Apparatus for spectral measurement on a bioreactor

Abstract

The present invention generally relates to spectral detection devices for use in process analysis techniques, in particular in biological processes, allowing for precise aligned coupling of a spectrometer with a holder. To this end, the invention provides a spectroscopic detection device (1) for spectroscopic measurement of a sterile sealed measurement volume (2) in biological process analysis, comprising a holder (3) and a spectrometer (5) which can be repeatedly coupled and decoupled from the holder (3), the holder (3) comprising a plastic body (30) and a window (7) which is hermetically fastened in the plastic body (30), the window (7) comprises a metal frame (70) and a window element (74) which is transparent to the radiation to be detected by the spectrometer (5) and which seals an opening (71) of the closed frame (70), the spectrometer (5) having a metal head (50) with an abutment surface (51) which can be brought into abutment with the window (7) in order to couple the spectrometer (5) to the holder (3), and wherein the contact surface (51) is in contact with the window (7) in order to couple the spectrometer (5) to the holder (3). The spectrum detection device (1) comprises a coupling device (10), by means of which the spectrometer (5) and the holding part (3) can be releasably coupled to each other in such a way that the abutment surface (51) and the window (7) are pressed against each other, in particular with a defined force, in the state in which the spectrometer (5) is coupled to the holding part (3).

Description

TECHNICAL FIELD

[0001] The present invention relates generally to a spectroscopic detection device for process analysis technology, in particular for biotechnological processes. The invention relates in particular to a device having a holding portion configured to couple an analytical detection spectrometer to a vessel volume or an aliquot of the volume. By this, the invention also relates to process control of production processes in bioreactor or flow cell systems, in particular for cultivation of biological material. Bioreactors are used for cultivation of microorganisms and animal and plant cells, thereby opening up a broad field of application for biotechnological production processes, in particular for material production and cell and cell product production in the field of biopharmaceuticals (so-called cell farming). There is a general need for further optimization of such processes. In particular for biopharmaceuticals, there is a need to push up product yields, thereby increasing profits. A variety of methods can be employed to manipulate and monitor production processes, to increase product yields and to reduce costs. BACKGROUND

[0002] Processes can be manipulated and monitored by determining the concentration of substrates and products. For cultivation in a bioreactor or photobioreactor, regular sampling is generally required to ensure sufficient process control. Such sampling and determination of substrate and product concentrations is often very time-consuming and is associated with a risk of contamination, which can lead to loss of batches in the bioreactor or photobioreactor, primarily due to the handling when opening the cultivation unit and the resource-intensive off-line analysis outside the respective reactor.

[0003] On the other hand, the manipulation of processes can be optimized for improved yields by real-time process control of key parameters. In order to increase product yields, it is particularly advantageous to monitor parameters such as temperature, metabolites or product-related substances in situ and to adjust the cultivation conditions in real time. For this purpose, in particular spectroscopic detection parameters are suitable, since optical detection enables contactless and contamination-free detection.

[0004] It is known to monitor bioreactors using spectroscopic methods such as Raman spectroscopy and fluorescence spectroscopy and corresponding spectrometers. In this case, the spectrometer is configured to detect one or more analytes present in the vessel volume. The analytes include in particular components of the substrates used in the process and components of the process products.

[0005] Raman spectrometer systems can be used for real-time parameter control. Such Process Analysis Technology (PAT) can be installed in a bioreactor or in any disposable or reusable vessel used for cultivation of biological material, in particular via a fiber-optic light guide and an immersion probe, since such a port forms an opening to the interior of the vessel. The ports of bioreactors or generally process stage units usually comply with specific standards, such as Ingold ports or PG 13.5 ports.

[0006] Generally, a spectrometer comprises, in addition to the spectrometer unit, a fiber-optic light guide and a sensor head of the immersion probe type. However, especially in the case of small containers or other limited spaces, for example in clean room environments, the required space can be limited. Furthermore, in clean room conditions, the operating personnel must wear personal protective equipment, especially gloves, so that their operation should also be mechanically easy to perform. Another problem is that biotechnological processes are often of long duration, and the spectrometer does not need to be assembled to the measuring volume throughout the entire duration, or cannot or should not be kept assembled due to process factors. The latter is the case, for example, in the following situations: - the measuring system cannot be autoclaved; - the measuring system drifts and needs to be recalibrated; - in reference measurements required, for example, for stoichiometry, especially before the logarithmic growth phase; or - the verification period has expired and recalibration is required.

[0007] Therefore, the spectrometer should be easy to couple with the measuring volume in order to perform the measurement. However, if the measuring position of the spectrometer is not accurately reset during repeated measurements, this can result in measurement inaccuracies. A further challenge is that the plastics commonly used in biotechnological processes cannot be precisely positioned due to their inherent tendency to deform. The main problem is that plastic parts, for example due to post-production shrinkage, cannot achieve the required precision.

[0008] Compact Raman spectrometers (see, for example, patent document CN109682791A) can not be integrated into a bioreactor in a high-performance and aseptic-safe manner, or the Raman system can consist of a housing (for example, a 19-inch format housing) in which one or more lasers are installed as light sources, fiber couplers, optical devices and detection units. The housing size can accommodate a laser with a power of up to 500 mW, for example, in order to achieve sufficient sensitivity in the measurement even with the losses caused by fiber technology. The light guide can achieve a certain flexibility through different fiber cable lengths. Similarly, different measurement probes can also be used. The laser power cannot be arbitrarily increased to compensate for losses in the optical path, otherwise the biological analyte would degrade beyond a certain binding threshold. Especially for compact bioreactor systems, which are generally installed with limited free space, the Raman systems of the prior art are limited in their practicality due to their space requirements.

[0009] According to the prior art, there is currently no system on the market that meets the following requirements: implementation of spectroscopic detection (especially Raman spectroscopy or fluorescence spectroscopy) with a compact system while maintaining the integrity of the container. SUMMARY

[0010] It is an object of the present invention to provide a spectroscopic measuring device, preferably for use in bioprocess analytics but also for other processes in a sterile sealed system, which is able to alleviate the above-mentioned problems, i.e. to reduce the space requirement, to simplify the handling, to provide a reproducible coupling to the volume of interaction, i.e. the part of the container volume which interacts with the spectroscopic analysis.

[0011] The technical solution of the present invention to achieve the above-mentioned objects is subject matter of the independent claim. Advantageous technical solutions of the present invention are subject matter of the dependent claims. In view thereof, the present invention provides a spectroscopic measuring device for spectroscopic measurements on a sterile sealed measuring volume in bioprocess analytics, the device having a port or holder and a spectrometer which is reproducibly couplable and decouplable from the holder. The holder comprises a plastic body and a window which is tightly fixed in the plastic body, the window comprising a metal frame and a window element which is transparent for the radiation to be detected by the spectrometer and which tightly closes the opening of the frame. The spectrometer has a metal head comprising an abutment surface which is abuttable against the window to couple the spectrometer to the holder. The spectroscopic measuring device further comprises a coupling device by which the spectrometer and the holder are releasably couplable to each other such that in the coupled state of the spectrometer and the holder the abutment surface and the window are pressed against each other. In this case, the force can in particular be defined or kept within a predetermined or permissible range independently of the operation of the coupling device. The material of the holder is particularly preferably plastic, since plastic is easy to sterilize with ionizing radiation, e.g. gamma radiation. On the other hand, plastic has the disadvantage of low dimensional stability, which can impede an exact alignment of the spectrometer relative to the wall of the container or more generally the wall of the container volume. However, since the spectrometer is directly abutted against the window which is made of a material other than plastic by means of the coupling device, an exact positioning of the spectrometer can surprisingly be achieved in a simple manner even if the holder is mainly made of plastic. For example, a significant advantage of an exact positioning of the holder at least in axial direction is that when the spectrometer is disassembled and reassembled, still comparable intensity values can be obtained. When measuring the intensity of a signal, e.g. a Raman signal with a focused laser beam, the measured value is sensitively dependent on the volume of interaction and thus to a large extent on the position of the focus relative to the window. Therefore, an exact spatial alignment of the spectrometer is very advantageous for obtaining mutually comparable values. For example, in Raman spectroscopy with a focused laser beam, the volume of interaction is essentially determined by the focusing cone. Even in fluorescence spectroscopy, intensity losses are related to reflection losses in phase changes, e.g. from liquid to solid phase, and also to losses in the transition from solid to gaseous phase, among others. Therefore, an exact positioning is also advantageous here.

[0012] In another aspect, the present application also relates to a method for monitoring a process in a bioprocess, wherein a spectrometer is assembled to a holder at a sterile, sealed container volume of a bioprocess facility in order to obtain a spectroscopic detection device according to the present disclosure, wherein signals dependent on the intensity of the radiation entering the spectrometer through the window from the measurement volume are measured by means of the spectroscopic detection device, wherein the spectrometer is disassembled and reconnected to the holder at a later point in time and the measurements are repeated, wherein preferably the signals are compared subsequently. Due to the reproducible alignment of the spectrometer, intensity-dependent signals can be compared with high accuracy even if the spectrometer is repeatedly docked or does not have to remain in the process permanently. Here, the interaction volume refers to the part of the container volume from which the spectrometer receives the radiation for the spectroscopic measurement. This volume can be very small, even essentially limited to the focus point of the focused excitation light beam. In the context of the present disclosure, the interaction volume refers to the volume adjacent to the spectrometer and detected by it in general. In the context of the present disclosure, the container volume refers to the total volume of the container which can be filled with a medium and is sterilely sealed. Accordingly, in the case of a reactor, the container volume is the volume in which the bioprocess takes place. In a flow cell, the container volume is defined by the corresponding volume of the flow cell.

[0013] The container providing the sterile, sealed container volume can be a single-use container ("single use") or a reusable container ("multi-use") in particular. The container volume can also be provided by a flow cell, in particular for so-called upstream or downstream processes, through which the medium to be analyzed can flow, and which can be part of a hose system. Here, the flow cell can also be configured as a single-use component or as a reusable component. A single-use component is used only once and then discarded, while a reusable component can be used again after cleaning and sterilization.

[0014] The containers include, for example, single-use bioreactors implemented as flexible bags (e.g. composite films made of polyethylene (PE) and polyvinyl alcohol (PVA)), single-use mixing systems with stirring means in flexible bags, single-use bioreactors with rigid polymer containers (e.g. polycarbonate (PC)), and reusable bioreactors made of stainless steel.

[0015] All these containers can be sterilized at least once in order to provide a sterile, sealed container volume during the process.

[0016] The device can be used for a variety of different processes, in particular for processes involving living cells, but also for any other reactions and processes, in particular cell-free processes.

[0017] Furthermore, in the context of the present disclosure, a sterile, sealed volume in particular refers to a helium leak rate of less than 1 · 10 -6 mbar · 1 / s, preferably less than 1 · 10 -7 mbar · 1 / s, particularly preferably less than 1 · 10-8 mbar·l / s volume or container.

[0018] The present invention is described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 A partially cut-away perspective view of a connector as part of a coupling device is shown.

[0020] Figure 2 The figure shows the spectrum detection device before the spectrometer and the holding portion are coupled to each other.

[0021] Figure 3 The working position of the device in which the spectrometer is coupled to the holding portion is shown.

[0022] Figure 4 A partially cut-away perspective view of the retaining portion is shown.

[0023] Figure 4a A schematic diagram of another embodiment of a spectral detection device is shown.

[0024] Figure 4b A perspective view of the connector is shown.

[0025] Figure 5 The holder is shown to have a plastic body and a plurality of adapters for adapting to different coupling devices.

[0026] Figure 6 A partially cutaway perspective view is shown before the holding portion is locked with the plugged-in adapter.

[0027] Figure 7 A cross-sectional perspective view is shown after the retaining portion and the adapter are locked together.

[0028] Figure 8 The spectrometer part is shown with a flange arranged on the shaft for fastening the spectrometer to a holding part.

[0029] Figure 9 Shows the application Figure 8 The holding portion of the spectrometer shown.

[0030] Figure 10 Shown Figure 8 The spectrometer shown is coupled to the Figure 9 The retaining portion shown.

[0031] Figure 11 A top view of the holding portion 3 is shown when viewed from the plug-in direction of the spectrometer 5 .

[0032] Figure 12 shows a spectrometer with its housing for fastening to Figure 11 A top view of the receiving portion of the retaining portion is shown.

[0033] Figure 13 The holding portion 3 is shown in a relative position to the housing 54 with the receptacle 44.

[0034] Figure 14 The holding portion is shown in a merging position before locking with the spectrometer.

[0035] Figure 15 The spectrometer 5 is shown in a locked position with the holding portion 3.

[0036] Figure 16 The bioprocess equipment is shown with its holding portion for assembling the spectrometer.

[0037] Figure 17 The spectral detection equipment 1 is shown in a schematic cross-sectional view with the spectrometer 5 and its optical components. DETAILED DESCRIPTION

[0038] Figures 1 to 3 An embodiment of the spectral detection equipment is shown, in which a defined force is generated by a spring, which brings the spectrometer into abutment with the viewing window.

[0039] In general, without being limited to the specific features of the illustrated examples, the basic principle of the present embodiments is that the equipment 1, in particular its coupling device 10, is configured to generate a force by elastic deformation of at least a portion of the spectral detection equipment 1, which brings the abutment face 51 of the spectrometer 5 into abutment with the viewing window 7 of the holding portion 3, which can also be referred to as a port, or according to the patent document DE 102018108325 B4 as a sensor receptacle, or according to the patent document EP 3747983 B1 as a composite element. This principle applies equally to the other embodiments illustrated. Figures 1 to 3 The basic principle of the illustrated embodiments is in particular that a force is generated by at least partially by a spring 103, which presses the spectrometer 5 and the holding portion 3 or the viewing window 7 arranged in the holding portion 3 against each other. In addition to or instead of the spring force, the pressing force can also be provided by a magnetic force of one or more magnets. Figures 1 to 3 A further embodiment that can be implemented in the example of Fig. 1 is that the spectrometer 5 and the holding portion 3 are coupled by means of a screw connection. In process analytical technology, when coupling by means of a screw connection, such as in fiber-optic spectrometer probes or free-beam spectrometers, there are currently still deficiencies in terms of long-term stability and coupling accuracy. The following embodiments are able to overcome the aforementioned deficiencies in a simple manner.

[0040] Figure 1 A partial cross-sectional perspective view of a connecting piece 110 forming part of the coupling device 10 is shown. Figure 2 and Figure 3 The spectral detection equipment 1 is shown as a whole with its holding portion 3 and the spectrometer 5 as well as the coupling device 10.

[0041] The connection 110 of the coupling device 10 comprises Figure 1 a threaded sleeve 101 and a spring 103. The coupling device 10 is configured such that a spring force of the spring 103 acts between the threaded sleeve 101 and the spectrometer 5 when the spring 103 is compressed. In particular, the spring 103 is compressed when the threaded sleeve 101 is moved in axial direction on the holding part 3. Figure 2 and Figure 3 It can be clearly seen that the spectrometer 5 is pressed in axial direction against the window 7 by the spring force. The coupling device 10 further comprises corresponding threads 104, 105 on the holding part 3 and the threaded sleeve 101, respectively, such that the threaded sleeve 101 can be screwed onto the holding part 3 and the spring 103 is compressed by moving the threaded sleeve 101 in axial direction on the holding part 3 and the abutment surface 51 of the spectrometer 5 is pressed against the window 7 by the spring force resulting from the compression of the spring 103. In addition or as an alternative to the spring force, the force for pressing the abutment surface 51 against the window 7 can also be provided by one or more magnets. For this purpose, it is conceivable to arrange one or more magnets on the end face of the metal head 50 of the spectrometer 5 (see Figure 2 ), which then jointly act with the metal frame 70 of the window 7 (see Figure 4 ). Figure 2 and Figure 3 The spectrometer 5 and the metal head 50 and its outer dimensions are only shown schematically.

[0042] In the present example, the thread 105 on the connection 110 is configured as an inner thread and the thread 104 on the holding part 3 is configured as a corresponding outer thread. It is understood by the person skilled in the art that the opposite configuration can also be used.

[0043] Figure 2 The spectrometer detection device 1 is shown with the spectrometer 5 arranged on the holding part 3 but not yet screwed. In this state, the spring 103 is not yet further compressed but can already be under pre-tension. In this state, the abutment surface 51 of the spectrometer 5 can already be in contact with the window 7, as in the shown example. However, in this position, the coupling device 10 generally does not yet exert a pressing force of the window against the spectrometer 5.

[0044] Figure 3The spectral detection device 1 is shown in the working position, i.e. after the coupling of the spectrometer 5 to the holding part 3. The coupling of the spectrometer 5 to the holding part 3 is effected by means of the handling coupling 10. The handling coupling 10 comprises a threaded sleeve 101 which is rotated relative to the holding part 3. In this way, the spring 103 is compressed as the threaded sleeve 101 is approached, so that a spring force acts between the spectrometer 5 and the holding part 3. In particular, the spectrometer 5 is advantageously provided with a support face 52 onto which the spring force is transmitted. In the present embodiment, the abutment force exerted by the spectrometer 5 onto the window 7 is essentially caused by the spring force of the compressed spring 103, which in turn is defined by a predetermined force. This makes it possible to avoid excessively high forces acting directly on the window 7 by means of the screwing, which could lead to damage to the window and to leaks. Furthermore, the spring 103 causes a screwing self-locking, which reduces the risk of the screwing coming loose during operation. It is therefore advantageous overall for the spring 103 to be dimensioned such that the spring force in the working position is lower than the force required to cause the window 7 and / or the fastening of the window 7 in the housing of the holding part 3 to be pressed out or damaged. Here, it is also possible to set a safety margin between the spring force applied and the critical force which leads to failure of the window. Preferably, the spring force of the spring 103 when compressed is at most 2 / 3 of the force required to press the window 7 out. On the other hand, the spectrometer 5 is pressed by means of the spring 103 with a sufficiently high force against the window 7 in order to fix the spectrometer 5 against the window 7 and thus to define precisely the position of the spectrometer 5 relative to the window 7, in particular the position of the spectrometer 5 relative to the adjacent measuring volume of the window 7. This also compensates for manufacturing tolerances which can exist in the screwing or makes them irrelevant.

[0045] Without being restricted to the present example or the embodiments described below, it is preferred for the coupling 10 to be configured such that, when the spectrometer 5 is coupled to the holding part 3, the abutment face 51 exerts an abutment force on the window 7 which is in the range from 10 N to 4 kN, preferably greater than 20 N, particularly preferably in the range from 50 N to 2 kN. These limits apply in particular if the abutment force is transmitted via the abutment face 51 to the transparent window element 74. If the abutment face 51 is supported on the metal frame 70, higher abutment forces can be used. Even if support is provided on the window element 74, higher forces can also be set depending on the configuration of the window 7. The force required to press the transparent element out of the window or, more generally, the critical force which leads to damage to the window 7 also depends on the diameter of the window 7. The smaller the window, the greater the force which can generally be applied. The criterion for measuring the range of abutment forces which is appropriate is therefore the product of the diameter of the transparent window element 74 and the abutment force, which should ensure a safe fastening of the spectrometer and should also avoid damage to the device 1. In another embodiment, the coupling 10 is configured such that the abutment force of the abutment face 51 against the window 7 multiplied by the diameter of the window element 74 is not more than 40 kN x mm. Preferably, however, the product is at least 0.1 kN x mm.

[0046] Preferably, the product is also in the range between these values.

[0047] The embodiment adopting screw connection and self-locking spring 103 can be further improved. Figures 1 to 3 As shown, the connector 110 can be of two-part construction, i.e., in addition to the threaded sleeve 101, there is another sleeve element 102. In this example, the threaded sleeve 101 forms the outer frame, while the sleeve element 102 forms the inner body. Figure 2 and Figure 3 As shown, a sleeve element 102 surrounds the shaft 53 of the spectrometer 5. A spring 103 acts on the sleeve element 102. The spring force of the spring 103 is transmitted via the sleeve element 102 to the support surface 52 of the spectrometer 5. The threaded sleeve 101 has an opening 107 facing away from the retaining portion 3 or toward the viewing window 7. After the abutment surface 51 abuts the viewing window 7, the sleeve element 102 extends through the opening 107 as the threaded sleeve 101 rotates further. The principle of this effect is that after the spectrometer 5 abuts the viewing window 7, it can no longer move axially toward the viewing window 7. Therefore, the sleeve element 102 is also fixed by the abutment surface 52. However, the threaded sleeve 101 continues to move axially toward the viewing window 7 due to the screw connection.

[0048] According to another improvement, a marking 112 can be provided on the sleeve element 102. For example, the marking can be a groove. The axial position of the marking 112 can be selected so that when it protrudes from the opening 107 or becomes visible, it indicates the predetermined end position of the screw connection, thereby indicating that the spectrometer 5 has been correctly assembled and positioned on the holding portion 3.

[0049] However, this may not prevent the operator from further tightening the threaded sleeve 101. In order to avoid damaging the coupling device 10 or the viewing window 7, according to an alternative or additional embodiment, the coupling device 10 has corresponding abutment surfaces 108, 109 on the threaded sleeve 101 and the retaining part 3, which limit the screwing depth of the threaded sleeve 101 on the retaining part 3. Figure 2 and Figure 3 As shown, the abutment surface can be formed by the end surface of the channel in the holding portion 3 for inserting the spectrometer 5. In the example shown, the abutment surface on the threaded sleeve 101 is formed by an annular protrusion protruding inwardly.

[0050] The holding part 3 and the window 7 arranged in the holding part 3 are further explained below according to preferred embodiments. Generally, the holding part 3 serves to create an optical access channel to a measurement volume in a bioprocess analysis. According to preferred embodiments, the holding part is attached to a bioreactor. Details regarding the holding part and the bioreactor provided with the holding part can be found in the patent document DE 102018108325 B4, which relates to details of a bioreactor and the connection of the holding part to the bioreactor as a whole are also considered subject matter of the present disclosure. In this document, the holding part is referred to as a sensor seat. Another use of the spectroscopic detection device 1 is the measurement of a flow cell. Flow cells are used in bioprocesses for process control and analysis of flowing media. Thus, generally, without being limited to specific examples and embodiments, another aspect of the present disclosure provides a bioprocess device having a spectroscopic detection device 1 for bioprocess analysis, wherein a window 7 of a holding part 3 of the device adjoins a sterile sealed measurement volume of the bioprocess device so that the spectrometer 5 can detect radiation from the measurement volume through the window 7. The bioprocess device can be a bioreactor or a flow cell and can also comprise a bioreactor or a flow cell.

[0051] Figure 4 A partial cutaway perspective view of an embodiment of the holding part 3 is shown. The holding part 3 comprises a plastic body 30, in which the window 7 is sealingly fastened, for example by means of fusion or adhesion. In order to be able to fixedly connect the plastic body 30 to a bioreactor in the form of a plastic bag, for example, in a preferred design the plastic body 30 has a flange 31 which frames the window 7, to which the bag body can be fastened, in particular by means of a welded connection.

[0052] The window 7 comprises a metal frame 70. The metal frame 70 has an opening 71. This opening 71 is closed by a transparent window element 74. Preferably, as shown, the transparent window element 74 is embedded in the opening 71. It is also conceivable that the window element 74 covers the opening 71. In order to fasten the window element 74, it is generally preferred to use a glass solder 76. In particular, a press fit can be achieved with the glass solder 76, in which the compression force resulting from the press fit keeps the window element 74 fixedly pressed into the opening 71. It is also conceivable that a glass piece is provided as the window element 74, which is connected directly to the metal frame 70, such as by fusion, so that no connection to a glass solder 76 is necessary. According to a certain embodiment, the transparent window element 74 is made of a single crystal material, such as a single crystal of a material such as aluminum oxide, yttrium oxide, zirconium oxide or the like. In a certain refinement, it is also possible to use a combination of materials such as yttrium-stabilized Zr02. Such a single crystal material is particularly excellent in Raman measurements, since it has only a small influence on the measurement.

[0053] In order to achieve as fixed a connection of the window 7 to the plastic of the plastic body 30 as possible, it is advantageous to enlarge the mutual connection surface of the plastic body and the metal frame 70 as much as possible. At the same time, the visible surface of the metal frame 7 facing the measuring volume should be as small as possible. This is advantageous in order to reduce the shadowing as much as possible when sterilizing using ionizing radiation. Therefore, generally preferred but not limited to the embodiment shown, the receptacle 70 has a shaft 77 which extends in the axial direction and whose outer surface is connected to the plastic body 30 (as shown in Figure 4

[0054] Although it is desirable to reduce the surface of the metal frame 70 facing the measuring volume as much as possible, generally not limited to the example shown, in other embodiments which are realized in addition to the example shown, the metal frame has a flange 78 which protrudes inward into the opening 71. The flange can in particular form a shoulder inside the metal frame 70 against which the spectrometer 5 can abut with its abutment surface 51. Therefore, not limited to a specific embodiment, in a refinement of the device 1, in the coupled-together state of the spectrometer 5 and the holder 3, the abutment surface 51 abuts or presses against the metal frame 70 of the window 7. According to an alternative or additional embodiment, the abutment surface 51 can also press against the transparent window element 74. In certain cases, however, it can be desirable to avoid high forces being transmitted to the window element 74, in particular in hard and brittle materials, if the spectrometer 5 is subjected to mechanical impacts.

[0055] The flange 78 also provides a higher mechanical stability in the radial direction, which is advantageous in the case of a press-fit of the window element 74 in the opening 71.

[0056] In a variant in which the magnets provide the pressing force of the abutment surface 51 entirely or partially, the metal frame 70 and in particular its flange 78 can be used as a counterpiece for the magnets in the head 50 of the spectrometer 5. In particular in a variant in which the magnets are used in combination with springs 103, the inside of the shaft 77 of the metal frame 70 can also be used as a counterpiece for the magnets in the head 50 of the spectrometer 5, in which case the magnets are particularly suitable for the first alignment and fixation of the head 50 in the shaft 77. In this case, the magnets can be arranged on the shaft of the head 50.

[0057] If magnets are used for the alignment and / or for providing the pressing force, it is preferred for the metal frame 70 to be made of a magnetic metal. If the metal frame 70 is made of steel, it is preferred for it to be made of ferritic steel or martensitic steel.

[0058] ​In a "Glass-to-Metal Seal" (GTMS) press-fit or sealed glass-to-metal press-fit, a transparent window element 74 and, if necessary, solder glass are embedded in a metal frame 70, for example, as pressed parts. The solder glass and, if necessary, the material of the transparent element are fused to the metal frame via a heat treatment. For press-fitting, the thermal expansion coefficient of the metal frame is also selected to be greater than that of the transparent element and, if necessary, the solder glass; the difference is preferably at least 3 ppm / K.

[0059] If necessary, the holder 3 can be coupled to different types of spectrometers. This is particularly easy to achieve when different coupling devices 10 can be used. To achieve this, according to another aspect, the holder 3 of the spectral detection device 1 according to the present disclosure is provided with at least one, and preferably multiple, different adapters 33. The plastic body 30 of the holder 3 is connectable to each of the different adapters 33 via a latching connection 36. One or more adapters 33 each include a portion of the coupling device 10 for coupling to the spectrometer 5. The latching connection 36 locks the adapter 33 at least in the axial direction (i.e., along the optical axis of the holder 3). This allows a force to be applied in the axial direction to the spectrometer 5 inserted into and coupled to the holder 3 via the coupling device 10, thereby pressing the spectrometer 5 against the window 7. Different adapters can be adapted to the respective requirements of different spectrometers or their coupling components, so that the focus position in the medium to be tested, and in particular the focus depth, is always reproducibly defined by the mechanical contact between a portion of the spectrometer and the window 7.

[0060] as Figure 2 and Figure 3 The example shown, Figure 4 The adapter 33 in the illustrated embodiment has a thread 104 for screwing into the threaded sleeve 101 and an abutment surface 108 for limiting the screwing depth.

[0061] exist Figure 4 Only the latch mechanism or latch connection 36 can be partially seen. Figures 5 to 7 The latch mechanism 36 and other possible adapters are explained in detail.

[0062] Figure 4a and Figure 4b Another embodiment of the spectrum detection device 1 is shown, in which different from the reference Figures 1 to 3 In the embodiment described above, the screw connection between the connecting member 110 and the holding portion 3 is implemented as a double helical thread. Figure 4a The connecting member 110 and the holding portion 3 are shown partially transparent so that the shapes of the internal thread on the connecting member 110 and the external thread on the holding portion 3 can be clearly seen. Figure 4b The connection piece 110 is shown in a perspective view so that the shape of the internal thread can be seen particularly clearly.

[0063] The internal thread formation of the connecting piece 110 is formed on the inside of the thread sleeve 101 in the form of protrusions extending along two helical lines 121, 122 or thread lines. Here, the two helical lines 121, 122 have the same pitch, but are rotated by 180° with respect to each other.

[0064] This achieves that the starting points 140 of the helical lines 121, 122 are at the same height with respect to the axis of the thread sleeve 101.

[0065] Preferably, the two helical lines 121, 122 each cover at most half a turn or 180°. This achieves that no reverse thread occurs inside the thread sleeve 101, so that the double helix formation can be manufactured easily. Preferably, however, the two helical lines 121, 122 each cover more than 160°, in order to provide the largest possible abutment surface when engaging the counterpiece of the double helix thread.

[0066] The counterpiece of the internal thread formation on the connecting piece 110 is located on the outside of the plastic body 30 of the holder 3, where it is formed by protrusions extending along two helical lines 131, 132 or thread lines. Here, the two helical lines 131, 132 have the same pitch, but are rotated by 180° with respect to each other.

[0067] This achieves that the starting points 140 of the helical lines 131, 132 are at the same height with respect to the axis of the plastic body 30.

[0068] Preferably, the helical lines 131, 132 of the external thread formation on the plastic body 30 cover more than one full turn, particularly preferably two full turns, around the plastic body 30.

[0069] The double helix screwing formed by this arrangement is particularly suitable for achieving a reliable screwing even if the plastic component, such as the holder 3, has relatively large manufacturing tolerances. For example, if the connecting piece 110 is made of metal, such as stainless steel, and the holder 3 is made of plastic, such as polyethylene (PE), the conventional shrinkage of the plastic can cause a dimensional deviation between the helical lines 121, 122 on the connecting piece 110 and the helical lines 131, 132 on the holder 3.

[0070] However, in contrast to conventional threads with only one helical line, the course of the double helix 121, 122 of the internal thread of the connecting piece 110 does not lie on the protrusions of one of the helical lines 131, 132 of the holder 3, but rather in the space between the thread teeth defined by the helical lines 131, 132. By this, one of the helical lines 131 represents the lower guide and the other helical line 132 represents the upper guide for the double helix internal thread of the connecting piece 110.

[0071] Here, due to the spring force provided by the spring 103, see Figure 1 ,Figure 2 and Figure 3 The double helix inner thread of the connecting piece 110 always abuts the respective upper limit of the double helix outer thread of the holding part 3.

[0072] The starting points 140 of the two helix lines 121, 122 or 131, 132 are exactly opposite, i.e. offset by 180°. Thereby, when the connecting piece 110 is placed on the holding part 3 for screwing, the two parts can uniformly abut each other and align along a common axis. This avoids that the inner thread of the connecting piece 110 and the outer thread of the holding part 3 get cross-threaded like with a standard thread having only a single entry. Additionally, by increasing the abutment surface of the thread assembly, the lower metal strength of the connecting piece 110 relative to the plastic of the holding part 3 can also be compensated.

[0073] The double helix thread described here by way of example for the connection between the connecting piece 110 and the holding part 3 can also be combined with other embodiments of the spectral detection device.

[0074] Figure 5 A plastic part 30 with a window 7 and two couplable adapters 33, 34 are shown. Each adapter 33, 34 in combination with the plastic part serving as a base piece forms a holding part 3 of different configuration, wherein the different holding parts 3 differ in the coupling mechanism of the spectrometer 5 or the coupling device 10. Here, the adapter 33 is equipped with a thread 104 to obtain a holding part 3 as shown in Figures 2 to 4 when the adapter 33 is locked with the plastic body 30.

[0075] Neither limited to the shown example nor to the embodiment with different adapters 33, 34, the holding part 3 or its plastic part 30 preferably has a shaft body 37. In this shaft body 37 the shaft body 77 of the window 7 can also be fastened, as shown in Figure 4 .

[0076] In a preferred embodiment, the latching connection 36 comprises latching lugs 38 on one of the plastic body 30 and the adapter 33, 34 and a corresponding groove 39 and a receptacle 40 for the latching lugs 38 on the other of the plastic body 30 and the adapter 33, 34, wherein the groove 39 and the receptacle 40 are arranged alternatingly around in the circumferential direction, wherein the groove 39 extends in the axial direction such that the latching lug 38 can be pushed into the groove 39 in the axial direction until a stop position, and wherein the plastic body 30 and the adapter 33, 34 can be locked with each other in such a way that a mutual rotation of the plastic body 31 and the adapter 33, 34 when the latching lug 38 is pushed into the stop position 390 of the groove 39 will move the latching lug 38 from the groove 39 into the receptacle 40 and lock it in the receptacle 40.

[0077] In order to facilitate the mutual rotation of the two parts of the holding portion 3, it is particularly preferred that the latching lugs 38 each have a sliding surface 380 on the respective part which is inclined relative to the tangential direction. The two parts, the plastic body 30 and the adapter 33 or 34, can then more easily be rotated relative to one another along the sliding surface 380 over the edge of the recess 39.

[0078] For further explanation, Figure 6 A partial cross-sectional perspective view of the holding portion 3 and the plugged-in adapter 34 before the latching connection 36 is closed is shown. The cross-section in this figure runs perpendicularly to the optical axis through the shaft 37 of the adapter 34 and the plastic body 31. It can also be seen in this cross-section that the shaft 77 of the window 7, which is preferably a tubular, cylindrical element, is connected to the shaft 37 of the plastic body 31. The profile of the latching lug 38 with its sliding surface 380, the recess 39 and the accommodation portion 40 can be clearly identified in this cross-sectional view. Before the closure, the latching lug 38 is still located in the recess 39 as shown. In order to move the latching lug 38 into the accommodation portion 40 and to close it, the adapter 34 is rotated clockwise in the configuration shown, so that the sliding surface 380 can slide over the edge of the recess 39 and finally snap into the accommodation portion 40, which is preferably shaped complementary to the latching lug 38 as shown, and to close it. Figure 7 A state in which the adapter 34 is completely assembled is shown. In this figure, the latching lug 38 is located in the accommodation portion 40 and the latching connection 36 is closed. The adapter 34 is connected to the plastic body 31 via the shaft 37 of the plastic body 31 and the shaft 77 of the window 7. The shaft 77 of the window 7 is connected to the shaft 37 of the plastic body 31. The shaft 77 of the window 7 is preferably a tubular, cylindrical element. Figures 5 to 7 In the embodiment shown, the latching lug 38 is arranged on the plastic body 30 and the recess 39 and the accommodation portion 40 are arranged on the adapter 33, 34. However, this configuration can also be reversed, i.e. the latching lug is arranged on the adapter 33, 34 and the recess 39 and the accommodation portion 40 are arranged on the plastic body 30. Furthermore, it is also conceivable that both parts have a recess 38 and an accommodation portion 40.

[0079] A further embodiment of a spectral detection device is described below, which likewise has a coupling device 10 with which a spectrometer 5 and a holding portion 3 can be coupled to one another in a releasable manner, so that in the coupled state of the spectrometer 5 and the holding portion 3, the abutment face 51 and the window 7 are pressed against one another with a limited force. The principle of this embodiment is that a flange 12, 13 is provided on the spectrometer 5 and on the holding portion 3, respectively, wherein the two flanges 12, 13 are clamped together by means of a closure clamp 115 to establish the coupling, wherein the flanges 12, 13 and the clamp 115 are designed such that a gap 15 remains between the two flanges 12, 13 when the clamp 115 is completely closed.

[0080] Figure 8A partial cross-sectional view of a portion of a spectrometer 5 according to this embodiment is shown. While generally not limited to the embodiment described herein in which coupling is established via a clamp, the spectrometer 5 preferably comprises a housing 54 on which a head 50 is disposed, the head 50 having a shaft 53 for coupling to the holder 3. Furthermore, it is particularly preferred to configure the spectrometer 5 with a free-beam region 17, as in the example shown. It is particularly preferred, without limitation to a specific embodiment, to employ free-beam optics for coupling radiation into or out of the measurement volume. Such free-beam optics allow for highly sensitive measurements and a very compact design of the spectrometer 5, making them particularly suitable for Raman measurements. To couple radiation into or out of the measurement volume, a lens 16 can be provided in a preferred embodiment, which can be arranged in particular in the head 50 or, in this example, in the shaft 53. Within the scope of this disclosure, free-beam optics refers to optical devices in which radiation is not continuously guided through a solid medium (such as an optical fiber) but rather propagates freely in a vacuum or gas-filled space (typically guided by optical elements such as lenses). The key point is that free-beam optics can be used to couple radiation into and / or out of the spectrometer head. In the spectrometer-coupled state, a lens can be present in the free-beam optics, which can also abut the viewing window 7 if necessary. In the latter case, the free-beam optics are arranged behind the lens from the perspective of the measurement volume.

[0081] It can also be seen that the abutment surface 51 is realized by the end surface of the hollow shaft 53. Therefore, the abutment surface 51 for aligning the spectrometer 5 with the window 7 of the holding portion 3 can be extremely small. In the example shown, the abutment surface 51 is only a linear surface on the edge of the head 5 of the spectrometer 5.

[0082] A surrounding flange 13 is provided on the shaft body for coupling the spectrometer 5 to the holding portion 3 , as will be described in detail below with reference to the accompanying drawings.

[0083] Figure 9 The embodiment shows a holding portion 3 suitable for coupling a spectrometer 5. The structure of the holding portion 3 in this embodiment is similar to that of the plastic body 30 and the window 7 in the above embodiment. Figure 4 In the example shown, a flange 12 is provided. As shown, the flange 12 can be constructed as an adapter, for example, Figure 5 As mentioned, the flange 12 can be connected to the plastic body 30 by means of a latching mechanism 36. In fact, the example shown corresponds to Figure 5 The holder 3 is shown coupled to an adapter 34 , so the adapter 34 may have the shape of the flange 12 shown in this figure.

[0084] In a preferred design, not limited to the specific examples shown, at least one flange 12, 13 has a bevel 14. Preferably, both flanges 12, 13 are provided with a bevel 14. Here, one or both bevels 14 are arranged on the side of the flange 12, 13 opposite the coupling side coupled to the other flange 13, 12. The one or more bevels 14 can be conical surfaces that encircle the flange 12, 13, among others. The effect of the bevel 14 is to divert the radial force exerted by the clamp when the clamp is closed into an axial force, which can then be used to press the abutment face 51 of the spectrometer 5 against the window 7.

[0085] In order to be able to facilitate the alignment of the spectrometer 5 to the holder 3, according to a further refinement, one of the flanges 12, 13 can be provided with a circumferential groove 18, and the other flange 13, 12 can be provided with a corresponding spring, which engages into the groove 18 when the two are coupled together. It is also conceivable to additionally or alternatively arrange magnets in order to facilitate the alignment and fixation of the spectrometer 5 to the holder 3. For example, one or more magnets can be arranged on the spectrometer 5, in particular on its head 50, and interact with a magnetically opposite counterpart on the holder 3.

[0086] Figure 10 A spectrometric device 1 assembled with the aid of the coupling device 10 is shown. Here, the spectrometer 5 is clamped together with the holder 3 at its flanges 12, 13 with the aid of a clamp 115. In particular, the clamp 115 is configured as a radially compressible clamp 116. The clamp 115 or clamp 116 can have bevels 140 that correspond to the bevels 14. If these bevels 140 are guided or pivoted radially inwards when the clamp 116 is tightened, they come into abutment with the bevels 14 on the flanges 12, 13. By tightening the clamp or more specifically the clamp 116, the flanges 12, 13 are generally pressed against one another. In the case of the bevels 14, 140, this is achieved by converting the radial compression into an axial force. In this way, the spectrometer 5 is pressed against the window 7 with its abutment face 51. At this point, the axial position of the flanges 12, 13 is chosen such that the flanges are still always spaced apart when the abutment face 51 abuts against the window 7, so that a gap 15 remains between the flanges 12, 13. The flanges 12, 13 on the holder 3 or at least the flanges 12, which are preferably made of plastic, are subjected to an elastic deformation. The resulting force presses the spectrometer 5 against the window and at the same time is limited, so that the window 7 is protected from damage. The flanges 12 on the holder 3 thus have the function of a disc spring. If the two flanges 12, 13 abut one another, however, only the two flanges 12, 13 bear the pressing force generated by the clamp. The abutment face 51 will then no longer exert a defined pressing force on the window 7.

[0087] The configuration of the coupling device 10 in this embodiment is essentially similar to a so-called Tri-Clamp, but a gap is left between the flanges 12, 13 without a seal.

[0088] In the aforementioned embodiments, the head 50 of the spectrometer 5 comprises a shaft body 53. Likewise, a shaft body 37 is provided on the holder 3, wherein the coupling device 10 is then arranged between the housing 54 and the window 7. By this, the coupling device 10 also increases the distance between the housing 54 of the spectrometer and the actual measurement volume, such as a bag of a bioreactor. However, the available space of the facility can be limited. Therefore, for a further embodiment, it can be desirable to shorten the distance between the housing 54 of the spectrometer 5 and the transparent window element 74 as much as possible. In another aspect of the disclosure, at least a part of the coupling device, preferably the entire coupling device 10, is arranged within the housing 54 of the spectrometer 5 when the spectrometer 5 and the holder 3 are coupled together. This feature is also independent of whether the coupling device 10 exerts a defined or limited pressing force against the window 7.

[0089] The part of the housing 54 of the spectrometer 5 that interacts with the coupling device 10 can also be provided in particular in the form of an adapter plate. This is particularly advantageous for retrofitting an existing spectrometer housing for use with the spectroscopic detection device 1 or for adapting the basic shape of the housing to different application purposes.

[0090] Therefore, in general, without being limited to a particular embodiment, a spectroscopic detection device 1 is also provided, in particular for spectroscopic measurements on a sterile, sealed measurement volume in a bioprocess analysis, wherein the device 1 has a holder 3 and a spectrometer 5 that is repeatedly couplable and decouplable from the holder 3, the spectrometer 5 having a housing 54, wherein the holder 3 comprises a plastic body 30 and a window 7 that is sealingly fastened in the plastic body 30, the window 7 comprising a metal frame 70 and a window element 74 that is transparent to the radiation to be detected by the spectrometer 5 and sealingly closes an opening 71 of the frame 70, wherein the spectrometer 5 has an abutment face 51 that abuts or can abut the window 7 in order to couple the spectrometer 5 with the holder 3, wherein the spectroscopic detection device 1 comprises a coupling device 10 with which the spectrometer 5 can be coupled to the holder 3 in a releasable manner, wherein the coupling device 10 is configured such that, in the coupled state of the spectrometer 5 and the holder 3, at least a part of the coupling device 10, preferably the entire coupling device 10, is arranged in the housing 54 of the spectrometer 5. The coupling device 10 encompasses all elements that establish a fixed coupling between the holder 3 and the spectrometer 5.

[0091] With reference to the embodiments of Figure 2 and Figure 3 the thread 104 on the holder 3 is to be attributed to the coupling device 10, regardless of whether the thread 104 is arranged on an adapter or is integrally formed with the plastic body.

[0092] The following describes an embodiment that enables a particularly flat design of the coupling device 10. In a further embodiment, as described above, the coupling device 10 can be arranged completely or partially in the housing 54 of the spectrometer 5 after coupling. Generally speaking, the coupling device 10 is configured to establish the coupling between the spectrometer 5 and the holder 3 by means of a plug-in rotational connection. This connection allows for targeted utilization of the ductility or deformability of the plastic of the holder 3.

[0093] Figure 11 The figure shows a top view of the holder 3 viewed from the plugging direction of the spectrometer 5. According to the embodiment design of the coupling device 10 using the plug-in connection, the coupling device 10 includes at least one, preferably at least two radially outwardly extending wings 42 on the plastic body 30 of the holder 3. The wings 42 are preferably also made of plastic. For example, Figures 4 to 7 As described in the embodiment of the present invention, these plastic wings can be integrally formed with the plastic body 30 or connected to the plastic body 30 via a suitable adapter (preferably locked). Figure 10 It is not shown in the illustration that the fin 42 has two opposite side faces, to which the spectrometer can be anchored so that the spectrometer can be fixed to the holding part 3 in the axial direction.

[0094] Figure 12 Shown Figure 11 The spectrometer 5 shown has a housing 44 suitable for holding the holder 3. The housing 44 surrounds an opening 55 for coupling in or out radiation for spectroscopic measurement. The housing 44 also includes an opening 45 into which a tab 42 can be inserted, or the housing 54 of the spectrometer 5 can be placed over the opening 45 via the tab 42, and the tab 42 can be introduced into the housing 44.

[0095] Figure 13 The holding part 3 is shown to be located opposite the housing 54 with the housing 44 before the holding part 3 is inserted into the housing 44 or conversely before the housing 54 is placed on the holding part 3. Two opposite sides 420, 422 of the wing 42 can be recognized in this figure. Here, the side 422 points in the direction of the window element or in the direction of the measuring volume, while the opposite side 420 points in the direction of the spectrometer 5. In order to align the holding part 3 with the spectrometer 5 more precisely, the holding part 3 can have a nozzle 46, which is introduced into the opening 55 when the spectrometer 5 is placed on the holding part 3. Preferably, the optics of the spectrometer 5 can be designed so that the radiation propagates as a free beam within the nozzle 46 to the window element. As shown Figure 12 and Figure 13 As shown, the housing opening 45 can have a shape that is adapted to the fins 42 of the holder 3. In this way, it can be ensured that the spectrometer 5 is placed in a predetermined orientation.

[0096] Another example Figure 13As shown, the accommodation 44 has a slit or slit-like gap 43 corresponding to the flap 42, into which the flap 42 can be turned in order to lock the spectrometer 5 to the holder 3. Thus, not limited to the shown specific example, in a refinement of the bayonet connection embodiment it is provided that the holder 3 has at least one, preferably at least two flaps 42 facing outwards in the radial direction of the holder, wherein the spectrometer 5 has an accommodation 44 with an opening 45, preferably arranged on or in the housing 54, and slit-like gaps 43 corresponding to the flaps 42, in particular located behind or below the opening 45 when viewed from the outside of the housing 54, wherein the flaps 42, the slit-like gaps 43 and the opening 45 are arranged such that, after the spectrometer 5 is placed on the holder and the flaps 42 are inserted into the opening 45 of the accommodation 44, the flaps 42 can be turned into the slit-like gaps 43 by mutual turning of the spectrometer 5 and the holder 3, so that the spectrometer 5 is locked to the holder 3 at least in the axial direction.

[0097] In an advantageous refinement, however, the accommodation 44 is of an asymmetric design, which is different from the arrangement of the flaps 42 on the holder 3. In the shown example, the left side has a stop face 47, while the other side does not have a stop face. In general, not limited to the specific example, at least one stop face 47 is arranged at the accommodation 44, which, after the spectrometer 5 is placed on the holder 3, only allows mutual turning of the spectrometer 5 relative to the holder 3 in a predetermined turning direction in order to fix the spectrometer 5 to the holder 3, i.e. a specific turning direction is defined. This design can avoid a wrong turning direction and define a turning angle, preferably 90°. This enables an easy assembly and a secure fixation. Figure 13

[0098] According to a further refinement, the thickness of the flap 42 exceeds the height of the slit-like gap 43 with an excess amount.

[0099] Preferably, the excess amount is in the range of 50 μιη to 150 μιη. The flap-like holding element or flap 42 can be clamped into the slit-like gap in a self-retaining manner due to its ductility. The excess amount can be configured to enable assembly by turning in a range of 0.2 Nm to 0.8 Nm of torsional force.

[0100] ​It is particularly preferred that the receptacle 44 on the spectrometer 5 is made of metal. In this way, the spectrometer 5 can be precisely positioned relative to the holder 3 even if the metal abutment surface 51 is not pressed against the window 7. This is mainly due to the fact that the flap 42 provides a large-area locking in the slit-like gap 43, which can compensate for misalignments. Without being limited to the above specific embodiment, according to another aspect of the present disclosure, there is provided a spectroscopic detection device 1, in particular for spectroscopic measurements of a sterile sealed measurement volume in a bioprocess analysis, having a holder 3 and a spectrometer 5 which is repeatedly couplable and decouplable from the holder 3, wherein the holder 3 comprises a plastic body 30 and a window 7 which is sealed fastened in the plastic body 30, the window 7 comprising a metal frame 70 and a window element 74 which is transparent for the radiation to be detected by the spectrometer 5 and which seals off an opening 71 of the frame 70, wherein the spectrometer 5 has a metal receptacle 44 on a housing 54 of the spectrometer 5, wherein the holder 3 has a flap 42 as a retaining element which projects radially outwards and the receptacle 44 has a slit-like gap 43 and an opening 45 for introducing the flap 42, which are arranged and configured such that, after the flap 42 has been introduced into the receptacle 44 by mutual rotation of the spectrometer 5 and the holder 3, the flap 42 can be turned into the slit-like gap 43 so that the spectrometer 5 is locked to the holder 3.

[0101] However, in this preferred design, the abutment surface 51 of the metal head of the spectrometer 5 to be coupled to the holder can be pressed against the assembly of the window 7 with a defined force. At this point, the flap 42, which has already been subjected to a high axial force by being locked in the slit-like gap, is deformed elastically. In this embodiment, the elastic deformation can define and limit the pressing force in that the plastic body 30 must be deformed under the force in order to introduce the receptacle 44 completely until the flap 42 reaches the axial position which is allowed to be introduced into the slit-like gap 43.

[0102] Figure 14 It is further shown that the holder 3 and the spectrometer 5 are in a converging position before locking, i.e. before rotation. For the sake of clarity, the abutment surface 51 which is preferably present on the metal head and the window are not shown in this figure.

[0103] The stop surface 47 at the protrusion from the accommodation 44 defines the start position of the fixed rotation. This defines the direction of rotation of the spectrometer 5, which is indicated by the arrow. Typically, the spectrometer 5 is rotated while the holding part 3 is fixed in place, because the holding part 3 is for example fixedly welded to the bag of the bioreactor. Advantageously, a further stop surface 48 is also provided to limit the rotation. Preferably, as shown, this further stop surface 48 is attached to the same protrusion. Preferably, such stop surfaces 47, 48 are provided for each flap 42, i.e. in the shown example a double stop surface is provided. If the spectrometer 5 is rotated until the flap 42 abuts against the stop surface 48, the spectrometer 5 is not only fixed in its axial position, but also in its angular direction.

[0104] Figure 15 It is shown that the spectrometer 5 is in a locked position with the holding part 3. Relative to the illustration in Figure 14 the flap 42 visible at this time has been rotated by 90° in the accommodation 44 and abuts against the stop surface 48. The figure also shows the lens missing in Figure 14 the metal head 50, which is supported on the shaft body 77 of the window 7. The shaft body 77 simultaneously forms the nozzle 46 or a part thereof, which extends from the holding part 3.

[0105] The preferred design of the spectrometer 5 and of the process apparatus, in particular bioprocess apparatus, having the spectrometric detection apparatus 1 of the present disclosure is described in the following.

[0106] Figure 16 It is shown that the bioprocess apparatus 60 and its holding part for assembling the spectrometer 5. The bioprocess apparatus 60 in this embodiment is a bioreactor 61, which comprises a container 62 in the form of a plastic bag 62, in which a bioreaction medium is present, such as a nutrient solution containing microorganisms. Here, the container volume within the plastic bag 62 forms the measurement volume 2. In case the plastic bag 63 is used as the container 62, typically a single-use or disposable bag is provided.

[0107] The bioreactor 61 can comprise a support container 64 to stabilize the plastic bag 63. According to the present disclosure, the holding part 3 is welded with the plastic bag 63. The holding part 3 carries the window 7 for coupling radiation in and out of the measurement volume 2, which can be accessed via an opening 65 in the support container 64, so that the spectrometer 5 can be placed and detect radiation from the measurement volume 2 through the window 7.

[0108] As already mentioned above, in a preferred embodiment the spectrometer 5 is equipped with free-beam optics 66. By avoiding light waveguides and fiber couplings in the light path, the laser power required for achieving comparable sensitivity can be significantly reduced in this compact configuration in a particularly advantageous manner compared to standard systems. Due to the reduced laser power, the energy input in the focal depth region of the medium is lower in in-situ concentration measurements. This avoids damaging heat-labile analytes, such as biological macromolecules.

[0109] The radiation to be detected is guided as free beam from the transparent window element 74 to the detector of the spectrometer 5. This does not exclude, however, that the radiation is guided and / or focused on the light path by optical elements such as lenses, prisms or polarizers. However, there is still a free-beam region behind such optical element(s). Figure 17 A schematic cross-sectional view of an embodiment of the spectroscopic detection device 1 with such a spectrometer 5 is shown.

[0110] As Figure 17 shown, this compact configuration comprises the bag wall of a bioreactor bag 63, the holding part 3 connected thereto and the spectrometer 5. According to a particularly preferred embodiment, the spectrometer 5 is embodied as a Raman spectrometer and comprises a focusing lens 16, a beam splitter 82, an excitation source in the form of a laser diode 80 and a spectrometer detector 81. Figure 17 The free-beam region 17 between the spectrometer detector 81 and the transparent window element 74 is shown.

[0111] It is understood by the skilled person that the present application is not limited to the embodiments described above, but that various embodiments within the scope of the present disclosure can also be combined with each other. This can provide coupling mechanisms that combine features of different embodiments. In Figures 8 to 10 or Figures 11 to 15 The spring 103 as shown in the example can also be provided in the coupling device 10 to define the counter-pressure force. Figures 1 to 3

[0112] List of reference signs 1 spectroscopic detection device 2 measurement volume 3 holding part 5 spectrometer 7 window 10 coupling device 12, 13 flanges of 10 14 bevels of 12, 13 15 gap between 12, 13 16 lens 17 free-beam region 18 recess 19 spring​ 30 Plastic body 31 Fastening flange 33, 34 adapter 36 Lock connection 37 3 axis 38 Locking lugs 39 grooves 40 38 accommodating part 42 wing 43 Slit-like gap 44 is a receiving portion for 42 in the housing 54 45 44 shell opening 46 nozzle 47, 48 stop surfaces 50 5 head 51 50 contact surface 52 5 support surface 53 5 axis 54 5 shell 55 54 opening 60 Bioprocessing Equipment 61 Bioreactor 62 containers 63 plastic bags 64 Support container Opening in 65 64 66 Free-Beam Optics 70 Frame Opening in 71 70 74 Window widgets 76 Glass solder 77 axis 78 70 flange 80 Laser Diode 81 Spectrometer Detector 82 beam splitter 101 threaded sleeve 102 sleeve element 103 Spring 104, 105 threads 107 Opening in 101 108, 109 contact surface 110 connectors 112 Marks 113 Annular protrusion on 101 115 fixture 116 clamp 121, 122 internal thread 131, 132 external thread 140 start of the helical line 380 sliding surface of 38 390 stop of 39 420, 422 opposite side surfaces of 42

Claims

1. A spectroscopic detection device (1) for spectroscopic measurement of a sterile, sealed measurement volume (2), in particular for use in bioprocess analysis, wherein: The device (1) comprises a holding portion (3) and a spectrometer (5), wherein the spectrometer (5) and the holding portion (3) can be repeatedly coupled and decoupled, wherein the holding portion (3) comprises a plastic body (30) and a window (7) sealed and fastened in the plastic body (30), wherein the window (7) comprises a metal frame (70) and a window element (74), wherein the window element (74) is transparent to radiation to be detected by the spectrometer (5) and seals an opening (71) of the frame (70), and wherein the spectrometer (5) has A metal head (50) is provided with an abutment surface (51), wherein the abutment surface (51) is capable of abutting against the window (7) to couple the spectrometer (5) to the holding portion (3), and wherein the spectrum detection device (1) comprises a coupling device (10), wherein the coupling device (10) is capable of releasably coupling the spectrometer (5) and the holding portion (3) to each other, so that when the spectrometer (5) is coupled to the holding portion (3), the abutment surface (51) and the window (7) are pressed against each other, in particular with a defined force.

2. Spectral detection device (1) according to the preceding claim, characterized in that The device (1) is configured to generate the force by elastic deformation of at least a portion of the spectral detection device (1); and / or to provide the force by at least one magnet, in particular arranged at the metal head (50) and cooperating with the metal frame (70) of the window (7).

3. The spectrum detection device according to any one of the preceding claims, characterized in that The coupling device (10) includes a threaded sleeve (101) and a spring (103), wherein the spring force of the spring (103) when compressed acts between the threaded sleeve (101) and the spectrometer (5), and wherein the coupling device (10) further includes threads (104, 105) corresponding to each other on the holding portion (3) and the threaded sleeve (101), so that the threaded sleeve (101) can be screwed onto the holding portion (3), and the spring (103) is compressed by the threaded sleeve (101) moving in the axial direction on the holding portion (3), and the abutment surface (51) of the spectrometer (5) is pressed against the window (7) under the action of the spring force generated by the compression of the spring (103), wherein the threads (104, 105) are preferably implemented as double helical threads.

4. Spectral detection device (1) according to the preceding claim, characterized in that The coupling device (10) comprises a sleeve element (102) surrounding the shaft (53) of the spectrometer (5), the spring (103) acts on the sleeve element (102), and the sleeve element (102) transmits the spring force of the spring (103) to the supporting surface (52) at the spectrometer (5), and wherein the threaded sleeve (101) has an opening (107) facing away from the retaining portion (3), and after the abutment surface (51) abuts the window (7), as the threaded sleeve (101) further rotates, the sleeve element (102) extends through the opening.

5. The spectrum detection device (1) according to any one of the two preceding claims, characterized in that The corresponding abutment surfaces (108, 109) on the threaded sleeve (101) and the retaining portion (3) limit the threaded depth of the threaded sleeve (101) on the retaining portion (3).

6. The spectral detection device (1) according to any one of the preceding claims, characterized by at least one of the following features: - in a state where the spectrometer (5) and the holding portion (3) are coupled together, the abutment surface (51) is pressed against the metal frame (70) of the window (7), - in a state where the spectrometer (5) and the holding portion (3) are coupled together, the abutment surface (51) is pressed against the transparent window element (74) of the window (7), The transparent window element (74) is held in the opening (71) in a press-fit manner.

7. The spectral detection device (1) according to any one of the preceding claims, characterized by at least one of the following features: - the device (1) comprises free-beam optics (66) for coupling radiation into or out of the measurement volume (2), - The spectrometer (5) is configured as a Raman spectrometer.

8. Spectral detection device according to the preceding claim, characterized in that The spectrometer (5) is designed such that the radiation to be detected is guided as a free beam from the transparent window element (74) to a detector of the spectrometer (5).

9. The spectral detection device (1) according to any one of the preceding claims, wherein: Flanges (12, 13) are respectively arranged at the spectrometer (5) and the holding portion (3), wherein the two flanges (12, 13) can be clamped together by closing a clamp (115) to establish a coupling, wherein the flanges (12, 13) and the clamp (115) are designed so that a gap (15) is left between the two flanges (12, 13) when the clamp (115) is fully closed.

10. Spectral detection device (1) according to the preceding claim, characterized by at least one of the following features: - At least one of the flanges (12, 13) has a bevel (14), wherein The inclined surface (14) is arranged on a side of the flange (12, 13) opposite to the coupling side coupled with the other flange (13, 12), - The clamp (115) is configured as a radial compression clamp (116).

11. The spectral detection device (1) according to any one of the preceding claims, characterized by at least one of the following features: - the coupling device (10) is configured such that when the spectrometer (5) is coupled to the holding portion (3), the pressing force of the abutment surface (51) against the window (7) is in the range of 10 N to 4 kN, - The product of the pressing force of the abutting surface (51) against the window (7) and the diameter of the window element (74) is in the range of 0.1 kN×mm to 40 kN×mm.

12. The spectral detection device (1) according to any one of the preceding claims, wherein: The coupling device (10) is configured such that, in a state where the spectrometer (5) is coupled to the holder (3), at least a portion of the coupling device (10), preferably the entire coupling device (10) is arranged in a housing (54) of the spectrometer (5).

13. The spectral detection device (1) according to any one of the preceding claims, wherein: The coupling device (10) is designed to produce a coupling between the spectrometer (5) and the holder (3) by means of a plug-in rotational connection.

14. Spectral detection device (1) according to the preceding claim, characterized in that The holding portion (3) has a wing (42) oriented outwardly in a radial direction of the holding portion (3), and wherein the spectrometer (5) has a receiving portion (44) preferably arranged on the housing (54) or in the housing (54) with an opening (45), and a slit-shaped gap (43) corresponding to the wing (42), wherein the wing (42), the slit-shaped gap (43) and the opening (45) are arranged so that after the spectrometer (5) is placed on the holding portion and the wing (42) is inserted into the opening (45) of the receiving portion (44), the wing (42) can be rotated into the slit-shaped gap (43) by mutual rotation of the spectrometer (5) and the holding portion (3), so that the spectrometer (5) is locked to the holding portion (3) at least in the axial direction.

15. Spectral detection device (1) according to the preceding claim, characterized by at least one of the following features: - at least one stop surface (47) is arranged at the accommodation portion (44); after the spectrometer (5) is placed on the holding portion (3), the stop surface (47) only allows the spectrometer (5) to rotate relative to the holding portion (3) in a predetermined rotation direction, thereby fixing the spectrometer (5) to the holding portion (3); - The thickness of the fin (42) exceeds the height of the slit-shaped gap (43).

16. A bioprocess device (60) comprising a spectroscopic detection device (1) for bioprocess analysis according to any one of the preceding claims, wherein: The viewing window (7) of the holding part (3) of the device adjoins the sterile, sealed measurement volume (2) of the bioprocess device, so that the spectrometer (5) can detect radiation from the measurement volume (2) through the viewing window (7).

17. A holding portion (3) suitable for a spectrum detection device (1) according to any one of claims 1 to 15, the holding portion comprising at least one, preferably a plurality of different adapters (33), wherein: The plastic body (30) of the retaining part (3) can be connected to the adapter (33) or to different adapters (33) by means of a latching connection (36), wherein the adapters (33) each have a part of the coupling device (10), wherein the latching connection (36) locks the adapter (33) at least in the axial direction.

18. The holder (3) according to the preceding claim, characterized in that The latching connection portion (36) comprises a latching lug (38) on one of the plastic body (30) and the adapter (33, 34), and comprises a corresponding groove (39) and a receiving portion (40) for the latching lug (38) on the other of the plastic body (30) and the adapter (33, 34), wherein the grooves (39) and the receiving portion (40) are alternately arranged in the circumferential direction, and wherein the grooves (39) extend in the axial direction so that the latching lug (38) can be The groove (39) is inserted in the axial direction until it stops in the groove (39), and the plastic body (30) and the adapter (33, 34) can be locked together, wherein when the locking lug (38) is inserted into the stop position (390) of the groove (39), the plastic body (30) and the adapter (33, 34) are rotated relative to each other so that the locking lug (38) moves from the groove (39) to the accommodating portion (40) and is locked in the accommodating portion (40).

19. A method for monitoring a process in a bioprocess, wherein a spectrometer (5) is assembled to a holder (3) at a sterile, sealed measurement volume (2) of a bioprocess facility, in order to obtain a spectroscopic detection device (1) according to any one of claims 1 to 10, and wherein, A signal is measured with the aid of the spectroscopic device (1) which is dependent on the intensity of radiation entering the spectrometer (5) from the measurement volume (2) through the viewing window (7), wherein the spectrometer (5) is removed and reconnected to the holder (3) at a later time, and the measurement is repeated, and wherein the measurement signals are subsequently compared.

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