Patent Publication Number: US-2017361966-A1

Title: Vial filling system with localized clean zone

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Patent Application Ser. No. 62/350,801, filed on Jun. 16, 2016, the entire disclosures of which are incorporated herein by reference. 
    
    
     The current disclosure concerns systems and methods for filling vials with a medium for therapeutic or diagnostic use, such as biological media. In particular, the disclosure concerns processing of such vials for transport in a more efficient manner while maintaining a level of sterility if required. 
     BACKGROUND 
     The packaging for storage and transport of fluids or other materials for a variety of therapeutic or diagnostic purposes is an important aspect of providing such materials to hospitals, physicians, patients or other end users. Medications have been placed in bottles, vials or other containers for easy use, such as by inserting a needle into a bottle to draw a dose or by applying the contents of a container directly to the patient or to equipment treating him or her. 
     Maintaining sterility for the vials and the filling and packaging process helps prevent infection or loss of effectiveness. For biological fluids or materials, sterility in preparation and packaging is essential, as microbes or other foreign substances can render such substances not merely ineffective but potentially destructive to a patient. Sterile filling followed by cryogenic storage and transportation is recommended or required for such biological materials. 
     Current options for containing and storing therapeutic fluids so as to maintain sterility include “open” vials, i.e. small containers with a threaded cap that is removed before filling and screwed on after the vial is filled. Such screw-top vials require that the cap be removed in a clean-chamber or other clean-room environment. While sterile filling in such an environment is possible, and the threaded connection between cap and vial provides an initial barrier to outside contamination, exposure of such vials to cryogenic temperatures (e.g. suspension in liquid nitrogen) can risk maintaining that mechanical seal. Another option is a “closed” system, in which each vial has a re-sealable septum through which the vial is filled. The septum is punctured and the vial is filled through the puncture, with the septum then being re-sealed with a laser. The puncturing, filling and sealing components must be kept in a clean room environment. The outer surface of the septum must also be cleaned or kept clean prior to puncturing so that there are no contaminants that can transfer into the vial, as by attaching to a filling needle. 
     Each of these methods require that vials be sterilized initially and then maintained in a clean room environment between the moment the individual vials are accessed by the person operating the filling system and the point at which the filled vial is sealed or re-sealed. That requires maintenance and validation of a clean room system, with cleaning and administrative procedures that add substantial cost and time to the filling process. A method in which filling could be performed, or a filling system operated, outside of a clean room environment would be desirable. 
     SUMMARY 
     Among other things, there is disclosed a vial-filling apparatus having a localized clean-air zone, allowing filling of sterile vials under a local sterile condition and without necessitating a full clean-room condition or protocol. Vials and other features associated with the system are also disclosed. In particular, disclosed is a system that includes a disposable clean-air zone including a manifold having an upper surface and a lower surface bounding an internal space, a clean-air inlet communicating with the internal space, and at least one slot in the lower surface adapted to accept at least a portion of a vial, so that such portion of the vial may enter the space through the slot. The manifold can include at least one opening in the upper surface and over the slot, whereby fluid can be passed through the opening and into a vial at least partially in the clean-air zone. 
     Particular embodiments include a fluid transfer assembly at least partially within the opening, the fluid transfer assembly including a nozzle extending into the space in the manifold and sized and configured to enter a fill tube of a vial, a fluid port in fluid communication with the nozzle, and an air flush port in fluid communication with the nozzle. Each such fluid transfer assembly can be fixed with respect to the manifold, and there may be multiple such fluid inlets above one or more such slots. The manifold includes a shroud around three sides of the slot in some embodiments, the shroud extending down from the lower surface. A guide may extend down from the lower surface and curve toward the slot, whereby clean air exiting the space through the slot is guided toward the slot. Such a guide may include a lower portion spaced from the slot and lower surface sufficiently to permit a portion of a vial to pass between the lower portion of the guide and the slot and lower surface. The clean-air inlet may be in the upper surface to one side of the manifold, and the slot may be on an opposite side of the manifold. For example, the clean-air inlet may be in the middle of the manifold, with the space of the manifold bounded by walls extending toward the slot and outward from the clean-air inlet. 
     The system may include one or more vials to be filled, and in particular embodiments each such vial has a chamber for holding fluid, a fill tube, a vent tube, and a flange around the fill tube, the flange sized and configured to enter the clean-air zone. At least one covering may be attached to one or more of the flanges of the vials and covering the respective fill tubes of the flanges prior to filling, to prevent contaminants from entering the fill tube. Such a covering may be attached to the flange by an adhesive, and/or by grips attached to the flange. The vials may include a rim extending above the flange and communicating with the fill tube, with the covering engaging both the rim and the flange. The covering is removable prior to filling so that filling need not be performed through the covering. The manifold may be movable with respect to the vials along an axis of the fill tube. 
     Embodiments of a system for filling vials with a biological fluid while maintaining sterility of the vials are also disclosed, which include a filling apparatus, a set of one or more vials to be filled, each of the vials having a respective fill tube with an upper flange, and a conveyor for moving the vials with respect to the filling apparatus. A manifold for providing a clean-air zone around the flanges of the vials during filling is connected to the apparatus. The manifold includes a clean-air inlet communicating with the internal space, and at least one slot in the lower surface adapted to accept at least a portion of a vial, so that such portion of the vial may enter the clean-air zone. The manifold may include a fluid inlet in the upper surface and over the slot, whereby fluid can be passed through the fluid inlet and into a vial at least partially in the clean-air zone. The fluid inlet may be a part of a fluid transfer assembly fixed with respect to the manifold, the fluid transfer assembly including a nozzle extending into the space in the manifold and sized and configured to enter a fill tube of a vial and an air flush port in fluid communication with the nozzle. 
     A system is disclosed that can perform rapid filling of vials along with sealing or re-sealing, labelling and packaging the filled vials for cryogenic storage. The system and its structures are designed to complete the filling of the vials within a localized sterile filling zone, removing the need to operate in a clean-room environment. The localized sterile filling zone includes a pre-sterilized, disposable component that in certain embodiments is changed out every time a new batch of media is to be filled into vials. This reduces the burden of cleaning the system between batches. 
     In particular embodiments, a closed heat-sealable vial is used, with the vials pre-packaged with a removable protective cover for the filling port of each vial. As the vials enter a sterile-air filling zone, the protective cover is removed. The sterile-air filling zone includes or is provided by a pre-sterilized, disposable component, and so does not require any cleaning prior to its use for filling. The filling zone is packaged, sterilized, and then installed on the filling machine. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic representation of a system for filling vials. 
         FIG. 2  is a side elevational and part schematic view of a portion of an embodiment of the system of  FIG. 1 . 
         FIG. 3  is a top and part schematic view of the portion shown in  FIG. 2 . 
         FIG. 4  is a perspective view of an embodiment of a vial used with the portion shown in  FIG. 2 . 
         FIG. 5  is a side elevational view of the embodiment shown in  FIG. 4 . 
         FIG. 6  is a top view of the embodiment of  FIG. 5 . 
         FIG. 7  is a side elevational view of an embodiment of a vial used with the portion shown in  FIG. 2 . 
         FIG. 8  is a side elevational view of an embodiment of a vial used with the portion shown in  FIG. 2 . 
         FIG. 9  is a side elevational view of an embodiment of a vial used with the portion shown in  FIG. 2 . 
         FIG. 10  is a side elevational and part schematic view of the portion shown in  FIG. 2 . 
         FIG. 11  is a front view of a set of several vials as shown in prior figures in an embodiment of a tray. 
     
    
    
     DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS 
     For the purposes of promoting an understanding of the principles of the disclosure, reference will now be made to the embodiments illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the claims is thereby intended, and alterations and modifications in the illustrated devices and methods, and further applications of the principles of the disclosure as illustrated therein are herein contemplated as would normally occur to one skilled in the art to which the disclosure relates. 
     Referring now to  FIG. 1 , there is shown schematically an embodiment of a system  20  for filling vials  22 , which can be operated outside of a clean room environment. System  20  includes a filling machine  24  that performs the necessary steps in filling vials  22 . As will be discussed further below, at least one disposable transfer piece or assembly  26  for filling vials, and a disposable manifold  28  for providing a clean air zone, are fixed or otherwise connected to machine  24 . 
     Vial  22  in the illustrated embodiment includes a rigid tubular body  32  with an internal chamber  34  for holding a fluid. A filling tube  36  is attached to vial  22 , as is a vent tube  38 . Filling tube  36  has a circular flange  40  in this example for connection of and/or sealing to a filling mechanism. The flange is preferably molded out of the same material as the filling tube  36 , but may also be a separately molded piece inserted into the filling tube. The opening to tube  36  is centered with respect to flange  40  in the illustrated embodiment. In some embodiments, flange  40  may be centered over body  32 , so that it occupies the same cross-sectional or lateral extent as body  32 . In some other embodiments, the flange consists of a continuous strip of flexible material, serving to link a row of vials together. Such a continuous flange may have sequential holes in it between the successive tube openings and serve as a locator point for a traction feed. Vent tube  38  includes a filter  42 , fitted in this embodiment within tube  38  at or just above the point where tube  38  joins body  32 . In the illustrated embodiment, tubes  36  and  38  are aside one another in a top surface of vial  22 . Each tube  36  and  38  has a respective internal passage that communicates with internal chamber  34 . As will be discussed further, during filling a fluid passes through filling tube  36  into chamber  34 , while vent tube  38  allows passage of air displaced by the fluid to escape through filter  42 . Filter  42  prevents contaminants from entering chamber  34  via tube  38 . Vial  22  may include features disclosed in U.S. Pat. No. 8,936,905 and/or U.S. Publication No. 2010/0196873, incorporated herein by reference in their entireties. 
     Tubes  36  and  38  may be made of a flexible plastic material, while body  32  may be of a rigid plastic material to withstand breakage or other damage that may affect the contents of vial  22 . Tubes  36  and  38  are connected to body  32  in a sealed fashion, for example by insertion of tubes  36  and  38  into holes in body  32 , or by insertion of a respective collar or fitting extending from body  32  into each of tubes  36  and  38 . An appropriate seal between tubes  36  and  38  and body  32  may be made by a weld or adhesive attachment, as specific examples. The material of tubes  36  and  38  in a particular embodiment is an overmolded material, heat-sealable by bars pressing in laterally against one or both of tubes  36  and  38 . Another example, shown in  FIG. 7 , shows a vent tube  38 ′ that is initially sealed at the top by a snap-off or break-away tab T. Tab T can be removed during filling, so that vent tube  38 ′ can allow passage of air from within chamber  34 . Alternatively, tube  38 ′ may remain sealed, to be cut or broken open (as with break-away tab T) by the clinician when the product is to be withdrawn from the vial. 
     Vial  22  includes an external covering  44  that protects the opening of filling tube  36 , and in the illustrated embodiment covers, sticks to and/or wraps around the surface of flange  40 . Covering  44  maintains filling tube  36 , and its passage and chamber  34  of vial  22 , isolated from the outside environment until it is removed at the time of filling vial  22 . In particular embodiments, covering  44  is a tape, band, strip, sticker, seal or other surface attached to the top of tube  36  and flange  40  prior to gamma sterilization of vial  22 . 
     For example, covering  44  may be a single elongated strip or tape covering multiple or all of a set of vials  22 . Covering  44  may be used by an operator and/or by system  20  to manipulate and align the set of vials  22 . The operator or the system can hold the set of vials  22  by covering  44  and use it to move the set of vials  22  to the filling apparatus of system  20 . The conveyor of system  20  (see, e.g.,  FIG. 3 ) can hold and move the set of vials  22 , or the covering  44  atop them, during filling. A leader of covering  44  can extend from vials  22  (e.g. approximately 10 to 20 inches from the set of vials  22 , indicated in  FIG. 9 ) so as to be threaded or otherwise attached onto or over one or more spools or rollers (not shown), so that the spool(s) or roller(s) lift covering  44  off of vials  22  and/or take up covering  44  as vials  22  are filled. The tape or other covering, including the leader, may be configured with periodically placed holes, placed between successive vials. The holes may serve as location points for a traction feeder. Covering  44  may have protrusion(s) or plug(s)  45  that are initially fitted into the end of respective fill tubes  36  of each vial  22 . Removing covering  44  removes such protrusions from each fill tube  36  to open it for filling. 
     Covering  44  may wrap around and/or stick to flange  40  (e.g.  FIGS. 7-9 ). As another example, flange  40  may include knobs or grips  46  (e.g.  FIG. 8 ) over or around which covering  44  can be placed, to help maintain covering  44  in place or provide leverage for its removal. Examples of such knobs  46  may penetrate into holes in covering  44 , similar to a snap for clothing. Another example of a grip is a hook-and-loop connection between covering  44  and flange  40 . 
     In some embodiments, fill tube  36  may extend beyond the upper surface of flange  40  (e.g.  FIGS. 7-8 ) to form a rim  47  that will protrude into covering  44  or permit entrance of plug  45  and enhance contact and sealing of covering  44  over tube  36 . As one example, rim  47  may have a thin skin of plastic or other sealing substance over it. A filling nozzle may be sharp enough and/or forced downward with sufficient force to penetrate such skin and thereafter inject fluid into tube  36  and chamber  34 . If no rim  47  is present, such skin may be placed or formed on flange  40  over tube  36 . In addition, or alternatively, fill tube  36  may be closed and have a parting line or puncture location, so that insertion of a nozzle into fill tube  36  opens fill tube at such parting line or puncture location, to permit filling. 
     Such a vial design has an interior (i.e. chamber  34  and tubes  36 ,  38 ) that is sterile, and is initially closed and isolated from the outside environment until filling operations commence on that vial, so that the sterility is maintained until the vial is filled. The outside surfaces of the vial that are contacted or penetrated during filling are covered (e.g. with covering  44 ) prior to gamma or other sterilization of the vial. Covering  44  is removed immediately before filling commences in preferred embodiments. 
     Several vials  22  may be attached or packaged together to move through the filling process, as indicated in  FIG. 2 . For example, a group of fifteen vials  22  is shown, and they may be connected indirectly, as by placement in a tray (e.g.  FIG. 10 ) that moves through the filling process, or directly, as by one or more connecting tabs formed or attached between adjacent vials  22 .  FIG. 2  shows a set of vials  22  without a covering  44 , and it will be understood that such a set could include a covering  44  as discussed herein. Bodies  32  of the vials  22  may be initially taped or otherwise linked together prior to introduction into system  20 . In that case, the tape or other link can be treated for easy separation of individual vials, as by scoring or perforating tape. Such a hold may be close and tight, e.g. with each vial  22  touching the next or with only a small gap, or it may include slack between adjacent vials  22  so that the vials may be spaced once they leave a box in which they are initially stored or when they leave system  20  after filling. As indicated above, covering  44  may be attached across a set of vials  22 , and may be used to hold the vials together. It will be understood that different numbers of vials may be connected together in different embodiments, depending on the size or capacity of filling machine  24  or manifold  28 , or other practical considerations. 
     The sterile initial packaging of vials  22 , prior to filling and for easy feeding into filling system  20 , is also contemplated. In particular embodiments, empty vials  22  may be packaged (sterile) in rows in a long box, with each row having its own covering  44  with a leader for feeding into system  20 . System  20  pulls the vials to the filling area (with a localized clean-air zone such as manifold  28 ) row by row, in a manner similar to that used for pulling bullets into a gun. If the rows are connected together, e.g. with a common covering  44 , all vials  22  can feed from the box into system  20  in a smooth motion. Alternatively, particular rows may be separate in order to attach and be fed into separate systems  20 , or separate filling and sealing apparatus. A box of empty vials  22  may include a spring or biased surface or platform (e.g. in the bottom or rear of the box) to assist in pushing vials from the box and toward or into system  20 . An example is a pin that extends through a slot in the box, such as through the bottom of the box, to advance the vials. 
     In other embodiments, a ribbon may run through a box of vials and around the vials, so that as the ribbon is pulled, the vials advance from the box toward or into system  20 . Preferably, such a ribbon is made of a slippery or non-stick material that allows the ribbon to easily slide along the vials. The vials would not rotate out of a desired filling orientation in that case. The ribbon passes through a fixture at the end of the box with a bearing that prevents the vials from rotating as the ribbon is pulled from the box. The fixture pushes the last vial in the box forward, as with a spring bias, while allowing the ribbon to slide freely over it as the slack is pulled up. 
     In some embodiments, multiple rows of vials may be within a single box. In such cases, when a particular row of vials is emptied from the box, the box is shifted laterally (manually or automatically) so that the next row of vials is in line for loading. 
     For filling vials  22 , disposable transfer assembly  26  is provided. It will be understood that “assembly”  26  may be a single piece or a collection of pieces connected or fixed together. A single assembly  26  is shown in  FIG. 10 , and as shown in  FIGS. 2-3 , multiple such assemblies can be used together. As indicated, the transfer assembly  26  includes a fluid inlet  50 , an air flush inlet  52 , a collar  54 , and a nozzle  56 . Fluid inlet  50  permits fluid to enter and pass through nozzle  56  into tube  36  of vial  22 . Inlet  50  is connected to a reservoir of fluid (not shown) via a disposable conduit  51   a . Air flush inlet  52  permits clean air to enter from a conduit  51   b  and pass through nozzle  56  into tube  36  of vial  22 . Air pressure through inlet  52  can push or pull fluid remaining in tube  36 , and may provide a clean air buffer over fluid within chamber  34  and/or tube  36  of vial  22 . In particular embodiments, collar  54  joins nozzle  56  and a fitting that includes both inlets  50  and  52 , and/or provides a surface that approaches or abuts flange  40  of vial  22  during filling. Collar  54  may also provide a connection with manifold  28 . The example of nozzle  56  is shown as cylindrical or conic, and may have a different shape compatible with tube  36 . Nozzle  56  may also have a sharpened forward end. Nozzle  56  remains in a clean-air zone, with clean air (e.g. flowing clean air) always surrounding it. In some embodiments, nozzle  56  has a flange (not shown) for engaging or mating with flange  40  on fill tube  36  during filling. Alternatively, collar  54  adjoining nozzle  56  can engage or seal to flange  40  during the filling process, while nozzles  56  enter fill tube  36  to dispense fluid into tube  36 . 
     Pumping of the fluid and control of its flow (as by one or more valves) is conducted by machine  24 , external to kit  26 . Examples of parts or embodiments of aspects of an exemplary machine  24  are shown and described in U.S. Application Ser. No. 62/234,943, incorporated herein by reference in its entirety. For instance, machine  24  may include actuated pinch valves to open and close tubes  36  and/or  38 . An externally-actuated syringe, or roller or peristaltic pump, may provide pumping operation to force fluid toward and into inlet  50 . In embodiments in which syringe pumps are used, clean air chamber  28  may preferably also hold or contain the syringes. For example, when the back side of the syringe plunger is exposed to the environment, the plunger is not necessarily considered an aseptic seal. To address this, the syringe bodies should have positive pressure clean air washed over them in such a way that no contaminants can enter the back side of the syringes. In one embodiment, the syringes are mounted to or inside of the disposable sterile air chamber  28 . The plungers are attached to actuators from below. Sterile air washing down from chamber  28 , as further noted below, keeps any contaminants from the actuators from coming up and entering the back side of the syringe at the plunger. 
     Embodiments of machine  24  may include other pieces, as indicated schematically in  FIGS. 3 and 10 . Sealing elements, such as heat or RF sealing jaw  60  and head  62  are provided for sealing tubes  36 ,  38  after filling is complete. Such elements may be for an individual vial, or may be elongated elements for sealing multiple vials at once. The embodiment indicated in  FIG. 2  includes a single jaw  60  and three heads  62  for sealing six vials  22 . A conveyor (represented schematically by sprockets  64  and belt  65 ) links to one or more of flange  40 , tube  36  and tube  38  of one or more vials  22 , so that vials  22  (collectively or individually) can be moved under nozzle(s)  56  for filling of each respective vial. 
     Heat sealer  60 ,  62  may be fixed with respect to manifold  28 , as noted above, or in other embodiments may be mounted on a laterally-sliding actuator. For example, the sealer clamps vials in the filling zone, i.e. below manifold  28 , and travels along with the filled vials while heat sealing is occurring. A new set of vials can enter the filling zone for filling while sealing of the just-filled set of vials is being finished. A lateral spring return moves the sealer back to the filling zone when sealing is complete, to begin the clamping and sealing of the next set of vials. 
     Alternative filling and sealing embodiments may include a needle that penetrates a septum on the flange. The septum may be re-sealed with a laser. Such needle penetration and filling along with the laser sealing is all conducted within a disposable clean-air chamber. 
     Clean-air chamber or manifold  28  attaches to one or more transfer assemblies  26 . As shown in the embodiment of  FIGS. 2-3 , a single manifold  28  may attach to several assemblies  26 , for example six or more. Manifold  28  provides a clean-air zone or space around fill tube  36  and flange  40  of each vial  22  that is within it. In the illustrated embodiment, manifold  28  is a generally laminar body  70  having an upper wall  72 , a lower wall  74  and a side wall  76 . Together the walls define an inner space  78 , that in the illustrated embodiment is generally planar, of a constant height. Walls  72  and  74  in this embodiment are parallel to each other, and side wall  76  extends between and perpendicular to them. The embodiment of  FIG. 3  shows manifold  28  in the rough shape of an irregular pentagon, having an apex  80  between angled edges  82  that are of the same length. The longest edge  84  is opposite apex  80 . 
     A clean-air inlet  86  has an inner passage that communicates with space  78 . In the illustrated embodiment, inlet  86  is in the upper wall  72  at apex  80 , with edge  84  opposite inlet  86 . Inlet  86  may have features for secure connection of a clean-air conduit  51   c , such as lip or flange  87 . 
     Along edge  84  opposite apex  80  are upper openings  90  through upper wall  72 , and one or more lower elongated channels or slots  92  through lower wall  74 , each communicating with space  78 . A collar or rim  94  extends up from upper wall  72  and extends around openings  90 . The illustrated embodiment shows six openings  90 , one for each filler assembly  26 , with one rim  94  around them. In other embodiments, there may be fewer than one opening for each kit, for example a single elongated opening in which multiple kits can fit, or there may be one rim  94  per opening  90 . Slot  92  extends along the whole length of edge  84  in the illustrated embodiment, and is surrounded on three sides by a shroud or skirt  96 . Channel(s)  92  allow for entry of the vials in to a filling zone, and also allow for laminar exit of the air out of the filling zone. While one channel  92  is shown in  FIG. 10 , in other embodiments there may be multiple channels, e.g. one for every two vials  22  being filled. In the illustrated embodiment, shroud  96  extends away from and on either side of edge  84 , so that shroud  96  defines an area that may be thought of as part of channel  92  that is below lower wall  74 . A curved guide or boss  98  connects to lower wall  74  between channel  92  and apex  80 , and curves away from apex  80 . Guide  98  forms a forward end of the area within shroud  96 , and extends a sufficient distance away from lower wall  74  and a sufficient distance toward edge  84  so that it can extend under at least a portion of a flange  40  of a vial  22 , as seen in  FIG. 10 . 
     Assemblies  26  are fitted to body  70  so that nozzle  56  extends into or through space  78  and remains in that clean-air zone. In particular embodiments, collar  54  of each individual kit  26  is securely fitted within rim  94 , as by a press or interference fit, or via an adhesive between them. In other embodiments, collar  54  is movable up and down (i.e. along the axis of nozzle  56 ) within rim  94 . A conduit (not shown) for conducting clean air is fitted to or within inlet  86  and extends to a pump or other source (not shown). As used herein, “clean air” is intended to mean air from which potential contaminants have been removed, for example air filtered with a pore size smaller than known contaminants, such as a filter having a pore size of 0.2 microns or less. The filter is preferably disposable and integrated with the rest of the disposable clean-air zone. Connection of the disposable clean-air zone to the filling machine includes hooking a pressurized air line to the disposable filter which in turn is connected to the clean-air zone. Pressurized clean air enters space  78  through inlet  86 . Space  78  constitutes some or all of the clean-air zone of this embodiment. Most or all of the clean air passes through space  78  with laminar exit through channel  92 . Preferably little or no clean air passes between rim  94  and collar  54  or through or aside assembly  26 , but rather constantly surrounds nozzle  56  during use so that no non-clean air approaches nozzle  56  and flange  40 . Guide  98  tends to push clean air passing out of space  78  away from apex  80  and toward edge  84 . 
     In this way, a constant localized clean-air zone is maintained above vials that are initially sterilized, around the sterilized nozzle through which a desired fluid is dispensed into the vials. As noted above, an example of system  20  includes a single manifold  28  in which six kits  26  are fitted. A set of vials  22  is conveyed to manifold  28 . Manifold  28  is laterally stationary in this embodiment, fixed to external structure or machinery, and vials  22  are moved into position beneath it for filling. Sealing heads and jaw(s)  60 ,  62  are also indicated schematically, so as to seal six vials at once. It will be understood that in other embodiments a different number of kits may be employed, and therefore a different number of vials may be filled simultaneously. 
     Vials  22  are conveyed to manifold  28  so that each respective nozzle  56  of kits  26  is directly above filling tube  36  of a respective vial  22 . Flange  40  of each respective vial sits on or above guide  98  of manifold  28 . Covering  44  is removed from flange  40  either manually or automatically as discussed herein. Clean air passes through manifold  28  as noted above to maintain a clean environment over each covered flange  40 . Assemblies  26  are lowered so that nozzles  56  enter fill tubes  36 . In embodiments in which kits  26  are fixed to manifold  28 , manifold  28  is also lowered so that flanges  40  of vials  22  enter slot(s)  92 , space  78  and/or the area within shroud  96 . 
     With non-clean air prevented from approaching flange  40  and tube  36  of each vial  22  by the flow through manifold  28 , filling of vial  22  takes place. The desired fluid is pumped through fluid inlet  50 , nozzle  56  and fill tube  36  into chamber  34 . When a desired amount of fluid has been pumped into vial  22 , and any clean air flush or air-pressure manipulation of fluid via flush inlet  52  and nozzle  56  is accomplished, tubes  36  and  38  are sealed by heat seal heads and jaw(s)  60 ,  62 . Sealing may occur prior to or after kits  26  (and manifold  28  if fixed to kits  26 ) are lifted away from vials  22 . Sealing should occur while flanges  40  are in the clean air zone, i.e. above guide  98  and/or within shroud  96 . Completion of sealing and lifting of the kits complete a cycle. Vials  22  are then moved so that the respective nozzles  56  of kits  26  are directly above filling tubes  36  of the next set of empty vials  22 . The cycle repeats, with the localized clean air zone established over the vials  22 , coverings  44  are removed from vials  22 , and filling tubes  36  and flanges  40  remain in the clean air zone until the filling tube  36  is sealed. 
     Machine  24  with its disposable transfer kit  26  and disposable chamber  28  provides a localized clean-air zone over the vials  22  prior to filling them. In the exemplary embodiments shown, kit  26  is integrated with or otherwise fixed to manifold  28  and its clean air zone, forming a disposable unit. Filling system features such as filling manifolds, tubing, pinch valves, tubing pumps or syringe pumps are fitted to the disposable unit of the manifold  28  and kit  26 . Sets of vials  22  are placed into system  20  and operated upon by the disposable unit. In alternative embodiments, manifold  28  and kit  26  can be initially integrated into original vial packaging. The set of vials are connected to the system mechanically and filling and sealing of the vials would occur within such packaging. 
     Once vials  22  are filled, the respective flanges  40  may be used to attach appropriate labelling. A sticker, imprint or other label with necessary information (e.g. identification of the fluid within the vial, date filled or “use by” date, lot information, and the like) may be attached to flange  40  of each vial  22 , or to at least one vial  22  of a set that remains together after filling. Alternatively, or additionally, labelling may be imprinted directly on the body  32  of a vial  22 , or on a label pre-affixed to body  32 . The labelling may be applied to the vial body in parallel with another vial operation such as during filling or heat sealing of the filling tubes. The vial label may be applied using an ink jet print head applying ink directly to the vial. 
     Vials  22  as described herein may be made by any effective method. One such method is by creating the vial body  32  and filter  42  as a one-piece thermoplastic item using blow-molding techniques. 
     A tray  100  may be provided, particularly designed to hold multiple vials  22  and to transfer such vials to system  20  for the filling process. Tray  100  may be attached to a conveyor, as indicated above, or may be connected or attached to manifold  28  during the filling process. Tray  100  may also have a removable lid for use during shipping and storage of filled vials. Preferably, tray  100  is engineered to provide controlled rate freezing in a cryogenic freezer. 
     The filling system  20  is modular in form. It includes in particular embodiments identical filling units that have a predetermined throughput. The transfer kit  26  conduits (not shown) may be connected using sterile welding or multiple drain ports on a reservoir to allow multiple kits  26  or systems  20  to pull fluid from the same source. Throughput is accordingly increased, i.e. the number of filled vials per unit time is larger, and redundancy is facilitated, so that a malfunction or other problem with one kit  26  or system  20  does not halt all filling of vials. 
     As previously noted, manifold  28  and assemblies  26  may be disposable in particular embodiments. A particular manifold  28  and assemblies  26  attached to it may be used for a particular fluid or batch of fluid coming from a reservoir, and/or for a particular number or batch of vials. Once the fluid or vials are exhausted, or a change in fluid to be dispensed is desired, manifold  28  and assemblies  26  (with disposable tubing or other conduits connecting them to clean air and/or fluid sources, if appropriate) may be disconnected and discarded in a suitable manner. A new manifold  28  and assemblies  26  (and any necessary conduits), previously sterilized, are connected to machine  24 . Filling of vials can then commence. 
     While the subject matter herein has been illustrated and described in detail in the exemplary drawings and foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only the preferred embodiment(s) have been shown and described and that all changes and modifications that come within the spirit of the disclosure are desired to be protected. It will be understood that structures, methods or other features described particularly with one embodiment can be similarly used or incorporated in or with respect to other embodiments.