Apparatus for spectroscopic measurements on bioreactors

Abstract

The invention relates generally to spectrometric apparatuses for process analysis technology, such as in particular for bioprocess technology, and allows an exactly aligned coupling of a spectrometer to a mounting. For this, the invention provides a spectrometric apparatus (1) for bioprocess analytics for spectroscopic measurement on sterile-sealed measurement volumes (2), wherein the apparatus (1) has a mounting (3) and a spectrometer (5) which can be repeatedly coupled to and uncoupled from the mounting (3), wherein the mounting (3) comprises a plastic body (30) and a window (7), which is secured in a sealing manner in the plastic body (30) and comprises a metal frame (70) and a window element (74) that is transparent to the radiation to be detected by the spectrometer (5) and closes an opening (71) of the frame (70) in a sealing manner, and wherein the spectrometer (5) has a metal head (50) with an abutting surface (51), which can be brought into abutment with the window (7) for the coupling of the spectrometer (5) and the mounting (3), and wherein the spectrometric apparatus (1) comprises a coupling device (10), with which the spectrometer (5) and the mounting (3) can be releasably coupled to one another in such a way that, in the coupled state of the spectrometer (5) and the mounting (3), the abutting surface (51) and the window (7) are pressed against one another by a force, in particular a limited force.

Description

[0001] DEVICE FOR SPECTROSCOPICAL MEASUREMENTS ON BIOREACTORS

[0002] Description

[0003] The invention generally relates to spectrometric devices for process analysis technology, particularly for bioprocess technology. In particular, the invention relates to a device with a holder configured to couple an analyzer-detecting spectrometer to a container volume or an aliquot of this volume. The invention thus also relates to process control in production processes in containers and systems for cultivating biological material, particularly bioreactors or flow cells. Bioreactors are used to cultivate microorganisms, animal, and plant cells, thus opening up a broad field of application for biotech production processes, particularly in the biopharmaceutical production of substances and the production of cells and cell products (so-called cellular agriculture). There is a general need to further optimize these processes.Especially in the production of biopharmaceuticals, improvements in product yield and thus profit increases are being driven. Various approaches are available for managing and controlling production processes, increasing product yield, and reducing costs.

[0004] Processes can be controlled and monitored by determining substrate and product concentrations. For cultivations conducted in bio- or photobioreactors, regular sampling is required to ensure adequate process control. This, along with the determination of substrate and product concentrations, is usually time-consuming and associated with a risk of contamination, which can even lead to the loss of the batch in the bio- or photobioreactor. Reasons for this include handling with the cultivation unit open and resource-intensive offline analysis performed outside the respective reactor.

[0005] On the other hand, process control and thus yield can be optimized by implementing real-time process control of key parameters. To increase product yield, in-situ monitoring of parameters such as temperature, metabolism-relevant substances, or product formation is particularly advantageous, as is real-time control of cultivation conditions. Spectroscopic parameter detection is particularly suitable for this purpose, especially since optical detection can be performed contactlessly and without contamination.

[0006] To monitor bioreactors, the use of spectroscopic methods such as Raman spectroscopy and fluorescence spectroscopy with corresponding spectrometers is known. These spectrometers are each configured to detect one or more analytes present in a container volume. The analytes include, in particular, both components of the substrates used in a process and components of the process products.

[0007] Raman spectrometer systems can be used for real-time parameter control. Such process analysis techniques (PAT) can be installed, particularly using fiber optic cables and immersion probes, at a port of a bioreactor, or generally any disposable or reusable container for cultivating biological material, as such a port forms an opening into the interior of the container. The port of a bioreactor, or generally of a process stage unit, often conforms to a specific standard, such as an Ingold port or a PG 13.5 port.

[0008] Typically, the spectrometer comprises a spectrometer unit, a fiber optic cable, and an immersion probe sensor head. However, the space requirement may be limited, especially for smaller containers or in other space-limited situations, e.g., in a cleanroom environment. Furthermore, under cleanroom conditions, operation by personnel should be mechanically simple due to the personal protective equipment required, such as protective clothing with gloves. A further problem is that biotechnological processes often run over extended periods, and the spectrometer does not need to be mounted in the measuring volume the entire time, or even cannot or should not remain mounted due to the process. This is the case, for example, when

[0009] - the measuring system cannot be autoclaved,

[0010] - in case of a drift of the measuring system, which requires recalibration, - in case of reference measurements, e.g. for chemometrics, especially before the log phase, or for

[0011] - Recalibration if a validated period is exceeded.

[0012] The spectrometer should therefore be easily coupled to the measurement volume for measurements. However, this can lead to measurement inaccuracies if the spectrometer's measurement position is not exactly re-established during a repeated measurement. Another challenge here is that the plastics often used in bioprocessing technology do not allow for precise positioning due to their easy deformability. A key problem is that the plastic parts generally cannot be manufactured with the required precision, for example, due to shrinkage after production.

[0013] Compact Raman spectrometers, such as those known from CN 109682791 A, may not be able to be integrated into bioreactors in a high-performance and sterile manner. Alternatively, the Raman systems may consist of a housing, e.g., in a 19-inch format, into which one or more lasers as light sources, fiber couplings, optics, and detection units are installed. The housings are dimensioned to accommodate lasers with a power of, for example, up to 500 mW in order to achieve sufficient measurement sensitivity despite the losses caused by the fiber optic technology. The fiber optics allow a certain degree of flexibility through various fiber cable lengths. The same applies to the possibility of using different measuring probe heads. The laser power cannot be increased arbitrarily to compensate for losses in the optical path; a biogenic analyte degenerates beyond a compound-specific threshold.Especially for compact bioreactor systems in particular and for installations with limited free space in general, state-of-the-art Raman systems are limited in their practicality due to their space requirements.

[0014] According to the state of the art, no system currently on the market meets the requirement of enabling spectroscopy, in particular Raman spectroscopy or fluorescence spectroscopy, including holding while preserving the integrity of the container as a compact system.

[0015] The invention is based on the object of providing a spectrometric device, preferably for bioprocess analysis, but possibly also for other processes in sterile-tight systems, which mitigates the above-mentioned problems of small space requirements, easy handling and reproducible coupling to an interaction volume, i.e. the part of the container volume interacting with the spectroscopic analysis.

[0016] This object is achieved by the subject matter of the independent claims. Advantageous embodiments of the invention are specified in the respective dependent claims. Accordingly, a spectrometric device for bioprocess analysis for spectroscopic measurement in sterile, sealed measurement volumes is provided, wherein the device has a port or a holder and a spectrometer that can be repeatedly coupled to and decoupled from the holder. The holder comprises a plastic body and a window sealingly fastened in the plastic body, which window comprises a metallic mount and a window element that is transparent to the radiation to be detected by the spectrometer and sealingly closes an opening in the mount. The spectrometer has a metallic head with a stop surface that can be brought into contact with the window to couple the spectrometer and the holder.The spectrometric device also comprises a coupling device with which the spectrometer and the holder can be detachably coupled to one another, such that, when the spectrometer and holder are coupled, the stop surface and the window are pressed against one another. In particular, the force can be limited or, independent of the operation of the coupling device, within a predetermined or permissible range. Plastic as the material for the holder is particularly preferred, among other things, as this facilitates sterilization with ionizing radiation, such as gamma radiation. A disadvantage, however, is the low dimensional stability, which prevents precise alignment of the spectrometer with respect to the container wall, or more generally, the wall of the container volume.Because the coupling device brings the spectrometer directly into contact with the window, which is not made of plastic, precise positioning of the spectrometer can be achieved in a surprisingly simple way, despite the holder otherwise being predominantly made of plastic. The advantage of exact positioning, at least in the axial direction, in relation to the holder becomes apparent when, for example, intensity values ​​are to be compared after the spectrometer has been removed and reattached. When measuring the intensity of a signal, such as a Raman signal with a focused laser beam, the measured value depends sensitively on the interaction volume and thus also strongly on the position of the focus in relation to the window. Therefore, precise spatial alignment of the spectrometer is very advantageous for recording comparable values.For example, in Raman spectroscopy with a focused laser beam, the interaction volume is essentially determined by the focusing cone. In fluorescence spectroscopy, the intensity losses due to the liquid-to-solid and especially solid-to-gas phase transitions are also associated with reflection losses, etc. Therefore, accurate positioning is also advantageous here.

[0017] In a further aspect, the invention therefore also relates to a method for monitoring a process in bioprocess engineering, in which a spectrometer is mounted on a holder on a sterile-tight container volume of a bioprocess plant, so that a spectrometric device according to this disclosure is obtained, and wherein a signal dependent on the intensity of radiation passing from the measuring volume through the window into the spectrometer is measured by means of this spectrometric device, and wherein the spectrometer is dismantled and reconnected to the holder at a later time and the measurement is repeated, and wherein a comparison of these signals is preferably then carried out. This comparison of intensity-dependent signals can be carried out with high precision through the reproducible alignment of the spectrometer, even though the spectrometer is repeatedly connected or does not have to remain permanently in the process.The interaction volume is understood to be the part of the container volume from which radiation for spectroscopic measurement is received by the spectrometer. This volume can be very small, for example, and can be essentially limited to the focus of a focused excitation light beam. For the purposes of this disclosure, the interaction volume is generally understood to be the volume adjacent to and detected by the spectrometer. For the purposes of this disclosure, the container volume is generally understood to be the entire volume of the container that can be filled with a medium and is sterile and tight. Accordingly, in the case of a reactor, the container volume is the volume in which the biological process takes place. For a flow cell, the container volume is given by the corresponding volume of the flow cell.

[0018] The container that provides the sterile, sealed container volume can, in particular, be a single-use or multi-use container. Particularly for upstream or downstream processes, the container volume can also be provided by a flow cell through which the medium to be analyzed flows and which can be part of a tubing system. The flow cell can also be designed as a single-use or multi-use component. A single-use component is used only once and then discarded, whereas a multi-use component can be cleaned and sterilized before being reused.

[0019] Examples of containers include disposable bioreactors designed as flexible bags (e.g. composite films made of polyethylene (PE) and polyvinyl alcohol (PVA)), disposable mixing systems with an agitator in a flexible bag, disposable bioreactors with a rigid polymer container (e.g. polycarbonate (PC)), and reusable bioreactors made of stainless steel.

[0020] All of these containers can be sterilized at least once in order to provide the sterile, tight container volume within a process.

[0021] The device can be used for various processes, in particular the spectrometric device can be used for processes involving living cells, but any other reactions and processes, in particular cell-free processes, are also conceivable as applications.

[0022] For the purposes of this disclosure, a sterile, sealed volume is understood to mean, in particular, a volume or a container which has a helium leak rate of less than 1 • 10' 6 mbar-l / s, preferably less than 1 • 10' 7 mbar-l / s, particularly preferably less than 1 - 10' 8 mbar-l / s.

[0023] The invention is explained in more detail below with reference to the accompanying figures. Brief description of the figures

[0024] Fig. 1 shows a perspective, partially cut-away view of a connecting element as part of the coupling device.

[0025] Fig. 2 shows a spectrometric device before coupling the spectrometer and holder.

[0026] Fig. 3 shows the device in working position with the spectrometer coupled to the holder.

[0027] Fig. 4 shows a bracket in a partially cutaway perspective view.

[0028] Fig. 4a shows another embodiment of the spectrometric device in a schematic representation.

[0029] Fig. 4b shows a perspective view of the connecting element.

[0030] Fig. 5 shows a holder with a plastic body and several adapters for adapting various coupling devices.

[0031] Fig. 6 shows the holder with an attached adapter before locking in a partially cut-away perspective view and

[0032] Fig. 7 the holder with locked adapter also in cut-away perspective view.

[0033] Fig. 8 shows part of a spectrometer with a flange arranged on a shaft for attaching the spectrometer to a holder.

[0034] Fig. 9 shows the holder suitable for the spectrometer shown in Fig. 8.

[0035] Fig. 10 shows the spectrometer from Fig. 8 coupled with a clamp to the holder according to Fig. 9.

[0036] Fig. 11 shows a holder 3 in plan view, seen in the direction of attachment of the spectrometer 5.

[0037] Fig. 12 shows a spectrometer with housing in plan view of a receptacle for attachment to the holder according to Fig. 11.

[0038] Fig. 13 shows the holder 3 and the housing 54 with the receptacle 44 in opposite position.

[0039] Fig. 14 shows the holder and the spectrometer in the joined position before locking.

[0040] Fig. 15 shows the spectrometer 5 and the holder 3 in the locked position. Fig. 16 shows a bioprocessing device with a holder for mounting a spectrometer.

[0041] Fig. 17 shows a spectrometric device 1 with a spectrometer 5 and its optical components in a schematic section.

[0042] Detailed description of the characters

[0043] Fig. 1 to Fig. 3 show an embodiment of the spectrometric device in which the defined force with which the spectrometer and the window are brought into contact is generated by a spring.

[0044] In general, without limitation to the specific features of the example shown, this embodiment is based on the device 1, in particular its coupling device 10, being designed such that the force with which the stop surface 51 of the spectrometer 5 and the window 7 of the holder 3, which can also be referred to as a port or as a sensor receptacle according to DE 10 2018 108 325 B4, or as a composite element according to EP 3 747 983 B1, are pressed together, is generated by elastic deformation of at least part of the spectrometric device 1. This principle also underlies the other embodiments shown in the figures. The embodiment of Figs. 1 to 3 is more specifically based on the force for pressing the spectrometer 5 and the holder 3, or the window 7 arranged in the holder 3, together being generated at least partially by a spring 103.In addition to or as an alternative to a spring force, the force for pressing together can also be provided as a magnetic force by one or more magnets. Another embodiment, realized in the example of Fig. 1 to Fig. 3, is that the spectrometer 5 and holder 3 are coupled by means of a screw connection. When coupling by means of a screw connection in process analysis technology, for example with fiber-bound spectrometer probes or for free-beam spectrometers, there has so far been a deficit regarding the long-term stability and precision of the coupling. The embodiment explained below can easily overcome these disadvantages.

[0045] Fig. 1 shows a perspective, partially cutaway view of a connecting element 110, which forms part of the coupling device 10. Figs. 2 and 3 show the spectrometric device 1 as a whole, with holder 3 and spectrometer 5, as well as the coupling device 10.

[0046] The connecting element 110 of the coupling device 10 comprises the threaded sleeve 101 shown in Fig. 1, as well as a spring 103. The coupling device 10 is designed such that the spring force of the spring 103 acts upon compression between the threaded sleeve 101 and the spectrometer 5. In particular, as becomes clearer from Fig. 2 and Fig. 3, the spectrometer 5 is pressed axially toward the window 3 by the spring force. The coupling device 10 further comprises mutually corresponding threads 104, 105 on the holder 3 and on the threaded sleeve 101, so that the threaded sleeve 101 can be screwed onto the holder 3, and by the movement of the threaded sleeve 101 in the axial direction towards the holder 3, the spring 103 is compressed and the stop surface 51 of the spectrometer 5 is pressed against the window 7 with the spring force generated by the compression of the spring 103.In addition to or as an alternative to the spring force, the force for pressing the stop 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, in particular on an end face of the metallic head 50 of the spectrometer 5 (see Fig. 2), which then interact with a metallic frame 70 (see Fig. 4) of the window 7. The spectrometer 5 with its metallic head 50 is shown only schematically with its external dimensions in Figs. 2 and 3.

[0047] In the example, thread 105 on connecting element 110 is designed as an internal thread, and thread 104 on holder 3 is designed as a corresponding external thread. It will be apparent to those skilled in the art that a reverse configuration is also possible.

[0048] Fig. 2 shows the spectrometric device 1 with the spectrometer 5 attached to the holder 3, but before screwing it in. In this state, the spring 103 is not yet further compressed, but may already be under pretension. The stop surface 51 of the spectrometer 5 can already come into contact with the window 7 in this state, as in the example shown. However, a contact force against the window is generally not yet exerted on the spectrometer 5 by the coupling device 10 in this position. Fig. 3 shows the spectrometric device 1 in the working position, i.e. after actuation of the coupling device 10. Actuation of the coupling device 10 consists in rotating the threaded sleeve 101 relative to the holder 3. In this way, as the threaded sleeve 101 approaches, the spring 103 is compressed, whereby the spring force acts between the spectrometer 5 and the holder 3.In particular, it is advantageous to provide a support surface 52 on the spectrometer 5, to which the spring force is transmitted. In this embodiment, the contact force from the spectrometer 5 to the window 7 is essentially caused by the spring force of the compressed spring 103 and thus a defined, predetermined force. This prevents very high forces from acting directly through the screw connection onto the window 7, which could potentially damage and leak the window. In addition, the spring 103 counter-tightens the screw connection and thus reduces the risk of the screw connection coming loose during operation. In general, it is therefore advantageous for the spring 103 to be dimensioned such that its spring force in the working position is lower than the force that would be required to push out, or more generally to damage, the window 7 and / or its fastening in the housing of the holder 3.A safety margin can easily be provided here between the applied spring force and the critical force for window failure. Preferably, the spring force, with the spring 103 compressed, is at most 2 / 3 of the force required to push out the window 7. However, since the spectrometer 5 is pressed against the window 7 with sufficiently high force by the spring 103, the spectrometer 5 rests firmly against the window 7, so that its position relative to the window 7 and, above all, relative to the measurement volume adjacent to the window 7 is precisely defined. This also compensates for possible manufacturing tolerances in a screw connection or makes them irrelevant.

[0049] Without being limited to this example or the embodiments described below, it is preferred if the coupling device 10 is designed such that the contact pressure of the stop surface 51 against the window 7 when the spectrometer 5 is coupled to the holder 3 is in a range from 10 N to 4 kN, preferably in the range from 20 N, particularly preferably in the range from 50 N to 2 kN. These limits apply in particular when the contact pressure is transmitted via the stop surface 51 to the transparent window element 74. If the stop surface is supported

[0050] 51 on the metallic frame 70, even higher contact forces can be used. Even with support on the window element 74, higher forces can also be provided depending on the design of the window 7. The force required to push out the transparent element in the window, or more generally the force that is critical for damaging the window 7, also depends on the diameter of the window 7. A smaller window can generally withstand a higher force. A measure of a good contact force range, which on the one hand ensures secure attachment of the spectrometer and on the other hand avoids damage to the device 1, is therefore given by the product of the diameter of the transparent window element 74 and the contact force.In a further embodiment, it is provided that the coupling device 10 is designed such that the product of the contact force of the stop surface 51 against the window 7 and the diameter of the window element 74 has an amount of 40 kN. x mm. However, this product is preferably at least 0.1 kN x mm. The product should therefore preferably be in a range between these values.

[0051] The embodiment with a screw connection and a counter spring 103 can be further improved. As can be seen from Figs. 1 to 3, the connecting element 110 can be formed in two parts, namely with a further sleeve element 102 in addition to the threaded sleeve 101. In the example, the threaded sleeve 101 forms an outer socket, and the sleeve element 102 forms an inner body. The sleeve element 102 surrounds a shaft 53 of the spectrometer 5, as shown in Figs. 2 and 3. The spring 103 acts on this sleeve element 102. The spring force of the spring 103 is transmitted via the sleeve element 102 to the support surface 52 on the spectrometer 5. The threaded sleeve 101 has an opening 107 facing away from the holder 3 or rearward with respect to the window 7, through which the sleeve element 102 emerges upon further rotation of the threaded sleeve 101 after the stop surface 51 has been brought into contact with the window 7.This is caused by the fact that the spectrometer 5, after being in contact with the window 7, can no longer be moved axially towards the window 7, so that the sleeve element 102 due to the contact with the support surface.

[0052] 52 is also fixed. The threaded sleeve 101, however, is moved further in the axial direction toward the window 7 by the screwing. According to a further development, 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 then be selected such that, by emerging from the opening 107 or becoming visible, it indicates the intended end position of the screw connection and thus the correct assembly and positioning of the spectrometer 5 on the holder 3.

[0053] Under certain circumstances, however, this may not prevent an operator from screwing in the threaded sleeve 101 even further. In order to avoid damage to the coupling device 10 or the window 7, an alternative or additional embodiment provides that the coupling device 10 has corresponding stop surfaces 108, 109 on the threaded sleeve 101 and the holder 3, which limit the screw depth of the threaded sleeve 101 on the holder 3. As can be seen from Fig. 2 and Fig. 3, a stop surface can be formed by the end face of the channel in the holder 3 into which the spectrometer 5 is inserted. In the example shown, the stop surface on the threaded sleeve 101 is formed by an inwardly projecting annular projection.

[0054] Further details of the holder 3 and the window 7 arranged in the holder 3 are explained below according to preferred embodiments. In general, the holder 3 serves to create optical access to a measuring volume in bioprocess analysis. According to a preferred embodiment, the holder is attached to a bioreactor for this purpose. Details on holders and bioreactors provided with holders are known from DE 10 2018 108 325 B4, which is also made the subject of the present disclosure in its entirety with regard to details on bioreactors and the connection of the holder to the bioreactor. In this publication, the holder is referred to as a sensor holder. Another use of a spectrometric device 1 is measurements on flow cells. Flow cells are used in bioprocess engineering for process control and analysis of flowing media.Therefore, in general, without limitation to specific examples and embodiments, a further aspect of this disclosure provides a bioprocessing device comprising a spectrometric device 1 for bioprocess analysis, wherein the window 7 of the holder 3 of this device adjoins a sterile, sealed measurement volume of the bioprocessing device, so that the spectrometer 5 can detect radiation from the measurement volume through the window 7. The bioprocessing device can be a bioreactor or a flow cell, or can comprise a bioreactor or a flow cell.

[0055] Fig. 4 shows an embodiment of a holder 3 in a partially cutaway perspective view. The holder 3 comprises a plastic body 30 in which a window 7 is sealed, for example, melted or glued in. In order to be able to firmly connect the plastic body 30, for example, to a bioreactor in the form of a plastic bag, the plastic body 30, in a preferred embodiment, has a flange 31 framing the window 7, to which the bag can be fastened, in particular firmly connected by welding.

[0056] The window 7 comprises a metallic frame 70. The metallic frame 70 has an opening 71. This opening 71 is closed by a transparent window element 74. Preferably, the transparent window element 74 is inserted into the opening 71 as shown. However, it would also be conceivable for the window element 74 to cover the opening 71. To attach the window element 74, it is generally preferred to use a glass solder 76. In particular, the glass solder 76 can be used to achieve pressure glazing, in which compression forces are generated by the glazing, which hold the window element 74 firmly pressed into the opening 71. It is also conceivable to provide a glass element as the window element 74, which is connected directly, for example by melting, to the metallic frame 70, so that a connection with a glass solder 76 is not necessary.According to one embodiment, a single-crystal material, such as a single crystal of one of the materials aluminum oxide, yttrium oxide, or zirconium oxide, is used as the transparent window element 74. In a further development, material combinations, such as yttrium-stabilized ZrCh, can also be used. Such single-crystal materials prove particularly advantageous in connection with Raman measurements, since the single-crystal material has only a minimal influence on the measurement.

[0057] To ensure that the window 7 is connected as firmly as possible to the plastic of the plastic body 30, it is advantageous if the mutual connection surface of the plastic body with the metallic mount 70 is as large as possible. At the same time, however, as little surface of the metallic mount 70 as possible should be visible in the direction of the measurement volume. This is advantageous in order to cause as little shadowing as possible during sterilization with ionizing radiation. For this reason, it is generally preferred, without limitation to the exemplary embodiments shown, if the mount 70 has a shaft 77 which extends in the axial direction and which is connected to the plastic body 30 at its outer surface, as also shown in Fig. 4.

[0058] Although a small surface of the metallic mount 70 facing the measurement volume is desirable, in a further embodiment implemented in the illustrated example, without limitation to the example shown, it generally has a flange 78 projecting inward into the opening 71. This flange can, in particular, form a shoulder inside the metallic mount 70, against which the spectrometer 5 then rests with its stop surface 51. Without limitation to more specific embodiments, a further development of the device 1 therefore provides that, when the spectrometer 5 and holder 3 are coupled together, the stop surface 51 rests against the metallic mount 70 of the window 7, or is pressed there. According to an alternative or additional embodiment, the stop surface 51 can also be pressed against the transparent window element 74.Under certain circumstances, however, high forces can be transmitted to the window element 74 due to mechanical impact on the spectrometer 5, which should be avoided, particularly in the case of brittle, hard materials.

[0059] The flange 78 also provides increased mechanical stability in the radial direction, which is advantageous when the window element 74 is held in the opening 71 in the form of a pressure glazing.

[0060] The metallic mount 70, and in particular its flange 78, can serve as a counterpart for magnets arranged in the head 50 of the spectrometer 5 in variants in which the force for pressing the stop surface 51 is provided entirely or partially using magnets. The inside of the shaft 77 of the metallic mount 70 can also serve as a counterpart for magnets arranged in the head 50 of the spectrometer 5, particularly in variants in which the magnets are used in combination with the spring 103. In this case, the magnets are particularly suitable for an initial alignment and fixation of the head 50 within the shaft 77. In this case, the magnets can be arranged on a shaft of the head 50.

[0061] If magnets are used for alignment and / or providing the contact force, it is preferable to manufacture the metallic holder 70 from a magnetic metal. If the metallic holder 70 is made from steel, ferritic or martensitic steels are preferred.

[0062] In a "glass-to-metal-seal" ("GTMS") pressurized glazing, or a sealed glass-to-metal pressurized glazing, the transparent window element 74 and, if applicable, a solder glass, for example, as a pressed piece, are inserted into the metallic frame 70. The solder glass and, if applicable, the material of the transparent element are fused to the metallic frame through heat treatment. For pressurized glazing, the thermal expansion coefficient of the metallic frame is also selected to be greater than the thermal expansion coefficient of the transparent element and, if applicable, the solder glass. The difference is preferably at least 3 ppm / K.

[0063] If necessary, different spectrometer types should be able to be coupled to the holder 3. This is particularly easy to accomplish if it is possible to use different coupling devices 10. To achieve this, according to a further aspect, a holder 3 for a spectrometric device 1 according to this disclosure is provided with at least one, preferably several different adapters 33, the plastic body 30 of which can be connected to the or each of the different adapters 33 by means of a locking connection 36, wherein the adapter(s) 33 each have a part of the coupling device 10 for coupling a spectrometer 5, wherein the locking 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 exerted in the axial direction via the coupling device 10 on a spectrometer 5 inserted and coupled into the holder 3, thus pressing the spectrometer 5 against the window 7. Various adapters allow adaptation to the respective requirements of different spectrometers or their coupling components, whereby the position, in particular the depth of the focal point in the medium to be examined, is always reproducibly defined by the mechanical contact between a part of the spectrometer and the window 7.

[0064] In the embodiment shown in Fig. 4, the adapter 33 has, as in the examples of Fig. 2 and Fig. 3, a thread 104 for screwing with a threaded sleeve 101, as well as a stop surface 108 for limiting the screwing depth.

[0065] The locking mechanism, or rather the locking connection 36, is only partially visible in Fig. 4. The locking mechanism 36 and other possible adapters are explained in more detail below with reference to Figures 5 to 7.

[0066] Figs. 4a and 4b show a further embodiment of the spectrometric device 1 in which the screw connection of the connecting element 110 to the holder 3 is designed as a double helix thread, unlike the embodiment described with reference to Figs. 1 to 3. Figure 4a shows the connecting element 110 and the holder 3 partially transparent, so that the shape of an internal thread on the connecting element 110 and an external thread on the holder 3 can be better seen. Figure 4b shows the connecting element 110 in perspective, so that the shape of the internal thread can be seen particularly well.

[0067] The connecting element 110 has an internal thread formed on the inside of the threaded sleeve 101 in the form of projections that run along two helix lines 121, 122 or screw lines. Both helix lines 121, 122 have the same pitch but are rotated 180° relative to each other. This ensures that the beginnings 140 of the helix lines 121, 122 are at the same height with respect to the axis of the threaded sleeve 101.

[0068] Preferably, each of the two helix lines 121, 122 covers a maximum of half a turn or 180°. This ensures that no undercuts occur within the threaded sleeve 101 and the double helix structure can be easily manufactured. However, each of the two helix lines 121, 122 preferably covers more than a 160° turn, so that when engaging with a counterpart for the double helix thread, the largest possible contact surface is provided. The counterpart of the internal thread formed on the connecting element 110 is located on the outside of the plastic body 30 of the holder 3. Here, an external thread is formed, which is formed by projections that run along two helix lines 131, 132 or screw lines. Both helix lines 131, 132 have the same pitch but are rotated by 180° relative to each other.This ensures that the beginnings 140 of the helix lines 131, 132 are at the same height with respect to the axis of the plastic body 30.

[0069] Preferably, the external thread formed on the plastic body 30 has more than one full turn, particularly preferably two full turns of the helix lines 131, 132 around the plastic body 30.

[0070] The double helix screw connection resulting from this arrangement is particularly suitable for enabling reliable screwing even with comparatively large manufacturing tolerances of plastic components such as the bracket 3. For example, if the connecting element 110 is made of a metal such as stainless steel and the bracket 3 is made of a plastic such as polyethylene (PE), the usual shrinkage of the plastic will result in dimensional deviations between the helix lines 121, 122 on the connecting element 110 and the helix lines 131, 132 on the bracket 3.

[0071] However, unlike a conventional thread with only one helix line, the internal thread with the double helix 121, 122 of the connecting element 110 does not run on the projections of one of the helix lines 131, 132 of the holder 3, but rather runs in the space between the threads defined by the helix lines 131, 132. Thus, one of the helix lines 131 represents a lower guide and the other helix line 132 represents the upper guide for the double helix internal thread of the connecting element 110.

[0072] Due to the spring force provided by the spring 103, see Figures 1, 2 and 3, the double helix internal thread of the connecting element 110 is guided neatly against the upper limit of the double helix external thread of the holder 3.

[0073] The starting point 140 of the two helix lines 121, 122 and 131, 132 is located exactly opposite each other or offset by 180°. As a result, when the connecting element 110 is attached to the bracket 3 for screwing, both parts rest evenly on one another and are both aligned along a common axis. This prevents the internal thread of the connecting element 110 from jamming against the external thread of the bracket 3, as occurs with standard threads with only one thread entry. In addition, the increased contact surface of the threaded components compensates for the lower strength of the plastic of the bracket 3 compared to the metal of the connecting element 110.

[0074] The double helix thread described here as an example for the connection between the connecting element 110 and the holder 3 can also be combined with other embodiments of the spectrometric device.

[0075] Fig. 5 shows a plastic part 30 with window 7, as well as two connectable adapters 33, 34. Each of the adapters 33, 34, in conjunction with the plastic part serving as the base element, results in a differently designed holder 3, wherein the various holders 3 differ with regard to the coupling mechanism for the spectrometer 5, or the coupling device 10. The adapter 33 is equipped with a thread 104, so that when this adapter 33 is locked to the plastic body 30, a holder 3 is obtained, as shown in Figs. 2 to 4.

[0076] Without limitation to the illustrated example and also not limited to the embodiment with the various adapters 33, 34, the holder 3, or its plastic part 30, preferably has a shaft 37. The shaft 77 of the window 7 can then also be fastened in this shaft 37, as already shown in Fig. 4.

[0077] The locking connection 36 comprises, in a preferred embodiment, locking lugs 38 on one of the parts, plastic body 30 and adapter 33, 34, and corresponding grooves 39 and receptacles 40 for the locking lugs 38 on the other of the parts, wherein the grooves 39 and receptacles 40 alternate circumferentially and wherein the grooves 39 extend in the axial direction, so that the locking lugs 38 can be pushed into the grooves 39 up to stops in the grooves 39 in the axial direction, and wherein the two parts, plastic body 30 and adapter 33, 34, can be locked together by rotating the plastic body 31 and adapter 33, 34 against each other when the locking lugs 38 are pushed in up to the stops 390 of the grooves 39, so that the locking lugs 38 are moved from the grooves 39 into the receptacles 40 and in the receptacles 40 lock.

[0078] To facilitate the rotation of the two parts forming the holder 3 relative to each other, it is particularly preferred if the locking lugs 38 each have sliding surfaces 380 arranged obliquely with respect to the tangential direction on the respective part. The plastic body 30 and adapter 33 or 34 can then be rotated more easily relative to each other in the direction in which the sliding surface 380 slides over the edge of the groove 39.

[0079] For further clarity, Fig. 6 shows the holder 3 in a perspective, partially cutaway view with the adapter 34 attached before the locking connection 36 is engaged. The section runs perpendicular to the optical axis through the adapter 34 and the shaft 37 of the plastic body 31. The section also shows the shaft 77 of the window 7, connected to the shaft 37 of the plastic body 31, as a tubular, preferably cylindrical element. The profiles of the locking lugs 38 with sliding surfaces 380, the grooves 39, and the receptacles 40 are clearly visible in the sectional view. Before locking, the locking lugs 38 are still located in the grooves 39, as shown.In order to move the locking lugs 38 into the receptacles 40 and thus lock them, in the configuration shown the adapter 34 is rotated clockwise so that the sliding surfaces 380 can slide over the edges of the grooves 39 and finally can snap into the receptacles 40, which are preferably shaped complementarily to the locking lugs 38, as shown, and lock into place. This state with the adapter 34 fully assembled is shown in Fig. 7. In the embodiments shown in Fig. 5 to Fig. 7, the locking lugs 38 are arranged on the plastic body 30 and the grooves 39 and receptacles 40 are arranged on the adapter 33, 34. This configuration can also be reversed, however, in which case the locking lugs are arranged on the adapter 33, 34 and the grooves 39 and receptacles 40 are arranged on the plastic body 30. Furthermore, configurations are also conceivable in which both parts have grooves 38 and receptacles 40.

[0080] The following describes a further embodiment of a spectrometric device which also has a coupling device 10, with which the spectrometer 5 and the holder 3 can be detachably coupled to one another such that, when the spectrometer 5 and the holder 3 are coupled, the stop surface 51 and the window 7 are pressed against one another with a limited force. This embodiment is based on the fact that a flange 12, 13 is provided on each of the spectrometer 5 and the holder 3, wherein for coupling purposes the two flanges 12, 13 are clamped together by closing a clamp 115, 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 fully closed.

[0081] Fig. 8 shows a partially cutaway view of part of the spectrometer 5 for this embodiment. In general, without limitation to the now-described embodiment with coupling via a clamp, the spectrometer 5 preferably has a housing 54 on which a head 50 with a shaft 53 for coupling to the holder 3 is arranged. Furthermore, it is particularly preferred to provide a spectrometer 5 with a free-beam region 17, as in the example shown. In particular, it is preferred, without limitation to specific embodiments, to provide the coupling or decoupling of radiation into or out of the measurement volume using free-beam optics. Such free-beam optics in particular allow sensitive measurements and a very compact design of the spectrometer 5, particularly for Raman measurements.In order to couple the 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 here in the shaft 53. In the context of this disclosure, free-jet optics is understood to mean optics in which the radiation is not guided continuously through solid media, such as optical fibers, but can propagate freely, typically however guided by optical elements such as lenses, in an evacuated or gas-filled space. It is essential here that, in particular, the coupling and / or decoupling of the radiation in the head of the spectrometer can take place using free-jet optics. When the spectrometer is coupled, a lens can be present in the free-jet optics, whereby the lens can optionally also rest against the window 7. In the latter case, the free-jet optics are arranged behind the lens as seen from the measurement volume.

[0082] As can also be seen, the stop surface 51 is realized by the end face of the hollow shaft 53. The stop surface 51, with which the spectrometer 5 is aligned with the window 7 of the holder 3, can therefore be very small and, in the example shown, is only a linear surface on the edge of the head 5 of the spectrometer 5.

[0083] A circumferential flange 13 is provided on the shaft, which serves to couple the spectrometer 5 and the holder 3, as will be explained in more detail in the following figures.

[0084] Fig. 9 shows a suitable holder 3 for coupling the spectrometer 5. The holder 3 of this example is constructed similarly to the examples explained above with regard to the plastic body 30 and the window 7. However, instead of a thread as in the example in Fig. 4, a flange 12 is provided. As can be seen, the flange 12 can be designed as an adapter and, for example, as explained with reference to Fig. 5, can be connected to the plastic body 30 by means of a locking mechanism 36. In fact, the example shown corresponds to a holder 3 according to Fig. 5 with a coupled adapter 34, which can therefore have the shape of the flange 12 shown here.

[0085] In a preferred embodiment, without limitation to the specific examples shown, at least one of the flanges 12, 13 has an inclined surface 14. Preferably, inclined surfaces 14 are provided on both flanges 12, 13. The one or both inclined surfaces 14 are arranged on the side of the flange 12, 13 opposite the coupling side for coupling with the other flange 13, 12. The one or more inclined surfaces 14 can in particular be conically shaped surfaces surrounding the flange 12, 13. The inclined surfaces 14 serve to easily redirect a force exerted radially by the clamp into an axially acting force when a clamp is closed, which can then be used to press the stop surface 51 of the spectrometer 5 against the window 7.

[0086] To facilitate alignment of the spectrometer 5 and the holder 3, according to a further development, a circumferential groove 18 can be provided on one of the flanges 12, 13, and a corresponding spring can be provided on the other flange 13, 12, which spring engages in the groove 18 when coupled together. It is also conceivable to additionally or alternatively arrange magnets to facilitate the alignment and fixing 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 magnetic counterparts on the holder 3.

[0087] Fig. 10 shows the spectrometric device 1 assembled by means of the coupling device 10. The spectrometer 5 and the holder 3 are clamped together at their flanges 12, 13 by means of a clamp 115. The clamp 115 is particularly preferably designed as a radially compressing clamp 116. The clamp 115 or clamp 116 can have inclined surfaces 140 corresponding to the inclined surfaces 14. If these inclined surfaces 140 are guided or pivoted radially inward when the clamp 116 is tightened, they come into contact with the inclined surface(s) 14 on the flanges 12, 13. Generally, by tightening the clamp, or more specifically by tightening the clamp, the flanges 12, 13 are then pressed against one another. In the case of the inclined surfaces 14, 140, this occurs by translating the radial compression into an axially acting force. Accordingly, the spectrometer 5 is pressed with its stop surface 51 against the window 7.The axial positions of the flanges 12, 13 are now selected such that they are still spaced apart when the stop surface 51 rests against the window 7, so that a gap 15 remains between the flanges 12, 13. The flanges 12, 13, or at least the flange 12 on the holder 3, which is preferably made of plastic, thus undergo a certain elastic deformation. The force generated thereby presses the spectrometer 5 against the window and is at the same time limited, so that damage to the window 7 is avoided. The flange 12 on the holder 3 thus functions, in a sense, as a disc spring. If, on the other hand, the two flanges 12, 13 were to come into contact, the contact pressure generated by the clamp would be absorbed by the two flanges 12, 13 alone. A defined contact pressure from the stop surface 51 on the window 7 would then no longer be present.

[0088] The coupling device 10 of this embodiment can be constructed essentially like a so-called Tri-Clamp connection, but with a gap instead of a seal between the flanges 12, 13.

[0089] In the embodiments described so far, the head 50 of the spectrometer 5 comprises a shaft 53. A shaft 37 is also provided on the holder 3, with the coupling device 10 then being arranged between the housing 54 and the window 7. The coupling device 10 thus also increases the distance between the housing 54 of the spectrometer and the actual measurement volume, such as the bag of a bioreactor. However, there may be little space available on the system. It would therefore be desirable for a further embodiment to keep the distance from the housing 54 of the spectrometer 5 to the transparent window element 74 as small as possible. In a further aspect of this disclosure, it is provided that at least parts of the coupling device, preferably the entire coupling device 10, are arranged within the housing 54 of the spectrometer 5 when the spectrometer 5 and holder 3 are coupled together.This feature is also independent of whether a defined or limited contact force is exerted on the window 7 by the coupling device 10 or not.

[0090] The part of the housing 54 of the spectrometer 5 that interacts with the coupling device 10 can, in particular, also be provided in the form of an adapter plate. This is particularly advantageous for retrofitting existing spectrometer housings for use with the spectrometric device 1 or for adapting basic housing shapes to different applications.

[0091] In general, without limitation to specific embodiments, a spectrometric device 1 for spectroscopic measurement on sterile, sealed measurement volumes, in particular for bioprocess analysis, is therefore also provided, wherein the device 1 comprises a holder 3 and a spectrometer 5, which can be repeatedly coupled to and decoupled from the holder 3 and has a housing 54, wherein the holder 3 comprises a plastic body 30 and a window 7 sealingly fastened in the plastic body 30, which window 7 comprises a metallic mount 70 and a window element 74 which is transparent to the radiation to be detected by the spectrometer 5 and sealingly closes an opening 71 of the mount 70, wherein the spectrometer 5 has a stop surface 51 which can be brought or is brought into contact with the window 7 for coupling the spectrometer 5 and the holder 3, and wherein the spectrometric device 1 comprises a coupling device 10,with which the spectrometer 5 and the holder 3 can be detachably coupled to one another, wherein the coupling device 10 is designed such that, when the spectrometer 5 and the holder 3 are coupled, at least 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 includes all elements that establish the fixed coupling between the holder 3 and the spectrometer 5. Based on the embodiment of Figs. 2 and 3, the thread 104 on the holder 3 would therefore be assigned to the coupling device 10, regardless of whether the thread 104 is arranged on an adapter or formed integrally with the plastic body.

[0092] The following describes an embodiment that enables a particularly flat design of the coupling device 10. In a further development, this can then be arranged, in particular as described above, entirely or partially after the coupling in the housing 54 of the spectrometer 5. Generally, a coupling device 10 is provided for this purpose, which establishes the coupling of the spectrometer 5 and the holder 3 by means of a plug-and-turn connection. This connection, in turn, allows the ductility, or deformability, of the plastic of the holder 3 to be specifically utilized.

[0093] Fig. 11 shows a holder 3 in plan view, seen in the plug-on direction of the spectrometer 5. According to one embodiment of this embodiment of the coupling device 10 with a plug-and-rotate connection, the coupling device 10 comprises 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. These plastic wings can be formed integrally with the plastic body 30, or connected to the plastic body 30 with a suitable adapter, preferably locked, as was described, for example, in the embodiments of Figs. 4 to 7. In the illustration in Fig. 10, it cannot yet be seen that the wings 42 have two opposite sides to which the spectrometer can be anchored, so that it can be fixed to the holder 3 in the axial direction.

[0094] A spectrometer 5 with a suitable receptacle 44 for the holder 3 according to Fig. 11 is shown in Fig. 12. The receptacle 44 surrounds an opening 55 for coupling or decoupling radiation for the spectrometric measurement. The receptacle 44 further comprises an opening 45 into which the wings 42 can be inserted, or with which the housing 54 of the spectrometer 5 can be slipped over the wings 42 and the wings 42 can be inserted into the receptacle 44.

[0095] Fig. 13 shows the holder 3 and the housing 54 with the receptacle 44 in comparison before inserting the holder 3 into the receptacle 44, or conversely before placing the housing 54 on the holder 3. In this illustration, the two opposite sides 420, 422 of the wings 42 can be seen. The side 422 points towards the window element, or in the direction of the measuring volume, while the opposite side 420 is directed towards the spectrometer 5. For more precise alignment of the holder 3 and spectrometer 5, the holder 3 can have a nozzle 46, which is inserted into the opening 55 when the spectrometer 5 is placed on the holder 3. The optics of the spectrometer 5 can preferably be designed such that the radiation propagates as a free beam within the nozzle 46 and up to the window element. As can be seen from Fig. 12 and Fig.As can be seen in Figure 13, the housing opening 45 can have a shape adapted to the wings 42 of the holder 3. In this way, the spectrometer 5 can be positioned in a predetermined orientation.

[0096] As can be further seen from Fig. 13, the receptacle 44 has slots or slot-shaped spaces 43 corresponding to the wings 42, into which the wings 42 can be screwed to lock the spectrometer 5 to the holder 3. Without being limited to the specific example shown, a further development of the embodiment with a plug-and-turn connection provides that the holder 3 has at least one, preferably at least two wings 42, which are oriented outwards in the radial direction of the holder, and wherein the spectrometer 5 has a receptacle 44, preferably arranged on or in the housing 54, with an opening 45, as well as slot-shaped spaces 43 corresponding to the wings 42, which are located behind or below the opening 45, particularly when viewed from the outside of the housing 54, wherein the wings 42, the slot-shaped spaces 43 and the opening 45 are arranged such thatthat the wings 42, after placing the spectrometer 5 on the holder and inserting the wings 42 into the opening 45 of the receptacle 44, the wings 42 can be rotated into the slot-shaped spaces 43 by a mutual rotation of the spectrometer 5 and the holder 3, so that the spectrometer 5 is locked at least in the axial direction on the holder 3.

[0097] However, in an advantageous further development, the receptacle 44, unlike the arrangement of the wings 42 on the holder 3, is not constructed symmetrically. In Fig. 13, in the example, a locking surface 47 is present on the left side, which is missing on the opposite side. In general, without limitation to the specific example, at least one locking surface 47 can be present on the receptacle 44, which, after the spectrometer 5 has been placed on the holder 3, only allows mutual rotation in a predetermined direction of rotation to fix the spectrometer 5 to the holder 3, or that a specific direction of rotation is specified. The design prevents incorrect direction of rotation and defines the angle of rotation (preferably 90°). This enables easy assembly and secure fixation.

[0098] According to another advantageous embodiment, the thickness of the wings 42 is oversized relative to the height of the slot-shaped spaces 43. The oversize is preferably in a range of 50 to 150 μm. Due to the ductility of the wing-like mounting elements, or wings 42, they squeeze into the slot-shaped spaces in a self-retaining manner. The oversize can be adjusted so that assembly can be performed with a rotary movement with a torsional force between 0.2 and 0.8 Nm.

[0099] Particularly preferably, the receptacle 44 on the spectrometer 5 is made of metal. This enables precise positioning of the spectrometer 5 relative to the holder 3, even when no pressing of a metallic stop surface 51 against a window 7 is provided. This is due, among other things, to the fact that the wings 42 provide a large-area locking in the slot-shaped spaces 43, which can average out inaccuracies. Without being limited to the specific embodiment explained above, according to another aspect of this disclosure, a spectrometric device 1 for spectroscopic measurement in sterile, sealed measurement volumes, in particular for bioprocess analysis, is provided, wherein the device 1 comprises a holder 3 and a spectrometer 5 that can be repeatedly coupled to and decoupled from the holder 3. The holder 3 comprises a plastic body 30 and a window 7 sealingly secured in the plastic body 30.which comprises a metallic mount 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 mount 70, and wherein the spectrometer 5 has a metallic receptacle 44 on a housing 54 of the spectrometer 5, wherein the holder 3 has radially outwardly oriented wings 42 as holding elements and the receptacle 44 has an opening 45 for inserting the wings 3 and slot-shaped spaces 43 that are arranged and designed such that after inserting the wings 42 into the receptacle 44, the wings 42 can be rotated into the slot-shaped spaces 43 by mutual rotation of the spectrometer 5 and the holder 3, so that the spectrometer 5 is locked to the holder 3.

[0100] Here too, however, in a preferred embodiment, a stop surface 51 of a metallic head of the spectrometer 5, which is to be coupled to the holder, can be pressed with a limited force against a component of the window 7. High axial forces can be absorbed here by the wings 42 locked in the slot-shaped spaces. An elastic deformation, which defines and limits the contact force, can be provided in this embodiment by, for example, requiring a certain deformation of the plastic body 30 under the application of force in order to fully insert the receptacle 44 until the wings 42 are in an axial position that allows it to be accommodated in the slot-shaped spaces 43.

[0101] For further explanation, Fig. 14 shows the holder 3 and the spectrometer 5 in their assembled position before locking, i.e., before rotation. For clarity, the stop surface 51, preferably present on a metal head, and the window are not shown.

[0102] The starting position for the fixing rotation is defined by the locking surface 47 on a projection extending into the receptacle 44. This determines the direction of rotation of the spectrometer 5 and indicates this with an arrow. Typically, the spectrometer 5 is rotated while the holder 3 is held in place, as the holder 3 is, for example, firmly welded to a bag of a bioreactor. It is also advantageous to provide an additional locking surface 48 to limit the rotation. Preferably, this additional locking surface 48 is attached to the same projection, as shown. Preferably, such locking surfaces 47, 48 are provided for each vane 42, thus twice in the example shown. If the spectrometer 5 is rotated until the vanes 42 stop against the locking surfaces 48, the spectrometer 5 is then fixed not only in its axial position, but also in its angular orientation.

[0103] Fig. 15 shows the spectrometer 5 and the holder 3 in the locked position. Compared to the illustration in Fig. 14, the visible wing 42 is now rotated by 90° in the receptacle 44 and rests against the locking surface 48. This figure also shows a lens, missing in Fig. 14, in a metallic head 50, which is supported on the shaft 77 of the window 7. The shaft 77 simultaneously forms the nozzle 46 protruding from the holder 3 or forms part of it.

[0104] Preferred embodiments of the spectrometer 5 and process engineering devices, in particular bioprocess engineering devices, which have a spectrometric device 1 according to this disclosure are described below.

[0105] Fig. 16 shows a bioprocessing device 60 with a holder for mounting a spectrometer 5. The bioprocessing device 60 of this embodiment is a bioreactor 61. This comprises a container 61 in the form of a plastic bag 62, in which a biological reaction medium, such as a nutrient solution with microorganisms, is located. The container volume within the plastic bag 62 forms the measurement volume 2. In the case of a plastic bag 63 as the container 62, a single-use application, or a single-use application of the bag, is typically provided.

[0106] The bioreactor 61 can have a support container 64 to stabilize the plastic bag 63. A holder 3 according to this disclosure is welded to the plastic bag 63. The holder 3 with the window 7 for coupling and decoupling radiation into and out of the measurement volume 2 can be made accessible via an opening 65 in the support container 64, so that a spectrometer 5 can be attached and detect radiation from the measurement volume 2 through the window 7.

[0107] As already mentioned, in a preferred embodiment, the spectrometer 5 is equipped with a free-beam optics system 66. By avoiding losses of optical fibers and fiber couplers in the optical path, a significantly lower laser power is required for comparable sensitivity in a compact design compared to standard systems. Due to the lower laser power, a lower energy input occurs in the region of the focal depth in the medium during in-situ concentration measurement. This avoids damage to even thermolabile analytes, such as biogenic macromolecules.

[0108] In particular, the radiation to be detected can be guided as a free beam from the transparent window element 74 to a detector of the spectrometer 5. However, this implies that the radiation is directed and / or focused along this optical path by optical elements such as lenses, prisms, or deflecting mirrors. However, free beam regions are present adjacent to the optical element(s). Fig. 17 shows an embodiment of a spectrometric device 1 with such a spectrometer 5 in a schematic section.

[0109] The compact structure, as shown by way of example in Fig. 17, comprises the wall of the bioreactor bag 63, the holder 3 connected thereto and the spectrometer 5. According to a particularly preferred embodiment, the spectrometer 5 is designed as a Raman spectrometer and includes the focusing lens 16, a beam splitter 82, the excitation source in the form of a laser diode 80 and the spectrometer detector 81. The free beam regions 17 between the spectrometer detector 81 and the transparent window element 74 are shown in Fig. 17.

[0110] It will be apparent to those skilled in the art that the invention is not limited to the embodiments described above, but that, within the scope of this disclosure, the various embodiments can also be combined with one another. Coupling mechanisms can be provided that combine features of different embodiments. For example, a spring 103, as in the embodiments of Figs. 1 to 3, can also be provided in a coupling device 10 according to Figs. 8 to 10 or Figs. 11 to 15 to limit the contact force.

Claims

Patent claims 1. A spectrometric device (1) for spectroscopic measurement in sterile, sealed measurement volumes (2), in particular for bioprocess analysis, wherein the device (1) comprises a holder (3) and a spectrometer (5) that can be repeatedly coupled to and decoupled from the holder (3), wherein the holder (3) comprises a plastic body (30) and a window (7) sealingly fastened in the plastic body (30), which window comprises a metallic mount (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 mount (70), and wherein the spectrometer (5) has a metallic head (50) with a stop surface (51) that can be brought into contact with the window (7) for coupling the spectrometer (5) and the holder (3), and wherein the spectrometric device (1) comprises a coupling device (10),with which the spectrometer (5) and the holder (3) can be detachably coupled to one another, such that in the coupled state of the spectrometer (5) and the holder (3), the stop surface (51) and the window (7) are pressed against one another with a particularly limited force.

2. Spectrometric device (1) according to the preceding claim, characterized in that the device (1) is designed such that the force is generated by elastic deformation of at least part of the spectrometric device (1) and / or that the force is provided by at least one magnet, which is arranged in particular on the metallic head (50) and cooperates with a metallic frame (70) of the window (7).

3. Spectrometric device according to one of the preceding claims, characterized in that the coupling device (10) comprises a threaded sleeve (101) and a spring (103), the spring force of which acts upon compression between the threaded sleeve (101) and the spectrometer (5), and wherein the coupling device (10) further comprises mutually corresponding threads (104, 105) on the holder (3) and on the threaded sleeve (101), so that the threaded sleeve (101) can be screwed onto the holder (3), and by the movement of the threaded sleeve (101) in the axial direction on the holder (3), the spring (103) is compressed and the stop surface (51) of the spectrometer (5) is pressed against the window (7) with the spring force generated by the compression of the spring (103), wherein the threads (104, 105) are preferably designed as double helix threads.

4. Spectrometric device (1) according to the preceding claim, characterized in that the coupling device (10) comprises a sleeve element (102) which surrounds a shaft (53) of the spectrometer (5) and on which the spring (103) acts and which transmits the spring force of the spring (103) to a support surface (52) on the spectrometer (5), and wherein the threaded sleeve (101) has an opening (107) facing away from the holder (3), through which opening the sleeve element (102) emerges upon further rotation of the threaded sleeve (101) after the stop surface (51) has rested on the window (7).

5. Spectrometric device (1) according to one of the two preceding claims, characterized by corresponding stop surfaces (108, 109) on the threaded sleeve (101) and holder (3), which limit the screw depth of the threaded sleeve (101) on the holder (3).

6. Spectrometric device (1) according to one of the preceding claims, characterized by at least one of the following features: - when the spectrometer (5) and holder (3) are coupled together, the stop surface (51) is pressed against the metallic frame (70) of the window (7), - - When the spectrometer (5) and holder (3) are coupled together, the stop surface (51) on the transparent window element (74) of the window (7) pressed, - the transparent window element (74) is held in the opening (71) in the form of a pressure glazing.

7. Spectrometric device (1) according to one of the preceding claims, characterized by at least one of the following features: - the device (1) comprises a free-beam optics (66) for coupling or decoupling radiation into the measuring volume (2), - the spectrometer (5) is designed as a Raman spectrometer.

8. Spectrometric 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. Spectrometric device (1) according to one of the preceding claims, wherein a flange (12, 13) is arranged on each of the spectrometer (5) and the holder (3), wherein for coupling the two flanges (12, 13) can be clamped together by closing a clamp (115), 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 fully closed.

10. Spectrometric 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 an inclined surface (14), wherein the inclined surfaces (14) are arranged on the side of the flange (12, 13) opposite the coupling side for coupling with the other flange (13, 12), - the clamp (115) is designed as a radially compressing clamp (116).

11. Spectrometric device (1) according to one of the preceding claims, characterized by at least one of the following features: - the coupling device (10) is designed such that the contact force of the stop surface (51) against the window (7) when the spectrometer (5) is coupled to the holder (3) is in a range from 10 N to 4 kN, - the product of the contact force of the stop surface (51) on the window (7) and the diameter of the window element (74) is in a range of 0.1 kNxmm to 40 kN x mm.

12. Spectrometric device (1) according to one of the preceding claims, wherein the coupling device (10) is designed such that in the coupled state of spectrometer (5) and holder (3), at least part of the coupling device (10), preferably the entire coupling device (10) is arranged in the housing (54) of the spectrometer (5).

13. Spectrometric device (1) according to one of the preceding claims, wherein the coupling device (10) is designed to establish the coupling of the spectrometer (5) and the holder (3) by means of a plug-and-turn connection.

14. Spectrometric device (1) according to the preceding claim, characterized in that the holder (3) has wings (42) which are oriented outwards in the radial direction of the holder (3), and wherein the spectrometer (5) has a receptacle (44) which is preferably arranged on or in the housing (54) and has an opening (45), as well as slot-shaped spaces (43) corresponding to the wings (42), wherein the wings (42), the slot-shaped spaces (43) and the opening (45) are arranged in such a way that the wings (42) after placing the spectrometer (5) on the holder and inserting the wings (42) into the opening (45) of the receptacle (44), the wings (42) can be rotated by a mutual rotation of the spectrometer (5) and the holder (3) into the slot-shaped Spaces (43) can be screwed in so that the spectrometer (5) is locked at least in the axial direction on the holder (3).

15. Spectrometric device (1) according to the preceding claim, characterized by at least one of the following features: - at least one locking surface (47) is provided on the holder (44) which, after placing the spectrometer (5) on the holder (3), allows a mutual rotation for fixing the spectrometer (5) to the holder (3) only in a predetermined direction of rotation, - the thickness of the wings (42) is excessive compared to the height of the slot-shaped spaces (43).

16. Bioprocessing device (60) comprising a spectrometric device 1 for bioprocess analysis according to one of the preceding claims, wherein the window (7) of the holder (3) of this device adjoins a sterile-tight measuring volume (2) of the bioprocessing device, so that the spectrometer (5) can detect radiation from the measuring volume (2) through the window (7).

17. Holder (3) configured for use in a spectrometric device (1) according to one of claims 1 to 15, with at least one, preferably several different adapters (33), wherein the plastic body (30) of the holder (3) can be connected to the or each of the different adapters (33) by means of a latching connection (36), wherein the adapter or adapters (33) each have a part of a coupling device (10), wherein the latching connection (36) locks the adapter (33) at least in the axial direction.

18. Holder (3) according to the preceding claim, characterized in that the locking connection (36) has locking lugs (38) on one of the parts plastic body (30) and adapter (33, 34), and on the other of the parts plastic body (30) and adapter (33, 34) corresponding grooves (39) and receptacles (40) for the locking lugs (38), wherein the grooves (39) and receptacles (40) alternate circumferentially and wherein the grooves (39) extend in the axial direction, so that the locking lugs (38) can be pushed into the grooves (39) in the axial direction up to stops in the grooves (39), and wherein the two parts, plastic body (30) and adapter (33, 34), can be locked together by rotating the plastic body (31) and adapter (33, 34) against each other when the locking lugs (38) are pushed in up to the stops (390) of the grooves (39), so that the locking lugs (38) are moved from the grooves (39) into the receptacles (40) and lock in the receptacles (40).

19. A method for monitoring a process in bioprocess engineering, in which a spectrometer (5) is mounted on a holder (3) on a sterile-tight measuring volume (2) of a bioprocess plant, so that a spectrometric device (1) according to one of claims 1 to 10 is obtained, and wherein by means of this spectrometric device (1) a signal dependent on the intensity of radiation passing from the measuring volume (2) through the window (7) into the spectrometer (5) is measured, and wherein the spectrometer (5) is dismantled and reconnected to the holder (3) at a later time and the measurement is repeated, and wherein a comparison of these measured signals is then carried out.

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