Flow cell for optical spectroscopy, and method for monitoring biotechnological processes

Abstract

The invention relates to a flow cell (1) for optical spectroscopy, which flow cell comprises: a housing (10) having a cavity which forms a measuring chamber (40); an inlet channel (20); an outlet channel (30); and an optical window (44) which seals an opening (43) of the measuring chamber (40). According to the invention, the optical window (44) is connected to the housing (10) by melting a glass connecting element (46), wherein a recess (48) is formed around the opening (43) and a supporting surface (45) for the optical window (44) is formed around the opening (43), at which supporting surface the optical window (44) contacts the housing (10). The invention also relates to the use of such a flow cell (1) in the process monitoring of a biotechnological process and in a biotechnological method which is monitored using such a flow cell (1).

Description

[0001] Flow cell for optical spectroscopy and methods for monitoring biotechnological processes

[0002] The invention relates to a flow cell for optical spectroscopy, comprising a measuring chamber with an optical window, an inlet channel, and an outlet channel. Further aspects of the invention relate to the use of such a flow cell for monitoring a biotechnological process and a method for monitoring a biotechnological process.

[0003] State of the art

[0004] Optical spectroscopy is used in many areas of technology and can be used, for example, to examine samples or monitor manufacturing processes. Light is introduced into a sample and the light transmitted or reflected by the sample is examined.

[0005] One application area for optical spectroscopy is the monitoring of biotechnological processes. These can be roughly divided into so-called upstream and downstream processes. Upstream processes include, in particular, the provision of starting materials, the cultivation of cells, and the conduct of fermentation processes. Downstream processes include, in particular, the separation and purification of the resulting products and quality control. Raman spectroscopy is particularly suitable for monitoring such biotechnological processes.

[0006] In the case of liquid samples or in the case of samples dissolved or suspended in a liquid, a flow cell can be used to perform spectroscopy. The flow cell comprises a measuring chamber with an inlet channel and an outlet channel and an optical window. WO2021 / 198427 describes a flow cell arrangement for use in the process control of a biological process. The flow cell arrangement comprises a monolithic cast glass body surrounding a measuring channel and fastening means with an alignment aid for aligning a sensor head. The glass body is made of a material transparent to UV light, for example quartz glass, and the measuring channel surrounded by it has at least one straight section with a constant cross-section.

[0007] A disadvantage of this flow cell arrangement is that the commonly used quartz glass generates unwanted signals in various measurements, especially in Raman spectroscopy, which interfere with the measurement.

[0008] WQ2021 / 198427 also lists other materials such as sapphire as possible alternatives to quartz glass. However, sapphire, in particular, is unsuitable for casting a glass body, so a monolithic body that hermetically seals the measuring channel cannot be manufactured from this material.

[0009] EP3610244B1 discloses a liquid cell with a measuring chamber and a measuring window, in which a pressure element presses the measuring window against a seal, thus sealing the measuring chamber. The seal can be in the form of an O-ring or a film, for example, made of PTFE. One disadvantage of this is that small dead volumes can form in the area of ​​the seal, where deposits can accumulate. Furthermore, the exact position of the measuring window is difficult to define, especially with thick seals such as an O-ring. However, a precisely defined distance between the focus in optical spectroscopy and the measuring window is desirable for good signal quality.

[0010] In view of the prior art, one object of the invention can be seen in providing a flow cell for optical spectroscopy applications, particularly in the biotechnology sector, which has a measuring chamber whose material does not generate its own measurement signal in the spectral range under investigation during a spectroscopic investigation. In particular, in the range between 50 cm -1 and 3800 cm -1 no interfering measurement signal is generated. Furthermore, the material should be compatible with the biological processes being studied or monitored. The measurement chamber should provide a good signal-to-noise ratio, particularly for Raman spectroscopy.

[0011] Disclosure of the invention

[0012] A flow cell for optical spectroscopy is proposed. The flow cell comprises a housing with a cavity forming a measuring chamber, an inlet channel, an outlet channel, and an optical window closing an opening of the measuring chamber. Furthermore, the optical window is connected to the housing by melting a glass connecting element. Preferably, a recess is formed around the opening, and a support surface for the optical window is formed around the opening, where the optical window contacts the housing.

[0013] The proposed connection of the optical window to the housing by melting a glass connecting element achieves, in particular, a hermetically sealed connection. Hermetically sealed is understood to mean that the connection between the optical window and the measuring chamber has a helium leak rate of less than 1-10' 5mbar l / sec and preferably in the range 1 ■ 10 -10 mbar l / sec to T10 -6 mbar l / sec. The helium leak rate is preferably measured according to DIN EN60068-2-17: 1995-05, ASTM F2391-05 (Reapproved 2016), or MIL-STD-883 rev.K -method 1014.15. The specified leak rates are also advantageously achieved in a test lasting at least 4 minutes. The optical window connection is thus also sterile-tight, preventing germs from penetrating the interior during biotechnological processes.

[0014] The proposed connection between the optical window and the measuring chamber or the flow cell housing requires no additional components, in particular no flexible elements such as elastomer seals. Such elastomer seals, for example in the form of O-rings, do not allow precise positioning of the optical window in relation to the measuring chamber or a flow cell housing, particularly since their instantaneous thickness depends on the contact pressure, and lead to dead volumes through which no flow occurs. The proposed connection, in contrast, is rigid and defines a fixed positional relationship between a surface of the optical window and the measuring chamber. This is particularly advantageous when optical examinations are carried out and a focus of an optic is to be located at a defined distance from a surface of the optical window facing the interior of the measuring chamber.

[0015] Preferably, a support surface for the optical window is formed around the opening of the measuring chamber, at which the optical window contacts the housing, wherein a width of the support surface of the optical window is narrower than 0.3 mm, preferably narrower than 0.2 mm and particularly preferably narrower than 0.1 mm. When melted onto the housing, an intimate, gap-free connection is produced between the glass connecting element and the housing and between the glass connecting element and the optical window. However, a small gap could possibly remain in the region of the support surface at which the optical window contacts the housing, wherein the volume within this possible gap is made as small as possible by minimizing the support surface.However, a certain width of the support surface is desirable, on the one hand, to simplify the assembly of the optical window, since the support surface provides a mechanical stop for the exact positioning of the optical window. On the other hand, the material of the glass connecting element can flow when the glass connecting element is melted, and flow of the material of the glass connecting element into the interior of the measuring chamber is undesirable. In the optimal case, the material of the glass connecting element flows into any gap that may be present between the optical window and the housing in such a way that the volume of the gap is exactly filled, but no material of the glass connecting element flows beyond the gap into the interior of the measuring chamber. For this purpose, it is preferred if the width of the support surface is at least 0.02 mm, more preferably at least 0.05 mm, and most preferably at least 0.1 mm.For example, a width of 0.1 mm is chosen for the support surface.

[0016] Preferably, a recess is formed in the housing around the opening, wherein the glass connecting element fills a space between the optical window and a wall of the recess, so that no gap remains between the wall of the recess and the glass connecting element.

[0017] The diameter of the recess is preferably selected to be between 20% and 35% larger than the diameter of the optical window. Preferred widths of the gap in which the glass connecting element is accommodated are therefore in the range of 0.6 mm and 1.0 mm. A gap that is as narrow as possible is advantageous for transferring compressive forces from the wall of the opening to the optical window. However, at very narrow widths, it becomes increasingly difficult to reliably manufacture the glass connecting element.

[0018] Preferably, the glass connecting element is flush with the recess. Furthermore, it is preferred that the optical window is flush with the glass connecting element, so that both are arranged flush with the recess. Alternatively, however, it can also be provided that the window and / or the glass connecting material are not flush with the recess. In particular, it can be provided that the glass connecting material is recessed and thus protected from mechanical influences by the protruding housing.

[0019] The optical window is preferably connected to the housing, in particular to a wall of a recess in the housing adjacent to the opening, via a glass connecting element consisting of a glass solder or designed as a shaped glass body. In the case of a metallic material for the housing, a hermetically sealed connection in the form of a glass-to-metal seal, glass-to-metal seal (GTMS), can then be formed by melting the glass material of the glass connecting element. In this case, the glass material of the glass connecting material also forms a chemical bond with the material of the housing, in particular with metal oxides on the surface of the metallic 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 too, a chemical bond is created between the glass connecting element and the housing during glazing.

[0020] The glass molded body can, for example, initially be provided in the form of a compact or sintered body obtained from glass powder and then fused to the housing and the optical window using a temperature treatment to form the glass connecting element. For stabilization, the compact can contain a binder in addition to the glass powder, which is later removed again during the temperature treatment. The temperature treatment can, for example, be carried out by heating the arrangement formed from the housing, glass molded body and optical window in an oven. Alternatively, the glass molded body can be specifically heated, for example using a laser, so that areas of the housing or the optical window that are not directly adjacent to the glass molded body are not heated or are only heated slightly. This can prevent changes to the respective materials due to the effect of temperature.

[0021] The glass connecting element preferably consists of or comprises a glass material selected for use in the flow cell so that it is resistant to the media introduced into the measuring chamber and, if possible, also releases no substances into these media. Accordingly, the glass material is preferably resistant to water, acids, and alkalis.

[0022] Glass materials with high chemical resistance are usually high-melting glasses and have a higher melting temperature and a higher glass transition temperature T g than low-melting glasses with low chemical resistance. Conventional low-melting glasses also often contain heavy metals, which are particularly undesirable in biotechnological applications.

[0023] Accordingly, it is preferred to select the glass bonding material so that it contains or comprises high-melting glass material. High-melting glass materials are considered here to be those which have a glass transition temperature T g of more than 470°C, preferably more than 500°C, more preferably more than 600°C, particularly preferably more than 750°C.

[0024] Combined with the high glass transition temperature T gThese high-melting glass materials also exhibit low dynamic viscosity when heated, so that during initial glazing, the glass material exhibits only low flowability compared to low-melting glasses. This flowability can be improved by further heating, but strong heat exposure places stress on the other materials added to the flow cell, particularly affecting their surface quality. Therefore, it is preferable to select glass materials with a glass transition temperature T g below 900°C, particularly preferably below 800°C. In order to avoid a deterioration of the surface quality, in particular of the inner walls of the measuring chamber, the glass material of the glass connecting element is preferably selected such that at a temperature of 1300°C it has at least a dynamic viscosity q of 1 ■ 10 5dPa s. This value is particularly preferably achieved at 1200°C, and most preferably at 1100°C. Accordingly, the initial glazing is preferably carried out at a temperature of less than 1300°C, particularly preferably less than 1200°C, and most preferably less than 1100°C. The dynamic viscosity of the glass, or the temperature at which the required viscosity is achieved, can be determined, for example, according to DIN ISO 7884-1:1998-02.

[0025] A dynamic viscosity of q of 1 ■ 10 5 dPa s is generally too viscous to achieve reliable glazing by the free flow of the glass material alone. Therefore, it is preferable to assist the flow of the glass material by applying force, for example, by applying a weight or a plunger. In conjunction with such an applied force, the glass material is also viscous at a dynamic viscosity of 1 ■ 10 5dPa s is able to conform to the optical window and the wall of the opening and establish a good connection.

[0026] If the glass connecting element is provided in the form of a compact for the glazing process, the provision of a mechanical stop by the support surface is particularly advantageous, since the optical window is then supported by the inside of the flow cell during the glazing process and only then can pressure be exerted on the compact.

[0027] The glass solder or the glass material of the shaped glass body is preferably selected from a borosilicate glass. For example, the chemically resistant glasses 8326 and 8800 from SCHOTT AG are suitable. The material of the housing is preferably selected from a metal or a metal alloy. Alternatively, the material of the housing is preferably selected from a ceramic. The material of the housing is particularly preferably selected from a steel, in particular a stainless steel, an austenitic or a femtic steel, an austenitic-femtic duplex steel, a nickel-copper alloy, a nickel-chromium-iron-niobium-molybdenum alloy, a nickel-chromium-molybdenum-tungsten alloy, a zirconium-niobium alloy, or a titanium-niobium alloy.

[0028] A suitable stainless steel is or includes, for example, AISI 316L pharmaceutical steel (material number 1.4404). This pharmaceutical steel is an austenitic stainless steel.

[0029] AISI 329A is a suitable austenitic-ferritic duplex steel (material number 1.4462).

[0030] Preferred ceramic materials for the housing include, in particular, porcelain, yttrium oxide (Y2O3), zirconium oxide (ZrC) (optionally stabilized with CaO, MgO, CeO2, TiO2, or Y2O3), magnesium aluminate (MgAl2O4), aluminum oxide (Al2O3), SiAlO-Al2O3, and silicon carbide (SiC). The ceramic materials are preferably polycrystalline, so they are preferably opaque.

[0031] If stainless steel is selected, its surface is preferably passivated. For example, a passivation layer can be formed using a chemical or electrochemical surface treatment.

[0032] The inner walls of the measuring chamber are preferably designed to have only a low level of roughness. The mean roughness Ra is preferably less than 0.8 pm, particularly preferably less than 0.5 pm. In combination with the proposed glazing at a temperature that is relatively low for high-melting glass materials, the material of the measuring chamber is protected, so that the high quality of the surface is maintained. If, for example, stainless steel is selected as the material for the inner walls of the measuring chamber, surface damage can occur due to abrasion of brittle metal oxide layers at excessively high processing temperatures. For example, martensitic Fe-Cr alloys form a brittle FeOx upper layer on a (Fe, Cr)Ox lower layer, so that surface changes occur 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 component of the housing that forms the inner walls of the measuring chamber is preferably formed in one piece and accordingly has no gaps, connecting materials, or surface changes caused by welding. Preferably, the entire housing is formed in one piece.

[0034] In order to meet the strict requirements for the production of biopharmaceuticals, the material is preferably selected so that it complies with the following standards: i) FDA approved materials e.g. ICH Q7, CFR 211 .65(a) - Code of Federal Regulations, USP <88> Class VI, animal derivative free, bisphenol A free ii) Sectoral chemical resistance - ASTM D 543-21 iii) Biocompatibility eg referred to US Pharmacopeia or tests referred to ISO 10993-1 (2018-08).

[0035] The material of the optical window is preferably selected from a glass, in particular a quartz glass or a borosilicate glass, a particularly monocrystalline crystal, in particular sapphire, a ceramic, in particular yttrium-doped zirconium dioxide (yttria-stabilized zirconia, YSZ), or a 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 are each metal oxides.

[0036] The optical window can additionally have one or more coatings or claddings in order to modify the mechanical properties, such as surface hardness and / or optical properties, such as reflection properties. In particular, an anti-reflection coating can be provided. The anti-reflection coating is preferably optimized for the wavelength of the excitation light and / or the signal (in particular the fluorescent light in fluorescence spectroscopy). The coating(s) can be arranged on both sides, i.e. on a side facing the interior of the measuring chamber and on a side of the optical window facing outwards. Alternatively, the coating(s) can be arranged on only one side or different coatings can be arranged on the two sides.For example, the side facing the interior of the measuring chamber can be free of coatings, while only the exterior side can be coated. This prevents the coating material from coming into contact with the media being analyzed. If only the exterior is coated, it does not need to be chemically resistant to the media being analyzed. Furthermore, anti-reflection coatings can generally be omitted on the interior, as reflection losses typically only occur at the transition between the optical window and the liquid medium in the measuring chamber.

[0037] In one embodiment of the flow cell, a first thermal expansion coefficient of the housing is matched to a second thermal expansion coefficient of the glass connecting element and to a third thermal expansion coefficient of the optical window. "Matched" here means that the thermal expansion coefficients differ by less than 3 ■ 10' 6 K' 1 , preferably by less than 2 ■ 10' 6 K' 1 , more preferably by less than 1 ■ 10' 6 K 1 differentiate.

[0038] Alternatively, a pressure glazing can be provided in which a first thermal expansion coefficient of the housing is greater than a second thermal expansion coefficient of the glass connecting element, and the first thermal expansion coefficient is preferably greater than a third thermal expansion coefficient of the optical window. It is preferred that the first thermal expansion coefficient is 3 ■ 10' 6 K -1or more, particularly preferably around 6 ■ 10' 6 K' 1 or more from the second and, if applicable, the third thermal expansion coefficient.

[0039] For an optical window made of sapphire, such a pressure glazing can be achieved, for example, with a stainless steel housing and a borosilicate glass connecting element. The first coefficient of thermal expansion of the housing is, for example, 16 ■ 10' when choosing an austenitic stainless steel. 6 K' 1 , the second thermal expansion coefficient is, for example, in the case of borosilicate glasses in the range of approximately 3 ■ 10' 6 K -1 up to approx. 7 ■ 10' 6 K -1 and the third thermal expansion coefficient for sapphire is approximately 5 ■ 10' 6 K' 1 In this example, the second and third thermal expansion coefficients are less than 3-10' 6 K -1different and thus adapted to each other. The first thermal expansion coefficient differs from both by more than 6 ■ 10' 6 K -1 and thus leads to a compressive force exerted by the housing, which is transferred from the glass connecting element to the optical element.

[0040] With such pressure glazing, compressive forces act on the glass connecting element and the optical window with reference to a longitudinal axis of the opening due to shrinkage of the housing after glazing, which counteracts the formation of gaps between the respective elements and thus promotes a hermetic seal. With isotropic thermal expansion, however, compressive forces also act in a direction parallel to the longitudinal direction of the opening, which are not necessary for this beneficial effect. These forces acting in the axial direction can have a negative impact on the optical element, particularly if it is composed of several components or layers. One example of this is an optical element made of yttrium-doped zirconium dioxide, which is coated with a layer consisting of yttrium oxide. The compressive forces acting in the axial direction could cause the coating to become detached.

[0041] In particular in such cases, it is preferred if the housing is designed in such a way that it has an anisotropic thermal expansion, wherein the first thermal expansion coefficient is present in a direction perpendicular to a longitudinal axis of the opening and a further thermal expansion coefficient of the housing along a direction parallel to the longitudinal axis of the opening has an amount 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 even more preferably less than 0.001 ■ 10 -6 K' 1 has.

[0042] Such a housing with anisotropic thermal expansion can, for example, be designed as a component made of a titanium-niobium alloy that has been modified using a thermomechanical process. In this thermomechanical process, the alloy components are first homogenized, for example, by a heat treatment at a temperature between 900°C and 1100°C for a period of 1 to 3 hours in an N2 or Ar atmosphere. Subsequently, the material structure and, in particular, the phase transitions in the material of the component can be determined using a cold rolling step. The cold rolling step can be followed by annealing at 700°C to 950°C for a period of 0.25 to 1 hour. Furthermore, a water quenching step can be provided.By means of an adjustment step, the thermal expansion, in particular the first thermal expansion coefficient and the further thermal expansion coefficient, can be adjusted or specifically changed over one or more thermal cycles.

[0043] Alternatively, the component can be obtained using an additive manufacturing process (3D printing), where the component is produced, for example, layer by layer by applying metal powder followed by sintering. In this case, a gradient in the composition of the resulting titanium-niobium alloy can be influenced, for example, by using varying amounts of titanium and niobium powder. Furthermore, by controlling the heat input during sintering, particularly the temperature and rate of heating and cooling, the formation of the various phases in the material can be influenced in order to specifically adjust the thermal expansion of the component.

[0044] An example of a composite element comprising such an outer component made of a titanium-niobium alloy and an inner component made of yttrium oxide-coated yttrium-doped zirconium dioxide is known from DE 10 2019 115 204 A1.

[0045] The materials for the measuring chamber, the wall of which is preferably formed by the housing of the flow cell itself, the optical window as well as the materials used to connect the optical window to the measuring chamber are thus preferably selected so that they are compatible with biotechnological processes.

[0046] With such a material selection, the measuring chamber is free of materials that hinder the growth of cell cultures, generate their own spectroscopic signals in the relevant spectral range, or are undesirable for other reasons in the processes being performed. For example, gold alloys, which are used in the prior art to produce press-in seals for windows or are contained in gold solders, are undesirable in many biotechnological processes. Accordingly, gold alloys are undesirable materials in the measuring chamber area. Thus, the flow cell is preferably free of gold alloys, in particular gold solders containing gallium, tin, and / or germanium, and / or free of materials that generate their own spectroscopic signals when excited by a spectroscopic light source, in particular a light source such as an LED or a laser with a wavelength of 532 nm, 633 nm, 775 nm, 785 nm, 830 nm, or 1064 nm.Particularly preferably, no spectroscopic signals should occur upon excitation with light having a wavelength of 532 nm, 785 nm or 1064 nm, and it is most preferred if the materials do not produce a spectroscopic signal upon excitation with light having a wavelength of 532 nm or 785 nm.

[0047] Providing a spectroscopic signal is considered to be the emission or scattering of light at a wavelength different from the excitation light or light source, for example, through inelastic scattering of light (as in Raman spectroscopy) or through absorption and re-emission of light (as in fluorescence spectroscopy). Hydrogen-containing compounds, such as plastics, in particular, can generate their own spectroscopic signals when excited at wavelengths relevant for spectroscopy.

[0048] Accordingly, it is particularly preferred if the flow cell, particularly in the region of the measuring chamber, is free of hydrogen-containing compounds such as plastics. This is advantageously achieved with the proposed flow cell in particular if the housing material is a metal, a metal alloy, or a ceramic, the optical element is made of glass, glass ceramic, ceramic, or a crystal, and a glass connecting element is used to connect the optical window to the housing. With the preferred material selection for the flow cell and in particular for the measuring chamber of the flow cell, the area illuminated during optical spectroscopy is free of materials that emit spectroscopic signals when excited by light. The proposed flow cell is therefore suitable for spectroscopic investigations and in particular for performing fluorescence spectroscopy.The proposed flow cell is also particularly well suited for performing Raman spectroscopy, since none of these interfering fluorescence signals are generated by the materials used in the measuring chamber.

[0049] The proposed flow cell, with its preferred material selection, is free of materials that inhibit or disrupt biotechnological processes. This allows the flow cell to be used for continuous monitoring of such processes, either temporarily or permanently connected to the system.

[0050] Particularly when using equipment for biotechnological applications, a distinction is usually made between multi-use and single-use designs. Multi-use designs are designed to be permanently resistant to the conditions used in sterilization processes. For example, in designs designed for steam sterilization, the selected materials must be resistant to the temperatures and reagents used, such as steam, sodium hydroxide, or ethylene oxide.

[0051] In single-use designs, however, it is only necessary that the materials selected for this design allow for single-use sterilization. For example, common plastics can be sterilized once using radiation such as gamma radiation, beta radiation, or X-rays. The proposed flow cell can have a housing made of metal or ceramic, allowing the flow cell to be easily sterilized multiple times and thus being particularly suitable for multiple uses (multi-use). Of course, it is also possible to use the proposed flow cell only once (single-use).

[0052] The proposed flow cells with a metal housing are particularly suitable for autoclaving. The flow cell is preferably designed to be autoclavable 10,000 times with a steam treatment at 141 °C. For the purposes of this disclosure, "autoclavable" also refers to autoclavable in the sense of DIN EN ISO 14937 and EN ISO 17665, which are applicable to medical devices.

[0053] The proposed flow cell is also particularly well suited for sterilization using radiation and is preferably suitable for sterilization with a dose of 100 kGy.

[0054] Flow cells with a metal housing, in combination with the hermetically sealed glazing of the optical window according to the invention, are also particularly pressure-resistant. The thickness of the housing material and the thickness of the window are preferably selected so that the flow cell can withstand an internal pressure in the measuring chamber of at least 10 MPa (100 bar).

[0055] The housing which forms the measuring chamber of the flow cell can additionally be overmolded with a polymer or plastic to form a jacket. The jacket can enclose the housing completely or at least partially, whereby even with a complete jacket the connections for access to the measuring chamber remain free. The jacket can be designed such that functional elements such as holders, alignment means or connectors are formed on it. For example, a nozzle with an external thread can be provided as a combined holding and alignment means, wherein the nozzle is provided with webs on an inward-facing wall for the alignment and precise positioning of a sensor head of a spectrometer. Suitable polymers for the jacket include in particular polyolefins such as polyethylene.

[0056] The optical window of the flow cell can be designed with flat surfaces or, for example, can be configured to act like a lens. Accordingly, it is preferable to select the shapes of the surfaces of the optical window from a flat surface, a convex surface, a concave surface, or combinations thereof, such as biconvex, plano-convex, convex-concave, plano-concave, and biconcave.

[0057] To simplify a mechanical connection to a spectrometer or a sensor head of a spectrometer, the proposed flow cell can comprise corresponding means. Such means can be used to establish a detachable mechanical connection, in particular for holding a spectrometer or a sensor head and / or for precise and reproducible alignment with respect to the position of the optical window of the flow cell. The holding means are preferably configured to establish a detachable connection.

[0058] Preferably, the flow cell comprises as an aid at least one holding means for holding a spectrometer or a sensor head of a spectrometer and / or at least one alignment means for aligning a spectrometer or a sensor head.

[0059] It is preferred that the flow cell and the holding means and / or the alignment means are designed such that the spectrometer or the sensor head can be attached to the flow cell such that no components are arranged between the optical window and the first optical element of the spectrometer or the sensor head. In particular, it is preferred if no optical fibers such as glass fibers are 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 in particular be an entrance opening or entrance aperture or a first lens. This enables the use of free-beam optics to connect a spectrometer to the proposed flow cell.

[0060] Alternatively, the flow cell may be provided with holding and / or alignment means for holding or aligning a light guide such as a glass fiber. This glass fiber can, in turn, be used to establish an optical connection to a spectrometer.

[0061] Preferably, the at least one holding means and / or the at least one alignment means are configured to interact with a counterpart on the spectrometer or the sensor head for a releasable locking connection. Such a locking connection can be achieved, for example, by a locking element that releasably engages a recess on the respective other component.

[0062] Furthermore, the holding means and / or the means for alignment can be designed, for example, as a flange, as depressions such as bores, as elevations such as pins, as threaded bores, as a groove, and combinations of these means. Corresponding counterparts are preferably provided on the sensor head or the spectrometer in order to interact with these holding means and / or alignment means. The holding means can also be designed to cooperate with an additional fixing means, such as screws or clamps. Furthermore, the holding means can be designed, in particular, as a bayonet lock in order to establish a detachable connection between the flow cell and a spectrometer or sensor head via a plug-and-twist movement.

[0063] The holding means can, in particular, also be designed and arranged to set a defined distance between an entrance aperture of the spectrometer or the sensor head and the flow cell, in particular the optical window of the flow cell. This distance can advantageously be standardized between different measuring devices such as flow cells, ports, or other sensor receptacles, so that a spectrometer or sensor head can be connected to the flow cell via the holding means without further adjustments. In this way, for example, a single spectrometer can be used for a variety of measuring devices and can be quickly reconnected.

[0064] The holding means(s) and / or the alignment means(s) can be formed integrally with the flow cell housing or as part of the flow cell housing. Alternatively, the flow cell can comprise an adapter that is removably or permanently mounted to the flow cell. A removably connected to a spectrometer or a sensor head can then be established via additional holding means and / or additional alignment means that are part of the adapter. If the flow cell comprises a polymer jacket, the holding means and / or alignment means can also be formed as part of this polymer jacket.

[0065] Due to the mechanically robust and hermetically sealed glazing of the optical window, the flow cell is advantageously designed so that a spectrometer or a sensor head, which is held on the flow cell or accommodated in an adapter or a holding means of the flow cell, can be removed and replaced while maintaining the tightness of the window. This enables a wide variety of measurements without disturbing or even contaminating the medium in the measuring cell. For introducing or discharging a medium or fluid into the measuring chamber of the flow cell, the flow cell has an inlet channel and an outlet channel. The inlet channel and the outlet channel are preferably arranged opposite one another on a common axis so that a laminar flow develops within the measuring chamber when a medium flows through them.Alternatively, the inlet and outlet channels are arranged on different axes relative to each other, so that a turbulent flow develops within the measuring chamber when a medium flows through them. If turbulent flow is desired, it is preferable to arrange the inlet and outlet channels tangential to the radius of a measuring chamber. The measuring chamber can be designed, for example, as a bore.

[0066] The inlet channel and / or the outlet channel preferably open into connectors for connecting hoses or pipes to enable integration of the flow cell into a fluid stream under investigation. For example, threaded connectors or hose nipples can be provided for this purpose.

[0067] The medium can, for example, be a liquid in which solids are possibly suspended. Laminar flow ensures a particularly smooth and even flow of the medium within the measuring chamber, whereby dead volumes through which no flow or a significantly lower flow is achieved can be largely avoided. Turbulent flow ensures good mixing of all components of the medium, whereby entrained or suspended solids in particular cannot settle. Accordingly, flow cell designs with an arrangement for turbulent flow are preferred for use with suspensions. Flow cell arrangements designed for turbulent flow also enable particularly representative measurements on the medium, since the occurrence of disruptive deposits is suppressed.A further aspect of the invention is the use of one of the flow cells proposed here for monitoring a biotechnological process.

[0068] The flow cell is particularly advantageous for monitoring perfusion cultures, in which a cell culture is continuously perfused by a medium flow. A partial or side stream of the flowing medium can be passed through the flow cell and continuously examined optically. This allows, for example, the concentration of nutrients, the presence of growth factors, or the concentration of metabolic products to be continuously monitored, and process control can be influenced based on these monitored parameters.

[0069] A further aspect of the invention is the provision of a method for monitoring a biotechnological process, wherein a medium for culturing cells circulates and flows through a vessel for receiving the cell culture. The method provides that the flowing medium is divided into a main stream and a side stream, the side stream is passed through one of the flow cells described herein, is spectroscopically analyzed within the flow cell, and the side stream is then preferably returned to the main stream.

[0070] Preferably, it is further provided that at least one parameter of the medium under investigation is determined via the spectroscopic analysis. This specific parameter is preferably used as a variable in an automated control process in order to control at least one parameter of the medium to a predetermined target value.

[0071] By using the proposed flow cell or carrying out the proposed method, in-situ or in-line process control can advantageously be carried out. Opening the apparatus to take samples is no longer necessary. This ensures that process control can be carried out continuously or at very short time intervals. This allows any changes in the monitored process to be quickly detected and, for example, intervened via automatic control systems. Due to the regular parameter monitoring and the resulting short delays, a control loop can be provided in particular to adjust the parameters required during the process to a predetermined target value. Thus, the proposed flow cell simplifies the automation of biotechnological processes or even enables it for the first time.

[0072] Secondly, the proposed flow cell can be firmly integrated into the apparatus thanks to the selection of process-compatible materials. Opening the system, with the associated risk of contamination, is advantageously avoided. The sterile integrity of the system is always maintained, even during ongoing optical examinations.

[0073] Advantageously, the proposed flow cell allows for the replacement of a measuring device used to measure the parameters of the medium without compromising the sterile integrity of the apparatus. Accordingly, the methods and processes may also include steps in which a measuring device, such as a spectrometer or a sensor head of a spectrometer, is replaced during the process. Accordingly, several different measuring devices can be used in the process to record one or more parameters of the medium flowing through the measuring chamber of the flow cell.

[0074] Using the proposed flow cell, the product flow can be optimized, particularly for continuous production. Continuous automated control enables optimized expansion at each process stage, ensuring that the output of an upstream process stage is balanced with the capacity of a downstream process stage. Reliable and reproducible process control at each process stage eliminates the need for buffers between individual process stages and increases the space-time yield, enabling process intensification.

[0075] It is understood that the features mentioned above and those to be explained below can be used not only in the combination specified in each case, but also in other combinations or on their own, without departing from the scope of the present invention.

[0076] Preferred embodiments and embodiments of the invention are illustrated 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.

[0077] In schematic form

[0078] Fig. 1a shows a first embodiment of a flow cell in a schematic sectional view from the side,

[0079] Fig. 1 b the flow cell of the first embodiment with a mounting adapter in a perspective sectional view,

[0080] Fig. 1c the flow cell of the first embodiment with the mounting adapter in a perspective view,

[0081] Fig. 2a shows a second embodiment of a flow cell in a perspective sectional view,

[0082] Fig. 2b the flow cell of the second embodiment in a further perspective view,

[0083] Fig. 2c the flow cell of the second embodiment with mounted sensor head in a view from above,

[0084] Fig. 3a shows a third embodiment of the flow cell in a perspective sectional view, Fig. 3b shows the flow cell of the third embodiment in a side view,

[0085] Fig. 3c the flow cell of the third embodiment with a mounted adapter in a perspective view,

[0086] Fig. 4 shows a fourth embodiment in a perspective view, and

[0087] Fig. 5 shows an embodiment of a flow cell with a jacket arranged around the housing.

[0088] Figures 1a to 1c show a first embodiment of a flow cell 1. Figure 1a shows the first embodiment of the flow cell 1 in a schematic sectional view from the side. The flow cell 1 has a housing 10, in the interior of 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. In the embodiment shown in Figure 1a, the connections 22, 32 are designed as screw connections and can be connected, for example, via screw-in connectors, to a liquid flow to be examined. In the embodiment shown in Figure 1a, the inlet channel 20 and the outlet channel 30 are located on the same axis and are arranged opposite one another.Such an arrangement is suitable for enabling a smooth laminar flow of a medium through the measuring chamber 40.

[0089] The measuring chamber 40 has an opening 43 on one side, located at the top in Figure 1a, which is closed by an optical window 44. The material of the optical window 44 is selected according to the optical examinations to be performed. For example, for conducting Raman spectroscopy, an optical window 44 made of UV-quality quartz glass is preferred, and an optical window 44 made of sapphire glass is particularly preferred. In the first embodiment of Figure 1a, the optical window 44 is connected to a 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 42 and hermetically seals the opening 43 of the measuring chamber 40.To produce this hermetically sealed connection, a precursor of the glass connecting element 46 can be provided in the form of a compact made of glass powder and inserted together with the optical window 44 into a recess 48 of the housing 10. The optical window 44 rests on the housing 10 on a narrow support surface 45 surrounding the opening 43. Through subsequent thermal treatment, for example, in a furnace or by heating with a laser, the compact is melted, resulting in the glass connecting element 46 fused to the optical window 44 and a wall of the recess 48.

[0090] Advantageously, by connecting the optical window 44 by melting the glass connecting element 46, a defined positional relationship results between a surface of the optical window 44 and the measuring chamber 40 or the housing 10 of the flow cell 1. This allows optical instruments such as a spectrometer or a sensor head 200 of a spectrometer (see Figure 2c) to be reproducibly arranged such that an optical focus lies at a defined distance from an inward-facing surface of the optical window 44 within the measuring chamber 40. To further facilitate such a reproducible arrangement, in the exemplary embodiment of Figure 1a, a flange is provided on the housing 10 of the flow cell 1 as a holding means 12. The flange also serves, in particular, as an alignment means in the form of a defined mechanical stop, with which a spectrometer or a sensor head 200 orThe probe head can be attached to the flow cell 1 in a reproducibly aligned manner. Due to the narrow support surface 45, the glass connecting element 46 is also brought very close to the opening 43, 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 remaining gap during the temperature treatment for glazing the optical window 44, without the material of the glass connecting element 46 penetrating beyond the edge of the opening 43 into the area of ​​the measuring chamber 40.

[0091] If other mechanical holding means 12 are desired for connection to a spectrometer or a sensor head 200 of a spectrometer, these can be designed differently according to requirements. It is also possible to provide an adapter 100, as shown in Figure 1b.

[0092] Figure 1b shows the flow cell 1 as described with reference to Figure 1a, with an adapter 100 fastened to the holding means 12 designed as a flange. The adapter 100, in turn, comprises a further holding means 12' for connection to a spectrometer or a sensor head 200. In the example shown, the further holding means 12' are designed as an internal thread. As shown in Figure 1b, such an adapter 100 can, in particular, also be used to precisely and reproducibly determine a distance between the flow cell 1 and an entrance aperture of the spectrometer or sensor head 200, as required for the respective spectrometer or sensor head 200 (cf. Figure 2c). For this purpose, the adapter 100 can, for example, comprise a tube section 102, wherein the required distance can be determined by selecting the length of the tube section 102.In the illustration in Figure 1b, the pipe section 102 is shown interrupted to indicate that its length can be adjusted as needed. Figure 1c shows the arrangement of flow cell 1 and adapter 100 described with reference to Figure 1b in a further perspective view.

[0093] Figures 2a to 2c show a second embodiment of a flow cell 1. Figure 2a shows the second embodiment of the flow cell 1 in a perspective sectional view.

[0094] Similar to that described with reference to the first embodiment of Figure 1a, the flow cell 1 has a housing 10, inside which a cavity is arranged, forming a measuring chamber 40. The measuring chamber 40 is designed here as a blind bore. An inlet channel 20 connects the measuring chamber 40 to a first connection nipple 23, and an outlet channel 30 connects the measuring chamber 40 to a second connection nipple 33. The connection nipples 23, 33 are designed for direct connection to hoses that carry a liquid flow to be analyzed. In the embodiment shown in Figure 2a, the inlet channel 20 and the outlet channel 30 are located on different axes and are not arranged opposite one another. Furthermore, it can be seen that the inlet channel 20 and the outlet channel 30 are each arranged tangentially to the radius of the measuring chamber 40.Such an arrangement is suitable for promoting a turbulent flow of a medium through the measuring chamber 40, which, for example, ensures good mixing and counteracts the deposition of solids.

[0095] The measuring chamber 40 has an opening 43 on the left side in Figure 2a, which is closed by an optical window 44. The material of the optical window 44 can again be selected according to the optical examinations to be performed. For example, for performing Raman spectroscopy, an optical window 44 made of UV-quality quartz glass is preferred, and an optical window 44 made of a crystalline material such as sapphire glass is particularly preferred. As described with reference to the first embodiment in Figure 1a, the optical window 44 is connected to a 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 hermetically seals the measuring chamber 40.

[0096] Figure 2b shows the flow cell 1 of the second embodiment from a different perspective. In this illustration, the holding means 12 designed as threaded holes can be seen. For a reproducible connection to a spectrometer or a sensor head 200, the latter can be connected to the threaded holes using corresponding screws. By providing a plurality of threaded holes, the position and alignment are also reproducibly determined. Furthermore, an optical diaphragm 16 is provided in the second embodiment. This can interact with corresponding tubular elements of a spectrometer or a sensor head 200 (cf. Figure 2c) and shield a light path between the spectrometer or sensor head 200 and the measuring chamber 40 of the flow cell 1 against the entry of extraneous light. Furthermore, the diaphragm 16 could also be connected to corresponding elements on the spectrometer orSensor head 200 form a positive connection and, similar to the holding means 12, support the precise alignment of the flow cell 1 to the spectrometer or the sensor head 200.

[0097] Figure 2c shows a connection of the flow cell 1 to a sensor head 200 in a top view. Only a small section of the sensor head 200 is shown. Figure 2c shows that the aperture 16 engages in a corresponding opening in the sensor head 200 and shields a light path between the sensor head 200 and the flow cell 1 from the entry of extraneous light from the environment. Furthermore, the aperture 16 has a dual function as an alignment means and serves to precisely align the sensor head 200 with respect to the flow cell 1. Screws serve as fastening means here, which interact with corresponding threaded holes as holding means 12 on the housing 10 of the flow cell 1.

[0098] Figures 3a to 3c show a third embodiment of the flow cell 1. The third embodiment largely corresponds to the second embodiment described with reference to Figure 2a. However, the holding means 12 are designed as a flange, and no additional aperture 16 is provided, since the flange 12 also performs this function. Figure 3a shows the flow cell 1 of the third embodiment in a perspective sectional view.

[0099] Figure 3b shows the flow cell 1 in a side view. This illustration clearly shows that in the third embodiment, the inlet channel 20 and the outlet channel 30, or the two connection nipples 23, 33, are arranged on different axes, with the axes running parallel to each other here. Alternatively, the two axes could also be arranged at an angle to each other.

[0100] Figure 3c shows the flow cell 1 according to the third embodiment together with an adapter 100, which is fastened to the 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, similar to that described with reference to the first embodiment of Figures 1a to 1c, is designed as an external thread and is arranged at the end of a pipe section 102. Via this external thread, for example, a sensor head 200 (see Figure 2c) can be connected to the adapter 100 and thus to the flow cell 1, wherein a predetermined distance and a predetermined alignment of the flow cell 1 to the sensor head is defined and reproducibly maintained. The distance can be adjusted by selecting the length of the pipe section 102, wherein the pipe section 102 is shown interrupted in Figure 3c.

[0101] Figure 4 shows a fourth embodiment of a flow cell 1 in a perspective view. The structure of the flow cell 1 largely corresponds to the first embodiment, which was described with reference to Figure 1a. In contrast to the first embodiment, no flange is provided as the holding means 12, but instead, here, for example, four bores are arranged as holding means 12. These can in particular be designed as threaded bores and enable simple attachment of a sensor head 200 or a spectrometer to the flow cell 1. Furthermore, it is of course possible to provide an adapter 100 and to attach it to the housing 10 of the flow cell 1 via the threaded bores, if, for example, different holding means 12 are required to attach a specific spectrometer.In this case, the adapter 100 can then be configured to have further holding means 12' which are configured for connection to this spectrometer.

[0102] Figure 5 shows an embodiment of a flow cell 1 with a jacket 150 made of a polymer material that partially surrounds the housing 10. The illustration is a sectional side view.

[0103] The housing 10 is constructed similarly to that described with reference to the embodiment of Figure 1a and is made, for example, from a ceramic material. The measuring chamber 40 is accommodated inside the housing 10, with the housing 10 providing the wall 42 of the measuring chamber 40. An opening in the housing 10 is closed by 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 a fluid flow via an inlet channel 20 and an outlet channel 30, with connections 22, 32 being provided for the connection.

[0104] Compared to the flow cell 1 shown in Figure 1a, the flow cell 1 shown in Figure 5 has a casing 150, which is preferably made of a polymer material and can be manufactured, for example, by injection molding. The housing 10 of the flow cell 1 can be inserted into an injection mold and overmolded with the polymer material.

[0105] The jacket 150 encloses a portion of the housing 10 which includes the optical window 44 and leaves the areas adjacent to the terminals 22, 32 free.

[0106] On the side of the housing 10 in which the optical window 44 is inserted, the casing 150 has a socket 152, on the outside of which a thread 154 is formed. This thread 154, in conjunction with the socket 152, serves as a holding and connecting means for receiving and securing a sensor head 200 (see Figure 2c). Several webs 156 are arranged on an inwardly facing wall of the socket 152. These webs 156 serve as a means for precisely positioning and aligning the sensor head 200. Since the casing 150 with the socket 152 is made of a polymer, the material is compliant and flexible. This allows the webs to be designed such that they form a frictional connection with the sensor head 200, thus ensuring precise and reproducible alignment of the sensor head 200.

[0107] Although the present invention has been described using preferred embodiments, it is not limited thereto but can be modified in many ways.

[0108] 1 flow cell

[0109] 10 housings

[0110] 12 holding devices

[0111] 12' additional holding devices

[0112] 16 optical aperture

[0113] 20 inlet channel

[0114] 22 first connection

[0115] 23 first connection nipple

[0116] 30 drainage channel

[0117] 32 second connection

[0118] 33 second connection nipple

[0119] 40 measuring chamber

[0120] 42 Wall measuring chamber

[0121] 43 Opening

[0122] 44 optical window

[0123] 45 contact surface

[0124] 46 glass connecting element (glass solder)

[0125] 48 Deepening

[0126] 49 Channel

[0127] 100 adapters

[0128] 102 pipe section

[0129] 150 coat

[0130] 152 nozzles

[0131] 154 screw threads

[0132] 156 jetty

[0133] 200 sensor head

Claims

A flow cell (1) for optical spectroscopy, comprising a housing (10) with a cavity forming a measuring chamber (40), an inlet channel (20), an outlet channel (30), and an optical window (44) closing an opening (43) of the measuring chamber (40), the optical window (44) being connected to the housing (10) by fusing a glass connecting element (46), characterized in that a recess (48) is formed around the opening (43), and a support surface (45) for the optical window (44) is formed around the opening (43), at which support surface the optical window (44) contacts the housing (10). Flow cell (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.Flow cell (1) according to claim 1 or 2, characterized in that the glass connecting element (46) fills a free space between the optical window (44) and a wall of the recess (48), so that no gap remains between the wall of the recess (48) and the glass connecting element (46). Flow cell (1) according to one of claims 1 to 3, characterized in that the glass connecting element (46) comprises or consists of a glass material having a glass transition temperature T. g of more than 470°C. Flow cell (1) according to 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 solder consisting of or as a A glass connecting element (42) formed from a glass molded body is connected. Flow cell (1) according to claim 5, characterized in that the glass solder or the glass material of the glass molded body is selected from a borosilicate glass. Flow cell (1) according to one of claims 1 to 6, characterized in that at least one component of the housing (10) which forms the cavity with the measuring chamber (40) is designed in one piece. Flow cell (1) according to one of claims 1 to 7, characterized in that the mean roughness Ra of the inner walls of the measuring chamber (40) is less than 0.8 pm, preferably less than 0.5 pm.Flow cell (1) according to one of claims 1 to 8, characterized in that the material of the housing (10) is selected from a metal or a metal alloy, wherein the material of the housing (10) is preferably selected from steel, in particular a stainless steel, an austenitic or a ferritic steel, a duplex steel, a nickel-copper alloy, a nickel-chromium-iron-niobium-molybdenum alloy, a nickel-chromium-molybdenum-tungsten alloy, a zirconium-niobium alloy and a titanium-niobium alloy or that the material of the housing (10) is selected from a ceramic, wherein the material of the housing (10) is preferably selected from a porcelain, yttrium oxide (Y2O3), zirconium oxide (ZrC), magnesium aluminate (MgAl2O4), aluminum oxide (Al2O3), SiAlON-Al2O3 and silicon carbide (SiC).Flow cell (1) according to one of claims 1 to 9, characterized in that the material of the optical window (44) is selected from a glass, in particular a quartz glass, a crystal, in particular sapphire, a ceramic, in particular yttrium-doped zirconium dioxide, or a glass ceramic. Flow cell (1) according to one of claims 1 to 10, characterized in that a first thermal expansion coefficient of the housing (10) is greater than a second thermal expansion coefficient of the glass connecting element (46), and the first thermal expansion coefficient is preferably greater than a third thermal expansion coefficient of the optical window (44). Flow cell (1) according to claim 11, characterized in that the housing (10) has an anisotropic thermal expansion, wherein the first thermal expansion coefficient is present in a direction perpendicular to a longitudinal axis of the opening (43), and a further thermal expansion coefficient of the housing (10) along a direction parallel to the longitudinal axis of the opening (43) 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 even more preferably less than 0.001 ■ 10 -6 K' 1Flow cell (1) according to one of claims 1 to 12, characterized in that the shapes of the surfaces of the optical window (44) are selected from a flat surface, a convex surface, a concave surface, or combinations thereof, such as biconvex, plano-convex, convex-concave, plano-concave, and biconcave. Flow cell (1) according to one of claims 1 to 13, characterized in that the flow cell (1) comprises a casing (150) which at least partially surrounds the housing (10), wherein the casing (150) is preferably made of a polymer material. Flow cell (1) according to one of claims 1 to 14, characterized in that it additionally comprises holding means (12, 12') for holding a spectrometer or a sensor head (200) of a spectrometer and / or alignment means for aligning a spectrometer or a sensor head (200). Flow cell (1) according to claim 15, characterized in that the flow cell (1) and the holding means (12, 12') and / or the alignment means are designed such that the spectrometer or the sensor head (200) can be attached to the flow cell (1) such that no components are arranged between the optical window (44) and a first optical element of the spectrometer or the sensor head (200). Flow cell (1) according to claim 15 or 16, characterized in that the holding means (12, 12') and / or the alignment means are designed to cooperate with a counterpart on the spectrometer or the sensor head (200) for a releasable snap-in connection. Flow cell (1) according to one of claims 15 to 17, characterized in that the holding means (12, 12') and / or the means for alignment are designed as flanges, as depressions, as elevations, as threaded bores, as grooves and combinations of these means.Flow cell (1) according to one of claims 1 to 18, characterized in that the inlet channel (20) and the outlet channel (30) are arranged opposite one another on a common axis, so that a laminar flow develops within the measuring chamber (40) when a liquid medium flows through them, or that the inlet channel (20) and the outlet channel (30) are arranged on different axes to one another, so that a turbulent flow develops within the measuring chamber (40) when a liquid medium flows through them. Use of the flow cell (1) according to one of claims 1 to 19 for monitoring a biotechnological process. Method for monitoring a biotechnological process, wherein a medium for cultivating cells circulates during the process and a. A vessel for holding the cell culture is flowed through, characterized in that the flowing medium is divided into a main stream and a side stream, the side stream is guided through a flow cell (1) according to one of claims 1 to 19, is spectroscopically examined within the flow cell (1), and the side stream is then fed back into the main stream. Method for monitoring a biotechnological process according to claim 21, characterized in that during monitoring, several measuring devices for recording parameters of the medium are used in the measuring chamber of the flow cell (1) and are connected to a holding means of the flow cell (1), without compromising the sterile integrity of the medium.

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