Method and apparatus for freezing or thawing a mixture containing water.

Abstract

The present invention relates to a method for freezing an injectable composition, particularly a pharmaceutical composition, comprising the steps of storing a quantity of a dispersion of the injectable composition in an aqueous dispersion medium in a vial, and cooling the vial by applying a cooling gas to the vial, wherein the cooling step is characterized by carrying out at least one of (A), (B), and (C), wherein (A) is an initial cooling control scheme before nucleation occurs in the dispersion layer, (B) is a crystallization control scheme during crystallization of the dispersion layer, and (C) is a final cooling control scheme after crystallization of the dispersion layer, and obtaining a dispersion after freezing is completed.

Description

Technical Field

[0001] The present disclosure generally relates to the field of freezing and thawing mixtures suitable for, for example, lyophilization of products including, but not limited to, injectable compositions, particularly pharmaceutical compositions, biological compositions, cosmetic compositions or medical nutrition products. In particular, the present disclosure relates to methods and apparatuses for freezing mixtures containing water. More generally, the methods and apparatuses are for solidifying fluid substances by removing heat by injecting a cryogenic gas onto a container. Additionally, methods of injecting thermally controlled gases and similar apparatuses can be used for the controlled thawing of initially frozen mixtures.

Background Art

[0002] Freeze drying, also known as lyophilisation, is a technique for removing water from a composition such that ice can be removed by sublimation after the composition has been frozen and placed under vacuum. Sublimation is the direct transition of a substance from the solid state to the gaseous state without passing through the liquid state. Freeze drying has been known for decades and is typically used for materials that are prone to spoilage, such as pharmaceuticals or foods, for example to facilitate storage, distribution and / or transportation of the materials.

[0003] A conventional method for carrying out this freeze-drying process involves placing a batch of containers, each container being supplied with a dispersion of the composition on a hollow shelf in a sealed chamber. As a thermal fluid flows through the hollow shelf, the shelf is cooled, thereby lowering the temperature of the container and the composition inside. At the end of this freeze cycle, the aqueous composition is frozen as a stopper at the bottom of the container, and then the pressure in the chamber is reduced while the shelf is gradually heated at the same time to sublimate the ice crystals formed in the frozen composition. During the sublimation process, water vapor is generated and leaves the surface of the stopper located at the bottom of the container. The ice-vapor interface, also called the sublimation front, slowly moves downward as the sublimation process progresses. Once the substantial portion of the ice crystals is removed, the porous structure of the composition remains. Generally, a secondary drying step follows to complete the freeze-drying cycle, where residual moisture is removed from the formulation void matrix by desorption at an elevated temperature and / or a suitable pressure.

[0004] Focusing on the freezing step, this step is considered one of the important steps for the quality of the final dried product, as the structure and morphology of the resulting dried product are established at this step. The freezing step is generally considered to consist of four separate stages: (I) First, the liquid is cooled until the temperature of the product falls below its crystallization point. Cooling below the crystallization point without crystallization occurring is generally called supercooling, also known as undercooling, and is the process of lowering the temperature of a liquid below its freezing point without the liquid becoming solid. Supercooling can occur in the presence of a seed crystal or nucleus, unless a crystalline structure can form around such a nucleus. (II) Next, nucleation occurs, which is the origin of the crystalline phase from the supercooled liquid. Nucleation indicates the start of crystallization. During crystallization, heat must be released by the product, and therefore there is a relative temperature rise due to this exothermic nature of ice crystallization. (III) Next, the product reaches a crystalline state during the crystallization stage, also known as the crystal growth stage. Here again, this process is an exothermic process in which heat is removed from the product. (IV) Finally, the solid is cooled further. At this stage, the final shape and size of the ice crystals are determined by a phenomenon called Ostwald aging.

[0005] The freezing step in freeze-drying is considered particularly important, but the actual control of all phases between freezing (I) to (IV) described above is limited in traditional shelf freeze-dryers. As mentioned above, the shelves are cooled indirectly via a thermal fluid (used as a means of transferring thermal energy), which cools the vials containing the product. This process is inherently slow, and the cooling of the shelves is usually limited to 1-2°C / min, which greatly limits the control capability. Furthermore, due to the cooling method, control is limited to the control of the thermal fluid, which has a very clear link to the product.

[0006] Regarding controlled nucleation, several improvements have been proposed to induce nucleation in order to reduce product variability: (A) inducing density shock by inducing a rapid sequence of suction vacuum and aeration, (B) inducing clouding of small ice crystals, and (C) inducing atomization of liquid nitrogen droplets.

[0007] All of the above methods (A) to (C) first apply a low temperature just below the normal crystallization point (supercooling) to ensure sufficient heat resistance. Subsequently, by applying such induction methods, the variability of crystallization is significantly reduced when crystallization occurs. Nevertheless, further improvement is still the goal.

[0008] International Publication No. 2013 / 036107 discloses a method for lyophilizing an injectable composition, comprising: A) storing a certain amount of dispersion or solution of an injectable composition in an aqueous dispersion or solution medium in at least one ready-to-use vial; B) rotating the vial for at least a certain period of time to form a dispersion or solution layer on the inner surface of the vial's perimeter wall; C) cooling and solidifying the vial during the rotation in step B, particularly to form ice crystals on the inner surface of the vial's perimeter wall; and D) drying the cooled composition to sublimate at least a portion of the ice crystals formed in the dispersion or solution by substantially uniformly heating the vial's perimeter wall. Cooling and freezing of the product in the vial is achieved by applying a cryogenic gas jet to the rotating vial.

[0009] In this method, the cooling of the product can be arbitrarily set between 0.5 and 100°C per minute. The thermal trajectories of the liquid and ice cooling phases are controlled using non-contact temperature measurement, and control of the cooling gas temperature and / or the time at a specific setpoint is maintained. This solution controls the temperature trajectories of the liquid phase and crystal water, but further improvements are needed.

[0010] "In-Situ X-ray Imaging Of Sublimating Spin-Frozen Solutions," Materials 2020, 13, 2953 (Goethals, W., Vanbillemont, B., Lammens, J., De Beer, T., Vervaet, C., Boone, MN) describes the structure of frozen materials treated by spin freeze-drying technology. The resulting product structures are visualized using micro-CT scanning technology. Some of the post-processing results show profiles consistent with “column”-like structures that facilitate water vapor escape.

[0011] In "Mechanistic modelling of infrared mediated energy transfer during the primary drying step of a continuous freeze-drying process," European Journal of Pharmaceutics and Biopharmaceutics 114(2017)11-2 (by Pieter-Jan Van Bockstal et al.), a mechanistic model was developed that allows for the calculation of the optimal dynamic IR heater temperature as a function of the primary drying progress, and therefore, the prediction of the primary drying endpoint based on the applied dynamic IR heater temperature. This model is compared with experimental validation. The mechanistic model did not consider the geometric structure shown in the aforementioned publication. As a result, the sublimation time is shorter than that modeled.

[0012] The development of (new) therapies requires a series of processing steps for active pharmaceutical ingredients (APIs) and / or drug product formulations. These steps include thawing, in addition to freezing and crystal formation. This thawing process affects the yield and efficacy of the API. This is done using immersion of the container containing the API into a heat-controlled layer. In such a bath, the final temperature is preferably guaranteed, but there is no predetermined path to reach it, and it depends on several physical conditions. For example, in some cases, a rapid initial temperature rise is essential, followed by a slow final thawing, or vice versa, which cannot be achieved by immersion alone.

[0013] For example, the method may involve rapidly transferring the ampoule containing the API to a 37°C water bath until only one or two small ice crystals remain (1-2 minutes). Rapid thawing is considered important, for example, to minimize damage to cell membranes. This method significantly increases the risk of contamination from the use of a heat bath, for example, if the ampoule is completely immersed in the heat bath or if the ampoule is accidentally closed.

[0014] In "The Impact of Varying Cooling and Thawing Rates on the Quality of Cryopreserved Human Peripheral Blood T Cells," Sci Rep 9, 3417 (2019), Baboo, J., Kilbride, P., Delahaye, M. et al., the interaction between different freezing scenarios and thawing processes is assessed for the survival of blood T cells. Diagrams of different ice structures following different freezing and thawing pathways are presented. By comparing various situations with cell survival, it is revealed that thawing can have a significant impact on cell viability depending on the initial freezing conditions. This publication provides a summary of survival success for different organisms by comparing, for example, the effects of cell type, cooling rate, and heating rate.

[0015] In "Thermostability of Biological Systems: Fundamentals, Challenges, and Quantification" (The Open Biomedical Engineering Journal, 2011, 5, 47-73, by Xiaoming He), the fundamental aspects of freezing and thawing related to thermodynamic energy transfer are described and compared with actual images. One example is given to visualize the effects of freezing scenarios on cellular structures: at very slow cooling rates, cellular dehydration prevails; at fast cooling rates, intracellular ice formation prevails; and at moderate cooling rates, both intracellular ice formation and cellular dehydration can occur. While cooling rate is used as a parameter for this study in this publication, it should be noted that from a physics perspective, the determinant is heat removal.

[0016] "Cell Size and Water Permeability as Determining Factors for Cell Viability after Freezing at Different Cooling Rates" (Applied and Environmental Microbiology, Jan. 2004, pp. 268-272; DOI: 10.1128 / AEM.70.1.268-272.2004, by F. Dumont et al.) presents differing results regarding cooling rates, particularly the relationship between cooling rate and cell viability for different organisms. The fact that they adopted cooling rate as the parameter to study is due to limitations in their apparatus, where only the cooling bath temperature can be monitored and controlled.

[0017] Finally, to generate the cryogenic gas used in the freeze-drying process to alter the temperature of the product, it is necessary to cool such gas using, for example, liquid nitrogen and a heat exchanger. This can lead to damage to the clean cryogenic gas. From both an environmental and cost perspective, this is undesirable.

[0018] Therefore, the object of the present invention is to solve the above-mentioned problems relating to freezing, freeze-drying, and thawing, and to further improve the methods of freezing, freeze-drying, and thawing. [Prior art documents] [Patent Documents]

[0019] [Patent Document 1] International Publication No. 2013 / 036107 [Non-patent literature]

[0020] [Non-Patent Document 1] Goethals, W., Vanbillemont, B., Lammens, J., De Beer, T., Vervaet, C., Boone, MN, “In-Situ X-ray Imaging Of Sublimating Spin-Frozen Solutions”, Materials,2020,13,2953 [Non-Patent Document 2] Pieter-Jan Van Bockstal et al., “Mechanistic modeling of infrared mediated energy transfer during the primary drying step of a continuous freeze-drying process”, European Journal of Pharmaceutics and Biopharmaceutics, 2017, 114, p.11-2 [Non-Patent Document 3] Baboo, J., Kilbride, P., Delahaye, M. et al., “The Impact of Varying Cooling and Thawing Rates on the Quality of Cryopreserved Human Peripheral Blood T Cells”, Scientific Reports, 2019, 9, 3417 [Non-Patent Document 4] Xiaoming He, “Thermostability of Biological Systems: Fundamentals, Challenges, and Quantification”, The Open Biomedical Engineering Journal, 2011, 5, 47 - 73 [[Non - Patent Document 5]] F.Dumont et al., “Cell Size and Water Permeability as Determining Factors for Cell Viability after Freezing at Different Cooling Rates”, Applied and Environmental Microbiology, January 2004, p.268 - 272 [[Mode for Carrying Out the Invention]]

[0021] To address one or more of the drawbacks considered in the prior art, the present invention is a method for changing the phase of a composition, particularly a pharmaceutical composition, comprising: storing an amount of the composition in a vial; changing the phase of the composition within the vial by applying a hot gas, where the step of changing the phase of the composition includes the step of freezing or thawing the composition, and the hot gas is a cooling gas or a heating gas respectively, the step of changing the phase of the composition is characterized by performing at least one of (A), (B), and (C), where (A) is an initial temperature change control scheme executed before entering a phase where the crystallization amount of the composition changes, (B) is a crystallization change control scheme during the process of the phase where the crystallization amount of the composition changes, and (C) is a final temperature change control scheme executed until the composition reaches its final temperature; after the phase change is completed, obtaining the composition, the initial temperature change control scheme (A) is (I) Performing an initial measurement on the vial and / or the composition to determine whether a phase has started in which the amount of crystallization of the composition changes; (II) Controlling the temperature and / or flow rate of the hot gas so that the temperature of the vial and / or the composition follows a predetermined initial temperature change over time; Repeating steps (I) and (II) until the initial measurement determines that a phase has started in which the amount of crystallization of the composition changes; The crystallization change control scheme (B) is (I) Performing a crystallization change measurement on the vial and / or the composition to determine whether there is no longer a change in the amount of crystallization in the composition; (II) Controlling the temperature and / or flow rate of the hot gas so that the temperature of the vial and / or the composition follows a predetermined crystallization change temperature change over time; Repeating steps (I) and (II) until there is no longer a change in the amount of crystallization in the composition; The final temperature change control scheme (C) is (I) Controlling the temperature and / or flow rate of the hot gas so that the temperature of the vial and / or the composition follows a predetermined change over time of the final temperature; (II) Performing a final temperature measurement on the vial and / or the composition to determine whether the vial and / or the composition has reached its predetermined final temperature; Repeating steps (I) and (II) until the final temperature measurement determines that the vial and / or the composition has reached its predetermined final temperature;

[0022] The method according to the present invention provides a suitable means for controlling an important freezing process. The present invention further provides an apparatus suitable for such a method.

[0023] The present invention further provides a method for improving cell survival after freezing.

[0024] The present invention relates to a method for freezing an injectable composition, particularly a pharmaceutical composition, comprising the steps of: storing a certain amount of dispersion of the injectable composition in an aqueous dispersion medium in a vial; rotating the vial for at least a certain period of time to form a dispersion layer on the inner surface of the peripheral wall of the vial; and cooling the vial by applying a cooling gas to the rotating vial during the rotation of the vial, wherein the cooling is characterized by performing at least one of (A), (B), and (C), where (A) is the initial cooling before nucleation occurs in the dispersion layer. The initial cooling control scheme (A) includes the steps of: (I) performing a nucleation measurement on the vial and / or dispersion to determine whether nucleation has occurred in the dispersion; (II) controlling the temperature and / or flow rate of the cooling gas so that the temperature of the vial and / or dispersion follows a change over time of a predetermined initial temperature; and the nucleation measurement determines that nucleation has occurred in the dispersion. The crystallization control scheme (B) includes the step of repeating steps (I) and (II) until crystallization is completed, wherein the crystallization control scheme (B) includes the steps of (I) performing a crystallization measurement on the vial and / or dispersion layer to determine whether crystallization has been completed in the dispersion layer, (II) controlling the temperature and / or flow rate of the cooling gas so that the temperature of the vial and / or dispersion follows the change over time of a predetermined initial cooling temperature, and (III) waiting for a predetermined time, and repeating steps (I) to (III) until the crystallization measurement determines that crystallization has been completed in the dispersion layer. A method is provided in which a final cooling control scheme (C) includes the steps of: (I) controlling the temperature and / or flow rate of a cooling gas so that the temperature of the vial and / or dispersion layer follows a change over time of a predetermined final cooling temperature; (II) performing a final temperature measurement on the vial and / or dispersion layer to determine whether the vial and / or dispersion layer has reached its predetermined final temperature; and repeating steps (I) and (II) until the final temperature measurement determines that the vial and / or dispersion layer has reached its predetermined final temperature.

[0025] In each control scheme, a predetermined time can be waited before repeating steps (I) and (II). This can be a control parameter indicating the amount of heat exchanged between the gas and the vial for a particular temperature and flow rate setting.

[0026] The phrase "dispersion of an injectable composition in an aqueous dispersion medium" means that any mixture of an injectable composition mixed with an aqueous medium is included. An injectable composition may be dissolved (meaning mixed at the molecular level), dispersed (meaning solid in a fluid), or emulsified (meaning liquid particles in another liquid) in an aqueous medium. Many injectable compositions are known in the art, and it may be difficult to describe a mixture as an emulsion, a dispersion (in the strict sense), or a solution. The present invention is independent of any particular form of the mixture of the injectable composition and the aqueous medium. Mixtures that need to be frozen (generally before lyophilization) include, in particular, proteins such as antibodies, receptor antagonists, and receptor agonists. In another embodiment, the mixture includes whole cells. Alongside proteins, cells, etc., there are often excipients that are not removed during the lyophilization process. Therefore, "injectable composition" means that it includes any components that remain in the lyophilized composition.

[0027] When a frozen composition is used for thawing, the components are removed almost entirely. Most commonly, this is applicable to all cells being frozen and thawed. For example, the current viability of CAR-T cells is about 10% after a freeze-thaw cycle. Therefore, a process that enables a higher viability is highly desirable. This invention enables substantially higher viability.

[0028] A dispersion is a mixture of an active pharmaceutical ingredient (API, also called a substance), possible excipients such as salts, buffers, cryoprotectants, or solubility protectants, and a possible solvent such as water. In some cases, a co-solvent such as ethanol may be applied to facilitate the dissolution of the API.

[0029] In the process of freezing whole cells, useful excipients are additives that diffuse into the cells and induce vitrification, thereby preventing the formation of ice crystals within the cells. Other protective agents affect osmotic pressure. Suitable cryoprotective agents include DMSO, glycerol, propanediol, dimethylhydrazine, sucrose, trehalose, mannitol, lactose, and polyvinylpyrrolidone.

[0030] In a method for freezing an injectable composition, preferably, after crystallization in the dispersion layer is completed, the flow rate of the cooling gas is changed to a predetermined value.

[0031] Preferably, in a method for freezing an injectable composition, the initial cooling control scheme further includes a step of inducing condensation nuclei, a step of inducing an artificial density gradient in the composition by sound waves or pressure waves, or a step of inducing thermal shock.

[0032] Preferably, in a method for freezing an injectable composition, sound waves or pressure waves are generated by inducing rotational fluctuations, thereby inducing condensation nuclei.

[0033] In a preferred embodiment, thermal shock is induced by fluctuations in the temperature or flow rate of the cooling gas.

[0034] In a preferred embodiment, nucleation measurements, crystallization measurements, final temperature measurements, and / or temperature measurements are performed using a thermal infrared camera that detects the IR emission of the vial, and the IR emission of the vial is converted into temperature information of the dispersed layer using an image processing module.

[0035] Preferably, temperature information is used in conjunction with a mathematical model to determine the characteristics of the dispersion layer in real time.

[0036] In a preferred embodiment, a process is applied that combines at least two of steps (A), (B), and (C), such as a process that applies A and B, or A and C, or B and C. It is even more preferable to apply a process that applies all three steps A, B, and C.

[0037] The freezing step results in a more defined frozen mixture than those in the prior art. Improved and defined parameters include crystal size, crystal boundaries, and overall cell viability. This is useful for several reasons. The usefulness of the improvements can vary depending on the application. For example, when antibodies are frozen for lyophilization, a clearly defined frozen mixture can substantially reduce the time required for (lyophilization) because the crystal size allows for cracking in the frozen layer and rapid sublimation of water. In the case of whole cells, the primary improvement may be improved viability. For example, current standards for freezing and thawing T cells only allow for about 10% cell viability. The method of the present invention allows for substantially higher viability.

[0038] Therefore, the present invention for freezing dispersions enables an improved freeze-drying process and an improved freeze / thaw process.

[0039] Accordingly, the present invention relates to a method for freeze-drying an injectable composition, particularly a pharmaceutical composition, wherein freezing is carried out as described above, and then drying is carried out under vacuum. The drying step in freeze-drying may be a conventional vacuum chamber, but is preferably a controlled drying process as described in International Publication No. 2013 / 036107.

[0040] The present invention further relates to a freezing apparatus for freezing injectable compositions, particularly pharmaceutical compositions, the freezing apparatus comprising: a freezing chamber including a rotating means for one or more vials, the freezing chamber being able to rotate for at least a certain period of time to form a dispersion layer on the inner surface of the peripheral wall of the vials, and including a cooling gas system for applying a cooling gas to the rotating vials as the vials rotate so that the vials are cooled; an exhaust from the freezing chamber for used cooling gas to exit the freezing chamber; and a heat exchange element at least partially surrounding the freezing chamber, in thermal contact with the freezing chamber, and cooling the freezing chamber by using the used cooling gas.

[0041] In another preferred embodiment of the present invention, a freezing apparatus for freezing injectable compositions, particularly pharmaceutical compositions, wherein the freezing apparatus comprises a freezing chamber including a rotating means for one or more vials, wherein one or more vials containing a certain amount of dispersion of an injectable composition in an aqueous dispersion medium can be rotated for at least a certain period of time to form a dispersion layer on the inner surface of the peripheral wall of the vials, and includes a cooling gas system for applying a cooling gas to the rotating vials as the vials rotate so that the vials are cooled; and exhaust from the freezing chamber for used cooling gas to exit the freezing chamber, further comprising control means for controlling the freezing process as described above. The present invention relates in particular to a freezing apparatus comprising control means for any of the above, and a combination of the above control means.

[0042] Preferably, in a freezing apparatus, the used cooling gas can flow through a heat exchange element, for example, to cool the freezing chamber.

[0043] Preferably, in the freezing apparatus, the heat exchange element is formed by a spirally wound channel and / or meandering channel surrounding the freezing chamber through which used cooling gas can flow.

[0044] Preferably, in a freezing apparatus, the heat exchange element is located within a double-wall structure surrounding the freezing chamber.

[0045] Preferably, the freezing apparatus includes control means for controlling the freezing process as described above.

[0046] In a more preferred embodiment, the present invention relates to a freeze-drying system for freeze-drying an injectable composition, particularly a pharmaceutical composition, comprising the above-described freeze-drying device and an annealing device and / or sublimation device, wherein the annealing device and / or sublimation device each comprises an annealing chamber and a sublimation chamber, and the annealing device and / or sublimation device each comprises a heat exchange element that is in thermal contact with the annealing chamber and / or sublimation chamber, respectively, and each heat exchange element cools the annealing chamber and / or sublimation chamber using a used cooling gas.

[0047] A More Preferred Embodiment: The present invention provides a freezing apparatus for freezing injectable compositions, particularly pharmaceutical compositions, the freezing apparatus for use in a freeze-drying process, comprising: a freezing chamber, in which one or more vials containing a certain amount of dispersion of an injectable composition in an aqueous dispersion medium are rotated for at least a certain period of time to form a dispersion layer on the inner surface of the peripheral wall of the vials, and a cooling gas system for applying a cooling gas at a cooling temperature to the rotating vials while the vials are rotating so that the vials are cooled; and an exhaust from the freezing chamber from which used cooling gas exits the freezing chamber, wherein the cooling gas system comprises a pre-cooling system in which the gas is pre-cooled before the cooling of the gas to a cooling temperature is carried out, and the pre-cooling system comprises a heat exchange element in thermal contact with the gas to be pre-cooled, the heat exchange element cooling the gas to be pre-cooled by using used cooling gas.

[0048] Preferably, the heat exchange element is formed by a first piping system through which a gas to be pre-cooled flows and a second piping system through which used cooling gas flows, and the first and second piping systems are in thermal contact with each other.

[0049] In a more preferred embodiment, the present invention provides a freezing apparatus for freezing an injectable composition, particularly a pharmaceutical composition, the freezing apparatus comprising: a freezing chamber having a rotating means, in which one or more vials containing a certain amount of dispersion of an injectable composition in an aqueous dispersion medium are rotated for at least a certain period of time to form a dispersion layer on the inner surface of the peripheral wall of the vial, and a cooling gas system for applying a cooling gas at a cooling temperature to the rotating vial while the vial is rotating so that the vial is cooled; and exhaust from the freezing chamber for used cooling gas to exit the freezing chamber, wherein the cooling gas system comprises a cooling system for cooling the gas to a cooling temperature, the cooling system comprising a compressor and a heat exchange element in thermal contact with the compressor, the heat exchange element cooling the compressor by using used cooling gas means for measuring the temperature of the vial during at least a certain time of the freezing process, and a control mechanism for influencing the flow rate and / or temperature of the cooling gas to adjust the cooling rate for at least a specific time of the freezing process. [Brief explanation of the drawing]

[0050] Here, embodiments will be described only as examples, with reference to the attached schematic diagrams where corresponding reference numerals indicate corresponding parts. [Figure 1] This diagram shows an exemplary freezing cycle. [Figure 2] A and B illustrate two methods for freezing a substance in a container or vial, which are known in the art. [Figure 3] A and B illustrate two embodiments of a freezing process using a flow of cryogenic gas, as is known from the art. [Figure 4]This demonstrates that a thermal IR camera can be used to "measure" the temperature of the outer surface of a container wall. [Figure 5] This is a variation of the arrangement shown in Figure 4, demonstrating that the thermal IR camera 61 can also be mounted in a way that is generally independent of the vial's position. [Figure 6] This illustrates possible non-contact measurements of an exemplary thawing cycle, for example, using a thermal IR camera. [Figure 7A] This describes a control scheme used by a control system to adaptively control the temperature and flow rate of the cryogenic gas during (sub)cooling, nucleation, and / or crystallization. [Figure 7B] This describes a control scheme used by a control system to adaptively control the temperature and flow rate of the cryogenic gas during (sub)cooling, nucleation, and / or crystallization. [Figure 7C] This describes a control scheme used by a control system to adaptively control the temperature and flow rate of the cryogenic gas during (sub)cooling, nucleation, and / or crystallization. [Figure 8] The first, second, and third alternative examples of the gas cooling system are shown schematically. [Figure 9] The first, second, and third alternative examples of the gas cooling system are shown schematically. [Figure 10] The first, second, and third alternative examples of the gas cooling system are shown schematically. [Figure 11] A schematic diagram of a spin freeze-drying system is shown, in which the exhaust gas from the freeze step is reused to conditioned the double-walled chamber. [Figure 12A] A schematic cross-section of the double-wall structure is shown. [Figure 12B] A schematic cross-section of the double-wall structure is shown. [Figure 13] A schematic diagram of a first heat exchanger that can be used to pre-cool a gas to be used as a cooling gas in a spin freeze dryer is shown. [Figure 14]A schematic diagram of a second heat exchanger that can be used to pre-cool the gas to be used as a cooling gas in a spin freeze dryer is shown. [Figure 15] An exemplary thawing cycle is shown. [Figure 16A] This document describes a control scheme that should be used by a control system to adaptively control the temperature and flow rate of low-temperature gas during the thawing of frozen products. [Figure 16B] This document describes a control scheme that should be used by a control system to adaptively control the temperature and flow rate of low-temperature gas during the thawing of frozen products. [Figure 16C] This document describes a control scheme that should be used by a control system to adaptively control the temperature and flow rate of low-temperature gas during the thawing of frozen products. [Figure 16D] This document describes a control scheme that should be used by a control system to adaptively control the temperature and flow rate of low-temperature gas during the thawing of frozen products. [Figure 16E] This document describes a control scheme that should be used by a control system to adaptively control the temperature and flow rate of low-temperature gas during the thawing of frozen products. [Figure 17] A schematic diagram of a gas cooling / heating system modified from the gas cooling system shown in Figure 8 is provided. [Figure 18] A schematic diagram of the gas heating system is shown. [Figure 19] This schematic diagram illustrates a thawing system in which exhaust gases from the thawing cycle are reused to conditioned the double-walled chamber of the thawing chamber. [Figure 20] An exemplary vial that may be used in the present invention is shown. [Figure 21] Figure 20 shows a table corresponding to the vials, including the dimensions of vials with specific R (Rohr) values. [Figure 22A] The results of non-contact measurements of a freezing cycle using the present invention at a cooling rate of 10°C / min and a crystallization rate of 3.815 W are shown. [Figure 22B]The results of non-contact measurements of a freezing cycle using the present invention at a cooling rate of 10°C / min and a crystallization rate of 7.630 W are shown.

[0051] The drawings are for illustrative purposes only and do not limit the scope or protection defined by the claims. Best mode for carrying out the invention

[0052] Embodiments of the present invention will be described in further detail below. However, it should be understood that these embodiments may not be construed as limiting the scope of protection of this disclosure.

[0053] Figure 1 shows an exemplary freezing cycle 1. The horizontal axis 2 represents time, and the vertical axis 3 relates to the temperature of the dispersion in the vial. For pure water, the freezing point is 0°C. For solutions, the freezing or solidification point is below this temperature. If sufficient crystallization seeds are not present (often in pharmaceutical environments with a small number of suspended particles), further sub-cooling occurs. Therefore, the composition may remain liquid below its physical freezing temperature.

[0054] Reference numeral 4 indicates the cooling of the liquid composition. At point 5, ice crystal formation occurs, and ice formation begins. Since this is an exothermic process, the temperature of the product rises. During ice crystallization 6 over ice crystallization time 10, the product remains almost thermally constant. In reality, with a constant energy decrease, less water is converted into ice. Therefore, in reality, the product does not remain exactly thermally constant, but shows a gradual decrease.

[0055] Another nucleation site 7 occurs when the excipient begins to crystallize. In this case, too, the temperature rises due to the exothermic nature of this process. Following this, the crystallization stage 8 occurs over the excipient crystallization time 11. It is possible that such excipient nucleation and crystallization may not occur in a particular product, or that nucleation and crystallization of two or more such excipients may occur. This depends on the chemical and physical composition of the product to be freeze-dried.

[0056] The lengths of both the excipient crystallization time 11 and the ice crystallization time 10 can be controlled, as will be further explained below. By controlling the duration of these crystallization stages, the formation of the crystal structure can be controlled to a greater degree.

[0057] After further cooling, annealing 9 can be performed to enlarge the size of the ice crystals or to optimize the crystallization shape of the excipient. Enlarging the size of the ice crystals may be important for optimizing the subsequent sublimation process. Optimizing the crystallization shape of the excipient may be important to avoid undesirable polymorphs of the excipient, such as hemihydrates when using mannitol.

[0058] Figure 2 shows two methods known in the art for freezing a substance in a container or vial.

[0059] Figure 2A shows an example of a container 20 containing a substance 21 to be frozen, where the container is held stationary in an upright position, and in this case, the frozen product is located at the bottom of the container.

[0060] Figure 2B shows an example of a container 20 containing a substance 21 that is frozen while the container is rotated around its longitudinal axis, resulting in the substance forming a layer, for example, a relatively thin layer or a diffusion layer, on the inner surface of the container's peripheral wall due to centrifugal force. In the prior art, a rotation speed of at least about 4000 RPM is typically used to obtain a layer of a certain thickness.

[0061] Focusing on spin freeze-drying, vial 21 rotates relative to axis 23 in the direction indicated by arrow 24. Since vial 21 rotates at high speed, for example 4000 revolutions per minute, the liquid is pressed against the sidewall of vial 21, forming a liquid dispersion with substantially uniform thickness. Subsequently, the liquid dispersion freezes with this uniform thickness.

[0062] In this example, the axis of rotation is oriented vertically, but any other orientation of the axis of rotation can be used, such as horizontally.

[0063] Figure 3 shows two embodiments of a refrigeration process using a flow of cryogenic gas 37. In Figure 3A, the flow of gas 37 is radial, and in Figure 3B, it occurs axially. The flow of cryogenic gas 37 is supplied by system 36. The state of the frozen shell is measured via an optical system 39 that detects electromagnetic radiation in the infrared or far-infrared range 38.

[0064] Figure 4 shows that the temperature of the outer surface of the container wall can be "measured" using a thermal IR camera 41. The camera does not detect temperature itself, but rather detects IR radiation, which can be converted into temperature information using an image processing module. Unlike conventional cameras that capture visible light, it is important to understand that a thermal IR camera does not actually "see inside" the container 40, even if the container is made of glass, and therefore cannot "easily see" its position, for example, when a crystallization front moves. In this regard, it should be noted that while the IR transmittance through, for example, borosilicate glass is not exactly zero, the effective transmittance is typically less than 10%. In this invention, the thermal IR camera 41 measures the temperature of the outer surface of the container 40.

[0065] In fact, this is one reason why it is not straightforward to use a thermal IR camera to determine the temperature of the product inside the container, especially since the camera is positioned to capture a thermal IR image of the outer surface of the container perimeter wall 44 rather than being directed at the product inside the container itself. This is a key difference from some prior art methods, where a thermal IR camera is also used to obtain temperature information, but the camera is directed towards the product itself rather than the outer wall 44 of the container. In other words, in embodiments of the present invention, the product inside the container does not need to be within the camera's field of view 42.

[0066] Thermal images captured by a thermal IR camera, or rather, thermal information extracted from such thermal images, can be used in conjunction with mathematical models to "monitor" the progress of freeze-drying in real time.

[0067] A mechanism model derived from the glass temperature of a vial, which includes compositional information regarding the crystallization front in the composition, uses, for example, the thermal properties of ice, the thermal properties of the specific glass used, the thermal properties of the cooling gas used, and the thermal properties of water as input parameters.

[0068] Measurements are taken for the glass temperature, the flow conditions of the cooling gas, and the temperature of the cooling gas, and these are used as inputs to the mechanism model for calculations.

[0069] The heat transfer characteristics of a flowing gas are determined using known equations and relationships from fluid dynamics. Next, the relationship between the temperature difference between the cooling gas and the glass in the vial, and the gas flow conditions, is determined. From this, the amount of energy transferred per unit time (the amount of power transferred by the cooling gas) can be determined, so that it is possible to determine how much water is converted to ice in a given time. Therefore, due to the concentricity of the composition caused by the rotating cylinder, the position of the crystallization front at a given time can be determined. Finally, from this, the temperature of the crystallization front can be determined.

[0070] Since a change in the position of the crystallization front alters the heat transfer from the vial to the cooling gas, the cooling gas power should be dynamically adjusted in a way that corresponds to the changing heat transfer.

[0071] If materials other than glass are used for the vial, the mathematical model needs to be modified accordingly.

[0072] Furthermore, instead of simply observing what is happening, mathematical models can be used to more efficiently and dynamically control the freezing process, but importantly, as will become even clearer, this does not compromise the quality of the product at any given time.

[0073] Physical phase transitions, crystallization, or melting transitions, respectively, from cooling in the case of freezing or heating in the case of thawing, can be determined using information from thermal measurements, for example, using an IR camera.

[0074] The slope of the temperature-time curve indicates rapid change. Therefore, by continuously determining the value obtained by dividing the temperature change by the time change (slope), the change in this time derivative indicates a change in the process. There are two moments for the start of freezing (nucleation). When the negative slope changes to a positive value, this indicates the start of nucleation. When this positive slope further changes to a small negative slope, this indicates the further start of crystallization. At the end of crystallization, this small negative slope changes to a larger negative slope, indicating the completion of crystallization and further cooling of the crystallized material. A similar explanation is also valid for subsequent phase transitions, such as the crystallization of excipients.

[0075] A similar approach can be applied to thawing. A sudden decrease in the positive gradient indicates that decrystallization is occurring. Once this phase is complete, the gradient increases until the next phase transition (e.g., ice melting) occurs. This phase transition ends when the gradient reaches a higher value.

[0076] By specifying a value corresponding to the indicated moment of change, the system uses this to adaptively set the control parameters for the next phase.

[0077] How image data obtained from a thermal camera can be converted into accurate temperature information is known in the art and therefore does not need to be described in further detail herein. It should suffice to say that this can be achieved, for example, by appropriate calibration and / or by correlating thermal image data with known temperature information, such as other means such as PtlOO probes and / or thermocouples, or other temperature sensing means. The calculation typically involves considering thermal coefficients such as the reflectance coefficient and / or emission coefficient of materials and their surfaces.

[0078] In an alternative embodiment, structural information regarding the formation of ice crystals in the composition during cooling and freezing can be monitored using an optical sensor including a light source configured to emit light in the near-infrared range (0.75–1.4 mm), preferably electromagnetic radiation in the (sub)terahertz range (300 GHz–10 THz). Terahertz radiation facilitates the identification of different polymorphs of the crystal structure. Using this monitoring instrument, which can be applied to each individual vial, the completion of the freezing step and the morphological structure of the crystals can be determined, thereby optimizing the duration of this step. The optical sensor is preferably positioned relative to the vial so as to be able to measure the dispersed layer. In another preferred embodiment, Raman spectroscopy is used to determine the vibrational modes of molecules contained in the composition. Depending on the measurement technique, a laser in the visible, near-infrared, or near-ultraviolet range can be used as the light source, but X-rays can also be used. The laser light can interact with molecular vibrations, phonons, or other excitations in the system, resulting in an up or down shift in the energy of the laser photons. The energy shift provides information about the vibrational modes in the system, and therefore about the state of the system. These vibrational modes can be detected by obtaining spectra that can be characterized using multivariate analysis techniques such as principal component analysis.

[0079] In a preferred embodiment, the gas temperature and flow rate are controlled based on temperature measurements, particularly IR measurements using, for example, a thermal IR camera. In a preferred embodiment, measurements relating to the structure of the composition in the vial (e.g., nucleation, crystallization, decrystallization, melting) are performed using spectroscopic techniques as described above. These measurement methods can be combined with the gas flow rate and temperature to be controlled, along with determining the structural information of the composition. As will be further described below, the structural information of the composition can indicate that a control point has been reached and that a particular control scheme can be terminated or another control scheme can be initiated. In this way, the freezing (and thawing process) described in the present invention can be controlled.

[0080] Figure 5 shows a modified configuration of the arrangement in Figure 4, demonstrating that the thermal IR camera 51 can be mounted in an inclined position, and can be mounted higher or lower relative to the container 50, although this is obviously just one example, and other positions are explicitly shown. The method can be applied, for example, to a cylindrical container that contains a product that is (partially) frozen in the form of a substantially thin layer against the inner wall of the container, in which case at least one thermal IR camera is preferably positioned to capture a large portion of the cylindrical wall of the container.

[0081] For example, the camera may be mounted such that, for practical reasons (e.g., spatial limitations within the device), the thermal image includes a portion of the top or bottom of the container, although data relating to the top and bottom is typically discarded. Such mounting can be used, for example, in arrangements where heat is supplied to the container by one or more IR radiators (not shown in Figure 5) to avoid, for example, a heater being located within the camera's field of view 52, ​​or to avoid undesirable reflections, or for any other reason.

[0082] The camera 51 can be fixedly mounted or movably mounted. In the latter case, the apparatus or system further comprises means (not shown) for moving the camera 51, which may be adapted to move the camera up and down in a plane substantially parallel to the longitudinal axis of the container 50 or substantially perpendicular to the axis of rotation, or to rotate the camera around an axis parallel to the longitudinal axis of the container, or any combination thereof. Such mounting means are known in the art and therefore do not need to be described in detail.

[0083] Moving the camera allows a single camera to monitor at least two or at least three containers, or even more. Where possible, the camera can also be mounted at a sufficiently large distance to allow simultaneous capture of thermal IR images of at least two or at least three containers. Such mounting can be used, for example, in a chamber where space for mounting camera 51 is limited.

[0084] The advantages of using a thermal IR camera are that it allows temperature determination without physical contact with the product, enables capturing multiple temperatures at once (in a single image depending on the camera's resolution), and the measurement is almost instantaneous, reducing the risk of contamination in contrast to, for example, the use of a probe inserted into the product.

[0085] Figure 6 shows possible non-contact measurements 60 of an exemplary freezing cycle, for example, using a thermal IR camera. The horizontal axis 61 represents time, and the vertical axis 62 represents temperature.

[0086] In the first step, (sub)cooling 63 is performed until the start of crystallization (nucleation) 64. The crystallization stage of water 65 shows a temperature that slowly decreases over time in this example. This is because the figure is intended to illustrate the dimensions of the walls of the container holding the product to be freeze-dried. As the ice layer thickens, the temperature of the entire container still decreases because more cold becomes available for the already formed ice, even though crystallization is an exothermic process. After the crystallization stage is complete, further cooling 66 is performed.

[0087] Although annealing or a second crystallization step is not shown in the examples, the present invention is not explicitly limited to the described freezing cycle. A control scheme for effectively controlling all parameters in the freezing cycle described above is described here.

[0088] Figures 7A to 7C show control schemes that should be used by a control system to adaptively control the temperature and flow rate of the cryogenic gas during (sub)cooling, nucleation, and / or crystallization.

[0089] Figure 7A shows the first part of the control scheme. In step 701, spin freezing is initiated. One or more vials containing the product to be freeze-dried are placed in the freeze-dryer, more specifically, in a compartment of the system where sub-cooling is performed. The vials are then rotated using a suitable mechanism known to those skilled in the art. For example, the vials are rotated after being vacuum-suctioned into a holder. Initially, cylindrical vials are rotated at a speed of 2000-4000 rpm. The vials may have shapes other than purely cylindrical. For example, different cross-sections of the vial taken along a rotation axis perpendicular to the axis of rotation may be rotationally symmetric.

[0090] In a preferred embodiment, the vial containing the composition is cooled uniformly. This can be achieved in several ways. For example, the vial can rotate and the cooling gas can be applied to the rotating vial, or the cooling gas supply system can rotate while the vial remains stationary. Another example is a cooling gas supply system shaped to cool the vial uniformly, for example, by a number of gas jets surrounding the vial (at least partially), or by a ring-shaped gas jet. Another method is to cool the vial uniformly over time, i.e., the vial may not be cooled uniformly at a particular moment, but it will be cooled uniformly over a period of time. For example, a number of gas jets can be positioned along a production line, and the vial is then cooled by applying cooling gas from each gas jet positioned at different locations relative to the vial.

[0091] Vials containing the composition do not need to be cooled uniformly; they can be cooled unevenly.

[0092] Preferably, the composition can be rotated so that a relatively thin dispersion layer forms along the walls of the vial, and then frozen. However, forming a relatively thin dispersion layer along the walls of the vial is not essential. The dispersion can be frozen in any form within the vial using a cooling gas.

[0093] In step 702, the gas flow rate is set to a specific value. This value may be a default value, for example, after a calibration freeze cycle has been performed on a similar type of product. Exemplary gas flow rates are between 1 l / min and 500 l / min, and are more preferably adjusted to the size of the container and the amount of substance to be contained.

[0094] Figure 20 shows an exemplary vial that may be used in the present invention. Figure 21 shows a table corresponding to the vials shown in Figure 20, including dimensions of vials having specific R (Rohr) values.

[0095] For a 2R (Rohr value) vial, the exemplary flow rate range may be approximately 1 to 100 l / min. For a 15R vial, the exemplary flow rate range may be approximately 5 to 250 l / min. For a 30R vial, the flow rate range may be approximately 10 to 500 l / min. Preferably, vials with an R value of 10 to 15R are used.

[0096] In a preferred embodiment, the container used in the present invention is a vial used in a pharmaceutical process, for example, a vial commonly used in a lyophilization process. In a preferred embodiment, the vial has a capacity of 2 to 40 ml, preferably less than 30 ml, more preferably less than 20 ml, more preferably less than 10 ml, more preferably less than 5 ml, and more preferably less than 3 ml.

[0097] This method is also applicable to other uses, such as products with beneficial uses for humans and animals, such as plasma. The size and shape of the containers used in these applications can vary depending on the container volume, for example, up to 1 liter, more preferably up to 3 liters, more preferably up to 5 liters, and more preferably up to 10 liters.

[0098] The flow rate range is related to the desire to limit the cooling rate in specific situations, but also to the heat capacity of the vial and its contents. The same applies to setting the crystallization orbit. If the cooling is controlled so that crystallization occurs gradually (usually over a longer period), different crystal sizes and arrangements can be achieved. Since all gas parameters can be controlled in essence, it becomes possible, for example, to rapidly cool, then slow down the cooling during the crystallization stage, and then rapidly cool again after crystallization is complete until the final temperature is reached.

[0099] Generally, the higher the flow rate, the more gas molecules come into contact with one or more vials, allowing the gas to extract heat more effectively from the composition.

[0100] In step 703, the gas temperature is set to a specific value. This value can also be predetermined so that it is determined after a calibration freeze cycle has been performed on a similar type of product. The lower the temperature of the gas used, the more heat is extracted from the composition at the same flow rate.

[0101] In this way, the cryogenic gas is injected onto the rotating vial. The resulting heat transfer cools the vial, and subsequently the products inside.

[0102] By controlling both the gas flow rate and temperature, it is possible to control the gas power exerted on the composition, i.e., the amount of energy transferred or converted from the composition per unit time, thus achieving better control. This is different from simply controlling the temperature of the cooling gas, which is generally less responsive to control changes and therefore more difficult to control.

[0103] Furthermore, modeling the effect of gas temperature on the thermal changes of the composition is more difficult because it directly depends on the amount of energy extracted from the composition and / or vial by the cooling gas. For example, at low flow rates of the cooling gas, the temperature of the cooling gas has less effect on the cooling of the composition being freeze-dried than at high flow rates.

[0104] In this way, the cooling rate of the liquid can be changed, and therefore, the cooling rate of the liquid is a parameter for inducing nucleation. This is because the cooling rate affects the supercooling temperature, cooling the product until the product temperature falls below the crystallization point.

[0105] In step 704, the vial is measured. The wall of the vial can be measured using an infrared thermometer, which is included in the control feedback loop. In this way, the state of the composition and the progress of the cooling stage can be measured.

[0106] In step 705, it is checked whether the composition is still in the liquid phase during cooling. If so, proceed to step 706. Otherwise, proceed to control point A.

[0107] The initiation of ice formation (nucleation) is characterized by a relatively rapid rise in temperature. This can be detected by continuous measurement of the vial temperature during the process. In alternative embodiments, this can also be determined directly using spectroscopic techniques such as NIR, Raman, or terahertz. Spectroscopic techniques are advantageous when structural information of the crystal is also required.

[0108] If the composition remains in the liquid phase during cooling, the control system checks in step 706 whether the temperature of the composition is following the cooling cycle. This can be a default value and may depend, for example, on the time it took for the composition to cool. However, this value does not need to be predetermined, as it can be determined based on the composition's responsiveness to cooling. If the temperature is deemed to be following the cycle, the control system returns to step 704. If the temperature is not following the cooling cycle, the control system proceeds to step 707.

[0109] In step 707, the gas temperature and / or flow rate are adjusted. For example, if the temperature of the composition in step 706 is considered too high and not in accordance with the cycle, the cooling gas temperature is reduced and / or the flow rate is increased. On the other hand, if the temperature of the composition in step 706 is determined to be too low, the cooling gas temperature is increased and / or the flow rate is decreased. The increase or decrease in the cooling gas temperature can be done in constant incremental steps or by changing the rate of change. For example, if the temperature of the composition is considered to be very high or very low in accordance with the freeze cycle, the temperature is reduced or increased more significantly. The flow rate can also control the amount of heat exchanged between the gas and the vial.

[0110] Steps 704-707 are repeated until the control system reaches control point A. At control point A, the composition is considered not to be in the liquid cooling phase, i.e., nucleation has occurred, which signifies the start of crystallization of the composition.

[0111] This initiation can be actively influenced by inducing condensation nuclei or by inducing an artificial density gradient in the liquid by sound waves or pressure waves. This can be done in many ways, for example, by inducing high-frequency rotational fluctuations, which lead to pressure waves in the fluid that induce nucleation promoters. For example, the rotational speed can be decelerated and / or accelerated to induce pressure waves in the fluid. In addition to mechanical inducers, thermal shock can be caused by rapid changes in the cryogenic gas jet, for example, changes in the temperature or flow rate of the cooling gas.

[0112] In this way, the temperature at which nucleation can begin can be influenced and therefore controlled, which also leads to the detailed control of the ice structure that initiates crystallization after nucleation has occurred.

[0113] Therefore, in a preferred embodiment of the present invention, the process includes a step of influencing nucleation by inducing an artificial density gradient in a liquid.

[0114] Referring to Figure 7B, after the start of crystallization, in step 711, the vial is measured, for example, in the same manner as in step 704. Thus, information regarding the temperature of the vial and the composition, as well as the state of the composition during the crystallization stage, can be obtained.

[0115] In step 712, the control system checks whether the composition is in the crystallization stage. This check can be performed at least in part based on the measurement in step 711. If the composition is no longer in the crystallization stage, the control system proceeds to control point B.

[0116] If the control system determines in step 712 that the crystallization stage is still in progress, it proceeds to step 713.

[0117] In step 713, the cooling gas flow rate is set. This can be done in the same way as in step 702. The gas flow rate is set to a specific value that may be a default value for the crystallization stage, such as after a calibration freeze cycle has been performed on a similar type of product. An example gas flow rate is 1 l / min to 500 l / min, and is more preferably adjusted to the size of the container and the amount of material to be contained, for example, as described above.

[0118] In step 714, the cooling gas temperature and / or flow rate are set. This can be done in the same way as in step 703. This value can also be predetermined for the crystallization step so that it is determined after a calibration freeze cycle has been performed for a similar type of product.

[0119] In step 715, the control system waits for a predetermined time to allow the cooling gas to act on the composition and crystallization to continue. After the predetermined time has elapsed, the control step proceeds to step 711, where the vial is measured again. Steps 711-715 are repeated until control point B is reached.

[0120] Since crystallization is an exothermic process, the removal of necessary heat can be controlled to reduce variations between vials. Furthermore, the rate of the crystallization process can be controlled to reduce stress on unstable components at this stage. Therefore, energy transfer from the vial to the cold gas flow can be controlled at this stage to overcome these problems. This can be done by controlling the temperature and / or flow rate of the cooling gas. The flow rate controls the efficiency of heat transfer to the cooling gas. Energy dissipation due to crystallization can thus be controlled along with the process parameters of cooling gas temperature and (process) time. Therefore, the rate of heat removal during crystallization can be changed. Initially, this may be simply ice, but during later crystallization stages, it may be the crystallization of excipients in the composition.

[0121] At control point B, the crystallization stage is considered complete. Next, the control system proceeds to step 721.

[0122] Referring to Figure 7C, from step 721 onward, the solid composition is further cooled. At this stage, the final shape and size of the ice crystals are determined by a process called Ostwald aging. In this already solid phase, other excipients in the formulation may induce crystallization, potentially leading to another cycle of crystallization control. This, too, can be associated with temperature control of the cryogenic gas or flow rate control of the cryogenic gas, including vial temperature within the control loop.

[0123] It should be noted that in this embodiment, only a single crystallization stage occurs. Depending on the composition, multiple crystallization stages may occur. If two or more crystallization stages occur, the control system can continue to control point A, and steps 711 to 715 are repeated until control point B is reached again. The gas flow rate and / or gas temperature, as well as the process time, may differ for different crystallization stages.

[0124] In step 721, the gas flow rate is adjusted. The gas flow rate can be set to a specific value, which can be a default value for further cooling stages and can be based on a calibration freeze cycle performed for a similar type of product. Exemplary gas flow rates are 1 l / min to 500 l / min and are more preferably adjusted to the size of the container and the amount of substance to be contained, as described above, for example.

[0125] In step 722, the vial is measured, for example, in the same manner as in step 704 and / or step 711. Thus, information regarding the temperature of the vial and the composition, as well as the state of the composition during the crystallization stage, can be obtained.

[0126] Next, in step 723, the control system checks whether the temperature is following a further cooling cycle. This can be done in the same manner as in step 706. The temperature value that the composition and / or vial should have may be a predetermined value and may depend, for example, on the time it took for the composition to cool. However, this value does not need to be predetermined, as it can be determined based on the composition's responsiveness to further cooling. If the temperature is following the cycle, the control system proceeds to step 725.

[0127] If the temperature is not in accordance with the cycle, the control system first proceeds to step 724. In step 724, the cooling gas temperature and / or flow rate are adjusted. This can be done in the same manner as in step 707. For example, if the temperature of the composition in step 723 is not in accordance with the cycle and is considered too high, the cooling gas temperature is lowered. On the other hand, if the temperature of the composition is determined to be too low in step 723, the cooling gas temperature is increased. The increase or decrease in the cooling gas temperature can be done in constant incremental steps or by changing the rate of change. For example, if the temperature of the composition is considered to be very high or very low according to the freeze cycle, the temperature is lowered or raised more significantly. Similarly, the flow rate can be adjusted; increasing the flow rate of the cooling gas increases the cooling rate, and decreasing the flow rate decreases the cooling. Next, the control system proceeds to step 725.

[0128] In step 725, the control system measures the vial in the same manner as in steps 722, 704, and / or 711, for example. Thus, information regarding the temperature of the vial and the composition, as well as the state of the composition during the crystallization stage, can be obtained.

[0129] In step 726, the control system checks whether the final temperature has been reached after further cooling. This is the final temperature for the entire freezing cycle. If the final temperature has not been reached, the control system proceeds to step 723 and repeats steps 723-726 until the final temperature is reached.

[0130] If the final temperature is reached, in step 727 the composition is considered ready and the freezing cycle is completed. The formation of the final ice structure can be modified by performing steps 721 to 727. For example, the specific surface area of ​​the ice structure, the shape of the ice crystals, and / or the way in which the ice crystals are bridged can be changed by performing steps 721 to 727.

[0131] The control schemes shown in Figures 7A to 7C can be implemented entirely by a control system or only partially. Figure 7A illustrates the initial cooling stage before nucleation occurs. Figure 7B illustrates the control between one or more crystallization stages. Figure 7C illustrates further cooling stages. The more parts of the control scheme are implemented, the more control is obtained over the freezing process. Implementing the control scheme at least partially yields one or more of the following advantages: (I) the rate of liquid cooling can be varied and used as one parameter of induced nucleation; (II) the temperature at which nucleation can begin can be varied, which can also lead to detailed control of the ice structure; (III) the rate of heat removal during crystallization can be varied (initially only for ice, but later also for the crystallization of excipients); (IV) the formation of the final ice structure can be varied.

[0132] Figures 8 to 10 schematically illustrate three alternative examples of a gas cooling system. A gas cooling system generally has an input gas to be cooled and an output cooling gas that can be used to cool a composition in a freeze-drying system. Furthermore, a gas cooling system can be used in conjunction with the control systems and control schemes for freezing in the freeze-drying systems described herein. However, a gas cooling system can be used with any freeze-drying system that uses a cooling gas to cool a composition to be freeze-dried.

[0133] Figure 8 schematically shows a first alternative example of the gas cooling system 800.

[0134] Gas 801, used as a cooling gas, is inserted into the gas inlet pipe 804A. Gas 801 is preferably an inert gas, such as nitrogen. The gas must be completely free of (dust) particles (live and non-live) to prevent contamination of the vial contents. The inflow rate of gas 801 can be controlled by valve 802. This can be, for example, a gate valve with a pneumatic membrane actuator, but any valve known to those skilled in the art can be used. A temperature sensor 803 is used to determine the temperature of the inflow gas 801. Those skilled in the art can use any suitable temperature sensor 803, such as a Pt100 temperature sensor or a resistance temperature detector. Gas 801 is generally not cold enough for use in the freeze-drying process and needs to be cooled before use.

[0135] The inlet pipe 804A branches into a primary pipe 804B and a secondary pipe 804C. The gas flowing through the primary pipe 804B flows through a heat exchanger 806. This heat exchanger is immersed in a liquid nitrogen bath 809.

[0136] The liquid nitrogen bath 809 has an inlet pipe 808 through which liquid nitrogen 807 flows into the bath. The liquid nitrogen extracts heat from the gas 801 via a heat exchanger 806. The liquid nitrogen evaporates due to the extracted heat and is extracted as evaporated nitrogen 811 from the outlet pipe 810.

[0137] The heat exchanger 806 can be, for example, a wound structure, a helical structure, or any other structure that allows heat exchange between liquid nitrogen and gas 801. An important consideration is that the contact surface between the primary piping 804B and the liquid nitrogen bath 809 should be as large as possible to maximize the amount of heat exchanged in the heat exchanger 806.

[0138] After the heat exchanger 806, the primary piping 804B is joined to the secondary piping 804C. The secondary piping does not need to pass through the heat exchanger 806 and, in fact, does not need to undergo any substantial cooling.

[0139] The flow rate of gas 801 flowing through secondary piping 804C can be controlled via valve 805, which can be the same type of valve as valve 802 or a different type of valve.

[0140] The primary piping 804B and the secondary piping 804C merge in the gas 801 outlet piping 804D. A temperature sensor 812, similar to or different from the temperature sensor 803, measures the gas flowing through the outlet piping 804D. If the temperature of the cooling gas 813 exiting the outlet piping 804D is too high, the valve 805 of the secondary piping 804C is (further) closed to force more gas 801 through the heat exchanger 806 by a percentage, thus obtaining a cooler cooling gas 813. Similarly, if the temperature of the cooling gas 813 exiting the outlet piping 804D is too low, the valve 805 of the secondary piping 804C is (further) opened to force less gas 801 through the heat exchanger 806 by a percentage, thus obtaining a warmer cooling gas 813.

[0141] As mentioned, valve 802 controls the flow rate of gas 801 flowing into the gas cooling system. Therefore, valve 802 also controls the flow rate of cooling gas 813 flowing out of the cooling system.

[0142] Therefore, the gas cooling system 800 allows the operator and / or control system to continuously control both the flow rate and temperature of the cooling gas as needed.

[0143] Figure 9 schematically shows a second alternative example of the gas cooling system 900. The second gas cooling system 900 operates according to the same principles as the first gas cooling system 800, with a few exceptions which will be described in more detail below.

[0144] Gas 901, which is to be used as a cooling gas, is inserted into the gas inlet pipe 904. The inflow rate of gas 901 can be controlled by valve 902. A temperature sensor 903 is used to determine the temperature of the inflow gas 901. Gas 901 is generally not cold enough for use in freeze-drying processes and needs to be cooled before use.

[0145] The gas flowing through pipe 904 flows through heat exchanger 906. This heat exchanger is immersed in liquid nitrogen bath 909.

[0146] The liquid nitrogen bath 909 has an inlet pipe 908 through which liquid nitrogen 907 flows into the bath. The liquid nitrogen extracts heat from the gas 901 via a heat exchanger 906. The liquid nitrogen evaporates due to the extracted heat and is extracted as evaporated nitrogen 911 from the outlet pipe 910.

[0147] Next, the gas flows through a heating element 905, which may or may not heat the gas coming out of the heat exchanger 906. A temperature sensor 912, similar to or different from the temperature sensor 903, measures the gas flowing through the piping after the heating element 905. If the temperature of the cooling gas 913 coming out of piping 804 is too high, the heating element 905 does not heat the gas too much. Similarly, if the temperature of the cooling gas 913 coming out of piping 904 is too low, the heating element 905 heats the gas more. In this way, the temperature of the cooling gas 913 flowing out of the gas cooling system 900 can be controlled.

[0148] As mentioned, valve 902 controls the flow rate of gas 901 flowing into the gas cooling system 900. Therefore, valve 902 also controls the flow rate of cooling gas 913 flowing out of the cooling system.

[0149] Therefore, the gas cooling system 900 also allows the operator and / or control system to control both the flow rate and temperature of the gas cooling system 900.

[0150] To replace the bath with liquid nitrogen, other cryogenic coolants can be considered. One such alternative is the application of dry ice (solid carbon dioxide) suspended in ethanol to reach -79°C. The use of such higher cryogenic temperatures may be advantageous when a low cooling rate or a slow crystallization process is required.

[0151] Figure 10 schematically shows a third alternative example of the gas cooling system 1000.

[0152] In the freeze-drying process, gas 1001, used as a cooling gas, enters the gas cooling system 1000 through the gas inlet pipe 1003. The inflow rate of gas 1001 can be controlled by valve 1002. In this case as well, gas 1001 is generally not cold enough for use in the freeze-drying process and needs to be cooled before use.

[0153] Gas 1001 enters the cooling chamber 1009. Gas 1001 is cooled in the cooling chamber 1009 by injecting liquid nitrogen 1004 into the cooling chamber 1009 via the inlet pipe 1006 and ejector 1007. The flow rate of liquid nitrogen 1004 can be controlled via valve 1005.

[0154] The ejector 1007 can carry liquid nitrogen 1004 in a high-speed jet. In this way, small droplets of liquid nitrogen 1004 enter the cooling chamber 1009 and exchange heat with the gas 1001 to be cooled. That is, the gas 1001 heats the liquid nitrogen 1004, and as a result, the gas 1001 is cooled. In this way, the liquid nitrogen 1004 becomes nitrogen gas.

[0155] The injector 1007 can form liquid nitrogen 1004 into tiny droplets, increasing the contact surface and promoting heat exchange. However, this is not essential. The liquid nitrogen 1004 can simply come into direct contact with the cooling gas 1001, and heat exchange can still occur.

[0156] The obtained gas exits the cooling chamber via the outlet pipe 1010. The gas then flows through a heating element 1011, which may or may not heat the gas exiting the cooling chamber 1009. A temperature sensor 1012 measures the gas 1013 flowing through the outlet pipe 1010 after the heating element 1011. Similar to the second alternative example of the gas cooling system 900, the temperature sensor 1012 measures the outlet gas 1013 and determines whether the heating element 1011 needs to heat the gas 1013. In this way, the temperature of the cooling gas 1013 exiting the gas cooling system 1000 can be controlled.

[0157] As mentioned, valve 1002 controls the flow rate of gas 1001 flowing into the gas cooling system 1000. Valve 1005 controls the flow rate of liquid nitrogen 1004 flowing into the gas cooling system 1000. Thus, both valves control the flow rate of cooling gas flowing out of the cooling system 1000.

[0158] As the cooling gas, it is best to use an inert gas that does not react with the liquid nitrogen injected into the cooling chamber 1009. Preferably, the cooling gas is nitrogen gas.

[0159] Any number of gas cooling systems 800, 900, and / or 1000 can be combined to deliver cryogenic cooling gas to any part of the freeze-drying system at the required flow rate. Furthermore, while liquid nitrogen was used as the cooling gas for the gas to be cooled in the above embodiment, it is not limited to this, and other suitable coolants can be used.

[0160] Figure 11 schematically shows the spin freeze-drying system 1100, in which the exhaust gas from the freeze-drying step is reused to conditioned the double-walled chamber.

[0161] The spin freeze-drying system 1100 comprises a spin freeze chamber 1103, an annealing chamber 1104, and a sublimation chamber 1105. The exhaust gas 1101 used for spin freeze enters a double-wall structure 1102. The double-wall structure 1102 can be, for example, a piping system wrapped around the spin freeze chamber 1103. In this way, the walls of the freeze chamber 1103 are cooled using the exhaust gas 1101.

[0162] The typical temperature of exhaust gas from spin freezing is approximately -90°C. By reusing the clean, low-temperature gas coming from the spin freezing chamber, this gas is not wasted. This is beneficial because energy was expended to obtain gas cold enough for spin freezing. Furthermore, cooling the walls of the spin freezing chamber reduces the energy expended to cool the composition.

[0163] The first connecting pipe 1106 connects the double-wall structure 1102 of the spin-freezing chamber 1103 to the double-wall structure of the annealing chamber 1104. Thus, the double-wall structure of the annealing chamber 1104 cools its walls using the remaining cryogenic gas used in the double-wall structure 1102 of the spin-freezing chamber 1103. The typical temperature of the exhaust gas in the first connecting pipe 1106 is about -60 degrees Celsius, and the exhaust gas is heated by cooling the walls of the spin-freezing chamber 1103.

[0164] The second connecting pipe 1107 connects the double-walled structure of the annealing chamber 1104 to the double-walled structure of the sublimation chamber 1105. Thus, the double-walled structure of the annealing chamber 1105 is cooled using the remaining cryogenic gas used in the double-walled structure 1102 of the spin-freezing chamber 1103 and the double-walled structure of the annealing chamber 1104. The typical temperature of the exhaust gas in the second connecting pipe 1107 is approximately -40 degrees Celsius, and the exhaust gas is heated by cooling the walls of the spin-freezing chamber 1103 and the annealing chamber 1104.

[0165] The spin freeze-drying system 1100 has a double-wall structure for the spin freeze chamber, annealing chamber, and sublimation chamber, but any combination of these chambers can have a double-wall structure. Furthermore, the double-wall structure does not need to be connected in a continuous manner and can be connected in parallel to the exhaust section of the spin freeze chamber. Not only can the exhaust gas from the spin freeze chamber be used, but any other coolant used in freeze-drying can be used. For example, the evaporative liquid nitrogen 811, 911 used in the first and second alternative examples of the gas cooling systems 800, 900 can be used to cool the chamber walls of the spin freeze-drying system 1100.

[0166] By using the excess cold air from the coolant of the spin-freezing system, the walls of the different chambers used during freeze-drying can be cooled. In this way, energy is conserved.

[0167] Since the chamber can have a double-wall structure, other permeable gases and fluids can also be used to control the temperature of the chamber walls. This can be advantageous when rapid cooling of the chamber walls is required after a sterilization process with saturated steam at temperatures above 121°C.

[0168] Figures 12A and 12B schematically show a cross-section of the double-wall structure 1202.

[0169] In Figure 12A, the double-wall structure comprises a piping system having a spirally wound channel 1203A. The coolant 1201 moves through the spirally wound channel 1203A. In this way, the double-wall structure 1202 cools the walls of the chamber it surrounds. As shown in Figure 11, this coolant can also be a reusable exhaust cooling gas.

[0170] In Figure 12B, the double-wall structure includes a piping system having a meandering channel 1203A. The coolant 1201 moves through the spirally wound channel 1203A.

[0171] Helical and meandering channels are examples of piping layouts in a double-walled structure. Other layouts can also be used. Preferably, the contact surface between the freeze-drying system and the inner wall of the chamber can be maximized to maximize heat exchange between the coolant 1201 and the inner wall of the chamber. As shown in Figure 11, this coolant can also be a reusable exhaust cooling gas.

[0172] Figure 13 schematically shows a first heat exchanger 1300 that can be used to pre-cool the gas to be used as a cooling gas in a spin freeze dryer.

[0173] The first piping system 1302 and the second piping system 1305 are brought into thermal contact. The first piping system 1302 can be wrapped around the second piping system 1305. The first piping system 1302 can transport gas 1301 to be pre-cooled by the heat exchanger 1300. The second piping system 1305 can transport gas 1304 coming from the exhaust of the spin freeze chamber of the spin freeze-drying system. For example, gas 1304 has been previously used to freeze the composition to be freeze-dried. Gas 1304 may also be used in other parts of the freeze-drying system. The gas 1301 to be pre-cooled may be, for example, sterile nitrogen gas.

[0174] Due to thermal contact between the first piping system 1302 and the second piping system 1305, heat is exchanged between the warmer gas 1301 to be pre-cooled and the cooler gas 1304 coming into the spin freeze dryer system. As a result, the warmer gas 1301 is cooled to become the pre-cooled gas 1303, and the cooler gas 1304 is heated to become gas 1306, which can then be used to cool other parts of the spin freeze dryer system or to pre-cool the gas to be used as a cooling gas within the spin freeze dryer.

[0175] The pre-cooled gas 1303 can be further cooled by a gas cooling system, such as the first, second, and third alternative examples of the gas cooling systems 800, 900, and 1000. Other methods can be used to further cool the gas to a suitable temperature so that the gas can be used to freeze the composition to be freeze-dried.

[0176] Figure 14 schematically shows a second heat exchanger 1400 that can be used to pre-cool the gas used as a cooling gas in a spin freeze dryer.

[0177] The gas 1401 to be pre-cooled is transported along the first piping system 1402. The second piping system 1405 is formed to at least partially surround the first piping system 1402. For example, the cooling gas 1404 from the exhaust of the spin freeze chamber of a spin freeze-drying system is transported along the second piping system 1405. Heat is exchanged between the cooling gas 1404 and the gas 1401 due to thermal contact between the first piping system 1402 and the second piping system 1405.

[0178] The gas 1403 exiting the first piping system 1402 is pre-cooled and can be further cooled by a gas cooling system, such as the first, second, and third alternative examples of the gas cooling systems 800, 900, and 1000. Other methods can be used to further cool the gas to a suitable temperature so that the gas can be used to freeze the composition to be freeze-dried.

[0179] The gas 1406 exiting the second piping system is generally warmer than the cooling gas 1404 entering the second piping system. If the gas 1406 exiting the second piping system is still sufficiently cold for other applications within the spin freeze-drying system, the gas 1406 can be further used to cool the components or coolant.

[0180] In another embodiment, the compressor-driven cooling circuit can be used in conjunction with a heat exchanger to cool the gas to be used as a cooling gas for the composition to be freeze-dried. In this case, exhaust gas from a specific part of the spin freeze-dryer can be used to provide cooling to the compressor system used in the compressor-driven cooling circuit.

[0181] The compressor operates according to the Carnot cycle. The gas is compressed into a liquid state (in this step, the temperature of the gas also rises). Next, the compressed liquid is cooled using a heat exchanger and coolant. Then, the liquid is evaporated and expanded, extracting heat from the object that needs to be cooled. Next, the expanded gas is compressed again in a repeating cycle. The object that needs to be cooled may be a freezing chamber, a sublimation chamber, an annealing chamber, or a cooling fluid. Thus, the exhaust gas from the freezing chamber can be used to cool the compressed liquid in this cycle.

[0182] It should be noted that the application of induced nucleation by external means, such as gas, generally presents further challenges regarding Good Manufacturing Practice (GMP) requirements. For example, all ducts and piping used can be included in the system's sterilization process. Using mechanical means to induce localized density changes can lead to increased particle generation. Therefore, it may be important to ensure a (strictly) directional flow of the cooling gas so that these particles are carried to the exhaust without entering the vicinity of the vial opening. In this way, contamination can be avoided.

[0183] Vials containing the freezing material can be used in the next step of the freeze-drying process. This freeze-drying process may be a conventional process that simply applies vacuum while increasing the temperature of the vacuum chamber. When vials containing the freezing material are used in a freeze-drying process, such a process is preferably a controlled freeze-drying process, such as the one described in International Publication No. 2018 / 033468(A1).

[0184] In other applications, vials containing frozen material can be used as is until the material thaws. Vials containing frozen material can be stored for longer periods, such as one day, one week, or even one month or several months. During this time, the frozen material can be transported to another location while being kept frozen by cooling it with, for example, liquid nitrogen or solid carbon dioxide.

[0185] Freeze-drying is often performed on proteins, but freeze-drying and / or freeze-thawing is preferably performed on a mixture of living cells in an aqueous medium.

[0186] Thawing is typically performed on frozen compositions containing crystallization excipients and ice. For example, the frozen composition being thawed may be the result of a freezing cycle as described above.

[0187] The thawing cycle can be carried out within a thawing chamber. The configuration of the thawing chamber may be similar to the configuration schematically shown in Figure 3A or Figure 3B. However, instead of using a cooling gas, generally, a gas that is relatively warmer than the vial containing the composition and / or frozen composition is used to heat the composition. In this way, when the heating gas reaches the vial containing the frozen composition, heat is extracted from the heating gas and supplied to the vial and subsequently to the composition. The gas can be an inert gas such as nitrogen, but other inert gases such as argon or helium may also be used. Carbon dioxide gas may also be used depending on the composition of the contents in the vial.

[0188] By rotating the vial containing the composition, heat is applied uniformly to the composition. Therefore, in a preferred embodiment, the composition can be rotated and heated by a heating gas flow.

[0189] As mentioned, in a preferred embodiment, the vial containing the composition is heated uniformly. This can be achieved in several ways. For example, the vial can rotate and the heating gas can be applied to the rotating vial, or the heating gas supply system can rotate while the vial remains stationary. Another example is a heating gas supply system that is shaped to heat the vial uniformly, for example, by a number of gas jets surrounding the vial (at least partially), or by a ring-shaped gas jet. Another method is to heat the vial uniformly over time, i.e., the vial may not be heated uniformly at a particular moment, but it is heated uniformly over a period of time. For example, a number of gas jets can be positioned along a production line, and the vial is subsequently heated by applying heating gas from each gas jet positioned at different locations relative to the vial.

[0190] Vials containing the composition do not need to be heated uniformly; they can be heated unevenly.

[0191] Figure 15 shows an exemplary thawing cycle. The horizontal axis 1501 represents time, and the vertical axis 1502 represents temperature.

[0192] In the first step, the composition is rapidly heated to a first eutectic point (1503). At this point, which is the lowest possible melting temperature of the component species involved, one of the excipients begins to decrystallize.

[0193] During the decrystallization time 1508 of the excipient, the excipient subsequently decrystallizes 1504. The length of the decrystallization time 1508 can be controlled as further described below.

[0194] Next, the composition is rapidly heated so that its temperature reaches the melting point of ice (1505). During the melting time 1509, the ice in the composition melts 1506. The length of the melting time 1509 can also be controlled as described further below.

[0195] If the composition is in a completely liquid state, the composition can be further rapidly heated (1507) to reach the final temperature.

[0196] Figures 16A to 16E show control schemes 1600A to E used by the control system to adaptively control the temperature and flow rate of the cryogenic gas during the thawing of the frozen product.

[0197] Figure 16A shows a portion of the control scheme 1600A that can be applied, for example, during the rapid heating stage 1503 of the thawing cycle.

[0198] In step 1601, the gas flow rate is set to a specific value. This value may be a default value, such as after a calibration thawing cycle has been performed on a similar type of product. Exemplary gas flow rates are between 1 l / min and 500 l / min, and are more preferably adjusted to the size of the container and the amount of substance to be contained. A faster flow rate allows more gas molecules to come into contact with one or more vials, thus heating the composition more effectively.

[0199] In step 1602, the gas temperature is set to a specific value. This value can also be predetermined so that it is determined after a calibration thawing cycle has been performed on a similar type of product. The warmer the gas used, the more heat is added to the composition for the same flow rate.

[0200] Therefore, a relatively warm gas is injected onto the vial containing the composition. The resulting heat transfer heats the vial and subsequently the product inside. Preferably, the vial is rotated to obtain an optimal heat distribution throughout the vial.

[0201] In step 1603, the vial is measured. The wall of the vial can be measured using an infrared thermometer (as described above in Figures 4 and 5), which is included in the control feedback loop. In this way, the state of the composition and the progress of the heating stage can be measured.

[0202] In step 1604, it is checked whether the composition has reached its eutectic point, at which point one of the excipients begins decrystallization. If so, the process continues at control point A. Otherwise, the process proceeds to step 1605.

[0203] If the composition has not yet reached its eutectic point during heating, the control system checks in step 1605 whether the temperature of the composition is following the thaw cycle. This can be a predetermined value and may depend, for example, on the time spent heating the composition. However, this value does not need to be predetermined, as it can be determined based on the composition's responsiveness to heating. If the temperature is deemed to be following the cycle, the control system returns to step 1603. If the temperature is not following the thaw cycle, the control system proceeds to step 1606.

[0204] In step 1606, the gas temperature and / or flow rate are adjusted. For example, if the temperature of the composition in step 1605 is not in line with the cycle and is considered too low, the heating gas temperature is increased. The increase or decrease in the heating gas temperature can be done in constant incremental steps or by changing the rate of change.

[0205] Steps 1603-1606 are repeated until the control system reaches control point A. At control point A, the composition is considered to have reached its eutectic point, at which point one of the excipients begins decrystallization. A predetermined time may have elapsed between step 1606 and step 1603.

[0206] Figure 16B shows, for example, a portion of a control scheme 1600B that can be applied during the excipient decrystallization step 1504 of the thawing cycle.

[0207] In step 1611, the gas flow rate is set to a specific value. This value may be a default value, such as after a calibration thawing cycle has been performed on a similar type of product.

[0208] In step 1612, the gas temperature is set to a specific value. This value can also be predetermined so that it is determined after a calibration thawing cycle has been performed on a similar type of product.

[0209] In step 1613, the vial is measured. The wall of the vial can be measured using an infrared thermometer, which is included in the control feedback loop. In this way, the state of the composition and the progress of the heating stage can be measured.

[0210] In step 1614, it is checked whether the composition contains a crystallization excipient at that point. If the composition no longer contains a crystallization excipient, the control scheme continues at control point B. Otherwise, the control scheme proceeds to step 1615.

[0211] If the composition still contains a crystallization excipient, the control system controls the flow rate of the heating gas in step 1615. This control may be based on measuring the temperature of the composition to check whether the temperature of the composition is following the decrystallization stage, or on a predetermined control function.

[0212] In step 1616, the temperature of the heating gas is controlled. This can be done, for example, based on a separate temperature measurement, such as the one performed in step 1615, or based on a predetermined control function.

[0213] Steps 1613-1616 are repeated until control point B is reached and the excipient decrystallizes. A predetermined amount of time may have elapsed between step 1616 and step 1613.

[0214] Figure 16C shows, for example, a portion of a control scheme 1600C that can be applied during the heating stage 1505 before the ice melts in a thawing cycle.

[0215] In step 1621, the gas flow rate is set to a specific value. This value may be a default value, such as after a calibration thawing cycle has been performed on a similar type of product.

[0216] In step 1622, the gas temperature is set to a specific value. This value can also be predetermined so that it is determined after a calibration thawing cycle has been performed on a similar type of product.

[0217] In step 1623, the vial is measured. The wall of the vial can be measured using an infrared thermometer, which is included in the control feedback loop. In this way, the state of the composition and the progress of the heating stage can be measured.

[0218] In step 1624, it is checked whether the ice in the composition has begun to melt. If the ice in the composition has begun to melt, the control scheme continues at control point C. Otherwise, the control scheme proceeds to step 1625.

[0219] If the ice contained in the composition does not begin to melt, the control system controls the flow rate of the heating gas in step 1625. This control may be based on a temperature measurement of the composition or on a predetermined control function to check whether the temperature of the composition is conforming to the heating stage.

[0220] In step 1626, the temperature of the heating gas is controlled. This can be done, for example, based on a separate temperature measurement, such as the one performed in step 1625, or based on a predetermined control function.

[0221] In step 1627, the temperature of the vial is measured and checked to see if the temperature is in accordance with the heating stage. If the temperature is appropriate, the control scheme continues in step 1623; otherwise, the gas temperature and / or gas flow rate are adjusted in step 1628. A predetermined amount of time may have elapsed between step 1628 and step 1623.

[0222] Steps 1623-1628 are repeated until control point C is reached and the ice in the composition begins to melt.

[0223] Figure 16D shows, for example, a portion of a control scheme 1600D that can be applied during the ice melting phase 1506 of the thawing cycle.

[0224] In step 1631, the gas flow rate is set to a specific value. This value may be a default value, such as after a calibration thawing cycle has been performed on a similar type of product.

[0225] In step 1632, the gas temperature is set to a specific value. This value can also be predetermined so that it is determined after a calibration thawing cycle has been performed on a similar type of product.

[0226] In step 1633, the vial is measured. The wall of the vial can be measured using an infrared thermometer, which is included in the control feedback loop. In this way, the state of the composition and the progress of the ice melting stage can be measured.

[0227] In step 1634, it is checked whether the composition contains ice in its dictionary. If the composition no longer contains ice, the control scheme continues at control point D. Otherwise, the control scheme proceeds to step 1635.

[0228] If the composition still contains a crystallization excipient, the control system controls the flow rate of the heating gas in step 1635. This control may be based on measuring the temperature of the composition to check whether the temperature of the composition is following the decrystallization stage, or on a predetermined control function.

[0229] In step 1636, the temperature of the heating gas is controlled. This can be done, for example, based on a separate temperature measurement, such as the one performed in step 1635, or based on a predetermined control function.

[0230] Steps 1633-1636 are repeated until control point D is reached and the ice in the composition melts. A predetermined amount of time may have elapsed between step 1636 and step 1633.

[0231] Figure 16E shows, for example, a portion of a control scheme 1600E applicable during the final heating stage 1507 after the ice contained in the composition has melted during the thawing cycle.

[0232] In step 1641, the gas flow rate is set to a specific value. This value may be a default value, such as after a calibration thawing cycle has been performed on a similar type of product.

[0233] In step 1642, the gas temperature is set to a specific value. This value can also be predetermined so that it is determined after a calibration thawing cycle has been performed on a similar type of product.

[0234] In step 1643, the vial is measured. The wall of the vial can be measured, for example, using an infrared thermometer, which is included in the control feedback loop. In this way, the state of the composition and the progress of the heating stage can be measured.

[0235] In step 1644, it is checked whether the composition has reached its serving temperature. This is the temperature target for the thawing cycle of this particular composition. If the serving temperature has been reached, the control scheme continues at control point C, and the product is ready for use. For example, the product can be extracted from the thawing chamber and processed further. Otherwise, the control scheme proceeds to step 1645.

[0236] If the operating temperature has not yet been reached, the control system controls the flow rate of the heating gas in step 1645. This control may be based on a temperature measurement of the composition or on a predetermined control function to check whether the temperature of the composition is in accordance with the heating stage.

[0237] In step 1646, the temperature of the heating gas is controlled. This can be done, for example, based on a separate temperature measurement, such as the one performed in step 1645, or based on a predetermined control function.

[0238] In step 1647, the temperature of the vial is measured and checked to see if the temperature is in accordance with the heating stage. If the temperature is appropriate, the control scheme continues in step 1643; otherwise, the gas temperature and gas flow rate are adjusted in step 1648.

[0239] Steps 1643-1648 are repeated until control point E is reached, and the composition is ready for use. A predetermined amount of time may have elapsed between step 1648 and step 1643. The thawing cycle is complete when control point E is reached.

[0240] Control schemes 1600A to 1600E can be combined to control a complete thawing cycle, or they can be applied only partially to control a portion of the thawing cycle for a particular composition. It is possible that two or more excipients in a particular composition may decrystallize, in which case control schemes 1600A to 1600B can be repeated as many times as necessary.

[0241] Figure 17 schematically shows a gas cooling / heating system that applies the gas cooling system shown in Figure 8. The primary piping 804B may have a separate valve for adjusting the flow rate of gas flowing into the heat exchange element 806. For example, the gas flow rate flowing into the heat exchange element 806 can be set to 0. In this way, only gas 801 flows through the secondary piping 804C.

[0242] The heating element in the outlet pipe 804D can raise the temperature of the gas 813 flowing out of the gas cooling / heating system so that the temperature of the gas 813 flowing out of the gas cooling / heating system is suitable for use in the thawing cycle. The temperature sensor 812 can control the temperature of the gas 813 that should be used as the heating gas in the thawing cycle.

[0243] The heating element can adjust the amount of power applied to the exhaust gas so that the amount of heating performed by the heating element can be controlled.

[0244] Similarly, Figure 10 can be used as a gas heating system by stopping the inflow of liquid nitrogen at the top by closing valve 1005 and heating the gas flowing into the system through piping 1003 by heating element 1011.

[0245] Figure 18 shows a schematic representation of the gas heating system 1800.

[0246] The gas to be heated flows into the pipe 1803. Valve 1802 controls the flow rate of gas 1801 flowing through the pipe 1803. Temperature sensor 1804A can measure the temperature of gas 1801 before it is heated by the heating element 1805. After the heating element 1805, temperature sensor 1804B can be placed to measure the temperature of the gas after it has been heated by the heating element 1805 and to control the heating element 1805. By comparing the temperature readings of the two temperature sensors 1804A and 1804B, the heating element 1805 can be controlled more effectively. One or more heating elements can be placed thereafter along the gas flow path. Gas 1806 is heated to a specific temperature so that the heated gas can be used in a thawing cycle for a specific temperature setting and a specific flow rate of gas 1806.

[0247] It should be noted that the gas still contains energy in the form of heat that can be reused after being used as a heating gas in the thawing chamber.

[0248] Figure 19 schematically shows the thawing system, in which exhaust gases from the thawing cycle are reused to conditioned the double-walled chamber of the thawing chamber.

[0249] The exhaust gas from the thawing chamber 1901 flows into a double-wall structure 1902 that at least partially surrounds the thawing chamber 1903. In this way, the remaining energy contained in the heating gas heats the thawing chamber, thereby heating it to a specific operating temperature and maintaining that temperature. The used exhaust gas 1904 flows out through the double-wall structure.

[0250] The double-wall structure can be formed using piping, similar to the cross-sections of the double-wall structure shown in Figures 12A and 12B.

[0251] Furthermore, in a heat exchange structure similar to those shown in Figures 13 and 14, the exhaust gas from the thawing chamber can be reused to preheat the gas to be used as the heating gas. By using this heat exchange structure, the exhaust gas from the thawing chamber preheats the gas to be used as the heating gas.

[0252] It should be noted that, in principle, the thawing chamber and the freezing chamber may be the same. In other words, the thawing chamber according to the present invention can also be used as a freezing chamber according to the present invention, and vice versa. In principle, the control scheme and the cooling / heating gas used in the process determine whether freezing or thawing is being performed. In a particular process, the product may be frozen and thawed in the same chamber according to the present invention.

[0253] This highlights the symmetry between the freezing and thawing methods described herein. Similarly, the freezing and thawing processes are improved by controlling the temperature and flow rate of the cooling / heating gas and using the control scheme described herein.

[0254] Two or more of the above embodiments can be combined in any suitable manner.

[0255] Experimental results Figures 22A and 22B show two experimental results of the present invention.

[0256] In other words, the temperature setpoint and product temperature of a specific vial i are determined by a time interval t in minutes. i The temperature is given as °C. In the experiment, a thermal IR camera was used to perform non-contact measurements of an exemplary freeze cycle. Thus, the measurements were performed on the wall of the container holding the product to be freeze-dried. In both experiments, the product is an aqueous dispersion of cells with a lysis-protecting agent.

[0257] The experiment is similar in that, in the first step, (sub)cooling is performed until crystallization (nucleation) begins. The crystallization stage of water shows a slow decrease in temperature over time. As the ice layer thickens, the overall temperature of the container continues to decrease because more cold becomes available for the already formed ice, even though crystallization is an exothermic process. After the crystallization stage is complete, further cooling is performed.

[0258] Both experiments are performed at a cooling rate of 10°C / min, as seen in the (sub)cooling / initial cooling stage and the further cooling / final cooling stage after the crystallization stage. In practice, the temperature setpoint curve is strictly followed, and the temperature and / or flow rate of the cooling gas are controlled so that the temperature of the vial and / or dispersion follows the time-dependent changes in the predetermined initial and final cooling temperatures.

[0259] During the crystallization stage, crystallization rates of 3.815 W and 7.630 W were used, respectively. In this case, the temperature and / or flow rate of the cooling gas were controlled so that the temperature of the vial and / or dispersion followed the change over time of a predetermined crystallization temperature indicated by the temperature setpoint.

[0260] Since the crystallization rate can be changed, it is possible to effectively control the total crystallization time. In other words, the greater the power of the cooling gas, the shorter the crystallization time.

[0261] In both experiments, it can be seen that the product temperature closely follows the temperature setpoint. Therefore, the parameters of the freezing cycle can be precisely controlled using the method described in the claims.

[0262] Clause 1. A method for freezing injectable compositions, particularly pharmaceutical compositions, A step of storing a certain amount of dispersion of an injectable composition in an aqueous dispersion medium in a vial, A step of cooling the vial by applying a cooling gas to the vial, wherein the cooling is characterized by performing at least one of (A), (B), and (C), where (A) is an initial cooling control scheme before nucleation occurs in the dispersion layer, (B) is a crystallization control scheme during crystallization of the dispersion layer, and (C) is a final cooling control scheme after the dispersion layer has crystallized, the step of cooling; A step of obtaining a dispersion after freezing is completed, and The initial cooling control scheme (A) is (I) Performing a nucleation measurement on the vial and / or the dispersion to determine whether nucleation has occurred in the dispersion; (II) Controlling the temperature and / or flow rate of the cooling gas so that the temperature of the vial and / or the dispersion follows the time-dependent change of a predetermined initial cooling temperature; Repeating steps (I) and (II) until the nucleation measurement determines that nucleation has occurred in the dispersion, and The crystallization control scheme (B) is (I) Performing a crystallization measurement on the vial and / or the dispersion to determine whether crystallization has ended in the dispersion; (II) Controlling the temperature and / or flow rate of the cooling gas so that the temperature of the vial and / or the dispersion follows the time-dependent change of a predetermined crystallization temperature; Repeating steps (I) and (II) until the crystallization measurement determines that crystallization has ended in the dispersion, and The final cooling control scheme (C) is (I) Controlling the temperature and / or flow rate of the cooling gas so that the temperature of the vial and / or the dispersion follows the time-dependent change of a predetermined final cooling temperature; (II) Performing a final temperature measurement on the vial and / or the dispersion to determine whether the vial and / or the dispersion has reached its predetermined final temperature; Repeating steps (I) and (II) until the final temperature measurement determines that the vial and / or the dispersion has reached its predetermined final temperature, a method. 2. A method for freezing an injectable composition according to Clause 1, wherein in at least one of (A), (B), and (C), the control scheme may wait for a predetermined time before repeating steps (I) and (II). 3. A method for freezing an injectable composition as described in Clause 1 or 2, wherein (A) and (B), (B) and (C), (A) and (C), or (A), (B) and (C) is performed. 4. A method for freezing an injectable composition according to any one of Clauses 1 to 3, wherein the initial cooling control scheme (A) further comprises the steps of inducing condensation nuclei in the distribution and / or inducing an artificial density gradient in the composition by sound waves or pressure waves and / or inducing a thermal shock in the distribution, preferably the sound waves or pressure waves are generated by inducing rotational fluctuations, and preferably the thermal shock is induced by fluctuations in the temperature or flow rate of the cooling gas. 5. The above method, The steps include rotating the vial for at least a certain period of time to form a dispersed layer on the inner surface of the vial's peripheral wall, A method for freezing an injectable composition according to any one of Clauses 1 to 4, further comprising the step of cooling a vial by applying a cooling gas to a rotating vial. 6. A method for freezing an injectable composition according to any one of Clauses 1 to 5, wherein nucleation measurements, crystallization measurements, and / or final temperature measurements are performed using a thermal sensor for capturing thermal information and / or a sensor for capturing spectral information, Preferably, the spectral information of the vial is converted into structural information of the dispersion using an image processing module. Preferably, a method in which thermal information and / or structural information are used in conjunction with a mathematical model to determine the properties of a dispersion in real time. 7. A method for freeze-drying an injectable composition, particularly a pharmaceutical composition, wherein freezing is carried out in accordance with any one of the clauses 1 to 6, and then drying is carried out by applying a vacuum and supplying heat. 8. A freezing apparatus for freezing injectable compositions, particularly pharmaceutical compositions, A freezing chamber for cooling one or more vials therein, wherein one or more vials contain a certain amount of dispersion of an injectable composition in an aqueous dispersion medium, and the freezing chamber includes a cooling gas system for applying a cooling gas to the vials so that the vials are cooled, The freezing device further, Control means for controlling the freezing process described in any one of clauses 1 to 6, Means for measuring the temperature of the vial during at least a certain time of the freezing process, An apparatus comprising a control mechanism for influencing the flow rate and / or temperature of a cooling gas and adjusting the cooling rate during at least part of the freezing process. 9. A freezing apparatus for freezing injectable compositions, particularly pharmaceutical compositions, A freezing chamber for cooling one or more vials therein, wherein one or more vials contain a certain amount of dispersion of an injectable composition in an aqueous dispersion medium, and the freezing chamber is equipped with a cooling gas system for applying a cooling gas to the vials so that the vials are cooled. The freezing apparatus includes a heat exchange element that at least partially surrounds the freezing chamber. The heat exchange element is in thermal contact with the freezing chamber. The heat exchange element cools the low-temperature freezing chamber by using used cooling gas from the freezing chamber, or by using another fluid or gas. Preferably, the used cooling gas can flow through the heat exchange element to cool the freezing chamber. Preferably, the heat exchange element is formed by spirally wound channels and / or meandering channels surrounding the freezing chamber, allowing used cooling gas to flow through the channels. Preferably, the apparatus is configured such that the heat exchange element is located within a double-wall structure surrounding the freezing chamber. 10. A freezing apparatus for freezing injectable compositions, particularly pharmaceutical compositions, A freezing chamber for cooling one or more vials therein, wherein one or more vials contain a certain amount of dispersion of an injectable composition in an aqueous dispersion medium, and the freezing chamber is equipped with a cooling gas system for applying a cooling gas to the vials so that the vials are cooled. The cooling system includes a heat exchange element that is in thermal contact with the gas to be cooled. The heat exchange element cools the gas using the used cooling gas from the freezing chamber. Preferably, the apparatus is formed by a heat exchange element consisting of a first piping system through which a gas to be cooled flows and a second piping system through which used cooling gas flows, wherein the first and second piping systems are in thermal contact with each other. 11. A freezing apparatus for freezing injectable compositions, particularly pharmaceutical compositions, A freezing chamber for cooling one or more vials therein, wherein one or more vials contain a certain amount of dispersion of an injectable composition in an aqueous dispersion medium, and the freezing chamber is equipped with a cooling gas system for applying a cooling gas to the vials so that the vials are cooled. The cooling gas system includes a cooling system that cools the gas to a cooling temperature. The cooling system comprises a compressor and a heat exchange element that is in thermal contact with the gas to be cooled. A device in which a heat exchange element cools a gas using used cooling gas from a freezing chamber. 12. The apparatus includes means for measuring the temperature of the vial during at least a certain time of the freezing process, A freezing apparatus according to any one of clauses 9 to 11, comprising a control mechanism for influencing the flow rate and / or temperature of the cooling gas and adjusting the cooling rate during at least a portion of the freezing process. 13. The freezing device, A freezing apparatus according to any one of the clauses 8 to 12, further comprising a rotating means for one or more vials, wherein one or more vials can be rotated for at least a certain period of time to form a dispersion layer on the inner surface of the peripheral wall of the vials, and a cooling gas system applies a cooling gas to the rotating vials so that the vials are cooled. 14. A freeze-drying system for freeze-drying injectable compositions, particularly pharmaceutical compositions, A freezing device as described in any one of clauses 8 to 13, It comprises an annealing apparatus and / or a sublimation apparatus, The annealing apparatus and / or sublimation apparatus each comprises an annealing chamber and a sublimation chamber, The annealing apparatus and / or sublimation apparatus comprises an annealing chamber heat exchange element and a sublimation chamber heat exchange element, respectively, which are in thermal contact with the annealing chamber and the sublimation chamber. A system in which an annealing / sublimation chamber heat exchange element cools the annealing chamber and / or sublimation chamber using used cooling gas from a freezing chamber, or using other low-temperature liquids or gases. 15. A method for thawing a frozen composition, particularly a pharmaceutical composition, A storage step comprising storing a certain amount of a frozen composition in a vial, preferably the frozen composition being a dispersion of an injectable composition in an aqueous dispersion medium, more preferably the frozen composition being a frozen dispersion layer on the inner surface of the peripheral wall of the vial, and more preferably the frozen composition being obtained by the method described in any one of the items 1 to 6. The steps include rotating the vial for at least a certain period of time, The steps include heating the vial by applying a heating gas to the rotating vial while the vial is rotating, A method comprising the step of obtaining a composition after thawing is complete. 16. A method for thawing a frozen composition, particularly a pharmaceutical composition, Storing a certain amount of the frozen composition in a vial, preferably, the frozen composition is a dispersion of an injectable composition in an aqueous dispersion medium, more preferably, the frozen composition is a frozen dispersion layer on the inner surface of the peripheral wall of the vial, and even more preferably, the frozen composition is obtained by the method according to any one of clauses 1 to 6, the storing step; Heating the vial by applying a heating gas to the vial; Obtaining the composition after thawing is completed, and including; The step of heating the vial is performed by performing at least one of (A), (B), (C), (D), and (E), (A) is an initial heating control scheme during the heating stage before reaching the eutectic point in the composition, (B) is a recrystallization control scheme during the recrystallization stage of the excipient, (C) is a secondary heating control scheme during the heating stage before reaching the melting point of water in the composition, (D) is a melting control scheme during the melting of the ice phase, and (E) is a final heating control scheme for reaching the use temperature of the composition; The initial heating control scheme (A) is; (I) Performing a eutectic point measurement on the vial and / or the composition to determine whether the composition has reached the eutectic point; (II) Controlling the temperature and / or flow rate of the heating gas so that the temperature of the vial and / or the composition follows the time-dependent change of a predetermined initial heating temperature; The eutectic point measurement includes repeating steps (I) and (II) until it is determined that the composition has reached the eutectic point; The recrystallization control scheme (B) is; (I) Performing a recrystallization measurement on the vial and / or the composition to determine whether recrystallization in the composition has ended; (II) Controlling the temperature and / or flow rate of the heating gas so that the temperature of the vial and / or the composition follows the time-dependent change of a predetermined recrystallization temperature; The recrystallization measurement includes repeating steps (I) and (II) until it is determined that recrystallization in the composition has ended; The secondary heating control scheme (C) is, (I) A step of performing a melting point measurement on the vial and / or composition to determine whether the composition has reached the melting point of the ice contained in the composition, (II) A step of controlling the temperature and / or flow rate of the heating gas so that the temperature of the vial and / or composition follows the change over time of a predetermined secondary heating temperature, The melting point measurement includes the step of repeating steps (I) and (II) until it is determined that the composition has reached its melting point. The melting control scheme (D) is (I) A step of performing a melting measurement on the vial and / or composition to determine whether or not the ice has finished melting in the composition, (II) A step of controlling the temperature and / or flow rate of the heating gas so that the temperature of the vial and / or composition follows a change in the time course of a predetermined melting temperature, The melting measurement includes the step of repeating steps (I) and (II) until it is determined that melting has finished in the composition, The final heating control scheme (E) is, (I) A step of performing a final temperature measurement on the vial and / or composition to determine whether the vial and / or composition has reached its predetermined final temperature, (II) A step of controlling the temperature and / or flow rate of the heating gas so that the temperature of the vial and / or composition follows the change over time of a predetermined final heating temperature, A method comprising the step of repeating steps (I) and (II) until a final temperature measurement determines that the vial and / or composition has reached its predetermined final temperature. 17. A method for thawing a frozen composition according to Clause 16, wherein in at least one of (A), (B), (C), (D), and (E) before repeating steps (I) and (II), the control scheme can wait for a predetermined time. 18. (A) and (B); (A) and (C); (A) and (D); (A) and (E); (B) and (C); (B) and (D); (B) and (E); (C) and (D); (C) and (E); (D) and (E); (A), (B) and (C); (A), (B) and (D); (A), (B) and (E); (A), (C) and (D); (A), (C) and (E); (A), (D) and (E); (B), (C) and (D A method for thawing a frozen composition according to clause 16 or 17, wherein (A), (B), (C), (D), and (E); (B), (D), and (E), (C), (D), and (E); (A), (B), (C), and (E); (A), (C), (D), and (E); (B), (C), (D), and (E); or (A), (B), (C), (D), and (E) is performed. 19. A method for thawing a frozen composition according to clauses 16-18, further comprising the steps of rotating the vial for at least a certain period of time and heating the vial by applying a heating gas to the rotating vial. 20. A method for thawing a frozen composition according to any one of clauses 16 to 19, wherein eutectic point measurement, decrystallization measurement, melting point measurement, melting measurement and / or final temperature measurement are performed using a thermal sensor for capturing thermal information and / or a sensor for capturing spectral information, Preferably, the spectral information of the vial is converted into structural information of the composition using an image processing module. Preferably, a method in which thermal information and / or structural information are used in conjunction with a mathematical model to determine the properties of a composition in real time. 21. A thawing apparatus for thawing frozen compositions, particularly pharmaceutical compositions, A thawing chamber comprising a rotating means for rotating one or more vials for at least a certain period of time, wherein one or more vials contain a certain amount of a freezing composition, preferably the freezing composition is a dispersion of an injectable composition in an aqueous dispersion medium, more preferably the freezing composition is a freezing dispersion layer on the inner surface of the peripheral wall of the vial, and more preferably the freezing composition is obtained by the method described in any one of the items 1 to 6, wherein the thawing chamber comprises The apparatus further includes a heating gas system for applying a heating gas to a rotating vial while the vial is rotating, so that the vial is heated. 22. A thawing apparatus for thawing frozen compositions, particularly pharmaceutical compositions, A thawing chamber for heating one or more vials therein, wherein one or more vials contain a certain amount of a freezing composition, preferably the freezing composition is a dispersion of an injectable composition in an aqueous dispersion medium, more preferably the freezing composition is a freezing dispersion layer on the inner surface of the peripheral wall of the vial, and more preferably the freezing composition is obtained by any one of the methods described in Clauses 1 to 6, comprising a thawing chamber, Furthermore, the system includes a heating gas system for applying a heating gas to the vial so that the vial is heated. A thawing apparatus further comprising control means for controlling the thawing process described in any one of clauses 16 to 20. 23. A thawing apparatus for thawing frozen compositions, particularly pharmaceutical compositions, A thawing chamber for heating one or more vials therein, wherein one or more vials contain a certain amount of a freezing composition, preferably the freezing composition is a dispersion of an injectable composition in an aqueous dispersion medium, more preferably the freezing composition is a freezing dispersion layer on the inner surface of the peripheral wall of the vial, and more preferably the freezing composition is obtained by the method described in any one of the items 1 to 6, comprising a thawing chamber, Furthermore, the system includes a heating gas system for applying a heating gas to the vial so that the vial is heated. The thawing device includes a heat exchange element that at least partially surrounds the thawing chamber. The heat exchange element is in thermal contact with the thawing chamber. The heat exchange element heats the thawing chamber using the used heating gas from the thawing chamber. Preferably, the used heating gas can flow through a heat exchange element to heat the thawing chamber. Preferably, the heat exchange element is formed by spirally wound channels and / or meandering channels surrounding the thawing chamber, allowing used heating gas to flow through the channels. Preferably, the apparatus is configured such that the heat exchange element is located within a double-wall structure surrounding the thawing chamber. 24. A thawing apparatus for thawing frozen compositions, particularly pharmaceutical compositions, A thawing chamber for heating one or more vials therein, wherein one or more vials contain a certain amount of a freezing composition, preferably the freezing composition is a dispersion of an injectable composition in an aqueous dispersion medium, more preferably the freezing composition is a freezing dispersion layer on the inner surface of the peripheral wall of the vial, and more preferably the freezing composition is obtained by any one of the methods described in Clauses 1 to 6, comprising a thawing chamber, Furthermore, the system includes a heating gas system for applying a heating gas to the vial so that the vial is heated. The heating gas system includes a heating system for heating the heating gas, The heating system includes a heat exchange element that is in thermal contact with the gas to be heated. The heat exchange element heats the gas using the used heated gas from the thawing chamber. Preferably, the apparatus is formed by a heat exchange element consisting of a first piping system through which a gas to be heated flows and a second piping system through which used heated gas flows, and the first piping system and the second piping system are in thermal contact with each other. 25. A thawing apparatus according to any one of clauses 22 to 24, wherein the thawing chamber comprises a rotating means for rotating one or more vials for at least a certain period of time, and the thawing apparatus comprises a heating gas system for applying heating gas to the rotating vials so that the vials are heated.

Claims

1. A method for changing the phase of a composition, particularly a pharmaceutical composition, A step of storing a certain amount of the composition in a vial, A step of changing the phase of the composition in the vial by applying a hot gas to the vial, The step of changing the phase of the composition includes the step of freezing or thawing the composition, wherein the hot gas is a cooling gas or a heating gas, respectively. The step of changing the phase of the composition is characterized by performing at least one of (A), (B), and (C), where (A) is an initial temperature change control scheme performed before the composition enters a phase in which the amount of crystallization changes; (B) is a crystallization change control scheme during the phase in which the amount of crystallization changes; and (C) is a final temperature change control scheme performed until the composition reaches its final temperature. The process includes the step of obtaining the composition after the phase change is complete, The initial temperature change control scheme (A) is, (I) A step of performing an initial measurement on the vial and / or the composition to determine whether a phase in which the amount of crystallization of the composition changes has begun, (II) A step of controlling the temperature and / or flow rate of the hot gas such that the temperature of the vial and / or the composition changes over time from a predetermined initial temperature, The initial measurement includes repeating steps (I) and (II) until it is determined that the phase in which the amount of crystallization of the composition changes has begun, and the crystallization change control scheme (B) is (I) A step of performing a crystallization change measurement on the vial and / or the composition to determine whether or not there is no longer any change in the amount of crystallization in the composition, (II) A step of controlling the temperature and / or flow rate of the hot gas such that the temperature of the vial and / or the composition follows a change over time of a predetermined crystallization change temperature, The step includes repeating steps (I) and (II) until there is no longer any change in the amount of crystallization in the composition, The aforementioned final temperature change control scheme (C) is (I) A step of controlling the temperature and / or flow rate of the hot gas such that the temperature of the vial and / or the composition changes over time to a predetermined final temperature, (II) A step of performing a final temperature measurement on the vial and / or the composition to determine whether the vial and / or the composition has reached its predetermined final temperature, The final temperature measurement includes repeating steps (I) and (II) until it is determined that the vial and / or the composition has reached its predetermined final temperature, method.

2. A method for changing the phase of a composition according to claim 1, wherein in at least one of (A), (B), and (C), the initial temperature change control scheme, the crystallization change control scheme, or the final temperature change control scheme may wait for a predetermined time before repeating steps (I) and (II).

3. A method for freezing an injectable composition according to claim 1 or 2, wherein the initial measurement, the crystallization change measurement, and / or the final temperature measurement are performed using a thermal sensor for capturing thermal information and / or a sensor for capturing spectral information.

4. The method according to any one of claims 1 to 3, wherein the step of changing the phase of the composition is to freeze the composition, The composition is injectable and stored in the vial as a dispersion of a certain amount of the composition in an aqueous dispersion medium. The initial temperature change control scheme is an initial cooling control scheme (X) before nucleation occurs in the dispersed layer, the crystallization change control scheme is a crystallization control scheme (Y) during the crystallization of the dispersed layer, and the final temperature change control scheme is a final cooling control scheme (Z) after the dispersed layer has crystallized. In the initial cooling control scheme (X), the initial measurement is a nucleation measurement for determining whether or not nucleation has occurred in the dispersion, the change in the initial temperature over time is the change in the initial cooling temperature over time, and steps (I) and (II) are repeated until the nucleation measurement determines that nucleation has occurred in the dispersion. In the crystallization control scheme (Y), steps (I) and (II) are repeated until the crystallization change measurement determines whether crystallization has been completed in the dispersion, and the change in the crystallization change temperature over time is a change in the crystallization temperature over time, and the crystallization change measurement determines that crystallization has been completed in the dispersion. A method in which the change in the final temperature over time is the change in the final cooling temperature over time in the final cooling control scheme (Z).

5. A method for freezing an injectable composition according to claim 4, wherein (X) and (Y), (Y) and (Z), (X) and (Z), or (X), (Y) and (Z) is carried out.

6. A method for freezing an injectable composition according to claim 4 or 5, wherein the initial cooling control scheme (X) further comprises the steps of inducing condensation nuclei in the distribution and / or inducing an artificial density gradient in the composition by sound waves or pressure waves and / or inducing a thermal shock in the distribution.

7. The method described above is The steps include rotating the vial for at least a certain period of time to form a dispersion layer on the inner surface of the peripheral wall of the vial, A method for freezing an injectable composition according to any one of claims 4 to 6, further comprising the step of cooling the vial by applying a cooling gas to the rotating vial.

8. A method for freezing an injectable composition according to any one of claims 4 to 7, wherein the method further comprises a step of applying a vacuum and drying while supplying heat.

9. The step of changing the phase of the composition is to thaw the composition. The composition is frozen, The initial temperature change control scheme is an initial heating control scheme (V) during the heating stage before the composition reaches its eutectic point, and / or a secondary heating control scheme (X) during the heating stage before the composition reaches the melting point of water; the crystallization change control scheme is a decrystallization control scheme (W) during the excipient decrystallization stage, and / or a melting control scheme (Y) during the melting of the ice phase; and the final temperature change control scheme is a final heating control scheme (Z) for reaching the serving temperature of the composition. In the initial heating control scheme (V) described above, the initial measurement is a eutectic point measurement for determining whether the composition has reached its eutectic point, the change in the initial temperature over time is the change in the initial heating temperature over time, and steps (I) and (II) are repeated until it is determined by the eutectic point measurement that the composition has reached its eutectic point. In the decrystallization control scheme (W), the crystallization change measurement is a decrystallization measurement for determining whether or not decrystallization has been completed in the composition, the change in the crystallization change temperature over time is the change in the decrystallization temperature over time, and steps (I) and (II) are repeated until the decrystallization measurement determines that decrystallization has been completed in the composition. In the secondary heating control scheme (X), the initial measurement is a melting point measurement that determines whether the composition has reached the melting point of the ice contained in the composition, the change in the initial temperature over time is the change in the secondary heating temperature over time, and steps (I) and (II) are repeated until it is determined by the melting point measurement that the composition has reached the melting point. In the melting control scheme (Y), the crystallization change measurement is a melting measurement that determines whether or not the melting of ice in the composition has finished, the change in the crystallization change temperature over time is the change in the melting temperature over time, and steps (I) and (II) are repeated until the melting measurement determines that the melting has finished in the composition. The method according to any one of claims 1 to 3, wherein in the final heating control scheme (Z), the change in the final temperature over time is the change in the final heating temperature over time.

10. (V) and (W); (V) and (X); (V) and (Y); (V) and (Z); (W) and (X); (W) and (Y); (W) and (Z); (X) and (Y); (X) and (Z); (Y) and (Z); (V), (W) and (X); (V), (W) and (Y); (V), (W) and (Z); (V), (X) and (Y); (V), (X) and (Z); (V), (Y) and (Z); (W), (X) and A method for thawing a frozen composition according to claim 9, comprising: (Y); (W), (X) and (Z); (W), (Y) and (Z); (X), (Y) and (Z); (V), (W), (X) and (Y); (V), (W), (X) and (Z); (V), (W), (Y) and (Z); (V), (X), (Y) and (Z); (W), (X), (Y) and (Z); or (V), (W), (X), (Y), and (Z).

11. A method for thawing a frozen composition according to claim 9 or 10, further comprising the steps of rotating the vial for at least a certain period of time and heating the vial by applying a heating gas to the rotating vial.

12. A method for thawing a frozen composition, particularly a pharmaceutical composition, A step of storing a certain amount of frozen composition in a vial, The steps include rotating the vial for at least a certain period of time, The steps include: heating the vial by applying a heating gas to the rotating vial while the vial is rotating; A method comprising the step of obtaining the composition after thawing is complete.

13. A freezing apparatus for freezing injectable compositions, particularly pharmaceutical compositions, A freezing chamber for cooling one or more vials therein, wherein the one or more vials contain a certain amount of dispersion of an injectable composition in an aqueous dispersion medium, and the freezing chamber comprises a cooling gas system for applying a cooling gas to the vials so that the vials are cooled, The aforementioned freezing device Control means for controlling the freezing process, Means for measuring the temperature of the vial during at least a certain time of the freezing process, The system further comprises a control mechanism for influencing the flow rate and / or temperature of the cooling gas and adjusting the cooling rate during at least a portion of the freezing process, An apparatus wherein the control means is for controlling the freezing process described in any one of claims 4 to 8.

14. A thawing device for thawing frozen compositions, particularly pharmaceutical compositions, A thawing chamber comprising a rotating means for rotating one or more vials for at least a certain period of time, wherein the one or more vials contain the amount of frozen composition contained in the vials, The apparatus further includes a heating gas system for applying a heating gas to the rotating vial while the vial is rotating, such that the vial is heated.

15. A thawing device for thawing frozen compositions, particularly pharmaceutical compositions, A thawing chamber for heating one or more vials therein, wherein the one or more vials contain a certain amount of a frozen composition, comprising: Furthermore, the system includes a heating gas system for applying a heating gas to the vial so that the vial is heated, The thawing device further comprises control means for controlling the thawing process described in any one of claims 9 to 11.

16. A thawing device for thawing frozen compositions, particularly pharmaceutical compositions, A thawing chamber for heating one or more vials therein, wherein the one or more vials contain a certain amount of a frozen composition, comprising: Furthermore, the system includes a heating gas system for applying a heating gas to the vial so that the vial is heated, The thawing device comprises a heat exchange element that at least partially surrounds the thawing chamber, The heat exchange element is in thermal contact with the thawing chamber. An apparatus wherein the heat exchange element heats the thawing chamber using the used heated gas from the thawing chamber.

17. A thawing device for thawing frozen compositions, particularly pharmaceutical compositions, A thawing chamber for heating one or more vials therein, wherein the one or more vials contain a certain amount of a frozen composition, comprising: Furthermore, the system includes a heating gas system for applying a heating gas to the vial so that the vial is heated, The heating gas system comprises a heating system for heating the heating gas, The heating system comprises a heat exchange element that is in thermal contact with the gas to be heated, An apparatus wherein the heat exchange element heats the gas using the used heated gas from the thawing chamber.

18. The thawing apparatus according to any one of claims 15 to 17, wherein the thawing chamber comprises a rotating means for rotating one or more vials for at least a certain period of time, and the thawing apparatus comprises a heating gas system for applying heating gas to the rotating vials so that the vials are heated.

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