Method for starting up an inline sensor arrangement, inline sensor arrangement and method for its pr

专利摘要:
The invention relates to an inline sensor arrangement and a method for starting up an inline sensor arrangement for acquiring measured values of a measured variable representing an analyte content of a measured medium, wherein the inline sensor arrangement (7) comprises a sensor which is designed to correlate with the measured variable The sensor has at least one provided for contact with the measuring medium sterile sensor element (5) and at least one housing (2) surrounding the sensor element (5) and the sensor element (5) in a relation to an environment of Housing (2) sealed chamber (14), the method comprising the steps of: performing a heat sterilization at least one of a housing outside of the housing (2) comprising part of the inline sensor assembly (7); Opening the housing (2) after completion of the heat sterilization; and bringing the sensor element (3) into contact with the measuring medium. The invention likewise relates to a method for producing an inline sensor arrangement.
公开号:CH711982A2
申请号:CH01693/16
申请日:2016-12-20
公开日:2017-06-30
发明作者:Hanko Michael；Eubisch Angela；Heymann Anne
申请人:Endress+Hauser Conducta Gmbh+Co Kg；
IPC主号:

专利说明:

Description: [0001] The invention relates to a method for starting up an inline sensor arrangement for acquiring measured values of a measured variable representing an analyte content of a measuring medium.
To determine the composition of measuring media, in particular liquids, such. pure liquids, liquid mixtures, emulsions or suspensions, a variety of analytical measuring instruments are used in process measurement technology and in analysis measurement technology. An analysis measuring device generally comprises a sensor, which is designed to generate an electrical measurement signal dependent on at least one analysis measurement variable of the measurement medium, and evaluation electronics which convert the measurement signal into the current value of the at least one analysis measurement variable in the measurement medium measured value. The analysis measurement variable may be, for example, a concentration or activity of an analyte or a parameter dependent on a concentration or activity of at least one analyte in the measurement medium. An analyte is understood as meaning one or more, in particular dissolved, substance or substances contained in the measuring medium, the concentration of which is to be determined or monitored in the measuring medium by means of the sensor. The evaluation electronics can be at least partially integrated in a measuring transducer which is located directly at the measuring point and has a housing with display and input means. At least a part of the evaluation electronics can also be arranged together with the sensor in a common housing.
Such analyzers are used in a variety of fields, e.g. for the monitoring and control of processes in the pharmaceutical, chemical, biotechnological or biochemical production, but also in processes of water treatment or wastewater treatment, as well as in environmental analysis. As far as an analysis measuring device is used in a process, the measuring medium is usually contained in a process container. Such a process container may e.g. a pipeline of a process plant or a reaction vessel, for example a fermenter, be.
Sensors that are integrated in the wall of a process container for monitoring a measured variable of a measuring medium contained in the process container, referred to as inline sensors. An inline sensor records the measured quantity directly in the measuring medium to be monitored. Inline sensors therefore do not require the removal and pretreatment of a sample from the process to determine an analytical process variable. For the integration of a sensor in the process wall manifold adapters and fittings, especially immersion or retractable fittings are known. An arrangement which comprises an in-line sensor integrated in the wall of a process container and, if appropriate, an evaluation electronics connected to the in-line sensor but remote from it, is referred to as an inline sensor arrangement. The in-line sensor can be fixed in the wall by means of a suitable adapter.
In processes that must be performed under sterile or aseptic conditions, as occur for example in biotechnology, pharmacy or food technology, all of the process media in contact with the process media parts of the process plant, in particular before the start of the process or between individual process steps all process containers and also the sensors integrated therein, usually sterilized, for example thermally by heat. The heat sterilization can be carried out by dry heat (usually with hot air between 160 ° C and 180 ° C as a sterilization medium) or by hot steam as a sterilization medium with pressure increase, for example by autoclaving in a pressure vessel, a so-called autoclave. For example, hot steam sterilization processes in which temperatures of at least 120 ° C. or more can occur are common. If the heat sterilization is carried out in an autoclave, the process-contacting parts of the process plant, if necessary, already connected to each other, are introduced into the autoclave and sterilized there. The sterilized parts are then removed from the autoclave and put into operation. Alternatively, a process plant by means of a so-called. SIP method (SIP is the abbreviation for the English term "sterilization in place") are sterilized, in which the process container to be sterilized including the integrated inline sensor arrays is sterilized with hot steam, which has a predetermined period of time is introduced into the process vessel. Inline sensor assemblies must therefore be able to withstand the conditions that occur, such as high temperatures and elevated pressures, without loss of functionality.
In bioprocess measurement, for example for monitoring, controlling and / or regulating biotechnological processes, sensors are also used which have biological recognition elements, e.g. those which, optionally, as receptors, selectively and specifically bind the analyte. Biological recognition elements can be proteins such as enzymes or antibodies, DNAVRNA fragments, cell organelles or whole 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 usually present with greatly reduced activity, mostly denatured irreversibly, i. destroyed in their native 3-D structure (conformation). Such biosensors can therefore in principle not readily be used as inline sensors in the wall of a process container and sterilized with this by means of a common SIP method.
Many sensors with biological recognition elements, e.g. those derived from mesophilic organisms which live in the temperature range of about 20-45 ° C, must not be exposed to elevated temperatures under SIP conditions, for example above 80 ° C, so as not to lose their functionality.
Sterilizable biosensors based on amperometric enzyme sensors are described in the literature. In M. Phelps, Development of a regenerable glucose biosensor sample for bioprocess monitoring, Master Thesis, University of British Columbia, 1993, a review of literature on such sensors is given. Strategies for ensuring a sterilizability of such biosensors while preserving their functionality include introducing the temperature-sensitive receptors arranged on a carrier, for example a working electrode, only after the sterilization process into a reaction space within a sensor housing, which is opposite to a membrane permeable to the respective analyte the process container is closed. In this case, the membrane represents the sterile barrier. The receptors may be immobilized on the subsequently introduced working electrode or in a solution received in the reaction space. When introducing the receptors, the sterile barrier must not be destroyed, making the handling of such in-line sensor arrays difficult.
A disadvantage of these known from the literature inline sensor arrangements in addition to the difficult handling and that a fluctuating measurement performance of the biosensors is observed. One reason for this is that the amount of subsequently introduced receptors is poorly reproducible. The previously known in-line sensor arrangements comprising biosensors are impractical, in particular not with regard to applications for monitoring industrial processes.
In the field of single-use technology, which is being used more and more frequently in bioprocesses, adapters or connectors have become known which allow the introduction of in advance, e.g. sterilized by gamma radiation, sensors in a, also pre-sterilized, disposable bioreactor (English term: single use fermentor) allow. However, these connectors are often unacceptable or not applicable for use in a process vessel multiple times used for a plurality of process batches of a conventional process equipment that is periodically cleaned and sterilized by one of the SIP sterilization methods described above.
The PALL Corporation, Port Washington, USA, for example, offers connectors under the name "Kleenpak II sterile connectors", which serve to introduce liquids or probes or sensors into a disposable process container. These connectors consist of two elements which can be connected to one another, wherein both elements are closed in their connection region in the unconnected state, each with a pull-out strip. The pull-out strips are made of aluminum foil with polyester coating. To introduce a probe into the bioprocess, the first element of the connector can be connected to and sterilized with the process container, the second element containing the probe can be sterilized with gamma sterilization or autoclaving. To insert the probe, the two connector elements are first loosely connected to each other, then the pull-out strips are removed by pulling out later, then the two elements connected tightly together and finally pushed the probe in through the first element of the connector into the process container inside.
A significant disadvantage of these connectors is that the connection between the two elements is not aseptically with high reliability, since the two outer surfaces of the pull-out strips of the elements are not sterile or sterilizable and thus a risk of contamination is given when pulling out of these strips. Furthermore, the risk of contamination is increased by the fact that directly after pulling the pull-out strips, the two elements are not tightly interconnected, whereby contamination by the non-sterile environment can not be excluded.
These connectors are not designed for reusable, sterilizable with SIP process, stainless steel process vessel.
It is therefore the object of the invention to provide an inline sensor arrangement and a method for their commissioning, which overcome the disadvantages described. Preferably, the inline sensor arrangement should also be universally applicable in multiply used, cleanable and sterilizable process containers, and allow the safe aseptic insertion of a sensor element of the inline sensor arrangement into a process vessel for measuring the measured quantity in a medium contained in the process vessel. Preferably, the in-line sensor arrangement should be suitable for introducing a biosensor with biological recognition elements, which does not withstand hot steam sterilization, in a process container to be sterilized at high temperatures.
This object is achieved by a method for starting up an inline sensor arrangement according to claim 1, an inline sensor arrangement according to claim 14 and a method for producing an inline sensor arrangement according to claim 30. Advantageous embodiments are specified in the dependent claims.
The method according to the invention for starting up an inline sensor arrangement for detecting measured values of a measured variable representing an analyte content of a measuring medium, wherein the inline sensor arrangement comprises a sensor which is designed to generate and output a measuring signal correlated with the measured variable, wherein the sensor comprises at least one sterile sensor element provided for contact with the measuring medium and at least one housing which surrounds the sensor element and encloses the sensor element in a chamber sealed against an environment of the housing, comprising the following steps:
Performing a heat sterilization of at least one part of the in-line sensor arrangement comprising a housing outside of the housing; Opening the housing after completion of the heat sterilization; and contacting the sensor element with the measuring medium.
This method allows the aseptic introduction of heat-labile sensors in a process vessel, which has been previously heat sterilized, while maintaining the functionality of the sensors. This is possible by using the in-line sensor arrangement described here and below, which contains a likewise sterile, sensor element located inside a tightly sealed, sterile chamber or which enables sterilization of the interior of the chamber including the sensor element, which in the closed Chamber located sensor element from damage by heat sterilization of the inline sensor assembly from the outside, eg while the in-line sensor assembly is sealingly connected to the process container, and which enables the sensor element to be aseptically contacted with a medium contained in the process container by opening the chamber in the sterilized region of the housing exterior to the interior of the process container ,
The subjected to heat sterilization part of the inline sensor array, for example, the entire with the interior of a sterile to be held process container in contact or to be brought into contact area of the inline sensor array, in particular the entire with the interior of the sterile process container to be held in Contacting housing outside of housing. By heat-sterilizing the outside of the housing, in particular a region of the outside of the housing which is brought into contact or in contact with the interior of the process container to be kept sterile, the sterile sensor element arranged in the chamber can be safely aseptic by opening the housing in this area be brought into contact with the interior of the process container and optionally introduced into this. Because the analyte-sensitive, i. during the heat sterilization of the outside of the housing, the sensor element is tightly enclosed in the chamber for detection of a quantity correlated with the analyte content, it is at least during the heat sterilization in front of a sterilizing medium, e.g. Hot steam, which touches the exterior of the housing during heat sterilization, protected. Although it has been found that biological recognition elements of the sensors described above used in bioprocessing technology can lose a large part of their functionality at high humidity and high temperatures, as occurs in hot steam sterilization, they also retain their heat sterilization properties at low atmospheric humidity temperatures of at least 110 ° C, their functionality substantially. Thus, despite the high temperatures during the heat sterilization of the outside of the housing, the tight enclosure of the sensor element in the chamber may contribute to maintaining the functionality of the sensor element, so that the sensor element subsequently introduced aseptically into the process vessel is functional.
The sensor element may be arranged on a sensor element carrier, wherein the housing adjacent to the sensor element surrounds at least a portion of the sensor element carrier, so that at least this portion is disposed within the chamber formed in the housing.
The measuring signal may be an electrical signal or an optical signal representing a measured value or a chronological sequence of measured values of the measured variable.
For commissioning, the inline sensor assembly may be integrated into a wall of a process vessel prior to heat sterilization, and the heat sterilization of the inline sensor assembly may be performed in a single process step along with heat sterilization of the process vessel, with the interior of the process vessel in contact, now sterilized housing after completion of the heat sterilization process container is opened out. This can be done, for example, in the context of a SIP method. The integration of the in-line sensor arrangement into the wall of the process container can take place by means of a fitting or a process connection, which is sealed to the inline sensor arrangement, in particular fluid-tight, ie. gas and / or liquid-tight, is connected. The connection is preferably such that the process container is sealed fluid-tight with respect to the surroundings of the process container. This is preferably accomplished by means of one or more hygienic sealing elements which are designed such that their surfaces which are in contact with the interior of the process container can be sterilized by means of a SIP method. This sealing element may e.g. a suitable hygienic molded seal, as they are known in principle from the prior art for valves and retractable fittings for use in hygienic applications.
The heat sterilization can also be carried out in an autoclave. In this case, the in-line sensor arrangement can already be connected to the process container and both can be placed in the autoclave and sterilized therein.
For aseptically opening the housing and bringing the sensor element into contact with the measuring medium, the area of the housing which is in contact with the interior of the process container can be designed hygienically, in particular edge-free, burr-free and gap-free.
To ensure that the sensor is not exposed to high humidity during the heat sterilization, the housing of the inline sensor assembly can be configured and sealed the chamber from the environment so that during the heat sterilization of the housing from the outside at a temperature of at least 110 ° C, the relative humidity prevailing inside the housing (also referred to as relative humidity) does not exceed 77%, preferably 23%, more preferably 3%, even more preferably 1%.
During the heat sterilization, the course of the relative humidity within the sensor element enclosing the sensor element can be monitored by means of a humidity sensor of the inline sensor arrangement. The humidity sensor may be part of the inline sensor arrangement.
The housing may comprise a wall formed of one or more housing components, which encloses the chamber gas-tight and which forms a barrier against the diffusion of water vapor into the chamber. Advantageously, an average water vapor permeability of the housing wall, i. an average of the water vapor permeability of the wall-forming components, at a temperature of 110 ° C, a prevailing between the chamber and the environment of the wall pressure difference of less than 5 bar and a difference prevailing in the chamber and in the vicinity of the wall relative humidity greater 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).
The wall or the wall forming housing components may be formed of a material through which water vapor can not or only to a small extent diffuse, e.g. Such a material may be glass, plastic or metal. It is also possible to use a composite material, e.g. a multilayer composite material. A multilayer composite material suitable for this purpose may, for example, comprise at least one plastic layer and one metal layer or a metallized layer. Also, multilayer materials of various plastic materials, e.g. Composite films, can be used for. As PET-PE, PET-PVCD / PE or PE-EVOH-PE or plastic composite films with metallic layers such. a composite of PET-aluminum-PE or aluminum-PET-aluminum. In addition, single or multi-layered aluminum or silica coated plastic materials may be used, e.g. PET-SiOx / PE.
The sensor element may comprise at least one biological recognition element for the analyte. Biological recognition elements can be proteins such as enzymes or antibodies, DNA / RNA fragments, cell organelles or whole cells and microorganisms. For example, the biological recognition element specifically binds the analyte or initiates a chemical reaction with the analyte. For example, the sensor may be an ampero-metric enzyme sensor. For example, as a recognition element, the sensor element may comprise an enzyme which is lyophilisable while retaining at least 10% of its activity. The sensor may be an enzyme-based glucose sensor, e.g. with glucose oxidase as the recognition element. In question here is a glucose oxidase-containing glucose sensor, which is manufactured and offered for sale under the name B.LV5, B.IV4 by Jobst Technologies GmbH, Freiburg, Germany. These amperometric, enzyme-based sensors may also include lactate oxidase as a detection element for lactate sensors, glutamate oxidase for glutamate sensors, glutaminase for glutamine sensors.
In addition or as an alternative to protection against excessively high atmospheric humidity, it may be advantageous, at least temporarily, in particular during the execution of the heat sterilization, to thermally isolate the sensor element from the environment of the housing, i. the environment of a housing outside of the housing, to decouple. The sensor element may be thermally decoupled from the environment of the housing, in particular during the above-described method for starting up until after the end of the heat sterilization. Advantageously, the sensor element is thermally decoupled from the environment of a housing outside of the housing such that during the heat sterilization of the inline sensor assembly, the temperature of the sensor element to less than 80 ° C, preferably less than 50 ° C, more preferably less than 35 ° C increases. In addition or as an alternative to ensuring a low relative humidity within the chamber, this can serve to avoid an impairment of the measuring properties of the sensor element, in particular insofar as it comprises biological recognition elements.
For the purpose of at least temporary thermal decoupling of the sensor element from the environment of the housing, the sensor element, for example, during a heat sterilization, be arranged spaced from the sterilized volume of the process container and by the parts in contact with the sterilization medium. By way of example, the process container may have a connection which surrounds a connection space communicating with the process container, and which is connected before the heat sterilization is carried out with a process connection of the inline sensor arrangement that is complementary to the connection. In this case, the process connection is connected to the housing of the inline sensor arrangement in such a way that the sensor element is arranged on a side facing away from the process container outside the connection space when the process connection and the connection of the process container are connected to one another. For example, an end face of the housing of the inline sensor arrangement can close the connection space if the connection of the process container is connected to the process connection of the inline sensor arrangement. In this case, only the end face of the housing comes into contact with the sterilization medium and is heated by it, while the sensor element is arranged behind the end face at a distance from the end face and is thus exposed to lower temperatures. In this way, a thermal decoupling of the sensor element from the interior of the process container, which can be subjected to heat sterilization, can be achieved.
Advantageously, the in-line sensor assembly can be cooled during its commissioning prior to heat sterilization, preferably to less than 8 ° C, more preferably less than -13 ° C, more preferably less than -20 ° C.
During the heat sterilization, the temperature profile of the at least one sensor element can be monitored by at least one temperature sensor / sensor of the inline sensor arrangement.
A suitable inline sensor arrangement, particularly for carrying out the method described above, for detecting measured values of a measured variable representing an analyte content of a measuring medium comprises: a sensor which is designed to generate and output a measuring signal correlated with the measured variable, wherein the sensor has at least one sterile sensor element provided for contact with the measuring medium, and a housing which surrounds the at least one sensor element and encloses the sensor element in a chamber sealed against an environment of the housing.
The inline sensor arrangement is, as already explained above, in particular designed to aseptically introduce a sensor element, in particular a heat-labile sensor element, into a process container which has been heat-sterilized beforehand. For this purpose, the inline sensor arrangement can be integrated in a wall of a process container, for example by means of a fitting or a container connection. By enclosing the sensor element in a sealed against the environment housing chamber, the likewise sterile sensor element during a heat sterilization of the housing to be brought into contact with or in contact with the interior of the process container housinusenseite of the housing, e.g. can be done together with the heat sterilization of the interior of the process container, be protected from the influence of the sterilization medium, and thus the functionality of the sensor element can be substantially obtained. Subsequently, as described above, the sensor element can be aseptically brought into contact with the interior of the process container or a measuring medium located therein by opening the housing in a region inside the process container and heat-sterilized, in particular together with the process container.
To ensure that the sensor during the heat sterilization of the housing from the outside is not exposed to high humidity, the housing of the inline sensor assembly can be configured and the chamber sealed from the environment so that during the heat sterilization of the housing from the outside at a temperature of 110 ° C, the prevailing within the housing relative humidity does not exceed a value of 77%, preferably of 23%, more preferably of 3%, even more preferably of 1%.
The in-line sensor arrangement may comprise at least one humidity sensor which is designed to detect measured values representing relative humidity within the chamber. The inline sensor arrangement may be further configured to detect a course of the measured values representing the relative humidity prevailing within the chamber by means of the humidity sensor at least during the execution of a heat sterilization of the inline sensor arrangement.
The housing may comprise a wall formed of one or more housing components, which tightly encloses the chamber and which forms a barrier against the diffusion of water vapor into the chamber. Advantageously, an average water vapor permeability of the wall, i. an average of the water vapor permeability of the wall-forming components, at a temperature of 110 ° C, a prevailing between the chamber and the environment of the housing pressure difference of less than 5 bar and a difference prevailing in the chamber and in the vicinity of the wall relative humidity greater 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).
In order to minimize the humidity in the chamber, the chamber may contain a desiccant, for example, silica gel, silica gel or zeolite.
It is also possible that the in-line sensor arrangement at least one leading into the chamber supply line for an anhydrous or water-poor fluid, in particular pure nitrogen or air having a water content of less than 50 ppmv (parts per million by volume) H20, on preferably less than 5 ppmv H20. The supply line may comprise a sterile filter arranged in the flow path of the fluid. It may be connected to a reservoir containing the fluid, in particular nitrogen or air. In the chamber can further lead to a derivative of the fluid, which preferably also includes a sterile filter. The inlet and the discharge are preferably arranged outside the process container.
The at least one sensor element may additionally or alternatively to the measures described above to ensure a low relative humidity within the chamber at least temporarily thermally decoupled from the environment of the housing outer side of the housing or thermally decoupled. For example, it may be thermally decoupled from the outside of the housing of the housing such that during the application of a temperature of 110 ° C having medium on at least a portion of the housing outside over a period of 15 min, the temperature of the sensor element, starting from an initial temperature of the sensor element of ° C at the beginning of this period increases by less than 55 ° C, preferably by less than 35 ° C, more preferably by less than 10 ° C. Such conditions occur, for example, in the case of heat sterilization of the outside of the housing, e.g. in the context of a SIP method carried out in a process container in which the inline sensor arrangement is integrated. In this case, the medium may be, for example, dry hot air or hot steam.
The in-line sensor arrangement can be provided with at least one temperature sensor / sensor which is designed to determine the temperature profile of the at least one sensor element, in particular during a heat sterilization of at least one partial area of the housing exterior.
The thermal decoupling can be achieved for example by a thermal insulation or thermal insulation of the sensor element from the outside of the housing, whereby the per unit time between housing outside and sensor element transmitted amount of heat compared to an embodiment of the inline sensor arrangement, in which no insulation or insulation of the Sensor element is provided from the housing outer side, is reduced, so that the temperature change of the sensor element is avoided or slowed down accordingly. Advantageously, the thermal decoupling is achieved in that between the sensor element and the housing outside a heat-insulating material is arranged and / or that at least temporarily prevails in the housing, a pressure of less than <100 mbar. In this case, a heat-insulating material is understood to mean in particular a homogeneous material of low thermal conductivity or an at least two-phase material with gas-filled cavities, in particular a microporous filling material. The low thermal conductivity material may advantageously have a thermal conductivity of <0.5 W irr1 K "1. The housing advantageously forms a gas-tight surrounding the sensor element chamber.
Alternatively or additionally, the inline sensor arrangement comprise means for active and / or passive cooling of the sensor element, whereby the amount of heat transmitted per unit time between the housing outside and sensor element heat is at least partially derived from the sensor element, so that the temperature change of the sensor element is avoided or slowed down , These means may include, for example, gas cooling, cooling with cooling liquid, Peltier cooling, cooling fins or other heat sink.
In order to enable a thermal decoupling of the sensor element from the outside of the housing by reducing the pressure within the housing, in particular to a pressure of less than <100 mbar, the housing may have an opening into the chamber gas outlet for evacuation, which gas-tight closable is. The housing forms in this embodiment with gas-tight closed gas outlet a gas-tight surrounding the sensor element chamber. The gas outlet may advantageously comprise a sterile filter. Advantageously, the gas outlet is arranged outside the process container when the sensor arrangement is integrated in the process container. The gas outlet may end in a development of this embodiment in a, in particular reversible, sealable connector, which is connectable to a vacuum pump. The housing or the chamber can therefore be evacuated, for example, immediately before the sterilization of the process container, into which the inline sensor arrangement is integrated, is carried out. Alternatively, it is also possible to integrate an in-line sensor arrangement in a wall of the process container, the housing has already been evacuated and then sterilized with a suitable sensor element with a suitable method. Under evacuation is understood here in particular the reduction of the pressure prevailing in the housing to a value <100 mbar. It is advantageous to carry out the sterilization of the housing with included sensor element in the final packaging with gamma rays. To better ensure that there is a suppression in the housing for thermal decoupling from the environment of the outside of the housing of the at least one sensor element, the housing can be vacuum-packed with the included sensor element in the final packaging with a Vakuumier.
In a further embodiment, the in-line sensor arrangement comprises a cooler for at least temporary thermal decoupling of the sensor element from the environment of the outside of the housing for at least temporary cooling of at least part of the inline sensor arrangement.
The cooler may be purely passive in nature, for example, it may comprise a standing with the sensor element in heat-conducting contact heat sink.
Additionally or alternatively, the cooler for actively cooling the sensor element may comprise at least one thermoelectric converter, e.g. a Peltier element. This is advantageously arranged so that it cools a sensitive surface of the sensor element intended for carrying out measurements for contact with the measuring medium.
In a further embodiment, the cooler may comprise a fluid cooling. This can advantageously have a fluid-flow-through channel structure in a sensor element carrier, on which the sensor element is arranged, and / or in the housing wall of the housing.
In order to improve the thermal decoupling, it is advantageous if the housing or at least one or more components forming the housing are formed of a thermally insulating plastic having a thermal conductivity of <0.5 W m_1 K_1, in particular of PEEK ,
For contacting the sensor element or a sensitive surface of the sensor element with a measurement medium located outside the housing, the housing may have a wall region, which is configured to bring the sensor element into contact with the environment of the housing. For example, the wall region may be designed to be opened in order to establish a connection between the sensor element or between the chamber containing the sensor element and the environment of the housing. This range Wan is arranged in a region of the housing, which includes a housing with the interior of the process container in contact or in contact standing outside of the housing.
The sensor element and the wall portion may be movable relative to each other in such a way that the sensor element can be moved out of the housing.
In one embodiment of the inline sensor arrangement, in which the sensor element is arranged on a sensor element carrier, the sensor element carrier can be mounted to be movable relative to the housing, so that a relative movement of the sensor element carrier to the housing causes a transport of the sensor element from the open housing out.
For example, the housing, in particular the chamber containing the sensor element, have a wall region which is designed as a predetermined breaking point. In order to establish a contact between the sensor element and the housing environment, the sensor element carrier may have a tip or edge which is designed such that, upon movement of the sensor element carrier relative to the wall region, which leads to contact of the end section of the sensor element carrier with the wall region, the wall region pierces or cuts. This wall region can be designed, for example, as an end wall of the housing which is in contact with the interior of the process container and / or facing the process container, which wall is formed, for example, by a membrane or film.
Alternatively, the housing may comprise a cap, a cover or a lock arrangement which is movable relative to the housing, so that the housing is opened by a movement of the cap, the cover or the lock assembly relative to a further housing part, such that a Contact between the sensor element and the environment of the housing is made. When the in-line sensor assembly is integrated with the process container, the cap, lid or lock assembly is in contact with the interior of the process container and can be sterilized with heat sterilization together with it, so that actuation of the lock assembly can not cause the nozzle to be sterilized Inside the process container comes into contact with unsterile parts or with a non-sterile environment.
As already described above in connection with the startup procedure, the sensor element can have biological recognition elements. The biological recognition element is, for example, an enzyme which can be lyophilisable while retaining at least 10% of its activity. For example, the sensor element may comprise glucose oxidase. The sensor may e.g. be an amperometric, in particular glucose oxidase comprehensive, en-zym-based sensor.
The housing may be formed of glass and / or have at least one metal layer and / or a layer of plastic and / or a plurality of, in particular acting as a diffusion barrier for water vapor, solid particles, in particular metal particles include , The metal particles may for example be embedded in the form of spheres or platelets in a plastic, which forms a wall or a seal or a splice or a potting of the housing.
The sensor element may comprise one or more electrodes, wherein the electrodes contacting lines extend through a channel formed within a sensor element carrier on which the sensor element is arranged.
The sensor may further comprise a measuring circuit connected to the lines and configured to detect an electrical signal correlating with the measured quantity. In the event that the sensor is designed as an amperometric sensor, the measuring circuit is used to apply a voltage between at least two electrodes of the sensor and to detect the current flowing and output this or an electrical signal derived therefrom as a measurement signal. The in-line sensor arrangement may comprise an evaluation circuit which is designed to determine measured values of the measured variable in the unit of the measured variable from the electrical signals output by the measuring circuit and via an interface to a higher-order unit or via a display device, e.g. a display.
The invention also relates to a method for producing an in-line sensor arrangement according to one of the embodiments described above. The method comprises: producing an in-line sensor arrangement with a sensor which is designed to generate and output a measurement signal correlated with the measured variable, wherein the sensor has at least one sensor element provided for contact with the measurement medium, and with one the sensor element and at least a housing surrounding a portion of the sensor element enclosing the sensor element in a chamber sealed against an environment of the housing; and sterilizing the at least one sensor element of the in-line sensor arrangement arranged in the chamber by means of irradiation by beta or gamma radiation.
The production of the in-line sensor arrangement may further comprise the tight closure of the chamber, wherein a present in the chamber after closure relative humidity is such that during a heat sterilization of the housing from the outside at a temperature of 110 ° C over a Period of 15 min within the
Chamber prevailing relative humidity a value of 77%, preferably of 23%, more preferably of 3%, even more preferably does not exceed 1%.
The method may further comprise thermally decoupling the at least one sensor element from the environment of a housing exterior of the housing.
The invention will be explained in more detail below with reference to the embodiments illustrated in the figures. Show it:
Figure 1 is a schematic representation of a first embodiment of an integrated in the wall of a process container inline sensor arrangement.
FIG. 2 is a schematic representation of a second exemplary embodiment of an inline sensor arrangement integrated in the wall of a process container; FIG.
3 shows a schematic illustration of a third exemplary embodiment of an in-line sensor arrangement integrated in the wall of a process container;
4 shows a schematic representation of a process connection of an inline sensor arrangement which is connected to a connection of a process container.
In Fig. 1 is shown schematically an in-line sensor arrangement 7, which in the wall of a process container 8, e.g. a pipeline or a fermenter is integrated. In the process container 8, a biotechnological, to be protected from contamination process is performed. In order to integrate the in-line sensor arrangement 1 into the process container 8, the inline sensor arrangement 7 may have a process connection (not shown in FIG. 1) which is fluid-tightly connected to a connection of the process container 8 that is complementary to the process connection. Alternatively, the in-line sensor arrangement 1 can be arranged in a fitting which is attached in a fluid-tight manner to a connection of the process container 8.
The in-line sensor arrangement 1 comprises a sensor which is essentially formed by an analyte-sensitive sensor element 5 and a measuring circuit connected to the sensor element 5. The analyte-sensitive sensor element 5 is intended to be brought into contact with it for measuring an analysis measured variable of a measuring medium. The sensor element 5 may for example comprise one or more electrodes which are modified with biological recognition elements. The recognition elements may comprise, for example, immobilized compounds specifically binding to the analyte surface at the electrode surface. As specific binding compounds are e.g. Enzymes or proteins in question. The sensor element 5 is arranged on a sensor element carrier 4. The sensor element carrier 4 is designed rod-shaped in the example shown here. Within the rod-shaped sensor element carrier 4, a float space, e.g. a channel extending in the axial direction, through which the sensor element 6 electrically conducts discharges are guided (not shown here).
At an end facing away from the process, the in-line sensor arrangement 7 has an electronics housing 11, in which the measuring circuit serving to acquire measured values is arranged. The measuring circuit is connected in an electrically conductive manner to the leads guided through the sensor element carrier 4 and is designed to generate electrical measuring signals correlating with the measured variable to be detected. In the example shown here, the sensor of the in-line sensor arrangement 7 is designed as an amperometric enzyme sensor. In this case, the measuring circuit is configured to apply or regulate a voltage between two electrodes of the sensor element 5 and to detect the current flowing through a measuring medium contacting both electrodes. The measuring circuit outputs the detected current or a value derived therefrom, in particular digital, as a measuring signal. The measuring circuit can be connected to a higher-level evaluation or control unit (not shown) which receives and processes the measuring signals output by the measuring circuit. The electronics housing 10 can have an interface, for example a primary side of a plug connection, for connection to the higher-level evaluation or control unit. The evaluation or control unit can be connected to the inline sensor arrangement 7 via a cable which comprises the secondary side of the plug connection.
The in-line sensor arrangement 7 comprises an additional housing 2 which surrounds a section of the sensor element carrier 4 projecting into the process container and comprising the sensor element 5. In the example shown here, the housing 2 comprises a plurality of housing components, namely a tubular shaft 3, which is closed by an end wall 9 at an end projecting into the process container 8, and an end of the shaft 3 opposite the wall with bellows 10 connected thereto The frontal wall 9 may be formed by a metal-plastic composite film, the material fit, eg is connected by means of an adhesive or potting with the tubular shaft 3. On its opposite side of the wall 9, the housing 2 is sealed by a casting (not shown) and connected to the electronics housing 11.
The housing 2 encloses the front, the sensor element 5 comprehensive portion of the sensor element carrier 4 completely in a gas-tight chamber 14, so that no connection between the enclosed in the housing 2 volume of the chamber 14 and the interior of the process container 7 is. The gas-tight chamber 14 contains a
Gas, e.g. Nitrogen, or a gas mixture, for example air. The humidity in the chamber 14 is such that at a temperature of 110 ° C, the relative humidity contained in the chamber is less than 77%. Additionally, a desiccant, e.g. Silica gel, zeolite, silica gel or the like be included to further reduce the relative humidity in the chamber 14.
The housing 2 forms a barrier to the diffusion of water or water vapor from the environment into the chamber. The average water vapor permeability of the housing 2 formed in the present example from a plurality of housing components made of different materials at a temperature of 110 ° C and a pressure difference between the environment and the chamber 14 is less than 5 bar and a difference in relative humidity within the chamber 14 and the environment less than 420 g / m2d or preferably even lower. The various materials of the components of the housing 2 are assembled so that the water vapor permeability of the housing 2 is on average below this value. Examples are PPSU, ECTFE, PEEK, PPS, PFA or PCTFE.
In question come as materials for the tubular shaft 3 glass, metal or plastics, which have a correspondingly low water vapor permeability. These are, for example, metals, or water vapor impermeable plastics.
In question come as materials for a housing, in particular for the tubular shaft or the end wall 9 also composite materials such. multilayer materials comprising at least one layer of a material which provides a high barrier to the ingress of water from the environment. For example, the composite material may comprise a foil having a layer of metal, e.g. Aluminum, and / or a layer of a barrier plastic include. For example, such a composite material may be a metal-coated plastic. In addition, a composite material suitable for the shank 3 or the end wall 9 may also comprise, instead of a continuous layer of the material with a high barrier effect, a plurality of layers in a base material, e.g. a plastic, comprising embedded particles of such a barrier material. The embedded particles may be, for example, metal particles.
The chamber 14 sealing encapsulants, adhesives or gaskets may also be high barrier materials. In particular, they may be formed of a barrier plastic or may be formed of composite materials, e.g. from a solid polymer comprising polymer.
It is possible that a potting or a gasket, which makes up only a small part of the wall bounding the chamber 14 compared to the shaft 3 and the end wall 9, formed from a potting or sealing material conventionally used for liquid analysis sensors are. If these materials have a low barrier effect to water vapor, this can be compensated for by selecting a material with very low water vapor permeability for the shaft 3 or the wall 9 so that the water vapor permeability of all the components of the housing enclosing the chamber 14 is on average below the water vapor permeability above limit remains.
The water vapor permeability of a material is given in the unit g / m2d. It is determined gravimetrically, for example on the basis of DIN 53 122-1 / DIN 53 122-A, by sealing a test container filled with a desiccant with a sample of the material to be investigated and exposing it to a defined test climate. The amount of water permeating the sample is determined by ways. Related standards are ISO 2528: 1995, ASTM E-96.
Before starting a biotechnological process, which is carried out under sterile or aseptic conditions, in the process container 8, the in-line sensor arrangement 7 can be tightly integrated in the housing wall of the process container 8. The chamber 14 and the sensor carrier 4 and the sensor element 5 are already sterile at this time. Sterilization of the chamber 14 and the elements arranged therein can be effected for example by means of irradiation with gamma radiation. The sterilization can advantageously already be carried out by the manufacturer during the production of the sensor element 5 or the inline sensor arrangement 7.
The commissioning of the inline sensor assembly 7 is carried out in the following manner: In a first step, the process container 8 is heat sterilized together with that portion of the outside of the housing 2 of the integrated inline sensor assembly 7, which is in contact with the process container 8, for example by means of a hot steam sterilization. The hot steam acts only on the outside of the housing 2, which is in contact with the interior of the process container. A typical temperature profile of the housing exterior exposed to the hot steam comprises a heating-up phase from an initial temperature, e.g. Room temperature (about 25 ° C), to 140 ° C over a period of 1 h, a phase of, for example, 1 h in length during which the temperature is maintained at 140 ° C and a subsequent cooling phase, during which over a period of, for example 4 h, the housing is cooled back to room temperature. To achieve complete sterilization, sealing elements that seal the connection of the in-line sensor assembly 7 with the process container 8 are hygienically designed, i. their surface areas which are in contact with the interior 6 of the process container 8 are completely accessible and sterilizable for the sterilization medium, in the present example hot steam. Also, the housing outside of the housing 2 which is in contact with the interior of the process container 8 is hygienically designed, i. it has no gaps or ridges or edges that are not completely accessible to the sterilization medium and thus can be sterilized.
After completion of sterilization and after cooling the process to temperatures of less than 80 ° C, preferably less than 60 ° C or even 40 ° C, a contact between the sensor element 5 and the chamber 14 and the interior 6 of the process container 8 in order to enable the acquisition of measured values in a measuring medium contained in the process container 8 or flowing through the process container 8.
In the present example, the process container 8 facing and standing in contact with the interior 6, frontal wall 9 of the housing 4 is designed so thin that it can be penetrated by a mechanical force. The wall 9 facing the end of the sensor element carrier 4 with the sensor element 5 has a tip or edge. Here and in the following description of further embodiments, the term "axially" with respect to a cylinder axis of symmetry of a sensor element carrier or a tubular housing shaft of the inline Sensor arrangement used. The bellows 10 can be contracted in such a way that the difference between the (measured in the axial direction) length of the housing 104 at relaxed state of the bellows 10 and the length of the housing 2 at maximum contracted bellows 10 is greater than the distance between the frontal Wall 9 and the sensor element 5, wherein this distance corresponds to a in the axial direction between the wall 9 and the farthest from the wall 9 arranged point of the sensor element 5 extending route. The inline sensor arrangement 7 can additionally have locking elements (not shown in FIG. 1) which fix the bellows in a contracted position. If the bellows 10 is contracted, the sensor element 5 thus penetrates the wall 9 and projects beyond the front end of the housing 2. In this way, the chamber 14 is opened towards the interior 6 of the process container 8 and the sensor element is brought into contact with a process medium contained in or flowing through the process container 8. The contact between the sensor element 5 and the interior 6 of the process container 8 is effected aseptically, since the sensor element 5 and the interior of the chamber 14 have already been sterilized before opening. There is also no possibility of contact with the non-sterile environment of the process container or with non-sterile parts of the in-line sensor arrangement 7 when the wall 9 is opened. In the contracted position of the bellows 10, the inline sensor arrangement 7 can serve to measure the quantity to be detected to monitor in the process container 8 contained or flowing through this measuring medium.
Alternatively, the in-line sensor arrangement 7 can be subjected to heat sterilization during startup together with the process vessel 8 in an autoclave. The sterilized process container can then be installed together with the sterilized inline sensor arrangement 7 in a biotechnological plant and used to carry out a biotechnological process. The aseptic introduction of the sensor element into the process container takes place in this embodiment in the same way as described above. In particular, a contact with unsterile parts or the unsterile environment is also excluded here.
After the completion of the biotechnological process, the sensor is discarded, since a re-sterilization of the process container 8 with the inline sensor assembly 7 according to the embodiment described here, in which the housing 2 is irreversibly destroyed during startup, is not possible. If the process container 8 is used again in order to carry out a new bioprocess, the inline sensor arrangement 7 is first exchanged for a not yet used, similar inline sensor arrangement 7 with an intact housing 2.
If the components of the housing 2 of the in-line sensor arrangement 7 enclosing the chamber 14 have on average a water vapor permeability of less than 420 g / (m2d), preferably less than 125 g / (m2d), more preferably less than 15 g / (m2d) or even less than 6 g / (m2d), for example, penetrates into the chamber 14 during the heat sterilization so little water vapor with hot steam that the relative humidity within the chamber 14 does not increase over the entire duration of the heat sterilization above a value of 77% or even significantly lower, e.g. below 23% or even below 3%. The relative humidity can remain below 1% even with a suitable choice of material of the housing. Such values may be achieved even if the relative humidity of the air trapped in chamber 14 during inline sensor assembly 7 is up to about 30% at room temperature (25 ° C). It has been shown that under these conditions, despite the high temperatures occurring in the heat sterilization, for example, according to the above-mentioned temperature profile, no destruction of the biological recognition elements occurs. This could be demonstrated, for example, for sensor elements of enzyme-based glucose sensors which comprise glucose oxidase as biological recognition elements, for example the glucose sensors manufactured and offered for sale under the name B.LV5, B.IV4 from Jobst Technologies GmbH, Freiburg, Germany.
The housing 2 may advantageously have an outer diameter of about 12 mm. Many standard valves used in process instrumentation for integrating sensors into the wall of process vessels are designed to accept rod-shaped sensors with an outside diameter of 12 mm. If the housing 2 has an outer diameter of 12 mm, it can easily be integrated into the wall 9 of the process container 8 by means of such conventional fittings.
The manufacture of the inline sensor arrangement 7 can be carried out so that the sensor element carrier 4 is inserted with the sensor element 5 arranged thereon in the already fixed to the wall 9 and the bellows 10 tubular shaft 3, while the housing 2 on his Wall 9 opposite side is still open. In a further step, the housing 2 can then be closed on this side by a casting to form the sensor element carrier 4 and the sensor element 5 surrounding chamber 14, wherein at least the sensor element 5 contacting electrical lines are passed through the potting to outside the chamber 14 to be connected to a measuring circuit. The circuit board comprising the measuring circuit is arranged in the electronics housing 11, which is fixed to the housing 2.
Before closing the chamber 14, the humidity in the chamber can be adjusted so that the relative humidity within the chamber 14 at a temperature of 110 ° C below the above limits remains. For example, a dried gas may be included in the chamber 14 and / or a desiccant may be added to the chamber 14. The manufacture may further include sterilizing the interior of the chamber 14 including the sensor carrier 4 and the sensor element 5 by means of gamma radiation. Alternatively, this can be done shortly before the commissioning of the in-line sensor arrangement 7 by the operator of the installation in which the biotechnological process to be monitored by means of the inline sensor arrangement 7 takes place.
FIG. 2 shows a schematic representation of a further exemplary embodiment of an inline sensor arrangement 107, which is integrated in the wall of a process container 108. The process container may be e.g. to be a pipeline or a fermenter consisting of a material suitable for the process carried out in the process vessel 108, for example biotechnological process, e.g. Stainless steel, is formed. The in-line sensor assembly 107 permits thermal decoupling of a sensor element 105 with biological recognition elements from components exposed to heat sterilization, e.g. In this way it can be ensured that even with a sterilization of the inline sensor array 107 by means of heat sterilization, the biological recognition elements are not exposed to temperatures that lead to a denaturation of the recognition elements and thus to a deterioration of functionality lead the sensor element 105.
The in-line sensor arrangement 107 comprises a sensor, which is essentially formed by an analyte-sensitive sensor element 105 and a measuring circuit connected to the sensor element 105. The sensor element 105 is intended to be brought into contact with the latter for measuring an analysis measured variable of a measuring medium contained in the process container 108. It may, for example, have one or more electrodes which are modified with biological recognition elements, for example analyte-specific binding substances such as enzymes or proteins. The sensor element 105 is arranged on a rod-shaped sensor element carrier 104. Within the rod-shaped sensor element carrier 104, a cavity, e.g. a channel extending in the axial direction, through which the sensor element 106 electrically conducts discharges are guided (not shown here).
At its end facing away from the process, the in-line sensor arrangement 107 has an electronics housing 111, in which the measuring circuit serving to acquire measured values is arranged. The measuring circuit is connected in an electrically conductive manner to the leads guided through the sensor element carrier 4 and is designed to generate electrical measuring signals correlating with the measured variable to be detected. The measuring circuit can be designed analogously to the measuring circuit of the embodiment shown in FIG. It can also be connected to a higher-level evaluation or control unit which receives and processes the measurement signals output by the measurement circuit. The electronics housing 111 can have an interface, for example a primary side of a plug connection, for connection to the higher-level evaluation or control unit. The evaluation or control unit can be connected to the inline sensor arrangement 107 via a cable which comprises the secondary side of the plug connection.
The in-line sensor arrangement 107 comprises an additional housing 102 which surrounds a portion of the sensor element carrier 104 projecting into the process container 108 and comprising the sensor element 105, and in a relation to the surroundings of the inline sensor arrangement, in particular with respect to the interior of the process container 108 gastight sealed, chamber 114 includes. In the example shown here, the housing 102 has a tubular shaft 103 and a wall 109 closing off the tubular shaft 103 at the front. On the wall 109 opposite side of the tubular shaft is closed by a potting and sealed. The chamber 114 enclosed in the housing 102 may be a gas, e.g. Nitrogen, or a gas mixture, for example air.
A gas line is guided through the electronics housing 111, whose first end opens into the interior of the housing 102, more precisely into the chamber 114, and whose second end has a connector 101. The connector 101 may be attached to the electronics housing 111. Advantageously, the connector 101 can be designed as a sterile connector. In order to reduce the pressure prevailing inside the housing 102, the connector 101 may be connected to a vacuum pump. The evacuation of the housing 102 or the lowering of the pressure prevailing in the housing 102 to a value of less than 100 mbar serves the thermal decoupling of the sensor element 105 arranged on the sensor element carrier 104 from the outside of the housing 102, i. the outer surface of the housing wall pointing towards the surroundings of the housing 102 or from the environment of the outside of the housing 102. The inside, i. the housing inner wall facing the chamber 114 of the housing 102 may be mirrored as a further measure for thermal decoupling.
To start up the in-line sensor arrangement 107, it can be integrated into the process container 108 in its housing wall prior to the start of a bioprocess. The chamber 114 and the sensor carrier 104 and the sensor element 105 are advantageously already sterile at this time. Advantageously, the sensor element 105 is thermally decoupled at this time even from the environment of the housing outside or outwardly directed housing wall surface. A sterilization of the interior of the housing 102 and the elements arranged therein can be effected for example by means of irradiation with gamma radiation. The sterilization can advantageously be carried out as well as the evacuation of the housing 102 already by the manufacturer in the manufacture of the inline sensor arrangement 107.
For thermal decoupling of the sensor element 104 from the outside of the housing 102, the volume trapped by the housing 102 can be evacuated by means of a vacuum pump connected to the connector 101 before or even after integration of the inline sensor arrangement 107 into the process vessel 108. wherein a pressure of less than 100 mbar is generated in the housing 102. Subsequently, the process container 108 can be sterilized together with the integrated inline sensor arrangement 107, for example by means of hot steam sterilization. The hot steam acts only on the outside of the housing 102. The evacuation of the housing 102 causes in addition to the insulating properties of the housing a thermal insulation of the sensor element 105 relative to the housing exterior. Thus, in a heat sterilization in which the outside of the housing, i. the outwardly directed wall surface of the housing 102 is exposed to a sterilization medium of a temperature of at least 110 ° C, at the location of the sensor element temperatures of <80 ° C, preferably <40 ° C. These do not affect the activity of the biological detection elements of the sensor element 102 and thus the functionality of the sensor or in a mass that, despite activity reduction to up to 10%, the sensitivity of the sensor is sufficient to monitor the respective process or the flowing process medium.
After completion of sterilization and after cooling the housing outside of the housing 102 and the environment of the inline sensor assembly 107 to less than 80 ° C, preferably less than 60 ° C or even as 40 ° C, a contact between the sensor element 105 and the chamber 114 and the interior of the process container 108 in order to introduce the sensor element 105 aseptically into the process container 108 and thus to enable the acquisition of measured values in a measuring medium contained in the process container 108 or flowing through the process container 108. In the present example, the end wall 109 of the housing 102 is designed so thin that it can be pierced by a mechanical force. The wall 109 facing the end of the sensor element carrier 104 with the sensor element 105 has a tip or edge. The sensor element carrier 104 is axially movably mounted, for example by means of a ballpoint pen mechanism, wherein the sensor element carrier 104 is movable so far in the axial direction relative to the wall 109, that the front edge or tip of the sensor element carrier 104 pierces the wall 109 and so far on the front side End of the housing 102 is moved out into the process container 108 that the sensor element 105 projects into the process container 108. In this position, the in-line sensor arrangement 107 can serve to monitor the measured variable to be detected of a process medium contained in or flowing through the process container 108.
Already in the production of the inline sensor arrangement 107, in which the sensor element 105 is tightly enclosed on the sensor element carrier 104 in the housing 102 or in the chamber 114 formed in the housing 102, the housing 102 or the chamber 114 first evacuated and then sterilized the housing interior with the sensor element 105, eg by gamma radiation. A user must then integrate the inline sensor arrangement 107 during commissioning only in a wall of a process container and can perform the same heat sterilization.
In order to prevent destruction of the biological recognition elements during heat sterilization of the process container 108 with the inline sensor assembly 107 integrated therein, the thermal decoupling of the sensor element 105 from the sterilization medium, here hot steam, exposed housing exterior of the inline serves In addition to this thermal decoupling, modifications to the in-line sensor assembly 107 described herein may advantageously be taken to maintain the relative humidity within the chamber 114 below a value of 77% or less during heat sterilization. As explained above, such a denaturation of the recognition elements can also be prevented. Conceivable measures for avoiding too high relative humidity in the chamber 114 are, for example, the use of materials with a low water vapor permeability of the components surrounding the chamber 114, as described with reference to the embodiment shown in FIG. 1, adding a desiccant to the chamber 114 the production of the in-line sensor arrangement 107 or the supply of an anhydrous or low-water fluid, in particular pure nitrogen or air having a water content of less than 50 ppmv H20, or even less than 5 ppmv H20 via a sterile filter, the fluid before entering into the chamber 114 happens, eg via the connector 101.
FIG. 3 schematically shows a further exemplary embodiment of an inline sensor arrangement 207. This in-line sensor arrangement 207 comprises a sensor with a sensor carrier 204, on which an analyte-sensitive sensor element 205 is arranged. These can be configured in the same way as the sensor or the sensor element carrier 4 and the sensor element 5 of the inline sensor arrangement 7 previously described with reference to FIG. 1. The sensor element 205 is connected via electrical lines which are within a channel formed in the sensor element carrier 204 can be guided, connected to a measuring circuit which is arranged in an electronics housing 211. The measuring circuit is designed to generate a measuring signal which is dependent on the measured variable detected by the sensor element 205 and to a higher-level unit, e.g. a transmitter. The measuring circuit and the higher-level unit can be connected to one another, for example, via a cable or via a radio link.
The sensor carrier 204 with the sensor element 205 is rigidly connected to the electronics housing 211 in the exemplary embodiment shown here. The electronics housing 211 closes at the rear a substantially cylindrical housing 202, which surrounds the sensor element carrier 204 with the sensor element 205 and encloses in a gas-tight manner in a chamber 214. This housing 202 is tightly secured in a wall of a process container 208 by means of a connecting device, not shown, so that the in-line sensor arrangement 207 is integrated into the process container 208. The housing 202 completely shields the sensor element 205 and the sensor element carrier 204 from the process container 208 by inclusion in the chamber 214.
The housing 202 comprises a wall region designed as a bellows 210. The bellows 210 can be contracted in such a way that the difference between the (measured in the axial direction) length of the housing 202 in the relaxed state of the bellows 210 and the length of the housing 202 at maximum contracted bellows 210 is greater than the distance between the frontal , the process container 208 facing the wall 209 of the housing 202 and the sensor element 205, said distance corresponding to a distance extending in the axial direction between the wall 209 and the farthest from the wall 209 arranged point of the sensor element 205 distance. The inline sensor arrangement 207 may additionally comprise locking elements (not shown in FIG. 2) which fix the bellows 210 in a contracted position.
The wall 209 may be formed as a membrane or as a relatively thin wall portion. For example, the wall may be a moisture impermeable film having at least one metallic layer having a low water vapor permeability. The end of the sensor element carrier 204 facing the wall 209 may have an edge or apex adapted to pierce the wall 209 and thus direct the chamber 214 towards the process container 208 by establishing communication between the interior of the housing 202 and the interior of the process container 208 to open.
For thermal decoupling of the sensor element 205 from the housing outer side of the housing 202, a Peltier element 212 is used, which is in surface contact with the sensor element carrier 204 facing the rear side of the sensor element 205. Electrical connections of the Peltier element 212 may be contacted via leads passing through the channel formed in the sensor element carrier 204. The Peltier element 212 can thus be operated by means of the measuring circuit. For heat dissipation, the Peltier element 212 may be in contact with a heat sink. This may include a fluid cooling formed within the sensor element carrier 204. By way of example, the fluid cooling can have a fluid-flowed cooling circuit formed as a channel structure within the sensor element carrier 204.
In alternative embodiments, it is also possible to actively cool the sensor element 205 solely by means of fluid cooling. This may be formed within the sensor carrier and / or within the housing interior of the housing 202 or within the wall of the housing 202. In another alternative embodiment, the heat sink cooperating with the Peltier element 212 may be formed of a material having a high heat capacity and / or a large surface, for example in the form of cooling plates or fins.
Before or after the integration of the in-line sensor arrangement 207 into a wall of the process container 208, the interior of the housing 202 can be sterilized with the sensor element 205 located therein in the chamber 214 and the sensor element carrier 204 by irradiation with gamma radiation.
When the process container 208 and the inline sensor arrangement 207 are put into operation, hot steam sterilization with the inline sensor arrangement 207 integrated into the wall of the process container 208 can be carried out in the form of a SIP method. At the same time takes place for thermal decoupling of the sensor element 205 from the hot steam exposed housing exterior, i. the outwardly directed wall surface of the housing 202 active cooling of the sensor element 205 by means of the Peltier element 212. Due to the action of the hot steam on the housing outer surface of the housing 202, this heats up to temperatures up to 120 ° C. At the same time, the thermally decoupled sensor element 205 is heated at most up to 80 ° C., preferably less than 40 ° C., so that the functionality of the sensor element 205 and thus of the sensor is maintained.
After completion of the sterilization, in particular after the temperature prevailing in the process container 208 has dropped to less than 60 ° C, preferably less than 40 ° C, the cooling of the sensor element 205 can be terminated. For contacting the sensor element 205 with the interior of the process container 208 or with a process medium contained in the process container 208, by exerting an axially acting force on the electronics housing 211 of the sensor element carrier 204 with the sensor element 205 disposed thereon on the frontal wall 209 of Housing 202 to be moved. In this case, the bellows 211 is contracted. With the front edge or tip of the sensor element carrier 204 in this way, the wall 209 can be pierced, and so the sensor element 205 aseptically be brought into contact with the interior of the process container 208. As described above, the bellows 210 is configured such that upon complete contraction of the bellows 210, the sensor element 205 extends beyond the length of the housing 202 so that the sensor element 205 is in contact with and in contact with the interior of the process container 208 Process medium can record measured values of the measured variable.
Due to the thermal decoupling of the sensor element 205 during the hot steam sterilization, impairment of the functionality of the sensor element 205 is effectively prevented, even if it comprises biological recognition elements in the form of denaturable enzymes or proteins. Additionally or alternatively, the in-line sensor assembly 207 may be configured such that during hot steam sterilization, the relative humidity within the chamber 214 remains below a value of 77%. For this purpose, the measures already described above in connection with the exemplary embodiments described in FIGS. 1 and 2 are suitable.
FIG. 4 shows a further exemplary embodiment of an inline sensor arrangement 307 in which a thermal decoupling of a sensor element 305 from a housing outside of the inline sensor arrangement 307 which is in contact with the interior of a process container 308 is achieved in that the sensor element from the process container 308, is arranged at a distance.
The in-line sensor arrangement 307 comprises in this embodiment, similar to the inline sensor arrangements of the previously described embodiments, the aforementioned sensor element 305, which may comprise, for example, an electrode modified with biological recognition elements for specific interaction with an analyte. The sensor element 305 is arranged on a rod-shaped sensor element carrier 304. Sensor element 305 and sensor element carrier 304 are surrounded by a housing 302, which comprises a tubular shaft 303, which is closed at an end facing the process container 308 by an end wall 309. At its other end, the tubular shaft 303 merges into a bellows 310. The housing 302 is sealed on its side opposite the wall 309, for example by means of a potting (not shown here), so that the housing 302 encloses a gastight chamber 314, in which the sensor element carrier 304 and the sensor element 308 are enclosed.
The in-line sensor arrangement 307 also has an electronics housing 311, in which a measuring circuit is housed, which is connected to the sensor element 305 in order to generate and output electrical measurement signals, which are correlated with the measured value detected by the sensor element 305 , The measuring circuit can be designed like the measuring circuits of the embodiments previously described with reference to FIGS. 1 to 3.
The housing 302 has, at its end associated with the process container 308, a process connection 315, which in the present example comprises a flange. This process connection 315 is connected to a complementary container connection 313 of the process container 308, for example by means of a fixation 316, e.g. a union nut. In the present example, the process connection 315 and the housing 302 are connected to one another such that the end wall 309 of the housing 302 lies in a plane with the surface of the process connection 315 which bears against the container connection 313. In this way, in a heat sterilization of the process container 308 by introducing a sterilization medium into the process container 308 only the end wall 309 with the hot steam in contact, but not the tubular side wall 303 of the housing 302 or other the chamber 314 surrounding components of the inline sensor assembly 307th ,
This is, more generally, achieved by having the container port 313, i. the tube attached to the container and the container-side flange connected thereto surround a connection space 317 which communicates with the interior 306 of the process container 308 and which is closed by the wall 309 at its end remote from the process container 308. In this way, it is ensured that a sterilization medium reaching into the process container 308 comes into contact only with the wall 309, but not with the other components of the inline sensor arrangement 307 which are in contact with the chamber 314. The process connection 315 is thus connected to the housing 302 of the inline sensor arrangement 307 in such a way that the sensor element 305 is arranged on the side of the housing wall facing away from the process vessel 308 and thus outside the connection space 317, when the process connection 315 and the container connection 313 are connected to one another are. In such an arrangement, the axially spaced from the wall 309 sensor element 305 is heated less than in an arrangement such as shown in Fig. 1, in which the side wall 3 of the housing 2 in a heat sterilization of the process container 8 in direct contact with a Sterilization medium used for this purpose comes.
The commissioning of the in-line sensor arrangement and the aseptic contacting of the sensor element 305 with a measuring medium contained in the process container 308 can otherwise take place in the same way as the startup of the inline sensor arrangement 207 described with reference to FIG ,
Further modifications and refinements of the inline sensor arrangement according to the invention are conceivable. For example, the housing surrounding the sensor element carrier and the sensor element and separating them from the interior of the process container during sterilization of the process container may also be designed in such a way that the connection between the sensor element and the interior of the process container is reversible. For this purpose, the housing wall may comprise, for example, an opening which can be closed reversibly by means of a lid or a cap in order to seal off the sensor element from the process container and which can be opened if a connection is to be established between the sensor element and the interior of the process container. The housing may also be formed by a treatment chamber of a submersible or retractable fitting or a lock device, which is designed such that the sensor element can be retracted with the sensor element carrier for measurement in the process container or retracted from the process container into a closed relative to the process vessel chamber can be. The chamber and / or the sensor element carrier can in this

权利要求:
Claims (32)
[1]
Case means for thermally decoupling the sensor element from the outside in contact with the interior of the process vessel, i. have the outwardly directed wall surface of the chamber or the housing. In all of these embodiments, repeated use of the housing for aseptically contacting Brin gene of a, in particular heat and / or moisture-sensitive sensor element with a measuring medium, which is contained in a pre-heat sterilized process container, without removing the whole inline sensor array possible, ie the same housing may remain in the wall of the process container for several production batches with sterilization of the process container carried out between the individual batches. It is particularly possible that the housing is permanently integrated in the process container, while the sensor element carrier and the sensor element arranged thereon can be exchanged for a structurally identical, other sensor element carrier and a sensor element arranged thereon. claims
1. A method for starting up an inline sensor arrangement for acquiring measured values of a measured variable representing an analyte content of a measuring medium, wherein the inline sensor arrangement comprises a sensor which is designed to generate and output a measuring signal correlated with the measured variable, wherein the sensor is at least a sterile sensor element provided for contact with the measuring medium and at least one housing surrounding the sensor element and enclosing the sensor element in a sealed against an environment of the housing chamber, the method comprising the steps of: - performing a heat sterilization at least one housing outside of the Housing comprehensive part of the inline sensor assembly; -Opening the housing after completion of the heat sterilization; and - bringing the sensor element into contact with the measuring medium.
[2]
2. The method of claim 1, wherein the opening of the housing and the bringing into contact of the sensor element with the measuring medium takes place aseptically.
[3]
3. The method of claim 1 or 2, wherein the in-line sensor assembly is tightly integrated into a wall of a process vessel prior to performing the heat sterilization, and the heat sterilization of the inline sensor array is performed in a single process step along with heat sterilization of the process vessel, and wherein the housing is opened after completion of the heat sterilization to the process container.
[4]
4. The method according to any one of claims 1 to 3, wherein performing the heat sterilization of the inline sensor array is carried out in an autoclave.
[5]
5. The method according to any one of claims 1 to 4, wherein the housing is configured and the chamber is sealed from the environment such that during the heat sterilization of the housing from the outside at a temperature of at least 110 ° C, the prevailing within the housing relative humidity Value of 77%, preferably of 23%, more preferably of 3%, even more preferably of 1%.
[6]
6. The method according to any one of claims 1 to 5, wherein the inline sensor arrangement has at least one moisture sensor and wherein by means of the humidity sensor at least during the execution of the heat sterilization a course of a prevailing within the housing moisture is detected.
[7]
A method according to any one of claims 1 to 6, wherein the housing has a wall formed of one or more housing components which tightly encloses the chamber and which forms a barrier to diffusion of water vapor into the chamber, the wall of one or more chambers a plurality of housing components is formed, and wherein the wall on the average at a temperature of 110 ° C, a prevailing between the chamber and the environment of the housing pressure difference of less than 5 bar and a difference prevailing in the chamber and in the vicinity of the wall relative Moisture greater than 67% has an average water vapor transmission of 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).
[8]
8. The method according to any one of claims 1 to 7, wherein the sensor element comprises at least one biological recognition element for the analyte, in particular a while retaining at least 10% of its activity lyophilisable enzyme.
[9]
9. The method according to any one of claims 1 to 8, wherein the sensor element is a, in particular glucose oxidase comprehensive, enzyme-based glucose sensor.
[10]
10. The method according to any one of claims 1 to 9, wherein the at least one sensor element is at least temporarily, in particular during the implementation of the heat sterilization, thermally decoupled from the environment of a housing outer side of the housing.
[11]
11. The method of claim 1, wherein the process vessel has a port surrounding a port space communicating with the process vessel, and prior to performing the heat sterilization, is connected to a process port of the in-line sensor array that is complementary to the port the process connection is connected to the housing of the inline sensor arrangement in such a way that the sensor element is arranged outside the connection space on a side facing away from the process container, when the process connection and the connection of the process container are connected to one another.
[12]
12. The method of claim 1, wherein the method further comprises: prior to performing the heat sterilization, cooling the in-line sensor assembly, preferably to less than 8 ° C, more preferably to less than -13 ° C, more preferably less than -20 ° C.
[13]
13. The method according to any one of claims 1 to 12, wherein the inline sensor arrangement comprises at least one temperature sensor / sensor and wherein the temperature profile of the at least one sensor element is monitored during the heat sterilization by the at least one temperature sensor / sensor of the inline sensor arrangement ,
[14]
14. Inline sensor arrangement for acquiring measured values of a measurement variable representing an analysis behavior of a measuring medium, comprising: a sensor which is designed to generate and output a measurement signal correlated with the measured variable, wherein the sensor has at least one intended for contact with the measurement medium having sterile sensor element; and - a surrounding the at least one sensor element housing, which encloses the sensor element in a sealed relative to an environment of the housing chamber.
[15]
15. Inline sensor arrangement according to claim 14, wherein the housing and the enclosed therein chamber configured in such a way and the chamber is sealed from the environment such that in a heat sterilization of the housing from the outside at a temperature of 110 ° C over a period of 15 min the relative humidity prevailing inside the housing does not exceed a value of 77%, preferably of 23%, more preferably of 3%, even more preferably of 1%.
[16]
16. Inline sensor arrangement according to claim 14, wherein the in-line sensor arrangement has at least one moisture sensor which is designed to detect measured values representing relative humidity prevailing inside the chamber.
[17]
17. Inline sensor assembly according to one of claims 14 to 16, wherein the housing comprises a wall formed from one or more housing components, which encloses the chamber sealed, with an average water vapor permeability of the wall at a temperature of 110 °, one between the chamber and the prevailing pressure difference of less than 5 bar in the vicinity of the wall and a difference of more than 67% in the chamber and in the vicinity of the wall relative humidity 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).
[18]
18. Inline sensor arrangement according to one of claims 14 to 17, wherein the chamber contains a desiccant.
[19]
19. Inline sensor arrangement according to one of claims 14 to 18, further comprising at least one opening into the chamber supply line for an anhydrous or low-water fluid.
[20]
20 inline sensor arrangement according to one of claims 14 to 19, wherein the at least one sensor element is at least temporarily thermally decoupled from the environment of a housing outer side of the housing or thermally decoupled.
[21]
21. Inline sensor arrangement according to claim 20, wherein the at least one sensor element is at least temporarily thermally decoupled from the environment of the housing outside of the housing such that during the action of a temperature of 110 ° C having medium on at least a portion of the housing outer side over a period 15 minutes, the temperature of the sensor element, starting from an initial temperature of the sensor element of 25 ° C at the beginning of this period by less than 55 ° C, preferably by less than 35 ° C, more preferably by less than 10 ° C, increases.
[22]
22. Inline sensor arrangement according to one of claims 14 to 21, wherein the inline sensor arrangement is provided with at least one temperature sensor / sensor, which is configured to detect the temperature of the at least one sensor element representing measured values.
[23]
23 inline sensor arrangement according to one of claims 20 to 22, wherein the at least one sensor element is at least temporarily thermally decoupled from the environment of the housing outside characterized in that between the sensor element and the housing outside a heat-insulating material is arranged and / or that at least temporarily in the housing has a pressure of less than <100 mbar.
[24]
24. Inline sensor arrangement according to claim 23, wherein the housing has a gas outlet opening into the chamber for evacuation, which can be closed in a gas-tight manner, and wherein the housing forms a gas-tightly closed gas outlet a gas-tight surrounding the sensor element chamber.
[25]
25. Inline sensor arrangement according to one of claims 14 to 24, comprising one of the at least temporary thermal decoupling of the sensor element from the environment of the housing exterior serving radiator for at least temporary cooling of at least a portion of the inline sensor array.
[26]
26. Inline sensor arrangement according to one of claims 14 to 25, wherein the housing has a wall portion which is adapted to bring the sensor element in contact with the environment of the housing.
[27]
27. Inline sensor arrangement according to claim 26, wherein the sensor element and the wall area relative to each other are movable in such a way that the sensor element can be moved out of the housing.
[28]
28. Inline sensor arrangement according to one of claims 14 to 27, wherein the sensor element biological recognition elements, in particular at least one retaining at least 10% of its functionality lyophilisable enzyme.
[29]
29 inline sensor arrangement according to one of claims 14 to 28, wherein the housing is formed of glass and / or at least one metal layer and / or a layer of plastic and / or a plurality of solid particles, in particular metal particles , includes.
[30]
30. A method for producing an inline sensor arrangement according to claim 14, comprising: producing an inline sensor arrangement with a sensor which is designed to generate and output a measurement signal correlated with the measured variable, wherein the sensor has at least one for Having contact with the measuring medium provided sensor element, and with a surrounding the sensor element and at least a portion of the sensor element housing, which encloses the sensor element in a sealed against an environment of the housing chamber; and sterilizing the at least one sensor element of the in-line sensor arrangement arranged in the chamber by means of irradiation by beta or gamma radiation.
[31]
31. The method of claim 30, wherein the manufacturing of the in-line sensor assembly comprises: - Gas-tight closure of the chamber, wherein an existing in the chamber after closure humidity is such that upon heat sterilization of the housing from the outside at a temperature of 110 ° C over a period of 15 min, the prevailing within the chamber relative humidity does not exceed a value of 77%, preferably of 23%, more preferably of 3%, even more preferably of 1%.
[32]
32. The method of claim 30 or 31, further comprising: - thermally decoupling the at least one sensor element from the environment of a housing outside of the housing.

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同族专利:

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公开号 | 公开日

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US10705044B2|2020-07-07|

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CN107014426B|2020-01-14|

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CH711982B1|2020-09-15|

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法律状态:
2020-09-30| PFA| Name/firm changed|Owner name: ENDRESS+HAUSER CONDUCTA GMBH+CO. KG, DE Free format text: FORMER OWNER: ENDRESS+HAUSER CONDUCTA GMBH+CO. KG, DE |

优先权:

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申请号 | 申请日 | 专利标题

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DE102015122446|2015-12-21|

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DE102016124647.6A|DE102016124647A1|2015-12-21|2016-12-16|Method for commissioning an inline sensor arrangement and inline sensor arrangement|

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