Flow cell for optical spectroscopy and method for monitoring biotechnological processes - Patent Application 20070122997

Abstract

A flow cell (1) for optical spectroscopy is proposed, comprising a casing (10) with a cavity forming a measurement chamber (40), an inlet channel (20), an outlet channel (30), and an optical window (44) closing an opening (43) of the measurement chamber (40). The optical window (44) is bonded to the casing (10) by melting a glass bonding element (46), a recess (48) is formed around the opening (43), and a mounting surface (45) for the optical window (44) is formed around the opening (43), and the optical window (44) contacts the casing (10) at the mounting surface (45). Further aspects of the invention relate to the use of the flow cell (1) for monitoring a biotechnological process, as well as a biotechnological method for monitoring using the flow cell (1).

Description

[Technical Field]

[0001] The present invention relates to a flow cell for optical spectroscopy, comprising a measurement chamber with an optical window, an inlet channel and an outlet channel. Another aspect of the invention relates to the use of such a flow cell for monitoring a biotechnological process and to a method for monitoring a biotechnological process.

[0002] Background technology Optical spectroscopy is used in many technical fields and can be used, for example, to inspect samples or to monitor manufacturing processes, where light is introduced into the sample and the light transmitted through or reflected from the sample is inspected.

[0003] An application field of optical spectroscopy is the monitoring of biotechnological processes, which can be roughly divided into so-called upstream and downstream processes. Upstream processes include, among other things, the preparation of starting materials, the cultivation of cells, and the execution of fermentation processes. Downstream processes include, among other things, the separation and purification of the resulting products, as well as the quality control. Raman spectroscopy is particularly suitable for monitoring such biotechnological processes.

[0004] For liquid samples, or samples dissolved or suspended in a liquid, a flow cell can be used to perform spectroscopy. The flow cell includes a measurement chamber with an inlet channel, an outlet channel, and an optical window.

[0005] WO 2021 / 198427 describes a flow cell device used for process monitoring of biological processes. The flow cell device includes a monolithic glass body cast to surround a measurement channel and a fixing means with an alignment aid for aligning a sensor head. The glass body is made of a UV-transparent material, such as quartz glass, and the measurement channel surrounded by the glass body has at least one straight section with a constant cross section.

[0006] A disadvantage of this flow cell arrangement is that the commonly used quartz glass generates undesirable signals that interfere with various measurements, especially Raman spectroscopy. WO 2021 / 198427 does mention other materials, such as sapphire, as possible alternatives to quartz glass. However, sapphire in particular is not suitable for casting glass bodies, so a monolithic body that hermetically encloses the measurement channel cannot be produced from this material.

[0007] EP 3610244 discloses a liquid cell with a measurement chamber and a measurement window, in which a crimping element presses the measurement window against a seal, thereby sealing the measurement chamber. The seal can be in the form of an O-ring or a film made of, for example, PTFE. A disadvantage of this approach is that a small dead volume is formed in the area of ​​the sealing element, which can lead to deposits. Furthermore, thick seals, especially those made of O-rings, make it difficult to accurately determine the position of the measurement window. However, for good signal quality, it is desirable to accurately determine the distance from the focus to the measurement window in optical spectroscopy.

[0008] In view of the prior art, the object of the present invention can be to provide a flow cell for optical spectroscopy, in particular in the field of biotechnology, having a measurement chamber in which the material does not generate a specific measurement signal in the spectral range of the test during spectroscopic testing. -1From 3800cm -1 In this range, no inherently disturbing measurement signals should be formed. Furthermore, the material of the flow cell should be compatible with the biological process being examined or monitored. Here, it is desirable that the measurement chamber allows a good signal-to-noise ratio, especially in Raman spectroscopy.

[0009] Disclosure of the Invention A flow cell for optical spectroscopy is proposed. The flow cell has a casing with a hollow space forming a measurement chamber, an inlet channel, an outlet channel, and an optical window closing an opening of the measurement chamber. The optical window is bonded to the casing by melting a glass bonding element. In this case, a recess is preferably formed around the opening, and a mounting surface for the optical window is formed around the opening, so that the optical window contacts the casing at the mounting surface.

[0010] By connecting the optical window to the casing by melting the glass connecting element, as proposed, a hermetically sealed connection is obtained, in particular, where hermetically sealed means that the connection between the optical window and the measurement chamber is 1·10 -5 Less than mbar·l / sec, preferably 1·10 -10 mbar·l / sec~1·10 -6 This means that the optical window has a helium leak rate in the range of mbar·l / sec. Preferably, the helium leak rate is measured in accordance with DIN EN 60068-2-17:1995-05, ASTM F2391-05 (Reapproved 2016), or MIL-STD-883 rev. K-method 1014.15. Advantageously, the above-mentioned leak rate is also obtained in tests lasting at least four minutes. The optical window thus provides a particularly sterile seal, preventing pathogens from reaching the interior during biotechnology processes.

[0011] Furthermore, the proposed connection between the optical window and the casing of the measurement chamber or flow cell does not require additional components, particularly flexible elements such as elastomeric seals. Such elastomeric seals, for example in the form of O-rings, do not allow for precise positioning of the optical window relative to the casing of the measurement chamber or flow cell. This is especially true because the thickness of the O-ring at that time depends on the clamping pressure, creating a dead volume where no flow occurs. In contrast, the proposed connection is rigid and defines a fixed positional relationship between the surface of the optical window and the measurement chamber. This is particularly advantageous when performing optical inspections in which the focal point of the optical system must be positioned at a defined distance from the surface of the optical window facing inward into the measurement chamber.

[0012] Preferably, a mounting surface for the optical window is formed around the opening of the measurement chamber, where the optical window contacts the housing. The width of the mounting surface of the optical window is less than 0.3 mm, preferably less than 0.2 mm, and particularly preferably less than 0.1 mm. When fused to the housing, a gap-free internal connection is formed between the glass coupling element and the housing and between the glass coupling element and the optical window. Note that small gaps may remain in the region of the mounting surface where the optical window may contact the housing, and the internal volume of such gaps is minimized by minimizing the mounting surface. However, since the mounting surface provides a mechanical stop for accurate positioning of the optical window, a certain width of the mounting surface is desirable for facilitating installation of the optical window. On the other hand, the material of the glass coupling element may flow when melted, which would be undesirable if the material of the glass coupling element flowed into the interior of the measurement chamber. In the best case, the material of the glass connecting element flows into the gap that may be present between the optical window and the housing, so that the volume of the gap is filled exactly, but the material of the glass connecting element does not flow across the gap into the interior of the measurement chamber. For this purpose, the width of the mounting surface is preferably 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 mounting surface.

[0013] Preferably, a recess is formed in the casing around the opening, and the glass coupling 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 coupling element.

[0014] The diameter of the recess is preferably selected to be 20% to 35% larger than the diameter of the optical window. Therefore, the preferred width of the gap in which the glass coupling element is accommodated is in the range of 0.6 mm to 1.0 mm. A gap width that is as small as possible is advantageous for allowing pressure to be transmitted from the wall of the opening to the optical window. However, if the width is too small, it becomes increasingly difficult to reliably manufacture the glass coupling element.

[0015] Preferably, the glass bonding element is bonded flush with the recess. Even more preferably, the optical window is bonded flush with the glass bonding element, so that the optical window and the glass bonding element are arranged flush with the recess. However, alternatively, the window and / or the glass bonding material may be configured not to be flush with the recess. In this case, in particular, the glass bonding material can be configured to be recessed and thus protected from mechanical influences by the protruding casing.

[0016] Preferably, the optical window is bonded to the casing, particularly to the wall of the casing recess adjacent to the opening, via a glass bonding element made of glass solder or formed as a glass molding. If a metallic material is used for the casing, a hermetically sealed bond in the form of a glass-to-metal seal (GTMS) can be formed by melting the glass material of the glass bonding element. In this case, the glass material of the glass bonding element also chemically bonds with the material of the casing, particularly with metal oxides on the surface of the metallic casing material. If a ceramic material is selected for the casing, ceramic components can usually be directly welded with the molten glass material, so that a chemical bond between the glass bonding element and the casing also occurs in this case during the glass sealing.

[0017] The glass molding can be prepared, for example, in the form of a compact or sintered body obtained from glass powder, and then fused to the casing and the optical window by heat treatment to form a glass bonding element. The compact can contain a binder in addition to the glass powder for stabilization, which is subsequently removed during the heat treatment. The heat treatment can be carried out, for example, by heating the assembly formed from the casing, the glass molding, and the optical window in an oven. Alternatively, the glass molding can be heated in a targeted manner, for example, via a laser, so that the areas of the casing or the optical window that are not directly adjacent to the glass molding are not heated at all or only slightly. This prevents the materials from being altered by heat.

[0018] The glass connecting element preferably consists of or includes a glass material, which is selected for use in the flow cell so as to be resistant to the medium introduced into the measuring chamber and to release as little substances as possible into the medium. Correspondingly, the glass material is preferably resistant to water, acids and alkalis.

[0019] Glass materials with high chemical resistance are usually high-melting glasses, which have higher melting points and higher glass transition temperatures T than low-melting glasses with low chemical resistance. g Additionally, commonly used low melting glasses often contain heavy metals that are undesirable, especially for biotechnology applications.

[0020] Correspondingly, it is preferred to select the glass bonding material so that it contains or contains a high-melting glass material, where the glass transition temperature T is above 470 ° C, preferably above 500 ° C, more preferably above 600 ° C, particularly preferably above 750 ° C. g are considered to be high melting point glass materials.

[0021] High glass transition temperature T gIn relation to this, the high-melting glass material here has a low dynamic viscosity when heated, so that the glass material has a lower fluidity during glass sealing than the low-melting glass. The fluidity here can be improved by further heating, but the strong thermal action requires additional materials to be added to the flow cell, which in particular impairs its surface quality. Therefore, the glass transition temperature T g It is preferable to select a glass material whose melting point is less than 900°C, particularly preferably less than 800°C.

[0022] To avoid deterioration of the surface quality, in particular of the inner wall of the measuring chamber, the glass material of the glass coupling element preferably has a thermal conductivity of at least 1·10°C at a temperature of 1300°C. 5 The kinematic viscosity η of the glass is preferably selected to have a kinematic viscosity η of 100 dPa·s. Particularly preferably, this value is reached already at 1200°C, most preferably already at 1100°C. Correspondingly, the glass sealing is preferably carried out at a temperature below 1300°C, particularly preferably below 1200°C, most preferably below 1100°C. The kinematic viscosity of the glass, or the temperature at which the required viscosity is reached, can be determined, for example, in accordance with DIN ISO 7884-1:1998-02.

[0023] 1·10 5 The kinematic viscosity η of dPa·s is so high that a reliable glass seal cannot generally be achieved by free flow alone. It is therefore advantageous to assist the flow of the glass material by the application of a force, for example via a mounted weight or plunger. In connection with such an application force, the glass material has a viscosity of 1·10 5 Even with a dynamic viscosity of dPa·s, they can still adhere to the walls of optical windows and apertures, forming good bonds.

[0024] If the glass joining element is prepared for the glass sealing process in the form of a pressed body, it is particularly advantageous to provide a mechanical stop through the mounting surface, since in this case the optical window is supported by the inner surface of the flow cell during the glass sealing process, and only then can pressure be applied to the pressed body.

[0025] The glass solder or glass material of the glass molding is preferably selected from borosilicate glasses, for example the chemically resistant glasses 8326 and 8800 from SCHOTT AG.

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

[0027] Suitable stainless steels include, for example, AISI 316L pharmaceutical steel (material number 1.4404), which is an austenitic stainless steel. AISI 329A is a suitable austenitic-ferritic duplex stainless steel (material number 1.4462).

[0028] Preferred ceramic materials for the casing include, inter alia, porcelain, yttrium oxide (YO), zirconium oxide (ZrO) (optionally stabilized with CaO, MgO, CeO, TiO, or YO), magnesium aluminate (MgAlO), aluminum oxide (AlO), SiAlON-AlO, and silicon carbide (SiC). Since the ceramic material is preferably formed polycrystalline, it is preferably non-light-transmitting.

[0029] If stainless steel is selected, its surface is preferably passivated, for example, by forming a passive layer using a chemical or electrochemical surface treatment.

[0030] The inner wall of the measuring chamber is preferably configured so that the measuring chamber has only a small roughness, with an average roughness value Ra of preferably less than 0.8 μm, particularly preferably less than 0.5 μm.

[0031] The combination of the relatively low temperature glass sealing for the proposed high melting point glass material protects the material of the measurement chamber, so that a high surface quality is maintained. For example, if stainless steel is selected as the material for the inner wall of the measurement chamber, too high a processing temperature can cause surface damage by polishing off the fragile metal oxide layer. For example, martensitic Fe-Cr alloys are prone to brittle FeO x The upper layer is (Fe,Cr)O x It is formed on an underlayer, which already causes surface changes at temperatures above 1100°C, and further increases in temperature cause significant surface damage.

[0032] For a high surface quality of the inner wall of the measuring chamber, at least the components of the casing that form the inner wall of the measuring chamber are preferably formed in one piece and accordingly do not have gaps, surface changes due to joining material or welding. Preferably, the entire casing is formed in one piece.

[0033] To meet the stringent requirements for biopharmaceutical manufacturing, the materials preferably each meet the following specifications: i) FDA approved materials, e.g., ICH Q7, CFR211.65(a)-Code of Federal Regulations, USP <88> Class VI, animal-derived ingredients free, bisphenol A free ii) Sectoral Chemical Resistance - ASTM Standard D543-21 iii) Testing for biocompatibility, e.g., according to the United States Pharmacopoeia or ISO 10993-1 (2018-08) It is configured to correspond to.

[0034] 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 zirconia (yttria-stabilized zirconia, YSZ) or glass-ceramic. Further examples of suitable materials include yttrium-doped aluminum oxide, lanthanum-doped yttrium oxide, aluminum-doped aluminum nitride, and magnesium-doped aluminum oxide. The dopants here are each metal oxides.

[0035] The optical window can additionally have one or more coatings or exteriors, for example to change the surface hardness and / or optical properties, such as reflection properties. In particular, an anti-reflection coating can be provided. In this case, the anti-reflection coating is preferably optimized for the wavelength of the excitation light and / or signal (especially fluorescence in fluorescence spectroscopy). The coating can be provided on both sides, i.e., on the surface facing the inside of the measurement chamber and on the surface facing the outside of the optical window. Alternatively, the coating can be provided on only one side, or on two sides with different coatings. For example, the surface facing the inside of the measurement chamber can be uncoated, while only the surface facing the outside can be coated. This prevents the coating material from coming into contact with the medium to be examined. If only the outer surface is coated, it does not need to be particularly chemically resistant to the medium to be examined. Furthermore, an anti-reflection coating can generally be omitted on the inner surface, since typically only small reflection losses occur during the transition from the optical window to the liquid medium in the measurement chamber.

[0036] In one embodiment of the flow cell, the first coefficient of thermal expansion of the casing is adapted to a second coefficient of thermal expansion of the glass bonding element and a third coefficient of thermal expansion of the optical window, where adapted means that the difference in the coefficients of thermal expansion is less than 3·10 -6 K -1 Less than 2·10 -6 K -1less than 1·10 -6 K -1 It is understood to be less than

[0037] Alternatively, a compression glass seal can be provided in which the first coefficient of thermal expansion of the casing is greater than the second coefficient of thermal expansion of the glass connecting element, which is advantageously greater than the third coefficient of thermal expansion of the optical window, whereby the first coefficient of thermal expansion is preferably 3·10 compared to the second and possibly third coefficients of thermal expansion. -6 K -1 More than 6.10, especially preferred -6 K -1 The above are different.

[0038] For optical windows made of sapphire, such a compressive glass seal can be obtained, for example, for a casing made of stainless steel and a glass coupling element made of borosilicate glass. The first thermal expansion coefficient of the casing is, for example, 16·10 if austenitic stainless steel is selected. -6 K -1 and the second thermal expansion coefficient is, for example, about 3·10 for borosilicate glass. -6 K -1 ~about 7·10 -6 K -1 and the third thermal expansion coefficient for sapphire is about 5·10 -6 K -1 In this example, the second and third thermal expansion coefficients are 3·10 -6 K -1 The first thermal expansion coefficient differs from both of the above by less than 6·10 -6 K -1 The glass coupling elements differ by a factor of 10, thus resulting in a pressure exerted by the casing, which is now transmitted from the glass coupling element to the optical element.

[0039] In such a compression glass seal, the shrinkage of the casing after glass sealing along the longitudinal axis of the opening exerts pressure on the glass bonding element and the optical window, preventing gaps from forming between the elements and promoting a hermetic seal. However, in the case of isotropic thermal expansion, pressure also acts in a direction parallel to the longitudinal axis of the opening, which is not necessary for beneficial effects. In particular, if the optical element is made of multiple components or layers, these axially acting forces can have a negative effect on the optical element. An example of this is an optical element made of yttrium-doped zirconium dioxide with a cladding made of a layer of yttrium oxide. Axial pressure can cause the cladding to separate.

[0040] In particular, in this case, the casing is configured to have anisotropic thermal expansion, with a first coefficient of thermal expansion being in a direction perpendicular to the longitudinal axis of the opening and another coefficient of thermal expansion of the casing being 1·10 along a direction parallel to the longitudinal axis of the opening. -6 K -1 Less than 0.1 10 -6 K -1 less than 0.01 10 -6 K -1 less than 0.001 10 -6 K -1 has a value less than

[0041] The casing with anisotropic thermal expansion coefficient can also be constructed as a component made of a titanium-niobium alloy modified, for example, by a thermomechanical method. In this thermomechanical method, the alloy components are first homogenized by heat treatment at temperatures between 900°C and 1100°C for 1-3 hours in an N or Ar atmosphere. A phase transformation in the material structure, and in particular in the material of the component, can then be induced by a cold rolling step. This can be followed by sintering at temperatures between 700°C and 950°C for 0.25-1 hour. A water quenching step can then be performed. The adaptation step allows the thermal expansion coefficient, in particular the first and second thermal expansion coefficients, to be adapted or tailored over one or more thermal cycles.

[0042] Alternatively, the component can be obtained by additive manufacturing (3D printing), for example by layer-by-layer deposition of metal powders followed by sintering. Here, the composition gradient of the resulting titanium-niobium alloy can be controlled, for example by using different amounts of titanium and niobium powders. Furthermore, by controlling the heat input during sintering, in particular the temperature and rate of heating and cooling, the formation of different phases in the material can be controlled, and the thermal expansion of the component can be tailored.

[0043] An example of a composite element comprising such an outer component made of a titanium-niobium alloy and an inner component made of yttrium-doped zirconia coated with yttrium oxide is known from DE 10 2019 115 204 A1.

[0044] Therefore, the materials for the measurement chamber, which preferably has walls formed by the flow cell casing itself, the materials for the optical window, and the materials used to connect the optical window and the measurement chamber are preferably selected to be compatible with bioengineering processes.

[0045] When such materials are selected, the measurement chamber does not contain materials that inhibit the growth of cultured cells, that produce specific spectroscopic signals in the relevant spectral region, or that are undesirable for other reasons in the process being performed. For example, the gold alloys contained in gold alloys or gold solders used in the prior art to manufacture press seals for windows are undesirable in many biotechnology processes. Accordingly, gold alloys are undesirable materials in the region of the measurement chamber. Therefore, the flow cell preferably does not contain gold alloys, especially gold solders containing gallium, tin, and / or germanium, and / or materials that produce specific spectroscopic signals upon excitation with a spectroscopic light source, especially a light source such as an LED or laser having a wavelength of 532 nm, 633 nm, 775 nm, 785 nm, 830 nm, or 1064 nm. Particularly preferably, no spectroscopic signals should be produced upon excitation with light having a wavelength of 532 nm, 785 nm, or 1064 nm, and it is particularly preferred that the material does not emit a spectroscopic signal upon excitation with light having a wavelength of 532 nm or 785 nm.

[0046] In this specification, emission of a specific spectroscopic signal refers in particular to the emission or scattering of light having a wavelength different from the wavelength of the excitation light or the wavelength of the light source, for example by inelastic scattering of light (as in Raman spectroscopy, for example) or by absorption and re-emission of light (as in fluorescence spectroscopy, for example). In particular, hydrogen-containing compounds, such as plastics, may form a specific spectroscopic signal upon excitation with wavelengths relevant for spectroscopy.

[0047] Accordingly, it is particularly preferred that the flow cell is free of hydrogen-containing compounds, such as plastics, especially in the region of the measuring chamber. This is advantageously achieved in the proposed flow cell, especially when the material of the housing is metal, metal alloy or ceramic, the optical elements consist of glass, glass ceramic, ceramic or crystal, and glass connecting elements are used to connect the optical window to the housing.

[0048] When the preferred material is selected for the flow cell, especially for the measurement chamber of the flow cell, there is no material that emits a spectroscopic signal when excited by light in the area that is illuminated when performing optical spectroscopy.Therefore, the proposed flow cell is suitable for performing spectroscopic examinations, especially fluorescence spectroscopy.The proposed flow cell is also particularly well suited for performing Raman spectroscopy, because the material used in the area of ​​the measurement chamber does not generate an interfering fluorescence signal there.

[0049] The proposed flow cell, in its preferred material selection, does not contain materials that inhibit or are a hindrance to biotechnological processes, which allows the use of the flow cell to continuously monitor such processes by temporarily or permanently connecting it to a system.

[0050] In particular, when equipment for biotechnology applications is used, a distinction is usually made between designs for multiple use and designs for single use. The multiple use versions are designed to withstand the conditions used in the sterilization process. For example, in the case of designs designed for steam sterilization, the materials selected must be resistant to the temperatures and reagents used in steam sterilization, such as water vapor, sodium hydroxide, or ethylene oxide.

[0051] In contrast, in single-use embodiments, the materials selected for the structural configuration herein only need to allow for one-time sterilization, for example, ordinary plastics only need to be sterilized once under the action of radiation such as gamma, beta, or X-rays.

[0052] The proposed flow cell can have a casing made of metal or ceramic, which allows the flow cell to be sterilized multiple times without any problems and is therefore particularly suitable for multiple use (multi-use). However, it is of course also possible to use the proposed flow cell only once (single case).

[0053] The proposed flow cell with a metal casing is particularly suitable for autoclaving. Preferably, the flow cell is configured to be autoclavable 10,000 times by steam treatment at 141°C. Autoclavable, within the scope of this disclosure, is also understood to be autoclavable in the sense defined in the standards DIN EN ISO 14937; EN ISO 17665 for medical products.

[0054] The proposed flow cell is also particularly well suited for sterilization using radiation, preferably at a dose of 100 kGy.

[0055] Flow cells with a metal casing are also particularly pressure-resistant in connection with the inventive hermetic glass sealing of the optical window, whereby the thickness of the casing material and the thickness of the window are preferably selected such that the flow cell can withstand an internal pressure of at least 10 MPa (100 bar) in the measurement chamber.

[0056] The casing forming the measurement chamber of the flow cell can additionally be injection-molded from a polymer or plastic, thereby forming the circumferential wall. In this case, the circumferential wall can completely or at least partially surround the casing, and even if completely surrounded, the connection for accessing the measurement chamber remains exposed. In this case, the circumferential wall can be formed so as to be in contact with a functional element, such as a holding part, an alignment means, or a connection part. For example, as a combined holding and alignment means, a connecting tube with an external thread can be provided, in which case the connecting tube has a web on its inward wall for orienting and accurately positioning the sensor head of the spectrometer. Suitable polymers for the circumferential wall include, in particular, polyolefins, such as polyethylene.

[0057] The optical window of the flow cell can be configured to have a flat surface or to act similarly to, for example, a lens. Correspondingly, preferably, the shape of the surface of the optical window 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.

[0058] To facilitate the mechanical connection with 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 form a detachable mechanical connection, in particular to hold the spectrometer or the sensor head, and / or for accurate and reproducible alignment with the position of the optical window of the flow cell. In this case, the holding means is preferably configured so that a detachable connection is formed.

[0059] Preferably, the flow cell comprises as auxiliary means at least one holding means for holding the spectrometer or the sensor head of the spectrometer and / or at least one positioning means for positioning the spectrometer or the sensor head.

[0060] In this case, the flow cell and the holding means and / or alignment means are preferably configured so that the spectrometer or sensor head can be attached to the flow cell without any components being arranged between the optical window and the first optical element of the spectrometer or sensor head. In particular, it is preferred that no optical waveguide, such as a glass fiber, is arranged between the optical window and the first optical element of the spectrometer or sensor head. The first optical element of the spectrometer or sensor head can be, in particular, an entrance opening or an entrance aperture or a first lens. This makes it possible to use free-beam optics to connect the spectrometer and the proposed flow cell.

[0061] Alternatively, the flow cell may be configured to include holding and / or alignment means for holding or aligning an optical waveguide, such as a glass fiber, which may also be used to form an optical coupling to a spectrometer.

[0062] Preferably, the at least one holding means and / or the at least one alignment means are configured to cooperate with a corresponding member provided on the spectrometer or the sensor head for a releasable locking connection, which may for example be formed by a locking element releasably engaging in a recess provided on the respective other component.

[0063] Furthermore, the holding means and / or alignment means can be configured as, for example, flanges, recesses, e.g., holes, protrusions, e.g., pins, threaded holes, grooves, or combinations of these means. In this case, a corresponding element is preferably provided on the sensor head or spectrometer for cooperation with the holding means and / or alignment means. The holding means can also be configured to cooperate with additional fixing means, e.g., screws or clamps.

[0064] Furthermore, the holding means can in particular be configured as a bayonet lock in order to form a detachable connection between the flow cell and the spectrometer or sensor head by means of a bayonet rotation movement.

[0065] The holding means can be configured and arranged in particular to adjust a defined distance from the entrance aperture of the spectrometer or sensor head to the flow cell, in particular the optical window of the flow cell. This distance can advantageously be standardized for various measuring means, such as flow cells, ports or other sensor pickups, so that the spectrometer or sensor head can be connected to the flow cell via the holding means without further adaptation. In this way, for example, a single spectrometer can be used for multiple measuring means, allowing for quick plug-in replacement.

[0066] The one or more retaining means and / or the one or more alignment means can be configured as an integral part of the casing of the flow cell or as part of the casing of the flow cell. Alternatively, the flow cell can have an adapter that is removably or permanently attached to the flow cell. In this case, a detachable connection with the spectrometer or sensor head can be formed via another retaining means and / or another alignment means that are part of the adapter. If the flow cell has a polymeric peripheral wall, the retaining means and / or alignment means can be configured as part of the polymeric peripheral wall.

[0067] The flow cell is advantageously configured with a mechanically robust and gas-tight glass seal of the optical window such that the spectrometer or sensor head held in the flow cell or housed in an adapter or holding means of the flow cell can be removed and replaced while maintaining the seal of the window, thereby enabling multiple measurements without disturbing or contaminating the medium present in the measurement cell.

[0068] The flow cell has an inlet channel and an outlet channel for introducing or discharging a medium or fluid into or from the measurement chamber of the flow cell. Preferably, the inlet channel and the outlet channel are arranged opposite each other on a common axis, so that a laminar flow is formed in the measurement chamber when the medium flows through them. Alternatively, if the inlet channel and the outlet channel are arranged on different axes, a turbulent flow is formed in the measurement chamber when the medium flows through them. If a turbulent flow is desired, the inlet channel and the outlet channel are preferably arranged to extend tangentially to the radius of the measurement chamber. In this case, the measurement chamber can be formed, for example, as a hole.

[0069] The inlet and / or outlet channels preferably open into connections for connection with hoses or tubes to allow integration of the flow cell into the liquid stream to be examined, for example, threaded connections or hose nipples can be provided for this purpose.

[0070] The medium can be, for example, a liquid, in which solids may be suspended. The laminar flow is guided to achieve a particularly static and uniform flow of the medium in the measuring chamber, whereby dead volumes with no or very little flow can be largely avoided. In the case of turbulent flow, good mixing of all components of the medium is achieved, and in particular, there is no risk of entrained or suspended solids settling out. Accordingly, an embodiment of the flow cell configured for turbulent flow is preferred for use with suspensions. The configuration of the flow cell designed for turbulent flow also allows for particularly representative medium measurements, since the occurrence of disruptive deposits is suppressed.

[0071] Another aspect of the present invention is the use of the flow cell proposed herein for monitoring biotechnological processes.

[0072] Particularly advantageously, the flow cell can be used to monitor perfusion cultures, in which the cell culture is constantly washed with a medium flow. In this case, a partial or secondary flow of the flowing medium is guided through the flow cell, allowing continuous optical inspection. This makes it possible to continuously monitor, for example, the concentration of nutrients, the presence of growth factors, or the concentration of metabolic products, and to control the process depending on these monitored parameters.

[0073] Another aspect of the present invention provides a method for monitoring a biotechnological process in which a medium for cultivating cells is circulated and flows through a vessel containing the cell culture, the method being configured to divide the flowing medium into a main stream and a side stream, guide the side stream through one of the flow cells described herein, examine it by spectroscopic analysis in the flow cell, and then preferably feed the side stream back into the main stream.

[0074] More preferably, the spectroscopic examination is arranged to determine at least one parameter of the examined medium, wherein the particular parameter is used as a quantity in a preferably automated control process for closed-loop control of the at least one parameter of the medium towards a set target value.

[0075] The use of the proposed flow cell or the implementation of the proposed method advantageously allows in situ or inline process control. Opening the device to withdraw samples is eliminated. This, on the one hand, allows process control to be performed continuously or at very short time intervals. This allows possible changes in the monitoring process to be quickly identified and interventions to be made, for example, via an automatic control system. Regular parameter control and the resulting short delays allow for the provision of closed-loop control circuits, in particular, for adjusting process parameters toward set target values. The proposed flow cell therefore simplifies or even makes possible for the first time the automation of biotechnological processes.

[0076] On the other hand, the proposed flow cell can be permanently integrated into the device based on the selection of process-compatible materials, advantageously avoiding the need to open the system, which is always associated with the risk of contamination. The sterile integrity of the system remains guaranteed at all times, even when optical inspection is in progress.

[0077] Advantageously, the proposed flow cell allows for the exchange of a measuring device used to measure a parameter of a medium without compromising the sterile integrity of the device. Thus, the method and process can also include a step of exchanging a measuring device, such as a spectrometer or its sensor head, during the execution of the method. Correspondingly, the method can use a plurality of different measuring devices to detect one or more parameters of a medium flowing through the measurement chamber of the flow cell.

[0078] The proposed flow cell can be used to optimize the product flow, especially for continuous production. Automated continuous control allows for optimized yield at each process step, which means that the output of the preceding process step is balanced with the capacity of the subsequent process step. Therefore, reliable and reproducible process control at each process step eliminates the need for buffers between individual process steps, increasing the space-time yield and thus enabling process integration.

[0079] It is clear that the features mentioned above and those to be described below can be used not only in the respective combinations mentioned, but also in other combinations or alone, without departing from the scope of the invention.

[0080] Preferred configurations and embodiments of the present invention are illustrated in the drawings and explained in more detail in the following description, where like reference numerals refer to identical, similar or functionally similar components or elements. The figures show, in schematic form: [Brief explanation of the drawings]

[0081] [Figure 1a] FIG. 1 is a schematic cross-sectional view showing a first embodiment of a flow cell as viewed from the side. [Figure 1b] FIG. 2 is a perspective cross-sectional view showing the flow cell of the first embodiment equipped with a mounting adapter. [Figure 1c] FIG. 1 is a perspective view showing a flow cell of a first embodiment equipped with a mounting adapter. [Figure 2a] FIG. 10 is a perspective cross-sectional view showing a second embodiment of a flow cell. [Figure 2b] FIG. 10 is another perspective view showing the flow cell of the second embodiment. [Figure 2c] FIG. 10 is a top view of the flow cell of the second embodiment to which the sensor head is attached. [Figure 3a] FIG. 10 is a perspective cross-sectional view showing a third embodiment of a flow cell. [Figure 3b] FIG. 10 is a side view of the flow cell of the third embodiment. [Figure 3c] FIG. 10 is a perspective view showing the flow cell of the third embodiment with an adapter attached. [Figure 4] FIG. 10 is a perspective view showing a fourth embodiment. [Figure 5] FIG. 1 shows an example of a flow cell having a peripheral wall arranged to surround a casing.

[0082] 1a to 1c show a first embodiment of a flow cell 1. FIG. 1a shows a schematic cross-sectional side view of the first example of the flow cell 1. The flow cell 1 has a casing 10, inside which a cavity forming a measurement chamber 40 is arranged. An inlet channel 20 connects the measurement chamber 40 to a first connection 22, and an outlet channel 30 connects the measurement chamber 40 to a second connection 32. In the example shown in FIG. 1a, the connections 22 and 32 are configured as threaded connections and can be connected, for example, via threaded connections, to a liquid stream to be tested. In the example shown in FIG. 1a, the inlet channel 20 and the outlet channel 30 are located on the same axis and are arranged opposite each other. This arrangement is suitable for enabling a static laminar flow of a medium through the measurement chamber 40.

[0083] 1a, the measurement chamber 40 has an opening 43 on its upper side, which is closed by an optical window 44. The material of the optical window 44 is selected depending on the optical examination to be performed. For example, when performing Raman spectroscopy, an optical window 44 made of preferably UV-quality quartz glass, particularly preferably sapphire glass, is used.

[0084] In the first embodiment of FIG. 1 a, the optical window 44 is connected to the wall 42 of the measurement chamber 40 using a glass connecting element 46. The glass connecting element 46 is fused to the optical window 44 and to the wall 42, hermetically sealing the opening 43 of the measurement chamber 40. To form such a hermetic connection, a precursor of the glass connecting element 46 in the form of a compact can be prepared from glass powder and mounted together with the optical window 44 in the recess 48 of the casing 10. The optical window 44 is mounted on the casing 10 at a narrow mounting surface 45 surrounding the opening 43. Subsequent heat treatment, for example in an oven or by heating with a laser, melts the compact, resulting in the glass connecting element 46 being fused to the optical window 44 and the wall of the recess 48.

[0085] Advantageously, bonding the optical window 44 by fusing the glass bonding element 46 results in a defined positional relationship between the surface of the optical window 44 and the measurement chamber 40 or casing 10 of the flow cell 1. This allows a reproducible positioning of an optical instrument, such as a spectrometer or a spectrometer sensor head 200 (see FIG. 2c), so that its optical focus is located at a defined distance to the inwardly facing surface of the optical window 44 inside the measurement chamber 40. To further facilitate such a reproducible positioning, in the embodiment of FIG. 1a, a flange is provided on the casing 10 of the flow cell 1 as the holding means 12. Here, the flange is in particular also used as an alignment means in the form of a defined mechanical stop, by means of which the spectrometer or sensor head 200 or probe head can be reproducibly aligned and fixed to the flow cell 1.

[0086] Furthermore, the narrow mounting surface 45 brings the glass connecting element 46 into very close proximity to the opening 43, so that no or only a small dead volume exists between the optical window 44 and the casing 10. If the width of the mounting 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 gaps that may remain during the heat treatment for sealing the glass at the optical window 44, without its material penetrating beyond the edge of the opening 43 into the area of ​​the measuring chamber 40.

[0087] If other mechanical holding means 12 are desired for connection to the spectrometer or its sensor head 200, this can be implemented differently depending on requirements. Furthermore, an adapter 100 can also be provided, as shown in Figure 1b.

[0088] FIG. 1b shows the flow cell 1 described with reference to FIG. 1a together with an adapter 100 fixed to a holding means 12 configured as a flange. The adapter 100 further includes another holding means 12' for connection to a spectrometer or sensor head 200. In the illustrated example, the other holding means 12' is configured as an internal thread. As shown in FIG. 1b, such an adapter 100 can also be used, in particular, to accurately and reproducibly set the required distance from the flow cell 1 to the entrance aperture of a respective spectrometer or sensor head 200 (see FIG. 2c). For this purpose, the adapter 100 can have, for example, a tubing section 102, the length of which can be selected to set the required distance. In the illustration of FIG. 1b, the tubing section 102 is shown interrupted, which allows the length of the tubing section 102 to be adapted as needed.

[0089] In FIG. 1c, the device consisting of the flow cell 1 and adapter 100 described with reference to FIG. 1b is shown in another perspective view.

[0090] 2a to 2c show a second embodiment of the flow cell 1. Here, in Fig. 2a, the second embodiment of the flow cell 1 is shown in a perspective cross-sectional view.

[0091] As described with respect to the first embodiment of FIG. 1a, the flow cell 1 has a casing 10, inside which a cavity forming a measuring chamber 40 is arranged. The measuring chamber 40 is here configured as a blind hole. An inlet channel 20 connects the measuring chamber 40 to a first connecting nipple 23, and an outlet channel 30 connects the measuring chamber 40 to a second connecting nipple 33. The connecting nipples 23, 33 are configured for direct connection to a hose guiding the liquid flow to be tested. In the embodiment shown in FIG. 2a, the inlet channel 20 and the outlet channel 30 are arranged on different axes and not opposite each other. Furthermore, 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 turbulent flow of the medium through the measuring chamber 40, for example, resulting in good mixing and preventing solids from accumulating.

[0092] The measurement chamber 40 has an opening 43 on the left side of Fig. 2a, which is closed by an optical window 44. The material of the optical window 44 can again be selected depending on the optical examination to be performed. For example, when performing Raman spectroscopy, an optical window 44 made of preferably UV-quality quartz glass is used, and particularly preferably an optical window 44 made of a crystalline material, such as sapphire glass.

[0093] 1a, the optical window 44 is coupled to the wall 42 of the measurement chamber 40 using a glass coupling element 46. The glass coupling element 46 is fused to the optical window 44 and to the wall of the recess 48, hermetically sealing the measurement chamber 40.

[0094] FIG. 2b shows the flow cell 1 of the second embodiment from another perspective. In this view, the holding means 12, formed as a threaded bore, can be seen. For reproducible connection with the spectrometer or sensor head 200, the holding means here can be connected to the threaded bore via a corresponding screw. By providing multiple threaded bores, the position and orientation can also be reproducibly set. Furthermore, in the second embodiment, an optical diaphragm 16 is provided. The optical diaphragm 16 can cooperate with a corresponding tubular element of the spectrometer or sensor head 200 (see FIG. 2c) to shield the light path between the spectrometer or sensor head 200 and the measurement chamber 40 of the flow cell 1 from the incidence of external light. Furthermore, the diaphragm 16 can also form a form-fit with a corresponding element of the spectrometer or sensor head 200 and, like the holding means 12, provide support during precise alignment of the flow cell 1 relative to the spectrometer or sensor head 200.

[0095] 2c shows a top view of the connection between the flow cell 1 and the sensor head 200. Only a small part of the sensor head 200 is shown here. It can be seen in FIG. 2c that the diaphragm 16 engages with a corresponding opening in the sensor head 200, blocking the light path between the sensor head 200 and the flow cell 1 from the incidence of extraneous light from the surroundings. Furthermore, the diaphragm 16 has a dual function here as an alignment means and is used to accurately align the sensor head 200 with respect to the flow cell 1. The fixing means used here is a screw, which cooperates with a corresponding threaded hole in the casing 10 of the flow cell 1 as the holding means 12.

[0096] 3a to 3c show a third embodiment of the flow cell 1. The third embodiment corresponds substantially to the second embodiment described with reference to FIG. 2a, except that the holding means 12 is configured as a flange and no additional throttle 16 is provided, since the flange 12 here assumes the function of the throttle 16. In this case, FIG. 3a shows the flow cell 1 of the third embodiment in a perspective cross-sectional view.

[0097] 3b shows the flow cell 1 in a side view. In this view, it can be clearly seen that in the third embodiment, the inlet channel 20 and the outlet channel 30 or the two connecting nipples 23, 33 are arranged on different axes, with the axes extending parallel to each other. However, the axes may alternatively be arranged at an angle to each other.

[0098] FIG. 3c shows a flow cell 1 according to a third embodiment, with an adapter 100 attached, for example, by welding, to a holding means 12 configured as a flange. The adapter 100 has another holding means 12', which, similarly to the first embodiment of FIGS. 1a-1c, is configured as an external thread and is arranged at the end of a tubing section 102. Via the external thread, for example, a sensor head 200 (see FIG. 2c) can be connected to the adapter 100 and thus to the flow cell 1, so that a set distance and a set orientation of the flow cell 1 relative to the sensor head are defined and reproducibly maintained. This distance can be adjusted by selecting the length of the tubing section 102. In FIG. 3c, the tubing section 102 is shown in an interrupted state.

[0099] FIG. 4 shows a perspective view of a fourth embodiment of the flow cell 1. Here, the structure of the flow cell 1 corresponds substantially to the first embodiment described with reference to FIG. 1a. Unlike the first embodiment, no flange is provided as the holding means 12. Instead, four holes, for example, are arranged as the holding means 12. These holding means 12 can be formed as threaded holes, which allows for easy attachment of the sensor head 200 or a spectrometer to the flow cell 1. Of course, if a different holding means 12 is required, for example, to attach a specific spectrometer, an adapter 100 can also be provided and attached to the casing 10 of the flow cell 1 via the threaded holes. In this case, the adapter 100 can be configured to have another holding means 12' configured to be connected to a spectrometer.

[0100] 5 shows an embodiment of a flow cell 1 with a peripheral wall 150 made of polymer material that partially surrounds the casing 10. The figure is shown in cross section from the side.

[0101] The casing 10 is constructed in the same manner as described for the embodiment of Fig. 1a and is manufactured, for example, from a ceramic material. The interior of the casing 10 accommodates a measuring chamber 40, with the casing 10 forming a wall 42 of the measuring chamber 40. The opening of the casing 10 is closed by an optical window 44, which is coupled to the casing 10 via a glass coupling element 46. The measuring chamber 40 can be connected to a fluid flow via an inlet channel 20 and an outlet channel 30, and connections 22, 32 are provided for this connection.

[0102] 5 has a peripheral wall 150, which is preferably made of a polymer material and can be manufactured by injection molding, for example, in comparison with the flow cell 1 shown in FIG. 1a. Here, the casing 10 of the flow cell 1 can be fitted into an injection mold and can be insert-molded with the polymer material.

[0103] Here, the peripheral wall 150 surrounds the portion of the casing 10 that includes the optical window 44, but leaves the areas that contact the connecting portions 22, 32 exposed.

[0104] The peripheral wall 150 has a connecting tube 152 on the side of the casing 10 where the optical window 44 is inserted, and the connecting tube 152 has a thread 154 formed on its outer surface. The thread 154 is connected to the connecting tube 152 as a holding and connecting means for receiving and fixing the sensor head 200 (see FIG. 2c). A plurality of webs 156 are arranged on the inward-facing wall of the connecting tube 152. These webs 156 are used as a means for accurately positioning and orienting the sensor head 200. Since the peripheral wall 150 with the connecting tube 152 is made of a polymer, the material is flexible and compliant. Therefore, the webs can be shaped in such a way that they form a frictional connection with the sensor head 200, thereby ensuring accurate and reproducible alignment of the sensor head 200.

[0105] Although the present invention has been described based on preferred embodiments, it is not limited thereto and can be modified in various ways. [Explanation of symbols]

[0106] 1 flow cell 10 Casing 12 Retention means 12' Alternative Retention Means 16 Optical Aperture 20 inlet channels 22 First connection 23 First connecting nipple 30 outlet channels 32 Second connection 33 Second connecting nipple 40 Measurement chamber 42 Measurement chamber wall 43 Aperture 44 Optical Window 45 Placement surface 46 Glass bonding element (glass solder) 48 recess 49 channels 100 adapter 102 Pipe section 150 Peripheral wall 152 Connecting pipe 154 threads 156 Web 200 sensor head

Claims

1. A flow cell (1) for optical spectroscopy, It includes a casing (10) having a hollow chamber forming a measuring chamber (40), an inlet channel (20), an outlet channel (30), and an optical window (44) that closes the opening (43) of the measuring chamber (40). The optical window (44) is bonded to the casing (10) by melting the glass bonding element (46). In flow cell (1), A recess (48) is formed around the opening (43), and a mounting surface (45) for the optical window (44) is formed around the opening (43), and the optical window (44) is in contact with the casing (10) on the mounting surface (45). A flow cell (1) characterized by the following features.

2. The flow cell (1) according to claim 1, wherein the width of the mounting 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 cell (1) according to claim 1 or 2, wherein the glass bonding 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 bonding element (46).

4. The glass bonding element (46) has a glass transition temperature T greater than 470°C. ｇ A flow cell (1) according to claim 1 or 2, comprising or consisting of a glass material having said glass material.

5. The flow cell (1) according to claim 1 or 2, wherein the optical window (44) is bonded to the wall of the casing (10), particularly the wall of a recess (48) in the casing (10) that is in contact with the opening (43), via a glass bonding element (42) made of glass solder or formed as a glass molded body.

6. The flow cell (1) according to claim 5, wherein the glass solder or glass material of the glass molded body is selected from borosilicate glass.

7. The flow cell (1) according to claim 1 or 2, wherein at least one component of the casing (10) that forms a hollow chamber having the measuring chamber (40) is integrally formed.

8. The flow cell (1) according to claim 1 or 2, wherein the average surface roughness value Ra of the inner wall of the measurement chamber (40) is less than 0.8 μm, preferably less than 0.5 μm.

9. The material of the casing (10) is selected from metal or metal alloy, and the material of the casing (10) is preferably selected from steel, especially 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 casing (10) is selected from ceramics, and the material of the casing (10) is preferably a pottery material, yttrium oxide (Y ２ O ３ ), zirconium oxide (ZrO ２ ), magnesium aluminate (MgAl ２ O ４ ), aluminum oxide (Al ２ O ３ ), SiAlON - Al ２ O ３ and silicon carbide (SiC). A flow cell (1) according to claim 1 or 2.

10. The material of the optical window (44) is selected from glass, in particular quartz glass, crystal, in particular sapphire, ceramic, in particular yttrium-doped zirconia or glass ceramic, according to claim 1 or 2.

11. The flow cell (1) according to claim 1 or 2, wherein the first thermal expansion coefficient of the casing (10) is greater than the second thermal expansion coefficient of the glass bonding element (46), and the first thermal expansion coefficient is preferably greater than the third thermal expansion coefficient of the optical window (44).

12. The casing (10) has an anisotropic degree of thermal expansion, The first coefficient of thermal expansion is located in a direction perpendicular to the longitudinal axis of the opening (43), Another coefficient of thermal expansion of the casing (10) is 1.10 along the direction parallel to the longitudinal axis of the opening (43). －６ K －１ A value less than 0.1 or 10 is preferred. －６ K －１ A value less than 0.01.10, particularly preferably 0.01.10 －６ K －１ A value less than 0.001.10, more preferably 0.001.10 －６ K －１ Having a value less than, The flow cell (1) according to claim 11.

13. The flow cell (1) according to claim 1 or 2, wherein 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 planoconvex surface, a convex-concave surface, a planoconcave surface, and a biconcave surface.

14. The flow cell (1) according to claim 1 or 2, wherein the flow cell (1) has a peripheral wall (150) that at least partially surrounds the casing (10), and the peripheral wall (150) is preferably made of a polymer material.

15. The flow cell (1) according to claim 1 or 2, further comprising a holding means (12, 12') for holding a spectrometer or a sensor head (200) of a spectrometer and / or an alignment means for aligning the spectrometer or sensor head (200).

16. The flow cell (1) according to claim 15, wherein the flow cell (1) and the holding means (12, 12') and / or the alignment means are configured such that the spectrometer or the sensor head (200) can be attached to the flow cell (1) without any components being placed 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, wherein the retaining means (12, 12') and / or the alignment means are configured to cooperate with a corresponding member of the spectrometer or sensor head (200) for a removable locking connection.

18. The flow cell (1) according to claim 15, wherein the retaining means (12, 12') and / or the alignment means are configured as a flange, a recess, a protrusion, a threaded hole, a groove, or a combination thereof.

19. The inlet channel (20) and the outlet channel (30) are arranged facing each other on a single common axis, thereby forming a laminar flow within the measurement chamber (40) when a liquid medium flows through it, or The inlet channel (20) and the outlet channel (30) are arranged on different axes from each other, thereby creating turbulence within the measurement chamber (40) when a liquid medium flows through it. A flow cell (1) according to claim 1 or 2.

20. Use of the flow cell (1) according to claim 1 or 2 for monitoring a bioengineering process.

21. In a method for monitoring a bioengineering process in which a medium for cell culture circulates and flows through containers containing cell cultures, The flowing medium is divided into a main flow and a side flow, the side flow is guided through a flow cell (1) according to claim 1 or 2, inspected by spectroscopy within the flow cell (1), and then the side flow is supplied back to the main flow. A method for monitoring a biotechnology process, characterized by the following features.

22. A method for monitoring a bioengineering process according to claim 21, wherein, during monitoring, a plurality of measuring devices are used to detect parameters of a medium in the measurement chamber of the flow cell (1) without impairing the sterile integrity of the medium, and these devices are connected to the holding means of the flow cell (1).

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