EP4196567A1

EP4196567A1 - Device for a sterile liquid transfer

Info

Publication number: EP4196567A1
Application number: EP21769049.4A
Authority: EP
Inventors: Holger MORSCHETT; Niklas TENHAEF
Original assignee: Forschungszentrum Juelich GmbH
Current assignee: Forschungszentrum Juelich GmbH
Priority date: 2020-08-14
Filing date: 2021-07-30
Publication date: 2023-06-21
Also published as: DE102020004956A1; WO2022033615A1

Abstract

The invention relates to a device for a sterile liquid transfer and to a system containing multiple devices according to the invention. The invention also relates to a device and a system for coupling one or more bioreactors to automated or robotizable liquid transfer equipment. The invention also relates to a method for producing the device according to the invention and to the use thereof.

Description

DEVICE FOR THE STERILE FLUID TRANSFER

The invention relates to a device for sterile liquid transfer, a method for its production and its use.

In biotechnology, bioreactors are standard equipment in production, research and development. For example, they are used routinely for the development and optimization of production processes or for the phenotyping of microorganisms, yeasts or fungi. In the development environment in particular, such devices are used under constantly changing questions or conditions. This requires a comparatively high level of flexibility, for example with regard to the process control, the size of the bioreactors and different sampling or analysis or the use of other different analysis devices in the periphery of the bioreactors.

In the operation of such reactors, inter alia, two typical operations occur. On the one hand, the addition of liquids, which has to be done continuously or in pulses (discontinuously), e.g. B. the addition of an inoculum or an inducer, and on the other hand the removal of sample volume for analysis purposes, such as a biomass determination or a metabolite analysis.

Traditionally, bioreactors, in particular small-scale systems on a laboratory scale, are sampled manually, for example with syringes, via sampling ports or corresponding manual dosing is carried out. Pump-based systems for adding or removing samples are also used. Some either remove culture broth or have an additional integrated cell separation, such as filtration. Alternatively, there are occasionally automated bioreactor systems in which one or more bioreactors are integrated directly into a sterile robot that can both take samples and add liquids, such as pipetting robots or so-called liquid handling systems. Such system solutions are very complex in their arrangement and consequently suffer from the disadvantage of not being very flexible, particularly not very flexible in terms of location, usable or convertible. Another serious disadvantage is that they have to be accommodated in a sterile environment, such as a so-called safety workbench (clean bench) or a laminar flow module, in order to ensure sterile sample handling. A further disadvantage of the known complete systems is also expressed in the lack of compatibility of individual elements with conventional equipment used in classic biotechnology. For example, the sterile sample handling unit cannot be included different, conventional laboratory reactors of common design, unless all devices can be accommodated in a sterile room unit. Even a simple retrofitting of common bioreactors with, for example, an automated/robot-controlled sampling unit from complete systems on the market is not possible if a complex sterile environment has to be set up for everything. This is problematic, for example, in small-scale systems on a laboratory scale or where a wide variety of equipment (reactors and/or peripheral devices) must be flexibly combined for constantly changing problems. The effort involved in providing a space-consuming and maintenance-intensive clean room module to ensure sterile sampling is always very high and therefore relatively too expensive for many applications in biotechnology and therefore not economical.

In addition, in the classic operation of biotechnology processes, operations regularly occur that require the personal presence of an operator, often also during the night. This is the case when liquids need to be added in pulses or samples need to be taken in pulses for analysis purposes. In addition to the disadvantageous obligation to be present at unconventional day and night times, manual operation has potentially higher fluctuations and error rates.

Even pump-based sampling systems, so-called autosamplers, cannot completely eliminate the disadvantages mentioned above. They either only allow samples to be taken or only liquids to be added. i.e. only unidirectional removal/dosing is possible, but not a change between the two operations. Thus, the flexibility of such systems is significantly limited. Furthermore, such autosamplers can generally only be preset in such a way that the samples are withdrawn from the reactor at fixed time intervals. This has the disadvantage that liquid is removed from the bioreactor according to a fixed time pattern even if this is unnecessary for the reaction. This represents some waste as the samples are then discarded. In addition, such excessive, z. T. unnecessary, sampling is an invasive procedure that influences the sampled process itself.

Robotized system solutions are currently only available as complete systems and have various of the disadvantages mentioned above. In particular, due to their complexity, they are very specific and therefore inflexible in use. In addition, they are spatially dependent on a sterile environment and their use is therefore locally inflexible. It is therefore the object of the invention to provide an alternative which no longer has the disadvantages of the prior art.

One object of the present invention is to provide a simple, inexpensive and sustainable alternative for sterile handling of sample liquids, which is equally suitable for both removing and adding liquids and is also suitable for automated or robotized operation. A further object of the present invention is to provide a sample handling unit for a sterile liquid transfer which is decoupled, ie independent, from a space-consuming sterile room environment, ie for example an inherently sterile, decoupled, transportable sample handling unit. A further object of the present invention is to provide an alternative device or a system solution that allows compatibility with current conventional equipment in the field of biotechnological processes and thus ensures a high level of local flexibility and compatibility with existing equipment or systems. Furthermore, the object of the present invention is to enable a sample handling unit to be compatible with existing robot types, for example common pipetting robots. A further object of the present invention is to enable an uncomplicated retrofitting of current bioreactors with an automated/robot-controlled sampling unit that is independent of a complex sterile room environment. It is a further object of the present invention to provide devices or systems and variants thereof for sample handling in which errors or measurement inaccuracies due to manual handling are largely ruled out and in which an unnecessary loss of liquid from the bioreactor, for example due to a sample volume that is too large Dead volume during sampling or unnecessarily many samplings does not occur.

These objects are advantageously achieved by the present invention as further detailed below.

The brief description of the present invention follows first, without the subject matter of the invention being thereby limited.

Advantageous configurations result from the entire disclosure below, ie both from the short general description and the following specific description, all claims, exemplary embodiments and further variants as well as the illustrations of the present invention. The subject matter of the present invention is a device for sterile liquid transfer with a first and a second component, characterized in that the first component has a cone and the second component has an integrated channel for extending the cone, the inlet of the cone being accessible via a sterile barrier , the transition from the cone to the integrated channel is reversibly tapered and/or closed by an elastic element and the outlet of the integrated channel has a connector element for connection to peripheral devices in biotechnology.

The invention also includes a device in which the outer diameter of a transfer channel (ADTK) introduced into the integrated channel to the inner diameter of the integrated channel (ID,K) in the ratio of ADTK:ID,K of at least 1:1.3 to 1:2 , preferably from at least 1:1.3 to 1:1.75, particularly preferably from 1:1.4 to 1:1.6, in particular from 1:1.5.

Also included according to the invention is a device in which the second component has a depression as a bearing device for the elastic element.

The subject matter of the present invention is also a device that enables unidirectional or bidirectional sterile liquid transfer.

Also included according to the invention is a device that enables manual and/or automated or robotizable sterile liquid transfer.

In a variant of the present invention, a device is included which is made of material which can be sterilized, preferably autoclaved, and is biologically compatible.

A further variant of the present invention includes a device which is characterized in that it can be used flexibly in terms of location and outside of a clean room module.

The subject matter of the present invention is also a system made up of a plurality of devices according to the invention, the devices being arranged in any spatial arrangement, preferably in a row.

The subject matter of the present invention is also a method for producing a device according to the invention or a system according to the invention.

The subject matter of the present invention is also the use of a device according to the invention or a system according to the invention for coupling to one or more bioreactors, analysis devices and/or peripheral devices of biotechnology. The invention also includes the use of a device according to the invention or a system according to the invention for manual and/or automated or robotized sterile liquid transfer by means of a pipetting robot or a so-called liquid handling system.

The present invention is explained further below, but this does not have a limiting effect on the subject matter of the invention.

The subject matter of the present invention is a device for sterile liquid transfer with a first and a second component, characterized in that the first component has a cone and the second component has an integrated channel for extending the cone, the inlet of the cone being accessible via a sterile barrier , the transition from the cone to the integrated channel is reversibly tapered and/or closed by an elastic element and the outlet of the integrated channel has a connector element.

According to the invention, the cone can have different configurations. “Cone” within the meaning of the invention is a funnel or cone or a shape similar to a truncated cone. For example, it can have an extension, a so-called “neck”. Or the cone according to the invention has no extension or no “neck” and ends with the underside of the first component.

According to the invention, the connector element serves in particular to connect the device according to the invention to peripheral devices in biotechnology. According to the invention, “connector element” is to be understood, for example, as a connecting element or coupling piece or a bridging element that is able to sterilely connect the device according to the invention to common peripheral devices in biotechnology, even outside of a clean room system. This can be a hose, for example, or a tubular connection with or without a hose. The tubular connection can be made of steel, plastic or injection molding, for example. The connection to the second component of the device according to the invention can take place, for example, by plugging, welding, fusing, pegging, screwing or other common connection variants that are known to the person skilled in the art. If a tubular connection with a hose is used, the hose can, for example, be slipped on, slipped on, welded or clamped, screwed or be made using other common connection variants that are known to the person skilled in the art. If only one tube is used as the connector element, it can be firmly fitted or pressed into a recess in the second component or welded to the second component. Peripheral devices can be, for example, a valve, a bioreactor, a pump, devices for sampling or addition, devices for sample analysis, a microscope, mass spectrometer, HPLC (high performance liquid chromatography), a flow cytometer (flow cytometer), a hose or hose set, preferably pre-sterilized and sealed sterile, or an extension connection with adapters of any size for all common inlets/outlets (ports) of bioreactors or fermenters, although this list is not exhaustive. According to the invention, another pipetting robot or another liquid handling system is also conceivable as a peripheral device.

A variant of a connector element according to the invention is a tube or channel, which in the broadest sense also includes a hose. It is advantageously inserted and permanently installed in the rear exit area of the integrated channel of the second component. The connector element and the second component are preferably made of the same material. This can be metal or plastic. According to the invention, stainless steel or titanium or polyethylene, polypropylene, polystyrene and/or waterproof materials or waterproof plastics for additive manufacturing (3D printing) are preferred. However, a combination of different materials, which are then permanently installed together, is just as advantageous. For example, this can be metal and plastic. In a further variant, the connector element is welded to the rear outlet of the second component. For this purpose, the exit area of the integrated channel of the second component can be recessed in a corresponding size, for example milled out, in order to be able to partially accommodate the connector element, so that the latter protrudes from the second component.

In further variants of the present invention, the connector element with tubular connection, preferably the part of the connector element protruding from the second component, has an area with a roughened surface in order to ensure increased adhesion, for example for connection to a peripheral device. This is particularly advantageous in the case of a connector element made of metal with a tubular connection with a hose. According to the invention, the tubular connection of the connector element can have, for example, one or more grooves, notches, small balls or other raised configurations that bring about an adhesion-enhancing, for example corrugated, surface. This has the advantage that the hose can be connected to the tubular connection firmly, securely and permanently in a sterile manner.

According to the invention, the connector element serves to make the device according to the invention compatible with any desired or required peripheral device of biotechnological process control. In order to ensure that the device according to the invention is a represents a closed and therefore sterile system and also outside of a clean room system serves the purpose of being sterilely connected to any periphery of the biotechnological process control, it is necessary that the connector element of the second component, similar to the sterile barrier in the first component of the device according to the invention, the system the device according to the invention closes sterile.

For this purpose, in further variants of the present invention, the device according to the invention can have a connecting element or closure element on the connector element. For example, a sterile barrier can be attached, analogously to a sterile barrier as installed on the first component. This variant is useful, for example, if the connector element has a recess into which a hose can be inserted. Furthermore, the connector element z. B. be completed by a tube that is sealed sterile. In a further variant of the present invention, such a termination can also represent a connection between the connector element and the peripheral device and through a hose or a hose set, preferably pre-sterilized and sealed in a sterile manner, with extension connections or additional adapters of any size for all common inlets and outlets ( Ports) be realized by bioreactors or fermenters. The respective connection can be made, for example, via a Luer-Lock®, or it can be plugged, flanged, welded, screwed or squeezed, or it can be made using other adapters.

In a variant of the device according to the invention, a plastic tube, also as a set, can be used as a closure element for a one-time use (single use). The hose can be welded directly to the connector element, for example. In a further variant of the device according to the invention, a reusable design of the device according to the invention and all of its components is preferred. Advantageously, the device according to the invention has the option of reversibly connecting the hose that is used or worn out as a result of repeated use. The invention includes connection or closure elements that are attached by flanging or plugging onto the connector element according to the invention, since most screwable adapters could cause further dead volume. For this purpose, the connector element according to the invention, as already described above, has an area with a roughened surface, which ensures increased adhesion for the connecting or sealing tube. The roughened surface is realized by one or more grooves, notches, beads or other raised configurations that can have an adhesion-enhancing effect, such as a corrugated surface, among other things. Other conceivable connection or closure measures are, for example, Luer-Lock®, flanging, welding, screwing or squeezing. Such measures are known to those skilled in the art. For the purposes of the present invention, a thermoplastic elastomer (TPE) such as Bioprene or silicone is suitable as the hose material because it can be sterilized or autoclaved, is robust and biologically inert. In all variants of the present invention, hoses with the smallest possible internal diameter are useful. In advantageous variants, the inner diameter of the TPE is 1 mm, for example. In this way, the volume of the hose section and thus an undesired dead volume can be limited in an advantageous manner. Smaller inner diameters of the hoses connected to the connector element can become problematic because of a possible blockage, especially with viscous media and/or filamentous microorganisms in the culture broth. This must be taken into account and adapted depending on the device design and the requirements of the biological process, which is known to the person skilled in the art.

In a further embodiment variant of the present invention, a transfer channel according to the invention can be introduced into the cone via a sterile barrier and further introduced into the integrated channel of the second component via an elastic element. For this purpose, the sterile barrier can be covered with a suitable sterile agent, such as an aqueous alcoholic solution or another suitable solution (manually by the operator or automated or robotized by the pipetting robot). This advantageously supports sterile liquid transfer through the transfer channel.

"Sterile barrier" is defined according to the invention as an elastic, after puncture, z. B. by means of a transfer channel, reclosing element. In a variant of the present invention, a sterile barrier can have a flat surface or a raised or a partially raised surface. The sterile barrier according to the invention can be selected from the group of materials such as silicone or rubber. In terms of the present invention, sterile barriers are conceivable as single-use solutions. However, preferred variants are sterile barriers that can be reused. According to the invention, such sterile barriers meet the requirement of being sterilizable or autoclavable. Sterilization can be accomplished by methods known to those skilled in the art, such as rinsing with alcohol-based disinfectants such as ethanol, isopropanol, or mixtures thereof, or by hydrogen peroxide, or by autoclaving, or by gamma radiation, or by UV irradiation. The invention includes sterile barriers such as a septum, particularly preferably a silicone septum.

The invention thus includes a variant of the present device in which the sterile barrier is an elastic element that closes again after it has been pierced. In a preferred variant of the present invention, the sterile barrier is a septum, preferably a silicone septum. Also included according to the invention is a device in which a sterile barrier is arranged in a holder. According to the invention, the sterile barrier can be inserted into the holder according to the invention by simply being pushed onto or pressed on and at the same time easily replaced, for example if it shows signs of wear and is no longer able to fulfill its function.

The sterile barrier holder itself has structures so that it can be firmly connected to the first component of the device according to the invention within the meaning of the present invention. In one variant, the sterile barrier holder can be attached, in another variant it can be screwed on. The holder can be attached, for example, by means of surface structures known to those skilled in the art on the holder and the inner wall of the first component, such as protuberances or indentations or grooves that enable clicking in and out. A so-called bayonet lock is also conceivable. In a preferred variant of the device according to the invention, the sterile barrier holder and the first component have a rotary thread that is compatible with one another, so that the holder can be screwed into the first component. Advantageously, the sterile barrier holder according to the invention can be easily replaced and at the same time can be firmly connected to the first component.

The sterile barrier holder of the present invention thus fulfills several functions according to the invention. On the one hand, it ensures that the sterile barrier does not slip during assembly in the device according to the invention and thus seals the device in a sterile manner; on the other hand, it ensures that the sterile barrier does not slip when it is pierced and in particular when a transfer channel is pulled out, is not dragged along and is pulled out of the device in whole or in part. The sterile barrier holder according to the invention thus advantageously ensures that sterile liquid transfer is guaranteed both in manual and in automated or robotized operation.

In addition, the device according to the invention and its variants are characterized in that they form a sterile unit that enables sterile liquid transfer independently of a clean room module or a clean room environment. Because of the sterile, sealed space above the cone of the first component, a firm and tight connection between the two components, a reversibly tapered or closed elastic element and a connector element connected to the outlet of the second component, which in turn is sealed to the outside with a sterile closure is, a self-contained sterile unit is formed in the embodiment of the device according to the invention. Due to the arrangement and configuration according to the invention, advantageous variants of the device according to the invention are integrated sterile barriers, which are created by special holders or storage devices inside the device. One or more supports or connector element(s) firmly fixed inside the device allow the peripheral connection, sampling, dosing or analysis elements to be moved to the outlets of the two components and the conical or integrated channel(s).

According to the invention, an “elastic element” means an elastic ring, preferably an O-ring or sealing ring. According to the invention, all elastic elements within the meaning of the invention that are made of temperature-stable elastic materials (thermoplastic elastomers) are included. In different variants of the present invention, the material of the elastic element is selected from the group consisting of silicone, caoutchouc, such as Perbunan, or gum arabic. Rubber is advantageous according to the invention.

According to the invention, a wide range of materials can be used for an elastic element, a connector element in the form of a hose or a sterile barrier in the sense of the present invention. Thermoplastic elastomers, polymers, composites or fibrous materials or mixtures thereof are advantageous. In general, the materials for these elements should be sufficiently reversibly deformable to ensure reliable and sterile sealability and secure functionality. According to the invention, this can also include a fabric tube as a connector element.

Also included according to the invention is a device in which the second component has a depression that serves as a bearing device for the elastic element. When the first and second components of the device according to the invention are assembled, the elastic element located in the depression is compressed. This depression ensures that the elastic element does not slip during assembly of the first and second components of the device according to the invention. This would have the disadvantage that the device would leak. Furthermore, the sink according to the invention has the effect that the elastic element is sufficiently, but not too strongly, compressed or squeezed together when the two components according to the invention are assembled. The person skilled in the art knows which material and which size should be selected for an O-ring in order to achieve the desired properties.

Advantageously, the transition of the cone into the integrated channel is reversibly tapered and/or closed according to the invention by an elastic element. The elastic element according to the invention thus fulfills several functions in an advantageous manner; it seals the device in the area of the connection of the first and second component, it closes the integrated channel of the second component reversible and it tapers the cone of the first component of the device according to the invention.

In advantageous variants of the present invention, the elastic element according to the invention prevents an undesired backflow of liquids, for example from the bioreactor or other peripheral devices that are connected to the device according to the invention via the connector element according to the invention. That is, the elastic element of the present invention has the advantageous effect that no check valve or the like has to be used. The elastic element used according to the invention also has the advantage that the liquid that may be entrained with the transfer channel from the reactor chamber via the integrated channel (e.g. when taking a sample or liquid) is scraped off on the elastic element and thus remains in the second channel. In a particularly advantageous manner, this contributes to the elastic element of the present invention optimally minimizing the formation of dead volumes during liquid transfer.

A further advantage of the elastic element according to the invention of the device according to the invention is that the elastic element serves as a shock-absorbing guide aid for an impingement of a transfer channel introduced into the device according to the invention that deviates from the ideal line. When inserting a transfer channel into the device according to the invention, the cone of the first component serves, so to speak, as a guiding aid for the introduced transfer channel, in order to center the latter for entry into the integrated channel of the second component. The elastic element present according to the invention further buffers this centering in order to advantageously prevent a very thin transfer channel, for example, from being damaged or bent during manual, automated or robotized entry into the integrated channel, or its tip even breaking off. As a result, the elastic element according to the invention makes it possible for the integrated channel to be designed as narrow as possible or necessary, in order to be able to minimize the dead volume during liquid transfer as much as possible.

Resources as well as time and costs are thus advantageously also reduced by means of the present invention, since the number or the exchange rate of transfer channels used during liquid transfer in the biotechnological process control can be significantly reduced.

A "transfer channel" according to the invention can be understood in the sense of the present invention, for example, as a probe, a pipette, a hollow body, a hollow needle, a cannula, a mandrel, a tube, a tubular element or a sample channel for sample removal or addition . According to the invention, the transfer channel can be introduced by hand, that is to say manually, or in an automated or robotized manner. Also included is a further variant of the device according to the invention, in which the inner diameter of the integrated channel (IDIK) according to the invention is at least 30%, preferably at least 30% to 100% (i.e. twice as large), particularly preferably at least 30% to 75%, very particularly preferably from 40% to 60%, in particular at least 50%, is greater than the outer diameter of the transfer channel (ADTK) according to the invention. According to the invention, all variants with all conceivable continuous or intermediate steps of 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 are included , 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 , 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 , 99 and 100%.

In a further variant of the present invention, a device is also included in which the outer diameter of a transfer channel (ADTK) introduced into the integrated channel to the inner diameter of the integrated channel (IDIK) has a ratio of ADTK:ID _iK of at least 1:1.3 . In a further variant of the present invention, a device is also included in which the outer diameter of a transfer channel (ADTK) introduced into the integrated channel to the inner diameter of the integrated channel (IDIK) in the ratio of ADTK: IDiK from 1:1.3 to 1:2 stands. A further variant of the present device according to the invention is characterized in that the outer diameter of a transfer channel (ADTK) introduced into the integrated channel to the inner diameter of the integrated channel (ID _iK ) in the ratio of ADTK: IDiK of at least 1: 1.3 to 1: 1 .75 stands. Also included according to the invention is a variant in which the ratio ADTK:IDIK is at least 1:1.4 to 1:1.6. A further advantageous variant of the present invention has an ADTK:ID^ ratio of at least 1:1.5. The present invention also includes all variants of seamless intermediate ranges of the ratios ADTK:IDIK..SO are also included according to the invention all intermediate ranges from at least 1:1.30 to 1:2, such as 1:1.31, 1:1.32 , 1:1.33, 1:1.34, 1:1.35, 1:1.36, 1:1.37, 1:1.38, 1:1.39, 1:1.40, 1 :1.42, 1:1.43, 1:1.441:1.45 1:1.461:1.471:1.481:1.49, 1:1.50, 1:1.51, 1:1.52, 1: 1.53, 1:1.54, 1:1.55, 1:1.56, 1;1.57, 1;1.58 1;1.59,1:1.60, 1:1.61 , 1:1.62, 1:1.63, 1:1.64, 1:1.65, 1:1.66, 1:1.67, 1:1.68, 1:1.69, 1 :1.70, 1:1.71, 1:1.72, 1:1.73, 1:1.74, 1:1.75, 1:1.76, 1:1.77, 1:1 .78, 1:1.79, 1:1.80, 1:1.81, 1:1.82, 1:1.83, 1:1.84, 1:1.85, 1:1.86 , 1:1.87, 1:1.88, 1:1.89, 1:1.90, 1:1.91 1:1.921:1.931:1.941:1.951:1.961:1.97 1:1.981:1 .99, 1:2.

In a further variant of the present invention, a device is included in which the outer diameter of the transfer channel (ADTK) is between 0.25 - 5.0 mm, preferably at least 0.3 mm, particularly preferably at least 0.5 mm and in particular at least 1 .0 mm. It is therefore understood, for example, for the ratio of ADTK:ID;« of at least 1:1.3 to 1:2 that with an outer diameter of the transfer channel of at least 0.25 mm, the inner diameter of the integrated channel is at least 0.325 to 0.5 mm amounts to. With an outside diameter of the transfer channel of 0.3 mm, the inside diameter of the integrated channel is at least 0.39 to 0.6 mm according to the invention. With an outside diameter of the transfer channel of 0.5 mm, the inside diameter of the integrated channel is at least 0.65 to 1.0 mm according to the invention. With an outside diameter of the transfer channel of 1.0 mm, the inside diameter of the integrated channel is at least 1.3 to 2.0 mm according to the invention. With an outside diameter of the transfer channel of 1.5 mm, the inside diameter of the integrated channel is at least 1.95 to 3.0 mm according to the invention. According to the invention, all continuous areas and all intermediate areas of the diameter of the respective transfer channel in relation to the integrated channel are also included. For example, with an outer diameter of the transfer channel of 5.0 mm, the inner diameter of the integrated channel is at least 6.5 to 10.0 mm according to the invention. According to the invention, all variants with all conceivable intermediate steps and continuous steps for transfer channel outer diameters between 0.25-5.0 mm and the resulting inner diameters for the integrated channel are included. The freely selectable outside diameter of the transfer channel thus determines the inside diameter of the integrated channel according to the invention. In particular, in a further advantageous variant of the present invention, the outside diameter of the transfer channel is 1.0 mm with an inside diameter of the integrated channel of 1.5 mm.

Due to the ratio of ADTK:IDiK according to the invention of at least 1:1.3 to 1:2, the present invention is characterized in an advantageous manner in that a large dead volume, which is disadvantageous when taking a sample with conventional devices, is optimally adapted to the required or available channel Diameter is adjusted and minimized. The inner diameter of the integrated channel can be determined, for example, by the preferred outer diameter of a robotic transfer channel, ie a robotic needle.

In a variant of the present invention, a device is included which is made of material which can be sterilized or autoclaved and is biologically inert or biocompatible. In a further variant of the present invention, a device is included which is made of material which is recyclable. Other variants according to the invention include a device which mainly or also only partly contains materials which can only be used once, ie for single use. Another variant of the present invention includes a device in which the components are made of metal or plastic polymers, preferably stainless steel, titanium, polyethylene, polypropylene, polystyrene and/or waterproof materials or waterproof plastics for additive manufacturing (3D printing). are made.

According to the invention, metals or plastic polymers, preferably stainless steel, titanium, polyethylene, polypropylene, polystyrene and/or waterproof materials or waterproof plastics for the additive manufacturing (3D printing).

A metal device according to the invention can be produced by milling or powder injection molding. A variant according to the invention of the present device made of plastic can be produced by 3D printing, injection molding, stereolithography or powder bed fusion. A device according to the invention in which at least its first and second component, its sterile barrier holder and its connector element consists of a single continuous material is characterized by the particular advantage of minimizing the risk of fractures, which means that leaks associated with unwanted contamination are almost completely avoided. In the case of components made of metal, they can be screwed according to the invention; in the case of components made of plastic, these can be welded, for example.

A further variant of the present invention is characterized in that the completely assembled device can be autoclaved or sterilized. It is particularly advantageous that the device according to the invention can be stored preassembled and autoclaved or sterilized for a long time and, if required, can be used very flexibly and quickly in terms of time and place. This minimizes the risk of leakage or contamination and also advantageously allows the device according to the invention and the system according to the invention containing one or more devices according to the invention to be used flexibly in terms of time and location, with sterile liquid transfer being ensured at all times. In addition, the use of reusable material contributes to the long service life of a device according to the invention or a system according to the invention, as a result of which resources are saved in the long term and costs are reduced.

A further variant of the present invention includes a device which is characterized in that it can be used flexibly in terms of location and outside of a clean room module. Here, the device according to the invention and its variants are characterized in that they form a sterile unit that enables sterile liquid transfer independently of a clean room module or a clean room environment. Because through the sterile sealed space above the cone of the first component, a firm and tight connection between the two components, a reversibly tapered or closed elastic element and a connector element connected to the outlet of the second component, which in turn is sealed to the outside with a steep closure element a self-contained Stehl unit in the embodiment of each device according to the invention and its variants. The connector element can be a hose or can be connected to a hose that is sealed in a sterile manner, for example with a Luer-Lock® connection, and/or can be closed with a cover.

The subject matter of the present invention is also a device that enables unidirectional and/or bidirectional sterile liquid transfer. According to the invention, this means liquid withdrawals and/or liquid additions. Sampling during a biotechnological process, for example, aims to analyze process parameters, such as B. pH value, oxygen concentration, temperature, optical density of the culture broth etc. or the analysis of biomass, metabolites and products, whereby this list is not to be understood as exhaustive. For the purposes of the invention, the addition of liquids means the addition required during a biotechnological process, e.g. B. of inoculum, inducer, selection media such as antibiotics, or solvents, although this list is not to be understood as exhaustive. In terms of the present invention, the device according to the invention and variants thereof allow both continuous and discontinuous, i. H. discontinuous, timed or pulsed liquid transfer. According to the invention, the present device is further characterized in that it additionally enables manual and/or automated or robotized sterile liquid transfer. The present invention is advantageously suitable for automated sampling, which according to the invention takes place independently of the pump. Thus, the present invention differs significantly from pump-controlled autosampler operation with all its disadvantages.

According to the invention, a device or a system of the type described above and variants thereof for coupling one or more bioreactors to automated or robotized liquid transfer devices, selected from the group containing pipetting robots or liquid handling systems, is also included within the meaning of the invention. and/or for coupling to biotechnology peripheral devices.

The subject matter of the present invention is also a system made up of a large number of several devices according to the invention, the devices being arranged in any spatial arrangement. According to the invention, several devices are preferred, which are aligned are arranged. Variants according to the invention also include systems in which several such alignments of devices are arranged next to one another. The individual devices are not connected to one another. In a further variant, other geometric arrangements can also be implemented. For example, circular or spiral or elliptical arrangements are also possible. Due to the advantageously high flexibility when using the device according to the invention, the spatial arrangement of the individual devices or systems according to the invention can always be adapted as a function of a conventional pipetting robot or liquid handling system.

By way of example, but not by way of limitation, a reusable device according to the invention is manufactured from metal by means of machining processes such as turning, drilling and/or milling. The first component is cut to the desired size and then various bores are milled. Core drilling is carried out for the septum holder, with the resulting “bottom” being face-milled. A through hole is made in the center of the bottom of the septum holder, which initially forms a channel. A cone is then milled into the previously drilled channel using a countersink. The cone can be milled down to the underside of the first component (referred to according to the invention as a variant without a neck) or end just before the underside of the first component, so that the cone has a so-called neck as a remnant of the channel in the lower area of the first component. These variants are further described in the following figures. A thread for the septum holder is then cut into the metal and several holes are drilled for later screwing the two components together. The septum holder is turned to size from round material, for example, and an inner bore is drilled in such a way that it is centered over the cone. Finally, an external thread is cut into the septum holder for screwing to the first component.

The second component of the device according to the invention is also cut to the desired dimensions and milled to match the first component. Then a continuous bore is made in the second component, which forms the integrated channel according to the invention. Using a countersink, a countersink is then milled into the previously drilled integrated channel, which forms the seat for the elastic element. Matching the holes in the first component for later screwing the two components together, holes are made on the top of the second component for the screw connection to the upper half and threads are cut. On the underside of the second component is the integrated channel drilled out from below, i.e. slightly enlarged, so that the connector element can be attached or accommodated there. In a variant of the present inventive device, a tubular connection of the connector element can be inserted into the drilled integrated channel and firmly connected to the second component, for example by welding. In variants of the present invention, the drilling of the integrated channel made from the underside of the second component can be made to different depths in the second component. This is selected depending on the connector element used. A tubular connection (with/without hose) requires the integrated channel to be drilled deeper from its underside than a recess on the underside of the second component, into which a connector hose can be inserted directly without a tubular connection.

In a further variant of the device according to the invention, feet can be attached to the underside of the second component, which are used for mounting on adapter plates. These adapter plates are used to adapt the device according to the invention to an inserted, freely selectable unit of a common pipetting robot and have the function of a positioning aid in the robot.

Several of the devices mentioned above can be mounted in any spatial arrangement on an adapter plate and form a system according to the invention made up of several devices. In another variant of the present invention, the steps described above for producing the device according to the invention are arranged multiple times in a row on a single first component, or several such rows are arranged next to one another in order to form a system of devices according to the invention. The individual devices are not connected to one another. Such a system can also be arranged on an adapter plate and used for positioning in a pipetting robot.

For the assembly of the two components according to the invention to form a device according to the invention, the elastic element is inserted into the recess of the second component and the first component is placed and screwed together by means of screws via the bores provided. Other functionally similar fasteners such. B. plug or click connections are also included according to the invention. Then the septum is inserted over the cone of the first component and fixed using the septum holder, which is screwed into the first component. Again, other functionally similar fasteners such. B. plug or click connections according to the invention. This firm fixation of the septum is important because the device according to the invention is thereby sealed sterilely from above on the one hand and on the other hand when piercing the transfer channel through the septum in the integrated channel of the second component does not slip or even when the transfer channel is pulled out the septum is carried along and consequently the device can no longer be operated steeply as a result. Furthermore, the connector element according to the invention is attached and fixed to the underside of the second component and the device according to the invention is thereby closed in a sterile manner from below. Finally, the entire device according to the invention can be attached to an adapter plate via feet.

By way of example, but not limitation, a device according to the invention is manufactured from disposable material using injection molding technology or additive processes or 3D printing.

In the production of the device according to the invention from plastic using injection molding technology, the first component is created using a previously produced negative mold with injection molding. In this case, negatives are provided in the mold for all recesses, such as recesses for the septum holder, cone and, if necessary, the small neck on the cone, so that these are then directly available in the molded part. Threads for the septum holder and the holes for screwing the first component to the second component are not required and are omitted. The second component is also produced in injection molding using a negative mold. In this case, negatives are provided in the mold for all cutouts, such as a cutout for the integrated channel, a depression for the elastic element, and a cutout for the seat of a connector element, so that these are subsequently present directly in the molded part. The procedure for this is familiar to the person skilled in the art and is based on the prior art. The septum holder is also injection molded using a negative mold. Here, negatives are provided in the mold for all recesses, such as the recess for the inner "bore" of the septum holder, so that these are then directly available in the molded part. The elastic element is then inserted into the second component and assembled with the first component and then welded. The septum is the first component to be inserted and then the septum retainer is inserted followed by welding the septum retainer. The connector element is then inserted into the recesses provided in the second component and also welded. Finally, the entire device can be mounted or welded onto an adapter plate.

In the manufacture of the device according to the invention from plastic via additive processes (3D printing), in contrast to the above processes in which metal bores etc. are either subsequently introduced or, as with injection molding, are reproduced in the form of negatives for the first component , simply no material applied to the appropriate positions in 3D printing. Threads for the septum holder or the bores for screwing the two components together are not required and are omitted. The same applies to the second component. With additive processes, the tubular connection of the connector element is, for example, a direct part of the component and does not have to be manufactured separately and then attached. Overall, the specialist should pay attention to the choice of material and the production technology, since the components must be waterproof. Especially with fused deposition modeling-based techniques (FDM; melt stratification), the connection between the layers is usually not conclusive enough to ensure this. A method is therefore advantageously chosen which is able to produce watertight materials, such as, for example, stereolithography or multi-jet modelling. Alternatively, where the process does not allow for the production of waterproof materials (as in FDM), a material is selected which is rendered waterproof by appropriate post-treatment. For example, the material used here is acrylonitrile butadiene styrene (ABS), which is vaporized with acetone after manufacture to make the device waterproof. The person skilled in the art is familiar with the corresponding procedures.

The septum holder is also manufactured using an additive process, in which case, in contrast to the processes in which bores etc. are either subsequently introduced or, for example, In injection molding, for example, negatives are used in the mold, while 3D printing simply means that no material is applied to the corresponding positions.

The elastic element is then inserted into the second component and the first and second components are joined together and glued or welded using suitable techniques known to those skilled in the art. The septum and septum retainer are then inserted and the septum retainer glued or welded using suitable techniques known to those skilled in the art. The connector element, possibly with a tubular connection, is inserted into the recesses provided in the second component and glued or welded using suitable technology according to the prior art. Finally, the entire device can be glued or welded to an adapter plate.

The subject matter of the present invention is also the use of a device according to the invention or a system according to the invention for coupling to one or more bioreactors and/or automated or robotized liquid transfer machines and/or to peripheral devices in biotechnology. A preferred variant includes coupling the device according to the invention or the system according to the invention to one or more bioreactors, one or more pipetting robots and the peripheral devices required in the biotechnological process control. In the context of the present invention, pipetting robots are to be understood as meaning all common liquid transfer machines. For example, this can be pipetting robots or liquid handling systems. Examples of a conventional type are at providers such. B. Tecan, Hamilton, Beckman Coulter or Perkin Elmer or other commercially available. According to the invention, any conventional or future-developed automatic machines can be coupled to the device according to the invention or the system according to the invention via interchangeable adapter plates. The peripheral devices within the meaning of the present invention include, for example, one or more valves, bioreactors, pumps, devices for taking or adding samples, devices for sample analysis, microscopes, mass spectrometers, HPLC or flow cytometers, this being a non-exhaustive selection and other conventional ones Includes devices that the skilled worker routinely uses in biotechnological processes.

The invention also includes the use of a device according to the invention or a system according to the invention independently of a clean room environment for manual and/or automated or robotized sterile liquid transfer, preferably by means of a pipetting robot, particularly preferably by means of a liquid handling system. The device according to the invention or a system according to the invention can be mounted on interchangeable adapter plates, which means that it can be used flexibly and is compatible with all current or future systems of liquid transfer machines or robots.

The device according to the invention and the system according to the invention with the described large number of advantageous elements are characterized in particular by the fact that an independent sterile unit is provided which is self-contained.

Due to the sterilizability or autoclavability of the self-contained unit according to the invention, the device or system of the present invention represents a piece of equipment that can be used universally, even outside of a clean room environment, i.e. independently of sterile workbenches or any integrated system solutions or housings , interchangeable, locally changeable and flexible, with minimal space requirements, non-static and highly compatible for the conversion or retrofitting of existing automated or robotized liquid transfer machines via exchangeable adapter plates.

Further advantages of the invention result from the dependent claims and from the following description of exemplary embodiments of the invention, which are shown schematically in the drawings. Uniform reference symbols are used in the drawings for identical or similar components. Features described or illustrated as part of one embodiment may also be used in another embodiment, to obtain another variant of an embodiment of the invention.

The subject matter of the invention is explained in more detail below with reference to figures, without the subject matter of the invention being restricted thereby. It is shown:

FIG. 1: Sections through embodiments of the device for sterile liquid transfer

Figure 2: Sections through other embodiments of the device for sterile

Fluid transfer with a cone without a neck

Figure 3: Sections through other embodiments of the device for sterile

Liquid transfer for a connector element without a tubular connection

FIG. 4: perspective representations of embodiments of the device for sterile liquid transfer

FIG. 5: Perspective representations in which several devices from FIG. 4 are arranged in a system for sterile liquid transfer

FIG. 6: Perspective representation of FIG. 5 as a wireframe representation

FIG. 1 shows sections of the device according to the invention in three variants. The first section on the left shows an embodiment of the device according to the invention comprising a first component 1 and a second component 2 for sterile liquid transfer with a view of a transfer channel 9 introduced into the device and with a view of the elastic element 7. In the second variant (middle) of Figure 1 a section is shown with a view of the elastic element 7 but without a view of the transfer channel 9. In the third variant (on the right) a section is shown without the elastic element 7 and without a transfer channel 9. The third variant (on the right) in FIG only for a better illustration of the individual sections of the device according to the invention, such as the view of the existing sink 11 for receiving the elastic element 7. In a device put into operation, the presence of the elastic element 7 is preferred and essential for the reasons mentioned above.

The first component 1 and the second component 2 can be made of metal or plastic polymers. The metal can be stainless steel or titanium. The plastic polymers can be polyethylene, polypropylene, polystyrene or waterproof materials or waterproof plastics for additive manufacturing (3D printing). The device with the first and second component (1, 2) can preferably be made of stainless steel or polypropylene. In all 3 variants of FIG. 1, the cone 3a in the first component 1 has a so-called neck 3b. This neck 3b can have a further guiding function when guiding the transfer channel 9 via the cone 3a into the integrated channel 4 of the second component, but is not essential. Necking can occur during fabrication of a metal fixture if the cone is not lowered to the bottom of the first component. Its presence/absence has no significant impact on the functionality of the present device.

The integrated channel 4 is reversibly narrowed and/or closed at its entrance by the elastic element 7 . The elastic element 7 can be made of silicone, rubber, for example Perbunan, or gum arabic. Rubber is advantageous according to the invention. The person skilled in the art also knows which material and size should be selected for an O-ring in order to achieve the desired properties. Correlations with the correlation between the diameter of the O-ring of the elastic element 7 and its reversible compression properties are known in the prior art.

When using an inner diameter of the integrated channel 4 with IDIK of 1.5 mm, an elastic element 7 made of rubber with an outer diameter of 3 mm and an inner diameter of 1 mm and a cord thickness of 1 mm can be inserted into the 0.75 mm deep depression 11 are inserted in order to rejuvenate the integrated channel 4 and at the same time allow a reversible piercing with a transfer channel 9 with an outer diameter with ADTK of 1.0 mm.

Furthermore, the connector element 8 is shown in FIG. 1 as a variant of the present invention, namely as a connector element with a tubular connection, here for reasons of simplification, without a closure element. The connector element 8 can be closed using a simple closure element or a hose or a hose set, with the hose or hose system in turn being closed by suitable elements.

Aluminum foil, hose clamps, sealing caps, Luer-Lock®, extension connections or additional adapters for all common inlets and outlets (ports) of bioreactors or peripheral devices in biotechnology are preferred for closing the hose or hose sets. The hose or the hose set is preferably closed with a hose clamp.

The hose or the hose set is preferably pre-sterilized and sealed in a sterile manner.

In addition to a hose or hose set, the aforementioned simple closure element can be a plastic or metal stopper or cap made of plastic or metal. The material for the closure element can be stainless steel, titanium, polyethylene, polypropylene, polystyrene or waterproof plastics for additive manufacturing (3D printing). The a simple closure element can also be silicone, rubber, for example Perbunan, gum arabic or bioprene.

The hose or the hose set can be made of common plastic polymers. This can preferably be made of Bioprene, silicone, rubber, for example Perbunan, or gum arabic. The hose or hose set is preferably made of silicone.

All materials used in the device can be sterilized so that the device as a whole can be used as a mobile, closed and sterile system.

The connector element 8 can preferably have a tubular connection in a device made of metal. The connector element 8 can be connected to the device (second component 2) by plugging, welding, fusing, pegging, screwing or other common connection variants.

The connector element 8 can preferably be welded to the second component 2 .

Preferably, the tubular connection of the connector element 8 can have one or more grooves, notches, beads or other raised configurations that cause an adhesion-enhancing, corrugated surface. These variants are not outlined in detail in FIG. 1 for reasons of clarity. Different variants, however, are outlined in FIG.

A hose can preferably be attached to the connector element 8 with a tubular connection. The tube can preferably be made of silicone.

The hose or hose set can be attached to the connector element 8 by plugging, welding, fusing, pegging, screwing or other common connection variants. The hose or the hose set can preferably be slipped onto the connector element 8 with its tubular connection.

The sterile barrier holder 10 fixes the sterile barrier 6 in the first component 1. The sterile barrier holder 10 can be attached or screwed in via a thread. The holder can be attached by means of surface structures known to those skilled in the art on the sterile barrier holder 10 and the inner wall of the first component 1 . This surface structure can be protuberances or indentations or grooves that allow clicking in and out. A bayonet lock is also a preferred variant. In a particularly preferred variant, the sterile barrier holder and the first component are compatible with one another Rotary thread on so that the holder can be screwed into the first component.

The individual connection variants are not outlined. However, they are known to the person skilled in the art by being named and can be provided by the person skilled in the art according to current specialist knowledge.

The sterile barrier 6 can be level (flat) or raised and, due to its material, is characterized by a puncture possibility for the transfer channel 9 .

Sterile barrier 6 preferably a septum. The sterile barrier 6 can particularly preferably be a septum made of silicone. In particular, the sterile barrier 6 is a raised silicone septum.

The space 5 shown in all three variants of FIG. 1 above the sterile barrier 6 can be covered with a suitable sterile agent, such as an aqueous alcoholic solution or another suitable solution. This advantageously supports sterile liquid transfer through the transfer channel. The sterile barrier 6 can preferably be covered with a layer of 70% ethanol.

The device in FIG. 1 with the first and second components (1, 2) can preferably be made of stainless steel, the ratio ADTK:ID,K being 1:1.5 and the outside diameter of the transfer channel 9 being 1.0 mm. The first component 1 has a cone 3a with a neck 3b. The second component 2 has a depression 11 . The elastic element 7 made of rubber is in the form of an O-ring in the depression 11 and has an outside diameter of 3 mm, an inside diameter of 1 mm and a cord thickness of 1 mm. The sterile barrier 6 is a raised silicone septum that is firmly screwed to a sterile barrier holder 10 on the first component 1 via a thread. The connector element 8 has a tubular connection that is inserted into the lower part of the second component 2 and welded. A hose made of silicone is attached to the tubular connection, which is closed sterile with a hose clamp. In this case, the connector element 8 with a tubular connection has corrugations at its end.

FIG. 2 shows further variants of the device according to FIG. 1, in which the cone 3b terminates at the lower end of the first component 1 and thus has no neck. All other elements and properties as described in FIG. 1 also apply to the variants in FIG.

FIG. 3 shows sections through further embodiments of the device for sterile liquid transfer for a connector element 8 without a tubular connection. The following variants can apply both to the embodiments in FIG. 1 and in FIG. 2 and are therefore not limiting for the invention. Here, Figure 3 shows examples of variants of Figure 2. The connector element 8 can preferably be represented solely by a hose, a hose set or another analogous functional connection that does not show a tubular connection as in FIGS. The connector element 8 can be introduced into a cutout/milling 8a at the lower end of the component 2 . The connector element can preferably be firmly fitted or pressed into the recess 8a of the second component 2 . If the device is made of metal, the recess can be made by milling. The connector element 8 can preferably be connected to the recess 8a by plugging, pressing in, welding, fusing, pegging, screwing or other common connection variants that are known to the person skilled in the art. The connector element 8 can preferably be firmly pressed into the recess 8a and welded to the second component 2 .

The connector element 8 can preferably be a hose. The hose material can be a thermoplastic elastomer (TPE). The material can preferably be sterilizable or autoclavable, robust and biologically inert. The hose can preferably have the smallest possible inner diameter. The tube can particularly preferably be made of TPE and have an inner diameter of 1 mm. In this way, the volume of the hose section and thus an undesired dead volume can be limited in an advantageous manner. The hose can preferably be made of silicone or bioprene, particularly preferably made of silicone.

FIG. 4 shows embodiments of the device for sterile liquid transfer from FIGS. 1 and 2 in a perspective view. A device for sterile liquid transfer is preferably shown here, namely in perspective obliquely from above, from above and from the longitudinal side.

In FIG. 4, component 1 is firmly connected to component 2 . In the case of a device made of metal, the two components can preferably be connected to one another by fastening elements 12 . The fastening elements 12 can preferably be pins, bayonets or screws. Particularly preferably, the fastening elements can be 12 screws. In a device made by injection molding or additive manufacturing (3D printing), the fasteners 12 may be unnecessary and absent.

The components can preferably be connected to one another by 4 fastening elements 12, particularly preferably by 4 screws. The sterile barrier holder 10 and the space above the sterile barrier 5 can be seen in the view from above and directly from above. Only the sterile barrier holder 10 can be seen in the view from the long side. The connector element 8 can also be seen in this view. In the perspective from the long side it can also be seen that the component 2 can have feet 14 which can be used for mounting on an adapter plate. The feet 14 can preferably be adapted to the adapter plate (not shown), the latter being able to be selected depending on the pipetting robot (not shown) used. The feet 14 can preferably also be used for easier handling of the device, for example during the preparatory assembly, such as the insertion of the elastic element 7 into the depression 11 or the assembly of the connector element 8.

In a further variant of the present invention, the component 2 can have a guide aid 13 in the area of the feet 14 . The guiding aid 13 can preferably be a recess (hole, slot) made in the base 14 in any shape, such as round, square, rectangular or polygonal. The recess can also be milled out later. The guide aid 13 can preferably be configured without sharp edges, particularly preferably round.

In this case, the guide aid 13 can accommodate one or more connector elements 8 . Each connector element 8 can preferably have its own guide aid 13 .

The connector element 8 can preferably be threaded through the guide aid 13 and connected to the outlet of the integrated channel 4 on the underside of the component 2 in the further course of assembly.

The guide aid 13 has the advantage that when using several connector elements in the form of a hose or when using a hose system made up of several hoses, sorting of the hoses is made easier and assignment to the respective peripheral devices is simplified. In addition, the connector elements 8 are pre-assembled more stably on the device due to a further guide.

FIG. 5 shows perspective representations in which several devices from FIG. 4 can be arranged in one system for sterile liquid transfer. A system can be arranged from several devices of Figures 1, 2 or 3 and all conceivable combinations.

The specific arrangement or the specific number of the individual devices can vary and can depend on the selection of the pipetting robot.

Preferably, the system may be an array of devices aligned in a row or with multiple rows arranged side-by-side. However, the arrangement of the individual devices can also be circular, spiral or elliptical. The selection and design of the pipetting needles (transfer channel) of the selected robot model can contain the device or a system containing several devices in its determine design. A system can preferably be a serial arrangement of several devices. The distance between the individual devices can depend on the selection and design of the pipetting needles (transfer channel) of the selected robot model. The distance between the individual devices in a system can preferably be 9 mm.

FIG. 6 shows embodiments of the device for sterile liquid transfer from FIG. 6 in a perspective representation as a wireframe representation. A system made up of several devices for sterile liquid transfer is preferably shown here, namely in perspective obliquely from above, from above and from the longitudinal side. The depiction as a wire grid can be used to produce the devices in FIGS. 1-4 or the system in FIG. 5 by means of injection molding technology or additive processes (3D printing). The illustration in FIG. 6 can preferably be used for 3D printing production.

In the view from the long side of FIG. 6, the device shown as a system can have a connector element 8 that is a tubular connection with a hose 15 that is explicitly shown here. In the preceding figures, a hose, if used, has not been drawn in for reasons of clarity.

In the view from the long side of FIG. 6, the device shown as a system can have a connector element 8 that shows preferred configurations of the tubular connection of the connector element 8, which can be corrugated, grooved or raised (e.g. hose nozzle or hose nipple). a recyclable one made of metal using machining processes such as turning, drilling or milling:

The following specific embodiment is described for 4 devices according to the invention arranged in a system according to the invention, in which the integrated channels all have a so-called neck (see FIG. 1) and are thus suitable for the liquid transfer of 4 bioreactors simultaneously. This production of the specific embodiment is not limiting for the present invention, since it takes place analogously for each individual device for liquid transfer for a bioreactor.

The first component is cut or milled from stainless steel to size (LxWxH 120x40x14 mm). In the first component, 4 core holes for PG13.5 threads (diameter 19.1 mm) with a depth of 12 mm for the septum holder are made and the bottom is milled flat. The four holes are centered along the longitudinal axis of the 4-part system (serial arrangement) placed. The distance to the edge and to each other is 24 mm. A through hole with a diameter of 1.5 mm is then made in the center of each of the 4 core holes (in the septum holder). Then, using a 60° cone transmitter, the continuous bore is provided with a 1 mm deep cone countersink, whereby the cone, possibly with a neck, is formed. A PG13.5 internal thread is cut into the core hole using a thread cutter. Along the longitudinal axis of the system component containing 4 core holes, 5 continuous holes (diameter 3 mm) are drilled on each side at a distance of 5 mm from the edge of the component. The distance from hole to hole is 24 mm in the longitudinal direction. These are later used to firmly connect the first and second components. The 4 septum holders are manufactured by cutting round steel with a diameter of 22 mm to 20 mm each. A continuous inner hole with a diameter of 12 mm is made in each case. A PG13.5 external thread is attached halfway along the length using a thread cutter. If desired, moldings for a spanner (e.g. 19 mm spanner) can be milled into the leftover piece. This makes it easier to screw the septum holder to the upper half. The lower half is cut/milled from stainless steel to size (LxWxH 120x40x8 mm). Analogous to the sample of the first component (as a 4-part system component), continuous bores (diameter 1.5 mm) are made for the integrated channels. On the entry side of the bores, a centered depression is milled out as a seat for the elastic element (diameter 2 mm, depth 0.75 mm). Furthermore, a total of 10 core holes (diameter 2.5 mm) are created on the same side of the component. Alignment is in line with the corresponding holes in the first component (4-part system component). An M3 thread is cut into each of the holes using a tap. On the opposite side of the second component (outlet side of the integrated channels), these are drilled out to a diameter of 3 mm (5 mm depth). These bores form the recess for accommodating the connector elements, here with a tubular connection. A tubular connection (external diameter 3 mm, internal diameter 1.5 mm, length 15 mm) is inserted into the bore and welded for each channel. The connector element, eg a hose, can be connected to this later. Finally, the feet are attached to the same side as the tubular connection of the connector elements for later assembly on an adapter plate (depending on the selected pipetting robot model) in order to position the 4-part system component in the robot.

The elastic elements can now be inserted into the finished depressions in the second component. Then the first and second (system of 4) components are screwed together with 10x M3 screws. A septum is inserted into each first component and this is fixed by screwing in the respective septum holder. The connector elements for the reactor connection are attached to the tubular connection on the underside of the second (system of 4) component and in the additionally fixed if necessary. The completed 4-part system assembly is attached to the robot adapter plate using its feet. Finally, the system according to the invention is sterilized and can be stored or used directly.

Claims

P atentClaims

1. Device for sterile liquid transfer with a first and a second component, characterized in that the first component has a cone and the second component has an integrated channel for extending the cone, the inlet of the cone being accessible via a sterile barrier, the transition from The cone in the integrated channel is reversibly tapered and/or closed by an elastic element and the outlet of the integrated channel has a connector element.

2. Device according to claim 1, characterized in that the outer diameter of a transfer channel (ADTK) introduced into the integrated channel to the inner diameter of the integrated channel (IDIK) in the ratio of ADTK: IDiKV of at least 1:1.3, preferably at least 1:1 3.3 to 1:2, particularly preferably from at least 1:1.3 to 1:1.75, very particularly preferably from 1:1.4 to 1:1.6, in particular from 1:1.5.

3. Device according to one of claims 1 or 2, wherein the outer diameter of the transfer channel (ADTK) is at least 0.25-5.0 mm, preferably at least 0.3 mm, particularly preferably at least 0.5 mm and in particular at least 1.0 mm.

4. Device according to one of claims 1-3, characterized in that the second component has a sink as a storage device for the elastic element.

5. Device according to one of claims 1 -4, wherein the elastic element consists of temperature-stable, elastic material selected from the group containing silicone, rubber or gum arabic.

6. Device according to one of claims 1 - 5, wherein the sterile barrier is an elastic element which closes again after piercing, preferably a septum.

7. Device according to one of claims 1-6, characterized in that the sterile barrier is present in an exchangeable holder.

8. Device according to one of claims 1-7, characterized in that it enables a unidirectional and / or bidirectional sterile liquid transfer.

9. Device according to one of Claims 1 - 8, characterized in that it enables manual and/or automated and/or robotized sterile liquid transfer.

10. Device according to one of claims 1 - 9, characterized in that it is made of material which is sterilizable, preferably autoclavable, and biologically compatible.

11. Device according to one of claims 1-10, characterized in that it is locally flexible and can be used outside of a clean room module.

12. Device according to one of claims 1-11, characterized in that the components are made of metal or plastic polymers selected from the group consisting of stainless steel, titanium, polyethylene, polypropylene, polystyrene and/or waterproof plastics for additive manufacturing .

13. Device for coupling one or more bioreactors to automated and/or robotized liquid transfer devices, selected from the group containing pipetting robots and liquid handling systems, and/or biotechnology peripheral devices.

14. System of several devices according to any one of claims 1-13, wherein the devices are arranged in any spatial arrangement, preferably in a row.

15. Use of a device according to any one of claims 1-13 or a system according to claim 14 for coupling to one or more bioreactors and/or automated and/or robotized liquid transfer machines and/or to peripheral devices in biotechnology.

16. Use of a device according to any one of claims 1 to 13 or a system according to claim 14, independently of a clean room environment for manual and/or automated and/or robotized sterile liquid transfer, preferably by means of a pipetting robot, particularly preferably by means of a liquid -Handling system.