Method and system for aseptically distributing a fluid comprising a target molecule

Abstract

The invention relates to a method for aseptically distributing a fluid comprising a target molecule in a system. The method comprises the steps of: providing a stop time threshold tt, providing an initial stop time ti, providing a timer, providing a state of the system, wherein the state of the system is selected from started or stopped, and carrying out a fluid processing step each time the state of the system changes from stopped to started. The fluid processing step comprises the steps of: reading in a timer reading step the stop time ts from the timer, purging in a fluid purging step at least a part of the fluid from the system, if the stop time ts minus the initial stop time ti is larger than the stop time threshold tt. flowing in a fluid flowing step the fluid from a source through a distribution device to at least one sink, monitoring in a monitoring step the state of the system, wherein the state of the system can be started or stopped, wherein the fluid flowing step and the monitoring step are carried out in parallel, and starting in a timer starting step a timer at the initial stop time ti, if in the monitoring step a change of the system state from started to stopped has been monitored.

Description

[0001] Method and System for Aseptically Distributing a Fluid comprising a Target Molecule

[0002] Technical Field of the Invention

[0003] The present invention is concerned with a method for aseptically distributing a fluid comprising a target molecule. Furthermore, the present invention is concerned with a system for aseptically distributing a fluid comprising a target molecule. More specifically, the present invention is concerned with such a method or system, wherein the fluid, which resided for a certain time in a feeding line of the system, is automatically purged upon restart of the flow rate.

[0004] Background of the Invention

[0005] In many drug production methods and systems, a final distribution step is involved. Thereby, the produced fluid is split in portions and delivered to containers, syringes, vials, ampoules, bottles, bioprocessing containers, or carbouys.

[0006] One example of a drug production method is a filtration step. When completing sterile filtration of a drug product, the system is typically connected to a filling line. This filling line usually comprises the fluid comprising the drug product. Sterile filtered fluids, as inter alia used in the pharmaceutical industry, can be very expensive, and thus, the loss of this fluid volume (for example, during the manufacture of biological therapeutics) can be costly. Further, during clinical trials, non-recoverable product may prevent manufacturers from preparing an adequate quantity of product, adversely impacting the ability to generate critical data that could lead to beneficial treatment. Cumulatively, the loss of even a few milliliters of fluid per filtration can represent a significant amount of money.

[0007] Drugs produced can be prone to environmental influence such as UV radiation, temperature, extractables and leachables in the flow path, or other parameters accelerating their decay. Hence, if a situation arises in which such decay occurs, the decayed product should be prevented from entering the distribution step, as it might pollute the already collected product.

[0008] Such situations may be caused by issues with the downstream equipment. In another scenario, the sterile filtration or drug production system itself may cause the system to pause the flow, i.e. by an alarm. This will leave product static within the flow path to the distribution step. Depending on the circumstances, such situations may arise many times during distribution of the product fluid.

[0009] US 11 ,787,680 B2 discloses a fluid distribution system comprising a pump, a manifold, a filler valve arrangement, and a control unit. While US 11 ,787,680 B2 is concerned with recovering as much fluid as possible from the system, it lacks a solution to the problem as set out above.

[0010] Summary of the Invention

[0011] Hence, it is an object of the present invention to provide a method or system for distributing a fluid comprising a target molecule, wherein a decayed product of the target molecule in the flow path due to stopped flow for a certain time does not pollute the collected charges.

[0012] It has been now surprisingly found out that this object is achieved by a method for aseptically distributing a fluid comprising a target molecule in a system, the method comprising the steps of providing a stop time threshold tt, providing an initial stop time tt, providing a timer, providing a state of the system, wherein the state of the system is selected from started or stopped, carrying out a fluid processing step each time the state of the system changes from stopped to started, the fluid processing step comprising the steps of

[0013] ■ reading in a timer reading step the stop time tsfrom the timer,

[0014] ■ purging in a fluid purging step at least a part of the fluid from the system, if the stop time tsminus the initial stop time t, is larger than the stop time threshold tt.

[0015] • flowing in a fluid flowing step the fluid from a source through a distribution device to at least one sink,

[0016] ■ monitoring in a monitoring step the state of the system, wherein the fluid flowing step and the monitoring step are carried out in parallel, and starting in a timer starting step a timer at the initial stop time f, , if in the monitoring step a change of the system state from started to stopped has been monitored. It has been further surprisingly found out that this object is achieved by a system for aseptically distributing a fluid comprising a target molecule, wherein the system comprises a source of the fluid comprising a target molecule, at least one sink for the fluid comprising the target molecule, a distribution device for distributing the fluid comprising the target molecule into the at least one sink, wherein the distribution device comprises an inlet fluidly connected to the source by a feeding line and at least one outlet, wherein each of the at least one outlet is fluidly connected by a distribution line to one of the at least one sink, a pump positioned at the feeding line, a controlling unit, a state detection device for detecting the state of the system, the state detection device being in communication with the controlling unit, a timer, the timer being in communication with the controlling unit, a fluid purging device, the fluid purging device being in communication with the controlling unit, wherein the timer is responsive to the state detection device via the controlling unit, and wherein the fluid purging device is responsive to the timer via the controlling unit.

[0017] The herein described method and system have the advantage that in situations when the target molecule may decay due to stopped flow in the system, the potentially problematic batches of fluid comprising said decayed target molecule are automatically purged from the system before any distribution to the downstream equipment. This reduces the need for operator interaction with the system, reduces downtimes and therefore reduces costs. Furthermore, the risk of polluting the already collected charges is significantly reduced.

[0018] Short Description of the Figures

[0019] Figure 1 shows a schematic representation of the most general embodiment of the system as disclosed herein.

[0020] Figure 2 shows a schematic representation of a preferred embodiment of the system as disclosed herein, wherein the system comprises a filter.

[0021] Figure 3 shows a schematic representation of a preferred embodiment of the system as disclosed herein, wherein the purging device comprises a purge container, a purge line, and a purge deviation.

[0022] Figure 4 shows a schematic representation of the embodiment of the system according to Figure 3, wherein the purging device further comprises a valve.

[0023] Figure 5 shows a schematic representation of a preferred embodiment of the system as disclosed herein further comprising a pump in the purge line. Figure 6 shows a schematic representation of the preferred embodiment of the system according to Figure 5, wherein the state detection device is part of the pump.

[0024] Reference Signs

[0025] 1 source of a fluid

[0026] 2 at least one sink

[0027] 3 distribution device I manifold

[0028] 4 inlet of the distribution device

[0029] 5 feeding line

[0030] 6 at least one outlet

[0031] 7 distribution line

[0032] 8 pump

[0033] 9 controlling unit

[0034] 10 state detection device

[0035] 11 timer

[0036] 12 purging device

[0037] 13 filter

[0038] 14 purge container

[0039] 15 purge line

[0040] 16 purge deviation

[0041] 17 valve

[0042] 18 force applying device

[0043] Definitions

[0044] The term ‘sterilization’ as used herein preferably denotes a method to destroy all forms of living microorganisms from a substance. As there always can be a certain probability of at least one microorganism to survive such procedure, the aim of sterilization is the reduction of initially present microorganisms or other potential pathogens. Preferably, sterilization is accepted to be achieved if the bioburden load of the substance of object to be sterilized is lower than 10'6. The bioburden load can be measured i.e. , according to ISO 11737-1 :2018. Sterilization can be achieved using several methods. In one sterilization process, the object is heated up to at least 105 °C to achieve a sterile object. Thereby, the object should not be deformed by the elevated temperature. Preferably, the heating step is performed in an autoclave. In another sterilization process, the object is brought into contact with toxic gases, such as a mixture of ethylene oxide and carbon dioxide. Filtration methods are also used to sterilize liquids, i.e., by using membrane filters, Seitz filters, and / or candle filters. Finally, sterilization can be achieved by indirect energy import into or onto the object, e.g., by ultrasonic waves, ultraviolet light, as well as by high energy particles (such as electrons, gamma, or X-rays).

[0045] The term ‘sterile’ as used herein preferably denotes the status of an object having a significantly reduced number of bacteria and / or viruses on its surface to reduce the risk of an infection. In particular, the term ‘sterile’ preferably denotes an object or substance, which has a bioburden load of lower than 10'6. The bioburden load can be measured i.e. , according to ISO 11737-1 :2018. A sterile substance or article is typically achieved by sterilization thereof.

[0046] The term ‘sterile air’ as used herein denotes air, which has been subjected to a sterilization process or which has been filtered by a sterile filter. The terms ‘sterile gas’ and ‘sterile air’ can be used equivalently, e.g., embodiments referring to sterile gas also encompass the use of sterile air, and vice versa.

[0047] The term ‘aseptically transporting’ or ‘aseptically distributing’ as used herein denotes the transport of a sterile substance, preferably a sterile liquid, in a closed system, wherein the sterility of the substance is not decreased.

[0048] The term ‘positive displacement pump’ as used herein denotes a pump, which moves a fluid by trapping a fixed volume of the fluid on a suction side and forcing the trapped volume into a discharge side. Some positive displacement pumps operate in a mode, wherein the volume of the cavity decreases while traveling to the discharge side. Generally, a positive displacement pump creates a pressure gradient between the suction side and the discharge side in that the pressure on the suction side is lower than the pressure on the discharge side. Typical positive displacement pumps are rotary-type positive displacement pumps, such as internal and external gear pumps, screw pumps, lobe pumps, shuttle block, flexible vane and sliding vane, circumferential piston, flexible impeller, helical twisted roots, and liquid-ring pumps. Other typical positive displacement pumps are reciprocating-type positive displacement pumps, such as piston pumps, plunger pumps, and diaphragm pumps. Finally, linear-type positive displacement pumps are, for example, rope pumps and chain pumps. A common feature of positive displacement pumps is that they form a barrier for the liquid against the intended pumping direction of the positive displacement pump. Hence, once a fluid volume has been moved from the suction side to the discharge side, the positive displacement pump does not allow a flow back of said fluid volume. This also holds true in case the pump stops working.

[0049] The term ‘peristaltic pump’ as used herein denotes a specific embodiment of a positive displacement pump, in particular a specific embodiment of a rotary-type positive displacement pump. Thereby, it is a specific feature of the peristaltic pump that the fluid to be pumped is contained in a flexible tube. The flexible tube runs through the housing of the circular peristaltic pump. The peristaltic pump comprises a rotor, which comprises a means to put pressure on the flexible tube, such as wipers or rollers attached to the external circumference of the rotor. Thereby, the means to put pressure on the flexible tube compresses the flexible tube as they rotate, whereby the flexible tube is closed under compression. The closing of the flexible tube forces the fluid to move through the flexible tube during rotation of the rotor. Furthermore, the closing of the flexible tube prevents the fluid from flowing back. As the flexible tube opens to its natural state after the wipers or rollers have passed, more fluid is drawn into the flexible tube. This process is called peristalsis. Preferably, the peristaltic pump comprises two or more rollers for compressing the flexible tube, thereby trapping a volume of fluid between them.

[0050] The term ‘source of sterile air’ as used herein denotes a device which provides sterile air continuously or up to a certain volume. Usually, the sterile air in the source of sterile air is present at a pressurized state in comparison to the pressure of the system it is connected to. Sources of sterile air might be air pumps in connection with sterile filters. Other embodiments comprise containers filled with sterile air, which exerts pressure on the contained air. The pressure exerted can be provided by means for putting pressure on the container or by filling the container with pressurized sterile air. Most preferably the source of sterile air is a bag comprising pressurized sterile air. Thereby, the bag is preferably made from an air-tight film comprising a polymer, preferably from a multilayer polymer film.

[0051] The term ‘sink’ as used herein denotes any device or container, which is intended to receive the filtered fluid. Usually, the filtered fluid is collected after filtering either to be packaged and sold or to be directly used i.e. in medical application or in research. Hence, the type of the filtered fluid sink depends on the use case the system or method is intended to serve the filtered fluid for. In one embodiment, the filtered fluid sink is a filtered fluid container, which simply collects the filtered fluid. In another embodiment, the filtered fluid sink is a manifold, which distributes the filtered fluid to many containers or other devices such as syringes. In even another embodiment, the filtered fluid sink could be a syringe either for being packaged and sold or for being used in a subsequent treatment or method. Other filtered fluid sinks may be vials, ampoules, bottles, bioprocessing containers, and carbouys.

[0052] The term ‘distributing’ as used herein denotes transporting the fluid to a sink. Preferably, the ‘distributing’ comprises transporting the fluid to at least two sinks, thereby dividing the volume of fluid and providing one part of the volume of the fluid to one of the at least two sinks and at least one further part to one or more remaining sinks of the at least two sinks.

[0053] The term ‘closed system’ as used herein denotes a system that allows the collection and processing (including filtration, and, if desired, the manipulation, e.g., separation of portions into components, storage, and preservation) of fluid, without exposing the contents of the system to the environment in which it is being used. Hence, in particular, a closed system is suitable for aseptically processing sterile fluids and components by shielding them from influences of the environment.

[0054] The use of the terms ‘a’ and ‘an’ and ‘the’ and ‘at least one’ and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0055] The use of the term ‘at least one’ followed by a list of one or more items (for example, ‘at least one of A and B’) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context.

[0056] The terms ‘comprising’ , ‘having’, ‘including’, and ‘containing’ are to be construed as open-ended terms (i.e., meaning ‘including, but not limited to’) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., ‘such as’) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element as essential to the practice of the invention.

[0057] The term ‘controlling unit’ as used herein denotes any suitable equipment configured to control the operation of at least one component of the system described herein when carrying out the distribution operation. The controlling unit may comprise a processor, a non-transitory computer readable medium bearing a fluid distribution program, a data storage device, and a display device. The processor may be arranged with the computer readable medium to execute the fluid distribution program. The processor is in operable arrangement with the display device to selectively display output information from the fluid distribution program and / or to receive input information from a graphical user interface displayed by the display device. The processor can be configured to act as a controller to selectively operate at least one component of the system, such as the pump and the valve arrangements, for example. In embodiments, the processor is in electrical communication with the pump(s) and the valve arrangements to selectively operate the valves based upon instructions from the fluid distribution program. The controller and the processor can comprise separate devices, and the controller can be in operable communicative arrangement with the processor. The controller can include a user input and / or interface device having one or more user-actuated mechanisms (e.g., one or more push buttons, slide bars, rotatable knobs, a keyboard, and a mouse) adapted to generate one or more user actuated input control signals. In embodiments, the controller can be configured to include one or more other user-activated mechanisms to provide various other control functions for the system described herein. The controller can be associated with the display device which is adapted to display a graphical user interface. The graphical user interface can be configured to function as both a user input device and a display device in embodiments. The display device can comprise a touch screen device adapted to receive input signals from a user touching different parts of the display screen. The controller can be in the form of a smart phone, a tablet, a personal digital assistant (e.g., a wireless, mobile device), a laptop computer, a desktop computer, or other type of device.

[0058] The term ‘fluid’ as used herein denotes a liquid comprising a solvent and at least one target molecule. The fluid may comprise a small amount of solid particles, which are usually filtered out before distribution. Preferably, the solvent is sterile water.

[0059] Detailed Description

[0060] The present invention is concerned with a system for aseptically distributing a fluid comprising a target molecule and a method for aseptically distributing a fluid comprising a target molecule. The method and the system are described in more detail in the following with reference to Figures 1 to 5 using the reference signs as set out above.

[0061] Method

[0062] As set out above, the herein described method is a method for aseptically distributing a fluid comprising a target molecule in a system, the method comprising the steps of providing a stop time threshold tt, providing an initial stop time t,, providing a timer, providing a state of the system, wherein the state of the system is selected from started or stopped, carrying out a fluid processing step each time the state of the system changes from stopped to started, the fluid processing step comprising the steps of

[0063] ■ reading in a timer reading step the stop time tsfrom the timer,

[0064] ■ purging in a fluid purging step at least a part of the fluid from the system, if the stop time tsminus the initial stop time t, is larger than the stop time threshold tt,

[0065] • flowing in a fluid flowing step the fluid from a source through a distribution device to at least one sink,

[0066] ■ monitoring in a monitoring step the state of the system, wherein the fluid flowing step and the monitoring step are carried out in parallel, and

[0067] ■ starting in a timer starting step a timer at the initial stop time f, , if in the monitoring step a change of the system state from started to stopped has been monitored.

[0068] Thereby the steps of providing a stop time threshold ttand of providing an initial stop time ti are carried out before any fluid flow is started. Hence, these steps can be carried out far ahead of carrying out the following steps. They may be even part of planning a method as described herein. More preferably, the step of providing an initial stop time ti is a step of having an initial stop time ti. In that way, the initial stop time t, is provided with the method itself.

[0069] Preferably, the step of providing the timer comprises the step of setting the timer to the initial stop time ti. More preferably, the step of providing the timer comprises the step of setting the timer to the initial stop time ti, if the timer is stopped and if the timer has no stop time tslarger than the stop time threshold tt.

[0070] Thereby, the stop time threshold tt depends on a variety of parameters and may be chosen by the skilled person. Generally, the stop time threshold tt should provide a time window, which ensures that the stability of the target molecule is assured and that further the composition is not altered in any other manner. Thus, parameters determining the stop time threshold tt are the target molecule itself, its decomposition tendency, its decomposition temperature, and its affinity for certain compounds found in the environment, such as oxygen, or other influences, such as UV radiation. Furthermore, the choice of the stop time threshold ttdepends on parameters at which the method is run, such as the temperature of the fluid, the temperature of the environment, and / or extractables leaching into the fluid. Thus, preferably, in the step of providing a stop time threshold tt, the stop time threshold tt depends on the stability of the target molecule and the fluid, more preferably depends on the decomposition tendency of the target molecule, the decomposition temperature of the target molecule, the affinity of the target molecule for compounds found in the environment, such as oxygen, the affinity of the target molecule to radiation, such as UV radiation, the temperature of the fluid, the temperature of the environment, and / or extractables leaching into the fluid.

[0071] The initial stop time t, may take in account influences, which start to destabilize the target molecule or the fluid earlier than the starting time of the timer. I.e. certain processes in view of the decay might already be present in a process or method preceding the presently described method. For example, the preceding production method includes separation steps at temperatures which may have an impact on the stability of the target molecule and the connection between the methods is continuous. In such situation, the initial stop time t, could be set to be sensitive to these influences as well. Nevertheless, preferably, the initial stop time t, is zero.

[0072] In the herein described method, the stop time threshold tt and / or the initial stop time t, is provided by the operator. Hence, the stop time threshold ttand / or the initial stop time ti are preferably provided by direct user input in the step providing a stop time threshold ttand / or the step of providing an initial stop time t, of the herein described method.

[0073] Alternatively, also preferably, the stop time threshold tt and / or the initial stop time t, are retrieved from a user input or from a data storage. Depending on the method, the target molecule, the fluid used, the system used, and a library of stop time thresholds ttand / or the initial stop times t, may be created and provided, from which the system may choose automatically. Most preferably, the stop time threshold tt is retrieved from a user input and the initial stop time t, is retrieved from data storage, as the initial stop time t, is defined by the system e.g. downstream equipment.

[0074] In the fluid flowing step, the fluid from the source is distributed via the distribution device into several sinks, such as bags, syringes, vials, ampoules, bottles, bioprocessing containers, and carbouys. The fluid flowing step can be a collecting step after for example a bioprocessing step. Thereby, product is collected and distributed in charges to several downstream containers for further distribution, i.e. on the market. Collection for in situ produced medicine to be used in subsequent treatment processes is also conceivable.

[0075] The distribution device as used in the fluid flowing step is preferably a manifold, to the outlets of which at least two sinks are connected. Typically, the flow through the distribution device is controlled by the fluid flowing step. However, alternatively, the distribution device comprises further means to adjust or control the flow such as valves and ports.

[0076] In a preferred embodiment of the herein described method, the fluid flowing step comprises at least one step of filtering the fluid between the source and the sinks. Usually, before collection of further in situ use, fluids comprising the target molecule are filtered to achieve high standards of purity. In the present invention, the filtering and distributing can be achieved in one method.

[0077] In another preferred embodiment, in the herein described method the fluid flowing step further comprises the step of mixing in a buffer mixing step the fluid comprising the target molecule with a buffer.

[0078] As set out above, in parallel to the fluid flowing step, a monitoring step is carried out. Thereby, it is monitored whether the flow rate in the fluid flowing step is greater than zero or not, which corresponds to a system state value of stopped or started, respectively.

[0079] Thereby, the monitoring step can use any means for determining the flow rate of the fluid in the fluid flowing step. For example, the flow rate can be measured directly indirectly, i.e. at a feeding line. Direct measuring steps include the usage of mechanical flowmeters. However, preferably, the method is carried out on a closed system. Hence, preferably, the measurement is carried out in an indirect manner. Hence, preferably, the measurement is carried out by means of optical flowmeters, sonar flowmeters, or thermal flowmeters. Most preferably, the fluid flowing step involves the usage of a pump, and the monitoring step is carried out by measuring the speed of the pump, even more preferably the state of the pump.

[0080] Alternatively, situations may arise, where the monitoring step also involves monitoring an external signal either alone or in addition to measuring the flow rate of the fluid. Such an embodiment can assure that situations are recognized, which lead to the outage of the total system, and which do not allow for a clear indication of the state of the flow rate after restart. Furthermore, other problems such as a sudden rise in temperature of the system could also lead to an alarm, which might be recognized by the monitoring step.

[0081] Hence, preferably, in the herein described method, in the monitoring step the state of the system is determined by the flow rate of the fluid, by the rotational speed of a pump, and / or by an external signal. Thereby, the external signal is preferably selected from a user input or an input from a controlling device. A situation may occur where the method is initiated without the operator's awareness, leading to a potential stability issue with the target molecule before it is detected. This could be caused by a power outage or any other abnormal abort of the method. To ensure that the method in this case is able to avoid pollution of the collected charges, a respective cycle of the step of the herein described method is also carried out at startup of the method. However, for the method to carry out the fluid purging step in the first cycle of the fluid processing step, the method needs to have the information that purging should occur. Hence, preferably, in the method the timer does not loose its information once the method has been stopped. In such an embodiment, in the first cycle of the fluid processing step, in the timer reading step, the time tsduring the potential power outage is read and compared to the stop time threshold tt. In an even more preferred embodiment of the method, the timer works independently from the method itself. Thus, should the method be unexpectedly stopped and restarted, the timer will have run in the meantime and in the timer reading step, the time tsduring the potential power outage is read and compared to the stop time threshold tt. In an alternative preferred embodiment, the method comprises the provision of an external state, preferably a power outage state, an the fluid purging step comprises the additional alternative condition that the power outage state is set to a state indicating a preceding power outage. Preferably, in such an embodiment, the fluid processing step comprises a step of resetting the external state, preferably a power outage state, after the fluid purging step.

[0082] Preferably, the timer is a timer, which runs independently from the method, i.e. , which does not depend on the runtime of the method described herein. This ensures that the information put on the timer survives a crash, i.e., an abnormal abortion, of the method and the timer can provide the stop time tson startup of the method as described herein.

[0083] The fluid purging step is usually carried out to remove the volume of fluid from a flow path between the source (1) and the distribution device (3), preferably from the whole flow path. Hence, this could be achieved by determining the flow path, from which the fluid should be removed, by switching valves and opening a vent and a port to let the fluid run out of the selected flow path. Alternatively, pressurized sterile air could be used to push the fluid out of the selected flow path. Further alternatively, pumps could be used to suck the fluid out of the flow path. However, these method steps all have the drawback that an empty flow path is achieved, which might have to be sterilized again, i.e. if the air of the vent used is not sterilized. Even if sterile pressurized air is used, either this air remains in the system or has to be replaced, i.e., by pure fluid. Both solutions have the drawback that the concentration of the collected fluid might be altered. Hence, preferably, in the fluid purging step, the flow path is changed in that the target of the flow path is directed to a purge fluid sink. Thus, in the herein described method the fluid purging step comprises the step of activating a purging force and / or the step of activating a purge fluid sink.

[0084] Preferably, the force in the step of activating a purging force is overpressure. More preferably, the step of activating overpressure comprises activating a pump. Preferably, the pump is a positive replacement pump, more preferably, the pump is a peristaltic pump.

[0085] Furthermore, preferably, in the herein described method the step of activating a purge fluid sink comprises the step of opening a flow path to a purge fluid container.

[0086] Hence, more preferably, the fluid purging step comprises the step of activating a purge fluid sink and the step of activating a purging force.

[0087] Most preferably, the fluid purging step comprises the step of opening a flow path to a purge fluid container and the step of activating overpressure comprises activating a pump. This achieves that the fluid from the source as used in the fluid flowing step is used to push the volume of fluid to be purged into the purge fluid container. As a result, after the fluid purging step is finished, the flow path is in a state ready for being distributed again.

[0088] System

[0089] As also already set out above, the herein described system is a system for aseptically distributing a fluid comprising a target molecule, wherein the system comprises: a source (1) of the fluid comprising a target molecule, at least one sink (2) for the fluid comprising the target molecule, a distribution device (3) for distributing the fluid comprising the target molecule into the at least one sink (2), wherein the distribution device (3) comprises an inlet fluidly (4) connected to the source (1) by a feeding line (5) and at least one outlet (6), wherein each of the at least one outlet (6) is fluidly connected by a distribution line (7) to one of the at least one sink (2), a pump (8) positioned at the feeding line (5), a controlling unit (9), a state detection device (10) for detecting the state of the system, the state detection device (10) being in communication with the controlling unit (9), a timer (11), the timer (11) being in communication with the controlling unit (9), a fluid purging device (12), the fluid purging device (12) being in communication with the controlling unit (9), wherein the timer (11) is responsive to the state detection device (10) via the controlling unit (9), and wherein the fluid purging device (12) is responsive to the timer (11) via the controlling unit (9).

[0090] Preferably, the at least one sink (2) comprises at least two sinks and the at least one outlet (6) comprises at least two outlets.

[0091] Such a system is depicted in Figure 1 and is suitable for carrying out a method as described herein. The timer (11) can be run in software on the controlling unit (9). However, preferably, the timer (11) is a hardware timer, which runs independently from the controlling device. For example, the timer could be the clock of a computer used as the controlling unit. More preferably, the timer (11) has a dedicated power source, more preferably a battery or a power source, which can bridge the duration of a power outage.

[0092] Preferably, the distribution device (3) is a manifold.

[0093] The source (1) of the fluid is placed in communication with feeding line (5). The source (1) can be a source container comprising the fluid to be distributed but can also be a production process for a fluid. Hence the source (1) could also be e.g. a bioreactor producing the fluid to be filtered.

[0094] Typically, the system includes a connector such that the source (1) and the distribution device (3) can both be placed in communication with the feeding line (5).

[0095] In a preferred embodiment, the pump (8) is a positive displacement pump. This has the advantage that fluid, which has passed the pump cannot flow back into the upstream part of the system. Hence, the pump has a barrier effect on back flow.

[0096] Furthermore, more preferably, the pump (8) is a peristaltic pump. This has the advantage that the pump can be attached to the feeding line (8) without having an influence on the integrity of the lines. Hence, system integrity is enhanced, and risk of contamination is reduced.

[0097] The system according to Figure 1 has the advantage that the controlling unit (9), the state detection device (10), the timer (11) and the purging device (12) form a closed loop system. Hence, upon a detection of a stopped state by the state detection device (10), the timer (11) is started. Once the timer (11) reaches a predetermined value stored in the controlling unit (9), the controlling unit sends a signal to the purging device (12) to purge at least a part of the fluid in upstream of the purging device. Should the state detection device (10) detect a change to a started state before the timer (11) reaches the predetermined value, no signal is sent to the purging device (12). Hence, the system according to Figure 1 allows for aseptically distributing a fluid with decreased need for interaction of an operator.

[0098] In a preferred embodiment of the herein described system according to Figure 2, the feeding line (5) comprises at least one filter (13) positioned between the pump (8) and the distribution device (3). Such a system allows for filtering and distributing the fluid with the advantages as discussed for the system according to Figure 1.

[0099] More preferably, in the system according to Figure 2, the feeding line (5) comprises at least one filter (13) positioned between the pump (8) and the purging device (12). This ensures that also fluid in the filter is purged if needed.

[0100] It should be noted that each of the embodiments of the system according to Figures 3, 4, and 5, as discussed in the following, could also comprise at least one filter (13) positioned between the pump (8) and the distribution device (3) as discussed for the system according to Figure 2.

[0101] The purging device (12) could be any device, which is suitable for removing a volume of fluid from the flow path between the source (1) and the distribution device (3), preferably from the whole flow path. The purging device (12) is a device, which is suitable for aseptically removing the volume of fluid from the flow path between the source (1) and the distribution device (3), preferably from the whole flow path. In one embodiment, the purging device could comprise a source for pressurized, preferably sterile, air, such as a vent, preferably with a sterile filter, preferably in combination with a valve to push the fluid out of the selected flow path or to let gravity remove the fluid from the selected flow path. In an alternative embodiment, pumps could be used to suck the fluid out of the flow path. However, as set out above for the process, these systems have the drawback that the emptied flow path is filled with gas.

[0102] Hence, the embodiment of the system according to Figure 3 shows a more detailed purging device (12). Thereby, the purging device (12) preferably comprises a purge container (14) fluidly connected by a purge line (15) to a purge deviation (16) in the feeding line (5) at a position between the pump (8) and the distribution device (3). Preferably, in the system according to Figure 3, the purge container (14) is a bag suitable for being filled with fluid. Preferably, the inlet of the purge container (14) or the purge line (15) comprise a back flow barrier. This can assure that the purged fluid stays in the purge container (14). The system according to Figure 3 has the advantage that the purge container (14) can be replaced by an empty purge container (14) or be emptied. Hence, the number of purge cycles of the system according to Figure 3 can be increased.

[0103] In an even more preferred embodiment of the system according to Figure 4, the purge line (15) comprises a valve, wherein the valve (17) is in communication with the controlling unit (9) and wherein the valve (17) is responsive to the timer (11) via the controlling unit (9). Hence, the purging can be controlled by the controlling unit in that the valve (17) is opened or closed.

[0104] Preferably, in the system as described herein, the purging device (12) comprises a force applying device (18) for applying a force on the fluid in the distribution device (3). More preferably, the force applied by the force applying device (18) is pressure. In the embodiment according to Figure 4, this can be accomplished by pump (8). However, also alternative positions of the force applying device (18) are conceivable, as shown in Figure 5.

[0105] In the system according to Figure 5, the force applying device (18) is selected from a pump in the purge line (15) or a pump in the feeding line (5) between the purge deviation (16) or valve (17) and the inlet of the distribution device (4), or both.

[0106] As set out above, in the system described herein the controlling unit (9) is suitable for carrying out the method as described herein.

[0107] Thus, in the herein described method, the state detection system (10) is selected from means for directly measuring the flow rate or indirectly measuring the flow rate. Directly measuring include the usage of mechanical flowmeters. However, preferably, the method is carried out on a closed system. Hence, preferably, the measurement is carried out in an indirect manner. Hence, preferably, the state detection system (10) is selected from optical flowmeters, sonar flowmeters, or thermal flowmeters. Even more preferably, the state detection system (10) is a sensor for measuring the speed of the pump (8). Most preferably, the state detection system (10) is a sensor for measuring the state of the pump. Such an embodiment is depicted in Figure 6. While Figure 6 shows the most preferred embodiment of state detection system (10) being integrated in the pump (8) for the embodiment of Figure 5, it should be understood that this preferred setup can be implemented in all embodiments shown and discussed herein. The most preferred and simplest setup of the system as disclosed herein is that the state detection system (10) is responsive to the state of the pump (8), i.e. if the pump is off, the state detection system determines the system state stopped. Likewise, if the pump is on, the state detection system (10) determines the system state started. It should be noted that in an alternative configuration of the most preferred embodiment as disclosed herein, the state detection system (10) is implemented in the controlling unit (9), preferably in software. As the pump (8) is already in communication with the controlling unit (9), the state detection system (10) implemented in the controlling unit (9) is able to retrieve the speed of the pump or, or preferably, the state of the pump.

[0108] Furthermore, preferably, the herein described system further comprises a device for receiving an external signal. More preferably, the device for receiving an external signal is selected from a switch, a computer, or a sensor.

[0109] Preferably, the device for receiving an external signal is connected to the controlling unit (9). Furthermore, preferably, the timer (11) is also responsive to the device for receiving an external signal. Preferably, the system comprises an uninterruptible power supply (UPS). Preferably the UPS is configured to support the system to recognize the power loss. Most preferably, the UPS is configured to set an external state, preferably a power outage state, to which the controlling unit (9) is responsive.

Claims

Claims:

1. A method for aseptically distributing a fluid comprising a target molecule in a system, the method comprising the steps of providing a stop time threshold tt, providing an initial stop time , providing a timer, providing a state of the system, wherein the state of the system is selected from started or stopped, carrying out a fluid processing step each time the state of the system changes from stopped to started, the fluid processing step comprising the steps of■ reading in a timer reading step the stop time tsfrom the timer,■ purging in a fluid purging step at least a part of the fluid from the system, if the stop time tsminus the initial stop time t, is larger than the stop time threshold tt.• flowing in a fluid flowing step the fluid from a source through a distribution device to at least one sink,■ monitoring in a monitoring step the state of the system, wherein the fluid flowing step and the monitoring step are carried out in parallel,■ starting in a timer starting step a timer at the initial stop time tt, if in the monitoring step a change of the system state from started to stopped has been monitored.

2. The method according to claim 1 , wherein the initial stop time t, is zero.

3. The method according to claims 1 or 2, wherein the value of the stop time threshold tt depends on the stability of the target molecule, preferably on the temperature of the fluid, the temperature of the environment, and / or extractables leaching into the fluid.

4. The method according to any of the preceding claims 1 to 3, wherein the fluid flowing step comprises at least one step of filtering the fluid between the source and the sinks.

5. The method according to any of the preceding claims 1 to 4, wherein in the monitoring step the state of the system is determined by the flow rate of the fluid,by the rotational speed of a pump, or by an external signal, wherein the external signal is preferably selected from a user input or an input from a controlling device.

6. The method according to any of the preceding claims 1 to 5, wherein the fluid purging step comprises the step of activating a purging force and / or the step of activating a purge fluid sink.

7. The method according to claim 6, wherein the step of activating pressure comprises activating a pump.

8. The method according to claims 6 or 7, wherein the step of activating a purge fluid sink comprises the step of opening a flow path to a purge fluid container.

9. A system for aseptically distributing a fluid comprising a target molecule, wherein the system comprises: a source (1) of the fluid comprising a target molecule, at least one sink (2) for the fluid comprising the target molecule, a distribution device (3) for distributing the fluid comprising the target molecule into the at least one sink (2), wherein the distribution device (3) comprises an inlet fluidly (4) connected to the source (1) by a feeding line (5) and at least one outlet (6), wherein each of the at least one outlet (6) is fluidly connected by a distribution line (7) to one of the at least one sink (2), a pump (8) positioned at the feeding line (5), a controlling unit (9), a state detection device (10) for detecting the state of the system, the state detection device (10) being in communication with the controlling unit (9), a timer (11), the timer (11) being in communication with the controlling unit (9), a fluid purging device (12), the fluid purging device (12) being in communication with the controlling unit (9), wherein the timer (11) is responsive to the state detection device (10) via the controlling unit (9), and wherein the fluid purging device (12) is responsive to the timer (11) via the controlling unit (9).

10. The system according to claim 9, wherein the at least one sink (2) comprises at least two sinks and / or the at least one outlet (6) comprises at least two outlets.11 . The system according to claims 9 or 10, wherein the feeding line (5) comprises at least one filter (13) positioned between the pump (8) and the distribution device (3), preferably positioned between the pump (8) and the purging device (12).

12. The system according to any of the preceding claims 9 to 11 , wherein the purging device (12) comprises a purge container (14) fluidly connected by a purge line (15) to a purge deviation (16) in the feeding line (5) at a position between the pump (8) and the distribution device (3).

13. The system according to any of the preceding claims 9 to 12, wherein the purge line (15) comprises a valve, wherein the valve (17) is in communication with the controlling unit (9) and wherein the valve (17) is responsive to the timer (11) via the controlling unit (9).

14. The system according to any of the preceding claims 9 to 13, wherein the purging device (12) comprises a force applying device (18) for applying a force on the fluid in the distribution device (3), wherein the force applying device (18) is preferably selected from a pump in the purge line (15) or a pump in the feeding line (5) between the purge deviation (16) or valve (17) and the inlet of the distribution device (4).

15. The system according to any of the preceding claims 9 to 14, wherein the controlling unit (9) is suitable for carrying out a method according to any of the preceding claim 1 to 8

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