Spectroscopic measurement device in bioreactors

Abstract

The present invention relates generally to a spectrometer for process analysis techniques, particularly for bioprocess techniques, enabling the precisely aligned connection of a spectrometer to a holder. To this end, the present invention relates to a spectrometer (1) for bioprocess analysis for spectroscopic measurement in a sterile sealed measuring volume (2), wherein the device (1) comprises a holder (3) and a spectrometer (5) that can be repeatedly attached to the holder (3), and the holder (3) comprises a plastic body (30) and a window (7) tightly fitted within the plastic body (30), wherein the window (7) comprises a metal frame (70) and is transparent to radiation to be detected by the spectrometer (5) and the frame ( The spectrometer (5) has a window element (74) that seals the opening (71) of (70), and the spectrometer (5) has a metal head (50) with a contact surface (51) that can be pressed against the window (7) to connect the spectrometer (5) and the holder (3), and the spectroscopic apparatus (1) has a coupling device (10) that can connect the spectrometer (5) and the holder (3) so that they can be separated from each other, and in the connected state of the spectrometer (5) and the holder (3), the contact surface (51) and the window (7) are pressed against each other with a particularly limited force.

Description

Technical Field

[0001] The present invention generally relates to spectrometers for process analysis technology, for example, particularly for bioprocess technology.In particular, the present invention relates to an apparatus comprising a holder configured to connect a spectrometer for analyte detection to a container volume or an aliquot of this volume.Thereby, the present invention also relates to containers and systems for culturing biological materials, particularly to process control during production processes in bioreactors or flow cells.Bioreactors are used for culturing microorganisms, animal cells and plant cells, thereby opening up a wide range of application fields for biotechnological production processes, particularly for the production of biopharmaceuticals and the production of cells and cell products (so-called cell agriculture). Usually, there is a need to further optimize the process.In particular, for the production of biopharmaceuticals, an improvement in product yield and thus an increase in profit are strongly demanded.Various different approaches are provided for the control and regulation of the production process, the improvement of product yield and the reduction of costs.

[0002] The control and regulation of the process can be carried out by calculating the substrate concentration and the product concentration.For this purpose, for the cultivation carried out in a bioreactor or a photobioreactor, usually, sampling is required for sufficient process control.This sampling and the calculation of the substrate concentration and the product concentration are often laborious and are associated with a risk of contamination that can lead to losses of batches present in the bioreactor or photobioreactor.The reason lies particularly in the handling when opening the culture unit and the resource-intensive offline analysis carried out outside each reactor.

[0003] On the other hand, process control and, consequently, yield can be optimized by implementing real-time process control of key parameters. To improve product yield, in particular, in-situ monitoring of parameters such as temperature, metabolism-related or product formation-related substances, as well as real-time adjustment of culture conditions, are advantageous. For this purpose, spectroscopic detection of parameters is particularly suitable because optical detection can be performed non-contact and without contamination.

[0004] To monitor bioreactors, the use of spectroscopy, such as Raman spectroscopy and fluorescence spectroscopy using appropriate spectrometers, is known. In this case, the spectrometer is configured to detect one or more analytes present in the container volume. In this case, the analytes include not only components of the substrates used in the process, but also components of the process products.

[0005] For real-time parameter control, a Raman spectrometer system may be used. Such process analysis techniques (PAT) may be performed, in particular, using a fiber optic guide and an immersion probe, at the ports of a bioreactor or any disposable or reusable container typically used for culturing biological materials, because such ports form openings leading to the interior of the container. The ports of a bioreactor or, generally, the ports of a process stage unit, often correspond to specific standards, such as Ingold ports or PG13.5 ports.

[0006] Typically, a spectrometer comprises a spectrometer unit, a fiber optic light guide, and an immersion probe sensor head. However, space requirements can be limited, especially in smaller containers or other space-constrained situations, such as cleanroom environments. Furthermore, in cleanroom conditions where the operator wears protective gear, particularly protective clothing with gloves, it is necessary that the operator's operation can be easily performed mechanically. Another issue is that biotechnology processes often run over longer periods, and the spectrometer does not need to be permanently installed in the measurement volume, or rather, cannot or should not be left installed depending on the process. The latter is, for example, - Examples of cases where the measurement system cannot be autoclaved. - Examples of drift in measurement systems requiring post-calibration. - For example, a case in which reference measures are used for chemometrics, especially before the logarithmic period or - Examples of post-calibration beyond the verified period That is the case.

[0007] Therefore, the spectrometer is required to be easily connectable to the volume to be measured for measurement. However, in this case, if the measurement position of the spectrometer is not accurately determined again during repeated measurements, the measurement will be inaccurate. In this case, there is also the challenge that plastics, which are often used in bioprocess technology, do not allow for accurate positioning due to their easy deformability. Particularly problematic is the fact that plastic components generally cannot be manufactured with the required precision due to, for example, shrinkage after manufacturing.

[0008] For example, a compact Raman spectrometer, such as the one publicly known under Chinese Patent Application Publication No. 109682791, may not be able to be incorporated into a bioreactor with high performance and sterility, or the Raman system consists of one or more lasers as light sources, a fiber coupling, an optical system unit, and a detection unit, all housed in a 19-inch housing. This housing is sized to accommodate lasers with an output of, for example, up to 500 mW, in order to achieve sufficient sensitivity during measurement despite losses due to the optical waveguide technology. The optical waveguide allows for a certain degree of flexibility due to the different fiber cable lengths, as well as the possibility of using various different measurement probe heads. The laser output cannot be arbitrarily increased to compensate for losses in the optical path, and regenerates the bioanalyte beyond the binding-specific threshold. In particular, especially in compact bioreactor systems, and generally in facilities with not much free space, the Raman systems of the prior art are limited in their practicality due to their required space.

[0009] According to prior art, currently available systems on the market do not meet the requirement of enabling spectroscopy, particularly Raman spectroscopy or fluorescence spectroscopy, while also including a retainer that maintains container integrity as a compact system.

[0010] The fundamental problem of the present invention is to provide a spectrometer that requires less space, is easy to handle, and reduces the aforementioned problems of reproducible linkage to an interaction volume, i.e., to a portion of the container volume that interacts with the spectroscopic analysis, preferably for bioprocess analysis, but in some cases for other processes in a sterile, sealed system.

[0011] This problem is solved by the subject matter of the independent claims. The advantageous configurations of the present invention are described in each dependent claim. According to the present invention, a spectrometer for bioprocess analysis for spectroscopic measurement in a sterile sealed measuring volume is identified, comprising a port or holder and a spectrometer that can be repeatedly engaged with the holder. The holder comprises a plastic body and a window tightly fitted within the plastic body, the window comprising a metal frame and a window element that is transparent to radiation to be detected by the spectrometer and seals the opening of the frame. The spectrometer has a metal head with a contact surface that can be pressed against the window for connecting the spectrometer and the holder. The spectrometer further comprises a coupling device that can detachably connect the spectrometer and the holder, in which case the contact surface and the window are pressed against each other. In particular, in this case the force may be limited, or may be limited within a predetermined or acceptable range, independent of the operation of the coupling device. Plastic as the material for the holder should be given particular preference. This is because it facilitates sterilization by ionizing radiation, such as gamma rays. On the other hand, a disadvantage is the low morphological stability, which hinders accurate alignment of the spectrometer with respect to the container wall or, generally, the walls of the container volume. However, the coupling device allows for surprisingly easy and accurate positioning of the spectrometer despite the holder being primarily made of plastic, by pressing the spectrometer directly against a window that is not made of plastic. The advantage of accurate positioning, at least axially, with respect to the holder becomes apparent, for example, when one wants to compare intensity values ​​with each other after removing and reassembling the spectrometer. In the case of measuring the intensity of a signal, such as a Raman signal from a focused laser beam, the measured value is highly sensitive to the interaction volume and, consequently, to the position of the focal point relative to the window. Therefore, accurate spatial alignment of the spectrometer is extremely advantageous for detecting comparable values. Thus, in the case of Raman spectroscopy with a focused laser beam, the interaction volume is substantially defined by the focusing cone.In fluorescence spectroscopy, intensity loss is linked to reflection loss and other factors due to phase transitions from liquid to solid, and especially from solid to gas. Therefore, accurate positioning is advantageous in fluorescence spectroscopy as well.

[0012] Accordingly, in a further embodiment, the present invention also relates to a method for monitoring a process in a bioprocess technology, comprising: mounting a spectrometer to a holder for a sterile-sealed measuring volume of a bioprocess facility, thereby maintaining the spectroscopic device according to the present disclosure; measuring a signal corresponding to the intensity of radiation that has entered the spectrometer from the measuring volume through a window; removing the spectrometer; reattaching it to the holder at a later time; repeating the measurement, preferably thereafter comparing the signals. This comparison of intensity-dependent signals can be performed with high accuracy by reproducible alignment of the spectrometer, even though the spectrometer does not need to be repeatedly connected or continuously left in the process. In this case, the interaction volume means the portion of the container volume that receives the radiation for spectroscopic measurement by the spectrometer. The volume may be extremely small in some cases, for example, substantially limited to the focal point of a focused excitation beam. In other words, the interaction volume, in the sense of the present disclosure, generally means the volume adjacent to and facing the spectrometer and detected by the spectrometer. In the sense of this disclosure, container volume generally refers to the total volume of a container that may be filled with a medium and is sealed in a sterile manner. Correspondingly, in the case of a reactor, the container volume is the volume in which the biological process takes place. In the case of a flow cell, the container volume is given by the corresponding volume of the flow cell.

[0013] Containers providing a sterile, sealed container volume may be single-use or multi-use containers. Particularly for so-called upstream or downstream processes, the container volume may be provided by a flow cell through which the medium to be analyzed flows, which in this case may be part of a tubing system. In this case, the flow cell may also be formed as a single-use or multi-use component. In this case, a single-use component is used only once and then discarded, whereas a multi-use component may be washed and sterilized and then reused.

[0014] Examples of containers include disposable bioreactors formed as particularly flexible bags (e.g., composite films made of polyethylene (PE) and polyvinyl alcohol (PVA)), disposable mixing systems with stirring mechanisms within flexible bags, disposable bioreactors with rigid polymer containers (e.g., polycarbonate (PC)), and reusable bioreactors formed from special steel.

[0015] All of these containers are sterilizable at least once, thereby providing a sterile, sealed container volume within the scope of the process.

[0016] The apparatus may be used in a variety of processes, and in particular, the spectrometer may be used in processes involving living cells, however, it can also be used in any other reaction and process, especially cell-free processes.

[0017] Furthermore, a volume sealed in a sterile condition, in the sense of this disclosure, is particularly 1.10 -6 Less than mbar·l / s, preferably 1·10 -7 Less than mbar·l / s, particularly preferably 1-10 -8 This refers to a volume or container with a helium leak rate of less than mbar·l / s.

[0018] The present invention will be described in detail below based on the accompanying drawings.

Brief Description of the Drawings

[0019] [Figure 1] It is a perspective partial cross-sectional view of a coupling element as part of a connecting device. [Figure 2] It is a view showing a spectroscopic device before the spectrometer and the holder are interconnected. [Figure 3] It is a view showing the device in the working position where the spectrometer is connected to the holder. [Figure 4] It is a perspective partial cross-sectional view of the holder. [Figure 4a] It is a schematic view of a further embodiment of the spectroscopic device. [Figure 4b] It is a perspective view of the coupling element. [Figure 5] It is a view showing a holder provided with a plastic body and a plurality of adapters for adapting various different connecting devices. [Figure 6] It is a perspective partial cross-sectional view of a holder provided with an externally fitted adapter before locking. [Figure 7] It is also a perspective cross-sectional view of the holder provided with a locked adapter. [Figure 8] It is a view showing a part of the spectrometer provided with a flange arranged on a shaft for attaching the spectrometer to the holder. [Figure 9] It is a view showing a holder fitting the spectrometer shown in FIG. 8. [Figure 10] It is a view showing the spectrometer shown in FIG. 8 connected to the holder shown in FIG. 9 by a clamp. [Figure 11] It is a plan view of the holder 3 as seen in the externally fitting direction of the spectrometer 5. [Figure 12] It is a view showing a spectrometer provided with a housing as seen towards the accommodating part for attaching to the holder shown in FIG. 11. [Figure 13] It is a view showing the opposing positions of the holder 3 and the housing 54 having the accommodating part 44. [Figure 14]This figure shows the combined position of the holder and the spectrometer before locking. [Figure 15] This figure shows the locking position between the spectrometer 5 and the holder 3. [Figure 16] This figure shows a bioprocess technology apparatus equipped with a holder for assembling a spectrometer. [Figure 17] This is a schematic cross-sectional view of a spectroscopic apparatus 1, which includes a spectrometer 5 and the optical components of the spectrometer 5.

[0020] Detailed description of the drawing Figures 1 to 3 show an embodiment of a spectrometer, in which a predetermined force is generated by a spring that brings the spectrometer and the window together.

[0021] In general, without limiting to the specific features of the illustrated examples, this embodiment is based on the fact that the apparatus 1, in particular its coupling device 10, is configured to generate a force between the contact surface 51 of the spectrometer 5 and the window 7 of the holder 3, which may be called a port or, according to German Patent No. 102018108325, a sensor holder or, according to European Patent No. 3747983, a composite element, by the elastic deformation of at least one member of the spectrometer 1. This principle is also based on further embodiments shown in the drawings. The embodiments in Figures 1 to 3 are based in particular on the generation of a force by a spring 103 to press the spectrometer 5 and the holder 3 or the window 7 located within the holder 3 against each other, at least partially. Additionally or alternatively to the spring force, the force for pressing against each other may be provided as a magnetic force by one or more magnets. A further embodiment realized in the examples in Figures 1 to 3 is that the connection between the spectrometer 5 and the holder 3 is made by screwing. Conventionally, in process analysis techniques, for example, when using fiber-connected spectrometer probes or screw-type connections for free-beam spectrometers, there are shortcomings in terms of the long-term stability and accuracy of the connection. This drawback can be easily overcome by the embodiments described below.

[0022] For this reason, Figure 1 shows a perspective partial cross-sectional view of the coupling element 110, which forms one of the members of the coupling device 10. Figures 2 and 3 show the entire spectrometer 1, which includes the holder 3, the spectrometer 5, and the coupling device 10.

[0023] The coupling element 110 of the coupling device 10 comprises a threaded sleeve 101 and a spring 103, as shown in Figure 1. The coupling device 10 is configured such that the spring force of the spring 103 when compressed acts between the threaded sleeve 101 and the spectrometer 5. In particular, in this case, as will become clearer based on Figures 2 and 3, the spectrometer 5 is pressed axially toward the window 3 by the spring force. Furthermore, the coupling device 10 is provided with corresponding threads 104 and 105 on the holder 3 and the threaded sleeve 101, so that the threaded sleeve 101 can be screwed into the holder 3. By moving the threaded sleeve 101 axially toward the holder 3, the spring 103 is compressed, and the spring force generated by this compression of the spring 103 presses the contact surface 51 of the spectrometer 5 against the window 7. In addition to or as an alternative to the spring force, a force to press the contact surface 51 against the window 7 may be provided by one or more magnets. For this purpose, in particular, one or more magnets can be placed on the end face of the metal head 50 of the spectrometer 5 (see Figure 2), in which case these magnets can be made to interact with the metal frame 70 of the window 7 (see Figure 4). The metal head 50 of the spectrometer 5 is only schematically shown in its external dimensions in Figures 2 and 3.

[0024] In this example, the thread 105 provided on the connecting element 110 is formed as a female thread, and the thread 104 provided on the retainer 3 is formed as a corresponding male thread. As will be obvious to those skilled in the art, the reverse configuration is also possible.

[0025] Figure 2 shows the spectrometer 1 with the spectrometer 5 pressed against the holder 3, in the state before screwing. In this state, the spring 103 is not yet compressed, but may already be under preload. The contact surface 51 of the spectrometer 5 may already be in contact with the window 7 in this state, as shown in the illustrated example. However, in this position, generally, no pressing force against the window is yet applied to the spectrometer 5 by the coupling device 10.

[0026] Figure 3 shows the spectrometer 1 in the working position, that is, after operation of the coupling device 10. Operation of the coupling device 10 involves rotating the threaded sleeve 101 relative to the holder 3. As the threaded sleeve 101 approaches, the spring 103 is compressed, and in this case, the spring force acts between the spectrometer 5 and the holder 3. It is particularly advantageous to provide a support surface 52 on the spectrometer 5 to which the spring force is transmitted. In this embodiment, the pressing force from the spectrometer 5 to the window 7 is substantially generated by the compressed spring 103 and, consequently, by a predetermined specific spring force. This prevents extremely high forces from acting directly on the window 7 through the screw, which could potentially damage the window 7 and cause it to lose its tightness. Furthermore, the spring 103 causes the screw to tighten, thus reducing the risk of the screw loosening during operation. Therefore, it is generally advantageous that the spring force of the spring 103 is sized such that, at the working position, it is less than the force required for extrusion or that would generally damage the window 7 and / or damage the mounting portion of the window 7 into the housing of the retainer 3. In the illustrated configuration, it is also possible to easily establish a safety margin between the applied spring force and the force that poses a risk of damaging the window. Preferably, the compressed spring force of the spring 103 is a maximum of 2 / 3 of the force required to push out the window 7. However, on the other hand, since the spectrometer 5 is pressed against the window 7 with a sufficiently high force by the spring 103, the spectrometer 5 is in immovable contact with the window 7, thereby precisely defining the position of the spectrometer 5 relative to the window 7, and especially with respect to the measuring volume adjacent to the window 7. This compensates for, or makes insignificant, any manufacturing errors during screwing.

[0027] Without limiting ourselves to this example or the embodiments described below, the coupling device 10 is preferably configured such that the pressing force of the contact surface 51 against the window 7 when the spectrometer 5 is coupled to the holder 3 is in the range of 10N to 4kN, preferably 20N or more, and particularly preferably 50N to 2kN. This limit is especially true when the pressing force is transmitted to the transparent window element 74 via the contact surface 51. If the contact surface 51 is supported by a metal frame 70, even higher pressing forces can be used. However, even when supported by the window element 74, similarly higher forces can be set depending on the configuration of the window 7. The force that poses a risk of pushing out the transparent element provided in the window or generally damaging the window 7 also depends on the diameter of the window 7. Smaller windows generally withstand higher forces. Therefore, to ensure secure mounting of the spectrometer and to avoid damage to the apparatus 1, a measure of a good range of pressing force is given by the product of the diameter of the transparent window element 74 and the pressing force. For this purpose, in a further embodiment, the coupling apparatus 10 is specified to be configured such that the product of the pressing force of the contact surface 51 to the window 7 and the diameter of the window element 74 does not exceed a value of 40 kN × mm. However, preferably, this product is at least 0.1 kN × mm. That is, preferably, the product is within the range between both values.

[0028] Embodiments with threading and a fastening spring 103 can be further improved. As is evident from Figures 1 to 3, the coupling element 110 may be formed from two parts, i.e., with an additional sleeve element 102 in addition to the threaded sleeve 101. In this example, the threaded sleeve 101 forms the outer frame, and the sleeve element 102 forms the inner body. The sleeve element 102 surrounds the shaft 53 of the spectrometer 5, as shown in Figures 2 and 3. A spring 103 acts on the sleeve element 102. The spring force of this spring 103 is transmitted through the sleeve element 102 to a support surface 52 provided on the spectrometer 5. The threaded sleeve 101 has an opening 107 on the opposite side of the holder 3 or at the rear with respect to the window 7, and when the threaded sleeve 101 is further rotated after the contact surface 51 is made contact with the window 7, the sleeve element 102 advances through the opening 107. This is achieved by the fact that the spectrometer 5 becomes immobile axially relative to the window 7 after being pressed against it, and thereby the sleeve element 102 is also fixed in position based on its contact with the support surface 52. In contrast, the threaded sleeve 101 continues to move axially toward the window 7 by screwing it in.

[0029] Furthermore, according to one improved embodiment, a marking 112 may be provided on the sleeve element 102. For example, this marking may be a groove. The axial position of the marking 112 may be selected so that the marking 112 indicates a specific end position of the screw thread and thus the precise assembly and positioning of the spectrometer 5 to the holder 3 by the advancement or visibility of the marking 112 from the opening 107.

[0030] However, depending on the circumstances, this may not prevent the operator from screwing the threaded sleeve 101 further. In the illustrated configuration, in order to avoid damage to the coupling device 10 or the window 7, according to alternative or additional embodiments, the coupling device 10 has corresponding contact surfaces 108, 109 provided on the threaded sleeve 101 and the retainer 3, and these contact surfaces 108, 109 limit the screwing depth of the threaded sleeve 101 into the retainer 3. As can be seen from Figures 2 and 3, one of the contact surfaces may be formed by the end face of the passage into which the spectrometer 5 is inserted, provided on the retainer 3. In the illustrated example, the contact surface provided on the threaded sleeve 101 is formed by an inwardly projecting annular projection.

[0031] Further details of the holder 3 and the window 7 located within the holder 3 are described below in accordance with preferred embodiments. Typically, the holder 3 is used to provide optical access to a measurement volume in bioprocess analysis. For this purpose, according to preferred embodiments, the holder is attached to a bioreactor. Details of the holder and the bioreactor equipped with the holder are publicly known in German Patent Invention No. 102018108325, which is also entirely subject to this disclosure with respect to details of the bioreactor and the attachment of the holder to the bioreactor. In that specification, the holder is referred to as a sensor holder. Another use of the spectrometer 1 is measurement in a flow cell. Flow cells are used in bioprocess technology for process control and analysis in a fluid medium. Accordingly, generally, without limiting to the examples and embodiments specified in further aspects of this disclosure, a bioprocess technology apparatus is identified, comprising a spectrometer 1 for bioprocess analysis, wherein a window 7 of the holder 3 of the apparatus is adjacent to a sterile-sealed measuring volume of the bioprocess technology apparatus, so that the spectrometer 5 can detect radiation from the measuring volume through the window 7. This bioprocess technology apparatus may be a bioreactor or a flow cell, or may comprise a bioreactor or a flow cell.

[0032] Figure 4 shows an embodiment of the retainer 3 in a perspective partial cross-sectional view. The retainer 3 comprises a plastic body 3, to which the window 7 is tightly fitted, for example, by fusion or bonding. In order to enable the plastic body 30 to be firmly bonded to a bioreactor, for example, in the form of a plastic bag, the plastic body 30 preferably has a flange 31 surrounding the window 7, to which the bag can be attached, and in particular can be firmly bonded by welding.

[0033] The window 7 comprises a metal frame 70. This metal 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 in the figure. However, it is also possible for the window element 74 to cover the opening 71. Generally, it is preferable to use glass solder 76 to attach the window element 74. In particular, compression sealing can be achieved with this glass solder 76, and during this compression sealing, the sealing generates a compressive force that presses the window element 74 into the opening 71 and holds it immovably. Alternatively, the window element 74 can be a glass element that is directly bonded to the metal frame 70, for example by fusion bonding, thereby eliminating the need for bonding with glass solder 76. In one embodiment, the transparent window element 74 is made of a single-crystal material, such as a single crystal of one of the materials: aluminum oxide, yttrium oxide, or zirconium oxide. In one improved embodiment, a material combination with, for example, yttrium-stabilized ZrO2 may be used. Such single-crystal materials have been found to be particularly advantageous in relation to Raman measurements, because the single-crystal material has only a minimal influence on the measurement.

[0034] In order for the window 7 to be bonded as firmly as possible to the plastic of the plastic body 30, it is advantageous for the bonding surface between the plastic body and the metal frame 70 to be as large as possible. However, at the same time, it is required that the surface of the metal frame 7 facing the measurement volume be as inconspicuous as possible. This is advantageous in order to minimize shielding during sterilization by ionizing radiation. For this reason, generally speaking, and not limited to the illustrated embodiment, it is preferable for the frame 70 to have a shaft portion 77 that extends in the axial direction and is bonded to the plastic body 30 on its outer circumferential surface, as shown in Figure 4.

[0035] Although a small surface of the metal frame 70 facing the measurement volume is desirable, the metal frame 70 generally has a flange 78 projecting inward into the opening 71, in further embodiments realized in the illustrated example, without being limited to the illustrated example. This flange 78 may form a stepped portion, particularly on the inside of the metal frame 70, in which case the spectrometer 5 contacts this stepped portion with its contact surface 51. Thus, in improved forms of the apparatus 1, without being limited to a particular embodiment, it is specified that, in the interconnected state of the spectrometer 5 and the holder 3, the contact surface 51 is in contact with or pressed against the metal frame 70 of the window 7. However, according to alternative or additional embodiments, the contact surface 51 may be pressed against a transparent window element 74. However, in this embodiment, depending on the circumstances, a high force may be transmitted to the window element 74 by a mechanical impact on the spectrometer 5, which is to be avoided, especially with brittle materials.

[0036] Furthermore, the flange 78 provides enhanced mechanical stability in the radial direction, which is preferable when the window element 74 is held within the opening 71 in a compression seal.

[0037] In variations where the force for pressing the contact surface 51 is provided entirely or partially using a magnet, the metal frame 70, particularly its flange 78, may be used as a corresponding portion for the magnet located within the head 50 of the spectrometer 5. In particular, in variations where the magnet is used in combination with a spring 103, the inner surface of the shaft portion 77 of the metal frame 70 may also be used as a corresponding portion for the magnet located within the head 50 of the spectrometer 5, in which case the magnet is particularly suitable for the initial alignment and positioning of the head 50 within the shaft portion 77. In this case, the magnet may be located within the shaft portion of the head 50.

[0038] When magnets are used for alignment and / or provision of pressing forces, it is preferable to manufacture the metal frame 70 from a magnetic metal. Accordingly, when the metal frame 70 is manufactured from steel, ferritic or martensitic steel is preferred.

[0039] In the case of "glass-metal sealing" ("GTMS"), compression sealing, or tight glass-metal compression sealing, a permeable window element 74 and optionally solder glass are inserted into a metal frame 70, for example, as a pressed product. By heat treatment, the solder glass and optionally the material of the permeable element are fused to the metal frame. For compression sealing, the coefficient of thermal expansion of the metal frame is further selected to be greater than that of the permeable element and optionally the solder glass. Preferably, in this case, the difference is at least 3 ppm / K.

[0040] In some cases, it is required that different types of spectrometers can be connected to the holder 3. This can be easily achieved, in particular, when different coupling devices 10 can be used. To achieve this, in a further embodiment, the holder 3 for the spectrometer 1 according to the present disclosure is provided with at least one, preferably a plurality of different adapters 33, the plastic body 30 of the holder 3 can be coupled to the adapters 33 or to each of the different adapters 33 by a locking coupling portion 36, in which case one or more adapters 33 each have a portion of the coupling device 10 for connecting a spectrometer 5, in which case the locking coupling portion 36 locks the adapter 33 at least axially, that is, along the optical axis of the holder 3. This allows force to be applied axially to the spectrometer 5 inserted and connected within the holder 3 via the coupling device 10, and thereby the spectrometer 5 can be pressed against the window 7. Various adapters allow for adaptation to the specific requirements of different spectrometers or their connecting components, in which case the focal position, particularly the depth, in the medium to be examined is always reproducibly defined by mechanical contact between a part of the spectrometer and the window 7.

[0041] In the embodiment shown in Figure 4, the adapter 33 has threads 104 for screwing into the threaded sleeve 101 and a contact surface 108 for limiting the screwing depth, as in the examples in Figures 2 and 3.

[0042] The locking mechanism or locking coupling 36 can only be partially seen in Figure 4. The locking portion 36 and further possible adapters will be described in detail below with reference to Figures 5 to 7.

[0043] Figures 4a and 4b show further embodiments of the spectrometer 1 in which the screw connection of the coupling element 110 to the holder 3 is formed as a double helix thread, unlike the embodiments described with reference to Figures 1 to 3. In this case, Figure 4a shows the coupling element 110 and the holder 3 partially visible, allowing for a better recognition of the shape of the female thread on the coupling element 110 and the shape of the male thread on the holder 3. In this case, Figure 4b shows the coupling element 110 in an oblique view, allowing for a particularly good recognition of the shape of the female thread.

[0044] The coupling element 110 has female threads formed on the inner surface of the threaded sleeve 101 in the form of projections extending along two helical wires 121, 122 or a winding wire. In this case, both helical wires 121, 122 have the same pitch but are rotated 180° relative to each other. This ensures that the starting ends 140 of the helical wires 121, 122 are at the same height with respect to the axis of the threaded sleeve 101.

[0045] Preferably, each of the two helical wires 121 and 122 extends for a maximum of 1 / 2 turn or 180°. This achieves the ability to easily manufacture a double helix structure without creating an undercut inside the threaded sleeve 101. However, preferably, each of the two helical wires 121 and 122 extends for more than 160° of turns, thereby providing the largest possible mounting surface when engaging with the corresponding portion for the double helix thread.

[0046] The corresponding portion of the female thread formed on the coupling element 110 is located on the outside of the plastic body 30 of the retainer 3. In the illustrated configuration, a male thread is formed by projections extending along two helical wires 131, 132 or a winding wire. In this case, both helical wires 131, 132 have the same pitch but are rotated 180° relative to each other. This ensures that the starting ends 140 of the helical wires 131, 132 are at the same height with respect to the axis of the plastic body 30.

[0047] Preferably, the male threads formed in the plastic body 30 have more than one full turn of the helical lines 131,132 centered on the plastic body 30, and particularly preferably two full turns.

[0048] The double helix threading resulting from this arrangement is particularly suitable for ensuring reliable threading even when the manufacturing tolerances of plastic components, such as the retainer 3, are relatively large. For example, if the connecting element 110 is made of metal, such as special steel, and the retainer 3 is made of plastic, such as polyethylene (PE), then the normal shrinkage of the plastic will cause a dimensional deviation between the helical wires 121, 122 in the connecting element 110 and the helical wires 131, 132 in the retainer 3.

[0049] However, in the illustrated configuration, the female threads of the coupling element 110, which have double helices 121 and 122, differ from conventional threads that have only one winding wire. Instead of being a projection of one of the helical wires 131 and 132 of the holder 3, they extend within the space between the thread grooves defined by the helical wires 131 and 132. As a result, one helical wire 131 forms the lower guide for the double helical female threads of the coupling element 110, and the other helical wire 132 forms the upper guide.

[0050] In this case, based on the spring force provided by the spring 103 (see Figures 1, 2, and 3), the double helix female threads of the coupling element 110 are guided to make orderly contact with the upper partitions of the double helix male threads of the retainer 3.

[0051] The starting points 140 of both helical lines 121,122;131,132 are located directly opposite each other or offset by 180°. This ensures that when the coupling element 110 is applied to the retainer 3 for screwing, both members are positioned to overlap each other uniformly and are aligned along a single common axis. This avoids the issue of the female threads of the coupling element 110 catching on the male threads of the retainer 3, as would occur with standard threads having only one thread entry point. Additionally, the increased surface area of ​​the threaded components compensates for the lower strength of the plastic of the retainer 3 compared to the metal of the coupling element 110.

[0052] The double helix threads illustrated in the drawings for the connection between the coupling element 110 and the retainer 3 may be combined with other embodiments of the spectrometer.

[0053] Figure 5 shows a plastic member 30 with a window 7 and two connectable adapters 33 and 34. Each adapter 33 and 34, in combination with the plastic member acting as a base element, produces a holder 3 formed in various shapes, in which case the various holders 3 differ with respect to the connecting mechanism or connecting device 10 for the spectrometer 5. In this case, the adapter 33 is formed with screw threads 104, so that when the adapter 33 is locked to the plastic body 30, a holder 3 as shown in Figures 2 to 4 is obtained.

[0054] Without being limited to the illustrated examples, and without being limited to embodiments with various different adapters 33, 34, the holder 3 or its plastic member 30 preferably has a shaft portion 37. In this case, the shaft portion 77 of the window 7 may be attached to this shaft portion 37, as already shown in Figure 4.

[0055] In a preferred embodiment, the locking coupling portion 36 is provided with a locking projection 38 on one of the members of the plastic body 30 and the adapters 33, 34, and the other member has a corresponding groove 39 for the locking projection 38 and a housing portion 40. In this case, the groove 39 and the housing portion 40 are alternately provided around the entire circumference in the circumferential direction, and the groove 39 extends in the axial direction. This allows the locking projection 38 to be pushed axially into the groove 39 up to a stopper provided in the groove 39. In this case, when the locking projection 38 is pushed up to the stopper 39 in the groove 39, the plastic body 30 and the adapters 33, 34 are rotated relative to each other, thereby moving the locking projection 38 from the groove 39 into the housing portion 40, and it becomes possible to lock it into the housing portion 40.

[0056] To facilitate the relative rotation of both members forming the retainer 3, it is particularly preferable that the locking projection 38 has a sliding surface 380 that is positioned obliquely to each portion with respect to the tangential direction. In this case, the plastic body 30 and the adapters 33;34, which are members, can be rotated relative to each other more easily in a direction in which the sliding surface 380 slides beyond the edge of the groove 39.

[0057] Figure 6 shows a partial cross-sectional view of the holder 3 with the adapter 34 attached before the locking coupling portion 36 is engaged, for further clarity. In Figure 6, the cross-section extends perpendicular to the optical axis through the adapter 34 and the shaft portion 37 of the plastic body 31. Within the cross-section, the shaft portion 77 of the window 7, which is coupled to the shaft portion 37 of the plastic body 31, can also be seen as a tubular, preferably cylindrical, element. The cross-sectional view clearly shows the distribution of the locking projection 38 with a sliding surface 380, the groove 39, and the housing portion 40. Before locking, the locking projection 38 is still located within the groove 39, as shown in the figure. In the illustrated configuration, the adapter 34 is rotated clockwise to move the locking projection 38 into the housing 40 and lock it in place. This allows the sliding surface 380 to slide over the edge of the groove 39, and ultimately snap into the housing 40, which is preferably molded complementary to the locking projection 38 as shown, and lock into place. The fully assembled state of the adapter 34 is shown in Figure 7. In the illustrated embodiments of Figures 5 to 7, the locking projection 38 is located on the plastic body 30, and the groove 39 and housing 40 are located on the adapters 33 and 34. However, this configuration may be reversed, in which case the locking projection is located on the adapters 33 and 34, and the groove 39 and housing 40 are located on the plastic body 30. Furthermore, a configuration in which both members have a groove 39 and a housing 40 is also possible.

[0058] Further embodiments of the spectrometer are described below, which also have a coupling device 10, which allows the spectrometer 5 and the holder 3 to be detachably coupled to each other, and when the spectrometer 5 and the holder 3 are coupled, the contact surface 51 and the window 7 are pressed together with a limited force. This embodiment is based on the fact that the spectrometer 5 and the holder 3 are each provided with one flange 12, 13, in this case both flanges 12, 13 are tightened together by closing a clamp 115 for coupling, and in this case the flanges 12, 13 and the clamp 115 are designed such that a gap 15 remains between both flanges 12, 13 when the clamp 115 is fully closed.

[0059] Figure 8 shows a partial cross-sectional view of a portion of the spectrometer 5 in this embodiment. Generally, without being limited to the described embodiment involving connection via a clamp, the spectrometer 5 preferably has a housing 54, the housing 54 having a head 50 with a shaft portion 53 for connection to the holder 3. Furthermore, it is particularly preferable to provide a spectrometer 5 having a free beam region 17, as shown in the illustrated example. In particular, without being limited to the specified embodiment, it is preferable to perform the incidence or emission of radiation into or out of the measurement volume by a free beam optical system. Indeed, such a free beam optical system enables highly sensitive measurements and an extremely compact structure for the spectrometer 5, especially for Raman measurements. To cause radiation to be incident on or out of the measurement volume, a lens 16 may be provided for this purpose, in a preferred embodiment, particularly located in the head 50 or, in the illustrated configuration, in the shaft portion 53. In this context, a free-beam optical system, as understood in this disclosure, means an optical system in which radiation can propagate freely, but typically through optical elements such as lenses, in a ventilated or gas-filled space, rather than being continuously guided through a solid medium, such as an optical fiber. In this case, it is particularly important that the incidence and / or emission of radiation can be carried out by the free-beam optical system at the head of the spectrometer. In this case, a lens may be present in the free-beam optical system when the spectrometer is coupled, and in this case, the lens may be in contact with the window 7. In the latter case, the free-beam optical system is positioned behind the lens with respect to the measurement volume.

[0060] As is further evident, the contact surface 51 is realized by the end face of the hollow shaft portion 53. This means that the contact surface 51 that aligns the spectrometer 5 with the window 7 of the holder 3 can be extremely small, and in the illustrated example, it is provided only by a linear surface on the edge of the head portion 5 of the spectrometer 5.

[0061] The shaft is provided with a flange 13 that extends around its entire circumference. This flange 13 is used to connect the spectrometer 5 and the holder 3, as will be explained in detail with reference to the following drawings.

[0062] Figure 9 shows a suitable holder 3 for connecting the spectrometer 5. The holder 3 in this example is constructed similarly to the example described above with respect to the plastic body 30 and the window 7. However, instead of threads as in the example of Figure 4, a flange 12 is provided. As is clear, this flange 12 may be formed as an adapter and may be coupled to the plastic body 30 by a locking portion 36, for example, as described with reference to Figure 5. In fact, the illustrated example corresponds to the holder 3 shown in Figure 5 with an adapter 34 connected, and therefore the adapter 34 may have the form of the flange 12 shown in Figure 9.

[0063] In a preferred configuration, without limiting to the specific example shown, at least one of the flanges 12, 13 has an inclined surface 14. Preferably, both flanges 12, 13 are provided with inclined surfaces 14. In this case, one or both inclined surfaces 14 are located on the side of the flanges 12, 13 opposite to the connecting side for connecting to the other flange 13, 12. One or more inclined surfaces 14 may be particularly conically shaped surfaces that extend around the entire circumference of the flanges 12, 13. The inclined surfaces 14 serve to easily convert the force applied by the clamp radially when the clamp is closed into an axial force, which can then be used to press the contact surface 51 of the spectrometer 5 against the window 7.

[0064] To facilitate easier alignment of the spectrometer 5 and the holder 3, in one improved configuration, a groove 18 extending around the entire circumference may be provided on one of the flanges 12, 13, and a corresponding key that engages with the groove 18 when interconnected may be provided on the other flange 13, 12. Additionally or alternatively, magnets may be provided to facilitate the alignment and positioning of the spectrometer 5 to the holder 3. In this case, for example, one or more magnets may be placed on the spectrometer 5, particularly its head 50, and may interact with corresponding magnetic portions on the holder 3.

[0065] Figure 10 shows the spectrometer 1 assembled by the coupling device 10. In this case, the spectrometer 5 and the holder 3 are clamped together by a clamp 115 at their respective flanges 12 and 13. Particularly preferably, this clamp 115 is formed as a clip 116 for radial compression. The clamp 115 or clip 116 may have an inclined surface 140 corresponding to an inclined surface 14. This inclined surface 140 is guided or swiveled radially inward when the clip 116 is tightened, so as to come into contact with the inclined surface 14 provided on the flanges 12 and 13. Generally, in this case, the clamping of the clamp or, in particular, the tightening of the clip, causes the flanges 12 and 13 to press against each other. In the case of the inclined surfaces 14 and 140, this occurs because radial compression is converted into an axial force. Accordingly, the spectrometer 5 is also pressed against the window 7 at its contact surface 51. The axial positions of flanges 12 and 13 are selected so that they remain spaced apart from each other when the contact surface 51 against the window 7, thereby leaving a gap 15 between flanges 12 and 13. This causes flanges 12 and 13, or at least flange 12 provided on the retainer 3, preferably made of plastic, to undergo some elastic deformation. The force generated by this is both pressed against the window and limited, thereby preventing damage to the window 7. Thus, flange 12 provided on the retainer 3 functions as a disc spring, so to speak. In contrast, if both flanges 12 and 13 were in contact with each other, the pressing pressure generated by the clamp could only be absorbed by both flanges 12 and 13. In this case, the specified pressing pressure from the contact surface 51 to the window 7 would no longer be applied.

[0066] The coupling device 10 in this embodiment may be substantially configured as a so-called tri-clamp coupling, but may also be configured with a gap between the flanges 12 and 13 instead of a seal.

[0067] In the embodiments described so far, the head 50 of the spectrometer 5 is provided with a shaft 53. The holder 3 is also provided with a shaft 37, in which case the coupling device 10 is positioned between the housing 54 and the window 7. This increases the distance between the spectrometer housing 54 and the original measurement volume, for example, the bioreactor bag. However, in some cases, only a small amount of space is provided for the equipment. Therefore, in further embodiments, it is desirable to keep the distance from the housing 54 of the spectrometer 5 to the transparent window element 74 as small as possible. For this purpose, in further aspects of the present disclosure, it is specified that at least a portion of the coupling device, preferably the entire coupling device 10, is positioned inside the housing 54 of the spectrometer 5 in the manner of interconnection between the spectrometer 5 and the holder 3. This feature is independent of whether a specified or limited pressing force is applied to the window 7 by the coupling device 10.

[0068] The portion of the housing 54 of the spectrometer 5 that interacts with the coupling device 10 may be provided in the form of an adapter plate. This is particularly advantageous for retrofitting an existing spectrometer housing for use with the spectrometer 1 or for adapting the basic shape of the housing to different applications.

[0069] Therefore, generally speaking, without being limited to the specified embodiments, a spectrometer 1 for spectroscopic measurement in a sterile sealed measuring volume, particularly for bioprocess analysis, wherein the apparatus 1 comprises a holder 3 and a spectrometer 5 having a housing 54 that can be repeatedly attached to and detached from the holder 3, wherein the holder 3 comprises a plastic body 30 and a window 7 tightly fitted within the plastic body 30, the window 7 comprising a metal frame 70 and a material that is transparent to radiation to be detected by the spectrometer 5 and the frame 70 Also specified is a spectrometer 1 comprising a window element 74 that seals an opening 71, in which case the spectrometer 5 may be pressed against the window 7 or has a contact surface 51 against which it is pressed, in order to connect the spectrometer 5 to the holder 3, and in this case the spectrometer 1 comprises a coupling device 10 that can detachably connect the spectrometer 5 and the holder 3, and the coupling device 10 is configured such that at least a part of the coupling device 10, preferably the entire coupling device 10, is located within the housing 54 of the spectrometer 5 when the spectrometer 5 and the holder 3 are connected. In this case the coupling device 10 includes all elements that form a rigid connection between the holder 3 and the spectrometer 5. Therefore, with respect to the embodiments of Figures 2 and 3, the threads 104 may be assigned to the coupling device 10, regardless of whether the threads 104 are located on an adapter or formed integrally with the plastic body in the holder 3.

[0070] The following describes embodiments that enable a particularly thin configuration of the coupling device 10. In this improved form, the coupling device 10 may be located entirely or partially within the housing 54 of the spectrometer 5 after coupling, as described above. Generally, for this purpose, a coupling device 10 is provided that forms the connection between the spectrometer 5 and the holder 3 by a junction rotation coupling. This coupling itself makes effective use of the ductility or deformability of the plastic of the holder 3.

[0071] For this reason, Figure 11 shows the holder 3 in a plan view as seen in the direction of external fitting of the spectrometer 5. The coupling device 10, according to the configuration of this embodiment of the coupling device 10 by interlocking rotation coupling, comprises at least one, preferably at least two, radially outward-extending blades 42 provided on the plastic body 30 of the holder 3. These blades 42 are preferably also formed from plastic. These plastic blades may be integrally formed with the plastic body 30, or they may be coupled, preferably locked, to the plastic body 30 by a suitable adapter, as described in the embodiments of Figures 4 to 7, for example. Although not yet visible in Figure 10, the blades 42 have two opposite faces, and the spectrometer may be anchored to these two faces, thereby allowing the spectrometer to be fixed in position to the holder 3 in the axial direction.

[0072] Figure 12 shows a spectrometer 5 having a suitable housing 44 for the holder 3 shown in Figure 11. The housing 44 surrounds an opening 55 for injecting or emitting radiation for spectroscopic measurement. Furthermore, the housing 44 has an opening 45 into which a blade 42 can be inserted, or into which the housing 54 of the spectrometer 5 can be placed over the blade 42 to introduce the blade 42 into the housing 44.

[0073] Figure 13 shows the holder 3 and the housing 54 having a accommodating section 44 in opposing positions before the holder 3 is inserted into the accommodating section 44 or, conversely, before the housing 54 is placed on the holder 3. The figure shows both opposite faces 420 and 422 of the vanes 42. In this case, face 422 is oriented towards the window element or the measurement volume, while the opposite face 420 is oriented towards the spectrometer 5. To more accurately position the holder 3 and the spectrometer 5, the holder 3 may have a tube section 46 that is inserted into the opening 55 when the spectrometer 5 is placed on the holder 3. In this case, the optical system of the spectrometer 5 may preferably be configured such that radiation propagates as a free beam inside the tube section 46 and to the window element. As can be seen from Figures 12 and 13, the housing opening 45 may have a shape that fits the vanes 42 of the holder 3. This ensures the placement of the spectrometer 5 in a specific orientation.

[0074] As can be further seen from Figure 13, the housing 44 has a slit or slit-shaped intermediate chamber 43 corresponding to the blade 42, into which the blade 42 may be screwed to lock the spectrometer 5 to the holder 3. Therefore, without limiting to the specific example shown, in an improved embodiment of the interlocking pivot coupling, the holder 3 has at least one, preferably at least two, blades 42 oriented radially outward from the holder, in which case the spectrometer 5 has a housing 44 having an opening 45 and a slit-shaped intermediate chamber 43 corresponding to the blades 42, preferably located in or within the housing 54, the slit-shaped intermediate chamber 43 being located behind or below the opening 45, particularly when looking at the housing 54 from the outside, in which case the blades 42, the slit-shaped intermediate chamber 43 and the opening 45 are such that the blades 42 can be twisted into the slit-shaped intermediate chamber 43 by rotating the spectrometer 5 and the holder 3 relative to each other after the spectrometer 5 has been placed on the holder and the blades 42 have been inserted into the opening 45 of the housing 44, thereby the spectrometer 5 is positioned to be locked to the holder 3 at least axially.

[0075] However, in advantageous improved configurations, the housing 44 is not symmetrically configured, unlike the arrangement of the blades 42 on the holder 3. In Figure 13, in this example, a blocking surface 47 is present on the left side, and this blocking surface 47 is absent on the opposite side. Generally, without limiting to special cases, for this reason, the housing 44 may have at least one blocking surface 47, which, after the spectrometer 5 is placed on the holder 3, allows for mutual rotation to fix the spectrometer 5 in position on the holder 3 in only one predetermined rotation direction, or a predetermined rotation direction is set. This design prevents incorrect rotation directions and defines a rotation angle (preferably 90°). This enables easy assembly and secure positioning.

[0076] In a more advantageous improved configuration, the thickness of the blade 42 is greater than the height of the slit-shaped intermediate chamber 43. Preferably, this greater dimension is in the range of 50 to 150 μm. Due to the ductility of the blade-shaped retaining element or the blade 42, the blade 42 is pushed into the slit-shaped intermediate chamber and self-retained. The greater dimension may be adjusted so that assembly can be performed by rotational movement with a torsional force of 0.2 to 0.8 Nm.

[0077] Particularly preferable, the housing 44 provided in the spectrometer 5 is made of metal. This allows for accurate positioning of the spectrometer 5 relative to the holder 3, even when the metal contact surface 51 is not pressed against the window 7. This is due in particular to the fact that the vanes 42 provide a large area of ​​locking within the slit-shaped intermediate chamber 43, allowing for complete leveling of unevenness. Thus, without limiting to the special embodiments described above, according to yet another aspect of the present disclosure, a spectrometer 1 for spectroscopic measurement in a sterile sealed measuring volume, particularly for bioprocess analysis, wherein the apparatus 1 comprises a holder 3 and a spectrometer 5 that can be repeatedly engaged with the holder 3, wherein the holder 3 comprises a plastic body 30 and a window 7 tightly fitted within the plastic body 30, the window 7 comprising a metal frame 70 and a window element that is transparent to radiation to be detected by the spectrometer 5 and seals the opening 71 of the frame 70. The spectrometer 5 comprises a metal housing 44 provided in the housing 54 of the spectrometer 5, and the holder 3 has a blade 42 as a holding element oriented radially outward, and the housing 44 has an opening 45 for introducing the blade 42 and a slit-shaped intermediate chamber 43, and the intermediate chamber 43 is arranged and configured such that, after the introduction of the blade 42 into the housing 44, the blade 42 can be twisted into the slit-shaped intermediate chamber 43 by the mutual rotation of the spectrometer 5 and the holder 3, thereby locking the spectrometer 5 to the holder 3.

[0078] However, in Figure 13, in a preferred embodiment, the contact surface 51 of the metal head of the spectrometer 5, which is to be connected to the holder, may be pressed against the components of the window 7 with a limited force. In this case, in the illustrated configuration, a high axial force can be absorbed by the vanes 42 already locked in the slit-shaped intermediate chamber. The elastic deformation that defines and limits the pressing force can be provided in this embodiment, for example, by the fact that some deformation of the plastic body 30 must occur under force in order to fully introduce the housing 44 to the vanes 42 in an axial position that allows it to be housed in the slit-shaped intermediate chamber 43.

[0079] Figure 14 shows the holder 3 and spectrometer 5 in their combined position before locking, i.e., before rotation, for further explanation. For clarity of the drawing, the metal head, preferably an existing contact surface 51, and the window are not shown.

[0080] The starting position for fixed rotation is defined by a blocking surface 47 provided on a protrusion that extends into the housing 44. This presets the rotation direction of the spectrometer 5, which is indicated by an arrow. Typically, the spectrometer 5 is rotated when the holder 3 is fixed in place, because the holder 3 is rigidly welded to, for example, the bag of a bioreactor. It is also advantageous to provide a further blocking surface 48 that restricts rotation. Preferably, as shown in the figure, this further blocking surface 48 is provided on the same protrusion. Preferably, such blocking surfaces 47, 48 are provided for each blade 42, i.e., double blocking surfaces in the illustrated example. Once the spectrometer 5 is rotated until the blade 42 contacts the blocking surface 48, the spectrometer 5 is fixed not only in terms of its axial position but also in terms of its angular orientation.

[0081] Figure 15 shows the spectrometer 5 and the holder 3 in the locked position. Unlike Figure 14, the visible vane 42 is rotated 90° within the housing 44 and is in contact with the blocking surface 48. In this figure, the lens that is missing in Figure 14 is shown inside the metal head 50, which is supported by the shaft portion 77 of the window 7. This shaft portion 77 simultaneously forms either a protruding tubular piece 46 or a part of the tubular piece 46 in the holder 3.

[0082] The following describes preferred embodiments of a spectrometer 5 and a process technology apparatus, particularly a bioprocess technology apparatus, having the spectrometer 1 according to this disclosure.

[0083] Figure 16 shows a bioprocess technology apparatus 60 equipped with a holder for assembling a spectrometer 5. In this embodiment, the bioprocess technology apparatus 60 is a bioreactor 61. This bioreactor 61 comprises a container 61 in the form of a plastic bag 62, which contains a biological reaction medium, such as a nutrient solution containing microorganisms. In the illustrated configuration, the container volume within the plastic bag 62 constitutes the measurement volume 2. In the case of a plastic bag 63 as the container 62, it is typically assumed that the bag will be used for single-use or one-time use.

[0084] The bioreactor 61 may have a support container 64 to stabilize the plastic bag 63. The holder 3 according to this disclosure is welded to the plastic bag 63. In this case, the holder 3, which has a window 7 for injecting and emitting radiation into the measurement volume 2, may be accessible through an opening 65 provided in the support container 64, so that a spectrometer 5 can be shone on it to detect radiation from the measurement volume 2 through the window 7.

[0085] As previously mentioned, in a preferred embodiment, the spectrometer 5 comprises a free-beam optical system 66. By avoiding losses in the optical waveguide and fiber coupler within the optical path, particularly advantageously, a significantly lower laser power is required in a more compact structure compared to a standard system for comparable sensitivity. During in-situ concentration measurements, the lower laser power results in less energy input in the depth of focus region within the medium. This avoids damage to thermally unstable analytes, such as biopolymers themselves.

[0086] In particular, the radiation to be detected may be guided as a free beam from the penetrating window element 74 to the detector of the spectrometer 5. However, this involves the radiation being directed and / or focused in the optical path by an optical element, such as a lens, prism, or deflection mirror. However, in this case, a free beam region exists following one or more optical elements. Figure 17 shows a schematic cross-sectional view of an embodiment of a spectroscopic apparatus 1 equipped with such a spectrometer 5.

[0087] The compact structure, as illustrated with reference to Figure 17, comprises the walls of a bioreactor bag 63, a holder 3 coupled to the bioreactor bag 63, and a spectrometer 5. In a particularly preferred embodiment, the spectrometer 5 is formed as a Raman spectrometer and incorporates 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 shows the free beam region 17 between the spectrometer detector 81 and a transmissive window element 74.

[0088] As will be obvious to those skilled in the art, the present invention is not limited to the embodiments described above, and different embodiments may be combined within the scope of this disclosure. For example, a connecting mechanism may be provided that links the features of different embodiments together. Accordingly, a spring 103, as in the embodiment shown in Figures 1 to 3, may be provided in the connecting device 10 shown in Figures 8 to 10 or Figures 11 to 15 to limit the pressing force. [Explanation of symbols]

[0089] 1 Spectrometer 2. Measurement volume 3 Holding body 5 spectrometer 7 windows 10 Coupling device 12, 13 10 flanges 14 Inclined surfaces provided at 12,13 15 Gap between 12 and 13 16 lenses 17 Free beam region 18 Groove 19 keys 30 Plastic Body 31 Mounting flange 33,34 Adapter 36 Locking joint 37 3 shaft 38 Locking protrusion 39 Groove Storage compartment for 40 38 42 feathers 43 Slit-shaped intermediate chamber 44 Housing section for 42 provided in housing 54 45 44 housing opening 46 Tube piece 47,48 Blocking surface 50 5 head 51 50 contact surface Support surface of 52 5 53 5 shaft 54 5 housing Openings provided at 55 and 54 60 Bioprocess Technology Equipment 61 Bioreactor 62 Container 63 Plastic Bags 64 Support container Openings provided at 65 and 64 66 Free-beam optical systems 70 frames Openings provided at 71 70 74 Window Elements 76 Glass Solder 77 Shaft 78 70 flange 80 Laser Diodes 81 Spectrometer detector 82 Beam Splitter 101 Threaded Sleeve 102 Sleeve Elements 103 spring 104,105 screw threads Openings provided at 107 and 101 108,109 Contact surface 110 connecting elements 112 Marking 113 101 Annular projection 115 Clamp 116 clips 121,122 Helical female threads 131,132 Helical male screw threads 140 The starting point of the spiral 380 38 sliding surface 390 39 stopper 420, 422 42 opposite sides

Claims

1. A spectrometer (1) for spectroscopic measurements in a sterile sealed measuring volume (2), particularly for bioprocess analysis, The apparatus (1) comprises a holder (3) and a spectrometer (5) that can repeatedly connect to and disconnect from the holder (3), The holder (3) comprises a plastic body (30) and a window (7) tightly fitted inside 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 seals the opening (71) of the frame (70), The spectrometer (5) has a metal head (50) that has a contact surface (51) that can be pressed against the window (7) in order to connect the spectrometer (5) and the holder (3), The spectroscopic apparatus (1) includes a coupling device (10) that can connect the spectrometer (5) and the holder (3) so that they can be detached from each other, and in the connected state of the spectrometer (5) and the holder (3), the contact surface (51) and the window (7) are pressed against each other with a particularly limited force.

2. The spectroscopic apparatus (1) according to claim 1, characterized in that the apparatus (1) is configured such that the force is generated by the elastic deformation of at least one member of the spectroscopic apparatus (1), and / or the force is provided by at least one magnet which cooperates with the metal frame (70) of the window (7), particularly located on the metal head (50).

3. The coupling device (10) includes a threaded sleeve (101) and a spring (103) that has a spring force acting between the threaded sleeve (101) and the spectrometer (5) when compressed. The coupling device (10) further comprises corresponding threads (104, 105) provided on the holder (3) and the threaded sleeve (101), thereby enabling the threaded sleeve (101) to be screwed onto the holder (3), and by moving the threaded sleeve (101) toward the holder (3) in the axial direction, the spring (103) is compressed, and the spring force generated by the compression of the spring (103) presses the contact surface (51) of the spectrometer (5) against the window (7), and the threads (104, 105) are preferably formed as double helix threads, as described in claim 1 or 2.

4. The spectroscopic apparatus (1) according to claim 3, wherein the coupling device (10) comprises a sleeve element (102) which surrounds the shaft portion (53) of the spectrometer (5), the spring (103) acts on the sleeve element (102), the sleeve element (102) transmits the spring force of the spring (103) to a support surface (52) provided on the spectrometer (5), the threaded sleeve (101) has an opening (107) on the opposite side of the holder (3), and when the threaded sleeve (101) is further rotated after the contact surface (51) is brought into contact with the window (7), the sleeve element (102) advances through the opening (107).

5. The spectroscopic apparatus (1) according to claim 3 or 4, characterized in that the threaded sleeve (101) and the holder (3) are provided with corresponding contact surfaces (108, 109) that limit the screwing depth of the threaded sleeve (101) into the holder (3).

6. In the interconnected state of the spectrometer (5) and the holder (3), the contact surface (51) is pressed against the metal frame (70) of the window (7). In the interconnected state of the spectrometer (5) and the holder (3), the contact surface (51) is pressed against the transparent window element (74) of the window (7). The permeable window element (74) is held within the opening (71) in a compression-sealed manner: A spectroscopic apparatus (1) according to any one of claims 1 to 5, characterized in that at least one of the features of the above is provided.

7. The apparatus (1) includes a free-beam optical system (66) for injecting or emitting radiation into the measurement volume (2), The spectrometer (5) is formed as a Raman spectrometer: A spectroscopic apparatus (1) according to any one of claims 1 to 6, characterized in that at least one of the features of the above is provided.

8. The spectroscopic apparatus according to claim 7, characterized in that the spectrometer (5) is configured such that the radiation to be detected is guided as a free beam from the transparent window element (74) to the detector of the spectrometer (5).

9. A spectrometer (5) and a holder (3) each have one flange (12, 13), and for connection, both flanges (12, 13) can be tightened together by closing a clamp (115), and the flanges (12, 13) and the clamp (15) are designed such that a gap (15) remains between both flanges (12, 13) when the clamp (115) is fully closed, as described in any one of claims 1 to 8.

10. At least one of the flanges (12, 13) has an inclined surface (14), and the inclined surface (14) is located on the side of the flange (12, 13) opposite to the connecting side for connecting with the other flange (13, 12). The clamp (115) is formed as a clip (116) for radial compression: The spectroscopic apparatus (1) according to claim 9, characterized in that at least one of the features of the above is provided.

11. The coupling device (10) is configured such that the pressing force of the contact surface (51) against the window (7) when the spectrometer (5) is coupled to the holder (3) is within the range of 10 N to 4 kN. The product of the pressing force of the contact 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: A spectroscopic apparatus (1) according to any one of claims 1 to 10, characterized in that at least one of the features of the above is provided.

12. The spectrometer (1) according to any one of claims 1 to 11, characterized in that, when the connecting device (10) is connected to the spectrometer (5) and the holder (3), at least a part of the connecting device (10), preferably the entire connecting device (10), is positioned inside the housing (54) of the spectrometer (5).

13. The spectroscopic apparatus (1) according to any one of claims 1 to 12, characterized in that the coupling device (10) is configured such that the connection between the spectrometer (5) and the holder (3) is formed by a joint rotation coupling.

14. The spectroscopic apparatus (1) according to claim 13, wherein the holder (3) has a blade (42) directed radially outward from the holder (3), and the spectrometer (5) preferably has a housing (44) having an opening (45) and a slit-shaped intermediate chamber (43) corresponding to the blade (42), and the blade (42), the slit-shaped intermediate chamber (43), and the opening (45) are arranged such that after the spectrometer (5) is placed on the holder and the blade (42) is inserted into the opening (45) of the housing (44), the blade (42) can be twisted into the slit-shaped intermediate chamber (43) by rotating the spectrometer (5) and the holder (3) relative to each other, thereby locking the spectrometer (5) to the holder (3) at least in the axial direction.

15. The housing portion (44) has at least one blocking surface (47) that, after the spectrometer (5) is placed on the holder (3), allows the rotation of the spectrometer (5) to be fixed in position on the holder (3) in only one predetermined rotational direction. The thickness of the blade (42) is excessive compared to the height of the slit-shaped intermediate chamber (43): The spectroscopic apparatus (1) according to claim 14, characterized in that at least one of the features of the above is provided.

16. A bioprocess technology apparatus (60), comprising a spectrometer 1 for bioprocess analysis according to any one of claims 1 to 15, wherein the window (7) of the holder (3) of the apparatus is adjacent to a sterile-sealed measuring volume (2) of the bioprocess technology apparatus, so that the spectrometer (5) can detect radiation from the measuring volume (2) through the window (7).

17. A holder (3) configured for use in a spectroscopic apparatus (1) according to any one of claims 1 to 15, comprising at least one, preferably a plurality of different adapters (33), wherein the plastic body (30) of the holder (3) is connectable to the adapters (33) or to each of the different adapters (33) by locking couplings (36), one or more of the adapters (33) each having a portion of a coupling device (10), and the locking couplings (36) lock the adapters (33) at least axially.

18. The locking coupling portion (36) is provided with a locking projection (38) on one of the plastic body (30) and the adapter (33, 34), and the other of the plastic body (30) and the adapter (33, 34) has a corresponding groove (39) for the locking projection (38) and a housing portion (40), the groove (39) and the housing portion (40) are alternately provided around the entire circumference in the circumferential direction, the groove (39) extends in the axial direction, thereby allowing the locking projection (38) to reach a stopper provided in the groove (39) The holder (3) according to claim 17, wherein the plastic body (30) and the adapters (33, 34), which are both members, can be pushed in the axial direction into the groove (39), and when the locking projection (38) is pushed into the stopper (390) of the groove (39), the plastic body (30) and the adapters (33, 34) are rotated relative to each other, thereby moving the locking projection (38) from the groove (39) into the housing portion (40) and locking into the housing portion (40), thereby enabling them to lock into each other.

19. A method for monitoring a process in bioprocess technology, comprising: attaching a spectrometer (5) to a holder (3) for a sterile, sealed measuring volume (2) of a bioprocess facility, thereby maintaining the spectroscopic device (1) according to any one of claims 1 to 10; measuring a signal corresponding to the intensity of radiation that has entered the spectrometer (5) from the measuring volume (2) through the window (7) using the spectroscopic device (1); removing the spectrometer (5); reattaching it to the holder (3) at a later time; repeating the measurement; and then comparing the measured signals.

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