Apparatus and method for monitoring and controlling the filling of a container with a pharmaceutical fluid in an aseptic environment

Abstract

The present invention involves a system and method for monitoring and controlling the aseptic dispensing of a pharmaceutical fluid into containers. The system employs a pharmaceutical fluid dispensing head to dispense droplets of the pharmaceutical fluid along a droplet path into the container and a droplet monitoring system to monitor the droplets produced and dispensed. The volume of at least one droplet is determined based on images of the droplet falling along the droplet path. The volume of pharmaceutical fluid dispensed is determined from the volume of the droplets. The pharmaceutical fluid dispensing head and the droplet monitoring system may be mutually integrated and may be used in systems using different mechanisms for moving containers, including rotary stage systems and robotic arms.

Claims

1. In a device specially adapted for bringing pharmaceutical products into particular physical or administering forms, a method for aseptically dispensing a predetermined amount of pharmaceutical fluid into a pharmaceutical container using a processor, the method comprising: providing a sterilizable chamber capable of maintaining an aseptic condition, the chamber comprising a pharmaceutical fluid dispensing head configured for producing a plurality of droplets of the pharmaceutical fluid and a droplet monitoring system comprising a digital imager and processor; establishing within the sterilizable chamber an aseptic condition; providing within the sterilizable chamber an aseptic pharmaceutical container; starting the dispensing of a plurality of droplets of the fluid from the dispensing head into the container along a droplet path; obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path; and the processor determining from the plurality of images if the predetermined volume of fluid was dispensed into the container including determining a volume of at least one of the plurality of droplets, and stopping the dispensing of droplets when the predetermined volume of fluid is dispensed into the container; wherein the determining the volume of the at least one of the plurality of droplets comprises: identifying first and second total portions of the at least one droplet appearing respectively to the left and to the right of the droplet path in at least one image of the at least one droplet; calculating first and second volumes of the at least one of the plurality of droplets by separately mathematically rotating respectively the first and second total portions of the droplet through 2 about the droplet path; and equating the volume of the at least one of the plurality of droplets to the average of the first and second volumes.

2. The method of claim 1, wherein obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises obtaining the plurality of images over a predetermined portion of the droplet path.

3. The method of claim 2, wherein obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises: determining from the plurality of images a portion of the droplet path where droplets have a stable shape; and selecting the at least one image of the at least one droplet to be from among images of the droplet taken when the droplet is in the portion of the droplet path where droplets have a stable shape.

4. The method of claim 1, wherein the determining from the plurality of images a volume of fluid dispensed into the container comprises determining a volume of each droplet dispensed into the container.

5. The method of claim 1, wherein obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises obtaining the plurality of images employing light reflected to the imager by a retroreflector.

6. The method of claim 1, wherein obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises obtaining the plurality of images by means of a telecentric lens.

7. The method of claim 1, further comprising moving at least one of the dispensing head and the container to position an opening of the container under the dispensing head to receive the droplets along a droplet path.

8. The method of claim 7, wherein moving at least one of the dispensing head and the container comprises operating an articulated robotic arm.

9. The method of claim 7, wherein moving the container comprises moving a container nest holding the container.

10. The method of claim 1, wherein providing within the sterilizable chamber an aseptic pharmaceutical container comprises providing the aseptic pharmaceutical container within a container nest.

11. A method for aseptically dispensing a pharmaceutical fluid into a pharmaceutical container, the method comprising: providing a sterilizable chamber capable of maintaining an aseptic condition, the chamber comprising a pharmaceutical fluid dispensing head configured for producing droplets of the pharmaceutical fluid and a droplet monitoring system comprising a digital imager; establishing within the sterilizable chamber an aseptic condition; providing within the sterilizable chamber an aseptic pharmaceutical container; dispensing a plurality of droplets of the fluid from the dispensing head into the container along a droplet path; obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path; and determining from the plurality of images a volume of fluid dispensed into the container by determining a volume of at least one of the plurality of droplets comprising: identifying first and second total portions of the at least one droplet appearing respectively to the left and to the right of the droplet path in at least one image of the at least one droplet; calculating first and second volumes of the at least one of the plurality of droplets by separately mathematically rotating respectively the first and second total portions of the droplet through 2 about the droplet path; and equating the volume of the at least one of the plurality of droplets to the average of the first and second volumes.

12. The method of claim 11, wherein obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises obtaining the plurality of images over a predetermined portion of the droplet path.

13. The method of claim 11, wherein obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises: determining from the plurality of images a portion of the droplet path where droplets have a stable shape; and selecting the at least one image of the at least one droplet to be from among images of the droplet taken when the droplet is in the portion of the droplet path where droplets have a stable shape.

14. The method of claim 11, wherein the determining from the plurality of images a volume of fluid dispensed into the container comprises determining a volume of each droplet dispensed into the container.

15. The method of claim 11, wherein the ceasing the dispensing of the fluid based on the volume of fluid dispensed into the container comprises ceasing the dispensing of the fluid when a total amount of fluid dispensed into the container equals a predetermined volume.

16. The method of claim 11, wherein obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises obtaining the plurality of images employing light reflected to the imager by a retroreflector.

17. The method of claim 11, wherein obtaining from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises obtaining the plurality of images by means of a telecentric lens.

18. The method of claim 11, further comprising moving at least one of the dispensing head and the container to position an opening of the container under the dispensing head to receive the droplets along a droplet path.

19. The method of claim 18, wherein moving the container comprises operating a robotic arm.

20. The method of claim 19, wherein operating a robotic arm comprises operating an articulated robotic arm.

21. The method of claim 18, wherein moving the container comprises moving a container nest holding the container.

22. The method of claim 18, wherein moving the dispensing head comprises operating a robotic arm.

23. The method of claim 22, wherein operating a robotic arm comprises operating an articulated robotic arm.

24. The method of claim 11, wherein providing within the sterilizable chamber an aseptic pharmaceutical container comprises providing the aseptic pharmaceutical container within a container nest.

25. The method of claim 11, further comprising ceasing the dispensing of the fluid based on the volume of fluid dispensed into the container.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The above-mentioned and other features and objects of this invention, and the manner of attaining them, will become more apparent and the invention itself will be better understood by reference to the following description of an embodiment of the invention taken in conjunction with the accompanying drawings, wherein:

(2) FIG. 1A is a drawing of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product. For the sake of clarity some surfaces are shown in cutaway form and others are shown as transparent.

(3) FIG. 1B is a plan view of one chamber of the apparatus of FIG. 1A.

(4) FIG. 1C shows a rotary stage of the apparatus of FIG. 1A and FIG. 1B.

(5) FIG. 1D shows a side view of a portion of the apparatus of FIG. 1A and FIG. 1B.

(6) FIG. 1E shows a pharmaceutical container tub cover seated in the rotary stage of FIG. 1A to FIG. 1D being removed.

(7) FIG. 1F shows pharmaceutical containers being filled with a pharmaceutical fluid substance in the apparatus of FIG. 1A to FIG. 1E.

(8) FIG. 1G provides a more detailed view of the cover removal components of the apparatus of FIG. 1A, FIG. 1B and FIG. 1E.

(9) FIG. 2A and FIG. 2B jointly form a drawing of a flow chart for a method of aseptically filling pharmaceutical containers with a pharmaceutical fluid substance in a spatially constrained environment.

(10) FIG. 3A is a drawing of subsystems of another embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product.

(11) FIG. 3B shows a portion of FIG. 3A in more detail.

(12) FIG. 4A is a drawing of subsystems of a further embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product.

(13) FIG. 4B shows a portion of FIG. 4A in more detail.

(14) FIG. 5A is a drawing of subsystems of yet a further embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product.

(15) FIG. 5B shows a portion of FIG. 5A in more detail.

(16) FIG. 6 shows a flow chart of a further method for filling nested pharmaceutical containers with a pharmaceutical fluid substance.

(17) FIG. 7A is a drawing of subsystems of another embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product based on the system of FIG. 5A and FIG. 5B.

(18) FIG. 7B is a drawing of a droplet monitoring system.

(19) FIG. 8 is a drawing of subsystems of another embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product.

(20) FIG. 9 is a drawing of subsystems of a further embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product.

(21) FIG. 10 is a drawing of subsystems of yet another embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product.

(22) FIG. 11 is a drawing of a flow chart for a method for aseptically dispensing a pharmaceutical fluid into a container.

(23) Corresponding reference characters indicate corresponding parts throughout the several views. Although the drawings represent embodiments of the present invention, the drawings are not necessarily to scale and certain features may be exaggerated in order to better illustrate and explain the present invention. The flow charts are also representative in nature, and actual embodiments of the invention may include further features or steps not shown in the drawings. The exemplifications set out herein illustrate embodiments of the invention, in one or more forms, and such exemplifications are not to be construed as limiting the scope of the invention in any manner.

DETAILED DESCRIPTION

(24) The embodiments disclosed below are illustrative and not intended to be exhaustive or limit the invention to the precise form disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art may utilize their teachings.

(25) The present invention relates to an apparatus and method for filing pharmaceutical containers with a pharmaceutical fluid substance in a spatially constrained environment. In FIG. 1A, filling system 1000 comprises sealable chamber 100 in communication with an ambient environment, sealable chamber 100 being capable of having an aseptic environment established within its interior and capable of maintaining that aseptic environment within its interior. The interior of sealable chamber 100 may be rendered aseptic by any one or more of treatments, including but not limited to treatment with a sterilant, such as steam, hydrogen peroxide vapor, ozone, nitrogen dioxide, and ethylene oxide. The structures and mechanisms to perform such sterilization steps are well known in the art and are not shown in FIG. 1A.

(26) Chambers 200 and 300 are separated from chamber 100 by upper wall 110 and lower wall 120 respectively and are not required to be capable of maintaining aseptic environments within their interiors. The communication of chamber 100 with the ambient environment may be via suitable aseptically sealable access door 102, schematically shown in broken outline in FIG. 1A. Suitable sealable doors and ports are well known in the art and will not be dwelt upon further in this specification. The ambient environment may be, for example, a clean room adapted for the handling of pharmaceuticals during production. Since space is at a premium in such spatially constrained clean environments, there is much merit in reducing the so-called footprint of equipment to be housed in the clean environment.

(27) The terms aseptic and sterilize and their derivatives are to be understood as follows for the purposes of the present specification. Establishing an aseptic condition in the interior of a chamber shall be understood to mean establishing that condition throughout the internal atmosphere of the chamber as well as on substantially all exposed interior surfaces of the chamber. This shall include the surfaces of all items, containers, subsystems and the like exposed to the interior atmosphere of the chamber. To the extent that extremely tight crevices or microscopic crevices may exist in the interior of the chamber such that a sterilizing gas or vapor may not perfectly penetrate into such tight regions, for example, the degree of sterilization in practical cases may not be total. This is acknowledged in both the industry and in the standards set for the industry. The action of establishing an aseptic condition within the interior of the chamber and sterilizing the interior of the chamber shall have the same meaning in this specification.

(28) Introducing into the interior of a chamber with an aseptic condition an item of which the surfaces are not suitably sterilized destroys the existing aseptic condition within the chamber. Conversely, introducing an aseptic or sterilized item into an interior of a chamber that does not have an aseptic condition within that interior does not render that interior aseptic. In fact, all it does is to destroy the aseptic condition of the surface of the item so introduced. Similarly, introducing filtered air, even with all biological entities filtered out, into an unsterilized chamber does not in any way sterilize the chamber or render it aseptic to a degree acceptable in the pharmaceutical industry. The reason is that the interior surfaces of the chamber are not sterilized by the introduction of such air. All that is achieved is to contaminate the filtered air with active biological species resident on the interior surfaces of the unsterilized chamber.

(29) In the interest of clarity and completeness, it should also be recorded that in the art the term aseptic is also sometimes used in association with the introduction of pharmaceutical fluids along aseptic tubes into bodies within controlled chambers. In such cases the term in the art refers to the condition inside the tube or to the fact that the pharmaceutical fluid may be filtered to a suitable degree. This in no way sterilizes or renders aseptic the interior of the chamber in question. The aseptic condition in such cases is confined to the interior of the tube bearing the pharmaceutical stream. Such streams are often filtered to a high degree, but such filtering affects only the interior of the particular tube and does not in any way sterilize the interior of the chamber.

(30) In some prior art systems, containers introduced into a chamber for the purposes of being filled with a pharmaceutical are routed through sterilizing subsystems. This kills biological species on the containers. When such sterilized containers are introduced into the chamber when the chamber itself is not aseptic the containers lose their aseptic condition as biological species contained within the chamber will deposit on the previously aseptic containers.

(31) It should also be pointed out that pharmaceutical or semiconductor clean rooms of any quality level, including Class 100, Class 10 or Class 1, even when employing laminar flow hoods and the like or any quality of HEPA (High Efficiency Particulate Air) filters or ULPA (Ultra Low Particulate Air) filters, cannot constitute an aseptic chamber because they do not have an assurable means to render the surfaces of the room sterile or aseptic. Standards for clean rooms exist from both the United States Federal Government and ISO (International Standards Organization). These specify in great detail to different standards the allowed particulate content of a cubic volume of air in such a clean room facility. None of these standards address the matter of biological species present on surfaces in the room. This serves to make the point that a chamber cannot be rendered aseptic by the management of its atmosphere or airflow only. Nor, conversely, can the chamber be rendered aseptic by the sterilization of only the surfaces of its interior.

(32) The text Guideline for Disinfection and Sterilization in healthcare Facilities, 2008 by Rutala et al from the Center for Disease Control lists a compendium of mechanisms and methods for sterilization. Our concern in this specification is specifically with those mechanisms for sterilizing the interior of a chamber; that is, sterilizing both the interior surfaces and the atmosphere within the chamber. Given the requirements, vapor base methods are most appropriate to the task. These include, but are not limited to, treatment with heated water vapor, hydrogen peroxide vapor, ozone, nitrogen dioxide, ethylene oxide, glutaraldehyde vapor or other suitable sterilizing gases and vapors. In one suitable method appropriate to the present invention, the sterilization is by means of hydrogen peroxide vapor which is then flushed using ozone before the chamber is employed in the filling of pharmaceutical containers.

(33) The subsystems of apparatus 1000 contained with sealable chamber 100 will now be described at the hand of FIG. 1A to FIG. 1G. Due to the compactness and density of components and subsystems of apparatus 1000, certain components and subsystems are omitted from the drawings of FIG. 1B to FIG. 1G in the interest of clarity and the focus is placed on components and subsystems most relevant to the supporting text in this specification. Planar rotary stage 130 is fully rotatable through 360 degrees in a horizontal plane parallel to lower wall 120 about rotary stage rotation axis 131 and may be raised and lowered by means of bellows feed-through 190. The use of bellows feed-through 190 allows chamber 100 to retain its aseptic condition during the motion of rotary stage 130. A suitable engine and gearing system 320 may be housed within chamber 300. Engines, for example stepper motors, as well as gearing systems suitable for rotating rotary stage 130 with suitable angular precision and repeatability are well known in the art and are not further discussed in this specification.

(34) As shown in FIG. 1C, at least three fiducial locating openings 132, 134, and 136 are provided in rotary stage 130. Fiducial locating opening 132 is employed for receiving container tubs 530 holding sterilized pharmaceutical containers 510 pre-packed in a predetermined pattern in container nests 500. Container tubs 530 are typically substantially rectangular and are sealed with peelable covers 520. Suppliers of pharmaceutical containers provide their product in this format to users of the apparatus of the present specification. Fiducial locating opening 134 is employed for receiving container closure tubs 630 holding sterilized pharmaceutical containers closures 610 pre-packed in a predetermined pattern in container closure nests 600. Container closure tubs 630 are typically substantially rectangular and are sealed with peelable tub covers not shown in FIG. 1A to FIG. 1G. The peelable covers of tubs 630 are functionally identical to peelable covers 520. Suppliers of pharmaceutical containers provide their product in this format to users of the apparatus of the present specification. In the interest of the compactness of system 1000, the rectangular axes of locating openings 132, 134, and 136 may be oriented at an angle with respect to the radial direction of rotary stage 130 in order to ensure a suitably small radius for rotary stage 130.

(35) Suitable container nests 500 and container closure nests 600; container tubs 530 and container closure tubs 630; and peelable tub covers 520 are described in co-pending U.S. patent application Ser. No. 14/912,145, filed Feb. 15, 2016, the disclosures of which is hereby incorporated in full. Alternative cover gripping arrangements for the removal of tub covers from tubs are also described in co-pending U.S. patent application Ser. No. 14/398,538, filed Nov. 3, 2014, the disclosures of which is hereby incorporated in full. The removal of tub covers may be controlled and monitored by the subsystem and method described in U.S. patent application Ser. No. 15/647,633, filed Jul. 17, 2017, the disclosures of which is hereby incorporated in full.

(36) In the interest of clarity, FIG. 1A to FIG. 1G show, and the associated text to follow below will describe, the use of single tub 530 of pharmaceutical containers 510 along with single tub 630 of container closures 610. In practice, container closures 610 are provided as multiple nests 600 per container closure tub 630. To this end rotary stage 130 may contain more than one fiducial locating opening 132 to each receive container tub 530 holding sterilized pharmaceutical containers 510 pre-packed in one container nest 500. In yet other implementations, more than one nest 500 of containers 510 may be present in a single pharmaceutical container tub 530.

(37) Fiducial locating opening 136 is specifically arranged to receive container nests 500 bearing pharmaceutical containers 510. Whereas tubs 530 and 630 naturally locate in fiducial locating openings 132 and 134 and are suspended by their own rims once in opening 132 and 134, containers 510 are correctly located in opening 136 and retained in position by some other mechanism. To this end, fiducial locating opening 136 comprises four fiducial retaining guides 137. Baseplate 138 is located within fiducial locating opening 136 as a loose component of system 1000, and rests on the horizontal portions at the bottoms of each of the four fiducial retaining guides 137 (see FIG. 1C and FIG. 1D). This arrangement allows baseplate 138 to move freely, guided by fiducial retaining guides 137. We shall return to this arrangement when discussing the closing of containers with container closures.

(38) FIG. 1E shows fiducial locating opening 136 as empty, while cover 520 is being peeled from container tub 530 in fiducial locating opening 132 (not visible) to expose nest 500 bearing pharmaceutical containers 510. At this point in the operation of system 1000, a cover similar to cover 520 has already been pealed from tub 630 in fiducial locating opening 134 (not visible) to expose nest 600 bearing container closures 610. FIG. 1G shows a close-up detailed view of the peeling of cover 520. Cover removal station 140 is rotatable about cover removal station rotation axis 144 parallel to rotary stage rotation axis 131 and comprises engagement tool 142, which, in this particular embodiment, is fork-shaped in order to engage with cover removal fixture 540 attached to cover 520. Cover removal fixture 540 is pre-attached to cover 520 before tub 530 is transferred into system 1000 via door 102 (See FIG. 1A). In the embodiment shown in FIG. 1E and FIG. 1G, cover removal fixture 540 is clipped to cover 520 and has a ball-shaped appendage to allow it to be engaged by engagement tool 142. Other combinations of cover removal fixtures and engagement tools are contemplated and system 1000 is not limited to the particular combination of cover removal fixture and engagement tool shown in FIG. 1A, FIG. 1E and FIG. 1G. Cover removal fixture 540, for example, may be manufactured as an integral part of cover 520 for use in filling systems such as filling system 1000. Or it may be clipped to cover 520 during the placement into tub 530 of nests 500 bearing containers 530 and during the placement into tub 630 of nests 600 bearing container closures 610.

(39) Rotary stage 130 may be lowered to assist in obtaining a less acute angle between cover 520 and tub 530. Too acute an angle may lead to the tearing of cover 520. Cover removal station 140 may be rotated while rotary stage 130 rotates so that the combined motions of cover removal station 140 and rotary stage 130 provide a low stress path for the removal of cover 520, thereby limiting the chances of tearing of cover 520. In particular, cover removal station 140 may be rotated to ensure that engagement tool 142 is not present above fiducial locating opening 132 when container tub 530 is placed in or removed from fiducial locating opening 132.

(40) In some embodiments, system 1000 comprises single cover removal station 140 for sequentially removing covers from tubs 520 and 620. In other embodiments, system 1000 may be equipped with two or more cover removal stations 140 for dedicated removal of covers from tubs 520 and 620 and other additional tubs. In some embodiments covers are simultaneously removed from tubs 520 and 620 and from other tubs, all the removal processes benefiting from a single rotary motion of rotary stage 130.

(41) In FIG. 1A, FIG. 1B, and FIG. 1F filling station 170 for filling pharmaceutical containers 510 with pharmaceutical fluid product comprises pharmaceutical fluid product feed line 172 supplying pharmaceutical fluid product to pharmaceutical fluid product dispenser head 174 (See FIG. 1F). Filling station 170 is rotatable about filling station rotation axis 176 parallel to rotary stage rotation axis 131. Filling station 170 and rotary stage 130 may simultaneously or sequentially rotate to place dispenser head 174 over an opening of any selected container 510 in nest 500 when nest 500 is seated in fiducial locating opening 136. This allows every container 510 in nest 500 to be filled with pharmaceutical fluid product by product dispenser head 174. When not engaged in filling containers 510, filling station 170 may be rotated to swing dispenser head 174 completely away from fiducial locating opening 136, thereby allowing nests 600 bearing container closures 610 to be placed on top of nest 500 with closure 610 directly on top of an opening of every container 510 residing in fiducial locating opening 136.

(42) Another term employed to describe dispenser head 174 is filling needle. Suitable filling needles and protective sheathing arrangements for such filling needles are described in co-pending U.S. patent application Ser. Nos. 14/890,223 and 15/199,771, the specifications of which are hereby incorporated in full.

(43) FIG. 1A and FIG. 1B show two vacuum pickup systems 150 and 160, each respectively comprising a plurality of suction cups 152 and 162 (See FIG. 1B). Vacuum pickup system 150 is arranged to pick up nests 500 of containers 510 by means of suction cups 152, and vacuum pickup system 160 is arranged to pick up nests 600 of containers 610 by means of suction cups 162. Vacuum pickup system 160 may be raised and lowered in order to allow suction cups 162 to engage with different nests 600 of container closures 610 contained at differing depths inside tub 630. To this end, vacuum pickup system 160 may comprise a bellows feed-through allowing vertical motion whilst maintaining the aseptic integrity of chamber 100. Suitable vacuum pumps, or vacuum lines from a vacuum source external to system 1000, may be connected to vacuum pickup systems 150 and 160, and ensure suitable vacuum at suction cups 152 and 162.

(44) Cameras 210 and 220 are disposed to view and record the positioning of suction cups 152 and 162 on nests 500 and 600 respectively. In the embodiment shown in FIG. 1A, cameras 210 and 220 are disposed within chamber 200 and view nests 500 and 600 through sealed windows 112 and 122 respectively. In other embodiments, cameras 210 and 220 may be disposed within chamber 100 and view nests directly from within chamber 100.

(45) Container closing ram system 180, shown in FIG. 1A, FIG. 1B, and FIG. 1D, comprises upper ram plate 182 disposed within chamber 100 above rotary stage 130, lower ram plate 184 disposed within chamber 100 below rotary stage 130, and ram drive 310 within chamber 300. Ram drive 310 is disposed for driving lower ram plate 184 vertically toward upper ram plate 182 via bellows feed-through 186. Loose base plate 138 of fiducial locating opening 136, when located above lower ram plate 184 by suitably rotating rotary stage 130, is pushed upward by ram plate 184 and is guided in the process by fiducial retaining guides 137 (See FIG. 1D). When closures 610 in closure nest 600 are ultimately pushed against upper ram plate 182, they are forced into the openings of containers 510 in nest 500. This creates a sandwiched nest of closed containers 510, each closed by a corresponding closure 610. As shown in FIG. 1D, nests 500 and 600 are forced together in the process to create a compound nest 500/600.

(46) Controller 400, shown in FIG. 1A and FIG. 1B, may communicate with the rest of system 1000 via control communications line 410, or may be contained physically within system 1000, for example, within chamber 200. Controller 400 may have suitable memory and a processor containing suitable software programming instructions which, when loaded in the memory executed by the processor, control the motions of ram system 180, vertical motion and rotating action of rotary stage 130, the application of vacuum to vacuum pickup systems 150 and 160, the imaging by cameras 210 and 220, the vertical motion of vacuum pickup system 160, any rotational or vertical motions required from cover removal stations 140 and filling station 170, as well as the on-and-off valving of pharmaceutical fluid product supply to dispenser head 174. Suitable valves and pumps, typically peristaltic pumps, required for pharmaceutical fluid product supply to dispenser head 174 are well known in the art and may be housed in chamber 200 or may be located outside system 1000. The various mechanical drives for the subsystems described above are well-known in the art, will not be discussed here in detail. These may typically be housed in chamber 200 of system 1000. The software, when executed by the processor, instructs the rotary stage to rotate to angular positions that are either predetermined or based on image information from the cameras and controls the cover removal stations, the filling station, the vacuum pickup systems, and the ram system to operate specifically in conjunction with the rotary stage.

(47) A method based on system 1000 for filling nested pharmaceutical containers with a pharmaceutical fluid product will now be described at the hand of the flow chart given in FIG. 2A, and which is continued in FIG. 2B. The method comprises providing [2010] filling apparatus 1000 comprising sterilizable chamber 100 capable of maintaining an aseptic condition, the chamber comprising rotary stage 130 with destination fiducial locating opening 136 and at least two source fiducial locating openings (132 and 134); filling station 170; at least one cover removal station 140; vertically oriented container ramming system 180; and at least one vacuum pickup system (for example 150 and/or 160). The method further comprises transferring [2020] into at least a first of the at least two source fiducial locating openings (132 and 134) at least one container tub 530 sealed by container tub cover 520 and containing container nest 500 bearing a plurality of pharmaceutical containers 510; and transferring [2025] into a second of the at least two source fiducial locating openings (134 and 132) container closure tub 630 sealed by a closure tub cover and containing at least one container closure nest 600 bearing a plurality of pharmaceutical container closures 610.

(48) The method further comprises aseptically sealing [2030] chamber 100 and establishing [2035] an aseptic condition within chamber 100. Establishing [2035] an aseptic condition within chamber 100 may comprise treating the interior of chamber 100 with any one or more of steam, hydrogen peroxide vapor, ozone, nitrogen dioxide, and ethylene oxide.

(49) The method further comprises operating [2040] the at least one cover removal station 140 and rotating rotary stage 130 to remove container tub cover 520 from the at least one container tub 530 and remove the closure tub cover from closure tub 630; operating rotary stage 130 and one of the at least one vacuum pickup systems (for example 150 and/or 160) to transfer to destination fiducial locating opening 136 container nest 500 bearing the plurality of pharmaceutical containers 510; and dispensing [2060] on an iterative and serial basis a pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers 510 by operating rotary stage 130 and filling station 170. The phrase iterative and serial is employed in this specification to describe the fact that the same operational steps are repeatedly used to fill the various containers and the fact that the containers are filled one after another, as opposed to simultaneously. In some embodiments multiple containers may be simultaneously filled using a filling station with multiple dispenser heads.

(50) Steps [2040], [2050], and [2060] each involves rotating rotary stage 130 and operating another device, being respectively cover removal station 140, one of the at least one vacuum pickup systems (for example 150 and/or 160), and filling station 170. The motions involved may be simultaneous in some cases or embodiments, and serial in other cases or embodiments. In some embodiments some of the motions may be simultaneous and others may be serial.

(51) Operating [2040] the at least one cover removal station 140 may comprise engaging an engagement tool (for example tool 142) with a cover removal fixture (for example fixture 540) pre-attached to the cover being removed. Operating [2050] one of the at least one vacuum pickup systems may comprise contacting container nest 500 with a plurality of suction cups 152 while applying a vacuum to suction cups 152. Dispensing [2060] a pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers may comprise disposing on an iterative and serial basis fluid product dispenser head 174 of filling station 170 over the openings of the at least a portion of the plurality of pharmaceutical containers 510. Operating [2050] rotary stage 130 and one of the at least one vacuum pickup systems may comprise operating camera 210 to obtain image information of container nest 500 bearing the plurality of pharmaceutical containers 510 and to position the one of the at least one vacuum pickup systems over container nest 500.

(52) The method further comprises operating [2070] one of the at least one vacuum pickup systems (for example 150 and/or 160) and rotary stage 130 to transfer to destination fiducial locating opening 136 one of the at least one container closure nests 600 bearing the plurality of pharmaceutical container closures 610 and positioning the at least one closure nest 600 to align closures 610 with containers 510; operating [2080] rotary stage 130 to jointly position aligned container nest 500 and closure nest 600 in ramming system 180; and operating [2090] ramming system 180 to force the plurality of container closures 610 into the plurality of containers 510.

(53) Operating [2070] one of the at least one vacuum pickup systems may comprise contacting container closure nest 600 with a plurality of suction cups 162 while applying a vacuum to suction cups 162. Operating [2090] ramming system 180 may comprise driving the plurality of pharmaceutical containers 510 toward upper ram plate 182 of ramming system 180.

(54) The operating [2070] rotary stage 130 and one of the at least one vacuum pickup systems may comprise operating camera 220 to obtain image information of the one of the at least one container closure nests 600 bearing the plurality of pharmaceutical container closures 610 and to position the one of the at least one vacuum pickup systems over the one of the at least one container closure nests 600.

(55) Providing [2010] a filling apparatus may comprise providing a filling apparatus further comprising controller 400 and a software program executable by controller 400. Any one or more of the aseptically sealing [2030] chamber 100; establishing [2035] an aseptic condition within chamber 100; operating rotary stage 130; operating the at least one cover removal station 140; operating [2070] one of the at least one vacuum pickup systems (150 and/or 160); operating filling station 170; and operating [2090] ramming system 180 may be done automatically by executing the software program in controller 400.

(56) In the embodiment described at the hand of FIGS. 1A to 1F, each of steps [2040], [2050], [2060], [2070], and [2080] comprises rotating a rotary stage, for example rotary stage 130, bearing the container nests and container closure nests.

(57) In other embodiments, a plurality of the steps of removing a container tub cover from at least one container tub 530; removing a container tub cover from at least one container closure tub 630; transferring to destination fiducial locating opening 136 container nest 500; dispensing a pharmaceutical fluid substance into pharmaceutical containers 510; transferring to destination fiducial locating opening 136 one of the at least one container closure nests 600; and positioning aligned container nest 500 and closure nest 600 in ramming system 180 comprises rotating a rotary stage bearing the container nests and container closure nests.

(58) In a general embodiment, at least one of the steps of removing a container tub cover from at least one container tub 530; removing a container tub cover from at least one container closure tub 630; transferring to destination fiducial locating opening 136 container nest 500; dispensing a pharmaceutical fluid substance into pharmaceutical containers 510; transferring to destination fiducial locating opening 136 one of the at least one container closure nests 600; and positioning aligned container nest 500 and closure nest 600 in ramming system 180 comprises rotating a rotary stage bearing the container nests and container closure nests.

(59) It is to be noted that neither filling system 1000, nor the associated method, needs to employ the vibratory bowls or escapements that are typical of the prior art. Unlike many prior art systems, filling system 1000 also does not require the use of gloves for use by an operator to access the interior of the chamber.

(60) The system above has been described as employing a controller that runs stored software running on a general-purpose computer platform, but it could also be implemented in whole or in part using special-purpose hardware.

(61) The system described above also employs fiducial openings defined in the rotary stage to hold tubs and nests, but it could also employ other types of fiducial structures that include other configurations of constraining surfaces sufficient to hold tubs and nests in place. Notched posts mounted on the rotary stage may hold tubs and/or nests above the rotary stage, for example. Further fiducial locating structures for holding tubs of nests for containers or container closures are described below at the hand of FIGS. 3A, 3B, 4A, and 5A.

(62) Another embodiment of a filling system according to the invention may be in all respects identical to the embodiments described above at the hand of FIGS. 1A and 1B, with the exception of vacuum pickup system(s) 150 or 160. FIGS. 3A and 3B show a portion of a filling system as described above. FIG. 3B, in particular, focuses on the general area of one of the vacuum pickup systems, by way of example, vacuum pickup system 150. In this alternative embodiment, vacuum pickup system 150 is replaced by reconfigurable vacuum pickup system 150. Vacuum pickup system 160 of FIGS. 1A and 1B may similarly be replaced by reconfigurable vacuum pickup system 160 of the same arrangement as vacuum pickup system 150. In the interest of clarity, vacuum pickup system 160 is not shown in FIG. 3A or 3B. In other embodiments, single reconfigurable vacuum pickup system 150 may be employed to pick up both container nests and container closure nests. Vacuum pickup system 150 may access the container nests and container closure nests by rotation of rotary stage 130.

(63) Vacuum pickup system 150 comprises two rotary arms 154a and 154b, in their turn respectively comprising pluralities of suction cups 152a and 152b. Vacuum pickup system 150 is arranged to pick up nests 500 of containers 510 by means of suction cups 152a and 152b. Vacuum pickup system 150 may also be arranged to pick up nests 600 of container closures 610 by means of suction cups 152a and 152b. As with vacuum pickup system 150, vacuum pickup system 150 may be raised and lowered in order to allow suction cups 152a and 152b to engage with different nests 600 of container closures 610 contained at differing depths inside tub 630.

(64) Suction cups 152a and 152b are arranged on rotary arms 154a and 154b as pluralities of sets of linearly arranged suction cups 152a and 152b, each set of linearly arranged suction cups 152a and 152b being arranged at a different angle perpendicular to the longitudinal axes of rotary arms 154a and 154b. This arrangement allows rotary arms 154a and 154b to be rotated about their longitudinal axes in order to orient different sets of linearly arranged suction cups 152a and 152b to engage with different nests 500 of containers 510. This allows the sets of suction cups 152a and 152b to be individually selectable for use. Rotation of rotary arms 154a and 154b may be performed manually. In other embodiments, rotation of rotary arms 154a and 154b may be by means of a suitable motorized drive incorporated in vacuum pickup system 150 and controlled by controller 400 shown in FIG. 1A.

(65) By selecting different sets of linearly arranged suction cups 152a and 152b via the rotation of rotary arms 154a and 154b, the sets of suction cups 152a and 152b may be disposed to engage with different container nests 500 bearing containers 510, or container closure nests 600 bearing container closures 610.

(66) FIGS. 3A and 3B show vacuum pickup system 150 as comprising two rotary arms, being rotary arms 154a and 154b. In other embodiments, one or more arms may be employed, all embodiments sharing the concept of a selectable configuration of suction cups. Whereas the selection of suction cup configurations in FIG. 3A and FIG. 3B is by means of rotation of arms 154a and 154b bearing suction cups 152a and 152b, the selecting in other embodiments may be on a different basis of configuration, including, for example without limitation, lateral translation of suction-cup-bearing arms in a plane parallel to the rotation plane of rotary stage 130 in order to engage different sets of suction cups with container nests or container closure nests. In FIGS. 3A and 3B suction cups are arranged in linear sets. In other embodiments non-linear arrangements of suction cups may be employed.

(67) Turning now to FIG. 3B specifically, we consider members 149 and 139 in more detail. In one embodiment, reconfigurable stopping member 149 is shown as having two different ends of which a first end may be selected for use by suitable rotation of reconfigurable stopping member 149 about stopping member rotation axis 141 to a predetermined set position. In the set position, reconfigurable stopping member 149 provides a hard stop for a proximal end of container 530 against the selected end of reconfigurable stopping member 149 along a direction parallel to the longitudinal axes of rotary arms 154a and 154b. In this embodiment, reconfigurable stopping member 149 may be rotated through 180 degrees to dispose the second end of reconfigurable stopping member 149 to stop container 530. The second end of reconfigurable stopping member 149 may be configured to stop the proximal end of container 530 at a different point than where the first end of reconfigurable stopping member 149 stops the proximal end of container 530.

(68) Restraining member 139 is configured to push against a distal end of container 530. While different mechanisms are contemplated to ensure the pushing action of restraining member 139, one particular suitable mechanism involves providing restraining member 139 with suitable spring loading to rotate about axis 143. By the above operation, reconfigurable stopping member 149 and restraining member 139 together allow container 530 to be positioned at an exact location parallel to the longitudinal axes of rotary arms 154a and 154b. The particular exact location is selectable by selecting the appropriate end of reconfigurable stopping member 149 to stop container 530. This arrangement allows containers 530 of different dimensions parallel to the longitudinal axes of rotary arms 154a and 154b to be located at exact predetermined locations with respect to sets of suction cups 152a and 152b.

(69) A particular set of suction cups 152a and 152b may be selected to match the selection of the particular end of reconfigurable stopping member 149. In this way, vacuum pickup system 150 may be set to a configuration that ensures that a selected size of container 530 is precisely positioned to allow container nests 500 within container 530 to be engaged by specific sets of suction cups 152a and 152b. Vacuum pickup system 150 is thereby reconfigurable to engage with nests of different sizes within containers of different sizes.

(70) In the interest of clarity, the description above, as well as FIGS. 3A and 3B, show an arrangement that allows for the exact positioning of containers 530 along only one dimension in the rotation plane of rotary stage 130, the dimension of the containers perpendicular to the one dimension being assumed to be identical. In such an arrangement, fiducial locating openings 132 and 134 are sized to constrain containers 530 in the perpendicular dimension in the rotation plane of rotary stage 130.

(71) In another embodiment, a further reconfigurable stopping member and restraining member may be added to the arrangement of FIG. 3A and FIG. 3B in order to address the positioning of container 530 in the perpendicular direction within the rotation plane of rotary stage 130. To allow the positioning of container 530 in this perpendicular direction, fiducial locating openings 132 and 134 are not sized to constrain containers in any direction within the rotation plane of rotary stage 130.

(72) In the embodiments described above, reconfigurable stopping member 149 has been described as having two ends of which one is selected for use at any one time by rotating reconfigurable stopping member 149 about stopping member rotation axis 141. In other embodiments, reconfigurable stopping member 149 may be shaped or configured to have more than two stopping ends, the ends being selectable by suitable rotation of reconfigurable stopping member 149 about stopping member rotation axis 141. In one embodiment, in which the reconfigurable stopping member has a very large number of stopping ends, the reconfigurable stopping member may assume the shape of a cam, representing a large plurality of possible stopping ends that may be selected via rotation of the reconfigurable stopping member about a suitable stopping member rotation axis.

(73) In general, the system described at the hand of FIGS. 3A and 3B comprises a reconfigurable fiducial nest positioning system. The reconfigurable fiducial nest positioning system comprises a movable platform comprising fiducial locating opening 132, reconfigurable stopping member 149, and restraining member 139. In the case of the system of FIGS. 3A and 3B, the movable platform is rotary stage 130. As explained later, other movable platforms are also contemplated. To the extent that, for example, tub 530 positionally constrains and locates nest 500 inside tub 530, any system that fiducially locates tub 530 inherently also fiducially locates nest 500.

(74) The various embodiments contemplated all comprise a reconfigurable vacuum pickup system that may be configured to engage its suction cups with corresponding areas on a pharmaceutical container nest. The containers in the container nest may be closed by corresponding container closures suspended in a container closure nest. The planar surface of the container closure nest may have an outline that leaves pass-throughs on its perimeter for the suction cups to pass through to engage with the container nest. By way of example, in FIG. 3a pass-throughs 602 are shown on the perimeter of closure nest 600. Alternatively or additionally, the container closure nest may have suitable openings in its planar interior to serve as pass-throughs for the suction cups to pass through to engage with the container nest. The vacuum pickup systems contemplated are further configured and disposed to pick up the combination of nested containers and their closures by the container nest, as opposed to by the closure nest.

(75) In a general embodiment, a nest handling subsystem comprises a reconfigurable vacuum pickup system for picking up container nests and/or container closure nests may comprise one or more arms bearing a plurality of sets of suction cups. By reconfiguration of the vacuum pickup system a set of suction cups may be selected from among the plurality of sets of suction cups, the selected set of suction cups being pre-arranged to engage with a particular container nest or container closure nest. The selection may be on the basis of one or both of the size and the shape of the nest. The nest handling system may further comprise at least one pair of a reconfigurable stopping member 149 and a restraining member 139 disposed proximate opposing ends of a fiducial locating opening 132 for holding a tub 530 containing container nests 500 bearing containers 510 in order to engage with opposing ends of tub 530. The stopping and restraining members are disposed to position tub 530 in a predetermined position that ensures that the selected set of suction cups may engage with the container nests and/or container closure nests.

(76) As is the case with opening 132, opening 134 of FIG. 3A may also be served by at least one set of a reconfigurable stopping member, being member 145 in this case, and a restraining member, being member 135 in this case. Reconfigurable stopping member 145 and restraining member 135 function with respect any tub in opening 134 in the same way as reconfigurable stopping member 149 and restraining member 139 function with respect any tub in opening 132.

(77) The various embodiments above have been described in terms of FIG. 1A to 1E and FIG. 3A, and FIG. 3B in which the vacuum pickup system 150, 160 is described as part of a pharmaceutical filling system 1000. However, vacuum pickup system 150, 160 may also be employed in its own right other apparatus not limited to the filling system of FIG. 1A to 1E, or, in fact, to filling systems in general. Some other example applications include, without limitation, lyophilizing systems. It may be applied to suitable nests of any objects arranged in a predetermined pattern. Furthermore, while system 1000 of FIG. 1A to FIG. 1E employs rotary stage 130, reconfigurable vacuum pickup system 150 may employ any suitable movable platform comprising suitable fiducial locating openings.

(78) The method described above at the hand of FIGS. 2A and 2B may now also be described in more detail with reference to FIG. 3A and FIG. 3B. Providing at least one vacuum pickup system as part of the providing a filling apparatus step [2010] may comprise providing at least one reconfigurable vacuum pickup system 150, the at least one reconfigurable vacuum pickup system 150 comprising a plurality of sets of suction cups 152a and 152b.

(79) Providing a filling apparatus step [2010] may comprise providing rotary stage 130 with destination fiducial locating opening 136 and at least two source fiducial locating openings 132, 134, each source fiducial opening having at least one pair of reconfigurable stopping member 149 and restraining member 139.

(80) Transferring step [2020] may comprise operating at least a first reconfigurable stopping member 149 to stop container tub 530 at a predetermined container tub position and operating at least first restraining member 139 to restrain container tub 530 at the predetermined container tub position.

(81) Transferring step [2025] may comprise operating at least a second reconfigurable stopping member 145 to stop container closure tub 630 at a predetermined closure tub position and operating at least second restraining member 135 to restrain container tub 630 at the predetermined closure tub position.

(82) Operating [2050] the at least one vacuum pickup system 150, 160 may comprise configuring the at least one reconfigurable vacuum pickup system 150, 160 to select a first predetermined set of suction cups disposed to engage with container nest 500.

(83) Operating [2070] of one of the at least one vacuum pickup system 150, 160 may comprise configuring the at least one reconfigurable vacuum pickup system 150, 160 to select a second predetermined set of suction cups disposed for engaging with container closure nest 600.

(84) The method may further comprise operating [2095] the at least one vacuum pickup system 150, 160 with the first predetermined set of suction cups selected to engage with container nest 500 and jointly remove container nest 500 and container closure nest 600 from ramming system 180.

(85) We have considered in FIG. 3A and FIG. 3B alternative embodiments of the arrangements of vacuum pickup systems 150 and 160 of FIG. 1A in the form of vacuum pickup systems 150 and 160; and the positioning arrangements associated with source openings 132 and 134 in the form of elements 135, 145, 139, and 149. We now turn our attention to alternative embodiments for the arrangements around destination opening 136 of FIG. 1A and FIG. 3A. FIG. 4A and its close up view in FIG. 4B show the system of FIG. 3A with a different embodiment of the arrangement around destination opening 136. While cameras 210 and 220 of FIG. 1A may be employed in conjunction with controller 400 and rotation of rotary stage 130 to position nest 500 at opening 136, and to position nest 600 over nest 500 at opening 136, the adjustable destination fiducial positioning system of FIG. 4A and FIG. 4B comprising rotary positioning elements 164a and 164b may be alternatively or additionally employed to accurately position nests 600 and 500.

(86) Typical industrial container nests are not manufactured to a dimensional standard, and, as a result, any system for filling and closing nested containers 510 should have a mechanism to accurately position differently sized nests 500 bearing containers 510. To this end, rotary positioning elements 164a and 164b may have different sets of paired positioning surfaces 167a, 167b and 163a, 163b allowing nests 500 of specific dimensions to be accurately fitted between such paired positioning surfaces. In FIG. 4B, nest 500 fits such that its two opposing ends in a first dimension touch mutually facing surfaces 167a and 167b of rotary positioning elements 164a and 164b respectively. By mutually counter-rotating elements 164a and 164b about respectively axes 166a and 166b, surfaces 167a and 167b may be made to face each other and may thereby allow the precise positioning between them of a nest of different length in the first dimension.

(87) As is evident from FIG. 4B, when surfaces 167a and 167b face each other, the nest positioned snugly between them may be retained in a precise and predetermined vertical position by resting on surfaces 165a and 165b of rotary positioning elements 164a and 164b respectively. When surfaces 163a and 163b face each other, the alternative nest positioned snugly between them may retained in a precise and predetermined vertical position by resting on surfaces 161a and 161b of rotary positioning elements 164a and 164b respectively. Elements 164a and 164b may be rotated manually about axes 166a and 166b respectively. In some embodiments, the rotation of elements 164a and 164b may be done automatically, for example, by motorized drives controlled by controller 400 and suitable control software. That control may be based on predetermined dimensional data relating to the nest being positioned between the surfaces of elements 164a and 164b. It may also be based, independently or in combination, on input data derived from imaging data obtained from cameras 210 and/or 220. Further, the rotation may take place as nest 500 is lowered into position so that the particular surfaces of elements 164a and 164b destined to engage with the opposing ends of nest 500 along the first dimension may serve as closing horizontal grip on nest 500 as the surfaces rotate toward the position in which they face each other. In this embodiment, the horizontal positioning and vertical positioning of a nest between elements 164a and 164b are not mutually independent.

(88) Another arrangement as shown in FIG. 4A and FIG. 4B for the first dimension of nest 500, may also be established for the second planar dimension of nest 500 perpendicular to the first dimension. This allows any nest 500 placed at opening 136 to be accurately located in a location predetermined by the choice of setting of rotary positioning elements 164a and 164b.

(89) Another embodiment of rotary positioning elements is shown in FIG. 5A and FIG. 5B. In contrast with the embodiment of FIG. 4A and FIG. 4B described immediately above, the horizontal positioning and vertical positioning of a nest between two mutually counter-rotatable elements 164a and 164b in FIG. 5A and FIG. 5B are mutually independent positioning actions. This is achieved by employing, in each of the two mutually perpendicular planar dimensions addressed in the embodiment immediately above, a pair of fixed opposing planar tabs 165a and 165b to position nest 500 in the vertical dimension, and a pair of rotary positioning elements 164a and 164b to position nest 500 in the first horizontal dimension. In this embodiment, each of elements 164a and 164b comprises two rotatable elements ganged on axles 166a and 166b respectively to rotate in unison and mutual alignment either side of planar tabs 165a and 165b within bosses 169a and 169b respectively. The sets of rotary elements 164a and 164b, beyond each being divided in to two ganged elements, serve to confine nest 500 in the horizontal dimension in the same fashion as rotary elements 164a and 164b in the embodiment of FIG. 4A and FIG. 4B described immediately above.

(90) While elements 164a and 164b may be designed to be of more complex shape, we show in FIG. 5A and FIG. 5B a very simple implementation in which surfaces 167a of rotary elements 164a and surfaces 167b of rotary elements 164b serve to position nest 500 in the first horizontal dimension. By rotating elements 164a joined by axle 166a counter-clockwise within boss 169a and rotating elements 164b joined by axle 166b clockwise within boss 169b, surfaces 163a and 163b may be made to face each other and thereby a nest of different length in the first horizontal dimension may be positioned and accurately located between elements 164a and 164b.

(91) Ganged elements 164a and 164b may be rotated manually about the axes of axles 166a and 166b respectively inside bosses 169a and 169b respectively. In some embodiments, the rotation of elements 164a and 164b may be done automatically by motorized drives controlled by controller 400 and suitable control software. That control may be based on predetermined dimensional data relating to the nest being positioned between the surfaces of elements 164a and 164b. It may also be based, independently or in combination, on input data derived from imaging data obtained from cameras 210 and/or 220. Further, the rotation may take place as nest 500 is lowered into position so that the particular surfaces of elements 164a and 164b destined to engage with the opposing ends of nest 500 along the first dimension may serve as closing horizontal grip on nest 500 as the surfaces rotate toward the position in which they face each other.

(92) FIG. 5A and FIG. 5B show a further set of paired mutually counter-rotatable rotary positioning elements, not numbered for the sake of clarity, ganged similarly to rotary elements 164a and 164b, and disposed to accurately locate nest 500 independently in the vertical dimension and in a second planar dimension of nest 500 perpendicular to the first dimension.

(93) In a further aspect, described at the hand of FIG. 6, a method is provided for filling nested pharmaceutical containers 510 with a pharmaceutical fluid substance, the method comprising: providing [6010] filling system 1000 comprising sterilizable chamber 100 capable of maintaining an aseptic condition, chamber 100 comprising filling station 170 and planar rotary stage 130 having destination locating structure 136, 164a, 164b, 164a, 164b; transferring [6020] into chamber 100 at least one container tub 530 sealed by container tub cover 520 and containing container nest 500 bearing a plurality of pharmaceutical containers 510; aseptically sealing [6040] chamber 100; establishing [6050] an aseptic condition within chamber 100; transferring [6060] into destination locating structure 136, 164a, 164b, 164a, 164b container nest 500 bearing the plurality of pharmaceutical containers 510 such that container nest 500 is held in place; and dispensing [6070] the pharmaceutical fluid substance into at least a portion of the plurality of pharmaceutical containers 510 by operating both rotary stage 130 and filling station 170. Operating filling station 170 may include rotating filling station 170. Dispensing the pharmaceutical fluid substance may comprise dispensing the pharmaceutical fluid substance on an iterative and serial basis into containers 510.

(94) Providing [6010] filling system 1000 may comprise providing a filing apparatus comprising at least one cover removal station 140 within chamber 100 and wherein transferring into the destination locating structure container tub 530 comprises removing container tub cover 520 from container tub 530 by operating both rotary stage 130 and the at least one cover removal station 140. Operating the at least one cover removal station 140 may comprise rotating the at least one cover removal station 140. Providing [6010] filling system 1000 may comprise providing within chamber 100 at least one cover removal station 140 having engagement tool 142, transferring [6020] into chamber 100 at least one container tub 530 may comprise attaching to container tub 520 cover removal fixture 540; and wherein operating the at least one cover removal station 140 comprises engaging engagement tool 142 with cover removal fixture 540.

(95) The method may further comprise transferring [6030] into chamber 100 container closure tub 630 sealed by a container closure tub cover and containing at least one container closure nest 600 bearing a plurality of pharmaceutical container closures 610. The method may further comprise positioning [6080] one of the at least one closure nests 600 to align closures 610 in the at least one closure nest 600 with corresponding containers 530 in container nest 500; transferring [6090] nests 500, 600 of aligned closures 610 and containers 510 to a ramming station by rotating rotary stage 130; and forcing [6100] closures 610 into corresponding containers 510. The method may further include adjusting tub locating structure 135, 145 to accommodate a size of closure nest tub 630. Positioning [6080] one of the at least one closure nest 600 may comprise: obtaining image information about the one of the at least one closure nests 600; and positioning the one of the at least one closure nests 600 based on the image information. Positioning [6080] one of the at least one closure nest 600 may comprise: applying a vacuum to suction cups 162, 152a, 152b, 152a, 152b; lifting container closure nest 600 with the suction cups; and operating rotary stage 130.

(96) Transferring [6020] into the destination locating opening container nest 500 may comprise: applying a vacuum to the suction cups; lifting container nest 500 with the suction cups; and operating rotary stage 130. The method may further include selecting one of a plurality of sets of suction cups and wherein the applying a vacuum to suction cups is performed for the selected set of suction cups. The selecting may include rotating one of the plurality of sets of suction cups into position. The method may further include adjusting destination locating structure 136, 164a, 164b, 164a, 164b to accommodate a size of container nest 500. The adjusting may be performed in two at least generally orthogonal directions. The method may further include adjusting tub locating structure 139,149 to accommodate a size of container nest tub 530.

(97) In a further aspect, a method is provided (see FIG. 1G) for removing within a controlled environment enclosure a container cover from a sealed container, for example tub 530 or tub 630, the sealed container being sealed by the container cover, for example cover 520, the method comprising: providing the container in controlled environment enclosure 100 with cover 520 sealed to a sealing surface of a lip of the container to seal the contents of the container against decontamination, cover 520 having cover removal fixture 540, decontaminating the sealed container in controlled environment enclosure 100, engaging cover removal fixture 540 with engagement tool 142, and removing the cover from the container using engagement tool 142. Engaging may involve engaging cover removal fixture 540 with fork-shaped engagement tool 142. Engaging may involve engaging a ball-shaped appendage on cover removal fixture 540.

(98) Providing may include providing sterilized pharmaceutical containers 510 or closures 610 in the sealed container, for example tub 530 or 630, before the decontaminating. Attaching may take place before the container is in controlled environment enclosure 100. Decontaminating the sealed container in controlled environment enclosure 100 may take place before removing cover 520. Removing cover 520 may include moving engagement tool 142 relative to container 530. Removing cover 520 may include moving both container 530 and engagement tool 142. The method may further comprise attaching cover removal fixture 540 to cover 520 before providing container 530 in the controlled environment enclosure.

(99) FIG. 7A shows a drawing of subsystems of a further embodiment of an apparatus for filling pharmaceutical containers with a pharmaceutical fluid product, based on the subsystems shown in FIG. 1A, FIG. 1C, FIG. 1F, FIG. 5A and FIG. 5B. For the sake of clarity, several subsystems have been omitted in order to show only aseptic sealable chamber 100 of FIG. 1A; rotary stage 130 of FIG. 1A and FIG. 1C; openings 132, 134, and 136 of FIG. 1C; with container nest 500 bearing pharmaceutical containers 510, nest 500 held in position by the arrangement shown in FIG. 5B. In FIG. 7A, fill arm 170 of FIG. 1A is replaced by articulated robotic fill arm 170. Any alternative fiducial arrangement for holding nest 500 may be employed as long as it allows the opening of each container 510 to be known with suitable accuracy and precision for reliably dispensing droplets of pharmaceutical fluid into containers 510.

(100) To the aforementioned elements in FIG. 7A is added a droplet monitoring subsystem 250, shown separately in FIG. 7B, comprising illuminating imager system 252, mirror 254, and retroreflector 256. Droplet monitoring subsystem 250 may be controlled by controller 400, to which end controller 400 is in communication with droplet monitoring subsystem 250. Controller 400 may comprise a memory and a processor. As in the case of fill arm 170 of FIG. 1A and FIG. 1F, articulated robotic fill arm 170 is supplied with pharmaceutical fluid via a pharmaceutical fluid product feed line 172. In FIG. 7A, fill arm 170 is equipped with a pharmaceutical fluid product dispenser head 174. Dispenser head 174 is arranged and configured to produce droplets of pharmaceutical fluid of consistent volume and within a limited range of droplet shapes to travel down along droplet path 710. To this end, dispenser head 174 may be equipped with a suitable nozzle. Controller 400 may control the dispensing action of dispenser head 174, to which end controller 400 may be in communication with dispenser head 174 or a pump supplying dispenser head 174 with pharmaceutical fluid. Imager system 252 may comprise a telecentric lens, thereby to render imager system 252 capable of making consistent size measurements of droplets produced by dispenser head 174.

(101) Illuminating imager system 252 is arranged and disposed to illuminate retroreflector 256 and to obtain high speed images of droplets 700 dispensed by dispenser head 174 to travel along droplet path 710 into any container 510. The line a-a in FIG. 7A and FIG. 7B indicates the light beam path. Since rotary stage 130 moves every container 510 along a circular path around the rotation axis of rotary stage 130, articulated robotic fill arm 170 is operated to move dispenser head 174 along a linear trajectory following the imaging path a-a of droplet monitoring subsystem 250. In this implementation, therefore, both rotary stage 130 and articulated robotic fill arm 170 are operated to position any container 510 for filling by dispenser head 174. Any operating of fill arm 170 may, in addition to the operating of rotary stage 130, be controlled via controller 400. To this end, controller 400 is in communication with both fill arm 170 and rotary stage 130, allowing controller 400 to coordinate the motion of fill arm 170 and rotary stage 130.

(102) Software may be supplied for loading into the memory of controller 400 and configured, when executed by the processor, for controlling dispensing of the pharmaceutical fluid droplets 700 by fluid dispensing head 174, and for collection of images of pharmaceutical fluid droplets 700 along droplet path 710. The software may also allow controller 400 to control robotic fill arm 170 and rotary stage 130.

(103) An alternative embodiment, shown in FIG. 8, shows another articulated robotic fill arm 170 into which alternative droplet monitoring subsystem 250 has been integrated. This particular embodiment employs two mirrors 254 and 258 along with illuminating imager system 252 and retroreflector 256. We retain the same numbering, namely 174, for dispenser head and 172 for pharmaceutical fluid product feed line. Illuminating imager system 252 is arranged and disposed to illuminate retroreflector 256 and to obtain via mirrors 254 and 258 high speed images of droplets 700 dispensed by dispenser head 174 to travel along droplet path 710 into any container 510. In this particular implementation, only articulated robotic fill arm 170 needs to be operated in order to position any container 510 held in nest 500 for filling by dispenser head 174 and rotary stage 130 may be held stationary during the positioning of filling of all containers 510 held in nest 500. In a more general case, both rotary stage 130 and articulated robotic fill arm 170 may be operated to position any container 510 for filling by dispenser head 174. Any operating of fill arm 170 may, in addition to the operating of rotary stage 130, be controlled via controller 400. To this end, controller 400 is in communication with both fill arm 170 and rotary stage 130. Imager system 252 may comprise a telecentric lens, thereby to render imager system 252 capable of making consistent size measurements of droplets produced by dispenser head 174.

(104) The use of droplet monitoring subsystems of the present invention is not limited to the rotary stage pharmaceutical filling systems of FIG. 1A to FIG. 8. They may also be employed in any system in which any fluid is dropwise dispensed into containers, whether nested or not. One group of filling systems suitable for filling pharmaceutical containers with a pharmaceutical fluid in an aseptic chamber using the droplet monitoring system of the present invention employs robotic arms to hold containers by means of a suitable end effector. The robotic arms may be articulated robotic arms and may be hermetically sealed to chamber 100. Suitable examples of such systems are provided in United States patent application Publication US2017/121046A1, United States Patent Publication Number US2016/0200461A1, United States Patent Publication Number US2016/0184986A1, United States Patent Publication Number US2016/0346777A1, and United States Patent Publication Number US2014/0196411A1, all wholly incorporated herein by reference. We describe below embodiments of the droplet monitoring subsystem of the present invention used in conjunction with an articulated arm of the type described in more detail in these four listed publications.

(105) FIG. 9 shows droplet monitoring system 250 of FIG. 7A and FIG. 7B implemented in a pharmaceutical container filling system having aseptic sealable chamber 100 in which container nest 500 bearing pharmaceutical containers 510 is held by end effector 810 of articulated arm 800. Articulated arm 800 may be a robotic articulated arm. In some embodiments, articulated robotic arm 800 may be controlled by suitable controller 400. To this end, as shown in FIG. 9, controller 400 is in communication with robotic arm 800. Robotic arm 800 may be of the type described in detail in the publications listed above and incorporated by reference. Controller 400 may be, for example without limitation, controller 440 used by the filling system described at the hand of FIG. 1 of United States Patent Publication Number US2016/0346777A1 or controller 13 of FIG. 1 of United States Patent Publication Number US2017/121046A1. Articulated arm 800 may be, for example without limitation, articulated arm 200 of FIG. 2 of United States Patent Publication Number US2016/0184986A1, articulated arm 22 of FIG. 1 of United States Patent Publication Number US2016/0200461A1, or articulated arm 30 of FIG. 2 of United States Patent Publication Number US2017/121046A1. Controller 400 may also be used to control droplet monitoring system 250, to which end it is in communication with droplet monitoring system 250.

(106) FIG. 10 shows the droplet monitoring system 250 of FIG. 8 employed in the same pharmaceutical container filling system as described at the hand of FIG. 9. Controller 400 may also be used to control droplet monitoring system 250, to which end it is in communication with droplet monitoring system 250.

(107) In further embodiments of the system, both dispensing head 174 and container(s) 510 may be moved by robotic arms, being robotic arms 170, 170 on the one hand and 800 on the other. Either or both of the robotic arms may be articulated robotic arms of the types described in the incorporated United States Patent Publications listed above. In yet further embodiments, both dispensing head 174 and container 510 may be in fixed positions, these particular embodiments pertaining, for example, to the filling of single container 510 at a time.

(108) The embodiments shown in FIGS. 7A, 7B, 8, 9 and 10 all employ a retroreflector 256, 256 illuminated by a light source housed in the illuminating digital imager system 252, 252. In other embodiments, droplets 700 may be backlit, or illuminated from any other angle. In such embodiments, the imager systems do not require an integrated illuminator and the illuminator may be disposed elsewhere separate from the imager.

(109) We now turn to a method, described at the hand of the flowchart in FIG. 11, for aseptically dispensing a pharmaceutical fluid into pharmaceutical container 510, the method comprising: providing [3010] sterilizable chamber 100, 100 capable of maintaining an aseptic condition, the chamber comprising pharmaceutical fluid dispensing head 174 configured for producing droplets 700 of the pharmaceutical fluid and droplet monitoring system 250, 250 comprising digital imager 252, 252; establishing [3020] within sterilizable chamber 100,100 an aseptic condition; providing [3030] within sterilizable chamber 100, 100 aseptic pharmaceutical container 510; dispensing [3040] a plurality of droplets 500 of the fluid from dispensing head 174 along droplet path 710 into container 510; obtaining [3050] from imager 252,252 a plurality of images of at least one of the plurality of droplets 700 along droplet path 710; and determining [3060] from the plurality of images a volume of fluid dispensed into container 510.

(110) The method may, in some embodiments, further comprise ceasing [3070] dispensing of the fluid based on the volume of fluid dispensed into container 510. In other embodiments, ceasing may be based on the length of time of dispensing of the pharmaceutical fluid into container 510 or on weighing of the amount of pharmaceutical fluid dispensed into container 510. The droplet information from the imager may therefore be used either in merely monitoring the pharmaceutical fluid dispensing process, or as a way of controlling the fluid dispensing process, as in when it forms the basis of the ceasing [3070].

(111) Determining [3060] from the plurality of images a volume of fluid dispensed into container 510 may comprise determining a volume of at least one of the plurality of droplets 700. Determining the volume of the at least one of the plurality of droplets 700 may comprise: identifying first and second total portions of the at least one droplet 700 appearing respectively to the left and to the right of droplet path 710 in at least one image of the at least one droplet 700; calculating first and second volumes of the at least one of the plurality of droplets 700 by separately mathematically rotating respectively the first and second total portions of droplet 700 through 2 about droplet path 710; and equating the volume of the at least one of the plurality of droplets 700 to the average of the first and second volumes. The term total portion is used in this specification to describe all of the side-on planar view of the droplet to either the left or the right side of droplet path 710. The two total portions of the droplet will not in general be quite equal. The two planar total portions, or approximate halves, are then taken and separately rotated in software about droplet path 710 to obtain two droplet volumes, which are then averaged to obtain the assumed volume of the droplet.

(112) Obtaining [3050] from imager 252,252 a plurality of images of at least one of the plurality of droplets 700 along the droplet path may comprise obtaining the plurality of images over a predetermined portion of the droplet path over which droplets 700 have a stable shape. In this specification, the shape of droplets may be considered stable when the droplets have distinctly detached from the dispensing head 174 and have assumed a shape confined to a predetermined perimeter as viewed by the imager, the shape being allowed to vary within that predetermined perimeter.

(113) Determining [3060] from the plurality of images a volume of fluid dispensed into container 510 may comprise determining a volume of each droplet 700 dispensed into container 510. Ceasing dispensing of the fluid based on the volume of fluid dispensed into container 510 may comprise ceasing dispensing of the fluid when a total amount of fluid dispensed into container 510 equals a predetermined volume. The predetermined volume may be, for example without limitation, a single adult human dosage volume of the pharmaceutical fluid. Other predetermined volumes may be integer multiples of dosages or volumes specified by a health authority, regulatory body, or MSDS sheet of the pharmaceutical fluid.

(114) In other embodiments, determining [3060] from the plurality of images a volume of fluid dispensed into container 510 may comprise determining a representative volume of droplet 700, counting the total number of droplets dispensed into container 510, and then multiplying the representative droplet volume with the number of droplets. Determining a representative volume of droplet 700 may comprise measuring only a first droplet and assuming it to be representative. In other embodiments, determining a representative volume of droplet 700 may comprise measuring a plurality of droplets and calculating an average droplet volume across the plurality of droplets.

(115) Obtaining [3050] from imager 252, 252 a plurality of images of at least one of the plurality of droplets 700 along droplet path 710 may comprise obtaining the plurality of images employing light reflected to the imager by retroreflector 256, 256. Obtaining from imager 252, 252 a plurality of images of at least one of the plurality of droplets 700 along droplet path 710 may comprise obtaining the plurality of images by using a telecentric lens. The telecentric lens may be incorporated within imager 252, 252. Providing within sterilizable chamber 100,100 aseptic pharmaceutical container 510 may comprise providing aseptic pharmaceutical container 510 within container nest 500.

(116) The method may further comprise moving at least one of dispensing head 174 and container 510 to position [3035] an opening of container 510 under dispensing head 174 to receive droplets 700 along droplet path 710. Moving the container may comprise operating robotic arm 800. Moving container 510 may comprise moving container nest 500 holding container 510. Operating robotic arm 800 may comprise operating an articulated robotic arm. Moving dispensing head 174 may comprise operating robotic arm 170, 170. Moving dispensing head 174 may comprise operating articulated robotic arm 170, 170.

(117) In the embodiments of FIGS. 7A, 7B, 8, 9 and 10, controller 400, 400 is also in communication with dispensing head 174, or the pump supplying it with pharmaceutical fluid, allowing thereby controller 400, 400 to regulate and turn on or off the flow of droplets via dispensing head 174. For the sake of clarity this communication line is not shown in FIGS. 7A, 7B, 8, 9 and 10.

(118) While this invention has been described as having an exemplary design, the present invention may be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains.