A module for a freeze-dryer system, a freeze-dryer system and a method for using the system

Abstract

The present invention is related to a sample heat exchanger module (200) for a freeze-dryer system (100) comprising - a first heat exchange element (201) made of thermally conductive material and comprising • a top surface (202); and • a plurality of straight passages (203, 204, 205) extending in different directions through the first heat exchange element (201), the passages being parallel to the top surface (202) and intersecting at the interior of the first heat exchange element (201); - a first cold source (206) comprising a cold end (207) with a maximum efficiency zone (208) that is in thermal contact with the first heat exchange element (201); and - a first heat source (209) comprising a maximum efficiency zone (210) in thermal contact with the first heat exchange element (201); wherein the straight passages (203, 204, 205) are arranged between the top surface (202) and the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209), and wherein the first cold source (206) and the first heat source (209) are controllable by a control unit (102) to decrease or increase the temperature of the first heat exchange element (201).

Description

[0001] A MODULE FOR A FREEZE-DRYER SYSTEM, A FREEZE-DRYER SYSTEM AND A METHOD FOR USING THE SYSTEM

[0002] DESCRIPTION

[0003] TECHNICAL FIELD OF THE INVENTION

[0004] The present invention belongs to the field of freeze-drying. Particularly, the present invention provides a sample heat exchanger module for a freeze-dryer system, which holds the samples to be freeze-dried, achieving a high thermal homogeneity. Besides, the invention is directed to a freeze-dryer system comprising the sample heat exchanger module, and to a method that uses the freeze-dryer system for determining an optimum working scheme of a freeze-drying cycle.

[0005] BACKGROUND OF THE INVENTION

[0006] Freeze-drying, also known as lyophilization, is a process that involves removing the water content from a material while preserving its structure and biological or chemical activity. Freeze-dried materials can preserve their properties for long periods without the need for refrigeration and, for this reason, freeze-drying is commonly used in various industries to preserve and extend the shelf life of various products.

[0007] As an industrial process, freeze-drying is used to process large batches of the same material. In this context, the homogeneity of the products to be freeze-dried is controlled and consistent thermal characteristics among all the products are expected. Moreover, the production is usually concentrated in a single manufacturing / production plant where one or a few large-capacity freeze-dryers are installed.

[0008] Production freeze-dryers are usually custom made and installed in their final location by the manufacturer while smaller units may be purchased “off-the-shelf’ and usually used for small batch productions, for pilot process validation and for process development. Nowadays, both cycle development and scale-up processes are not standardized, and each company uses a relatively different approach to achieve them mostly like any other industrial process. For logistic and economic reasons, freeze-drying cycles are usually developed in small scale freeze-drying systems and later adapted, i.e. scaled, to each one of the production systems that will be used for production. This scaling process is needed to compensate for the inevitable differences in performance between development scale and production scale systems and for the differences between production systems running in parallel.

[0009] Besides the interest of freeze-drying as an industrial process, freeze-drying is also of great value in clinical and research laboratories, for the preservation, concentration, and stabilization of a wide range of biological materials, such as cells, tissues, and proteins, to produce stable reagents, such as enzymes and antibodies, or to concentrate samples by removing the water content, allowing for higher concentrations of the material of interest for easier handling and analysis.

[0010] Small scale freeze-drying systems, created to help in the process of freeze-drying cycle development and scale-up, can be found in many research laboratories nowadays. However, such small scale freeze-drying systems are no more than downsized, and often downgraded, versions of industrial equipment and present the same problems of their full-size versions, significantly limiting their usability as a laboratory grade equipment.

[0011] Like any industrial equipment, small scale freeze-drying systems are designed to be handled by highly trained personnel usually dedicated to that single task and, as a result, their human-machine interfaces are not optimized to be user friendly and to simplify the work of a laboratory technician that needs to handle dozens of different systems for different tasks every day. Since industrial systems are usually meant to be kept and handled in dedicated spaces, manufacturers do not dedicate too much effort in reducing noise and heat emissions, making most of them unsuitable to be kept in a common laboratory space with other equipment.

[0012] In contrast with what happens in a production plant, freeze-drying is typically used in a laboratory to process small quantities of different samples and, most commonly, there is small room for planning ahead since those samples are usually obtained during a working day. Adding to this, each sample type may demand for totally different temperature profiles during the freeze-drying process and laboratories either have multiple dedicated freeze-dryers running in parallel or need to perform several consecutive freeze-drying runs, each one specific for a single type of sample. Freeze- drying different samples simultaneously irrespective of their properties will certainly result in products with different quality levels, something not acceptable for most scientific and clinical applications.

[0013] One way of mitigating the problem of fitting multiple freeze-drying runs in a single day is to optimize the freeze-drying cycle design aiming to minimize the full cycle length without compromising the quality of the process. However, freeze drying is a slow process, a balance of heat and mass fluxes that can be divided into three main phases: 1) freezing, 2) primary drying and 3) secondary drying. Freezing is an exothermic process where heat is removed from the materials until their molecules lose the energy needed to maintain their freedom of movement. During this process, most of the solvent (usually water) crystalizes and is separated from the solutes, effectively drying them. During primary drying, the crystalized solvent mass is removed by sublimation, an endothermic process where the solvent changes directly from solid to gas under vacuum. The resulting gas mass is then removed from the space above the materials by deposition, an exothermic process where the solvent changes directly from gas to solid, over a cold surface commonly known in the field as “condenser”. During secondary drying, the remaining water bound to the partially dried material is removed by desorption by the action of heat (endothermic process) until a desired moisture content is reached. Of the three main phases described above, primary drying is the most time-consuming but also the one that can be optimized the most.

[0014] During a freeze-drying cycle, there is only direct control over the chamber pressure and the shelf temperature. The product temperature will change in response to those two parameters and the dynamics of the freeze-drying process itself. The most common practice in lyophilization is to control the chamber pressure and shelf temperature at constant setpoint values throughout the primary drying phase. Those setpoint values are usually chosen conservatively, leading to a very low energy efficiency for the cycle. Common values for the chamber pressure setpoint are between 0.05 and 0.3 mbar while the shelf temperature is maintained at a constant value that ensures that the product temperature does not exceed, by a certain conservative margin, the critical value beyond which the product appearance is unacceptable. The entire freeze-drying process can take a long time to finish if these input conditions are not optimized.

[0015] During primary drying, the setpoints of chamber pressure and shelf temperature for maximum cycle efficiency (maximum sublimation rate leading to a shorter cycle time) are those that maintain the product temperature as close as possible to its critical value, without crossing the capability limits of the equipment. However, at every instant during the primary drying, the product resistance to the water vapour flow increases, due to the increasing cake length, and, as a result, those constant optimal setpoints also change.

[0016] To account for this fact, most common practice defines those constant setpoints based on the largest value of product resistance, which occurs at the end of the primary drying when the cake length is maximum. This ensures that the product temperature remains below its limit at any point in the cycle, although the most optimal operation throughout the primary drying process would be achieved by varying the chamber pressure and shelf temperature as a function of time, instead of maintaining them at constant setpoints.

[0017] The varying setpoint approach can be employed in response to real time variations in product temperature instead of relying on predefined setpoints chosen by the user. This strategy can be seen as a closed loop strategy and should be the strategy that provides the best results when trying to minimize the primary drying time during freeze-drying. However, that means a series of temperature sensors need to be placed in contact with the products to be freeze-dried to obtain real-time feedback, which may not be possible due to contamination concerns, and because the samples chosen to provide feedback may not be representative of the rest of product samples as the presence of a temperature sensor inside a small container with product may, by itself, alter the measures.

[0018] Alternatively, this varying shelf temperature and chamber pressure setpoint approach can be employed through a predefined list of setpoint for shelf temperature and chamber pressure that is followed by the system without considering any feedback about the realtime product temperature. This can be seen as an open-loop strategy. Mathematical models and / or experimental data can be used to identify the optimum shelf temperature and chamber pressure setpoints as a function of time. Several simulation and optimization models have been developed to help with the design of freeze-drying cycles, mostly focused on the modeling of primary drying heat and mass fluxes. Those models have proven to reasonably agree with experimental data and, at least some of them, can be used to obtain said list of variable setpoints. Unfortunately, mathematical models are highly dependent on the precise knowledge about several properties and constants related with the freeze-drying system, the sample containers and the samples, values that can be experimentally obtained but at the cost of a long and tedious process the outcomes of which are, most of the times, only approximations to the reality.

[0019] Applying a varying setpoint approach, either through an open-loop or closed loop strategy, is only possible within the capabilities of the freeze dryer in use. The optimum setpoints may change at a high rate and the freeze dryer needs to be able to adapt to those changes at the same rate or the process will not result as intended.

[0020] Most of the available freeze dryers in the market employ multi-stage refrigeration systems to achieve the very low temperatures needed to freeze the samples and to cool down the condenser surface. These refrigeration systems are complex and bulky and need to be placed away from the sample shelves and condenser. The heat transfer between the product / condenser and the cooling or heating sources relies on a coolant liquid, usually Ethylene Glycol, Propylene Glycol or Silicone Oil, that circulates through the system.

[0021] The use of a circulating coolant provides an effective way to transfer heat between two surfaces physically separated and differently shaped. However, these coolants act as thermal intermediaries between the product / condenser and the cooling or heating sources, compromising the heat transfer efficiency. The additional thermal mass associated with the coolant and the tubing, together with the thermal losses along the coolant travel path, may result in a high thermal inertia that can significantly slow down temperature adjustments. For this reason, it is challenging to achieve rapid temperature changes, particularly in large systems with large coolant masses and long pipes, making it virtually impossible to create the complex temperature profiles required when a varying setpoint approach is employed to a freeze-drying process.

[0022] In JP2000136754A, a system for freeze-drying employing a Stirling refrigerator is described. The disclosed design uses the cold end of a Stirling cryocooler to cool a liquid that is pumped through the system. This design has the drawback of having circulating coolants in the system.

[0023] As such, there is a need for a new and improved system and method for freeze-drying, addressing the needs of laboratory users that mitigate or solve the deficiencies and problems present in conventional freeze-drying systems.

[0024] SUMMARY OF THE INVENTION

[0025] The present invention provides a solution for the aforementioned problems, by proposing a sample heat exchanger module for a freeze-dryer system according to claim 1 , a freeze-dryer system according to claim 16 and a method for determining an optimum working scheme for products to be freeze-dried according to claim 22. In the dependent claims, preferred embodiments of the invention are defined.

[0026] In a first inventive aspect, the invention provides a sample heat exchanger module for a freeze-dryer system, the sample heat exchanger module comprising:

[0027] • a first heat exchange element made of thermally conductive material, the first heat exchange element comprising: a top surface; a plurality of straight passages extending in different directions through the first heat exchange element, the passages being parallel to the top surface and intersecting at the interior of the first heat exchange element;

[0028] • a first cold source comprising a cold end with a maximum efficiency zone that is in thermal contact with the first heat exchange element;

[0029] • a first heat source comprising a maximum efficiency zone in thermal contact with the first heat exchange element; wherein the straight passages are arranged between the top surface and the maximum efficiency zones of the first cold source and the first heat source, and wherein the first cold source and the first heat source are controllable by a control unit to decrease or increase the temperature of the first heat exchange element.

[0030] The sample heat exchanger module of the first inventive aspect can be integrated into a freeze-dryer system to perform a lyophilisation (i.e. freeze-drying) process on a product. Throughout the present document, a product will be understood as a material to be subjected to the freeze-drying process; for example, a biological material.

[0031] The sample heat exchanger module is intended to support the product to be freeze-dried and to provoke the temperature variations required during a freeze-drying process in the product. To achieve this, the sample heat exchanger module comprises: a first heat source and a first cold source, which generate heat fluxes needed to vary the temperature of the product; and a first heat exchange element, which is in thermal contact with the heat and cold sources.

[0032] The first heat source generates its heat flux to transmit heat and the first cold source generates its heat flux to remove heat; that is, the direction of the heat fluxes of the first heat source and the first cold source is contrary.

[0033] The first heat source and the first cold source comprise, each one, a maximum efficiency zone in thermal contact with the first heat exchange element. Throughout the present document, it will be understood that two elements are in thermal contact when one of the element transfers heat to the other by being in direct connection (i.e. the two elements are touching each other) or in indirect connection (i.e. the heat transfer is performed through one or more additional element).

[0034] In an embodiment, the first heat exchange element is in direct thermal contact with the first heat source and / or the first cold source. In other embodiment, it is in indirect thermal contact with the first heat source and / or the first cold source through an additional element, e.g. a thermal paste.

[0035] In the maximum efficiency zones of the first heat source and the first cold source, the heat flux is maximized. Consequently, the temperature transmission between the sources and the first heat exchange element is maximized. In an embodiment, the maximum efficiency zones are identified by the manufacturer of the first heat source and / or the first cold source. In an embodiment, the maximum efficiency zones are estimated empirically.

[0036] The first heat exchange element comprises a top surface and a plurality of straight passages that extend in different directions through the interior of the first heat exchange element. Such passages are parallel to the top surface and intersect inside the first heat exchange element. This specific design of the first heat exchange element is capable of effectively shaping the heat flux between the first cold and first heat sources and the top surface of the first heat exchange element, resulting in a maximum temperature difference at said top surface of less than 1 ° C. In this way, the sample heat exchanger module of the present invention advantageously allows a high thermal homogeneity of the top surface of the first heat exchange element.

[0037] This top surface of the first heat exchange element is intended to support the product to be freeze-dried. The product to be freeze-dried may be placed in a sample container. The sample container may be arranged in a sample receiving element. In use, the sample container and / or the sample receiving element supporting the sample container are located on the top surface of the first heat exchange element.

[0038] Cold sources, for example cryocoolers, and heat sources have small area surfaces compared to the top surface of the first heat exchange element. The conductive heat transfer from said sources and the top surface of the first heat exchange element is not instantaneous and temperature gradients can be formed at the top surface of the first heat exchange element. Depending on the thermal conductivity of the material of the first heat exchange element, those gradients can be pronounced, considerably affecting the quality of the freeze-drying process and limiting the possibility of employing a closed- loop strategy for carrying out the freeze-drying process, since the samples of product chosen to provide feedback may not be representative of the whole product being freeze- dried. These temperature gradients are reduced as much as possible through the previously described design of the first heat exchange element.

[0039] In particular, the plurality of straight passages act as a barrier to straight-line heat transfer between the sources (first cold source and first heat source) and the closest point of the top surface of the first heat exchange element. In this way, the shortest possible conductive path between the sources and every point in the top surface of the first heat exchange element will be similar, achieving a great thermal homogeneity in the top surface of the first heat exchange element.

[0040] The sample heat exchanger module, as mentioned before, comprises the first cold source and the first heat source. Both types of sources are controllable by a control unit that commands them to provide a cold and / or a heat flux to the first heat exchange element.

[0041] The cold source comprises a cold end with a maximum efficiency zone that is in thermal contact with the first heat exchange element. In an embodiment, the cold source is or comprises a cryocooler. Throughout the present document, a cryocooler will be understood as a refrigeration device designed to reach cryogenic temperatures (preferably from -40°C to -100°C).

[0042] In an embodiment, the cryocooler is selected from the group of Stirling Cryocoolers, Gifford-McMahon Cryocoolers, and Pulse-tube Cryocoolers.

[0043] In a more specific embodiment of the invention, the cold source is a Free Piston Stirling Cryocooler (FPSC). This is a type of cryogenic refrigeration device that uses a free piston Stirling cycle to produce refrigeration. In a free piston cryocooler, there is no rigid mechanical connection between the displacer and the piston, which allows the piston to move freely back and forth within a cylinder, in a motion controlled by the interaction of the magnetic fields generated by a linear motor with the magnets on the piston. The use of an FPSC allows for greater control and flexibility as well as improved efficiency and reliability. Also, the absence of rigid connections and moving seals reduces the risk of mechanical failure and allows for greater design freedom while the linear motor used to drive the piston can be precisely controlled to optimize the operation of the cryocooler and improve its performance.

[0044] Regarding the first heat source, it comprises a maximum efficiency zone that is also in thermal contact with the first heat exchange element. In an embodiment, the heat source comprises at least one resistive heating element selected from the group of metallic resistance, semiconductor, thick film, polymer, and ceramic heating elements.

[0045] In an embodiment, the thermally conductive material of the first heat exchange element is selected from the group consisting of aluminum, copper, iron, magnesium, silver, an alloy of aluminum, an alloy of copper, an alloy of iron, an alloy of magnesium and an alloy of silver. In an embodiment, the first heat exchange element is made of a mix of materials as long as said mix of material is thermally conductive.

[0046] In an embodiment, the thermal conductivity of the thermally conductive material is greater than 150 w / mK, preferably 200 w / mK.

[0047] In an embodiment, the first heat exchange element comprises:

[0048] • a first inner plane being spaced from and parallel to the top surface;

[0049] • a second inner plane being spaced from and parallel to the top surface, wherein the first inner plane is arranged between the top surface and the second inner plane, and wherein the second inner plane: is contiguous to the maximum efficiency zones of the first cold source and the first heat source, or passes through the maximum efficiency zones of the first cold source and the first heat source, preferably through the centre of the maximum efficiency zone of the first cold source and through the centre of the maximum efficiency zone of the first heat source;

[0050] • a top portion defined between the top surface and the second inner plane, wherein the top portion has a vertical axis of symmetry and a plurality of vertical planes of symmetry, wherein each of the vertical planes of symmetry: contains the vertical axis of symmetry; divides the top portion in two halves that are substantially equal in shape and size; and intersects the first inner plane in an intersection line; wherein each straight passage extends along a different intersection line.

[0051] According to this embodiment, the first heat exchange element comprises a first inner plane and a second inner plane. Throughout this document, the inner planes will be understood as virtual planes parallel to the top surface and containing at least one point belonging to the heat exchange element. In an embodiment, the first inner plane and / or the second inner plane is arranged inside the first heat exchange element and divides the first heat exchange element into two parts. In an embodiment, the first inner plane and / or the second inner plane is a horizontal plane.

[0052] Both the first and second inner planes are spaced from and parallel to the top surface, being the first inner plane arranged between the top surface and the second inner plane. Besides, the second inner plane: is contiguous to the maximum efficiency zones of the first cold source and the first heat source, or passes through the maximum efficiency zones of the first cold source and the first heat source.

[0053] The term “contiguous” should be understood as touching at a point or along a boundary. In an embodiment the second inner plane is contiguous to the maximum efficiency zone of the first cold source and to the maximum efficiency zone of the first heat source. In an embodiment, the second inner plane passes through the maximum efficiency zone of the first cold source and through the maximum efficiency zone of the first heat source. In a preferred embodiment, the second inner plane passes through the centre of the maximum efficiency zone of the first cold source and through the centre of the maximum efficiency zone of the first heat source, such centres of both types of sources being aligned.

[0054] In an embodiment, the second inner plane is arranged between the first inner plane and a bottom surface of the first heat exchange element. In an embodiment, the second inner plane defines at least partially a bottom boundary of the first heat exchange element.

[0055] The first heat exchange element further comprises a top portion defined between the top surface and the second inner plane. The top portion has a vertical axis of symmetry, that is, a virtual axis that extends vertically through the top portion and that passes through the centres of the top surface, the first inner plane and the second inner plane Also, the top portion has a plurality of vertical planes of symmetry, that is, a plurality of virtual planes that extend vertically through the top portion. Each of the vertical planes of symmetry:

[0056] • contains the vertical axis of symmetry;

[0057] • divides the top portion in two halves that are substantially equal in shape and size; and

[0058] • intersects the first inner plane in an intersection line.

[0059] Each of the plurality of straight passages extends along a different intersection line.

[0060] With this specific configuration having the straight passages extending along a different intersection line, the thermal homogeneity achieved at the top surface of the first heat exchange element is improved. In other words, a greater reduction of the temperature gradients in the top surface is achieved.

[0061] In an embodiment:

[0062] - the distance between the top surface and the first inner plane is

[0063] - the distance between the second inner plane and the first inner plane is W2; and

[0064] - the distances and H2comply the following relation: 0.4

[0065] With this specific configuration of distances among the first inner plane, the second inner plane and the top surface of the first heat exchange element, advantageously the thermal homogeneity achieved at the top surface is further improved. Thus, a greater reduction of the temperature gradients in the top surface is achieved.

[0066] In an embodiment, and H2are equal.

[0067] In an embodiment, the height h of each straight passage complies the following relation:

[0068] (W, * 0.5) > h > 0 wherein is the distance between the top surface and the first inner plane.

[0069] With this specific height of the straight passages, the thermal homogeneity achieved at the top surface is improved. In the same way, a greater reduction of the temperature gradients in the top surface is achieved.

[0070] In an embodiment, the width w of each straight passage complies the following relation: wherein: is the distance between the top surface and the first inner plane;

[0071] H2is the distance between the second inner plane and the first inner plane; and

[0072] L is the maximum length of the top surface in a direction perpendicular to the plane of symmetry that contains the intersection line along which the straight passage extends. With this specific width of the straight passages, the thermal homogeneity achieved at the top surface is improved. Thus, a greater reduction of the temperature gradients in the top surface is achieved.

[0073] In an embodiment, the centre of the maximum efficiency zone of the first heat source and the centre of the maximum efficiency zone of the first cold source are placed substantially on the same plane.

[0074] In an embodiment, the first heat source comprises a plurality of heating elements, each one having a maximum efficiency zone.

[0075] In an embodiment wherein the first heat source comprises a plurality of heating elements, each one having a maximum efficiency zone, the maximum efficiency zones of the plurality of heating elements of the first heat source are distributed around, and equidistant from, the maximum efficiency zone of the first cold source. In an embodiment, the heating elements of the first heat source are evenly distributed around the maximum efficiency zone of the first cold source, forming the vertices of a regular polygon centered at said maximum efficiency zone of the first cold source.

[0076] In an embodiment wherein the first heat source comprises a plurality of heating elements, each one having a maximum efficiency zone:

[0077] - the maximum efficiency zone of the first cold source and the maximum efficiency zones of the heating elements of the first heat source are aligned with a vertical plane of symmetry; and / or

[0078] - the maximum efficiency zone of the first cold source is aligned with a vertical axis of symmetry; and / or

[0079] - the maximum efficiency zones of the heating elements of the first heat source are placed equidistantly with respect to the vertical axis of symmetry.

[0080] In an embodiment, the first heat exchange element has a bottom surface and comprises a plurality of indentations open at the bottom surface, wherein the indentations are configured to receive, at least, the maximum efficiency zone of the first cold source and the maximum efficiency zone of the first heat source. The indentations of this embodiment are dimensioned to receive at least the maximum efficiency zone of the first cold source and the maximum efficiency zone of the first heat source, so the first heat exchange element is in thermal contact with such first cold source and first heat source. This thermal contact can be direct or indirect.

[0081] In an embodiment, the first heat source comprises a plurality of heating elements, each one having a maximum efficiency zone and the first heat exchange element has a bottom surface and comprises a plurality of indentations open at the bottom surface, wherein the indentations are configured to receive, at least, the maximum efficiency zone of the first cold source and the maximum efficiency zones of the plurality of heating elements of the first heat source. In an embodiment, the indentations configured to receive the maximum efficiency zones of the plurality of heating elements of the first heat source are distributed around, and equidistant from, the indentation configured to receive the maximum efficiency zone of the first cold source In an embodiment, the indentations configured to receive the maximum efficiency zones of the plurality of heating elements of the first heat source are evenly distributed around the maximum efficiency zone of the first cold source, forming the vertices of a regular polygon centered at said indentation configured to receive the maximum efficiency zone of the first cold source.

[0082] In an embodiment, the first heat exchange element has a bottom surface and comprises a plurality of indentations open at the bottom surface, and the first heat source comprises a plurality of heating elements, each one having a maximum efficiency zone; wherein the indentations are configured to receive, at least, the maximum efficiency zone of the first cold source and the maximum efficiency zones of the plurality of heating elements of the first heat source, and wherein:

[0083] - each indentation is aligned with a vertical plane of symmetry; and / or

[0084] - the indentation configured to receive the maximum efficiency zone of the first cold source is aligned with the vertical axis of symmetry; and / or

[0085] - the indentations configured to receive the maximum efficiency zones of the heating elements of the first heat source are placed equidistantly with respect to the vertical axis of symmetry.

[0086] The indentations of this embodiment are dimensioned to receive at least the maximum efficiency zones of the first cold source and the maximum efficiency zone of the heating elements of the first heat source, so the first heat exchange element is in thermal contact with such first cold source and heating elements. This thermal contact can be direct or indirect.

[0087] With this specific arrangement of the first cold source and / or the first heat source, the thermal homogeneity achieved at the top surface is improved. In the same way a greater reduction of the temperature gradients in the top surface is achieved.

[0088] In an embodiment, the plurality of heating elements are rod-shaped ceramic heating elements.

[0089] In an embodiment, the first heat exchange element has a bottom surface and both the maximum efficiency zone of the first cold source and the maximum efficiency zone of the first heat source are arranged on the bottom surface of the first heat exchange element, in thermal contact with said bottom surface. This thermal contact can be direct or indirect.

[0090] In an embodiment, the first heat source comprises at least one thermal link and the maximum efficiency zone of said first heat source is located at the thermal link. Alternatively or simultaneously, in an embodiment, the first cold source comprises at least one thermal link and the cold end of said first cold source (and the maximum efficiency zone of said first cold source) is located at the thermal link.

[0091] In an embodiment, the sample heat exchanger module comprises an intermediate homogenization element arrangeable on the top surface of the first heat exchange element. In this embodiment, when at least one sample receiving element and / or at least one sample container is arranged on the sample heat exchanger module, the intermediate homogenization element is arranged between the first heat exchange element and the at least one sample receiving element and / or sample container, so that a bottom surface of the at least one sample receiving element and / or sample container is in thermal contact with the top surface of the first heat exchange element through the intermediate homogenization element. In an embodiment, the intermediate homogenization element is made of a material comprising anisotropic thermal conductivity, preferably a thin sheet of multilayer graphite.

[0092] In an embodiment, the thickness of the sheet of multilayer graphite is between 10 and 100 micrometers. Advantageously, a homogenization element placed between the first heat exchange element and at least one sample receiving element further improves the temperature homogeneity.

[0093] In this way, a bottom portion of each sample receiving element and / or sample container is in thermal contact with the top surface of the first heat exchange element either directly or through the intermediate homogenization element.

[0094] In an embodiment, the sample heat exchanger module comprises:

[0095] • first temperature sensing means for measuring the temperature of the first heat exchange element, the first temperature sensing means being adapted to send said temperature to a control unit; and / or

[0096] • second temperature sensing means for measuring the temperature of the products to be freeze-dried, the second temperature sensing means being adapted to send said temperature to a control unit.

[0097] In this embodiment, at least one temperature sensing means may be used to measure the temperature of the product to be freeze-dried. In addition or alternatively, at least one temperature sensing means may be used to measure the temperature of the first heat exchange element. These temperature sensing means are adapted to send the temperature to a control unit that, in turn, is configured to control the first cold and first heat sources to vary the temperature of the first heat exchange element according to such temperature measured.

[0098] In an embodiment, the first temperature sensing means and / or the second temperature sensing means are selected from the group consisting of Thermocouples, Resistance temperature detectors (RTDs), Infrared sensors, and / or Fiber optic sensors.

[0099] In a more specific embodiment of the invention, the first and / or second temperature sensing means are RTDs. RTDs work by measuring the change in resistance of a metal wire as the temperature changes. They provide high accuracy and stability over a wide range of temperatures.

[0100] In an embodiment, the sample heat exchanger module comprises first temperature sensing means dedicated to measure the temperature of the first heat exchange element and second temperature sensing means intended to be placed in contact with the product to be freeze-dried and being adapted to measure its temperature. With this configuration, the voltage provided to the first heat source and the first cold source of the sample heat exchanger module may be controlled, by a control unit, in response to either the heat exchange element temperature (open-loop mode) or the product temperature (closed loop mode) or both.

[0101] In a second inventive aspect, the invention provides a freeze-dryer system for the cryopreservation of products, the freeze-dryer system comprising:

[0102] • a freeze-drying chamber,

[0103] • at least one sample heat exchanger module according to any embodiment of the first inventive aspect attached to the freeze-drying chamber,

[0104] • at least one condenser module attached to the freeze-drying chamber, and

[0105] • pressure reduction means for reducing pressure inside the freeze-drying chamber.

[0106] In this second inventive aspect, the sample heat exchanger module of any of the embodiments of the first inventive aspect is integrated in a freeze-dryer system and, thanks to this, the freeze-dryer system has solid-state heat exchange capabilities. This system is intended to be used for cryopreserving products or material, such as biological material.

[0107] The system comprises a freeze-drying chamber, at least one condenser module (also known in the field simply as “condenser”), and pressure reduction means to reduce the pressure inside the chamber.

[0108] The freeze-drying chamber is a closed compartment that houses, at least partially, the sample heat exchanger module and the condenser module inside.

[0109] The condenser module acts during the primary drying phase of the freeze-drying process. In particular, during primary drying, crystalized solvent mass formed during the freezing phase is removed by sublimation, an endothermic process where said solvent changes directly from solid to gas under vacuum. The resulting gas mass is then removed from the space above the products by deposition, an exothermic process where the solvent changes directly from gas to solid, over a cold surface of the condenser module.

[0110] The pressure reduction means for reducing the pressure inside the chamber also come into action during the primary drying phase of the freeze-drying process, as the sublimation of the solvent is performed under vacuum. Thus, said pressure reduction means, controlled by a control unit, allow to reduce the pressure inside the chamber to generate the vacuum.

[0111] In an embodiment, the freeze-dryer system further comprises at least one sample receiving element, the at least one sample receiving element being arrangeable in thermal contact with the top surface of the first heat exchange element.

[0112] In an embodiment, the extent of the top surface of the first heat exchange element is equal to or greater than the sum of the extents of the bottom surfaces of the sample receiving elements, so that the whole extent of the bottom surfaces of the sample receiving elements are placed on the top surface of the first heat exchange element when said sample receiving elements are arranged on the top surface of the first heat exchange element.

[0113] In an embodiment, the sample receiving element comprises a plurality of indentations open at its top surface and configured to receive a plurality of sample containers. Each sample container is received in an indentation. In an embodiment, the indentations match in number to, and complement in contour and / or depth, the sample containers intended to be received in the sample receiving element.

[0114] In an embodiment, the sample containers received in the indentations rest on the bottoms of the indentations and are surrounded by the thermally conductive material so that they receive the temperature of the first heat exchange element in their bottom parts and their side walls through the sample receiving element.

[0115] In an embodiment, the at least one condenser module comprises:

[0116] • a second heat exchange element made of a thermally conductive material and having a top surface, an opposed bottom portion, and a stepped cone-shape with a plurality of tiered sections along its height between the top surface and the bottom portion, wherein each section has a different diameter;

[0117] • a second cold source comprising a cold end in thermal contact with the bottom portion of the second heat exchange element, the second cold source being controllable by a control unit;

[0118] • a second heat source in thermal contact with the bottom portion of the second heat exchange element and being controllable by a control unit; and

[0119] • third temperature sensing means for measuring the temperature of the second heat exchange element.

[0120] In this embodiment, the condenser module comprises a second heat exchange element, which is formed of a thermally conductive material. Said second heat exchange element comprises a top surface and a bottom portion, defined as the condenser’s top surface and the condenser’s bottom portion, and has a stepped cone shape with a series of tiered sections along its height between the top surface and the bottom portion, each section presenting a different diameter.

[0121] Advantageously, this second heat exchange element has a high ice deposition efficiency and homogeneity, achieved by the presence of the stepped cone shape. This specific design favors homogeneous ice deposition through all the surface available.

[0122] The third temperature sensing means allow to measure the temperature of the second heat exchange element. Said third temperature sensing means are adapted to send the measures to a control unit that, in turn, will control the second heat source and / or the second cold source to increase or decrease the temperature of the second heat exchange element.

[0123] In an embodiment, the material of the second heat exchange element is selected from the group consisting of aluminum, copper, iron, magnesium, silver, an alloy of aluminum, an alloy of copper, an alloy of iron, an alloy of magnesium and an alloy of silver. In an embodiment, the second heat exchange element is made of a mix of materials as long as said mix of material is thermally conductive. In an embodiment, the thermal conductivity of the thermally conductive material is greater than 150 w / mK, preferably 200 w / mK.

[0124] In an embodiment, the second heat exchange element is a solid block, preferably of unitary construction.

[0125] The condenser module further comprises a second heat source and a second cold source, which are controllable by a control unit, as mentioned before.

[0126] In particular, the second cold source comprises a cold end in thermal contact with the condenser’s bottom portion. In an embodiment, the second cold source is or comprises a cryocooler. Said cryocooler, in an embodiment, is selected from the group of Stirling Cryocoolers, Gifford-McMahon Cryocoolers, and Pulse-tube Cryocoolers. In a preferred embodiment of the invention, the cold source of the condenser module is a Free Piston Stirling Cryocooler (FPSC). The use of an FPSC allows for greater control and flexibility as well as improved efficiency and reliability. The absence of rigid connections and moving seals reduces the risk of mechanical failure and allows for greater design freedom while the linear motor used to drive the piston can be precisely controlled to optimize the operation of the cryocooler and improve its performance.

[0127] In an embodiment, the second heat source comprises at least one resistive heating element, selected from the group of metallic resistance, semiconductor, thick film, polymer, and ceramic heating elements.

[0128] In an embodiment, the second heat source comprises a plurality of rod-shaped ceramic heating elements, each having a hot end, arranged concentrically around, and equidistant to, the center of the cold end of the cold source.

[0129] In an embodiment, a set of indentations open at the condenser’s bottom portion matching in number to, and complementing in contour and depth to, ends of the second heat source and the second cold source, the set of indentations being in thermal contact with both sources.

[0130] In an embodiment, the third temperature sensing means are selected from the group consisting of Thermocouples, Resistance temperature detectors (RTDs), Infrared sensors, and Fiber optic sensors.

[0131] In a more specific embodiment of the invention, the third temperature sensing means are RTDs. Advantageously, RTDs provide high accuracy and stability over a wide range of temperatures.

[0132] In a preferred example, a set of three temperature sensing means is used. Two of the temperature sensing means are dedicated to measure the temperature of the first and the second heat exchange elements and the other are intended to be placed in contact with the product to be freeze-dried and dedicated to measure its temperature. In a preferred embodiment of the invention, the voltage provided to the first heat source and the first cold source of the sample heat exchanger module and to the second heat source and the second cold source of the condenser module may be controlled by a control unit in response to either the temperatures of the first and second heat exchange elements (open-loop mode) and / or the product temperature (closed loop mode).

[0133] In an embodiment, the freeze-dryer system comprises

[0134] • first connecting means for attaching the at least one sample heat exchanger module to the freeze-drying chamber in a hermetically and thermally isolated way; and / or

[0135] • second connecting means for attaching the at least one condenser module to the freeze-drying chamber in a hermetically and thermally isolated way.

[0136] In use, the sample heat exchanger module and / or the condenser module is / are intended to be in functional connection with a freeze-drying chamber in such a way that the first heat exchange element and / or the second heat exchange element is / are in direct contact with the inner volume defined by the freeze-drying chamber. Throughout the whole document, “functional connection” will be understood as the connection between two elements that allows them to comply with the tasks for which they are configured.

[0137] In the present embodiment, the system comprises first connecting means for attaching the sample heat exchanger module to the freeze-drying chamber in a hermetically and thermally isolated way and / or second connecting means for attaching the condenser module to the freeze-drying chamber in a hermetically and thermally isolated way. In a more particular embodiment, the first connecting means and / or the second connecting means comprise: a piece made of a thermal insulation material and comprising a top face and a bottom face; and at least two sealing rubber elements, one arranged in each face of the piece.

[0138] In an embodiment, the piece(s) is / are made of a thermal isolation material selected from the group consisting of Polyurethane, Polystyrene, Polyethylene, Polypropylene, Polyimide, Polycarbonate, Polyvinyl Chloride, Poly (methyl methacrylate), Polyether Ether Ketone, and Polytetrafluoroethylene.

[0139] In an embodiment, the thermal conductivity of the thermal isolation material is lower than 1 w / mK, preferably lower than 0.5 w / mK.

[0140] In an embodiment, the piece(s) is / are of unitary construction.

[0141] In an embodiment, the sealing rubber elements are made of a material selected from the group consisting of Silicone, Fluorosilicone, Fluorcarbon (Viton), EPDM (Ethylene Propylene Diene Monomer), and Nitrile (Buna-N).

[0142] In an embodiment, the system comprises two or more sample heat exchanger modules, each of the two or more sample heat exchanger modules and the at least one condenser module being independently controllable by a control unit.

[0143] Advantageously, a system comprising more than one sample heat exchanger modules allows different freeze-drying processes to be performed simultaneously within the same freeze-drying chamber space. With this configuration, the samples of product to be dried that present significantly different properties can be placed with separate sample heat exchanger modules within the same freeze-drying chamber space. The pressure reduction means maintain the same level of pressure across the entire chamber while the temperature of each sample heat exchanger module can be controlled independently, making it possible to customize the drying conditions for each type of product, allowing different drying protocols to be run simultaneously.

[0144] In an alternative embodiment, the system comprises a single sample heat exchanger module. In this embodiment, all the samples of product to be freeze-dried are preferably homogeneous in terms of properties that can affect the freeze-drying process, namely the total water content, total mass, maximum safe temperature, and / or the vapor resistance of the dry product, to avoid significant differences in the final moisture content among the different product samples.

[0145] In an embodiment, the system comprises a single condenser module. In an embodiment, the system comprises a plurality of condenser modules.

[0146] In an embodiment, the freeze-drying chamber comprises a single compartment. In this embodiment, a chamber with a single compartment is employed in functional connection with at least one condenser module and at least one sample heat exchanger module.

[0147] In an embodiment, the freeze-drying chamber comprises a product compartment and a condenser compartment, wherein the product compartment and the condenser compartment are in fluid communication through a passageway.

[0148] In this embodiment, the chamber is split into two different compartments, namely, a product compartment that houses the at least one sample heat exchanger module and a condenser compartment that houses the at least one condenser module. Both compartments are in fluid communication through a passageway; that is, fluids can pass from one compartment to the other going across the passageway.

[0149] This dual-compartment design offers some advantages like the possibility of isolating the product from the condensed material to perform pressure-rise tests and to defrost the condenser without compromising the product integrity.

[0150] In an embodiment, the sectional area of the passageway is large enough to avoid chocked flow during the drying phases of the freeze-drying process. Through the whole document, the “chocked-flow” will be understood as a phenomenon that occurs when the water vapor passing through the passageway reaches the speed of sound.

[0151] During the primary drying phase of the freeze-drying process, water vapor is generated. Is removal depends both on the capacity of the condenser module and on the resistance of the passageway to the water vapor flow. In this way, the water vapor has to pass from the product compartment to the condenser compartment through the passageway in order to be removed but, if said water vapor reaches the speed of sound, it cannot be removed at the same rate as it is being generated.

[0152] For a fixed pressure, a way to increase the amount of water vapor passing through the passageway per unit of time is to increase the section of the passageway. In this way, the sectional area of the passageway according to this embodiment is of a size that allows that the water vapor passes through the passageway, at least, at the same rate this water vapor is being generated. Advantageously, the chocked-flow phenomenon is avoided, guaranteeing that the water vapor is removed at a rate equal or greater than the rate of water vapor generation.

[0153] In an embodiment, the freeze-dryer system comprises a control unit adapted to:

[0154] - act on the first cold source and / or the first heat source of the at least one sample heat exchanger module to decrease and / or increase the temperature of the first heat exchange element; and / or

[0155] - act on the second cold source and / or the second heat source of the at least one condenser module to decrease and / or increase the temperature of the second heat exchange element; and / or

[0156] - act on the pressure reduction means to reduce the pressure inside the freeze- drying chamber.

[0157] In an embodiment, the control unit is selected from the group of Programmable logic controllers (PLCs), Microprocessor-based controllers, Computer-based control systems and Manual control systems. In a preferred embodiment, the control unit for operating the components of the system is a PLC. A PLC is an industrial-grade electronic device that can be programmed to control various processes in the freeze-dryer system, such as temperature, vacuum level, and cycle time. PLCs are reliable, robust, and can handle complex processes with multiple inputs and outputs. Besides, they can also be integrated with other systems, such as data logging and alarm systems.

[0158] In an embodiment, the control unit is further adapted to:

[0159] - receive and / or generate a working scheme of a freeze-drying cycle, wherein the working scheme comprises a plurality of equations, each equation representing the variation of the temperature of the product or the variation of the temperature of the first heat exchange element during the course of a stage of the freeze-drying cycle;

[0160] - receive the sensed temperatures from the first temperature sensing means and / or from the second temperature sensing means; and

[0161] - depending on the sensed temperatures, act on the first cold source and / or the first heat source of the sample heat exchanger module to comply with the equations of the working scheme.

[0162] In this embodiment, the control unit is adapted to receive the different measures taken by the first temperature sensing means and / or the second temperature sensing means.

[0163] As mentioned before, the control unit is in charge of commanding the first cold source and the first heat source. Said control unit receives and / or generates a working scheme - or working recipe - for the freeze-drying process. Throughout this document, the working scheme will be understood as a set of equations of a plurality of stages of the freeze-drying cycle understandable by the control unit. Throughout this document, a stage will be understood as a part of a freeze-drying cycle that is defined by the following parameters:

[0164] - an initial temperature setpoint;

[0165] - a target temperature setpoint to be reached by the product to be freeze-dried during the stage;

[0166] - the time to hold the target temperature; and

[0167] - the maximum product temperature change rate.

[0168] In this way, the equations represent the variation of temperature of the product to be freeze-dried or the variation of the temperature of the first heat exchange element during the course of the stages.

[0169] In an embodiment, the freeze-drying cycle comprises three stages (freezing, primary drying and secondary drying). In other embodiments, the freeze-drying cycle comprises more than three stages.

[0170] The control unit receives sensed temperatures from the first temperature sensing means, which measures the temperature of the first heat exchange element, and / or sensed temperatures from the second temperature sensing means, which measures the temperature of the product samples. Once the control unit has received the temperatures, it acts on the first cold source and / or the first heat source of the sample heat exchanger module to comply with the equations of the working scheme; that is, to reach the temperature values during the course of the stages stipulated in the working scheme.

[0171] In an embodiment, the control unit is further adapted to receive sensed temperatures from the third temperature sensing means and to act on the second cold source and / or the second heat source of the condenser module according to the sensed temperatures.

[0172] In an embodiment, the system comprises pressure sensing means for measuring the pressure inside the freeze-drying chamber, the pressure sensing means being adapted to send the pressure measures to the control unit, and wherein the control unit is further adapted to:

[0173] - receive and / or generate a working scheme of a freeze-drying cycle, wherein the working scheme comprises a plurality of pressure equations, each pressure equation representing the variation of the pressure inside the freeze- drying chamber during the course of a stage of the freeze-drying cycle;

[0174] - receive the sensed chamber pressure from the pressure sensing means; and

[0175] - depending on the sensed chamber pressure, act on the pressure reduction means to comply with the pressure equations of the working scheme.

[0176] In this embodiment, the system further comprises pressure sensing means, which take measures of the pressure inside the freeze-drying chamber and are adapted to send the measures to the control unit.

[0177] Thus, the control unit is adapted to receive the different measures taken by the pressure sensing means and, optionally, from the first and / or second temperature sensing means, if any. Once the control unit has received the measures, it acts on the components of the system of this invention, namely, on the pressure reduction means and, optionally, on the first heat source and / or the first cold source.

[0178] In an embodiment, the control unit is further adapted to receive sensed temperatures from the third temperature sensing means and to act on the second cold source and / or the second heat source of the condenser module according to the sensed temperatures. As well as the pressure reduction means, the pressure sensing means also come into action during the primary drying phase of the freeze-drying process, as the sublimation of the solvent is performed under vacuum. Thus, the pressure reduction means and the pressure sensing means allow the system to carry out such sublimation. In particular, the pressure sensing means measure the pressure inside the chamber and send their measures to the control unit, which in turn acts on the pressure reduction means to decrease the pressure if the measures indicate so.

[0179] In particular, in an embodiment the control unit is in charge of controlling the pressure reduction means inside the freeze-drying chamber. Said control unit receives a working scheme - or working recipe - for the products to be freeze-dried. The working scheme, as mentioned before, will be understood as a set of equations of a plurality of stages understandable by the control unit. In this particular embodiment, the working scheme comprises a plurality of equations defining the pressure values inside the chamber that must be reached along the stages of the freeze-drying process in order to accomplish the three phases thereof.

[0180] The control unit receives the sensed chamber pressure from the pressure sensing means and acts on the pressure reduction means for reducing pressure inside the freeze-drying chamber to comply with the equations of the working scheme; that is, to reach the pressure values during the course of the stages stipulated in the working scheme.

[0181] In an embodiment, the pressure reduction means comprise a vacuum pump selected from the group of Rotary vane pumps, Turbo molecular pumps, Diaphragm pumps and Scroll pumps.

[0182] In a preferred embodiment of the invention, the vacuum pump used is a Scroll pump, which is oil-free and uses two interleaved spirals to compress air and generate a vacuum.

[0183] In an embodiment, the pressure sensing means comprise one or a combination of elements selected from the group consisting of Pirani gauges, Capacitance manometers, Thermocouple gauges and Ionization gauges. The pressure sensing means comprise a single pressure measure device or a combination of multiple different devices. In a preferred embodiment of the invention, a combination of a Pirani gauge and capacitance manometer is employed. Capacitance manometers work by measuring the capacitance between two electrodes as the pressure changes. They are not affected by the presence of condensable gases and can measure very low vacuum levels with a high degree of accuracy. Pirani gauges work by measuring the thermal conductivity of the gas, which changes as the pressure decreases and may be affected by the presence of water vapor or other condensable gases. When calibrated under the same conditions, the simultaneous reading of both systems provide information about the pressure inside the vacuum chamber and, additionally, information about the composition of the gas inside said chamber, helping to determine the end of primary and secondary drying phases.

[0184] In a third inventive aspect, the invention provides a computer-implemented method for determining an optimum working scheme of a freeze-drying cycle using the system of the second inventive aspect, said method comprising the following steps: a) receiving, the control unit, input data, the input data comprising the number of different stages of the freeze-drying cycle to be included in the optimum working scheme and the following parameters for each stage:

[0185] • a target temperature setpoint to be reached by the product to be freeze-dried during the stage;

[0186] • the time to hold the target temperature setpoint once reached; and

[0187] • a maximum product temperature change rate; b) receiving, the sample heat exchanger module, at least one sample container that comprises a sample of the product; c) generating, the control unit, a first working scheme of the freeze-drying cycle, the first working scheme comprising a first equation for each stage, the first equations representing the variation of the product temperature as a function of time during each stage; wherein the first equation for each stage is created by the control unit based on the parameters of said stage and on a model equation that provides an expected temperature as a function of time, the model equation comprising at least one adjustable parameter; d) performing a first freeze-drying cycle, and during the first freeze-drying cycle:

[0188] - receiving, the control unit, sensed temperatures of the product from the second temperature sensing means; and depending on the sensed temperatures of the product, acting on the first cold source and / or the first heat source of the sample heat exchanger module to comply with the first working scheme; and

[0189] - receiving, the control unit, sensed temperatures from the first temperature sensing means; e) generating, the control unit, a second working scheme, the second working scheme comprising a second equation for each stage, wherein the second equations represent the variation of the temperature of the first heat exchange element as a function of time during each stage, wherein the second equation for each stage is calculated by fitting the model equation of the stage to the temperatures sensed in step d) by the first temperature sensing means during the course of the stage; wherein the fitting is performed by adjusting one or more of the at least one adjustable parameter; f) returning, by the control unit, the second working scheme as the optimum working scheme of the freeze-drying cycle.

[0190] The method of the third inventive aspect aims to determine an optimum working scheme of a freeze-drying cycle using the system of the second inventive aspect, particularly the embodiments in which the system comprises a control unit.

[0191] The method requires that the control unit receives the number of stages that form part of the freeze-drying cycle as well as the parameters that define each stage; that is:

[0192] • the target temperature setpoint to be reached by the product to be freeze-dried during the stage;

[0193] • the time to hold the target temperature setpoint once reached; and

[0194] • a maximum product temperature change rate.

[0195] In an embodiment, the freeze-drying cycle comprises three stages (freezing, primary drying and secondary drying). In other embodiments, the freeze-drying cycle comprises more than three stages.

[0196] In an embodiment, the parameters that the method uses as input data are estimated after studying and obtaining the thermal fingerprint of the product to be freeze-dried. A thermal fingerprint study encompasses a comprehensive understanding of the product's behavior during the freeze-drying process, including both macroscopic and microscopic aspects. Obtaining a thermal fingerprint typically involves conducting thermal analysis experiments, such as differential scanning calorimetry (DSC) or thermogravimetric analysis (TGA) and performing freeze-drying microscopy (FDM) studies. FDM complements thermal analysis data by providing visual observations of structural changes, ice crystal formation, collapse, and other phenomena that occur during freeze- drying.

[0197] During the freezing phase, the non-frozen product is expected to decrease its temperature at a predefined rate until water nucleation occurs and then the partially frozen product is expected to cool even further down to a temperature that assures all the material turns into a solid. Then, after the chamber pressure is decreased to a setpoint somewhere below the triple point of water, the product temperature is expected to remain below but as close as possible to the critical temperature value beyond which the material is expected to collapse. Later, during secondary drying phase, the product can withstand higher temperatures without collapsing and a gradual increase up to temperatures way above room temperature are expected at this phase.

[0198] In step b), the sample heat exchanger module receives at least one sample container that comprises a product to be freeze-dried. Said sample container, besides, receives second temperature sensing means that measure the temperature of the product samples and sends the measures to the control unit of the system.

[0199] Steps a) and b) may be performed in any order. In an embodiment, step a) is performed before step b). In an embodiment, step a) is performed after step b). In an embodiment, step a) is performed simultaneously with step b).

[0200] The method continues with the generation, by the control unit, of a first working scheme of the freeze-drying cycle. This first working scheme comprises a first equation for each of the stages, the first equations representing the variation of the product temperature as a function of time during each stage. The control unit obtains such equations taking into account the parameters of the stages received as input data and also considering a model equation that provides an expected temperature as a function of time. This model equation comprises at least one adjustable parameter. In an embodiment, the control unit obtains the equations of the first working scheme taking into account also an initial temperature of the product sample measured by the second temperature sensing means.

[0201] During the execution of the first freeze-drying cycle, the control unit receives the temperatures measured by the second temperature sensing means and controls the first cold source and / or the first heat source of the sample heat exchanger module to comply with the equations of the first working scheme; that is, to decrease or increase the temperature of the first heat exchange element in order to vary the temperature of the product samples to achieve the expected product temperatures during the course of the stages.

[0202] Therefore, along the first freeze-drying cycle, the method lets the system control the temperature of the first heat exchange element in response to the product temperature profile established (the equations of the first working scheme).

[0203] At the same time, during the execution of the first freeze-drying cycle, the control unit further receives the temperatures of the first heat exchange element sensed by the first temperature sensing means.

[0204] Next, the control unit generates a second working scheme comprising a second equation for each stage. These second equations represent the variation of the temperature of the first heat exchange element as a function of time during each stage.

[0205] The control unit obtains each second equation of the second working scheme by fitting the model equation of the stage to the temperatures sensed by the first temperature sensing means during the course of the stage. Such fitting is performed by adjusting one or more of the at least one adjustable parameter of the model equation.

[0206] Finally, the control unit returns the second working scheme as the optimum working scheme of the freeze-drying cycle.

[0207] A regular closed-loop mode makes it possible to optimize the freeze-drying process at the cost of using sensors in contact with the products that can lead to a contamination of said products. To avoid this disadvantage, the method of the invention uses a closed- loop strategy just in an exploratory way to provide a working scheme of the first heat exchange element that can be used, afterwards, in open-loop mode to obtain the same profile of product temperatures. In this way, a double advantage is achieved for the subsequent freeze-drying processes: there is no product contamination and the process is optimized since time varying temperature setpoints are used (but without the need for real time product temperature feedback).

[0208] More advantageously, when compared with a mathematical model-based definition of the varying setpoints, the method of the invention provides a higher precision, being less labor intensive and demanding for less expertise in data handling and modeling.

[0209] In an embodiment, the first and the second temperature sensing means take measures every 60 seconds.

[0210] In an embodiment, the model equation of each stage is:

[0211] - a generalized logistic function model;

[0212] - a 5-parameter logistic regression function model;

[0213] - a quadratic polynomial equation model;

[0214] - a cubic polynomial equation model; or

[0215] - a quartic polynomial equation model.

[0216] In an embodiment, the model equation of each stage is defined as follows: where

[0217] • t is an independent variable representing the time;

[0218] • T(t) is the temperature at time t;

[0219] • To is the temperature at the beginning of the stage;

[0220] • Tf is the target temperature at the end of the stage;

[0221] • a is the maximum product temperature change rate at said stage;

[0222] • p is a parameter that defines the asymmetry of the curve for said stage; and

[0223] • y is the inflection point in the transition between To and Tf at said stage.

[0224] In an embodiment, the adjustable parameters adjusted by the control unit in step c) are y and / or p. In an embodiment, the adjustable parameters adjusted by the control unit in step e) are To, Tf, a, y and / or p.

[0225] In an embodiment, the value of the parameter p in step c) is set to 1 and / ory is calculated in step c) as follows:

[0226] In a fourth inventive aspect, the invention provides a computer-implemented method for determining N optimum working schemes for simultaneous freeze-drying cycles carried out on N different products using the system of the second inventive aspect, the system comprising N sample heat exchanger modules, and the method comprising the following steps:

[0227] (i) receiving, the control unit, input data, the input data comprising, for each one of the simultaneous freeze-drying cycles, the number of different stages of the freeze-drying cycle to be included in the corresponding optimum working scheme and the following parameters for each stage:

[0228] • a target temperature setpoint to be reached by the n-th product to be freeze-dried during the stage;

[0229] • the time to hold the target temperature setpoint once reached; and

[0230] • a maximum product temperature change rate;

[0231] (ii) generating, the control unit, N first working schemes, one for each simultaneous freeze-drying cycle, according to step c) of the method of the third inventive aspect;

[0232] (iii) receiving, each sample heat exchanger module, at least one sample container with a sample of one of the N different products;

[0233] (iv) performing, for each one of the N different products and their corresponding first working scheme, the steps d)-f) of the method of the third inventive aspect.

[0234] When multiple products with different thermal fingerprints are to be freeze-dried, a particular embodiment of the system of the present invention may be employed. Such embodiment comprises the use of a plurality of sample heat exchanger modules in parallel in the same freeze-drying chamber. The method of this embodiment allows to perform the method of the third inventive aspect for a plurality of products at the same time. It requires that the control unit receives the input data for each one of the simultaneous freeze-drying cycles so that it can generate a plurality of first working schemes. The method also requires having at least one sample container for each sample heat exchanger module, each container comprising one of the different products to be freeze-dried.

[0235] The rest of the method steps are the same as the method steps of the third inventive aspect, but executed for each of the sample heat exchanger modules.

[0236] In an embodiment, the control unit obtains the equations of the first working schemes taking into account also an initial temperature of the product samples measured by the second temperature sensing means.

[0237] In a fifth inventive aspect, the invention provides a computer-implemented method for detecting a failure in the system of the second inventive aspect, wherein the method comprises the following steps: a1) obtaining, the control unit, the optimum working scheme by executing the steps a)-f) of the method of the third inventive aspect; b1) receiving, the sample heat exchanger module, at least one sample container that comprises a sample of the product; c1) performing a freeze-drying cycle, and during the freeze-drying cycle:

[0238] - receiving, the control unit, sensed temperatures from the first temperature sensing means; and depending on the temperatures sensed by the first temperature sensing means, acting on the first cold source and / or the first heat source of the sample heat exchanger module to comply with the optimum working scheme; and

[0239] - receiving, the control unit, sensed temperatures of the product from the second temperature sensing means; d1) comparing the temperatures of the product sensed in step c1) with the temperatures of the product sensed in step d) of the method of the third inventive aspect; e1) if the comparison between the temperatures of the product sensed in step c1) deviates from the temperatures of the product sensed in step d) beyond a predefined error margin, reporting a system failure.

[0240] The invention also provides a method for detecting system failures. This method requires to execute the method of the third inventive aspect and to perform a second freeze- drying cycle, which is executed in closed-loop mode.

[0241] Firstly, the control unit executes the method of the second inventive aspect to obtain an optimum working scheme.

[0242] The sample heat exchanger module receives one or more sample containers that comprise a new sample of the product; and said sample container(s) receive the second temperature sensing means.

[0243] Next, the second freeze-drying cycle is performed. During such cycle:

[0244] - the control unit receives the temperatures of the first heat exchange element from the first temperature sensing means and acts on the first cold source and / or the first heat source of the sample heat exchanger module to comply with the optimum working scheme; and

[0245] - the control unit also receives the sensed temperatures of the product from the second temperature sensing means.

[0246] Finally, the control unit compares the sensed temperatures of the product with the temperatures of the product that were sensed during the execution of the method of the third inventive aspect. If the comparison is outside a predefined error margin, the control unit reports a system failure, for example, by issuing an alarm.

[0247] In an embodiment, the error margin is between 1°C and 1.5°C.

[0248] All features described in this specification, including the claims, description and drawings, can be combined in any way except for combinations of mutually exclusive features.

[0249] DESCRIPTION OF THE DRAWINGS These and other characteristics and advantages of the invention will become clearly understood in view of the detailed description of the invention which becomes apparent from a preferred embodiment of the invention, given just as an example and not being limited thereto, with reference to the drawings.

[0250] Figure 1a-1 i These figures show several views and schemes of a sample heat exchanger module according to different embodiments of the invention.

[0251] Figure 2a-2d These figures show several views of a sample heat exchanger module according to an embodiment of the invention. In particular, a perspective view from below of the sample heat exchanger module with a detailed view of its components (Figure 2a) and an exploded view of its components (Figure 2b); and a perspective view from above of the sample heat exchanger module with a detailed view of its components (Figure 2c) and an exploded view of its components (Figure 2d).

[0252] Figure 3a-3d These figures show a modular freeze-dryer system for the cryopreservation of products according to several embodiments of the invention.

[0253] Figure 4a-4d These figures show several views of a condenser module according to an embodiment of the invention. In particular, a perspective view from below of the condenser module with a detailed view of its components (Figure 4a) and an exploded view of its components (Figure 4b); and a perspective view from above of the condenser module (Figure 4c) and a detailed and an exploded views of its components (Figure 4d).

[0254] Figure 5 This figure shows a workflow detailing an embodiment of the method of the present invention for obtaining an optimum working scheme of a freeze-drying cycle.

[0255] Figure 6 This figure shows the measures taken by different temperature and pressure sensing means during a freeze-drying cycle employing an open-loop mode with invariable temperature setpoints of the first heat exchange element.

[0256] Figure 7 This figure shows the measures taken by different temperature and pressure sensing means during a freeze-drying cycle employing a closed-loop mode with variable temperature setpoints of the first heat exchange element.

[0257] Figure 8 This figure shows the measures taken by different temperature and pressure sensing means during a freeze-drying cycle employing an open-loop mode with variable temperature setpoints of the first heat exchange element.

[0258] DETAILED DESCRIPTION OF THE INVENTION

[0259] Figures 1 a-1 i show a sample heat exchanger module (200) for a freeze-dryer system (100) according to different embodiments of the invention.

[0260] Figure 1a shows an embodiment of a sample heat exchanger module (200) comprising:

[0261] • a first heat exchange element (201) made of thermally conductive material, the first heat exchange element (201) comprising: a top surface (202); a plurality of straight passages (203, 204, 205) extending in different directions through the first heat exchange element (201), the passages being parallel to the top surface (202) and intersecting at the interior of the first heat exchange element (201);

[0262] • a first cold source (206) comprising a cold end (207) with a maximum efficiency zone (208) that is in thermal contact with the first heat exchange element (201);

[0263] • a first heat source (209) comprising a maximum efficiency zone (210) in thermal contact with the first heat exchange element (201); wherein the straight passages (203, 204, 205) are arranged between the top surface (202) and the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209), and wherein the first cold source (206) and the first heat source (209) are controllable by a control unit (102) to decrease or increase the temperature of the first heat exchange element (201).

[0264] In this embodiment, the first heat source (209) comprises a plurality of heating elements, each one having a maximum efficiency zone (210). In other embodiments, other configurations of the first heat source (209) are valid in the context of the invention.

[0265] In an embodiment, the first heat exchange element (201) is formed of a thermally conductive material selected from the group consisting of aluminium, copper, iron, magnesium, silver, an alloy of aluminium, an alloy of copper, an alloy of iron, an alloy of magnesium and an alloy of silver.

[0266] Figure 1b depicts a front view and a section view of the sample heat exchanger module (200) shown in Figure 1a, further comprising:

[0267] • a first inner plane (211) being spaced from and parallel to the top surface (202);

[0268] • a second inner plane (212) being spaced from and parallel to the top surface (202), wherein the first inner plane (211) is arranged between the top surface (202) and the second inner plane (212), and the second inner plane (212) passes through the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209), preferably through the centre of the maximum efficiency zone (208) of the first cold source (206) and through the centre of the maximum efficiency zone (210) of the first heat source (209);

[0269] • a top portion (213) defined between the top surface (202) and the second inner plane (212), wherein the top portion (213) has a vertical axis of symmetry (214) and a plurality of vertical planes of symmetry (215), wherein each of the vertical planes of symmetry (215): contains the vertical axis of symmetry (214); divides the top portion (213) in two halves that are substantially equal in shape and size; and intersects the first inner plane (211) in an intersection line; wherein each straight passage (203, 204, 205) extends along a different intersection line.

[0270] As it can be seen in Figure 1 b: - the distance between the top surface (202) and the first inner plane (211) is and

[0271] - the distance between the second inner plane (212) and the first inner plane (211) is H2.

[0272] In an embodiment, the distances and H2comply the following relation: 0.4

[0273] In an embodiment, H2= H .

[0274] In an embodiment, the height h of each straight passage (203, 204, 205) complies the following relation:

[0275] (W, * 0.5) > h > 0

[0276] In an embodiment, the width w of each straight passage (203, 204, 205) complies the following relation: wherein L is the maximum length of the top surface (202) in a direction perpendicular to the vertical plane of symmetry (215) that contains the intersection line along which the straight passage (203, 204, 205) extends.

[0277] Figure 1c (left column) shows different shapes of the top surface (202) of the first heat exchange element (201) that are valid in the context of the invention. For each one, a plurality of vertical planes of symmetry (215) are shown.

[0278] Figure 1c (right column) depicts the same top surfaces (202) showing examples of the parameter L (black arrow) for different vertical planes of symmetry (215).

[0279] Figure 1d depicts the first heat exchange element (201) of the sample heat exchanger module (200) of figure 1a, further showing a plurality of indentations (216) open at a bottom surface (217) of the first heat exchange element (201). The indentations are configured to receive, at least, the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zones (210) of the plurality of heating elements of the first heat source (209).

[0280] Figure 1e shows two different schemes of arrangements of the first cold source (206) and the first heat source (209) for different shapes of the first heat exchange element (201).

[0281] In these schemes:

[0282] - each indentation (216) is aligned with a vertical plane of symmetry (215);

[0283] - the indentation configured to receive the maximum efficiency zone of the first cold source (206) is aligned with the vertical axis of symmetry (214); and

[0284] - the indentations (216) configured to receive the maximum efficiency zones (210) of the heating elements of the first heat source (209) are placed equidistantly with respect to the vertical axis of symmetry (214).

[0285] Figures 1f-1 i show embodiments of the sample heat exchanger module (200) of the invention, wherein the arrangement of the first heat exchange element (201) and the first cold source (206) and the first heat source (209) is different from the one depicted in Figures 1a-1 b.

[0286] Figure 1f shows a sample heat exchanger module (200) according to an embodiment of the invention in which the first heat exchange element (201) has a bottom surface (217) in thermal contact with the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zone (210) of the first heat source (209). In this embodiment, the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zone (210) of the first heat source (209) are arranged on the bottom surface (217) of the first heat exchange element (201).

[0287] All the features of the sample heat exchanger module (200) depicted in Figure 1f are the same as the features of the sample heat exchanger module (200) depicted in Figure 1a, except the arrangement of the first cold source (206) and the first heat source (209) previously mentioned. Whereas in the embodiment of Figure 1a, the first heat exchange element (201) comprises indentations (216) open at the bottom surface (217) of the first heat exchange element (201) and said indentations are configured to receive at least the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zones (210) of the heating elements of the first heat source (209), in the embodiment of Figure 1f the first heat exchange element (201) does not comprise indentations (216) open at the bottom surface (217) for receiving the maximum efficiency zones (208, 210) of the first cold source (206) and of the heating elements of the first heat source (209). In the embodiment of Figure 1f the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zone (210) of the first heat source (209) are arranged on the bottom surface (217) of the first heat exchange element (201).

[0288] Figure 1g depicts a front view of the sample heat exchanger module (200) shown in Figure 1 f, wherein the first heat exchange element (201) comprises:

[0289] • a first inner plane (211) being spaced from and parallel to the top surface (202);

[0290] • a second inner plane (212) being spaced from and parallel to the top surface (202), wherein the first inner plane (211) is arranged between the top surface (202) and the second inner plane (212), and the second inner plane (212) is contiguous to the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209);

[0291] • a top portion (213) defined between the top surface (202) and the second inner plane (212), wherein the top portion (213) has a vertical axis of symmetry (214) and a plurality of vertical planes of symmetry (215), wherein each of the vertical planes of symmetry (215): contains the vertical axis of symmetry (214); divides the top portion (213) in two halves that are substantially equal in shape and size; and intersects the first inner plane (211) in an intersection line; wherein each straight passage (203, 204, 205) extends along a different intersection line.

[0292] In this embodiment, the second inner plane (212) is at least partially coincident with a bottom boundary of the first heat exchange element (201), in particular a bottom surface of the first heat exchange element (201).

[0293] Figure 1 h shows a sample heat exchanger module (200) according to an embodiment of the invention in which the first heat source (209) comprises at least one thermal link (226) and the first cold source (206) comprises at least one thermal link (225) and wherein the cold end of the first cold source (206) is located at the thermal link (225) of the first cold source (206). The maximum efficiency zone (210) of the first heat source (209) and the maximum efficiency zone (208) of the first cold source (206) are located in their corresponding thermal link (225, 226). In this embodiment, the first heat exchange element (201) has a bottom surface (217) in thermal contact with the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209). More specifically, in this embodiment, the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zone (210) of the first heat source (209) are arranged on the bottom surface (217) of the first heat exchange element (201). In an embodiment, the thermal links (225, 226) are heat pipes. In an embodiment, the thermal links (225, 226) are flexible.

[0294] All the features of the sample heat exchanger module (200) depicted in Figure 1h are the same as the features of the sample heat exchanger module (200) depicted in Figure 1f, except that in the sample heat exchanger module (200) depicted in Figure 1 h the first cold source (206) and the first heat source (209) comprise the thermal links (225, 226) previously mentioned. In the embodiments depicted in Figures 1h and 1f, the first heat source (209) comprises a plurality of heating elements, each one having a maximum efficiency zone (210). In other embodiments, other configurations of the first heat source (209) are valid in the context of the invention.

[0295] Figure 1i depicts a front view of a sample heat exchanger module (200) according to an embodiment of the invention. All the features of the sample heat exchanger module (200) depicted in Figure 1i are the same as the features of the sample heat exchanger module (200) depicted in Figure 1g, except for the presence of thermal links (225, 226) in the first cold source (206) and the first heat source (209), as disclosed in connection with Figure 1h.

[0296] Figures 2a-2d show several views of a sample heat exchanger module (200) for a freeze- dryer system according to other embodiment of the invention. As it can be seen, in this embodiment the sample heat exchanger module (200) comprises a first heat exchange element (201), a first cold source (206) and a first heat source (209). The first heat exchange element (201) is made of thermally conductive material and comprises a top surface (202) and two straight passages (203, 205), wherein the passages extend in different directions through the first heat exchange element (201). The passages (203, 205) are parallel to the top surface (202) and intersect at the interior of the first heat exchange element (201). In other embodiments, the number of passages may be greater than two.

[0297] Additionally to the heat exchanger module (200), Figures 2a-2d show two sample receiving elements (218) and first connecting means (219). The first connecting means (219) are used for attaching the sample heat exchanger module (200) to a freeze-drying chamber (103). The sample receiving elements (218) are configured to receive one or more sample containers (216) and to rest on the top surface (202) of the first heat exchange element (201) during use of the heat exchanger module (200). Although two sample receiving elements (218) are shown, in other examples, the number of sample receiving elements (218) can be one or more than two. In other embodiments, the sample containers rest on the top surface (202) of the first heat exchange element (201) without using a sample receiving element (218).

[0298] As it can be seen in Figures 2b and 2d, in this embodiment the sample heat exchanger module (200) further comprises an intermediate homogenization element (220) arranged on the top surface (202) of the first heat exchange element (201). In an embodiment, said intermediate homogenization element (220) is made of a material comprising anisotropic thermal conductivity, more preferably a thin sheet of multilayer graphite. This intermediate homogenization element (220) is optional.

[0299] During use of the sample heat exchanger module (200), the bottom portion of each sample receiving element (218) is in thermal contact with the top surface (202) of the first heat exchange element (201) of the sample heat exchanger module (200). In this embodiment, this thermal contact is indirect as it is performed through the intermediate homogenization element (220). As it can be seen, this intermediate homogenization element (220) is placed between the first heat exchange element (201) and the sample receiving elements (218) with the objective of improving the temperature homogeneity.

[0300] In other examples not shown, the sample heat exchanger module (200) does not comprise the intermediate homogenization element (220) and the thermal contact is direct, that is, the bottom portion of the sample receiving elements (218) contacts the top surface (202) of the first heat exchange element (201) of the sample heat exchanger module (200).

[0301] In other embodiments not shown, the sample containers rest on the top surface (202) of the first heat exchange element (201) without using a sample receiving element (218). The thermal contact between the sample containers and the top surface (202) of the first heat exchange element (201) may be made with or without an intermediate homogenization element (220).

[0302] Figures 2a-2d further show the first cold source (206) and the first heat source (209). In this particular example, a set of indentations (216) open at the bottom surface (217) of the first heat exchange element (201) matching in number to, and complementing in contour and depth, the first heat source (209) and the cold end of the first cold source

[0303] (206), being in thermal contact with them. In other examples, other configurations are possible as long as both the first cold source (206) and the first heat source (209) are in thermal contact with the first heat exchange element (201) and the straight passages (203, 205) are arranged between the top surface (202) and the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209).

[0304] In an embodiment the first cold source (206) comprises a cryocooler having a cold end

[0305] (207) in thermal contact with the first heat exchange element (201), as mentioned before. In an embodiment, said cryocooler is selected from the group of Stirling Cryocoolers, Gifford-McMahon Cryocoolers, and Pulse-tube Cryocoolers. In an example, the cold source (206) is a Free Piston Stirling Cryocooler (FPSC).

[0306] Figure 2a depicts that the first heat source (209) comprises in this embodiment a plurality of heating elements, each having a maximum efficiency zone, that are arranged concentrically around, and equidistant to, the center of the cold end (207) of the first cold source (206). In an embodiment, the heating elements are rod-shaped ceramic heating elements.

[0307] In other examples, the first heat source (209) comprises at least one resistive heating element selected from the group of metallic resistance, semiconductor, thick film, polymer, and ceramic heating elements. Figures 2b and 2d show first temperature sensing means (221) for measuring the temperature of the first heat exchange element (201) and Figures 2c and 2d show second temperature sensing means (222) for measuring the temperature of the product to be freeze-dried. Both types of temperature sensing means (221 , 222) are optional and they are adapted to send the temperatures they measure to a control unit (102), which is not shown in Figure 2a-2d. With this configuration, the voltage provided to the first heat source (209) and the first cold source (206) may be controlled, by the control unit (102), in response to either the temperature of the first heat exchange element (201 ) in an openloop mode or the product temperature in a closed-loop mode.

[0308] In other examples, the sample heat exchanger module (200) just comprises the second temperature sensing means (222) for measuring the temperature of the product to be freeze-dried or the first temperature sensing means (221) for measuring the temperature of the first heat exchange element (201) or none.

[0309] In an embodiment, the first temperature sensing means (221) and / or the second temperature sensing means (222) are selected from the group of Thermocouples, Resistance temperature detectors (RTDs), Infrared sensors and Fiber optic sensors.

[0310] In use, the sample heat exchanger module (200) is intended to be in functional connection with a freeze-drying chamber (103) of a freeze-dryer system (100) in such a way that the first heat exchange element (201) is in direct contact with the inner volume defined by the freeze-drying chamber (103). To achieve this, the freeze-dryer system (100) may comprise first connecting means (219) shown in Figure 2b and Figure 2d, the first connecting means (219) being used for attaching the sample heat exchanger module (200) to the freeze-drying chamber (103) in a hermetically and thermally isolated way.

[0311] In this example, the first connecting means (219) comprise a piece (223) and two sealing rubber elements (224) located in both faces (top and bottom) of the piece (223). Other configurations are possible in the context of the invention, as long as such configurations allow to attach the sample heat exchanger module (200) to the freeze-drying chamber (103) in a hermetically and thermally isolated way.

[0312] The piece (223) is preferably formed of a thermal isolation material selected from the group consisting of Polyurethane, Polystyrene, Polyethylene, Polypropylene, Polyimide, Polycarbonate, Polyvinyl Chloride, Poly (methyl methacrylate), Polyether Ether Ketone, and Polytetrafluoroethylene.

[0313] The sealing rubber elements (224) are preferably formed of a material selected from the group consisting of Silicone, Fluorosilicone, Fluorcarbon (Viton), EPDM (Ethylene Propylene Diene Monomer), and Nitrile (Buna-N).

[0314] Figures 3a-3d show several embodiments of a modular freeze-dryer system (100) for the cryopreservation of products according to the invention.

[0315] Figures 3a and 3b show two freeze-dryer systems (100) for the cryopreservation of products according to embodiments of the invention. These systems (100) comprise:

[0316] • a freeze-drying chamber (103);

[0317] • one sample heat exchanger module (200) attached to the freeze-drying chamber (103), for example the sample heat exchanger module (200) shown in previous Figures 2a-2d;

[0318] • one condenser module (300) attached to the freeze-drying chamber (103);

[0319] • pressure reduction means (104) for reducing pressure inside the freeze- drying chamber (103);

[0320] • two sample receiving elements (218) arranged in thermal contact with the top surface (202) of the first heat exchange element (201) of the sample heat exchanger module (200), the sample receiving elements (218) being optional in other examples;

[0321] • a control unit (102), which is optional in other examples; and

[0322] • pressure sensing means (101) for measuring the pressure inside the freeze-drying chamber (103), the pressure sensing means (101) being adapted to send the pressure measures to the control unit (102). In other examples, these pressure sensing means (101) are optional.

[0323] As it can be seen in both Figures 3a and 3b, the difference between the embodiments depicted is the number of compartments of the freeze-drying chamber (103).

[0324] In Figure 3a, the freeze-drying chamber (103) comprises a single compartment (105). In this particular configuration, the single compartment (105) is in functional connection with both the condenser module (300) and the sample heat exchanger module (200).

[0325] On the contrary, in Figure 3b, the freeze-drying chamber (103) comprises two compartments, namely a product compartment (106) and a condenser compartment

[0326] (107), which are in fluid communication through a passageway (108).

[0327] In this configuration, the product compartment (106) houses the sample heat exchanger module (200) and the condenser compartment (107) houses the condenser module (300). Both compartments (106, 107) are in fluid communication through a passageway

[0328] (108); that is, fluids can pass from one compartment to the other compartment going through the passageway (108). Preferably, the sectional area of the passageway (108) is large enough to avoid chocked flow during the drying phases of the freeze-drying process.

[0329] The systems (100) shown in both Figures 3a and 3b are intended for cryopreserving products or material, such as biological material. As it can be seen, the sample heat exchanger module (200) shown in Figures 2a-2d is integrated in the freeze-dryer system (100), the sample heat exchanger module (200) comprising a first heat source (209), a first cold source (206), a first heat exchange element (201), first temperature sensing means (221) and second temperature sensing means (222).

[0330] The control unit (102) is adapted to act on the components of the system (100) of this invention, namely, on the first heat source (209), on the first cold source (206) and on the pressure reduction means (104).

[0331] The control unit is preferably selected from the group of Programmable logic controllers (PLCs), Microprocessor-based controllers, Computer-based control systems and Manual control systems. In a preferred embodiment, the control unit for operating the system is a PLC.

[0332] In an embodiment, the control unit (102) of the system (100) is adapted to:

[0333] - receive and / or generate a working scheme of a freeze-drying cycle, wherein the working scheme comprises a plurality of equations, each equation representing the variation of the temperature of the product or of the first heat exchange element during the course of a stage of the freeze-drying cycle; - receive the sensed temperatures from the first temperature sensing means (221) and / or from the second temperature sensing means (222); and

[0334] - depending on the sensed temperatures, act on the first cold source (206) and / or the first heat source (209) of the sample heat exchanger module (200) to comply with the equations of the working scheme.

[0335] In an embodiment, the control unit (102) is further adapted to:

[0336] - receive and / or generate a working scheme of a freeze-drying cycle, wherein the working scheme comprises a plurality of pressure equations, each pressure equation representing the variation of the pressure inside the freeze- drying chamber (103) during the course of a stage of the freeze-drying cycle;

[0337] - receive the sensed chamber pressure from the pressure sensing means (101); and

[0338] - depending on the sensed chamber pressure, act on the pressure reduction means (104) to comply with the pressure equations of the working scheme.

[0339] As mentioned before, the control unit (102) is in charge of commanding the first cold source (206), the first heat source (209) and the pressure reduction means (104). Said control unit (102) receives and / or generates a working scheme - or working recipe - of the freeze-drying cycle.

[0340] The control unit (102) receives the sensed temperatures from the first temperature sensing means (221), which measure the temperature of the first heat exchange element (201), and / or from the second temperature sensing means (222), which measure the temperature of the products. Once the control unit (102) has received the temperatures, it acts on the first cold source (206) and / or the first heat source (209) of the sample heat exchanger module (200) to comply with the predefined working scheme; that is, to reach the temperature values defined by the equations of the working scheme.

[0341] Simultaneously or alternatively, the control unit (102) receives the sensed chamber pressure from the pressure sensing means (101) and acts on the pressure reduction means (104) for reducing pressure inside the freeze-drying chamber to comply with the predefined working scheme; that is, to reach the pressure values defined by the equations of the working scheme. In an example, the pressure reduction means (104) comprise a vacuum pump selected from the group of Rotary vane pumps, Turbo molecular pumps, Diaphragm pumps and Scroll pumps. In a more specific example, the vacuum pump used is a Scroll pump, which is oil-free and uses two interleaved spirals to compress air and generate a vacuum.

[0342] In an example, the pressure sensing means (101) comprise one or a combination of elements selected from the group consisting of Pirani gauges, Capacitance manometers, Thermocouple gauges and Ionization gauges. In a preferred example, a combination of a Pirani gauge and capacitance manometer is employed.

[0343] Figures 3c and 3d show embodiments of a modular freeze-dryer system (100) according to the invention. These systems (100) are similar to the ones shown in Figures 3a and 3b, respectively, with the exception of having two different sample heat exchanger modules (200) attached to the freeze-drying chamber (103) instead of only one. In these systems, the two sample heat exchanger modules (200) and the condenser module (300) are independently controllable by the control unit (102).

[0344] In the system (100) comprising a single sample heat exchanger module (200) and a single condenser module (300), as the ones shown in Figures 3a and 3b, all the products to be freeze-dried are preferably homogeneous in terms of properties that can affect the freeze-drying process, namely the total water content, total mass, maximum safe temperature, or the vapor resistance of the dry product, to avoid significant differences in the final moisture content among the different product samples.

[0345] On the contrary, the system (100) comprising more than one sample heat exchanger module (200), as the ones shown in Figures 3c and 3d, allows different freeze-drying processes to be performed simultaneously within the same freeze-drying chamber (103) space. With this configuration, the samples of product to be freeze-dried that present significantly different properties are associated with separate sample heat exchanger modules (200) within the same freeze-drying chamber (103) space. The pressure reduction means (104) maintain the same level of pressure across the entire chamber (103) while the temperature of each sample heat exchanger module (200) is controlled independently, making it possible to customize the drying conditions for each type of product, allowing different drying protocols to be run simultaneously. Finally, as it can be seen in both Figures 3c and 3d, the difference between the depicted systems is the number of compartments of the freeze-drying chambers (103). In Figure 3c, the freeze-drying chamber (103) has a single compartment (105) in functional connection with both the condenser module (300) and the sample heat exchanger modules (200). On the contrary, in Figure 3d, the freeze-drying chamber (103) comprises two compartments, namely a product compartment (106), which houses the two sample heat exchanger modules (200), and a condenser compartment (107), which houses the condenser module (300). The product compartment (106) and the condenser compartment (107) are in fluid communication through a passageway (108). Preferably, the sectional area of the passageway (108) is large enough to avoid chocked flow during the drying phases of the process.

[0346] Figures 4a-4d show several views of a condenser module (300) according to an embodiment of the invention. This condenser module (300) is intended to be part of a modular freeze-dryer system (100) for the cryopreservation of products, for instance the ones depicted in Figures 3a-3d.

[0347] In this example, the condenser module (300) comprises a second heat exchange element (301), a second cold source (302), a second heat source (303) and third temperature sensing means (304).

[0348] The second heat exchange element (301), as it can be seen in Figures 4a-4d, comprises a top surface (306), an opposed bottom portion (307), and a stepped cone-shape with a plurality of tiered sections along the height between the top surface (306) and the bottom portion (307), wherein each section has a different diameter.

[0349] This second heat exchange element (301) of the condenser module (300) achieves a high ice deposition efficiency and homogeneity due to the presence of the stepped cone shape. This specific design favors homogeneous ice deposition through all the surface available.

[0350] The second heat exchange element (301) is made of a thermally conductive material. In an example, the material of the second heat exchange element (301) is selected from the group consisting of aluminum, copper, iron, magnesium, silver, an alloy of aluminum, an alloy of copper, an alloy of iron, an alloy of magnesium and an alloy of silver. Figure 4a further shows the second cold source (302) and the second heat source (303), both types of sources (302, 303) being controllable by the control unit (102).

[0351] In this particular example, as it can be seen in Figure 4b, a set of indentations (308) open at the bottom portion (307) of the second heat exchange element (301) matching in number to, and complementing in contour and depth, the ends of the second heat (303) and second cold (302) sources, being in thermal contact with them. In other examples, other configurations are possible as long as both sources (302, 303) are in thermal contact with the bottom portion (307) of the second heat exchange element (301).

[0352] Regarding the second cold source (302), as it can be seen in Figure 4b, it comprises a cryocooler having a cold end (309) in thermal contact with the bottom portion (307) of the second heat exchange element (301). In an embodiment, said cryocooler is selected from the group of Stirling Cryocoolers, Gifford-McMahon Cryocoolers, and Pulse-tube Cryocoolers. In a more specific example, the second cold source (302) is a Free Piston Stirling Cryocooler (FPSC).

[0353] On the other hand, as it can be seen in Figure 4a, the second heat source (303) comprises a plurality of rod-shaped ceramic heating elements, each having a hot end, that are arranged concentrically around, and equidistant to, the center of the cold end (309) of the second cold source (302).

[0354] In other examples, the second heat source (303) comprises at least one resistive heating element selected from the group of metallic resistance, semiconductor, thick film, polymer, and ceramic heating elements.

[0355] Figure 4a, 4b and 4d further show third temperature sensing means (304) for measuring the temperature of the second heat exchange element (301). This third temperature sensing means (304) are adapted to send the temperature they measure to the control unit (102) of the system (100), which is not shown in Figures 4a-4d. With this configuration, the voltage provided to the second heat and the second cold sources (303, 302) may be controlled, by the control unit (102), in response to the temperature of the second heat exchange element (301). In an example, the third temperature sensing means (304) are selected from the group of Thermocouples, Resistance temperature detectors (RTDs), Infrared sensors and Fiber optic sensors.

[0356] In use, the condenser module (300) is intended to be in functional connection with the freeze-drying chamber (103) of the freeze-drying system (100) in such a way that the second heat exchange element (301) is in direct contact with the inner volume defined by the freeze-drying chamber (103). To achieve this, the system (100) may comprise second connecting means (305) shown in Figure 4b and Figure 4d, the second connecting means (305) being used for attaching the condenser module (300) to the freeze-drying chamber (103) in a hermetically and thermally isolated way.

[0357] In this example, the second connecting means (305) comprise a piece (310) and two sealing rubber elements (311) located in both faces (top and bottom) of the piece (310). Other configurations are possible in the context of the invention, as long as such configurations allow to attach the module (300) to the freeze-drying chamber (103) in a hermetically and thermally isolated way.

[0358] The piece (310) is preferably formed of a thermal isolation material selected from the group consisting of Polyurethane, Polystyrene, Polyethylene, Polypropylene, Polyimide, Polycarbonate, Polyvinyl Chloride, Poly (methyl methacrylate), Polyether Ether Ketone, and Polytetrafluoroethylene.

[0359] The sealing rubber elements (311) are preferably formed of a material selected from the group consisting of Silicone, Fluorosilicone, Fluorcarbon (Viton), EPDM (Ethylene Propylene Diene Monomer), and Nitrile (Buna-N).

[0360] Figure 5 shows a workflow detailing a method for determining an optimum working scheme of a freeze-drying cycle according to the invention, using the system (100) shown in any of Figures 3a-3d, said method comprising the following steps: a) receiving, the control unit (102), input data, the input data comprising the number of different stages of the freeze-drying cycle to be included in the optimum working scheme and the following parameters for each stage:

[0361] • a target temperature setpoint to be reached by the product to be freeze-dried during the stage; • the time to hold the target temperature setpoint once reached; and

[0362] • a maximum product temperature change rate; b) receiving, the sample heat exchanger module (200), at least one sample container that comprises a sample of the product; c) generating, the control unit (102), a first working scheme of the freeze-drying cycle, the first working scheme comprising a first equation for each stage, the first equations representing the variation of the product temperature as a function of time during each stage; wherein the first equation for each stage is created by the control unit (102) based on the parameters of said stage and on a model equation that provides an expected temperature as a function of time, the model equation comprising at least one adjustable parameter; d) performing a first freeze-drying cycle, and during the first freeze-drying cycle:

[0363] - receiving, the control unit (102), sensed temperatures of the product from the second temperature sensing means (222); and depending on the sensed temperatures of the product, acting on the first cold source (206) and / or the first heat source (209) of the sample heat exchanger module (200) to comply with the first working scheme; and

[0364] - receiving, the control unit (102), sensed temperatures from the first temperature sensing means (221); e) generating, the control unit (102), a second working scheme, the second working scheme comprising a second equation for each stage, wherein the second equations represent the variation of the temperature of the first heat exchange element (201) as a function of time during each stage, wherein the second equation for each stage is calculated by fitting the model equation of the stage to the temperatures sensed in step d) by the first temperature sensing means (221) during the course of the stage; wherein the fitting is performed by adjusting one or more of the at least one adjustable parameter; f) returning, by the control unit (102), the second working scheme as the optimum working scheme of the freeze-drying cycle.

[0365] In an embodiment, the control unit (102) obtains the equations of the first working scheme taking into account also an initial temperature of the product sample measured by the second temperature sensing means (222).

[0366] In an example, the method is adapted for determining N optimum working schemes for simultaneous freeze-drying cycles carried out on N different products. In this case, the system used for executing the method comprises N sample heat exchanger modules and the method steps are executed for each of the sample heat exchanger modules.

[0367] In an embodiment, the model equation of each stage is:

[0368] - a generalized logistic function model;

[0369] - a 5-parameter logistic regression function model;

[0370] - a quadratic polynomial equation model;

[0371] - a cubic polynomial equation model; or

[0372] - a quartic polynomial equation model.

[0373] Figure 6 represents the measures taken by different temperature and pressure sensing means of the freeze-dryer system (100) of an embodiment of the present invention during a freeze-drying cycle employing an open-loop mode with invariable temperature setpoints of the first heat exchange element (201); that is, the temperatures of the sample heat exchanger module (200) are fixed at each phase of the freeze-drying process and linear transitions are established between phases. This open-loop method is widely used in the field of the invention.

[0374] In particular, the freeze-drying cycle was performed to a 5% mannitol and antibody formulation using the system (100) according to an embodiment of the present invention.

[0375] The curve 601 represents the temperature of the first heat exchange element (201) belonging to the sample heat exchanger module (200) measured by the first temperature sensing means (221).

[0376] The curve 602 represents the temperature of the products measured by the second temperature sensing means (222).

[0377] The curve 603 represents the temperature of the second heat exchange element (301) belonging to the condenser module (300) measured by the third temperature sensing means (304).

[0378] The curve 604 represents the pressure of the freeze-drying chamber (103) measured by a Pirani pressure sensor, which forms part of the pressure sensing means (101) in this embodiment.

[0379] The curve 605 represents the pressure of the freeze-drying chamber (103) measured by a capacitive pressure sensor, which forms part of the pressure sensing means (101) in this embodiment.

[0380] The curve 606 represents the moment of primary drying end defined as the moment where the measurements represented by curves 604 and 605 are the same.

[0381] A formulation comprising a monoclonal antibody supplemented with 5% mannitol was characterized by Differential Scanning Calorimetry and Freeze-Drying Microscopy to obtain a thermal fingerprint. From such thermal fingerprint, the invariable temperature setpoints of the first heat exchange element (201) were established.

[0382] Thus, according to the Differential Scanning Calorimetry study, it was established that the product should be solidified at -40°C before performing an annealing step at -10°C to crystalize the mannitol. According to the Freeze-Drying Microscopy study, the formulation presents collapse around -17°C and -20°C was established as the critical product temperature. Finally, the dry product is known to be stable at room temperature and a final temperature of 25°C was established for the secondary drying phase.

[0383] The system (100) used to carry out the open-loop method comprises a dual chamber (106, 107), a single sample heat exchanger module (200) and a single condenser module (300). The control unit (102) was set to receive feedback from the first temperature sensing means (221) that measures the temperature of the first heat exchange element (201), the system (100) thus working in an open-loop mode as mentioned before.

[0384] During the freezing phase of the process, according to the invariable temperature setpoints, the control unit (102) ordered to cool the first heat exchange element (201) from room temperature down to -40°C at a rate of 1°C / minute and kept that temperature stable for 2 hours (601) in order to allow the product to solidify.

[0385] Then the control unit (102) ordered to warm the first heat exchange element (201) up to -10°C at a rate of 1 °C / minute and kept that temperature stable for 2 hours allowing for a process of annealing of the crystalized product. Then, the control unit (102) ordered to cool the first heat exchange element (201) down to -40°C at a rate of 1 °C / minute (601) to resolidify the product. This freezing phase of the process took about 10 h to complete.

[0386] The product experiences changes in its temperature (602); at about 2 hours after the start of the process, a sharp increase of product temperature (602) is observed, reflecting the moment of water crystallization, and it may also be observed that the product temperature measures during the freezing phase closely encompass the sample heat exchanger module temperatures (601).

[0387] After the product is frozen, the primary drying of the process begins. At this point, the control unit (102) ordered the pressure reduction means (104), e.g. a vacuum pump, to evacuate the freeze-drying chamber (103) to a pressure of 0.07mBar monitoring the pressure reduction by means of the pressure sensing means (101). At the same time, the control unit (102) ordered to cool the second heat exchange element (301) from room temperature down to -55°C and kept that temperature stable through the rest of the process (603).

[0388] As shown in Figure 6, the temperature of the second heat exchange element (603) of the condenser module (300) is significantly lower than the product temperature (602). In this way, two surfaces are created with different water vapour pressures, which translates into a dynamic flux of water from the product (at higher temperature) to the condenser (at lower temperature). The higher the difference between the two temperatures, the faster the process is. Using a vacuum pump to remove the noncondensable gases from the freeze-drying chamber (103) reduces the resistance to this flux and facilitates the process.

[0389] The low temperature of the condenser module and the low chamber pressure create the conditions for the sublimation of the water ice present in the product (thus turning into water vapor) and the deposition of the water vapor (turned into ice) on the second heat exchange element (301) of the condenser module.

[0390] Since the sublimation is an endothermic process, the product is naturally cooled down and it may be observed that the product temperature measures are usually lower than the first heat exchange element (201) temperature measures. During the primary drying, the frozen product is gradually transformed into a porous dry product (cake) through which the water vapor needs to travel. This cake creates a resistance to water vapor and exerts pressure over the ice surface of the “not yet dry” product. As a result of this increased pressure, the ice temperature at the sublimation front increases. Since the cake thickness gradually increases throughout the primary drying, the product temperature increases as a response (602) and, if not controlled, the product temperature could eventually reach a value where the cake melts back, collapsing and stopping the process. To avoid this, the temperature of the first heat exchange element (201) must be maintained at a value that avoids the critical product temperature to be reached.

[0391] Then the control unit (102) ordered to warm up to -20°C at a rate of 1 °C / minute and kept that temperature stable until the end of primary drying.

[0392] When all the ice is removed by sublimation from the product, the remaining gas inside the drying chamber (103) is almost completely dry and, therefore, the measures of the capacitive pressure sensor (i.e. Capacitance manometer) and the Pirani pressure sensor (i.e Pirani gauges) coincide defining the end of primary drying (606).

[0393] The Pirani pressure sensor and the capacitive pressure sensor work in a different way. The pressure measures of the Pirani pressure sensor depend on the gas thermal conductivity and the gas composition. On the contrary, the pressure measures of the capacitive pressure sensor do not depend on the gas composition.

[0394] During the primary drying phase, the gas in the chamber is mostly composed by water vapor, which is more conductive than the nitrogen or the atmosphere air. In this way, as both the Pirani pressure sensor and the capacitive pressure sensor are calibrated in a pure nitrogen atmosphere, the pressure measures of the Pirani pressure sensors are always higher than the measures of the capacitive pressure sensors, as long as the gas being measured in the chamber contains water. When sublimation ends, the system leaves dry air to enter in the chamber in order to maintain the pressure established, so the measures of the Pirani pressure sensor are similar than the measures of the capacitive pressure sensor. Thus, with this specific combination of sensors, it can be known when the freeze-dryer system is not generating water vapor and the material is dried.

[0395] At the end of the primary drying phase, there is still water adsorbed to the product that can be removed by desorption at higher temperatures. This comprises the secondary drying phase of the freeze-drying process and is responsible for achieving a very low moisture content necessary to avoid product spoiling during its storage.

[0396] Then, during the secondary drying phase, the control unit (200) ordered to warm up to 25°C at a rate of 1 °C / minute and kept that temperature stable for 6 hours before ending the process.

[0397] The cycle lasts a total of 50 hours to complete, with the primary drying phase lasting around 26 hours to complete.

[0398] Keeping a fixed temperature for the first heat exchange element during primary drying, as it is the case of the process shown in Figure 6, means that it is needed to start the process at a product temperature lower enough to allow for its gradual warming while avoiding its collapse before all the ice is removed. Starting at a lower product temperature at a fixed condenser temperature means a lower temperature / vapor pressure difference and, therefore, a slower process.

[0399] A most efficient primary drying strategy implies using working schemes of the freeze- drying cycle, the working scheme comprising a plurality of equations, each equation representing the variation of the temperature of the product or of the first heat exchange element during the course of a stage of the freeze-drying cycle. To maintain a fixed product temperature as high as possible but below its critical temperature, a freeze-dryer system (100) can be used in a closed loop approach with working schemes, the freeze- dryer system (100) being equipped with temperature sensing means (221 , 222) and a sample heat exchanger module (200) with very low temperature inertia, as the one of the present invention. The resulting measurements are illustrated in Figure 7.

[0400] The system (100) comprises a dual chamber (106, 107), a single sample heat exchanger module (200) and a single condenser module (300). The control unit (102) was set to receive feedback from the second temperature sensing means (222) that measure the temperature of the products; therefore, the system (100) works in a closed-loop mode. Figure 7 represents the measures taken by different temperature and pressure sensing means of a freeze-dryer system (100) according to the present invention during a freeze- drying cycle employing a closed-loop mode, the execution of the freeze-drying cycle being based on working schemes. In particular, the freeze-drying cycle was performed to a 5% mannitol and antibody formulation using the system (100) according to an embodiment of the present invention.

[0401] The curve 701 represents the temperature of the first heat exchange element (201) belonging to the sample heat exchanger module (200) measured by the first temperature sensing means (221).

[0402] The curve 702 represents the temperature of the products measured by the second temperature sensing means (222).

[0403] The curve 703 represents the temperature of the second heat exchange element (301) belonging to the condenser module (300) measured by the third temperature sensing means (304).

[0404] The curve 704 represents the pressure of the freeze-drying chamber (103) measured by a Pirani pressure sensor, which forms part of the pressure sensing means (101).

[0405] The curve 705 represents the pressure of the freeze-drying chamber (103) measured by a capacitive pressure sensor, which forms part of the pressure sensing means (101).

[0406] The curve 706 represents the moment of primary drying end defined as the moment where the measurements 704 and 705 are the same.

[0407] A formulation comprising a monoclonal antibody supplemented with 5% mannitol was characterized by Differential Scanning Calorimetry and Freeze-Drying Microscopy to obtain a thermal fingerprint. According to the Differential Scanning Calorimetry study, it was established that the product should be solidified at -40°C before performing an annealing step at -10°C to crystalize the mannitol. According to the Freeze-Drying Microscopy study, the formulation presents collapse around -17°C and -20°C was established as the critical product temperature. Finally, the dry product is known to be stable at room temperature and a final temperature of 25°C was established for the secondary drying phase.

[0408] Firstly, input data comprising the number of stages of the freeze-drying cycle and their parameters were received by the control unit (102) of the system (100) according to the previous fingerprint.

[0409] A total of 6 stages were defined; wherein stages 1 to 4 were defined to be performed at atmospheric pressure while keeping the second heat exchange element (301) at room temperature, and wherein stages 5 and 6 were defined to be performed at 0.07 mBar keeping the second heat exchange element (301) at -55°C.

[0410] For each step from 1 to 6 a target product temperature, a product temperature change rate and a time to hold the target product temperature was provided to the control unit (102) of the system (100):

[0411] • for stage 1 the target product temperature was 4°C, the change rate was 1°C / min and the hold time was 15 minutes;

[0412] • for stage 2 the target product temperature was -40°C, the change rate was 1°C / min and the hold time was 2h;

[0413] • for stage 3 the target product temperature was -10°C, the change rate was 1°C / min and the hold time was 2h;

[0414] • for stage 4 the target product temperature was -40°C, the change rate was 1°C / min and the hold time was 15 min;

[0415] • for stage 5 the target product temperature was -20°C, the change rate was 1°C / min and the hold time was 30h;

[0416] • for stage 6 the target product temperature was 25°C, the change rate was 1°C / min and the hold time was 6h.

[0417] The initial product temperature of stage 1 is the temperature measured by the second temperature sensing means (222) at the beginning of the freeze-drying cycle. The initial product temperature of the rest of the stages is the target product temperature of its previous stage.

[0418] With this information, the control unit (102) generated a first working scheme of the freeze-drying cycle comprising a first equation for each stage, the first equations representing the variation of the product temperature as a function of time during each stage; wherein the first equation for each stage is created by the control unit (102) based on the parameters of said stage and on a model equation that provides an expected temperature as a function of time, the model equation comprising at least one adjustable parameter.

[0419] According to the first working scheme, the control unit (102) ordered to cool the first heat exchange element (201) which, in turn, cooled the product samples from room temperature down to 4°C at a rate of 1 °C / minute and kept that temperature stable for 15 minutes (702).

[0420] Afterwards, the control unit (102) ordered to cool the first heat exchange element (201) which, in turn, cooled the product samples from 4°C to -40°C at a rate of 1 °C / minute and kept that temperature stable for 2 hours (702).

[0421] Then the control unit (102) ordered to warm the first heat exchange element (201) which, in turn, warmed the product samples up to -10°C at a rate of 1 °C / minute, kept that temperature stable for 2 hours, and cooled the product samples down to -40°C at a rate of 1 °C / minute (702). This temperature was hold 15 minutes.

[0422] At this point, the pressure reduction means (104), e.g. a vacuum pump, evacuated the freeze-drying chamber (103) to a pressure of 0.07 mBar using a capacitive pressure gauge as pressure sensing means (101). At the same time, the control unit (102) cooled the second heat exchange element (301) from room temperature down to -55°C and kept that temperature stable through the rest of the process (703).

[0423] Then the control unit (102) ordered to warm up the product samples to -20°C at a rate of 1 °C / minute and kept that temperature stable for about 30 hours, based on previous experience of freeze-drying the same product.

[0424] Then, the control unit (102) ordered to warm the product samples up to 25°C at a rate of 1 °C / minute and kept that temperature stable for 6 hours before ending the process.

[0425] Contrary to the profiles observed in Figure 6, the temperatures of the first heat exchange element (701) are now reactive to the product temperatures (702), being the product temperature (702) more stable and linear. In this approach, where the first heat exchange element (701) adapts to reach the product temperature established by the first working scheme, the difference between the product temperature (702) and the condenser temperature (703) remains constant and as high as possible, which maintains the sublimation-deposition flux at its maximum and optimizes the process efficiency. As a result, the end of primary drying in this scenario (706) occurs 26 hours after the start of the freeze-drying process while, in the approach illustrated in Figure 6, the end of primary drying (706) occurs 36 hours after the start of the freeze-drying process.

[0426] The cycle lasts a total of 50 hours to complete, as it was established to last a fixed time, with the primary drying phase lasting around 16 hours to complete. The resulting process was clearly more efficient than the traditional process in open-loop mode with invariable temperature setpoints for the first heat exchange element during primary drying (see Figure 6).

[0427] This closed-loop approach is, in theory, the most efficient way to optimize the primary drying in a freeze-drying process. However, it implies that the second temperature sensing means (222) must be used in direct contact with the products to be freeze-dried with potential risk of contaminating those products. Moreover, if the second temperature sensing means (222) are not well placed, the feedback may be misleading and result in a failed process and loss of products.

[0428] For this reason, the method of the invention is a better approach. The method of the invention uses the previous closed-loop method described for Figure 7 but, during the execution of the freeze-drying cycle, the control unit (102) receives the temperatures of the first sample heat exchange element (201) by means of the first temperature sensing means (221) that provide the conditions to achieve the most stable and higher product temperature throughout the process (especially during primary drying). Using these temperatures of the first sample heat exchange element (201), the control unit (102) generates an optimum open-loop working scheme.

[0429] In particular, the optimum working scheme generated by the control unit (102) comprises an equation for each stage that represents the variation of the temperature of the first heat exchange element (201) as a function of time during the stage. The control unit (102) generates the equations by fitting the model equation of the stage (according to the first working scheme) to the temperatures sensed by the first temperature sensing means (221) during the course of the stage. The fitting is performed by adjusting one or more of the at least one adjustable parameter.

[0430] In this way, an optimized working scheme that is not influenced by a mispositioned second temperature sensing means (222) and avoids possible cross-contaminations between different products being freeze-dried can be used.

[0431] Figure 8 depicts the measures taken by different temperature and pressure sensing means of a freeze-dryer system (100) according to the invention during a freeze-drying cycle employing an open-loop mode, the execution of the freeze-drying cycle being based on the optimized working scheme generated according to the method of the invention.

[0432] As mentioned before, the process depicted in Figure 8 uses the optimum working scheme obtained with the method of the invention to be used in open-loop mode that reproduces the same process achieved in closed-loop (Figure 7) but with the advantage that no temperature sensing means have to be placed in the products, avoiding their contamination. With this process of Figure 8, the same time reduction (with respect to the process shown in Figure 6) is achieved until the end of the secondary drying phase.

[0433] The curve 801 represents the temperature of the first heat exchange element (201) belonging to the sample heat exchanger module (200) measured by the first temperature sensing means (221).

[0434] The curve 802 represents the temperature of the products measured by the second temperature sensing means (222).

[0435] The curve 803 represents the temperature of the second heat exchange element (301) belonging to the condenser module (300) measured by the third temperature sensing means (304).

[0436] The curve 804 represents the pressure of the freeze-drying chamber (103) measured by a Pirani pressure sensor, which forms part of the pressure sensing means (101). The curve 805 represents the pressure of the freeze-drying chamber (103) measured by a capacitive pressure sensor, which forms part of the pressure sensing means (101).

[0437] The curve 806 represents the moment of primary drying end defined as the moment where the measurements 804 and 805 are the same.

[0438] As a result of the method of the invention, an optimum working scheme is generated to mimic the response of the system (100) during the closed loop process. The goal is to reproduce the same process in open-loop mode with a set of equations representing the temperature variations of the first heat exchange element (201) during the freeze-drying cycle.

[0439] The optimum working scheme is introduced in the control unit (102) of the system (100) shown in Figure 2b with a dual chamber (106, 107), a single sample heat exchanger module (200) and a single condenser module (300). The control unit (102) was set to receive feedback from the first temperature sensing means (221) so the system (100) works in an open-loop mode.

[0440] The control unit (102) proceeded to reproduce the temperatures (801) of the first heat exchange element (201) until the moment of setting the pressure of 0.07 mBar (705).

[0441] After that, the control unit (102) proceeded to reproduce the next temperatures until the end of primary drying which was determined by the control unit (102) when the measure of a Pirani pressure sensor was equal to the measure of the capacitive pressure sensor. Both the Pirani pressure sensor and the capacitive pressure sensor form the pressure sensing means (101).

[0442] Then, the control unit (102) ordered to warm up the first heat exchange element (201) according to the temperature of the optimum working scheme until the end of secondary drying ending the process.

[0443] The cycle lasted a total of 37 hours with the primary drying phase lasting around 16 hours to complete. The resulting process was clearly more efficient than the traditional process (see Figure 6) and in line with the results obtained during the closed-loop run (shown in Figure 7) with the advantage of avoiding the use of temperature sensors in contact with the product which could contaminate them.

[0444] Further aspects and embodiments of the invention are defined in the following clauses:

[0445] Clause 1.- A sample heat exchanger module (200) for a freeze-dryer system (100), the sample heat exchanger module (200) comprising:

[0446] • a first heat exchange element (201) made of thermally conductive material, the first heat exchange element (201) comprising: a top surface (202); a plurality of straight passages (203, 204, 205) extending in different directions through the first heat exchange element (201), the passages being parallel to the top surface (202) and intersecting at the interior of the first heat exchange element (201);

[0447] • a first cold source (206) comprising a cold end (207) with a maximum efficiency zone (208) that is in thermal contact with the first heat exchange element

[0448] (201);

[0449] • a first heat source (209) comprising a maximum efficiency zone (210) in thermal contact with the first heat exchange element (201); wherein the straight passages (203, 204, 205) are arranged between the top surface (202) and the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209), and wherein the first cold source (206) and the first heat source (209) are controllable by a control unit (102) to decrease or increase the temperature of the first heat exchange element (201).

[0450] Clause 2.- The sample heat exchanger module (200) according to Clause 1 , wherein the first heat exchange element (201) comprises:

[0451] • a first inner plane (211) being spaced from and parallel to the top surface

[0452] (202);

[0453] • a second inner plane (212) being spaced from and parallel to the top surface (202), wherein the first inner plane (211) is arranged between the top surface (202) and the second inner plane (212), and the second inner plane (212) passes through the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209), preferably through the centre of the maximum efficiency zone (208) of the first cold source (206) and through the centre of the maximum efficiency zone (210) of the first heat source (209);

[0454] • a top portion (213) defined between the top surface (202) and the second inner plane (212), wherein the top portion (213) has a vertical axis of symmetry (214) and a plurality of vertical planes of symmetry (215), wherein each of the vertical planes of symmetry (215): contains the vertical axis of symmetry (214); divides the top portion (213) in two halves that are substantially equal in shape and size; and intersects the first inner plane (211) in an intersection line; wherein each straight passage (203, 204, 205) extends along a different intersection line.

[0455] Clause 3.- The sample heat exchanger module (200) according to the preceding Clause, wherein

[0456] - the distance between the top surface (202) and the first inner plane (211) is Hi;

[0457] - the distance between the second inner plane (212) and the first inner plane (211) is H2and

[0458] - the distances and H2comply the following relation: 0.4

[0459] Clause 4.- The sample heat exchanger module (200) according to any of Clauses 2 or 3, wherein the height h of each straight passage (203, 204, 205) complies the following relation:

[0460] (W, * 0.5) > h > 0 wherein is the distance between the top surface (202) and the first inner plane (211).

[0461] Clause 5.- The sample heat exchanger module (200) according to any of Clauses 2-4, wherein the width w of each straight passage (203, 204, 205) complies the following relation: wherein: is the distance between the top surface (202) and the first inner plane (211);

[0462] H2is the distance between the second inner plane (212) and the first inner plane (211); and

[0463] L is the maximum length of the top surface (202) in a direction perpendicular to the vertical plane of symmetry (215) that contains the intersection line along which the straight passage (203, 204, 205) extends.

[0464] Clause 6.- The sample heat exchanger module (200) according to any of the preceding Clauses, wherein the first heat exchange element (201) has a bottom surface (217) and comprises a plurality of indentations (216) open at the bottom surface (217), and wherein the first heat source (209) comprises a plurality of heating elements, each one having a maximum efficiency zone (210); wherein the indentations are configured to receive, at least, the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zones (210) of the plurality of heating elements of the first heat source (209), and wherein:

[0465] - each indentation (216) is aligned with a vertical plane of symmetry (215); and / or

[0466] - the indentation configured to receive the maximum efficiency zone of the first cold source (206) is aligned with the vertical axis of symmetry (214); and / or

[0467] - the indentations (216) configured to receive the maximum efficiency zones (210) of the heating elements of the first heat source (209) are placed equidistantly with respect to the vertical axis of symmetry (214).

[0468] Clause 7.- The sample heat exchanger module (200) according to any of the preceding Clauses, further comprising:

[0469] • first temperature sensing means (221) for measuring the temperature of the first heat exchange element (201), the first temperature sensing means (221) being adapted to send said temperature to a control unit (102); and / or

[0470] • second temperature sensing means (222) for measuring the temperature of the product (222) to be freeze-dried, the second temperature sensing means (222) being adapted to send said temperature to a control unit (102).

[0471] Clause 8.- A freeze-dryer system (100) for the cryopreservation of products, the freeze- dryer system (100) comprising:

[0472] • a freeze-drying chamber (103),

[0473] • at least one sample heat exchanger module (200) according to any of the preceding Clauses attached to the freeze-drying chamber (103),

[0474] • at least one condenser module (300) attached to the freeze-drying chamber (103), and

[0475] • pressure reduction means (104) for reducing pressure inside the freeze-drying chamber (103).

[0476] Clause 9.- The freeze-dryer system (100) according to Clause 8, further comprising at least one sample receiving element (218), the at least one sample receiving element (218) being arrangeable in thermal contact with the top surface (202) of the first heat exchange element (201).

[0477] Clause 10.- The freeze-dryer system (100) according to Clause 8 or 9, wherein each of the at least one condenser module (300) comprises:

[0478] • a second heat exchange element (301) made of a thermally conductive material and having a top surface (306), an opposed bottom portion (307), and a stepped cone-shape with a plurality of tiered sections along the height between the top surface (306) and the bottom portion (307), wherein each section has a different diameter;

[0479] • a second cold source (302) comprising a cold end (309) in thermal contact with the bottom portion (307) of the second heat exchange element (301), the second cold source (302) being controllable by a control unit (102);

[0480] • a second heat source (303) in thermal contact with the bottom portion (307) of the second heat exchange element (301) and being controllable by a control unit (102); and

[0481] • third temperature sensing means (304) for measuring the temperature of the second heat exchange element (301).

[0482] Clause 11.- The freeze-dryer system (100) according to any of Clauses 8-10 further comprising a control unit (102) adapted to: - act on the first cold source (206) and / or the first heat source (209) of the at least one sample heat exchanger module (200) to decrease and / or increase the temperature of the first heat exchange element (201); and / or

[0483] - act on the second cold source (302) and / or the second heat source (303) of the at least one condenser module (300) to decrease and / or increase the temperature of the second heat exchange element (301); and / or

[0484] - act on the pressure reduction means (104) to reduce the pressure inside the freeze-drying chamber (103).

[0485] Clause 12.- The freeze-dryer system (100) according to Clause 11 , wherein the control unit (102) is further adapted to:

[0486] - receive and / or generate a working scheme of a freeze-drying cycle, wherein the working scheme comprises a plurality of equations, each equation representing the variation of the temperature of the product or of the first heat exchange element during the course of a stage of the freeze-drying cycle;

[0487] - receive the sensed temperatures from the first temperature sensing means (221) and / or from the second temperature sensing means (222); and

[0488] - depending on the sensed temperatures, act on the first cold source (206) and / or the first heat source (209) of the sample heat exchanger module (200) to comply with the equations of the working scheme.

[0489] Clause 13.- The freeze-dryer system (100) according to any of Clauses 11-12 further comprising pressure sensing means (101) for measuring the pressure inside the freeze- drying chamber (103), the pressure sensing means (101) being adapted to send the pressure measures to the control unit (102), and wherein the control unit (102) is further adapted to:

[0490] - receive and / or generate a working scheme of a freeze-drying cycle, wherein the working scheme comprises a plurality of pressure equations, each pressure equation representing the variation of the pressure inside the freeze- drying chamber (103) during the course of a stage of the freeze-drying cycle;

[0491] - receive the sensed chamber pressure from the pressure sensing means (101); and

[0492] - depending on the sensed chamber pressure, act on the pressure reduction means (104) to comply with the pressure equations of the working scheme. Clause 14.- A computer-implemented method for determining an optimum working scheme of a freeze-drying cycle using the system (100) of any of Clauses 11-13, said method comprising the following steps: a) receiving, the control unit (102), input data, the input data comprising the number of different stages of the freeze-drying cycle to be included in the optimum working scheme and the following parameters for each stage:

[0493] • a target temperature setpoint to be reached by the product to be freeze-dried during the stage;

[0494] • the time to hold the target temperature setpoint once reached; and

[0495] • a maximum product temperature change rate; b) receiving, the sample heat exchanger module (200), at least one sample container that comprises a sample of the product; c) generating, the control unit (102), a first working scheme of the freeze-drying cycle, the first working scheme comprising a first equation for each stage, the first equations representing the variation of the product temperature as a function of time during each stage; wherein the first equation for each stage is created by the control unit (102) based on the parameters of said stage and on a model equation that provides an expected temperature as a function of time, the model equation comprising at least one adjustable parameter; d) performing a first freeze-drying cycle, and during the first freeze-drying cycle:

[0496] - receiving, the control unit (102), sensed temperatures of the product from the second temperature sensing means (222); and depending on the sensed temperatures of the product, acting on the first cold source (206) and / or the first heat source (209) of the sample heat exchanger module (200) to comply with the first working scheme; and

[0497] - receiving, the control unit (102), sensed temperatures from the first temperature sensing means (221); e) generating, the control unit (102), a second working scheme, the second working scheme comprising a second equation for each stage, wherein the second equations represent the variation of the temperature of the first heat exchange element (201) as a function of time during each stage, wherein the second equation for each stage is calculated by fitting the model equation of the stage to the temperatures sensed in step d) by the first temperature sensing means (221) during the course of the stage; wherein the fitting is performed by adjusting one or more of the at least one adjustable parameter; f) returning, by the control unit (102), the second working scheme as the optimum working scheme of the freeze-drying cycle.

[0498] Clause 15.- The computer-implemented method according to Clause 14, wherein the model equation of each stage is:

[0499] - a generalized logistic function model;

[0500] - a 5-parameter logistic regression function model;

[0501] - a quadratic polynomial equation model;

[0502] - a cubic polynomial equation model; or - a quartic polynomial equation model.

Claims

CLAIMS1.- A sample heat exchanger module (200) for a freeze-dryer system (100), the sample heat exchanger module (200) comprising:• a first heat exchange element (201) made of thermally conductive material, the first heat exchange element (201) comprising: a top surface (202); a plurality of straight passages (203, 204, 205) extending in different directions through the first heat exchange element (201), the passages being parallel to the top surface (202) and intersecting at the interior of the first heat exchange element (201);• a first cold source (206) comprising a cold end (207) with a maximum efficiency zone (208) that is in thermal contact with the first heat exchange element(201);• a first heat source (209) comprising a maximum efficiency zone (210) in thermal contact with the first heat exchange element (201); wherein the straight passages (203, 204, 205) are arranged between the top surface (202) and the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209), and wherein the first cold source (206) and the first heat source (209) are controllable by a control unit (102) to decrease or increase the temperature of the first heat exchange element (201).2.- The sample heat exchanger module (200) according to claim 1 , wherein the first heat exchange element (201) comprises:• a first inner plane (211) being spaced from and parallel to the top surface(202);• a second inner plane (212) being spaced from and parallel to the top surface (202), wherein the first inner plane (211) is arranged between the top surface (202) and the second inner plane (212), and wherein the second inner plane (212): is contiguous to the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209), orpasses through the maximum efficiency zones (208, 210) of the first cold source (206) and the first heat source (209), preferably through the centre of the maximum efficiency zone (208) of the first cold source (206) and through the centre of the maximum efficiency zone (210) of the first heat source (209);• a top portion (213) defined between the top surface (202) and the second inner plane (212), wherein the top portion (213) has a vertical axis of symmetry (214) and a plurality of vertical planes of symmetry (215), wherein each of the vertical planes of symmetry (215): contains the vertical axis of symmetry (214); divides the top portion (213) in two halves that are substantially equal in shape and size; and intersects the first inner plane (211) in an intersection line; wherein each straight passage (203, 204, 205) extends along a different intersection line.3.- The sample heat exchanger module (200) according to the preceding claim, wherein- the distance between the top surface (202) and the first inner plane (211) is Hi;- the distance between the second inner plane (212) and the first inner plane (211) is H2and- the distancesand H2comply the following relation:0.44.- The sample heat exchanger module (200) according to any of claims 2 or 3, wherein the height h of each straight passage (203, 204, 205) complies the following relation:(W, * 0.5) > h > 0 whereinis the distance between the top surface (202) and the first inner plane (211).5.- The sample heat exchanger module (200) according to any of claims 2-4, wherein the width w of each straight passage (203, 204, 205) complies the following relation:wherein: is the distance between the top surface (202) and the first inner plane (211);H2is the distance between the second inner plane (212) and the first inner plane (211); andL is the maximum length of the top surface (202) in a direction perpendicular to the vertical plane of symmetry (215) that contains the intersection line along which the straight passage (203, 204, 205) extends.6.- The sample heat exchanger module (200) according to any of the preceding claims, wherein the first heat source (209) comprises a plurality of heating elements, each heating element having a maximum efficiency zone.7.- The sample heat exchanger module (200) according to the preceding claim, wherein the maximum efficiency zones of the plurality of heating elements of the first heat source (209) are distributed around, and equidistant from, the maximum efficiency zone of the first cold source (206).8.- The sample heat exchanger module (200) according to the preceding claim, wherein the heating elements of the first heat source (209) are evenly distributed around the maximum efficiency zone of the first cold source (206).9.- The sample heat exchanger module (200) according to any of claims 6-8, wherein:- the maximum efficiency zone of the first cold source (206) and the maximum efficiency zones of the heating elements of the first heat source (209) are aligned with a vertical plane of symmetry; and / or- the maximum efficiency zone of the first cold source (206) is aligned with a vertical axis of symmetry; and / or- the maximum efficiency zones of the heating elements of the first heat source (209) are placed equidistantly with respect to the vertical axis of symmetry.10.- The sample heat exchanger module (200) according to any of the preceding claims, wherein the first heat exchange element (201) has a bottom surface (217) and comprises a plurality of indentations open at the bottom surface (217), wherein theindentations are configured to receive, at least, the maximum efficiency zone of the first cold source (206) and the maximum efficiency zone of the first heat source (209).11.- The sample heat exchanger module (200) according to any of the preceding claims and claim 6, wherein the first heat exchange element (201) has a bottom surface (217) and comprises a plurality of indentations (216) open at the bottom surface (217); wherein the indentations are configured to receive, at least, the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zones (210) of the plurality of heating elements of the first heat source (209), and wherein:- each indentation (216) is aligned with a vertical plane of symmetry (215); and / or- the indentation configured to receive the maximum efficiency zone of the first cold source (206) is aligned with the vertical axis of symmetry (214); and / or- the indentations (216) configured to receive the maximum efficiency zones (210) of the heating elements of the first heat source (209) are placed equidistantly with respect to the vertical axis of symmetry (214).12.- The sample heat exchanger module (200) according to any of claims 1-10, wherein the first heat exchange element (201) has a bottom surface (217) and wherein the maximum efficiency zone (208) of the first cold source (206) and the maximum efficiency zone (210) of the first heat source (209) are arranged on said bottom surface (217), in thermal contact with said bottom surface (217).13.- The sample heat exchanger module (200) according to any of the preceding claims, wherein the first cold source (206) comprises at least one thermal link (225) and wherein the cold end of the first cold source (206) is located at the thermal link (225).14.- The sample heat exchanger module (200) according to any of the preceding claims, wherein the first heat source (209) comprises at least one thermal link (226) and wherein the maximum efficiency zone (210) of the first heat source (209) is located at the thermal link (226).15.- The sample heat exchanger module (200) according to any of the preceding claims, further comprising:• first temperature sensing means (221) for measuring the temperature of the first heat exchange element (201), the first temperature sensing means (221) being adapted to send said temperature to a control unit (102); and / or• second temperature sensing means (222) for measuring the temperature of the product (222) to be freeze-dried, the second temperature sensing means (222) being adapted to send said temperature to a control unit (102).16.- A freeze-dryer system (100) for the cryopreservation of products, the freeze-dryer system (100) comprising:• a freeze-drying chamber (103),• at least one sample heat exchanger module (200) according to any of the preceding claims attached to the freeze-drying chamber (103),• at least one condenser module (300) attached to the freeze-drying chamber (103), and• pressure reduction means (104) for reducing pressure inside the freeze-drying chamber (103).17.- The freeze-dryer system (100) according to claim 16, further comprising at least one sample receiving element (218), the at least one sample receiving element (218) being arrangeable in thermal contact with the top surface (202) of the first heat exchange element (201).18.- The freeze-dryer system (100) according to claim 16 or 17, wherein each of the at least one condenser module (300) comprises:• a second heat exchange element (301) made of a thermally conductive material and having a top surface (306), an opposed bottom portion (307), and a stepped cone-shape with a plurality of tiered sections along the height between the top surface (306) and the bottom portion (307), wherein each section has a different diameter; a second cold source (302) comprising a cold end (309) in thermal contact with the bottom portion (307) of the second heat exchange element (301), the second cold source (302) being controllable by a control unit (102);• a second heat source (303) in thermal contact with the bottom portion (307) of the second heat exchange element (301) and being controllable by a control unit (102); and• third temperature sensing means (304) for measuring the temperature of the second heat exchange element (301).19.- The freeze-dryer system (100) according to any of claims 16-18 further comprising a control unit (102) adapted to:- act on the first cold source (206) and / or the first heat source (209) of the at least one sample heat exchanger module (200) to decrease and / or increase the temperature of the first heat exchange element (201); and / or- act on the second cold source (302) and / or the second heat source (303) of the at least one condenser module (300) to decrease and / or increase the temperature of the second heat exchange element (301); and / or- act on the pressure reduction means (104) to reduce the pressure inside the freeze-drying chamber (103).20.- The freeze-dryer system (100) according to claim 19, wherein the control unit (102) is further adapted to:- receive and / or generate a working scheme of a freeze-drying cycle, wherein the working scheme comprises a plurality of equations, each equation representing the variation of the temperature of the product or of the first heat exchange element during the course of a stage of the freeze-drying cycle;- receive the sensed temperatures from the first temperature sensing means (221) and / or from the second temperature sensing means (222); and- depending on the sensed temperatures, act on the first cold source (206) and / or the first heat source (209) of the sample heat exchanger module (200) to comply with the equations of the working scheme.21 .- The freeze-dryer system (100) according to any of claims 19-20 further comprising pressure sensing means (101) for measuring the pressure inside the freeze-drying chamber (103), the pressure sensing means (101) being adapted to send the pressure measures to the control unit (102), and wherein the control unit (102) is further adapted to:- receive and / or generate a working scheme of a freeze-drying cycle, wherein the working scheme comprises a plurality of pressure equations, each pressure equation representing the variation of the pressure inside the freeze- drying chamber (103) during the course of a stage of the freeze-drying cycle;- receive the sensed chamber pressure from the pressure sensing means (101); and- depending on the sensed chamber pressure, act on the pressure reduction means (104) to comply with the pressure equations of the working scheme.22.- A computer-implemented method for determining an optimum working scheme of a freeze-drying cycle using the system (100) of any of claims 19-21 , said method comprising the following steps: a) receiving, the control unit (102), input data, the input data comprising the number of different stages of the freeze-drying cycle to be included in the optimum working scheme and the following parameters for each stage:• a target temperature setpoint to be reached by the product to be freeze-dried during the stage;• the time to hold the target temperature setpoint once reached; and• a maximum product temperature change rate; b) receiving, the sample heat exchanger module (200), at least one sample container that comprises a sample of the product; c) generating, the control unit (102), a first working scheme of the freeze-drying cycle, the first working scheme comprising a first equation for each stage, the first equations representing the variation of the product temperature as a function of time during each stage; wherein the first equation for each stage is created by the control unit (102) based on the parameters of said stage and on a model equation that provides an expected temperature as a function of time, the model equation comprising at least one adjustable parameter; d) performing a first freeze-drying cycle, and during the first freeze-drying cycle:- receiving, the control unit (102), sensed temperatures of the product from the second temperature sensing means (222); and depending on the sensed temperatures of the product, acting on the first cold source (206) and / or the first heat source (209) of the sample heat exchanger module (200) to comply with the first working scheme; and- receiving, the control unit (102), sensed temperatures from the first temperature sensing means (221); e) generating, the control unit (102), a second working scheme, the second working scheme comprising a second equation for each stage, wherein the second equations represent the variation of the temperature of the first heat exchange element (201) as a function of time during each stage, wherein the second equation for each stage is calculated by fitting the model equation of the stage to the temperatures sensed in step d) by the first temperature sensing means (221) during the course of the stage; wherein the fitting is performed by adjusting one or more of the at least one adjustable parameter; f) returning, by the control unit (102), the second working scheme as the optimum working scheme of the freeze-drying cycle.23.- The computer-implemented method according to claim 22, wherein the model equation of each stage is:- a generalized logistic function model;- a 5-parameter logistic regression function model;- a quadratic polynomial equation model;- a cubic polynomial equation model; or- a quartic polynomial equation model.

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