Medical container filling apparatus

Abstract

A medical container filling apparatus comprising a medical container, at least one medical container holder 144 and a transport apparatus for moving the medical container holder along a predetermined

Description

Technical Field [0001 ] The present invention provides a medical container filling apparatus. More specifically, the present invention provides an apparatus for selecting, opening, filling, closing and replacing a capped vial for storage. Background Art

[0002] The present invention is particularly well suited to cryovials, but can also be used for non-cryogenic storage containers such as septum capped vials, vials, syringes, tubes, cartridges or bespoke containers. The following background refers to cryovials, but it will be understood that other container types exhibit one or more of the same problems.

[0003] Cryogenic storage vials are containers for storage of biological materials including cells, medicines, vaccines, etc. in very low temperatures (typically below -153°C). Cryogenic vials typically comprise a cylindrical container having a base and an end opening. A lid or cap is provided to seal the vial, typically via a screw thread.

[0004] It is importantthat cryovials are de-capped, filled with a high degree of accuracy and re-capped quickly and reliably. The contact time of biological materials with cryopreservatives should also be minimised to avoid damage.

[0005] Many cryovial filling procedures are highly manual. This can be problematic in terms of cost, accuracy and the ability to operate in a sterile environment. It can also be slow.

[0006] Cryovials for medial use need to be filled in a GMP environment. GMP stands for "Good Manufacturing Practice" and relates to the standards or guidelines required for filling by the relevant organisation. For example, in the UK, GMP inspection is carried out by the Medicines and Healthcare products Regulatory Agency (MHRA), and follows the EU Commission Directive 2003 / 94 / EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use. Generally GMP means consistent high quality, that the medicines are appropriate for their intended use and that they meet the requirements of the marketing authorisation or clinical trial authorisation.

[0007] An example of the prior art is the SARTORIUS (RTM) Fill-lt (TM) system. Some disadvantages of this system are: (1) vials are left uncapped for an extended time period, between multiple fills; (2) there is a significant amount of non-hygienically designed hardware overthe open vials; (3) there is no fill weight confirmation; (4) the general design is not of hygienic construction; and, (5) a single pump is used to fill multiple units, such that accuracy of the fills is reduced.

[0008] These factors increase the potential for product contamination and reduce product consistency. Summary of Invention

[0009] According to a first aspect of the present invention there is provided a medical container filling apparatus for filling a medical container having a removeable cap, the apparatus comprising: a medical container de-capping station; a medical container filling station; a medical container capping station; a medical container indexer configured to present a medical container to the decapping station, the filling station and the re-capping station in successive steps.

[0010] Advantageously the present invention provides minimal time between de-capping, filling and re-capping. [0011 ] The indexer may be a linear or rotary indexer.

[0012] Preferably the indexer has a plurality of equally spaced indexing positions, and wherein the indexing positions relating to the de-capping station, the filling station and the re-capping station are adjacent.

[0013] Preferably the apparatus has a plurality of medical container holders, each medical container holder configured to carry a medical container, wherein the medical container holders are indexed bythe indexer.

[0014] Preferably each medical container holder comprises a formation for engagement with a medical container to inhibit relative rotation thereof.

[0015] Preferably the formation is defined on a replaceable insert.

[0016] Preferably each of the medical container holders comprises a torque reaction formation configured to react torque applied thereto in at least one position of the medical container holder.

[0017] Preferably the orientation of the medical container holder is maintained by cooperating formations on the medical container holder and a moving part of the indexer.

[0018] Preferably the cooperating formations comprise one of a concave shape and a convex shape on the indexer and a corresponding other of the convex shape and concave shape on the medical container holder.

[0019] Preferably the concave shape and a convex shape comprise corresponding "V" shapes.

[0020] Preferably the orientation of the medical container holder is maintained by cooperating formations on the medical container holder and a static part of the indexer.

[0021] Preferably the cooperating formations comprise a projection and a corresponding recess in sliding contact.

[0022] Preferably the projection is a rail on a static part of the indexer, and the recess is a groove on the medical container holder.

[0023] Preferably at least one of the de-capping station and the re-capping station comprise a formation for engagement with the torque reaction formation to inhibit rotation thereof during de-capping and / or re-capping.

[0024] Preferably the apparatus has a weigh cell configured to determine a change in weight of a medical container at the filling station.

[0025] Preferably the indexer is configured to release contact with the medical container or medical container holder at the weigh cell.

[0026] Preferably the indexer comprises a member having an opening receiving the medical container or medical container holder, the member configured to propel the medical container or medical container holder by movement thereof, wherein the opening is configured such that the medical container or container holder can fit within the opening without contacting any sides thereof.

[0027] Preferably the indexer is configured to propel the medical container or medical container with the member onto the weigh cell in a first direction, and to move in a second, opposite, direction to remove any contact between the member and the medical container or medical container holder.

[0028] Preferably the apparatus has a controller configured to carry out closed loop control of a fluid pumpto dispense fluid based on the received signal from the weigh cell.

[0029] According to a second aspect there is provided a method of filling a medical container comprising the steps of: providing: a medical container de-capping station; a medical container filling station; and, a medical container capping station; providing a medical container; indexing the medical container in successive steps between the de-capping station, the filling station and the re-capping station.

[0030] The step of indexing may take place on a linear or circular path. [0031 ] Preferably the method comprises the steps of: providing a medical container holder; holding the medical container with the medical container holder; indexing the medical container holder.

[0032] Preferably the method comprises the steps of: holding the medical container and / or medical container holder in a rotation sense during a de-capping and I or re-capping operation.

[0033] Preferably the method comprises the steps of: providing a weigh cell; and, determining a change in weight of the medical container at the filling station using the weigh cell.

[0034] Preferably the method comprises the steps of: releasing contact with the medical container or medical container holder at the weigh cell such that the medical container or medical container holder is only in contact with the weigh cell.

[0035] Preferably the method comprises the steps of: carrying out closed loop control of a fluid pump to dispense fluid based on a received signal from the weigh cell.

[0036] According to a third aspect of the invention there is provided a medical container filling apparatus comprising: a medical container storage buffer; a medical container transfer system; a medical container filling assembly having: at least one medical container holder; a fluid reservoir; a pump; an outlet; and, a weigh cell configured to determine a change in weight of a medical container in the medical container holder; a controller configured to control the pump and to receive a signal from the weigh cell; wherein the medical container transfer system is configured to move medical container between the storage buffer and the filling assembly; and, wherein the controller is configured to carry out closed loop control of the pump to dispense fluid based on the received signal from the weigh cell.

[0037] Advantageously the present invention provides for a highly accurate real-time measurement of dose.

[0038] Preferably the control comprises the steps of: controlling the pump to dispense a dose of fluid into the medical container in a plurality of stages, comprising the steps of: dispensing a first stage of fluid by controlling the pump; measuring the weight of the dispensed fluid with the weigh cell during or after the first stage to generate measurement data; and, dispensing a second stage of fluid by controlling the pump based on the measurement data.

[0039] Preferably: the data is a rate of dispense; and, the step of dispensing the second stage comprises the step of using the rate of dispense to control deactivation of the pump to meet a desired total dose.

[0040] Preferably: the step of using the rate of dispense to control deactivation of the pump to meet a desired total dose comprises the step of deactivating the pump to account for at least one of: any liquid in flight between the outlet and the medical container; and, any deceleration of the pump. [0041 ] Preferably the control comprises the steps of: controlling the pump to dispense a dose of fluid into the medical container; measuring the weight of the dispensed fluid during or after dispensing; tracking the mean fill weight over multiple cycles; and, adjusting at least one parameter of the pump to correct for any drift in the mean fill weight away from the target fill weight.

[0042] Preferably the controller utilises an algorithm to compensate for airflow disturbances.

[0043] Preferably the controller is programmed with a fluid priming sequence, the fluid priming sequence including the step of ejecting gas between the fluid reservoir and the outlet and detecting when gas has been ejected by a looking for a consistent change in the weight of the medical container during filling.

[0044] According to a fourth aspect there is provided a method of filling a medical container comprising the steps of: providing: a medical container storage buffer; a medical container transfer system; a medical container filling assembly having: at least one medical container holder; a fluid reservoir; a pump; an outlet; and, a weigh cell configured to determine a change in weight of a medical container in the medical container holder; using the medical container transfer system to move a medical container between the storage buffer and the filling assembly; and, carrying out closed loop control of the pump to dispense fluid based on a received signal from the weigh cell.

[0045] Preferably the method comprises the steps of: controlling the pump to dispense a dose of fluid into the medical container in a plurality of stages, comprising the steps of: dispensing a first stage of fluid by controlling the pump; measuring the weight of the dispensed fluid with the weigh cell during or after the first stage to generate measurement data; and, dispensing a second stage of fluid by controlling the pump based on the measurement data.

[0046] Preferably: the data is a rate of dispense; and, the step of dispensing the second stage comprises the step of using the rate of dispense to control deactivation of the pump to meet a desired total dose.

[0047] Preferably: the step of using the rate of dispense to control deactivation of the pump to meet a desired total dose comprises the step of deactivating the pump to account for at least one of: any liquid in flight between the outlet and the medical container; and, any deceleration of the pump.

[0048] Preferably the method comprises the steps of: controlling the pump to dispense a dose of fluid into the medical container; measuring the weight of the dispensed fluid during or after dispensing; tracking the mean fill weight over multiple cycles; and, adjusting at least one parameter of the pump to correct for any drift in the mean fill weight away from the a target fill weight.

[0049] Preferably the controller utilises an algorithm to compensate for airflow disturbances.

[0050] Preferably the controller is programmed with a fluid priming sequence, the fluid priming sequence including the step of ejecting gas between the fluid reservoir and the outlet and detecting when gas has been ejected by a looking for a consistent change in the weight of the medical container during filling.

[0051] According to a fifth aspect of the invention there is provided a medical container filling apparatus comprising: a medical container storage buffer configured to hold and rotate a plurality of stored medical containers about a buffer axis; a medical container handler configured to rotate a transfer head on a circular handler path about a transfer system axis offset from the buffer axis; such that by rotation of one or both of the storage buffer and the handler, the transfer head can be positioned at any of the plurality of medical containers in use.

[0052] Advantageously the present invention provides a highly agile system that can operate in a small footprint

[0053] Preferably the apparatus comprises a reject storage facility configured to store a plurality of rejected medical containers, wherein the medical container handler is configured to selectively place medical containers into the reject storage facility.

[0054] Preferably the medical container handler comprises a chassis comprising: a formation for receiving a medical container storage cassette; and, the reject storage facility.

[0055] Preferably the apparatus comprises a medical container filling assembly having a medical container holder having at least one position on the circular handler path.

[0056] Preferably the medical container holder is configured to indexthe medical container around a circular path to a filling station.

[0057] Preferablythe medical container holder is configured to indexthe medical container around the circular path to a de-capping station and a re-capping station either side of the filling station.

[0058] According to a sixth aspect there is provided a method of handling a medical container comprising the step of: providing a medical container storage buffer configured to hold and rotate a plurality of stored medical containers about a buffer axis; and, a medical container handler configured to rotate a transfer head on a circular handler path about a transfer system axis offset from the buffer axis; rotating one or both of the storage buffer and the handler to position the transfer head at any of the plurality of medical containers in the storage buffer.

[0059] Preferablythe method comprises the steps of: providing a medical container filling assembly having a medical container holder having at least one position on the circular handler path; and, using the medical container handler to move a medical container from the storage buffer to the medical container filling assembly.

[0060] Preferablythe method comprises indexing the medical container around a circular path to a filling station. [0061 ] Preferably the method comprises indexing the medical container around the circular path to a de-capping station and a re-capping station either side of the filling station.

[0062] According to a seventh aspect there is provided a medical container filling apparatus comprising: a medical container; at least one medical container holder; a transport apparatus for moving the medical container holder along a predetermined path; wherein the orientation of the medical container holder is maintained by cooperating formations on the medical container holder and either a moving part of the transport apparatus or on a static part of the filling apparatus.

[0063] Advantageously the present invention provides for a system that can maintain orientation of the holder which is beneficial for container handling.

[0064] Preferably the cooperating formations comprise one of a concave shape and a convex shape on the transport apparatus and a corresponding other of the concave shape and convex shape on the medical container holder.

[0065] Preferably the cooperating formations comprise convex and concave "V" shapes.

[0066] Preferably the cooperating formations comprise a projection and a corresponding recess in sliding contact

[0067] Preferably the projection is a rail on a static part of the apparatus, and the recess is a groove on the medical container holder.

[0068] Preferably each medical container holder comprises a formation for engagement with a medical container to inhibit relative rotation thereof.

[0069] Preferably the formation is defined on a replaceable insert.

[0070] Preferably the filling apparatus comprises at least one of a de-capping station and a re-capping station, wherein at least one of the de-capping station and re-capping station comprise a formation for engagement with the medical container holder to inhibit rotation thereof during de-capping and / or re-capping. [0071 ] Preferably the predetermined path is linear.

[0072] Preferably the predetermined path is circular.

[0073] Preferably the transport apparatus comprises a rotating member.

[0074] Preferably the transport apparatus comprises a rotating plate.

[0075] Preferably the apparatus comprises: a controller configured to control rotation of the transport apparatus; a weigh cell for weighing a medical container holder positioned thereon; wherein the controller is configured to: move the transport apparatus in a first direction to position the medical container holder on the weigh cell; and, move the transport apparatus in a second direction to remove contact between the medical container holder and the transport apparatus during the weighing process.

[0076] According to an eight aspect there is provided a method of filling a medical container comprising the steps of: providing: a medical container; and, at least one medical container holder; holding the medical container with the medical container holder; moving the medical container holder along a predetermined path; maintaining the orientation of the medical container holder by cooperating formations on the medical container holder and either a moving part of the transport apparatus or on a static part of the filling apparatus.

[0077] Preferably the cooperating formations comprise one of a concave shape and a convex shape on the transport apparatus and a corresponding other of a concave shape and a convex shape on the medical container holder.

[0078] Preferably the cooperating formations comprise a concave and a concave "V" shape.

[0079] Preferably the cooperating formations comprise a projection and a corresponding recess in sliding contact.

[0080] Preferably the projection is a rail on a static part of the apparatus, and the recess is a groove on the medical container holder.

[0081] Preferably each medical container holder comprises a formation for engagement with a medical container to inhibit relative rotation thereof.

[0082] Preferably the formation is defined on a replaceable insert.

[0083] Preferably the filling apparatus comprises at least one of a de-capping station and a re-capping station, wherein at least one of the de-capping station and re-capping station comprise a formation for engagement with the medical container holder to inhibit rotation thereof during de-capping and / or re-capping.

[0084] The predetermined path may be circular or linear.

[0085] Preferably the transport apparatus comprises a rotating member.

[0086] Preferably the transport apparatus comprises a rotating plate.

[0087] Preferably the method comprises the steps of: providing a weigh cell for weighing a medical container holder positioned thereon; moving the transport apparatus in a first direction to position the medical container holder on the weigh cell; and, moving the transport apparatus in a second direction to remove contact between the medical container holder and the transport apparatus during the weighing process. Brief Description of Drawings

[0088] An embodiment of the present invention will now be described with reference to the following figure in which: FIGURE 1 is a perspective view of a first apparatus in accordance with the present invention; FIGURE 2 is a perspective detail view of a part of the first apparatus of Figure 1; FIGURE 3 is a detail view of a vial for use with the apparatus of Figure 1; FIGURE 4 is a perspective detail view of a part of the first apparatus of Figure 1; FIGURE 5 is a perspective detail view of a part of the first apparatus of Figure 1; FIGURE 6 is an exploded view of a part of the first apparatus of Figure 1; FIGURE 7 is a detail view of a part of the first apparatus of Figure 1; FIGURE 8 is a plan view of the first apparatus of Figure 1; FIGURE 9 is a detail view of a part of the first apparatus of Figure 1; FIGURE 1 Oa is a detail view of a part of the first apparatus of Figure 1; FIGURE 1 Ob is an exploded view of a part of the first apparatus of Figure 1; FIGURE 11 is a detail view of a part of the first apparatus of Figure 1; FIGURE 12 is a plan view of a part of the first apparatus of Figure 1; FIGURE 13 is a detail view of a part of the first apparatus of Figure 1; FIGURE 14 is a detail view of a part of the first apparatus of Figure 1; FIGURE 1 5 is a first flow diagram of a method according to the invention; FIGURE 1 6 is a second flow diagram of a method according to the invention; FIGURE 1 7 is a perspective view of a medical container holder according to a second embodiment; FIGURE 1 8 is a plan view of the holder of Figure 1 7; FIGURE 1 9 is a partially exploded perspective view of the holder of Figure 1 7; and, FIGURE 20 is a plan and underside view of the holder of Figure 17. Description of the first embodiment Configuration

[0089] Referring to Figure 1, a cryovial filling system 1 00 is shown. The system comprises a base 1 02, a vial storage assembly 1 04, a gripper transfer arm assembly 105, an uncapping, filling and recapping station assembly 106 and a pump assembly 108. The storage assembly 1 04, uncapping, filling and recapping station assembly 1 06 and pump assembly are all mounted on the base with the filling station assembly 106 between the vial storage assembly 104 and pump assembly 1 08. There is also provided a controller 1 09. Storage assembly 104

[0090] Figure 2 shows the vial storage assembly 1 04 in more detail. A shaft 11 0 projects upwardly from the base 1 02 to meet a carriage 112. The carriage 112 comprises a base plate 114 having features necessary to locate a range of racks, in this case shown having a plurality of upstanding fingers 116. The carriage defines a space for receiving a rack 118 (described below). On at least one side of the carriage, adjacent the space, there is provided a reject rack 105. The reject rack 105 is attached to the carriage 112 and comprises a plurality of openings 1 07 for receiving rejected vials. A controlled rate freezer compatible cryovial rack 118 is located on the carriage 112. The carriage is configured to rotate about a carriage axis CA, being vertical in use. [0091 ] The cryovial rack 11 8 is configured to be inserted into a cryovial storage chamber for long term storage. It has a base plate 120 and a pair of offset support plates 122, 124. The support plates 122, 124 have aligned openings for receiving cryovials 126 therein.

[0092] The rack 118 depicted is an example of a particular freezer rack. The carriage 112 is adaptable with fingers 116 to ensure accurate and repeatable positioning of a range of cryovial racks, which are compatible with a plurality of controlled rate freezers available on the market.

[0093] An example cryovial 126 is shown in more detail in Figure 3. The vial shown in a Corning [XX[ type vial, although this is shown only as an example and it will be understood that the present invention can be used with a range of vials and other containers. Each cryovial 126 comprises a container portion 128 in the shape of a cylinder with a sidewall 130, a closed end 132 and an open end 134. Three fingers 136a, b, c protrude axially from the closed end 132. The open end has a screwthreaded formation (not visible). The cryovial also comprises a cap 138 having a complimentary threaded formation configured to engage the threaded formation on at the open end of the container portion 128. The cap can thereby close the container portion.

[0094] The cryovial rack 118 can therefore be filled with cryovials, both empty (waiting to be filled) and filled. Gripper assembly 105

[0095] The gripper assembly 1 05 comprises a shaft 140 extending upwardly from the base 102. A gripper arm 142 extends normal to the shaft 140 parallel and distal to the base 102. At the end of the gripper arm 142 is the gripper head 144. The gripper head is known in the art and is configured to pick the cryovials 126 by the cap to remove and replace them from and to the rack 11 8. The shaft 140 can rotate about a gripper axis GA, and also move vertically along the axis GA to approach and lift the cryovials 126. Filling station assembly 106

[0096] The filling station assembly 106 is shown in more detail in Figure 5. It comprises a carousel 145 having a lower plate 146, an upper plate 148 a de-capping base 150, a decapping gripper 152, a re-capping base 154, a re-capping gripper 156, a weigh cell 158 and a filler tube arm 160. In addition, the assembly 106 comprises a plurality of cap holders 204 and vial holders 206.

[0097] The lower plate 146 is shown in more detail in Figure 6. It is generally annular having a circular outer edge 1 62 and an inner edge 164. A rail 166 protrudes from the surface of the lower plate 146 having a first section 168, a second section 170 and a third section 172. The rail sections 168, 1 70, 1 72 lie on a circular path. Between the sections 168, 170, 172 there are provided circular apertures 174, 176, 178.

[0098] The upper plate 148 is generally annular having a circular outer edge 180 and a circular inner edge 182. Multiple apertures 184a - 1 84h are provided though the plate 148. The apertures are shaped as shown in Figure 7. The apertures lie on a circular path 186 between the inner and outer edges 180, 182. The apertures are hexagonal having two parallel short sides 188a, 188b and four longer sides 1 90a - 190d. The vertices are rounded. The short sides 188a, 188b are opposing and positioned generally parallel to and on opposite sides of the path 186. Two pairs of longer sides 190a, 190b; 190c, 190d form "V" shaped ends with (rounded) points on the path 1 86. This gives the apertures an elongated diamond appearance having a length L and a width W where L>W. The apertures are positioned on a radius AR (Figure 12).

[0099] The upper plate 148 is configured to rotate about a turret axis TA, being parallel to CA and GA (Figure 1). [01 00] The de-capping base 1 50 and re-capping base 1 54 are substantially similar, and the de-capping base 150 is shown in Figure 13. It comprises a head 232 being generally cylindrical with a support surface 234 defining an engagement protrusion 236. The engagement protrusion is generally rectangular in shape having two short sides 238, 240 and two long sides 242, 244. [01 01 ] The head 232 is mounted to be driven in a rotational sense about a de-capping axis DCX. It is also mounted to be linearly moveable along the axis DCX and biased into an advanced (upper) position by an internal resilient arrangement (utilising lost motion via a compression spring).

[0102] The de-capping gripper 152 and re-capping gripper 156 are substantially similar (they are mirror images of each other). By way of example, the grippers 152, 156 are configured to selectively grip and thereby retain the caps in both a linear and rotational sense. Referring to Figure 14, the cap grippers 152, 156 are shown. The de-capping gripper 152 comprises a head 246 mounted on an arm 248 being rotatable about a de-capping gripper axis DCGX. It will be noted that the axis DCGX is offset from the turret axis TA about which the vials are disposed (at radius AR). Therefore, rotation ofthe head 246 about DCGX moves it between radius AR and RCH. This allows the head 246 to move caps between the vials in the capping bases 150, 154 and the adjacent cap holders 204.

[0103] The weigh cell 158 comprises a force transducer configured to determine the weight of an item positioned on its load platform. The weight cell 158 is configured to provide a "live" weight output at a frequency of up to 1000 Hz.

[0104] The filler tube arm 160 is configured to hold a filler tube (described below) for dosing of material directly into a vial positioned over the weigh cell 1 58. As such, the end ofthe arm 160 and the weigh cell 1 58 are aligned overthe central aperture 1 76 ofthe lower plate 162.

[0105] The cap holders 204 are configured to hold a cap 138 ofthe vials 126. Referring to Figure 8 the cap holder is shown in more detail. It comprises a base 205 having a pedestal 208 and three spaced-apart upstanding fingers 210 defining an area for receipt of part of the cap 138 (as shown). The cap holders are attached to the upper plate 148 at regular positions on a radius CHR (Figure 12) which is <AR. The fingers 210 are provided to locate the cap axially within a suitable tolerance.

[0106] The vial holders 206 (also known as pucks) are configured to each hold a vial 126 (with or without a cap 138). Referring to Figures 10a to 11 each vial holder 206 has a housing 212 being generally cylindrical with an opening 214 therethrough. An internal annular flange is provided within the opening 214 (not visible). On the outside of the housing 212 there is provided an annular collar 216 and a pedestal 21 8. The pedestal has a rectangular cross-section groove 220 running from one side to the other, in a slight arcuate form (to be described below). Each holder 206 further comprises a fastener 222 and an insert 224. The insert 224 comprises a base 226 and three upstanding fingers 228. It also defines a protrusion 230 which is internally threaded. The insert 224 is inserted into the opening 214 and dropped into engagement with the internal annular flange. There it is secured in position with respect to the housing 212 with the fastener 222 which is inserted from the underside. [01 07] The vial holders 206 are positioned such that the rail 166 enters the grooves 220 on each, locking them to a circular path. They are also positioned within the apertures 184 of the upper plate 148 such that rotation of the latter about TA propels the vial holders 206 around the rail 166. Pump assembly 108

[0108] The pump assembly 108 (referring to Figure 1) comprises a reservoir of pumped fluid which may be in a range of flexible or rigid containers 192, a pump inlet tube 194, a pump 196, a pump outlet tube 198 and a filler tube 200. The pump assembly 108 is mounted on a post 202 extending upwardly from the base 102. Controller [01 09] The controller 1 09 controls the operation of the system 100, and more specifically: • Communicates with the storage assembly 104 to drive the assembly in rotation (optionally having position feedback if required); • Communicates with the gripper assembly 1 05 to: o drive the arm 142 in rotation about GA; and, o control the gripper head 144 to grip and release vials; • Communicates with the filling station assembly 106 to: o rotate the upper plate 148 relative to the lower plate 146; o control the de-capping head 1 52 to move, grip and release caps; o control the re-capping head 156 to move, grip and release caps; o receive data from the weigh cell 158 in real-time. • Communicates with the pump assembly 1 08 to control the pump 1 96. Assembly

[0110] As shown in Figure 1, the storage assembly 1 04, gripper assembly 105, filling station assembly 1 06 and assembly 108 are installed on the base, and each functionally connected to the controller 109.

[0111] Referring to Figure 8, the three rotating assemblies, each of which holds one or more vials, are the storage assembly 104 (having an axis of rotation CA), the gripper assembly 105 (having an axis of rotation GA) and the filling station assembly 106 are rotating components (or comprise rotating components). Each of the openings in the cryovial rack 118 having a vial 126 therein has a rotational path about axis CA. Two examples of these paths are shown - path 126a' for a vial 126a and path 126b' for a vial 126b.

[0112] The gripper head 144 has a path 144', on which axis CA lies (or the centre of the rack 118). As such, a combined rotation of the head 144 about axis GA and rack 118 about axis CA enables the head 144 to reach any of the vials (as can be demonstrated by the crossing of the path 144' with both 126a' and 126b').

[0113] Similarly, the path 144' intersects the path 184' of the vials as they move in the filling station assembly 106 in the apertures 184 (at radius AR about axis TA). Use

[0114] Referring to Figure 1 5, the sequence of operation of the system is illustrated. At step 1000, a rack 118 is filled with cryovials 126.

[0115] At step 1002, the rack 118 is positioned in the carriage 112 such that it is supported and can be driven in rotation about the axis CA.

[0116] At step 1004, the carriage 112 (and as such the rack 118) is rotated about axis GA such that a vial for filling is positioned on the path 144' of the gripper 144. [011 7] At step 1006, the gripper assembly rotates the gripper 144 about the axis GA until the gripper 144 is over the relevant vial.

[0118] At step 1008 the gripper 144 picks the relevant vial.

[0119] At step 1010, the gripper 144 is rotated until the vial 126 is over a vial holder 206.

[0120] At step 1012, the gripper 144 releases the vial 126 such that is enters the opening 214 of the holder 206.

[0121] At step 1014, the holder 206 and vial 126 is then moved along the path 184' by rotation of the upper plate 148. The vial is positioned between the de-capping base 150 and the de-capping gripper 152. It will be noted that as the vial passes onto the de-capping gripper 152 the protrusion 236 engages the groove 220. At this point, the groove 220 is no longer in engagement with the rail 166 (although it is aligned with it).

[0122] At step 1016, the de-capping head 152 moves into engagement with the cap of the vial, and grips the cap. The de-capping base 150 then rotates its head 232 to thereby rotate the holder 206. This motion acts to unscrew the cap, and as the unscrewing motion creates axial motion, the compression spring within the de-capping base 150 is compressed to take up this motion. The de-capping base 150 is configured to rotate by full 360 rotations only to ensure that the holder 206 remains aligned with the rail 166.

[0123] At step 1018, once unscrewed, the de-capping head lifts the cap, and moves it to the adjacent cap holder where it is deposited.

[0124] At step 1020 the upper plate 148 is rotated to position the holder 206 (and open vial) between the filler tube 200 and the weigh cell 1 58. In this position, the entire weight exerted by the holder 206 and vial (and its contents) are supported by the weigh cell.

[0125] At step 1022, the pump 196 is activated and closed-loop dispensing of fluid is undertaken into the open vial until the desired weight is met.

[0126] At step 1024, the upper plate 148 is rotated to position the holder 206 (and open vial) between the re-capping base 154 and the re-capping head 156. The re-capping head 152 is moved into engagement with the cap of the vial, before picking it up and positioning it in line with and adjacent the filled vial. The re-capping head depresses the cap onto the vial thus depressing the head of the re-capping base against the compression spring.

[0127] At step 1026, the re-capping base 154 rotates its head 232 to thereby rotate the holder 206. This motion acts to rescrew the cap, and as the screwing motion creates axial motion, the compression spring within the de-capping base 1 50 resiliently extends to take up this motion. The re-capping base 156 is configured to rotate by full 360 rotations only to ensure that the holder 206 remains aligned with the rail 166.

[0128] At step 1028, the upper plate 148 is rotated to position the holder 206 (and filled, capped vial) to a position on the path 144' of the gripper 144.

[0129] At step 1030, the gripper picks and places the filled, capped vial back into the rack 11 8 (the rack 118 may need to be rotated to facilitate positioning).

[0130] It will be noted, that the filling station assembly 106 has a plurality of vial holder 206 - cap holder 204 pairs (eight in this case). Therefore the aforementioned process can be operated on several vials at the same time, as demonstrated by Figure 1 6 where vials are being un-capped, filled, and re-capped simultaneously. [0131 ] Step 1022 (closed loop control of the pump 1 96) may be carried out in a number of ways, all of which utilise data collected from the weigh cell to influence control of the pump. Examples are: Multi-stage

[0132] In one embodiment, a dose (i.e., a desired total amount of liquid dispensed into a container) is made up of several stages. Each stage is determined by pump control-typically in terms of the duration of pumping (a number of seconds, or milliseconds for pumps with a constant flow rate).

[0133] In such a system, a first stage may be undertaken (being less than the total dose) and data collected from the weigh cell as to the weight dispensed. The dispensed weight may then be used to inform / adjust the next stage (depending on whether it was over / under expected). Rate feedback

[0134] In another embodiment, the rate of dose pump delivery may be measured during either a single stage (as above) to provide feedback control for the duration of following stage(s).

[0135] Alternatively, The rate of pump delivery may be updated for the next dose.

[0136] The rate may be determined over a single stage or single dose (weight / time) or in a more detailed manner (for example, generating and adjusting a variable dispense rate curve characteristic for the pump).

[0137] In each case, the step of using the rate of dispense to control deactivation of the pump to meet a desired total dose comprises the step of deactivating the pump to account for either liquid in flight between the outlet and the medical container and I or any deceleration of the pump due to e.g. inertia of pump components. Mean fill weight

[0138] In a further embodiment, the mean fill weight is tracked over multiple cycles the pump control corrected for any drift in the mean fill weight away from a target fill weight. Description of the second embodiment Configuration

[0139] Selected components of the second embodiment are shown in Figures 1 7 to 19. The primary difference between the first embodiment and the second embodiment is in the configuration of the filling station assembly.

[0140] A vial holder 306 (also known as a puck) according to the second embodiment of the present invention is shown in Figures 17 to 1 9. Like the pucks 206, each is configured to hold a vial 126 (with or without a cap 138). Referring to Figures 1 7 to 19 each vial holder 306 has a housing 312 being generally cylindrical with an opening 314 therethrough. An internal annular flange is provided within the opening 314 (not visible). [0141 ] On the outside of the housing 312 there is provided an annular drive collar 316 and a pedestal 318.

[0142] The annular drive collar 316 comprises two pairs of opposed flats 400, 402, 404, 406 in plan (see Figure 18). This gives it a square profile (albeit with rounded corners).

[0143] The pedestal has an X (or +) shaped groove 320. Each holder 306 further comprises an insert 324 and a fastener 322 in the form of a radial dowel pin. The opening 314 is accessible through the sidewall of the housing 312 with an openable closure 31 5. The insert 324 comprises a base 326 and three upstanding fingers 328. The insert 324 is inserted into the opening 314 and dropped into engagement with the internal annular flange. There it is secured in position with respect to the housing 212 with the fastener 322 which is inserted from the side. The closure 31 5 is secured in place with two resilient and flexible bands 31 7, 319 (Figure 17). The closure 315 helps to grip the vial, and like the insert 324 can be adapted to suit different vials.

[0144] Like the filling station 106, the station of the second embodiment has two offset plates, the upper of which rotates to advance the pucks 306 around from the de-capping, to filling, to re-capping. Instead of being supported on a rail, the base of the puck 306 (specifically the pedestal 318) slides on the smooth planar surface of the lower plate.

[0145] Unlike the first embodiment, the orientation of the puck 306 is set by the interaction between a plate 348 and the drive collar 316 as depicted in Figure 18. The plate 348 is the same as the plate 148 in the first embodiment. Rotation of the plate 348 pushes the collar 31 6, and because of the corresponding V-shape of the opening and the collar 31 6 the puck 306 sits in one of four set orientations (it has two planes of symmetry). Importantly, the X-shaped groove in the base is always in one of four identical orientations (see Figure 20).

[0146] In use, the plate 348 pushes the pucks around as perthe first embodiment. The main difference is that instead of a rail ensuring puck orientation, this is achieved via a mating cooperation between the plate 348 and puck collar 31 6. When the puck 306 passes over a de-capping or re-capping station, the X-shaped groove 320 is engaged by a torque drive to produce the required torque between vial body and cap as described above.

[0147] Like the first embodiment, the plate 348 moves the puck 306 onto a weigh cell. Once in position, because the aperture 384 is larger than the collar 316, the plate 348 is back driven by a small amount such that there is no longer contact between the puck 306 and plate 306. This ensures an accurate, live weight reading.

Claims

1. A medical container filling apparatus comprising:a medical container;at least one medical container holder;a transport apparatus for moving the medical container holder along a predetermined path;wherein the orientation of the medical container holder is maintained by cooperating formations on the medical container holder and either a moving part of the transport apparatus or on a static part of the filling apparatus.

2. A medical container filling apparatus according to claim 1, wherein the cooperating formations comprise one of a concave shape and a convex shape on the transport apparatus and a corresponding other of the concave shape and convex shape on the medical container holder.

3. A medical container filling apparatus according to claim 2, wherein the cooperating formations comprise convex and concave "V" shapes.

4. A medical container filling apparatus according to claim 3, wherein the cooperating formations comprise a projection and a corresponding recess in sliding contact.

5. A medical container filling apparatus according to claim 4, wherein the projection is a rail on a static part of the apparatus, and the recess is a groove on the medical container holder.

6. A medical container filling apparatus according to any of claims 1 to 5, wherein each medical container holder comprises a formation for engagement with a medical container to inhibit relative rotation thereof.

7. A medical container filling apparatus according to claim 6, wherein the formation is defined on a replaceable insert.

8. A medical container filling apparatus according to any of claims 1 to 7, wherein the filling apparatus comprises at least one of a de-capping station and a re-capping station, wherein at least one of the de-capping station and re-capping station comprise a formation for engagement with the medical container holder to inhibit rotation thereof during decapping and / or re-capping.

9. A medical container filling apparatus according to any of claims 1 to 8 wherein the predetermined path is linear.

10. A medical container filling apparatus according to any of claims 1 to 8 wherein the predetermined path is circular.

11. A medical container filling apparatus according to claim 10, wherein the transport apparatus comprises a rotating member.

12. A medical container filling apparatus according to claim 11, wherein the transport apparatus comprises a rotating plate.

13. A medical container filling apparatus according to any of claims 1 to 12, comprising:a controller configured to control rotation of the transport apparatus;a weigh cell for weighing a medical container holder positioned thereon;wherein the controller is configured to:move the transport apparatus in a first direction to position the medical container holder on the weigh cell; and,move the transport apparatus in a second direction to remove contact between the medical container holder and the transport apparatus during the weighing process.

14. A method of filling a medical container comprising the steps of:providing:a medical container; and,at least one medical container holder;holding the medical container with the medical container holder;moving the medical container holder along a predetermined path;maintaining the orientation of the medical container holder by cooperating formations on the medical container holder and either a moving part of the transport apparatus or on a static part of the filling apparatus.

15. A method according to claim 14, wherein the cooperating formations comprise one of a concave shape and a convex shape on the transport apparatus and a corresponding other of a concave shape and a convex shape on the medical container holder.

16. A method according to claim 15, wherein the cooperating formations comprise a concave and a concave "V" shape.

17. A method according to claim 16, wherein the cooperating formations comprise a projection and a corresponding recess in sliding contact.

18. A method according to claim 17, wherein the projection is a rail on a static part of the apparatus, and the recess is a groove on the medical container holder.

19. A method according to any of claims 14 to 18, wherein each medical container holder comprises a formation for engagement with a medical container to inhibit relative rotation thereof.

20. A medical container filling apparatus according to claim 19, wherein the formation is defined on a replaceable insert.

21. A method according to any of claims 14 to 20, wherein the filling apparatus comprises at least one of a de-capping station and a re-capping station, wherein at least one of the de-capping station and re-capping station comprise a formation for engagement with the medical container holder to inhibit rotation thereof during de-capping and I or recapping.

22. A method according to any of claims 14 to 21 wherein the predetermined path is circular.

23. A method according to any of claims 14 to 21 wherein the predetermined path is circular.

24. A method according to claim 23, wherein the transport apparatus comprises a rotating member.

25. A method according to claim 24, wherein the transport apparatus comprises a rotating plate.

26. A method according to any of claims 14 to 25, comprising the steps of:providing a weigh cell for weighing a medical container holder positioned thereon;moving the transport apparatus in a first direction to position the medical container holder on the weigh cell; and,moving the transport apparatus in a second direction to remove contact between the medical container holder and the transport apparatus during the weighing process.27

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