Freezing device or thawing device

Abstract

Freezing device or thawing device for a medium (2) to be frozen or thawed comprising - a chamber (3) configured for receiving at least one container (4), preferably at least one bottle, filled with the medium (2), preferably a pharmaceutical liquid, and configured for receiving a heat transfer liquid (5) which has a lower freezing point than the medium (2), - and at least one flexible membrane (6) configured to separate the at least one container (4) from the heat transfer liquid (5), wherein the freezing device (1) has the function that the medium (2) in the at least one container (4) is frozen or thawed by transferring heat from the medium (2) through the at least one container (4) and the at least one membrane (6) to the heat transfer liquid (5), or vice versa.

Description

[0001] The present disclosure is concerned with a freezing device or thawing device for a medium to be frozen or thawed and a freezing or thawing method for freezing a medium. The medium is preferably a pharmaceutical liquid.

[0002] In the biopharmaceutical production process it is common to freeze large quantities of medium that occurs in the production process in order to store the medium, or transport the medium to a place where it can be filled in ampules or similar receptacles which are for example suitable for administering the drug.

[0003] Essentially two ways are known how containers are embodied which hold the medium during these freezing, storing, and transporting processes.

[0004] On the one hand there are so-called single use bags which are essentially plastic bags which are filled with the medium and then regularly put into an outer container, also called shell. These outer containers can easily be optimised for the use with plate freezers so that the applicant at the time of writing recommends this type of handling of pharmaceutical media. Disclosures concerning this mode of handling can for example be found in EP 4032824 A1 and EP 3685109 A1.

[0005] On the other hand, in the biopharmaceutical production process simple plastic bottles are still the most used primary packaging for media. For freezing the media in bottles blast freezers are known which bring the bottles in contact with a heat transfer gas for transferring heat from the medium.

[0006] A hybrid freezer which is capable of functioning as a plate freezer and alternatively or additionally as a blast freezer is disclosed in EP 4169499 A1.

[0007] However, also in such an embodiment the freezing of medium in bottles is worthy of improvement because the heat transfer from the bottle to the heat transfer gas is obviously not as efficient as in a plate freezer where the heat transfer occurs between two relatively large surfaces in contact with each other. Freezing and thawing times in blast freezers are therefore considerably longer than in plate freezers.

[0008] Additionally, the freezing of medium in bottles in blast freezers suffers from other disadvantages. Because the cold gas usually enters the freezer from a certain side the heat transfer lacks spatial homogeneity inside the blast freezer for example because of dead zones in the cold gas flow.

[0009] Inhomogeneous and slow freezing in bottles can often lead to freezing ice-fronts which create mechanical stress on the bottle and, more importantly, forced flow of the still liquid phase in the bottle, e.g., as so-called volcano, where medium from the centre of the bottle gets ejected by the ice-fronts to the top of the bottle as the last point of freeze is in the very centre of the bottle.

[0010] Such inhomogeneity in combination with longer freezing and thawing times leads to another detrimental effect because it creates gradients in concentrations, e.g., of proteins, which result from freezing and subsequent thawing of the solutions (cryoconcentration gradients).

[0011] Experiments the applicant has conducted show that such detrimental effects are significant and much larger in medium that has been frozen in bottles compared to single use bags in shells. It can therefore be concluded that the established bottle packaging has, at least in the production environment as opposed to the lab environment, a significant effect on integrity of the medium and drug efficacy.

[0012] The object of the present disclosure is to improve the freezing process for media stored in containers which are not necessarily adapted to being frozen in plate freezers regarding efficiency and preferably integrity of the medium.

[0013] This object is attained with the freezer according to claim 1, namely a freezing device for a medium to be frozen or thawed comprising a chamber configured for receiving at least one container, preferably at least one bottle, filled with the medium, preferably a pharmaceutical liquid, and configured for receiving a heat transfer liquid which has a lower freezing point than the medium, and at least one flexible membrane configured to separate the at least one container from the heat transfer liquid, wherein the freezing device has the function that the medium in the at least one container is frozen by transferring heat from the medium through the at least one container and the at least one membrane to the heat transfer liquid, or vice versa.

[0014] The object of the present disclosure is attained with a freezing or thawing method for freezing or thawing a medium, preferably a pharmaceutical liquid, disposed in at least one container, particularly preferably a bottle, wherein the method comprises the following steps at least partially, preferably completely, immersing the at least one container filled with the medium in a heat transfer liquid, which has a lower freezing point than the medium, using at least one flexible membrane to separate the at least one container from the heat transfer liquid, and transferring heat from the medium through the at least one container and the at least one membrane to the heat transfer liquid until the medium in the at least one container is frozen, or vice versa.

[0015] One central aspect of the present disclosure is that the heat transfer liquid and the flexible membrane can adapt to the shape of the at least one container and in this way maximise the heat transfer surface between the container and the heat transfer liquid available for the heat transfer.

[0016] In this manner the at least one container does not have to be of any regular shape, such that medium stored for example in bottles can be frozen as effectively as for example in a plate freezer.

[0017] Liquids regularly have a much higher heat capacity and a much higher heat transfer coefficient than gases. Freezing medium in the at least one container according to the present disclosure is therefore much more efficient than with a blast freezer.

[0018] At the same time the at least one container is protected from contamination with the heat transfer liquid because the at least one flexible membrane separates the heat transfer liquid from the at least one container.

[0019] According to the disclosure the detrimental effects mentioned initially are suppressed or even eliminated because of the homogeneous and swift freezing.

[0020] In the context of the present disclosure the at least one flexible membrane is also referred to as the at least one membrane.

[0021] It is clear for persons skilled in the art that the freezing device and the freezing method according to the present disclosure can just as effectively be used for thawing operations as for freezing operations, as the heat is simply transferred in the other direction compared to the freezing operation. In other words, for thawing operations the heat transfer from the medium in the at least one container through the at least one container and the flexible membrane to the heat transfer liquid goes the other way, i.e., vice versa.

[0022] The heat transfer liquid has a lower freezing point than the medium. This ensures that the at least one container can be extracted from the chamber after the medium in the at least one container is frozen.

[0023] The heat transfer liquid according to the present disclosure can be understood as any substance which has a liquid portion and is fluid, i.e., any substance with a finite viscosity. This encompasses for example also most, if not all, dispersions, gels, and the like. According to the present disclosure the finite viscosity allows the heat transfer liquid to adapt to the shape of the at least one container such that the heat transfer surface can be maximised as mentioned.

[0024] The at least one flexible membrane is essentially impermeable for the heat transfer liquid such that the at least one container, such as a bottle, is separated from the heat transfer liquid.

[0025] Essentially impermeable for the heat transfer liquid can be understood to mean that on the time scales the at least one flexible membrane is used in contact with the heat transfer liquid during the freezing and thawing processes the heat transfer liquid does not penetrate through the at least one flexible membrane in a quantity that would detrimentally affect the integrity of the at least one container, or the medium contained therein, and preferably the pharmaceutical production process as a whole.

[0026] The at least one container does not have to be introduced or received in the chamber in its entirety. It is rather sufficient for the present disclosure that the at least one container is inside the chamber so far that the desired degree of freezing or the desired temperature is present in the at least one container.

[0027] In preferred embodiments the at least one container is received inside the chamber in its entirety.

[0028] In preferred embodiments the medium in the at least one container is brought to a temperature between -30°C and - 90°C, preferably between -35°C and -85°C and particularly preferably between -40°C and -80°C.

[0029] The at least one container does not have to be completely filled with the medium. Although a high degree of filling, e.g., to more than 70%, 80%, or 90% of the volume, of the at least one bottle is preferred, embodiments are conceivable where a lower degree of filling is conceivable or beneficial.

[0030] For example, it may be advantageous to use a smaller degree of filling if there is not enough medium to be frozen available. It may be better to freeze this medium with a bottle filled to a smaller degree of filling instead of discarding this medium.

[0031] Protection is also sought for an arrangement comprising the freezing device according to the present disclosure and the at least one container, preferably filled with the medium, received in the chamber.

[0032] Media, e.g., liquids and / or suspensions or the like, which can be frozen, transported, stored, and or thawed according to the present disclosure can for example be protein solutions, products of a separation process after a production step, antibody solutions, and / or other highly valuable products or educts in the pharmaceutical, in particular biopharmaceutical, production process.

[0033] Of course, many different kinds of medium can be frozen and thawed with device or method according to the present disclosure.

[0034] Protection is additionally sought for the use of the freezing device or the arrangement according to the present disclosure in a freezing or thawing method according to the present disclosure.

[0035] Particularly advantageous embodiments of the present disclosure are defined in the dependent claims.

[0036] A heat exchanger can be provided which is in fluid communication with the heat transfer liquid when it is disposed in the chamber, wherein the heat exchanger is configured to receive heat from the heat transfer liquid. A heat exchanger makes it possible to easily transfer and discharge the heat the heat transfer liquid receives from the medium (and potentially the at least one container and the at least one membrane and the environment).

[0037] The heat transfer liquid is preferably in the liquid phase, and preferably essentially stable, at least in the temperature range between -50°C to 50°C, preferably at least in the temperature range between -90°C to 50°C. Most freezing and thawing processes in the biopharmaceutical production process happen in the temperature range between -50°C and 50°C such that a heat transfer liquid which is in the liquid phase, and preferably essentially stable, in this range retains the advantages of the present disclosure for most freezing and thawing processes in the biopharmaceutical production process.

[0038] Using a heat transfer liquid which is also in the liquid phase, and preferably essentially stable, in the temperature range between -90°C and 50°C widens the applicability of the present disclosure to freezing and thawing processes which require lower temperatures, e.g., for inhibiting degradation of the medium or proteins contained therein.

[0039] The term "essentially stable" according to the present disclosure can be understood to mean that the temperature transfer liquid does not degrade on the time frames of the freezing and thawing processes in which it is used such that its properties of being liquid and having a lower freezing point than the medium, and preferably the impermeability of the at least one membrane, are affected such that a detrimental influence on the freezing and thawing process results.

[0040] The heat transfer liquid is in preferred embodiments a glycol and / or a silicone oil. A glycol is an aliphatic diol. Certain silicone oils are preferred for low temperature applications because there are silicone oils with freezing points at or below -90°C.

[0041] In preferred embodiments the at least one flexible membrane comprises or consists of a plastic film, preferably a thermoplastic film, particularly preferably a polyethylene film.

[0042] In preferred embodiments the chamber comprises at least one opening, preferably on an upper side of the chamber, for introducing the at least one container into the chamber, preferably wherein the at least one membrane is attached to a rim of the opening, particularly preferably completely all along the rim of the opening.

[0043] The shape of the at least one opening is in preferred embodiments adapted the shape of the at least one container. For example, if the at least one container is of circular or rectangular base area (e.g., a bottle), the shape of the at least one opening is correspondingly circular or rectangular as well as slightly bigger such that the at least one container can be introduced into the chamber with ease.

[0044] If the at least one membrane is attached to a rim of the opening, preferably completely all along the rim of the opening, there is little or no room for the heat transfer liquid to escape and enter a space between the at least one container and the at least one flexible membrane.

[0045] In particularly preferred embodiments there is precisely one opening for every container to be received in the chamber for one freezing operation. The openings in this embodiments therefore define compartments such that every container has a defined position inside the chamber which contributes to process security.

[0046] In particularly preferred embodiments for each container received in the chamber there is exactly one flexible membrane. The advantage of the present disclosure that the heat transfer liquid and the at least one membrane can adapt to the shape of the at least one container can in this way be maximise because each membrane can adapt exactly to one container.

[0047] In particular in connection with having precisely one opening per container and / or the plastic frame mentioned below such embodiments are optimises with respect to effective heat transfer to and from the medium as well as easy and practical manufacturing.

[0048] The chamber, preferably the upper side of the chamber, can in preferred embodiments comprise a plastic frame in which the at least one opening is arranged, and preferably the at least one flexible membrane is attached to the plastic frame by a welding operation. From a manufacturing perspective such embodiments can be preferred because of the ease and practicality of attaching the at least one membrane to the chamber and / or the rim of the opening, in particular if the at least one membrane is a plastic film, preferably a thermoplastic film.

[0049] The chamber can be a metal chamber, for example made from steel, with a plastic top cover or frame, as mentioned before.

[0050] Alternatively, the chamber body is completely made from a plastic. In such embodiments the chamber body can be made from the same plastic as the top cover or frame, or the frame can be embodied integrally with the chamber body.

[0051] Additionally, or alternatively, the chamber can comprise an insulation.

[0052] Preferable embodiments of the insulation comprise a plastic foam, particularly preferably a polyurethane foam, because such foams are simple to produce and acquire, and are very effective heat insulators.

[0053] The freezing device according to the present disclosure can be delivered to the entity acquiring the freezing device with or without the liquid filled into the chamber and / or disposed in the chamber.

[0054] In particularly preferred embodiments the medium is a result and / or an intermediary product and / or an educt in a biopharmaceutical production process. In the context of such processes the present disclosure realises its potential as the media mentioned are extremely hard to produce in large quantities and therefore represent a vast value, not just in a monetary sense, but also in its potential for treating or curing individuals. While the effort in manufacturing and operating freezing devices or carrying out freezing or thawing methods according to the present disclosure may in some embodiments be larger than for blast freezers of the prior art, the advantages for a more efficient and more secure handling of these media outweigh the additional effort by a large margin.

[0055] Further details and advantages of the present disclosure are apparent from the figures and the accompanying description of the figures. The figures show: Fig. 1a schematic side sectional view of an embodiment of a freezing device, Fig. 2a schematic top view of the embodiment of Fig. 1, and Fig. 3another schematic side sectional view of the embodiment of Fig. 1.

[0056] Fig. 1 shows an embodiment of a freezing device 1 which comprises a chamber 3 in which the heat transfer liquid 5 is disposed inside the chamber 3 in a schematic side sectional view.

[0057] The heat transfer liquid 5 in this example is silicone oil, which can be cooled down to -80°C and / or -90°C without freezing or degrading.

[0058] An upper side 9 of the chamber 3 comprises an opening 8 through which a container 2, such as a bottle, filled with the medium 2, in this case a biopharmaceutical liquid such as a protein or antibody solution, can be introduced into the chamber 3.

[0059] A flexible membrane 6 is present which separates the container 4 from the heat transfer liquid 5.

[0060] The chamber 3 and the flexible membrane 6 in this embodiment are made from plastic the exact type of which is chosen to withstand the desired temperature ranges of the heat transfer liquid, for example between -50°C to 50°C or between -90°C to 50°C.

[0061] In this embodiment the flexible membrane 6 is a polyethylene film.

[0062] The flexible membrane 6 is attached to the rim of the opening 8 all along the rim, which is in this exemplary embodiment circular, see Fig. 2.

[0063] The flexible membrane 6 is attached to the rim of the opening by a welding process.

[0064] Fig. 1 shows the container 4 partially introduced into the chamber 3 and partially immersed in the heat transfer liquid 5 which is under certain situations enough to start freezing or thawing the medium 2 in the container 4. In preferred embodiments the container 2 is subsequently fully introduced into the chamber 3 and immersed in the heat transfer liquid 5, see. Fig. 3.

[0065] A heat exchanger 7 is present in the chamber 3. The function of the heat exchanger 7 is to discharge or supply the heat to the heat transfer liquid 5 as necessary to effect the desired freezing or thawing of the medium 2 in the container 4.

[0066] How heat exchangers 7 with this function can be made is in and of itself known to persons skilled in the art.

[0067] Optionally there is an insulation 7 of the chamber 3, for example in the form of a polyurethane foam.

[0068] The thickness of the insulation 11 can for example be 150mm.

[0069] In Fig. 1 the thickness of the insulation 7 is not necessarily drawn to scale in comparison for example to the wall thickness of the chamber 3, but merely indicates the possibility of the presence of an insulation.

[0070] Fig. 2 shows a schematic top view of the embodiment of Fig. 1.

[0071] As can be seen there are six openings 8 although they have not all been furnished with a reference numeral.

[0072] The shape of the openings 8 has in this example be chosen circular corresponding to the circular base shape of the bottles seen in Figs. 1 and 3.

[0073] Of course, six openings 8 are purely to be seen as an example. For concrete applications the number of openings 8 would be chosen by persons skilled in the art according to the needed containers 4 which have to be frozen or thawed at the same instance and potentially according to the available cooling or heating capacity, e.g., of the heat exchanger 7.

[0074] Each of the openings 8 is configured such that one container 4 can be introduced into the chamber 3 through each opening 8. Additionally, although not shown explicitly, in Fig. 2 for each opening there is precisely one elastic membrane 6 such that at each of the openings 8 precisely one elastic membrane 6 separates the respective container 4 from the heat transfer liquid 5. Accordingly, for each compartment comprising an opening 8 and an elastic membrane 6 the situation would be just as or similar to what is depicted in Fig. 1.

[0075] Fig. 3 is another schematic side sectional view of the embodiment of Fig. 1.

[0076] Here, the container 4 has been introduced completely into the chamber 3 and the container 4 is completely submersed in the heat transfer liquid 5.

[0077] As can be seen the heat transfer liquid 5 and the flexible membrane 6 adapt to the shape of the container such that there is a much better heat transfer from the medium 2 in the container 4 through the container 4 and the flexible membrane 6 to the heat transfer liquid 5 compared to the heat transfer with gas instead of liquid in a blast freezer. At the same time the container 4 does not need to be of an exact prismatic shape as would be required by plate freezers.

[0078] Tests the applicant has carried our indicate that the advantage is also present for more irregularly shaped containers 4 than depicted in Figs. 1 and 3. For example, a spherically shaped container 4 or a container with concavities could easily be used for freezing or thawing of media 2 according to the present disclosure.

[0079] For the sake of completeness, it is mentioned that the arrows pointing towards the left in Fig. 3 signify negative heat which is transferred from the heat exchanger 7 to the membrane 6, container 4, and medium 2 inside the container4.

[0080] The control of the heat exchanger 7 can for example be effected by controlling the supply of secondary fluid which supplies or discharges heat from the heat transfer liquid in the heat exchanger 7.

[0081] In preferred embodiments the heat exchanger 7 can be controlled according to the sensor signals of a temperature sensor in the chamber 3 which is in heat communication with the heat transfer liquid 5.

[0082] For example, the heat exchanger 7 can be controlled to keep the heat transfer liquid 5 at a constant -40°C, -50°C, - 80°C, or -90°C or at temperature values between the values listed.List of reference numerals:

[0083] 1freezing device 2medium (to be frozen or thawed) 3chamber 4container 5heat transfer liquid 6flexible membrane 7heat exchanger 8opening 9upper side 10plastic frame 11insulation 12cover

Claims

1. Freezing device or thawing device for a medium (2) to be frozen or thawed comprising - a chamber (3) configured for receiving at least one container (4), preferably at least one bottle, filled with the medium (2), preferably a pharmaceutical liquid, and configured for receiving a heat transfer liquid (5) which has a lower freezing point than the medium (2), - and at least one flexible membrane (6) configured to separate the at least one container (4) from the heat transfer liquid (5), wherein the freezing device (1) has the function that the medium (2) in the at least one container (4) is frozen or thawed by transferring heat from the medium (2) through the at least one container (4) and the at least one membrane (6) to the heat transfer liquid (5), or vice versa.

2. Freezing device or thawing device according to claim 1, wherein a heat exchanger (7) is provided which is in fluid communication with the heat transfer liquid (5) when it is disposed in the chamber (4), wherein the heat exchanger (7) is configured to receive heat from the heat transfer liquid (5).

3. Freezing device or thawing device according to one of the preceding claims, wherein the heat transfer liquid (5) is in the liquid phase, and preferably essentially stable, at least in the temperature range between -50°C to 50°C, preferably at least in the temperature range between -90°C to 50°C.

4. Freezing device or thawing device according to one of the preceding claims, wherein the heat transfer liquid (5) is a glycol and / or a silicone oil.

5. Freezing device or thawing device according to one of the preceding claims, wherein the at least one flexible membrane (6) comprises or consists of a plastic film, preferably a thermoplastic film, particularly preferably a polyethylene film.

6. Freezing device or thawing device according to one of the preceding claims, wherein the chamber (3) comprises at least one opening (8), preferably on an upper side (9) of the chamber (3), for introducing the at least one container (4) into the chamber (3), preferably wherein the at least one membrane (6) is attached to a rim of the opening (8), particularly preferably completely all along the rim of the opening (8).

7. Freezing device or thawing device according to claim 6, wherein there is precisely one opening (8) for every container (4) to be received in the chamber (3) for one freezing operation.

8. Freezing device or thawing device according to claim 6 or 7, wherein the chamber (3), preferably the upper side (9) of the chamber (3), comprises a plastic frame (10) in which the at least one opening (8) is arranged, and wherein the at least one flexible membrane (6) is attached to the plastic frame (10) by a welding operation.

9. Freezing device or thawing device according to one of the preceding claims, wherein the chamber (3) comprises an insulation (11), preferably comprising a plastic foam, particularly preferably a polyurethane foam.

10. Freezing device or thawing device according to one of the preceding claims, wherein for each container (4) received in the chamber (3) there is exactly one flexible membrane (6).

11. Freezing device or thawing device according to one of the preceding claims, wherein the heat transfer liquid (5) is disposed in the chamber (3).

12. Arrangement comprising the freezing device or thawing device (1) according to one of the preceding claims and the at least one container (4), preferably filled with the medium (2), received in the chamber (3).

13. Freezing method or thawing method for freezing or thawing a medium (2), preferably a pharmaceutical liquid, disposed in at least one container (4), particularly preferably a bottle, wherein the method comprises the following steps - at least partially, preferably completely, immersing the at least one container (4) filled with the medium (2) in a heat transfer liquid (5), which has a lower freezing point than the medium (2), - using at least one flexible membrane (6) to separate the at least one container (4) from the heat transfer liquid (5), and - transferring heat from the medium (2) through the at least one container (4) and the at least one membrane (6) to the heat transfer liquid (5) until the medium (2) in the at least one container (4) is frozen, or transferring heat from the heat transfer liquid (5) through the at least one membrane (6) and the at least one container (4) to the medium (2) until the medium (2) in the at least one container (4) is thawed.

14. Freezing method or thawing method according to claim 13, wherein the medium (2) is a result and / or an intermediary product and / or an educt in a biopharmaceutical production process.

15. Use of a freezing device or thawing device (1) according to one of the claims 1 to 11 and / or an arrangement according to claim 12 in a freezing method or thawing method according to claim 13 or 14.

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