Freeze dryer and a method for inducing nucleation in products

Abstract

The invention relates to a freeze dryer and a method for inducing controlled nucleation in liquid products. The freeze dryer for inducing nucleation in water based products (44) to be freeze-dried comprises a product chamber (12) adapted for housing a vapor gas and the products (44), a condensation chamber (16) connected to the product chamber (12) over an isolation valve (36) in a gas conductive manner, said condensation chamber (16) being provided with a gas pump (18), a gas transfer line (20) connecting the product chamber (12) with at least one cooling device (22) being adapted to generate ice-crystals when said vapor gas is withdrawn from the product chamber through the cooling device (22) in a first gas flow direction (streaked arrow), the freeze dryer being adapted to—after the generation of the ice crystals in the cooling device (22)—convey a flushing gas through the gas transfer line (20) in a second gas flow direction (white arrow) going reverse to said first gas flow direction in order to thereby entrain the ice-crystals from the cooling device (22) into the product chamber (12) to induce nucleation of the products (44) therein. The freeze dryer is particular in that the gas transfer line (20), which comprises the cooling device (22), is separated from the gas pump (18) at least by the condensation chamber (16), the condensation chamber (16) providing a gas passage for the withdrawn vapor gas during the withdrawal in the first gas flow direction, and a gas passage and/or gas storage for the flushing gas during the conveying in the second gas flow direction.

Claims

1. Freeze dryer for inducing nucleation in water based products to be freeze-dried, comprising a product chamber for housing a vapor gas and the products, a condensation chamber connected to the product chamber over an isolation valve in a gas conductive manner, said condensation chamber being provided with a gas pump, a gas transfer line connecting the product chamber with at least one cooling device generating ice-crystals when said vapor gas is withdrawn from the product chamber through the cooling device in a first gas flow direction, and the freeze dryer —after the generation of the ice crystals in the cooling device—conveying a flushing gas through the gas transfer line in a second gas flow direction going reverse to said first gas flow direction in order to thereby entrain the ice-crystals from the cooling device into the product chamber to induce nucleation of the products therein, wherein the gas transfer line, which comprises the cooling device, is separated from the gas pump at least by the condensation chamber, the condensation chamber providing a gas passage for the withdrawn vapor gas during withdrawal in the first gas flow direction, and a gas passage and/or gas storage for the flushing gas during conveying in the second gas flow direction.

2. The freeze dryer according to claim 1, where the gas transfer line comprises at least a first valve closing during switching between the first gas flow direction and the second gas flow direction.

3. The freeze dryer according to claim 2, where the first valve is arranged between the cooling device and the condensation chamber.

4. The freeze dryer according to claim 1, where the condensation chamber is connected through at least a second valve to a source of flushing gas, such as dry air or nitrogen, for providing said flushing gas for said gas passage and/or gas storage.

5. The freeze dryer according to claim 1, where the gas transfer line comprises a gas filter arranged between the condensation chamber and the cooling device, optionally also comprising a third valve arranged between the gas filter and the condensation chamber.

6. The freeze dryer according to claim 1, where the cooling device is directly connected with the product chamber without interconnection with any valve or port.

7. The freeze dryer according to claim 1, where the cooling device comprises at least one tubular pipe having an inner cooling surface whereupon the ice crystals are formed and which surface surrounds a pipe volume, the tubular pipe having opposing ends, at least one end being connected to the gas transfer line and forming part thereof.

8. The freeze dryer according to claim 1, where the cooling device comprises multiple tubular pipes arranged within the gas transfer line in parallel AND/OR in series.

9. The freeze dryer according to claim 1, where the cooling device OR the gas transfer line is provided with a gas inlet comprising a fourth valve for clean water vapor injection upstream OR downstream of the cooling device.

10. Using a freeze dryer according to claim 1 for inducing nucleation in products to be freeze-dried, wherein the steps: a) cooling the products in the product chamber to a super-cooled state, b) with a gas pump withdrawing a vapor gas via the gas transfer line from the product chamber in a first gas flow direction through the cooling device and then through the condensation chamber while cooling the vapor gas in the cooling device to thereby generate ice-crystals therein, c) conveying a flushing gas in a second gas flow direction reverse to the first gas flow direction from the condensation chamber via the gas transfer line through the cooling device into the product chamber such that the ice-crystals from the cooling device are flushed into the product chamber to induce controlled nucleation of the products therein, where the above steps a), b) and c) are carried out before sublimation of the products is carried out as part of a freeze drying process.

11. A method of inducing controlled nucleation of water based products to be freeze dried in a freeze dryer, comprising the steps: a) cooling the products in a product chamber of the freeze-dryer to a super-cooled state b) withdrawing a vapor gas from the product chamber via a gas transfer line in a first gas flow direction through a cooling device and through a condensation chamber of a freeze dryer while cooling the vapor gas in the cooling device to thereby generate ice-crystals therein, c) conveying a flushing gas in a second gas flow direction reverse to said first gas flow direction from the condensation chamber via the gas transfer line through the cooling device into the product chamber such that the ice-crystals from the cooling device are flushed into the product chamber to induce controlled nucleation of the products therein, where the above steps a), b) and c) are carried out before sublimation of the products is carried out as part of a freeze drying process in the freeze dryer.

12. The method according to claim 11, further comprising that the flushing gas conveyed from the condensation chamber via the gas transfer line is filtered by a gas filter arranged in the gas transfer line between the condensation chamber and the cooling device.

13. The method according to claim 11, further comprising that the vapor gas being withdrawn from the product chamber is withdrawn with a gas pump connected to the condensation chamber via a vacuum line separate from the gas transfer line.

14. The method according to claim 11, further comprising an isolation valve connecting the product chamber and the condensation chamber, which isolation valve is closed at least during step b) and/or the isolation valve is closed during step c), and/or the isolation valve is also closed before step b).

15. The method according to claim 11, further comprising that at least one of the cooling device; the product chamber; and the gas transfer line is sterilized by conveying hot steam therethrough after operation, at least in a separate step to steps a), b), c) and to the vacuum drying during sublimation.

16. The method according to claim 11, further comprising that the temperature of a cooling surface of the cooling device ranges between −30° C. and −90° C. during step b), optionally also before step b).

17. The method according to claim 11, further comprising that a controlled and dosed amount of sterile water, preferably in the form of water vapor, is introduced into the cooling device, optionally via a fourth valve, through the gas transfer line, during step c).

18. The method according to claim 11, further comprising that a dry flushing gas is applied in step c), optionally through a second valve, and that said dry flushing gas is cooled by condensing coils in the condensation chamber during step c).

19. The method according to claim 11, further comprising that the temperature of a cooling surface of the cooling device ranges between −50° C. and −70° C. during step b), optionally also before step b).

Description

(1) In the following, embodiments of the invention are described with reference to the drawing, where same reference numerals are to reference the same features, comprising

(2) FIG. 1 shows a schematic layout of an embodiment of the freeze dryer according to the invention.

(3) FIG. 2 shows a cross section of a first embodiment of the cooling device,

(4) FIGS. 3a and 3b show two side views of a second embodiment of the cooling device along its longitudinal extension,

(5) FIGS. 4a and 4b show two 3D views of a third embodiment of the cooling device, with and without outer pipe.

(6) FIGS. 5a and 5b show two 3D views of a fourth embodiment of the cooling device, with and without outer pipe.

(7) In FIG. 1 is shown a freeze dryer comprising a product chamber 12, which houses stacked shelves 40, 42, on which vials 44 containing a liquid product are arranged. A condensation chamber 16 is directly connected to the product chamber 12 via a gas passage. An isolation valve 36 is provided in a known manner in the form of a mushroom valve to open or close the gas passage; here the isolation valve 36 is shown closed. The condensation chamber 16 comprises condensing coils 50 through which a cooling fluid may be passed, see the small arrows indicating cooling fluid entering and exiting the cooling pipe ends 52 in order to achieve condensation of vapor in any gas contained in the condensation chamber 16. Thereby, the freeze dryer can be operated in a conventional freeze drying cycle comprising 1) freezing of the product using a heating/cooling system 46 2) evacuation to low pressures near vacuum around 1-10 mbar and sublimation under the triple point of water in the frozen product 44 during uniform heating of the products in the vials 44 using heating/cooling system 46. Before freezing and drying, however, there is in the field of liquid product freeze drying a desire to provide a nucleation induction.

(8) In FIG. 1 is shown a freeze dryer according to one embodiment of the invention for inducing nucleation in the products, where the freeze dryer comprises a gas transfer line 20 connecting the product chamber 12 and the condensation chamber 16 in a gas conveying manner. This means that vapor gas can be transported from the product chamber 12 to the condensation chamber 16 via the gas transfer line 20 in a first gas flow direction, indicated by the streaked arrow. Flushing gas, such as dry air, can also be transported or conveyed from the condensation chamber 16 along the gas transfer line 20 into the product chamber 12 in a second gas flow direction, indicated by the white arrow, which direction is oriented opposite to the first gas flow direction.

(9) The gas transfer line 20 comprises a cooling device 22. In FIG. 1 the cooling device 22 is provided on a top part of the freeze dryer. However, the cooling device may also be provided on any side thereof, in a bottom part of the freeze dryer, or even as an integral part of the product chamber 12 and connected to the gas transfer line 20. The gas transfer line 20 also comprises a gas filter 34 and first and third valves V1, V3 adapted to open or close the gas transfer line 20. With regard to the first gas flow direction, the cooling device 22 is arranged downstream of the product chamber 12 and upstream of the first valve V1, while the gas filter 34 is arranged downstream of the cooling device 22 and the first valve V1, and upstream of the condensation chamber 16, the third valve V3 is arranged between the gas filter 34 and the condensation chamber 16, and the first valve V1 arranged between the cooling device 22 and the gas filter 34.

(10) Advantageously, an additional vapor gas inlet 32 is connected with the gas transfer line 20 to supply additional water vapor into the cooling device 22 in case there is not enough vapor gas in the product chamber and from evaporation from the products to produce the necessary amount of ice crystals within the cooling device 22. The gas inlet 32 comprises a fourth valve V4 to open or close the gas inlet 32. The additional water vapor may be injected into the cooling device 22 for generating further ice crystals therein, preferably at an upstream end thereof when vapor gas is flowing in the first gas flow direction.

(11) The condensation chamber 16 has a dry gas inlet valve V2, a second valve, for connecting the condensation chamber 16 to a source of dry gas, such as dry atmospheric air or nitrogen. The second valve V2 provides flushing gas to be stored in or passed by the condensation chamber 16. The second valve V2 is for closing or opening into a dry gas supply (not shown) either ambient atmospheric air or a pressurized nitrogen gas container, or the like. A gas pump 18 in the form of a vacuum pump is connected to the condensation chamber 16 via a vacuum line 30 containing a fifth valve V5.

(12) In the following, an embodiment of a method of inducing controlled nucleation of the products according to the invention is described:

(13) The vials 44 containing a liquid product, such as a vaccine in solution, are placed on trays or shelves 40, 42 within the product chamber 12. The chamber 12 and its contents may be pre-sterilized in a conventional manner. The isolation valve 36 between the product chamber 12 and the condensation chamber 16 may stay closed during all steps of the inventive method or may stay open during cooling the products to a super-cooled state.

(14) The temperature of the cooling device 22 on an inner cooling surface thereof (to be described in detail below) is reduced to a temperature ranging between −30° C. and −90° C., preferably ranging between −50° C. and −70° C.

(15) The products in the product chamber 12 are cooled by having the isolation valve 36 closed and cooling by the heating/cooling system 46 directly via the shelves 40, 42 upon which the vials 44 comprising the liquid product are placed to a super-cooled state, at the atmospheric pressure (as at sea level) and at temperatures around or below 0° C., at which state the product does not freeze without induced nucleation. The temperature at which the product can be kept in a super-cooled state also depends on the type and makeup of the product to be freeze dried. The super-cooled state may preferably be kept for a predetermined time period in order to ensure uniform temperatures is obtained in all the products, in time ranges around 10 to 180 minutes, depending on number and sizes of the vials or containers being in the product chamber.

(16) Some examples of liquid products at atmospheric pressures (at sea level) are: A 5% sucrose solution is super-cooled until reaching a temperature of −6° C. or slightly above. A 3% mannitol solution is super-cooled until reaching a temperature of −7° C. or slightly above. A 1% NaCl, 3% mannitol solution is super-cooled until reaching a temperature of −8° C. or slightly above.

(17) In other words, a super-cooled state in the product is caused to occur. In liquid solutions this often occurs within a temperature range between −5° C. and −10° C. and at atmospheric pressures. This temperature range also applies for other highly water containing products such as biologicals and biopharmaceuticals, e.g. coagulation factors, cellular-derived vaccines, immunoglobulins, biotechnological products, monoclonal antibodies growth factors, cytokines, recombinant vaccines, proteins, collagen, and the like. The freeze dryer and method for inducing nucleation may also be applicable for other water rich products such as seafood, soups, fruits, meat, or the like.

(18) The isolation valve 36 is now closed or kept closed. Then vapor gas from the product chamber 12 is withdrawn via the gas transfer line 20 into the cooling device 22 to generate ice-crystals therein by evacuating over the gas filter 34 and the condensation chamber 16 with the gas pump 18 over the separate vacuum line 30. Alternatively, the vapor gas may be drawn out of the product chamber 12 during the cooling of the products to a super-cooled state. A reduced pressure within the product chamber is thereby reached, i.e. in the range below 30 mbar. This is achieved by withdrawing gas from the product chamber 12 via the gas transfer line 20 and through the condensation chamber 16 by the vacuum pump 18 with valves V1, V3, V5 open, while the valve V2 and isolation valve 36 are closed.

(19) The vapor gas being withdrawn from the product chamber 12 for generating the ice crystals with the cooling device 22 originates from a) the natural evaporation of the liquid product within the vials 44, b) residual humidity or humid gas between the vials 44 and in the product chamber 12.

(20) Optionally, additional humid air may be injected during this withdrawal by clean water vapor injected into or upstream the cooling device 22 via opening valve V4 from a gas inlet 32.

(21) Preferably, the condensation chamber 16 is not cooled down during the withdrawing of vapor gas from the product chamber 12 for forming the ice crystals within the cooling device 22, in order that no ice crystals are formed within the condensation chamber 16.

(22) Once sufficient ice crystals are formed within the cooling device 22, the first valve V1 and third valve V3 are closed and the same pressure level is maintained within the cooling device 22 in its cooling volume as is in the product chamber 12. Alternatively, either first valve V1 or third valve V3 is closed.

(23) Second valve V2 is opened to supply nitrogen (not shown) into the condensation chamber 16 and fill it until atmospheric pressure is reached, after which the second valve V2 is closed again.

(24) First valve V1 and third valve V3 are opened, either simultaneously or preferably first valve V1 and then valve V3, which opens the passage from the condensation chamber 16 to the product chamber 12 through the gas transfer line 20. Fifth valve V5 can be closed to protect the gas pump 18 and keep the low pressure inside the condensation chamber 16, this valve V5 is optional. The hereby build-up pressure differential between the product chamber 12, which is at a pressure below 10 mbar, and the condensation chamber 16, which is at atmospheric pressure or above, results in a powerful flow of dry flushing gas contained within the condensation chamber 16 being conveyed along the gas transfer line 20 through the cooling device 22 and into the product chamber 12. This flow of flushing gas through the cooling device 22 rips of the ice crystals from the cooling surface 24 and flushes these into the product chamber 12. The liquid product starts to nucleate upon contact with ice crystals due to its super-cooled temperature and does so in a uniform way and, tests have shown, substantially immediately and at the same time, which thereby freezes the product in a consistent and uniform way, which provides the owner or operator of the freeze dryer with a high quality dried product exhibiting uniform quality, as well as longer storage stabilities.

(25) While travelling along the gas transfer line 20, the dry flushing gas flows through the gas filter 34 in order to ensure no contaminants are entrained from the condensation chamber 16 via the flushing gas, which thereby maintains the hygiene and sterility of the products and product chamber. Contamination of the liquid product by the flushing gas needs to be avoided, in particular under GMP conditions.

(26) Once the nucleation has been initiated, first valve V1 and third V3 (again alternatively, valve V1 or valve V3) are closed and the isolation valve 36 is opened. The vacuum pump 18 is then used to generate a vacuum within the product chamber 12 and the condensation chamber 16 while the condensation chamber 16 is cooled down to proceed in a manner corresponding to the conventional freeze drying process of liquid products.

(27) FIG. 2 shows a first embodiment of the cooling device 22. A component of the cooling device 22 is a tubular pipe i.e. a longitudinal cylindrical inner pipe 21 comprising an inner volume 26 around the longitudinal pipe axis A. The pipe 21 has a cross section corresponding to the cross section of the gas transfer line 20. In an advantageous embodiment, it forms an integral part of the gas transfer line 20, and in an embodiment, it is a GMP-approved type hygienic two inch diameter pipe being 500 mm long. The inner pipe 21 has two opposing ends 23, 25 each of which is connected, either mechanically or by welding, to respective portions of the gas transfer line 20, as shown in Fig. Alternatively, only one of these ends 23, 25 is connected to the gas transfer line 20 and other end is connected to the product chamber 12, or in an embodiment the inner pipe 21 forms an integral part of the gas transfer line 20, or forms a pipe part thereof. Vapor gas, when flowing or being conveyed through the gas transfer line 20 in the first gas flow direction inside the inner volume 26 of the inner pipe 21 may then enter the cooling device 22 at the second end 25 and leave at the first end 23. The cooling device 22 comprises a cooling surface 24 that surrounds the inner volume 26, and provides cooling when a cooling medium flows behind the cooling surface 24, see more information below. Thereby the vapor in the gas condenses as water droplet on this surface 24, which droplets turn into ice crystals due to the continued cooling from the surface 24.

(28) When a flushing gas enters in a second gas flow direction in reverse to the first gas flow direction the flushing gas will enter the inner pipe 21 at the first end 23, flow through the inner pipe inside said inner volume 26 and exit at the second end 25 from where it is conveyed into the product chamber 12. The inner pipe 21 surrounds the inner volume 26 in which the vapor gas was being deposited as ice crystals and in which the flushing gas is flushing down along and inside the deposited ice crystals. The inner volume 26 is surrounded by the cooling surface 24 which is the inner surface of the inner pipe 21. When flowing through the inner pipe 21, the gas flows along the cooling surface 24 which takes the thermal energy from the gas to cool the same down. The cooling surface 24 is kept continuously cooled at least during the nucleation process. Alternatively, the cooling surface 24 may only cool until after vapor gas has entered and condensed to ice crystals.

(29) The thermal energy taken from the vapor gas withdrawn against the cooling surface of the inner cooling volume 26 may be guided away according to different alternatives. FIG. 2 shows an outer cylindrical pipe 27 surrounding the inner pipe 21 and defining an outer volume 28 through which a cooling medium, such as liquid nitrogen, is passed. The cooling medium is conveyed along the outer surface 29 of the inner pipe 21 where it draws along the thermal energy from the inner pipe 21 and the vapor gas therein, respectively. The thermal energy is continuously guided away by a continuous flow of cooling medium through the outer volume 28. The cooling medium enters the outer volume 28 through an entry port 28a and leaves the outer volume 28 through an exit port 28b, using not shown cooling medium pumps.

(30) FIGS. 3A and 3B show a second embodiment of the cooling device 22. Two redundant cooling coils 285a, 285b are provided in a circumferential direction in the shape of two helical coils, one on each side of a sight glass SG provided centrally along the longitudinal direction of the inner pipe 21. The two coils 285a, 285b are provided within the outer volume 28 between the outer pipe 27 (not shown in FIGS. 3A and 3B) and the inner pipe 21. However, the skilled person can apply his knowledge and provide only one such coil, or more than two such cooling coils. By providing at least two cooling coils, one of these may fail but the cooling device 22 still provide a cooled surface 24 within the cooling device 22.

(31) FIGS. 4a and 4b show a third embodiment of the cooling device 22. FIG. 4a shows the encapsulated state of the cooling device 22 in which the outer volume 28 is surrounded by an outer pipe 27. FIG. 4b shows the cooling device 22 with a removed outer pipe 27 in order to show further details of the cooling device 22.

(32) As shown in FIGS. 4a and 4b, one or more cooling coils 285a, 285b may be located within the outer volume 28 located between the inner pipe 21 and the outer pipe 27 (not shown in FIG. 4B). The cooling medium flows through the cooling coils 285a, 285b, preferably in a continuous manner and thereby continuously cools down any gas within the inner pipe 21. A heat transfer medium may advantageously be provided between outer pipe 27 and inner pipe 21 within the outer volume 28 and surrounding the cooling coils 285a, 285b. The heat transfer medium may be a silicon oil.

(33) The cooling coils 285a, 285b are preferably provided with longitudinal coil elements 56 arranged in parallel to the longitudinal axis A of the inner pipe 21. Two longitudinal coil elements 56 are arranged next to each other in a circumferential direction, and likewise on the opposite longitudinal side thereof. Adjacent coil elements 56 are connected by U-shaped elements 58 at their connecting ends. Thereby, the cooling medium is guided along the inner pipe 21 mostly in a longitudinal direction parallel to the inner pipe 21, rather than in a circumferential direction as in case of a helical coil, see FIGS. 3A and 3B. This achieves a homogeneous temperature distribution along and across the entire length of the inner pipe 21 and thereby improves the heat transfer.

(34) A redundancy is achieved by the provision of at least two separate cooling coils 285a, 285b. Longitudinal coil elements 56 of different cooling coils 285a, 285b are preferably arranged adjacently, such that longitudinal coil elements of different coil 285a, 285b alternate in a circumferential direction. The cooling distribution is thereby improved, and even in case of a failure of a coil circuit, a homogeneous cooling distribution can be achieved with the remaining circuit or circuits, respectively.

(35) FIGS. 5A and 5B show a fourth embodiment of the cooling device 22. The outer volume 28 is connected to a heat transfer medium inlet 62 and connected to a filter 60. The heat transfer medium, such as silicone oil, often expands during heating such as under sterilization of the gas transfer line 20 and inner pipe 22. The filter 60 is a moisture filter to let air out and in freely in the volume 28 without any risk that water enters into in the medium by sucking wet air back. FIG. 5A shows the encapsulated state of the cooling device in which the outer volume 28 is surrounded by the outer pipe. FIG. 5B shows the cooling device 22 with removed outer pipe in order to better show the positioning of the cooling coils, which are the same as for the embodiment shown in FIGS. 4B and 4B. Further, a temperature probe 64 is provided, which adjusts and controls the temperature of the heat transfer medium.