Continuous freeze-drying system and continuous freeze-drying method having a rotating spiral tube

Abstract

This invention provides a continuous freeze-drying system that offers improved control over the resulting product. [Solution] A continuous freeze-drying system comprises a drying apparatus configured to receive frozen particles of a substance and dry the particles. The drying apparatus comprises a rotatable tubular member having an inlet section, an outlet section, and an intermediate helical section. The freeze-drying system also comprises a vacuum pump system for maintaining a vacuum within the tubular member and a temperature control system configured to control the temperature within the tubular member. Furthermore, the system comprises a drive unit for rotating the rotating tubular member and thereby transporting the particles. A control system is also provided for controlling the drive unit and the temperature control system so that the received frozen particles are dried by the time they reach the end of the outlet section. The disclosure also relates to a freeze-drying method for freeze-drying a substance.

Description

Technical Field

[0001] The present disclosure relates to a freeze-drying system, and more particularly to a freeze-drying system for continuous freeze-drying of substances. The present disclosure also relates to a method for performing continuous freeze-drying.

Background Art

[0002] Freeze-drying or lyophilization is a dehydration process at low temperature and low pressure. This is utilized in many different fields to preserve or stabilize the properties of materials over long periods under various conditions. Freeze-drying is particularly suitable for heat-sensitive products such as certain foods, or pharmaceutical or biological preparations such as vaccines or microorganisms. In fact, freeze-drying can improve the stability of pharmaceuticals and effectively preserve the functionality or activity of active pharmaceutical ingredients because the temperatures used during the process are limited.

[0003] A typical freeze-drying process includes three basic steps. First, a freezing step is performed on a liquid solution to freeze the product. The liquid solution can include a solvent and a solute dissolved in the solvent. Alternatively, a dispersion medium in which a dispersoid is dispersed may be used. Control of the freezing process is very important because the size and distribution of ice crystals can significantly affect the efficiency of the next step. Subsequently, primary drying is performed under a low-temperature and low-pressure environment. Thus, the pressure around the frozen material is reduced and heat is applied. In this way, the substance is dried by removing ice by sublimation, thereby producing a dried product. Finally, secondary drying is performed, which consists of removing residual adsorbed water by desorption. Secondary drying is also performed under vacuum conditions.

[0004] Freeze-drying systems and methods can be classified according to different criteria. A first distinction can be made between batch manufacturing and continuous manufacturing. Batch manufacturing is the most common approach. In batch manufacturing, the freeze-drying process is carried out in a predetermined series of separate tasks, where batches of raw materials are introduced into the system and discharged after a predetermined time. Such tasks can typically occur in different locations, leading to significant delays in cycle time and increasing the number of intermediate operations. Conversely, continuous manufacturing integrates different steps, which are executed continuously without interruption. Continuous manufacturing offers several advantages, including increased flexibility, improved energy efficiency, increased productivity, and enhanced quality assurance.

[0005] Continuous manufacturing can be particularly advantageous for freeze-drying products in the pharmaceutical or biological fields due to the reduction in the number of operations and improved quality assurance.

[0006] In fact, the manufacture, processing, packaging, or storage of biological products and pharmaceuticals are required to adhere to the strict standards of current Good Manufacturing Practices (cGMP). In this regard, several standards exist that are applicable to equipment in sterile environments; see, for example, Annexes 1 and 15 of EU GMP Part 1, or 21 CFR Part 211 Subpart D, which was in effect as of March 2024. Additionally, several design guidelines for equipment, such as ASME BPE, provide a comprehensive set of rules.

[0007] Lyophilization systems can also be classified based on whether they operate with vials, i.e., single-dose units, or with bulk materials. Lyophilization systems operating with vials have shown some advantages for certain products, such as pharmaceuticals, for example, by improving dose control. However, these systems must be designed for complex loading and unloading operations and must take into account a very wide range of container shapes and / or dimensions. Furthermore, the use of vials can result in non-uniform product characteristics, including non-uniformity between vials due to different individual conditions during the freeze or dry process, such as different local temperatures.

[0008] Due to these challenges, freeze-drying systems operating on bulk materials in solid or liquid form are increasingly being proposed for continuous freeze-drying machines. Thus, several systems and methods for continuous freeze-drying of materials are already known. Nevertheless, such known solutions still exhibit some drawbacks or limitations. As a result, even though the advantages of continuous processing are recognized, freeze-dried pharmaceuticals, e.g., drugs, are still manufactured using batch techniques. The lag of the pharmaceutical industry in food manufacturing, for example, is due to pharmaceutical regulatory requirements. These include, among other things, much stricter requirements for sterility, product quality, and precise dosage in the case of drugs. Currently, continuous freeze-dryers are considered unable to adequately control these parameters and are therefore not yet suitable for large-scale industrial production in the pharmaceutical industry. Among other things, physical damage to the resulting product or the difficulty in adjusting the freeze-drying process are identified as challenges for proposed systems for continuous processing. [Overview of the project] [Problems that the invention aims to solve]

[0009] This disclosure aims to provide a freeze-drying system and method that at least partially mitigates one or more of the aforementioned drawbacks and improves controllability of the resulting product. [Means for solving the problem]

[0010] In one aspect of the present disclosure, a continuous freeze-drying system is provided. The system comprises a dryer configured to receive frozen particles of a material and dry the particles. The dryer comprises a rotatable tubular member having an inlet section, an outlet section, and an intermediate helical section. The freeze-drying system also comprises a vacuum pump system for maintaining a vacuum within the tubular member and a temperature control system configured to control a desired temperature within the tubular member. Furthermore, the system comprises a drive unit for rotating the rotatable tubular member and thereby transporting the particles. A control system is also provided for controlling the drive unit and the temperature control system so that the received frozen particles are dried by the time they reach the end of the outlet section.

[0011] According to this aspect of the present disclosure, a freeze-drying system having improved capabilities is provided. The substance may first comprise a solution containing a solvent, such as water, and a solute. The solution may then be frozen. The solute may comprise a pharmaceutical product, such as one used for diagnostic or therapeutic purposes.

[0012] The use of tubular members, more specifically tubular members including an intermediate helical section, i.e., helical tubes, results in the smooth transport of frozen particles or granules. The tubular members provide a smooth surface that allows the frozen particles to dry uniformly as they move forward. Specifically, the frozen particles are in direct contact with the heated surface of the tubular member. This results in more uniform heat transfer to the frozen particles than other existing systems, such as those in which particles are supplied in vials or other types of containers.

[0013] The movement of the particles is induced by the rotation of a tubular member having a drive unit, resulting in gentle and smooth handling of the particles. Thus, the particles do not experience vibration or bouncing during the drying step. Such vibration or bouncing motion can be seen in some prior art systems that utilize a vibration system, such as a vibrating conveyor, to enable uniform heating of the particles. Specifically, some prior art systems include multiple trays or platforms within the drying apparatus. Such platforms are typically arranged at different heights and may be inclined to facilitate the movement of frozen particles during drying. Frozen particles jump or fall between trays, for example, from an upper platform to a lower platform. Such jumps can cause mechanical damage to the particles during the drying process. In contrast, in the system according to this disclosure, the structural integrity of the particles is maintained, and therefore the active properties of the material are protected and preserved. This aspect is particularly relevant in the case of pharmaceuticals or biological preparations. Furthermore, the formation of particle clusters is minimized by providing continuous rotational motion of the tubular member during the drying sequence. In addition, the rotational motion of the tubular member results in excellent heat transfer through continuous mixing of the granular frozen product, i.e., frozen particles. This excellent heat transfer capability allows for a significant reduction in the drying time of the particles.

[0014] The freeze-drying system according to this embodiment includes a control system configured to control the drive unit and the temperature control system. Such a control system improves the flexibility or versatility of the system. In fact, different substances, particularly chemicals or pharmaceuticals, may require different drying conditions, such as temperature or time. Therefore, the drying process can be controlled by optimizing the combination of temperature and conveying speed. Furthermore, the pressure during drying can also be controlled by the control system.

[0015] The control system can be configured to adjust the rotational speed of the tubular member by controlling the drive unit and to adjust the temperature by a temperature control system. These parameters can be adjusted according to the requirements of a particular substance. Such control can also improve the quality of the resulting product, more specifically, the homogeneity and uniformity of the dried particles or granules. Thus, it is also possible to adjust the parameters during different freeze-drying sequences of the same substance while monitoring the properties of the resulting particles. In this way, by adjusting different parameters, particles with properties within a specific predetermined quality range can be obtained. Furthermore, in one example, the control system can also be configured to control the process pressure, more specifically the pressure within the volume of the tubular member.

[0016] The control system may also be adjusted based on the amount of material being processed. In fact, different processing times, temperatures, and / or pressures may be required for effective drying of the particles, depending on the mass and / or volume of particles processed per unit time.

[0017] Further advantages can be obtained by using a drying apparatus having a substantially hollow or empty volume with a smooth inner surface. Thus, the rotation of the tubular member itself induces the movement of particles from one end of the tubular member to the opposite end. Mechanisms or complex devices, for example, that include moving parts are not housed inside the vacuumed, unobstructed volume of the tubular member. The tubular member provides a substantially smooth surface with a very limited number of corners and areas, including narrow bends and curves.

[0018] At least two advantages can be obtained from such an unobstructed or open space within a tubular member. On the one hand, optimal use of the processed material makes it possible to achieve higher efficiency and smooth transport along the tubular member, thus avoiding material waste during the transport process. On the other hand, cleaning of the drying equipment is also facilitated by such an unobstructed space. Therefore, after using a freeze-drying system to freeze-dehydrate one material, residues of processed material particles can be effectively removed before using the freeze-drying system to process a different material. Cleaning and sterilization can be performed using clean-in-place (CIP) and / or steam-in-place (SIP) processes. With respect to SIP, multiple ports may be provided for introducing steam at relatively high temperatures, e.g., in the range of 120°C to 135°C. As a result, adequate sterility of the freeze-drying system and associated processes is achieved. This embodiment is particularly relevant to the processing of pharmaceuticals, as current Good Manufacturing Practices (cGMP) impose stringent requirements to avoid cross-contamination when using equipment to manufacture and / or process different materials.

[0019] Another aspect of the present disclosure provides a method for freeze-drying a substance. The method includes the step of providing frozen particles of the substance into a drying apparatus, which comprises a tubular member that is rotatable under vacuum. The method also includes the step of transferring the frozen particles to an inlet section of the tubular member, which also includes an outlet section and an intermediate helical section. The frozen particles are then transported along the tubular member from the inlet section to the outlet section while rotating the tubular member and controlling the temperature along the tubular member to a desired temperature, thereby continuously drying the particles during transport. The pressure of the process can also be controlled while the frozen particles are being transported. The method also includes the step of collecting the dried particles at a collection station.

[0020] According to this further aspect of the present disclosure, an improved freeze-drying process is achieved. In particular, enhanced control of the sublimation drying sequence is provided. The process according to this further aspect exhibits the advantages already described with reference to the corresponding freeze-drying system. Thus, it provides enhanced control over the properties of the dried particles or granules while simultaneously preserving the relevant properties of the dried particles by providing a gentle treatment of the particles. Accordingly, the method according to the present disclosure is particularly suitable for processing biological preparations or pharmaceuticals that require compliance with cGMP. Thus, the drying of particles during the sublimation process in a vacuum-filled tubular member is carried out in a smooth, uniform, clean, and repeatable manner.

[0021] Throughout this disclosure, the inlet section of a rotatable tubular member is understood as the section of the tubular member that receives frozen particles, while the outlet section of the tubular member is understood as the section of the tubular member that discharges dry granules. The intermediate helical section is located between the inlet and outlet sections and is understood as the section of the tubular member comprising a helical tube. Thus, the inlet section extends from the point where frozen particles are received by the tubular member to the beginning of the helical section of the tube, while the outlet section extends from the end of the helical tube to the point where dry particles are discharged from the rotatable tubular member. Nevertheless, in some examples, the intermediate helical section may extend substantially along the entire length of the tubular member, and as a result, the inlet and outlet sections may simply correspond to the ends of such a helical section.

[0022] Throughout this disclosure, the terms dry particles, granules, or powder can be used interchangeably.

[0023] Non-limiting examples of this disclosure are described below with reference to the attached drawings. [Brief explanation of the drawing]

[0024] [Figure 1] This diagram schematically shows an example of a drying apparatus for use in a freeze-drying system. [Figure 2] It is a diagram schematically showing the distribution of temperature stages in a drying device according to one example. [Figure 3] It is a diagram schematically showing an example of a drive unit for rotating a tubular member of a drying device. [Figure 4] It is a diagram schematically showing an example of a spiral tubular member having characteristic parameters. [Figure 5A] It is a diagram schematically showing an example of a vacuum freezing device for use in a freeze-drying system. [Figure 5B] It is a diagram schematically showing another example of a vacuum freezing device for use in a freeze-drying system. [Figure 6] It is a diagram schematically showing a continuous freeze-drying system including a vacuum freezing device connected to a drying device according to one example. [Figure 7] It is a flowchart of an example of a freeze-drying method. [Figure 8] It is a flowchart of another example of a freeze-drying method.

Embodiments for Carrying Out the Invention

[0025] Here, embodiments of the present disclosure are referred to in detail, and one or more examples thereof are shown in the drawings. Each example is provided as an illustration of the present disclosure, not as a limitation. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the teachings. For example, features illustrated or described as part of one embodiment can be used with another embodiment to obtain still another embodiment. Therefore, the present disclosure is intended to cover modifications and variations that fall within the scope of the appended claims and their equivalents.

[0026] FIG. 1 shows an example of a drying device 10 for use in a freeze-drying system, more specifically a continuous freeze-drying system.

[0027] The system comprises a dryer 10 configured to receive frozen particles of a material, dry the particles, and collect the dried particles. The dryer 10 comprises a rotatable tubular member 13 having an inlet section 131, an outlet section 133, and an intermediate helical section 132. The freeze-drying system also comprises a vacuum pump system 21 for maintaining a vacuum within the tubular member 13 and a temperature control system 22 configured to control a desired temperature within the tubular member 13. Furthermore, the system comprises a drive unit 18 for rotating the rotatable tubular member 13 and thereby transporting the particles. A control system 23 is also provided for controlling the drive unit 18 and the temperature control system 22 so that the received frozen particles are dried by the time they reach the end of the outlet section 133. In one example, the control system 23 is also configured to control the pressure within the system.

[0028] In one example of this disclosure, a station may be provided within the drying apparatus 10 to receive frozen particles or granules. Thus, as schematically shown in Figure 1, the inlet section 131 of the tubular member 13 may be connected to the receiving station 12. As described above, the receiving station 12 may be configured to receive frozen particles. The connection between the inlet section 131 of the tubular member 13 and the receiving station 12 may include a rotary joint 14.

[0029] In this example, the receiving station 12 may include a container 121, and frozen particles may be continuously supplied to the container 121. To provide a smooth and clean transfer between the receiving station 12 and the rotatable tubular member 13, a rotary joint 14 may be provided between the end of the receiving station 12 and the inlet section 131 of the tubular member 13. A valve 122 may be provided in the receiving station 12. The valve 122 may be configured to control the flow of frozen particles from the container 121 of the receiving station 12 to the tubular member 13. In one example, the valve 122 may be automated to dynamically control the flow of frozen particles and adjust the speed and conditions of the drying process.

[0030] Furthermore, the temperature inside the receiving station 12 may also be controlled to prevent the thawing or deterioration of the frozen particles. Therefore, the temperature control system 22 may be configured to control a desired temperature inside such a receiving station 12.

[0031] To collect the dried material after the freeze-dehydration process, in one example of the present disclosure, the outlet section 133 of the tubular member 13 can be connected to a separation station 16 which can be connected to a collection station 17. The separation station 16 may be configured to separate the dried particles. The separation station 16 may use cyclone separation or may include a cyclone for separating the dried particles from the residual vapor. Also, similar to the receiving station 12, the connection between the outlet section 133 of the tubular member 13 and the separation station 16 may include a rotary joint 15 as shown in Figure 1.

[0032] The separation station 16 may include a container 161 for receiving dry particles (which may also be called granules, powder, or granular powder). As described above, a cyclone, filter, or equivalent system may be placed inside the container 161 to facilitate the separation of the dry particles from the vapor. A rotating joint 15 may be provided to ensure a smooth and clean transfer between the rotating tubular member 13 and the stationary container 161. Furthermore, a valve 162 may be provided in the separation station 16. In this way, the dry powder may be collected from the container 161 while isolating the inside of the tubular member 13. In some examples, the valve 162 may be automated, i.e., configured to operate in an automated manner. Similarly, an automated system may be provided for collecting the dry particles or granules from the container 161 and transferring them to a collection station 17 to proceed to the next processing step, e.g., loading the dry product into a vial.

[0033] A valve system 171, such as a load lock system, may be located between the separation station 16 and the collection station 17. By controlling the valve system 171, the dry particles may be continuously transferred in a controlled manner from the container 161 of the separation station 16 to the collection station 17. The collection station 17 may also be known as a dosing station and may be configured to distribute the received dry particles into desired doses.

[0034] As shown in Figure 1, the vacuum pump system 21 may be configured to maintain a specific vacuum level within the internal volume of the drying apparatus 10. In particular, the vacuum pump system 21 may be configured to maintain vacuum not only in the tubular member 13 but also in the receiving station 12 and the separation station 16. In practice, the internal volumes of such elements can constitute a single volume during operation, since their respective valves 122 and 162 may remain open.

[0035] To control the vacuum level, i.e., pressure, within the internal volume of the drying apparatus 10, the vacuum pump system 21 may comprise several vacuum pumps configured to reach a specific limit or basic vacuum degree. One or more microvalves may be provided to introduce a controlled amount of inert gas, such as nitrogen N2, into the volume. In other words, the microvalves may be used as a controlled leak system for introducing a controlled flow of nitrogen so that a desired pressure is maintained. As shown in Figure 1, these microvalves may be located in different places. In particular, in the example shown in Figure 1, the first microvalve may be located within the receiving section 12, more specifically, after the vessel 121 and before the tubular member 13. Another intermediate microvalve may be located downstream of the rotary joint 15. A third microvalve may be located in the discharge line 212. Of course, it is understood that other locations and / or additional microvalves may be provided. The control system 23 may be configured to control the microvalves based on pressure readings provided by the pressure sensors 214. Multiple pressure sensors 214 may be provided, but at any given time only one may be used by the control system 23 to control the pressure.

[0036] The drying apparatus 10 exhibits different advantages as described above. In particular, the drying apparatus 10 allows for proper control of the drying process while the frozen particles are dried by sublimation within the tubular member 13, that is, while the frozen particles are dried by converting the solvent ice into vapor without passing through the liquid phase. The vapor generated in the tubular member 13 is discharged through the discharge line 212, and the vacuum level during the drying process is maintained by a controlled leakage system comprising a vacuum pump system 21 and one or more microvalves as described above. In particular, the ambient pressure inside the drying apparatus 10, more specifically inside the tubular member 13, is lower than the vapor partial pressure of the solvent at the corresponding temperature.

[0037] Furthermore, in one example, a steam condenser 213 may be placed before the vacuum pump system 21 to condense and remove steam from the system. In particular, the condenser 213 may be configured to capture sublimated water vapor to help maintain the vacuum level and prevent rehydration of the products.

[0038] Valves 211 may be provided to control the connection between the drying volume, for example, the internal volume of the tubular member 13 (as well as the internal volumes of the receiving station 12 and the separation station 16) and the vacuum pump system 21. As shown in the example in Figure 1, the discharge line 212 may be provided downstream of the container 161 located in the separation station 16. Valves 211 may be provided between such container 161 and the vacuum pump system 21. A further valve 162 may be provided between the tubular member 13 and the container 161. Thus, during the drying of frozen particles, both valves 211,162 may be opened to connect the tubular member 13 to the vacuum pump system 21.

[0039] In one example, the vacuum pump system 21 may comprise one or more primary vacuum pumps and one or more Roots pumps. In one example, two or more discharge lines 212 may be provided, each connected to a condenser 213. Thus, a first discharge line 212 may be used until the corresponding condenser 213 is saturated. Thereafter, a thawing step may be performed on the condenser 213 of the first discharge line 212. Then, a second discharge line 212 having a corresponding condenser 213 may be used to continue the process continuously.

[0040] The intermediate helical section 132 improves controllability over the drying conditions of the particles. In particular, improved control over the temperature and cycle time of the drying process is achieved.

[0041] In one example, the drive unit 18 may be configured to adjust the rotational speed of the tubular member 13 between 0.05 rpm and 10.00 rpm. Thus, different rotational speeds may be selected depending on, for example, the material to be dried, the size of the frozen particles, and / or the amount or flow of particles to be processed. In particular, the rotational speed may be adjusted over a relatively wide range to cover various scenarios. In a variation of this example, the rotational speed may be pre-adjusted and kept substantially constant during the drying cycle. In another variation, the control system 23 may be used to control the drive unit 18 during the drying cycle and to change the rotational speed of the tubular member 13 during such a drying cycle.

[0042] In different examples of this disclosure, the drive unit 18 may be provided with different configurations. As an example, Figure 3 schematically shows a configuration in which a servo motor 183 is used to rotate a tubular member 13. The speed and position of the tubular member 13 may be precisely adjusted by the driver of the servo motor 183 after taking into account commands provided by the control system 23. As shown in Figure 3, the servo motor 183 may be mounted on a frame 19 or coupled to a wheel 182 using a belt 181. The wheel 182 may be firmly attached to the tubular member 13 or may be integrally formed with it. As also shown in Figure 1, the drive unit 18 may be located in the exit section 133 of the tubular member 13. In this example, a drive unit 18 comprising a single servo motor 183 is provided. Nevertheless, other examples may comprise a drive unit 18 having multiple servo motors that can be positioned at different locations along the tubular member 13.

[0043] In one example, the rotatable tubular member 13 may be inclined with respect to the horizontal such that the inlet section 131 may be in a higher vertical position than the outlet section 132. The inclination of the tubular member 13 can facilitate the progression or movement of particles along the tubular member 13 due to the action of gravity. The inclination may be chosen so that a specific average translational velocity is obtained for the particles while they undergo the drying process. Providing such an inclination may be particularly useful in systems comprising a tubular member 13 in which the intermediate helical section 132 does not extend along the entire length of the tubular member 13. In such cases, substantially linear sections may be present in the inlet section 131 and / or outlet section 133 of the tubular member 13. The movement of particles along such substantially linear sections can be facilitated by such an inclination.

[0044] Furthermore, the inclination of the tubular member 13 can be particularly advantageous in facilitating drainage when using a clean-in-place (CIP) process for cleaning and sterilization.

[0045] The inclination of the tubular member 13 is schematically shown in Figure 1 and labeled α. A frame 19 may be provided to accommodate different parts of the drying apparatus 10, and as a result, inclination α may be provided in the system. The progression or movement of particles along the tubular member 13, particularly along the inlet section 131 and the outlet section 133, is facilitated by the action of gravity. The inclination α may be selected so that a specific average translational velocity is obtained for the particles of the material while the particles undergo the drying process. The inclination may be selected according to the specific needs of the material being processed, as well as the rotational speed. Thus, the dynamics of the drying process can be optimized by a combination of temperature, pressure, and conveying speed. The conveying speed can be controlled by adjusting the rotational speed of the tubular member 13 and selecting an appropriate inclination α.

[0046] Furthermore, in some examples, the tubular member may be tiltable, and a tilting device may be provided. The tilting device may be configured to adjust the tilt of the tubular member 13. Specifically, the tilt between the tubular member 13 and the horizontal direction may be between 0° and 45°, more specifically between 5° and 40°.

[0047] In a modified version, the tilting device may include at least one adjustable beam 191 of the frame 19, the position of which may be adjustable relative to the rest of the frame 19. The adjustable beam 191 may be located at one end of the frame 19 structure corresponding to the upper end position of the tubular member 13, while the hinge or pivot point may be located at the lower end of the tubular member 13. Specifically, by adjusting the inclination of the tubular member 13, the inclination α can be adjusted over a relatively wide range, increasing the flexibility and versatility of the freeze-drying system.

[0048] In one example, a tilting device, such as an adjustable beam 191, may be controlled in real time, i.e., during the drying process. In this way, controllability can be increased to ensure uniform drying of the frozen particles over time.

[0049] In one example of this disclosure, as schematically shown in Figure 2, a plurality of temperature stages 231 to 233 may be defined along the tubular member 13. The temperature control system 22 may be configured to individually control the temperatures of temperature stages 231 to 233. Furthermore, in one example, controlled temperature stages may also be provided in the receiving station 12. The temperature stages in the receiving station 12 may be configured to prevent damage to or melting of frozen particles. Specifically, temperatures in the range of -45°C to 0°C, more specifically in the range of -30°C to -10°C, may be provided to the receiving station 12. Thus, the temperature control system 22 may also be configured to control the temperatures of the temperature stages defined in the receiving station 12.

[0050] The definition of multiple temperature stages can improve the controllability of the drying process. Furthermore, the number of temperature stages and the temperature at each temperature stage can be controlled by the temperature control system 22 so that different temperatures can be defined based on the physical properties of the material being processed, particle size, and / or processing volume or flow. The definition of multiple temperature stages facilitates a continuous and stepwise heat supply, and facilitates the sublimation and drying of frozen particles entering the inlet section 131 while they are sequentially transported to positions corresponding to different temperature stages and finally discharged at the end of the outlet section 133.

[0051] Although the temperature control system 22 is schematically shown in Figure 1 as a single block, it will be understood that the temperature control system 22 may actually comprise multiple components that can be located in different places. Thus, the temperature control system may comprise coolers (e.g., a mechanical refrigeration system) and / or heaters (e.g., electric heating wires or electric heating blankets) for defining temperatures at different locations. Furthermore, different elements such as physical enclosures or housings may be arranged around specific parts of the tubular member 13 to define temperature stages. Such enclosures or housings can improve temperature uniformity at each temperature stage.

[0052] Furthermore, as already mentioned, the receiving station 12 of the drying apparatus 10 may also have temperature stages. Therefore, one or more components of the temperature control system 22 may also be provided at the location of such receiving station 12. The components may include a mechanical refrigeration system such as an air conditioning system or coils that are arranged around the area and function as evaporators that expand as the refrigerant fluid passes through them. Also, to facilitate the uniformity of the corresponding temperature, a physical enclosure or housing may also be arranged around the receiving station 12 (or part thereof).

[0053] In the example shown in Figure 1, the components of the temperature control system 22 may include one or more heating wires or blankets 222 that can be wrapped around the outer surface of the tubular member 13, more specifically, around the intermediate helical section 132 and the outlet section 133 of the tubular member 13. Furthermore, an insulating cover or jacket may be placed on the outer surface of the tubular member 13 to improve the uniformity of the temperature of the heated section of the tubular member 13. Desired temperature uniformity and selection can also be facilitated by an appropriate control strategy in the control system 23 that controls the temperature control system 22. In another example, a hot air blowing system may be arranged to supply hot air to the surrounding environment of a particular section of the tubular member 13. In this case, an enclosure or housing may be provided to contain a specific volume of hot air around the desired section of the tubular member 13 to achieve a uniform temperature at each temperature stage.

[0054] Furthermore, in other examples, a cooler may be provided to obtain a low temperature, i.e., a temperature below room temperature. This may be particularly the case for temperature stages arranged around the inlet section 131 of the tubular member 13. Cooling can be provided by arranging a thermoelectric element, such as a Peltier element, which can be attached to the outer surface of the tubular member 13. Furthermore, a chiller, freezer, or similar device may be provided to cool the air in a controlled volume surrounding a desired section of the tubular member 13. In one example, an air conditioning system may be provided to cool the air, for example, a forced convection system with a fan may be arranged to cool a specific portion of the tubular member 13. Thus, in examples such as those shown in Figures 1 and 2, the cooling system may be arranged in a region overlapping at least a portion of the inlet section 131 and at least a portion of the intermediate helical section 132 to define a first temperature stage 231. To ensure proper and uniform cooling, an enclosure or housing 221 may be arranged to contain the air in a controlled volume, as also shown in Figure 1. Such a cooling system may also be located in a receiving station 12 where particularly low temperatures may be required to prevent the thawing or degradation of frozen particles.

[0055] The temperature range of a specific section of the tubular member 13, particularly the intermediate helical section 132 or the outlet section 133, may be maintained at a temperature substantially corresponding to the ambient temperature, i.e., the room temperature of the processing plant where the freeze-drying system is located. In such cases, the temperature control system 22 may also be equipped with an HVAC system used for air conditioning the facility. In other examples, the intermediate helical section 132 and the outlet section 133 may be kept at a low temperature by a cooling system.

[0056] In one example, the multiple temperature stages may include at least three temperature stages, namely a first temperature stage including the inlet section 131, a second temperature stage including at least a portion of the intermediate spiral section 132, and a third temperature stage including the outlet section 133. The temperature control system 22 may also be configured to adjust the temperature so that it rises from the inlet section 131 to the outlet section 133. Furthermore, as already shown, additional temperature stages may be provided in the receiving station 12. The temperature in the receiving station 12 may be kept sufficiently low to prevent melting or damage of frozen particles. In particular, the temperature inside the receiving station 12 may be lower than the temperature in the inlet section 131 of the tubular member 13. Thus, in this variation, the temperature control system 22 may be configured to adjust the temperature so that it rises from the receiving station 12 to the outlet section 133 of the tubular member 13.

[0057] In one example, the temperature stages of the tubular member may substantially coincide with those of different sections of the tubular member 13. Nevertheless, other examples may include different distributions of temperature stages. In particular, multiple temperature stages may be located within the intermediate helical section 132. In other examples, the temperature of at least a portion of the intermediate helical section 132 may be substantially equal to the temperature of at least a portion of the inlet section 131 or the outlet section 133, thus resulting in temperature stages that overlap with two of the sections 131-133 of the tubular member 13.

[0058] In a variation of this example schematically shown in Figure 2, a first temperature stage 231 may be provided covering the inlet section 131 and the first portion of the intermediate helical section 132. A second temperature stage 232 may be provided around the central portion of the intermediate helical section 132. Finally, a third temperature stage 233 may be provided extending over the last portion of the intermediate helical section 132 and the outlet section 133. In this way, it is possible to gradually increase the temperature within the intermediate helical section 132, thereby enhancing control of the drying process. The distribution of temperature stages may depend on the specific needs of the process, namely the physical properties of the material and / or the amount being processed.

[0059] More specifically, the temperature of the tubular member 13 in the first temperature stage may be in the range of -20°C to 25°C, more specifically between -10°C and 20°C. The temperature of the second temperature stage may be in the range of -20°C to 60°C, more specifically between 25°C and 60°C. The temperature of the third temperature stage may be in the range of 0°C to 60°C, more specifically between 25°C and 60°C. Furthermore, an additional temperature stage may be provided in the receiving station 12, in which case the temperature may be in the range of -45°C to 0°C, more specifically between -30°C and -10°C.

[0060] The temperature at each temperature stage can be varied over a wide range, thus increasing the flexibility of the system. Different temperatures may be selected to ensure smooth and continuous sublimation of the frozen particles during the drying stage.

[0061] In other examples, as already mentioned above, the intermediate helical section 132 may extend substantially along the entire length of the tubular member 13. Thus, different temperature stages may be defined within the intermediate helical section 132, while the inlet section 131 and outlet section 133 may simply correspond to the ends of the intermediate helical section 132.

[0062] To control the temperature, the temperature control system 22, i.e., the heater and / or cooler of the temperature control system 22, may be controlled by a control system 23, as also shown in Figure 1. The control system 23 is shown in Figure 1 as a single module that provides control signals for the rotational speed ω of the motor 18 and the temperature control system 22. Nevertheless, although a single module is shown in Figure 1, it should be understood that this is merely a schematic diagram. In particular, in some examples, the control system 23 may comprise a distributed control system, i.e., a control system having multiple distinct components. Alternatively, in other examples of this disclosure, a centralized control unit may be provided.

[0063] In addition to temperature and rotational speed, the pressure within the tubular member may also be controlled by the control system 23. Therefore, in the examples of this disclosure, a micrometer valve may be provided to control the flow of an inert gas, such as nitrogen, which can be introduced into the volume of the dryer 10 to adjust the pressure value. In particular, the pressure at a specific control location within the dryer 10 may be adjusted from 0.001 mbar to 2 mbar. Therefore, precise control of the pressure within the dryer 10 may be obtained by using a preferred location as a reference point. Thus, in the modifications of this disclosure, the pressure may be controlled at the inlet or outlet of the intermediate helical section 132. Alternatively, the pressure may also be controlled by taking a reference point at another location along the tubular member 13, such as a substantially linear inlet section 131 or outlet section 133, or at another location in the dryer 10, such as a receiving station 12, a separation station 16, or a discharge line 212.

[0064] Precise pressure control can be ensured by this embodiment. To convert ice in frozen particles into vapor without passing through the liquid phase, the ambient pressure must be lower than the solvent partial pressure at the corresponding temperature.

[0065] The specific geometric shape of the tubular member 13, and more specifically the specific geometric shape of the intermediate helical section 132, including its helical shape, can significantly affect the efficiency of the freeze-drying process and the quality of the resulting dried particles. In one example of this disclosure, the tubular member 13 may have a radius 63 in the range of 5 to 35 cm, and the intermediate helical section 132 may extend over at least 50% of the length of the central axis of the tubular member 13. The radius of the tubular member 13 may be substantially constant.

[0066] The length of the central axis of the tubular member 13 refers to the total straight-line distance from the starting point of the inlet section 131 to the ending point of the outlet section 133, where the starting and ending points indicate the direction of particle flow. A combination of substantially linear and helical sections may be beneficial for optimizing the process. In particular, the helical shape may allow for a reduction in the overall dimensions of the freeze-drying system, more specifically the drying apparatus 10.

[0067] In one example, the intermediate helical section 132 may extend over substantially 100% of the length of the tubular member 13. Thus, the inlet section 131 and outlet section 133 do not have to indicate a corresponding length and may simply correspond to the first and second ends of the intermediate helical section 132 from which frozen particles are received (inlet section 131) or discharged (outlet section 133). In yet another example, the intermediate helical section 132 may reach only one end of the tubular member 13 on either side, i.e., either the inlet section 131 or the outlet section 133 may substantially include an end of the intermediate helical section 132 that does not have a corresponding length.

[0068] Furthermore, not only the dimensions of the pipe itself, but also the characteristics of the helix can significantly affect the process. Therefore, the parameters of the intermediate helical section 132 may be selected to optimize the drying process. Figure 4 schematically shows the characteristic parameters of such a helical arrangement. In one example, the intermediate helical section 132 may include at least two turns. Also, the helical radius 61 may be between 25 and 100 cm, and the helical pitch 62 may be between 10 and 100 cm.

[0069] Such parameters may be selected to achieve a suitable drying process while meeting the overall mechanical and structural requirements of the pipe.

[0070] Figure 1 includes a receiving station 12 used to receive frozen particles. Different methods and systems can be used to obtain such frozen particles. In some examples, frozen particles may be obtained by first freezing the material as a thin sheet. The thin sheet may then be divided into pieces of appropriate dimensions. In other examples, the material may simply be frozen into a large mass, which may then be broken up into particles of the desired dimensions. In yet another example, the raw material can be frozen as it moves along an elongated conveyor surrounded by cooling coils. A crushing area for crushing and grinding the particles may be located at the end of the conveyor.

[0071] Unfortunately, processes involving the destruction or crushing of frozen sheets and / or lumps can result in significant structural damage. Therefore, the resulting frozen particles may have degraded material properties, particularly when biological preparations or pharmaceuticals are considered. Thus, methods involving milder handling and improved control of the material are preferred, especially when involving the freeze-drying of products requiring careful handling.

[0072] Therefore, in the examples of the present disclosure, the freeze-drying system may comprise a mild freeze-drying apparatus. Figures 5A and 5B schematically show a vacuum freeze-drying apparatus 30 according to two examples of the present disclosure. The vacuum freeze-drying apparatus 30 may comprise a liquid container 31 configured to contain a liquid substance 311. The vacuum freeze-drying apparatus 30 may also comprise a vacuum chamber 32 that is in fluid communication with the liquid container 31 via at least one nozzle 33. The nozzle 33 may be configured to receive the liquid substance 311 from the liquid container 31 and spray droplets 139 into the vacuum chamber 32 in a controllable manner. The vacuum freeze-drying apparatus 30 may comprise a discharge line 37 connected to a vacuum pump system 34. A valve 38 may be provided in the discharge line 37 to control the vacuum level in the vacuum chamber 32. A micrometer valve 321 may be provided to introduce a controlled amount of inert gas, such as nitrogen, to control the pressure in the vacuum chamber 32. In particular, closed-loop control can be assumed to allow the introduction of an amount of nitrogen such that the measured pressure in the vacuum chamber 32 is maintained within a predetermined value.

[0073] In one example, a freeze-drying system can be envisioned that includes a single vacuum pump system that serves both the vacuum freezing and drying functions. In other words, the vacuum pump system 21 shown in Figure 1, and the vacuum pump systems 34 shown in Figures 5A and 5B, may actually be combined into a single vacuum pump or a vacuum pump system.

[0074] The liquid substance 311 may include a solution comprising a solvent, such as water, and a solute dissolved in the solvent. Alternatively, the liquid substance may include a dispersion comprising a dispersed phase in a dispersion medium. The solute or dispersed phase may include a pharmaceutical or biological substance to be processed, such as a pharmaceutical or chemical substance constituting an active ingredient in a pharmaceutical product.

[0075] In one example, the nozzle 33 may be located above the vacuum chamber 32, and the injected liquid substance may fall in the form of a spray. The design of the vacuum freezing apparatus 30, such as the vertical dimensions of the vacuum chamber 32, and the operating conditions, such as the liquid injection rate, the viscosity of the solvent, and the temperature or pressure inside the vacuum chamber 32, can be selected so that the droplets 139 are properly frozen before reaching the bottom section of the vacuum chamber 32.

[0076] According to these examples, the droplets 139 may be injected in a controlled manner, and a fine spray may be obtained. Furthermore, the vacuum level in the vacuum chamber 32 may be at a level that allows vacuum freezing of the droplets 139 to be achieved when the droplets 139 fall into the vacuum chamber 32. Thus, frozen particles 39 may be obtained uniformly and efficiently from the droplets 139. In particular, the pressure in the vacuum chamber 32 may be at a pressure that causes evaporation of the solvent on the outer surface of the droplets 139. As a result of this evaporation, heat is removed from the droplets 139, and they subsequently freeze.

[0077] In one example, a valve 35 may be provided between the liquid container 31 and the nozzle 33. The flow of liquid may be controlled by adjusting the pressure in the liquid container 31, or the valve 35 may be simply controlled in an on / off manner so that liquid flow occurs only after appropriate vacuum conditions are present in the vacuum chamber 32. The flow rate of liquid may also be controlled by adjusting the pressure in the liquid container 31, and as a result, an increase in pressure may increase the amount of liquid injected into the vacuum chamber 32 per unit time. Furthermore, in other examples, the valve 35 may be adjusted to control the flow rate of liquid.

[0078] Since the vacuum freezing process is known to those skilled in the art, only the main principles of the mechanism will be summarized here. Thus, droplets 139 can be sprayed from the nozzle 33. In some examples, depending on the design of the nozzle 33, the injected liquid may initially be in a columnar liquid state. As the liquid flows through the vacuum chamber 32, it gradually disperses, thus resulting in the formation of droplets 139.

[0079] Such substantially spherical droplets 139 exhibit a large specific surface area, i.e., a large surface area-to-volume ratio, resulting in shorter freezing and drying times. The vacuum conditions within the vacuum chamber 32 cause water (or other solvent) to vaporize from the surface of the droplets 139, and heat is removed by a phase transition. Once the heat is removed, the temperature of the droplets 139 decreases, initiating a self-freezing process on the surface of the droplets 139. This process proceeds from the surface to the inner core of the droplet 139 until the entire droplet 139 is frozen, yielding frozen particles 39.

[0080] This process results in the formation of uniform frozen particles, i.e., particles with substantially uniform shape and size. A uniform concentration distribution is also achieved. Furthermore, since no mechanical crushing or destruction process is involved, the structural integrity of the particles is maintained. A further advantage of this process is that the vacuum freezing process is ultrafast, almost instantaneous. Therefore, quality and reproducibility can be improved. Stability is also improved. In particular, the control of ice nucleation, control of microstructure, and the stability of active pharmaceutical ingredients can be enhanced by such a rapid process. The rapid freezing mechanism is one in which cells, proteins, or other active elements that may be present in the solution cannot be degraded.

[0081] In one example, the sprayed liquid may contain a solution in which a pharmaceutical substance is dissolved in a solvent such as water. Different concentrations can be used depending on the processed product, i.e., the solute, and the solvent used. A pressure of 0.5 mbar or less, specifically less than 0.1 mbar, may be maintained in the vacuum chamber 32, and the nozzle 33 may be configured to spray droplets 139 of about 200 μm into the chamber 32.

[0082] The nozzle 33 may be configured to deliver the liquid substance 311 in a controlled manner. Therefore, in one example of this disclosure, the size of the nozzle 33 may be adjustable to control the size of the droplet 139. The size of the droplet 139 can significantly affect the dynamics of the vacuum freezing process. Therefore, the nozzle 33 may be adjusted to achieve a desired size. In some cases, different nozzles 33 may be provided, but in other cases, a nozzle 33 with adjustable dimensions may be selected to more optimally adjust the characteristics of the droplet 139.

[0083] In one example, frozen particles 39 having dimensions in the range of 100 μm to 500 μm may be obtained using a vacuum freezing apparatus 30 shown in either Figure 5A or Figure 5B. Clearly, controlling the size of the frozen particles 39 can also allow for control of the size of the dried product, i.e., the size of the dried particles or granules. Smaller frozen particle sizes can significantly reduce the drying time, and therefore the cycle time of the freeze-drying process can be shortened.

[0084] Apart from the size of the droplets 139 formed, the configuration of the nozzle 33 may be adjusted to control the rate at which the liquid is injected into the vacuum chamber 32. Such a rate can also affect the dynamics of the vacuum freezing process and, therefore, the properties of the resulting frozen particles. This rate can also be controlled or influenced by adjusting the pressure in the liquid container 31.

[0085] In the modified example shown in Figure 5A, one or more trays 36 (or similar receptacles) can be placed at the bottom of the internal volume of the vacuum chamber 32. The trays 36 may be configured to collect frozen particles 39. Furthermore, the vacuum freezing apparatus 30 may include a cooling system (not shown) configured to maintain the trays 36 at a low temperature, specifically down to -50°C.

[0086] The tray 36 can be used to effectively collect and maintain the frozen particles 39. To ensure that the properties of the frozen particles 39 are maintained, the temperature of the tray 36 can be maintained at a sufficiently low temperature, i.e., a temperature that does not allow for a phase transition of the frozen particles. For example, in one example, the tray 36 may be kept at a low temperature of -30°C to -50°C to prevent the frozen particles 39 from melting or degrading. Furthermore, the collection of frozen particles in the tray 36 can facilitate the subsequent handling of the particles, especially when it involves an automated system, such as the transfer of the particles to a drying apparatus by a robot.

[0087] In another example schematically shown in Figure 5B, the vacuum chamber 32 itself may have a tapered bottom 55. The tapered bottom 55 can facilitate the accumulation and collection of frozen particles 39. This example may be particularly suitable in a freeze-drying system that includes a direct connection between the vacuum freezing device 30 and the drying device 10.

[0088] When implementing a freeze-drying system that includes both a drying device and a freezing device, it is necessary to transfer the frozen particles from the freezing device to the drying device. For this purpose, in one example of the present disclosure, a transition step may be provided between the freezing device and the drying device. The transition step may be configured to transport the frozen particles from the freezing device to the drying device, or it may be configured to maintain the frozen particles at a low temperature during transport.

[0089] The transition phase may include, for example, an automated transport system equipped with a robot. Furthermore, the transition phase may include the use of a load lock system for loading the frozen particles into the dryer. In particular, in an example including a vacuum freezer 30 as shown in Figure 5A, the tray 36 containing the frozen particles may be transported and maintained at a low temperature during the transition phase, or it may be transferred to a dryer 10 as shown in Figure 1 via an automated airlock system. Subsequently, the frozen particles in the tray 36 may be poured into a container 121 at the receiving station 12. A load lock system may be provided for transferring the frozen particles to the receiving station 12.

[0090] In one example, the transition stage may include a valve system for connecting or isolating the vacuum freezing apparatus 30 and the drying apparatus 10. On the one hand, the valve system may be open to allow the transport of frozen particles from the vacuum freezing apparatus 30 to the drying apparatus 10. On the other hand, when no material is being transported, the valve system may be closed. In this way, the freezing of droplets and the drying of already frozen particles can be carried out simultaneously, or in parallel and continuously.

[0091] Figure 6 provides a schematic diagram of a freeze-drying system 5 comprising a vacuum freezer 30 and a dryer 10. In this example, a vacuum freezer 30 as shown in Figure 5B may be used. The bottom 55 of the vacuum freezer 30 may be connected to an intermediate chamber 54 via a first valve 52. Subsequently, the intermediate chamber 54 may be connected to a container 53 via a second valve 51. The container 53 may substantially correspond to a container 121 of the receiving station 12 of the dryer 10, as schematically shown in Figure 1.

[0092] In this example, a continuous freeze-drying process can be provided. Thus, the frozen particles 3 can be initially accumulated at the bottom 55 of the vacuum chamber 32. After a certain amount of frozen particles 39 have been collected, the first valve 52 may be opened to transfer such frozen particles 39 to the intermediate chamber 54. Subsequently, the first valve 52 may be closed again, and the second valve 51 may be opened to transfer the frozen particles 39 to the container 53. After the transfer of the frozen particles 39, the second valve 51 may also be closed. The frozen particles 39 may then be transported to a tubular member 13 that rotates through a rotary joint 14 to start the drying process. Then, while some of the frozen particles 39 are being dried in the drying apparatus 10, new frozen particles can be generated in the vacuum freeze apparatus 30.

[0093] A pressure control system, such as a vacuum pump system, may be provided in the intermediate chamber 54. Thus, the pressure in the intermediate chamber 54 may be equal to that of either the vacuum chamber 32 of the vacuum freezing apparatus 30 or the vessel 53 of the drying apparatus 20. Therefore, the pressure in the intermediate chamber 54 may be adjusted before opening the corresponding valves 52, 51. Alternatively, in another example, a flow connection or bypass, such as a duct or pipe with a controllable valve, may be provided between the intermediate chamber 54 and the internal volumes of the vacuum freezing apparatus 30 and the drying apparatus 10. Such a controllable valve may be controlled to allow connection between the volumes so that the respective pressures are equalized before opening the valves 52, 51 that allow the transfer of frozen particles. Other solutions may include the use of a load lock system.

[0094] Furthermore, different configurations can be envisioned to accommodate different freezing and drying times. For example, in another example, multiple drying units 10, as shown in Figure 6, may be connected to the same vacuum freezing unit 30. Multiple first valves 52, second valves 51, and intermediate chambers 54 may be arranged, each connecting the vacuum freezing unit, i.e., its bottom 55, to its respective drying unit 10. In this way, a balance can be achieved between the freezing and drying processes, which are usually faster. As a result, the processing capacity of the freeze-drying system can be increased.

[0095] In other examples, alternative coupling mechanisms can be envisioned for connecting the vacuum freezing device 30 and the drying device 10. In other words, different coupling mechanisms can be envisioned to enable the transfer of frozen particles 39 from the vacuum freezing device 30 to the drying device 10. Thus, in another example, a rotary valve may be used. Such a rotary valve may include one or more cavities for collecting the frozen particles 39. As the valve rotates, the frozen particles 39 can be continuously and automatically transferred to the drying device 10. As in the above example, a pressure adjustment system may be provided in the coupling mechanism to enable connection to either the vacuum freezing device or the drying device.

[0096] Figure 7 shows a flowchart of an example of Method 100 for freeze-drying a substance according to the present disclosure. Method 100 includes the step in block 110 of providing frozen particles of the substance into a drying apparatus. The drying apparatus comprises a tubular member that is rotatable under vacuum. Block 120 of Method 100 includes the step of transferring the frozen particles to the inlet section of the tubular member, which also includes an outlet section and an intermediate helical section. Block 130 then transports the frozen particles along the tubular member from the inlet section to the outlet section while rotating the tubular member and controlling the temperature along the tubular member to a desired temperature, thereby continuously drying the particles during transport. In some examples, it is also possible to control the pressure. Block 140 then collects the dried particles into a collection station.

[0097] Method 100 provides enhanced control over the drying sequence. In particular, Method 100 facilitates gentle handling of particles by conveying them along the spiral tube, i.e., along the intermediate spiral section of the tubular member, by rotating the tubular member, while providing enhanced control over the properties of the dried particles. Furthermore, as already described with reference to the system shown in Figure 1, Method 100 may be particularly suitable for processing biological or pharmaceutical products to observe cGMP.

[0098] In one example, the rotatable tubular member 13 may be inclined with respect to the horizontal direction. This can promote the translational motion of particles during the drying process.

[0099] In one example of method 100, the step of controlling the temperature along the tubular member in block 130 may include the step of individually controlling the temperature at at least three different temperature stages along the length of the tubular member.

[0100] In this example, as the frozen particles are transported along the tubular member and the temperature gradually increases, a more optimized, smooth, and continuous drying process may be obtained.

[0101] Furthermore, the freeze-drying system may include a receiving station for receiving frozen particles. Therefore, additional temperature stages can be defined in the receiving station to prevent damage or melting of the frozen particles before they are transferred to the tubular member. The temperatures in such temperature stages may be controlled individually. As a result, in some examples, the temperature may be controlled individually in at least four different temperature stages, including at least three individual states along the length of the tubular member and another temperature stage within the receiving station.

[0102] Furthermore, in other examples of method 100, the step of rotating the tubular member in block 130 may include the step of controlling and adjusting the rotation speed, particularly in the range of 0.05 to 10 rpm, while the particles are being conveyed.

[0103] In this example, the rotational speed may be adjusted over a wide range even during the drying cycle. Therefore, method 100 may be dynamically adjusted so as to ensure improved properties of the dried material.

[0104] In yet another variation of Method 100, the pressure at a position within the internal volume of the tubular member may be monitored, and the vacuum level may be controlled to be between 0.001 mbar and 2 mbar.

[0105] Similar to the example described above, the improved pressure control during the implementation of Method 100 may also provide more dynamic adjustment of process conditions, thereby improving the properties of the dried material.

[0106] Furthermore, other examples can provide even better control over the drying process. In such examples, the state of the particles can be monitored while they are being transported along the tubular member in block 130. The temperature, rotation speed, and / or pressure can be adjusted according to the monitored state. Specifically, the conditions may include at least one of the temperature and residual moisture of the particles at a given position in the tubular member.

[0107] This method allows for closed-loop control of the freeze-drying process. Therefore, the physical and / or chemical state of the particles can be monitored while they are being transported along the tubular member. As a further example, the formation of particle clusters can also be monitored. For this purpose, several sensors can be distributed along the length of the tubular member. For example, windows may be placed on the surface of the tubular member, and non-contact temperature and / or humidity sensors may be provided. Readings from such sensors can be supplied to a control system, for example, the control system 23 shown in Figure 1.

[0108] The control system 23 can then actively control different operating conditions of the dryer, such as rotational speed, pressure, incline, temperature distribution along the tubular member 13, or temperature within the receiving station 12. Different control strategies may be implemented in the control system 23 to control different variables. Thus, as a non-limiting example, on-off control, proportional control, or PID control methodologies may be implemented for temperature control at different locations on the tubular member 13 and pressure control during the process. The window can also be used for visual inspection of the process. A camera may be provided for this purpose. In examples involving such closed-loop control, a bypass system may be provided in the dryer 10 to bypass potentially unsuitable material. In particular, a specific valve may be located after the tubular member 13, i.e., after the outlet section 133 of the tubular member 13. Such a valve may be connected to a container configured to receive unsuitable material.

[0109] Figure 8 provides an example of Method 200 for providing frozen particles of a substance. Method 200 includes the step of storing the substance in liquid form in a container in block 210. Block 220 of Method 200 includes the step of evacuating the chamber until a specific vacuum level is reached. Subsequently, in block 230, the liquid substance stored in the container is sprayed into the evacuated chamber through at least one spray nozzle to generate frozen particles by vacuum freezing. The frozen particles are collected in the bottom section of the chamber in block 240. Finally, Method 200 includes the step of transferring the frozen particles to a drying apparatus in block 250.

[0110] As already described with reference to the vacuum freezing apparatus 30 shown in Figures 5A and 5B, Method 200 can provide very uniform frozen particles. In particular, the vacuum level achieved in block 220 can be selected to result in optimal vacuum freezing of the droplets. Such optimization may also take into account the nozzle design and / or operating conditions.

[0111] In one example, block 220 may include evacuating the chamber until a specific value of 0.5 mbar or lower is reached, for example, a vacuum level lower than 0.1 mbar. Furthermore, block 230, which includes spraying a liquid substance into the evacuated chamber, may not be carried out until the collection tray 36 located at the bottom of the vacuum chamber 32 or the bottom 55 of the vacuum chamber 32 reaches a specific value, for example, a temperature lower than -50°C. In this way, it is possible to ensure that the continuously produced frozen particles maintain their properties after deposition and collection.

[0112] The flowcharts shown in Figures 7 and 8 can be combined when using a freeze-drying system 5 such as the one shown in Figure 6.

[0113] This specification uses examples to disclose teachings including preferred embodiments and to enable a person skilled in the art to carry out the teachings, including creating and using any apparatus or system and performing any incorporated methods. The patentable scope is defined by the claims and may include other examples conceivable by a person skilled in the art. Such other examples are intended to be within the claims if they have structural elements not different from the language of the claims, or if they include equivalent structural elements not substantially different from the language of the claims. Aspects from the various embodiments described, as well as other known equivalents of each such aspect, can be mixed and adapted by a person skilled in the art to construct additional embodiments and techniques in accordance with the principles of this application. Where reference numerals related to the drawings are placed in parentheses in the claims, they are merely for clarity of the claims and should not be construed as limiting the claims.

Claims

1. A continuous freeze-drying system, A drying apparatus configured to receive frozen particles of a substance and dry the particles, comprising a rotatable tubular member having an inlet section, an outlet section, and an intermediate helical section, A vacuum pump system for maintaining a vacuum inside the tubular member, A temperature control system configured to control a desired temperature within the tubular member, A drive unit for rotating the rotating tubular member to transport the particles, A control system for controlling the drive unit and the temperature control system so that the received frozen particles are dried before reaching the end of the outlet section, A continuous freeze-drying system equipped with the following features.

2. The system according to claim 1, wherein the inlet section of the tubular member is connected to a receiving station, the receiving station is configured to receive the frozen particles, and the connection between the inlet section of the tubular member and the receiving station is provided with a rotary joint.

3. The system according to claim 1 or 2, wherein the outlet section of the tubular member is connected to a separation station, the separation station is configured to separate dry particles from vapor, and the connection between the outlet section of the tubular member and the separation station is provided with a rotary joint.

4. The system according to any one of claims 1 to 3, wherein the tubular member is inclined with respect to the horizontal direction such that the inlet section is at a higher vertical position than the outlet section, and in particular the tubular member is tiltable and is provided with a tilting device, the tilting device being configured to adjust the inclination of the tubular member between 0° and 45° with respect to the horizontal direction.

5. The system according to any one of claims 1 to 4, wherein a plurality of temperature stages are defined along the tubular member, and the temperature control system is configured to individually control the temperatures of the temperature stages.

6. The system according to claim 5, wherein the plurality of temperature stages include at least three temperature stages, namely a first temperature stage including the inlet section, a second temperature stage including at least a portion of the intermediate spiral section, and a third temperature stage including the outlet section, and further, the temperature control system is configured to control the temperature so that the temperature rises from the inlet section to the outlet section.

7. The system according to any one of claims 2 to 6, wherein temperature stages are defined in the receiving station, and the temperature control system is configured to individually control the temperatures of the temperature stages defined in the receiving station.

8. The system according to any one of claims 1 to 7, wherein the tubular member has a radius in the range of 5 to 35 cm, the helical section extends over at least 50% of the length of the central axis of the tubular member and includes at least two turns, further wherein the helical radius is between 25 and 100 cm and the helical pitch is between 10 and 100 cm.

9. The system includes a vacuum freezing apparatus configured to receive the substance in a liquid state and freeze the substance to produce frozen particles of the substance, and the vacuum freezing apparatus is A liquid container configured to contain the aforementioned liquid substance, A vacuum chamber that is in fluid communication with the liquid container via a nozzle, Equipped with, The nozzle is configured to receive the liquid substance from the container and spray droplets into the vacuum chamber in a controllable manner. The system according to any one of claims 1 to 8.

10. The system according to claim 9, wherein one or more trays are positioned at the bottom of the internal volume of the vacuum chamber, the trays are configured to collect the frozen particles, and the vacuum freezing apparatus further comprises a cooling system configured to maintain the trays at a low temperature, specifically -30°C to -50°C.

11. The system according to any one of claims 9 or 10, wherein a transition step is provided between the vacuum freezing apparatus and the drying apparatus, the transition step is configured to transport the frozen particles from the vacuum freezing apparatus to the drying apparatus, and the transition step is configured to maintain the frozen particles at a low temperature during transport.

12. A freeze-drying method for freeze-drying a substance, wherein the method is: A step of providing frozen particles of a substance into a drying apparatus equipped with a tubular member that can rotate under vacuum, A step of transferring the frozen particles to the inlet section of the tubular member, wherein the tubular member also comprises an outlet section and an intermediate helical section, The steps include: continuously drying the particles while conveying them along the tubular member from the inlet section to the outlet section, while rotating the tubular member and controlling the temperature along the tubular member to a desired temperature; The steps include collecting the dried particles at a collection station, A freeze-drying method, including the following.

13. The method according to claim 12, wherein the step of controlling the desired temperature along the tubular member includes the step of individually controlling the desired temperature in at least three different temperature stages along the length of the tubular member.

14. The method according to claim 12 or 13, wherein the step of providing frozen particles of a substance into a drying apparatus includes the step of transferring the frozen particles to a receiving station of the drying apparatus, and the method further includes the step of individually controlling the temperature in the receiving station.

15. The method according to any one of claims 12 to 14, wherein the state of the particles is monitored while the particles are being transported along the tubular member, and further, the temperature, rotation speed and / or pressure are adjusted according to the monitored state, specifically, the state includes at least one of the temperature and residual moisture of the particles at a predetermined position in the tubular member.

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