In-line sensors for process applications and methods for operating in-line sensors

Abstract

The present invention relates to an inline sensor for measuring the analyte content in a medium to be measured, the sensor comprising an outer tube, an inner tube, a support non-detachably connected to the inner tube, and a sensor element non-detachably connected to the support, the support being movable relative to the outer tube along the longitudinal axis of the sensor in the direction of the medium to be measured from a radiation irradiation position to a high-temperature steam sterilization position, and from the high-temperature steam sterilization position to a measurement position, and being lockable at the high-temperature steam sterilization position and the measurement position, the support being positioned such that at the radiation irradiation position, a gap exists between the support and the cavity of the outer tube in the cavity of the outer tube so that the sensor element located inside the sensor and in the support is in contact with the surroundings, at the high-temperature steam sterilization position, the medium-side end of the support being positioned to hermetically seal the sensor element located inside the sensor and in the support with respect to the surroundings of the sensor, and at the measurement position, the sensor element being positioned to be in contact with the surroundings after high-temperature steam sterilization.

Description

Technical Field

[0001] The present invention relates to an in-line sensor for measuring a measured value of a measured quantity representing an analyte content in a measurement target medium. Further, the present invention relates to a method for manufacturing the in-line sensor and a method for operating the in-line sensor.

Background Art

[0002] In order to determine the composition of a measurement target medium, particularly liquids such as pure liquids, liquid mixtures, emulsions, suspensions, etc., various analytical measurement devices are used in process measurement and analytical measurement. An analytical measurement device generally comprises a sensor designed to generate an electrical measurement signal that depends on at least one analytical measured quantity, and an electronic evaluation device that determines a measured value representing the current value of at least one analytical measured quantity in the measurement target medium from the measurement signal. The analytical measured quantity can be, for example, the concentration or activity of an analyte in the measurement target medium, or a parameter that depends on the concentration or activity of at least one analyte in the measurement target medium.

[0003] As used herein, an analyte means one or more substances contained in the measurement target medium, particularly dissolved substances, the concentration of which in the measurement target medium is to be determined or monitored by the sensor. The electronic evaluation device may be at least partially incorporated into a measuring transducer having a housing with display elements and input elements, which is directly arranged at the measurement point. At least a portion of the electronic evaluation device may be arranged together with the sensor in a common housing.

[0004] Such analytical measurement devices are used in various fields, for example, not only for monitoring and controlling processes in pharmaceutical, chemical, biotechnology or biochemical manufacturing, but also for processes in water treatment and sewage treatment, environmental analysis, etc. As long as the analytical measurement device is used in a process, the measurement target medium is usually contained in a process container. Such process containers include, for example, the piping of a process plant and reaction vessels such as bioreactors and fermenters.

[0005] A bioreactor, often also called a fermenter, is a vessel used to cultivate specific microorganisms, cells, or small plants under optimal conditions.

[0006] Sensors integrated into the wall of a process vessel to monitor the amount of a medium to be measured contained within the process vessel are called inline sensors. Inline sensors detect the amount to be measured directly from the medium being monitored. Therefore, in inline sensors, there is no need to take and pre-process samples from the process to determine the amount to be analyzed. Various adapters and fittings are known for integrating sensors into process walls, particularly immersion or movable fittings (armatures). An inline sensor configuration is a configuration comprising an inline sensor integrated into the wall of a process vessel, and, where applicable, a measurement circuit and electronic evaluation device connected to the inline sensor but positioned separately. The inline sensor may be fixed to the wall by an appropriate adapter.

[0007] For example, in processes that must be carried out under sterile or near-sterile conditions, such as in biotechnology, pharmaceuticals, and food engineering, all components of the process plant that come into contact with the process medium, specifically all process vessels and sensors incorporated therein, are typically sterilized (e.g., by heat) before the process starts or between individual process steps. Thermal sterilization is carried out by dry heat (typically using hot air at 160°C to 180°C as the sterilization medium) or by autoclaving in a pressurized vessel called an autoclave, using superheated steam under pressure as the sterilization medium. For example, superheated steam sterilization, which can generate temperatures of at least 120°C or higher, is common. When thermal sterilization is performed in an autoclave, process plant components that come into contact with the process and may already be connected to each other are placed in the autoclave and sterilized there. The sterilized components are then removed from the autoclave and brought back into operation.

[0008] Alternatively, the process plant may be sterilized by a method called SIP (SIP is an abbreviation for "Sterilization In Place"). In this method, the process vessel to be sterilized, including the incorporated in-line sensors, is sterilized by superheated steam introduced into the process vessel for a predetermined period of time. Therefore, the in-line sensors must be able to withstand the resulting conditions of high temperature, high humidity, and high pressure without compromising their functionality.

[0009] For example, in bioprocesses used for monitoring, controlling, and / or regulating biotechnology processes, sensors are also used that have biological recognition elements immobilized on the surface of a sensor element, such as a sensor element that selectively and specifically binds to and / or reacts with an analyte as a receptor. These biological recognition elements may be proteins such as enzymes and antibodies, DNA / RNA fragments, organelles, whole cells, or microorganisms. Such sensors are called biosensors. [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] After a typical superheated steam sterilization process, the receptors or biological recognition elements of such biosensors, particularly proteins, organelles, or microorganisms, generally experience a significant decrease in activity and are often irreversibly denatured, meaning their original three-dimensional structure (conformation) is destroyed. Therefore, such biosensors cannot be used as in-line sensors on the walls of process vessels and sterilized together with the process vessel by a typical SIP method unless additional measures are taken.

[0011] For example, many sensors that have biological recognition elements derived from mesothermic organisms that grow in a temperature range of approximately 20 to 45°C should not be exposed to high-temperature SIP conditions, such as 80°C, in order to prevent loss of function.

[0012] Sterilizable biosensors based on amperometric enzyme sensors have been described in the literature. M. Phelps' master's thesis, "Development of a Renewable Glucose Biosensor Probe for Bioprocess Monitoring" (University of British Columbia, 1993), provides an overview of the literature on such sensors. One method described therein for ensuring the sterilizability of such biosensors while maintaining functionality is to introduce a temperature-sensitive receptor, placed on a support including a working electrode, into a reaction chamber within a sensor housing isolated from the process vessel by a membrane permeable to the corresponding analyte, only after the sterilization process. In this example, the membrane functions as a sterile barrier. In this case, the receptor may be immobilized on the later-introduced working electrode or present in a solution contained within the reaction chamber. Handling of this type of in-line sensor is difficult because the sterile barrier must not be destroyed during receptor introduction.

[0013] In addition to being difficult to handle, these inline sensors known from the literature also have the drawback of exhibiting variability in the measurement performance of biosensors. One reason for this is the difficulty in reproducing the amount of receptors bound to the matrix that is introduced later. Conventional inline sensors with biosensors are not practical, especially for applications such as monitoring industrial processes.

[0014] In the field of single-use technologies, which are increasingly being used in bioprocesses, adapters or connectors are known that allow sensors, pre-sterilized by gamma irradiation, to be introduced into pre-sterilized single-use bioreactors. However, these connectors are often unacceptable or inapplicable for large-capacity process vessels in conventional process plants, which are sterilized, for example, by SIP sterilization.

[0015] Therefore, an object of the present invention is to provide an inline sensor that overcomes the aforementioned drawbacks, as well as a method for manufacturing the same and a method for starting up (operating) it. Furthermore, an object is to eliminate the drawbacks of the start-up (operation) of conventional inline sensors. The inline sensor is preferably universally usable in sterilizable process vessels and allows for the safe and aseptic introduction of the sensor element of the inline sensor into the process vessel to measure the amount of a medium contained in the process vessel. The inline sensor is preferably suitable for introducing a biosensor having a biological recognition element that cannot withstand superheated steam sterilization into a process vessel that is sterilized at high temperatures. [Means for solving the problem]

[0016] This objective is achieved by the inline sensor according to the present invention, the sensor configuration according to the present invention comprising the inline sensor, the method for manufacturing the inline sensor according to the present invention, and the method for starting up (operating) the inline sensor. Advantageous improved embodiments are described in the disclosed embodiments.

[0017] This sensor enables the aseptic introduction of a temperature-sensitive sensor into a pre-sterilized process vessel while maintaining its functionality. This is made possible by using the in-line sensor described herein and below, and the design according to the present invention enables the easy setup of a sensor system within a process vessel and the monitoring of the manufacturing process, preferably using biotechnology.

[0018] The present invention relates to an inline sensor (1) for measuring a measured amount representing the analyte content in a medium (6) to be measured, and the inline sensor is The sensor comprises an outer tube (2), an inner tube (3), a support (4) non-removably connected to the inner tube (3), and at least one sensor element (5) non-removably connected to the support (4). The inner tube (3) and the support (4), which is non-removably connected to the inner tube and includes at least one sensor element (5), are movable relative to the outer tube (2) in one direction along the longitudinal axis (L) of the sensor (1) and in the direction of the medium to be measured (6), from the radiation irradiation position to the high-temperature steam sterilization position and from the high-temperature steam sterilization position to the measurement position, and are lockable in both the high-temperature steam sterilization position and the measurement position. (i) The outer tube (2) A roughly cylindrical cavity (7), At least one first connecting element (9) on the outer wall (8) at the end opposite to the medium, The third connecting element (11) on the inner wall (10), At least one sealing element (12), preferably a first sealing element (12) and at least one second sealing element (13), on the inner wall (10) of the media-side end, It has, (ii) The inner tube (3) The outer wall (15) has a fourth connecting element (14) that is designed to engage with a third connecting element (11) on the inner wall (10) of the outer tube at the measurement position, At the end opposite the medium, Connected to a shell (17), the inside (19) of the shell is provided with at least one second connecting element (20) designed so that one or more first connecting elements (9) snap into place on the outer wall (8) of the outer tube in the high-temperature steam sterilization position. The electronic equipment housing (16) is connected to the inner tube (3) in an airtight and liquid-tight manner and is connected airtight and liquid-tight and detachably by fastening elements (18), wherein the fastening elements (18) are preferably located at the ends and consist of or include detachable and preferably screwable transport locks (18), The transport lock (18) is designed to prevent the inner tube from accidentally or unintentionally moving from the high-temperature steam sterilization position to the measurement position when installed, and to allow movement after removal. The end of the inner tube released by the transport lock (18) has at least one third overhang (21) designed to prevent the inner tube (3) and the associated support (4) containing the sensor element (5) from moving beyond the measurement position. (iii) The support (4) is non - detachably connected to the inner surface of the inner tube, preferably at its medium - side end, by a portion of its outer shell opposite the medium. (iv) At least one sensor element (5) is designed to acquire a value depending on the measured quantity of the medium, and the sensor element is in gas communication with the interior of the sensor. At the radiation - irradiation position, the support (4) is arranged in the cavity (7) of the outer tube such that there is at least one gap (22) between the support (4) and the cavity (7) of the outer tube so that the interior of the sensor and the sensor element (5) arranged in the support (4) are in contact with the surroundings, preferably in gas communication. At the high - temperature steam sterilization position, the support (4) is arranged such that the medium - side end of the support (4) hermetically seals the sensor element (5) arranged inside the sensor and in the support (4) from the surroundings of the sensor. At the measurement position, the support (4) is arranged such that the sensor element (5) is arranged at a position where it contacts the surroundings, preferably the measurement - target medium (6) after high - temperature steam sterilization. Preferably, the surroundings and the measurement - target medium are sterilized.

[0019] The in - line sensor according to the present invention, the sensor configuration according to the present invention, the manufacturing method of the in - line sensor according to the present invention, and the startup (operation) method of the in - line sensor according to the present invention have the advantage of providing a sterilizable sensor that can be installed in a process vessel simply by moving the inner tube in one direction along the longitudinal axis of the in - line sensor, and meet the high hygiene requirements in the food industry, biotechnology, and / or pharmaceutical manufacturing such as biopharmaceuticals. The area of the in - line sensor located in the process vessel and in contact with the surroundings or the medium is designed to be hygienic.

[0020] After the sensor is installed in the process vessel, the surroundings mean the interior of the process vessel.

[0021] In particular, the present in-line sensor is capable of autoclave treatment, and the activity of the sensor is not substantially affected by heat and / or humidity, preferably not affected at all. Therefore, the arrangement according to the present invention is extremely easy to handle and is thus extremely user-friendly.

[0022] In one embodiment, all elements of the in-line sensor that come into contact with the medium to be measured are made of materials suitable for radiation sterilization. In any embodiment, these materials are harmless to the living organisms and / or the medium to be cultured. The materials of the in-line sensor are also capable of being sterilized using high-temperature steam at the high-temperature steam sterilization position.

[0023] In one embodiment, the member constituting the outer surface of the housing is preferably composed of one or more materials that are completely impermeable or only slightly permeable to water vapor. Possible materials include glass, plastic, and metal. For example, composite materials composed of a plastic layer and a metal layer, or multilayer plastic materials composed of composite films can also be used. The inner tube is preferably composed of metal or a metal alloy.

[0024] In one embodiment, each component or part of the sensor that is non-detachably connected to each other may be formed by material bonding, shape bonding, and / or mechanical bonding, or may be integrally formed, preferably as a multi-component injection-molded part.

[0025] That the inner tube (3) and the support (4) that is non-detachably and shape-bonded to the inner tube and includes at least one sensor element (5) are movable along the longitudinal axis (L) of the sensor (1) with respect to the outer tube (2) means that, on the one hand, linear movement along the movement axis L is performed. In addition to the linear movement, for example, by transmitting the movement via a screw, or by locking the inner tube with respect to the outer tube at the high-temperature steam sterilization position and / or the measurement position via at least one bayonet lock, a rotational movement can also be made.

[0026] The movement of the inline sensor along its longitudinal axis (L) may be performed manually or, for example, by a pneumatically driven actuator.

[0027] In embodiments where movement is linear only, the inline sensor element has at least one, preferably two, anti-rotation devices (25) to prevent the inner tube (3) from rotating relative to the outer tube (2) about the longitudinal axis (L) of the sensor.

[0028] The anti-rotation device is a conventional device known in the prior art.

[0029] The term "radiation" as used herein refers to radiation suitable for sterilization or disinfection. This radiation includes ultraviolet rays, X-rays, gamma rays, and particle beams, particularly electron beams. Preferably, the radiation is ionizing radiation, more preferably electron beams or gamma rays, and even more preferably gamma rays.

[0030] In an advantageous embodiment, the gas inside the sensor mainly consists of a protective gas, preferably one or more noble gases, and the protective gas consists of one or more noble gases, preferably argon. The gas inside the sensor preferably has a volume fraction of oxygen and / or nitrogen of less than 1 vol%, preferably less than 0.5 vol%, and more preferably less than 0.1 vol%.

[0031] In the radiation sterilization position, the sensor interior includes all cavities or hollow spaces within the sensor that are enclosed by the sensor's outer shell and accessible from the opening on the medium side. In the thermal sterilization position, the sensor interior means the entire interior of the sensor that is hermetically sealed from the periphery by at least one sealing ring facing the medium side (facing the medium).

[0032] In one embodiment, at least the second connecting element (20) is positioned on the shell (17) of the inner tube, along the longitudinal axis (L) of the inline sensor, closer to the end opposite to the medium, relative to the third connecting element (11) provided on the inner wall (10) of the outer tube.

[0033] In one embodiment, at least the first connecting element and at least the second connecting element are complementary to each other, at least partially, and preferably completely.

[0034] In one embodiment, at least the third connecting element and at least the fourth connecting element are complementary to each other, at least partially, and preferably completely.

[0035] In a preferred embodiment, the connecting elements, which are at least partially complementary to each other, consist of a notch or at least one groove and at least one overhang that is at least partially complementary thereto.

[0036] In one embodiment, the notch or groove is provided with a stepped shoulder at the end opposite to the medium, which prevents movement in the direction opposite to the measurement position of the inner tube.

[0037] In one embodiment, the inline sensor has, in each case, at least two first grooves and / or two first grooves as second and / or fourth connecting elements, and further has at least two first overhangs and / or two second overhangs as third and / or fourth connecting elements. The inline sensor also has at least two third overhangs. The first and second grooves, and the first, second and third overhangs, may be the same or different in shape, preferably the same. In yet another embodiment, each connecting element has at least one groove and at least one overhang, and the first connecting element snaps into or engages with the second connecting element, and the third connecting element snaps into or engages with the fourth connecting element, thereby ensuring snap-fitting or engagement with at least partially complementary connecting elements.

[0038] In one embodiment of an inline sensor, at least one, preferably a first and an optional second, sealing element seals, in a thermal sterilization position, preferably a high-temperature steam sterilization position, at least a portion of the medium-side of the support including at least one sensor element, as well as the inside of the sensor and at least one sensor element contained within it, from the periphery of the inline sensor in a liquid-tight and airtight manner.

[0039] In one embodiment, the first and second sealing elements may be part of a single integrated component, preferably designed as a multi-component injection-molded part. In another embodiment, the first and at least the second sealing elements may exist as separate components. In a preferred embodiment, the sealing elements are O-rings.

[0040] The sensor interior is the space enclosed by the outer tube, inner tube, and electronic housing. The portion of the sensor interior located on the non-medium side of at least one sealing element can be sealed airtight and liquid-tight from the surroundings by moving the sensor from a radiation sterilization position to a high-temperature steam sterilization position. This step is performed before removing the sensor from at least one radiation-sterilized package.

[0041] In the high-temperature steam sterilization position, the first seal element is pressed by the support (5), and as a result, the radiation-sterilized interior of the sensor is sealed liquid-tight and airtight from the surroundings. In the measurement position, at least one seal element, preferably the first seal element (12) and at least the second seal element (13), is pressed by the support (5), and at least a portion of the interior of the sensor, located on the side of at least one seal element that is not on the medium side, is sealed liquid-tight and airtight from the surroundings, preferably the sterilized surroundings, or the medium, preferably the sterilized medium.

[0042] In a preferred embodiment, the sealing element is an O-ring.

[0043] In one embodiment, the support is designed to be cylindrical, preferably upright, and its surface, preferably its outer surface, includes a cavity in which at least one recess and at least one arbitrary sensor element are disposed, preferably the recess is not included in the portion of the support facing the medium (facing the medium).

[0044] The portion of the support facing the medium includes the portion of the support located on the medium side of the recess. At least the first sealing element on the outer tube is pressed by the support in the high-temperature steam sterilization position and is pressed against the portion of the support on the medium side. In the measurement position, the portion of the support located on the side of the recess that is not on the medium side is pressed by at least one sealing element, preferably a first and at least a second sealing element.

[0045] In one embodiment, the outer tube has an opening on the medium side that is designed to bring at least one medium-side end of the support and at least one sensor element located inside the support into contact with the surroundings, and preferably with the medium to be measured, at the measurement position after thermal sterilization, for example, autoclaving, and preferably the surroundings, and more preferably with respect to the medium to be measured, sterilized.

[0046] Thermal sterilization can be performed by dry heat under pressure (typically using hot air at 160°C to 180°C as the sterilization medium) or by using superheated steam as the sterilization medium, such as autoclaving in a pressurized vessel called an autoclave. For example, superheated steam sterilization, which can generate temperatures of at least 120°C, is common. When thermal sterilization is performed in an autoclave, process plant components that come into contact with the process, which may already be connected to each other, are placed in the autoclave, sterilized there, and then removed from the autoclave and put back into operation. Alternatively, the process plant may be sterilized by a method known as SIP (short for "Sterilization in Place"), in which the process vessel to be sterilized, including in-line sensors built into the process vessel, is sterilized by superheated steam introduced into the process vessel for a predetermined time. Therefore, the in-line sensors must be able to withstand the conditions that arise, such as high temperature and high pressure, without losing their function.

[0047] In one embodiment, the sensor interior of the inline sensor contains a desiccant, specifically composed of a hydrophilic material, preferably composed of or containing zeolite, glass, or ceramic, and more preferably composed of or containing aluminum oxide (alumina) and / or titanium oxide (titania) and / or silicon oxide (silica).

[0048] In any embodiment, the inner tube includes at least one, preferably more than one, ventilation opening to establish gas communication between the sensor element and the desiccant placed inside the inner tube. The opening can be designed, for example, as a hole, slit, or gap, and is designed so that the desiccant placed inside the inner tube remains inside the inner tube. Gas communication occurs at both the radiation irradiation position and the high-temperature steam sterilization position.

[0049] In one embodiment, the inline sensor includes, in addition to at least one sensor element, a humidity sensor designed to detect a quantity to be measured that represents the relative humidity in the chamber.

[0050] Additionally or alternatively, the inline sensor includes a temperature sensor designed to detect a measurement representing the temperature inside the sensor. In a preferred embodiment, the temperature sensor is located inside the inner tube of the inline sensor. For example, the temperature sensor is a Pt100 sensor. In one embodiment, the temperature sensor is located within a support, preferably in a recessed area of ​​the support.

[0051] In one embodiment, the inner tube of the inline sensor is designed such that, when the housing is externally heat-sterilized at a temperature of 110°C for 15 minutes, the relative humidity inside the housing does not exceed 77%, preferably 23%, more preferably 3%, and more preferably 1%.

[0052] The housing of the inline sensor may include a wall or outer surface of the housing formed by one or more sensor components that come into contact with the surroundings, sealing the inside of the sensor and forming a barrier against the diffusion of water vapor into the sensor at the high-temperature steam sterilization location. The average water vapor permeability of the wall, i.e., the average value of the water vapor permeability of the components constituting the wall, is 420 g / (m³) under the conditions of a temperature of 110°C, a pressure difference between the chamber and the surroundings of the housing wall of less than 5 bar, and a relative humidity difference between the inside of the chamber and the surroundings of the wall of more than 67%. 2 d) Less than 125 g / (m 2 d) Less than 15 g / (m 2 d) Less than 6 g / (m 2 d) It is desirable that it be less than d

[0053] During high-temperature steam sterilization by SIP, surfaces located within the process vessel that are not airtight or liquid-tight from the surroundings are sterilized.

[0054] In one embodiment, the inner tube is designed such that, when a medium at a temperature of 110°C acts on at least a portion of the outer surface of the housing for 15 minutes, the temperature of the sensor elements rises by less than 55°C, preferably less than 35°C, and more preferably less than 10°C from an initial temperature of 25°C at the start of the 15 minutes, so that at least one sensor element is at least temporarily thermally isolated.

[0055] Alternatively or additionally, the inline sensor may include active and / or passive sensor element cooling means, which release at least a portion of the heat transferred between the outer surface of the housing and the sensor element per unit time, thereby avoiding or delaying temperature changes of the sensor element. For example, the cooling means may include a gas cooling system, a cooling system using a coolant, a thermoelectric element such as a Peltier cooling system, cooling fins, or other heat sinks.

[0056] A cooling system using a coolant and / or coolant gas may preferably be designed as a flow path structure within the housing wall of the inline sensor.

[0057] To improve thermal decoupling, the housing or one or more components constituting the housing should have a thermal conductivity of 0.5 Wm -1 K -1 It is preferable to use the following heat-insulating plastics, particularly PEEK.

[0058] The gas cooling system may include a space filled with an insulating medium, such as air.

[0059] When starting up (operating) the inline sensor, it is preferable to cool the sensor to preferably 8°C or below, more preferably 4°C or below, before heat sterilization. In one embodiment, it is cooled to below 0°C. During heat sterilization, the temperature change of at least one sensor element may be monitored via at least one temperature probe / temperature sensor of the inline sensor.

[0060] In one embodiment, a transport lock on the inline sensor in its mounted state prevents accidental or unintended movement from a heat sterilization position, preferably a high-temperature steam sterilization position, to a measurement position. When the transport lock is removed, the movement is released. In one embodiment, the transport lock includes a predetermined breaking point that irreversibly breaks the transport lock when it is removed. In one embodiment, the transport lock is designed as a first anti-rotation mechanism.

[0061] In one embodiment, the inline sensor has at least one, preferably two, additional anti-rotation mechanisms, which are not configured as transport locks, that prevent the inner tube from rotating relative to the outer tube around the longitudinal axis (L) of the sensor.

[0062] In one embodiment, the outer tube comprises fittings (armatures), piping, process vessels, particularly bioprocess vessels, preferably connection parts for attachment to fermentation tanks, preferably threads, particularly PG13.5 threads.

[0063] The integration of the inline sensor configuration into the process vessel wall may be done via a fitting (armature) or process connection that is tightly, specifically fluid-tightly, i.e., airtightly and / or liquid-tightly connected to the inline sensor configuration. Preferably, this connection ensures that the process vessel is fluid-tightly sealed to its surroundings. This is preferably achieved by one or more sanitary sealing elements designed such that their surfaces, which come into contact with the inside of the process vessel by the SIP process, are sterilizable. For example, this sealing element may be a suitable sanitary molded gasket, essentially known from the prior art relating to fittings and replaceable fittings used in sanitary applications.

[0064] Process vessels include, for example, single-use process vessels (often made of plastic) designed for single-use, and conventional reusable vessels, often made of glass or stainless steel. Process vessels may be designed as small or large bioreactors or fermenters. Sensors are used, for example, in process automation technologies, biotechnology / biological manufacturing methods, particularly in the production of biopharmaceuticals, the life sciences sector, and the food and beverage industry.

[0065] In a preferred embodiment, the inline sensor is designed as a one-way sensor or a single-use sensor.

[0066] In one embodiment, the sensor includes one or more electrodes, and the electrode wires are routed through an inline sensor, preferably through an inner tube of the inline sensor.

[0067] In one embodiment, the inline sensor has an amperometric or potentiometric reference system. This reference system is electrically connected to the inline sensor in an inline sensor configuration and can be located outside the inline sensor. Alternatively, the reference system may be configured as an inline sensor by, for example, placing the reference system inside the sensor, for example, inside the inner tube.

[0068] In one embodiment, the inline sensor is an optical sensor, preferably an optical glucose sensor.

[0069] The present invention further relates to a sensor according to the present invention or a sensor configuration including an embodiment thereof, wherein the inline sensor has an electronic housing on the end opposite to the medium to which a measuring circuit used for acquiring measurement values ​​can be electrically connected, and the measuring circuit is designed to be electrically connected to a higher-level evaluation or control unit that receives and further processes the measurement signal output from the measuring circuit.

[0070] In a preferred embodiment, the measurement circuit is located outside the inline sensor.

[0071] If the sensor is designed as an amperometric sensor, the measurement circuit is responsible for applying a voltage between at least two electrodes of the sensor, detecting the resulting current, and outputting this current or the electrical signal derived therefrom as a measurement signal. An inline sensor may include an evaluation circuit designed to determine a measurement of the quantity under test in units of the quantity under test from the electrical signal output from the measurement circuit and output it via an interface to a higher-level unit or indicator, such as a display. The electronic evaluation device may be incorporated into a measurement transducer that is at least partially located directly at the measurement point, and this transducer has a housing with display and input elements. At least a portion of the electronic evaluation device may be located in a common housing together with the sensor.

[0072] In one embodiment, at least one sensor element of the inline sensor according to the present invention is a biosensor element, the biosensor element includes at least one biological recognition element for analytes, the biological recognition element is preferably a protein, more preferably an enzyme.

[0073] The biological recognition element is preferably embedded in a polymer matrix.

[0074] In one embodiment, at least one sensor element of the inline sensor according to the present invention is an enzyme-based sensor element, preferably lactate oxidase, glutamate oxidase, glutaminase, or glucose oxidase, and more preferably a sensor element containing glucose oxidase.

[0075] The glucose oxidase enzyme, acting as a biocatalyst, converts the analyte glucose into gluconic acid and hydrogen peroxide. This process consumes oxygen. Increases in hydrogen peroxide concentration or decreases in oxygen concentration are recorded amperometrically depending on the selected electrolytic potential.

[0076] The present invention also relates to a method for manufacturing the sensor described in any of the above claims, (i) Position the inner tube at the first radiation irradiation position inside the outer tube, (ii) Attach the transport lock, (iii) The sensor is airtightly packaged in at least one radiation-sterilizable flexible package, preferably at least one radiation-sterilizable bag. Includes steps, Steps (i) to (iii) are carried out under a protective gas atmosphere.

[0077] In a preferred embodiment, the sensor is packaged in two sterilizable flexible packaging, preferably two sterilizable bags. The packaging is suitable for radiation sterilization, preferably gamma ray sterilization. The first inner packaging is preferably optically transparent and more preferably made of a film with higher barrier properties against oxygen and water vapor compared to ordinary polyethylene film. The second outer packaging is preferably optically opaque and more preferably made of a metal composite foil, preferably an aluminum composite foil.

[0078] The present invention also relates to an inline sensor according to the present invention or a method for starting up (operating) an embodiment thereof, (i) Position the inner tube at the first radiation irradiation position inside the outer tube, (ii) Attach the transport lock, (iii) The sensor is airtightly packaged in at least one radiation-sterilizable flexible package, preferably at least one radiation-sterilizable bag. Includes steps, Steps (i) to (iii) are carried out under a protective gas atmosphere. (iv) The sensor, including the sensor element, enclosed in flexible packaging, is sterilized with sterilizing radiation. (v) In a protective gas atmosphere, the sensor is moved from the radiation irradiation position to the high-temperature steam sterilization position by moving the inner tube (3) along the longitudinal axis of the sensor (1) toward the medium to be measured (6) in at least one radiation-sterilized package, preferably a bag, and the inside of the sensor housing the sensor element (5) is sealed in a gamma-ray sterilized protective gas atmosphere. (vi) Remove the sensor from at least one radiation-sterilized package, preferably a bag, (vii) Attach the sensor to the process vessel, (viii) The sensor is preferably heat-sterilized with high-temperature steam, and sterilization is preferably performed by autoclaving or on-site sterilization. (ix) After heat sterilization is complete, remove the transport lock (18) (x) Move the inner tube (3) to the measurement position and bring the sensor element (5) into contact with the medium to be measured, preferably in an aseptic manner. (xi) Connect the electronic equipment housing to the evaluation and / or control unit. Includes steps.

[0079] In one embodiment, prior to step (i), the inner tube is filled with a desiccant. [Brief explanation of the drawing]

[0080] [Figure 1] This is a side view of the inline sensor according to the present invention at the radiation irradiation position. [Figure 2] This is a side view of the in-line sensor according to the present invention at a high-temperature steam sterilization location. [Figure 3] This is a side view of the inline sensor according to the present invention at the measurement position. [Modes for carrying out the invention]

[0081] Figure 1 shows an inline sensor 1, which mainly comprises an inner tube 3 and an outer tube 2. The inner tube 3 is axially movable within the outer tube 2 along the longitudinal axis of the inline sensor. A rotation prevention mechanism 25 prevents the inner tube from rotating relative to the outer tube around the longitudinal axis of the sensor. The inner tube 3 is non-detachably connected at the medium-side end to the end of the support 4 opposite to the medium side, preferably by shape coupling (fitting), and the support contains a sensor element 5. The sensor element 5 is located in a recess 23 of the support. At the radiation irradiation position, the inner tube, the support associated with the inner tube, and the sensor element 5 contained within the support are located on the non-medium side of the first and second sealing elements 12, 13. This creates gaps 22 between the support 4 and the outer tube 2, and between the inner tube 3 and the outer tube 2, which allows the inside of the sensor to be filled with a protective gas, such as argon gas, at the radiation irradiation position for radiation sterilization. The inner tube is also connected hermetically, preferably non-removably, and more preferably by shape coupling, to the electronic equipment housing 16 at the end opposite to the medium. The outside of the inner tube is connected to the shell 17 and a detachably connected fastening element or transport lock 18 at the end opposite to the medium. The fastening element is preferably designed as a transport lock and includes an anti-rotation mechanism, such as a screw. A third sealing element 26 is positioned between the transport lock and the electronic equipment housing, and this sealing element is preferably designed as an O-ring. The sensor has a medium-side / medium-contact side portion and a non-medium-contact side portion. The outer tube 2 has a screw 24, e.g., a PG13.5 screw 24, at the end region of the portion opposite to the medium for mounting the inline sensor 1 to a fitting, process vessel, piping, or fermenter. If the screw 24 is configured as an external screw, the fitting has a corresponding internal screw. The medium-side or medium-contact side portion has a length similar to that of typical sensors used in process automation, i.e., about 120 mm, 225 mm, or 360 mm in length. The inline sensor is packaged in at least one, preferably two, flexible, radiation-sterilizable packaging and sterilized by radiation suitable for disinfection or sterilization, the radiation being ultraviolet, X-ray, gamma rays or electron beams.

[0082] Figure 2 shows the inline sensor 1 in the high-temperature steam sterilization position. The support 4 is surrounded on the medium side by a first sealing element 12, such as a sealing ring, and the inside of the sensor located on the side of the sealing ring that is not on the medium side is airtightly sealed from the surroundings. The transition to the high-temperature sterilization position, preferably the high-temperature steam sterilization position, is easily performed by a first connecting element 9 provided by shape coupling on the outer wall 8 of the outer tube 2 on the side opposite to the medium, and a second connecting element 20 provided by shape coupling inside the shell 17. After moving to the high-temperature sterilization position, preferably the high-temperature steam sterilization position, the sensor is removed from at least one radiation-sterilized package, and a connector 24, preferably a screw, is attached to the container to be sterilized. The connector 24 is preferably attached to the outer wall 8 of the outer tube 2 by mechanical coupling (non-shape coupling). In the high-temperature steam sterilization position, the sensor element is airtight and liquid-tightly isolated from the container sterilized by high-temperature steam.

[0083] Figure 3 shows the inline sensor 1 at the measurement position. After high-temperature sterilization, preferably high-temperature steam sterilization, the sensor is moved to the measurement position. To further move the inner tube axially relative to the outer tube in the direction of the medium to be measured 6, the fastening element, preferably the transport lock 18, is removed. Locking along the longitudinal axis of the sensor is achieved by the interaction of the third and fourth connecting elements.

[0084] All embodiments of the inline sensors and methods described above can be combined in any way as technically possible.

[0085] The symbols should not be understood as limiting the scope of what is protected by the claims. The symbols are used solely to facilitate understanding of the claims. [Explanation of symbols]

[0086] (1) Inline sensor (2) Outer tube (3) Inner tube (4) Support (5) Sensor element (6) Medium to be measured (7) Cavity of the outer tube (8) Outer wall of the outer pipe (9) First linking element (10) Inner wall of the outer tube (11) Third link element (12) First seal element (13) Second seal element (14) Fourth connecting element (15) Outer wall of the inner pipe (16) Electronic equipment housing (17) Shell (18) Fastening elements, transport locks (19) Inside the shell (20) Second link element (21) Third overhang (22) Gap (23) Recess (24) Connections, screws (25) Inner tube rotation prevention mechanism (26) Third seal element (27) Ventilation openings

Claims

1. An inline sensor (1) for measuring a measured value of the amount to be measured, which represents the analyte content in the medium to be measured (6), The sensor comprises an outer tube (2), an inner tube (3), a support (4) non-removably connected to the inner tube (3), and at least one sensor element (5) non-removably connected to the support (4), wherein the inner tube (3) and the support (4), which is non-removably connected to the inner tube and includes at least one sensor element (5), are movable relative to the outer tube (2) in one direction along the longitudinal axis (L) of the sensor (1) and in the direction of the medium to be measured (6), from a radiation irradiation position to a high-temperature steam sterilization position, and from the high-temperature steam sterilization position to a measurement position, and are lockable in both the high-temperature steam sterilization position and the measurement position. (i) The outer tube (2) is A roughly cylindrical cavity (7) and At least one first connecting element (9) on the outer wall (8) of the end opposite to the medium, The third connecting element (11) on the inner wall (10), On the inner wall (10) of the end facing the medium, there is at least one, preferably a first sealing element (12) and at least one second sealing element (13) It has, (ii) The inner tube (3) is The outer wall (15) has a fourth connecting element (14) that is designed to engage with the third connecting element (11) on the inner wall (10) of the outer tube at the measurement position, At the end opposite to the aforementioned medium, Connected to a shell (17), the inside (19) of the shell is provided with at least one second connecting element (20) designed such that one or more first connecting elements (9) snap into the outer wall (8) of the outer tube in the high-temperature steam sterilization position. The electronic equipment housing (16) is airtight and liquid-tightly connected to the inner tube (3) and airtight, liquid-tightly, and detachably connected to a fastening element (18), wherein the fastening element (18) is preferably located at the end and consists of or includes a detachable, preferably screwable, transport lock (18). The transport lock (18) is designed to prevent the inner tube from moving accidentally or unintentionally from the high-temperature steam sterilization position to the measurement position when installed, and to allow movement after removal. The end of the inner tube that is released by the transport lock (18) has at least one third overhang (21) designed to prevent the inner tube (3) and the support (4) including the sensor element (5) associated with the inner tube (3) from moving beyond the measurement position. (iii) The support (4) is non-removably connected to the inner surface of the inner tube at the portion of its outer shell opposite to the medium, preferably at the end facing the medium. (iv) The at least one sensor element (5) is designed to acquire a value that depends on the amount of the medium to be measured, and the sensor element is in gas communication with the inside of the sensor, The support (4) is positioned at the radiation irradiation position within the cavity (7) of the outer tube, and at least one gap (22) is provided between the support (4) and the cavity (7) of the outer tube, so that the inside of the sensor and the sensor element (5) positioned on the support (4) are in contact with the surroundings, preferably in gas communication. In the high-temperature steam sterilization position, the support (4) is positioned such that the end of the support (4) facing the medium airtight seals the sensor element (5) located inside the sensor and within the support (4) to the surrounding area of ​​the sensor. At the measurement position, the support (4) is positioned such that the sensor element (5) is in contact with the surroundings and preferably with the measurement target medium (6) after high-temperature steam sterilization, and preferably the surroundings and the measurement target medium are sterilized. In-line sensor (1).

2. At least the second connecting element (21) is positioned on the shell (17) in a location closer to the end opposite to the medium, along the longitudinal axis (L) of the inline sensor, relative to the third connecting element (11) on the inner wall (10) of the outer tube. The inline sensor (1) according to claim 1.

3. The at least first connecting element (9) and the at least second connecting element (21), and The third connecting element (11) and the at least fourth connecting element (14) are, At least partially, preferably completely, they are complementary to one another. The inline sensor (1) according to claim 1 or claim 2.

4. The first, second, third, or fourth connecting element is provided with a stepped shoulder at the end opposite to the medium to prevent the inner tube from moving in the direction opposite to the measurement position. The inline sensor (1) according to any of the above claims.

5. The first sealing element (12) and any second sealing element (13) surround at least a portion of the support (4) that faces the medium and liquid-tightly and airtightly houses the at least one sensor element (5) in the high-temperature steam sterilization position, and liquid-tightly and airtightly seal the inside of the sensor and the at least one sensor element (5) housed inside from the periphery of the inline sensor (1). The inline sensor (1) according to any of the above claims.

6. The support (5) is designed to be cylindrical, preferably upright, and its surface, preferably outer surface, includes at least one recess (24) in which the at least one sensor element is placed, and any cavity, preferably the recess (24) is not included in the portion of the support (5) that faces the medium. The inline sensor (1) according to any of the above claims.

7. The outer tube (2) has an opening on the medium side designed to bring the end of the support (5) facing the medium and the at least one sensor element (5) disposed within the support into contact with the surrounding, preferably the medium to be measured, at the measurement position, and after high-temperature steam sterilization, the surrounding, preferably the medium to be measured, is sterilized. The inline sensor (1) according to any of the above claims.

8. The sensor contains a desiccant, the desiccant is particularly composed of or contains a hydrophilic material, the desiccant is preferably composed of or contains zeolite, glass, or ceramic, and more preferably contains aluminum oxide and / or titanium oxide and / or silicon oxide. The inline sensor (1) according to any of the above claims.

9. The sensor comprises, in addition to the at least one sensor element, a temperature sensor, preferably located inside the inner tube, configured to measure a measurement value representing the internal temperature of the sensor. The inline sensor (1) according to any of the above claims.

10. The inner tube is designed such that, when the external heat sterilization of the housing is performed at a temperature of 110°C for 15 minutes, the relative humidity inside the housing does not exceed 77%, preferably 23%, more preferably 3%, and more preferably 1%. The inline sensor (1) according to claim 9.

11. The outer tube (2) is equipped with fittings, pipes, process vessels, especially bioprocess vessels, preferably connection parts (24) for attachment to fermentation tanks, preferably threads (24), especially PG13.5 threads. The inline sensor (1) according to any of the above claims.

12. The inline sensor element has at least one, preferably two, anti-rotation mechanisms (25) that prevent the inner tube (3) from rotating relative to the outer tube (2) around the longitudinal axis (L) of the sensor. The inline sensor (1) according to any of the above claims.

13. The sensor has an amperometric reference system or a potentiometric reference system. The inline sensor (1) according to any of the above claims.

14. The at least one sensor element is a biosensor element, and the biosensor element includes at least one biological recognition element for analytes, the biological recognition element is preferably a protein, preferably an enzyme. The inline sensor (1) according to any of the above claims.

15. The aforementioned sensor element is an enzyme-based sensor element, preferably lactate oxidase, glutamate oxidase, glutaminase, or glucose oxidase, and more preferably a sensor element containing glucose oxidase. The inline sensor (1) according to claim 15.

16. An inline sensor configuration (1) including the inline sensor described in any of the above claims, The in-line sensor configuration has an electronic housing at the end opposite to the medium to which a measurement circuit used for acquiring measurement values ​​can be electrically connected, and the measurement circuit is designed to be electrically connected to a higher-level evaluation or control unit that receives and further processes the measurement signal output from the measurement circuit. Inline sensor configuration (1).

17. The measurement circuit is preferably located outside the sensor. The inline sensor configuration according to claim 16.

18. A method for manufacturing a sensor (1) according to any of the above claims, (i) Position the inner tube (3) at the first radiation irradiation position within the outer tube, (ii) Attach the transport lock (18), (iii) The sensor (1) is airtightly packaged in at least one radiation-sterilizable flexible package, preferably at least one radiation-sterilizable bag. The steps include (i) through (iii), which are carried out under a protective gas atmosphere. A method for manufacturing a sensor (1).

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

20. A method for operating an inline sensor (1) according to any one of claims 1 to 16, the method according to claim 18 or 19, followed by the steps of the method according to claim 18 or 19, (iv) The sensor, which includes the sensor element and is enclosed in flexible packaging, is sterilized with sterilizing radiation. (v) In a protective gas atmosphere, within a sterilized package, the inner tube (3) is moved along the longitudinal axis of the sensor (1) in the direction of the medium to be measured (6), thereby moving the sensor from the radiation irradiation position to the high-temperature steam sterilization position, and the inside of the sensor housing the sensor element (5) is sealed in a sterilized protective gas atmosphere. (vi) Remove the sensor from the sterilized bag, (vii) The sensor is attached to the process vessel, (viiii) The sensor is heat-sterilized, preferably by high-temperature steam, and sterilization is preferably performed by autoclaving or on-site sterilization. (ix) After the heat sterilization is complete, remove the transport lock (19) (x) Move the inner tube (3) to the measurement position and bring the sensor element (5) into contact with the medium to be measured, preferably in an aseptic manner. (xi) Connect the electronic equipment housing to the evaluation and / or control unit. Steps including How inline sensors operate.

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