing the material to be dried in the drying chamber and a drying step of heating the material to be dried after the preliminary freezing step to dry the material to be dried, it has a nucleation step of nucleating the material to be dried before the preliminary freezing step. The nucleation step includes a step of cooling the drying chamber, the main pipe, and the cold trap and maintaining the inside of the drying chamber at a temperature for nucleation of the material to be dried, and a frosting step of attaching ice particles to the inner wall of the main pipe by a gas containing moisture such as nitrogen, air, or sterile steam introduced into the main pipe or the moisture in the air in the chamber simultaneously with or after the step of cooling and maintaining the temperature of the material to be dried, After the frosting step, a depressurization step of depressurizing the inside of the main pipe and the inside of the drying chamber; After the depressurization step, a step of rapidly introducing gas into the main pipe to lift ice particles adhering to the inner wall of the main pipe, and transporting the lifted ice particles into the drying chamber, including an ice particle production and transport step; A freeze-drying method of a freeze-drying apparatus, characterized by the above.

4. The main pipe is provided with a main valve for opening and closing a gas flow path between the drying chamber and the cold trap. The freeze-drying method of the freeze-drying apparatus according to claim 3, characterized by this.

5. A vacuum pump is connected to the cold trap. In the depressurization step, the cold trap is depressurized by driving the vacuum pump, and the main valve is set to open to depressurize the drying chamber through the main pipe. The freeze-drying method of the freeze-drying apparatus according to claim 2, characterized by this.

6. A vacuum pump is connected to the main pipe. In the depressurization step, the inside of the main pipe is depressurized by driving the vacuum pump, and the main valve is set to close to depressurize the drying chamber through the main pipe. The freeze-drying method of the freeze-drying apparatus according to claim 4, characterized by this.

7. In the depressurization step, the pressure inside the main pipe and the inside of the drying chamber is 50 to 10 Torr. The freeze-drying method of the freeze-drying apparatus according to any one of claims 1 to 6, characterized by this.

8. In the ice particle production and transport step, the temperature of the main pipe is set to about -15°C or lower. The freeze-drying method of the freeze-drying apparatus according to any one of claims 1 to 7, characterized by this.

9. The gas introduced into the main pipe in the frosting step is a gas containing moisture, such as sterile steam, nitrogen, air, etc., a gas with a humidity of 50% or more, air containing moisture in the drying chamber, and air containing moisture flowing in from the container insertion door when the container is inserted into the drying chamber. The freeze-drying method of the freeze-drying apparatus according to any one of claims 1 to 8, characterized by this.

10. As a means for introducing gas into the main pipe and the drying chamber, it has a gas introduction passage communicating with the outside of the freeze-drying apparatus and a gas introduction valve for opening and closing the gas introduction passage. The freeze-drying method of the freeze-drying apparatus according to any one of claims 1 to 9, characterized by this.

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