In-line sensors for process application, and method for putting the in-line sensors into operation

Abstract

The invention relates to an in-line sensor for measuring measurement values of a measurand representing an analyte content in a medium to be measured, the sensor comprising: an outer tube; an inner tube; a support which is non-detachably connected to the inner tube; and at least one sensor element which is non-detachably connected to the support, wherein the inner tube and the support which is non-detachably connected to the inner tube and contains the at least one sensor element are movable relative to the outer tube along the longitudinal axis of the sensor in the direction of the medium to be measured from an irradiation position to a hot-steam-sterilization position and from the hot-steam-sterilization position to a measuring position, and can be locked in both the hot-steam-sterilization position and the measuring position, wherein the outer tube has a cavity, wherein, in the irradiation position, the support is positioned in the cavity of the outer tube in such a way that a gap is present between the support and the cavity of the outer tube, so that the interior of the sensor and the sensor element located in the support are in contact with the surroundings, and, in the hot-steam-sterilization position, the support is positioned in such a way that the medium-facing end portion of the support gas-tightly seals the sensor interior and the sensor element located in the support with respect to the surroundings of the sensor, and, in the measuring position, the support is positioned in such a way that the sensor element is positioned so as to be in contact with the surroundings following hot-steam-sterilization.

Description

[0001] Inline sensors for process applications and procedures for commissioning the inline sensors

[0002] The invention relates to an inline sensor for detecting measured values ​​of a measurand representing the analyte content of a measuring medium. The invention further relates to a method for manufacturing the inline sensor and a process for commissioning the sensor.

[0003] To determine the composition of measuring media, particularly liquids such as pure liquids, liquid mixtures, emulsions or suspensions, a wide variety of analytical measuring devices are used in process measurement technology and analytical measurement technology. An analytical measuring device generally comprises a sensor designed to generate an electrical measurement signal dependent on at least one analytical measurement variable of the measuring medium, as well as evaluation electronics that determines from the measurement signal a measured value representing the current value of the at least one analytical measurement variable in the measuring medium. The analytical measurement variable can, for example, be a concentration or activity of an analyte or a parameter dependent on a concentration or activity of at least one analyte in the measuring medium.

[0004] An analyte is one or more substances contained in the measuring medium, particularly dissolved substances, whose concentration in the measuring medium is to be determined or monitored by the sensor. The evaluation electronics can be at least partially integrated into a measuring transducer arranged directly at the measuring point, which has a housing with display and input devices. At least part of the evaluation electronics can also be arranged together with the sensor in a common housing.

[0005] Such analytical measuring devices are used in a wide variety of areas, for example, for monitoring and controlling processes in pharmaceutical, chemical, biotechnological, or biochemical production, but also in water or wastewater treatment processes, as well as in environmental analysis. When an analytical measuring device is used in a process, the measuring medium is usually contained in a process vessel. Such a process vessel can be, for example, a pipeline in a process plant or a reaction vessel, such as a bioreactor or fermenter.

[0006] A bioreactor, often also called a fermenter, is a container in which certain microorganisms, cells or small plants are cultivated under the most optimal conditions possible.

[0007] Sensors that are integrated into the wall of a process vessel to monitor a measured variable of a measuring medium contained in the process vessel are referred to as inline sensors. An inline sensor detects the measured variable directly in the measuring medium to be monitored. With inline sensors, therefore, no extraction and pre-treatment of a sample from the process is required to determine an analytical measured variable. A wide variety of adapters and fittings, in particular submersible or retractable fittings, are known for integrating a sensor into the process wall. An arrangement that comprises an inline sensor integrated in the wall of a process vessel and, if appropriate, a measuring circuit and evaluation electronics connected to the inline sensor, but preferably separate from it, is referred to as an inline sensor arrangement. The inline sensor can be attached to the wall using a suitable adapter.

[0008] For processes that must be carried out under sterile or aseptic conditions, such as those found in biotechnology, pharmaceuticals, or food technology, all parts of the process plant that come into contact with the process media, in particular all process containers and the sensors integrated therein, are generally sterilized before the start of the process or between individual process steps, for example by thermal sterilization using heat. Heat sterilization can be achieved using dry heat (usually using hot air between 160°C and 180°C as the sterilization medium) or using superheated steam as the sterilization medium under increased pressure, for example by autoclaving in a pressure vessel, a so-called autoclave. Common methods include superheated steam sterilization processes, in which temperatures of at least 120°C or more can occur.If heat sterilization is performed in an autoclave, the process-wetting parts of the process system, possibly already connected to each other, are placed in the autoclave and sterilized there. The sterilized parts are then removed from the autoclave and put into operation.

[0009] Alternatively, a process system can be sterilized using a so-called SIP process (SIP is the abbreviation for "sterilization in place"), in which the process vessel to be sterilized, including the integrated inline sensor, is sterilized with superheated steam that is introduced into the process vessel over a specified period of time. Inline sensors must therefore be able to withstand the resulting conditions, such as high temperatures, humidity, and increased pressures, without loss of functionality.

[0010] In bioprocess measurement technology, for example for the monitoring, control and / or regulation of biotechnological processes, sensors are also used that have immobilized biological recognition elements on the surface of a sensor element, for example those that, possibly as receptors, selectively and specifically bind and / or convert the analyte. Biological recognition elements can be proteins such as enzymes or antibodies, DNA / RNA fragments, cell organelles or entire cells and microorganisms. Such sensors are referred to as biosensors. After a typical hot steam sterilization process, the receptors or biological recognition elements of such biosensors, in particular proteins, cell organelles or microorganisms, are usually present with greatly reduced activity, usually irreversibly denatured, i.e. destroyed in their native three-dimensional structure (conformation).Such biosensors cannot therefore simply be inserted as inline sensors into the wall of a process container and sterilized with it using a common SIP process.

[0011] Many sensors with biological recognition elements, e.g. those derived from mesophilic organisms living in the temperature range of approximately 20-45 °C, must not be exposed to elevated temperatures under SIP conditions, e.g. above 80 °C, in order not to lose their functionality.

[0012] Sterilizable biosensors based on amperometric enzyme sensors have been described in the literature. M. Phelps, "Development of a regenerable glucose biosensor probe for bioprocess monitoring," Master's Thesis, University of British Columbia, 1993, provides an overview of the literature on such sensors. Strategies described therein to ensure the sterilizability of such biosensors while retaining their functionality include introducing the temperature-sensitive receptors arranged on a carrier, for example, containing a working electrode, only after the sterilization process into a reaction chamber within a sensor housing. This reaction chamber is sealed from the process container by a membrane permeable to the respective analyte. In this case, the membrane represents the sterile barrier.The receptors can be immobilized on the subsequently inserted working electrode or in a solution contained in the reaction chamber. The sterile barrier must not be destroyed during the insertion of the receptors, which makes handling such inline sensors difficult.

[0013] A disadvantage of these inline sensors, known from the literature, is not only their difficulty in handling but also the inconsistent measurement performance of the biosensors. One reason for this is that the quantity of receptors subsequently introduced and bound to a matrix is ​​difficult to reproduce. The inline sensors known to date, which include biosensors, are not suitable for practical use, especially with regard to applications for monitoring industrial processes.

[0014] In the field of single-use technology, which is increasingly used for bioprocesses, adapters or connectors have become known which enable the introduction of sensors that have been sterilized in advance, for example using gamma radiation, into a disposable bioreactor that has also been sterilized in advance. However, these connectors are often not accepted or cannot be used for the use of large-volume process vessels in a conventional process plant that is sterilized, for example, using SIP sterilization methods. It is therefore the object of the invention to provide an inline sensor, a method for its production and its commissioning which overcome the disadvantages described. Furthermore, the disadvantages of commissioning an inline sensor from the prior art are to be overcome.Preferably, the inline sensor should be universally applicable in sterilizable process containers and allow the safe aseptic insertion of a sensor element of the inline sensor into a process container for measuring the measured variable in a medium contained in the process container. Preferably, the inline sensor should be suitable for inserting a biosensor with biological detection elements that cannot withstand hot steam sterilization into a process container that is sterilized at high temperatures.

[0015] This object is achieved by an inline sensor according to the invention, a sensor arrangement according to the invention containing the inline sensor, and a method according to the invention for producing an inline sensor and for commissioning an inline sensor. Advantageous embodiments are specified in the disclosed embodiments.

[0016] This sensor enables the aseptic insertion of heat-labile sensors into a previously heat-sterilized process vessel while maintaining the functionality of the sensors. This is made possible by using the inline sensor described here and below, which, thanks to its inventive design, enables simple commissioning of the sensor system in the process vessel and the monitoring of manufacturing processes, preferably using biotechnology.

[0017] The invention relates to an inline sensor (1) for detecting measured values ​​of a measured variable representing an analyte content of a measuring medium (6), comprising an outer tube (2), an inner tube (3), a support (4) non-detachably connected to the inner tube (3) and at least one sensor element (5) non-detachably connected to the support (4), wherein the inner tube (3) and the support (4) non-detachably connected to the inner tube, containing the at least one sensor element (5), are movable relative to the outer tube (2) along the longitudinal axis (L) of the sensor (1) from an irradiation position into a hot steam sterilization position and from the hot steam sterilization position into a measuring position, each unidirectionally in the direction of the measuring medium (6), and are lockable in the hot steam sterilization position and the measuring position, wherein

[0018] (i) the outer tube (2) has a substantially cylindrical cavity (7), has at least one first connecting element (9) on an outer wall (8) at the end facing away from the medium, has a third connecting element (11) on an inner wall (10), and has at least one sealing element (12), preferably a first (12) and at least one second sealing element (13), on the inner wall (10) at the end facing the medium;

[0019] (ii) the inner tube (3) has a fourth connecting element (14) on an outer wall (15), which is designed to engage, in the measuring position, with a third connecting element (11) on the inner wall of the outer tube (10) and is connected to a sleeve (17) at its end facing away from the medium, wherein the inner side of the sleeve (19) has at least one second connecting element (20) which is designed to allow one or more first connecting elements (9) to snap into the outer wall of the outer tube (8) in the hot steam sterilization position; an electronics housing (16) which is connected to the inner tube (3) in a gas-tight and liquid-tight manner and is detachably connected to the inner tube by means of a securing element (18), wherein the securing element (18) preferably consists of or comprises a terminal, removable, preferably unscrewable, transport lock (18),wherein the transport lock (18) is designed, in the installed state, to prevent accidental and unintentional transfer of the inner tube from the hot steam sterilization position to the measuring position and to release the movement after removal; wherein the end of the inner tube released by the transport lock (18) has at least one third overhang (21) which is designed to prevent movement of the inner tube (3) and the carrier (4) connected thereto containing the sensor element (5) beyond the measuring position,

[0020] (iii) the carrier (4) is non-releasably connected with a medium-side portion of its outer shell to a medium-side portion, preferably to a medium-side end portion, of the inner surface of the inner tube; and

[0021] (iv) the at least one sensor element (5) is designed to record a value dependent on a measured variable of a medium, wherein the sensor element is in gas contact with an interior of the sensor, the carrier (4) is positioned in the irradiation position in the cavity of the outer tube (7) such that at least one gap (22) is arranged between the carrier (4) and the cavity of the outer tube (7), so that the interior of the sensor and the sensor element (5) arranged in the carrier (4) are in contact with the environment, preferably in gas contact, the carrier (4) is positioned in the hot steam sterilization position such that the medium-facing end section of the carrier (4) seals the sensor interior and the sensor element (5) arranged in the carrier (4) in a gas-tight manner from the environment of the sensor, and the carrier (4) is positioned in the measuring position such that the sensor element (5) is positioned to, after hot steam sterilization with the environment,preferably to be in contact with the measuring medium (6), wherein preferably the environment and the measuring medium are sterilized.,

[0022] The inline sensor according to the invention, the sensor arrangement according to the invention, the manufacturing method of the inline sensor according to the invention, and the method for commissioning the inline sensor according to the invention have the advantage that a sterile sensor that can be installed in a process container is provided merely by a unidirectional movement of the inner tube along the longitudinal axis of the inline sensor, which meets the high hygiene requirements in the food industry, biotechnology, and / or the production of pharmaceuticals, for example, biologics. The areas of the inline sensor located inside the process container and in contact with the environment or the medium are designed for hygiene.

[0023] After the sensor is installed in the process vessel, the environment is the interior of the process vessel.

[0024] In particular, the inline sensor can be autoclaved, with the sensor activity being essentially, preferably not negatively, affected by heat and / or humidity. An arrangement according to the invention is thus particularly easy to handle and thus particularly user-friendly.

[0025] In one embodiment, all elements of the inline sensor that come into contact with the measuring medium are made of materials suitable for radiation sterilization. In all embodiments, these materials are non-toxic to the biological organisms and / or media to be cultivated. The materials of the inline sensor are also steam sterilizable in the hot steam sterilization position.

[0026] In one embodiment, the components forming the exterior of the housing preferably consist of one or more materials through which water vapor cannot diffuse or can only diffuse to a limited extent. Possible materials include glass, plastic, or metal. Composite materials, for example, consisting of a plastic layer and a metal layer, or multilayer plastic materials consisting of composite films, are also possible. The inner tube is preferably made of a metal or a metal alloy.

[0027] In one embodiment, the individual components or parts of the sensor, which are non-detachably connected to one another, can be formed in a materially bonded, positively connected and / or non-positively connected manner, alternatively in one piece, preferably as multi-component injection-molded parts. The mobility of the inner tube (3) and of the carrier (4), which is non-detachably and positively connected to the inner tube and contains the at least one sensor element (5), relative to the outer tube (2) along the longitudinal axis (L) of the sensor (1) means that, on the one hand, a translational movement occurs along the movement axis (L). In addition to the translational movement, a rotational movement can occur, for example by imparting the movement via a thread or by locking the inner tube in the hot steam sterilization position and / or measuring position relative to the outer tube via at least one bayonet lock.

[0028] The movement along the longitudinal axis (L) of the inline sensor can be carried out manually or via an actuator, whereby the actuator is driven pneumatically, for example.

[0029] In an embodiment in which the movement is exclusively translational, the inline sensor element has at least one, preferably two anti-rotation devices (25) which prevent a rotational movement of the inner tube (3) relative to the outer tube (2) about the longitudinal axis (L) of the sensor.

[0030] The anti-twist devices are state-of-the-art anti-twist devices.

[0031] The radiation is radiation suitable for sterilization or disinfection. It includes UV radiation, X-ray radiation, gamma radiation, or particle radiation, especially electron radiation. The radiation is preferably ionizing radiation, more preferably electron radiation or gamma radiation, and even more preferably gamma radiation.

[0032] In an advantageous embodiment, the gas volume in the interior of the sensor is largely formed from a protective gas, preferably from one or more noble gases, wherein the protective gas consists of one or more noble gases, preferably argon. The gas volume in the interior of the sensor advantageously contains oxygen and / or nitrogen in a volume fraction of less than 1% by volume each, preferably less than 0.5% by volume each, more preferably less than 0.1% by volume each.

[0033] In the radiation sterilization position, the interior of the sensor comprises the entire cavity or hollow space of the sensor, which is enclosed by the outer shell of the sensor and is accessible from the medium-side opening. In the heat sterilization position, the interior of the sensor is the entire interior of the sensor, which is sealed from the surroundings of the sensor by at least one medium-side sealing ring. In one embodiment, the at least second connecting element (20) is arranged on the shell (17) of the inner tube opposite the third connecting element (11) on the inner wall of the outer tube (10) along the longitudinal axis (L) of the inline sensor, closer to the end facing away from the medium.

[0034] In one embodiment, the at least first and the at least second connecting element are at least partially, preferably completely, complementary to one another.

[0035] In one embodiment, the at least third and the at least fourth connecting element are at least partially, preferably completely, complementary to one another.

[0036] In a preferred embodiment, the connecting elements, which are at least partially complementary to one another, consist of a notch or at least one groove and at least one overhang which is at least partially complementary thereto.

[0037] In one embodiment, the notches or grooves comprise a stepped shoulder at their end facing away from the medium, which prevents movement of the inner tube opposite to the direction of the measuring position.

[0038] In one embodiment, the inline sensor has, as connecting elements, at least two first and two grooves as second and fourth connecting elements, respectively, and at least two first overhangs and two second overhangs as third and fourth connecting elements, respectively. In addition, the inline sensor has at least two third overhangs. The first and second grooves, as well as the first, second and third overhangs, are each of the same or different, preferably of the same design. In another embodiment, the connecting elements each have at least one groove and at least one overhang, ensuring that locking or engagement into the at least partially complementary connecting elements takes place by the first connecting elements locking or engaging with the second connecting elements and the third connecting elements locking or engaging with the fourth connecting elements.

[0039] In one embodiment of the inline sensor, the at least one, preferably the first and optionally the second sealing element in the heat sterilization position, preferably the hot steam sterilization position, encloses at least one medium-side section of the carrier comprising the at least one sensor element and the sensor interior and the at least one sensor element contained therein in a liquid-tight and gas-tight manner with respect to the environment of the inline sensor.

[0040] In one embodiment, the first and second sealing elements can be part of a one-piece component, which is preferably formed as a multi-component injection-molded part. In an alternative embodiment, the first and at least the second sealing elements can be separate. In a preferred embodiment, the sealing elements are O-rings.

[0041] The sensor interior is the space enclosed by the outer tube, the inner tube, and the electronics housing. The parts of the sensor interior that are located on the non-medium side of at least one sealing element can be sealed gas- and liquid-tight from the environment by transferring the sensor from the radiation sterilization position to the hot steam sterilization position. This step occurs before removing the sensor from the at least one radiation-sterilized package.

[0042] In the hot steam sterilization position, the first sealing element is compressed by the carrier 5, thereby sealing the radiation-sterilized sensor interior in a liquid- and gas-tight manner from the environment. In the measuring position, the at least one, preferably the first 12 and the at least second sealing element 13 are compressed by the carrier 5, whereby at least one of the at least one sealing elements arranged not on the medium side is sealed in a liquid- and gas-tight manner from the environment, preferably the sterilized environment, or the medium, preferably the sterilized medium.

[0043] In a preferred embodiment, the sealing elements are O-rings.

[0044] In one embodiment, the carrier is designed as a circular cylinder, preferably as a vertical circular cylinder, the surface of which, preferably on the lateral surface, comprises at least one recess and optionally a cavity in which the at least one sensor element is arranged, wherein the recess is preferably not encompassed by the medium-side section of the carrier.

[0045] The medium-side section of the carrier comprises the part of the carrier that is located on the medium side of the recess. The at least first sealing element on the outer tube is compressed at the medium-side portion of the carrier in the hot steam sterilization position. In the measuring position, the section that is located on the non-medium side of the recess is compressed by at least one sealing element, preferably the first and at least second sealing elements.

[0046] In one embodiment, the outer tube has an opening on the medium side, which is designed to bring at least one medium-side end section of the carrier and the at least one sensor element arranged in the carrier into contact with the environment, preferably with the measuring medium in the measuring position after heat sterilization, for example autoclaving, wherein preferably the environment, more preferably the measuring medium, are sterilized.

[0047] Heat sterilization can be carried out using dry heat (usually using hot air between 160 °C and 180 °C as the sterilization medium) or using hot steam as the sterilization medium under increased pressure, for example by autoclaving in a pressure vessel, the autoclave. Common examples are hot steam sterilization processes, in which temperatures of at least 120 °C or more can occur. If heat sterilization is carried out in an autoclave, the parts of the process system that come into contact with the process, possibly already connected to one another, are placed in the autoclave, sterilized there, then removed from the autoclave and put into operation. Alternatively, a process system can be sterilized using a so-calledSterilization in place (SIP) is the abbreviation for "sterilization in place" (SIP). In this process, the process vessel to be sterilized, including the integrated inline sensor, is sterilized with superheated steam that is introduced into the process vessel over a specified period of time. Inline sensors must therefore be able to withstand the resulting conditions, such as high temperatures and increased pressures, without loss of functionality.

[0048] In one embodiment, the sensor interior of the inline sensor contains a drying agent, wherein in particular the drying agent consists of or contains a hydrophilic material, wherein the drying agent preferably consists of or contains the group of substances of zeolites, a glass or a ceramic, more preferably of aluminum oxide and / or titanium oxide and / or silicon oxide.

[0049] In all embodiments, the inner tube contains at least one ventilation opening, preferably several ventilation openings, to establish gas contact between the sensor element and the desiccant located in the inner tube. The openings can be formed, for example, as holes, slots, or gaps, wherein the openings are designed such that the desiccant located in the inner tube remains in the inner tube. Gas contact is present in both the irradiation position and the hot steam sterilization position.

[0050] In one embodiment, the inline sensor comprises, in addition to the at least one sensor element, a humidity sensor which is designed to detect a measured variable representing the relative humidity prevailing within the chamber.

[0051] Additionally or alternatively, the inline sensor comprises a temperature sensor configured to detect measured values ​​representing the temperature of the sensor interior. In a preferred embodiment, the temperature sensor is arranged in the inner tube of the inline sensor. For example, the temperature sensor is a Pt100 sensor. In one embodiment, the temperature sensor is arranged in the carrier, preferably in the region of the carrier's recess.

[0052] In one embodiment, the inner tube of the inline sensor is designed such that, during heat sterilization of the housing from the outside at a temperature of 110°C over a period of 15 minutes, the relative humidity prevailing within the housing does not exceed a value of 77%, preferably 23%, more preferably 3%, even more preferably 1%. The housing of the inline sensor can comprise a wall or housing outer side formed from one or more components of the sensor that are in contact with the environment, which tightly encloses the sensor interior and forms a barrier against the diffusion of water vapor into the interior of the sensor in the hot steam sterilization position. Advantageously, an average water vapor permeability of the wall, i.e.an average value of the water vapor permeability of the components forming the wall, at a temperature of 110 °C, a pressure difference between the chamber and the environment of the housing wall of less than 5 bar and a difference in the relative humidity in the chamber and in the environment of the wall of more than 67% less than 420 g / (m2d), preferably less than 125 g / (m2d), more preferably less than 15 g / (m2d), even more preferably less than 6 g / (m2d).

[0053] During hot steam sterilization using SIP, the surfaces inside the process container that are not gas- and liquid-tight sealed against the environment are sterilized.

[0054] In one embodiment, the inner tube is designed such that during heat sterilization, the at least one sensor element is at least temporarily thermally decoupled such that during the action of a medium having a temperature of 110°C on at least a partial area of ​​the housing exterior over a period of 15 minutes, the temperature of the sensor element increases by less than 55°C, preferably by less than 35°C, more preferably by less than 10°C, starting from an initial temperature of the sensor element of 25°C at the beginning of this period.

[0055] Alternatively or additionally, the inline sensor can comprise means for actively and / or passively cooling the sensor element, whereby the amount of heat transferred per unit of time between the housing exterior and the sensor element is at least partially dissipated from the sensor element, thus preventing or slowing down the temperature change of the sensor element. These means can include, for example, gas cooling, cooling with coolant, a thermoelectric converter, such as a Peltier cooler, cooling fins, or another heat sink.

[0056] Cooling with cooling liquid and / or cooling gas can advantageously be designed as a fluid-flowable channel structure in a housing wall of the inline sensor.

[0057] To improve thermal decoupling, it is advantageous if the housing or at least one or more components forming the housing are made of a thermally insulating plastic with a thermal conductivity of < 0.5 W m-1 K-1 , in particular PEEK. Gas cooling can, for example, comprise a space filled with a thermal insulator, such as air.

[0058] Advantageously, the inline sensor can be cooled during commissioning prior to heat sterilization, preferably to 8°C or below 8°C, more preferably to 4°C or below 4°C. In one embodiment, cooling occurs below 0°C. During heat sterilization, the temperature profile of the at least one sensor element can be monitored by at least one temperature sensor of the inline sensor.

[0059] In one embodiment, the transport lock of the inline sensor, when installed, prevents accidental or unintentional movement from the heat sterilization position, preferably the hot steam sterilization position, to the measuring position. Movement is released after the transport lock is removed. In one embodiment, the transport lock comprises a predetermined breaking point, which irreversibly destroys the transport lock upon removal. In one embodiment, the transport lock is designed as a first anti-rotation lock.

[0060] In one embodiment, the inline sensor has at least one further, preferably two further anti-rotation devices, which are not designed as transport devices and which prevent a rotational movement of the inner tube relative to the outer tube about the longitudinal axis (L) of the sensor.

[0061] In one embodiment, the outer tube comprises a connection, preferably a thread, in particular a PG13.5 thread for installation in a fitting, pipeline, process vessel, in particular bioprocess vessel, preferably fermenter.

[0062] The inline sensor arrangement can be integrated into the wall of the process container by means of a fitting or a process connection which is connected to the inline sensor arrangement in a tight, in particular fluid-tight, i.e. gas- and / or liquid-tight manner. The connection is preferably such that the process container is fluid-tightly sealed from the environment of the process container. This is preferably achieved by means of one or more hygienic sealing elements which are designed such that their surfaces in contact with the interior of the process container can be sterilized using an SIP process. This sealing element can, for example, be a suitable hygienic molded seal, as is generally known from the prior art for fittings and retractable fittings for use in hygienic applications.

[0063] Process vessels include single-use containers (often made of plastic) or traditional, reusable containers, often made of glass or stainless steel. The process vessel is also designed as a small- or large-scale bioreactor or fermenter. The sensor is used, for example, in process automation technology or biotechnological / biological manufacturing processes, particularly in the production of biopharmaceuticals or in the life sciences and food and beverage industries.

[0064] In a preferred embodiment, the inline sensor is designed as a disposable sensor or single-use sensor.

[0065] In one embodiment, the sensor comprises one or more electrodes, wherein lines contacting the electrodes run within the inline sensor, preferably within the inner tube of the inline sensor.

[0066] In one embodiment, the inline sensor has an amperometric or potentiometric reference system. This can be electrically connected to the inline sensor in the form of an inline sensor arrangement and arranged outside the inline sensor. Alternatively, the reference system can be included in the inline sensor, for example, by arranging the reference system in the sensor interior, for example, inside the inner tube.

[0067] In one embodiment, the inline sensor is an optical sensor, preferably an optical glucose sensor.

[0068] The invention also relates to a sensor arrangement containing the sensor according to the invention or an embodiment thereof, wherein the inline sensor has an electronics housing at the end facing away from the medium, to which the measuring circuit used to record measured values ​​can be electrically connected, wherein the measuring circuit is designed to be electrically connected to a higher-level evaluation or control unit which receives and further processes the measuring signals output by the measuring circuit.

[0069] In a preferred embodiment, the measuring circuit is arranged outside the inline sensor.

[0070] If the sensor is designed as an amperometric sensor, the measuring circuit serves to apply a voltage between at least two electrodes of the sensor and to record the current flowing therewith and to output this or an electrical signal derived therefrom as a measurement signal. The inline sensor can comprise an evaluation circuit which is designed to determine measured values ​​of the measurand in the unit of the measurand from the electrical signals output by the measuring circuit and to output them via an interface to a higher-level unit or via a display device, e.g. a display. The evaluation electronics can be at least partially integrated into a measuring transducer arranged directly at the measuring point, which has a housing with display and input means. At least part of the evaluation electronics can also be arranged together with the sensor in a common housing.In one embodiment, the at least one sensor element of the inline sensor according to the invention is a biosensor element, wherein the biosensor element comprises at least one biological recognition element for the analyte, wherein the biological recognition element is preferably a protein, preferably an enzyme.

[0071] The biological recognition element is preferably embedded in a polymer matrix.

[0072] In one embodiment, the at least one sensor element of the inline sensor according to the invention is an enzyme-based sensor element, preferably a lactate oxidase, glutamate oxidase, glutaminase or glucose oxidase, more preferably a glucose oxidase-comprising sensor element.

[0073] In its function as a biocatalyst, the glucose oxidase enzyme converts the analyte glucose into gluconic acid and hydrogen peroxide. Oxygen is consumed in the process. The increase in hydrogen peroxide concentration or the decrease in oxygen concentration is recorded amperometrically, depending on the chosen electrolysis potential.

[0074] The invention also relates to a method for producing a sensor according to one of the preceding claims, comprising the steps:

[0075] (i) Placing the inner tube in the outer tube in the first irradiation position,

[0076] (ii) Installation of the transport lock

[0077] (iii) gas-tight packaging of the sensor within at least one radiation-sterilizable flexible package, preferably within at least one radiation-sterilizable bag, wherein steps (i) to (iii) are carried out under a protective gas atmosphere.

[0078] In a preferred embodiment, the sensor is packaged in two sterilizable flexible packages, preferably two sterilizable bags. The packages are radiation-sterilizable, preferably gamma-sterilizable. The first, inner package is preferably optically transparent, more preferably made of a film with better barrier properties for oxygen and water vapor than conventional polyethylene films. The second, outer package is preferably optically opaque, more preferably made of a metal composite film, preferably an aluminum composite film.

[0079] The invention also relates to a method for commissioning an inline sensor according to the invention or an embodiment thereof, comprising the steps: (i) mounting the inner tube in the outer tube in the first irradiation position

[0080] (ii) Installation of the transport lock

[0081] (iii) gas-tight packaging of the sensor within at least one radiation-sterilizable flexible package, preferably within at least one radiation-sterilizable bag, wherein steps (i) to (iii) are carried out under a protective gas atmosphere

[0082] (iv) Sterilizing the sensor enclosed in the at least one flexible package containing the sensor element by means of sterilizing radiation

[0083] (v) Transferring the sensor from the irradiation position to a hot steam sterilization position in the radiation-sterilized at least one package, preferably bag, under a protective gas atmosphere by moving the inner tube (3) along the longitudinal axis of the sensor (1) in the direction of the measuring medium (6), wherein the interior of the sensor containing the sensor element (5) is enclosed in the gamma-sterilized protective gas atmosphere

[0084] (vi) Unpacking the sensor from at least one radiation-sterilized package, preferably bag

[0085] (vii) Mounting the sensor to a process vessel

[0086] (viii) heat sterilization of the sensor, preferably by hot steam, with sterilization preferably being carried out by autoclaving or on-site sterilization,

[0087] (ix) Remove the transport lock (19) after completion of heat sterilization

[0088] (x) moving the inner tube (3) into the measuring position and bringing the sensor element (5) into contact with the measuring medium, wherein the contacting is preferably carried out aseptically and

[0089] (xi) Connecting the electronics housing to an evaluation and / or control unit.

[0090] In one embodiment, prior to step (i), the inner tube is filled with a desiccant.

[0091] They show:

[0092] Fig. 1: The side view of the inline sensor according to the invention in the irradiation position. Fig. 2: The side view of the inline sensor according to the invention in the hot steam sterilization position.

[0093] Fig. 3: the side view of the inline sensor according to the invention in the measuring position.

[0094] Fig. 1 shows an inline sensor 1, which essentially comprises an inner tube 3 and an outer tube 2. The inner tube 3 is mounted axially movable in the outer tube 2 along the longitudinal axis of the inline sensor. The anti-rotation devices 25 prevent rotation of the inner tube relative to the outer tube about the longitudinal axis of the sensor. The inner tube 3 is non-releasably connected, preferably positively, with its medium-side end to an end of the carrier 4 facing away from the medium, wherein the carrier encompasses the sensor element 5. The sensor element 5 is arranged in a recess 23 in the carrier. In the irradiation position, the inner tube, the carrier connected thereto, and the sensor element 5 encompassed by the carrier are located on the non-medium side of the first and second sealing elements 12 and 13.This creates a gap 22 between the carrier 4 and the outer tube 2, as well as between the inner tube 3 and outer tube 2, whereby in the irradiation position the interior of the sensor can be filled with a protective gas, for example argon gas, and sterilized by radiation. The inner tube is also connected in a gas-tight manner, preferably non-detachably, more preferably positively, to an electronics housing 16 at the end facing away from the medium. The outer side of the inner tube is connected at the end facing away from the medium to a sleeve 17 and a detachably connected securing element or transport lock 18. The securing element is preferably designed as a transport lock, wherein the securing element comprises an anti-twist device, for example a thread. A third sealing element 26 is arranged between the transport lock and the electronics housing, wherein this sealing element is preferably designed as an O-ring. The sensor has a medium-side ora medium-contacting part and a non-medium-contacting part. At the end area of ​​the medium-side part facing away from the medium, the outer tube 2 comprises a thread 24, for example a PG 13.5 thread 24, for installing the inline sensor 1 in a fitting, a process vessel, pipeline or fermenter. If the thread 24 is designed as an external thread, the fitting has a corresponding internal thread. The medium-side or medium-contacting part has a length similar to that of common sensors in process automation, i.e. approximately 120 mm, 225 mm or 360 mm. The inline sensor is packaged in at least one, preferably two flexible and radiation-sterilizable packages and sterilized using radiation suitable for disinfection or sterilization, wherein the radiation is UV, X-ray, gamma radiation or electron beams.

[0095] Fig. 2 shows an inline sensor 1 in the hot steam sterilization position. The carrier 4 is enclosed on the medium side by the first sealing element 12, for example a sealing ring, whereby the interior of the sensor, which is located on the non-medium side of the sealing ring, is sealed gas-tight from the environment. Transfer to the heat sterilization position, preferably the hot steam sterilization position, is mediated on the side facing away from the medium via the first connecting elements 9, which are positively attached to the outer wall 8 of the outer tube 2, and the second connecting elements 20, which are positively attached to the inside of the sleeve 17. After transfer to the heat sterilization position, preferably the hot steam sterilization position, the sensor is removed from the at least one radiation-sterilized package, and the connection 24, preferably a thread, is installed in the container to be sterilized.The connection 24 is preferably installed in a force-fitting manner on the outer wall 8 of the outer tube 2. In the hot steam sterilization position, the sensor element is gas- and liquid-tightly insulated from the hot steam sterilized vessel.

[0096] Fig. 3 shows an inline sensor 1 in the measuring position. The sensor is transferred to the measuring position after heat sterilization, preferably hot steam sterilization. To allow the inner tube to be moved further axially relative to the outer tube in the direction of the measuring medium 6, the securing element, preferably the transport lock 18, is removed. Locking along the longitudinal axis of the sensor is achieved through the interaction of the third connecting elements and the fourth connecting elements.

[0097] All embodiments of the inline sensor and the method described above can be combined with each other, provided this is technically possible.

[0098] Reference signs are not intended to limit the scope of the subject matter protected by the claims. They serve solely to make the claims easier to understand.

[0099] List of reference symbols

[0100] (1) Inline sensor

[0101] (2) Outer tube

[0102] (3) Inner tube

[0103] (4) Carrier

[0104] (5) Sensor element

[0105] (6) Measuring medium

[0106] (7) Cavity of the outer tube

[0107] (8) Outer wall of the outer tube

[0108] (9) first connecting element or first connecting elements

[0109] (10) Inner wall of the outer tube

[0110] (11) third connecting element or third connecting elements

[0111] (12) first sealing element

[0112] (13) second sealing element

[0113] (14) fourth connecting element or fourth connecting elements

[0114] (15) Outer wall of the inner tube

[0115] (16) Electronics housing

[0116] (17) Cover

[0117] (18) Securing element, transport lock

[0118] (19) Inside of the cover

[0119] (20) second connecting element or second connecting elements

[0120] (21) third overhang or third overhangs

[0121] (22) Gap

[0122] (23) Recess

[0123] (24) Connection, thread

[0124] (25) Anti-rotation device or anti-rotation devices of the inner tube

[0125] (26) Third sealing element

[0126] (27) Ventilation opening

Claims

Patent claims 1. Inline sensor (1) for detecting measured values of a measured variable representing an analyte content of a measuring medium (6), comprising an outer tube (2), an inner tube (3), a support (4) permanently connected to the inner tube (3), and at least one sensor element (5) permanently connected to the support (4), wherein the inner tube (3) and the support (4) permanently connected to the inner tube, containing the at least one sensor element (5), are movable relative to the outer tube (2) along the longitudinal axis (L) of the sensor (1) from an irradiation position into a hot steam sterilization position and from the hot steam sterilization position into a measuring position, each unidirectionally in the direction of the measuring medium (6), and are lockable in the hot steam sterilization position and the measuring position, wherein (i) the outer tube (2) has a substantially cylindrical cavity (7), has at least one first connecting element (9) on an outer wall (8) at the end facing away from the medium, has a third connecting element (11) on an inner wall (10), and has at least one, preferably a first (12) and at least one second, sealing element (13) on the inner wall (10) at the end facing the medium; (ii) the inner tube (3) has a fourth connecting element (14) on an outer wall (15), which is designed to engage in the measuring position with a third connecting element (11) on the inner wall of the outer tube (10) and is connected to a sleeve (17) at its end facing away from the medium, wherein the inner side of the sleeve (19) has at least one second connecting element (20) which is designed to allow one or more first connecting elements (9) to snap into the outer wall of the outer tube (8) in the hot steam sterilization position, an electronics housing (16) which is connected to the inner tube (3) in a gas-tight, liquid-tight and detachable manner and is connected to a securing element (18) in a gas-tight, liquid-tight and detachable manner, wherein the securing element (18) preferably consists of or comprises a terminal, removable, preferably unscrewable, transport lock (18), wherein the transport lock (18) is designed, in the installed state, to prevent accidental and unintentional transfer of the inner tube from the hot steam sterilization position to the measuring position and to release the movement after removal; wherein the end of the inner tube released by the transport lock (18) has at least one third overhang (21) which is designed to prevent movement of the inner tube (3) and the carrier (4) connected thereto containing the sensor element (5) beyond the measuring position, (iii) the carrier (4) is permanently connected to a medium-side portion of its outer shell, preferably to a medium-side end portion, of the inner surface of the inner tube; and (iv) the at least one sensor element (5) is designed to record a value dependent on a measured variable of a medium, wherein the sensor element is in gas contact with an interior of the sensor, the carrier (4) is positioned in the irradiation position in the cavity of the outer tube (7) such that at least one gap (22) is arranged between the carrier (4) and the cavity of the outer tube (7), so that the interior of the sensor and the sensor element (5) arranged in the carrier (4) are in contact with the environment, preferably in gas contact, the carrier (4) is positioned in the hot steam sterilization position such that the medium-facing end section of the carrier (4) seals the sensor interior and the sensor element (5) arranged in the carrier (4) in a gas-tight manner from the environment of the sensor, and the carrier (4) is positioned in the measuring position such that the sensor element (5) is positioned to, after hot steam sterilization with the environment,preferably to be in contact with the measuring medium (6), wherein preferably the environment and the measuring medium are sterilized., 2. Inline sensor (1) according to claim 1, wherein the at least second connecting element (21) on the sleeve (17) is or are arranged closer to the end facing away from the medium than the third connecting element (11) on the inner wall of the outer tube (10) along the longitudinal axis (L) of the inline sensor.

3. Inline sensor (1) according to claim 1 or 2, wherein the at least first (9) and the at least second connecting element (21) and the third (11) and the at least fourth (14) connecting element are at least partially, preferably completely, complementary to each other 4. Inline sensor (1) according to one of the preceding claims, a first, second, third or fourth connecting element comprises a stepped shoulder at its end facing away from the medium, which prevents movement of the inner tube opposite to the direction of the measuring position.

5. Inline sensor (1) according to one of the preceding claims, wherein the first (12) and optionally the second sealing element (13) in the hot steam sterilization position encloses at least one medium-side section of the carrier (4) comprising the at least one sensor element (5) in a liquid-tight and gas-tight manner and seals the sensor interior and the at least one sensor element (5) contained therein in a liquid-tight and gas-tight manner from the environment of the inline sensor (1).

6. Inline sensor (1) according to one of the preceding claims, wherein the carrier (5) is designed as a circular cylinder, preferably as a vertical circular cylinder, and comprises on the surface, preferably on the lateral surface, at least one recess (24) and optionally a cavity in which the at least one sensor element is arranged, wherein preferably the recess (24) is not encompassed by the medium-side section of the carrier (5).

7. Inline sensor (1) according to one of the preceding claims, wherein the outer tube (2) has an opening on the medium side, which is designed to bring at least one medium-side end section of the carrier (5) and the at least one sensor element (5) arranged in the carrier into contact with the environment, preferably with the measuring medium in the measuring position after hot steam sterilization, wherein preferably the environment, preferably the measuring medium, are sterilized.

8. Inline sensor (1) according to one of the preceding claims, wherein the sensor interior contains a drying agent, wherein in particular the drying agent consists of a hydrophilic material or contains this, wherein the drying agent preferably consists of the group of substances of the zeolites, a glass or a ceramic, more preferably of aluminum oxide and / or titanium oxide and / or silicon oxide or contains this.

9. Inline sensor (1) according to one of the preceding claims, wherein the sensor comprises, in addition to the at least one sensor element, a temperature sensor which is designed to detect measured values representing the temperature of the sensor interior and which is preferably arranged in the inner tube.

10. Inline sensor (1) according to claim 9, wherein the inner tube is designed such that when the housing is heat sterilized from the outside at a temperature of 110°C over a period of 15 minutes, the relative humidity prevailing within the housing does not exceed a value of 77%, preferably 23%, more preferably 3%, even more preferably 1%.

11. Inline sensor (1) according to one of the preceding claims, wherein the outer tube (2) comprises a connection (24), preferably a thread (24), in particular a PG13.5 thread for installation in a fitting, pipeline, process vessel, in particular bioprocess vessel, preferably fermenter.

12. Inline sensor (1) according to one of the preceding claims, wherein the inline sensor element has at least one, preferably two anti-rotation devices (25) which prevent a rotational movement of the inner tube (3) relative to the outer tube (2) about the longitudinal axis (L) of the sensor.

13. Inline sensor (1) according to one of the preceding claims, wherein the sensor has an amperometric or potentiometric reference system.

14. Inline sensor (1) according to one of the preceding claims, wherein the at least one sensor element is a biosensor element, wherein the biosensor element comprises at least one biological recognition element for the analyte, wherein the biological recognition element is preferably a protein, preferably an enzyme.

15. Inline sensor (1) according to claim 15, wherein the sensor element is an enzyme-based sensor element, preferably a lactate oxidase, glutamate oxidase, glutaminase or glucose oxidase, more preferably a glucose oxidase-comprising sensor element.

16. Inline sensor arrangement (1) containing an inline sensor according to one of the preceding claims, wherein the inline sensor arrangement has an electronics housing at the end facing away from the medium, to which the measuring circuit used to record measured values can be electrically connected, wherein the measuring circuit is designed to be electrically connected to a higher-level evaluation or control unit which receives and further processes the measuring signals output by the measuring circuit.

17. Inline sensor arrangement according to claim 16, wherein the measuring circuit is preferably arranged outside the sensor.

18. A method for producing a sensor (1) according to one of the preceding claims, comprising the steps: (i) Mounting the inner tube (3) in the outer tube in the first irradiation position, (ii) Installation of the transport lock (18) (iii) - gas-tight packaging of the sensor (1) within at least one radiation-sterilizable flexible package, preferably in at least one radiation-sterilizable bag, wherein steps (i) to (iii) are carried out under a protective gas atmosphere.

19. The method according to claim 18, wherein prior to step (i) the inner tube is filled with a desiccant.

20. Method for commissioning an inline sensor (1) according to one of claims 1 to 16 and following the method steps of claim 18 or 19, comprising the steps: (iv) Sterilizing the sensor enclosed in the flexible package containing the sensor element by means of sterilizing radiation (v) Transferring the sensor from the radiation position to a hot steam sterilization position in a sterilized package under a protective gas atmosphere by moving the inner tube (3) along the longitudinal axis of the sensor (1) in the direction of the measuring medium (6), wherein the interior of the sensor containing the sensor element (5) is enclosed in the sterilized protective gas atmosphere (vi) Unpacking the sensor from the sterilized bag (vii) Mounting the sensor to a process vessel (viii) heat sterilization of the sensor, preferably by hot steam, preferably by autoclaving or on-site sterilization, (ix) Remove the transport lock (19) after completion of heat sterilization (x) moving the inner tube (3) into the measuring position and bringing the sensor element (5) into contact with the measuring medium, wherein the contacting is preferably carried out aseptically and (xi) Connecting the electronics housing to an evaluation and / or control unit.

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