Method for controlling af freeze-drying process and freeze drying apparatus suited therefor

Abstract

A method for controlling a freeze-drying process in a freeze-drying apparatus (1) comprising a drying chamber (10) containing a material (101) to be dried, a condenser chamber (20) comprising a condenser (201) connected to a vacuum device (40) and fluidly connected to the drying chamber through a path (30) having a flow area available for fluid flow through the path (30), the freeze-drying apparatus having a device (301) for controlling the flow area of the path, and the drying chamber (10) comprising an inert gas inlet (50) for supplying an inert gas to the drying chamber (10). The method comprises obtaining (1001) a sequence of pressure set-points (p Cha,SP,i ) of the freeze-drying process, controlling (1002) a chamber pressure (p Cha,PV ) of the drying chamber (10) according to the sequence of pressure set-points (p Cha,SP,i ) by manipulating at least one of the device (301) for controlling the flow area of the path (30) and the inert gas inlet (50) to control the supply of inert gas to the drying chamber (10), and controlling (1003) a temperature (T Con,PV ) of the condenser (201) as a function of the sequence of pressure set-points (p Cha,SP,i ) to maintain a target temperature (T Con,SP,i ).

Description

[0001] Method for controlling af freeze-drying process and freeze drying apparatus suited therefor The present invention relates to a method for controlling a freeze-drying apparatus. In particular, it relates to freeze-drying apparatuses comprising a drying chamber containing a material to be dried by removal of a substance through subli- mation, a condenser chamber comprising a condenser and connected to a vacuumdevice, which condenser chamber is fluidly connected to the drying chamberthrough a path having a flow area available for fluid flow through the path, and to a method for controlling a freeze-drying process in such a freeze-drying apparatus. Most often, the substance to be removed is H2O. Background Freeze-drying is a process for drying a product without having liquid pre- sent. The drying takes place at temperatures and pressures below the triple point of the substance to be removed to avoid having liquid present. This requires a low product temperature, which gives relative slow drying rates but prevents heat dam- age of the product. To keep the drying process running and the product below the triple point, a constant removal of gases is needed as well as a constant heat inputto the product. Heat is supplied to product through heated product shelves. Thesublimated gases are removed by deposition as solid on cooled pipes and any resid- ual non-condensable gases are removed by a vacuum pump. A typical application of freeze-drying is to dry food, nutraceutical, or pharmaceutical products where H2O is the substance to be removed, but freeze-drying can also be used for other products and to remove other liquids. The terminology in the following will assume H2O is the substance to be dried away. On a general level freeze-drying involves four steps: Freezing the product, loading the frozen product onto suitable trays or into suitable containers (or vice versa) and into a freeze-dryer, typically on a trolley carrying the trays or for GMPreasons via an automatic loading system, drying the product at reduced pressure inthe freeze-dyer, and unloading the dried product. The drying process in the freeze- dryer involves evacuating the drying chamber by a vacuum pump to below the tri- ple-point and supplying heat for the phase transition (heat of sublimation). To han- dle the vapor generated in the drying chamber, condensers (vapor traps) are ar- ranged between the vacuum pump and drying chamber, to condense / deposit the vapor by cooling. The condenser should condense substantially all the vapor and prevent vapour from entering the vacuum pump. The condenser has a critical role in the freeze-drying process and represents a significant portion of the operational cost due to cooling / refrigeration duty. The condenser temperature needs to have at a temperature sufficient for the vapour condense / deposit at the prevailing conditions at the condenser. This means the condenser temperature needs to be below the product temperature. During operation of a freeze-drying process, ice formation on the condenser and potentially uneven vapour distribution around the condenser hinders efficient use of the condenser. In addition, a low condenser temperature leads to a pressure differential between material to be dried and the condenser, promoting continuous sublimation by removing vapor and preventing pressure build-up around product. In practice, this has led to freeze drying processes where the condenser is operated at very low temperatures, for instance -70 °C or lower, especially for freeze-drying pharmaceutical products. Maintaining these low tem- peratures leads to high refrigeration energy costs for the freeze-drying process. Presence of non-condensable gases, like air or nitrogen, will reduce the vapor cap-ture efficiency of the condenser coils because steam becomes diluted around thecoils. In more detail, a freeze-drying process does not generally maintain a fixed set of conditions throughout the process, where conditions in this context refers to for example drying chamber pressure and shelf temperature. Rather a freeze-drying apparatus involves a sequence of phases, e.g., primary drying and secondary drying, having different conditions. In addition, each of these phases may involve a se- quence of changing conditions. The sequence of conditions for a given freeze-drying process is sometimes referred to as a recipe. The recipe is designed provide a freeze- dried product with the desired characteristics, e.g., by observing temperature con- straints of the product. In addition, optimizing the recipe also has the potential to shorten processing time to increase productivity, as is described in Bano et al (2020), Ind. Eng. Chem. Res.2020, 59, 5056−5071. These recipes are typically provided as a pre-defined sequence of conditions for a particular material to freeze-dried, but re- cently there has also been an interest in developing dynamic recipes, wherein the sequence of conditions is optimized online based on process measurements, to op- timize processing times. Afreeze-drying recipe typically includes a sequence of set-points for thedrying chamber pressure and the shelf-temperature. The latter is typically controlled by way of a heating fluid exchanging heat with the shelfs in the drying chamber. The drying chamber pressure is affected by several factors, incl. the vacuum pump which evacuates the condenser, and the condenser coils which remove sublimated vapour to prevent pressure build up. US3077036 proposes to control the drying chamber pressure as a function of the temperature of the material being dried, by varying the surface temperature of the condenser or alternatively by throttling the communica- tion between the drying chamber and the condenser. More recently the typical means of controlling the drying chamber pres-sure to its set-points, has been by way of an inert gas supply to the drying chamber.The inert gas is typically nitrogen, and the supply provides a reliable means of achieving the desired drying chamber pressure, supplying inert gas to increase the pressure, and stopping the supply to lower pressure. This method has worked well, but there is an ever-increasing focus improving the energy efficiency of freeze-drying process. Accordingly, an object of the invention is to provide an improved method for controlling freeze-drying processes, in particular to increase energy efficiency and to ensure low energy usage without reducing capacity or compromising product quality. Summary of the Invention These and further objects of the invention are achieved by a method for controlling a freeze-drying process in a freeze-drying apparatus, which freeze-drying apparatus comprises a drying chamber containing a material to be dried by removal of a substance, a condenser chamber comprising a condenser and connected to a vacuum device, which condenser chamber is fluidly connected to the drying cham- ber through a path having a flow area available for fluid flow through the path, the freeze-drying apparatus having a device for controlling the flow area of the path and the drying chamber comprising an inert gas inlet for supplying an inert gas to the drying chamber, which method comprises the steps of -obtaining a sequence of pressure set-points, pCha,SP,i, of the freeze-dryingprocess, -controlling a chamber pressure, pCha,PV, of the drying chamber accordingto the sequence of pressure set-points, pCha,SP,i, by manipulating at least one of the device for controlling the flow area of the path and the inert gas inlet to control the supply of inert gas to the drying chamber, and -controlling a temperature, TCon,PV, of the condenser as a function of thesequence of pressure set-points, pCha,SP,i, to maintain a target temperature, TCon,SP,i, where the target temperature, TCon,SP,i, is lower than an equivalent satura-tion temperature TCha,SP,i, of the frozen liquid, solid or ice to be removed from thematerial at a condenser pressure, pCon,SP,i, being lower than the pressure set-point, pCha,SP,i. By controlling the condenser temperature according to the sequence ofpressure set points to maintain such a target temperature, an overall increase incondenser temperature is achieved, compared to the prior art method using a fixed low condenser temperature. In this way, the refrigeration cost of the process is re- duced and thus the energy efficiency is increased. However, controlling the conden- ser temperature in isolation provides inferior control of the pressure and thus of the condenser as the condenser is a slow acting manipulator of the drying chamberpressure. The invention thus combines control of condenser temperature with thecontrol of the drying chamber by the means of manipulating the flow area in the path between drying chamber and the condenser chamber and / or by manipulating the inert gas inlet to control and minimize the supply of inert gas to the drying chamber. This control strategy provides a freeze-drying process with good control the freeze-drying process (tracking of set-points) while also reducing energy costs. Itwas found that using the means for controlling the flow area in the path to controlthe drying chamber pressure improved the feasibility of maintaining the tempera- ture difference compared to using an inert gas supply or condenser temperature tocontrol the drying chamber pressure. When using the inert gas supply, a lower con-denser temperature was required. Investigations revealed that the inert gas inhibit- ed effective utilization of the condenser. The inhibition was likely due to local accu- mulation of inert gas in the condenser chamber and dilution of the gas, hindering effective use of the condenser and thus necessitating reduced condenser tempera- tures. Nevertheless, a small amount of inert gas may still be needed for optimization purposes. Thereby, it becomes possible to operate the freeze dryer in a manner that keep refrigeration energy costs very low, and possibly even as low as physically and practically possible, while ensuring the same product quality as with conventional operation mode. The solution achieves energy efficiency by not making the conden- ser coils any colder than necessary but also by limiting the amount of non- condensable gases used to regulate and control chamber pressure. By generally increasing the condenser temperature, the traditionally used compressor cooling with HFC refrigerants and / or liquid nitrogen can also be largely replaced by a compressor with carbon dioxide and / or air cooling, which operates in accordance with the Brayton cycle, in favor of a hybrid system. This in turn provides for a simpler and more efficient system. Further, less cooling power is needed, and thereby less liquid nitrogen and / or electrical energy is needed. This saves power, energy, and costs. In some freeze-drying apparatuses, the configuration of the means for con- trolling the flow area of the path may not be able to achieve the pressure set point with sufficient low tolerance by itself in the drying chamber, in which case the inert gas inlet can be used as a supplemental means for controlling the chamber pressure. This may be the situation if the means for controlling the flow area of the path is close to its extreme positions (fully open or fully closed), where mechanical limita- tions and tolerances of a particular freeze-drying apparatus may prove a hindrance for precise control of the chamber pressure. This could be the case, if the method is used in an existing freeze-drying apparatus, where the means for controlling the flow area of the fluid path was not designed for continuous control of its position throughout its range of motion. Therefore, the drying chamber further comprises an inert gas inlet for sup- plying an inert gas to the drying chamber, and the step of controlling the drying chamber pressure, pCha,PV, may further comprise manipulating the inert gas inlet to control the supply of inert gas to the drying chamber. Thereby, a further way of controlling the drying chamber pressure, pCha,PV, becomes possible, which in turn provides for an even more precise freeze-drying process control. The inert gas is most often nitrogen (N2) which is a relatively cheap and readily available option. Other inert gases, such as a suitable noble gas, e.g., argon (Ar), or pharmaceutical air, may also be used. With such a method there is provided a way to obtain dynamic control of chamber pressure by dynamically and simultaneously regulate to maximize conden- ser temperature and minimize amount of communication throttling while at the same time dynamically minimize the amount of injected non-condensable gases, preferably to zero. Combined, these control strategies ensure a very high energy efficiency without reducing equipment capacity or product quality because recipe set-points are satisfied always. The condenser pressure, pCon,SP,i, may be lower than the pressure set point, pCha,SP,i, by a predefined pressure difference, ∆pSP,i, wherein the predefined pressure difference, ∆pSP,i, is defined as ∆pSP,i = pCha,SP,i*∆pfactor, where ∆pfactor is a factor being between 0 and 1. Alternatively, the predefined pressure difference, ∆pSP,i, is definedby a pressure difference derived from a calculated temperature difference, ΔTSP,between the equivalent saturation temperature, TCha,SP,i, at the pressure set point, pCha,SP,i, and the temperature, TCon,SP,i, of the condenser, that is ∆pSP,i= pCha,SP,i- pCon,SP,i. Thereby, it is ensured that pressure difference and thus a flow of gas be- tween the drying chamber and the condenser chamber is upheld, such that the dry- ing process is not slowed down or does not stop inadvertently. The factor, ∆pfactor, may be below 0.9, below 0.7, or below 0.5. The step of controlling the temperature, TCon,PV, of the condenser may comprise controlling the temperature, TCon,PV, of the condenser to maintain a calcu- lated temperature difference, ΔTSP, to the equivalent saturation temperature, TCha,SP,i, such that the target temperature, TCon,SP,i, is lower than the equivalent satu- ration temperature, TCha,SP,i. Thereby, a method is provided with which an even more efficient system may be obtained. Further, even less cooling power is needed. This saves even more power, energy, and costs. The step of controlling the chamber pressure, pCha,PV, by manipulating at least one of the device for controlling the flow area of the path and the inert gas inlet to control the supply of inert gas to the drying chamber, that is by using flow path throttling and / or nitrogen inflow rate control, and the step of controlling the temperature, TCon,PV, of the condenser may be performed concurrently. Thereby, a more precise control, and thus a more efficient and precise freeze-drying process is provided for. The temperature difference, ΔTSP, may be 20 K or less, 5 to 15 K, 7.5 to 12 K, 10 K or less, or 5 to 10 K. Keeping the temperature difference, ΔTSP, as low as possible provides for an optimization of the operation of the freeze-drying apparatus and thus the freeze- drying process. Consequently, a further increased efficiency is obtained. At least the step of controlling the chamber pressure, pCha,PV, of the drying chamber and the step of controlling the temperature, TCon,PV, of the condenser may be performed by any one of an optimization routine, a proportional integral derivative, PID, controller, a fuzzy logic, and a machine learning device. Thereby a a further increased efficiency of the method is or may be obtained. Manipulating at least the device for controlling the flow area of the path may further comprise, during the freeze-drying process, determining a set inflow of inert gas, FIGSP, into the drying chamber, a minimum inflow of inert gas FIGSPmininto the drying chamber, an actual pressure difference, ∆pPV, between an actual meas- ured pressure, pCha,PVin the drying chamber and an actual measured pressure,pCon,PV, in the condenser chamber, where ∆pPV = pCha,PV - pCon,PV, and a maximum al-lowed relative pressure difference, ∆pmax, between the actual measured pressure, pCha,PV, in the drying chamber and the actual measured pressure, pCon,PV, in the con- denser chamber, where ∆pmax = pCha,SP,i*∆pfactor,max, where ∆pfactor,max is a maximum value for a factor ∆pfactor, and where ∆pfactoris a factor being between 0 and 1, and, ifdetermining that FIGSP > FIGSPmin and ∆pPV < ∆pmax, reducing a set position, Lset, of thedevice for controlling the flow area of the path and, if determining that FIGSP ≤ FIGSPminor ∆pPV ≥ ∆pmax, increasing the set position, Lset,.Thereby, a particularly efficient and precise control of the supply of inert gas to the drying chamber, and thus of controlling the drying chamber pressure, is provided for. This will reduce the consumption of the inert gas. The set position, Lset, may be increased by ramping up or by increasing theset position stepwise or in increments. Likewise, the set position, Lset, may be de-creased by ramping down or by decreasing the set position stepwise or in incre- ments. Manipulating at least the device for controlling the flow area of the path may comprise, at the beginning of the freeze-drying process, moving the device forcontrolling the flow area of the path to a set position, Lset, being equal to a maximalset position, Lmax. Thereby, the flow area is maximized, which in turn allows for evacuating the drying chamber to the desired initial drying chamber pressure in a particularly fast and efficient manner. Manipulating at least the device for controlling the flow area of the path may comprise, during the freeze-drying process, determining, an actual pressuredifference, ∆pPV, between an actual measured pressure, pCha,PV in the drying cham-ber and an actual measured pressure, pCon,PV, in the condenser chamber, where ∆pPV= pCha,PV - pCon,PV, and a maximum allowed relative pressure difference, ∆pmax, be-tween the actual measured pressure, pCha,PV, in the drying chamber and the actual measured pressure, pCon,PV, in the condenser chamber, where ∆pmax= pCha,SP,i*∆pfactor,max, where ∆pfactor,maxis a maximum value for a factor ∆pfactor, and where ∆pfactoris a factor being between 0 and 1,, and, if determining that ∆pPV<∆pmax, reducing the set position, Lset, and, if determining that ∆pPV ≥ ∆pmax, increasingthe set position, Lset.Alternatively, manipulating at least the device for controlling the flow areaof the path may comprise measuring the actual pressure difference, ∆pPV, betweenan actual measured pressure, pCha,PV in the drying chamber and an actual measuredpressure, pCon,PV, in the condenser chamber, where ∆pPV = pCha,PV - pCon,PV, by using asuitable sensor device or other measurement device, and, based on the measure- ment manipulating the device for controlling the flow area of the path by using a controller, such as for instance a PID controller. Thereby, it may be ensured continuously that the actual pressure difference, ∆pPV, is, at all times during the drying process, kept within the maximum allowed relative pressure difference, ∆pmax. Thereby, a more precise freeze-drying process and thus resulting freeze-dried material is obtained. The maximum allowed relative pressure difference, ∆pmax, between the actual measured pressure, pCha,PV, in the drying chamber and the actual measured pressure, pCon,PV, in the condenser cham- ber may be given by a recipe for freeze-drying a specific material to be dried. The step of obtaining the sequence of the pressure set-points, pCha,SP,i, maycomprise providing a pre-defined sequence of pressure set-points, pCha,SP,i, for the freeze-drying process. Such a pre-defined sequence for the freeze-drying process may for instancebe given by a recipe for freeze-drying a specific material to be dried. Thereby, it is ensured that the relevant recipe is kept to throughout the freeze-drying process, which in turn ensures that a freeze-dried product or material of sufficiently high quality to fulfill the relevant standards is obtained. The step of obtaining the sequence of the pressure set-points, pCha,SP,i, may comprise dynamically determining the pressure set-points, pCha,SP,i, during the freeze-drying process by an optimization routine. Thereby, it is ensured that the relevant recipe is kept to throughout the freeze-drying process, which in turn ensures that a freeze-dried product or material of sufficiently high quality to fulfill the relevant standards is obtained. The path between the drying chamber and condenser chamber comprisesa longitudinal axis, L, extending along the path between the drying chamber and condenser chamber, and the device for controlling the flow area of the path may be configured to be displaceable in a direction being parallel with the longitudinal axis, L. Thereby, the construction of the device for controlling the area of the flow path and of the control system may be simpler and more robust. Furthermore, more easy and precise control of the area of the flow path and thus also the pressure or pressure change may be obtained. The drying chamber comprises a plurality of shelves configured for receiv- ing the material to be dried, and the step of controlling a temperature, TCon,PV, of the condenser may comprise controlling the temperature, TCon,PV, of the condenser to be lower than a temperature, TShelve,PV, of the shelves. Thereby, it becomes possible to omit the otherwise necessary dynamic cooling of the condenser to keep the condenser temperature, TCon,PV, sufficientlylow. This in turn saves cooling power and thus energy, both to initial cooling andcolling during the freeze-drying process. The method may further comprise determining if the drying chamber pres- sure, pcha,PV, reaches a predetermined maximal pressure, pmax-x, and if the drying chamber pressure reaches the predetermined maximal pressure, pmax-x, initiating an emergency cooling procedure in which at least one of the following is carried out: the condenser is set to emergency cooling, and the device for controlling the flow area of the path is triggered to open ful- ly, i.e., to move to the maximal set position, Lmax. Thereby, overheating and / or over-pressurizing of the drying chamber andits contents, especially the material to be dried, may be avoided in a simple and effi-cient manner. The flow area may be defined as the free area between the device for con- trolling the flow area of the path and a wall of the freeze-drying apparatus, particu- larly a wall of the path, over which a free flow of gas between the drying chamber and the condenser chamber may occur. The device for controlling the flow area of the path may comprise a first surface facing the drying chamber and second surface facing the condenser cham-ber, the first surface being convex or flat, and the second surface being convex orflat. Thereby, a particularly simple device for controlling the flow area of the path may be provided for, while especially ensuring a tight closure of the path when the device for controlling the flow area of the path is in its closed position (Lset = 0 %). The device for controlling the flow area of the path may be a valve, such as a mushroom valve or a butterfly valve. Such valves are advantageous since they are simple of construction and easy to move with a high degree of precision or low tolerance. The sequence of pressure set-points, pCha,SP,i, of the freeze-drying process may be a sequence of pressure set-points for the pressure prevailing in the drying chamber. The material to be freeze-dried may be a pharmaceutical composition. The invention further relates to a freeze-drying apparatus comprising a dry- ing chamber for containing a material to be dried by removal of a substance, a con- denser chamber comprising a condenser and connected to a vacuum means, which condenser chamber is fluidly connected to the drying chamber through a path hav- ing a flow area available for fluid flow through the path, the freeze-drying apparatus having a device for controlling the flow area of the path, , and the drying chamber having an inert gas inlet for supplying an inert gas to the drying chamber, the freeze- drying apparatus further comprising a control system, the control system being con- figured to control to the device for controlling the flow area of the path and to con- trol a temperature of the condenser and to control the inert gas inlet for supplying an inert gas to the drying chamber, which control system comprises a data processor and a memory with executable code enabling the data processor to, when executingthe executable code, cause the control system to perform a method according to theinvention. The invention further relates to a non-transient computer-readable storage medium comprising executable code, which code, when executed by a data proces- sor operatively connected to a freeze-drying apparatus, causes the freeze-drying apparatus to perform a method according to the invention. Brief Description of the Drawings Fig.1 shows a schematic, cross-sectional view of a freeze-drying apparatus according to the invention. Fig.2 shows a schematic, cross-sectional view of another freeze-drying ap- paratus according to the invention. Fig.3 shows an enlarged, schematic, cross-sectional view of the detail III of the freeze-drying apparatus according to Fig.2. Fig.4 shows an example of the link between saturation pressure and satu- ration temperature where numbers are representative of the solid-gas interphase of H2O. Fig.5 shows a flow diagram illustrating steps of a method according to the invention.Figs. 6A, 6B and 7 show flow diagrams illustrating further steps of a methodaccording to the invention. Fig.8 shows a graph illustrating the shelf temperature, the condenser tem- perature, and the drying chamber pressure, respectively, as a function of time dur- ing a conventional freeze drying process. Fig.9 shows a graph illustrating the shelf temperature, the condenser tem- perature, and the drying chamber pressure, respectively, as a function of time dur- ing a freeze drying process and using a condenser temperature set point, TConSet, be- ing below the drying chamber temperature by Tcc= 5 K and a device for controlling the flow area of the path being fully open, i.e., open by Lset= 100 %, at all times. Fig. 10 shows a graph illustrating the shelf temperature, the condenser temperature, and the drying chamber pressure, respectively, as a function of time during a freeze drying process according to the invention and using a condenser temperature set point, TConSet, being below the drying chamber temperature by Tcc=10 K and a device for controlling the flow area of the path being dynamically open bybetween 10 and 50 %, i.e.10 % ≤ Lset≤ 50 %. Detailed Description Fig.1 shows a schematic, cross-sectional view of a freeze-drying apparatus1 according to the invention. Fig. 2 shows further details of the freeze-drying appa-ratus 1 according to the invention. Generally, the freeze-drying apparatus 1 comprises a drying chamber 10, a condenser chamber 20 and a flow path 30 extending between and connecting the drying chamber 10 and the condenser chamber 20. The flow path 30 further com- prises a longitudinal axis L as shown on Fig.1. The drying chamber 10 contains a material 101 to be dried by removal of a substance. The substance to be removed may often be H2O but can be other sub-stances. Referring now to Fig. 2, the drying chamber 10 further comprises a pluralityof shelves 102. The material 101 to be dried is placed on the shelves 102. The drying chamber 10 may further comprise a drain 103. The drying chamber 10 further com- prises an inert gas inlet 50 for supplying an inert gas to the drying chamber 10. The inert gas is non-condensable at typical minimum condenser coil temperatures. The inert gas may for instance be nitrogen (N2) that has a boiling point at - 196 °C. The inert gas inlet 50 comprises an inlet valve 51 configured to control the inflow of inert gas. The drying chamber 10 further comprises a system 60 configured for cooling and heating the shelves 102. The material 101 may in principle be any feasible material which it is de- sired to freeze-dry. For instance, the material 101 is or comprises a pharmaceutical composition. The material 101 may be provided in vials or other suitable recepta- cles. The material 101 may be provided in a solution, where the solvent for instance may be water, ethanol, or butanol. The condenser chamber 20 comprises a condenser 201 with an actively cooled surface to deposit and collect the substance to be removed. The cooled sur- face is typically shaped as cooled hollow tubes. The hollow tubes allow the flow of an internal cooling fluid. The condenser chamber 20 may further comprise a drain 202. The condenser chamber 20 is connected to a vacuum device 40. The vacuum device 40 is configured to evacuate the condenser chamber 20 and through the flowpath 30 also the drying chamber 10. The cooled surfaces of the condenser 201 isfurthermore connected to a cooling device 70. The cooling device 70 is configured to cool the condenser 201. To this end the cooling device 70 supplies a coolant, such as liquid nitrogen, LN2, through an inlet 71 and circulates the coolant through a circuit and back out through an outlet 72. The condenser chamber 20 is fluidly connected to the drying chamber 10 through the flow path 30 (also simply denoted path 30). The path 30 comprises a flow area available for fluid flow through the path 30. The freeze-drying apparatus 1 further comprises a device 301 configured to control the flow area of the path 30. The device 301 is shown in further detail in Fig. 3. The device 301 for controlling the flow area of the path 30 is configured to be dis- placeable in a direction being parallel with the longitudinal axis L of the path 30 be- tween the drying chamber 20 and condenser chamber 10, cf. the arrow 307 and the exemplary displaced device 301a shown with dotted lines in Fig. 3. The flow area may be defined as the free area between the device 301 and the wall of the freeze- drying device 1 over which a free flow of gas between the drying chamber 10 and the condenser chamber 20 may occur. More specifically, the flow area may be de- fined as the free area between the device 301 and the wall of the freeze-drying de- vice 1 at the transition between the path 30 and the condenser chamber 20 as shown by the dashed lines A in Fig.3. The device 301 for controlling the flow area of the path may be a valve. Insuch a case the device 301 comprises a valve stem 303 and a valve body 304 – cf.Figs.2 and 3. Suitable types of valves comprise a mushroom valve (cf. Figs.2 and 3), and a butterfly valve (cf. Fig.1). The device 301 for controlling the flow area A of the path 30 may be hydraulically actuated or electrically actuated. As shown in Fig. 3, the valve comprises a convex surface 305 facing the drying chamber 10 and an op- posite flat surface 306 facing the condenser chamber 20. It is also feasible that both surfaces 305 and 306 are convex or flat, or that the surface 305 is flat and the sur- face 306 is convex. In this case, the flow area may also be defined as the free areabetween the surface 305 of the device 301 facing the drying chamber 10 and thewall of the freeze-drying device 1 at the transition between the path 30 and the condenser chamber 20. The freeze-drying apparatus 1 further comprises a control system 302 (Fig.2). The control system 302 is configured to control to the device 301 for controllingthe flow area of the path to adjust the set point Lset. The control system is further configured to control the inert gas inlet 50 for supplying an inert gas to the dryingchamber. The control system 302 may be a hydraulically actuated control system oran electrically actuated control system. The control system 302 is connected to the device 301. If the device 301 is a valve, the control system 302 may be connected to the valve stem 303 of the device 301, or to an extension of the valve stem 303, as is shown schematically in Fig. 2. The control system 302 is further connected to the inert gas inlet 50. For instance, and as shown schematically in Fig.2, the control sys- tem 302 may be connected to the inlet valve 51 of the inert gas inlet 50, such as to a valve stem of the inlet valve 51, or to an extension of the valve stem of the inlet valve 51. The control system 302 is also connected to the cooling system 73, and to the shelve cooling / heating system 60 to control temperature levels and flow rates and the vacuum system 40. Generally, when freeze-drying a material 101, a recipe is followed. The pa- rameters used in the recipe depends on the specific material to be freeze-dried. The freeze-drying process is divided into phases, such as freezing, primary drying and secondary drying. In the freezing phase, the shelves 102 are cooled to a set temper- ature. In the primary drying and secondary drying phases, the actual freeze-drying takes place. The secondary drying phase is aimed at reaching the final desired prod- uct and residual moisture content. Each phase may contain one or several segments. Each segment is defined by a number of parameters, where the most important pa- rameters are the set temperature, Tshelve,SP, of the shelves 102, the set pressure, pCha,SP,i, in the drying chamber 20 and the segment length in minutes. In addition, a recipe comprises a recipe header, in which parameters are stored that are relevant for the entire process and not just for one segment. An exemplary parameter of theheader could be “ECO Mode yes / no”, defining whether the freeze-drying apparatus1 is to be operated in an eco-mode, such as one according to the invention, or in a conventional mode. Fig. 4 shows an exemplary saturation curve correlating gas pressure, psat,and ice temperature, Tsat, exactly at the surface of the ice. For the curve shown, theice is frozen water, H2O. It applies that psat, = f(Tsat) and that Tsat = g(psat). The third axis denotes volume, V, and also sown is the triple point, TP. It is common to charac- terize a freeze dryer 1 as having or running with a given temperature difference ΔTSP, which is defined in Fig. 4 as the difference in temperature between a given drying chamber pressure, pcha,PV, and the saturation curve. It applies that the freeze dryer 1 operates closed to ideal operation when the temperature difference ΔTSP is small. As is illustrated on Fig. 4, the derived temperature set point for the conden- ser, Tcon,SP,i, must be lower than the derived saturation temperature for the sub- stance, Tcha,SP,i, here frozen water, to force the substance to move from product to cooling surface in condenser and thereby dry the product as intended. Referring now to Fig.5, the general principles of controlling a freeze-drying process in a freeze-drying apparatus 1 as described above employing a method ac- cording to the invention will be described. In a first step 1001 a sequence of pressure set-points, pCha,SP,i, of the freeze- drying process is obtained. The sequence of pressure set-points, pCha,SP,i, are general- ly defined in a recipe for freeze-drying a given material 101. Obtaining the sequence of the pressure set-points, pCha,SP,i, may therefore comprise providing a pre-defined sequence, such as a recipe, for the freeze-drying process. Alternatively, obtaining the sequence of the pressure set-points, pCha,SP,i, may comprise dynamically deter- mining the pressure set-points, pCha,SP,i, during the freeze-drying process by an opti- mization routine. The sequence of pressure set-points, pCha,SP,i, generally defines the pressure desired to be obtained in the drying chamber 10 during the various stages for freeze-drying defining the freeze-drying process or defined in the recipe. The sequence of the pressure set-points, pCha,SP,i, may be used as an input to an optimiza- tion routine, a proportional integral derivative, PID, controller, a fuzzy logic, an AI device, or a machine learning device. For instance, the step 1001 of obtaining the sequence of the pressure set-points, pCha,SP,i, may further comprise using or feeding the sequence of the pressure set-points, pCha,SP,i, as an input to an optimization rou- tine, a PID controller, an AI device or a machine learning device. According to the method, the chamber pressure, pCha,PV, of the drying chamber 10 is then in a step 1002 controlled according to the sequence of pressure set-points, pCha,SP,i. The control is obtained by manipulating the device 301 for con-trolling the flow area of the path 30, thereby setting the flow area of the path 30.Alternatively, or additionally, the control is obtained by manipulating the inert gas inlet 50, thereby setting a flow rate of a supply of inert gas to the drying chamber 10. Further, in a step 1003, a temperature, TCon,PV, of the condenser 201 is con- trolled as a function of the sequence of pressure set-points, pCha,SP,i, to maintain a target temperature, TCon,SP,i. The target temperature, TCon,SP,i, is lower than the equivalent saturation temperature, TCha,SP,i, of the frozen liquid, solid or ice to be removed from the material 101 at a condenser pressure, pCon,SP, being lower than the pressure set-point, pCha,SP,i. The condenser pressure, pCon,SP, may for instance be lower than the pres- sure set point, pCha,SP,i, by a predefined pressure difference, ∆pSP,i. The predefined pressure difference ∆pSP,imay be defined as ∆pSP,i= pCha,SP,i*∆pfactor, where ∆pfactoris a factor being between 0 and 1. Alternatively, the predefined pressure difference ∆pSP,imay be defined by a pressure difference derived from a calculated tempera- ture difference, ΔTSP, between the equivalent saturation temperature, Tcha,SP,i, at the pressure set point, pcha,SP,i, and the temperature, Tcon,SP,i, of the condenser. That is,∆pSP,i = pCha,SP,i - pCon,SP,i. The predefined pressure difference factor, ∆pfactor, may bechosen such that it is below 0.9, below 0.7 or below 0.5. The calculated temperaturedifference, ΔTSP, may be 20 K or less, such as 5 to 15 K or 7.5 to 12 K, or 10 K or less,such as 5 to 10 K. In an approach, step 1002 is performed as described further above, that is by controlling the condenser pressure, pCon,PV, of the condenser chamber 20 accord- ing to the sequence of pressure set-points, pCha,SP,i. The step of controlling 1003 the temperature, TCon,PV, of the condenser 201 may then comprise controlling the tem- perature, TCon,PV, of the condenser 201 to maintain a calculated temperature differ- ence ΔTSPto the equivalent saturation temperature, TCha,SP,i, such that the target temperature, TCon,SP,i, of the condenser 201 is lower than the equivalent saturation temperature, TCha,SP,i. The temperature difference, ΔTSP, may be 20 K or less, such as 5 to 15 K or 7.5 to 12 K, or 10 K or less, such as 5 to 10 K. Step 1003 may generally also comprise controlling the temperature, TCon,PV, of the condenser 201 to be lower than a temperature, TShelve,PV, of the shelves 102. Steps 1002 and 1003 are performed for each freeze-drying phase and each segment of the respective phases defined in the recipe. For each freeze-drying phase and each segment of the respective phases defined in the recipe, the set pres- sure, pCha,SP,i, and the equivalent saturation temperature, TCha,SP,i, is kept for the de-fined time interval, for instance a number of seconds or minutes. Steps 1002 and1003 may be performed concurrently. Step 1004 shown in Fig.5 is an optional safety step to be discussed further below. Steps 1002 and 1003 may be performed manually, such as by a user ma- nipulating or setting the control device 302. Alternatively, steps 1002 and 1003 may be performed by an optimization routine, a PID controller, an AI device, or a ma-chine learning device. For instance, the optimization routine, the PID controller, theAI device or the machine learning device may employ a suitable machine learningalgorithm which is configured to receive the sequence of pressure set-points, pCha,SP,i, as an input and to control the chamber pressure, pCha,PV, of the drying cham-ber 10 according to the sequence of pressure set-points, pCha,SP,i, and manipulate thecondenser temperature, TCon,PV, the device 301 for controlling the flow area of the path 30 and the inert gas inlet 50 systematically and explore and learn from the re- sponse in the chamber pressure, pCha,PV, in relation to the chamber pressure set points, pCha,SP,i. The general objective of the control procedure or method according to the invention is to obtain a slow and crude regulation of the chamber pressure, Pcha,PV, using the derived temperature set point for the condenser 201, Tcond,SP,i, by perform- ing step 1003 and a fast and accurate regulation of the chamber pressure, Pcha,PV, using manipulation of the set point, Lset, of the device 301 and / or the input set point, FIGSP, for the flow rate of inert gas through the gas inlet 50 by performing step 1002. The classical approach within freeze drying is to obtain the necessary accu- rate regulation by manipulation of the input set point, FIGSP, for the flow rate of inert gas through the gas inlet 50. The classical approach manipulates the input set point, FIGSP, to minimize the difference between the actual chamber pressure, Pcha,PV, and the chamber pressure set point, Pcha,SP,i. In some embodiments of the present inven- tion the classical approach is still active. The method of the invention has as an ob- ject that manipulation of the set point, Lset, of the device 301 provides as much of the accurate regulation of the chamber pressure, Pcha,PV, as possible, while only the final fine tuning is provided by manipulation of the input set point, FIGSP, for the flow rate of inert gas through the gas inlet 50. Manipulating the device 301 for controlling the flow area of the path 30generally comprises moving the device 301 to a set position, Lset. The set position,Lset, indicates the degree of opening of the device 301 for controlling the flow areaof the path 30. The set position, Lset, is most often indicated in percent, and thus as a value between 0 % (fully closed) and 100 % (fully open), but may also be indicated in a length unit, such as mm or cm. Referring now to Figs.6A and 6B, different approaches for performing step 1002 will be described. Fig. 6A illustrates an approach in which both the set point, Lset, of the device 301 and the input set point, FIGSP, for the flow rate of inert gas through the gas inlet 50 are manipulated. Fig. 6B illustrates an approach in which only the set point, Lset, of the device 301 is manipulated. It is noted that the wording “step” is used for the sake of simplicity, while in practice at least steps 1002 and 1003, including the below described sub-steps of step 1002, may be performed in quick succession or even concurrently. Referring first to Fig. 6A, an approach in which both the set point, Lset, ofthe device 301 and the input set point, FIGSP, for the flow rate of inert gas through the gas inlet 50 are manipulated will be described. In this approach, step 1002 com- prises sub-steps 1002a-1002c. When manipulating the inert gas inlet 50 of the freeze-drying apparatus 1to control the supply of inert gas to the drying chamber 10, the manipulation will cause a set inflow of inert gas, FIGSP, into the drying chamber 10 to vary. Therefore, during the freeze-drying process and illustrated as sub-step 1002a in Fig. 6A, a set inflow of inert gas, FIGSP, into the drying chamber 10, and a minimum inflow of inert gas, FIGSPmin, into the drying chamber 10 are determined. Lset is manipulated according to an error or difference between an actual drying chamber pressure, pCha,PV, and the pressure set-point, pCha,SP,i. The manipula- tion can be proportional control, integral control, or proportional-integral control. Having an integral control component is preferred to avoid offsets. This manipula- tion can be supplemented by conditions on the pressure difference between drying chamber and condenser chamber, and conditions on the supply of inert gas if the method comprises manipulation of the inert gas supply 50. Therefore, during the freeze-drying process and illustrated as a sub-step 1002b in Fig. 6A, an actual pressure difference, ∆pPV, between the drying chamber 10 and the condenser chamber 20, and a maximum allowed relative pressure differ- ence, ∆pmax, between the drying chamber 10 and the condenser chamber 20 is de- termined in a step 1002b. ∆pmaxis given as pCha,SP,i*∆pfactor,max, where ∆pfactor,maxis a maximum value for a factor ∆pfactor, and where ∆pfactoris a factor being between 0 and 1. The actual pressure difference, ∆pPV, is defined as the pressure difference between an actual measured pressure, pCha,PV, in the drying chamber 10 and an ac- tual measured pressure, pCon,PV, in the condenser chamber 20. Based on the above described determined values, and as illustrated as a sub-step 1002c in Fig.6A, the set position, Lset, of the device 301 is decreased, suchas for instance ramped down or decreased stepwise, if it is determined that FIGSP >FIGSPmin and ∆pPV < ∆pmax, and the set position, Lset, of the device 301 is increased,such as for instance ramped up or increased stepwise, if it is determined that FIGSP≤ FIGSPmin or ∆pPV ≥ ∆pmax. When the actual measured pressure in the drying chamber, pCha,PV, equals the input absolute pressure set point, pCha,SP,i, the set position, Lset, ofthe device 301 is no longer manipulated, nor is the inflow of inert gas, FIGSP, into thedrying chamber 10. When the actual measured pressure in the drying chamber, pCha,PV, does not equal the input absolute pressure set point, pCha,SP,i, the set position, Lset, of the device 301 is manipulated. Referring now to Fig. 6B, an approach in which only the set point, Lset, ofthe device 301 is manipulated is disclosed. In this approach, step 1002 comprisessub-steps 1002d-1002f. At the beginning of the freeze-drying process, the device 301 may, as illus-trated as a sub-step 1002d be moved to a set position, Lset, being equal to a maximalset position, Lmax, to evacuate the drying chamber 10 to the desired initial pressure. The desired initial pressure is typically given as the first pressure set-point, pCha,SP,1, of the sequence of pressure set-points, pCha,SP,i, obtained in step 1001. The maximal set position, Lmax, generally corresponds to the device 301 being fully open. Again, Lset is manipulated according to an error or difference between an actual drying chamber pressure, pCha,PV, and the pressure set-point, pCha,SP,i. The ma- nipulation can be proportional control, integral control, or proportional-integral con-trol. Having an integral control component is preferred to avoid offsets. This ma-nipulation can be supplemented by conditions on the pressure difference between drying chamber and condenser chamber, and conditions on the supply of inert gas if the method comprises manipulation of the inert gas supply 50. Therefore, during the freeze-drying process and as illustrated as a sub-step 1002e in Fig. 6B, an actual pressure difference, ∆pPV, between the drying chamber 10 and the condenser chamber 20, and a maximum allowed relative pressure differ- ence, ∆pmax, between the drying chamber 10 and the condenser chamber 20 is de- termined. ∆pmaxis given as pCha,SP,i*∆pfactor,max, where ∆pfactor,maxis a maximum value for a factor ∆pfactor, and where ∆pfactoris a factor being between 0 and 1. The actual pressure difference, ∆pPV, is defined as the pressure difference between an actual measured pressure, pCha,PV, in the drying chamber 10 and an actual measured pres- sure, pCon,PV, in the condenser chamber 20. Based on the above described determined values, and as illustrated as a sub-step 1002f in Fig. 6B, the set position, Lset, of the device 301 is decreased, forinstance ramped down, if it is determined that ∆pPV < ∆pmax, and the set position,Lset, of the device 301 is increased, for instance ramped up, if it is determined that∆pPV ≥ ∆pmax. To decrease or ramp down the set position, Lset, of the device 301, the device 301 is moved towards it closed position such as to decrease the flow area ofthe path 30. To increase or ramp up the set position, Lset, of the device 301, the de-vice 301 is moved towards its fully open position such as to increase the flow area of the path 30. When the actual measured pressure in the drying chamber, pCha,PV, equals the input absolute pressure set point, pCha,SP,i, the set position, Lset, of the de-vice 301 is no longer manipulated, nor is the inflow of inert gas, FIGSP, into the dryingchamber 10. When the actual measured pressure in the drying chamber, pCha,PV, does not equal the input absolute pressure set point, pCha,SP,i, the set position, Lset, of the device 301 is manipulated. The method may further optionally comprise a safety mechanism. The safety mechanism comprises a step 1004 (Fig. 5) involving two sub-steps 1004a-b (Fig.7). In a first sub-step 1004a, the drying chamber pressure, pcha,PV, is monitored and it is determined if the drying chamber pressure, pcha,PV, reaches a predetermined maximal pressure, pmax-x. In a second sub-step 1004b, if it is determined that the drying chamber pressure reaches the predetermined maximal pressure, pmax-x, an emergency cooling procedure is initiated. The emergency cooling procedure may involve one or both of setting the condenser 201 to emergency cooling and trigger- ing the device 301 to open fully, that is triggering the device 301 to be moved to aset position, Lset, being equal to a maximal set position, Lmax.Example In the following an example of a freeze-drying process using a method and a freeze-drying apparatus 1 according to the present invention will be described. It is noted that the specific method and test recipe used for obtaining the measurements in this example was chosen since the measurements were made using laboratory scale equipment. In the present example the material 101 to be freeze-dried is mannitol 3 %. The solvent used in the freeze-drying process is water. A test recipe for freeze-drying 136 R10 vials each containing 5 ml of mannitol 3 % is shown in table 1.

[0002] Table 1 – Test Recipe for Mannitol 3 %StepPhase Segment Time (min) TemperaturePressure no. no. of shelves, in drying TShelve,SP (°C) chamber, pCha,SP,i (mbar)1 Loading 1 5 20.02 Freezing 1 80 -45.03 Freezing 2 100 -45.04 Primary Drying 1 5 -45.0 0.4005 Primary Drying 2 90 10.0 0.4006 Primary Drying 3 5 10.0 0.3007 Primary Drying 4 90 10.0 0.3008 Primary Drying 5 5 10.0 0.2009 Primary Drying 6 90 10.0 0.20010 Primary Drying 7 5 10.0 0.10011 Primary Drying 8 90 10.0 0.10012 Secondary Drying 1 30 40.0 0.05013 Secondary Drying 2 120 40.0 0.05014 Stopping Tempera- 1 10 20.0 0.050ture Referring to table 1, the freeze-drying process is initiated at step no 1. At steps no 2 and 3, the shelves 102 are frozen to the set temperature, here -45 °C. At step 4, the drying chamber 10 is evacuated to the first pressure set point, pCha,SP,1, here being 0.400 mbar, and the condenser is cooled to the condenser temperature set point, TConSet. The condenser temperature set point, TConSet, is used in this exam- ple as another way of expressing TCon,SP,i. Steps 4-11 is the primary drying process, PD, here comprising eight segments with a constant shelf temperature, Tshelve,SP, and gradually decreasing drying chamber pressure, pCha,SP,i, as defined in the recipe. Steps 12-13 is the secondary drying process, SD, here comprising two segments with a constant shelf temperature, Tshelve,SP, and a further decreased drying chamber pressure, pCha,SP,i. Finally, in step 14 the shelves are heated to a stopping tempera- ture, typically being room temperature, and the freeze-drying process is terminated. Calculation of the condenser temperature set pointThe condenser temperature set point, TConSet, for a given segment is calcu- lated based on three parameters, namely the actual drying chamber pressure, pcha,PV, the actual condenser pressure, pCon,PV, and the set drying chamber pressure, pCha,SP,i, for the segment. Furthermore, the condenser temperature set point, TConSet, is below the chamber temperature by at least a constant parameter, Tcc, which is chosen to be between 5 K and 20 K. In the present example, Tccis chosen to be 10 K. The set drying chamber pressure, pCha,SP,i, of the segment is given in therecipe. The set drying chamber pressure, pCha,SP,i, of the segment is converted into a drying chamber temperature, Tcha,SP,i, using tabulated values or an algorithm suitable for the solvent used in the process, in the present case water. This algorithm is a mathematical function configured to map the curve from the phase diagram for the relevant pressure range (e.g., 0 to 0.8 mbar). Depending on the chamber pressure regulation, the condenser tempera- ture set point, TConSet, is lowered by a further variable term, Tcr, being between 0 K and 5 K. It is noted that the variable term Tcr depends on the error between the ac- tual chamber pressure, pCha,PV, and the set drying chamber pressure, pCha,SP,i. In this case, Tcr is determined by integrating said error. Therefore, in practice, the variable term Tcr will be slowly increasing and decreasing, such as ramping up and down, like an integral part of a PID controller. This variable term Tcr, is optional, but may be advantageous when a low Tcc is selected, such as 5 K. Thus, the condenser temperature set point, TConSet, may now be calculatedas TConSet = TCha,SP,i - Tcc - Tcr, where Tcc is a invariable temperature adjustment term.If for example using water as the solvent and the set drying chamber pres- sure, pCha,SP,i, is 0.200 mbar, the corresponding drying chamber temperature, TCha,SP,i, is -36 °C. If the constant Tccis set to 10°C and the variable term Tcris 0°C because the actual pressure in the drying chamber 10 is under the set point, the condenser tem-perature set point, TConSet, becomes TConSet = -36 °C – 10 °C – 0 °C = -46 °C.In addition, it must be ensured that the condenser 201 is always colder than the shelves 102. Furthermore, it is possible to employ a defense strategy, where if the dry- ing chamber pressure reaches a predetermined maximal pressure, pmax-x, then an emergency cooling procedure is initiated such that the condenser 201 is set to emergency cooling. Calculation of the degree of opening of the device for controlling the flow area of the path The degree of opening of the device 301 for controlling the flow area of the path 30 is determined as follows. The following variable parameters are used. Lset: The set position of the device 301 during freeze-drying if the device 301 should be open. The device 301 is closed for instance during pressure rise measurements, PRM. Lact: The actual position of the device 301. FIGSP: Set flow of inert gas, such as nitrogen, through the inlet valve 51 and through the inert gas inlet 50 into the drying chamber 10. pcha,PV: The actual measured drying chamber pressure. pcon,PV: The actual measured condenser chamber pressure. ∆pPV: The actual pressure difference between the drying chamber 10 andthe condenser chamber 20, ∆pPV = pCha,PV - pCon,PV.Furthermore, the following constant parameters are used. Lmin: Minimum opening of the device 301 during freeze-drying. This param- eter is hard coded, for instance to 7 %, but in dependence of the mechanical proper- ties of the device 301. Lmax: Maximum opening of the device 301 during freeze-drying. LPRM: The set position of the device 301 after a pressure rise measurement, PRM. This parameter is hard coded, for instance to 20 %. FIGSPmin: Minimum flow for inert gas, for instance nitrogen, through the in- ert gas inlet 50 into the drying chamber 10. ∆pmax: Maximum allowed relative pressure difference between the drying chamber 10 and the condenser chamber 20. LHy: Hysteresis. An acceptable difference between Lset and Lact. If the posi-tion of the device 301 is within the tolerance set by LHy, then the valve will not bemoved. This parameter may be set to for instance + / - 2 %.Now, at the beginning of the drying phase the set position of the device 301, Lset, is set to be equal to Lmax.Thereby the lowest ∆pPVis obtained. During the drying phase, if FIGSP> FIGSPminand ∆pPV< ∆pmaxf, Lsetis slowly decreasing, for instance ramping down, like the integral part of a PID controller, i.e. the error in drying chamber pressure is integrated. During the drying phase, if FIGSP≤ FIGSPminor ∆pPV≥ pmax, Lset is slowly increasing, for instance ramping up. Also, a defense strategy may be employed, such that if the drying chamber pressure reaches the predetermined maximal pressure of the drying chamber, pmax-x, the device 301 is triggered to open fully, that is 100 %. Results Five test runs were conducted using the recipe for mannitol 3 % given in Table 1 above. Test runs 1, 3 and 4 were reference test runs done in a conventional manner. Test run 2 was performed using a freeze-drying apparatus 1 according tothe invention, albeit without the use of the device 301 in the sense that the device301 was kept fully open, that is Lset = 100 %, throughout the test run. Test run 5 was performed using a method and a freeze-drying apparatus 1 according to the inven- tion, now also using the device 301 to control the flow area between the drying chamber 10 and the condenser chamber 20 by dynamic variation of the flow area of the path 30. The results in the form of energy consumption for each of the test runs ap-pear from table 2 below, where PD denotes primary drying, and SD denotes second-ary drying. Table 3 below shows the results in the form of residual moisture in per- cent at the average, edge, and center, respectively, of the freeze-dried material 101 for each of test runs. Residual moisture may be used a proxy for the quality of the final product leaving the freeze-drying apparatus. Table 2 – Test results, Energy consumptionPhase Run 1 Run 2 Run 3 Run 4 Run 5 UnitDynamic con-No Tcc = 5 No No Tcc = 10Kelvin denser tempera- K K ture Dynamic deviceNo No No No Yes301 used? Total drying16.3 17.6 16.8 17.8 16.8 Hourstime Average conden-PD 579 322 714 699 316 Wattser cooling pow-SD 611 441 757 731 505 Watter Average electri-PD 1689 374 2170 2192 415 Wattcal power need-SD 1912 728 2373 2341 952 Watted for condenser cooling Electrical powerPD 23.4 5.7 31.1 33.7 6 kWhneeded for con-SD 4.7 1.8 5.8 5.8 2.3 kWhdenser coolingTotal 28.1 7.5 36.9 39.5 8.3 kWhduring drying Table 3 – Residual moisture in % after freeze dryingRun 1 Run 2 Run 3 Run 4 Run 5Average 1.8 1.72 2.09 1.74 1.58Edge 1.85 1.76 2.06 1.61 1.47Center 1.67 1.68 2.14 1.87 1.69Standard0.15 0.06 0.18 0.2 0.13deviation As may be seen from Table 2, the total electrical power consumption needed for the condenser cooling for test runs 2 and 5 are 7.5 kWh and 8.3 kWh, respectively. This is considerably lower than for the reference test runs 1, 3 and 4, where the total energy consumption needed for the condenser cooling lies at be- tween 28 kWh and 40 kWh. Thus, the conventional freeze-drying process uses four to five times as much electrical power for the condenser cooling as the method ac-cording to the invention. The method according to the invention may thus providean electrical power saving for the condenser cooling of as much as 80 % as com- pared to the conventional method. At the same time, the total drying time for test runs 2 and 5 is only marginally longer than for the reference test runs 1, 3 and 4, namely by no more than approximately one hour. As may be seen from Table 3, the residual moisture in the freeze-dried ma- terial 101 for test run 2 is comparable to the reference test runs 1, 3 and 4, while the residual moisture in the freeze-dried material 101 for test run 5 is lower than for the reference test runs 1, 3 and 4. Also, for both test run 2 and 5, the standard deviation is smaller than for the reference test runs 1, 3 and 4. Hence, the method according to the invention provides for a freeze dried product being more uniform while at the same time comprising about the same amount of residual moisture as would be the case if using a conventional method. This shows that product quality is not compro- mised by the energy savings obtained. This is a consequence of a similar environ- ment around the product regardless of using the conventional method or the meth- od according to the present invention of controlling chamber pressure. Referring now to Figs. 8, 9 and 10 graphs illustrating the shelf temperature, cf. curve 80, the condenser temperature, cf. curve 81, and the drying chamber pres- sure, cf. curve 82, during a freeze drying process are shown. In each figure, the X- axis denotes time, t, the left hand Y-axis denotes pressure, p, and the right hand Y- axis denotes temperature, T. Fig.10 further illustrates the degree of opening of the device 301, cf. curve 83, during the freeze-drying process. For the curve 83, the right hand Y-axis denotes the degree of opening in %. Fig. 8 illustrates test run 1, that is one of the reference test runs, using a condenser temperature set point, TConSet, of -70 °C and a device 301 being fully open, i.e., open by 100 %, at all times. Fig.9 illustrates test run 2, using a condenser temperature set point, TConSet, being below the drying chamber temperature, TCha,SP,i, by Tcc= 5 K and a device 301 being fully open, i.e., open by 100 %, at all times. Fig.10 illustrates test run 5, using a condenser temperature set point, TCon-Set, being below the drying chamber temperature, TCha,SP,i, by Tcc= 10 K and a device 301 being dynamically open by between 10 and 50 %. As may be seen from Fig.8, the conventional method results in a conden- ser temperature fluctuating greatly, cf. curve 81, as a result of fluctuations in the drying chamber pressure, cf. curve 82. It is noted that it generally applies that the drier the product the more stable the drying chamber pressure becomes. In comparison, referring to Fig.9, it may be seen that using a method with a condenser temperature set point, TConSet, being below the drying chamber temper- ature by Tcc = 5 K and a device 301 being fully open, i.e., open by 100 %, at all times, greatly reduces the fluctuations in the condenser temperature, cf. curve 81. In further comparison, now referring to Fig.10, it may be seen that using a method according to the present invention results in an even further reduction in the fluctuations in the condenser temperature, and furthermore also an extremely stable drying chamber pressure, even when the material 101 being freeze-dried is still very moist. Thereby, dynamic adaptations of the condenser temperature, which would otherwise be necessary, may now be omitted. List of reference numerals1 Freeze-drying apparatus10 Drying Chamber101 Material 102 Shelves 103 Drain 20 Condeser chamber 201 Condenser 202 Drain 30 Path 301 Device for controlling flow area of path 302 Control device 303 Stem 304 Body 40 Condenser outlet50 Inert gas inlet51 Control valve 60 Solvent inlet61 Solvent circuit62 Solvent outlet 70 Cooling liquid inlet71 Cooling liquid circuit72 Cooling liquid outlet80 Shelf temperature curve81 Condeser temperature curve82 Chamber pressure curve83 Opening degree curve1001- Method steps 1004

[0003] List of abbreviationsA Flow area of path (only used for lines on Fig. 3)FIGSPInput set point for inflow rate of non-condensable gases FIGSPmin Input limiter for set point for inflow rate of non-condensable gasesL Longitudinal axis of freeze-drying apparatusLactActual set position of the device for controlling the flow area of the path LHyHysteresis, or acceptable difference between LSetand LactLmax Maximal set position of the device for controlling the flow areaof the path LminMinimum set position of the device for controlling the flow area of the path LPRMSet position of the device for controlling the flow area of the path after a pressure rise measurement (PRM) LSet Set position of the device for controlling the flow area of the path pCha,PV Actual measured absolute pressure in drying chamber pCha,SP,i Input absolute pressure set points of the drying process or drying chamber pCon,PV Actual measured condenser chamber pressure pCon,SP,i Derived absolute saturation pressure of solid at temperature TCon, SP,i psat Gas pressure at surface of ice pmax,x Predetermined maximal pressure of the drying chamber ∆pfactor Input factor between 0-1, ∆pSP,i = pCha,SP,i*∆pfactor ∆pfactor,max Maximum value for the input factor ∆pmaxInput limiter for pressure difference. Also denoted maximum allowed relative pressure difference. ∆pmax = pCha,SP,i*∆pfactor,max.∆pPV Actual derived pressure difference, ∆pPV = pCha,PV - pCon,PV∆pSP,i Derived pressure difference set point, ∆pSP,i = pCha,SP,i - pCon, SP,iTCha,PVActual measured temperature in the drying chamber TCha,SP,iDerived saturation temperature of solid at absolute pressure pCha,SP,iTCon,PVActual measured temperature of the condenser TCon, SP,iDerived temperature set point for condenser, TCon, SP,i =TCha,SP,i -ΔTSP. Also denoted target temperature. TConSetSet temperature of condenser (condenser temperature set point). TConSet = TCha,SP,i - Tcc - TcrTcr Variable temperature adjustment term Tcc Invariable temperature adjustment term TsatTemperature at surface of ice Tshelve,SPInput set point temperature for liquid in product shelves in chamber ΔTmaxInput limiter for temperature differenceΔTPV Actual derived temperature difference, ∆TPV=TCha,PV - TCon,PVΔTSPCalculated temperature difference, typically ΔTSP= Tcc+ Tcr

Claims

P A T E N T C L A I M S1. A method for controlling a freeze-drying process in a freeze-drying appa- ratus (1), which freeze-drying apparatus (1) comprises a drying chamber (10) con- taining a material (101) to be dried by removal of a frozen liquid, solid or ice, a con- denser chamber (20) comprising a condenser (201) and connected to a vacuum de- vice (40), which condenser chamber (20) is fluidly connected to the drying chamber through a path (30) having a flow area available for fluid flow through the path (30), the freeze-drying apparatus having a device (301) for controlling the flow area of the path, and which drying chamber (10) further comprises an inert gas inlet (50) for supplying an inert gas to the drying chamber (10), which method comprises the steps of: obtaining (1001) a sequence of pressure set-points (pCha,SP,i) of the freeze- drying process, controlling (1002) a chamber pressure (pCha,PV) of the drying chamber (10) according to the sequence of pressure set-points (pCha,SP,i) by manipulating at least one of the device (301) for controlling the flow area of the path (30) and the inert gas inlet (50) to control the supply of inert gas to the drying chamber (10), and controlling (1003) a temperature (TCon,PV) of the condenser (201) as a func- tion of the sequence of pressure set-points (pCha,SP,i) to maintain a target tempera- ture (TCon,SP,i), wherein the target temperature (TCon,SP,i) is lower than an equivalent satu- ration temperature (TCha,SP,i) of the frozen liquid, solid or ice to be removed from the material (101) at a condenser pressure (pCon,SP,i) being lower than the pressure set point (pCha,SP,i).

2. The method according to claim 1, wherein the condenser pressure(pCon,SP,i) is lower than the pressure set point (pCha,SP,i) by a predefined pressure dif-ference ∆pSP,i, wherein the predefined pressure difference ∆pSP,i is defined as ∆pSP,i =pCha,SP,i *∆pfactor, where ∆pfactor is a factor being between 0 and 1, or wherein the predefined pressure difference ∆pSP,iis defined by a pressure difference derived from a calculated temperature difference (ΔTSP) between the equivalent saturation temperature (Tcha,SP,i) at the pressure set point (pcha,SP,i) andthe temperature (Tcon,SP,i) of the condenser, that is ∆pSP,i = pCha,SP,i - pCon,SP,i.

3. The method according to claim 2, wherein ∆pfactoris below 0.9, below 0.7, or below 0.

5.

4. The method according to any one of the above claims, wherein thestep of controlling (1003) the temperature (TCon,PV) of the condenser (201) comprises controlling (1003) the temperature (TCon,PV) of the condenser (201) to maintain a calculated temperature difference (ΔTSP) to the equivalent saturation temperature (TCha,SP,i) such that the target temperature (TCon,SP,i) of the condenser (201) is lower than the equivalent saturation temperature (Tcha,SP,i).

5. The method according to any one of claims 2 to 4, wherein the calculat- ed temperature difference (ΔTSP) is 20 K or less, such as 5 to 15 K or 7.5 to 12 K, preferably 10 K or less, such as 5 to 10 K.

6. The method according to any one of the preceding claims, wherein at least the step (1002) of controlling the chamber pressure (pCha,PV) of the drying chamber (10), and the step (1003) of controlling the temperature (TCon,PV) of thecondenser (201) is performed by any one of:an optimization routine, a PID controller, and a machine learning device.

7. The method according to any one of the preceding claims, wherein the step (1002) of controlling the chamber pressure (pCha,PV) of the drying chamber (10),and the step (1003) of controlling the temperature (TCon,PV) of the condenser (201), are performed concurrently.

8. The method according to any one of the above claims, wherein manipu- lating at least the device (301) for controlling the flow area of the path (30) further comprises during the freeze-drying process: determining (1002a; 1002b) ^a set inflow of inert gas (FIGSP) into the drying chamber (10),^ a minimum inflow of inert gas FIGSPmin into the drying chamber (10),^ an actual pressure difference (∆pPV), between an actual measuredpressure (pCha,PV) in the drying chamber (10) and an actual meas- ured pressure (pCon,PV) in the condenser chamber (20) wherein ∆pPV= pCha,PV - pCon,PV, and^ a maximum allowed relative pressure difference (∆pmax) between theactual measured pressure (pCha,PV) in the drying chamber (10) and the actual measured pressure (pCon,PV) in the condenser chamber (20), where ∆pmax = pCha,SP,i*∆pfactor,max, where ∆pfactor,max is a maxi- mum value for a factor ∆pfactor, and where ∆pfactor is a factor being between 0 and 1, and, if determining that FIGSP > FIGSPmin and ∆pPV < ∆pmax, reducing (1002c) a setposition (Lset), of the device (301) for controlling the flow area of the path (30) and, ifdetermining that FIGSP ≤ FIGSPmin or ∆pPV ≥ ∆pmax, increasing the set position (Lset).

9. The method according to any one of the above claims, wherein manipu- lating at least the device (301) for controlling the flow area of the path (30) compris- es one or more of the following: at the beginning of the freeze-drying process moving (1002d) the device (301) for controlling the flow area of the path (30) to a set position (Lset) being equal to a maximal set position (Lmax); and during the freeze-drying process, determining (1002e) an actual pressuredifference (∆pPV) between an actual measured pressure (pCha,PV) in the drying cham- ber (10) and an actual measured pressure (pCon,PV) in the condenser chamber (20)wherein ∆pPV = pCha,PV - pCon,PV, and a maximum allowed relative pressure difference(∆pmax) between an actual measured pressure (pCha,PV) in the drying chamber (10) and an actual measured pressure (pCon,PV) in the condenser chamber (20), where ∆pmax= pCha,SP,i*∆pfactor,max, where ∆pfactor,maxis a maximum value for a factor ∆pfactor, and where ∆pfactoris a factor being between 0 and 1, and (1002f), if determining that∆pPV < ∆pmax, reducing the set position (Lset), and, if determining that ∆pPV ≥ ∆pmax,increasing the set position (Lset).

10. The method according to any one of the preceding claims, wherein the path (30) between the drying chamber (20) and condenser chamber (10) comprises a longitudinal axis (L) extending along the path (30) between the drying chamber (20) and condenser chamber (10), and wherein the device (301) for controlling the flow area of the path (30) is configured to be displaceable in a direction being paral- lel with the longitudinal axis (L).

11. The method according to any one of the preceding claims, wherein the drying chamber (10) comprises a plurality of shelves (102) configured for receiving the material (101) to be dried, and wherein the step (1003) of controlling a tempera- ture (TCon,PV) of the condenser (201) comprises controlling the temperature (TCon,PV) of the condenser (201) to be lower than a temperature (TShelve,SP) of the shelves (102).

12. A freeze-drying apparatus (1) comprising a drying chamber (10) for con- taining a material (101) to be dried by removal of a liquid, a condenser chamber (20) comprising a condenser (201) and connected to a vacuum means (40), which con- denser chamber (20) is fluidly connected to the drying chamber through a path (30) having a flow area available for fluid flow through the path (30), the freeze-drying apparatus having a device (301) for controlling the flow area of the path,wherein the freeze-drying apparatus (1) further comprises a control sys- tem, the control system being configured to control to the device (301) for control- ling the flow area of the path and to control a temperature of the condenser (201), which control system comprises a data processor and a memory with exe- cutable code enabling the data processor to, when executing the executable code, cause the control system to perform a method according to any one of claims 1 to 12.

13. A non-transient computer-readable storage medium comprising exe-cutable code, which code, when executed by a data processor operatively connected to a freeze-drying apparatus, causes the freeze-drying apparatus to perform a meth- od of any one of claims 1 to 12.