Abstract:
An apparatus for establishing aseptic/sterile connections including a substantially flexible, substantially transparent sterile barrier enclosing a terminal end of a conduit and a resilient, deformable support card which further includes an adhesive perimeter covered by a release paper and a rolling membrane with a continuous, removable, yieldable, flexible strip material. A portion of the rolling membrane is removably adhered to the support card and overlies the end of the conduit. A force applied to the free end of the rolling membrane withdraws the entire rolling membrane to expose the end of the conduit so that an aseptic/sterile connection is achieved by adhering opposing support cards together, removing the rolling membrane to create a sterile corridor between a first sterile barrier and a second sterile barrier, and mating the terminal end of a first conduit and a second conduit together.

Description:
BACKGROUND OF INVENTION 
     1. Field of Invention 
     The present invention relates generally to a method and apparatus to form sterile connections, and more particularly, a method and apparatus for inexpensively creating sterile connections in non-sterile environments. 
     2. Background of the Invention 
     Presently, the pharmaceutical industry is comprised of two manufacturing systems. The first manufacturing system is the traditional system that uses clean rooms, stainless steel reactors, holding tanks, and piping to maintain sterile conditions during manufacture. The second manufacturing system is state-of-the-art biotechnology manufacturing that uses an assortment of disposable plastic bags and flexible sterile tubing. With the traditional manufacturing methods, clean-in-place and steam-in-place systems are required to assure that the stainless steel reactors and piping remain clean and sterile. A sterile clean room is also required during traditional manufacturing processes so that when necessary connections are made that breach the sterile piping, the environment does not contaminate the fluid flow. Maintaining a clean room is time consuming and difficult to validate. In contrast, the state-of-the-art biotechnology methods use plastic bags and tubing sets that can be sterilized prior to implementation in the manufacturing process and are completely disposable. Biotechnology manufacturing methods require significantly less capital because no initial investment in expensive stainless steel reactors or piping is required. 
     The tubing in biotechnology manufacturing is used between process containers and equipment that require sterile connections. A sterile tube welding machine can be used to weld the thermoplastic tubing in a sterile manner without the need for a laminar flow cabinet or similar environmental control device. The tube welder sterilizes a cutting blade or wafer then moves the blade through the two ends of the tubing to be joined. Once both ends of the tubing have been cut, the machine aligns the ends of the tubes while maintaining a high temperature. After the thermoplastic tubes cool, a sterile weld is formed. Another system utilizes a self contained HEPA system and a sterile plastic connector to create the union; still using the heated blades. 
     The various types of sterile tubing welders have disadvantages in that there is a limited range of the size of tubing that can be welded by one particular tube welding machine. A tube welding machine is also usually limited in applicability to specific tube materials such as thermoplastic. Furthermore, tube welding machines are typically large, heavy, lack versatility, and expensive. 
     The biotechnology approach, out of necessity, requires large amounts of disposable flexible tubing. This tubing is used to convey the sterile contents of one bag to another. Each time a connection is made to add or remove contents of a bag, only one of four systems noted below can be used; each system has significant shortcomings. 
     
       
         
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Cost per 
                   
               
               
                 Device 
                 Connection 
                 Comments 
               
               
                   
               
             
             
               
                 Terumo Sterile 
                 US $ 3.00 to 
                 Clean room required one-quarter inch 
               
               
                 Connection 
                 5.00 
                 O.D. maximum size; lab scale and 
               
               
                 Device 
                   
                 R&amp;D applications only. Requires 
               
               
                   
                   
                 thermoplastic elastomer (herein “TPE”) 
               
               
                   
                   
                 for tube material. 
               
               
                 Wave Ree- 
                 US $ 4.00 to 
                 Clean room required; tubing up to ¾″ 
               
               
                 welder 
                 7.00 
                 O.D. in size; requires TPE material; 
               
               
                   
                   
                 new and unproven design; expensive 
               
               
                   
                   
                 at US $ 35,000.00 per typical 
               
               
                   
                   
                 application. 
               
               
                 CPT Aseptic 
                 US $ 7.00 to 
                 ½ by ¾ and ⅜ by ⅝ inch tubing; 
               
               
                 Connection 
                 10.00 
                 heavy and large; expensive at 
               
               
                 Device 
                   
                 US $ 35,000.00 per typical application; 
               
               
                   
                   
                 uses only C-Flex TPE tubing. 
               
               
                 Manual System 
                 US $ 10.00 to 
                 Manual method requires clean room and 
               
               
                   
                 25.00 
                 clean hood utilizing sterile 
               
               
                   
                   
                 utensils and connections; training in 
               
               
                   
                   
                 sterile technique required. 
               
               
                   
               
             
          
         
       
     
     All of the systems listed above require the use of thermoplastic tubing (no silicone) except the manual system. The ideal aseptic/sterile connection system would have the following characteristics: 
     1. Applicability to a wide array of tubing materials and sizes; 
     2. Inexpensive to assemble and maintain; 
     3. Requires no capital equipment; 
     4. Operates without a clean room; 
     5. Disposable; 
     6. Reliable and repeatable; and 
     7. Operator independent. 
     The current systems in use presently fall short of meeting the ideal criteria. Thus, there is a need for a disposable aseptic connection system that does not require a tube welding machine. A disposable aseptic connection system that does not employ a tube welding machine could be used regardless of the tubing material, size or location, at a competitive cost. Additionally, once a company commits to this type of connector, all pre-sterile bags and tube sets can be supplied with the appropriate disposable aseptic connection system fittings already in place. Therefore, connections are simple, repeatable and validatable. 
     Prior art describes varying apparatus for accomplishing sterile connections using a disposable aespetic connection system. By way of example, U.S. Pat. No. 4,418,945 to Kellog describes sterile connectors having strips that are withdrawn to expose the ends of conduits attached to cooperating connectors. U.S. Pat. No. 4,149,534 to Tenczar describes sterile connectors for joining conduits having an adhesive release positioned on adjoining faces of the connectors. U.S. Pat. No. 4,030,494 to Tenczar describes sterile fluid connectors having cooperating heat penetratable and fusible plastic barriers for coupling two conduits. U.S. Pat. No. 4,022,205 to Tenczar describes sterile fluid connectors having cooperating adhesive surfaces that are jointly punctured upon coupling two conduits. U.S. Pat. No. 4,019,512 to Tenczar describes an adhesively sterile connector having a protective member that is progressively pulled away. U.S. Pat. No. 3,865,411 to Rowe et al. describes a sterile connector having an adhesive release and two connectors are used to make a connection. Rowe et al. teaches to align the adhesive portions; then the free ends of the adhesive are pulled thereby exposing the free ends of the connectors to form a sealed, sterile fluid passage. 
     Notwithstanding the existence of such prior art disposable aseptic connection systems, there is a need for an improved and more efficient apparatus and method for using a disposable aseptic connection system that can be used as either a temporary or permanent connection. 
     An objective of the present invention is to provide a disposable aseptic connection system that is a temporary and disposable connection. 
     Another objective of the present invention is to provide a disposable aseptic connection system that is adaptable to a permanent connection. 
     Another objective is to provide a connection that is reliable and repeatable. 
     Still another objective is to provide a disposable aseptic connection system that is operator independent. 
     Another objective is to provide a connection system that is applicable to a wide array of tubing materials and sizes. 
     Another objective is to provide a disposable aseptic connection system that is inexpensive to assemble and maintain and requires no expensive equipment. 
     Another objective is to provide an aseptic connection system that can operate without a clean room. 
     Another objective is to provide a connection means that is compatable with the standard sanitary fittings common to the biotechnology industry. 
     It is, therefore, to the effective resolution of the aforementioned problems and shortcomings of the prior art that the present invention is directed. 
     However, in view of the prior art at the time the present invention was made, it was not obvious to those of ordinary skill in the pertinent art how the identified needs could be fulfilled. 
     SUMMARY OF INVENTION 
     The present invention solves significant problems in the art by providing an apparatus for establishing an aseptic/sterile connection comprising a substantially flexible, substantially transparent sterile barrier enclosing a terminal end of a conduit, a resilient, deformable support card fixed to the sterile barrier having an outer face disposed about the terminal end of the conduit having an adhesive perimeter covered by a release paper, and a rolling membrane comprising a continuous, removable, yieldable, flexible strip material, a portion of which is removably adhered to the support card and overlies the end of the conduit, the rolling membrane having a free end whereby a force applied to the free end thereof withdraws the entire rolling membrane to expose the end of the conduit whereby an aseptic/sterile connection is achieved by adhering opposing support cards together, removing the rolling membrane thereby creating a sterile corridor between a first sterile barrier and a second sterile barrier, and mating the terminal end of a first conduit and a second conduit together. 
     Adhesive material is applied to the exposed side of the rolling membrane while the side of the rolling membrane abutting the sterile barrier enclosure is free of adhesive material and treated with a release coating. This is preferred so that no residue of adhesive could possibly contaminate a fluid path established through the sterile corridor. 
     A biocidal agent may be integrated into the adhesive perimeter and the rolling membrane to combat contamination by both fungi and bacteria. A variety of biocides may be utilized such as Intercide® ABF available from Akros Chemicals America in New Brunsick, N.J. 
     An important aspect of the invention is that each opposing connection is oriented in the proper fashion. The rolling membrane on each opposing connection must be correctly oriented or the membrane will be impossible to properly withdraw. If the opposing support cards are adhered in an incorrect orientation, a sterile connection cannot be made and the support cards must be pulled apart and discarded. To prevent incorrect orientation of the support cards, an embodiment of the present invention includes an orientation-specific latching means on the support card wherein two opposing support cards may only latch together in a single orientation. This is achieved by configuring each latch point in a predefined, geometric configuration. The orientation-specific latching means mechanically biases two opposing support cards together to provide a sterile connection. 
     In one embodiment of the invention, the novel connector is used with annular sanitary fittings. One and one half inch diameter sanitary fittings are standard in the biopharmaceutical manufacturing art. Polymer snap fittings are mechanical latches including one or more latching arms and corresponding latching notches. The latches in this embodiment snap together in an internal circumferential direction to form a genderless connector. The genderless connector provides the advantages of easy manipulation and reduced inventory requirements. 
     An internal circumferential direction defines a direction of the latches that snap together around the circumference of the inside of opposedly aligned fittings. The circumferential latches provide the proper orientation of one fitting relative to the other to ensure that the opposedly aligned rolling membranes achieve a sterile connection. Snap fittings are not capable of maintaining a sterile connection indefinitely due to the creep characteristics of the polymer. Therefore, a polymer snap fitting requires additional support to provide a permanent sterile connection. Prior art snap fittings include externally located latches so that the standard sanitary clamps cannot be used. However, the present embodiment of the novel invention provides low profile latches with internal circumferential orientation so that standard stainless steel clamps can be used in adapting the snap fitting connection to a permanent connection. Stainless steel sanitary clamps are readily available in the industry and can be used to adapt the novel temporary snap fitting connection to a permanent connection at the operator″s discretion. The stainless steel clamp encircles and permanently secures the snap fitting. 
     The properly aligned and opposedly aligned support cards that are coupled with the mechanical latching means results in the joining of both rolling membranes whereby adhesion of the rolling membranes is constrained to be simultaneous. Therefore, the sterile surface of one card to that of the opposing card is exposed concurrently forming a sterile connection. 
     The invention further comprises a resilient gasket surrounding the periphery of the terminal end of the conduit wherein opposing gaskets are mechanically biased against each other thereby forming a substantially fluid-tight connection between two conduits. 
     An advantage of the current invention is that the connection can be used as a temporary connection or adapted to a permanent connection with the use of a standard stainless steel clamp. Thus, two markets are served. 
     Another advantage of the present invention is the internal circumferential latching means that orientates one fitting to the other to assure alignment of one rolling membrane with the other. A radially directed latch would require a longer latch length and would then interfere with the clamp or require design modifications to the tapered section of the fitting around which the clamp rests. However, the present invention has the advantage that it can be used with standard sanitary fittings and the novel latching means can be manually activated or will be automatically engaged when the clamp is closed. 
     These and other important objects, advantages, and features of the invention will become clear as this description proceeds. 
     The invention accordingly comprises the features of construction, combination of elements, and arrangement of parts that will be exemplified in the description set forth hereinafter and the scope of the invention will be indicated in the claims. 
    
    
     BRIEF DESCRIPTION OF DRAWINGS 
     For a fuller understanding of the nature and objects of the invention, reference should be made to the following detailed description, taken in connection with the accompanying drawings, in which: 
     FIG. 1 is a side view of rolling membrane attached to the support card. 
     FIG. 2 is an elevated, partially sectional front view of the rolling membrane and support card. 
     FIG. 3 is an elevated, partially sectional rear view of the rolling membrane and support card. 
     FIG. 4 is an elevated, front view of the card adhesive label and rolling membrane. 
     FIG. 5 is an elevated, rear view of the card adhesive label and rolling membrane. 
     FIG. 6 is an elevated, partially sectional side view of the sterile barrier. 
     FIG. 7 is an elevated, partially sectional side view of two opposing rolling membranes aligned to mate two sterile barriers together. 
     FIG. 8 is an elevated, partially sectional side view of two opposing rolling membranes and two opposing adhesive card perimeters adhered to each other. 
     FIG. 9 is an elevated, partially sectional side view of the rolling membrane being withdrawn to open a sterile corridor between the two sterile barriers. 
     FIG. 10 is an elevated, partially sectional side view of the rolling membrane fully withdrawn between the two sterile barriers. 
     FIG. 11 is an elevated, partially sectional side view showing the mating of each conduit together within the sterile corridor formed between the two sterile barriers. 
     FIG. 12 is an elevated, partially sectional side view of an embodiment of the invention using a genderless connector. 
     FIG. 13 is an elevated, partially sectional front view of the latching support card according to the invention. 
     FIG. 14 is an elevated, partially sectional side view of the latching support card according to the invention. 
     FIG. 15 is an elevated, partially sectional rear view of the latching support card according to the invention. 
     FIG. 16 is an elevated front view of the foam biasing pad according to the invention. 
     FIG. 17 is an elevated, partially sectional side view of the foam biasing pad according to the invention. 
     FIG. 18 is an elevated, partially sectional side view of an embodiment of the invention utilizing a latching card. 
     FIG. 19 is an elevated, partially sectional front view of an embodiment of the invention utilizing a latching card. 
     FIG. 20 is an exploded, perspective view of an embodiment of the invention utilizing sanitary fittings with internally circumferential orientated latches. 
     FIG. 21 is an exploded side view of an embodiment of the invention utilizing sanitary fittings with internally circumferential orientated latches. 
     FIG. 22 is a perspective view of a pair of connectors of the present invention aligned to be assembled. 
     FIG. 23 is an elevated side view of a pair of connectors of the present invention aligned to be assembled. 
     FIG. 24 is a perspective view showing the connectors fully assembled. 
     FIG. 25 is an elevated side view of the connectors fully assembled. 
     FIG. 26 is a perspective view of the rolling membrane being withdrawn to open a sterile corridor between the two sanitary fittings. 
     FIG. 27 is an elevated side view of the rolling membrane being withdrawn to open a sterile corridor between the two sanitary fittings. 
     FIG. 28 is a perspective view of the rolling membrane being withdrawn to open a sterile corridor between the two sanitary fittings. 
     FIG. 29 is an elevated side view of the rolling membrane being withdrawn to open a sterile corridor between the two sanitary fittings. 
     FIG. 30 is a perspective view of the rolling membrane fully withdrawn between the two sanitary fittings. 
     FIG. 31 is an elevated side view of the rolling membrane fully withdrawn to open a sterile corridor between the two sanitary fittings. 
     FIG. 32 is a perspective view of the stainless steel clamp engaged with the sanitary fittings. 
     FIG. 33 is an elevated view of the stainless steel clamp engaged with the sanitary fittings. 
     FIG. 34 is a perspective view of the annular adhesive label in a partially folded orientation. 
     FIG. 35 is a perspective view of the annular adhesive label in a further partially folded orientation. 
     FIG. 36 is a perspective view of the annular adhesive label in a fully folded orientation. 
     FIG. 37 is a perspective view of the annular adhesive label in a fully folder position and covered with release paper. 
    
    
     DETAILED DESCRIPTION 
     Referring initially to FIGS. 1-5, a support card  20  is provided which is substantially resilient and deformable. A card adhesive label  30  is provided having an adhesive front card label surface  130  forming a sterile safety zone and a non-adhesive rear card label surface  140 . A conduit aperture  60  is provided through the support card  20  and the card adhesive label  30 . A rolling membrane  40  is shown folded in FIGS. 1-3 and extended in FIGS. 4-5. The rolling membrane  40  has a first membrane fold  70 , a second membrane fold  80  and a membrane pull grip  50 . The area between the first membrane fold  70  and the second membrane fold  80  on the front of the card adhesive label  30  forms a front first fold release coating  90 . This front first fold release coating  90  is in contact with the adhesive front card label surface  130 . While in contact, the sterile safety zone is protected from contamination, even in a contaminated setting. The area between the second membrane fold  80  and the membrane pull grip  50  on the front of the card adhesive label  30  forms a front second fold adhesive coating. The area between the first membrane fold  70  and the second membrane fold  80  on the rear of the card adhesive label  30  forms a rear first fold release coating  100 . The area between the second membrane fold  80  and the membrane pull grip  50  on the rear of the card adhesive label  30  forms a rear second fold release coating  110 . 
     It can be seen in FIG. 1 that when the rolling membrane  40  is folded, the front first fold release coating  90  comes into contact with the front card label surface  130  thereby protecting the sterile safety zone. The rear first fold release coating  100  abuts the rear second fold release coating  110 . The front second fold adhesive coating  120  is then exposed for adhesion to the adhesive coating  120  of an opposing rolling membrane. It can also be seen that the membrane pull grip  50  is disposed below the lower edge of the support card  20 . Externally exposed adhesive surfaces, such as the front second fold adhesive coating  120 , are covered by a release paper (not shown) that prevent drying of the adhesive material. 
     In FIG. 6, the support card  20  is fixed to one end of a sterile barrier  150  enclosing a conduit fitting  160 . It is preferred that the sterile barrier  150  be constructed of a clear, flexible polymer material. Constructing the sterile barrier  150  out of substantially transparent material permits the user to easily view the manipulation of the conduits. The flexibility of the sterile barrier  150  enables the manipulation itself. The polymer material is preferred for its durability and its fluid containment qualities. Accordingly, the preferred sterile barrier  150  is flexible and movable. The conduit fitting  160  may be a male/female connector, a genderless connector, or the like. The sterile barrier  150  forms a sterile field  170  wherein the conduit fitting  160  and the interior of the sterile barrier  150  is aseptic/sterile. A barrier port  180  in the sterile barrier  150  provides an external fluid path from the conduit fitting  160  to an exterior tube  190 . In this illustrative embodiment, a ladish fitting  210  mates with an external fluid path. A tubing clamp  200  is engaged by default thereby maintaining the sterility of the sterile field  170 . However, the area from the tubing clamp  200  to the ladish fitting  210  is not sterile and therefore is sterilized once coupled to the fluid path. Once sterilized, both sides of the tubing clamp  200  are then aseptic/sterile and the tubing clamp  200  is disengaged. Well-known sterilization methods for this application typically include steam-in-place procedures. 
     In FIG. 7, two opposing sterile barriers  150  are aligned so that the front second fold adhesive coating  120  of each rolling membrane  40  mirror each other. This alignment is important as the rolling membrane  40  may be withdrawn in only one linear direction. Once the two front second fold adhesive coating  120  surfaces are in contact, as shown in FIG. 8, the entire adhesive surface area of the front card label surface  130  also comes into contact thereby sealing each opposing support card  20  together. In FIG. 9, the membrane pull grip  50  is pulled away from the longitudinal axis of the sterile corridor thereby exposing the conduit aperture  60 . With the front card label surface  130  already sealed, the sterile safety zone of each opposing card comes into contact with each other without exposure to the outside environment. In FIG. 10, the rolling membrane  40  is completely withdrawn to an unfolded configuration and the conduit apertures  60  are aligned to form a sterile corridor between each sterile barrier  150 . In FIG. 11, each conduit fitting  160  is moved towards the conduit aperture  60 , until both conduit fittings  160  mate with each other, thereby forming a secure fluid path. In a preferred embodiment, a genderless connector  250  is employed for the conduit fitting  160  as shown in FIG.  12 . The genderless connector  250  provides the advantages of easy manipulation and reduced inventory requirements. 
     As indicated previously, the rolling membrane  40  must be withdrawn in a singular linear direction. Accordingly proper orientation of each opposing support card  20  is critical. The invention further comprises a third embodiment which abrogates the need for a flexible, transparent barrier. In the third embodiment, a mechanical latching means biases two opposing conduits together in strict orientation. While the user is unable to view the actual mating of the two or more conduits, the mechanical latching embodiment may provide a simple and efficiently manufactured connection system for the appropriate application. In FIGS. 13-15, a latching support card  270  is provided having at least one or more latching arms  280  and corresponding latching notches  290  arranged in a predetermined configuration to permit latching in only one orientation. The latching support card  270  may serve an additional purpose of providing mechanical force to bias two conduit ends to form a fluid path without additional fittings. In an illustrative embodiment, the latching support card  270  of FIG. 14 has a gasket channel configured to receive a gasket  320  of FIG. 18. A substantially resilient foam biasing pad  310  shown in FIGS. 16-18 pushes opposing latching support cards  270  away from each other as they are engaged by said latching arms  280 . The compression force generated by the latching mechanisms seals each opposing gasket  320  against each other thereby forming a fluid path between the two conduits. 
     In an alternative embodiment, the novel connector is used with annular sanitary fittings  400 . FIGS. 20 and 21 show the polymer sanitary snap fittings with novel mechanical latches including one or more latching arms  410  and corresponding latching notches  420  arranged in an internal circumferential manner on the sanitary fitting  400 . The internal circumferential latches provide the proper orientation of one fitting  400  relative to the other to ensure that the opposedly aligned adhesive labels  405  attached to the sanitary fitting  400  achieve a sterile fluid connection. In FIGS. 22 and 23, two adhesive labels  405  are aligned so that the front second fold adhesive coating  120  of each adhesive label  405  mirror each other. This alignment is important as the rolling membrane  40  may be withdrawn in only one linear direction. Once the two front second fold adhesive coating  120  surfaces are in contact, as shown in FIGS. 24 and 25, the entire adhesive surface area of the front card label surface  130  also comes into contact thereby sealing each sanitary fitting  400  together. In FIGS. 26-29, the membrane pull grip  50  is pulled away from the longitudinal axis of the sterile conduit  190  thereby exposing the conduit aperture  60 . With the front card label surface  130  already sealed, the sterile safety zone of each opposing sanitary fitting  400  comes into contact with each other without exposure to the outside environment. In FIGS. 30 and 31, the rolling membrane  40  is completely withdrawn to an unfolded configuration and the conduit apertures  60  are aligned to form a sterile corridor. The rolling membrane  40  is then removed by tearing away at fold  70 . 
     Complementary stainless steel sanitary clamps  450  shown in FIGS. 32 and 33 can be used with the sanitary fitting  400  to adapt a temporary snap fitting to a permanent connection. Thus, this embodiment of the novel invention provides a low profile latch, one that will not interfere with the clamp in adapting the snap fitting to a permanent connection and is heretofore unknown in the art. 
     FIGS. 34-37 show the steps of folding rolling membrane  40  into a ready position onto annular support card  407  and covered by release paper  460 . The removable release paper  460  is provided with a pull tab  465  so that the release paper can be easily removed from adhesive face  120  when connecting two sanitary fittings  400 . 
     It will be seen that the objects set forth above, and those made apparent from the foregoing description, are efficiently attained and since certain changes may be made in the above construction without departing from the scope of the invention, it is intended that all matters contained in the foregoing description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense. 
     It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween. Now that the invention has been described.