Abstract:
Methods for the sterile transfer of a solution are disclosed, including sterilizing the inlet to a connector by flowing a sterilizing fluid around the connector inlet, sterilizing a penetrating element for the connector by flowing a sterilizing solution around the penetrating element, and penetrating the sterilized inlet by the sterilized penetrating element in order to transfer the solution through the penetrating element on the connector. Apparatus for such sterile transfer of a solution is also provided.

Description:
This application is a continuation of U.S. application Ser. No. 08/793,349 filed Feb. 20, 1997, which is a 371 of PCT/SE95/00795 filed Jun. 28, 1995. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to a method and a connection unit for the sterile transfer of solution through a connector. 
     BACKGROUND OF THE INVENTION 
     The present invention is intended to be used in conjunction with an on-line sterilizing arrangement, such as described European Application No. 428,009. This application describes a continuous heat sterilizing arrangement in which a solution is heated during transport in a conduit to a high temperature, for example about 130° C., and is maintained at this temperature for a predetermined period in order to effect sterilization. Thereafter, the solution is cooled to the temperature at which it is to be used. The sterilization step takes place at a high pressure, which is achieved with a pump and throttle arrangement. 
     A heat exchanger is generally used in this system to provide the heat energy. The sterilization arrangement is used for sterilizing infusion solutions such as Ringer&#39;s solution, other medical solutions such as dialysis solutions, purified water to obtain sterilized water, or other such solutions. 
     The sterilizing arrangement according to European Application No. 428,009 is provided with a shunt conduit which in principle connects the inlet to the outlet so that the solution which is in the system can be circulated in a closed circuit. In this manner, the temperature of the circulating solution can be raised to, for example, 120° C. in order to sterilize the device itself. 
     The solution which has been sterilized with the above-described sterilizing arrangement can be used directly, for example in dialysis or infusion. In certain circumstances it is also desirable to transfer the sterilized solution to storage bags for later use, or for delivery to other departments within the hospital. For this purpose, disposable sets of tubes are available which terminate with a bag. 
     Normally, such bags are filled with a medical solution, whereafter the set of tubes is sealed and the disposable article is then sterilized in its entirety, i.e. with the medical solution within the bag. Such sterilizing can be effected with gamma-sterilization or by means of autoclaving. 
     Alternatively, the set of tubes can be provided with a medical solution after the set of tubes has been sterilized. In such cases, a sterile connector is normally used which comprises a membrane which is broken when used. Those parts which are connected together are sterile. With such a sterile connector, there is always the risk that bacteria which may reside on the outer side of the membrane are introduced with the connector device and contaminate the interior of the connector. 
     European Application No. 230,864 describes a sterile connection of two containers in which the connection takes place in a sterilized chamber which is maintained under aseptic conditions by means of a chemical disinfectant. Chemical disinfection, however, does not guarantee sterility, and at the same time the risk for bacteria contamination is still present. 
     SUMMARY OF THE INVENTION 
     In accordance with the present invention, these and other objects have now been realized by the invention of a method for the sterile transfer of a solution from a first location associated with a penetrating element to a second location through a connector having an inlet, the method comprising sterilizing the inlet of the connector by flowing a sterilizing solution around the inlet of the connector, sterilizing the penetrating element by flowing a sterilizing solution around the penetrating element, and penetrating the sterilized inlet by the sterilized penetrating element so as to transfer the solution from the first location to the second location through a connector. 
     In accordance with one embodiment of the method of the present invention, the sterilizing of the inlet of the connector and the sterilizing of the penetrating element both comprise heat sterilizing. Preferably, the heat sterilizing is carried out at a temperature of greater than about 120° C. Most preferably, the heat sterilizing is also carried out at a pressure of greater than about 2 atmospheres (absolute pressure). 
     In accordance with another embodiment of the method of the present invention, the sterilizing of the inlet of the connector and the sterilizing of the penetrating element are carried out simultaneously by use of the same sterilizing solution. In a preferred embodiment, the method includes maintaining the penetrating element and the inlet of the connector within a common bore, and circulating the sterilizing solution in a closed circuit including a heater for the sterilized solution. Most preferably, the method includes sterilizing the common bore and sealing at least a portion of the sterilized common bore with the inlet of the connector during the penetrating step. 
     In accordance with the apparatus of the present invention, apparatus is provided for the sterile transfer of a solution from a first location associated with an inlet to the apparatus to a second location through a connector having an inlet, the apparatus comprising a housing defining a bore in fluid communication with the inlet, the connector being insertable into the bore, a penetrating element disposed within the bore, recirculation means for recirculating a sterilizing solution around the penetrating element and the inlet of the connector located within the bore, and activation means for causing the penetrating element to penetrate the inlet of the connector within the bore whereby the solution can be transferred from the first location to the second location. 
     In accordance with one embodiment of the apparatus of the present invention, the apparatus includes sealing means for sealing a portion of the penetrating element and the inlet of the connector sterilized by the sterilizing solution. In a preferred embodiment, the sealing means also acts to seal the recirculation means when the activation means causes the penetrating element to penetrate the inlet of the connector, thereby creating a closed sterilized region. 
     In accordance with another embodiment of the apparatus of the present invention, the apparatus includes heating means for heating the sterilizing solution to a temperature of greater than about 120° C. In a preferred embodiment, the apparatus also includes pressure means for increasing the pressure of the sterilizing solution to a pressure of greater than about 2 atmospheres (absolute pressure). 
     In accordance with another embodiment of the apparatus of the present invention, the sealing means comprises a cover over the inlet of the connector, whereby the penetrating element penetrates the cover when the activation means causes the penetrating element to penetrate the inlet of the connector. 
     The object of the present invention is to provide both a method and a connection unit which permit sterile connection for transfer of a sterilized solution to a previously sterilized disposable set of tubes in a manner such that bacterial contamination is completely eliminated. The set of tubes can end with a connection bag, or may lead to an infusion device or a dialysis machine or other medical equipment. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The present invention is described in greater detail in the following detailed description, which includes reference to the embodiments of the invention shown in the drawings, in which: 
     FIG. 1 is a schematic representation of the sterilizing arrangement according to European Application No. 428,009; 
     FIG. 2 is a representation similar to that of FIG. 1, showing, however, the connection of a connecting unit according to the present invention therein; 
     FIG. 3 is a side, elevational, cross-sectional view of the connection unit of the present invention, in a stand-by position; 
     FIG. 4 is a side, elevational, cross-sectional view of a connector intended to be used in accordance with the present invention; 
     FIG. 5 is a top, plan view of the connector according to FIG. 4; 
     FIG. 6 is a side, elevational view similar to that of FIG. 3, showing the connection unit of the present invention in an open position for introduction of the connector according to FIG. 4 therein; 
     FIG. 7 is a side, elevational view similar to that of FIG. 6, showing the connection unit of the present invention with in situ connector in a sterilizing position; 
     FIG. 8 is a side, elevational view, similar to that of FIG. 6, showing the connection unit of the present invention in a filling position; 
     FIG. 9 is a side, elevational, cross-sectional view similar to that of FIG. 3, showing the connection unit of the present invention in another adaptation; 
     FIG. 10 is an enlarged, partial, side, cross-sectional view of a portion of the connection unit of the present invention according to an alternative embodiment threof; and 
     FIG. 11 is a side, elevational, partially cross-sectional view, similar to that of FIG. 3, showing a further adaptation of the connection unit of the present invention. 
    
    
     DETAILED DESCRIPTION 
     A sterilizing arrangement according to European Application No. 428,009 is shown in FIG. 1. A solution which is to be sterilized is introduced through inlet  5  and flows through a valve  12  to a pump  8 . The pump  8  increases the pressure of the solution and pumps the solution to a first heat exchanger  2 . 
     The solution passes across the primary side of the heat exchanger  2  and is fed to a heating arrangement  3 . The solution is transported from the heating arrangement  3  in a delay conduit  15  of a length such that the residence time permits sterilizing of the solution which has been heated by the heating arrangement  3 . 
     The solution is then fed from the conduit  15  to the heat exchanger  2  where the solution passes across the secondary side of the heat exchanger and heats the incoming solution on the primary side. 
     The solution is transported from the heat exchanger  2  to a second heat exchanger  6 , and passes across its primary side. A heating medium is provided on the secondary side of the heat exchanger  6 , which heating medium can be cold water if further cooling is required, and which flows from an inlet  10  to an outlet  11 . The solution flows from the heat exchanger  6  by means of a throttle arrangement  7  and a valve  13  to an outlet  9 . 
     A shunt conduit  14  is connected between the inlet  5  downstream of the valve  12  and the outlet  9  upstream of the valve  13 . The function of the shunt conduit  14  is to allow recirculation of the solution in the system without any new solution being introduced through the inlet  5  or removed by the outlet  9 . By shutting off the cooling means supply to the second heat exchanger  6 , the solution in the closed circulating system can be heated to a high temperature, for example 120° C., for sterilizing the system. 
     In addition, a bleed valve  4  is arranged downstream of the throttle valve  7  and upstream of the outlet valve  13 . 
     The connection unit  20  according to the present invention is arranged in cooperation with the shunt conduit  14  and shown in FIG.  2 . The connection unit has an inlet  21  for incoming solution from the throttle valve  7 , an outlet  23  for solution which is to be recirculated in the shunt conduit  14  and an outlet  22  for exiting sterile solution. 
     In FIG. 3, the connection unit  20  according to the present invention is shown in a stand-by position. The connections of the various conduits according to FIG. 2 are shown in FIG.  3 . Accordingly, there is an inlet  21  (positioned behind the unit  20  in FIG. 3) which is connected to the throttle valve  7  and the bleed valve  4 . In addition, there is an outlet  23  to the shunt conduit  14 . A piston  19  is shown in a closed position and closes the opening  22  which will be explained in greater detail below. 
     The inlet  21  opens into a cylindrical bore  25  through a tube  26  which is concentric with the bore  25  and which terminates with a penetration element in the form of a point  27 . Solution from the throttle valve  7  can thus be fed through the inlet conduit  24  to the inlet  21  and subsequently to the tube  26  and, through the point  27 , into the bore  25  and further through the outlet  23  to the shunt conduit  14 . 
     In FIG. 3, the bore  25  is sealed at its upper end by the piston  19  which cooperates with an O-ring seal  28  arranged in the side of the bore. 
     The operation in the stand-by position as shown in FIG. 3 thus permits the sterilizing arrangement according to European Application No. 428,009 to be used with recirculation according to the present invention. 
     When the connection unit  20  is to be used for filling of a disposable set of tubes, a connector  30  as shown in FIGS. 4 and 5 is used. FIG. 4 is a cross-sectional view taken through the connector. The connector consists of a cylinder  31  of a diameter such that it fits in the bore  25  and seals against the O-ring  28 . At the lower region of the cylinder  31  there is a reduced portion  32  on which a cover  33  is arranged. The cover  33  can be of rubber. In addition, the connector  30  has a semi-cylindrical-shaped engagement portion  34  of such dimension that the piston  19  fits therein. Finally, a connection portion  35  is provided to which a tube is connected. The tube leads to a container which is to be filled or some other suitable device, such as a dialysis machine. In FIG. 5, the connector  30  is seen from above. 
     The connection unit according to the present invention can be used to fill a container connected to the connector  30 . This takes place in the following manner (see FIGS.  6 - 8 ). Firstly, it is assured that the connecting unit is depressurized by means of opening the bleed valve  4 . Thereafter, the piston  19  is displaced by means of an activating device  36 , to the position shown in FIG.  6 . By means of this displacement of the activating device  36 , an opening  22  is revealed in the side of the connection unit which leads to a cavity  27 . The bore  35  opens into this cavity. Accordingly, the opening to the bore  25  is exposed. 
     The connector  30  is introduced through the opening  22  so that the lower region  32  is located immediately above the bore  25  and can be downwardly displaced into the bore  25  so that the cylinder  31  cooperates with the O-ring  28 . This position is shown in FIG.  7 . 
     The correct introduction of the connector into the bore  25  is facilitated by means of the engagement portion  34  cooperating with the piston  19  and snap fastening therewith during the insertion of the connector  30  through the opening  22 . Thereafter, the activating device is displaced downwardly to the position shown in FIG.  7 . 
     As is evident from FIG. 7, the connector  30  is only partially introduced into the bore  25 . The connector  30  is introduced into the bore  25  by a distance such that the O-ring  28  cooperates with the cylindrical surface of the connector  30  so that sealing of the bore  25  is achieved. At the same time, the connector  30  is so high up that the point  27  does not reach the cover  33  on the connector  30 . 
     The sterilizing arrangement according to FIG. 2 has a particular sterilizing position in which the solution is heated to a high temperature, for example 120° C. This is achieved by means of cold water no longer being supplied to the secondary side of the second heat exchanger  6 , and the heating arrangement  3  being operated so that the temperature in the recirculating system increases to 120° C. In this manner, the pressure in the entire circulation conduit rises to a pressure of about 2 atmospheres (absolute pressure, i.e. an overpressure of one atmosphere). This pressure arises automatically, since the valves  12  and  13  are closed. 
     In the position shown in FIG. 7, the sterilizing arrangement is activated so that a solution with a temperature of about 120° C. circulates through the conduit  24 , inlet  21 , tube  26  and point  27  to the bore  25 , and may flow around the cover  33  of the connector  30 , and further through the outlet  23  to the shunt conduit  14  as described above. This position is maintained for as long as it requires for the bore  25  and the lower portion of the connector  30  to become sterilized. 
     When a sufficiently long period of time has elapsed for the sterilization to have been achieved, the drainage valve  4  is activated and the sterilizing arrangement is adjusted so that solution which is to be sterilized is introduced through the inlet  5 , and is allowed to flow through the system. For this to occur, the shunt conduit  14  is closed by means of the valve  29  (see FIG.  3 ). The bleed valve  4  is open until normal operation is attained in the system. 
     When normal operation is attained, the activating device  36  is activated to press the connector  30  downwardly to its lower position as shown in FIG. 8 at the same time that the valve  4  is closed. In this position, the point  27  penetrates the cover  33  so that access is gained to the interior of the connector. At the same time, the outer peripheral portions of the cover  30  seal against the base of the bore so that the outlet  23  is closed off. In this manner, all solution which enters through the inlet  21  has to flow into the connector  30  and to a connected storage bag or dialysis machine or other medical equipment. 
     By means of this embodiment of the connecting unit hereof, the outer portion of the connector  25  and the point  27  are sterilized before these two parts cooperate with each other. In this manner, the risk of bacteria entering the connector  30  when the cover or membrane  33  is penetrated is totally eliminated. 
     When filling of a storage bag is completed, the bag is sealed in a suitable manner, for example by means of heat welding in a known manner. 
     It is also possible to make the cover  33  of a rubber material provided with slots which seal in a sterile manner after removal of the point  27 . Such a connector is previously known from European Application No. 116,986. 
     As has been previously mentioned, the sterilizing solution is heated to a high temperature, for example about 121° C. The pressure in the bore  25  thus becomes about 2 atmospheres. In order to assure sterility, it is necessary that circulation continues for about 20 minutes. 
     It may be desirable to reduce this time, and this can be achieved by increasing the temperature to, for example, 130° C. and a pressure of 2.7 atmospheres. In this manner, the time can be reduced to about two minutes. It must be ensured, however, that the hot sterilizing solution reaches all the regions which are to be sterilized. 
     As is apparent from FIG. 3, the cover  33  is provided with a depression in which the point  27  is positioned during the sterilizing cycle. The region which must be sterilized is this depression as well as the region of the cover which forms the seal against the base of the bore  25 . In addition, the actual penetrating part  27  must be sterilized. An effective sterilizing at high temperature can be attained if the point  27  is shaped as a cone provided with a plurality of small holes. The sterilizing solution will thus spray the inside of the depression of the cover  33  which will thereby be intensely treated with sterilizing solution. 
     It is preferred that the cover  33  be made from a material which tolerates high temperatures up to at least about 150° C. The remaining part of the connector  33  can be more or less effectively insulated from the warm sterilizing solution, for example by means of the cover  33 , which extends a certain amount upwardly along the cylindrical outer surface of the connector. 
     The connection unit according to the present invention can of course be used independently of the sterilizing arrangement, as is apparent from European Application No. 428,009. Thus, an arrangement can be used as shown in FIG.  9 . The sterile solution which is to be transferred to a container through the connector  30  is fed through a conduit  41  and a non-return valve  42 . A pump  43  feeds the sterile solution in the conduit  41  to the inlet  21 . When the connection unit is in the sterilizing position shown in FIG. 9, the solution which is introduced through the conduit  21  has to flow out through the outlet  23  to the shunt conduit  44 . The shunt conduit  44  extends through a heating arrangement  45  back to the inlet of the pump  43 . 
     When the pump  43  is actuated, the solution circulates in a closed circuit through the inlet  21  and the bore  25  to the outlet  23  by means of the shunt conduit  44  and the heating arrangement  45  back to the pump  43 . No further solution can be introduced through the inlet  41 . 
     When the cover  33  of the connector  30  and the bore  25 , as well as the penetrating element  27 , are to be sterilized, the heating arrangement  45  is activated and heats the solution which circulates in the circuit to a temperature of about 120° C. The pressure in the circulating solution rises but because of the non-return valve  42  the solution does not boil. When the solution has circulated at 120° C. for a sufficiently long time, for example about 20 minutes, the heating arrangement  45  is disconnected and the still circulating solution is allowed to cool. When a sufficiently low temperature has been attained, which is measured by a temperature sensor  46 , the activating device  36  is activated to press the connector  30  to the position shown in FIG.  8 . The temperature at which this activation occurs is dependent on the material of the connector  30 . If PVC-material is used, it is preferred that the temperature has decreased to at least about 80° C. Measurements can alternatively be carried out using a pressure sensor  48 , possibly in combination with the temperature sensor  46 . 
     When the connector  30  is pushed down to its bottom position, the cover  33  seals the outlet  23  so that the circulation in the conduit  44  ceases. The pump  43  continues to operate and thereby draws solution from the conduit  41  through the non-return valve  42  and feeds the solution through the inlet  21  and the connector  30  to a storage bag or the like connected to the connector  30 . 
     The sterilizing of the penetrating member  27  and the connector  30  can take place using the sterile solution which is introduced through the conduit  41 , and which is heated with the heating arrangement  45 . 
     Alternatively, pure water can be circulated in the circulation circuit  44 . When the sterilizing is completed, a valve  47  is adjusted which is shown with dashed lines in FIG.  9  and the contents of the pump  43 , the inlet  21 , the bore  25  and the outlet  23  can pass to an outlet at the same time as the sterile solution which is to be fed in passes through the conduit  41 , the pump  43 , the inlet  21  and to the bore  25  and further through the outlet  23 . At the same time, the pressure drops to about atmospheric pressure. When a sufficiently long time has expired for all the water to have been replaced, the activating device  36  is activated so that filling is initiated. 
     An alternative embodiment of the bore  25  is shown in FIG.  10 . Thus, the bore is provided with a lower expansion  51 . In this manner, the sterilizing solution will circulate around the entire lower portion of the connector  30  so that it becomes sterilized. This embodiment is suitable if the connector  30  is made from a material which tolerates temperatures in the order of about 120° C. without deformation, such as polycarbonate. 
     Furthermore, the penetrating element  52  is provided with a conical region  53  which, when activation of the activating device and downward displacement of the connector  30  take place, cooperates with the cover or seal  33  of the connector at the same time that cooperation occurs with the base of the bore. In this manner, the region which must be sterile to allow sterile transfer to be able to take place is further restricted. 
     In order to facilitate the recirculation, the conical region  52  is provided with a plurality of holes  54  so that the sterilizing solution can flow through the tip  55  of the penetrating element as well as through the opening  54 . In this manner, a larger circulation flow is maintained during the sterilizing phase. 
     Two outlets  56  and  57  corresponding to the outlet  23  are shown in FIG.  10 . These outlets can be tangentially arranged to ensure the best flow properties in the bore  25 . It is also possible to use the conduit  56  as an inlet as well as the inlet  52  in order to further increase the flow. Further variations will be apparent to a skilled person. A further variant of the present invention is shown in FIG. 11, which can be used to connect a bag containing sterile solution to a machine in which the sterile solution is to be used, for example a dialysis machine or an infusion tube. 
     The sterile solution is in a storage bag or a device which is connected by means of a connector  30  shown on the left in FIG.  11 . The connector  30  is connected to a connector  35  of a user who is to use the sterile solution. The two connectors  30  and  30 ′ are each inserted in respective bores  25  and  25 ′ with respective points  27  and  27 ′. The bores  25  and  25 ′ are connected to each other by means of a communication passage  61 . During the sterilizing phase, a solution, which can be water, is circulated by the pump  8  to the tip  27 ′, around the cover  33 ′, into the bore  25 ′ and through the communication passage  61  to the other bore  25 , further around the cover  33 , to the point  27  and by means of the heating arrangement  3  back to the pump  8 . By activating the heating arrangement  3 , the circulating solution is heated to about 121° C. In this manner, an inner pressure of about 2 atmospheres is reached. When the thus initiated sterilizing has gone on for about 20 minutes, a valve  62  is switched before the pump  8  to its second position so that the heating arrangement  3  is by-passed by the conduit  63 . The circulation continues until the temperature which is sensed by a temperature sensor  64  has fallen to a safe temperature, for example about 60° C. 
     The second bore  25 ′ is connected to a valve  66  and a flexible storage bag  67  through a conduit  65 . 
     When the temperature has dropped to a suitable level, the activating device  36  is activated on the left-side connector  30  and presses the connector  30  down to its lower position. This causes the point  27  to penetrate the cover  33  and the cover  33  seals the passage  61  and the bore  25 . A sterile connection between the connector  30  with the point  27  has thus been attained. 
     The sterile solution which is supplied by the connector  30  flows through the point  27 , the conduit  63 , the valve  62  and the pump  8  to the point  27 ′. The solution flows from the point  27 ′ further to the bore  25 ′. Since the conduit  61  is closed at its left end by means of the cover  33 , the solution cannot pass through the conduit  61 . Instead, the solution flows through the conduit  65  through the now open valve  66  to the storage bag  67 . 
     When a sufficient quantity of sterile solution has flowed along this path and has displaced all solution which has been used for sterilizing, which occurs after approximately one minute, the activating device  36 ′ is activated and connects the connector  30 ′ with the point  27 ′ which penetrates the cover  33 ′ which simultaneously seals against the base of the bore  25 ′. In this manner, the conduit  25  is sealed off whereby the valve  66  can be closed. A sterile connection between the connector  30  and the connector  30 ′ has now been attained. 
     In the embodiment of the connection unit which is shown in FIGS. 3-9, the bore  25  is preferably arranged in a heat-insulating material such as polycarbonate. In this manner, the regions of the connector  30  above the cover  33  are prevented from being heated to a great degree during the sterilizing phase. This makes it possible for cheap material for the connector  30 , such as PVC, to be used without the risk of deformation during the sterilizing phase. 
     The sterile solution can be infusion solutions, dialysis solutions or other medical solutions such as physiological sodium chloride solution, and the like. 
     The sterile solution can also be water, which is filled in bags through the connector. The bags contain a salt in powder form and are sterilized by suitable means so that the interior of the connector, the bags and their contents are sterile. When the bags are to be used, they are connected to the sterilizing arrangement  1  according to FIG.  2  and water is added to the bags. In this manner, the salt is dissolved and a medical solution is provided ready for use. The salt can contain several substances, such as a concentrate which is used in hemodialysis. The salt can also contain further substances, such as medically active substances in connection with infusion. 
     Suitably, the sterile solution itself is also used for the sterilizing phase. That portion of the sterile solution which has been used for sterilizing can be disposed of and new sterile solution used for filling the connector. 
     As has been mentioned above, a particular solution such as physiological sodium chloride solution or water can be used for the heat-sterilizing phase of the connector&#39;s outer portion, whereafter the solution is disposed of and replaced by the sterile solution which is to be added to the connector, such as dialysis solution, peritoneal dialysis solution (containing i.e. glucose) infusion solution, and the like. 
     The invention is not restricted to the above-described embodiment but can be modified within the scope of the invention in a manner obvious for the skilled person. The various described components can be combined in other ways than those which have been shown in the drawings.