System for controlling freeze-drying process of freeze dryer having plate stack system and method of generating design space

Abstract

The invention relates to a system suitable for controlling a freeze-drying process in a freeze dryer (1) having a suspended plate stack system (2) comprising at least one heatable plate (3), the plate stack (2) being suspended from another heatable plate (3) or an upper platen (4), wherein each heatable plate (3) of the stack of plates (2) is connected to each other or to the upper platen (4) by mechanical connection means (5), and a method for monitoring and controlling a freeze-drying process comprising the use of said system.

Description

Technical Field

[0001] The present invention relates to a system suitable for controlling a freeze-drying process in a freeze-dryer having a plate stack system, and also relates to a method suitable for generating a design space and a method for monitoring and controlling a freeze-drying process including the use of the above-mentioned system, so that it can be used for the commercial production of drugs, cosmetics or foods. Background Art

[0002] Freeze drying is an important step in the manufacture of many injectable or parenteral drugs. Freeze drying is also a key technology used in the GMP regulated field.

[0003] Freeze drying is a physicochemical process that increases the stability of a product by removing water from it. This technology is used in particular for injectable products or pharmaceutical products that are very unstable in aqueous solutions and must be stored at low temperatures in a refrigerator. During freeze drying, for example, vials or ampoules pre-filled with the drug are placed in a special freeze drying chamber. First, the product is frozen by lowering the temperature in this chamber. Subsequently, the pre-frozen product is subjected to sublimation of the solvent (usually water) in an atmosphere with a very low solvent vapor pressure. In this way, the water and most of the solvent are removed from the product, making the product more stable and its shelf life longer.

[0004] Freeze drying allows these products to be preserved at low temperatures and room temperature, greatly facilitating the logistics of their storage, transportation and distribution.

[0005] Various methods and systems have been developed to control and monitor freeze-drying cycles, process conditions, and the quality of the product obtained by freeze-drying.

[0006] For example, an early design such as that described in US Pat. No. 3,176,408 describes a freeze drying apparatus and method for articles of the same size and type, wherein the articles are located in a sealed chamber, shelves and trays are provided for supporting the frozen articles to be freeze dried, means for freeze drying the articles stored on the trays and means for responding directly to the weight loss of the articles due to sublimation, wherein the apparatus includes at least two load cells located below the shelves (see Figure 1 2 ) to automatically control the freeze drying device, wherein the means for responding to weight loss includes means for changing the pressure in the chamber. The shelf of the device may have two load cells, which are arranged below the fixed shelf and connected to a weight recorder and a controller via wires. Depending on the measured weight, the temperature or pressure provided to the device may change.

[0007] Subsequently, patent document CN206670234 disclosed a freeze dryer for performing a freeze drying process, which includes a chamber with three fixed shelves in the chamber for placing vials to be freeze dried. The shelf includes a resistance strain type weighing sensor and a sensor mounting bracket fixedly connected to the center of each shelf. The bottom of one end of the strain type weighing sensor is fixedly connected to the sensor bracket by a mounting bolt. The bottom of the other end of the resistance strain type weighing sensor is provided with an adjusting bolt for adjusting the height position of the resistance strain type weighing unit, and the side of the strain type weighing sensor weighing unit is provided with a sensor output end, i.e., a sensor. The weighing system determines the amount of material produced during the processing by measuring the change in weight over time. The device includes a strain gauge for each partition.

[0008] These strain gauges are connected to a control device (which can be a PLC) that collects the weight measurements from the strain gauges and displays them on a screen. The operator can then determine the optimal freeze-drying time based on the weight changes displayed on the screen.

[0009] In addition to observing whether the indicator light 11 is on, the operator can determine whether the experiment is over when directly observing that the value displayed on the display screen no longer changes. In addition, the device includes a timer 12, which is configured to record the measured weight value of the strain gauge load cell every 30 minutes until two consecutive measured values ​​are stable and the ice in the material is completely sublimated. The light 11 receives a signal from the electronic control unit 13 and lights up, thereby guiding the operator to terminate the process. The disadvantage of this system is that it limits the control and termination of the process to a manual process performed by the operator.

[0010] Recent publications such as US2020340743 A describe a non-invasive system and method that uses a network of wireless gas temperature and ambient pressure sensors to monitor and control the freeze-drying process; in particular, the method can use an arbitrary mathematical model to determine in real time the sublimation rate of the solvent stored in the vial inside during the freeze-drying process.

[0011] More specifically, US2020340743A describes a system comprising:

[0012] A wireless pressure and gas temperature sensor, a housing coupled to a fluid surrounding the housing; a power source disposed within the housing, an electronic module electrically coupled to the power source, comprising a microcontroller and a wireless transceiver, wherein the wireless pressure sensor together with the electronic module is adapted to provide ambient pressure and gas temperature values, the sensors being located inside different vials that are placed on a shelf inside a freeze-drying chamber together with vials containing the product to be freeze-dried. In addition, the system comprises a vacuum pump adapted to change the pressure of the freeze-drying chamber, and a heat exchanger adapted to change the temperature of the freeze-drying chamber, wherein

[0013] The control unit is adapted to collect pressure and gas temperature data from one or more wireless pressure sensors and to calculate the sublimation rate of the product to be freeze-dried using the collected pressure temperature and gas data.

[0014] The control unit of the system calculates the sublimation rate as follows: by applying a predetermined initial limit condition on a channel representing the space within the freeze-drying chamber and near the freeze-drying bottle tray, iteratively minimizing a penalty function associated with the difference between the calculated spatial pressure information and the collected spatial pressure information, the penalty function comprising:

[0015] Calculate the spatial temperature and gas supply information of the distribution locations of one or more wireless pressure and gas temperature sensors, and calculate the difference between the calculated spatial pressure information and the collected spatial pressure information; in addition, calculate the penalty function of the relevant intermediate reference value and the relevant limit condition between the collected and calculated spatial pressure information, determine the new limit condition that causes the calculated penalty function to decrease, and calculate the sublimation rate by applying the relevant limit condition with the penalty function in g.

[0016] Therefore, there is a need to design systems and methods for monitoring different freeze-drying processes in different industries, and the systems and methods can be applicable to different freeze-drying containers and can create a design space adjusted according to the actual conditions of the freeze-drying process. In addition, they are also used as a reference or model for predicting future values ​​of conditions in containers (such as vials) suitable for freeze-drying during the freeze-drying process.

[0017] Likewise, there is a need to develop systems and methods to facilitate determination of optimal conditions for conventional lyophilization processes in large-scale and small-scale production, or to determine the limits at which such processes may fail in the production process. Summary of the invention

[0018] For example, the system of the first aspect of the present invention is applicable to the freeze-drying process of, for example, an injectable product, which can monitor parameters that directly damage the quality of the freeze-dried product, thereby integrating it into the quality control of the product through the control process according to the concept of "quality by design". Similarly, it is also applicable to freeze-dried products used in food, because they can preserve the flavor of the product over time.

[0019] The system of the first aspect of the invention has the following advantages: it can directly obtain the mass of the plate stack (2) and the heatable plate, and then calculate the flow rate of water vapor sublimated in the freeze dryer by using a weighing sensor. In addition, the system can obtain key process parameters, helping manufacturers to obtain a "design space" based on "design quality" in a simple and robust way.

[0020] In addition, the system makes it easier to monitor different freeze-drying processes in different industries, can be used for different freeze-drying containers, and can create a design space adjusted according to the actual conditions of the freeze-drying process. In addition, it is also used as a reference or model to predict future values ​​of conditions in containers (such as vials) suitable for freeze-drying during the freeze-drying process. The system can also determine the optimal conditions for conventional freeze-drying processes in large-scale and small-scale production, or determine the limits or ranges based on the process at which the production process may fail and validate the production process.

[0021] Therefore, the system of the first aspect of the present invention is a system suitable for controlling the freeze drying process of a freeze dryer (1), the freeze dryer (1) having a plate stack system (2) comprising at least one heatable plate (3), wherein the plate stack (2) is suspended on another heatable plate (3) or on an upper platen (4), wherein each heatable plate (3) of the plate stack (2) is connected to each other or to the upper platen (4) via a mechanical connection device (5), wherein the system comprises:

[0022] I. at least one pressure sensor (6) for measuring the absolute pressure in the freeze-drying chamber;

[0023] II. at least one temperature sensor (7) for determining the temperature of each heatable plate (3);

[0024] III. at least one product temperature sensor (8) for measuring the temperature of the product and located in a container suitable for freeze drying;

[0025] IV. at least one strain gauge (9) configured to be located on the upper portion of each heatable plate (3) and / or the upper platen (4) constituting the freeze dryer (1);

[0026] wherein at least one strain gauge (9) is connected to the mechanical connection device (5);

[0027] V. The control unit (10) comprises a processor (11) and a display device (12), wherein the control unit (10) is configured to automatically and simultaneously collect and analyze measurement values ​​from at least sensors (6), (7), (8) and (9), and to display at least one of the measurement values ​​on a working map of the display device (12),

[0028] The sensors (6), (7), (8) and (9) are data-connected to the control unit (11) via electronic devices (13A, 13B, 13C, 13D).

[0029] A second aspect of the present invention relates to a freeze dryer (1), comprising:

[0030] a freeze drying chamber (14),

[0031] Upper pressing plate (4),

[0032] a heatable plate (3) for storing samples,

[0033] A suspended plate stack system (2) comprising at least one heatable plate (3) for placing a sample suitable for a freeze-drying process, wherein the plate stack (2) is suspended on another heatable plate (3) or an upper platen (4), wherein each heatable plate (3) of the plate stack 2 is connected to each other or to the upper platen (4) by a mechanical connection device (5);

[0034] The system according to claims 1-21; and

[0035] Optionally, the heatable plate (3) of the freeze dryer (1) is a movable plate.

[0036] A third aspect of the present invention relates to a method suitable for generating a design space for a sample, comprising a container for freeze drying containing a product, during a freeze drying process in a freeze drying chamber of a freeze dryer (1) comprising a system according to claims 1 to 22, preferably a freeze dryer (1) according to any one of claims 23 and 24, wherein the method comprises:

[0037] i. placing a sample to undergo a freeze-drying process in the chamber (14);

[0038] ii. freeze-drying the sample;

[0039] iii. During the entire freeze-drying process of step ii), using at least one strain gauge (9) to measure the weight change of the sample at different time intervals;

[0040] iv. measuring the temperature of the heatable plate (3) at different time intervals using a temperature sensor (7) throughout the freeze-drying process in step ii);

[0041] v. During the entire freeze-drying process of step ii), measuring the temperature of the sample product at different time intervals using a temperature sensor (8);

[0042] vi. measuring the absolute pressure in the freeze-drying chamber at different time intervals during the entire freeze-drying process of step ii);

[0043] wherein steps iii), iv), v) and vi) are performed simultaneously in real time to provide measurements of chamber pressure, temperature of the heatable plate (3), product temperature, weight change of the sample, and

[0044] wherein the measured values ​​are collected by a control unit (10), and the measured values ​​or at least one of the parameters obtained by the control unit (10) from the measured values ​​are represented on a working diagram by a display device (12), wherein the working diagram comprises at least a graphical representation of the measured values ​​collected by the control unit (10) or the parameters obtained by the control unit (10), wherein the graphical representation of at least one of the measured values ​​or parameters, and

[0045] Constraints of the design space can optionally be established.

[0046] A fourth aspect of the present invention relates to a method for monitoring and controlling a sample, said sample comprising a container suitable for freeze drying, said container containing a product, typically during freeze drying in a freeze drying chamber (2) of a freeze dryer (1) comprising a system according to claims 1 to 22, preferably a freeze dryer (1) according to any one of claims 23 and 24, wherein said method comprises at least the following steps:

[0047] i. placing a sample to undergo a freeze-drying process in the chamber (14);

[0048] ii. freeze-drying the product;

[0049] iii. Optionally, during the entire freeze-drying process in step ii), at least one strain gauge (9) is used to measure the weight change of the sample at different time intervals;

[0050] iv. During the entire freeze-drying process in step ii), the temperature of the heatable plate 3 is measured at different time intervals using a temperature sensor (7);

[0051] v. Optionally, during the entire freeze-drying process of step ii), the product temperature of the sample is measured at different time intervals using a temperature sensor (8);

[0052] vi. measuring the absolute pressure in the freeze-drying chamber at different time intervals during the entire freeze-drying process of step ii);

[0053] wherein step iii), step iv), step v), and step vi) are performed simultaneously in real time to provide measured values ​​of chamber pressure, temperature of the heatable plate (3), product temperature, and weight change of the sample, and

[0054] wherein the measured values ​​are collected by a control unit (10), and the measured values ​​or at least one of the parameters obtained by the control unit (10) through the measured values ​​are represented on a working diagram by a display device (12), wherein the working diagram comprises at least a graphical representation of the measured values ​​collected by the control unit (10) or the parameters obtained by the control unit (10), wherein the graphical representation represents at least one of the measured values ​​or the parameters;

[0055] a. by using the control unit (10), comparing the temperature and pressure measurements of the heatable plate (3) obtained in at least the working diagram of each product in step ii) with the values ​​of the sample or standard sample previously obtained in the same step ii) in the design space according to the third aspect;

[0056] b. If necessary, according to the deviation of the result obtained in step e) from the design space of the sample or standard sample, the absolute pressure and temperature parameters of each process in the freeze dryer are optionally adjusted by the control unit (10). BRIEF DESCRIPTION OF THE DRAWINGS

[0057] The above and other advantages and features will be more fully understood from the following detailed description of exemplary embodiments with reference to the accompanying drawings, which should be regarded as illustrative and not restrictive, wherein:

[0058] Figure 1 A graphic or representation of a workspace.

[0059] Figure 2. Figure 2A is a working diagram (graph) showing the relationship between the chamber pressure and the mass flow rate and plate temperature isotherms. Figure 2B It is a working diagram (graph) showing the relationship between chamber pressure and mass flow rate and product temperature isotherms.

[0060] Figure 3 It is a working diagram (graph) showing the throttling flow limit or throttling point of the freeze dryer.

[0061] Figure 4 It is a working diagram (graph) showing the throttling flow, product and plate temperature isotherms.

[0062] Figure 5It is a schematic diagram of an embodiment of a plate stack 2 and a system of the first aspect of the present invention and a freeze dryer and its components of the second aspect together: 1. Freeze dryer; 2. Suspended plate stack; 3. Heatable plate; 4. Upper pressure plate; 5. Mechanical connection device; 6. Pressure sensor; 7. Temperature sensor (heatable plate); 8. Product temperature sensor; 9. Strain gauge; 10. Control unit, which includes 11. Processor; 12. Display device, 13. Electronic device; 14. Freeze drying chamber; 15. Heating device; 16. Junction box; 17. Memory for storing data; 18. Battery; 19. Antenna. DETAILED DESCRIPTION

[0063] The system of a first aspect of the present invention is a system suitable for controlling a freeze drying process of a freeze dryer (1), the freeze dryer (1) having a suspended plate stack system (2) comprising at least one heatable plate (3), wherein the plate stack (2) is suspended on another heatable plate (3) or an upper platen (4), wherein each heatable plate (3) of the plate stack (2) is connected to each other or to the upper platen (4) via a mechanical connection device (5), wherein the system comprises:

[0064] I. at least one pressure sensor (6) for measuring the absolute pressure in the freeze-drying chamber;

[0065] II. at least one temperature sensor (7) for determining the temperature of the heatable plate (3);

[0066] III. at least one product temperature sensor (8) for measuring the temperature of the product and located in a container suitable for freeze drying;

[0067] IV. at least one strain gauge (9) configured to be located on the upper portion of each heatable plate (3 and / or the upper platen (4) constituting the freeze dryer (1);

[0068] wherein at least one strain gauge (9) is connected to the mechanical connection device (5);

[0069] V. The control unit (10) comprises a processor (11) and a display device (12), wherein the control unit (10) is configured to automatically and simultaneously collect and analyze measurement values ​​from at least sensors (6), (7), (8) and (9), and to display at least one of the measurement values ​​on a working diagram of the display device (12),

[0070] The sensors (6), (7), (8) and (9) are data-connected to the control unit (11) via electronic devices (13A, 13B, 13C, 13D).

[0071] The system of the first aspect has the advantage that it can be installed and used in large commercial freeze dryers and small laboratory freeze dryers. And it has the advantage that it can be installed without affecting the normal function of the freeze dryer.

[0072] Thus, in all aspects of the invention, the load cell of the present invention is adapted to be capable of operating in vacuum conditions, while the most important challenge to be overcome is operating in very low temperature environments.

[0073] In a more preferred embodiment, the system of the first aspect is adapted for use in a freeze dryer comprising a movable heatable plate (3).

[0074] In another preferred embodiment of the system of the first aspect, the freeze dryer is a freeze dryer with a top piston system.

[0075] In another preferred embodiment, the freeze dryer to which the system of the first aspect is applicable comprises at least one freeze drying chamber (14), an upper pressure plate (4), a suspended heatable plate (3) suitable for storing containers suitable for freeze drying, a hydraulic piston, a heating device (15) and a device for modifying and controlling the pressure in the chamber.

[0076] In the present invention, the term "sample" includes a container suitable for freeze drying, wherein the container contains a product suitable for freeze drying. Preferably, the product includes a solvent, a cosmetic or pharmaceutically acceptable active ingredient or a product suitable for food use. In another preferred embodiment, the container suitable for freeze drying samples in any aspect of the present invention is selected from vials, ampoules, syringes, cartridges, bulk trays, microtubes and flasks.

[0077] In the present invention, the term "standard sample" refers to a sample that can be used as a reference or a calibration sample for subsequent industrial manufacturing.

[0078] Typically, the hydraulic piston can raise and lower all the heatable plates (3) that make up the plate stack (2). When the freeze-dried sample is a product placed in vials, the vials are closed in the chamber. This is performed by a hydraulic piston that, as the plates are lowered, presses the upper plate against the lid of each vial until the lid is closed.

[0079] Freeze dryers with hydraulic pistons are commonly used in the pharmaceutical, cosmetic and food industries, and therefore the system of the first aspect is a highly versatile system that can be used in most commercial freeze dryers. Preferably, a freeze dryer with a top piston is used.

[0080] Generally speaking, the freeze-drying chamber is a space for placing the sample to be freeze-dried. The sample is located on the heatable plate (3). The combination of the heatable plate and the upper pressing plate is called a plate stack (2). The plate stack (2) includes at least one heatable plate (3), which is suspended on another heatable plate (3) or the upper pressing plate (4) through a mechanical connection device (5). The plate stack (2) may also have other suspended heatable plates (3), which are in turn suspended on the suspension plate (3) immediately above them through a mechanical connection device (5).

[0081] Typically, the freeze dryer (1) also comprises a condenser, which may be, for example, a coil, for collecting any water vapor sublimated from the sample placed in the freeze drying chamber (14).

[0082] In a preferred embodiment, the system of the first aspect comprises at least two strain gauges (9), more preferably at least four strain gauges (9).

[0083] In the present invention, each strain gauge (9) is configured to be connected to the mechanical connection device (5); the mechanical connection device (5) has the characteristics of adapting to the shape of the heatable plate (3) of the freeze dryer. In a preferred embodiment of the system of the first aspect, at least one strain gauge (9) is configured to be connected to the upper part of the mechanical connection device (5) and to the upper part of the heatable plate (3) or the upper pressing plate (2), so as to obtain more accurate and repeatable measurements. In another more preferred embodiment of the system of the first aspect, the at least strain gauge (3) is configured to be connected to the upper part of the mechanical connection device (5) directly or indirectly through a tool (20).

[0084] In the present invention, the tool (20) or compressive force transmitting structure is located at the connection point between the load cell and the point where the force is generated.

[0085] Generally, the mechanical connection means (5) is a metal element for connecting and supporting the weight of the lower or immediately lower heatable plate (3). The mechanical connection means (5) is configured to support the weight of the lower heatable plate (3) to form a plate stack (2). The mechanical connection means (5) is configured to extend through the heatable plate (3) or the upper platen (4) so ​​that the end of the device is located above the heatable plate (3) or the upper platen (4), as the case may be.

[0086] In a particular embodiment, the mechanical connection means (5) may be selected from a cylindrical rod, preferably, the cylindrical rod is selected from a hollow or solid cylindrical rod, a metal shaft and a metal rail. More preferably, the mechanical connection means (5) comprises a metal selected from steel and stainless steel.

[0087] In a preferred embodiment of the system of the present invention, the control unit (10) is located outside the freeze dryer, and the processor (11) is selected from a CPU or a PLC unit. Preferably, the control unit (10) comprises a processor (11), a network interface, a display device (12), a user input device and a storage unit, and the display device (12) is selected from a display or a screen.

[0088] The control unit (10) may be a server, a desktop computer, a laptop computer, a tablet computer or any other suitable type of computing device.

[0089] In another preferred embodiment of the system of the present invention, the system may have two control units (10), one control unit (10EA) is located outside the freeze dryer, and the other control unit (10EB) is connected to the freeze dryer, and both are data-connected to the pressure sensor (6), the plate temperature sensor (7), the product temperature sensor (8) and at least the strain gauge (9), wherein the external control unit (10EA) is data-connected to the control unit (10EB) of the freeze dryer via the processor (11).

[0090] In another preferred embodiment of the system of the invention, at least the strain gauge (9) is configured to measure the weight of the heatable plate (3), and the control unit (10) is configured to calculate the weight change of the heatable plate (3) of the freeze dryer. In the system of the invention, each strain gauge (9) is configured to measure the weight of the heatable plate (3) of the freeze dryer. The weight change of the heatable plate (3) of the freeze dryer is acquired by the control unit (10) and used to calculate the mass flow occurring in the freeze dryer container during the freeze drying process, i.e. the mass flow of solvent vapor sublimated from the frozen product.

[0091] In a preferred embodiment of the system of the present invention, the system further comprises at least one junction box (16) configured to unify the input signals of each strain gauge (9) into a single output signal directed to the control unit (10). Preferably, the junction box (16) is an analog junction box or a digital junction box and / or is located outside the freeze dryer (1). In this way, the signals from each strain gauge load cell are unified, which helps to obtain more reliable and repeatable measurements of the weight of the heatable plate (3) and the weight of the plate stack (2). This also makes the installation of the system easier and helps to reduce the risk of equipment damage.

[0092] In a more preferred embodiment of the system of the first aspect, the junction box (13) is an analog junction box or a digital junction box.

[0093] In the present invention, the term "analog junction box" may be understood as a junction box configured to convert analog signals of a weighing sensor into digital signals and unify the obtained digital signals into a single output signal.

[0094] In the present invention, the term "digital junction box" may be understood as a junction box configured to unify the digital input signals of the weighing sensors into a single output signal.

[0095] In the present invention, the term "mass flow rate" or "mass flow rate" is the mass of a substance (solvent or any volatile substance) sublimated from the frozen product in the freeze-drying container per unit time, which passes through a given surface per unit time. Its unit is mass divided by time, so in the International System of Units it is kg / sec.

[0096] In the present invention, the pressure sensor (6) is adapted to detect the absolute pressure in the freeze-drying chamber. Preferably, the pressure sensor is adapted to withstand temperatures up to 121°C, thereby withstanding the conditions of a cyclic sterilization process.

[0097] In a preferred embodiment of the system of the first aspect, the pressure sensor (6) is a capacitive sensor or a Pirani type sensor. Preferably, the pressure sensor (6) is located in the freeze-drying chamber (14) and is connected to the control unit (10) via the electronic device (13A).

[0098] In a preferred embodiment of the system of the first aspect, the temperature sensors (7) and (8) are selected from thermocouples, Type sensors, PT100 sensors and thermocouples.

[0099] Preferably, the pressure and temperature sensors (7) and (8) are adapted to withstand temperatures in the range of -60°C to 130°C and / or are capable of measuring pressures between 0.001 and 1 mbar, thereby withstanding the conditions of a periodic sterilization process.

[0100] In a preferred embodiment of the system of the invention, the system comprises at least one temperature sensor (8) located in a container suitable for freeze drying. Preferably, the system comprises at least one product temperature sensor (8) located in at least one container suitable for freeze drying, preferably located inside the container and / or in contact with the product.

[0101] In another preferred embodiment of the system of the present invention, the system comprises at least one product temperature sensor (8) located in at least one freeze-drying container on each heatable plate (3), so that the product temperature measurement is more accurate, thereby generating a design space more suitable for the actual conditions of the freeze-drying process. Preferably, the product temperature sensor (8) is wireless.

[0102] In a preferred embodiment of the system of the present invention, the heating device (15) is a thermal fluid heating device, and the temperature sensor (7) is configured to be located on the heating device (15), for example, it is connected to a flange.

[0103] In a more preferred embodiment of the system of the first aspect, the system comprises at least one temperature sensor (7) per system, which is located on the heating device (15) before the heating device enters the heatable plate (3). The temperature of the heating device corresponds to the temperature of the heatable plate (3).

[0104] The plate temperature sensor (7) may be located on the thermal fluid heating device (15), or in a recess on the thermal fluid heating device (15).

[0105] For example, the thermal fluid heating device (15) can be a collector; therefore, the plate temperature sensor (7) is preferably located at the fluid inlet of the collector. The temperature at the collector inlet corresponds to the temperature of the heatable plate (3).

[0106] In another preferred embodiment of the system of the present invention, the temperature sensor (7) is arranged on the heatable plate (3), more preferably, it is located inside the heatable plate (3), so as to obtain more reliable and more accurate temperature measurement.

[0107] In a preferred embodiment, the system of the first aspect comprises at least one temperature sensor (7) located on the heating device (15) before the heating device enters the heatable plate (3), and a temperature sensor (7) located on at least one heatable plate (3), preferably located inside the heatable plate (3), and more preferably located on the heating device operating inside the heatable plate (3).

[0108] Preferably, the system of the first aspect comprises at least one temperature sensor (7) located in a container suitable for freeze drying, the container being located on one of the heatable plates (3) constituting the freeze dryer.

[0109] In a more preferred embodiment of the system of the first aspect, the temperature sensors (7) and (8) are wireless and the electronic devices (13B and 13C) are also wireless. In this way, installation is easier and faster and safer because the risk of damage to the electronic devices (13B and 13C) due to board movement is reduced when they are in the form of wires. In another more preferred embodiment of the system of the first aspect, the temperature sensor (8) has an external memory (17) for storing data, an external battery (18) and an external antenna (19), the antenna (19) being configured to transmit data to the control unit (10); the antenna (19) is preferably configured to emit radio signals. The external memory (17) and the external antenna (19) can be located.

[0110] In a preferred embodiment of the system of the first aspect, the electronic device (13A, 13B, 13C, 13D) is wireless or digital and is configured to be sterilizable, for example, protected by a coating resistant to temperatures up to 121°C and water vapor, thereby withstanding the conditions of a periodic sterilization process.

[0111] A second aspect of the present invention relates to a freeze dryer (1), comprising

[0112] - a freeze drying chamber (14),

[0113] - Upper pressing plate (4),

[0114] - a heatable plate (3) for storing the sample,

[0115] - a suspended plate stack system (2) comprising at least one heatable plate (3) for placing a sample suitable for a freeze-drying process, wherein the plate stack (2) is suspended on another heatable plate (3) or on an upper platen (4), wherein each heatable plate (3) of the plate stack (2) is connected to each other or to the upper platen (4) by a mechanical connection device (5);

[0116] - A system according to claims 1-21, and

[0117] Optionally, the heatable plate (3) of the freeze dryer (1) is a movable plate.

[0118] In a preferred embodiment, the freeze dryer (1) of the second aspect is a freeze dryer with a top piston system.

[0119] A third aspect of the present invention relates to a method suitable for generating a design space for a sample, comprising a container suitable for freeze drying containing a product, during a freeze drying process in a freeze drying chamber (2) of a freeze dryer (1) comprising a system according to claims 1 to 22, preferably a freeze dryer (1) according to any one of claims 23 and 24, wherein the method comprises:

[0120] vii. placing a sample for freeze drying in the chamber (14);

[0121] viii. freeze-drying the product;

[0122] ix. During the entire freeze-drying process of step ii), using at least one strain gauge (9) to measure the weight change of the sample at different time intervals;

[0123] x. measuring the temperature of the heatable plate (3) at different time intervals using a temperature sensor (7) throughout the freeze-drying process in step ii);

[0124] xi. During the entire freeze-drying process of step ii), measuring the temperature of the sample product at different time intervals using a temperature sensor (8);

[0125] xii. During the entire freeze-drying process in step ii), the absolute pressure in the freeze-drying chamber is measured at different time intervals;

[0126] wherein steps iii), iv), v) and vi) are performed simultaneously in real time to provide measurements of chamber pressure, temperature of the heatable plate (3), product temperature, weight change of the sample, and,

[0127] The measurement values ​​are collected by a control unit (10), and at least one of the measurement values ​​or parameters obtained by the control unit (10) from the measurement values ​​is represented on a working diagram by a display device (12). The working diagram comprises at least a graphical representation of the measurement values ​​collected by the control unit (10) or the parameters obtained by the control unit (10), wherein the graphical representation of at least one of the measurement values ​​or parameters, and

[0128] Constraints of the design space can optionally be established.

[0129] In a preferred embodiment of the method of the third aspect, the working diagram graphically represents at least two and / or three of the measured values ​​collected by the control unit (10) and the parameters obtained by the control unit (10) from the measured values.

[0130] The term "working diagram" includes, for example, a graphical representation of measured values ​​collected or parameters obtained by the control unit (10), wherein at least one of the measured values ​​or parameters obtained by the control unit (10) is represented, or at least two of the measured values ​​and / or parameters are represented, or at least three of the measured values ​​and / or parameters are represented.

[0131] In the present invention, the term "design space" can be understood as the definition of the range of parameters of the freeze-drying process, within which the obtained product can be guaranteed to have the desired quality attributes. An example of the design space of a product sample is Figure 1 shown.

[0132] The temperature of the heatable plate (3), the chamber pressure and the weight of the heatable plate (3) are measured at several time intervals (e.g., fixed time intervals such as every minute). The values ​​measured at each time interval are applied to the heat and mass transfer balance model of the mechanical combination to infer / calculate the conditions in the container suitable for freeze drying at these time intervals, and calculate the heat transfer coefficient accepted by the freeze-dried product and the resistance constant of the dried product to the passage of steam, so that these calculated constants are applied to the heat and mass transfer balance model to represent a 2D or 3D map or graph. This representation is also called design space.

[0133] Based on the temperature of the heatable plate (3), the temperature of the product, the pressure and the weight of the heatable plate (3) measured by sensors or probes inside or outside the freeze-drying chamber, process conditions or parameters suitable for the sample or product in the container for freeze-drying are calculated.

[0134] In another preferred embodiment of the method of the third aspect and the fourth aspect of the present invention (if necessary), the measurement of the weight change of the sample in step ii) is performed by the control unit (10) and a value of the steam mass flow rate is given, wherein the measurement of the weight change of the sample in step ii) is based on the weight change measured by the strain gauge (9) on the heatable plate (3) containing the sample and is determined based on the number of samples on each heatable plate (3).

[0135] In another more preferred embodiment of the method of the third aspect and the fourth aspect of the present invention, the number of samples located on each heatable plate (3) has been determined in advance and input into the control unit (10), or is obtained from the outside by the control unit (10) through a server, or is manually input into the control unit (10) by a user.

[0136] In another more preferred embodiment of the method of the third aspect and the fourth aspect of the present invention, the working diagram of the design space is drawn by the control unit (10) to establish the relationship between the chamber pressure and / or the product temperature and / or the mass flow rate in the form of a 2D or 3D diagram.

[0137] Therefore, an advantage of the method of generating a design space of the third aspect is that it can be used as a reference or model for predicting future values ​​of conditions in a container (e.g., a vial) suitable for lyophilization over an appropriate time period (e.g., the next hour, the next two hours, etc.), such as can be used in the method of the fourth aspect of the invention.

[0138] Constructing the 2D or 3D design space according to the method of the third aspect also has the following advantages, and it is easier to determine the optimal conditions of the conventional freeze-drying process in large-scale production and small-scale production, or to determine the limits of possible failure of the production process based on the process and the limits or ranges for validating the production process.

[0139] In addition, it can also calculate or estimate the process control limits for specific freeze-drying containers, equipment and production environment configurations. Similarly, the third aspect of the method can also be used to predict the impact of changes in process conditions on process yield, completion time and product quality, or to understand possible deviations in the production process.

[0140] In a preferred embodiment of the method of the third aspect and the fourth aspect of the present invention, the freeze-drying process of step ii) comprises at least the following steps:

[0141] 1) Freezing the product of step i) at a temperature ranging from -0 to -60°C;

[0142] 2) reducing the pressure in the freeze-drying chamber (2) to between 0.9 atm and 0.0002 atm;

[0143] 3) performing primary drying on the product obtained in step 2);

[0144] 4) performing secondary drying on the product obtained in step 3);

[0145] 5) Sterilization, and

[0146] 6) Optionally discharge the product.

[0147] In a preferred embodiment of the method of the third aspect and the fourth aspect of the present invention, the freeze-drying process of step ii) comprises at least the following steps:

[0148] 1) freezing the product of step i) at a temperature ranging from 0 to -60°C;

[0149] 2) reducing the pressure in the freeze-drying chamber (2) to between 0.9 atm and 0.0002 atm;

[0150] 3) performing primary drying on the product obtained in step 2) at a temperature range of -50°C to 20°C or -50°C to -40°C;

[0151] 4) secondary drying the scraped surface obtained in step 3) at a temperature in the range of 20° C. to 70° C. or 40° C. to 70° C.;

[0152] 5) Sterilization, and

[0153] 6) Optionally, the product obtained in step 4) or step 5) is discharged.

[0154] In the freeze drying process, primary drying removes water by sublimating ice in the product (which has been previously frozen) under vacuum conditions. By providing heat, the ice will sublime and avoid passing through the liquid phase. During primary drying, the water vapor generated at the sublimation interface is discharged through the pores of the product structure.

[0155] Primary drying is carried out at temperatures ranging from freezing to conventional temperatures between 20°C and 40°C.

[0156] After the sublimation process is complete, secondary drying is performed to remove any or most of the remaining liquid or moisture. This drying is performed, for example, by desorption and evaporation of unfrozen water from the pre-dried material. This can result in a final product moisture level close to or even below 2%.

[0157] Secondary drying is carried out at a temperature ranging from 20°C to 70°C from the temperature at which primary drying is completed. Therefore, when the ice disappears, free water begins to be discharged by evaporation, achieving secondary drying.

[0158] In another preferred embodiment of the method of the third aspect of the invention, the control unit (10) is configured to establish a relationship between the chamber pressure, the mass flow rate and the product temperature, wherein the relationship is represented by the control unit (10) in a 2D or 3D working diagram. This relationship can be established by applying a mass balance and an energy balance in the sublimation process of the primary drying. This relationship can be calculated for each different product temperature.

[0159] Therefore, in another preferred embodiment, the control unit (10) is configured to establish the relationship between the chamber pressure, the mass flow rate and the product temperature in a 2D working diagram at different product temperatures (different product isotherms) during the freeze-drying process.

[0160] In another preferred embodiment, the control unit (10) is configured to establish the relationship between the chamber pressure, the mass flow rate and the plate temperature in a 2D working diagram at different plate temperatures during the freeze-drying process.

[0161] In another preferred embodiment, the control unit (10) is configured to establish a relationship between the chamber pressure, the mass flow rate, the different product temperatures (product isotherms) and the different plate temperatures (plate temperature isotherms) in a 2D working diagram at different plate temperatures during the freeze-drying process.

[0162] The heat transfer coefficient between the plate and the product and the resistance coefficient of the dry product to be freeze-dried to the steam flow are used to determine the relationship between the chamber pressure and the mass flow rate for each heatable plate (3) at each temperature. The parameters are obtained experimentally and input to the control unit (10).

[0163] To calculate the heat transfer coefficient (Kv) between the freeze dryer and the product to be freeze-dried, the following steps are required:

[0164] 1.- Fill a container suitable for freeze-drying, e.g. fill a vial with water.

[0165] 2.- Adjust the plate temperature to achieve the required pressure for each product or sample.

[0166] 3. Insert the temperature sensor into the container.

[0167] 3.- Adjust the temperature of the heatable plate of the freeze dryer to a fixed temperature value.

[0168] 4. Adjust the chamber pressure of the freeze dryer to a specific fixed value.

[0169] 5.-Measure the product temperature value (Tb).

[0170] 6.- Determine the mass flow rate.

[0171] 7.- Calculate Kv.

[0172] 8. Repeat points 4-8 for different pressure values ​​within the entire working range that makes up the freeze-drying process and calculate Kv at the different pressure values ​​using the following formula:

[0173] pressure

[0174]

[0175] A v = the external area of ​​a lyophilization container portion, such as the external area of ​​a vial.

[0176] T s = Plate temperature.

[0177] T b = Temperature of the product at the bottom of the vial.

[0178] dm / dt = steam mass flow rate

[0179] ΔH s = Heat of sublimation of ice

[0180] This results in a 2D working diagram in which different values ​​of Kv are represented against different pressure values.

[0181] To calculate the resistance coefficient (Rp) of the dry product to be freeze-dried to steam flow, the following steps are required:

[0182] 1. Fill a container, such as a vial, with the product.

[0183] 2. Insert the temperature sensor into the container.

[0184] 3. Adjust the temperature of the heatable plate of the freeze dryer to a fixed temperature value.

[0185] 4. Adjust the chamber pressure of the freeze dryer to a specific fixed value.

[0186] 5. Measure the product temperature value (Tb).

[0187] 6. Determine the mass flow rate.

[0188] 7. Calculate R p . Calculate Rp.

[0189] 8. Repeat points 4-8 for different pressure values ​​throughout the working range that makes up the lyophilization process, applying the following formula:

[0190]

[0191] A p = the interior area of ​​a lyophilization container portion, such as the interior area of ​​a vial.

[0192] P i =The vapor pressure of ice when it sublimates.

[0193] P c = Chamber pressure.

[0194] P i =f(Tb)Balance sheet

[0195] This allows a 2D working diagram (graph) to be obtained, in which different values ​​of Rp are represented relative to different chamber pressures.

[0196] Once K is determined v Value and R p value, we can calculate the plate temperature T s Different values ​​of T are used to calculate different points of the plate temperature and product temperature isotherms that will be configured. For example, using T bEach value of dm / dt represents a different plate temperature isotherm.

[0197] like Figure 2A and 2B As shown, in a preferred embodiment, the following steps are required to establish the relationship between the chamber pressure, the mass flow rate and the product temperature (product temperature isotherm):

[0198] 1. Select product temperature (T b ) and chamber pressure (P c ), and the sublimation rate is calculated using the following formula:

[0199] dm / dt=(P i -P c ) / R p

[0200] P i =f(T b )(balance)

[0201] 2. Repeat the calculation for different chamber pressures P c .

[0202] 3. Draw lines on the graph.

[0203] 4. Repeat the operation for other product temperature values ​​T b .

[0204] In a preferred embodiment of the method of the third aspect of the invention, once the design space is established, the method further comprises an additional step; the additional step comprises establishing constraints of the design space.

[0205] In another preferred embodiment of the method of the third aspect, it comprises an additional step vii), wherein the limits of the design space are established, which comprises establishing the maximum limit of the evaporation mass flow rate (throttling or throttling point) allowed by the freeze-drying device according to the pressure measured by the pressure sensor (6) and the critical product temperature. In another more preferred embodiment, the control unit (10) is configured to establish the throttling.

[0206] In the present invention, the process of establishing the maximum limit of the evaporation mass flow rate allowed by the freeze-drying equipment based on the pressure of the freeze-drying chamber is called the throttling point or throttling. Figure 3 and 4 An example of a design space showing established throttling is shown.

[0207] In a preferred embodiment of the method of the present invention, the throttling point or throttling performs the following steps:

[0208] 1. Add water to the freeze dryer to a known level.

[0209] 2. Freeze at -40°C.

[0210] 3. Prepare the system to begin primary drying.

[0211] 4. Primary drying is performed at different chamber pressures.

[0212] 5. Verify the maximum evaporation mass flow rate achievable at each chamber pressure.

[0213] The critical temperature of the product is a parameter for establishing the above-mentioned limit. Preferably, the critical temperature is determined at least by a method selected from DSC, TGA and FDM. Specifically, the critical temperature is a relevant parameter for designing the primary drying stage of a freeze-drying cycle.

[0214] The maximum product temperature allowed during the primary drying process is determined to determine the critical temperature of the product; for an amorphous product, this temperature may be the disintegration temperature; for a crystalline product, this temperature may be the melting temperature. The critical temperature is necessary to determine the maximum temperature allowed for the product during the primary drying process. The critical temperature of the primary drying is a parameter input to the control unit (10) to perform step vi). In a preferred embodiment of the solution of the third aspect of the present invention, the control unit (10) is configured to establish a relationship between the chamber pressure and the mass flow rate for the temperature of the heatable plate (3), for example, by using an average value obtained by using the control unit (10) in the case of using temperature sensors of more than one plate (3) present in the freeze dryer. Wherein, the relationship is represented by a 2D working diagram of the control unit (10) at different temperatures of the heatable plate (3) during the freeze drying process.

[0215] A fourth aspect of the present invention relates to a suitable freeze-drying method, the method comprising a product, typically during freeze-drying in a freeze-drying chamber (2) of a freeze-dryer (1) comprising a system according to the first aspect, the freeze-dryer comprising a system according to the first aspect, preferably a freeze-dryer (1) according to any one of claims 23 and 24, wherein the method comprises at least the following steps:

[0216] vii. placing a sample for freeze drying in the chamber (14);

[0217] viii. freeze-drying the sample;

[0218] ix. Optionally, during the entire freeze-drying process in step ii), at different time intervals, at least one strain gauge (9) is used to measure the weight change of the sample;

[0219] x. measuring the temperature of the heatable plate (3) using a temperature sensor (7) at different time intervals during the entire freeze-drying process in step ii);

[0220] xi. Optionally, during the entire freeze-drying process in step ii), the temperature of the sample product is measured at different time intervals using a temperature sensor (8);

[0221] xii. During the entire freeze-drying process in step ii), the absolute pressure in the freeze-drying chamber is measured at different time intervals;

[0222] wherein steps iii), iv), v) and vi) are performed simultaneously in real time to provide measurements of chamber pressure, temperature of the heatable plate (3), product temperature, weight change of the sample, and

[0223] wherein the measured values ​​are collected by a control unit (10), and the measured values ​​or at least one of the parameters obtained by the control unit (10) from the measured values ​​are represented on a working diagram by a display device (12). wherein the working diagram comprises at least a graphical representation of the measured values ​​collected by the control unit (10) or the parameters obtained by the control unit (10), wherein the graphical representation represents at least one of the measured values ​​or parameters;

[0224] c. by using the control unit (10), comparing the temperature and pressure measurements of the heatable plate (3) obtained in at least the working diagram of each product in step ii) with the values ​​of the sample or standard sample previously obtained in the same step ii) in the design space according to the third aspect;

[0225] d. If necessary, according to the deviation of the result obtained in step e) from the design space of the sample or standard sample, the absolute pressure and temperature parameters of each process in the freeze dryer are optionally adjusted by the control unit (10).

[0226] In a preferred embodiment of the method of the fourth aspect of the present invention, the control unit (10) is configured to use the obtained pressure value and the heat transfer coefficient between the freeze dryer and the product to be freeze-dried measured at different chamber pressures, and / or the resistance coefficient of the dry product to be freeze-dried to the steam flow measured at different chamber pressures as inputs to the heat and mass transfer model to calculate the mass flow rate in the freeze-drying chamber at different times and different product temperatures in a 2D or 3D working diagram.

[0227] In a preferred embodiment of the method of the fourth aspect of the invention, the control unit (10) is configured to subsequently establish the relationship between the chamber pressure, the mass flow rate and the product temperature in a 2D or 3D working diagram at different product temperatures.

Claims

1. A system suitable for controlling a freeze drying process of a freeze dryer, the freeze dryer (1) having a suspended plate stack system (2) comprising at least one heatable plate (3), wherein: The plate stack (2) is suspended on another heatable plate (3) or an upper platen (4), wherein each heatable plate (3) of the plate stack (2) is connected to each other or to the upper platen (4) via a mechanical connection device (5); The system comprises: VI. at least one pressure sensor (6) for measuring the absolute pressure in the freeze-drying chamber; VII. At least one temperature sensor (7) for measuring the temperature of each heatable plate (3); VIII. At least one product temperature sensor (8) for measuring the temperature of the product and located in a container suitable for freeze drying; IX. At least one strain gauge (9), which is configured to be located on the upper part of each heatable plate (3) and / or the upper pressing plate (4) constituting the freeze dryer (1); wherein at least one strain gauge (9) is connected to the mechanical connection device (5); X. The control unit (10) comprises a processor (11) and a display device (12), wherein the control unit (10) is configured to automatically and simultaneously collect and analyze measurement values ​​from at least the sensors (6), (7), (8) and (9), and to display at least one of the measurement values ​​on a working diagram of the display device (12), The sensors (6), (7), (8) and (9) are data-connected to the control unit (11) via electronic devices (13A, 13B, 13C, 13D).

2. A system according to any preceding claim, wherein: The freeze dryer is a freeze dryer with a top piston system and / or wherein the heatable plate (3) of the freeze dryer is a movable plate.

3. System according to any of the preceding claims, each heatable plate comprising at least two strain gauges (9), preferably at least four strain gauges (9).

4. A system according to any preceding claim, wherein: The freeze dryer (1) comprises at least one freeze drying chamber (14), an upper pressing plate (4), a heatable plate (3) suitable for storing containers suitable for freeze drying, a heating device (15) and a device for modifying the pressure of the chamber.

5. A system according to any preceding claim, wherein: At least one strain gauge (9) is configured to be connected to the upper part of the mechanical connection device (5), and / or the mechanical connection device (5) is configured to pass through the heatable plate (3) or the upper pressing plate (4), so that the end of the device is located above the heatable plate (3) or the upper pressing plate (4), and the strain gauge (9) is configured to be connected to the upper end.

6. A system according to any preceding claim, wherein: At least the strain gauge (9) is configured to be connected to the upper portion of the mechanical connection device (5) directly or indirectly via a tool (20).

7. A system according to any preceding claim, wherein: The control unit (10) is located outside the freeze dryer, and the processor is selected from a CPU or a PLC unit.

8. A system according to any preceding claim, wherein: The system may have two control units (10), one control unit (10EA) being located outside the freeze dryer and the other control unit (10EB) being connected to the freeze dryer, and both being data-connected to the pressure sensor (6), the temperature sensor (7), the product temperature sensor (8) and at least one strain gauge (9), wherein the external control unit (10EA) is data-connected to the control unit (10EB) of the freeze dryer via the processor (11).

9. A system according to any preceding claim, wherein: At least one strain gauge (9) is configured to measure the weight of the heatable plate (3), and the control unit (10) is configured to calculate the weight change of the heatable plate (3) within the freeze dryer.

10. The system according to any one of claims 3 to 9, further comprising at least one junction box (16) configured to unify the input signals of each strain gauge (9) into a single output signal directed to the control unit (10).

11. A system according to the preceding claim, wherein: The junction box (16) is an analog junction box or a digital junction box, and / or is located outside the freeze dryer (1).

12. A system according to any preceding claim, wherein: The plate temperature sensor (7) and the product temperature sensor (8) are selected from thermocouples and PT100 type sensors.

13. A system according to any preceding claim, wherein: The system comprises at least one plate temperature sensor (7) located on the heating device (15) before entering the heatable plate; the system preferably also comprises at least one plate temperature sensor (7) for each heatable plate (3) comprising the freeze dryer.

14. A system according to any preceding claim, wherein: The plate temperature sensor (7) located on the heatable plate (3) is configured to be placed inside the heatable plate (3).

15. A system according to any preceding claim, wherein: The heating device (15) is a thermal fluid heating device, and the temperature sensor (7) is configured to be located on the heating device (15).

16. System according to any of the preceding claims, wherein the system comprises at least one product temperature sensor (8) located in at least one container suitable for freeze drying, preferably wherein the system comprises one product temperature sensor (8) per heatable plate (3).

17. The system according to any of the preceding claims, wherein the product temperature sensor (8) is configured to be placed in a container suitable for freeze drying; the product temperature sensor (8) is preferably wireless.

18. A system according to any preceding claim, wherein said electronic means (13A, 13B, 13C, 13D) are wireless or digital.

19. System according to any of the preceding claims, wherein the temperature sensors (7) and (8) and the corresponding electronics (13B and 13C) are wireless.

20. A system according to the above claim, wherein the wireless temperature sensor (8) has a memory (17) for storing data, a battery (18) and an antenna (19) configured to transmit data to the control unit (10); the antenna is preferably configured to emit radio signals.

21. A system according to any of the preceding claims, wherein the pressure sensor (6) is a capacitive or Pirani type sensor; preferably a pressure sensor suitable for withstanding temperatures in the range of -60°C to 130°C and / or configured to measure pressures between 0.01 and 1 mbar.

22. The system according to any of the preceding claims, wherein the pressure sensor (6) is configured to be located inside the freeze-drying chamber (14) and is connected to the control unit (10) via the electronic device (13A).

23. A freeze dryer (1), comprising: a freeze drying chamber (14), Upper pressing plate (4), A heatable plate (3) for storing samples, A suspended plate stack system (2) comprising at least one heatable plate (3) for placing a sample suitable for a freeze-drying process, wherein the plate stack (2) is suspended on another heatable plate (3) or an upper platen (4), wherein each heatable plate (3) of the plate stack is connected to each other or to the upper platen (4) via a mechanical connection device (5); characterized in that comprising a system according to any one of claims 1 to 21, and Optionally, the heatable plate (3) of the freeze dryer (1) is a movable plate.

24. Freeze dryer (1) according to the preceding claim, wherein the freeze dryer (1) is a freeze dryer with a top piston system.

25. A method suitable for generating a design space for a sample, comprising a container for freeze drying containing a product, during freeze drying in a freeze drying chamber of a freeze dryer (1) comprising a system according to claims 1 to 22, preferably a freeze dryer (1) according to any one of claims 23 and 24, wherein the method comprises: a. placing a sample for freeze drying in the chamber (14); b. freeze-drying the product; c. measuring the weight change of the sample at different time intervals using at least one strain gauge (9) during the entire freeze-drying process of step ii); d. measuring the temperature of the heatable plate (3) at different time intervals using a temperature sensor (7) throughout the freeze-drying process in step ii); e. During the entire freeze-drying process in step ii), measuring the temperature of the sample product at different time intervals using a temperature sensor (8); f) during the entire freeze-drying process in step ii), measuring the absolute pressure within the freeze-drying chamber at different time intervals; wherein steps iii), iv), v) and vi) are performed simultaneously in real time to provide measurements of chamber pressure, temperature of the heatable plate (3), product temperature, weight change of the sample, and The measured values ​​are collected by a control unit (10), and at least one of the measured values ​​or the parameters obtained by the control unit (10) through the measured values ​​is represented on a working diagram by a display device (12), wherein the working diagram comprises at least a graphical representation of the measured values ​​collected by the control unit (10) or the parameters obtained by the control unit (10), and wherein the graphical representation of at least one of the measured values ​​or the parameters and optionally establishing limits for the design space.

26. Method according to the preceding claim, wherein the working diagram graphically represents at least two and / or three measured values ​​collected by the control unit (10) and parameters obtained by the control unit (10) from said measured values.

27. The method according to the preceding claim, wherein the freeze-drying process of step ii) comprises at least the following steps: a) freezing the sample in step i) at a temperature ranging from -0 to -60°C; b) reducing the pressure in the freeze-drying chamber (2) to between 0.9 atm and 0.0002 atm; c) performing primary drying on the product obtained in step b); d) secondary drying the product obtained in step c), and e) optionally discharging the product.

28. A method for generating a design space according to any one of claims 24 to 27, wherein the measurement of the weight change of the sample in step ii) is performed by the control unit (10) and gives a value of the steam mass flow rate, wherein the measurement of the weight change of the sample in step ii) is in response to the weight change measured by the strain gauge (9) on the heatable plate (3) containing the sample and is determined based on the number of samples on each heatable plate (3).

29. A method for generating a design space according to the preceding claims, wherein the number of samples located on each heatable plate (3) has been previously determined and input into the control unit (10), or has been externally obtained by the control unit (10) via a server, or has been manually input into the control unit (10) by a user.

30. A method for generating a design space according to any one of claims 27-28, wherein the control unit (10) is configured to establish a relationship between the chamber pressure and the mass flow rate for each temperature of each heatable plate (3) in the freeze dryer, and wherein the relationship is represented by the control unit (10) in a 2D working diagram at different temperatures, and each heatable plate (3) is affected by different temperatures during the freeze drying process.

31. A method for generating a design space according to any one of claims 27-28, wherein the container suitable for sample lyophilization is selected from the group consisting of vials, ampoules, syringes, cartridges, bulk trays, microtubes and flasks.

32. The method according to any one of claims 27 to 30, comprising an additional step vii) comprising establishing the limits of the design space, comprising:

1. In steps b), e) and d) of the freeze-drying process, a maximum limit on the evaporation mass flow rate allowed by the freeze-dryer is established according to the pressure measured by the pressure sensor (6), and 2. Determine the critical product temperature.

33. Method according to any of the preceding claims, wherein the control unit (10) is configured to establish a limitation of the mass flow rate of portion 1.

34. The method according to any one of claims 31-32, wherein the critical temperature of the product is determined by at least one method selected from DSC, TGA and FDM, and the temperature is input to the control unit (10).

35. A method for monitoring and controlling a sample comprising a container suitable for freeze drying, said container containing a product, typically during freeze drying in a freeze drying chamber (2) of a freeze dryer (1) comprising a system according to claims 1 to 22, preferably a freeze dryer (1) according to any one of claims 23 and 24, wherein said method comprises at least the following steps: xiii. placing a sample for freeze drying in the chamber (14); xiv. freeze-drying the product; xv. Optionally, during the entire freeze-drying process of step ii), at least one strain gauge (9) is used to measure the weight change of the sample at different time intervals; xvi. During the entire freeze-drying process of step ii), measuring the temperature of the heatable plate (3) at different time intervals using a temperature sensor (7); xvii. Optionally, during the entire freeze-drying process in step ii), the temperature of the sample product is measured at different time intervals using a temperature sensor (8); xviii. During the entire freeze-drying process in step ii), the absolute pressure within the freeze-drying chamber is measured at different time intervals; wherein steps iii), iv), v) and vi) are performed simultaneously in real time to provide measurements of chamber pressure, temperature of the heatable plate (3), product temperature, weight change of the sample, and, wherein the measured values ​​are collected by a control unit (10), and at least one of the measured values ​​or parameters obtained by the control unit (10) through the measured values ​​is represented on a working diagram by a display device (12), wherein the working diagram comprises at least a graphical representation of the measured values ​​collected by the control unit (10) or the parameters obtained by the control unit (10), and wherein the graphical representation represents at least one of the measured values ​​or parameters; By using the control unit (10), the temperature and pressure measurements of the heatable plate (3) obtained in at least the working diagram of each product in step ii) are compared with the values ​​of the sample or standard sample previously obtained in the same step ii) in the design space according to the third aspect; If necessary, the absolute pressure and temperature parameters of each process in the freeze dryer are optionally adjusted by the control unit (10) according to the result of step e) and the deviation of the result obtained from the design space of the sample or standard sample.

36. According to the method described in the above claims, the control unit (10) is configured to use the obtained pressure value and the heat transfer coefficient between the freeze dryer and the product to be freeze-dried measured at different chamber pressures, and / or the resistance coefficient of the product to be dried to the steam flow measured at different chamber pressures as inputs of the heat and mass transfer model, so as to calculate the mass flow rate in the freeze-drying chamber at different times and different product temperatures in a 2D or 3D working diagram.

37. A method according to the preceding claim, wherein the control unit (10) is configured to subsequently establish the relationship between the chamber pressure, the mass flow rate and the product temperature in a 2D or 3D working diagram at different product temperatures.

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