Streaming unit for optical spectral analysis and method for monitoring biotechnological process

Abstract

The invention relates to a flow cell (1) for optical spectroscopic analysis, comprising a housing (10) having a cavity forming a measurement chamber (40), an inlet channel (20), an outlet channel (30) and an optical window (44) sealing an opening (43) of the measurement chamber (40). According to the invention, the optical window (44) is connected to the housing (10) by means of a molten glass connection element (46), a recess (48) being formed around the opening (43), and a support surface (45) for the optical window (44) being formed around the opening (43), on which support surface the optical window (44) contacts the housing (10). Other aspects of the invention relate to the use of such a flow unit (1) for monitoring a process of a biotechnological process and the use of such a flow unit (1) in a biotechnological method monitored using such a flow unit (1).

Description

Technical Field

[0001] The invention relates to a flow cell for optical spectroscopic analysis, comprising a measuring chamber with an optical window, an inlet channel and an outlet channel. Other aspects of the invention relate to the use of such a flow cell for monitoring a biotechnological process and to a method for monitoring a biotechnological process. Background Art

[0002] Optical spectroscopy is used in many technical fields and can be used, for example, to detect samples or monitor production processes. In this case, light is introduced into the sample and the light transmitted or reflected by the sample is detected.

[0003] One area of ​​application of optical spectroscopy is the monitoring of biotechnological processes. This is roughly divided into so-called upstream and downstream processes. The upstream process here includes in particular the provision of raw materials, the cultivation of cells and the fermentation process. The downstream process includes in particular the separation and purification of the obtained products and quality control. Raman spectroscopy is particularly suitable for monitoring such biotechnological processes.

[0004] In case of liquid samples, or samples dissolved or suspended in a liquid, a flow cell can be used for the spectroscopic analysis. A flow cell comprises a measuring chamber with inlet and outlet channels and an optical window.

[0005] WO 2021 / 198427 describes a flow cell assembly for process control of bioprocesses. The flow cell assembly comprises a monolithic cast glass body surrounding a measuring channel and a fixing mechanism with an orientation aid for orienting a sensor head. The glass body is made of a material transparent to UV light, such as quartz glass, and the measuring channel surrounded by it has at least one straight section with a constant cross section.

[0006] A disadvantage of such flow cell components is that the quartz glass commonly used generates unwanted signals that interfere with the measurement in various measurements, especially in Raman spectroscopy. WO 2021 / 198427 also introduces other materials such as sapphire as possible alternatives to quartz glass. However, sapphire is particularly unsuitable for casting glass bodies, so that a monolithic body that hermetically seals the measuring channel cannot be produced from this material.

[0007] EP 3610244 B1 discloses a liquid cell with a measuring chamber and a measuring window, wherein a pressure element presses the measuring window against a seal, thereby sealing the measuring chamber. The seal can be designed in the form of an O-ring or a film, for example, made of PTFE. A disadvantage here is that, on the one hand, a small dead volume is formed in the region of the seal, in which deposits can occur. In addition, in particular in the case of thick seals, such as in O-rings, it is difficult to define the exact position of the measuring window. However, for good signal quality, a precisely defined spacing between the focus and the measuring window is desirable in optical spectroscopy.

[0008] In view of the prior art, the object of the present invention can be regarded as providing a flow cell for optical spectroscopic analysis purposes, in particular in the field of biotechnology, which has a measuring chamber, the material of which does not generate its own measurement signal in the spectral range to be detected during the spectral detection. In particular, within 50 cm -1 and 3800cm -1 In the range between 100 and 150 °C, no interfering measurement signals of its own should be generated. Furthermore, its materials should be compatible with the bioprocess being detected or monitored. In this case, the measuring chamber should achieve a good signal-to-noise ratio, especially for Raman spectroscopy. Summary of the invention

[0009] The present invention proposes a flow cell for optical spectroscopy. The flow cell comprises a housing having a cavity for constructing a measuring chamber, an inlet channel, an outlet channel and an optical window, and the optical window seals the opening of the measuring chamber. In addition, it is provided that the optical window is connected to the housing by a molten glass connecting element. It is preferably provided that a recess is constructed around the opening and a support surface for the optical window is constructed around the opening, on which the optical window contacts the housing.

[0010] The proposed connection of the optical window to the housing is achieved by means of a fused glass connecting element, in particular a hermetically sealed connection. Here, “hermetically sealed” means that the connection between the optical window and the measuring chamber has a thickness of less than 1·10 -5 mbar·l / sec helium leak rate, and preferably 1·10 -10 mbar·l / sec to 1·10 -6mbar l / sec. Preferably, the helium leak rate is measured according to DIN EN 60068-2-17:1995-05, ASTM F2391-05 (re-approved in 2016) or according to K-method 1014.15 revised to MIL-STD-883. Advantageously, the stated leak rates are achieved in each case even in the case of tests lasting at least 4 minutes. The connection of the optical window is therefore also sterile-tight, so that microorganisms cannot penetrate into the interior in biotechnological processes.

[0011] Furthermore, the proposed connection between the optical window and the measuring chamber or the housing of the flow cell does not require further components, in particular no flexible elements such as elastomeric seals. Such elastomeric seals, for example in the form of O-rings, do not allow the optical window to be positioned precisely relative to the measuring chamber or the housing of the flow cell, in particular because their current thickness is related to the clamping force and results in dead volumes through which no fluid passes. In contrast, the proposed connection is rigid and defines a fixed positional relationship between the surface of the optical window and the measuring chamber. This is particularly advantageous when carrying out optical detection, and the focal point of the optical mechanism should here be located at a defined distance from the surface of the optical window facing the interior of the measuring chamber.

[0012] Preferably, a support surface for the optical window is constructed around the opening of the measuring chamber, and the optical window contacts the housing at the support surface, wherein the width of the support surface of the optical window is narrower than 0.3mm, preferably narrower than 0.2mm, and particularly preferably narrower than 0.1mm. When melted onto the housing, a tight, gapless connection is established between the glass connecting element and the housing and between the glass connecting element and the optical window. However, in the region of the support surface (where the optical window contacts the housing on the support surface), a small gap may be retained if necessary, wherein the volume in this possible gap is formed as small as possible by minimizing the support surface. However, a certain width of the support surface is desirable in order to simplify the installation of the optical window on the one hand, because the support surface provides a mechanical stop for the precise positioning of the optical window. On the other hand, when melting the glass connecting element, the material of the glass connecting element can flow, wherein the material of the glass connecting element is not expected to flow into the interior of the measuring chamber. In the best case, the material of the glass connecting element flows into the possible gap between the optical window and the housing so that the volume of the gap is accurately filled, but there is no material flow of the glass connecting element beyond the gap into the interior of the measuring chamber. For this purpose, it is preferred that the width of the support surface is at least 0.02 mm, particularly preferably at least 0.05 mm and very particularly preferably at least 0.1 mm. For example, a width of 0.1 mm is selected for the support surface.

[0013] Preferably, a recess is formed in the housing around the opening, wherein the glass connecting element fills the space between the optical window and the wall of the recess, so that no gap remains between the wall of the recess and the glass connecting element.

[0014] The diameter of the recess is preferably selected to be 20% to 35% greater than the diameter of the optical window. The preferred width of the gap in which the glass connecting element is accommodated is therefore in the range of 0.6 mm to 1.0 mm. A gap with as small a width as possible is advantageous in order to be able to transfer pressure from the wall of the opening to the optical window. However, with very small widths, it becomes increasingly difficult to reliably produce the glass connecting element.

[0015] Preferably, the glass connecting element ends flush with the recess. It is also preferred that the optical window is connected flush to the glass connecting element so that both are arranged together flush with the recess. However, as an alternative to this, it can also be provided that the window and / or the glass connecting material do not end flush with the recess. In particular, it can be provided that the glass connecting material is retracted and is therefore protected from mechanical influences by the protruding housing.

[0016] Preferably, the optical window is connected to the housing, in particular to the wall of the recess of the housing adjacent to the opening, by a glass connecting element composed of glass solder or a glass connecting element constructed as a glass forming body. In the case of a metal material for the housing, a hermetic sealed connection in the form of a glass-to-metal seal (GTMS) can be formed by melting the glass material of the glass connecting element. Here, the glass material of the glass connecting material also forms a chemical bond with the material of the housing, in particular with the metal oxide on the surface of the metal housing material. If a ceramic material is selected for the housing, the components of the ceramic can usually be directly dissolved by the molten glass material, so that in this case, a chemical connection is also generated between the glass connecting element and the housing during the glass joining process.

[0017] The glass forming body can, for example, first be provided in the form of a pressed part or sintered body obtained from a glass powder and subsequently be melted to the housing and the optical window by temperature treatment in order to form a glass connecting element. For stabilization, the pressed part can contain a binder in addition to the glass powder, which is subsequently removed again during the temperature treatment. The temperature treatment can be carried out, for example, by heating the assembly formed by the housing, the glass forming body and the optical window in a furnace. As an alternative to this, for example, a laser can be used to heat the glass forming body in a targeted manner so that areas of the housing or the optical window that are not directly adjacent to the glass forming body are not heated or are only slightly heated. Corresponding changes in the material due to temperature influences can thereby be avoided.

[0018] The glass connecting element preferably consists of or includes a glass material which is selected for use in a flow cell such that it is resistant to the medium introduced into the measuring chamber and preferably also does not release any substances into the medium. Accordingly, the glass material is preferably resistant to water, acids and alkalis.

[0019] Glass materials with high chemical resistance are usually high melting point glasses and have higher melting temperatures and higher glass transition temperatures T than low melting point, low chemical resistance glasses. g Furthermore, conventional low-melting glasses often contain heavy metals, which are undesirable, in particular in the case of biotechnological applications.

[0020] Therefore, it is preferred that the glass bonding material is selected so as to contain or include a high melting point glass material. Here, the glass transition temperature T g Glass materials having a temperature above 470° C., preferably above 500° C., more preferably above 600° C., particularly preferably above 750° C. are regarded as high-melting.

[0021] In addition, with a high glass transition temperature T g In this connection, a glass material with a high melting point has a low dynamic viscosity when heated, so that when the glass is joined, the glass material has only a small fluidity compared to a glass with a low melting point. This fluidity can be improved by further heating, but the strong thermal effect on the other materials joined to the flow cell, so that in particular the surface quality thereof is impaired. Therefore, it is preferred to select a glass material whose glass transition temperature T g Below 900°C, particularly preferably below 800°C.

[0022] In order to avoid a deterioration in the surface quality, in particular of the inner wall of the measuring chamber, the glass material of the glass connecting element is preferably selected such that it has a relative humidity of at least 1·10 at a temperature of 1300° C. 5 The dynamic viscosity η of the glass is dPa·s. This value is particularly preferably reached at 1200° C. and most preferably at 1100° C. Therefore, the glass joining is preferably carried out at a temperature below 1300° C., particularly preferably below 1200° C., most preferably below 1100° C. The dynamic viscosity of the glass or the temperature at which the required viscosity is reached can be determined, for example, according to DIN ISO 7884-1: 1998-02.

[0023] 1.10 5 The dynamic viscosity η of dPa·s is too viscous to achieve reliable glass fitting usually only by the free flow of the glass material. Therefore, it is preferred to assist the flow of the glass material by force (for example, by a placed weight or a die). In connection with such force, the glass material is even 1·10 5Even with a dynamic viscosity of 0.1 dPa·s, it can adhere closely to the optical window and the wall of the opening and produce a good connection.

[0024] If the glass connecting element is provided for the glass joining process in the form of a pressed part, it is particularly advantageous to provide a mechanical stop via the support surface, since during the glass joining process the optical window is supported by the inner side of the flow cell and pressure can only be exerted on the pressed part in this way.

[0025] The glass material of the glass solder or the glass forming body is preferably selected from borosilicate glasses. For example, the chemically resistant glasses 8326 and 8800 from SCHOTT AG are suitable.

[0026] The material of the housing is preferably selected from metals or metal alloys. Alternatively, the material of the housing is preferably selected from ceramics. Particularly preferably, the material of the housing is selected from steel, in particular stainless steel, austenitic steel or ferritic steel, austenitic-ferritic dual-phase steel, nickel-copper alloy, nickel-chromium-iron-niobium-molybdenum alloy, nickel-chromium-molybdenum-tungsten alloy, zirconium-niobium alloy, titanium-niobium alloy.

[0027] A suitable stainless steel is or includes pharmaceutical steel such as AISI 316L (material number 1.4404). The pharmaceutical steel is an austenitic stainless steel.

[0028] AISI 329A is a suitable austenitic-ferritic dual phase steel (material number 1.4462).

[0029] Preferred ceramic materials for the housing include, in particular, porcelain, yttrium oxide (Y2O3), zirconium oxide (ZrO2) (if necessary stabilized with CaO, MgO, CeO2, TiO2 or Y2O3), magnesium aluminate (MgAl2O4), aluminum oxide (Al2O3), SiAlON-Al2O3 and silicon carbide (SiC). The ceramic materials are preferably polycrystalline, so that they are preferably opaque.

[0030] If stainless steel is selected, its surface is preferably passivated. For example, a chemical or electrochemical surface treatment can be used to form a passivation layer.

[0031] The inner wall of the measuring chamber is preferably designed in such a way that it has only a slight roughness. The average roughness Ra is preferably less than 0.8 μm, particularly preferably less than 0.5 μm.

[0032] In combination with the proposed glass mosaic, the material of the measuring chamber is protected at relatively low temperatures for glass materials with high melting points, thereby keeping the high quality of the surface unchanged. If, for example, stainless steel is chosen as the material for the inner wall of the measuring chamber, surface damage may occur at too high a processing temperature due to abrasion of the brittle metal oxide layer. For example, martensitic Fe-Cr alloys in (Fe, Cr)Ox The brittle FeO layer is formed on the bottom layer. x The top layer causes surface changes even at temperatures above 1100°C, and significant surface damage occurs as the temperature increases further.

[0033] To ensure a high surface quality of the inner wall of the measuring chamber, at least the housing components forming the inner wall of the measuring chamber are preferably constructed in one piece and accordingly have no gaps, connecting materials or surface changes caused by welding. Preferably, the entire housing is constructed in one piece.

[0034] In order to meet the more stringent manufacturing requirements for biopharmaceuticals, materials are preferably selected such that they meet the following criteria in each case:

[0035] i) FDA approved materials, such as ICFH Q7, CFR 211.65(a)-Code of Federal Regulations, USP <88> Class VI, no animal derivatives, no BPA;

[0036] ii) Industry Chemical Resistance - ASTM D 543-21;

[0037] iii) Biocompatibility, e.g., testing with reference to the United States Pharmacopoeia or with reference to ISO 10993-1 (2018-08).

[0038] Preferably, the material of the optical window is selected from glass, in particular quartz glass or borosilicate glass, in particular single crystal, in particular sapphire, ceramic, in particular yttrium-doped zirconium dioxide (yttrium-stabilized zirconium oxide, YSZ) or glass ceramics. Other examples of suitable materials include yttrium-doped aluminum oxide, lanthanum-doped yttrium oxide, aluminum-doped aluminum nitride and magnesium-doped aluminum oxide. Here, the dopant is respectively a metal oxide.

[0039] The optical window may additionally have one or more coatings or sheaths to improve mechanical properties, such as the hardness of the surface and / or optical properties, such as reflective properties. In particular, an anti-reflection coating may be provided. Here, the anti-reflection coating is preferably optimized for the wavelength of the excitation light and / or signal (especially the fluorescence in the fluorescence spectroscopy analysis). One or more coatings may be arranged on both sides, i.e., on one side facing the inside of the measuring chamber and on one side of the optical window facing the outside. Alternatively, it may be provided that the one or more coatings are only arranged on one side or different coatings are arranged on both sides. For example, the side facing the inside of the measuring chamber may not have a coating, and only the side facing the outside may be coated. Thus, the material of the coating is avoided from contacting the medium to be analyzed. If only the outside is coated, it is not particularly necessary to require chemical resistance relative to the medium to be analyzed. In addition, the anti-reflection coating may usually be omitted on the inside, because usually only small reflection losses occur in the transition between the optical window and the liquid medium in the measuring chamber.

[0040] In one embodiment of the flow cell, the first coefficient of thermal expansion of the housing is adapted to the second coefficient of thermal expansion of the glass connecting element and to the third coefficient of thermal expansion of the optical window. In this context, “adapted” is understood to mean that the difference in the coefficients of thermal expansion is less than 3·10 -6 K -1 , preferably less than 2·10 -6 K -1 , more preferably less than 1·10 -6 K -1 .

[0041] Alternatively, a press fit can be provided, wherein the first thermal expansion coefficient of the housing is greater than the second thermal expansion coefficient of the glass connecting element, and the first thermal expansion coefficient is preferably greater than the third thermal expansion coefficient of the optical window. Preferably, the first thermal expansion coefficient differs from the second thermal expansion coefficient and, if appropriate, from the third thermal expansion coefficient by 3.10. -6 K -1 or more, particularly preferably 6.10 -6 K -1 or more.

[0042] For an optical window made of sapphire, such a pressure fit can be achieved, for example, for a housing made of stainless steel and a glass connecting element made of borosilicate glass. When austenitic stainless steel is selected, the first thermal expansion coefficient of the housing is, for example, 16·10 -6 K -1 , for example in the case of borosilicate glass, the second thermal expansion coefficient is approximately 3·10 -6 K -1 Until about 7.10 -6 K -1 The third thermal expansion coefficient of sapphire is about 5·10 -6 K -1 In this example, the second and third thermal expansion coefficients differ by less than 3·10 -6 K -1 , and thus adapt to each other. The first thermal expansion coefficient differs from the two by more than 6·10 -6 K -1 , and thus results in a pressure exerted by the housing, which is transmitted from the glass connecting element to the optical element.

[0043] In this pressure fitting, due to the shrinkage of the housing after the glass fitting, pressure acts on the glass connecting element and the optical window relative to the longitudinal axis of the opening, which reacts to form a gap between the corresponding elements and thus promotes a gas-tight seal. However, in the case of isotropic thermal expansion, the pressure also acts in a direction parallel to the longitudinal direction of the opening, which is not necessary for this advantageous effect. These forces acting in the axial direction can have a negative impact on the optical element, especially when the optical element is composed of multiple components or layers. An example of this is an optical element made of yttrium-doped zirconium dioxide, which is coated with a layer made of yttrium oxide. Due to the pressure acting in the axial direction, the sheath may be peeled off.

[0044] In this case in particular, it is preferred that the housing is designed such that it has an anisotropic thermal expansion, wherein a first thermal expansion coefficient exists in a direction perpendicular to the longitudinal axis of the opening and a further thermal expansion coefficient of the housing in a direction parallel to the longitudinal axis of the opening has a value of less than 1·10 -6 K -1 , preferably less than 0.1·10 -6 K -1 , particularly preferably less than 0.01·10 -6 K -1 And still more preferably less than 0.001·10 -6 K -1 The numerical value of .

[0045] Such a housing with anisotropic thermal expansion can be implemented, for example, as a component made of a titanium-niobium alloy, which is modified by a thermomechanical method. In this thermomechanical method, the alloy components are first homogenized, for example, by temperature treatment at a temperature between 900° C. and 1100° C. in an N2 or Ar atmosphere for a period of 1 to 3 hours. Subsequently, a phase change in the material structure and, in particular, the material of the component can be carried out by a cold rolling step. After the cold rolling step, annealing can be performed at 700° C. to 950° C. for 0.25 to 1 hour. In addition, a water quenching step can also be provided. Through the adaptation step, the thermal expansion, in particular the first thermal expansion coefficient and the other thermal expansion coefficients can be adapted or changed in a targeted manner in one or more thermal cycles.

[0046] Alternatively, the component can be obtained via an additive manufacturing process (3D printing), wherein the component is obtained, for example, by applying metal powder layer by layer and subsequent sintering. In this case, for example, the composition gradient of the titanium-niobium alloy obtained can also be influenced by using different amounts of titanium powder and niobium powder. In addition, by controlling the heat inflow during sintering, in particular the temperature and rate of heating and cooling, the formation of different phases in the material can be influenced in order to adjust the thermal expansion of the component in a targeted manner.

[0047] An example of a composite element is known from DE 10 2019 115 204 A1, which comprises such an outer component made of a titanium-niobium alloy and an inner component made of yttrium-doped zirconium dioxide coated with yttrium oxide.

[0048] The materials for the measuring chamber, the walls of which are preferably formed by the housing of the flow cell itself, the optical window and the material for connecting the optical window to the measuring chamber are therefore preferably selected such that they are compatible with biotechnological processes.

[0049] With such a material selection, the measuring chamber does not contain materials that hinder the growth of cell cultures, generate their own spectroscopic analysis signals in the relevant spectral range, or are undesirable during the execution process for other reasons. For example, the press-fit seals used to make windows in the prior art or the gold alloys contained in the gold solder are undesirable in many biotechnological processes. Accordingly, the gold alloys in the area of ​​the measuring chamber are undesirable materials. Therefore, the flow cell preferably does not contain gold alloys, especially gold solders containing gallium, tin and / or germanium, and / or does not contain materials that generate their own spectroscopic analysis signals when excited with a spectroscopic analysis light source, especially with a light source with a wavelength of 532nm, 633nm, 775nm, 785nm, 830nm or 1064nm, such as LEDs or lasers. It is particularly preferred that when excited with light with a wavelength of 532nm, 785nm or 1064nm, no spectroscopic analysis signals are generated, wherein it is very particularly preferred that when excited with light with a wavelength of 532nm or 785nm, the material does not provide a spectroscopic analysis signal.

[0050] In this context, emission or scattering of light having a wavelength different from the wavelength of the excitation light or light source is considered in particular to provide a separate spectroscopic analysis signal, for example by inelastic scattering of light (such as in Raman spectroscopy) or by absorption and re-emission of light (such as in fluorescence spectroscopy). In particular, hydrogen-containing compounds such as plastics can generate their own spectroscopic analysis signals when excited with wavelengths that are relevant for the spectroscopic analysis.

[0051] Accordingly, it is particularly preferred that the flow cell is free of hydrogen-containing compounds, such as plastics in particular, in the region of the measuring chamber. Advantageously, this is achieved in the case of the proposed flow cell, in particular when the material of the housing is metal, metal alloy or ceramic, the optical element is composed of glass, glass ceramic, ceramic or crystal and a glass connecting element is used to connect the optical window to the housing.

[0052] In a preferred choice of materials for the flow cell and in particular for the measuring chamber of the flow cell, the region which is illuminated when performing optical spectroscopy is free of materials which emit spectroscopy signals when stimulated with light. The proposed flow cell is therefore suitable for spectroscopy detection and in particular for performing fluorescence spectroscopy. Furthermore, the proposed flow cell is particularly well suited for performing Raman spectroscopy, since no fluorescence signals which interfere with these processes are generated due to the materials used in the region of the measuring chamber.

[0053] With the preferred material selection, the proposed flow cell is free of materials that hinder or interfere with biotechnological processes. This allows these processes to be continuously monitored using the flow cell, which is temporarily or permanently connected to the system.

[0054] In particular when using equipment for biotechnological applications, a distinction is often made between designs for multiple use (multiple use) and designs for single use (single use). Embodiments for multiple use are designed so that they are permanently resistant to the conditions used in the sterilization method. For example, in designs designed for steam sterilization, the selected materials must be resistant to the temperatures and reagents used therein, such as water vapor, sodium hydroxide or ethylene oxide.

[0055] On the contrary, in the embodiment for single use, only the material selected for this structural form needs to allow single-use sterilization.For example, conventional plastic material can be single-use sterilized under the effect of radiation (for example gamma radiation, beta radiation or X-ray radiation).

[0056] The proposed flow unit can have a housing made of metal or ceramic, so that the flow unit can be sterilized many times without any problem and is particularly suitable for multiple uses (multiple uses). Of course, it is also possible to only use the proposed unique (single use) flow unit.

[0057] The proposed flow unit with a housing made of metal is particularly suitable for autoclaving. Preferably, the flow unit is designed such that it can be autoclaved 10,000 times with a steam treatment at 141° C. Within the scope of the present disclosure, “autoclaving” is also referred to as autoclaving in the sense of DIN EN ISO 14937; EN ISO 17665, which is applicable to medical products.

[0058] The proposed flow unit is also particularly suitable for sterilization using radiation and preferably for sterilization at a dose of 100 kGy.

[0059] A flow cell with a housing made of metal in combination with the hermetically sealed insertion of the optical window according to the invention is also particularly pressure-resistant. Preferably, the thickness of the housing material and the thickness of the window are selected such that the flow cell withstands an internal pressure of at least 10 MPa (100 bar) in the measuring chamber.

[0060] The housing forming the measuring chamber of the flow cell can be additionally encapsulated with a polymer or plastic injection molding to form a sheath. In this case, the sheath can completely or at least partially wrap around the housing, wherein even in the case of complete encapsulation, the connector for entering the measuring chamber remains free. In this case, the sheath can be designed so that functional elements such as retaining members, orientation mechanisms or connectors are constructed thereon. For example, a pipe with an external thread can be provided as a combined retaining and orientation mechanism, wherein the pipe is provided with a tab for orienting and precisely positioning the sensor head of the spectrometer on the inner-facing wall. Suitable polymers for the sheath include in particular polyolefins, such as polyethylene.

[0061] The optical window of the flow cell can be implemented with a flat surface, or can be constructed so that it acts like a lens, for example. Accordingly, the shape of the surface of the optical window is preferably selected from a flat surface, a convex surface, a concave surface or a combination thereof, such as a biconvex surface, a plano-convex surface, a convex-concave surface, a plano-concave surface and a biconcave surface.

[0062] In order to simplify the mechanical connection to the spectrometer or the sensor head of the spectrometer, the proposed flow cell can have corresponding auxiliary means. Such auxiliary means can be used to establish a releasable mechanical connection, in particular for holding the spectrometer or the sensor head and / or for a positionally accurate and reproducible orientation with respect to the optical window of the flow cell. Here, the holding means is preferably arranged so as to establish a releasable connection.

[0063] Preferably, the flow unit comprises, as auxiliary means, at least one holding mechanism for holding the spectrometer or a sensor head of the spectrometer and / or at least one orienting mechanism for orienting the spectrometer or the sensor head.

[0064] It is preferred that the flow cell and the holding and / or orientation mechanism are designed in such a way that the spectrometer or the sensor head can be attached to the flow cell in such a way that no components are arranged between the optical window and the first optical element of the spectrometer or the sensor head. It is particularly preferred that no optical conductor, such as a glass fiber, is arranged between the optical window and the first optical element of the spectrometer or the sensor head. The first optical element of the spectrometer or the sensor head can be, in particular, an entry opening or an entry hole or a first lens. This enables the free-beam optical element to be used to connect the spectrometer to the proposed flow cell.

[0065] Alternatively, it can be provided that holding means and / or orientation means for holding or orienting an optical conductor, such as a glass fiber, are arranged on the flow unit. The glass fiber can in turn be used to establish an optical connection to a spectrometer.

[0066] Preferably, at least one holding device and / or at least one orientation device is configured to cooperate with a counterpart on the spectrometer or the sensor head in order to achieve a releasable latching connection. Such a latching connection can be achieved, for example, by a latching element which releasably engages in a recess of the corresponding other component.

[0067] Furthermore, the holding means and / or the means for orientation can be configured, for example, as flanges, as recesses, such as holes, as protrusions, such as plugs, as threaded holes, as notches, and combinations of these means. In this case, preferably corresponding counterparts are provided on the sensor head or the spectrometer to cooperate with these holding means and / or orientation means. The holding means can also be configured to cooperate with additional fixing means, such as screws or clamps.

[0068] Furthermore, the holding means can be designed in particular as a bayonet closure in order to produce a detachable connection between the flow cell and the spectrometer or sensor head by means of a plug-in and rotational movement.

[0069] The holding mechanism can also be constructed and arranged in particular for adjusting a defined spacing between an inlet aperture of a spectrometer or sensor head and a flow cell, in particular an optical window of a flow cell. This spacing can advantageously be standardized between different measuring mechanisms (e.g. flow cells, ports or other sensor receptacles), so that a spectrometer or sensor head can be connected to a flow cell via the holding mechanism without further adaptation. In this way, for example, a single spectrometer can be used for multiple measuring mechanisms and can be quickly swapped.

[0070] One or more retaining mechanisms and / or one or more orientation mechanisms can be constructed integrally with the housing of the flow cell or as part of the housing of the flow cell. Alternatively, the flow cell can include an adapter, which is releasably or fixedly mounted on the flow cell. A releasable connection with a spectrometer or sensor head can be established by means of additional retaining mechanisms and / or additional orientation mechanisms (which are part of the adapter). If the flow cell includes a polymer sheath, the retaining mechanisms and / or orientation mechanisms can also be constructed as part of the polymer sheath.

[0071] By means of the mechanically strong and hermetically sealed vitrification of the optical window, the flow cell is advantageously designed in such a way that a spectrometer or a sensor head held at the flow cell or accommodated in an adapter or a holding device of the flow cell can be detached and replaced while maintaining the tightness of the window. As a result, multiple measurements are possible without disturbing or even contaminating the medium located in the measuring cell.

[0072] In order to introduce or lead a medium or fluid into or out of a measuring chamber of a flow cell, the flow cell has an inlet channel and an outlet channel. Preferably, the inlet channel and the outlet channel are arranged relative to each other on a common axis, so that a laminar flow is formed in the measuring chamber when the medium flows through. As an alternative, the inlet channel and the outlet channel are arranged on different axes from each other, so that a turbulent flow is formed inside the measuring chamber when the medium flows through. If turbulent flow is desired, it is preferred that the inlet channel and the outlet channel are arranged to extend tangentially to the radius of the measuring chamber. The measuring chamber can be configured as a hole, for example.

[0073] The inlet channel and / or the outlet channel preferably lead into a connector for connection with a hose or a tube so that the flow cell can be integrated into the liquid flow to be detected. For example, a threaded connector or a hose connector can be provided for this purpose.

[0074] The medium can be, for example, a liquid in which solid matter is suspended if necessary. A particularly smooth and uniform flow of the medium in the measuring chamber is achieved by laminar flow guidance, wherein dead volumes that are not traversed or are traversed significantly less are largely avoided. In the case of turbulent flow, a good mixing of all components of the medium is achieved, wherein in particular entrained or suspended solid matter cannot settle. Therefore, an embodiment of the flow cell with a turbulent arrangement is preferably used for suspension applications. The arrangement of the flow cell designed for turbulent flow also enables particularly representative measurements of the medium, since the occurrence of interfering deposits is suppressed.

[0075] Another aspect of the invention is the use of one of the flow units presented here for monitoring a biotechnological process.

[0076] Particularly advantageously, flow cells can be used to monitor perfusion cultures, wherein the cell culture is continuously flushed with a medium flow. Partial flows or tributaries of the flowing medium can be guided through the flow cell and can be continuously optically detected. Thus, for example, the concentration of nutrients, the presence of growth factors or the concentration of metabolites can be continuously monitored and process control can be influenced as a function of these monitored parameters.

[0077] Another aspect of the invention is to provide a method for monitoring a biotechnological process, in which a medium for culturing cells circulates and flows through a container for accommodating the cell culture. In the method, it is provided that the flowing medium is divided into a main flow and a side flow, which is guided through one of the flow cells described herein, is detected in the flow cell by spectroscopic analysis, and then the side flow is preferably supplied back to the main flow.

[0078] Furthermore, it is preferably provided that at least one parameter of the detected medium is determined by spectroscopic detection. The determined parameter is preferably used as a variable in an automated control process in order to adjust at least one parameter of the medium to a predefined setpoint value.

[0079] By using the proposed flow cell or carrying out the proposed method, on-site or online process control can be advantageously performed. The opening of the device for extracting the sample is eliminated. This achieves, on the one hand, that process control can be performed continuously or in very short time intervals. This makes it possible to quickly identify possible changes in the monitored process and, for example, intervene by an automatic control system. By regular parameter monitoring and the resulting short delays, in particular, a control loop can be set so that the parameters required in the process are adjusted to a predetermined setpoint value. Therefore, the proposed flow cell simplifies the automation of biotechnological processes or even realizes the automation of biotechnological processes for the first time.

[0080] On the other hand, due to the selection of process-compatible materials, the proposed flow unit can be firmly integrated into the device. Opening the system due to the risk of contamination that always accompanies this is advantageously avoided. During the ongoing optical inspection, the sterile integrity of the system is also always maintained.

[0081] Advantageously, the proposed flow cell allows the replacement of measuring instruments for measuring medium parameters without compromising the sterile integrity of the device. Accordingly, the method and process may also include a step in which a measuring instrument, such as a spectrometer or a sensor head of a spectrometer, is replaced during the execution of the method. Accordingly, a plurality of different measuring instruments may be used in the method for detecting one or more parameters of a medium flowing through a measuring chamber of the flow cell.

[0082] When using the proposed flow unit, the product flow can be optimized, especially for continuous production. By continuous automatic regulation, an optimized yield can be achieved in each process stage, which means that the outflow of the preceding process stage is consistent with the capacity of the following process stage. Therefore, reliable and reproducible process execution in each process stage makes it unnecessary to provide buffers between the individual process stages and increases the space-time yield, which enables process centralization.

[0083] It is to be understood that the features mentioned above and those yet to be explained below can be used not only in the respectively indicated combination but also in other combinations or alone, without departing from the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0084] Preferred embodiments and implementations of the invention are shown in the drawings and are explained in more detail in the following description, wherein the same reference numerals refer to the same or similar or functionally identical components or elements.

[0085] This is shown here in schematic form:

[0086] Figure 1a A first embodiment of a flow cell is shown from the side in a schematic cross-sectional view,

[0087] Figure 1b A flow cell of a first embodiment with a mounting adapter is shown in a perspective sectional view,

[0088] Figure 1c A flow cell of a first embodiment with a mounted adapter is shown in a perspective view,

[0089] Figure 2a A second embodiment of a flow cell is shown in a perspective view,

[0090] Figure 2b The flow unit of the second embodiment is shown in another perspective view.

[0091] Figure 2c A flow cell with an assembled sensor head according to a second exemplary embodiment is shown in a view from above.

[0092] Figure 3a A third embodiment of a flow cell is shown in a perspective sectional view,

[0093] Figure 3b A flow cell according to a third embodiment is shown in a view from the side.

[0094] Figure 3c A flow cell of a third embodiment with an assembled adapter is shown in a perspective view,

[0095] Figure 4 A fourth embodiment is shown in perspective view, and

[0096] Figure 5 An embodiment of a flow cell having an enclosure arranged around a housing is shown. DETAILED DESCRIPTION

[0097] Figures 1a to 1c A first embodiment of a flow cell 1 is shown. Figure 1aA first embodiment of a flow cell 1 is shown in a schematic sectional view from the side. The flow cell 1 has a housing 10, inside which a cavity is arranged, which forms a measuring chamber 40. An inlet channel 20 connects the measuring chamber 40 to a first connection 22, and an outlet channel 30 connects the measuring chamber 40 to a second connection 32. Figure 1a In the illustrated embodiment, the connectors 22, 32 are designed as threaded connectors and can be connected to the liquid flow to be detected, for example, via a threaded connector. Figure 1a In the embodiment shown in FIG. 4 , the inlet channel 20 and the outlet channel 30 are located on the same axis and are arranged opposite to each other. This arrangement is suitable for allowing the medium to flow smoothly through the measuring chamber 40 in a laminar manner.

[0098] Measuring room 40 Figure 1a The upper side of the optical window 44 has an opening 43, which is sealed by an optical window 44. The material of the optical window 44 is selected according to the optical detection to be performed. For example, in order to perform Raman spectroscopy, it is preferred to use an optical window 44 composed of quartz glass with UV quality and particularly preferably an optical window 44 composed of sapphire glass.

[0099] Optical window 44 Figure 1a In the first embodiment of the present invention, the optical window 44 is connected to the wall 42 of the measuring chamber 40 using a glass connecting element 46. The glass connecting element 46 is melted to the optical window 44 and the wall 42 and hermetically seals the opening 43 of the measuring chamber 40. In order to establish such a hermetically sealed connection, a precursor of the glass connecting element 46 in the form of a pressed part composed of glass powder can be provided and inserted into the recess 48 of the housing 10 together with the optical window 44. The optical window 44 is placed on a narrow support surface 45 surrounding the opening 43 on the housing 10. Through subsequent temperature treatment, for example, temperature treatment in a furnace or by heating with the aid of a laser, the pressed part is melted and a glass connecting element 46 melted to the optical window 44 and the wall of the recess 48 is obtained.

[0100] Advantageously, the connection of the optical window 44 by means of the fused glass connecting element 46 results in a defined positional relationship between the surface of the optical window 44 and the measuring chamber 40 or the housing 10 of the flow cell 1. This allows a reproducible arrangement of optical instruments such as a spectrometer or a sensor head 200 of a spectrometer (see Figure 2c ), so that the optical focus is located in the measuring chamber 40 at a defined distance from the inwardly directed surface of the optical window 44. In order to further simplify this reproducible arrangement, Figure 1a In the embodiment of the present invention, a flange is provided on the housing 10 of the flow cell 1 as a holding means 12. The flange also serves here in particular as an orientation means in the form of a defined mechanical stop, by means of which the spectrometer or sensor head 200 or probe head can be fixed on the flow cell 1 in a reproducibly oriented manner.

[0101] Furthermore, the glass connecting element 46 is guided very closely to the opening 43 by the narrow support surface 45, so that there is no or only a small dead volume between the optical window 44 and the housing 10. If the width of the support surface 45 is optimally adapted to the properties of the glass connecting element 46, the glass connecting element 46 can completely or at least almost completely fill any gap that remains during the heat treatment for the fitting of the glass to the optical window 44, without the material of the glass connecting element 46 penetrating beyond the edge of the opening 43 into the region of the measuring chamber 40.

[0102] If further mechanical holding means 12 are desired for connection to a spectrometer or a sensor head 200 of a spectrometer, the holding means can be designed differently depending on the requirements. Figure 1b As shown, an adapter 100 may be provided.

[0103] Figure 1b As shown in reference Figure 1a The described flow cell 1 has an adapter 100 fixed to a holding means 12 implemented as a flange. The adapter 100 in turn includes a further holding means 12' for connection to a spectrometer or sensor head 200. In the example shown, the further holding means 12' is implemented as an internal thread. Figure 1b As shown, such an adapter 100 can also be used in particular to accurately and reproducibly determine the flow cell 1 and the inlet aperture of the spectrometer or sensor head 200 for the corresponding spectrometer or sensor head 200 (see Figure 2c ) required spacing. For this purpose, the adapter 100 can include, for example, a tube section 102, wherein the required spacing can be determined by selecting the length of the tube section 102. Figure 1b In the illustration of , the pipe section 102 is shown discontinuously in order to clearly illustrate that its length can be adapted as required.

[0104] Figure 1c Another perspective view shows the reference Figure 1b The described arrangement consists of a flow cell 1 and an adapter 100 .

[0105] exist Figures 2a to 2c A second embodiment of a flow cell 1 is shown in FIG. Figure 2a Here, a second exemplary embodiment of a flow cell 1 is shown in a perspective sectional view.

[0106] With reference Figure 1aSimilar to the first embodiment described, the flow cell 1 has a housing 10, inside which is arranged a cavity which forms a measuring chamber 40. The measuring chamber 40 is configured here as a blind hole. The inlet channel 20 connects the measuring chamber 40 to a first connecting sleeve 23, and the outlet channel 30 connects the measuring chamber 40 to a second connecting sleeve 33. The connecting sleeves 23, 33 are configured to be directly connected to a hose that guides the liquid flow to be detected. Figure 2a In the embodiment shown in FIG. 4 , the inlet channel 20 and the outlet channel 30 are located on different axes and are not arranged opposite each other. In addition, it can be seen that the inlet channel 20 and the outlet channel 30 are each arranged to extend tangentially to the radius of the measuring chamber 40. This arrangement is suitable for promoting turbulence of the medium through the measuring chamber 40, which, for example, ensures good mixing and counteracts the deposition of solid matter.

[0107] Measuring room 40 Figure 2a The left side of the optical window 44 has an opening 43, which is sealed by an optical window 44. The material of the optical window 44 can again be selected depending on the optical detection to be performed. For example, to perform Raman spectroscopy, an optical window 44 composed of UV-quality quartz glass is preferably used, and an optical window 44 composed of a crystalline material, such as sapphire glass, is particularly preferably used.

[0108] As reference Figure 1a As described in the first embodiment of the present invention, the optical window 44 is connected to the wall 42 of the measuring chamber 40 using a glass connecting element 46. The glass connecting element 46 is fused to the optical window 44 and the wall of the recess 48 and seals the measuring chamber 40 gas-tightly.

[0109] exist Figure 2b , the flow cell 1 of the second embodiment is shown from another angle. In this figure, a holding mechanism 12 configured as a threaded hole can be seen. In order to be reproducibly connected to the spectrometer or sensor head 200, the spectrometer or sensor head can be connected to the threaded hole by corresponding screws. Here, by providing a plurality of threaded holes, the position and orientation can also be determined reproducibly. In addition, an optical baffle 16 is provided in the second embodiment. This optical baffle can be connected to a corresponding tubular element of the spectrometer or sensor head 200 (see Figure 2c ) cooperates with and shields the optical path between the spectrometer or sensor head 200 and the measuring chamber 40 of the flow cell 1 from external light. In addition, the baffle 16 can also form a form fit with a corresponding element on the spectrometer or sensor head 200 and, similar to the holding mechanism 12, supports the form fit in the precise orientation from the flow cell 1 to the spectrometer or sensor head 200.

[0110] Figure 2cThe connection of the flow cell 1 to the sensor head 200 is shown in a view from above. Only a small detail of the sensor head 200 is shown here. Figure 2c As can be seen in the figure, the baffle 16 engages in a corresponding opening in the sensor head 200 and shields the light path between the sensor head 200 and the flow cell 1 from the entry of external light from the surroundings. In addition, the baffle 16 has a dual function as an orientation means and serves to precisely orient the sensor head 200 relative to the flow cell 1. Screws that cooperate with corresponding threaded holes as holding means 12 on the housing 10 of the flux cell 1 serve as fixing means.

[0111] Figures 3a to 3c A third embodiment of a flow cell 1 is shown. The third embodiment corresponds largely to the Figure 2a The second exemplary embodiment described, however, differs in that the holding means 12 is designed as a flange and no additional stop 16 is provided, since the flange 12 also assumes this function. Figure 3a A flow cell 1 according to a third exemplary embodiment is shown in a perspective sectional view.

[0112] Figure 3b The flow cell 1 is shown in a side view. It can be clearly seen in this figure that in the third embodiment, the inlet channel 20 and the outlet channel 30 or the two connecting sleeves 23, 33 are arranged on different axes, wherein these axes extend parallel to each other. However, as an alternative to this, the two axes can also be arranged at an angle to each other.

[0113] Figure 3c 1 shows a flow cell 1 according to a third embodiment together with an adapter 100, which is fixed to a holding means 12 designed as a flange, for example by means of a welded connection. The adapter 100 has a further holding means 12', which is similar to the one described with reference to FIG. Figures 1a to 1c As described in the first embodiment of the present invention, the sensor head 200 (see FIG. 1 ) is designed as an external thread and arranged at the end of the pipe section 102. By means of the external thread, for example, the sensor head 200 (see FIG. 1 ) can be Figure 2c ) is connected to the adapter 100 and thus to the flow cell 1, wherein a predetermined distance and a predetermined orientation of the flow cell 1 relative to the sensor head are maintained in a defined and reproducible manner. In this case, the distance can be adjusted by selecting the length of the tube section 102, wherein Figure 3c The pipe section 102 is shown discontinuously in FIG.

[0114] Figure 4 A fourth exemplary embodiment of a flow cell 1 is shown in a perspective view. In this case, the flow cell 1 corresponds largely to the reference 1 in terms of its structure. Figure 1aThe first embodiment described. Unlike the first embodiment, no flange is provided as the holding means 12, but four holes are arranged as holding means 12 as an example. These holes can be implemented in particular as threaded holes and can realize simple fixing of the sensor head 200 or the spectrometer on the flow cell 1. In addition, of course, an adapter 100 can be provided, and if, for example, a different holding means 12 is required to fix a specific spectrometer, the adapter 100 can be fixed to the housing 10 of the flow cell 1 via the threaded holes. In this case, the adapter 100 can be configured so that it has an additional holding means 12', which is provided for connecting to the spectrometer.

[0115] Figure 5 An exemplary embodiment of a flow cell 1 is shown having a casing 150 made of a polymer material, which partially surrounds the housing 10. The illustration is a sectional view from the side.

[0116] The housing 10 and the reference Figure 1a The measuring chamber 40 is constructed similarly to the embodiment described in and is made of a ceramic material, for example. The measuring chamber 40 is accommodated in the interior of the housing 10, wherein the housing 10 provides a wall 42 of the measuring chamber 40. The opening in the housing 10 is sealed with an optical window 44, which is connected to the housing 10 via a glass connecting element 46. The measuring chamber 40 can be connected to the fluid flow via the inlet channel 20 and the outlet channel 30, wherein connectors 22, 32 are provided for the connection.

[0117] and Figure 1a Compared to the flow cell 1 shown, Figure 5 The flow unit 1 shown has a casing 150 which preferably consists of a polymer material and can be produced, for example, by injection molding. In this case, the housing 10 of the flow unit 1 can be inserted into an injection molding die and injection-molded with a polymer material.

[0118] In this case, the covering 150 surrounds the section of the housing 10 which includes the optical window 44 and leaves free the region adjoining the connections 22 , 32 .

[0119] The sheath 150 has a pipe 152 on the side of the housing 10 into which the optical window 44 is inserted, and a thread 154 is formed on the outside of the pipe. The thread 154 is used in combination with the pipe 152 as a holding and connecting mechanism to accommodate and fasten the sensor head 200 (see Figure 2c). A plurality of tabs 156 are arranged on the inwardly directed wall of the connecting piece 152. These tabs 156 serve as means for precisely positioning and orienting the sensor head 200. Since the outer sleeve 150 with the connecting piece 152 is made of a polymer, the material is flexible and pliable. This allows the tabs to be configured in such a way that they form a friction fit with the sensor head 200 and thus ensure a precise and reproducible orientation of the sensor head 200.

[0120] Although the invention has been described with reference to preferred exemplary embodiments, it is not restricted thereto but can be modified in many ways.

[0121] List of Reference Numerals

[0122] 1 Flow unit

[0123] 10 Shell

[0124] 12 Holding mechanism

[0125] 12' Additional holding mechanism

[0126] 16 optical baffles

[0127] 20Entranceway

[0128] 22 First joint

[0129] 23 First connecting sleeve

[0130] 30 Exit Channel

[0131] 32 Second connector

[0132] 33 Second connecting sleeve

[0133] 40 Measurement Room

[0134] 42 Measurement room wall

[0135] 43 Opening

[0136] 44 Optical Window

[0137] 45 Support surface

[0138] 46 Glass connecting components (glass solder)

[0139] 48 concavity

[0140] 49 channels

[0141] 100 adapters

[0142] 102 pipe section

[0143] 150 Packing Department

[0144] 152 Takeover

[0145] 154 thread

[0146] 156 splice

[0147] 200 sensor head.

Claims

1. A flow cell (1) for optical spectroscopy, comprising a housing (10) having a cavity forming a measuring chamber (40), an inlet channel (20), an outlet channel (30) and an optical window (44) sealing an opening (43) of the measuring chamber (40), wherein the optical window (44) is connected to the housing (10) by a fused glass connecting element (46), characterized in that A recess (48) is formed around the opening (43), and a support surface (45) for an optical window (44) is formed around the opening (43), wherein the optical window (44) contacts the housing (10) at the support surface (45).

2. The flow unit (1) according to claim 1, characterized in that The width of the support surface (45) of the optical window (44) is narrower than 0.3 mm, preferably narrower than 0.2 mm, and particularly preferably narrower than 0.1 mm.

3. The flow unit (1) according to claim 1 or 2, characterized in that: The glass connecting element (46) fills the free space between the optical window (44) and the wall of the recess (48), so that no gap remains between the wall of the recess (48) and the glass connecting element (46).

4. The flow cell (1) according to any one of claims 1 to 3, characterized in that The glass connecting element (46) comprises a glass material or consists of a glass material having a glass transition temperature T greater than 470° C. g .

5. The flow cell (1) according to any one of claims 1 to 4, characterized in that The optical window (44) is connected to the housing (10), in particular to a wall of a recess (48) of the housing (10) adjacent to the opening (43), via a glass connecting element (42), which is formed from glass solder or is designed as a glass molded body.

6. The flow unit (1) according to claim 5, characterized in that The glass material of the glass solder or the glass forming body is selected from borosilicate glass.

7. The flow cell (1) according to any one of claims 1 to 6, characterized in that At least one component of the housing (10) is formed in one piece and forms a cavity with the measuring chamber (40).

8. The flow cell (1) according to any one of claims 1 to 7, characterized in that The average roughness Ra of the inner wall of the measuring chamber (40) is less than 0.8 μm, preferably less than 0.5 μm.

9. The flow cell (1) according to any one of claims 1 to 8, characterized in that The material of the housing (10) is selected from metals or metal alloys, wherein the material of the housing (10) is preferably selected from steel, in particular stainless steel, austenitic steel or ferritic steel, duplex steel, nickel-copper alloy, nickel-chromium-iron-niobium-molybdenum alloy, nickel-chromium-molybdenum-tungsten alloy, zirconium-niobium alloy and titanium-niobium alloy, or The material of the shell (10) is selected from ceramics, wherein the material of the shell (10) is preferably selected from porcelain, yttrium oxide (Y2O3), zirconium oxide (ZrO2), magnesium aluminate (MgAl2O4), aluminum oxide (Al2O3), SiAlON-Al2O3 and silicon carbide (SiC).

10. The flow cell (1) according to any one of claims 1 to 9, characterized in that The material of the optical window (44) is selected from glass, in particular quartz glass, crystal, in particular sapphire, ceramic, in particular yttrium-doped zirconium dioxide or glass ceramic.

11. The flow cell (1) according to any one of claims 1 to 10, characterized in that The first thermal expansion coefficient of the housing (10) is greater than the second thermal expansion coefficient of the glass connecting element (46), and the first thermal expansion coefficient is preferably greater than the third thermal expansion coefficient of the optical window (44).

12. The flow unit (1) according to claim 11, characterized in that The housing (10) has anisotropic thermal expansion, wherein a first thermal expansion coefficient exists in a direction perpendicular to the longitudinal axis of the opening (43), and another thermal expansion coefficient of the housing (10) in a direction parallel to the longitudinal axis of the opening (43) has a thermal expansion coefficient of less than 1·10 - 6 K -1 , preferably less than 0.1·10 -6 K -1 , particularly preferably less than 0.01·10 -6 K -1 And more preferably less than 0.001·10 -6 K -1 The numerical value of .

13. The flow cell (1) according to any one of claims 1 to 12, characterized in that The shape of the surface of the optical window (44) is selected from a flat surface, a convex surface, a concave surface or a combination thereof, such as a biconvex surface, a plano-convex surface, a convex-concave surface, a plano-concave surface and a biconcave surface.

14. The flow cell (1) according to any one of claims 1 to 13, characterized in that The flow unit (1) comprises a casing (150) which at least partially surrounds the housing (10), wherein the casing (150) is preferably made of a polymer material.

15. The flow cell (1) according to any one of claims 1 to 14, characterized in that The flow cell (1) additionally comprises a holding mechanism (12, 12') for holding a spectrometer or a sensor head (200) of the spectrometer and / or an orientation mechanism for orienting the spectrometer or the sensor head (200).

16. The flow unit (1) according to claim 15, characterized in that The flow cell (1) and the holding device (12, 12') and / or the orientation device are designed in such a way that the spectrometer or sensor head (200) can be attached to the flow cell (1) in such a way that no components are arranged between the optical window (44) and the first optical element of the spectrometer or sensor head (200).

17. The flow cell (1) according to claim 15 or 16, characterized in that The holding means (12, 12') and / or the orientation means are arranged to cooperate with a counterpart on the spectrometer or sensor head (200) to achieve a releasable latching connection.

18. The flow cell (1) according to any one of claims 15 to 17, characterized in that The holding means (12, 12') and / or the means for orientation are configured as flanges, recesses, projections, threaded holes, notches, and combinations of these means.

19. The flow cell (1) according to any one of claims 1 to 18, characterized in that The inlet channel (20) and the outlet channel (30) are arranged opposite each other on a common axis so that a laminar flow is formed in the measuring chamber (40) when a liquid medium flows through. The inlet channel (20) and the outlet channel (30) are arranged on different axes relative to one another, so that turbulence is generated within the measuring chamber (40) when a liquid medium flows through.

20. Use of a flow cell (1) according to any one of claims 1 to 19 for monitoring a biotechnological process.

21. A method for monitoring a biotechnological process in which a medium for cultivating cells is circulated and flows through a container for accommodating the cell culture, characterized in that A flowing medium is divided into a main stream and a side stream, the side stream is passed through a flow cell (1) according to any one of claims 1 to 19, a spectral detection is performed in the flow cell (1), and the side stream is subsequently supplied back to the main stream.

22. The method for monitoring a biotechnological process according to claim 21, characterized in that During monitoring, a plurality of measuring instruments are used to detect parameters of a medium in a measuring chamber of the flow cell (1), and the plurality of measuring instruments are connected to a holding mechanism of the flow cell (1) without compromising the sterile integrity of the medium.

Images