EP4357009A1 - Procédé et appareil de fonctionnement d'un processus en aval continu - Google Patents

Procédé et appareil de fonctionnement d'un processus en aval continu Download PDF

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Publication number
EP4357009A1
EP4357009A1 EP22201978.8A EP22201978A EP4357009A1 EP 4357009 A1 EP4357009 A1 EP 4357009A1 EP 22201978 A EP22201978 A EP 22201978A EP 4357009 A1 EP4357009 A1 EP 4357009A1
Authority
EP
European Patent Office
Prior art keywords
arrangement
bioprocess
conveying
liquid
liquid stream
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
EP22201978.8A
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German (de)
English (en)
Inventor
Bernhard Diel
Michael Rodenberg
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.)
Sartorius Stedim Biotech GmbH
Original Assignee
Sartorius Stedim 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 Sartorius Stedim Biotech GmbH filed Critical Sartorius Stedim Biotech GmbH
Priority to EP22201978.8A priority Critical patent/EP4357009A1/fr
Priority to PCT/EP2023/074974 priority patent/WO2024083408A1/fr
Publication of EP4357009A1 publication Critical patent/EP4357009A1/fr
Pending legal-status Critical Current

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/48—Mixing liquids with liquids; Emulsifying characterised by the nature of the liquids
    • B01F23/483—Mixing liquids with liquids; Emulsifying characterised by the nature of the liquids using water for diluting a liquid ingredient, obtaining a predetermined concentration or making an aqueous solution of a concentrate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/49—Mixing systems, i.e. flow charts or diagrams
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/21—Measuring
    • B01F35/211—Measuring of the operational parameters
    • B01F35/2112—Level of material in a container or the position or shape of the upper surface of the material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/21—Measuring
    • B01F35/2132—Concentration, pH, pOH, p(ION) or oxygen-demand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/21—Measuring
    • B01F35/2133—Electrical conductivity or dielectric constant of the mixture
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/22—Control or regulation
    • B01F35/2201—Control or regulation characterised by the type of control technique used
    • B01F35/2202—Controlling the mixing process by feed-back, i.e. a measured parameter of the mixture is measured, compared with the set-value and the feed values are corrected
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/20—Measuring; Control or regulation
    • B01F35/22—Control or regulation
    • B01F35/221—Control or regulation of operational parameters, e.g. level of material in the mixer, temperature or pressure
    • B01F35/2211—Amount of delivered fluid during a period
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/80—Forming a predetermined ratio of the substances to be mixed
    • B01F35/83—Forming a predetermined ratio of the substances to be mixed by controlling the ratio of two or more flows, e.g. using flow sensing or flow controlling devices
    • B01F35/831—Forming a predetermined ratio of the substances to be mixed by controlling the ratio of two or more flows, e.g. using flow sensing or flow controlling devices using one or more pump or other dispensing mechanisms for feeding the flows in predetermined proportion, e.g. one of the pumps being driven by one of the flows
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/80—Forming a predetermined ratio of the substances to be mixed
    • B01F35/83—Forming a predetermined ratio of the substances to be mixed by controlling the ratio of two or more flows, e.g. using flow sensing or flow controlling devices
    • B01F35/833—Flow control by valves, e.g. opening intermittently
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/23—Mixing of laboratory samples e.g. in preparation of analysing or testing properties of materials

Definitions

  • the invention relates to a method for operating a continuous downstream process according to the preamble of claim 1, a bioprocess arrangement for operating a continuous downstream process according to claim 25, an electronic process control of the proposed bioprocess arrangement according to claim 26, the use of an electronic process control for implementing a proposed method according to claim 28, a computer program for the proposed electronic process control according to claim 29 and a computer-readable storage medium for storing the computer program according to claim 30.
  • the method in question for operating a continuous downstream process finds application in the context of a bioprocess for the production and/or quality control of biopharmaceutical bioproducts, in particular proteins, vectors, cells and the like, whereby a continuous stream from an upstream unit, in particular an upstream chromatography unit, can be provided for a downstream unit, in particular a downstream chromatography or filtration unit.
  • downstream process refers to all processes used to separate and purify fermentation products from a fermentation broth of a biotechnological process. This term includes mechanical, thermal, electrical and physico-chemical processes.
  • bioprocess here refers to biotechnological and biopharmaceutical processes involved in the production of therapeutic bioproducts, such as vaccines, biologics, components for cell or gene therapy, or non-therapeutic bioproducts such as pigments, biofuels or nutrients.
  • therapeutic bioproducts such as vaccines, biologics, components for cell or gene therapy, or non-therapeutic bioproducts such as pigments, biofuels or nutrients.
  • bioproducts can either be produced by living cells or the cell itself can constitute the bioproduct or the bioproduct can be the result of cell-free production based on cell components that are either of natural or non-natural origin.
  • a first virus inactivation step is usually carried out.
  • the implementation of a continuous virus inactivation step represents a challenge for process development in the context of process intensification.
  • the known method for operating a continuous downstream process (EP 2 867 359 B1 ), from which the invention is based, is used for the semi-continuous inactivation of viruses during a protein production process, eliminating the need to use large storage tanks for virus inactivation. This is because smaller, stirred mixing tanks are used for virus inactivation, which creates better conditions for the product and saves installation space. Furthermore, the incubation time for complete virus inactivation can be shortened from a minimum of one hour to a maximum of one hour.
  • a known method for operating a continuous downstream process in particular a continuous inline dilution process ( WO 2015 117 884 A1 ), comprises a first and at least one second chromatography column, a plurality of buffer vessels, and an additional inline dilution system having an inlet and a bioprocess outlet.
  • the additional inline dilution system requires additional manufacturing space and results in increased material costs, higher structural complexity, and higher maintenance costs.
  • the known processes only provide limited efficiency in terms of the long process times that endanger the bioproduct on the one hand and in terms of the manufacturing costs and the use of production space on the other.
  • the implementation of the known process for operating a continuous downstream process, in particular a continuous virus inactivation or inline dilution process is relatively complex.
  • the invention is based on the problem of designing and developing the known method for operating a continuous downstream process in such a way that its implementation is simplified.
  • the fundamental consideration is that the electronic process control adjusts a filling level in the compensation tank by controlling and/or regulating the conveying arrangement in order to avoid falling below a minimum filling level, in order to ensure a continuous flow of liquid from the bioprocess arrangement.
  • compensation tank is to be understood broadly here and means any vessel or container designed to hold liquids. This can be made of flexible or rigid materials, in particular metal, glass, plastic or the like. Additionally or alternatively, the compensation tank can be designed for multiple use or as a single-use container.
  • the special structure of the proposed method for operating a continuous downstream process has the advantage of converting a, in particular discontinuous, liquid stream from an upstream process step, in particular an upstream protein A chromatography step, which can fluctuate in terms of volume and product concentration, i.e. in which, for example, no liquid stream flows at all at times and in which the product concentration can usually fluctuate during the chromatography phases, into a continuous liquid stream and continuously releasing this liquid stream into a downstream process step following a proposed continuous downstream process, in particular a continuous virus inactivation or inline dilution process.
  • continuous liquid flow here means a liquid flow that is not interrupted, for example by incubation in a container or the like, but which may vary in flow rate.
  • the electronic process control adjusts a filling level in the equalization tank by controlling and/or regulating the conveying arrangement in such a way that a predefined minimum filling level in the equalization tank is not undercut.
  • the electronic process control adjusts a fill level in the expansion tank in such a way that a predefined target fill level is reached or the fill level is maintained in a target fill level range. This enables the user not only to avoid the expansion tank running dry, but also to set a predefined target fill level. This is preferably above the minimum fill level and is in particular set again after the fill level has fallen below the target fill level or has exceeded it.
  • the preferred embodiments according to claim 3 or 4 relate to details of the at least one conveying device assigned to the conveying arrangement and enable flexible fluid controllability in a simple manner.
  • conveying arrangement is to be understood broadly here and means any type of arrangement that is set up to convey and/or adjust, in particular interrupt, the conveying of liquids, in particular pump arrangements with at least one pump and/or valve arrangements with at least one valve.
  • a pump and such a valve then each form a "conveying device" of the conveying arrangement.
  • conveying devices that are designed as metering pumps, in particular as peristaltic pumps, rotary piston pumps or diaphragm pumps.
  • valves that are set up to produce a selective and quantitative fluid connection, preferably a continuous valve, control valve or the like.
  • the electronic process control derives an actual value for a fill level parameter in the equalization tank from the process data in a monitoring routine.
  • the electronic process control adjusts the conveying capacity of the first, second and/or third conveying device to prevent the minimum fill level from being undershot. This embodiment enables the electronic process control to react to any deviation from the minimum fill level and to prevent it from being undershot by adjusting the corresponding pumps.
  • the adjustment is made depending on a deviation between the derived actual value for the fill level parameter and a predefined target value for the fill level parameter corresponding to the predefined target fill level in the equalization tank, the conveying capacity of the first, second and/or third conveying device for achieving the target fill level, or depending on a deviation between the derived actual value for the fill level parameter and a predefined limit value of the predefined target fill level range in the equalization tank, the conveying capacity of the first, second and/or third conveying device for maintaining the fill level in the target fill level range.
  • the electronic process control generates a first model from the process data.
  • the degree of adjustment of the conveying capacity is derived from this first model.
  • the first model represents the dependency between the fill level parameter in the equalization tank on the one hand and the conveying capacity of the first, second and/or third conveying device on the other hand.
  • the bioprocess arrangement has a first bioprocess inlet and a fourth conveying device associated therewith, which is designed for the metered delivery of a liquid flow into the line arrangement.
  • a further liquid flow can be supplied via the additional bioprocess inlet.
  • the concentrate flow is combined with the diluent flow in the equalization tank to form a first liquid flow containing a target factor and then combined with a second liquid flow in a precisely predefined volume ratio to form a third, reactive liquid flow.
  • This simple process control allows predefined conditions, in particular virus-inactivating or buffer-diluting conditions, to be created in a particularly simple manner.
  • the bioprocess system has at least one mixer for mixing the third, reactive liquid stream. This enables the homogenization of a target parameter, in particular the pH or the conductivity, in a particularly simple manner.
  • a particularly preferred embodiment according to claim 10 shows that the bioprocess arrangement has a residence time arrangement downstream of the mixer for providing a minimum residence time of a liquid stream.
  • This residence time arrangement ensures the required incubation time of a liquid stream, in particular with virus-inactivating agents, in a particularly simple manner.
  • the sensor arrangement generates process data into which liquid parameters of the first liquid stream containing a target factor and liquid parameters of the third, reactive liquid stream flow.
  • the electronic process control Based on an actual value for the liquid parameter determined by the measurement, the electronic process control carries out a virus inactivation routine in order to adjust a target value for the liquid parameter, in particular a target pH or a target conductivity, in a liquid stream.
  • a virus inactivation routine in order to adjust a target value for the liquid parameter, in particular a target pH or a target conductivity, in a liquid stream.
  • a further preferred embodiment according to claim 13 relates to a disposal line which is designed to discharge a liquid flow from the bioprocess arrangement.
  • This variant offers the advantage that liquid flows or parts thereof which are not further passed through the Bioprocess arrangement, can be diverted and in particular can be discharged from the bioprocess arrangement for further use or disposed of. This enables so-called priming of the system, ie flooding the line arrangement with buffer, disposal of (partial) liquid flows that are no longer required and/or the like, and generally increases the flexibility of the proposed method.
  • a valve arrangement with at least one valve is provided for the selective fluidic connection of the respective line to the line arrangement.
  • the further preferred embodiment according to claim 15 relates to the design of the bioprocess arrangement with a second bioprocess inlet, to which a fifth conveying device is assigned, whereby a fourth, neutralizing liquid flow is introduced and combined with the third, reactive liquid flow to produce a fifth, resulting liquid flow.
  • This offers the advantage of a particularly simple neutralization of the conditions, in particular those which inactivate viruses.
  • the bioprocess arrangement has at least one second mixer which is designed to mix the fifth, resulting liquid stream.
  • This mixer enables the homogenization of the neutralizing conditions, in particular the pH, in a particularly simple manner and allows continuous operation of the process.
  • the preferred embodiments according to claims 18 and 19 relate to the preferred measuring positions and measuring parameters of the sensors of the sensor arrangement, so that process data can be generated in a particularly simple and efficient manner.
  • the electronic process control carries out a neutralization routine in order to adjust a target value for a liquid parameter, in particular the pH or the conductivity, in a liquid flow. This allows the continuous adjustment of an otherwise deviating value, in particular by adjusting the base concentration or by adjusting the buffer concentration, in order to keep it as constant as possible and thus enables continuous virus inactivation or continuous inline dilution in a particularly efficient manner.
  • the electronic process control generates a second model from the process data and the degree of adjustment of the conveying capacity of the fourth and/or fifth conveying device is derived from this second model.
  • the first model and/or the second model is a statistical or analytical model. This ensures particular flexibility in the applicability and efficiency of the proposed method.
  • the preferred embodiment according to claim 22 relates to the continuous exit of a liquid stream from the bioprocess arrangement and underpins the connectability of the proposed process with a downstream, preferably continuous, process in a particularly simple manner.
  • the preferred embodiment according to claim 23 relates to the design of the first and/or second mixer.
  • a centrifugal pump is used for dynamic inline mixing, through which the fluid flows in the opposite direction to the intended operation.
  • This embodiment opens up the possibility of the impeller of the centrifugal pump rotating in the opposite direction to the intended direction acting as a mixer, which makes it possible to set a variable mixing performance by speed control without causing an increase in pressure in the system.
  • the proposed method is carried out in combination with chromatography methods and/or with filtration methods. This offers the possibility of easily integrating the proposed method into an already existing process.
  • a bioprocess arrangement for operating a continuous downstream process, in particular a continuous virus inactivation or inline dilution process, during a bioprocess, wherein the bioprocess arrangement has an equalization tank, with a first fluid inlet, set up to introduce a concentrate flow, in particular a product or buffer concentrate flow, into the equalization tank, with at least a second fluid inlet, set up to introduce a diluent flow, in particular a product or buffer diluent flow, into the equalization tank, with a fluid outlet, set up to discharge a liquid flow from the equalization tank, wherein the bioprocess arrangement has a conveying arrangement for conveying fluid, which is assigned to the first fluid inlet and the second fluid inlet for conveying at least one liquid flow into the equalization tank, and the fluid outlet for conveying a liquid flow from the equalization tank, and wherein the bioprocess arrangement has an electronic process control.
  • the bioprocess arrangement has an electronic process control.
  • the electronic process control adjusts a filling level in the equalization tank by controlling and/or regulating the conveying arrangement in such a way that a predefined minimum filling level in the equalization tank is not undercut.
  • the electronic process control has a data processing system for implementing a proposed method.
  • a computer-readable storage medium for storing the proposed computer program.
  • a proposed method for operating a continuous downstream process in particular a continuous virus inactivation or inline dilution process, is shown.
  • This is used in the downstream process of a bioprocess using a bioprocess arrangement 1, in particular in the production, purification and/or quality control of biopharmaceutical products, such as during the production of a protein.
  • proteins can be growth factors, hormones, enzymes and in particular antibodies, antibody derivatives or the like.
  • the proposed method can be used to ensure that a biopharmaceutical product does not contain any active virus particles of any type above a certain threshold value set by, for example, the manufacturer and/or regulatory authorities, etc., in particular no active virus particles at all.
  • the proposed method can be used for continuous inline dilution, in particular of buffers.
  • the target protein can originate either directly or indirectly from a bioreactor, in particular after processing steps, in particular steps of the downstream process, such as filtration, precipitation, and/or chromatographic separation steps or the like, have been carried out.
  • chromatographic steps can be, for example, affinity chromatography steps, in particular affinity chromatography steps using protein A.
  • the bioprocess arrangement 1 has a compensation tank 2 with a first fluid inlet 3, designed to introduce a concentrate flow, in particular a product or buffer concentrate flow, into the compensation tank 2, and with at least one second fluid inlet 4, designed to introduce a diluent flow, in particular a product or buffer diluent flow, into the compensation tank 2.
  • the compensation tank 2 is here and preferably a stirred compensation tank 2, as in Fig.1 and Fig.2 and is therefore designed for homogenization.
  • product concentrate stream here means a liquid stream that essentially contains product from an upstream process step, in particular eluate from an upstream chromatography step.
  • buffer concentrate stream here means a liquid stream that essentially contains buffer, in particular a concentrated buffer, which is diluted inline for further use in the bioprocess.
  • product diluent stream here means a liquid stream that essentially contains solvent that is designed to dilute a product from an upstream process step, in particular buffer that is suitable for the respective product.
  • buffer diluent stream here means a liquid stream that essentially contains solvent designed to dilute a buffer, in particular water.
  • the bioprocess arrangement 1 has a fluid outlet 5, designed to discharge a liquid flow from the equalization tank 2.
  • the bioprocess arrangement 1 also has a conveying arrangement 6 for conveying fluid, which is assigned to the first fluid inlet 3 and the second fluid inlet 4 for conveying at least one liquid flow into the equalization tank 2, and to the fluid outlet 5 for conveying a liquid flow from the equalization tank 2.
  • the bioprocess arrangement 1 has an electronic process control 7.
  • fluid conveyance is to be understood broadly in this case and means any type of conveyance and/or adjustment, in particular interruption, of the conveyance of fluids, in particular liquids.
  • the electronic process control 7 adjusts a filling level in the equalizing tank 2 by controlling and/or regulating the conveying arrangement 6 in such a way that a predefined minimum filling level in the equalizing tank 2 is not undercut. This ensures a continuous liquid flow ( Fig.1 ).
  • minimum fill level is to be understood broadly here and preferably means any type of fill level in the expansion tank that has been defined, preferably by a user, as a minimum fill level. According to a particularly preferred embodiment, the minimum fill level is preferably less than 50%, more preferably less than 25%, more preferably less than 10%, more preferably less than 5% of the total volume of the expansion tank 2.
  • the electronic process control 7 adjusts a fill level in the equalizing tank 2 by controlling and/or regulating the conveying arrangement 6 such that a predefined target fill level is reached or that the fill level is maintained in a target fill level range.
  • target level here means any level that is defined, preferably by the user, as the level to be achieved.
  • a “target level range” is a range between an upper limit and a lower limit for the fill level within which the fill level is maintained.
  • the conveying arrangement 6 preferably has a first conveying device 8 for conveying fluid, which is assigned to the first fluid inlet 3. Additionally or alternatively, the conveying arrangement 6 preferably has a second conveying device 9 for conveying fluid, which is assigned to the second fluid inlet 4. Furthermore additionally or alternatively, the conveying arrangement 6 preferably has a third conveying device 10 for conveying fluid, which is assigned to the fluid outlet 5.
  • the bioprocess arrangement 1 preferably has a bioprocess outlet 11 which is designed to discharge a liquid from the bioprocess arrangement 1.
  • the bioprocess arrangement 1 also has a line arrangement 12 with at least one line 13 for fluidically connecting the fluid outlet 5 of the compensation tank 2 to the bioprocess outlet 11. This discharge from the bioprocess outlet 11 preferably takes place when a liquid stream has passed through the proposed method and is passed to a downstream process step, preferably to a downstream chromatography step or the like, for further processing.
  • the third conveyor device 10 is here and preferably, as in Fig.1 and Fig.2 to be seen, for fluid conveyance through at least one line 13 of the line arrangement 12.
  • the bioprocess arrangement 1 has a sensor arrangement 14 for generating process data 15, with at least one sensor 16 assigned to the compensation tank 2.
  • the at least one sensor 16 in the compensation tank 2 is preferably designed as a fill level sensor, which is further preferably set up to measure a fill level and/or to measure a change in a fill level per unit of time. Further preferably, the fill level sensor is set up to measure a fill level parameter.
  • the term "fill level parameter" is to be understood here in a broad sense.
  • the fill level parameter is preferably a very general measure of the filling of the expansion tank 2 with liquid and can be represented by a percentage filling of the expansion tank 2, a certain mass, a certain volume, a certain concentration or the like.
  • the fill level parameter can be represented by a certain fill level at a certain point in time or as a change in the fill level over time, which can also represent the flow rate.
  • liquid is also to be understood in a broad sense. It includes not only a pure liquid as such, but also emulsions and suspensions, e.g. a heterogeneous mixture of at least two different liquids or a heterogeneous mixture consisting of solid parts and liquid.
  • the at least one sensor 16 in the compensation tank 2 can be designed as a force sensor, preferably as a load cell, which is further preferably set up to measure a force, in particular a mass and/or to measure a change in a mass per unit of time.
  • this force in particular the mass and/or the change in a mass per unit of time, can be converted into a fill level and/or into the change in a fill level per unit of time.
  • the electronic process control 7 derives at least one actual value for a fill level parameter in the equalizing tank 2 from the process data 15 in a monitoring routine 17, preferably in an information query 18.
  • the electronic process control 7 adjusts, preferably in an adjustment step 20, the conveying capacity of the first, second and/or third conveying device 8, 9, 10 to prevent the minimum fill level from being undershot, as in Fig.3 shown.
  • the electronic process control 7 adjusts the conveying capacity of the first, second and/or third conveying device 8, 9, 10 to achieve the target filling level depending on a deviation between the derived actual value for the filling level parameter and a predefined target value for the filling level parameter corresponding to the predefined target filling level in the compensation tank 2.
  • the electronic process control 7 adjusts the conveying capacity of the first, second and/or third conveying device 8, 9, 10 to maintain the fill level in the target fill level range depending on a deviation between the derived actual value for the fill level parameter and a predefined limit value of the predefined target fill level range in the compensation tank 2.
  • device is to be understood broadly here and includes not only any subtraction between a measured value and a target value, but also any other type of mathematical deviation including a variance, a difference and/or an integral of a difference or the like.
  • the conveying capacity of at least the first and/or second conveying device 8, 9 is adjusted, preferably increased.
  • the conveying capacity of at least the third conveying device 10 is preferably adjusted, more preferably reduced.
  • the electronic process control 7 in the monitoring routine 17 derives a fill level parameter in the equalization tank 2 from the process data 15 and determines a deviation from a predefined target fill level in the equalization tank 2, the electronic process control 7 preferably adapts the conveying capacity of at least the first and/or second conveying device 8, 9, more preferably this is increased. This has the result that more liquid is delivered into the equalization tank 2 so that a continuous liquid flow flowing out of the equalization tank 2 can be maintained.
  • the liquid flow fed into the equalization tank 2 to achieve a predefined target fill level is preferably the concentrate flow and/or the diluent flow.
  • a supply of a liquid flow to maintain a continuous liquid flow out of the equalizing tank 2 does not exceed a level which would result in a target factor concentration in the equalizing tank 2 falling below, unless the continuous liquid flow out of the equalizing tank 2 would otherwise come to a standstill.
  • target factor here means a product, preferably an eluate, or a buffer.
  • target factor concentration here means a product concentration, preferably eluate concentration, or a buffer concentration. It should be noted that, as already indicated above, the supply of a liquid flow into the equalization tank 2 does not exceed a level that falls below a preferably predefined product concentration, preferably eluate concentration, or a preferably predefined buffer concentration. This can preferably be set by the user of the proposed method before and/or during the method for operating a continuous downstream process.
  • the delivery capacity is preferably adjusted, and more preferably reduced, at least for the third delivery device 10. This in turn results in the flow rate of the liquid flow flowing out of the equalizing tank 2 being reduced, but a continuous liquid flow flowing out of the equalizing tank 2 can be maintained. It is particularly preferred that, in order to maintain a continuous flow, the delivery capacity of at least the first and/or second delivery device 8, 9 is first adjusted, and more preferably increased.
  • An adjustment of the conveying capacity of at least the third conveying device 10 is preferably carried out when the adjustment of the conveying capacity of at least the first and/or second conveying device 8, 9 is not sufficient to maintain a continuous liquid flow.
  • the conveying capacity of the third conveying device 10 is preferably kept essentially constant. Otherwise, a changing flow rate would mean that the residence time of a liquid flow in the bioprocess arrangement 1, described in more detail later, could fall below a predefined minimum residence time.
  • a model here always means a mathematical model.
  • the degree of adjustment of the conveying capacity of the conveying arrangement 6 is preferably derived from the first model 21.
  • the first model 21 further preferably represents the dependency between the fill level parameter, preferably the change in the target fill level per time, in the equalizing tank 2 on the one hand and the conveying capacity of the first, second and/or third conveying device 8, 9, 10 on the other hand.
  • the first model 21 is preferably set up to predict future target fill levels, preferably at a predefined point in time, in the equalizing tank 2 depending on the change in the level per time.
  • the bioprocess arrangement 1 has a first bioprocess inlet 22 downstream of the equalizing tank 2, which is designed to introduce a liquid flow into the line arrangement 12 of the bioprocess arrangement 1. This is preferably located downstream of the third conveying device 10.
  • the conveying arrangement 6 preferably has a fourth conveying device 23, which is assigned to the first bioprocess inlet 22 and is designed to meteredly discharge a liquid flow into the line arrangement 12.
  • the concentrate stream is combined with the diluent stream to form a first liquid stream 24 containing a target factor.
  • This first liquid stream 24 containing a target factor preferably contains either the biopharmaceutical target product, such as an antibody or a vector, as well as viruses as a result of the process.
  • this first liquid stream 24 preferably contains a target buffer as a target factor, such as an equilibration, washing or elution buffer or the like.
  • target factor therefore means a specific property of the liquid in the liquid stream 24, as already mentioned above.
  • the first liquid stream 24 containing a target factor is preferably introduced through the fluid outlet 5 from the equalization tank 2 into the at least one fluidically connected line 13 of the line arrangement 12. This is then combined in a predefined volume ratio with a second liquid stream 25 introduced through the first bioprocess inlet 22 and conveyed by the fourth conveying device 23, preferably to form a third, reactive liquid stream 26, in order to set a predefined target value for a liquid parameter, in particular for a pH and/or a conductivity, in the third, reactive liquid stream 26.
  • the second liquid stream 25 has, as a property necessary to fulfil the intended function, either virus-inactivating conditions, in particular a pH of less than 3.
  • the virus-inactivating conditions, in particular the pH, of the second liquid stream 25 are selected such that after combining with the first liquid stream 24 containing a target factor, the resulting third, reactive liquid stream 26 also has virus-inactivating conditions, in particular a pH of 3 to 3.8 and/or a detergent concentration of between 0.05% and 10% (v/v).
  • virus-inactivating conditions in particular a pH of 3 to 3.8 and/or a detergent concentration of between 0.05% and 10% (v/v).
  • the pH is achieved by adding an acid such as lactic acid, ascorbic acid, acetic acid, hydrochloric acid, phosphoric acid, citric acid, glycine, succinic acid and/or sulfuric acid or the like.
  • the virus-inactivating reagent can contain an acid with a titratable group with a pKa between 2.0 and 4.3.
  • the virus-inactivating conditions can be selected such that the concentration of the acid can be up to 100 mM and yet have sufficient buffer properties to enable effective virus inactivation on the one hand and not to damage the protein product on the other, e.g. through acid denaturation.
  • the virus-inactivating conditions can be created by a non-ionic detergent having a chromophoric group.
  • Such detergents can be, for example, Triton-X 100 and other polyethylene oxides.
  • the virus-inactivating conditions can be selected with the proposed method such that virus inactivation by a factor of at least 1 ⁇ 10 1 , preferably at least 1 ⁇ 10 3 , more preferably at least 1 ⁇ 10 6 can be achieved, in particular regardless of whether it is precisely one specific virus type, several virus types and/or a plurality of different virus types.
  • the virus-inactivating conditions can be selected such that less than 1 ppm, preferably less than 1 ppb, of the volume of the third, reactive liquid stream 26 has a residence time which is shorter than that which would be necessary for effective virus inactivation by a factor of at least 1 ⁇ 10 1 , in particular of at least 1 ⁇ 10 6 .
  • the second liquid stream 25 is preferably mixed for virus inactivation with the first liquid stream 24 containing a target protein in a precisely predefined volume ratio of these two liquid streams 24, 25 to one another, so that it can be ensured that the conditions in the third, reactive liquid stream 26 for fulfilling the intended function are actually present and homogeneously distributed.
  • a volume ratio can be, for example, 19:1, with nineteen parts of the first liquid stream 24 containing a target protein and one part of the second, virus-inactivating liquid stream 25.
  • the second liquid stream 25 has buffer-diluting conditions as a property necessary to fulfill the intended function, preferably that the second liquid stream 25 consists of dilution buffer and/or water or the like.
  • the buffer-diluting conditions of the second liquid stream 25 are selected such that after merging with the first liquid stream 24 containing a target factor, the resulting third, reactive liquid stream 26 also has buffer-diluting conditions, in particular a target buffer concentration.
  • the Dilution to produce a target buffer concentration is achieved by adding a dilution buffer and/or water or the like.
  • the bioprocess arrangement 1, preferably downstream of the first bioprocess inlet 22, has a first mixer 27, set up for fluid mixing.
  • the third, reactive liquid stream 26 is preferably passed through the first mixer 27 for fluid mixing.
  • This mixer 27 is preferably designed as an inline static mixer, in particular as a radial or laminar static mixer or the like, as in Fig.2
  • a plurality of static mixers can be connected in series.
  • a dynamic mixer can also be provided as the first mixer 27.
  • fluid mixing is to be understood broadly in this context and means any type of mixing of a fluid, in particular a liquid, that goes beyond simply passing the fluid through a line, in particular a hose or pipeline.
  • the bioprocess arrangement 1, here and preferably downstream of the first mixer 27, has a residence time arrangement 28 fluidically connected to the first mixer 27 for providing a minimum residence time of a liquid flow (see Fig.2 ).
  • the third reactive liquid stream 26 is preferably passed through the residence time arrangement 28 to provide a minimum residence time.
  • the above-described supply of a liquid stream into the equalization tank 2 to maintain a continuous liquid stream results in the concentration in the equalization tank 2, preferably the product concentration or buffer concentration, changing. Both parameters can have an influence on a logarithmic reduction in the viral load, so that the residence time of the liquid stream in the residence time arrangement 28 is at least 15 minutes, preferably up to 1 hour, so that such changes also remain uncritical.
  • fluidically connected here means a tight connection that allows a fluid to move internally from one area to another, at least unidirectionally, preferably bidirectionally. In this case, the fluid connection is also released by mechanical release.
  • “Dwell time arrangement” here means an arrangement which, when properly assembled, serves to allow a certain volume flow, consisting of one or more combined fluid, in particular liquid, flows, to “dwell” within this arrangement, in that the dwell time arrangement 28 is designed in such a way that the distance to be covered by the volume flow is artificially extended, so that a multiple distance relative to the extension of the component must be covered.
  • the dwell times of the individual fluids to be inactivated Volume fractions must be as uniform as possible in order to obtain a reproducible inactivation result.
  • the sensor arrangement 14 for generating the process data 15 has at least one sensor 29 for measuring a liquid parameter, in particular a pH and/or a conductivity, of the first liquid stream 24 containing a target factor, which is preferably designed as a pH sensor and is set up to measure a pH in the first liquid stream 24 containing a target factor.
  • the sensor 29 is preferably designed as a conductivity sensor, which is further preferably set up to measure a conductivity in the first liquid stream 24 containing a target factor.
  • the sensor 29 is here and preferably arranged downstream of the equalization tank 2 and upstream of the first bioprocess inlet 22 ( Fig.2 ).
  • the sensor arrangement 14 here and preferably has at least one sensor 30, 31, preferably at least two sensors 30, 31, for measuring a liquid parameter, in particular a pH and/or a conductivity, of the third, reactive liquid stream 26.
  • the sensor 30 is arranged here and preferably downstream of the first mixer 27.
  • the sensor arrangement 14 here and preferably downstream of the residence time arrangement 28 has at least one sensor 31 for measuring a liquid parameter in the third, reactive liquid stream 26.
  • the sensor 31 is used in particular to measure a flow rate and/or a protein concentration, preferably by means of UV measurement.
  • the measurement of the flow rate preferably serves to determine the required residence time of the third, reactive liquid stream 26 in the residence time arrangement 28 with particular precision. This is because, as already discussed above, a changing flow rate results in the residence time of a liquid stream in the residence time arrangement 28 required for the intended process also changing. The residence time of a liquid stream in the residence time arrangement 28 can thus be adjusted by adjusting the flow rate.
  • the measurement of the UV absorption preferably serves to determine the target factor concentration, in particular a protein concentration, particularly precisely.
  • the electronic process control 7 can control the conveyor arrangement 6 in such a way that the flow direction of the third, reactive liquid stream 26 is diverted via a line 13 of the line arrangement 12, which will be described in more detail later, and the third, reactive liquid stream 26 can be continuously passed on to a subsequent process step or disposed of in a subsequent disposal step.
  • a predetermined minimum protein concentration can be set particularly at the beginning (during or immediately after the so-called priming) or towards the end of a continuous downstream process, in particular a continuous virus inactivation process.
  • the electronic process control 7 preferably adjusts the conveying capacity of the fourth conveying device 23 in a virus inactivation routine 32 to set the target value for the liquid parameter in the third, reactive liquid stream 26. This is preferably done as a function of a deviation between an actual value determined by the measurement for the liquid parameter of the first liquid stream 24 containing a target factor and the predefined target value for the liquid parameter in the third, reactive liquid stream 26.
  • the conductivity preferably enables the electronic process control 7 to derive a buffer concentration. If, according to this embodiment, the actual pH in the first liquid stream 24 containing a target protein deviates from the target value of the liquid parameter in the third, reactive liquid stream 26, it is preferably possible for the electronic process control 7 to adjust the actual value of the liquid parameter, preferably the actual pH or the actual conductivity, in the third, reactive liquid stream 26 by controlling and/or regulating the fourth conveying device 23, which is preferably set up for the metered release of acid, buffer and/or water.
  • the actual pH in the first liquid stream 24 containing a target factor can preferably be determined on the one hand and the electronic process control 7 can calculate the necessary volume and/or volume flow to be supplied in order to achieve the target value of the liquid parameter in the third, reactive liquid stream 26, in particular the target pH, on the other hand, on the basis of the process data 15.
  • the actual conductivity in the first liquid stream 24 containing a target factor can preferably be determined on the one hand and the electronic process control 7 can calculate the necessary volume and/or volume flow to be supplied in order to achieve the target value for the liquid parameter in the third, reactive liquid stream 26, in particular the target conductivity, on the basis of the process data 15.
  • the line arrangement 12 preferably downstream of the residence time arrangement 28, has a disposal line 33 which is designed to discharge a liquid flow from the bioprocess arrangement 1.
  • Disposal line here means a line 13 of the line arrangement 12 for establishing a fluid connection, whereby this offers the user of the proposed method the possibility of not necessarily directing liquid flows introduced into the bioprocess arrangement 1 to the bioprocess outlet 11 and out of it. This is particularly advantageous if the bioprocess arrangement 1 is to be installed in front of a proposed continuous Downstream process is flushed with, for example, buffer, in particular in a first proposed continuous downstream process with a newly used buffer and/or with a newly used concentrate stream, in particular a new product or buffer concentrate stream.
  • this final diluted buffer can be continuously discharged from the bioprocess arrangement 1 through the disposal line 33 and used directly in a downstream process step, in particular in a downstream chromatography step.
  • the line arrangement 12 is assigned a valve arrangement 34 with at least one valve for the selective fluidic connection of at least one line 13 of the line arrangement 12, in particular the disposal line 33.
  • the bioprocess arrangement 1, here and preferably downstream of the disposal line 33, has a second bioprocess inlet 35, which is designed to introduce a liquid flow into the line arrangement 12 of the bioprocess arrangement 1.
  • the conveying arrangement 6 preferably has a fifth conveying device 36. This is preferably assigned to the second bioprocess inlet 35 and designed for the metered discharge of a liquid flow into the line arrangement 12.
  • the third, reactive liquid stream 26 is combined here and preferably downstream of the residence time arrangement 28 with a fourth, neutralizing liquid stream 37 introduced through the second bioprocess inlet 35 to form a fifth, resulting liquid stream 38 in order to neutralize the predefined target value for the liquid parameter in the fifth, resulting liquid stream 38.
  • Neutralization here means the partial or complete reversal of the previous change in the liquid parameter and thereby the elimination and/or removal of the virus-inactivating conditions, in particular by the reaction of equal amounts of acids, for example 1.5 to 3 M acetic acid, or acid derivatives, for example 2 M glycine, and bases, for example 1 to 2 M HEPES pH 8 or Tris pH 11.
  • This fourth, neutralizing liquid stream 37 serves to neutralize, deplete and/or remove the virus-inactivating conditions.
  • a fifth, resulting liquid stream 38 is created, which can be discharged from the bioprocess arrangement 1 through the bioprocess outlet 11 and has a pH, preferably a pH between 5 and 8.5, which enables further processing.
  • the mixing of these two liquid streams 26, 37 also takes place in a precisely predefined volume ratio, so that it can be ensured that the neutralizing conditions in the fifth, resulting liquid stream 38 are actually present and homogeneously distributed to fulfill the intended function.
  • a fourth, neutralizing liquid stream 37 is optional.
  • additional diluting buffer, water or the like can be added to the third, reactive liquid stream 26 through the second bioprocess inlet 35.
  • nothing can be added, such that the third, reactive liquid stream 26 leaves the bioprocess assembly 1 through the bioprocess outlet 11.
  • the respective conveying device (8, 9, 23, 36), in particular all conveying devices which are designed for the metered delivery of a liquid flow, is designed as a dosing pump, more preferably as a hose pump, rotary piston pump or diaphragm pump, or as a valve, in particular a continuous valve, control valve or the like.
  • the bioprocess arrangement 1 has, here and preferably downstream of the second bioprocess inlet 35, at least one second mixer 39, set up for fluid mixing.
  • the fifth, resulting liquid stream 38 is preferably passed through the at least second mixer 39 for fluid mixing and, after fluid mixing has taken place, is discharged from the bioprocess arrangement 1 through the bioprocess outlet 11.
  • This second mixer 39 can also be designed as an inline static mixer, in particular as a radial or laminar, static mixer or the like, as in Fig.2
  • a plurality of static mixers can be connected in series.
  • a dynamic mixer can also be provided as the second mixer 39.
  • the sensor arrangement 14 for generating the process data 15 has at least one sensor 40 for measuring a liquid parameter of the fifth, resulting liquid stream 38, in particular a pH and/or a conductivity.
  • the sensor 40 is here and preferably arranged downstream of the second mixer 39.
  • the electronic process control 7 preferably adjusts the conveying capacity of the fifth conveying device 36 in a neutralization routine 41 to set the target value for the liquid parameter in the fifth, resulting liquid stream 38. This is preferably done depending on a deviation between an actual value determined by the measurement for the liquid parameter of the third, reactive liquid stream 26 and a predefined target value for the liquid parameter in the fifth, resulting liquid stream 38.
  • the conductivity preferably enables the electronic process control 7 to derive a buffer concentration. If, according to this embodiment, the actual pH in the third, reactive liquid stream 26 deviates from the target value for the liquid parameter in the fifth, resulting liquid stream 38, it is preferably possible for the electronic process control 7 to adjust the actual value of the liquid parameter, preferably the actual pH or the actual conductivity, in the fifth, resulting liquid stream 38 by controlling and/or regulating the fifth conveying device 36, which is preferably set up for the metered dispensing of base, buffer and/or water.
  • the actual pH in the third, reactive liquid stream 26 can preferably be determined on the one hand and, on the other hand, the electronic process control 7 can calculate the necessary volume and/or volume flow to be supplied in order to achieve the target parameter in the fifth, resulting liquid stream 38, in particular the target pH, on the basis of the process data 15.
  • the actual conductivity in the third, reactive liquid stream 26 can preferably be determined on the one hand and, on the other hand, the electronic process control 7 can calculate the necessary volume and/or volume flow to be supplied in order to achieve the target value in the fifth, resulting liquid stream 38, in particular the target conductivity, on the basis of the process data 15.
  • the respective sensor 16, 29, 30, 31, 40 for generating the process data 15 measures at least one parameter from the group comprising pH value, conductivity, fill level, change in fill level per time, conveying capacity of at least one conveying device, flow rate of at least one liquid stream, protein concentration and/or other spectrophotometric properties of at least one liquid stream.
  • at least two of them can measure the same or different parameters.
  • the electronic process control 7 can generate a second model 42 from the process data 15.
  • the degree of adjustment of the conveying capacity of the fourth and/or fifth conveying device 23, 36 is preferably derived from the second model 42.
  • the second model 42 preferably represents the dependency between the liquid parameter of the third, reactive liquid flow 26 on the one hand and the conveying capacity of the fourth conveying device 23 on the other hand. Additionally or alternatively, the second model 42 preferably represents the dependency between the liquid parameter of the fifth, resulting liquid flow 38 on the one hand and the conveying capacity of the fifth conveying device 36 on the other hand.
  • at least the conveying arrangement 6 is preferably controlled by the electronic process control 7.
  • the electronic process control 7 is preferably controlled by the electronic process control 7.
  • the electronic process control 7 calculates which volume, volume flow or the like of the second liquid flow 25 must be added to the first liquid flow 24 containing a target factor in order to Target value of the liquid parameter in the third, reactive liquid stream 26, in particular the target pH or the target conductivity. Additionally or alternatively, here and preferably, as in Fig.2 shown, on the basis of the process data 15, the electronic process control 7 calculates which volume, volume flow or the like of the fourth liquid stream 37 must be added to the third, reactive liquid stream 26 in order to produce the target value of the liquid parameter in the fifth, resulting liquid stream 38, in particular the target pH or the target conductivity.
  • the second model 42 calculates the degree of adjustment of the delivery capacity of the fourth delivery device 23 preferably based on at least one characteristic curve between the conductivity measured in the first liquid stream 24 containing a target factor and a corresponding buffer concentration. Additionally or alternatively, the second model 42 calculates the degree of adjustment of the delivery capacity of the fifth delivery device 36 preferably based on at least one characteristic curve between the conductivity measured in the third, reactive liquid stream 26 and a corresponding buffer concentration.
  • the first model 21 and/or the second model 42 is a statistical model or an analytical model.
  • statistical model refers to a mathematical model in which some or all of the input data has some randomness, expressed, for example, by a probability distribution, so that for a given set of input data, the output is not reproducible but is described by a probability distribution. Output data is obtained by running the model many times with a new input value taken from the probability distribution on each run.
  • analytical model refers to a quantitative model used to answer a specific question. Its main goal is to provide a closed formula for certain characteristics.
  • analytical models are mathematical models that have a closed solution, i.e. the solution of the equations used to describe changes in a system can be expressed as a mathematical analytical function.
  • Continuous here means that the liquid flow 25, 35 leaving the bioprocess arrangement 1 is not interrupted, for example by incubation in a container or the like, and that it can vary in terms of flow rate.
  • At least the first and/or second mixer 27, 39, preferably all mixers, are set up for inline mixing of a liquid flow and are designed as a static mixer or as a centrifugal pump, in particular a centrifugal centrifugal pump. It is also preferred that the centrifugal pump is flowed through in the opposite direction to the intended operation for dynamic inline mixing.
  • the proposed method can be carried out in combination with an upstream, preferably discontinuous or continuous, chromatography method, in particular affinity chromatography and ion exchange chromatography methods. Additionally or alternatively, the proposed method is carried out in combination with an upstream, preferably discontinuous or continuous, filtration method, in particular tangential flow filtration method or the like. Additionally or alternatively, the proposed method is followed by a continuous chromatography or filtration method.
  • the proposed method can be used in combination with all purification, filtration, chromatography, separation, centrifugation, concentration and/or sedimentation processes or other processes that can be assigned to downstream processes during a bioprocess.
  • a bioprocess arrangement 1 for operating a continuous downstream process, in particular a continuous virus inactivation or inline dilution process, during a bioprocess.
  • the bioprocess arrangement 1 has an equalization tank 2, with a first fluid inlet 3, set up to introduce a concentrate flow, in particular a product or buffer concentrate flow, into the equalization tank 2, and with at least one second fluid inlet 4, set up to introduce a diluent flow, in particular a product or buffer diluent flow, into the equalization tank 2.
  • the bioprocess arrangement 1 has a fluid outlet 5, which is set up to discharge a liquid flow from the equalization tank 2.
  • the bioprocess arrangement 1 has a conveying arrangement 6 for conveying fluid, which is assigned to the first fluid inlet 3 and the second fluid inlet 4 for conveying at least one liquid flow into the equalization tank 2.
  • the conveying arrangement 6 is assigned to the fluid outlet 5 for conveying a liquid flow from the compensation tank.
  • the bioprocess arrangement 1 has an electronic process control 7.
  • the electronic process control 7 is Control and/or regulation of the conveying arrangement 6 adjusts a fill level in the equalizing tank 2. This adjustment is carried out in such a way that a predefined minimum fill level in the equalizing tank 2 is not undercut in order to thereby ensure a continuous flow of liquid from the bioprocess arrangement 1.
  • At least one component of the bioprocess arrangement 1, preferably all components, is designed as a single-use component.
  • an electronic process control 7 of the proposed bioprocess arrangement 1 is claimed.
  • the line arrangement 12 is assigned a valve arrangement 34 with at least one valve for the selective fluidic connection of the at least one line 13, preferably all lines, of the line arrangement 12.
  • the electronic process control 7 is set up by controlling and/or regulating at least the conveyor arrangement 6 to carry out a method according to the proposal.
  • the electronic process control 7 preferably has a data processing system for implementing a proposed method.
  • a computer program is claimed for the proposed electronic process control 7.
  • a computer-readable storage medium for storing the proposed computer program is claimed. All statements on the proposed method for operating a continuous downstream process, on the proposed bioprocess arrangement 1, Reference may be made in this respect to the proposed electronic process control 7, to the proposed use and to the proposed computer program.

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EP22201978.8A 2022-10-17 2022-10-17 Procédé et appareil de fonctionnement d'un processus en aval continu Pending EP4357009A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE29909434U1 (de) * 1999-05-29 1999-12-09 Oden Corp., Buffalo, N.Y. Vorrichtung zum kontinuierlichen Mischen eines Flüssigkeitsstroms
JP2006084457A (ja) * 2004-08-20 2006-03-30 Daicel Chem Ind Ltd クロマトグラフィー装置及び溶剤組成調整装置
DE102007050335A1 (de) * 2007-10-18 2009-04-23 Bayer Technology Services Gmbh Anordnung und Verfahren zur Bereitstellung eines vorzugsweise zeitlich veränderlichen Flüssigkeitsgemisches
WO2015117884A1 (fr) 2014-02-07 2015-08-13 Cmc Biologics A/S Système et procédé de chromatographie pour capturer un biopolymère

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9809799B2 (en) 2012-06-29 2017-11-07 Emd Millipore Corporation Methods for inactivating viruses during a protein purification process

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE29909434U1 (de) * 1999-05-29 1999-12-09 Oden Corp., Buffalo, N.Y. Vorrichtung zum kontinuierlichen Mischen eines Flüssigkeitsstroms
JP2006084457A (ja) * 2004-08-20 2006-03-30 Daicel Chem Ind Ltd クロマトグラフィー装置及び溶剤組成調整装置
DE102007050335A1 (de) * 2007-10-18 2009-04-23 Bayer Technology Services Gmbh Anordnung und Verfahren zur Bereitstellung eines vorzugsweise zeitlich veränderlichen Flüssigkeitsgemisches
WO2015117884A1 (fr) 2014-02-07 2015-08-13 Cmc Biologics A/S Système et procédé de chromatographie pour capturer un biopolymère

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