Patent Publication Number: US-2021162192-A1

Title: Aseptic Connector

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of U.S. application Ser. No. 15/625,401 filed Jun. 16, 2017, allowed, which is a divisional of U.S. application Ser. No. 14/385,307 filed Sep. 15, 2014, abandoned, which claims priority benefit of PCT/SE2013/050328 filed Mar. 25, 2013, which claims the benefit of Application No. 1250301-7 filed in Sweden on Mar. 27, 2012, the entire contents of each of which are incorporated by reference herein. 
    
    
     TECHNICAL FIELD 
     The present invention relates to an aseptic connector and a first connection unit for such an aseptic connector. 
     Such an aseptic connector is arranged for creating aseptic and sterile connections in sterile and in non-sterile environments. 
     BACKGROUND ART 
     The biotechnology industry uses different manufacturing systems for creating aseptic and sterile connections between process containers and equipment, such as plastic bags and pumps. A known manufacturing system uses controlled environments such as clean rooms or cabinets to ensure aseptic connections during manufacture. When necessary connections are made in such a controlled environment that breaches sterile tubing and piping, the environment does not contaminate the fluid flow passage. However, maintaining a clean room is time consuming, difficult and costly to validate. 
     Another known manufacturing system uses disposable plastic bags connected to flexible thermoplastic tubes, which requires special connections to assure that the bags and tubes remain clean and sterile. A sterile tube welding machine can be used to weld the thermoplastic tubing in a sterile manner without the need for a clean room, a laminar flow cabinet or similar environmental control device. After the thermoplastic tubes cool, a sterile weld is formed. A tube welding machine is however also usually limited in applicability to specific tube size and materials, such as thermoplastic. Furthermore, tube welding machines are typically large, heavy, lack versatility, and expensive. 
     Known are also pre-sterile bags and tube sets which can be supplied with the appropriate disposable aseptic connection system fittings already in place. These, connections are simple, repeatable and validatable. 
     Single use systems, also called disposable systems are more and more used in the bioprocess industry. For example separation or reaction systems such as chromatography systems, filter systems or bioreactor systems have today at least partly been provided as disposable systems. This eliminates the need for cleaning and cleaning validation before processing, in between processes and cycles or after processing before re-use as required for conventional re-usable equipment. With disposable systems cross-contamination is avoided. 
     Bioburden control of single-use equipment during manufacturing of the equipment itself is required to eliminate cleaning needs before bringing single-use equipment into product contact. This is usually achieved by manufacturing of single-use equipment in controlled environment (clean room), often followed by sterilisation processes (gamma irradiation). The demands of the level of bioburden control can differ for different applications. However, bioburden control to a certain degree of the equipment is not only required for some applications, but also considered as the preferable for most of the applications using disposable equipment. The production of this equipment in controlled environments is required to guarantee a low initial level of contaminants prior to the bioburden control procedure. Sterility and asepsis are terms used to define the state of a system, a piece of equipment or a fluid conduit as being in control of bioburden levels to different degrees. 
     Prior art describes varying apparatus for accomplishing sterile connections using a disposable aseptic connection system. 
     Document U.S. Pat. No. 6,679,529 discloses an apparatus for establishing an aseptic and sterile connection comprising a 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. 
     WO2011/084101 A1 discloses stackable separation elements with folded films for establishing sterile connection between the elements. These elements are however not suitable for connecting complex systems of apparatuses and tubing. They are further not suitable for establishing separate connections for a plurality of fluids. 
     Notwithstanding the existence of such prior art apparatus for establishing an aseptic and sterile connection, there is a need for an improved and more efficient apparatus that can be used as either a temporary or permanent connection. 
     When a large number of equipment is connected to a process container it requires a large number of such prior art apparatuses for establishing an aseptic and sterile connection for each tubing to be connected individually. The physical size increases and ease of use reduces. The number of apparatuses and tubing are often perceived as a hazzle which will be complicated to handle. 
     SUMMARY OF THE INVENTION 
     An objective problem to be solved by the present invention is to reduce the number of such prior art apparatuses when a large number of equipment has to be connected to a process container. 
     Another objective problem to be solved by the present invention is to provide a connection that is reliable and repeatable. 
     A further objective problem to be solved by the invention is to provide multiple aseptic connections for a plurality of different fluids in one connector. 
     A further objective problem to be solved by the invention is to provide an aseptically connectable manifold for distributing or collecting a fluid to/from a plurality of containers. 
     A further objective problem to be solved by the present invention is to provide an aseptic connector which is applicable to a wide array of tubing sizes. 
     A further objective problem to be solved by the present invention is to provide an aseptic connector that is inexpensive to assemble and maintain and requires no complicated equipment to assemble. 
     A further objective problem to be solved by the present invention is to provide an aseptic connector that is compatible with the standard sanitary fittings common to the biotechnology industry. 
     These objects above are achieved by an aseptic connector according to claim  1  and a first connection unit for such an aseptic connector according to claim  11 . 
     Since at least two first ports are arranged on the first connection unit at least two equipments can be connected to for example a process container using only one aseptic connector. 
     When a large number of equipment is connected to a process container a reduced number of aseptic connectors for establishing the aseptic and sterile connection for each pipe or tube can be achieved. The physical size decreases and ease of use increases. The number of apparatuses and tubing will be less complicated to handle. 
     With this invention any desired number of containers, bags, pumps and other equipment can be connected to each other in a system in an aseptic way which reduces the number of aseptic connectors. Furthermore, these systems can be built in an environment that is not bioburden controlled and the system with all its connections will still be aseptic on process side. 
     Since at least one second port is arranged on the second connection unit an aseptic connector arranged as manifold may be achieved. 
     According to an aspect of the invention the number of openings in the terminal end surface corresponds to the number of ports arranged on the connection unit. This configuration facilitates the connection of containers, bags, pumps and other equipment that can be connected to each other and also reduces the number of aseptic connectors. 
     A further aspect of the invention is to provide a sterile circuit, comprising a first connection unit, fluidically connected with at least two lengths of tubing. This is achieved with a sterile circuit according to the claims. An advantage of this is that the setup of complex sterile systems is facilitated. A further advantage is fluid supply and removal systems for e.g. screening systems with a plurality of bioreactors can be made compact and easily handled. 
     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 THE DRAWINGS 
       Further aspects, advantages and features of the invention can be derived from the following detailed description of exemplary embodiments of the invention, with reference to the drawings. 
         FIG. 1  shows a side view of a first embodiment of an aseptic connector according to the invention, 
         FIG. 2  shows a side view of the first embodiment of the aseptic connector in  FIG. 1 , 
         FIG. 3  shows a first connection unit according to the first embodiment in perspective, 
         FIG. 4  shows a side view of a second embodiment of an aseptic connector according to the invention, 
         FIG. 5  shows a view in perspective of a third embodiment of an aseptic connector according to the invention, 
         FIG. 6  shows a view in perspective of a fourth embodiment of an aseptic connector according to the invention, 
         FIG. 7  shows a view in perspective of the first embodiment of the aseptic connector according to the invention provided with a clamp means, and 
         FIG. 8  shows a view in perspective of a fifth embodiment of an aseptic connector according to the invention. 
     
    
    
     DETAILED DESCRIPTION 
       FIG. 1  shows a first embodiment of an aseptic connector  100  comprising a first connection unit  102  provided with a first terminal end surface  104  and a second connection unit  106  provided with a second terminal end surface  108 . Said first and second terminal end surfaces  104 ,  108  are each provided with at least one first and second opening  110 ,  112 . In the first embodiment two first openings  110  are arranged in the first terminal end surface  104  and two second openings  112  are arranged in the second terminal end surface  108 . 
     The first and second openings  110 ,  112  are sealed by at least one film  114  arranged on said first and second connection units  102 ,  106 . The contact surfaces between the film  114  and each connection unit  102 ,  104  are aseptic. The film  114  is adapted to be mated with a corresponding film  114  on the other connection unit when said first and second connection units  102 ,  104  are connected to each other. Thereafter, the mated films  114  are adapted to be pulled out together two and two after mating such that corresponding first and second openings  110 ,  112  in said first and second terminal end surfaces  104 ,  108  are mated aseptically. The films  114  can e.g. be folded over and be connected to, or form, tabs protruding outside the connection units, which makes the tabs suitable for pulling. 
     In the first embodiment disclosed in  FIG. 1 , two first ports  116  are arranged on the first connection unit  102 , which first ports  116  have fluid connection with respective first opening  110  in the first terminal end surface  104 . The fluid connection between the first ports  116  and the first openings  110  forms a respective first passage  117  for fluids. On the second connection unit  106  two second ports  118  are arranged, which second ports  118  have a fluid connection with respective second opening  112  in the second terminal end surface  108 . The fluid connection between the second ports  118  and the second openings  112  forms a respective second passage  119  for fluids. Therefore, according to the first embodiment the number of openings  110 ,  112  in the respective terminal end surface  104 ,  108  corresponds to the number of ports  118 ,  116  arranged on the connection unit  102 ,  106 . 
     Pipes or tubes  120 , such as flexible thermoplastic tubes are intended to be connected to the ports  116 ,  118  by pushing them over the projecting ports  116 ,  118 , so that a mechanical retention of the pipes or tubes  120  is achieved in order to form a leak-tight seal. The pipes or tubes  120  may also be connected to process containers and equipment, such as plastic bags and pumps (not disclosed). The ports  116 ,  118  may have equal or different diameters, so that the aseptic connector  100  is applicable to a wide array of pipe and tube  120  sizes. In the embodiment disclosed the ports  116 ,  118  projects out of the connection units  102 ,  106 . However, it is also possible to arrange the ports  116 ,  118  as apertures (not disclosed) in the connection unit  102 ,  106 , so that the pipes or tubes  120  are pushed into and installed in the aperture. 
     A gasket  122  is arranged around each opening  110 ,  112 . Said gasket  122  being adapted to mate with a corresponding gasket  122  or terminal end surface  104 ,  108  on the other connection unit  102 ,  106  which the connection unit  102 ,  106  possibly should be connected with when the films  114  have been released from the connection units  102 ,  106 . The gasket  122  can possibly also be arranged around a suitable number of openings  110 ,  112 . Also, a foam layer  124 , such as a compressible foam layer, is arranged around each gasket  122 , which foam layer  124  is adapted to be compressed around each gasket  122  when two connection units  102 ,  106  are mated. The foam layer  124  provided around the gaskets  122  leads to that the units can be pressed together to a first aseptic connection position where the protective films  114  can be removed without exposing the aseptic process side to the environment, which may be non-sterile. The purpose of the compressible foam layers  124  is to provide the required degree of volumetric variability to allow for an expansion of the two opposite foam layers  124  against each other to remain asepsis when removing the adjacent folded films  114  by pulling. 
     In  FIG. 1  the films  114  are double folded over said openings  110 ,  112  and a single sheet of the uppermost layer of the film  114  is reaching outside the terminal end surfaces  104 ,  108  and adapted to be pulled together with another single sheet of another film  114  when the films  114  are released from the connection units  102 ,  106 . The film  114  is suitably provided to the units  102 ,  106  before the units are subjected to sterilisation. This means that the connection unit  102 ,  106  with the attached film  114  can be treated in a non sterile environment while the contents of the connection unit  102 ,  106  confined by its openings and ports including the openings and ports still are kept sterile or aseptic. In  FIG. 1  only one film  114  is arranged in each terminal end surface  104 ,  108 . It is however possible to arrange films  114  for each opening in the terminal end surface  104 ,  108 . The connection units  102 ,  106  are provided with orientation specific locking means  126  arranged to mechanically lock the connection units  102 ,  106  to each other. 
       FIG. 2  shows the first embodiment of the aseptic connector  100  when the first and second connection units  102 ,  106  are connected. In this position the locking means  126  mechanically locks the connection units  102 ,  106  to each other. The openings are orientated to substantially coincide when said first and second connection units  102 ,  106  are connected to each other, which is disclosed in  FIG. 2 . 
       FIG. 3  shows a first connection unit  102  according to the first embodiment in perspective. In the first terminal end surface  104 , two first openings  110  are provided. The first openings  110  are arranged to be sealed by the film  114  arranged on the first connection unit  102 , so that the contact between the film  114  and the first connection unit  102  is aseptic. Two first ports  116  are arranged on the first connection unit  102 , which first ports  116  have fluid connection with the respective first opening  110  in the first terminal end surface  104 . A gasket  122  is arranged around each first opening  110  and a foam layer  124  is arranged around each gasket  122 , which foam layer  124  is adapted to be compressed around each gasket  122  when two connection units are mated. 
       FIG. 4  shows an aseptic connector  200  according to a second embodiment of the present invention. In this second embodiment two first ports  216  are arranged on the first connection unit  202 , which first ports  216  have fluid connection with two first openings  210  in the first terminal end surface  204 . On the second connection unit  206  only one second port  218  is arranged, which has a fluid connection with two second openings  212  in the second terminal end surface  208 . The first and second openings  210 ,  212  are orientated to substantially coincide when said first and second connection units  202 ,  206  are connected to each other. In  FIG. 4  the films  214  are removed, so that the gaskets  222  arranged around each opening  210 ,  212  mates with a corresponding gasket  222  on the other connection unit which the connection unit possibly should be connected with when the films  214  have been released from the connection units  202 ,  206 . Also, the foam layers  224  arranged around each gasket  222  are compressed when the two connection units  202 ,  206  are mated. The aseptic connector  200  according to this second embodiment is arranged as a manifold. 
       FIG. 5  shows an aseptic connector  300  according to a third embodiment of the present invention in perspective. In this third embodiment two first ports  316  are arranged on the first connection unit  302 , which first ports  316  have fluid connection with only one first opening  310  in the first terminal end surface  304 . On the second connection unit  306  only one second port  318  is arranged, which has a fluid connection with only one second opening  312  in the second terminal end surface  308 . The first and second openings  310 ,  312  are orientated to substantially coincide when said first and second connection units  302 ,  306  are connected to each other. 
       FIG. 6  shows an aseptic connector  400  according to a fourth embodiment of the present invention in perspective. In this fourth embodiment three first ports  416  are arranged on the first connection unit  402 , which first ports  416  have fluid connection with three first openings  410  in the first terminal end surface  404 . On the second connection unit  406  only one second port  418  is arranged, which has a fluid connection with three second openings  412  in the second terminal end surface  408 . The first and second openings  410 ,  412  are orientated to substantially coincide when said first and second connection units  402 ,  406  are connected to each other. In this embodiment also at least one of the first ports  416  is provided with a valve  428 , which is arranged to control fluid flow through the first connection unit  402  and the aseptic connector  400 . The valve  428  can be of the type which opens and closes the port  416 . However, it is also possible to arrange the valve as a three-way valve (not disclosed). 
     In  FIG. 6  the aseptic connector  400  may be provided with measuring means  436  comprising sensors for measuring and monitoring for example pressure, velocity in flow, temperature and conductivity. Also, radio frequency identification (RFID) tags may be used in combination with the sensors in the measuring means  436 . The measuring means  436  may be located within the connector  400  and in contact with the fluid in the connector  400 , or located on a location outside the connector  400 . The RFID tags may communicate with a computer (not disclosed) for collecting information about the measured values. Preferred geometries of the measurement means  436  are round or circular, but other geometries can be used for similar purposes. 
     In  FIG. 7  the aseptic connector  100  according to the first embodiment is provided with a clamp  130 , which at least partially encloses the connector  100 . The clamp  130  comprises two shells  132  which are arranged at the periphery of first and second connection units  102 ,  106  and locked with a strap  134 . The clamp  130  urges the first and second connection units  102 ,  106  in a direction to each other and prevents any leakage of fluid from the aseptic connector  100 . The clamp  130  also prevents the first and second connection units  102 ,  106  to be unintentional disconnected. 
       FIG. 8  shows an aseptic connector  500  according a fifth embodiment. In addition to the first embodiment above the aseptic connector  500  according the fifth embodiment has four first ports  516  arranged on the first connection unit  502 , which first ports  516  have fluid connection with four first openings  510  in the first terminal end surface  504 . On the second connection unit  506  also four second ports  518  are arranged, which have a fluid connection with four second openings  512  in the second terminal end surface  508 . The first and second openings  510 ,  512  are orientated to substantially coincide when said first and second connection units  502 ,  506  are connected to each other. The first and second openings  510 ,  512  are sealed by films  514  arranged on said first and second connection units  502 ,  506 . A gasket  522  is arranged around each first opening and a foam layer  524  is arranged around each gasket  522 . In the fifth embodiment the films  514 , gaskets  522  and foam layer  524  are disclosed when arranged at the second connection unit  506 . However, films  514 , gaskets  522  and foam layer  524  are also arranged at the first connection unit  502 , but not disclosed in  FIG. 8 . The first and second connection units  502 ,  506  according to the fifth embodiment have a substantial rectangular configuration in comparison to the substantial circular configuration of the connection units in the embodiments above. 
     Preferably, the aseptic connector  100 ;  200 ;  300 ;  400 ;  500  according to the invention is a disposable unit, i.e. adapted to be used only once. One advantage with disposable systems is that there is no need for cleaning and bioburden control before using the systems because disposable systems are already aseptic in some degree and they should not be used again and need therefore not be cleaned between uses. Therefore the aseptic connector  100 ;  200 ;  300 ;  400 ;  500  according to this invention is particularly interesting in disposable systems. 
     In a further aspect of the invention, a sterile circuit is disclosed, which comprises at least one first connector unit  102 ;  202 ;  302 ;  402 ;  502  as discussed above and at least two lengths of tubing  120 ;  220  fluidically connected to the unit, preferably to the ports  116 ;  118 ;  216 ;  316 ;  416 ;  516 ;  518 . The sterile circuit may be presterilized, e.g. by irradiation or autoclaving and it may be packaged in a sterile container, such as e.g. a sterile pouch or bag. The sterile circuit may further comprise at least one container, such as a storage bag or a bioreactor bag, which is fluidically connected to at least one of the tubing lengths  120 ;  220 . The first connector unit of the sterile circuit may be aseptically connected to a second connector unit, which may, or may not, form a part of a second sterile circuit with at least one length of tubing fluidically connected to the second connector unit. 
     The provision of sterile circuits greatly facilitates the setup of complex sterile systems, such as bioreactors with multiple lines for feeding nutrients, gases etc and for removal of culture fluid and/or metabolites etc. One sterile circuit may be attached to one bioreactor via one or more lengths of tubing or it may be attached to a plurality of bioreactors. The latter is particularly suitable for screening experiments such as high throughput screening experiments where a large number of small bioreactors are used and it is of imperative need to have a compact system for supply and removal of fluids. 
     The word aseptic used in this description and in the claims shall have a broad definition, i.e. include any level of bioburden control. The bioburden control or asepsis can be measured as organisms/ml or CFU (colony forming units). In one embodiment of the invention the level of asepsis should be below 100 CFU/ml. The latter corresponds to bioburden control levels required for food grade products. Low levels of bioburden can be achieved by sterilisation processes. For example the aseptic connector  100 ;  200 ;  300 ;  400 ;  500  of the invention can be subjected to gamma sterilization. Other possible methods are autoclaving or bioburden control by ethylene dioxide. 
     In all embodiments described above parts and surfaces being in contact with a process fluid are suitably selected from materials that are in accordance with typical material requirements in (bio-) pharmaceutical manufacturing or food grade quality. 
     For example, materials are suitably in compliance with USP Class VI and 21 CFR 177. Furthermore they are suitably of animal-free origin and compliance to EMEA/41O/01. 
     Features and components of the different embodiments above may be combined within the scope of the invention.