Method for filtering a large volume of a medium using a pre-sterilizable, at least partially automated, disposable filtration device

Description

[0001] The invention relates to a method for filtering a large volume of a medium using a pre-sterilizable, at least partially automated disposable filtration device.

[0002] In the field of single-use technology development for biopharmaceutical applications, filtration elements are enjoying increasing popularity and are now widely used. In recent years, for example, single-use filtration technologies have continuously evolved and are no longer used exclusively in laboratories and process development. Rather, single-use filtration elements are now also commonly used in commercial manufacturing processes for pharmaceutical products for clinical phases 1 to 3 (development stages in drug development) or in the commercial production of such active ingredients. Currently available single-use filtration devices are limited to smaller filter elements, which in turn are restricted to the pure "filtration" functionality.

[0003] WO 2017 / 032560 A1 discloses a fully pre-sterilizable, ready-to-connect, and integrity-testable disposable filtration device designed for large-volume filtration processes. This disposable filtration device comprises a plurality of disposable filter capsules of a standard size arranged in a predetermined grid and connected to each other by lines. The filter capsules are supported by a rigid holder.

[0004] WO 2016 / 177650 A1 discloses a modular system for the continuous, microbiologically reduced production or processing of a biopharmaceutical, biological macromolecular product from a heterogeneous cell culture fluid mixture. The system comprises the following modules: a filtration module, a chromatography module, an ultrafiltration module or diafiltration module, a dialysis module, and a module for continuous virus removal. The modular system is closed and microbiologically reduced. A special feature of the system is the possibility of automatic filter replacement under microbiologically reduced conditions. The completion of the venting of the new filter is detected on the unfiltered side by a pressure sensor, a fill level sensor, a scale, or a liquid detector.

[0005] However, with previous disposable filtration elements, the question of integration into automated processes was not considered. With the introduction of disposable filtration technology into commercial production, as described above, not only the scaling, i.e., the required filter size and thus the filtration area, but also the need for automated filtration processes is increasing. This requires the embedding of filtration elements in hose lines, plastic piping, disposable sensors, and connection systems, which can then be integrated into a holistic process solution only when connected to a suitable monitoring and control system.

[0006] In the field of disposable filtration technology, there is therefore a need for a ready-to-use disposable filtration device that enables a partially or fully automated filtration process, especially on a large scale. The object of the invention is to further develop further cost-effective application possibilities based on (partially) automated disposable filtration devices designed for large volumes.

[0007] This object is achieved by a method having the features of claim 1. Advantageous and expedient embodiments of the method according to the invention are specified in the subclaims.

[0008] The inventive method for filtering a large volume of a medium is carried out using a pre-sterilizable, at least partially automated disposable filtration device. The device comprises an unfiltered material inlet, a filtrate outlet, a main line running between the unfiltered material inlet and the filtrate outlet, filter elements arranged in the main line, a vent line, and sensors for detecting specific process parameters and control devices for adjusting specific process parameters, including a feed pump at the unfiltered material inlet and a vent valve at the vent outlet.The method according to the invention comprises the following process steps: a) filling the disposable filtration device with medium at a low flow rate; b) venting the disposable filtration device through the vent line; c) closing the vent line; d) rinsing the disposable filtration device, in particular the filter elements; e) filtration of the medium using the filter elements; f) post-rinsing at a high flow rate; and g) closing the main line; wherein process steps f) and g) are optional. The presence of liquid at the filtrate outlet is determined from an input flow signal of a flow sensor at the unfiltrate inlet and the known system volume, or at least in process step e), an inlet pressure at the unfiltrate inlet detected by the inlet pressure sensor is used as the controlled variable, or at least in process step e), the flow is controlled via a characteristic curve of the feed pump, the inlet pressure sensor, and a venting liquid detector.The sensors and control devices are connected to an external monitoring and control system that is designed to evaluate and process sensor data and to control the control devices based on one or more control algorithms.

[0009] The invention is based on the realization that, depending on the level of automation, certain components of the disposable filtration device can be dispensed with if other available data are cleverly incorporated into the control or regulation of the process sequence. Furthermore, the installation effort on the part of the user can be kept to a minimum, since the disposable filtration device can be prefabricated and pre-sterilized as a compact unit with the components required depending on the level of automation. This simplifies both the handling of the disposable filtration device itself and the implementation of the desired filtration process for the user – in addition to the cost savings due to the elimination of components.

[0010] For fully automated systems with minimal equipment requirements, the presence of liquid at the filtrate outlet of the disposable filtration device is determined from an input flow signal and the known system volume. A liquid detector at the filtrate outlet is not required.

[0011] Furthermore, at least in process step e), an inlet pressure measured by an inlet pressure sensor is used as the control variable. A pressure sensor at the filtrate outlet is not required.

[0012] Furthermore, at least in process step e), the flow is controlled via a feed pump characteristic curve, an inlet pressure sensor, and a vent fluid detector. A flow sensor is not required.

[0013] Furthermore, process step g) can be performed by simply blocking the main line with a shut-off valve either at the unfiltered water inlet or the filtrate outlet. The shut-off valve can be controlled via a feed pump characteristic curve, an inlet pressure sensor, and a vent fluid detector. Thus, a simple shut-off valve can be used instead of an inlet control valve or an outlet control valve if control is not absolutely necessary.

[0014] Furthermore, a vent fluid detector can be used on a sterile air filter housing or on a distribution or collection pipe for idle monitoring and / or air accumulation. This vent fluid detector is provided in addition to or instead of a vent fluid detector on the vent line to achieve earlier blocking of the vent line if necessary.

[0015] The optional process step f) is preferably carried out under pressure monitoring.

[0016] To expand the functionality, additional components can be provided on the disposable filtration device and incorporated into the process: As part of an automated acid or alkali dosing system, a pH sensor integrated into the disposable filtration device can be used to automatically adjust a pH value.

[0017] An automated actuator can be used for one or more, preferably sterile, samplings, preferably at predetermined time and / or fraction intervals.

[0018] Automated rinsing medium access can be used for pre-rinsing or wetting the filter elements.

[0019] An automated drainage outlet or an automated gas access can be used to remove flushing or wetting medium or a process feed.

[0020] For process monitoring and / or documentation or data archiving purposes, at least one of the following sensors integrated into the disposable filtration device can be used: - capacitive, inductive, ultrasonic, vibration, or conductive sensor for level measurement or liquid detection; temperature sensor; pH sensor; conductivity sensor; TOC sensor; sensor for turbidity measurement.

[0021] Further features and advantages of the invention will become apparent from the following description and the accompanying drawings, to which reference is made. In the drawings: Figure 1 a perspective view of a disposable filtration device with connecting lines and other connecting elements; and Figure 2a schematic side view of a (semi-)automated disposable filtration device.

[0022] In Figure 11 shows an example of a (semi-)automated, disposable filtration device 10 designed for large volumes, which is similar to the device known from WO 2017 / 032560 A1. A plurality of filter capsules 12 are held in position by a rigid holder 14 in a predetermined arrangement (grid). The term "filter capsule" is to be understood generally here and is intended to refer to any independently mountable assembly with one or more filter elements (membranes) installed in one or more filter units. The holder 14 comprises support columns 16, which are connected to one another by cross struts 18. Feet 20 ensure secure support of the device 10. Holding means 22 for the individual filter capsules 12 are provided on the cross struts 18. The filter capsules 12 are completely or at least largely connected to one another by rigid, pressure-resistant pipes 24.The specific route of the pipes 24 shown here as examples is determined by the intended operation of the filtration device (parallel or series connection of the filter capsules 12), whereby the pipes 24 have the necessary branches 26 to the individual filter capsules 12. Where necessary, the pipes 24 are attached to the holder 14. The essential components of the rigid holder 14, the rigid housings of the filter capsules 12 and the rigid pipes 24 are all preferably made of the same material. This material and any other materials used in the device 10 (e.g., for any flexible hose lines) are sterilizable, in particular by means of gamma radiation, and autoclavable. The disposable filtration device 10 can thus be sterilized in the pre-assembled, i.e., ready-to-connect state and then packaged or packaged and then sterilized.The disposable filtration device 10 is designed for a large-volume filtration process. In particular, the filter capsules 12 provide a sufficiently large filtration area for such a process.

[0023] In Figure 1Examples of lines, branches, and connections are shown that can be provided for the integration of certain sensors and control devices for automating the disposable filtration device 10. An inlet valve 28 is connected to an unfiltrate inlet of the rigid disposable filtration device 10 via a piece of hose. Upstream of the inlet valve 28, a branch 30 is provided, on one branch of which a Tri-Clamp connection 32 is provided, and on the other branch of which a reinforced intermediate hose section 34 and an inlet hose line 36 connected thereto with a first sterile connector 38 are provided. A filtrate outlet of the rigid disposable filtration device 10 is connected to an outlet valve 40 via a piece of hose.Downstream of the outlet valve 40, a branch 42 is provided, one of whose branch lines has a Tri-Clamp connection 44, and the other branch of which has a reinforced intermediate hose section 46 and an outlet hose line 48 connected thereto with a second sterile connector 50. A reinforced vent line 52 leads from a vent outlet of the disposable filtration device 10 to an air filter holder carrying a sterile air filter 54.

[0024] Based on the Figure 2The exemplary configuration of a disposable filtration device 10 shown in the figure illustrates the integration of sensors and control devices for automating the disposable filtration device 10. For the sake of clarity, not all components and line branches are intentionally shown. As already mentioned, hose connections (and possibly additional ones) are provided at an unfiltered material inlet 56, a filtrate outlet 58, and a vent outlet (or air inlet) 60 of the disposable filtration device 10 for the sensors and control devices described below, all of which are designed as disposable components.

[0025] A flow sensor 62 for determining the flowing volume per unit time, an inlet pressure sensor 64, and an inlet control valve 66 are provided at the unfiltrate inlet 56. An outlet fluid detector 68, an outlet control valve 70, and an outlet pressure sensor 72 are provided at the filtrate outlet 58. A vent control valve 74 and a vent fluid detector 76 are provided at the vent outlet 60.

[0026] A fundamental prerequisite for complete or partial (individual process steps) automation of the disposable filtration device 10 is that the integrated sensors and control devices are connected to a monitoring and control system 78 via electrical lines, thus enabling control of the entire process or the respective process step. The electrical lines serve, on the one hand, to operate the sensors and control devices and, on the other hand, where provided, to transmit and / or receive data or signals required for monitoring and / or control. Alternatively, the data or signal transmission can also be carried out wirelessly.The control and monitoring system 78 is not a disposable component, but rather an electronic system located remotely from the filter capsules 12, which contains suitable software and hardware for evaluating and processing sensor data and for controlling the control devices based on one or more control algorithms.

[0027] In the following, various automation options are described by way of example, and the components absolutely necessary for this purpose and their arrangement are explained, as well as those that are not required. In addition to the actual pre-sterilizable disposable filtration device 10 with the filter elements and the monitoring and control system 78, these can be individual or multiple components, the type and arrangement of which can be Figure 2shown as an example and described above as an example, or they are components whose type and arrangement are explained in more detail in the context of the applications described below. A) Full automation with less equipment required:

[0028] Fully automating a filtration process performed with the disposable filtration device 10, with less equipment than a corresponding manually performed process, offers the possibility of achieving the same basic functionality with less construction effort, system scope, and lower costs. This is particularly important when the user's installation space, control system capacity, and / or financial budget are limited.

[0029] As a basic function, a filtration process is assumed here as an example, which includes the following process steps: filling the disposable filtration device 10 with low flow and simultaneous venting; closing the vent line 52; rinsing, filtration and post-rinsing with pressure monitoring at high flow; closing the main line (simply, ie either at the inlet or at the outlet).

[0030] This basic function can be achieved with only a part of the equipment of the Figure 2 shown disposable filtration device 10, in particular: without liquid detector 68 at the filtrate outlet 58, since the presence of liquid at the filtrate outlet 58 can be determined from the input flow signal of the flow sensor 62 and the known system volume; without pressure sensor 72 at the filtrate outlet 58, since the inlet pressure is used as the controlled variable; without flow sensor 62, if the flow is controlled via the characteristic curve of the feed pump 80, the inlet pressure sensor 64 and the vent liquid detector 76; without control valve 70 at the filtrate outlet 58, since the inlet pressure is used as the controlled variable and, if necessary, shut-off is carried out by a manual valve; use of a simple shut-off valve (only on / off) instead of the inlet control valve 66 orof the output control valve 70, since regulation is not absolutely necessary and the shut-off valve is controlled via the characteristic curve of the feed pump 80, the inlet pressure sensor 64 and the venting liquid detector 76; use of a venting liquid detector on the housing of the sterile air filter 54 or on a distributor or collector pipe (not shown here) serving as a common venting pipe, in addition to or instead of the venting liquid detector 76 on the vent line 52, wherein the venting liquid detector is used simultaneously for idle monitoring and / or air accumulation monitoring in order to achieve earlier blocking of the vent line 52. . B) Partial automation with less equipment required:

[0031] Partial automation of a reduced basic function performed with the disposable filtration device 10 is possible with significantly reduced construction effort, system scope, and lower costs compared to a purely manual implementation. In this case, the disposable filtration device 10 can be operated by a single operator. In principle, a single partial automation function or any combination of the following equipment options is possible: Inlet pressure sensor 64, vent fluid detector 76 on the vent line 52 or on the sterile air filter 54, controlled / regulated feed pump 80, manually operated simple vent valve 74 (on / off only). The setup or preparation of the disposable filtration device 10 is done manually, while the time-consuming process steps such as rinsing and filtration are regulated via the inlet pressure or controlled via the characteristic curve of the feed pump 80. Inlet pressure sensor 64, flow sensor 62, vent fluid detector 76 on the vent line 52 or on the sterile air filter 54, controlled / regulated feed pump 80, manually operated simple vent valve 74 (on / off only). The setup or preparation of the disposable filtration device 10 is done manually, while the time-consuming process steps such as rinsing and filtration are regulated via the flow and inlet pressure.Inlet pressure sensor 64, flow sensor 62, vent fluid detector 76 on the vent line 52 or on the sterile air filter 54, controlled / regulated feed pump 80, automated inlet control valve 66, manually operated simple vent valve 74 (on / off only). The setup or preparation of the disposable filtration device 10 is done manually, while the time-consuming process steps such as rinsing and filtration are controlled via the flow and inlet pressure, with the control of start-up and shut-down ramps possible. C) Minimum equipment:

[0032] The basic function can also be implemented with minimal equipment, with maximally reduced construction effort, system scope, and costs. In this case, two people should be available for operation at least temporarily. The minimum equipment required is: Inlet pressure sensor 64, controlled / regulated feed pump 80, manually operated simple vent valve 74 (open / close only). Setup or preparation and venting of the disposable filtration device 10 are performed manually, ideally by two people, while the time-consuming process steps such as rinsing and filtration are regulated via the inlet pressure or controlled via the characteristic curve of the feed pump 80. D) Extended functionality:

[0033] To expand functionality, additional sensors, actuators, and devices can be integrated into the disposable filtration device 10. This eliminates the need for separate units or process steps, as well as the associated savings in equipment, space, and costs. Examples include: Automated acid / alkali dosing using a pH sensor to adjust the pH value; sampling at specified time and / or fraction intervals (take one), as well as sterile sampling (for quality control) by an automated actuator; automated rinsing medium access (for pre-rinsing, wetting); automated drainage outlet (removal of rinsing or wetting medium, process feed); automated gas access (for emptying rinsing and process fluid). E) Advanced measurement technology:

[0034] For continuous process monitoring and documentation / data archiving in sensitive or highly regulated, or even very high-value processes, the integration of additional inline and / or online-capable sensors is advantageous. Examples include: Level measurement or liquid detection using capacitive, inductive, ultrasonic, vibration, or conductive sensors. One application example is the monitoring and documentation of the complete filling of all filter capsules 12 in filtration processes where full use of the filter surface is necessary for the filtration function or for regulatory reasons, such as virus filtration or depth filtration with a limitation of the surface load (filtrate quantity / filter surface) due to breakthrough behavior. Temperature measurement using a temperature sensor. One application example is the monitoring and documentation of specified temperature specifications for the entire process duration, such as in aseptic processes, which must be permanently operated in the temperature range of 2 °C to 4 °C to minimize microbiological activity, or the monitoring of the temperature input through the pump. pH measurement using a pH sensor.One application example is the monitoring and documentation of buffer solution production and filling. Conductivity measurement using a suitable sensor. One application example is the monitoring and documentation of buffer solution production and filling, salting-out and chromatography processes, as well as pre-rinsing and cleaning processes. TOC (total organic carbon) measurement using a suitable sensor. One application example is the monitoring and documentation of pre-rinsing and cleaning processes during production and filling. Turbidity measurement using a suitable sensor. One application example is the monitoring and documentation of breakthrough-prone processes such as depth or fiber pre-filter processes. List of reference symbols

[0035] 10 Disposable filtration device 12 Filter capsule 14 Bracket 16 Support column 18 Cross brace 20 Base 22 Holding device 24 Pipe 26 Branch 28 Inlet valve 30 Branch 32 Tri-Clamp connection 34 Intermediate hose section 36 Inlet hose line 38 First sterile connector 40 Outlet valve 42 Branch 44 Tri-Clamp connection 46 Intermediate hose section 48 Outlet hose line 50 Second sterile connector 52 Vent line 54 Sterile air filter 56 Unfiltered liquid inlet 58 Filtrate outlet 60 Vent outlet 62 Flow sensor 64 Inlet pressure sensor 66 Inlet (control) valve 68 Outlet liquid detector 70 Outlet (control) valve 72 Outlet pressure sensor 74Vent (control) valve 76Vent fluid detector 78Control and monitoring system 80Feed pump

Claims

1. Method of filtering a large volume of a medium using a pre-sterilizable, at least partially automated single-use filtration device (10) which includes an unfiltrate inlet (56), a filtrate outlet (58), a main line running between the unfiltrate inlet (56) and the filtrate outlet (58), filter elements arranged in the main line, a venting line (52) at a venting outlet (60) of the filter elements, and sensors for detecting specific process parameters, including an inlet pressure sensor (64) at the unfiltrate inlet (56), and regulating means for adjusting specific process parameters, including a feed pump (80) at the unfiltrate inlet (56) and a venting valve (74) at the venting outlet (60), comprising the following process steps: a) filling the single-use filtration device (10) with medium using low flow; b) venting the single-use filtration device (10) through the venting line (52); c) closing the venting line (52); d) rinsing the single-use filtration device (10), in particular the filter elements; and e) filtering the medium using the filter elements, characterized in that i) the presence of liquid at the filtrate outlet (58) is determined from an inlet flow signal of a flow sensor (62) at the unfiltrate outlet (56) and the known system volume, or ii) at least in process step e), an inlet pressure detected by the inlet pressure sensor (64) arranged at the unfiltrate inlet (56) is used as a regulating variable, or iii) at least in process step e), the control of the flow is carried out via a characteristic curve of the feed pump (80), the inlet pressure sensor (64) and a venting liquid detector (76), wherein the sensors and regulating means are connected to an external monitoring and control system (78) which is adapted for evaluating and processing sensor data and for piloting the regulating means based on one or more control algorithms.

2. Method according to claim 1, characterized in that the method further comprises the following process steps: f) re-rinsing using high flow; and g) closing the main line.

3. Method according to claim 2, characterized in that process step g) is carried out by simply shutting off the main line using a shut-off valve either at the unfiltrate inlet (56) or at the filtrate outlet (58).

4. Method according to claim 3, characterized in that the control of the shut-off valve is carried out via a characteristic curve of a feed pump (80), an inlet pressure sensor (64) and a venting liquid detector (76).

5. Method according to any one of the preceding claims, characterized in that a venting liquid detector on a housing of a sterile air filter (54) or on a distributing or collecting pipe is used for draining supervision and / or for air accumulation supervision.

6. Method according to any one of claims 2 to 4 or claim 5, insofar as it refers back to claim 2, characterized in that process step f) is carried out with pressure supervision.

7. Method according to any one of the preceding claims, characterized in that a pH sensor integrated in the single-use filtration device (10) is used for the automated adjustment of a pH value during dosing of an acid or base.

8. Method according to any one of the preceding claims, characterized in that an automated actuator is used during one or more, preferably sterile, samplings, preferably at predetermined time and / or fraction intervals.

9. Method according to any one of the preceding claims, characterized in that an automated rinsing medium access is used during a pre-rinsing or wetting of the filter elements.

10. Method according to any one of the preceding claims, characterized in that an automated drainage output or an automated gas access is used during a discharge of rinsing or wetting medium or a process run-up.

11. Method according to any one of the preceding claims, characterized in that at least one of the following sensors integrated in the single-use filtration device (10) is used during a process supervision and / or documentation or data archiving: - a capacitive, inductive, ultrasonic, vibration or conductive sensor for level measurement and / or liquid detection; - a temperature sensor; - a pH sensor; - a conductivity sensor; - a TOC sensor; - a sensor for turbidity measurement.