METHOD AND DEVICE FOR TRANSFERRING A SUBSTANCE BETWEEN CLOSED SYSTEMS
The invention relates to a method and to a device for transferring a substance between closed systems (G1 G/Z, Z, G+G/Z), which prior to the transfer are connected in a sterile manner and can be disconnected from each other in a sterile manner, and wherein means for transferring the substance are provided. The goal is to enable a contamination-free transfer of the substance without gas inclusions between closed systems. This is achieved with respect to the method in that the pressure differences occurring during the transfer of the substance are compensated for within the system. This is achieved with respect to the device in that a pressure compensating unit (1) is provided, which has a sterile flow connection to at least one system (G, G/Z, Z, G+G/Z).
The invention concerns a method for transfer of a substance between closed systems, in which the closed systems, namely at least one source system and at least one target system are at least simply connected in sterile fashion before transfer, in which case the substance enters the target system and, after transfer of the substance, the target system and the source system can be separated from each other in sterile fashion.
The present invention also concerns a device for transfer of a substance between closed systems, especially for performance of the method in which the systems can be connected in sterile fashion to each other and can be separated in sterile fashion from each other and have means to transfer the substance.
Operating free of contamination in closed systems under conditions of cleanroom technology is known per se in many areas of technology, especially medical technology. A system is considered closed, if it at least cannot exchange matter with the surroundings.
There is often the requirement precisely in medical technology to introduce matter into the closed system so that any contamination is ruled out and processing or investigation can occur there. This includes for example preparations of cell populations, their cryopreservation and removal of samples for laboratory studies from these preparations, while guaranteeing a closed state of the system.
Sterile connection techniques like “sterile docking” and “sterile welding” are already known from the U.S. Pat. No. 6,022,344 with which thermoplastic tubes of two closed systems could be connected in sterile fashion to each other and also separated in sterile fashion again. “DOCKING” involves the making of cuts under the influence of temperature and direct sealing of both ends of two plastic tubes. “WELDING” involves separation of the connection with compression under temperature to form a homogeneous cross-sectional surface and cutting so that two closed interfaces are formed. Sterile connection, however, can also be produced independently of the aforementioned connection techniques, like sterile docking and sterile welding by mounting and sealing plastic vessels and tubes under cleanroom conditions and sterilization measures in known fashion.
Removal of substance under a sterile bench in the clean room by means of syringes is also known from practice, which has shortcomings because a closed state of the system is abandoned.
A specific application from matter or substance that is to be introduced to the closed system pertains to stem cells, which are recovered from patient blood during apheresis treatment. Before a cancer patient is subjected to chemotherapy, stem cells are taken from him. Only then does the patient receive chemotherapy. Since stem cells are broken down during this chemotherapy, the removed stem cells are later supplied to the patient.
Apheresis treatment proceeds by taking blood from the patient and transferring it in a closed system. Centrifugal forces act in the closed system during which the blood is broken down into components. Cell populations that contain stem cells are separated to initially secure them. The remaining blood is returned directly to the patient. The separated cell populations, depending on their purpose, are provided with additives, for example, for the patient's own plasma and foreign plasma.
This substance present as a cell suspension must be made storable in order to be later supplied to the patient. Making it storable can only occur using the chemical compound dimethyl sulfoxide, subsequently called DMSO, in a freezing bag for cryopreservation. The chemical compound DMSO serves to concentrate the cell fluid in the preparation in order to compensate for differences there between different osmotic pressures. The stem cell substance is protected from destruction/bursting of the cells by this. The freezing bag consists of ethylene vinyl acetate, a plastic which is also abbreviated EVA.
While the stem cell preparation can be further treated under sterile conditions, addition of the chemical compound DMSO represents the weak link with respect to maintaining a closed system. Even addition of DMSO through a filter, as is known from DE 101 24 487 A, cannot prevent contaminants, like viruses or toxic gases, from entering the closed system. Because of its aggressiveness relative to plastics DMSO also cannot be positioned in the bag system by the producer and subjected there to sterilizing pretreatment. Storage of the chemical compound DMSO in any case must be conducted over the long term in chemically inert vessels, for example, made of borosilicate glass with a solvent-resistant closure.
DE 101 51 343 A1 deals with a bag system for cryopreservation of body fluids. There the substance is transferred to another closed system from a glass ampule, which is situated within a closed system. Transfer occurs via a sterile connection, which is accomplished before transfer during production of a closed system. After transfer, sterile separation occurs with disposal of the emptied source systems filled beforehand under sterile conditions. A shortcoming in this bag system with respect to transfer is that volume-precise metering is not possible and air inclusions cannot be avoided in defined fashion within the substance being transferred but depend on the skill of the person handling the flexible bag. Air inclusions in the substance cannot be ruled out and can adversely influence the effects and results of later applications, for example, mixing processes. Continuity of transfer is also not guaranteed. A further shortcoming is that the only solution to compensate pressure differences in the system is seen in releasing excess air via filters into the surroundings. As already stated in conjunction with DE 101 24 487 A1, however, even a filter cannot prevent contaminants like viruses or toxic gases from entering the closed system.
Starting from the already known prior art the underlying task of the invention is to provide a method and device in which contamination-free transfer of the substance is made possible without gas inclusions between closed systems.
The aforementioned task is solved with reference to the method by the features of claim 1. The method of the type in question is characterized by the fact that pressure differences occurring during transfer of the substance are compensated within the system.
The aforementioned task is solved with respect to the device by the features of claim 8. A device of the type in question is characterized by the fact that a pressure compensation device is provided which is in sterile flow connection with at least one system.
Starting from DE 101 51 343 A1, it was initially known relative to the method that compensation of pressure differences there occurs by discharging air from the bag system into the environment, in which case it is tolerated that contaminated surrounding air enters the closed system, despite filters. It was recognized according to the invention that the sterility of the closed system need not be abandoned in any way when the pressure differences are compensated exclusively within the system. This finding is implemented by means of the device according to the invention in that a pressure compensation device is provided which is in sterile flow connection with at least one system. In other words: displaced air advantageously is not released to the surrounding air but trapped in a pressure compensation device and available there in conjunction with substance removal processes so that no vacuum is formed. The device according to the invention can be used as a disposable article at the location of preparation, for example, in the blood bank or transplantation laboratory. Standardized industrially produced disposable articles according to the invention enormously expand sterile work and widen the use possibility of substances.
Pressure compensation can occur anywhere volume changes of the substance occur. Generally this could occur both in the source system and in the target system. In one application in which the source system consists merely of a sterile, sheathed ampule with transfer device that can be connected in sterile fashion, pressure compensation could also be fully switched to the target system and the partial vacuum developing in the source system tolerated, since the empty ampule after sterile separation from the target system is disposed of.
Implementation of volume-precise transfer of the substance is of essential importance to the invention, since this achieves a situation in which the substance is transferred in metered fashion. This includes semiquantitative metering processes or metering with calibrated metering devices.
In principle, the substance could be actively transferred from the source system to the target system or actively removed from the source system. With respect to desired metering, calibrated syringes or carpules could then be used. As an alternative, the substance could reach the target system under the influence of gravity. Metering could occur here via a calibrated drip chamber. Transfer devices, like syringes, carpules, drip chambers, could in turn form closed systems or be components of closed systems.
In implementation of the method the source system could be connected to several different target systems. Multiple connection of the source system to one or more target systems could be possible in succession or simultaneously. Partial amount transfer of the substance is made possible by this.
During the method it could happen that the target system becomes the source system when the received substance is conveyed to another target system. This could either happen after a first sterile connection and separation or the device is set up so that a function change occurs by opening and closing of metering valves. A metering valve between the source and target system initially opened to receive the substance is closed after filling of the target system. If substance is transferred to another target system from the filled target system by opening another metering valve, the filled target system now has a source function.
In a source system that is marketed in the form of a blister package and then directly available for use the substance could preferably be introduced under sterile conditions to the source system under cleanroom conditions, which is then closed in sterile fashion to form a blister package. In a simple practical example a container could be filled in the plant under cleanroom conditions and closed, then go to the laboratory physician who produces sterile connection to a target system and can thus transfer the prepared substance. A differently configured but likewise simple practical example proposes to produce a container at the plant without substance, which contain means to transfer the substance—here to remove it from a source system available in the laboratory or delivered at the same time.
According to a preferred variant of the device according to the invention, the closed system, which can be a source system, a target system or also a system with source and target function, could have a container for the substance. The container separates the surroundings from the internal space of the closed system in which the substance could already be contained. The pressure compensation device could be bonded to the container and be present as a rubber bag. The connector of the pressure compensation device could be welded into the container so that the closed state of the system is not interrupted. As an alternative, the pressure compensation device could also be an integral component of the container via a special shaping method.
The means for transfer of the substance could include at least one connector for sterile connection to at least one connection of another closed system. The connector could be designed as a thermoplastic tube. Like the pressure compensation device, the connector to the container of the system could also be bonded in sterile fashion. The connector or plastic tube could have a length that permits repeated sterile connection and separation. Going further, several connectors or plastic tubes could be provided for multiple connection to another closed system or several other closed systems.
In terms of design, the container of a device according to the invention could include a base plate. This base plate could consist of a rigid plastic and have holding devices and/or connection sites that concern the connection. In order for the objects contained in the container to be examinable, the container could be transparent at least in the flexible areas of the wall. Transparency, for example, permits metered substance removal or filling and in a special practical example positioning or mounting of the transfer device within the container. Otherwise, at least a view of the amount of substance available is furnished by transparency. In addition, the container could also have a cover plate. The flexible wall, especially the bellows, or also an enclosure could extend between the cover plate and base plate. A stabilization element could be arranged on the bottom of the cover plate, which contributes to fastening of a receptacle for the substance arranged within the container during transport. The holding devices could be assigned to the base plate and/or cover plate and also have the function of spacers or stabilizers in addition to the holding function.
A particularly easy-to-handle variant of the at least partially flexible container consists of designing the flexible wall in the form of a bellows. This bellows could be strongly deformed in all directions based on an extremely tear-proof thin material, which could also be stretchable. This deformation is reversible. Because of the limited material thickness objects situated in the interior of the container could be grasped, joined to each other or positioned or otherwise manipulated. For the gripping movement it is particularly important that the wall include at least two opposite flexible areas. With respect to production of the container the bellows could be welded or glued in sealed fashion to the base plate and cover plate.
A further variant of the device according to the invention proposes sterile connection of the closed systems already at the plant. In particular, this concerns the combination of a source system and a source and target system into an overall system. Specifically, the source system could be connected in sterile fashion to a closed source and target system in the sense of a metering device and form an overall system. It is understood that an overall system can also contain more than two closed systems. The possibility exists after emptying of the source system to separate this in sterile fashion and dispose of it or to use it elsewhere for partial amount removal. Successive separation can occur in any system with a source function, if the previous source system is completely emptied or emptied as desired.
Gravity-operated devices according to the invention without metering function are generally pure source systems. The substance is transferred to the other closed system from the source system under the influence of gravity. The source system could then have a container in which the substance is contained and whose connection in the operating position points toward the floor.
According to a first very simple practical example of the device according to the invention the container itself could form the receptacle for the substance and be present, for example, as a collapsible, flexible bag. This practical example permits cost-effective production and storage of substances, like preparation solutions, at the location of use, while maintaining a closed condition of the systems.
In the first practical example the connection could open into the container, on the one hand, especially extend minimally into the substance and be provided there with a reclosable closure. On the other hand, the connection could emerge from the container and be welded with its free end in sterile fashion to the other system or already be welded.
Reclosability of the end of the connection extending into the substance permits partial removal of substances, like preparation solutions, naturally heeding sterile connection and disconnection. Formation of the closure as a snap closure made of sealing material, which is equipped with fastening bridges and can be operated through the flexible wall of the container, is of special significance for the first practical example. The fastening bridge serves for nonclosability of the closure. The closure ensures that the substance does not reach the connection before sterile connection has occurred and is possibly contaminated. The material of the container present as a bag is soft, but strong enough not to be damaged during manipulation of the closure.
In terms of design, the container could also include in its bag form a base plate through which the connection is passed through in sealed fashion. A pressure compensation device can be arranged so that it opens into the area of the container filled with air or inert gas, which always points up in the operating position.
According to the simple and particularly cost-effective modification of the first practical example of the device according to the invention, a metering valve that could be advantageously operated from the outside could be provided so that at least estimated partial amounts can be removed.
A variant of the first practical example suitable for volume-precise transfer consists of the fact that the source system present there as a bag is already connected in a sterile fashion at the plant to a source/target system in the form of a calibrated drip chamber and forms an overall system. In this way the metering device is contained in the overall system as an intrinsic closed system which is also gravity-operated. Here again a metering valve can be assigned to the source system. An overall system that also contains additional closed systems in addition to the source system and the metering device with combined source and target function is also conceivable. In each case, however, sterile connection at the plant between the systems applies in each case as a method step prior to substance transfer.
The container in larger package sizes could have a volume between 30 mL and 1000 mL. With small amounts so-called “minibags” reach a volume between 10 mL and 30 mL. These “minibags” are prescribed for individual use and can each contain the maximum required amount of substance for the intended preparation.
A special second practical example of the device according to the invention consists of the fact that it is formed as a gravity-operated metering device. For this purpose at least two connections can be provided for the system, which include an inlet and an outlet pointing toward the floor in the operating position. A calibrated drip chamber can be provided as container of the system, in which the substance is at least temporarily contained. The substance is fed via the inlet from a source system and discharge through the outlet to a target system. A metering valve can be assigned to the inlet and/or outlet. For the closed condition of the system it is important that the inlet and outlet are arranged sealed on the drip chamber. For example, the drip chamber could include a base plate, cover plate and transparent plastic jacket between the cover and base plate. With this container design the connector of the pressure compensation device, especially via the cover plate, could open in sealed fashion into the drip chamber.
The calibrated drip chamber with the two connectors that can be connected in sterile fashion in the second practical example forms a closed system in the sense of the gravity-operated metering device, which is both a source and target system. The thing to do is have the source system for the aforementioned gravity-operated metering device also release the substance by gravity into the calibrated drip chamber after sterile connection of the connectors. The amount of substance arriving from the source system could be regulated via the metering valve with the inlet.
A third practical example of the device according to the invention, which is also based on the gravity principle, proposes to arrange a receptacle in the form of a bottle or ampule in the container of the source system, within which the substance is situated and whose closure points toward the floor in the operating position. According to a preferred design the receptacle could be fastened to a cover plate in the container. An eye could be provided on the outside of the cover plate so the container can be suspended like a drop. The connector could be welded into the base plate opposite the cover plate.
In the third practical example in question the means for transfer of the substance could include a short cannula for outlet of the substance, especially a liquid, and a long cannula for air or inert gas supply. The cannulas could puncture the closure of a receptacle in the operating position and extend into the receptacle.
In a simple variant of the third practical example only the short cannula could be in a flow connection with the sterile-connectable connector in the operating position. A connection piece connected to the short cannula could then extend in the form of a plastic tube into a plastic tube of the connector that is larger in terms of cross section. The connector is welded onto the base plate of the container and plastic tube connected to the short cannula passes through a passage opening in the base plate in sealed fashion. The long cannula opens into the container equipped with a bellows to which the pressure compensation device is connected. In the rest position a bellows is deployed and accommodates the two cannulas. The cannulas are prevented from puncturing the closure of the receptacle by a holding device. The shaping of the receptacle can be utilized to fix the holding device and the holding device can also be supported on the base plate. The holding device according to a preferred design variant that is particularly easy to handle could be present in the form of a flexible slit sleeve. As long as the cannulas are not in use, they are arranged in the holding device which protects the flexible wall of the container, bellows from puncturing. The sleeve is supported in the rest state, on the one hand, against the base plate of the container and on the other hand against the shoulders of the receptacle. In the operating position the sleeve is manipulated from the outside via the bellows, positioned around the ampule barrel and the cannulas puncture the closure. The bellows of the container is then collapsed.
In this variant the volume of the receptacle could be predetermined so that the removed amount can be estimated. The arrangement of a metering valve on a connection improves volume- and time-precise metering of the amount intended for the other closed system.
A somewhat more demanding variant of the third practical example with more precise metering capability proposes that the container include a calibrated drip chamber. This drip chamber could be directly welded to the base plate of the container and with appropriate sealing and sterility of all connectors and connection pieces be a component of the source system. Both cannulas (both long and short cannulas) are in flow connection with the drip chamber via connection pieces. The short cannula within the container could be assigned a metering valve which can be operated via the bellows of the container. The connector for connection to another system can start from the calibrated drip chamber, which expediently points toward the floor in the operating position.
As an alternative to a welded-on drip chamber, however, an overall system prepared sterile at the plant could also be formed, consisting of a source system and metering device in the sense of a combination of a source and target system. The large cannula could then also open directly into the pressure compensation device. In this alternative only one pressure compensation device is advantageously provided, which ensures pressure compensation in the container and in the receptacle of the source system, as well as in the calibrated drip chamber of the target and source system—in short, in all components of the closed overall system.
Finally, there is also the possibility of connecting the connector of the source system according to the third practical example subsequently in sterile fashion to a gravity-operated metering device according to the second practical example. Here again the source system could be assigned a metering valve.
As an alternative to a gravity-operated device according to the invention according to the first three practical examples, the fourth practical example deals with a variety of uses of a calibrated syringe with an ampule plunger and ampule barrel as means for active metered transfer of the substance.
Force application can occur manually by the user. However, the syringe can also be introduced into an electric motor pump system known per se, in which metering can be programmed precisely in terms of time and volume.
On the one hand, the syringe could be filled within a container from a receptacle containing the substance or on the other hand the ampule barrel of the syringe could already be filled with substance or finally be filled by filling the syringe with substance from another source system. The ampule barrel of the syringe simultaneously forms a generally temporary receptacle for the substance, since transfer occurs via the syringe. The syringe could be operated from the outside via the at least partially flexible wall of the container, especially via its bellows.
The system including the syringe could have superimposed source and target function, if filling with substance and delivery of substance occur in the same system.
According to one variant of the fourth practical example the syringe could be arranged within the container and be operable from the outside via an at least partially flexible wall of the container, especially via its bellows. In addition to the syringe, a cannula could also be contained, which can also be handled via the bellows. The syringe would be initially packed with the cannula. The stopper of the receptacle would then be punctured and the syringe filled, i.e., filled with substance within the system. The cannula would then be removed and the filled syringe connected to the connector oriented toward the target system with a connection piece in the form of a tubular connector. Finally, the ampule plunger would be forced into the ampule barrel so that the substance flows into the connector and into the target system connected in sterile fashion.
The connection piece could also be present in the form of an internal line. The internal line in the rest state could extend through a passage opening of the container into the connector and be wound in a spiral within the container. The internal line then initially extends into the plastic tube only far enough so that it can be connected without hindrance to the connector of the other closed system. The internal line could have a smaller cross section than the connection with a plastic tube of the connection leading to the other closed system and consist of a rigid, flexible material with a sliding surface. Polypropylene, for example, could be considered as material. The free end of the internal line extending into the container could be connected to the syringe in order to be operated.
This variant with internal line permits precise positioning of the free end of the internal line in the other system and can serve both to deliver the substance and to receive the substance. Advance of the internal line through the connector connected in sterile fashion to a specific withdrawal site in the other closed system could be accomplished via the flexible wall of the container. In the case of substance removal the removed substance could be blood or umbilical cord samples that are to be furnished to the laboratory. The status of the preparation and its compatibility for the patient must be determined in the laboratory. Via the syringe on the internal line the sample is removed from the other system and introduced in the first sterile system to the receptacle, here via the suction and ejection movements of the syringe through a cannula and the stopper of a preferably evacuated ampule. After “retrieval” of the internal line via the bellows into the first system, separation of the withdrawal system can be carried out. During transfer of a substance situated in the receptacle of the container into the other closed system the connection between the syringe and cannula is initially produced, the substance taken up with it, the cannula then removed and the syringe connected to the internal line, whose free end was already positioned in the target system. The substance is conveyed through the internal line to the destination with the plunger movement. After transfer, the internal line is retracted into the first system via the connected plastic tubes of both systems and the systems are separated in sterile fashion.
As already mentioned, the ampule barrel of a syringe according to another modification of the first practical example of the device according to the invention could simultaneously form the receptacle for the substance, the ampule barrel according to another variant of the fourth practical example could then be positioned in a holding device on the base plate and have a connection in the form of a plastic tube, which passes through the base plate in sealed fashion and serves for sterile connection to another system. The ampule barrel could already be filled in advance with the substance in this case.
Another modification of the fourth practical example of the device according to the invention proposes to provide the ampule barrel with a cannula with a cannula closure, which can be opened and closed via the flexible wall of the container. More rapid emptying and filling of the pressure compensation device is achieved according to the variable gas volume in the container, if the container includes two chambers with two connection pieces for preferably one pressure compensation device or also two smaller separate pressure compensation devices. The first chamber could then contain the ampule plunger and the second chamber could contain the ampule barrel with the cannula and the closure. Deviating from other practical examples in which the connector is welded into a base plate, here the second chamber of the container could itself form the connector for sterile connection to the connector of another closed system on the end facing away from the first chamber for the ampule plunger.
The other closed system, here the source system, could be present in the practical example in question in the form of an ampule containing the substance. This ampule could in turn have a plastic enclosure with a connector for sterile connection of the connection of the container or second chamber, in short the connector of the first closed system. The enclosed ampule with a connector connectable in sterile fashion in itself forms a closed system and with respect to aggressive substances could consist of borosilicate glass and be equipped with an elastomer puncture stopper. Finally, the cannula of the device according to the invention is moved through the connections to the ampule, the ampule plunger is forced into the ampule barrel and air or inert gas is injected into the ampule after puncturing of the elastomer stopper. The ampule contents are then under pressure and fine metering is then possible during removal of the substance. The ampule plunger is now withdrawn from the ampule barrel during drawing in of the substance and the two systems are separated in sterile fashion. The now filled closed system is available as source system for sterile connection again to a target system.
In another variant of the fourth practical example the ampule plunger and the ampule barrel could be in a flow connection. The ampule barrel can have a connector that can be connected in sterile fashion to another closed source system. In addition, a metering valve could be provided. The connector could be present as a plastic tube that extends into the ampule plunger. The ampule barrel could have a connection that can be connected in sterile fashion in a closed target system away from the ampule plunger, which is also provided with a metering valve.
To draw in substance from the source system the connection of the ampule barrel is closed, that of the ampule plunger opened and the latter moved out of the ampule barrel. The substance then flows from the source system into the target system, which is represented in this situation by the syringe. To convey the drawn-in substance to the target system, the metering valve is closed on the side of the ampule plunger and opened on the side of the ampule barrel. The ampule plunger is introduced to the ampule barrel and the substance thus transferred to the target system. In this situation the syringe is the source system. Another advantageous application is obtained, if the ampule barrel is from both directions to the mixing container or target system. This can be done, if filling occurs only partially via the ampule plunger, i.e., the ampule plunger is not placed in the maximum introduction position. If the metering valve on the side of the ampule plunger is then closed and the metering valve on the side of the ampule barrel opened and the now only half introduced ampule plunger withdrawn, suction of substance occurs from the source system connected in a sterile fashion on the side of the ampule barrel. Two different substances are then situated proportionately in the syringe, which were transferred in sterile fashion from both directions and can then be introduced to another target system as a mixture. The device according to the invention just described represents a particularly elegant solution for laboratory work, which gets by without additional mixing containers on this account.
A special advantage in this variant of the fourth practical example is also the space-saving design of the container, which consists of a combination of an enclosure in the area of the ampule barrel and a bellows in the area of the ampule plunger. The device according to the invention because of this can be tightened better in a known syringe pump, since the container is reduced to a minimum. Advance of the substance is continuously guaranteed by the alternation of suction and ejection. The effective connection of the syringe to a syringe pump makes it possible to accomplish transfer of substance automatically at pre-established times.
A modification of the variant of the fourth practical example just described consists of the fact that an overall system is formed with a source system according to the second practical example. The source system here has a receptacle in the form of an ampule facing the floor with its opening in the operating state. During filling of the ampule plunger of the syringe, substance is drawn in from the source system and the ampule barrel filled. The syringe is the target system here. When substance is conveyed to another target system, the syringe is then the source system. The overall system could already be produced at the plant and the source and combined source/target system could be connected in sterile fashion via a connection piece that extends to the tip of the ampule plunger.
The overall system could also be formed by the fact that two source systems are connected to a syringe and substance is removed by means of the syringe, on the one hand, from a source system via the ampule plunger and, on the other hand, substance is removed from the other source system via the ampule barrel. Mixing could then occur in the syringe and the new substance could be transferred to another target system after sterile separation and reconnection.
Regardless of how the syringe is accommodated in the container in the closed system, the syringe together with the container could be incorporated in an ordinary syringe pump. Transfer of substance can therefore be accomplished automatically at pre-established times.
Another variant of the fourth practical example proposes the syringe again as mixing vessel. Substances are drawn into the ampule barrel from closed source systems via a multipath closure. This naturally does not occur to complete filling of the ampule barrel. After the substances (for example, plasma and a mixture of white blood cells and plasma) have entered the ampule barrel, this branch is closed and the branch that concerns introduction of DMSO is opened. Several DMSO-source systems can then be coupled and contain rupture ampules within sterile containers. The DMSO branch is also closed and a third branch opened, via which any air drawn into the system is released into the container that contains the syringe. Finally the third branch (corresponding to the pressure compensation device) is closed and a fourth branch of the multipath closure opened, to which at least one freezing bag or also several series-connected and separately closable freezing bags are connected in sterile fashion. The mixture is now ejected into the freezing bags by means of ampule plungers. The container in this variant is a foil enclosure dimensioned so that it has sufficient free volume for the system's gas/air. The generously dimensioned foil enclosure is provided here with reference to the mixing syringe and DMSO rupture ampules whose future openings point downward. If the rupture ampules are broken, natural separation of liquid and gas occurs since the liquid flows to the output of the container and any system gas/air rises upward into the free space of the container. The question of incorrect mixing of substances in system gas/air therefore does not come up in the container for the mixing syringe, since the gas, air escapes into the container via the pressure compensation branch. The pressure compensation device in this practical example is therefore not designed as a welded-on bag, but is achieved by dimensioning of the container and the arrangement of the substance outlet or via a branch of the pressure compensation opening into the container without adversely affecting the substance.
According to a fifth practical example the substance could be contained in a carpule or its carpule barrel, which is preferably calibrated. Carpule includes the carpule plunger movable in the carpule barrel. As in a variant according to the fourth practical example, the thing to do here is to construct the container from two chambers, one pressure compensation device being provided per chamber. A cannula can be provided in the first chamber, which faces the carpule barrel or its puncture stopper with its tip and extends with its opposite end into the connector. The connector could also be present here as a plastic tube that can be connected in sterile fashion, which is to be connected in a sterile fashion to the connector of another system, a target system.
The second chamber could consist of a cylindrical section and a bellows, in which case the carpule barrel is contained within a cylindrical section as well as part of the carpule plunger and the rest of the carpule plunger is contained within the bellows. This chamber and a coupling tube of the first chamber could be movable relative to each other and preferably fastenable in a predetermined position to each other with respect to performance of the puncture process. Transfer of substance occurs after a flow connection is made to the connector in that the carpule plunger displaces a sliding stopper within the carpule barrel. The carpule according to the fifth practical example permits batchwise and volume-precise delivery of substance from the carpule barrel of the first closed system into another closed system. The device according to the fifth practical example could be particularly useful as a disposable article.
A receptacle within a closed system, the source system, already containing a substance for transfer, is expediently closed after filling in order to prevent emergence of substance within the container. A closure is naturally provided that is easy to open and also can be closed. The closure in ampules, bottles or the carpule barrel could be in the form of a puncture stopper. The puncture stopper could consist of elastomer and preferably be teflon-coated. As an alternative to a receptacle in the form of evacuated supply vessel with puncture stopper, commercial sample vessels closable airtight with a screw closure or snap closure could also be used. Substance receptacles made of borosilicate glass are preferably used, which are suitable for aggressive substances that attack plastic. An aggressive substance could be, for example, dimethyl sulfoxide (DMSO), which is to be transferred into another system that contains the stem cells of a patient for their storage. This practical example is especially significant with respect to storage stability of the substance DMSO of two years in the borosilicate glass receptacle. A connection consisting of PVC is only briefly contacted during transfer of DMSO so that the dissolution processes are not set in motion. By sterile connection of the connections of both systems the DMSO enters the other closed system, which is present for example in the form of a freezing bag with a stem cell preparation. Apart from DMSO, another substance can also be contained in the receptacle which is incompatible with another component. Closed systems that are pure target systems could be tube and bag systems.
With respect to the fourth and fifth practical example the connector of a system with source function could be connectable in sterile fashion to another closed system, which contains an internal line. The internal line could be manipulated via the bellows of the container and permits precise positioning in another target system. The cross section of the internal line is smaller than that of the connector of the source and target system.
With respect to the sterility of the device desired form the outset, its components before connection could be arranged with the other closed system within a sterile package. A blister package is preferably prepared. The package could also have a smooth surface without undercuts or recesses so that disinfection and introduction to the clean room is facilitated. Disinfection could occur with 70% ethanol so that the requirements for introduction of the package into cleanroom areas are met. Additional evacuation of the package is also possible. Pyrogen freedom of the package could also be produced and it could be gamma-sterilized.
A particular advantage of the device according to the invention lies in the fact that inexpensive receptacles, like ampules, bottles, syringes, carpules and connections which are otherwise used in open systems can be applied to fully closed systems. This is possible because the arrangement of the inexpensive source systems can occur in a closed system in a corresponding container or plastic enclosure, which can interact with the other closed systems. Inexpensive source systems could therefore be used in a device according to the invention and made accessible to medical and scientific work. In principle, storage of any substance for complex preparation steps within a receptacle in a closed system is desirable.
There are different possibilities of configuring and modifying the instructions of the present invention advantageously. For this purpose the patent claims, on the one hand, and the following application of several practical examples in addition to variance of the device, on the other hand, are referred to by means of the drawing. In conjunction with the explanation of the mentioned practical examples of the invention preferred embodiments and modifications of the instructions are also generally explained. In the drawing
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According to the invention a pressure compensation device 1 is provided, which is in sterile flow connection with at least one system G, G/Z, Z, G+G/Z. In the present five practical examples with all their variants the pressure compensation device 1 is bonded, namely welded to system G, G/Z, Z, G+G/Z.
The means to transfer substance includes at least one connector 2 for sterile connections with at least one additional system G, G/Z, Z, G+G/Z. Generally the connectors 2 are formed as thermoplastic tubes.
In all practical examples a container 3 is provided to form system G, G/Z, Z and the connector 2 is welded in sterile fashion to container 3 of system G, G/Z, Z.
Depending on the variant, the container 3 has a base plate 4 and/or cover plate 5 and/or at least one holding device 6.
It is shown in
The first practical example of a very simple design of the device according to the invention according to
In both variants of the first practical example the connector 2 extends slightly with one end in sealed fashion through the base plate 4 in container 3 into the substance and is provided there with a reclosable snap closure 8. The snap closure 8 consists of a sealing material, is equipped with a fastening bridge 9 and can be operated through the flexible wall of the container 3. The connector 2 has a metering valve 13. The connector 2 in
The device according to the invention according to the variant depicted in
In the second practical example according to
A device according to
The components of a device according to the invention according to all practical examples are arranged with a sterilized blister package 16 before sterile connection to another closed system G, G/Z, Z, which is shown as an example in
The variant depicted in
Another variant of the device with four inlets 10 is shown in
Finally a fourth variant of the second practical example of the device according to the invention is shown in
The third practical example of the device according to the invention is depicted in
The variant of the third practical example depicted in
The device depicted in
-
- sterile connection of connector 2 of the closed source system G to the connector 2 of target system Z,
- removal of a stabilizer (not shown here),
- compression of the bellows 7 and puncturing of the puncture stopper 20 with both cannulas 18, 19, filling of the pressure compensation device 1 with the air displaced from container 3,
- introduction of the substance through the short cannula 18 into connector 2,
- regulation of transfer of substance of source system G via metering valve 13.
A somewhat more demanding variant of the third practical example is depicted in
Another variant of the third practical example of the device according to the invention shows in
One difference is that an overall system G+G/Z is prescribed there, which consists of a source system G and a combined source/target system G/Z as shown in
Another difference is that the holding device 6 is designed in the form of a slotted sleeve, which is supported in the rest position in
The container 3 as in
According to the variants of the four practical examples depicted in
A stabilizer 22 is provide in the container 3 according to
The device depicted in
-
- connection of the ampule barrel 26 of the syringe to cannula 28—here via a Luer lock connection,
- puncturing of the puncture stopper 20 of receptacle 17 and introduction of the cannula 28 into the substance,
- suction of the substance into the ampule barrel 26 by extension of the ampule plunger 25,
- loosening of the cannula 28 and positioning in the protective device 23 in the holding device 6,
- as shown in
FIG. 8B , connection of the ampule barrel 26 to the connection piece 15—here via a Luer lock connection, - tightening of the syringe in an syringe pump 29,
- transfer of the substance from the ampule barrel 26 into the connection piece 15, connector 2 and finally into system Z by introducing ampule plunger 25 into ampule barrel 26,
- sterile disconnection of the systems G and Z after transfer.
In
-
- connection of the ampule barrel 26 to the internal line 27—here via a Luer lock connection,
- suction of the substance from system G into the ampule barrel 26 by retracting the ampule plunger 25 and filling the syringe,
- loosening of the internal line 27 from the ampule barrel 26,
- connection of the ampule barrel 26 to cannula 28,
- puncturing of the puncture stopper 20 of receptacle 17 and introduction of the substance from the ampule barrel 26 into the receptacle 17 by introducing the ampule plunger 25 into ampule barrel 26,
- removal of the cannula 28 from the receptacle 17, loosening of the cannula 28 from the ampule barrel 26 and positioning in the protective device 23,
- withdrawal of the internal line 27 from system G, spiral winding and arrangement,
- sterile disconnection of systems G and Z after transfer,
- reuse of the filled receptacle 17 in the clean room.
The syringe depicted in
The variant of the fourth practical example of the device according to the invention depicted in
The other closed system G apparent from
-
- removal of the device from the blister package 16 shown in
FIG. 11A , - sterile connection of connector 2 of the closed system G/Z with connector 2 of the enclosed ampule of the closed system G and removal of the cannula closure 31 in
FIG. 11B , - in
FIG. 11C : puncture of the puncture stopper 20 of the ampule of system G, introduction of cannula 28 into the ampule of system G, - in
FIG. 11D : introduction of the ampule plunger 25 into ampule barrel 26 and introduction of air from the ampule barrel 26 into the ampule of system G containing the substance, in which case an overpressure is formed there so that fine metering of the substance is made possible during removal without a vacuum effect; on size reduction of chambers 32, 33 the pressure compensation device 1 is filled with air from chambers 32, 33, - in
FIG. 11E : beginning of suction of the substance from system G into the ampule barrel 26 by filling of the ampule plunger 25 from the ampule barrel 26, in which the system G/Z has a target function; on increasing size of chambers 32, 33 air enters them from the pressure compensation device 1, - in
FIG. 11F : suction of substance from system G into the ampule barrel 26 is completed, sterile disconnection of connector 2 of the closed system G/Z from the connector 2 of system G occurs, - in
FIG. 11G : readiness for sterile connection with another closed system Z in order to transfer the substance transferred from system G/Z, which now has a source function, into system Z.
- removal of the device from the blister package 16 shown in
In the other variant of the fourth practical example of the device according to the invention depicted in
For suction of substance from source system G the connector 2 on the ampule barrel 26 is closed, the one on ampule plunger 25 is opened and the latter moved out form the ampule barrel 26. The substance then flows from source system G into ampule barrel 26. The specially designed syringe here is a combination of source and target system G/Z. During filling the target function comes into play, during transfer to target system Z the source function does. To convey the substance drawn from system G into system G/Z into the target system Z the metering valve 13 is closed on the side of the ampule plunger and opened on the side of the ampule barrel. The ampule plunger 25 is introduced to the ampule barrel 26 and thus transfers the substance to system Z.
The connector 2 emerging from the ampule barrel 26 in
An overall system G+G/Z consisting of a closed source system G with the features of the source system according to
A fifth practical example of the device according to the invention according to
A sliding stopper 37 is movable over the carpule plunger 34. The carpule plunger 34 is arranged in the second chamber 33, which includes a bellows 7 and a cylindrical section in the form of a stable sleeve 38. The end of the carpule plunger 34 is glued to the cover plate 5 on which the bellows 7 is arranged. The bellows 7 then grades into the stable sleeve 38, which also accommodates the carpule barrel 35. An annular shoulder 40 facing radially inward is provided on the end of the sleeve 38 on the carpule barrel side, against which the carpule barrel 35 is supported. The sleeve 38 on the end of the carpule barrel 35 on the plunger side also has an annular shoulder 41 facing radially inward, which counteracts an axial movement of the carpule plunger 35. While the annular shoulder 40 is already molded onto sleeve 38, the annular shoulder 41 is formed by introducing a ring into sleeve 38 after introduction of the carpule barrel 35 into sleeve 38, which is welded to sleeve 38 and thus forms the annular shoulder 41.
The first chamber 32 is welded onto the annular shoulder 40 of sleeve 38. The chambers 32, 33 are in flow connection to the slightest degree but not sufficient to use only one pressure compensation device 1. In addition, the first chamber 32 has a coupling tube 39 and in it a bellows 7 welded onto the base plate 4. The coupling tube 39 overlaps the free end of the stable sleeve 38, both components are movable relative to each other and contain snap-in devices in the form of a recess 42 and protrusion 43 which engage in the operating position and fix the position of cannula 36 in carpule barrel 35.
The device present as a source system G already filled at the plant with substance according to the fifth practical example is operated as follows:
-
- sterile connection of connector 2 of the closed system G to the connector 2 also present as a plastic tube of the closed system Z,
- movement of the coupling tube 39 with bellows 7 and the cannula 36 of the first chamber 32 welded onto the base plate 4 onto the stable sleeve 38 of the second chamber 33 up to recess 40, in which case the cannula 36 punctures the puncture stopper 20 of the carpule barrel 35 filled with substance and is immersed in the substance and the protrusion 41 snaps into recess 40; the pressure compensation device 1 there is filled with air through the volume reduction of the first chamber 32,
- the bellows 7 of the second chamber 33 and the carpule plunger 34 are moved to the sliding stopper 37 and in this case the pressure compensation device 1 there is filled with air through the volume reduction of the second chamber 33,
- the sliding stopper 37 is pushed in the carpule barrel 35 in the direction of cannula 36 and substance displaced into cannula 36 and the desired amount of substance transferred to receptacle system Z;
- after substance transfer in the desired amount sterile disconnection of connector 2 of the closed system G occurs form the connector 2 of system Z.
With respect to further features not shown in the figures, the general part of the description is referred to. Finally, it is pointed out that the instructions according to the invention are not restricted to the practical examples just explained.
LIST OF REFERENCE NUMBERS
- 1 Pressure compensation device
- 2 Connector
- 3 Container
- 4 Base plate
- 5 Cover plate
- 6 Holding device
- 7 Bellows
- 8 Snap closure
- 9 Fastening bridge
- 10 Inlet
- 11 Outlet
- 12 Calibrated drip chamber
- 13 Metering valve
- 14 Cross connector/system connection
- 15 Connection piece
- 16 Blister package
- 17 Receptacle
- 18 Short cannula
- 19 Long cannula
- 20 Puncture stopper
- 21 Eye
- 22 Stabilizer
- 23 Protective device
- 24 Holding plate
- 25 Ampule plunger
- 26 Ampule barrel
- 27 Internal line
- 28 cannula
- 29 Syringe pump
- 30 Valve
- 31 Cannula closure
- 32 First chamber
- 33 Second chamber
- 34 Carpule plunger
- 35 Carpule barrel
- 36 Cannula
- 37 Sliding stopper
- 38 Cylindrical section, sleeve
- 39 Coupling tube
- 40 Annular shoulder
- 41 Annular shoulder
- 42 Recess
- 43 Protrusion
- G closed system/source system
- Z closed system/target system
- G/Z closed system with source and target function
- G+G/Z overall system consisting of G and G/Z
Claims
1.-58. (canceled)
59. A method for transfer of a substance between closed systems, said method comprising:
- providing closed systems, namely at least one source system and at least one target system, which are simply connected in sterile fashion before transfer, in which the substance reaches the target system and in which after transfer of the substance the target system and the source system can be separated from each other in sterile fashion, wherein pressure differences occurring during transfer of the substance are compensated within the system.
60. The method according to claim 59, wherein pressure compensation occurs where volume changes of the substance occur.
61. The method according to claim 59, wherein the substance is transferred in metered fashion.
62. The method according to claim 59, wherein the substance is transferred active from the source system, especially by a calibrated syringe or carpule, to the target system or wherein the substance is actively removed from the source system, especially by a calibrated syringe or that the substance reaches the target system under the influence of gravity.
63. The method according to claim 59, wherein the source system is connected in sterile fashion to several other source systems.
64. The method according to claim 59, wherein the target system becomes the source system when the received substance is conveyed to another target system.
65. The method according to claim 59, wherein the substance is introduced to the source system in sterile fashion under cleanroom conditions, which is closed in sterile fashion.
66. A device for transfer of a substance between closed systems, said device comprising:
- closed systems configured to be connected in sterile fashion to each other and configured to be separated in sterile fashion from each other and which have means for transfer of the substance, wherein a pressure compensation device is provided, which is in flow connection in sterile fashion to at least one system.
67. The device according to claim 66, wherein the pressure compensation device is bonded to one system.
68. The device according to claim 66, wherein the means for transfer includes at least one connector for sterile connection to at least one additional system.
69. The device according to claim 68, wherein a container is provided and wherein the connector is bonded in sterile fashion to the container of system.
70. The device according to claim 69, wherein the container includes a base plate or a cover plate or at least one holding device.
71. The device according to claim 69, wherein at least part of the wall of the container is designed flexible so that means to transfer the substance can be operated at least partially from outside via the flexible wall, especially via a bellows.
72. The device according to claim 66, wherein one system is a component of an overall system and a sterile connection also exists within the overall system.
73. The device according to claim 69, wherein the substance can be transferred from one system, especially under the influence of gravity, into the other closed system, the connector facing the floor in the operating position.
74. The device according to claim 73, wherein the connector of one system with one end opens into the container and preferably extends minimally into the substance and has a snap-in closure of sealing material with a fastening bridge which can be operated via the flexible wall of the container.
75. The device according to claim 73, wherein the container has a preferably collapsible bed with a volume between 30 mL and 1000 mL or 10 mL to 30 mL.
76. The device according to claim 66, wherein at least two connectors are provided, which include an inlet and an outlet facing the floor in the operating position.
77. The device according to claim 76, wherein a calibrated drip chamber is provided as container, in which the substance is at least temporarily contained.
78. The device according to claim 77, wherein the calibrated drip chamber forms a closed system with connectors in the sense of a gravity-operated metering device and is both source and target system.
79. The device according to claim 77, wherein the inlet and the outlet open in sealed fashion into the drip chamber.
80. The device according to claim 76, wherein a metering device is assigned to the connector.
81. The device according to claim 69, wherein a receptacle is contained in the container of the system in the form of a bottle or ampule within which the substance is situated and whose closure faces the floor in the operating position.
82. The device according to claim 81, wherein the means for transfer of the substance includes a short cannula for transfer of the substance, especially a liquid, and a long cannula for air or inert gas supply, in which the cannulas puncture the closure of the receptacle in the operating position and extend into the receptacle and in which the short cannula is in flow connection with the connection.
83. The device according to claim 82, wherein the long cannula opens into the container.
84. The device according to claim 82, wherein the short cannula and the long cannula in the rest position are arranged in a holding device in the form of a slotted sleeve, which is supported on one side against the base plate of the container, and against the receptacle on the other side and which encloses the receptacle in the operating position, whereas the cannulas puncture the closure of the receptacle.
85. The device according to claim 82, wherein the volume of the receptacle is predetermined so that the amount removed can be estimated and the closure preferably includes a metering valve.
86. The device according to claim 81, wherein the container includes a calibrated drip chamber into which at least a short cannula extends via a connection piece and on which the connection facing the floor in the operating position is provided.
87. The device according to claim 86, wherein the long cannula opens into the pressure compensation device, which ensures pressure compensation in container and in the receptacle as well as the calibrated drip chamber of the overall system.
88. The device according to claim 66, wherein the means to transfer substance includes at least one calibrated syringe with an ampule plunger and an ampule barrel.
89. The device according to claim 88, wherein the syringe is arranged within a container and can be operated from the outside via an at least partially flexible wall of the container especially via a bellows.
90. The device according to claim 88, wherein the ampule barrel simultaneously forms an at least temporary receptacle for the substance.
91. The device according to claim 88, wherein the system has an overlapping source and target function if filling with substance and release of substance occur in the same system.
92. The device according to claim 88, wherein a connection piece in flow connection with the connector is provided for connection to the syringe within the container.
93. The device according to claim 92, wherein the connection piece is present in the form of an internal line.
94. The device according to claim 90, wherein a receptacle with substance in the form of an ampule with a puncture stopper is provided in the container.
95. The device according to claim 88, wherein the ampule barrel includes a cannula with a cannula closure, which can be manipulated from the outside via the flexible wall of the container.
96. The device according to claim 95, wherein the container includes two chambers, both of which are in flow connection with the pressure compensation device.
97. The device according to claim 96, wherein the first chamber contains the ampule plunger and wherein the second chamber contains the ampule barrel with the cannula.
98. The device according to claim 96, wherein the second chamber of the container forms the connector for sterile connection to the connector of the source system or the connector of the target system on the end facing away from the first chamber.
99. The device according to claim 88, wherein the system has a container in the form of a plastic enclosure and that an ampule containing the substance is arranged within the plastic enclosure with a puncture stopper made of elastomer.
100. The device according to claim 88, wherein the ampule plunger is in flow connection with the ampule barrel.
101. The device according to claim 100, wherein the ampule plunger can be connected in sterile fashion to a closed system via a connector equipped with a metering valve and wherein the connection extends into the ampule plunger and opens from there into the ampule barrel.
102. The device according to claim 101, wherein the ampule barrel has a connector for sterile connection to a closed system equipped with a metering valve facing away from the ampule plunger.
103. The device according to claim 102, wherein for suction of substance from the closed system the metering valve adjacent to the ampule barrel is closed and the metering valve adjacent to the ampule plunger is opened.
104. The device according to claim 103, wherein for transfer of the substance drawn into the ampule barrel to the target system the metering valve adjacent to the ampule barrel is opened and the metering valve adjacent to the ampule plunger is closed.
105. The device according to claim 100, wherein the container includes a bellows in the area of the ampule plunger and wherein the bellows is connected in sealed fashion to the ampule barrel.
106. The device according to claim 100, wherein the closed system includes a short cannula for transfer of the substance, especially a liquid, and a long cannula for air or inert gas supply, in which the cannulas puncture the closure of the receptacle in the operating position and extend into the receptacle and in which the short cannula is in flow connection with the connection, and wherein the long cannula opens into the container.
107. The device according to claim 106, wherein the source system is in sterile connection with the ampule plunger via a connection piece of the short cannula and wherein the source system and the closed system comprising the syringe form an overall system.
108. The device according to claim 88, wherein the syringe can be tightened in a syringe pump so the transfer of substance can be accomplished automatically at pre-established times or over a determined period with precise volume.
109. The device according to claim 66, wherein the means for transfer of substance includes a carpule with a carpule plunger and a carpule barrel containing the substance.
110. The device according to claim 109, wherein the container includes two chambers.
111. The device according to claim 110, wherein the first chamber includes a cannula, which faces the carpule barrel with its tip and extends into the connector with its opposite end.
112. The device according to claim 110, wherein the second chamber comprises a cylindrical section and a bellows, in which the carpule barrel is contained within the cylindrical section as well as part of the carpule plunger and in which the rest of the carpule plunger is contained within the bellows.
113. The device according to claim 110, wherein the second chamber and a coupling tube of the first chamber are movable relative to each other and can preferably be fastened to each other in a predetermined position.
114. The device according to claim 66, wherein the connection is connected in sterile fashion to a closed system, which contains an internal line and wherein the system containing the internal line transfers the substance to the next closed system.
115. The device according to claim 66, wherein the components of the device or the closed system are arranged within a sterile package before sterile connection to the other closed system.
116. The device according to claim 115, wherein the package has a smooth surface on which a disinfectant, especially 70% ethanol, can be applied.
Type: Application
Filed: Jul 30, 2009
Publication Date: Aug 11, 2011
Inventor: Walter Pobitschka (Bad Homburg)
Application Number: 13/057,089
International Classification: B65B 1/04 (20060101);
