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EP3768817A1 - Dispositif et procédé pour le prélèvement stérile d'échantillons - Google Patents

Dispositif et procédé pour le prélèvement stérile d'échantillons

Info

Publication number
EP3768817A1
EP3768817A1 EP19712977.8A EP19712977A EP3768817A1 EP 3768817 A1 EP3768817 A1 EP 3768817A1 EP 19712977 A EP19712977 A EP 19712977A EP 3768817 A1 EP3768817 A1 EP 3768817A1
Authority
EP
European Patent Office
Prior art keywords
valve
shut
bioreactor
sensor
line
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19712977.8A
Other languages
German (de)
English (en)
Inventor
Bernd-Ulrich Wilhelm
Jan MILLAUER
Ronnie WILHELM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BBI Biotech GmbH
Original Assignee
BBI Biotech GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BBI Biotech GmbH filed Critical BBI Biotech GmbH
Publication of EP3768817A1 publication Critical patent/EP3768817A1/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M23/00—Constructional details, e.g. recesses, hinges
    • C12M23/40—Manifolds; Distribution pieces
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
    • C12M33/12—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus by pressure
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M27/00—Means for mixing, agitating or circulating fluids in the vessel
    • C12M27/02—Stirrer or mobile mixing elements
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M29/00—Means for introduction, extraction or recirculation of materials, e.g. pumps
    • C12M29/14—Pressurized fluid
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M33/00—Means for introduction, transport, positioning, extraction, harvesting, peeling or sampling of biological material in or from the apparatus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M37/00—Means for sterilizing, maintaining sterile conditions or avoiding chemical or biological contamination
    • C12M37/02—Filters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M37/00—Means for sterilizing, maintaining sterile conditions or avoiding chemical or biological contamination
    • C12M37/04—Seals
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/48—Automatic or computerized control
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/02—Devices for withdrawing samples
    • G01N1/10—Devices for withdrawing samples in the liquid or fluent state
    • G01N1/14—Suction devices, e.g. pumps; Ejector devices
    • G01N2001/1418—Depression, aspiration

Definitions

  • the application relates to a sampling device and a method of using the device.
  • EP 2305790 shows such a device, wherein a sample can be manually removed by means of a sterile syringe with a so-called Luer-Lock cone via a connection of autoclavable culture vessels.
  • the device comprises a self-opening when placing the syringe and automatically closing when removing automatic valve.
  • the device is characterized in that between the automatic valve and the connection is provided a closing valve which closes towards the automatic valve.
  • the device of EP 2305790 further shows a spur with an air filter and a check valve, which via a tee is connected to a passage line between the automatic valve and the connection.
  • a syringe is connected to the branch line and the flask is pushed out until the culture solution is completely pushed back out of the lines into the culture vessel.
  • Manual operation requires regular external intervention. Especially with longer attempts a manual operation is complex and costly. Furthermore, a faulty operation can lead to contamination of the bioreactor or the sample.
  • the present application has for its object to develop a device for sampling, in which a contamination of the sample or the bioreactor is avoided and which is designed so that it can be used fully automatically.
  • a device has a connectable to a bioreactor riser, a stub and a
  • Discharge line are connected by means of a T-type connection.
  • the extraction line has a first shut-off valve.
  • the stub is optionally connected to a positive pressure source or connected and the extraction line with a pump.
  • the device has a control unit for controlling the overpressure source, the pump and the first shut-off valve.
  • the overpressure source, the pump and the first shut-off valve can be automatically controlled by activating the individual components in a predetermined order from the control unit.
  • samples can be taken. taken or measurements carried out in the funded medium.
  • the valves, the overpressure source and the pump or other possible components of the device may comprise and / or be connected to corresponding actuators and / or motors in order to enable such activation or actuation triggered by the control unit.
  • Activation or actuation in the case of valves means opening and closing, for example.
  • the pump and the overpressure source this is to be understood as switching on and off. In general, this may be understood to mean, for example, a change in an operating state, which in the present case can preferably be carried out without human intervention and controlled by the control unit.
  • T-type connection via which the riser, the stub and the extraction line are connected to each other, all connections are to be understood that allow a connection of three lines, that is, for example, compounds whose geometry rather a Y-like Represent connection.
  • the use of a standardized and / or commercially available T-piece represents a possible embodiment but is not mandatory in the meaning of the application.
  • the lines may be formed, for example, as tubes.
  • the overpressure source may be formed, for example, as a syringe or syringe-like. It may thus be, for example, a container with a movable bolt, which can be lowered similar to a syringe to generate an overpressure.
  • the overpressure source can also be designed as a process gas source or as a sterile gas source, for example as a gas line or pressurized container.
  • the process gas is preferably a gas which does not influence or negatively influence the biological process inside the reactor.
  • overpressure gas can be used in example nitrogen.
  • the process gas source or sterile Gas source can be provided in the form of a correspondingly connected, for example, replaceable gas tank or in the form of a gas line.
  • the overpressure source may also include a pump for generating a pressure.
  • the overpressure source is automatically controlled, so has a mechanism that electronically controlled the overpressure.
  • the pump which is connected to the extraction line, can be designed, for example, as a peristaltic pump, for example as a peristaltic pump or roller pump.
  • the extraction line is preferably designed as a flexible hose, at least in the area of the pump.
  • the pump is used to generate a negative pressure. The suppression allows the sample to be sucked out of the culture vessel which can be connected to the device, for example into a sample vessel which can be connected to the withdrawal line.
  • Sample vessel is made of plastic or stainless steel, for example.
  • the extraction line can be closed and the riser blown through the pressure source, which is connected to the stub, who the.
  • the pumped medium can be pushed out of the riser.
  • the line volume to be passed through which must be emptied by means of the overpressure source, can be reduced here, thereby enabling easier, faster and more reliable cleaning or flushing.
  • the risk of contamination is reduced because gas, process gas, outside air, sample material or foreign bodies can not get into the lines closed by the first shut-off valve.
  • the first shut-off valve and other valves which can be installed according to the application into the device are designed in one embodiment as electrically or pneumatically controllable valves to allow automation of the sampling process.
  • the valves are preferably configured or arranged not in contact with the media, for example as hose pinch valves.
  • the device described permits, as mentioned, an automated sampling, for example by a pre-programmed execution of steps in which the pump or the overpressure source are switched on or off and the first shut-off valve and possible further shut-off valves are opened or closed. For example, these steps may be time-controlled, executed at preprogrammed intervals, and repeated.
  • Possible further components of the device may also be in communication with the control unit and receive control signals from the control unit and, in some embodiments, also send signals or data to the control unit. Possible embodiments, which include further components as well as possible interactions of the components with the control unit are described below.
  • a system according to this application comprises, for example, a device as described in the application or a device according to one of the Pa tentments and connected to the riser bioreactor.
  • the bioreactor may be, for example, an autoclavable or steam sterilizable or otherwise sterilizable vessel.
  • the stub between the pump and the T-type connection has a sterile filter, so that when using a non-sterile overpressure source, the lines continue to be kept sterile.
  • an optional check valve may further be provided in the stub line. This, when combined with a sterile filter between the sterile filter and the T-type connection, is arranged to be open for fluid flow in the direction of the T-type connection and closed in the opposite direction.
  • Another optional check valve may be located in the sampling line. It is directed to allow fluid flow from the T-type connection toward the pump and prevent flow in the opposite direction.
  • the device may further comprise a second shut-off valve is arranged in the riser, preferably designed as an electrically controllable valve and connectable to the control unit, so that also functions that relate to this second shut-off valve, can be automated.
  • a second shut-off valve is arranged in the riser, preferably designed as an electrically controllable valve and connectable to the control unit, so that also functions that relate to this second shut-off valve, can be automated.
  • the device may further comprise one or more sensor units, for example arranged in the riser and / or in the
  • Each of the one or more sensor units may include one or more sensors that serve to detect one or more measurements that describe a condition or property of the sample.
  • a sensor unit can also be arranged in the bioreactor in order to measure measured values of the sample still present in the bioreactor. For example, a thermometer placed in the bioreactor can constantly monitor the temperature in the reactor.
  • At least one of the sensor units is connected to the control unit and configured to send measured values to the control unit and / or configured to be controlled by the control unit to who.
  • Sensors connected to the control unit can initiate a preprogrammed step sequence for sampling or for further measurements by means of a signal transmitted to the control unit.
  • Sampling or measurement can be triggered, for example, by a value measured by the sensor which exceeds or falls below a preset limit, for example. So the sample is taken when a particular event occurs.
  • the preprogrammed sampling steps may thus be event driven in this sense, i. be triggered by the measurement of a specific value by a sensor.
  • the measured value is transmitted from the sensor to the control unit, which in turn sends the appropriate signals for sampling to the units required for sampling, such as pumps, shut-off valves and overpressure sources.
  • time-controlled sampling which is predefined times are automatically controlled by the control unit takes place, for example, a start time and time intervals are set by a user.
  • Timed and event controlled sampling can be used as alternatives or in combination. It is also possible that the timing and the event control interact with each other and represent boundary conditions for each other. For example, sampling may be performed at a particular time provided that a particular sensor signal is present or sampling is performed on a particular sensor signal provided that at least a predetermined amount of time has elapsed since the last sampling.
  • sensors various physical, chemical or biological sensors can be used.
  • Examples of these are mechanical, electrical, optical or microelectromechanical sensors, electrochemical sensors, enzyme sensors or bioarray or biochip sensors.
  • optical sensors can be used for spectral analysis or for measuring an optical density.
  • chemical sensors can be used for pH measurement or for oxygen measurement.
  • Enzyme sensors can be used to detect the reaction of an enzyme proportional to the concentration of a substrate, such as glucose, lactate, glutamate, glutamine, etc.
  • the sensors can, depending on which measured variable is to be detected, be designed as non-contact sensors or media-contacting sensors.
  • a measurement by means of a sensor in contact with the media usually results in the sample not being able to be pumped back into the bioreactor since it is consumed or changed by the measurement, for example by a chemical reaction or a biological process they would contaminate the remaining material in the bioreactor.
  • a non-contact measurement is provided which is suitable for determining whether the sample material in the bioreactor has already reached a state in which the media-contacting measurement makes sense. For example, it can be determined by means of an upstream optical analysis whether a reaction in the bioreactor has progressed far enough to carry out a media-contacting measurement. On the basis of such an upstream non-contact measurement can also be determined whether a sampling should take place.
  • the non-contacting sensors upstream in the line thus acquire, for example, measured values which make it possible to decide whether a further measurement is to be performed and / or a sample is taken.
  • a first sensor unit with a non-contact sensor and a second sensor unit with a media-contacting sensor are arranged one after the other, wherein preferably at least one shut-off valve is arranged between the two sensor units.
  • This allows an upstream measurement by means of the non-contact sensor, whereupon, based on the measured values determined by the non-contact sensor, which are preferably transmitted to the control unit, preferably automatically, for example by comparison with user-defined values, decide thereon. whether the sample is either pumped back into the bioreactor or whether the sample is pumped on to be analyzed and / or removed by the media-contacting sensor.
  • a first sensor unit is present in the riser, this may for example be on the bioreactor side facing the second from shut-off valve. In one embodiment, this first sensor unit is equipped only with non-contact sensors.
  • the second sensor unit may be arranged between the first shut-off valve and the pump.
  • the one or more sensors of the second sensor unit can be designed as media-contacting sensors or as contactless sensors.
  • the sample can then be discarded, stored or made available for other measuring methods.
  • the pumping and / or pumping back is made possible by pump and valve arrangements proposed in the application.
  • a signal attenuation in an absorption measurement carried out by means of a sensor of the first sensor unit may indicate an increase in the biomass, ie an increased number of cells.
  • a substrate for example glucose
  • the concentration of which is then measured by means of a media-contacting measurement in an enzyme sensor of the second sensor unit.
  • the second measurement with the enzyme sensor is expensive and the sensor is typically limited in the number of measurement cycles. Therefore, the measurement with the sensor of the second sensor unit is only started when the sensor of the first sensor unit has pointed to a sufficient cell concentration.
  • the substrate concentration should in one embodiment, for example, despite cell concentration can be kept constant, which can be ensured via an automatic feedback to a possible substrate pump, which is also coupled to the control unit and controllable by this.
  • measurements of the substrate concentration by means of the first sensor unit are carried out closely in time.
  • Another object of the invention relates to the practical handling of the sampling device. This includes, for example, preparatory steps that are necessary to enable a safe and contamination-free reaction process and safe and contamination-free sensor measurements and probing.
  • safe and contamination-free handling by a device according to the application can be further facilitated by one or more sterile couplings that allow for sterilization of individual components or portions of the device and also replacement of sensors or other components , in some embodiments, even during the reaction process, allow.
  • sterile couplings are for example as described below or in the figures of this application or shown integrated into the lines.
  • the sterilization of the media-contacting sensors of the sensor units is often a challenge for a person skilled in the art, since they must be sterile in some cases due to their direct contact with the sample, but often can not be sterilized together with the bioreactor, since they do not temperature resistant and thus not autoclavable or steam sterilizable.
  • the bioreactor is preferably sterilized by autoclaving, for example, the media-contacting sensors are not suitable for these types of sterilization and must instead be sterilized by, for example, gamma sterilization, electron beam sterilization, plasma sterilization, or ethylene oxide sterilization. This can equally apply to other components of the device, so that the solution presented here of this problem is analogously applicable to other components.
  • the media-contacting sensors may also be non-sterile and are according to the application sterile couplings separated from a sterile part of the device or arranged separable.
  • the non-contact sensors unlike the media-contacting sensors, are typically easy to integrate into the device because they have no direct contact with the sample and can be removed before sterilization. In the arrangement of non-contact sensors, accordingly, additional possibilities arise, which are utilized in the described arrangements. The same situation can apply, for example, to the shut-off valves used, if they are configured, for example, as pinch valves.
  • the sterile couplings used include, for example, two
  • joinable sockets These are provided at two cable ends, which should be connectable to each other.
  • the nozzles can be placed on top of each other in a liquid-tight manner and pulled apart to separate the cable ends.
  • the disconnected conduit ends are preferably sealed by the sterile coupling.
  • the line ends are at least before they are placed on each other for the first time sealed by the sterile coupling liquid-tight.
  • the stubs may be formed as two complementary plastic stubs, each of the stubs may have a membrane which seals the respective line end and which can be pulled out after attachment or coupling of the two plastic stub to release a fluid path through the sterile coupling.
  • membrane which seals the respective line end and which can be pulled out after attachment or coupling of the two plastic stub to release a fluid path through the sterile coupling.
  • One embodiment provides for the use of plastic gamma sterilizable disposable couplings.
  • the use of steel-steel or steel-plastic couplings is provided, wherein in the latter case preferably a steel coupling piece on the side of the bioreactor and a plastic coupling piece on the side of the sensor is arranged.
  • the one or more sterile coupling can be arranged, for example, in the riser line and / or in the extraction line and enable separation and connection of a line section and the components located thereon from the rest of the device.
  • a sterile coupling in the riser as the first component after the bioreactor be arranged.
  • the sampling device can be separated from the bioreactor with all shut-off valves, non-return valves, sensor units and possible further components as well as a first coupling socket.
  • the bioreactor itself remain a portion of the riser and a second coupling socket.
  • the bioreactor with the riser section and the second coupling stub are autoclaved prior to coupling the coupling stubs together.
  • the remaining part of the device can then be sterilized, for example, by gamma sterilization or by another method for which the sensors used are designed.
  • a sterile coupling can be arranged, for example, between the first shutoff valve and the second sensor unit. Then the bioreactor and the first and the second shut-off valve are located on the side of the first coupling stub and the second sensor unit is located on the side of the second coupling stub, together with possible further components, such as flushing lines and / or mixing chambers.
  • This section also typically includes the stub line with check valve and sterile filter.
  • the section on the side of the second coupling socket, which comprises the second sensor unit with the media-contacting sensor It can also be nonsterile or it can be gamma sterilized, for example.
  • the media-contacting sensor may be, for example, a glucose sensor or an enzymatic sensor.
  • the arrangement can prevent a sample that passes through the second shut-off valve and thus inevitably enters the potentially unsterile area contaminating the bioreactor. This arrangement of the sterile coupling allows replacement of the second sensor unit during operation by separating the sterile coupling.
  • the sterile part of the device comprising the bioreactor and the first and second shut-off valves remains unaffected by the exchange.
  • the second sensor unit is decoupled, further non-contact measurements can be carried out with the possible first sensor unit.
  • the lifetime of, for example, enzymatic sensors is limited to a few weeks. With the device described here, a measurement over a longer period of time is made possible because the sensor, whose lifetime has expired, can be decoupled during operation and then a new sensor can be reconnected.
  • a system in the sense of the application is designed so that the device for sampling is integrated into the bioreactor.
  • the sampling device may be incorporated into an outer plate such as a faceplate or side plate of the bioreactor.
  • Such an arrangement is particularly space-saving and allows a simple provision of the sampling system.
  • the user is prevented from having to assemble, plug hoses, and check the connections. For example, he only has to mount the outer plate equipped with the sampling system on the bioreactor.
  • Such a compact arrangement or integration allows a rapid analysis, wherein in addition only a small volume of media must be removed from the bioreactor for a sensor measurement by means of a sensor of the first and / or the second sensor unit.
  • a system includes, for example at least one sampling step, in which the first and the second shut-off valve are open and the sample is sucked by the pump from the Biore actuator. Furthermore, it may comprise at least one step for blowing through the extraction line, wherein an overpressure is applied to the stub line by means of the overpressure source, with simultaneous operation of the stub line
  • first shut-off valve and closed second shut-off valve may comprise at least one step for blowing through the riser by applying an overpressure by means of the overpressure source with the second shut-off valve open and the first shut-off valve closed.
  • the duration of the individual steps can be programmed in advance. Depending on the duration of a certain effect is achieved. For example, a larger amount of sample is taken from a longer-lasting sampling step.
  • the steps for blowing through for example, be so long that in the fürpustzeit, according to the size of the overpressure source provided by the overpressure, something as much air is introduced into the Wegzupustende pipe as in the Vietnamesezupustenden pipe has room to ensure on the one hand that the Pipe is completely puffed, but no unnecessarily high pressure is built up and / or not excessive
  • Process gas or other gas used for blowing through in example the bioreactor or the sample vessel is introduced.
  • the steps mentioned can be carried out once or several times in a single sampling.
  • the riser is puffed before and after sampling.
  • the steps can be done manually or programmed and fully automatic.
  • the execution of the steps can be initiated, for example, time-controlled or event-controlled, for example based on a value measured by a sensor, automatically.
  • time-controlled or event-controlled for example based on a value measured by a sensor, automatically.
  • the selection may be limited to a start time, an interval between sampling and a number of sampling.
  • the sampling event triggered by a measured by a device arranged in the Steiglei sensor value so for example the following procedure can be used: At a certain time, for example, a pre-programmed time or triggered by an input from the user, when open Absperrven valves, generated by the pump a negative pressure. However, this suppression is only so strong that organisms are sucked into the riser and preferably do not reach the level of the sensor up to the T-type connection or into the extraction line. The sensor then performs a measurement. Based on the result of the measurement, which may be, for example, above or below a specified limit, sampling is then either performed or not.
  • the pump will continue to generate a suppression and organisms will be directed through the sampling line into a sample vessel and subsequently blow through the lines as described above. If the measured value is such that no sampling is to be carried out at the time, for example because the process in the bioreactor has not progressed far enough, then the first shut-off valve can be automatically closed again and an overpressure can be provided with the second shut-off valve open and the organisms in the riser are returned to the bioreactor. After a specified time interval, a new measurement can then be carried out by means of the sensor in the riser, as just described, and it can again be decided whether the sample should be taken or not.
  • steps for preparing a measurement such as rinsing steps in which a buffer solution is pumped into the tube system, steps for dilution or pressure filtration or for the other pretreatment of the sample.
  • steps for preparing a measurement such as rinsing steps in which a buffer solution is pumped into the tube system, steps for dilution or pressure filtration or for the other pretreatment of the sample.
  • a mixing chamber may further be integrated into the line system, preferably after the first shut-off valve.
  • the control unit may for example be part of a bioreactor control or integrated into it.
  • the valves, the pump and the overpressure source can be connected to the bioreactor control and controlled via the bioreactor control, for example via the control of an xCUBIO reactor.
  • FIG. 1 shows a bioreactor system, a bioreactor and a device for sampling, comprising a first sensor arrangement
  • FIG. 2 shows the bioreactor system with a second sensor arrangement
  • FIG. 3 shows the bioreactor system with a third sensor arrangement
  • FIG. 4 shows the bioreactor system from FIG. 3 with a flushing line
  • FIG. 5 shows the bioreactor system with the first sensor arrangement and a sterile coupling
  • FIG. 6 shows the bioreactor system with the second sensor arrangement and the sterile coupling
  • FIG. 7 shows the bioreactor system with the third sensor arrangement and the sterile coupling
  • FIG. 8 shows the bioreactor system from FIG. 6 with an alternative arrangement of the sterile coupling
  • FIG. 9 shows the bioreactor system from FIG. 6, additionally comprising a mixing chamber
  • Figure 10 is a tabular listing of a sequence of steps for using the bioreactor system.
  • a bioreactor system is shown, wherein a bioreactor 11, which is formed in example as autoclavable or steam-sterilizable vessel, is connected to a riser 1 of a device for sampling.
  • the riser 1 is connected on the side facing away from the bioreactor 11 with a spur line 2 and a sampling line 3 T-like, for example by means of a tee.
  • the extraction line has a pump 7, for example a roller pump or peristaltic pump, with which a negative pressure in the extraction line 3 can be generated.
  • the extraction line 3 has a first shut-off valve 4.
  • the riser 1 has a second shut-off valve 8 with which the riser 1 can be closed.
  • a first sensor unit 10 which is equipped with one or more sensors.
  • the first sensor unit is preferably equipped with contactless sensors, eg with optical sensors.
  • the device according to the application is not limited to the fact that one or more sensors must be provided in a single first sensor unit 10. It is also possible to distribute several sensors over several sensor units.
  • the stub line 2 has on the side facing away from the T-like connection on a pressure source 5 for generating an overpressure in the stub 2.
  • Such a back pressure source 5 may be formed as a simple syringe or other gas source, such as a pressurized gas container or a container with a movable pin, preferably by automatically lowering the bolt, similar to a syringe , put under pressure can be.
  • the gas used to generate the overpressure can be, for example, a process gas, nitrogen or air.
  • it can come from a sterile gas source.
  • the originating from the pressure source 5 gas can be filtered by an additional possible sterile filter 6, which is arranged in the Stichlei device before it comes into contact with the organisms in the bioreactor 11 or in the other lines 1, 2.
  • a check valve 9 is provided, which is arranged on the T-like connection facing side of the sterile filter 6 in the stub 2.
  • This check valve serves as an additional security measure, but it can also be dispensed with, since in the stub pipe preferably no suppression arises, which causes the organisms get into the stub, but in the stub 2 is generated before preferably overpressure for blowing through, while suppressors preferably only is generated in the sampling line 3.
  • Sampling line 3 has a pump 7 for generating a negative pressure in the extraction line 3, in particular with respect to the riser 1 and with respect to the bioreactor 11, on. Furthermore, the extraction line 3, a first shut-off valve 4. Optionally, the extraction line 3 may further comprise a check valve, not shown, which allows fluid flow only from the T-type connection in the direction of the pump 7, but not in the opposite direction.
  • the bioreactor 11 may be autoclaved together with the hoses 1, 2, 3 formed as hoses, with hoses preferably being kept closed to prevent contamination after sterilization.
  • the sterile coupling 6 helps to prevent contamination.
  • the shut-off valves 4, 8 can be mounted.
  • the first sensor unit 10 can preferably be attached to the outside of the ascending pipe 1 designed as a hose and, for example, to measure an optical density through the hose.
  • the device After sterilization, the device can be constructed as described above and a reaction started in the bioreactor.
  • control unit 13 Via a control unit 13, the pump 7, the overpressure source 5, as well as the first and the second shut-off valve 4, 8 are controlled.
  • the communication connection of the individual components with the control unit 13 is indicated in the figure by dashed lines.
  • the control unit 13 can be programmed, for example, so that the removal operation is carried out at predetermined intervals. For this purpose, for example, a start time, an interval between the sampling and a number of sampling can be specified by the user.
  • the control unit 13 can also be in communication with the sensor 10 so that a sample is triggered by means of a preprogrammed step sequence, which is explained in detail below, when a measured value measured by the sensor of the first sensor unit 10 is a fixed one Criterion fulfilled.
  • a sampling provided at a given time will only be carried out if the measured value measured fulfills such a criterion.
  • a sampling can be started at a fixed point in time, sample material from the biorector 11 being pumped into the riser line at least as far as the first sensor unit 10. Based on the measured values acquired by the sensor of the first sensor unit 10, the sample is either further pumped and removed or pumped back into the bioreactor.
  • this makes it possible to perform multiple sampling or measurements over a longer period of time and to minimize the need for human interaction.
  • control unit 13 which receives signals from the individual components or to the individual Sends components.
  • sterile compressed air can be preliminarily introduced into the branch line 2 by means of the overpressure source, in conjunction with the sterile filter 6, wherein the first shut-off valve is preferably kept closed while the second shut-off valve is opened.
  • the first shut-off valve is preferably kept closed while the second shut-off valve is opened.
  • the pump 7 is started, wherein the first shut-off valve 4 is preferably kept closed initially. Then, the first from shut-off valve 4 is opened and the second shut-off valve 8 is kept closed to create a negative pressure in the extraction line 3, or to produce an overpressure in the bioreactor 11 and at least a portion of the riser 1 compared to the extraction line 3. In a later step, the second shut-off valve 8 is then opened, and thus upon further operation of the pump 7, a fixed amount of organisms in the bioreactor 11 are pumped or sucked from the bioreactor 11 into the riser 1. These organisms pass through the first sensor unit 10 arranged in the riser 1 and are measured by means of the one sensor or by means of at least one of the plurality of sensors of the first sensor unit 10 and the measured values are transmitted to the control unit 13.
  • the organisms can then be forced back into the bioreactor 11, for example, depending on the measured values thus acquired, which are adjusted, for example, in the control unit 13 with user-defined threshold values, by closing the first shut-off valve 4 by the control unit 13 and the overpressure source 5 is activated.
  • both Absperrven tile 4, 8 can be closed.
  • the steps relating to the back-feeding of the sample after the measurement are provided in the devices according to the application in which one or more sensors are arranged in the riser 1. As will be explained below in connection with other figures, not all devices provide sensors in the riser 1, so that the steps to backfire are provided in methods of using feedforward. directions without sensors in the riser 1 typically find no application.
  • the sample can be removed by passing the first sensor unit 10 by continuing to operate the pump 7 with open shut-off valves 4, 8 into the extraction line 3 and through the extraction line 3, for example, in a sample vessel (not shown) is pumped.
  • the second shut-off valve 8 is then closed again and an overpressure in the branch line is generated by the overpressure source 5.
  • the sampling line is impressedgepus tet.
  • the first shut-off valve 4 can be closed and the second shut-off valve 8 can be opened while the overpressure source 5 remains switched on.
  • the pump 7 can be turned off. So the riser 1 is blown through.
  • the duration of this fürpust Kunststoffs the riser 1 can be selected so that only a small amount of gas is introduced into the biore- reactor.
  • the steps for blowing through the extraction line 3 and the riser 1 may, in order to avoid contamination, be carried out not only after but also before sampling.
  • FIG. 2 shows the bioreactor system, wherein a second sensor unit 10 'is arranged in the extraction line 3 instead of the first sensor unit 10 shown in FIG.
  • the second sensor unit 10 ' may include non-contact and / or media-contacting sensors, provided that the media-contacting sensors are suitable for being sterilized together with the bioreactor.
  • the sampling steps are carried out in a manner similar to that described in connection with FIG. 1, but there is no possibility here of pumping the sample back into the reactor after the measurement. As mentioned above, therefore, typically no steps to repress the sample are performed. Instead, the sample is withdrawn as described above, and when taken, readings are taken which can be assigned to the sample taken.
  • the advantage of this arrangement is that the second sensor unit 10 'through the shut-off valves 4, 8 can be separated from the bioreactor, so that the sensors of the second sensor unit 10 'can be cleaned by blowing through the extraction line 3 and unwanted contact of the sensors with the organisms from the bioreactor can be avoided between the measurements.
  • FIG. 3 shows the bioreactor system, the sampling device comprising as a combination of the embodiments shown in FIGS. 1 and 2 both the first sensor unit 10 and the second sensor unit 10 '. This combines the advantages of both devices described above.
  • the device can accordingly be operated as described in connection with FIG.
  • the second sensor unit 10 ' may be configured to send a signal to the control unit 13 when the sample arrives at or passes the second sensor unit 10' during the sampling process.
  • the sampling can then be ended, for example, as soon as the sample arrives at the second sensor unit 10 ', for example by the second shut-off valve 8 being closed by the control unit.
  • This allows the volume of samples taken to be checked. For example, it can be ensured that each sample has the same volume or approximately the same volume.
  • volume control is preferable to timing, especially if the viscosity of the sample or the pressure ratios in the bioreactor system are not constant and change, for example, during the reaction or during withdrawal.
  • a combination of the described volume control with a time control is also possible.
  • FIG. 4 shows the bioreactor system from FIG. 3, wherein a purge line 14 is provided in the withdrawal line 3, between the first shut-off valve 4 and the second sensor unit 10 '.
  • About the purge line 14 can, for example, sterile gas and / or liquids are fed into the extraction line 3.
  • This can for example be used to clean the extraction line 3 itself, in which case the second sensor unit 10 'does not have to be contained in the sampling device.
  • it can also be used to clean the sensors of the second sensor unit 10 or be necessary for the use of the sensors of the second sensor unit 10 'if, for example, buffers used to protect enzymatic sensors are or extend their life, are fed via the purge line 14 in the extraction line.
  • solutions for calibrating the sensors of the second sensor unit 10 ' can be flowed.
  • these are supplied via the purge line 14 between two removal processes and then, with the first shut-off valve 4 open and the second shut-off valve 8 closed, the withdrawal line is blown with sterile gas by means of the overpressure source 5 in order to produce the following Measurement should be possible no residues of the inflowing solution, which could adversely affect a measurement.
  • the method steps described here, which relate to the flushing line can also be carried out in modified devices, for example, no first sensor unit 10 is required for this purpose.
  • FIG. 5 shows the bioreactor system as in FIG. 1, wherein an optional purge line 14 is additionally arranged on the extraction line and a sterile coupling is provided between the first sensor unit 10 and the bioreactor 11.
  • the sterile coupling comprises two coupling stubs 12.1, 12.2, which can be connected to each other to produce an outwardly dense Fluidverbin tion between two hose or pipe ends on which the Kuppiungs- are arranged.
  • a first coupling stub 12.1 is in the riser 1 on the side of the first sensor unit 10 angeord net and a second coupling stub 12.2 in the riser on the side of the bioreactor 11, so that the bioreactor 11 together with a part of the riser 1 and the second Kuppiungsstutzen 12.2 can be separated from the other com ponents of the sampling device.
  • the illustrated embodiment with the sterile coupling is particularly advantageous if the sensor or one of the sensors of the first sensor unit 10 'is designed as a sensor in contact with the media. Media-contacting sensors are common not steam sterilizable and therefore can not be sterilized together with the bioreactor.
  • Sterile coupling permits separate sterilization of the section of the device comprising the sensor or media-contacting sensors, for example by gamma sterilization, plasma sterilization or by means of ethylene oxide.
  • the coupling sockets connected in each case to the sections are designed to be sterilizable. For example, lying on the side of the first sensor unit 10 first coupling nozzle 12.1 gammasterilisierbar and be made of plastic or steel and lying on the side of the bioreactor 11 second coupling nozzle 12.2 steam sterilizable and out of plastic or metal out forms.
  • FIG. 6 shows the bioreactor system, wherein the sterile coupling is arranged at the same position as in the example of FIG. 5, but, as also shown in FIG. 2, instead of the first sensor unit 10 only the second sensor unit 10 'is provided.
  • This arrangement is particularly advantageous when the second sensor unit comprises media-contacting sensors.
  • the purge line 14 allows, as described above, the cleaning and / or calibration of the sensors, on the other hand, a separate sterilization of the media-contacting sensors is made possible by the sterile coupling.
  • the use of such a system is otherwise as described in connection with Figure 2.
  • the sterile coupling allows the bioreactor 11 separate sterilization of the media-contacting sensors of the second sensor unit 10 '.
  • the sterile filter 6 and the check valve 9 can then be gamma sterilized together with the second sensor unit 10 ', for example, and then connected to the autoclaved bioreactor 11.
  • the shut-off valves 4, 8 may for example be designed as a pinch valves and installed after sterilization.
  • FIG. 7 shows a combination of the embodiments from FIGS. 5 and 6.
  • the sterile coupling is furthermore arranged as the first component after the bioreactor 11 in the riser 1.
  • the device comprises both the first sensor unit 10 and the second sensor unit 10 'and a Spülli- direction.
  • both sensor units 10, 10 ' can be sterilized separately from the bioreactor, for example if both sensor units have media-contacting sensors.
  • the use of the system shown is otherwise as described in connection with Figure 3, wherein in addition the advantages of the flushing line described above can be exploited.
  • Figure 8 shows the bioreactor system, wherein the sterile coupling is arranged instead of in the riser line 1 in the extraction line 3. In this case, the sterile coupling between the first shut-off valve 4 and the purge line 14 is positioned.
  • Bioreactor 11 can then, for example, be steam-sterilized together with non-return valve 9 and sterile filter 6 and riser 1, stub 2, a part of extraction line 3 and first coupling stub 12.1, with stop valves 4, 8 again after sterilization. can be stalled.
  • the second sensor unit and the flushing line 14, as well as the associated section of the extraction line 3 and the second coupling connection 12.2 can either be sterilized separately or be non-sterile.
  • such an arrangement can also have a first sensor unit 10 and / or a sterile coupling arranged as in FIGS. 5 to 7.
  • FIG. 9 shows the bioreactor system, wherein the sensors and the sterile coupling are arranged as in FIG. 6, but a mixing chamber 16 is provided in the extraction line 3 between the second sensor unit and the first shut-off valve 4.
  • a purge line 15 is connected to the mixing chamber 16 and, moreover, it has a mixing chamber outlet 17 with a valve.
  • the mixing chamber 16 may also be a media-contacting sensor befin, such as a pH sensor.
  • the removed sample first enters the Mixing chamber before it passes the second sensor unit 10 'and can be left in the mixing chamber 16 by a corresponding short-term shutdown of the pump 7 and / or by actuation of valves for a certain period of time.
  • valves for this purpose, other valves may be provided in possible embodiments.
  • the sample can be pretreated before it is pumped further along the sampling line to be measured by the second sensor unit 10 'and subsequently removed or discarded.
  • a medium can be added to dilute the sample. It is also possible for chemicals to be introduced into the mixing chamber 16 via the flushing line 15, for example, which make sensor measurement possible. For example, it is possible to add acids or bases which shift the pH of the sample in such a way that a measurement with a sensor of the second sensor unit 10 'is possible.
  • the mixing chamber can be emptied via the mixing chamber drain 17 and cleaned with the aid of the flushing line 15.
  • FIG. 10 shows in tabular form a possible sequence of steps for using the bioreactor system according to the invention, which can be triggered automatically, for example, by the control unit.
  • the steps S1 to S10 are carried out in the order listed here.
  • a duration of each step is usually a few seconds.
  • the status of the valves 4, 8 or of the pump 7 and of the overpressure source 5 during each step is indicated by "0" or "1" in the corresponding columns. In this case, “0” stands for "closed” or “off” and “1” for "open” or “on”.
  • the valves 4, 8 are closed and the pump 7 and the overpressure source 5 are switched off.
  • step S2 is initiated.
  • pressure is applied to the spur line 2 by switching on the overpressure source 5, while all other components remain in the "0" position, in which, in addition to the activated overpressure source 5, the second shut-off Valve 8 opened and the riser 1 gepufetet.
  • the overpressure source 5 is switched off in order to reduce the pressure in the riser 1 while the second shut-off valve 8 is still open.
  • step SS all valves 4, 8 are then closed again and the overpressure source 5 is left in the switched-off state, while the pump 7 is approached.
  • step SS by opening the first shut-off valve 4 with simultaneous pump operation, an overpressure is generated in the riser 1 with respect to the withdrawal line 3.
  • S7 By a subsequent additional opening of the second shut-off valve 8, the complete fluid path from the bioreactor 11 to the pump 7 is released in S7 so that organisms can be removed.
  • the duration of this removal process S7 varies depending on how much volume is to be removed.
  • the second shut-off valve 8 and thus the riser 1 is closed again in S8, so that the
  • Sampling line 3 can be blown through and cleaned.
  • the overpressure source 5 is additionally switched on. This step is performed so long as to ensure that the entire sample has entered the sample vessel.
  • the riser pipe 1 is blown by the first shut-off valve 4 is closed and the second shut-off valve 8 is opened again, continue operation of the pressure source 5.
  • steps 8 and 9 are after the removal process in the riser 1 remaining organisms back to the reactor 11 been supplied and in the withdrawal line remaining organisms have been supplied to the sample removed, so that the process has no or a negligibly small Totvolu men.

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Abstract

L'invention concerne un dispositif pour le prélèvement d'échantillons de bioréacteurs , comprenant une colonne montante (1) pouvant être connectée à un bioréacteur, une conduite de dérivation (2) et une conduite de prélèvement (3) qui sont connectées au moyen d'une connexion en forme de T. La conduite de prélèvement (3) comprend une première vanne d'arrêt (4), la conduite de dérivation (2) est connectée à une source de pression positive (5) et la conduite de prélèvement est connectée à une pompe (7). Dans le dispositif pour le prélèvement d'échantillons, la source de pression positive (5), la pompe (7) et la première vanne d'arrêt (4) peuvent être contrôlées de manière automatique par une unité de contrôle. L'invention concerne en outre un procédé pour l'utilisation d'un tel dispositif pour le prélèvement d'échantillons.
EP19712977.8A 2018-03-23 2019-03-20 Dispositif et procédé pour le prélèvement stérile d'échantillons Pending EP3768817A1 (fr)

Applications Claiming Priority (2)

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DE102018204477.5A DE102018204477A1 (de) 2018-03-23 2018-03-23 Vorrichtung und verfahren zur sterilen probenahme
PCT/EP2019/057000 WO2019180098A1 (fr) 2018-03-23 2019-03-20 Dispositif et procédé pour le prélèvement stérile d'échantillons

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CN118556180A (zh) * 2021-11-17 2024-08-27 俄罗斯科学院丘马科夫免疫和生物制品研发联邦科学中心(脊髓灰质炎研究所) 用于生物反应器的采样器
FI20245638A1 (en) * 2024-05-20 2025-11-21 Nordic Bioproducts Group Oy Pressure control system, method and apparatus for controlling pressure

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DE10252217B4 (de) * 2002-11-11 2005-06-09 Sartorius Ag Probenahmeventil und damit durchführbares Verfahren zur sterilen Entnahme von Proben aus Fermentern oder Bioreaktoren
DE102004001916B4 (de) * 2004-01-14 2006-02-16 Max Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Vorrichtung und Verfahren zur Probenahme
DE102004045785B3 (de) * 2004-09-22 2006-05-18 Sartorius Ag Zugabe- und Probenahmeventil und Verfahren zur sterilen Zugabe von Medien
DE202005000060U1 (de) * 2005-01-04 2005-03-17 Avicomp Controls Gmbh Anordnung zur Entnahme und Rückführung eines zu analysierenden strömenden Mediums
EP1856240A2 (fr) * 2005-03-01 2007-11-21 MedImmune Vaccines, Inc. Dispositif de collecte de virus de la grippe
WO2010108091A2 (fr) * 2009-03-20 2010-09-23 Pbs Biotech, Inc. Système aseptique automatisable de prélèvement d'échantillons
DE102009043699A1 (de) 2009-10-01 2011-04-07 Infors Ag Vorrichtung zur Probenahme
US9322749B2 (en) * 2012-11-05 2016-04-26 Bend Research, Inc. Automatic sampling system for sampling from enclosed containers
NL2010931C2 (nl) * 2013-06-07 2014-12-09 Beheersmij G A Ch M Jentjens B V Productaanzuiginrichting.
US20160258846A1 (en) * 2013-10-08 2016-09-08 Sartorius Stedim Biotech Gmbh Extraction device and method for obtaining a sample of a medium to be extracted
US10190950B2 (en) * 2014-10-31 2019-01-29 General Electric Company Semi-automated sampling system for aseptic sampling
DE102015109080B3 (de) * 2015-06-09 2015-11-12 Guspaf Gmbh Probeentnahmeeinrichtung für Flüssigkeiten und/oder Gase mit einer Probeflasche und einem Reinigungsmodul

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