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. Patent 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 51a. Air flush inlet 52 permits clean air to enter from a conduit 51b 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 Serial 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 51c, 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.

As examples of the features, combinations and devices disclosed herein, the following clauses are provided:

1. A vial-filling apparatus, comprising:

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,

wherein the manifold also includes 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. 2. The apparatus of clause 1, further comprising 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.

3. The apparatus of clause 2, wherein each fluid transfer assembly is fixed with respect to the manifold. 4. The apparatus of any preceding clause, including multiple said fluid inlets above one or more said slots.

5. The apparatus of any preceding clause, wherein the manifold includes a shroud around three sides of the slot, the shroud extending down from the lower surface.

6. The apparatus of clause 5, wherein the manifold includes a guide extending down from the lower surface and curving toward the slot, whereby clean air exiting the space through the slot is guided toward the slot.

7. The apparatus of clause 6, wherein the guide includes 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.

8. The apparatus of any preceding clause, wherein the clean-air inlet is in the upper surface to one side of the manifold, and the slot is on an opposite side of the manifold. 9. The apparatus of clause 8, wherein the clean-air inlet is in the middle of the manifold, and wherein the space of the manifold is bounded by walls extending toward the slot and outward from the clean-air inlet. 10. The apparatus of any preceding clause, further comprising a plurality of vials to be filled, each such vial having 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.

11. The apparatus of clause 10, further comprising at least one covering, the at least one covering 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.

12. The apparatus of clause 11, wherein the covering is attached to the flange by an adhesive.

13. The apparatus of clause 11, wherein the covering is attached to the flange by grips attached to the flange.

14. The apparatus of clause 11, wherein the vials include a rim extending above the flange and communicating with the fill tube, and wherein the covering engages both the rim and the flange.

15. The apparatus of clause 11, wherein the covering is removable prior to filling so that filling need not be performed through the covering. 16. The apparatus of clause 11, wherein the manifold is movable with respect to the vials along an axis of the fill tube.

17. A system for filling vials with a biological fluid while maintaining sterility of the vials, comprising:

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;

a conveyor for moving the vials with respect to the filling apparatus; and a manifold for providing a clean-air zone around the flanges of the vials during filling, and for connecting to the filling apparatus, the manifold including 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.

18. The system of clause 17, wherein the manifold also includes 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. 19. The system of clause 18, wherein the fluid inlet is 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. 20. Systems or apparatus according to any of the previous clauses, including or using a packaged quantity of sterile empty vials.

21. Systems or apparatus according to clause 20 wherein the sterile empty vials are in rows, with each row having its own covering with a leader for feeding into the system or apparatus.

22. Systems or apparatus according to clause 21, wherein rows are connected together, e.g. with a common covering. 23. Systems or apparatus according to clause 20, wherein the vials are packaged with a spring or biased surface or platform to assist in pushing vials toward or into the system or apparatus.

24. Systems or apparatus according to clause 20, wherein a ribbon runs around the vials so that as the ribbon is pulled, the vials advance toward or into the system or apparatus.

It will be understood that apparatuses and/or systems of any of the above clauses can include or be augmented with features identified in other clauses, or disclosed and described in connection with features identified in other clauses.

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.