Technical Field

The invention relates to a foam mitigation device , to a bioreactor arrangement comprising a foam mitigation device , and to a method for operating a foam mitigation device .

Background Art

Bioreactors typically serve for culturing microorganisms or cells . For doing so , a culture medium including microorganisms and/or cells is introduced into a casing of the bioreactor and is treated there , e . g . by means of stirring, supplying oxygen, etc . During such operation of the bioreactor, foam is generated in the casing of the bioreactor on the surface of the culture medium . Such foam is not desired in view of its capability for clogging filters , pipes or other elements of the bioreactor, and in view of interfering with a proper fermentation process . In order to mitigate foam in the interior of the bioreactor, chemical anti foaming agents are supplied which in turn may again impact the fermenting and desired product or make a later puri fication step in downstream more complex .

In yet a di f ferent approach ultrasonic waves are used to mitigate the foam in the bioreactor . US 2020/ 0115669 Al discloses such a bioreactor providing an ultrasound transducer within the casing of the bioreactor for mitigating foam from a surface of the culture medium .

However, this solution relies on the integration of the foam mitigation into the bioreactor . Existing bioreactors without foam mitigation capabilities may not be equipped or upgraded with ultrasonic means later on . In addition, there is a need to clean the ultrasound transducer manually after its operation which is cumbersome and contributes to a down time of the bioreactor.

Disclosure of the Invention

Hence, it is a general object of the invention to provide a foam mitigation device also applicable to existing bioreactors.

Now, in order to implement this and still further objects of the invention, a foam mitigation device is introduced comprising a housing with an inlet for receiving a fluid, such as an exhaust gas from a bioreactor, and an outlet. An ultrasonic transducer is at least partially arranged in the housing. It serves for mitigating, i.e. reducing or destroying foam resident in the interior of the housing. Accordingly, the ultrasound transducer is configured to emit, in response to a controlled actuation, ultrasonic waves for mitigating such foam. A cleaning and / or sterilization arrangement is provided and arranged to clean and / or sterilize an interior of the housing. The cleaning and / or sterilization arrangement is provided for either one of cleaning and sterilizing, or for both. Preferably, the cleaning arrangement is provided for conducting a cleaning in place (CIP) , i.e. a cleaning of the interior absent a disassembly of the device. Preferably, the sterilization arrangement is provided for conducting a sterilization in place (SIP) , i.e. a sterilization of the interior absent a disassembly of the device. In the case of both cleaning and sterilization being implemented, the cleaning arrangement can be provided and arranged separate from the sterilization arrangement, i.e. cleaning and sterilizing are conducted via two different hardware elements. In a different embodiment of both cleaning and sterilization, however, the same hardware is used for cleaning and sterilization, wherein preferably the cleaning is performed prior to the sterilization. Accordingly, the process of both cleaning and sterilization is conducted by the same hardware elements, however, in sequence, e.g. by using different agents, i.e. a cleaning agent first, and a sterilization agent later.

The present foam mitigation device is a device separate from the bioreactor / fermenter. Accordingly, existing bioreactors without any integrated foam mitigation means may also benefit from the later-on addition of such foam mitigation device. I.e. the present foam mitigation device is capable for retrofit. The inlet of the foam mitigation device only needs to be connected to an exhaust pipe / outlet of the bioreactor, for which reason either the inlet of the foam mitigation device may be adapted to conform to the diameter of the exhaust of the bioreactor, or an adapter may be used. The foam mitigation device itself, i.e. its interior volume may be designed subject to the size of the bioreactor and the expected amount of foam to be received. The foam is not mitigated at the place of generation, i.e. the bioreactor, but in the foam mitigation device separate from the bioreactor, which foam mitigation device receives the exhaust fluid from the bioreactor including foam if any. This avoids a direct impact of the foam mitigation on the fermentation medium in the bioreactor. Any residuals from the foam mitigation process including portions of the fermentation medium may flow back in liquid phase to the bioreactor, such that concentrations of components in the fermentation medium are not altered in response to the foam mitigation. The flow back may be supported by gravity in case the foam mitigation device is arranged above the bioreactor and its inlet is straight connected to an exhaust pipe of the bioreactor.

The ultrasonic transducer applies a physical way for mitigating foam rather than a chemical way, e.g. in case of anti-foam agents being used. This is also preferred in view of the residuals from the foam mitigation flowing back into the bioreactor . The present foam mitigation device does not impact the fermentation medium as anti- foam agents do or centri fugal foam mitigation does . In addition, it is preferred to activate the ultrasonic transducer only in case of foam being detected in the foam mitigation device . Even more preferable , the power supplied to the ultrasonic transducer can be varied resulting in variable ultrasonic mitigation power . This allows for an optimal mitigation of foam, subj ect to the amount of foam detected in the housing of the foam mitigation device .

The present foam mitigation device comprises the cleaning and / or sterili zation arrangement in place for cleaning and / or sterili zing its interior . The cleaning preferably avoids foam residuals from one fermentation process be introduced in the fermentation medium of a subsequent fermentation process thereby falsifying the subsequent fermentation medium . The sterili zation preferably kills or reduces all living organism prior fermentation with the desired organism . The cleaning and / or sterili zation arrangement may be electrically controlled so as to start and stop a cleaning and / or sterili zation operation without any manual interaction with the foam mitigation device . The foam mitigation device does not need to be opened and / or otherwise disassembled . Such automated cleaning and / or sterili zation allows for lower downtimes than conventional , manual cleaning operations and it allows to use the device in a fully automated production environment . Hence , in a preferred embodiment , the cleaning and / or sterili zation arrangement is configured to clean and / or sterili ze the interior of the housing in a closed state of the housing and in response to a controlled actuation . The cleaning and / or sterili zation can be electrically controlled, e . g . by means of a control unit automatically initiating a cleaning and / or sterili zation of the interior of the housing, preferably by means of controllably supplying a detergent and / or steam into the interior of the housing . The control unit preferably is assigned to the foam mitigation device . However, in a di f ferent embodiment , functions of the control unit may also be embodied in a control unit for controlling the respective bioreactor . Preferably, the control unit is attached to a control rack or is attached to the housing of the foam mitigation device .

In a preferred embodiment , the cleaning and / or sterili zation arrangement comprises at least one spray unit ( for example : spray noz zle , spray ball or similar ) for supplying the detergent into the interior of the housing . The control unit may control the spray unit . The spray unit preferably is arranged in the interior of the housing, e . g . at the end of an arm which also acts as a channel for providing the detergent to the spray unit . Hence , such channel reaches into the interior of the housing and is attached to the wall of the housing or reaches through such wall , preferably in a sealed manner . The channel may also contain a valve that is controlled by the control unit to supply the spray unit with the detergent or steam . The channel may be connected to a supply line that is connected at its other end to a detergent reservoir and / or a steam generator . The switchover preferably is made with a valve group that is controlled by the control unit . A pump may also be provided to pump the detergent from such a reservoir into the channel and to the spray unit or let the cleaning agent circulating in a loop . It may also be the pump that is controlled by the control unit to controllably deposit the detergent into the interior of the housing via the spray unit . When steam is applied, the generation and / or supply is also controlled by the control unit .

Preferably, the spray unit has the shape of a spray ball allowing to spray the detergent in nearly all directions . The detergent may be a chemical detergent for chemically decomposing any residuals in the foam mitigation device, and / or may be a thermal detergent for thermally removing any residuals, and / or may a gaseous or liquid detergent applied under high pressure into the housing. In particular, different detergents may be applied during the cleaning process in sequence, preferably all supplied into the interior of the housing by means of the spray unit/s. E.g. in a first cleaning cycle the detergent may be NaOH, in a subsequent sterilization cycle steam may be used, and in a subsequent sterilization cycle, another sterilization agent may be used. E.g. one cycle of the sterilization process may include a thermal treatment, e.g. with steam, e.g. of a temperature exceeding 121° C for at least twenty minutes. To assist the thermal treatment the foam mitigation device can also be equipped with a double jacket for heating / cooling. Also possible is that the cleaning agent is circulating from the inlet to the outlet or vice versa through the foam mitigation unit.

Summarizing, the present foam mitigation device allows for a higher yield in the fermentation process, includes an in-situ cleaning and / or in-situ sterilization, is easy to handle, saves resources such as energy and detergent, and is cost-efficient. A smart foam mitigation process is applied allowing for a dosed usage of ultrasound.

Preferably, the interior of the housing does not provide for any dead spaces with respect to the cleaning arrangement. This may include, that screws or other fasting means for attaching housing parts to each other are arranged from the outside of the housing, with as little passing through into the interior of the housing. All attached components and the whole interior of the foam mitigation device are preferably dead leg free. The device preferably complies with applicable pharmaceutical production standards. Accordingly, the interior of the housing is desired to be cleaned in-situ and sterili zed in-situ .

Preferably, the ultrasound transducer to be excited to emit ultrasonic waves destroying or mitigating foam comprises an ultrasonic plate arranged in the housing, preferably separating the interior volume into two , i . e . a first volume and a second volume . A distance of the ultrasonic transducer plate from the top and bottom of the housing may depend on resonance considerations . In such scenario , it is very preferred that the cleaning arrangement comprises at least two spray units for supplying the detergent into the interior of the housing, one being arranged in the first volume for cleaning parts confining the first volume , and the other one arranged in the second volume for cleaning parts confining the second volume .

Preferably, the ultrasonic transducer plate is connected to an ultrasonic transducer shaft reaching through the second volume , e . g . for supporting the ultrasonic transducer plate to the housing . In one embodiment , the housing may of cylindrical shape , and the ultrasonic transducer shaft coincides with the longitudinal axis of the housing . In such scenario , a single spray unit arranged in the second volume may not be suf ficient to clean e . g . all the circumference of the shaft . For this reason, it is preferred to provide a further spray unit arranged in the second volume in order to also reach the portions of the shaft in the shadow of the detergent spray from the other spray unit . Preferably, the second and the third spray unit are arranged opposite each other . Accordingly, it is preferred that the cleaning arrangement comprises at least three spray units , preferably including corresponding channels , supply lines , etc . The detergent reservoir may be common to all spray units , as may be the pump .

It is preferred that the housing comprises a bucket shaped body and a lid closing an opening of the body . The lid is removable attached to the body . Although the housing is not meant to be opened for cleaning purposes as laid out above , it may be beneficial to make the interior of the housing accessible for maintenance purposes , for example . Nevertheless , in a preferred embodiment the foam mitigation unit can be detached from the bioreactor for manual cleaning and sterili zation in an autoclave i f needed . For only manual cleaning and sterili zation the spray units can also be blind plugged and not installed . The body may be of cylindrical shape with a longitudinal axis , the shaft coinciding with the longitudinal axis , and the plate being arranged orthogonal to the longitudinal axis , preferably taking a circular shape .

In such embodiment , the inlet preferably is arranged in the bottom of the body while the outlet is arranged in the lid . An extension of the ultrasonic transducer shaft , which is referred to as mechanical ampli fier protrudes the lid and is sealed against the lid by means of a seal . The mechanical ampli fier may ampli fy the excitation of the excited ultrasonic waves . Preferably, an ultrasonic transducer flange arranged in or attached to the lid is connected to the ultrasonic transducer shaft and / or to the mechanical ampli fier . It preferably radially extends from the ultrasonic transducer shaft . The ultrasonic transducer flange preferably is used to electrically control the emission of ultrasonic waves by the ultrasonic transducer plate . It may have a portion reaching through the lid which portion may serve as contact for electrically exciting the ultrasonic transducer plate via the flange and the shaft . The flange preferably shows a hygienic design as does the bottom side of the lid facing the interior of the housing . Hygienic design refers to the cleanability of the interior of the housing, and in particular to the in-situ cleanability of the housing by means of the cleaning arrangement . This preferably includes the absence of surfaces not accessible by the cleaning arrangement , i . e . the absence of shadowed surfaces or dead spaces with respect to the cleaning arrangement .

The ultrasonic transducer plate preferably is arranged in the housing between the inlet and the outlet . It preferably is arranged and/or dimensioned to allow a fluid exchange between the first volume and the second volume . In case of the ultrasonic transducer plate following a cross sectional shape of the housing, it preferably is dimensioned little smaller in diameter than the cross section of the housing . Preferably, a gap is provided between the ultrasonic transducer plate in its mounting position and a wall of the housing allowing for the fluid exchange between the first volume and the second volume . Or, the ultrasonic transducer plate may have one or more holes allowing for the fluid exchange . Then, the ultrasonic transducer plate may even lie against the housing wall without a gap there between .

Another important embodiment of the present invention refers to the control of the ultrasonic transducer plate , and hence , to the control of the foam mitigation . It is desired to control the foam mitigation optimi zed as to its needs . For this purpose , a first foam detection sensor is arranged and configured to detect foam exceeding a first level in the housing, which first foam detection sensor . E . g . DC free impedance measurement preferably is embodied DC free . The first level preferably is between the inlet and the ultrasonic transducer plate . Subj ect to the measurement principle , the first foam detection sensor may also be arranged between the inlet and the ultrasonic transducer plate , and in one embodiment may be arranged at the first level . Accordingly, in view of the allocation of the inlet , the outlet and the ultrasonic transducer plate , detecting foam exceeding a first level in the first volume between the inlet and the ultrasonic transducer plate implies detecting a moderate occurrence of foam in the foam mitigation device . Accordingly, at least when the first foam detection sensor indicates the foam reaching the first level , the ultrasonic transducer is desired to start with the foam mitigation . Hence , subj ect to a signal from the first foam detection sensor, the ultrasonic transducer is activated . In case , the ultrasound transducer already is activated in such instance , the power may be increased when the foam exceeds the first level . On the other hand, in case the foam falls again below the first level after it has exceeded the first level - all of which is sensed by the first foam detection sensor - the ultrasound transducer may be deactivated again, or its power, in particular its cleaning power, may be reduced .

Accordingly, by means of the control unit being configured to , in response to a signal from the first foam detection sensor, control the ultrasonic transducer, the present foam mitigation not only is implemented as a brute force mitigation such as in the prior art , but represents a controlled foam mitigation dependent on the foam level in the housing, and hence , subj ect to the amount of foam detected in the housing . Such control implements a smart foam reduction along the needs rather than a permanent pure foam destruction . The control unit preferably is configured to control the ultrasonic transducer in a manner optimi zed to a minimum need for foam mitigation rather than to the maximum foam mitigation capability . The controlled foam mitigation process saves energy and allows a dosed ultrasonic wave generation such that the less foam is detected in the foam mitigation device the less ultrasonic waves are generated, per time and / or per amount .

In another embodiment , either in addition to the first foam detection sensor or alternatively, the detection of foam, and in particular the detection of the amount of foam in the interior of the housing, can be performed by way of analyzing the power of the ultrasonic radiation . The higher the power required to mitigate foam the higher the volume of foam in the housing . This enables additional means for controlling the foam mitigation process in an energy-ef ficient way . In a further embodiment , either in addition to the first foam detection sensor or alternatively, the control of the foam mitigation device ultrasonic transducer may depend on an input signal from the associate bioreactor, in particular from an input signal of a foam detection sensor in the bioreactor . Hence , the trigger may be received from the bioreactor the foam mitigation device is connected to . In particular, a start and / or a stop may be controlled in response to such signal . In this scenario , but also in case of the first foam detection sensor controlling the ultrasonic transducer, process data and/or arti ficial intelligence predictions may be used in controlling the ultrasonic transducer, in order to perform sel f optimi zation .

However, in case the foam reaches a second level in the housing of the foam mitigation device above the first level , in direction of the flow of the fluid, other means may preferred to be taken to reduce the foam . In view of this definition, the second level can be considered as high level , while the first level can be considered rather as low level with respect to a foam level in the housing . Preferably, the second level is defined such, that it can be assumed that the volume / magnitude of foam generated in the bioreactor and migrated into the foam mitigation device no longer can be mitigated there by the ultrasonic transducer, even i f driven at highest power . In such extreme case , it is desired to control the generation of foam in the bioreactor, since it is desired to avoid foam exiting the foam mitigation device through its exhaust outlet which may be detrimental . Hence , in case the foam exceeding such second high level in the foam mitigation device , the control unit may generate a signal for the bioreactor to initiate means to reduce the generation of foam in the bioreactor, e . g . by means of stopping or reducing stirring, and / or by stopping or reducing the supply of oxygen into the bioreactor, or by stopping the entire fermentation process as an emergency shutdown . The second level again is defined along the longitudinal axis of the housing, and is arranged in the second volume . Preferably, a second foam detection sensor is provided and also is arranged in the second volume and is configured to detect foam exceeding a second level in the housing, by which second foam detection sensor a DC free impedance measurement is embodied . Presently, the second foam detection sensor is arranged at this second level , and also detects when foam reaches this second level .

In case the bioreactor the foam mitigation device is connected to comprises its own foam detection sensor for detecting a defined level of foam in the bioreactor, such bioreactor foam detection sensor preferably supplies its signal to the control unit of the foam mitigation device . Preferably, the control unit of the foam mitigation unit is configured to allow to switch over to use this bioreactor foam detection sensor as a first level sensor, and the first , lower foam detection sensor of the foam mitigation unit as second level sensor to control for example power of the ultrasonic transducer . In such scenario , the second foam detection sensor in the foam mitigation device may either be shut of f , or may act as an emergency switch for switching of f the bioreactor operations .

Any of the first , second or bioreactor foam detection sensor preferably is based on an impedance measurement . For example , such foam detection sensor may comprise a sensing electrode : In the event of the sensing electrode being immersed in foam and in case an electric current is applied to the sensing electrode , the electric current may flow to another electrode or to earth or through an electronic circuit ( e . g . ampli fiers ) to detect foam . Impedance of the foam can be measured and indicates foam at the level of the sensing electrode . In one embodiment , the control unit can, preferably via the electronic circuit and electric current signal , di f ferentiate between liquid, foam, media or any other substance in contact with the sensing electrode subj ect to the impedance measured and / or subj ect to other parameters of the electric signal applied to the sensing electrode such as frequency, slope , etc . , or can j ust detect the presence of a fluid at a set trigger level , again subj ect to the impedance and / or other signal parameters .

Alternatively, any of the first , second or bioreactor foam detection sensor preferably is based on an optical measurement , e . g . based on the emission of light .

Preferably, the ultrasonic transducer plate is made from titanium, but can also be made from stainless steel . While other components of the foam mitigation device preferably are made from stainless steel , titanium is preferred for the ultrasonic transducer plate , and generally for the ultrasonic transducer including e . g . the ultrasonic transducer shaft , the mechanical amplifier, and the ultrasonic transducer flange , i f applicable , for the following reason : The detergent preferably includes caustic soda NaOH which often is requested by the pharma industry for cleaning bioreactors and accessories . Stainless steel is chemically resistant against NaOH, such that maj or portion of the housing preferably are made from stainless steel . However, stainless steel is not as flexible to generate same waves in the ultrasonic range as titanium, and hence , is not recommended as material for the ultrasonic transducer plate . Instead, titanium is flexible enough such that the ultrasonic transducer plate and possible other components of the ultrasonic transducer are made from titanium or at least comprise titanium . However titanium is not chemically resistant against NaOH . For this purpose , it is preferred to have the ultrasonic transducer plate , and preferably other components of the ultrasonic transducer, made from titanium coated by a coating chemically resistant against NaOH . Such coating preferably is made from diamond like carbon ( DLC ) or a similar material combination . Accordingly, such ultrasonic transducer plate generates ultrasonic waves and at the same time is resistant against the preferred detergent NaOH . For this purpose , such foam mitigation device can be admitted for CIP processes

( Clean in Place ) , complies with current and/or any applicable GxP requirements , and, thus , does not need to be disassembled or opened prior to cleaning .

According to another aspect of the present invention, a bioreactor arrangement is provided comprising a bioreactor and a foam mitigation device according to any of the preceding embodiments , attached to the bioreactor or to an exhaust of the bioreactor . The foam mitigation device is arranged with a longitudinal axis of its housing arranged upright .

According to a further aspect of the present invention, a method is provided for controlling a foam mitigation device according to any of the previous embodiments , comprising the step of controlling the cleaning arrangement to supply a detergent into the interior of the housing . Preferably, the ultrasonic transducer is controlled subj ect to a signal supplied by a first foam detection sensor arranged and configured to detect foam exceeding a first level in the housing of the foam mitigation device . More preferably, the ultrasonic transducer is controlled, subj ect to the signal , to one or more of activate and deactivate the ultrasonic transducer, increase and decrease the cleaning power of the ultrasonic transducer . Even more preferable , the control unit is configured to supply - in response to a signal supplied by a second foam detection sensor arranged and configured to detect foam exceeding a second level in the housing, the second, higher level exceeding the first , lower level - a control signal for a bioreactor the foam mitigation sensor is connected to .

According to a further aspect of the present invention, a computer program element is provided comprising computer program code means for performing a method according to any of the preceding embodiments when executed on a control unit of a foam mitigation device . Preferably, process data and /or arti ficial intelligence predictions are used to optimi ze overall performance .

Furthermore , for simple applications and small bioreactors , the foam mitigation device can in one embodiment be fully operated manually or semi-automated without installing any level sensors , by j ust powering on / of f the ultrasonic manually or via control signal .

Brief Description of the Drawings

The invention will be better understood and obj ects other than those set forth above will become apparent when consideration is given to the following detailed description thereof . Such description makes reference to the annexed drawings , wherein :

Figure 1 shows a perspective view, partially cut open, of a foam mitigation device , according to an embodiment of the present invention;

Figure 2 shows a block diagram of a bioreactor arrangement according to an embodiment of the present invention;

Figure 3 shows a method for controlling a foam mitigation device according to an embodiment of the present invention .

Detailed Description of the Drawings Figure 1 shows a perspective view of a foam mitigation device 10 according to an embodiment of the present invention . The front quarter of the foam mitigation device 10 is cut open in order to allow a view into the interior of the foam mitigation device 10 .

The foam mitigation device 10 comprises a housing 1 including a bucket shaped body 11 and a lid 12 covering an opening in the body 11 . Body 11 and lid 12 define an interior of the housing 1 . An ultrasonic transducer 2 is arranged in the housing 1 . The ultrasonic transducer 2 comprises an ultrasonic transducer plate 21 and an ultrasonic transducer shaft 22 .

The housing 1 essentially is of cylindrical shape , with a bottom B represented by a portion of the body 11 , and a top T represented by the lid 12 . The ultrasonic transducer shaft 22 is arranged in the longitudinal axis of the cylindrical housing 1 , and holds / supports the ultrasonic transducer plate 21 . Hence , the ultrasonic transducer plate 21 separates the interior of the housing 1 into a first volume VI between the bottom B of the housing 1 and the plate 21 , and a second volume V2 between the plate 21 and the top T of the housing 1 .

An extension of the ultrasonic transducer shaft 22 is referred to as mechanical ampli fier 23 , protrudes the lid 12 and is sealed against the lid 21 by means of a seal 122 . An ultrasonic transducer flange 24 arranged and/or attached to the lid 12 is connected to the ultrasonic transducer shaft 22 and / or the mechanical ampli fier 23 , and preferably extends radially from the ultrasonic transducer shaft 22 . The ultrasonic transducer flange 24 shows a hygienic design as generally does the bottom side of the lid 12 facing the interior of the housing 1 . Hygienic design refers to the cleanability of the interior of the housing 1 , and in particular to the cleanability of the housing 1 by means of a cleaning arrangement 6 introduced below . The hygienic design preferably includes the absence of surfaces not accessible by the cleaning arrangement 6 , i . e . the absence of shadowed surfaces with respect to the cleaning arrangement 6 . The ultrasonic transducer flange 24 may have a portion reaching through the lid 12 which portion may serve as contact for electrically exciting the ultrasonic transducer plate 21 via the flange 24 and the shaft 22 . The mechanical ampli fier 23 may ampli fy the excitation of the excited ultrasonic waves .

The bottom B of the housing 1 comprises an inlet 111 for a fluid F, i . e . a liquid or gas , preferably an exhaust gas from a bioreactor, entering the interior of the housing 1 potentially together with foam . An outlet 121 is provided in the top T of the housing 1 , i . e . presently in the lid 12 . Inlet 111 and outlet 121 each include an opening in the respective housing wall , and possibly a pipe or channel attached to the respective housing wall , or integrated therewith .

In case the ultrasonic transducer 2 is activated or excited, ultrasonic waves emitted from the ultrasonic transducer 2 and in particular from its ultrasonic transducer plate 21 mitigate and at the best destroy foam resident in the interior of the housing 1 , which foam enters the housing 1 through the inlet 111 together with e . g . the exhaust gas . The fluid F passes the ultrasonic transducer plate 21 on its way from the inlet 111 to the outlet 121 through a gap G between a lateral edge of the ultrasonic transducer plate 21 and a wall of the housing body 11 . Given that the fluid F preferably is exhaust gas from a bioreactor, it carries organisms and / or other side products not desired to remain in the interior of the housing 1 of the foam mitigation device 10 . Hence , a cleaning arrangement 6 is provided for cleaning the interior of the housing 1 . Preferably, the cleaning arrangement 6 is arranged and configured such that a cleaning of the interior of the housing 1 can be performed without any opening of the foam mitigation device 10 , i . e . without removing the lid 12 from the body 11 . Instead, it is preferred to have the lid 21 remain on the body 11 during the cleaning operation and fully rely on an electrically controlled cleaning process by means of one or more spray units. The present foam mitigation device 10 comprises three spray units 61, 63 and 65 arranged in the interior of the housing 1, each supported by and arranged at the end of a channel 62, 64, and 66 supplying a detergent to the spray units 61, 63, 65. The spray units 61, 63, 65 are presently implemented as spray balls in view of their shape. The shape of a spray ball is desired in view of enabling each spray unit to spray detergent in nearly each direction. Presently, each channel 62, 64, 66 reaches in a sealed manner through the wall of the housing 1.

The deposition of the detergent into the housing 1 by way of the cleaning arrangement 6 is electrically controlled. For this reason, a control unit 7 is provided, only schematically indicated in Figure 1 as a box. The control unit 7 may e.g. be attached to the housing 1, or may be arranged elsewhere. A cleaning operation may be triggered in the control unit 7 by means of a suitable trigger such as a sensor signal or a state reached in a state control scheme. The control unit 7 controls a deposition of the detergent through the spray units 61, 63, 65 as indicated by arrows leading from the control unit 7 to the respective channels 62, 64, 66. This is just a schematic representation given that there are different ways in activating the deposition of the detergent into the housing 1, and / or stopping it again, and / or controlling the amount of the detergent deposited and / or controlling the pressure by which the detergent is deposited: The control unit 7 may e.g. control the respective spray unit 61, 63, 65 itself, or it may control a valve in a supply line for the detergent connected to the respective channel 62, 64, 66, or it may control a valve in the respective channel 62, 64, 66, or it may control a pump pumping the detergent into the respective supply line. It is presently preferred to provide three spray units 61 , 63 , 65 in the interior of the housing 1 in order to enable the detergent to reach every part of the housing 1 defining the interior, and any other part inside the housing 1 . Summari zing, any part in the housing 1 that is exposed to the fluid F and that may carry residuals from the fluid F and / or the foam can be reached by the detergent and, thus , can be cleaned by means of the cleaning arrangement 6 .

By means of the first spray unit 61 , the first volume VI between the inlet 111 and the ultrasonic transducer plate 21 can be reached and cleaned . By means of the second spray unit 63 and the third spray unit 65 , the second volume V2 between the ultrasonic transducer plate 21 and the outlet 121 can be reached and cleaned . It is preferred to arrange the second and the third spray unit 63 , 65 opposite from each other . Since the ultrasonic transducer shaft 22 is arranged in the longitudinal axis of the housing 1 , the second volume V2 cannot be cleaned by a single spray unit only . There always is a side of the ultrasonic transducer shaft 22 arranged in the shadow of the sprayed detergent , and hence , not cleaned .

The present foam mitigation device 10 comprises two foam detection sensors 5 and 4 . The first foam detection sensor 5 is arranged in the first volume VI and is and configured to detect foam exceeding a first level LI in the housing . The first level LI is defined along the longitudinal axis of the housing 1 , and hence , also is arranged in the first volume VI . Presently, the first foam detection sensor 5 is arranged at this first level LI , and also detects when foam reaches this first level LI .

The control unit 7 receives a signal from the first foam detection sensor 5 in case the foam in the interior of the housing 1 reaches the first low level LI . In response to such signal the control unit 7 preferably activates the ultrasonic transducer 2 , or increases power to the ultrasonic transducer 2 in case the ultrasonic transducer already is activated . Accordingly, foam reaching the first level LI indicates a need to mitigate the foam by means of the ultrasonic transducer 2 .

The second foam detection sensor 4 ( also called high level sensor ) is arranged in the second volume V2 and is configured to detect foam exceeding a second level L2 in the housing 1 . The second upper level L2 again is defined along the longitudinal axis of the housing 1 , and hence , also is arranged in the second volume V2 . Presently, the second foam detection sensor 4 is arranged at this second level L2 , and also detects when foam reaches this second level L2 . In case the foam is detected to reach the second level L2 , it is desired to control the generation of foam in the bioreactor given that it can be assumed that the volume / magnitude of foam generated in the bioreactor and migrated into the foam mitigation device 10 no longer can be mitigated there by the ultrasonic transducer 2 . On the other hand, foam exiting the foam mitigation device 10 through the exhaust outlet 121 may be detrimental and undesired . Hence , the control unit 7 may generate a signal s for the bioreactor to initiate means to reduce the generation of foam in the bioreactor, e . g . by means of stopping or reducing stirring, and / or by stopping or reducing the supply of oxygen into the bioreactor and / or by stopping the entire fermentation process .

The housing 1 comprises an inspection window 112 for visual inspection of the operation and / or state in the interior of the foam mitigation device 10 .

Figure 2 illustrates a bioreactor arrangement according to an embodiment of the present invention . A bioreactor 8 is schematically illustrated in form of a vessel . A stirrer 82 is provided for stirring a fermentation medium contained in the bioreactor 8 . An oxygen sup- ply 83 is provided for supplying oxygen into the bioreactor 8 . Stirrer 82 and oxygen supply 83 are electrically controlled by means of a bioreactor control unit 81 . An exhaust pipe is arranged in the top of the bioreactor 8 allowing exhaust gas to escape from the bioreactor 8 . Such exhaust gas may contain foam . A foam mitigation device 10 , such as the one illustrated in Figure 1 , is arranged on top of the bioreactor, the inlet 111 of which is connected to the exhaust pipe , or is equal to the exhaust pipe of the bioreactor 8 . The outlet 121 of the foam mitigation device 10 supplies the exhaust gas absent foam to the outside world . The control unit 7 of the foam mitigation device 10 preferably supplies a control signal s to the bioreactor control unit 81 , e . g . in case the second foam detection sensor (not shown in Figure 2 ) indicates foam exceeding the second level L2 in the foam mitigation device 10 , which is a level higher than the first level LI , thereby indicating a large amount of foam present in the foam mitigation device . In such case , the signal s may trigger in the bioreactor control unit 81 to change the operation of the stirrer 82 and / or the oxygen supply into the bioreactor 8 via the oxygen supply pipe 83 . Other means of the bioreactor 8 may be controlled, too , in view of the signal s , preferably means that impact the generation of foam in the bioreactor 8 . Preferably, those means are deactivated or reduced in power in order to generate less foam in the bioreactor 8 .

Figure 3 shows a flow chart representing a method for controlling a foam mitigation device according to an embodiment of the present invention . In particular, the foam mitigation device is the foam mitigation device of Figure 1 . Step S O indicates a normal operation of a bioreactor the foam mitigation device is connected to . In step S I , the first foam detection sensor is monitored, i f the foam has reached the first level LI in the foam mitigation device . In case of no (n) , the monitoring is continued . In case of yes ( y) , the ultrasound transducer in the foam mitigation device is activated in step S2 in order to mitigate foam therein . In step S3 , it is monitored, i f the first foam detection sensor indicates that the foam in the foam mitigation device has fallen below the first level LI again . I f so ( y) , then the ultrasonic transducer in the foam mitigation device is deactivated in step S4 again, and it is continued monitoring in step S I , i f the foam exceeds the first level LI again . I f the first level LI is not underrun again in step S3 (n) , it is monitored in step S5 i f the second foam detection sensor indicates the foam in the foam mitigation device exceeding the second level L2 . In case so ( y) , the signal s is provided to the bioreactor in step S 6 , to take means there to reduce the foam generation in the bioreactor . It is subsequently monitored in step S7 , i f the foam in the foam mitigation device has fallen again below the second level L2 . I f not (n) , the monitoring continues . I f so ( y) , however, it the monitoring of step S3 is continued, i f the foam falls below the first level LI again .

At any time during this process , a message may be received from the bioreactor, respectively its control unit that the bioreactor operation has terminated . This is indicated as step S 10 . In case of such message received at the control unit of the foam mitigation device , the ultrasonic transducer may be deactivated, i f still active , and the cleaning arrangement of the foam mitigation device is controlled to clean the interior of the housing of the foam mitigation device , all in step S i l . Preferably, such cleaning process may be executed for a defined period in time . Alternatively, one or more sensors may be provided in / at the housing of the foam mitigation device to sense a cleaning level of the interior of the housing . The cleaning process may only be stopped when such cleaning sensor detects a sufficiently cleaning level inside the housing .