DE102017115428B4 - Cold finger device for a disposable container - Google Patents

Abstract

Cold finger device (26) for a disposable container (36) for use in a disposable bioreactor device with a cold finger (10), which has a hollow base body (12) for receiving a heat transfer medium, and a flexible one surrounding the cold finger (10) Hose sleeve (28) which is tightly fastened on the one hand in an upper region of the base body (12) and on the other hand to a first sterile connector (32).

Description

The invention relates to a cold finger device for a disposable container, in particular for use in a disposable bioreactor device.

During the cultivation of organisms, large amounts of heat are released through metabolic processes. So that the optimal cultivation temperature can be maintained and readjusted during the cultivation process, the bioreactor must be able to dissipate this heat. With conventional reusable bioreactors made of glass or stainless steel, the heat is dissipated via a double-walled boiler. A cooling liquid flows through the jacket, via which the heat is transported away.

Another possibility for regulating the temperature in a conventional bioreactor is the so-called cold finger. Conventional cold fingers are usually designed as stainless steel sleeves that are filled with a cooling medium or through which it flows. The cold fingers are in direct contact with the medium in the bioreactor and thus ensure effective heat dissipation.

In the field of single-use bioreactors in particular, where a flexible container is used as a cultivation chamber, temperature control is a challenge. Currently, double-walled holders for single-use bioreactors are available. The holder encloses the flexible disposable container so that a liquid flowing between the walls of the holder can be used to regulate the temperature. However, due to the film material of the flexible container, the heat transfer is impaired. It should also be noted that air pockets can occur if the flexible container is not properly attached to the inner wall of the holder. Such air inclusions also impair the heat transfer. Furthermore, the heat exchange area is often limited. Thus, in particular, cultivations with high heat production, such as that of microorganisms, are difficult to implement in single-use bioreactors.

From the US 8 910 494 B2 a container arrangement with a flexible disposable container is known which can be inserted into a support container. The support container has baffles on its inner support surface, in each of which a temperature control system is integrated. The tempering system of the baffles either has parallel tubes through which a tempering liquid can be passed at a predetermined temperature, or the tempering system is formed by two vertical plates arranged at an acute angle to one another through which the tempering liquid can flow. In both cases, the baffles with their temperature control systems do not come into direct contact with the liquid medium in the container, since the flexible wall of the disposable container separates the liquid medium from the baffles.

the EP 2 034 007 A2 shows a fermenter with a heating lance which is held in the upper area of the fermenter by a sealing passage. The heating lance has an outer tube which is closed at the lower end with a blind plate. An inner tube, which is open at the lower end, runs concentrically in it. The inner tube ends a little way above the blind plate. At the upper end, the inner tube is closed with a lid. A warm heating medium flows via a flow line downwards into the space between the outer and the inner tube as far as the blind plate 61. From there, the heating medium rises upwards in the interior of the inner tube. The inner pipe communicates with a return line,

The introduction of certain additional components, such as a stirrer drive, an emptying pipe or a sensor, into a container through hose-like sheaths that are connected on the one hand to a container opening and on the other hand to the respective component is from the EP 2 065 085 A1 , the DE 10 2013 109 819 A1 or the DE 10 2013 109 820 A1 known. After insertion, the additional components are separated from the contents of the container by the casing.

The object of the invention is to enable an effective and, overall, the most cost-effective heat exchange possible in a disposable container filled with medium.

This object is achieved by a cold finger device with the features of claim 1. Advantageous and expedient embodiments of the cold finger device according to the invention are specified in the associated subclaims.

The invention provides a cold finger device for a disposable container, which is provided in particular for use in a disposable bioreactor device. The cold finger device according to the invention comprises a cold finger which has a hollow base body for receiving a heat transfer medium. The cold finger device further comprises a flexible hose sleeve surrounding the cold finger. The hose casing is tightly fastened on the one hand in an upper region of the base body and on the other hand to a first sterile connector.

The first sterile connector of the cold finger device can be connected to a suitable second sterile connector provided on the bioreactor. In the sterilized state, the tubular casing then provides a sterile barrier between the Sterile connector and the upper outer area of the base body, which protrudes from the disposable container of the bioreactor device and is in contact with the (usually non-sterile) environment. This construction makes it possible to insert a sterilized cold finger into the interior of a disposable bioreactor without fear of contamination of the medium located therein, since the flexible hose casing seals the interior of the bioreactor from the environment. For this purpose, the hose sleeve does not necessarily have to be attached directly to the base body or to the first sterile connector of the cold finger device, but elements can also be arranged in between, if necessary. It is crucial that the sealing effect with respect to the upper outer area of the base body and the first sterile connector is guaranteed. It can be inserted into the interior of the single-use bioreactor without any problems, since the hose casing is flexible and can be folded or squeezed when it is inserted.

In contrast to elaborately designed and expensive double-walled or cooling sleeve solutions, the inexpensive cold finger device according to the invention enables more effective heat exchange, since the cold finger, more precisely the wall of the base body surrounding the cavity, represents a heat exchange surface, the inside of which is in direct contact with the heat transfer medium , while at the same time the outside of the wall is in direct contact with the medium (culture medium or cell suspension) in the disposable container. The cold finger device according to the invention is therefore particularly suitable for microbial applications in which large amounts of heat are produced.

In addition, the cold finger protruding into the disposable container of the cold finger device according to the invention can be used specifically as a flow breaker during the mixing of the medium in the disposable container in order to improve the mixing efficiency and the introduction of oxygen. For a further increase, several cold finger devices according to the invention can be used as flow breakers.

Another advantage results from the fact that the cold finger device according to the invention can be subsequently installed in a disposable bioreactor by means of the sterile connector. Accordingly, the single-use bioreactors in which the cold finger device according to the invention are to be used can be designed to be very space-saving.

A particularly advantageous aspect of the invention is that the cold finger device, including the base body, the flexible hose sleeve and the first sterile connector (and any other components), can be sterilized separately as a prefabricated structural unit. The individual components of the cold finger device are preferably each formed from a plastic material that can be sterilized in particular by gamma rays, beta rays or by autoclaving.

In principle, a preheated heat transfer medium can simply be filled into the cavity of the cold finger base body, which then absorbs or emits heat from the medium in the disposable container once. However, in order to achieve effective heat dissipation or heat supply and controlled temperature control of the medium in the disposable container, an inlet connection for feeding the heat transfer medium into the cavity of the base body and an outlet connection for discharging the heat transfer medium from the cavity should be provided. The connections should be arranged in the upper area of the base body, that is to say outside the area of the base body which is sealed by the hose casing and which comes into contact with the medium in the disposable container.

To ensure that the heat transfer medium fed into the cavity of the base body absorbs or releases as much heat as possible before it is removed from the cavity again, a guide tube can be provided that connects to the drain connection and protrudes into the cavity. The guide pipe thus prevents the heat transfer medium from taking the shortest route between the inlet connection and the outlet connection (so-called "short-circuit flow").

So that the main body of the cold finger can be pushed into the interior of the disposable container in a simple manner, the first sterile connector of the cold finger device should have a correspondingly dimensioned inner opening. Depending on the shape of the base body, it is sufficient if at least the lower area of the base body can be pushed through.

A holding element protruding from the main body can also be provided which limits the sliding of the main body through the opening of the first sterile connector. In this way, a defined penetration depth can be specified.

The holding element protruding from the base body can also be used advantageously for fastening the upper end of the hose casing.

According to a further development of the invention, at least one light source is attached to the base body of the cold finger. The irradiation with light is of particular importance in the cultivation of plant cells. The heat generated when the medium is irradiated in the disposable container can then be immediately absorbed and dissipated by the heat transfer medium in the cold finger.

The invention also provides a disposable bioreactor device with a flexible disposable container for receiving a medium, in particular a cultivation medium or a cell suspension, and with a cold finger device according to the invention as described above.

The main body of the cold finger can preferably be introduced into the interior of the disposable container through a port in a side wall, a top wall or a bottom of the disposable container.

The cold finger device is best attached and sealed by connecting the first sterile connector of the cold finger device to a second sterile connector attached to the port and the base body of the cold finger at least partially (i.e. at least the lower area of the base body) through the two sterile connectors into the interior of the disposable Container is inserted.

In this case, an edge of the first sterile connector can form a stop for the holding element protruding from the base body of the cooling finger, if such a holding element is provided.

As already indicated, several cold finger devices according to the invention can be introduced into the interior of the disposable container in order to increase the mixing efficiency and the introduction of oxygen into the bioreactor. The cold finger devices form flow breakers for the medium in the disposable container while it is being mixed.

• - 1 einen Kühlfinger für eine erfindungsgemäße Kühlfingervorrichtung;
• - 2 eine erfindungsgemäße Kühlfingervorrichtung;
• - 3 die Kühlfingervorrichtung vor der Konnektierung mit einem Bioreaktor;
• - 4 die Kühlfingervorrichtung nach dem Konnektieren und Einbringen in den Bioreaktor;
• - 5a und 5b mehrere in einen Bioreaktor eingebrachte Kühlfingervorrichtungen, die gleichzeitig als Strömungsbrecher fungieren, in Seitenansicht bzw. Draufsicht; und
• - 6 eine in einen Bioreaktor eingebrachte Kühlfingervorrichtung mit integrierter Lichtquelle.

Further features and advantages of the invention emerge from the following description and from the accompanying drawings, to which reference is made. In the drawings show:

• - 1 a cold finger for a cold finger device according to the invention;
• - 2 a cold finger device according to the invention;
• - 3 the cold finger device prior to connection to a bioreactor;
• - 4th the cold finger device after connection and introduction into the bioreactor;
• - 5a and 5b several cold finger devices introduced into a bioreactor, which simultaneously function as flow breakers, in a side view or top view; and
• - 6th a cold finger device with an integrated light source inserted into a bioreactor.

In 1 is a cold finger 10 for a cold finger device for a disposable container, which is intended in particular for use in a disposable bioreactor device.

The cold finger 10 has a hollow body 12th on, which in the embodiment shown here has a substantially cylindrical shape. In an upper first end face 14th of the main body 12th are an inlet connection 16 and a drain connection 18th arranged, through which a circulating heat transfer medium (which acts as a coolant or heating medium depending on the operating mode) into the cavity 22nd of the main body 12th can be conveyed in and out of this again. This is indicated by the arrows in 1 indicated.

To the drain connection 18th closes up in the vicinity of the lower, second end face 20th of the main body 12th into the cavity 22nd protruding guide tube 24 so that the heat transfer medium only comes out of the cavity 22nd can be transported out if it was previously in the guide tube 24 has occurred. This ensures that the heat transfer medium takes up a large part of the cold finger 10 flows through it before it leaves it again in order to be able to absorb or release as much heat as possible.

The basic body 12th and the connections 16 , 18th are made of a solid plastic that can be sterilized, in particular by gamma rays, beta rays or autoclaving. At least the main body 12th but can also be formed from a flexible, for example film-based plastic material, which can also be sterilized. The thickness of the cavity 22nd surrounding wall of the base body 12th is dimensioned in such a way that, on the one hand, it allows a good heat exchange with the environment, but on the other hand it reliably withstands the pressure of the circulating heat transfer medium.

In 2 is a cold finger device 26th with a cold finger 10 shown as described above. The cold finger 10 is made of a foldable hose cover 28 surround. An upper first end of the hose cover 28 is on one of the main body 12th radially protruding retaining element 30th fastens and seals the essential part of the outer area of the base body 12th , especially the lower area of the base body 12th , from the connections 16 , 18th away. The holding element 30th itself is in turn on an upper section of the cold finger 10 attached, here in the area of the upper first Face 14th . A lower second end of the hose cover 28 is on the outer circumference of a first sterile connector 32 tightly fastened all around. The first sterile connector 32 has an internal opening 34 through which the base body 12th fits through, but not the retaining element 30th .

The hose cover 28 is made of a flexible plastic material that can also be sterilized, in particular by gamma rays, beta rays or by autoclaving. Thanks to the tight fastening of its ends, the hose casing 28 act as a sterile barrier (or at least as part of one), as will be explained in more detail below. There is also the first sterile connector 32 consists of a sterilizable material, the in 2 Cold finger device shown 26th prefabricated as a unit and sterilized as a whole.

3 shows schematically a single-use bioreactor device with a flexible single-use container 36 , in which there is a medium to be mixed, in particular a culture medium or a cell suspension. There is an agitator for this 38 provided, which is not described in detail here. The disposable container 36 is to just below the upper container wall 40 filled with the medium. The interior of the disposable container 36 with the medium is through one in the upper container wall 40 formed port 42 accessible. The port 42 is with a second sterile connector 44 provided on the first sterile connector 32 is matched. This means that the second sterile connector 44 with the first sterile connector 32 can be tightly connected and an inner opening of the same or similar size as the first sterile connector 32 Has.

As in 3 indicated by the arrows, the two sterile connectors 32 , 44 tightly connected, so that the interior of the disposable container 36 in flow connection with the space between the base body 12th of the cold finger 10 and the surrounding hose casing 28 stands, but not with the environment outside of the hose sleeve serving as a sterile barrier 28 .

After connecting the two sterile connectors 32 , 44 becomes the cold finger 10 down into the disposable container 36 introduced, as in 4th shown. The base body is used for this 10 through the sterile connectors 32 , 44 pushed down, with the hose cover 28 is folded or compressed. The cold finger 10 can be pushed down until the retaining element 30th on the edge of the first sterile connector 32 rests on (if necessary with a folded-up hose cover in between 28 ).

After insertion, the cold finger protrudes 10 in the disposable container 36 , being a substantial part of the body 12th is in direct contact with the medium in the disposable container. On the other hand are the inlet connection 16 and the drain connection 18th outside of the disposable container 36 freely accessible. Thanks to the hose cover serving as a sterile barrier 28 is the one about the connections 16 , 18th accessible cavity 22nd of the cold finger 10 hermetically from the inside of the disposable container 36 separated, which thanks to the sterile connectors 32 , 44 and the one close to the upper portion of the body 12th attached hose cover 28 is tightly closed.

For tempering (cooling or heating) the medium in the disposable container 36 becomes a heat transfer medium through the cold finger 10 pumped. In cooling mode, this is done via the inlet connection 16 supplied heat transfer medium has a lower temperature than the medium in the disposable container 36 . There is therefore a heat transfer from the medium in the disposable container 36 to the heat transfer medium in the cold finger 10 instead, the wall of the base body 12th of the cold finger 10 whose outside is in direct contact with the medium in the disposable container 36 and the inside of which is in direct contact with the heat transfer medium, serves as a heat exchange surface. The heated heat transfer medium is discharged through the drain connection 18th discharged.

In heating mode, the heat exchange takes place in the opposite direction, ie the supplied heat transfer medium gives off heat through the wall of the base body 12th to the medium in the disposable container 36 off before it comes off the cold finger 10 is discharged.

In the 5a and 5b an embodiment is shown in which multiple cold finger devices 26th are used. Due to the larger number of cold finger devices 26th and the overall increased effective heat exchange area enables faster or finer adjustable heat exchange. The cold finger devices serve at the same time 26th as a flow breaker arrangement to ensure more effective mixing of the medium in the disposable container 36 to reach. The cold finger devices 26th are arranged for this purpose at locations suitable for flow technology.

Another embodiment is in 6th shown. Here is a light source 46 on the cold finger 10 attached, with of course also several light sources 46 in the cold finger 10 can be integrated. For certain processes, such as the cultivation of plant cells, irradiation of the medium is required in the disposable container 36 with light required or conducive. The irradiation can, however, result in undesirable heat generation. A heat transfer to the medium in the disposable container 36 If necessary, however, can be largely prevented by removing the from the light source 46 heat given off by the cold finger 10 pumped heat transfer medium is discharged.

List of reference symbols

10

Cold finger

12th

Base body

14th

upper face

16

Inlet connection

18th

Drain connection

20th

lower face

22nd

cavity

24

Guide tube

26th

Cold finger device

28

Hose cover

30th

Retaining element

32

first sterile connector

34

opening

36

Disposable container

38

Agitator

40

upper container wall

42

port

44

second sterile connector

46

Light source

Claims (13)

Cold finger device (26) for a disposable container (36) for use in a disposable bioreactor device with a cold finger (10), which has a hollow base body (12) for receiving a heat transfer medium, and a flexible one surrounding the cold finger (10) Hose sleeve (28) which is tightly fastened on the one hand in an upper region of the base body (12) and on the other hand to a first sterile connector (32). Cold finger device (26) according to Claim 1 , characterized in that it can be sterilized as a prefabricated structural unit, in particular by gamma rays, beta rays or by autoclaving. Cold finger device (26) according to Claim 1 or 2 , characterized by an inlet connection (16) for feeding the heat transfer medium into the cavity (22) of the base body (12) and an outlet connection (18) for discharging the heat transfer medium from the cavity (22) of the base body (12). Cold finger device (26) according to Claim 3 , characterized in that a guide tube (24) protruding into the cavity (22) connects to the drain connection (18). Cooling finger device (26) according to one of the preceding claims, characterized in that the first sterile connector (32) has an inner opening (34) through which the base body (12) of the cooling finger (10) can at least partially be pushed. Cooling finger device (26) according to one of the preceding claims, characterized by a holding element (30) protruding from the base body (12) which limits the base body (12) from being pushed through the opening (34) of the first sterile connector (32). Cooling finger device (26) according to one of the preceding claims, characterized in that an upper end of the hose casing (28) is attached to a holding element (30) protruding from the base body (12). Cooling finger device (26) according to one of the preceding claims, characterized in that at least one light source (46) is attached to the base body (12) of the cooling finger (10). Disposable bioreactor device with a flexible disposable container (36) for receiving a medium and a cold finger device (26) according to one of the preceding claims. Disposable bioreactor device according to Claim 9 , characterized in that the base body (12) of the cold finger (10) through a port (42) in a side wall, a top wall (40) or a bottom of the disposable container (36) into the interior of the disposable container ( 36) is insertable. Disposable bioreactor device according to Claim 10 , characterized in that the first sterile connector (32) of the cold finger device (26) can be connected to a second sterile connector (44) attached to the port (42), the base body (12) of the cold finger (10) at least partially through the sterile connectors (32) , 44) can be introduced into the interior of the disposable container (36). Disposable bioreactor device according to one of the Claims 9 until 11 , characterized in that an edge of the first sterile connector (32) forms a stop for a holding element (30) protruding from the base body (12) of the cooling finger (10). Disposable bioreactor device according to one of the Claims 9 until 12th , characterized in that several cold finger devices (26) in the interior of the disposable container (36) can be inserted and form flow breakers for the medium in the disposable container 36 when it is mixed.

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