Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M39/00—Tubes, tube connectors, tube couplings, valves, access sites or the like, specially adapted for medical use
  • A61M39/10—Tube connectors; Tube couplings
  • A61M39/16—Tube connectors; Tube couplings having provision for disinfection or sterilisation
  • A61M39/18—Methods or apparatus for making the connection under sterile conditions, i.e. sterile docking
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M2207/00—Methods of manufacture, assembly or production
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
  • F16L—PIPES; JOINTS OR FITTINGS FOR PIPES; SUPPORTS FOR PIPES, CABLES OR PROTECTIVE TUBING; MEANS FOR THERMAL INSULATION IN GENERAL
  • F16L2201/00—Special arrangements for pipe couplings
  • F16L2201/40—Special arrangements for pipe couplings for special environments
  • F16L2201/44—Special arrangements for pipe couplings for special environments sterile
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
  • F16L—PIPES; JOINTS OR FITTINGS FOR PIPES; SUPPORTS FOR PIPES, CABLES OR PROTECTIVE TUBING; MEANS FOR THERMAL INSULATION IN GENERAL
  • F16L33/00—Arrangements for connecting hoses to rigid members; Rigid hose-connectors, i.e. single members engaging both hoses
  • F16L33/30—Arrangements for connecting hoses to rigid members; Rigid hose-connectors, i.e. single members engaging both hoses comprising parts inside the hoses only

Definitions

• the present invention relates to connection of flexible tubing, and more particularly to an apparatus for substantially sterile connection of flexible tubing.
• the invention also relates to a method for substantially sterile connection of sterile tubing.
• Single use systems also called disposable systems are more and more used in the bioprocess industry.
• separation or reaction systems such as chromatography systems, filter systems or bioreactor systems have today at least partly been provided as disposable systems.
• 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).
• 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, hereby reducing for example endotoxin levels.
• Typical applications of aseptic connectors in biomanufacturing are connections between fluid lines, separation units (filters, chromatography columns, adsorbers, membrane adsorbers, expanded or fluidized bed adsorbers) or reaction units (bioreactors, reaction or (bio-)conversion units that for example utilize enzymatic conversions).
• 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.
• Aseptic connectors can be used to interconnect single-use equipment and also single-use equipment and conventional re-use equipment that is bioburden controlled (sanitized, sterilized etc.).
• Available aseptic connectors are for example ReadyMateTM connectors from GE Healthcare and KleenpackTM from Pall. These use removable protective films to ensure asepsis and are applied to lengths of tubing and/or equipment in a manufacturing operation, after which the tubing/equipment with the connectors is gamma sterilized. This means that they are only useful for preassembled circuits.
• the current approach is to use heat welding of flexible tubing. Welders for this purpose use electrically heated wafers to cut and weld tubing, and are commercially available from e.g. GE Healthcare (Sterile Tube Fuser) and Sartorius Stedim Biotech (BioWelderTM). These equipments are stationary, heavy and require electrical connection. Accordingly there is a need for lighter and more convenient devices to be used in aseptic connection of flexible tubing in e.g. bioprocessing settings.
• One aspect of the invention is to provide an apparatus for substantially sterile connection of flexible tubing, which apparatus is small, has a low weight, does not require electrical connection and is generally convenient to use. This is achieved with an apparatus as defined in claim 1.
• One advantage is that the apparatus can be handheld and used to connect tubing in situ, even in inconvenient locations which are not possible to access with heavy electrical welding
• a further advantage is that also non-weldable tubing may be connected, e.g. rubber tubing.
• Another aspect of the invention is to provide a simple and convenient method for substantially sterile connection of flexible tubing directly in a bioprocess setting. This is achieved with a method as defined in the claims. Further suitable embodiments of the invention are described in the dependent claims. Brief description of drawings
• Figure 1 shows an apparatus of the invention through the different steps of the method of the invention.
• Figure 2 shows an embodiment of the apparatus of the invention with a sterilant reservoir.
• Figure 3 shows an alternative embodiment of the apparatus of the invention and its use.
• Figure 4 shows further embodiments of the apparatus, with different types of connectors.
• Figure 5 shows an embodiment comprising a connector with a removable protective film/cap.
• Figure 6 shows an embodiment where the connector comprises a notched metal tube.
• Figure 7 shows a rotary embodiment of the apparatus of the invention.
• the present invention discloses an apparatus 1;11;61 for substantially sterile connection of flexible tubing, as illustrated by Figs. 1-4 and 7.
• This apparatus comprises: i) At least one tubing holder 2;12;62, which is adapted to receive one or more lengths of flexible tubing 3;13;63 and which is also equipped with one or more sterilant applicators 4;14;64.
• the sterilant applicator(s) is/are adapted to apply a sterilant to the or each said lengths of tubing 3; 13;63 when the tubing length(s) is/are received in the tubing holder 2;12;62.
• the tubing holder(s) may each comprise an essentially cylindrical port of a diameter suitable to receive a length of tubing and the port may e.g. lead into a tubing end receiver located in a connector holder 6 or into a cutting and connecting compartment 19.
• the port(s) can suitably be covered with protective film(s) or cap(s), to be removed before receiving the length(s) of tubing.
• the sterilant applicator(s) may e.g. each be a tubular or slit tubular layer of a flexible open-porous material (e.g. a polymer foam) arranged on the inner surface of the cylindrical port(s).
• the sterilant applicator(s) may contain an imbibed liquid sterilant, such as hydrogen peroxide or an aqueous hydrogen peroxide solution, e.g. comprising 3 - 60 wt. % or 25-35 wt % hydrogen peroxide.
• the sterilant applicator(s) may also, or alternatively, be fluidically connected or fluidically connectable to a sterilant reservoir 33 comprising a liquid sterilant, such as hydrogen peroxide or an aqueous hydrogen peroxide solution, e.g. comprising 3 - 60 wt. % or 25-35 wt % hydrogen peroxide.
• the sterilant can alternatively also be a solution comprising ethanol (typically a 60 - 80 wt% aqueous ethanol solution), hypochlorite (typically a 0.5 - 10 wt % aqueous sodium hypochlorite solution) etc.
• ethanol typically a 60 - 80 wt% aqueous ethanol solution
• hypochlorite typically a 0.5 - 10 wt % aqueous sodium hypochlorite solution
• Aqueous hydrogen peroxide solutions possess germicidal properties over a
• At least one cutter 5;15;65 which is movable in relation to the tubing holder 2;12;62 and adapted to cut the length(s) of tubing 3;13;63.
• the cutter(s) can be a blade or a similar device with a sharp edge, e.g. a sharp edge on a tubing holder, or it can alternatively be a heated wafer or even e.g.
• the cutter(s) can be movable in a direction essentially transverse to the length(s) of tubing received in the tubing holder(s).
• the cutter or each cutter may be movable in a plane interfacing a tubing holder and a connector holder, or a cutting and connecting compartment, in a direction towards the length of tubing received in the tubing holder.
• the cutter(s) can be movable independently or together with the connector holder.
• the connector holder is movable in relation to the tubing holder 2;12;62 to a position where the or each cut length of tubing 3;13;63 and the sterile tubing connector 7;17;67 are aligned and can be urged together.
• the compartment suitably extends in a direction essentially parallel to the tubing port(s) and to the length(s) of tubing received in the tubing holder(s).
• the apparatus also comprises a sterilant reservoir 33, adapted to supply sterilant to the sterilant applicator(s) 4;14;64, such as each sterilant applicator.
• the sterilant reservoir may e.g. comprise a breakable ampoule 31 containing a sterilant.
• Such a breakable ampoule may e.g. be contained in an ampoule compartment 30, which is fluidically connected to the or each sterilant applicator(s) via fine tubing or conduits 32 inside one or more of the tubing holder(s) and/or the connector holder.
• the sterilant will partially fill the ampoule compartment and flow towards the sterilant applicator(s) by e.g. gravity or capillary suction, filling or partially filling the sterilant applicator(s) with sterilant.
• the sterilant reservoir 33 may also be integrated with the or each sterilant applicator(s) 4;14;64. It is e.g.
• sterilant applicators pre-filled with sterilant and covered with e.g. a protective film which may be removed before insertion of the tubing length(s).
• a protective film or cap may e.g. be integrated with a protective film or cap covering a port, as described above.
• applicator(s) may as described above be e.g. an aqueous solution comprising hydrogen peroxide, e.g. a solution comprising 3 - 60 wt % or 25 - 35 wt % hydrogen peroxide.
• the apparatus further comprises a movable cover 20 (not shown in Figure 1), which in a closed position delimits a cutting and connecting compartment 9;19 and in an open position allows removal of the cut and connected length(s) of tubing.
• the device can e.g. be supplied with the cover in a closed position and presterilized by e.g. gamma irradiation, such that the cutting and connecting compartment is substantially sterile. After cutting the tubing length(s) and urging together with the connector, the cover may then be opened to allow the removal. The cover may be temporarily locked in the closed position by a removable seal or tape etc. to prevent premature opening of the cover.
• the movable cover 20 may be one integral cover or it may be divided into a plurality of part covers.
• the apparatus 1;11;61 may be adapted for either linear or rotary movement of the connector holder 6;16;66 and cutter(s) 5;15;65 in relation to the tubing holder(s) 2;12;62.
• Linear versions are illustrated in Figs. 1-4 and a rotary version in Fig. 7. Specific advantages of the rotary version are that the cutters 65 may be easier to keep sterile and that a compact design can be achieved.
• the tubing connector 7;17;67 is a hose barb connector.
• the tubing connector can further be e.g. a straight two-way connector 7;17;67, a three-way T-connector 40 or an angled connector, such as an angled two-way connector 41, as illustrated in Fig. 4.
• the tubing connector 50 comprises a port 51 covered with a removable protective film or cap 52. Suitable such ports are described in e.g. US6679529, WO1994008173A1, which are hereby incorporated by reference in their entirety.
• the removable film or cap ensures that the connector with the attached tubing length(s) is substantially sterile and it can later be connected aseptically to another port with removable film or cap without having to use a LAF bench or similar.
• the tubing holder is adapted to receive a length of tubing at a point distant from the ends of said length of tubing.
• the tubing holder may comprise a recess arranged to receive a portion of said length of tubing and a movable cover (either separate or forming a part of movable cover 20) arranged to be movable from an open position to a closed position where it covers the recess with the tubing portion.
• a movable cover either separate or forming a part of movable cover 20
• One or more sterilant applicators is/are arranged to apply sterilant to the tubing portion, such as over the entire tubing portion received in the tubing holder.
• the sterilant applicator(s) can e.g.
• the apparatus can be used to disconnect a length of tubing already attached in both ends.
• the apparatus can suitably comprise two sterile tubing connectors, of which one or both can be blind connectors and/or one or both can be tubing connectors comprising a port covered with a removable protective film or cap as described above and in Fig. 5. It is of course also possible to use a three-way tubing connector as illustrated in Fig. 4 b) in order to connect a further length of tubing. If the length of tubing is filled with liquid, it is advantageous if it is drained before disconnection.
• the tubing connector 57 is prepared from a deformable plastic and a central part of said tubing connector is concentrically contained in a notched metal tube 58 adapted to upon external compression cut off the tubing connector and fluidically seal off the cut tubing connector ends.
• the inside of the metal tube may have a sharp transverse edge, which upon compression with e.g. a pair of pliers can cut the plastic of the connector.
• the connector Upon a slight bending of the compressed assembly, the connector can be cut off, leaving the ends sealed by the compressed metal tube ends. This allows for convenient aseptic disconnection once the tubing connection is no longer needed.
• the metal tube can suitably be made from an easily deformable metal such as e.g.
• the deformable plastic may e.g. be a polyolefin such as polypropylene or polyethylene.
• the or each cutter 5;15;65 comprises a blade or a sharp edge of the connector holder 2;12;62.
• the movements in c) and d) may be linear or rotational and the position in d) may be a linear position or an angular position.
• the flexible tubing can be flexible plastic tubing (e.g. plasticised PVC) or flexible elastomeric tubing (e.g. thermoelastomer tubing or rubber tubing, including silicone rubber).
• the tubing can suitably be flexible enough to allow manual cutting with a blade and is suitably free from metal reinforcements.
• the wall thickness of the tubing may e.g. be 0.5-5 mm, such as 1-3 mm, and the inner diameter of the tubing may e.g. be 1-20 mm, such as 2-10 mm.
• the length(s) of tubing 3;13;63 may be sealed at both ends and presterilized, e.g. by exposure to gamma irradiation. The sealed ends may have circular cross sections to allow for easy introduction in circular cylindrical ports.
• the method further comprises before step b) a step of fluidically connecting the sterilant in the sterilant reservoir 33 with the or each sterilant applicator 4;14;64.
• the sterilant reservoir comprises a breakable ampoule 31 with sterilant (e.g. an aqueous hydrogen peroxide solution)
• this step may comprise the breakage of the breakable ampoule.
• the method further comprises a step of breaking an ampoule 31
• the method further comprises a step of opening a cover 20 between steps e) and f).

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• Health & Medical Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
• Biomedical Technology (AREA)
• Pulmonology (AREA)
• Engineering & Computer Science (AREA)
• Anesthesiology (AREA)
• Epidemiology (AREA)
• Hematology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Infusion, Injection, And Reservoir Apparatuses (AREA)
• Apparatus For Disinfection Or Sterilisation (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (1)

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Family Applications (1)

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Cited By (4)

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Citations (9)

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• 2014
  • 2014-05-19 EP EP14801447.5A patent/EP2999513B1/en active Active
  • 2014-05-19 CN CN201480029055.3A patent/CN105209107B/zh active Active
  • 2014-05-19 JP JP2016515314A patent/JP6442486B2/ja active Active
  • 2014-05-19 US US14/892,649 patent/US10195416B2/en active Active
  • 2014-05-19 WO PCT/SE2014/050609 patent/WO2014189446A1/en not_active Ceased

Patent Citations (9)

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