System for controlling a freeze-drying process in a freeze-dryer equipped with a plate stack system and method for generating a design space

Abstract

The present 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), wherein the plate stack (2) is suspended from either another heatable plate (3) or an upper pressing plate (4), and each heatable plate (3) of the plate stack (2) is coupled to one another or to the upper pressing plate (4) by mechanical connection means (5). The present invention also relates to a method for monitoring and controlling a freeze-drying process including the use of the above 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 to a method suitable for generating a design space, and to a method for monitoring and controlling a freeze-drying process including the use of the above system so as to be usable for the commercial production of pharmaceutical products, cosmetics or foods.

Background Art

[0002] An important step in manufacturing many pharmaceutical products for injection or parenteral use is freeze-drying. Freeze-drying is also an important technology for departments regulated by GMP. Freeze-drying is a physico-chemical process that removes water from a product to enhance its stability. This technique is particularly used for injection products or drugs that can be very unstable in aqueous solution and must be stored in a cold freezer at low temperature. In the freeze-drying process, for example, vials or ampoules pre-filled with a pharmaceutical product are placed in a special freeze-drying chamber. First, the product is frozen by lowering the temperature in the chamber. Subsequently, the sublimation of the solvent (usually water) in the previously frozen product takes place in an atmosphere where the solvent vapor pressure is very low. By thus removing moisture and many solvents from the product, the product becomes more stable and its shelf life can be extended.

[0003] Freeze-drying makes it possible to keep these products at low temperature and room temperature, and significantly facilitates their storage, transportation and distribution logistics. Various methods and systems have been developed for controlling and monitoring freeze-drying cycles, process conditions, and the quality of products obtained by freeze-drying.

[0004] For example, an early design such as that described in U.S. Patent No. 3,176,408 is a freeze-drying apparatus and method for articles of the same size and type, the articles being disposed within a sealed chamber, shelves, and trays created to support the frozen articles to be freeze-dried, means for freeze-drying the articles deposited on the trays, and means for responding directly to the weight loss of the articles due to sublimation, the apparatus comprising at least two load cells disposed beneath the shelves (see FIGS. 1 and 2) for automatically controlling the freeze-drying means, and the means for responding to the weight loss including a device for varying the pressure within the chamber. The shelves of the apparatus can be disposed beneath the fixed shelves and have two load cells connected by wires to a weight recording device and a controller. Depending on the measured weight, the heat or pressure supplied to the apparatus can vary.

[0005] Subsequently, Chinese Utility Model Patent No. 206670234 discloses a freeze-dryer for performing a freeze-drying process, which includes a chamber having three fixed shelves on which vials to be freeze-dried are deposited. The shelves include a resistance strain gauge weighing sensor and a sensor mounting bracket fixedly connected to the center of each shelf. The bottom of one end of the strain gauge weighing sensor is fixedly connected to the sensor mounting bracket by a mounting bolt. An adjustment bolt for adjusting the height position of the resistance strain gauge load cell is provided at the bottom of the other end of the strain gauge weighing sensor, and a sensor output terminal is provided on the side of the strain gauge load cell. A gauge system is used to determine the amount of material resulting from the process by measuring the change in weight over time. The apparatus comprises one strain gauge for each shelf.

[0006] The strain gauges are connected to a control device (which can be a PLC) that collects the weight measurement values of the gauges and displays them on a screen. Subsequently, the operator can determine the optimal freeze-drying time based on the weight fluctuations displayed on the screen. In addition to observing whether the indicator light 11 is lit, the operator can determine the end of the experiment when directly observing that the value shown on the display screen no longer changes. Further, the apparatus includes a timer 12 configured to record the measured weight value of the strain gauge load cell once every 30 minutes until two consecutive measured values are stable and the ice in the material is completely sublimated. The lamp 11 is lit upon receiving a signal from the electronic control unit 13, whereby the operator completes the process. This system has the drawback of limiting the control and completion of the process to a manual process performed by the operator.

[0007] Recent publications such as U.S. Patent Application Publication No. 2020340743 describe a non-invasive system and method for monitoring and controlling a lyophilization process using a network of wireless gas temperature and ambient pressure sensors. In particular, this method enables determining the sublimation rate of the solvent from the vials deposited inside in real time using any mathematical model during the lyophilization process.

[0008] More specifically, U.S. Patent Application Publication No. 2020340743 describes a system comprising a wireless pressure and gas temperature sensor, a housing fluidly coupled to its surrounding environment, a power source disposed within the housing, and an electronic module electrically coupled to the power source and including a microcontroller and a wireless transceiver, wherein the wireless pressure sensor is adapted to provide ambient pressure and gas temperature values together with the electronic module, and the sensor is disposed inside different vials arranged on a shelf in a lyophilization chamber together with the vials containing the product to be lyophilized. Moreover, the system further comprises a vacuum pump adapted to change the lyophilization chamber pressure and a heat exchanger adapted to change the temperature inside the lyophilization chamber. The control unit is adapted to collect pressure and gas temperature data from one or more wireless pressure sensors and calculate the sublimation rate of the product to be lyophilized using the collected pressure temperature and gas data.

[0009] The control unit of the system calculates the sublimation rate in the following manner, i.e., by applying predetermined initial boundary conditions to a channel representing the space adjacent to the tray of the lyophilization vials in the lyophilization chamber, which iteratively minimizes a penalty function associated with the difference between the calculated space pressure information and the collected space pressure information, which includes calculating information regarding the space temperature and gas supply at the distributed positions of one or more wireless pressure and temperature sensors and calculating the difference between the calculated space pressure information and the collected space pressure information, and further, this calculates a penalty function of an associated intermediate criterion between the collected and calculated space pressure information and the associated boundary conditions, determines new boundary conditions that reduce the calculated penalty function, and calculates the sublimation rate by applying the associated boundary conditions together with the penalty function.

[0010] Therefore, there is a need to design systems and methods for monitoring various lyophilization processes for various industries, which can be applied to various lyophilization containers, and which, in addition to being used as a criterion or model for predicting future values of the conditions within a container suitable for lyophilization, such as a vial, during the lyophilization process, can also create a design space adjusted to the actual conditions of the lyophilization process. Similarly, it is also necessary to develop systems and methods that facilitate the identification of the optimal conditions of the daily lyophilization process in both large - scale and small - scale manufacturers, or the limits beyond which the process can fail in the above - mentioned manufacturing process. Summary of the Invention

[0011] The system according to the first aspect of the present invention is applicable, for example, to the freeze-drying process of injection products that enables monitoring of parameters that directly impair the quality of freeze-dried products, and thus is incorporated into product quality control by controlling the process in accordance with the "Quality by Design" concept. Similarly, this is also applicable to freeze-dried products for use in food, as it enables them to preserve the flavor of said products over time.

[0012] The system according to the first aspect of the present invention has the advantage of directly obtaining the weight of the plate stack (2) and the heatable plates and subsequently being able to calculate the flow of water vapor sublimating in the freeze-dryer through the use of load cells. Furthermore, this enables obtaining important process parameters to assist the manufacturer in obtaining the "design space" in a simple and robust manner based on "Quality by Design".

[0013] Additionally, the system facilitates monitoring of various freeze-drying processes in various industries, which can be applied to various freeze-drying containers, and can also create a design space adjusted to the actual conditions of the freeze-drying process. In addition to being used as a reference or model for predicting future values of the conditions inside a container suitable for freeze-drying, such as a vial, during the freeze-drying process, it can also identify the optimal conditions for the daily freeze-drying process, the limits beyond which the process may fail, and the limits or ranges for performing verification of the above manufacturing process, for both large-scale and small-scale manufacturers.

[0014] Therefore, the system of the first aspect is a system suitable for controlling the 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 either another heatable plate (3) or an upper pressing plate (4), and each heatable plate (3) of the plate stack (2) being coupled to one another or to the upper pressing plate (4) by mechanical connection means (5). The system is I. at least one pressure sensor (6) suitable for detecting the absolute pressure in the freeze-drying chamber; II. at least one temperature sensor (7) suitable for measuring the temperature of the heatable plate (3); III. at least one product temperature sensor (8) suitable for measuring the temperature of the product and suitable for being arranged inside a receptacle suitable for freeze-drying; IV. at least one strain gauge (9) configured to be arranged on the upper part of each heatable plate (3) and / or the upper pressing plate (4) of the freeze-dryer (1), wherein at least one strain gauge (9) is coupled to the mechanical connection means (5); at least one strain gauge (9); V. a control unit (10) comprising a processor (11) and a display device (12), the control unit (10) being configured to automatically and simultaneously collect and analyze the measured values from at least the sensors (6), (7), (8) and (9), and to represent at least one of the measured values on a working map on the display device (12); The sensors (6), (7), (8) and (9) are in data connection with the control unit (11) via electronic means (13A, 13B, 13C, 13D); and a control unit (10).

[0015] The second aspect of the invention is a freeze-dryer (1) comprising a freeze-drying chamber (14); an upper pressing plate (4); A heatable plate (3) suitable for depositing a sample, A hanging plate stack system (2) comprising at least one heatable plate (3) suitable for depositing a sample suitable for a lyophilization process, wherein the plate stack (2) is suspended from either another heatable plate (3) or an upper pressing plate (4), A hanging plate stack system (2), wherein each heatable plate (3) of the plate stack (2) is coupled to one another or to the upper pressing plate (4) by mechanical connection means (5), Comprising the system according to any one of claims 1 to 21, Optionally, the heatable plate (3) of the lyophilizer (1) is a movable plate, relating to a lyophilizer (1).

[0016] A third aspect of the present invention is a method suitable for generating a design space for a sample comprising a product and comprising a receptacle suitable for lyophilization during a lyophilization process inside a lyophilization chamber of a lyophilizer (1) comprising the system according to any one of claims 1 to 22, preferably the lyophilizer (1) according to either claim 23 or 24, the method comprising: i. Depositing a sample to undergo a lyophilization process inside the chamber (14); ii. Performing a lyophilization process on the product; iii. Measuring fluctuations in the weight of the sample by using at least one strain gauge (9) at different time intervals throughout the lyophilization process of step ii); iv. Measuring the temperature of the heatable plate (3) by using a temperature sensor (7) at different time intervals throughout the lyophilization process of step ii); v. Measuring the temperature of the product of the sample by using a temperature sensor (8) at different time intervals throughout the lyophilization process of step ii); vi. measuring the absolute pressure inside the freeze-drying chamber at different time intervals throughout the freeze-drying process of step ii), Steps iii), iv), v) and vi) are executed simultaneously in real time to provide measurements of the chamber pressure, the temperature of the heatable plate (3), the product temperature, and the weight variation of the sample, The said measurements are collected by the control unit (10), and at least one of the said measurements or a parameter obtained by the control unit (10) via the said measurements is represented on a working map by the display device (12), the working map including at least a representation within a graph of the said measurements collected by the control unit (10) or the parameters obtained by the control unit (10), the graph representing at least one of the measurements or parameters and optionally establishing the limits of the design space, relating to a method.

[0017] A fourth aspect of the present invention is a method for monitoring and controlling, during the freeze-drying process, inside the freeze-drying chamber (2) of a freeze-dryer (1) comprising the system according to any one of claims 1 to 22, preferably the freeze-dryer (1) according to any one of claims 23 and 24, a sample comprising a receptacle suitable for freeze-drying containing a product, the method comprising at least i. depositing the sample to undergo the freeze-drying process inside the said chamber (14); ii. performing a freeze-drying process on the said product; iii. optionally, measuring the weight variation of the sample by using at least one strain gauge (9) at different time intervals throughout the freeze-drying process of step ii); iv. measuring the temperature of the heatable plate (3) by using a temperature sensor (7) at different time intervals throughout the freeze-drying process of step ii); v. Optionally, measuring the temperature of the sample product by using a temperature sensor (8) at different time intervals throughout the lyophilization process of step ii); vi. Measuring the absolute pressure inside the lyophilization chamber at different time intervals throughout the lyophilization process of step ii), wherein steps iii), iv), v) and vi) are executed simultaneously in real time to provide measurements of the chamber pressure, the temperature of the heatable plate (3), the product temperature, and the weight variation of the sample, the said measurements are collected by the control unit (10), and at least one of the said measurements or the parameters obtained by the control unit (10) through the said measurements is represented on a working map by a display device (12), the working map includes at least a representation within a graph of the said measurements collected by the control unit (10) or the parameters obtained by the control unit (10), the graph represents at least one of the measurements or parameters, the step of measuring; a. By using the control unit (10), comparing, during the same step ii), at least the temperature of the heatable plate (3) and the measured value of the pressure obtained in the working map for each product during step ii) with the previously obtained values in the design space according to the third aspect for the sample or the standard sample; b. Optionally, when necessary, adjusting the absolute pressure and temperature parameters in the lyophilizer for each process based on the results of the steps deviating from the results obtained for the design space of the sample or the standard sample through the control unit (10). A method is related to this.

Brief Description of the Drawings

[0018] The above and other advantages and features should be considered by way of illustration and not limitation, and will be more fully understood from the following detailed description of the exemplary embodiments with reference to the accompanying drawings.

Figure 1

Figure 2A

Figure 2B

Figure 3

Figure 4

Figure 5

Mode for Carrying Out the Invention

[0019] The system of the first aspect is a system suitable for controlling a freeze drying process in a freeze dryer (1) having a hanging plate stack system (2) including at least one heatable plate (3), the plate stack (2) being suspended from either another heatable plate (3) or an upper pressing plate (4), and each heatable plate (3) of the plate stack (2) being coupled to each other or to the upper pressing plate (4) by mechanical connection means (5). The above system I. At least one pressure sensor (6) suitable for detecting the absolute pressure inside the freeze-drying chamber, II. At least one temperature sensor (7) suitable for measuring the temperature of the heatable plate (3), III. At least one product temperature sensor (8) suitable for measuring the temperature of the product and suitable for being arranged inside a receptacle suitable for freeze-drying, IV. At least one strain gauge (9) configured to be arranged on the upper part of each heatable plate (3) and / or the upper pressing plate (4) of a freeze-dryer (1), At least one strain gauge (9) is a strain gauge (9) coupled to mechanical connection means (5), V. A control unit (10) comprising a processor (11) and a display device (12), the control unit (10) being configured to automatically and simultaneously collect and analyze measurement values from at least the sensors (6), (7), (8) and (9) and represent at least one of the measurement values on a working map on the display device (12), The sensors (6), (7), (8) and (9) are connected to the control unit (10) for data connection to the control unit (11) through electronic means (13A, 13B, 13C, 13D).

[0020] 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. This has the advantage that it can be installed without affecting the proper functioning of the freeze-dryer. Thus, in all aspects of the present invention, the load cell of the present invention is adapted to be able to operate under vacuum conditions, and the most important problem to overcome is to do so in a very low temperature environment. In a more preferred embodiment, the system of the first aspect is suitable for a freeze-dryer equipped with a movable heatable plate (3). In another preferred embodiment of the system of the first aspect, the freeze dryer is a freeze dryer having an upper piston system.

[0021] In another more preferred embodiment, the system of the first aspect is suitable for a freeze dryer comprising at least one freeze-drying chamber (14), an upper pressing plate (4), a suspended heatable plate (3) suitable for depositing a receptacle suitable for freeze-drying, a hydraulic piston, heating means (15), and means for changing and controlling the chamber pressure.

[0022] In the context of the present invention, the term sample includes a receptacle suitable for freeze-drying, including a product suitable for undergoing a freeze-drying process. Preferably, the product includes a solvent, a cosmetically or pharmaceutically acceptable active ingredient, or a product suitable for food use. In another preferred embodiment, a receptacle suitable for freeze-drying any sample of an aspect of the present invention is selected from the list consisting of vials, ampoules, syringes, cartridges, bulk trays, microtubes and flasks.

[0023] In the context of the present invention, the term standard sample refers to a sample that can be used as a reference or to calibrate a sample for subsequent industrial production. Typically, the hydraulic piston provides the possibility of raising and lowering all the heatable plates (3) that make up the plate stack (2). When the freeze-dried sample is a product deposited in a vial, the vial is closed inside the chamber. This is carried out by a hydraulic piston that presses the upper plate against the cap of each vial until it closes as the plate is lowered. Freeze dryers having a hydraulic piston are frequently 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 commercially available freeze dryers. Preferably, the system has an upper piston freeze dryer.

[0024] Generally, a freeze-drying chamber is a space where a sample to undergo a freeze-drying process is placed. The sample is placed on a heatable plate (3). A set of heatable plates, together with an upper pressing plate, is called a plate stack (2). The plate stack (2) comprises at least one heatable plate (3) suspended from another heatable plate (3) or the upper pressing plate (4) by mechanical connection means (5). The plate stack (2) can have another suspended heatable plate (3) suspended from the suspended plate (3) directly above it by mechanical connection means (5). Generally, a freeze dryer (1) further comprises a condenser, which can be, for example, a coil for collecting all water vapor sublimating from a sample deposited in a freeze-drying chamber (14). 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).

[0025] In the context of the present invention, each strain gauge (9) is configured to be coupled to mechanical connection means (5), and the mechanical connection means (5) has the feature of conforming 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 coupled to the upper portion of the mechanical connection means (5) and on the upper portion of the heatable plate (3) or the pressing plate (2), so as to be configured to obtain more accurate and reproducible measurement values. In another more preferred embodiment of the system of the first aspect, at least the strain gauge (3) is configured to be coupled to the upper portion of the mechanical connection means (5) either directly or indirectly via a tool (20).

[0026] In the context of the present invention, the tool (20) or the compression force transmission structure is disposed at the joint between the load cell and the point where this force is generated. Generally, the mechanical connection means (5) is a metal element adapted to connect and support at least the weight of the lower or directly underlying heatable plate (3). The mechanical connection means (5) supports the weight of the directly underlying heatable plate (3) and is configured to form a plate stack (2). The mechanical connection means (5) is configured to pass through the heatable plate (3) or the upper pressing plate (4) such that the ends of the said means are located above the heatable plate (3) or the upper pressing plate (4) as required.

[0027] In a particular embodiment, the mechanical connection means (5) is preferably selected from the list consisting of a cylindrical rod, a metal shaft and a metal guide, preferably selected from a hollow or solid cylindrical rod. More preferably, the mechanical connection means (5) comprises a metal selected from the list consisting of steel and stainless steel. In a preferred embodiment of the system of the present invention, the control unit (10) is external to 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) selected from a monitor or a screen, a user input device, and a memory unit.

[0028] The control unit (10) can be a server, a desktop computer, a laptop computer, a tablet, or any other suitable type of computing device(s). In another preferred embodiment of the system of the present invention, the system can have two control units (10) both data-connected to a pressure sensor (6), a plate temperature sensor (7), a product temperature sensor (8), and at least a strain gauge (9), namely, a control unit (10EA) external to the freeze dryer, and another control unit (10EB) connected to the freeze dryer, and the external control unit (10EA) is data-connected to the control unit (10EB) of the freeze dryer through the processor (11).

[0029] In a preferred embodiment of the system of the present 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 variation in the weight of the heatable plate (3) of the freeze dryer. In the system of the present invention, each strain gauge (9) is configured to measure the weight of the heatable plate (3) of the freeze dryer. The variation in the weight of the heatable plate (3) of the freeze dryer is obtained by the control unit (10) and is used to calculate the mass flux occurring in a receptacle suitable for freeze drying during the freeze drying process, in other words, the mass flux of the vapor of the solvent sublimating from the frozen product.

[0030] In a preferred embodiment of the system of the present invention, the system further comprises at least one junction box (16) configured to integrate 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 arranged outside the freeze dryer (1). In this way, the signals from each strain gauge load cell are integrated, which helps to obtain more reliable and reproducible measurements of the weight of the heatable plate (3) and the weight of the plate stack (2). This also helps to make the installation of the system easier and reduces the risk of equipment damage. 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.

[0031] In the context of the present invention, the term "analog junction box" is understood as a junction box configured to convert the analog signal of a load cell into a digital signal and integrate the resulting digital signal into a single output signal. In the context of the present invention, the term "digital junction box" is understood as a junction box configured to integrate the digital input signals of a load cell into a single output signal. In the context of the present invention, the term mass flux or mass flow rate is the mass of the substance (solvent or any volatile substance) sublimating from the frozen product in the freeze-drying container passing through a given surface per unit time. Its unit is mass divided by time, and thus, in SI units, it is kilograms per second.

[0032] In the context of the present invention, the pressure sensor (6) is suitable for detecting the absolute pressure within the freeze-drying chamber. Preferably, the pressure sensor is adapted to withstand temperatures up to 121 °C and thereby to withstand the conditions of a regular sterilization process. In a preferred embodiment of the system according to the first aspect, the pressure sensor (6) is a capacitance sensor or a Pirani-type sensor. Preferably, the pressure sensor (6) is arranged inside the freeze-drying chamber (14) and configured to be connected to the control unit (10) by electronic means (13A).

[0033] In a preferred embodiment of the system according to the first aspect, the temperature sensors (7) and (8) are selected from the list consisting of thermocouples, sensors of the Tempris® type, as well as sensors of the PT100 type and thermocouples. Preferably, the pressure sensor (7) and the temperature sensor (8) are adapted to withstand temperatures in the range from -60 °C to 130 °C and / or measure pressures from 0.001 mbar to 1 mbar and are thereby configured to withstand the conditions of a regular sterilization process. In a preferred embodiment of the system according to the present invention, the system comprises at least one temperature sensor (8) in a receptacle suitable for freeze-drying. Preferably, the system comprises at least one product temperature sensor (8) arranged in at least one receptacle suitable for freeze-drying, preferably arranged inside the receptacle and / or in contact with the product.

[0034] In another preferred embodiment of the system of the present invention, the system comprises at least one product temperature sensor (8) in at least one receptacle suitable for freeze-drying each heatable plate (3). In this way, the product temperature measurement becomes more accurate, and it is possible to generate a design space that is better adjusted to the actual conditions of the freeze-drying process. More preferably, the product temperature sensor (8) is wireless. In a preferred embodiment of the system of the present invention, the heating means (15) is a heat fluid heating means, and the temperature sensor (7) is arranged on the heating means (15) and configured to be coupled, for example, to a flange. In a more preferred embodiment of the system of the first aspect, the system comprises at least one temperature sensor (7) for each system, arranged on the heating means (15) before the heating means enters the heatable plate (3). The temperature of the heating means corresponds to the temperature of the heatable plate (3).

[0035] The plate temperature sensor (7) can be arranged on the heat fluid heating means (15) or inside a groove included in the heat fluid heating means (15). The heat fluid heating means (15) can be, for example, a collector. Therefore, the plate temperature sensor (7) is preferably arranged at the fluid inlet of the collector. The temperature at the collector inlet corresponds to the temperature of the heatable plate (3). In another preferred embodiment of the system of the present invention, the temperature sensor (7) is arranged on the heatable plate (3), more preferably inside the heatable plate (3), so as to obtain a more reliable and accurate temperature measurement.

[0036] In a more preferred embodiment, the system of the first aspect comprises at least one temperature sensor (7) arranged on the heating means (15) before the heating means enters the heatable plate (3), and one temperature sensor (7) arranged on at least one heatable plate (3), preferably inside the heatable plate (3), more preferably on the heating means extending inside the heatable plate (3). Preferably, for each heatable plate (3) of the system of the first aspect provided with a freeze dryer, at least one temperature sensor (7) disposed within a receptacle suitable for freeze drying and disposed on one heatable plate (3) is provided.

[0037] In a more preferred embodiment of the system of the first aspect, the temperature sensors (7) and (8) are wireless, and the electronic means (13B and 13C) are wireless. In this way, the installation becomes easier, and since the risk of damage when the electronic means (13B and 13C) are in the form of wires due to the movement of the plates is reduced, the installation is also faster and safer. 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) configured to communicate the data to the control unit (10), and the antenna (19) is preferably configured to emit a wireless signal. The external memory (17) and the external antenna (19) can be disposed thereon. In a preferred embodiment of the system of the first aspect, the electronic means (13A, 13B, 13C, 13D) are wireless or digital and are configured to be sterilizable, for example, protected by a coating resistant to high temperatures up to 121° C. and steam, and thus are configured to withstand the conditions of a regular sterilization process.

[0038] A second aspect of the present invention is a freeze dryer (1), a freeze drying chamber (14), an upper pressing plate (4), a heatable plate (3) suitable for depositing a sample, a hanging plate stack system (2) comprising at least one heatable plate (3) for depositing a sample suitable for a freeze drying process, wherein the plate stack (2) is suspended from either another heatable plate (3) or the upper pressing plate (4), Each heatable plate (3) of the plate stack (2) is coupled to one another or to the upper pressing plate (4) by mechanical connecting means (5), a suspended plate stack system (2), and 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, relating to a freeze dryer (1). In a preferred embodiment, the freeze dryer (1) of the second aspect is a freeze dryer having an upper piston system.

[0039] A third aspect of the present invention is a freeze dryer (1) comprising a system according to any one of claims 1 to 22, preferably a method suitable for generating a design space for a sample comprising a receptacle suitable for freeze drying during a freeze drying process inside the freeze drying chamber of the freeze dryer (1) according to any one of claims 23 and 24, the method comprising: vii. depositing a sample to undergo a freeze drying process inside the chamber (14); and viii. performing a freeze drying process on the product; and ix. measuring fluctuations in the weight of the sample by using at least one strain gauge (9) at different time intervals throughout the freeze drying process of step ii); and x. measuring the temperature of the heatable plate (3) by using a temperature sensor (7) at different time intervals throughout the freeze drying process of step ii); and xi. measuring the temperature of the product of the sample by using a temperature sensor (8) at different time intervals throughout the freeze drying process of step ii); and xiii. measuring the absolute pressure inside the freeze drying chamber at different time intervals throughout the freeze drying process of step ii). Steps iii), iv), v) and vi) are executed simultaneously in real time to provide measurements of the chamber pressure, the temperature of the heatable plate (3), the product temperature, and the weight variation of the sample, The above measurements are collected by the control unit (10), and at least one of the above measurements or the parameters obtained by the control unit (10) via the above measurements is represented on a working map by the display device (12), and the working map includes at least a representation within a graph of the above measurements collected by the control unit (10) or the parameters obtained by the control unit (10), and the graph represents at least one of the measurements or parameters, and optionally establishes the limits of the design space, relating to a method.

[0040] In a preferred embodiment of the method of the third aspect, the graph of the working map represents at least two and / or three of the measurements collected by the control unit (10) and the parameters obtained by the control unit (10) through the above measurements. The term working map includes, for example, a representation in a graph of the measurements collected or the parameters obtained by the control unit (10), and at least one of the above measurements or the above parameters, or at least two of the above measurements and / or the above parameters, or at least three of the above measurements and / or the parameters obtained by the control unit (10) are represented.

[0041] In the context of the present invention, the term design space is understood as delimiting the range of each parameter of the lyophilization process within which it is ensured that the resulting product has the required quality attributes. An example of the producer sample design space is shown in FIG. 1. The temperature of the heatable plate (3), the chamber pressure, and the weight of the heatable plate (3) are measured at several time intervals (for example, at regular time intervals such as every minute). The values measured at each time interval, in addition to calculating the heat transfer coefficient received by the product to be lyophilized and the resistance constant of the dry product to the passage of vapor to represent a 2D or 3D map or graph, are applied to a mechanistic integrated heat and mass transfer equilibrium model to infer / calculate the conditions within a receptacle suitable for lyophilization at those time intervals, and these calculated constants are applied to the heat and mass transfer equilibrium model. This representation is also called the design space.

[0042] The process conditions or parameters of the sample or product within a receptacle suitable for lyophilization are calculated based on the temperature, pressure of the heatable plate (3) and the product, and the weight of the heatable plate (3) measured by sensors / probes inside or outside the lyophilization chamber. In another more preferred embodiment of the method according to the third and fourth aspects (if necessary) of the present invention, the measurement of the weight variation of the sample in step ii) is performed by the control unit (10), giving a value of the vapor mass flux, and the measured value of the weight variation of the sample in step ii) is determined based on the number of samples placed on each heatable plate (3) in response to the weight variation measured by the strain gauge(s) (9) of the heatable plate (3) containing the sample.

[0043] In another more preferred embodiment of the method according to the third and fourth aspects of the present invention, the number of samples placed on each heatable plate (3) is predefined and input to the control unit (10), or obtained externally through a server by the control unit (10), or manually input to the control unit (10) by the user. In another more preferred embodiment of the method according to the third and fourth aspects of the present invention, the working map of the design space is executed by a control unit (10) that establishes the relationship between chamber pressure and / or product temperature and / or mass flux in the form of a 2D or 3D graph. Therefore, the creation of the design space of the method according to the third aspect can be used, for example, for the method according to the fourth aspect of the present invention, during an appropriate time period (e.g., the next 1 hour, the next 2 hours, etc.), as a criterion or model for predicting future values of the conditions inside a container suitable for lyophilization, such as a vial.

[0044] The construction of the above-mentioned 3D or 2D design space by the method according to the third aspect also has the advantage of making it easier to identify the optimal conditions of the daily lyophilization process in both large-scale and small-scale manufacturers, the limits where the process may fail, and the limits or ranges for performing the verification of the manufacturing process. Furthermore, it becomes possible to calculate or estimate the limits of process control for a specific lyophilization receptacle, equipment, and the configuration of the manufacturing environment. Similarly, the method according to the third aspect can be used to predict the influence of variations on process conditions, process yield, the time until completion, and product quality, or to understand the deviations that may occur during manufacturing.

[0045] In a preferred embodiment of the method according to the third and fourth aspects of the present invention, the lyophilization process of step ii) includes at least 1) a step of freezing the product of step i) within a temperature range of -0°C to -60°C, 2) a step of reducing the pressure inside the lyophilization chamber (2) to a range of 0.9 atm to 0.0002 atm, 3) a step of primary drying the product obtained in step 2), 4) a step of secondary drying the product obtained in step 3), 5) a step of sterilizing, 6) optionally, a step of discharging the product.

[0046] In a preferred embodiment of the method according to the third and fourth aspects of the present invention, the lyophilization process of step ii) comprises at least 1) freezing the product of step i) within a temperature range of 0 °C to -60 °C; 2) reducing the pressure in the lyophilization chamber (2) to a value within the range of 0.9 atm to 0.0002 atm; 3) subjecting the product obtained in step 2) to primary drying within a temperature range between -50 °C and 20 °C or between -50 °C and 40 °C; 4) subjecting the product obtained in step 3) to secondary drying within a temperature range between 20 °C and 70 °C or between 40 °C and 70 °C; 5) sterilizing; 6) optionally, discharging the product obtained in step 4 or 5).

[0047] In the lyophilization process, primary drying removes water by sublimating ice from the product (previously frozen product) under vacuum conditions. By supplying heat, the ice sublimates, avoiding passage through the liquid phase. During primary drying, the water vapor generated at the sublimation interface is removed through the pores of the product structure. Primary drying is carried out from the freezing temperature to a temperature range typically between 20 °C and 40 °C. After the sublimation process is completed, secondary drying is carried out to remove any or most of the remaining liquid or moisture. This drying is carried out, for example, by desorbing and evaporating the non-freezable water found in the previously dried material. In this way, a final product moisture result close to 2% or even less than 2% can be obtained.

[0048] Secondary drying is carried out from the temperature at which primary drying is completed to a temperature range between 20 °C and 70 °C. Thus, when the ice disappears, free water begins to be removed by evaporation, resulting in secondary drying. In another preferred embodiment of the method according to the third aspect of the present invention, the control unit (10) is configured to establish a relationship between the chamber pressure, the mass flux, and the product temperature, and the said relationship is represented by the control unit (10) in a 3D or 2D working map. This relationship can be established by applying the mass balance and the energy balance during the sublimation process of the primary drying. This relationship can be executed for each different product temperature.

[0049] Therefore, in another preferred embodiment, the control unit (10) is configured to establish, in a 2D working map, the relationship between the chamber pressure, the mass flux, and the product temperature at different product temperatures (different product isotherms) during the freeze-drying process. In another preferred embodiment, the control unit (10) is configured to establish, in a 2D working map, the relationship between the chamber pressure, the mass flux, and the plate temperature at different plate temperatures during the freeze-drying process. In another preferred embodiment, the control unit (10) is configured to establish, in a 2D working map, the relationship between the chamber pressure, the mass flux, different product temperatures (product isotherms), and different plate temperatures (plate temperature isotherms) at different plate temperatures during the freeze-drying process. The heat transfer coefficient between the plate and the product and the resistance coefficient of the dried product to be freeze-dried with respect to the vapor flow are used to establish the relationship between the chamber pressure and the mass flux for each temperature of each heatable plate (3). The said parameters are obtained experimentally and supplied to the control unit (10).

[0050] The following steps are executed to calculate the heat transfer coefficient (Kv) between the freeze-dryer and the product to be freeze-dried. 1. Fill a container suitable for freeze-drying, for example a vial, with water. 2. Adjust the plate temperature so as to reach the desired pressure for each product or sample. 3. Insert a temperature sensor into the container. 3. Adjust the temperature of the heatable plate of the freeze dryer to a fixed temperature value. 4. Adjust the chamber pressure of the freeze dryer to a specific fixed value. 5. Measure the product temperature value (Tb). 6. Determine the mass flow rate. 7. Calculate Kv. 8. Repeat steps 4 to 8 for different pressure values including the entire operating range of the freeze-drying process to calculate Kv for different pressure values by applying the following formula. Pressure

Number

[0051] The following steps are performed to calculate the resistance coefficient (Rp) of the dried product to be freeze-dried with respect to the vapor flow. 1. Fill a container, for example, a vial, with the product to be freeze-dried. 2. Insert a temperature sensor into the container. 3. Adjust the temperature of the heatable plate of the freeze dryer to a fixed temperature value. 4. Adjust the chamber pressure of the freeze dryer to a specific fixed value. 5. Determine the product temperature value (Tb). 6. Determine the mass flow rate. 7. Calculate R p Calculate Rp. 8. Repeat steps 4 to 8 for different pressure values including the entire operating range of the freeze-drying process by applying the following formula.

Number

[0052] In a preferred embodiment, to establish the relationship between chamber pressure, mass flux, and product temperature (product temperature isotherm), as seen in FIGS. 2A and 2B, the following steps are performed. 1. Select the product temperature (T b ) and chamber pressure (P c ), and calculate the sublimation rate (dm / dt) using the following equation. dm / dt = (P i - P c ) / R p P i = f(T b )(equilibrium) 2. Repeat the calculation for different values of the chamber of P c . 3. Draw a line on the graph. 4. Repeat the operation for other product temperature values T b . In a preferred embodiment of the method according to the third aspect of the present invention, the method includes an additional step after the design space has been established. This additional step includes establishing the limits of the design space.

[0053] In another preferred embodiment of the method according to the third aspect, the method includes an additional step vii) of establishing the limits of the design space, which includes establishing the maximum limit (choke flow or choke point) of the evaporation mass flow rate allowed by the lyophilization equipment based on 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 choke flow. In the context of the present invention, the process for establishing the maximum limit of the evaporation mass flow rate allowed by the lyophilization equipment based on the pressure in the lyophilization chamber is called the choke point or choke flow. An example of the design space representing the established choke flow is shown in FIGS. 3 and 4.

[0054] In a preferred embodiment of the method of the present invention, steps below the choke point or choke flow are performed. 1. Fill the lyophilizer with water to a known height. 2. Freeze at -40°C. 3. Prepare the system to start primary drying. 4. Perform primary drying at different chamber pressures. 5. Verify the maximum vapor flow rate achievable at each chamber pressure. The critical temperature of the product is a parameter used to establish the above limits. Preferably, the critical temperature is determined by a method selected from at least the list consisting of DSC, TGA, and FDM. Specifically, the critical temperature is a relevant parameter for designing the primary drying stage of the lyophilization cycle.

[0055] To determine the critical temperature of the product, the maximum product temperature allowed during primary drying is determined. This temperature can be the collapse temperature in the case of an amorphous product or the melting temperature in the case of a crystalline product. The critical temperature is necessary to establish the highest temperature allowed for the product during primary drying. The critical temperature for primary drying is a parameter supplied to the control unit (10) for performing step vi). In a preferred embodiment of the method according to the third aspect of the present invention, the control unit (10) uses, for example, the average value obtained by the control unit (10) when two or more temperature sensors of the plate (3) present in the lyophilizer are used, to establish the relationship between the chamber pressure and the mass flux for the temperature of the heatable plate (3), and the said relationship is represented in a 2D working map at different temperatures of the heatable plate (3) during the lyophilization process by the control unit (10).

[0056] A fourth aspect of the present invention relates to a lyophilizer (1) comprising a system according to the first aspect, preferably to a suitable lyophilization method for including a product during the lyophilization process inside the lyophilization chamber (2) of the lyophilizer (1) according to any one of claims 23 and 24, the said method comprising at least vii. depositing a sample to undergo the lyophilization process inside the said chamber (14); viii. performing a lyophilization process on the said product; ix. optionally, measuring the weight variation of the sample by using at least one strain gauge (9) at different time intervals throughout the lyophilization process of step ii); x. measuring the temperature of the heatable plate (3) by using a temperature sensor (7) at different time intervals throughout the lyophilization process of step ii); xi. optionally, measuring the temperature of the product of the sample by using a temperature sensor (8) at different time intervals throughout the lyophilization process of step ii); xii. A step of measuring the absolute pressure inside the freeze-drying chamber at different time intervals throughout the freeze-drying process of step ii), Steps iii), iv), v) and vi) are executed simultaneously in real time to provide measured values of the chamber pressure, the temperature of the heatable plate (3), the product temperature, and the weight variation of the sample, The above measured values are collected by the control unit (10), and at least one of the above measured values or the parameters obtained through the above measured values by the control unit (10) is represented on the working map by the display device (12). The working map includes at least a representation within a graph of the above measured values collected by the control unit (10) or the parameters obtained by the control unit (10). The graph includes a step of measuring that represents at least one of the measured values or parameters, c. By using the control unit (10), at least the temperature of the heatable plate (3) and the measured value of the pressure obtained in the working map for each product during step ii) are compared with the previously obtained values in the design space according to the third aspect for the sample or the standard sample during the same step ii), d. Optionally, if necessary, based on the result of step e) that deviates from the result obtained for the design space of the sample or the standard sample, a step of adjusting the absolute pressure and temperature parameters in the freeze-dryer for each process through the control unit (10). The method is related to this.

[0057] In a preferred embodiment of the method according to the fourth aspect of the present invention, the control unit (10) is configured to apply the obtained pressure values, as well as 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 dried product to be freeze-dried with respect to the vapor flow measured at different chamber pressures, as inputs to the heat and mass transfer model, in order to calculate the mass flux inside the freeze-drying chamber at different times and different product temperatures in the 2D or 3D working map. In a preferred embodiment of the method according to the fourth aspect of the present invention, the control unit (10) is subsequently configured to establish the relationship between the chamber pressure, the mass flux, and the product temperature in a 2D or 3D working map at different product temperatures.

Claims

1. A system suitable for controlling a freeze-drying process in a freeze-dryer (1) having a hanging plate stack system (2) comprising at least one heatable plate (3), wherein said plate stack (2) is suspended from either another heatable plate (3) or an upper pressing plate (4), and each heatable plate (3) of said plate stack (2) is coupled to each other or to said upper pressing plate (4) by mechanical connection means (5), Said system comprises, VI. At least one pressure sensor (6) suitable for detecting the absolute pressure within the freeze-drying chamber, VII. At least one temperature sensor (7) suitable for measuring the temperature of the heatable plate (3), VIII. At least one product temperature sensor (8) suitable for measuring the temperature of said product and suitable for being disposed inside a receptacle suitable for freeze-drying, IX. At least one strain gauge (9) configured to be disposed on the upper part of each heatable plate (3) and / or the upper pressing plate (4) of said freeze-dryer (1), Said at least one strain gauge (9) being at least one strain gauge (9) coupled to the mechanical connection means (5), X. A control unit (10) comprising a processor (11) and a display device (12), Said control unit (10) being configured to automatically and simultaneously collect and analyze the measurement values from at least said sensors (6), (7), (8) and (9), and to represent at least one of said measurement values on a working map on the display device (12), Said sensors (6), (7), (8) and (9) being in data connection with said control unit (11) through electronic means (13A, 13B, 13C, 13D), a system comprising a control unit (10).

2. The system according to claim 1, wherein said freeze-dryer is a freeze-dryer having an upper piston system and / or said heatable plate (3) of said freeze-dryer is a movable plate.

3. The system according to claim 1 or 2, comprising at least two strain gauges (9), preferably at least four strain gauges (9) for each heatable plate.

4. The freeze dryer (1) according to any one of claims 1 to 3 comprises at least one freeze-drying chamber (14), an upper pressing plate (4), a heatable plate (3) suitable for depositing a receptacle suitable for freeze-drying, heating means (15), and means for changing the chamber pressure.

5. The at least one strain gauge (9) is configured to be coupled to the upper portion of the mechanical connection means (5), and / or the mechanical connection means (5) is configured such that an end of the means is located above the heatable plate (3) or the upper pressing plate (4), and the strain gauge (9) is coupled to the upper end portion, and is configured to pass through the heatable plate (3) or the upper pressing plate (4). The system according to any one of claims 1 to 4.

6. The at least one strain gauge (9) is configured to be directly or indirectly coupled to the upper portion of the mechanical connection means (5) via a tool (20). The system according to any one of claims 1 to 5.

7. The control unit (10) is external to the freeze dryer, and the processor is selected from a CPU or a PLC unit. The system according to any one of claims 1 to 6.

8. The system may have two control units (10) both data-connected to the pressure sensor (6), the temperature sensor (7), the product temperature sensor (8), and the at least one strain gauge (9), namely, a control unit (10EA) external to the freeze dryer, and another control unit (10EB) connected to the freeze dryer. The external control unit (10EA) is data-connected to the control unit (10EB) of the freeze dryer through a processor (11). The system according to any one of claims 1 to 7.

9. The 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 fluctuations in the weight of the heatable plate (3) of the freeze dryer. The system according to any one of claims 1 to 8.

10. The system according to any one of claims 3 to 9, further comprising at least one junction box (16) configured to integrate the input signals of the respective deflection gauges (9) into a single output signal directed towards the control unit (10).

11. The system according to claim 10, wherein the junction box (16) is an analog junction box or a digital junction box and / or is arranged outside the freeze dryer (1).

12. The system according to any one of claims 1 to 11, wherein the temperature sensors for the plate (7) and the product (8) are selected from the list consisting of thermocouples and PT100 type sensors.

13. The system according to any one of claims 1 to 12, comprising at least one plate temperature sensor (7) arranged on the heating means (15) before entering the heatable plate, and the system preferably further comprises at least one plate temperature sensor (7) for each heatable plate (3) of the freeze dryer.

14. The system according to any one of claims 1 to 13, wherein the plate temperature sensor (7) arranged on the heatable plate (3) is configured to be arranged inside the heatable plate (3).

15. The system according to any one of claims 1 to 14, wherein the heating means (15) is a heat fluid heating means and the temperature sensor (7) is configured to be arranged on the heating means (15).

16. The system according to any one of claims 1 to 15, comprising at least one product temperature sensor (8) arranged in at least one receptacle suitable for freeze drying, and preferably the system comprises one product temperature sensor (8) for each heatable plate (3).

17. The system according to any one of claims 1 to 16, wherein the product temperature sensor (8) is configured to be deposited inside a receptacle suitable for freeze drying, and the product temperature sensor (8) is preferably wireless.

18. The system according to any one of claims 1 to 17, wherein the electronic means (13A, 13B, 13C, 13D) are wireless or digital.

19. The system according to any one of claims 1 to 18, wherein the temperature sensors (7) and (8) and the corresponding electronic means (13B and 13C) are wireless.

20. The wireless temperature sensor (8) has a memory (17) for storing data, a battery (18), and an antenna (19) configured to communicate the data to the control unit (10), and the antenna is preferably configured to emit a wireless signal. The system according to any one of claims 1 to 19.

21. The pressure sensor (6) is a capacitance or Pirani type sensor, and is preferably a pressure sensor configured to withstand temperatures in the range of -60°C to 130°C and / or measure pressures from 0.01 mbar to 1 mbar. The system according to any one of claims 1 to 20.

22. The pressure sensor (6) is disposed inside the lyophilization chamber (14) and is configured to be connected to the control unit (10) by the electronic means (13A). The system according to any one of claims 1 to 21.

23. A lyophilizer (1), comprising a lyophilization chamber (14), an upper pressing plate (4), a heatable plate (3) suitable for depositing a sample, a hanging plate stack system (2) comprising at least one heatable plate (3) for depositing a sample suitable for the lyophilization process, wherein the plate stack is suspended from either another heatable plate (3) or the upper pressing plate (4), each heatable plate (3) of the plate stack is coupled to each other or to the upper pressing plate (4) by mechanical connection means (5), the hanging plate stack system (2), and a system according to any one of claims 1 to 21, Optionally, the heatable plate (3) of the lyophilizer (1) is a movable plate, the lyophilizer (1).

24. The lyophilizer (1) according to claim 23, wherein the lyophilizer (1) has an upper piston system.

25. A freeze dryer (1) comprising the system according to any one of claims 1 to 22, preferably during the freeze-drying process inside the freeze-drying chamber of the freeze dryer (1) according to any one of claims 23 and 24, a method suitable for generating a design space for a sample comprising a receptacle suitable for freeze-drying containing a product, a. depositing a sample to undergo a freeze-drying process inside the chamber (14); b. performing a freeze-drying process on the product; c. measuring the weight variation of the sample by using at least one strain gauge (9) at different time intervals throughout the freeze-drying process of step ii); d. measuring the temperature of the heatable plate (3) by using a temperature sensor (7) at different time intervals throughout the freeze-drying process of step ii); e. measuring the temperature of the product of the sample by using a temperature sensor (8) at different time intervals throughout the freeze-drying process of step ii); f. measuring the absolute pressure inside the freeze-drying chamber at different time intervals throughout the freeze-drying process of step ii), where steps iii), iv), v) and vi) are executed simultaneously in real time to provide measurements of chamber pressure, the temperature of the heatable plate (3), product temperature, and the weight variation of the sample, the measurements are collected by a control unit (10), and at least one of the measurements or parameters obtained through the measurements by the control unit (10) is represented on a working map by a display device (12), the working map including at least a representation within a graph of the measurements collected by the control unit (10) or the parameters obtained by the control unit (10), the graph represents at least one of the measurements or parameters and optionally establishes the limits of the design space.

26. The method according to claim 25, wherein the graph of the working map represents at least two and / or three of the measurements collected by the control unit (10) and the parameters obtained by the control unit (10) through the measurements. Claim 27 The freeze-drying process of step ii) comprises at least a) freezing the product of step i) within a temperature range of from -0°C to -60°C; b) reducing the pressure within the freeze-drying chamber (2) to a range from 0.9 atm to 0.0002 atm; c) subjecting the product obtained in step b) to primary drying; d) subjecting the product obtained in step c) to secondary drying; e) optionally, discharging the product, and the method according to claim 26. Claim 28 The measurement of the weight variation of the sample in step ii) is carried out by the control unit (10), gives a value of the vapor mass flux, and the measured value of the weight variation of the sample in step ii) is determined based on the number of samples placed on each heatable plate (3) in response to the weight variation measured by the strain gauge(s) (9) of the heatable plate (3) comprising the sample, and is a method suitable for generating the design space according to any one of claims 24 to 27. Claim 29 The number of samples placed on each heatable plate (3) is predefined and input to the control unit (10), or obtained externally by the control unit (10) through a server, or manually input to the control unit (10) by the user, and is a method suitable for generating the design space according to claim 28. Claim 30 The control unit (10) is configured to establish the relationship between the chamber pressure and the mass flux for each temperature of each heatable plate (3) present within the freeze-dryer, and the relationship is represented by the control unit (10) in a 2D working map at different temperatures received by each heatable plate (3) during the freeze-drying process, and is a method suitable for creating the design space according to claim 27 or 28. Claim 31 The receptacle suitable for freeze-drying the sample is selected from the list consisting of vials, ampoules, syringes, cartridges, bulk trays, microtubes and flasks, and is a method suitable for creating the design space according to claim 27 or 28. Claim 32 1. Establishing a maximum limit of the evaporation mass flow rate acceptable by the freeze-drying apparatus based on the pressure measured by the pressure sensor (6) during steps b), c) and d) of the freeze-drying process; 2. Determining a critical product temperature; Including additional step vii) which includes establishing the limits of the design space, according to the method of any one of claims 27 to 30.

33. The method according to claim 32, wherein the control unit (10) is configured to establish the limit of the mass flow rate in section 1.

34. The method according to claim 31 or 32, wherein the critical temperature of the product is determined by a method selected from at least the list consisting of DSC, TGA and FDM, and the temperature is supplied to the control unit (10).

35. A freeze-dryer (1) comprising the system according to claims 1 to 22, preferably during the freeze-drying process inside the freeze-drying chamber (2) of the freeze-dryer (1) according to any one of claims 23 and 24, a method for monitoring and controlling a sample comprising a receptacle suitable for freeze-drying containing a product, at least: xiii. Depositing a sample to undergo a freeze-drying process inside the chamber (14); xiv. Performing a freeze-drying process on the product; xv. Optionally, measuring the weight variation of the sample by using at least one strain gauge (9) at different time intervals throughout the freeze-drying process of step ii); xvi. Measuring the temperature of the heatable plate (3) by using a temperature sensor (7) at different time intervals throughout the freeze-drying process of step ii); xvii. Measuring the temperature of the product of the sample by using a temperature sensor (8) at different time intervals throughout the freeze-drying process of step ii); xviii. Measuring the absolute pressure inside the freeze-drying chamber at different time intervals throughout the freeze-drying process of step ii), Steps iii), iv), v) and vi) are executed simultaneously in real time to provide measured values of the chamber pressure, the temperature of the heatable plate (3), the product temperature, and the weight variation of the sample. The measured values are collected by the control unit (10), and at least one of the measured values or the parameters obtained through the measured values by the control unit (10) is represented on the working map by the display device (12). The working map includes at least a representation in a graph of the measured values collected by the control unit (10) or the parameters obtained by the control unit (10). The graph represents at least one of the measured values or parameters and includes a step of measuring the absolute pressure, By using the control unit (10), at least the temperature of the heatable plate (3) and the measured value of the pressure obtained in the working map for each product during step ii) are compared with the values previously obtained in the design space according to the third aspect for the sample or standard sample during the same step ii). Optionally, if necessary, based on the result of step e) deviating from the result obtained for the design space of the sample or standard sample via the control unit (10), a method including a step of adjusting the absolute pressure and temperature parameters in the freeze dryer for each process.

36. The control unit (10) is configured to apply the obtained pressure value, 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 dried product to be freeze-dried with respect to the vapor flow measured at different chamber pressures as inputs to the heat and mass transfer model in order to calculate the mass flux inside the freeze-drying chamber at different times and different product temperatures in a 2D or 3D working map. The method according to claim 35.

37. The control unit (10) is subsequently configured to establish the relationship between the chamber pressure, the mass flux, and the product temperature in a 2D or 3D working map at different product temperatures. The method according to claim 36.

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