Patent Application
20230256407
The invention relates to a device assembly for producing bioconjugates, in particular antibody-drug conjugates.
Synthesis of bioconjugates (bioconjugation) is a chemical strategy to establish stable covalent bonds between a biomolecule and another molecule or material. Especially, molecules that are undergoing some type of biospecific affinity interaction within cells can be linked together and “frozen” in the act of binding to each other with the use of crosslinking agents. This technology represents a new trend especially in the pharmaceutical industry since the biomolecules are able to recognize certain surface structures in organisms and thus can bring a coupled active ingredient to specific locations in the organism.
A particular class of biopharmaceutical drugs produced by bioconjugation are antibody-drug conjugates (ADCs) which are designed as a targeted therapy for treating cancer. ADCs are complex molecules composed of a monoclonal antibody linked to a biologically active cytotoxic payload or drug (toxin). They can be designed to distinguish between healthy and diseased tissue. Thus, unlike chemotherapy, ADCs are capable of killing tumor cells while sparing healthy cells.
In the production of ADCs, at present, glass or stainless steel vessels are used for the conjugation reaction, i.e. for coupling the toxin to the biomolecule. These vessels are capable of ensuring the desired reaction conditions, such as a certain constant temperature. However, the use of reusable components in a process device is disadvantageous in that between two uses of the process device an intensive cleaning and further preparations are required which are time-consuming and involve high costs. Moreover, during cleaning it is possible that the operator of the process device comes into contact with remaining toxins, thus exposing him or her to a high health risk.
For changing the buffer or concentrating the bioconjugate, the glass or stainless steel vessels are usually combined with other process devices. This constitutes an obstacle to automation and process safety since a plurality of different devices and process steps are involved.
US 2005/0175619 A1 discloses a method of producing an antibody conjugate with at least one effector moiety based on a conjugation reaction in a solution comprising at least 5% by volume of an alcohol. The antibody conjugation process, including antibody reduction step and final filtration and formulation steps of conjugate product, are performed in a “single-pot” enclosed recirculation/ultrafiltration apparatus. However, this would not be possible if, instead of alcohol, another common solvent was used, because lumps would form during the conjugation which would block the filter membrane in the filtration process following the conjugation reaction.
US 2019/0270769 A1 shows how unit operations can be combined to create a continuous ADC production and processing method. In particular, single-pass tangential flow filtration or countercurrent diafiltration is linked to conjugation reactions to facilitate the concentration of ADCs and also to remove unconjugated products from the conjugation reaction and exchange the purified ADC into a formulation buffer. Such a continuous process is not suitable for conjugation reactions in solvents where lumps would form and block the filter membrane during concentration of the ADC.
It is an object of the invention to overcome the above drawbacks and to enable a more efficient and safe production of bioconjugates, especially ADCs, using common solvents.
The above problem is solved by a device assembly for producing bioconjugates according to claim 1. Advantageous and expedient embodiments of the invention are apparent from the dependent claims.
The invention provides a device assembly for producing bioconjugates, in particular antibody-drug conjugates, comprising a conjugation unit for performing a bioconjugation reaction in a medium, a first filtration unit for separating precipitates and/or agglomerates, and a second filtration unit for performing an ultrafiltration (UF) and/or a diafiltration (DF) process. The first filtration unit is arranged in a flow path between the conjugation unit and the second filtration unit. The device assembly further comprises a single control unit for controlling the transfer of medium from the conjugation unit through the first filtration unit to the second filtration unit and for controlling the ultrafiltration and/or diafiltration process.
The invention combines three major unit operations of a bioconjugate production process in a single device assembly. Thanks to the control unit it is possible to enable a highly automated batch process, including a bioconjugation reaction step yielding bioconjugate, a filtration step for separating undesired precipitates and/or agglomerates from the medium containing the bioconjugate, and an UF/DF process for purifying and concentrating the bioconjugate. The filtration step after the bioconjugation reaction and before the UF/DF process ensures that the filter membranes of the second filtration unit will not become clogged by the precipitates and/or agglomerates. Thanks to the automation, no human interaction is necessary at the device assembly during the process. Thus, the device assembly (except for an operating panel) can be placed behind a glass pane, under a fume hood or in an isolator (isolated room) separated from the operator. This significantly increases the safety of the operating personnel in view of the toxic substances involved.
In accordance with the current trend towards single-use concepts in the pharmaceutical process development and production, it is preferred that those components of the device assembly which come into contact with medium during the process, hereinafter referred to as wetted components, are configured as single-use components. The single-use components are disposed of after use so that there is no costly and time-consuming effort of cleaning, checking and validating the components for their next use. Considering the highly toxic substances involved in ADC production, this is highly appreciated.
However, a major challenge with respect to the use of single-use components is the fact that the solvents that are typically used in bioconjugate production cause (at least partial) dissolution of many materials that single-use components are typically made of. Such solvents include dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), propylene glycol (PG), acetonitrile (ACN) and n-methyl-2-pyrrolidone (NMP).
It is to be noted that initially the solvent concentration is very high, while the supply of other fluids/solutions during the conjugation reaction and the further process steps reduces the solvent concentration. Therefore, a first group of wetted components of the device assembly that come into contact with medium having a very high solvent concentration are preferably configured as single-use components made from one or more materials of a first group of materials consisting of: high-density polyethylene (HDPE); polyamide (PA); polybutylene terephthalate (PBT); polytetrafluoroethylene (PTFE); polypropylene (PP); polyethylene terephthalate (PET); ceramics; glass. These materials are resistant to a 100% concentration of the above-mentioned solvents. For example, a line connecting a toxin reservoir with a reaction vessel of the conjugation unit has to be made of such a material.
A second group of wetted components of the device assembly that come into contact with medium having a lower solvent concentration are preferably configured as single-use components made from one or more materials of a second group of materials consisting of: low-density polyethylene (LDPE); (reinforced) platinum cured silicone (Si(Pt)); thermoplastic elastomer (TPE); thermoplastic polyolefin (TPO); thermoplastic vulcanizate (TPV); ethylene propylene diene monomer rubber (EPDM); silicone. These materials are resistant at least to a 20% concentration of the above-mentioned solvents. Of course, the second group components can also be made from a material of the first group of materials which are 100% resistant.
Irrespective of the above, not all of the wetted components of the device assembly need to be made from the above-mentioned materials. Especially the filter membranes used in the filtration units of the device assembly can be made from one or more of the following materials, which are all resistant to a 100% concentration of the solvents mentioned further above: nylon; polytetrafluoro-ethylene (PTFE); polypropylene (PP) fleece. Commercially available Hydrosart® high performance membranes (stabilized cellulose based membranes) are at least resistant to a 20% concentration of those solvents.
The single-use components of the device assembly are preferably pre-sterilized so that bioburden testing before use of the components is not necessary.
According to a preferred embodiment of the device assembly, the conjugation unit comprises a flexible conjugation bag where the conjugation reaction takes place. The conjugation bag is held by a first bag holder.
In view of the high commercial value of the product, it is generally desired that after each process step as little medium as possible remains in the respective components of the device assembly. Therefore, when the conjugation reaction is terminated, the conjugation bag should be emptied as far as possible. This is facilitated by a bag holder having a bottom surface and a draining opening formed at a lowest point of the bottom surface. Accordingly, the conjugation bag has a bottom portion resting on the bottom surface of the first bag holder such that an outlet formed in the bottom portion of the conjugation bag is located at the draining opening of the first bag holder. With this configuration a draining line can be easily connected to the low-positioned outlet of the conjugation bag. It is particularly preferred that the draining opening in the bottom surface of the first bag holder has a conical shape. The main advantage of such a design is a minimum hold-up volume. During the draining process the medium level is kept higher due to the conical draining opening. Accordingly, a stirrer stays in contact with the medium longer. This results in a better stirring performance especially at low volumes.
A temperature control system for controlling the temperature of the medium in the conjugation bag can be used to provide optimum reaction conditions. According to a preferred construction, the first bag holder includes a double-walled containment, through which a heat transfer fluid flows. It is thus possible to adjust the temperature in the conjugation bag as desired.
A pH sensor arranged in the conjugation bag and coupled to the control unit of the device assembly enables pH monitoring during the conjugation reaction. The pH measurements provide information about the progress of the conjugation reaction and can be used to determine when a sufficient amount of bioconjugate has been formed and the conjugation reaction can be terminated. Further stop criterions can be involved in this decision.
When the conjugation reaction is terminated, the medium of the conjugation bag needs to be transferred to the second filtration unit for purification and concentration of the product. For an automated transfer, the conjugation unit preferably comprises a controllable draining valve allowing the medium to drain from the conjugation bag. Further, the first filtration unit comprises a transfer pump for transferring the medium from the conjugation unit through the first filtration unit to the second filtration unit. Both the controllable valve and the transfer pump are coupled to the control unit of the device assembly.
Before the UF/DF filtration, the filter device of the first filtration unit removes the precipitates and/or agglomerates from the medium so that they cannot block the filter membranes used for purification and concentration of the product in the second filtration unit. The membrane of the filter device of the first filtration unit has a pore size of less than 0.8 μm, preferably about 0.2 μm or less. Such membranes are commonly used for sterile filtration. Of course, the pore size must not be smaller than the diameter of the bioconjugate.
According to an advantageous aspect of the invention, the second filtration unit comprises a single-use loop-assembly for recirculating the medium in the ultrafiltration and/or diafiltration process. The single-use loop-assembly can be mounted to and/or dismounted from a basic structure of the device assembly as a whole, preferably together with a single-use conjugation bag and a single-use recirculation bag and other single-use components of the device assembly. The single-use loop-assembly is preconfigured and, if possible, can already be preassembled before it is mounted to a basic structure of the device assembly. This significantly facilitates the handling of the components used in the UF/DF process, and false connections are ruled out from the outset. Furthermore, the design of the single-use loop-assembly can be optimized with respect to the dead volume (hold-up volume). A small dead volume allows a more effective purification and concentration and less product loss.
The single-use loop-assembly preferably includes a recirculation pump, at least one sensor, tubing and connectors, which—together with a recirculation bag—are major components of a regular UF/DF filtration assembly. It is generally preferred that all single-use components that had contact with medium can be dismounted as one single unit (the single-use loop assembly plus further wetted single-use components).
As mentioned before, as little medium as possible should remain in the respective components of the device assembly. Similar to the conjugation bag and the first bag holder, the recirculation bag is preferably held in a second bag holder having a bottom surface and a draining opening formed at a lowest point of the bottom surface. Accordingly, the recirculation bag has a bottom portion resting on the bottom surface of the second bag holder such that an outlet formed in the bottom portion of the recirculation bag is located at the draining opening of the second bag holder. With this configuration a draining line can be easily connected to the low-positioned outlet of the recirculation bag.
A temperature control system can be used to control the temperature of the medium in the recirculation bag. According to a preferred construction, the second bag holder includes a double-walled containment, through which a heat transfer fluid flows. It is thus possible to adjust the temperature in the recirculation bag as desired.
A conductivity sensor arranged in the recirculation bag and coupled to the control unit of the device assembly enables monitoring of the conductivity of the circulating medium during the UF/DF filtration process. The conductivity measurements provide information about the purity and concentration of the bioconjugate in the circulated medium. A predetermined conductivity value can be set as a threshold for determining when the UF/DF filtration process is to be terminated. Further stop criterions can be involved in this decision, e.g. based on pH or volume of the permeate.
Due to the high toxicity of the substances involved in bioconjugate production, especially in ADC production, a very high safety standard has to be guaranteed. In particular, any contact of toxic medium with the operator of the device assembly or with the environment is to be avoided. In view of these requirements, especially the single-use loop-assembly includes controllable valves, preferably pinch valves, allowing an automated change of flow paths without human interaction. It is thus possible to let the control unit of the device assembly control the flow of the medium as required in the respective process steps. This allows the device assembly (except for an operating panel) to be placed in a restricted area remote from the operator.
The controllable valves of the device assembly are even more advantageous. Before dismounting and disposal of the single-use loop-assembly together with the other single-use components (conjugation bag, recirculation bag, tubing, connectors etc.) as a whole, the valves can be controlled such that they create a confinement for the residual medium. Since it is safely captured, neither the operator nor the environment can come into contact with the toxic medium during dismounting and removal.
In a preferred embodiment of the device assembly, a dip tray is arranged below the single-use loop-assembly to further increase the safety standard. The dip tray has a bottom surface and a draining means formed at a lowest point of the bottom surface so that any medium leaking from the single-use loop-assembly can be collected in a waste tank placed below the draining means. The draining means can be a simple hole or a valve, e.g. a manual ball valve.
The second filtration unit, where the UF/DF process is performed, preferably comprises at least one cross-flow filter cassette held in a filter press. The filter press allows great flexibility with respect to the type, number and arrangement of filter cassettes.
The control unit of the device assembly is preferably configured to control at least one of the following: temperature of the heat transfer fluid flowing through the double-walled first bag holder; temperature of the heat transfer fluid flowing through the double-walled second bag holder; the controllable valves of the conjugation unit and/or the second filtration unit, especially the valves of the single-use loop-assembly; the transfer pump; the recirculation pump.
For easier handling of the whole device assembly, especially with respect to moving it into a restricted area for operation, all components of the device assembly, except for an operating panel coupled to the control unit, can be mounted on a trolley. The mechanically decoupled operating panel allows the operator to make any adjustments in a safe place remote from the device assembly.
Further features and advantages of the invention will become apparent from the following description and from the accompanying drawing to which reference is made. In the drawings:
As shown in
The conjugation unit comprises a first bag holder 14 for accommodating a flexible single-use conjugation bag 16 (shown separately in
The conjugation bag 16 (see
Regardless of the size, a bottom portion of the conjugation bag 16 rests on the bottom surface 22 of the first bag holder 14 such that a lower outlet port of the conjugation bag 16 is located directly above or in the draining opening 24. The lower outlet port is connected to a conjugation outlet hose line (draining line) 30 through the draining opening 24. The conjugation outlet hose line 30 can be opened and blocked by a draining valve 32, preferably a pinch valve, which is controlled by the control unit 28. Since the lower outlet port is placed at the lowest point of the bottom surface 22, the conjugation bag 16 can be completely emptied by gravity without any active draining means when the conjugation outlet hose line 30 is opened by the draining valve 32.
The conjugation unit comprises an impeller system (not visible in
As can be seen in
The conjugation bag 16 is equipped with a single-use pH sensor 48 (probe). Other single-use sensors for detecting parameters of interest in connection with the conjugation reaction can be provided as well. The sensors are connected to the control unit 28.
The conjugation unit also comprises a first temperature control system coupled to the control unit 28 for controlling the temperature of the medium in the conjugation bag 16. A heat transfer fluid can be pumped through the double-walled containment 18 of the first bag holder 14 to cool or heat the medium in the conjugation bag 16 as desired. A temperature sensor transmits the current temperature value to the control unit 28. The temperature sensor can be arranged at the bottom surface 22 of the first bag holder 14, for example.
Further, a first sterile venting filter 50 (see
The conjugation outlet hose line 30 is part of a flow path extending between the conjugation bag 16 and a recirculation bag 52 of a second filtration unit for performing an ultrafiltration and/or a diafiltration process which will be described later. A peristaltic transfer pump 54 and a single-use filter device 56 are integrated into this flow path, forming a first filtration unit of the device assembly 10.
The general type and the specific configuration of the filter device 56 can be chosen according to the given requirements of the separation process. In the embodiment shown in
The membrane of the filter device 56 has a pore size of less than 0.8 μm. Preferably, the filter device 56 is a sterile filter with a pore size of about 0.2 μm or less, which is yet larger than the size of the bioconjugate formed in the medium of the conjugation bag 16. Thus, the filter device 56 is capable of effectively separating precipitates and/or agglomerates (or other unwanted lumps) from the medium containing the bioconjugate that have also formed unintentionally during the conjugation reaction in the conjugation bag 16.
The second filtration unit of the device assembly 10 comprises the already mentioned recirculation bag 52 (shown separately in
In a bottom portion of the recirculation bag 52 a lower outlet port is connected to a recirculation outlet hose line (draining line) 60 which can be opened or closed by a draining valve 62, preferably a pinch valve (see
Instead of or in addition to a single-use pH sensor as used in the conjugation bag 16, the recirculation bag 52 is equipped with a single-use conductivity sensor 68. Other single-use sensors for detecting parameters of interest in connection with the filtration process running in the second filtration unit can be provided as well. The sensors are connected to the control unit 28.
Like the conjugation bag 16 and the recirculation bag 52, also the first bag holder 14 and the second bag holder 58 have a similar design, including—inter alia—a draining opening 24 at the bottom surface 22 for the recirculation outlet hose line 60 and a load cell 26 connected to the control unit 28. A second sterile venting filter 70 (see
The recirculation outlet hose line 60 is part of a tubing of the second filtration unit leading to one or more single-use filter cassettes 72 held in a filter press 74. The filter cassettes 72 are self-contained units configured for cross-flow filtration, in particular for an ultrafiltration or diafiltration process. Several filter cassettes 72 can be connected in parallel or in series.
The type, number and arrangement of filter cassettes 72 can be chosen according to the given requirements of the UF/DF process. The nominal molecular weight limit (NMWL) or the molecular weight cutoff (MWCO) of the membranes of the filter cassettes 72 is adapted to the size and weight of the bioconjugate so that the unbound small-sized and lighter components of the medium are washed out to the permeate side while the larger-sized and heavier bioconjugate is kept in the retentate. The total membrane area of the filter cassette(s) 72 preferably ranges from 0.1 to 1.4 m2.
The second filtration unit further comprises a single-use recirculation pump 76, tubing, connectors, sensors 78 and further controllable valves 80, preferably pinch valves, enabling the blocking and unblocking of a variety of flow paths. Such flow paths include the path for recirculating the medium in the second filtration unit, and can further include paths for supplying buffer to the recirculation bag 52, discharging waste medium, flushing etc. The sensors 78 are pressure sensors and/or flow meters arranged in the feed, permeate and retentate lines of the tubing. An optional UV probe can be arranged in the permeate line for UV spectroscopy in order to detect any product in the permeate line in case of a defective membrane. Like the conductivity sensor 68 in the recirculation bag 52, the sensors 78 transmit their measured values or signals to the control unit 28. The pinch valves 80 are all controlled by the control unit 28.
Thus, the second filtration unit is capable of performing a complete UF/DF process for purifying and concentrating the bioconjugate, controlled by the control unit 28 without human interaction.
A special characteristic of the second filtration unit is that the recirculation pump 76, the tubing, the connectors 46, the sensors 78 and the valves 80 used in the UF/DF process are single-use components configured as a preassembled unit, hereinafter referred to as single-use loop-assembly. The complete single-use loop-assembly can be mounted to and dismounted from a basic structure of the device assembly 10 as a whole.
The pre-configured tubing design of the single-use loop assembly ensures a minimum dead volume (hold-up volume), e.g. below 300 mL. This is very important in view of the high monetary value of the bioconjugate product.
Below the single-use loop-assembly a dip tray 82 is arranged. The dip tray 82 has a bottom surface and a draining means, e.g. a ball valve, formed at a lowest point of the bottom surface. Thus, in case of a leakage, the leaking fluid is collected in the dip tray 82 and can be guided to a waste tank positioned below the draining means.
The device assembly 10 further comprises an operating panel 84, preferably a touchscreen, which is part of the control unit 28. With the operating panel 84 an operator can make all selections and adjustments that are necessary before and after the bioconjugate production process, which itself is performed highly automatically. The operating panel 84 also serves to inform the operator of the current settings and status of the process and allows interaction, if necessary.
In the embodiment shown in
All of the components that come into contact with toxic medium (wetted components) are dedicated single-use components that will not be used again and therefore need not be cleaned and sterilized after use. The wetted components are made from materials that are especially resistant to the following solvents which could be used in connection with the conjugation reaction: dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), propylene glycol (PG), acetonitrile (ACN), n-methyl-2-pyrrolidone (NMP).
A first group of the wetted components, especially wetted components of the conjugation unit, are resistant to a 100% concentration of the solvents (i.e. the pure solvents). This first group includes a toxin supply line 86 which leads from the reservoir 42 (here a bottle), containing toxin solved in 100% solvent, to the conjugation bag 16.
Since the mixing with other fluids/solutions during the conjugation reaction and the UF/DF filtration process dilutes the solvent, a second group of the wetted components, especially the wetted components of the second filtration unit, only have to be resistant to at least a 20% concentration of the solvents. This also applies to the other supply lines 40 because they are connected to the conjugation bag 16 below the liquid level so that instant dilution occurs there.
The wetted components of the first and second groups may be made from one or more of the following materials (100% resistant): high-density polyethylene (HDPE); polyamide (PA); polybutylene terephthalate (PBT); polytetrafluoro-ethylene (PTFE); polypropylene (PP); polyethylene terephthalate (PET); ceramics; glass. The wetted components of the second group may also be made from one or more of the following materials (20% resistant): low-density polyethylene (LDPE); (reinforced) platinum cured silicone (Si(Pt)); thermoplastic elastomer (TPE); thermoplastic polyolefin (TPO); thermoplastic vulcanizate (TPV); ethylene propylene diene monomer rubber (EPDM); silicone.
In the following, operation of the device assembly 10 in a bioconjugate production process is described.
Before the device assembly 10 can be used, the single-use components are provided and mounted to the basic structure of the device assembly 10. In particular, the conjugation bag 16 and the recirculation bag 52 are placed in the respective bag holders 14, 58 and integrity tested, or the other way round. The single-use loop-assembly, including the recirculation pump 76, the tubing, the connectors 46, the sensors 78 and the valves 80 used in the UF/DF process, is mounted, step-by-step or as a whole, to the basic structure of the device assembly 10. The necessary connections between the single-use loop-assembly and the conjugation bag 16 and the recirculation bag 52 and any further connections are made via sterile connectors 46.
After the preparations, the operator starts the bioconjugate production process at the operating panel 84. The conjugation bag 16 is filled with the fluids/solutions necessary to start the conjugation reaction. The reaction conditions are monitored, and the peristaltic pumps 44 controlled by the control unit 28 supply fluids/solutions as required while the conjugation reaction takes place. The temperature in the conjugation bag 16 is adjusted via the first temperature control unit.
The conjugation reaction is terminated when the pH measured by the pH sensor 48 exceeds a predetermined threshold value. Further stop criterions may be involved, like expiry of a set time period or analysis of a sample taken from the conjugation bag 16. The control unit 28 then opens the draining valve 32 and activates the transfer pump 54.
The medium leaves the conjugation bag 16 through the conjugation outlet hose line 30 and passes through the filter device 56. Thereby the precipitates and/or agglomerates are separated from the filtrate. The filtrate containing the bioconjugate is directed to the recirculation bag 52.
When all of the filtrate has entered the recirculation bag 52, the UF/DF process for purifying and concentrating the bioconjugate in the second filtration unit is started. The control unit 28 activates the recirculation pump 76 to keep the medium circulating in the single-use loop-assembly with the filter cassettes 72. Here, the permeate with the unbound reactants is guided to a waste tank while the retentate with the bioconjugate is kept in the loop. Since the precipitates and/or agglomerates have been removed by the filter device 56, they cannot clog the membranes of the filter cassettes 72. Buffer is supplied/exchanged as required with the aid of the corresponding valves 80 which are controlled by the control unit 28.
The UF/DF process is terminated when the conductivity value measured by the conductivity sensor 68 in the recirculation bag 52 exceeds a predetermined threshold value. Further stop criterions may be involved, like expiry of a set time period or evaluation of a UV spectrum measured by the UV probe or analysis of a sample taken from the conjugation bag 16.
The control unit 28 controls the pinch valves 80 such that the retentate with the purified and concentrated bioconjugate can be extracted from the single-use loop-assembly through a harvest line into a container for further processing. Since the dead volume of the single-use loop-assembly is very low, only a small amount of the valuable medium remains in the loop-assembly.
Before the single-use loop-assembly, including the connected filter cassettes 72, is removed from the basic structure of the device assembly 10 together with the bags 16, 52, the tubing (including the supply and other hose lines 30, 40, 60, 66, 86), the connectors 46, the sensors 48, 68, 78 and the pinch valves 80 as a whole, the control unit 28 closes all peripheral pinch valves 80 to create a confinement for the residual medium in the loop-assembly. The sealed single-use loop-assembly together with the other single-use components is dismounted and disposed of as a whole, i.e. its components are not separated from each other. This enables a very high safety standard since the toxic medium cannot exit the loop-assembly and come into contact with the operator and the environment.
The device assembly 10 is particularly useful for preclinical or clinical production of ADCs.
The device assembly 10 can also be used without the conjugation unit and the first filtration unit, serving as a conventional UF/DF filtration device assembly with a disposable single-use loop-assembly.
| Number | Date | Country | Kind |
|---|---|---|---|
| 20185516.0 | Jul 2020 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/068408 | 7/2/2021 | WO |
