KR102780251B1 - Apparatus and method for monitoring and controlling the filling of a container with a pharmaceutical fluid in an aseptic environment - Google Patents

Abstract

The present invention relates to a system and method for monitoring and controlling the aseptic dispensing of a fluid medication into a container (510). The system (1000) employs a fluid medication dispensing head (174, 174') for dispensing droplets (700) of the fluid medication along a droplet path (710) within the container, and a droplet monitoring system (250, 250') for monitoring the generated and dispensed droplets. At least one droplet volume is determined based on images of the droplets falling along the droplet path. The volume of the dispensed fluid medication is determined from the droplet volume. The fluid medication dispensing head and the droplet monitoring system may be integrated with each other and may use different mechanisms for moving the container and may be used in a system including a rotational stage system (130) and a robotic arm (170', 170", 800).

Description

{APPARATUS AND METHOD FOR MONITORING AND CONTROLLING THE FILLING OF A CONTAINER WITH A PHARMACEUTICAL FLUID IN AN ASEPTIC ENVIRONMENT}

The present invention relates to the medical field as exemplified by IPC Classification A61, and more particularly to devices and associated methods for sterilizing and sterilizing pharmaceutical substances and containers for pharmaceutical substances, including the transfer of pharmaceutical substances to medical or veterinary patients for administrative reasons. In one aspect, the present invention relates to the programmed and automated operation of such devices, constructed and arranged to fill a pharmaceutical container with a predetermined quantity of a liquid or other substance.

The subject of filling pharmaceuticals into pharmaceutical containers is a major aspect of the pharmaceutical industry. This subject is strictly regulated by various governmental and public authorities in various countries. Technically, this subject is challenging in that pharmaceutical products need to be filled into the containers under very strict aseptic conditions. Very specific procedures are prescribed for this operation, making the handling of pharmaceuticals very different from the handling of other industrial products, especially semiconductors, which also require extreme and consistent environmental conditions. In fact, the parallels between handling semiconductors in a semiconductor "clean room" and handling pharmaceuticals in an aseptic isolator are superficial. While both use a "clean room" in common, there are no unique aseptic requirements associated with semiconductor manufacturing.

The filling of pharmaceutical containers with fluid medications requires the special handling of both the containers and the fluid medications themselves in an aseptic manner. This results in complex mechanisms and procedures, many of which can be automated to one degree or another. Often, the manufacturing equipment for fluid medication processing is bulky and expensive. This poses challenges for smaller operations, particularly in small-scale production and development environments. As technology in this area advances, the need for smaller, more compact devices, particularly for filling and compounding fluid medications, becomes apparent.

Prior art is typically characterized by the use of vibratory bowls and escapements. Additionally, many prior art systems employ gloves worn by the operator to gain access into the chamber interior.

In one overall aspect, the present invention features a method for filling nested pharmaceutical containers with a pharmaceutical fluid substance, such as a liquid, solution or suspension, having therapeutic properties. The method comprises the steps of providing a filling system comprising a sterile chamber capable of maintaining sterile conditions, the chamber comprising a filling station and a planar rotational stage having a destination fiducial locating structure comprising a constraining surface. The method also comprises the steps of transferring at least one container tub within the chamber, the at least one container tub being sealed by a container tub cover and comprising a container nest having a plurality of pharmaceutical containers, aseptically sealing the chamber, and establishing aseptic conditions within the chamber. A container nest having a plurality of pharmaceutical containers is transported within a destination-based positioning structure such that the container nest is held in place by the restraining surface, and both the rotating stage and the filling station are operated such that a fluid pharmaceutical substance is dispensed into the interior of at least some of the pharmaceutical containers among the plurality of pharmaceutical containers.

In certain embodiments, the step of operating the filling station may comprise rotating the filling station. The step of dispensing the fluid pharmaceutical substance may comprise dispensing the fluid pharmaceutical substance into the container on an iterative and serial basis. The step of providing the filling system may comprise providing a filling device comprising at least one cover removal station within the chamber, and the step of transferring the container nest into the destination reference positioning structure may comprise operating both the rotating stage and the at least one cover removal station to remove the container tub cover from the container tub. The step of operating the at least one cover removal station may comprise rotating the at least one cover removal station. The step of providing the filling system may comprise providing at least one cover removal station having an engaging tool within the chamber, and the step of transferring the at least one container tub into the chamber may comprise attaching a cover removal fixture to the container tub cover, and the step of operating the at least one cover removal station may comprise engaging the engaging tool with the cover removal fixture.

The method may further comprise a step of transporting a container closure tub, which is sealed by a container closure tub cover and includes at least one container closure nest having a plurality of pharmaceutical container closures, into the chamber. The method may further comprise a step of positioning one of the at least one closure nest so as to align a closure within the at least one closure nest with a corresponding container within the container nest; a step of rotating the rotation stage to transport the aligned closure and the nest of containers to a ramming station; and a step of forcing the closure into the interior of the corresponding container. The step of positioning one of the at least one closure nest may comprise a step of acquiring image information about one of the at least one closure nest; and a step of positioning one of the at least one closure nest based on the image information.

The step of placing one closed nest from among the at least one closed nest may include the steps of applying a vacuum to a suction cup, elevating the container closed nest using the suction cup, and operating the rotation stage. The step of transferring the container nest into the interior of the destination positioning opening may include the steps of applying a vacuum to the suction cup, elevating the container nest using the suction cup, and operating the rotation stage. The step of dispensing the fluid pharmaceutical substance may include the steps of operating the rotation stage and the filling station simultaneously and/or serially, and the step of removing the container tub cover may include the steps of operating the rotation stage and the at least one cover removal station simultaneously and/or serially.

In another overall aspect, the present invention is characterized by a system for filling nested pharmaceutical containers with a fluid pharmaceutical substance, the system comprising a sterile chamber capable of maintaining sterile conditions, the chamber comprising a filling station, a planar rotational stage having a rotational stage rotation axis, the planar rotational stage including a destination reference positioning structure including constraining surfaces configured and positioned to receive and secure a nest of pharmaceutical containers having a plurality of pharmaceutical containers.

In certain embodiments, the filling station can include a fluid product dispenser head, the filling station being rotatable about a filling station rotation axis that is parallel to the rotational stage rotation axis, such that in combination with the rotation of the rotational stage, the dispensing head is positioned over one of the plurality of medication containers held within the container nest within the reference positioning structure. The chamber can further include at least one cover removal station, and the rotational stage can further include a first origin reference positioning structure including a restraining surface configured to receive and grip a medication container closure tub, the medication container closure tub comprising at least one medication container nest having a plurality of medication container closure portions, the medication container closure tub being sealed with a container closure tub cover, and at least one second origin reference positioning structure configured to receive and grip a medication container tub, the medication container nest being sealed with a container closure tub cover, the medication container tub comprising a plurality of medication containers.

The at least one cover removal station can be rotated about a cover removal rotation axis that is parallel to the rotation axis of the rotation stage, and can be arranged and configured to remove the container tub cover from the at least one container tub and the container closure tub cover from the container closure tub in combination with the rotation of the rotation stage. The at least one cover removal station can include a fastening tool, and the fastening tool can be arranged and configured to fasten fastening fixtures pre-attached to the container tub cover and the container closure tub cover.

The system further comprises at least one camera arranged to acquire image information of at least one of the container nest and the closed nest, and a controller, wherein the chamber further comprises at least one vacuum pick-up system including a suction cup arranged to be engaged with the container nest and the container closed nest, wherein the at least one vacuum pick-up system is capable of, under the control of the controller, elevating a medicine container nest from a medicine container tub fixed to one of the at least one second origin reference positioning openings in combination with the rotation of the rotation stage, depositing the medicine container at the destination reference positioning opening in combination with the rotation of the rotation stage, and elevating a medicine container closed nest from a medicine container closed tub fixed to the first origin reference positioning opening and depositing the container closed nest on top of the medicine container nest.

The controller may be operable to direct the at least one camera to provide the image information to the controller, and the controller may be operable to control the rotation of the rotation stage so as to position the closure within the closed nest corresponding to a container within the container nest. The system may further include a ram system configured to force the closure into the interior of the corresponding container.

The system may further include at least one rotatable cover removal station having a cover removal station rotation axis parallel to the rotational stage rotation axis, at least one vacuum pick-up system for positioning the container closure nest on the container nest such that the closure of the container closure nest corresponds to a container within the container nest, and a ram system for forcing the closure into the interior of the container, and the filling station may be a rotatable filling station having a filling station rotation axis parallel to the rotational stage rotation axis and including a fluidic drug dispensing head. The system may further include at least one camera for acquiring image information of at least one of the container nest and the closure nest, and a controller including a memory and a processor. The controller may be operable to command the rotatable stage to rotate to one of the angular positions that is preset and based on the image information, and to control the at least one cover removal station, the filling station, the at least one vacuum pick-up system, and the ram system in cooperation with the rotatable stage.

In another overall aspect, the present invention is characterized by a system for filling nested pharmaceutical containers with a fluid pharmaceutical substance, the system comprising means for establishing and maintaining sterile conditions within a chamber, means for restraining a nest of containers having a plurality of pharmaceutical containers within said chamber, and means for transferring the nest of containers from a container tub to said restraining means within said chamber. The system also comprises means for rotating said restraining means within said chamber, and means for dispensing said fluid pharmaceutical substance into the interior of at least some of the pharmaceutical containers among the plurality of pharmaceutical containers in said container nest while said container nest is restrained by said restraining means.

In another aspect, a system for filling nested pharmaceutical containers with a fluid pharmaceutical substance is provided, the system comprising a sterile chamber capable of maintaining sterile conditions, the chamber comprising: a planar rotational stage having a rotational stage rotational axis; a plurality of locating structures disposed with respect to the rotational stage at different positions about the rotational stage rotational axis, the locating structures holding a nest of pharmaceutical container parts at different positions about the rotational stage rotational axis; and a container filling station having a dispensing head for filling the pharmaceutical container parts while the pharmaceutical container parts are secured within the nest at one of the locating structures. The positioning structure may include a surface associated with a first tub-holing opening within the rotational stage for gripping a first tub comprising at least one nest of the container portion, a surface associated with a second tub-holing opening within the rotational stage for gripping a second tub comprising at least one nest of the closure, and a surface associated with a destination nest-holing opening within the rotational stage for gripping at least one nest.

The chamber may further include at least one vacuum pick-up system comprising a suction cup arranged to engage with the container nest and the container closure nest fixed on the rotation stage, the at least one pick-up system being configured in combination with the rotation of the rotation stage to elevate the medicine container nest from the medicine container tub, deposit the medicine container nest within the destination opening in combination with the rotation of the rotation stage, elevate the medicine container closure nest from the medicine container closure portion, and deposit the medicine container closure nest on top of the medicine container nest.

At least one of the positioning structures can include a reconfigurable positioning structure having one or more adjustable positioning surfaces for positioning the tub relative to the rotational stage. The reconfigurable positioning structure can include at least one pair of reconfigurable stopping members and a restraining member positioned oppositely across an opening in the rotational stage to precisely position the tub, including at least one nest, in a first predetermined position. The stopping member can be adjusted to stop the tub at the first predetermined position by rotary adjustment, and the restraining member can be positioned to restrain the tub within the first predetermined position.

At least a first reconfigurable positioning structure among the above reconfigurable positioning structures can include a rotary positioning element having a rotational axis parallel to a face of the rotary stage and a plurality of different positioning surfaces selectable by rotating the rotary positioning element. At least one reconfigurable positioning structure among the above reconfigurable positioning structures can include a pair of opposing rotary positioning elements, each of the rotary positioning elements having a rotational axis parallel to a face of the rotary stage and a plurality of different positioning surfaces selectable by rotating the rotary positioning elements to accommodate different nest widths.

At least one of the reconfigurable positioning structures can include at least a first pair of opposing positioning elements defining positioning surfaces opposing each other along a first positioning axis that is at least generally parallel to a plane of the rotational stage, and at least a second pair of opposing positioning elements defining positioning surfaces opposing each other along a second positioning axis that is at least generally parallel to the plane of the rotational stage and at least generally perpendicular to the first positioning axis. In each of the first pair and the second pair of positioning elements, at least one of the positioning elements can include a rotational positioning element having a rotational axis that is parallel to the plane of the rotational stage and including a plurality of different positioning surfaces.

The system may further include a reconfigurable vacuum pick-up system, wherein the reconfigurable vacuum pick-up system comprises a first set of suction cups arranged in a first pattern, a second set of suction cups arranged in a second pattern different from the first pattern, and a selection mechanism operative to position the first set of suction cups or the second set of suction cups to engage with at least one of the nests of the medication container portion while at least one of the nests of the medication container portion is secured by one of the plurality of positioning structures. The selection mechanism of the reconfigurable vacuum pick-up system may include a rotary mechanism operative to position the first set of suction cups or the second set of suction cups to an engaging position.

The system may further include at least one cover removal station positioned to remove a cover from a tub containing at least one nest of pharmaceutical packaging material secured within one of the positioning structures. The at least one cover removal station is rotatable about a cover removal station rotation axis that is parallel to the rotational stage rotation axis, such that in combination with the rotation of the rotational stage, the tub cover is removed. The at least one cover removal station may include an engagement tool positioned and configured to engage a cover removal fixture on the tub cover.

The above charging station is rotatable about a charging station rotation axis that is parallel to the rotation axis of the rotation stage, so that, in combination with the rotation of the rotation stage, a dispensing head is positioned on top of one of the plurality of medicine containers gripped by one of the positioning structures.

The system may further include at least one camera positioned to acquire image information about at least one nest among the nests of the pharmaceutical container portion. The system may further include a ram system configured to force the nested closure into the interior of a corresponding nested container.

The system may further include at least one rotatable cover removal station having a cover removal station rotation axis parallel to the rotational stage rotation axis; at least one vacuum pick-up system for positioning a container closure on a container nest such that the closure within the closure nest corresponds to a container within the container nest; and a ram system for forcing the closure within the container, wherein the filling station is a rotatable filling station having a filling station rotation axis parallel to the rotational stage rotation axis and having a fluid product dispenser head.

The system may further include at least one camera for acquiring image information of at least one nest among the container nest and the closed nest, and a controller including a memory and a processor, wherein the controller is operable to command the rotation stage to rotate to an angular position that is one of preset and based on the image information, and to control the at least one cover removal station, the charging station, the at least one vacuum pick-up system, and the ram system to operate together with the rotation stage.

In another aspect, a system for filling nested pharmaceutical containers with a fluid pharmaceutical substance is provided, the system comprising: means for establishing and maintaining sterile conditions within a chamber; means for constraining a nest of containers having a plurality of pharmaceutical containers within the chamber; means for transferring the container nest from a container tub within the chamber to the constraining means; means for rotating the constraining means within the chamber; and means for dispensing a fluid pharmaceutical substance into the interior of at least some of the pharmaceutical containers among the plurality of pharmaceutical containers within the container nest while the container nest is constrained by the constraining means.

In another aspect, a method for filling nested pharmaceutical containers with a fluid pharmaceutical substance is provided, the method comprising the steps of: providing a filling system comprising a sterile chamber capable of maintaining aseptic conditions, the chamber comprising a filling station and a planar rotational stage having a destination positioning structure; transferring into the chamber at least one container tub, the container tub being sealed by a container tub cover and comprising a container nest having a plurality of pharmaceutical containers; aseptically sealing the chamber; establishing a sterile condition within the chamber; transferring the container nest having the plurality of pharmaceutical containers into the destination positioning structure, thereby securing the container nest; and operating both the rotational stage and the filling station to dispense the fluid pharmaceutical substance into the interior of at least some of the pharmaceutical containers among the plurality of pharmaceutical containers. The step of operating the filling station may include rotating the filling station. The step of dispensing the fluid pharmaceutical substance may include the step of dispensing the fluid pharmaceutical substance into the interior of the container in a repetitive and continuous manner.

The step of providing the charging station may include the step of providing a charging device comprising at least one cover removal station within the chamber, and the step of transferring the container tub into the destination positioning structure may include the step of operating both the rotating stage and the at least one cover removal station to remove the container tub cover from the container tub. The step of operating the at least one cover removal station may include the step of rotating the at least one cover removal station. The step of providing the charging system may include the step of providing at least one cover removal station having a fastening tool within the chamber, and the step of transferring the at least one container tub within the chamber may include the step of attaching a cover removal fastener to a container tub cover, and the step of operating the at least one cover removal station may include the step of fastening the fastening tool to the cover removal fastener.

The method may further comprise the step of transporting a container closure tub containing at least one container closure nest having a plurality of pharmaceutical container closures and sealed with a container closure tub cover into the chamber. The method may further comprise the steps of positioning one closure nest among the at least one closure nest so as to align the closure within the at least one closure nest with a corresponding container within the container nest; rotating the rotation stage to transport the aligned closure and the nest of containers to a ramming station; and forcing the closure into the interior of the corresponding container. The method may further comprise the step of adjusting the tub positioning structure so as to accommodate a size of the closed nest tub. The step of positioning one closure nest among the at least one closure nest may comprise the steps of acquiring image information about one closure nest among the at least one closure nest; and positioning one closure nest among the at least one closure nest based on the image information. The step of placing one closed nest from among the at least one closed nest may include the steps of applying a vacuum to a suction cup, elevating the container closed nest using the suction cup, and operating the rotation stage.

The step of transporting the container nest into the interior of the destination positioning opening may include the steps of applying a vacuum to the suction cups, the step of elevating the container nest using the suction cups, and the step of operating the rotation stage. The method may further include the step of selecting one suction cup from among the plurality of sets of suction cups, and the step of applying the vacuum to the suction cups may be performed for the suction cups of the selected set. The step of selecting one suction cup may include the step of rotating one suction cup from among the plurality of sets of suction cups into a home position. The method may further include the step of adjusting the destination positioning opening so as to accommodate a size of the container nest. The step of adjusting the destination positioning structure may be performed in at least two generally orthogonal directions. The method may further include the step of adjusting the tub positioning structure so as to accommodate a size of the container nest tub.

In another overall aspect, the present invention features a container assembly for holding nested pharmaceutical container portions. The container assembly comprises a container, the container comprising a bottom, a top lip providing a horizontal top sealing surface having a peripheral outline, and a side wall positioned between the bottom and the top lip. The container assembly also comprises a peelable container cover made of a sheet of flexible material sealed to the sealing surface of the top lip of the rectangular container to seal the contents of the container, and a cover removal fixing portion on the top of the container cover.

The sealed peelable container cover may include a portion extending outwardly of the peripheral contour of the upper sealing surface of the container, and the cover removal fixing member may be positioned on the portion of the peelable container cover extending outwardly of the peripheral contour of the upper sealing surface of the container. The container may be rectangular and may include four side walls. The cover removal fixing member may include an appendage that enables the cover removal fixing member to be fastened by a fastening tool. The cover removal fixing member may include a ballshaped appendage that enables the cover removal fixing member to be fastened by a fastening tool. The peelable container cover is heat sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using a chemical agent. The peelable container cover is sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using a chemical agent. The peelable container cover is sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using irradiation. The peelable container cover is sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using plasma. The peelable cover can be made of a plastic material. The peelable cover can be made of an impermeable laminated foil. The peelable cover can be made of a polymeric membrane. The cover removal fixing portion can be clipped to a portion of the peelable container cover that extends outside the peripheral contour of the upper sealing surface of the container. The sealed container can accommodate a sterilized pharmaceutical container or a closure.

In another aspect, a method for removing a container cover from a sealed container within a controlled environment enclosure is provided, wherein the sealed container is sealed by the container cover, the method comprising the steps of: providing a cover sealed to a sealing surface of a lip of the container, the cover being capable of sealing the contents of the container against decontamination within the controlled environment enclosure, the cover having a cover removal fastener; decontaminating the sealed container within the controlled environment enclosure; engaging the cover removal fastener with a fastening tool; and removing the cover from the container using the fastening tool. The engaging step may include engaging the cover removal fastener with a fork-shaped fastening tool. The engaging step may include engaging a ball-shaped attachment on the cover removal fastener.

The step of providing may comprise, prior to the step of removing the contamination, providing a sterilized pharmaceutical container or closure within the sealed container. The step of attaching may be performed prior to the container being positioned within the controlled environment enclosure. The step of decontaminating the sealed container within the controlled environment enclosure may be performed prior to the step of removing the cover. The step of removing the cover may comprise moving the fastening tool relative to the container. The step of removing the cover may comprise moving both the container and the fastening tool. The method may further comprise, prior to the step of providing the container within the controlled environment enclosure, attaching the cover removal fixture to the cover.

In another aspect, a method for removing a cover from a tub sealed with a cover within a sterile environment is provided, the method comprising the steps of: providing a sterile chamber capable of maintaining sterile conditions, the chamber comprising a fluid medication dispensing head configured to generate droplets of a fluid medication and a droplet monitoring system including a digital imaging unit; establishing sterile conditions within the sterile chamber; providing a sterile medication container within the sterile chamber; moving at least one of the dispensing head and the container such that an opening in the container is positioned beneath the dispensing head to receive the droplet along a droplet path; dispensing a plurality of droplets of the fluid medication into the chamber along the droplet path; acquiring a plurality of images of at least one droplet from the imaging unit along the droplet path; and determining a volume of the fluid medication dispensed into the container from the plurality of images. The method may further include a step of stopping dispensing of the fluid medication based on a volume of the fluid medication dispensed into the container.

The step of determining a volume of the fluid medicine dispensed into the container from the plurality of images may comprise the step of determining a volume of at least one droplet from the plurality of droplets. The step of determining the volume of at least one droplet from the plurality of droplets may comprise the steps of: identifying first and second total portions of the at least one droplet that appear on the left and right sides of the droplet path, respectively, in at least one image of the at least one droplet; computing first and second volumes of the at least one droplet from the plurality of droplets by separately mathematically rotating the first and second total portions of the droplet as it passes through a circle around the droplet path, respectively; and equating the volume of the at least one droplet from the plurality of droplets to an average of the first and second volumes.

From the imaging unit, the step of acquiring multiple images of at least one droplet among the plurality of droplets along the droplet path may include the step of acquiring multiple images above a set portion of the droplet path. Optionally, the step of acquiring multiple images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit may include the step of determining a portion of the droplet path in which the droplets have a stable shape from the plurality of images, and, if the droplet is located in a portion of the droplet path in which the droplet has a stable shape, the step of selecting at least one image of the at least one droplet from among the images of the taken droplets.

The step of determining a volume of the fluid medication dispensed into the container from the plurality of images may include the step of determining a volume of each droplet dispensed into the container. The step of stopping dispensing the fluid medication based on the volume of the fluid medication dispensed into the container may include the step of stopping dispensing the fluid medication when the total amount of the fluid medication dispensed into the container is equal to the set volume. The step of acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit may include the step of acquiring the plurality of images by taking light reflected by the retroreflective unit to the imaging unit. The step of acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit may include the step of acquiring the plurality of images by a telecentric lens. The step of providing the sterile medication container within the sterile chamber includes the step of providing the sterile medication container within a container nest.

The method may further include the step of moving at least one of the dispensing head and the container, such that an opening in the container is positioned beneath the dispensing head to receive the droplet along the droplet path. The step of moving the container may include the step of operating a robotic arm. The step of moving the dispensing head may include the step of operating the robotic arm, wherein the robotic arm may be an articulated robotic arm.

In another aspect, a system for aseptic dispensing of a fluid medicine into a container is provided, the system comprising: a sealable sterile chamber capable of maintaining aseptic conditions; a fluid medicine dispensing head configured to generate droplets of the fluid medicine within the chamber; a droplet monitoring system comprising a digital imaging unit positioned within the chamber to acquire images of droplets dispensed by the fluid medicine dispensing head; a controller comprising a memory and a processor, the controller communicating with the fluid medicine dispensing head and the digital imaging unit; and software for controlling dispensing of the fluid medicine droplet by the fluid medicine dispensing head, the software configured to collect images of the fluid medicine droplet along a droplet path when the software is loaded into the memory and executed by the processor.

The system can further include at least one of a fluid dispensing head placement system in communication with the controller and a container placement system, wherein the software can be configured to further control at least one of the fluid dispensing head placement system and the container placement system. The fluid dispensing head placement system can include a robotic arm, which can be an articulated robotic arm. The articulated robotic arm can be hermetically sealed to the chamber. The container placement system can include a robotic arm. The robotic arm used in the container placement system can include an end effector arranged to hold a nest of containers. The robotic arm used in the container placement system can include an articulated robotic arm, and in some embodiments, the articulated robotic arm can be hermetically sealed to the chamber. The droplet monitoring system can include a retroreflector arranged to reflect light passing through the droplet onto the digital imaging unit. The digital imaging unit can include a telecentric lens.

The system and method according to the present invention do not require the use of vibratory bowls or escapements. Furthermore, the system and method do not require gloves. Therefore, the system and method according to the present invention can cope with the demand for compact and small-scale filling and compounding of fluid medicines.

By referring to the following description of an embodiment of the present invention together with the attached drawings, the above-described features and objects of the present invention and other features and objects and methods accompanying the same will become clearer, and the present invention itself will be better understood.
Figure 1a is a drawing of a device for filling a pharmaceutical container with a pharmaceutical fluid product. For clarity, some surfaces are shown as having their interiors visible, while other surfaces are shown as transparent.
Figure 1b is a plan view of one chamber constituting the device illustrated in Figure 1a.
Figure 1c shows the rotation stage of the device shown in Figures 1a and 1b.
FIG. 1d is a side view showing a portion of the device illustrated in FIGS. 1a and 1b.
FIG. 1e shows a state in which the medicine container tub cover seated on the rotation stage of FIGS. 1a to 1e is removed.
Figure 1f shows a pharmaceutical container filled with a fluid pharmaceutical substance in the device of Figures 1a to 1e.
FIG. 1g is a drawing showing a cover removal component of the device illustrated in FIGS. 1a, 1b, and 1e in more detail.
Figures 2a and 2b are combined to form a flowchart illustrating a method for aseptically filling a pharmaceutical container with a pharmaceutical fluid substance in a spatially confined environment.
FIG. 3a is a diagram illustrating a subsystem according to another embodiment of a device for filling a pharmaceutical container with a pharmaceutical fluid product.
Figure 3b is a drawing showing a part of Figure 3a in more detail.
FIG. 4a is a diagram illustrating a subsystem according to another embodiment of a device for filling a pharmaceutical container with a fluid pharmaceutical product.
Figure 4b is a drawing showing a part of Figure 4a in more detail.
FIG. 5a is a diagram illustrating a subsystem according to another embodiment of a device for filling a pharmaceutical container with a fluid pharmaceutical product.
Figure 5b is a drawing showing a part of Figure 5a in more detail.
Figure 6 illustrates a flow chart of another method for filling nested pharmaceutical containers with a fluid pharmaceutical substance.
FIG. 7a is a diagram illustrating a subsystem according to another embodiment of a device for filling a pharmaceutical container with a fluid pharmaceutical product, based on the system of FIGS. 5a and 5b.
Figure 7b is a diagram of a droplet monitoring system.
FIG. 8 is a diagram illustrating a subsystem of another embodiment of a device for filling a pharmaceutical container with a fluid pharmaceutical product.
FIG. 9 is a diagram illustrating a subsystem of another embodiment of a device for filling a pharmaceutical container with a fluid pharmaceutical product.
FIG. 10 is a diagram illustrating a subsystem of another embodiment of a device for filling a pharmaceutical container with a fluid pharmaceutical product.
Figure 11 illustrates a flow chart of a method for aseptically dispensing a fluid pharmaceutical into a container.
Corresponding reference numerals in the various drawings designate corresponding parts. While the drawings illustrate embodiments of the invention, the drawings are not necessarily drawn to scale, and certain features may be exaggerated to better illustrate and explain the invention. The flowcharts are also representative in nature, and actual embodiments of the invention may include other features or steps not shown in the drawings. While the examples described herein illustrate embodiments of the invention in one or more forms, such examples should not be construed as limiting the scope of the invention in any way.

The embodiments disclosed below are illustrative and are not intended to limit or restrict the invention to the precise form disclosed in the detailed description set forth below. Rather, the embodiments are chosen and described so that one skilled in the art can utilize the teachings disclosed in the embodiments.

The present invention relates to a device and method for filling a pharmaceutical container with a fluid pharmaceutical substance in a spatially constrained environment. In FIG. 1A, a filling system (1000) includes a sealable chamber (100) in communication with an ambient environment, the sealable chamber (100) having an aseptic environment established therein and capable of maintaining the aseptic condition therein. The interior of the sealable chamber (100) can be sterilized by one or more of a number of treatment methods, including but not limited to treatment with a sterilant such as steam, hydrogen peroxide, vapor, ozone, nitrogen dioxide, and ethylene oxide. Structures and mechanisms capable of performing such sterilization steps are well known in the art and are not shown in FIG. 1A.

The chambers (200, 300) are each separated from the sealable chamber (100) by an upper wall (110) and a lower wall (120), and it is not required that an aseptic environment be maintained within them. Communication with the surrounding environment of the sealable chamber (100) can be accomplished through a suitable aseptically sealable access door (102), schematically illustrated in dashed lines in FIG. 1A. Suitable sealable doors and ports are well known in the art and will not be considered in more detail herein. For example, the surrounding environment may be a clean room adapted to process pharmaceuticals during their manufacture. In such a spatially constrained clean environment, space is at a premium, and there is a great advantage in reducing the so-called "footprint" of the equipment that must be housed in such a clean environment.

The terms "aseptic" and "sterilize" are to be understood as follows for the purposes of this specification: establishing sterile conditions within a chamber is to be understood as establishing such conditions throughout substantially all interior surfaces of the chamber, as well as the entire interior atmosphere of the chamber. This includes all surfaces of all items, containers, subsystems, etc., that are exposed to the interior atmosphere of the chamber. In practice, the degree of sterilization may not be complete, for example, to the extent that extremely tight crevices or microscopic crevices exist within the chamber, such that the sterilizing gas or steam cannot fully penetrate into such tight areas. This is recognized both in the industry and in standards established for the industry. The operations of establishing sterile conditions within a chamber and "sterilizing the interior of the chamber" shall have the same meaning herein.

When introducing sterile conditions into a chamber, the existing sterile conditions inside the chamber are compromised by items whose surfaces are not properly sterilized. Conversely, introducing sterile or aseptic items into a chamber that does not have an aseptic condition inside does not make the chamber sterile. In fact, the sterile conditions on the surfaces of the items introduced in this way are only compromised. Similarly, introducing filtered air into a non-sterile chamber, which has been filtered of all biological entities, does not in any way sterilize or render the chamber aseptic to a degree acceptable to the pharmaceutical industry. This is because the interior surfaces of the chamber are not sterilized by such introduction of air. All that is achieved is that the filtered air becomes contaminated with active biological species on the interior surfaces of the non-sterile chamber.

For the sake of clarity and completeness, it should also be noted that the term "sterile" is also commonly used in the art in connection with the introduction of a fluid pharmaceutical along a sterile tube into the interior of a body within a controlled chamber. In such cases, the term in the art refers to the conditions within the tube or to the fact that the fluid pharmaceutical can be filtered to a suitable degree. This does not sterilize or render aseptic the interior of the chamber in question. In such cases, the aseptic conditions are limited to the interior of the tube containing the pharmaceutical stream. This stream is often filtered to a high degree, but such filtration only affects the interior of the particular tube and does not sterilize the interior of the chamber at all.

In some prior art systems, containers introduced into the chamber for the purpose of being filled with a drug are routed through a sterilizing subsystem. This kills any biological species on the container. If such a sterile container is introduced into the chamber when the chamber itself is not sterile, the container loses its sterility condition because the biological species confined within the chamber will deposit on the previously sterile container.

It should also be noted that even when laminar flow hoods are used, or HPPA (High Efficiency Particulate Air) filters or ULPA (Ultra Low Particulate Air) filters of any quality are used, pharmaceutical or semiconductor cleanrooms of any quality level, including "Class 100", "Class 10" or "Class 1", cannot constitute aseptic chambers because they do not have the means to ensure that the surfaces of such cleanrooms are sterile or aseptic. Standards for cleanrooms exist from both the US Federal Government and the International Standards Organization (ISO). These are different standards that specify in great detail the allowable particulate content of the cubic volume of air within such cleanrooms. None of these standards address the issue of biological species present on surfaces within such cleanrooms. This helps to argue that chambers cannot be made sterile simply by controlling the atmosphere or airflow within the chamber. Conversely, a chamber cannot be made sterile by sterilizing only the surfaces inside the chamber.

The text "Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008" by Rutala et al. of the Centers for Disease Control and Prevention lists an overview of mechanisms and methods for sterilization. In this specification, our interest is particularly in those mechanisms for sterilizing the interior of the chamber, i.e., sterilizing both the interior surfaces of the chamber and the atmosphere. Given the requirements, steam-based methods are best suited for the task. These methods include, but are not limited to, treatment with heated water steam, hydrogen peroxide vapor, ozone, nitrous oxide, ethylene oxide, glutaraldehyde vapor, or other suitable sterilizing gases and vapors. In one suitable method suitable for the present invention, the sterilization process is performed with hydrogen peroxide vapor, followed by a flushing with ozone prior to the chamber being applied to fill the pharmaceutical container.

The subsystems of the device (1000) included in the sealing chamber (100) will now be described with reference to FIGS. 1A to 1G. Due to the compactness and density of the components and subsystems of the device (1000), certain components and subsystems are omitted from the drawings of FIGS. 1B to 1C for the purpose of brevity, and the focus is on those components and subsystems most relevant to the text supporting this specification. A planar rotary stage (130) can rotate a full 360 degrees about a rotary stage rotation axis (131) in a horizontal plane parallel to the lower wall (120) and can be raised and lowered by a bellows feed-through (190). By using the bellows feed-through, the chamber (100) can be maintained in an aseptic condition while the rotary stage (130) is in operation. A suitable engine and gearing system (320) may be accommodated within the chamber (300). Engines and gearing systems suitable for rotating the rotational stage (130), for example a stepper motor, having suitable angular precision and repeatability are well known in the art and are not discussed further herein.

As shown in FIG. 1c, the rotation stage (130) is provided with at least three fiducial locating openings (132, 134, 136). The fiducial locating openings (132) are adapted to receive a container tub (530) holding a sterilized pharmaceutical container (510) pre-packed in a predetermined pattern within the container nest (500). The container tub (530) is typically substantially rectangular and sealed with a peelable cover (520). Suppliers of pharmaceutical containers provide their products to users of the device of the present disclosure in this format. The reference positioning opening (134) is adapted to receive container closure tubs (630) that hold sterilized pharmaceutical container closures (closures, 610) pre-packed in a predetermined pattern in the container closure nest (600). The container closure tubs (630) are typically substantially rectangular and are sealed with a peelable tub cover, not shown in FIGS. 1A to 1G. The peelable cover of the container closure tub (630) is functionally identical to the peelable cover (520). A supplier of pharmaceutical containers provides a product having such a shape to a user of the device of the present disclosure. To achieve a small space occupancy of the system (1000), the rectangular axis of the reference positioning openings (132, 134, 136) may be oriented at an angle with respect to the radial direction of the rotation stage (130) so as to secure an appropriately small radius with respect to the rotation stage (130).

Suitable container nests (500) and container closure nests (600); container tubs (530) and container closure tubs (603); and peelable tub covers (620) are described in U.S. Patent Application No. US 2016/0200461, published on July 14, 2016, the disclosure of which is incorporated herein in its entirety. Alternative cover gripping arrangements for removing a tub cover from a tub are also described in U.S. Patent Application No. US 2016/0251206, published on September 1, 2016, the disclosure of which is incorporated herein in its entirety. Removal of the tub cover can be controlled and monitored by the subsystems and methods described in PCT International Publication No. WO2018/049516 A1, published March 22, 2018, the disclosure of which is fully incorporated herein.

For clarity, FIGS. 1A-1G and the associated text described below illustrate the use of a single tub (530) of a pharmaceutical container (510) along a single tub (630) of a container closure (610). In practice, the container closures (610) are provided as a plurality of nests (630) for a single container closure tub (630). For this purpose, the rotation stage (130) may include more than one reference positioning opening (132) each of which accommodates a respective container tub among the container tubs (530) that accommodate a pre-packed sterilized pharmaceutical container (510) in the container nest (500). In other embodiments, there may be more than one nest (530) of containers (510) within a single pharmaceutical container tub (530).

A fiducial positioning opening (136) is specifically arranged to accommodate a container nest (500) having a pharmaceutical container (510). The container tub (530) and the container closure tub (630) are naturally positioned in the fiducial positioning opening (132, 134) and are suspended within the opening (132, 134) by their rims, while the pharmaceutical container (510) is precisely positioned in the opening (136) and retained in position by some other mechanism. For this purpose, the fiducial positioning opening (136) includes four fiducial retaining guides (137). As a loose component of the system (1000), the base plate (138) is positioned within the reference positioning opening (136) and is seated horizontally below each of the four reference point fixing guides (137) (see FIGS. 1c and 1d). This arrangement allows the base plate (138) to move freely while being guided by the reference point fixing guides (137). We will return to this arrangement when discussing the closure of containers using container closures.

FIG. 1e shows a state where the cover (520) is peeled off from the container tub (530) at the reference positioning opening (132, not visible) to expose a container nest (510) having a pharmaceutical container (530), but the reference positioning opening (136) is empty. At this point, while the system (1000) is operating, a cover similar to the cover (520) has already been peeled off from the closed container tub (630) at the reference positioning opening (134, not visible) to expose a nest (600) having a container closure (610). FIG. 1g shows an enlarged detail view of the cover (520) peeled off. A cover removal station (140) is rotatable about a cover removal station rotation axis (144) that is parallel to the rotation stage rotation axis (131) and includes an engagement tool (142), which in this particular embodiment is fork-shaped to engage a cover removal fixture (540) attached to the cover (520). The cover removal fixture (540) is pre-attached to the cover (520) prior to the container tub (530) being transported through the door (102, see FIG. 1A) into the system (1000). In the embodiments shown in FIGS. 1E and 1G, the cover removal fixture (540) is clipped to the cover (520) and has a ball-shaped appendage to be engaged by the engagement tool (142). Other combinations of cover removal fasteners and fastening mechanisms may be contemplated, and the system (1000) is not limited to the specific combinations of cover removal fasteners and fastening mechanisms illustrated in FIGS. 1A, 1E, and 1G. For example, the cover removal fastener (540) may be manufactured as an integral part of the cover (520) for use in a charging system, such as the charging system (1000). Alternatively, the cover removal fastener may be clipped to the cover (520) while being placed within the tub (530) of the nest (500) having the container (530), and while being placed within the tub (630) of the nest (600) having the container closure (610).

The rotation stage (130) can be lowered to help obtain a less acute angle between the cover (520) and the tub (530). Too much of an acute angle can cause the cover (520) to be ripped off. The cover removal station (140) can be rotated while the rotation stage (130) is rotating, thereby providing a less stressful path associated with removing the cover (520) due to the combined movement of the cover removal station (140) and the rotation stage (130), thereby limiting the possibility of the cover (520) being ripped off. In particular, the cover removal station (140) can be rotated to ensure that the fastening mechanism (142) is not present on top of the reference positioning opening (132) when the container tub (530) is placed within or removed from the reference positioning opening (132).

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

In FIGS. 1A, 1B and 1F, a filling station (170) for filling a pharmaceutical container (510) with a pharmaceutical fluid product includes a fluid product feed line (172) that supplies the fluid product to a fluid product dispensing head (174, see FIG. 1F). The filling station (170) can rotate about a filling station rotation axis (176) that is parallel to the rotation stage rotation axis (131). When the nest (500) is seated in the reference positioning opening (136), the filling station (170) and the rotation stage (130) can rotate simultaneously or sequentially so as to position the dispensing head (174) over the opening of any selected container (510) within the nest (500). As a result, all containers (510) within the nest (500) can be filled with a fluid medicine by the medicine dispensing head (174). If the filling station is not engaged with the filling container (510), the filling station (170) can rotate to swing the dispensing head (174) in a direction completely away from the reference positioning opening (136), so that the container closing portion (610) is positioned directly above the opening of all containers (510) residing in the reference positioning opening (136), such that the nest (600) having the container closing portion (610) can be positioned at the top of the nest (500).

Another term that has been employed to describe the dispensing head (174) is "filling needle". Suitable filling needles and protective sheathing arrangements for such filling needles are described in U.S. Patent Application Nos. US 2016/0346777 and US 2017/0121046, published on December 1, 2016 and August 31, 2017, respectively, the disclosures of which are fully incorporated herein by reference.

Figures 1a and 1b illustrate two vacuum pickup systems (pickup systems 150, 160), each of which includes a plurality of suction cups (152, 162, see Figure 1b). The vacuum pickup system (150) is arranged to pick up a nest (500) of containers (510) by means of the suction cups (152), and the vacuum pickup system (160) is arranged to pick up a nest (600) of containers (610) by means of the suction cups (162). The vacuum pickup system (160) can be raised or lowered, such that the suction cups (162) can engage different nests (600) of container closures (610) contained within the tub (630) at different depths. For this purpose, the vacuum pick-up system (160) may include a bellows feeder capable of vertical movement while maintaining the aseptic integrity of the chamber (100). A suitable vacuum pump or vacuum line from a vacuum source external to the system (1000) may be connected to the vacuum pick-up system (150, 160) and ensure an appropriate vacuum in the suction cups (152, 162).

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

A container closing ram system (180) illustrated in FIGS. 1A, 1B, and 1D includes an upper ram plate (182) positioned above a rotation stage (130) within a chamber (100), a lower ram plate (184) positioned below the rotation stage (130) within the chamber (100), and a ram drive (310) positioned within the chamber (300). The ram drive (310) is positioned to vertically drive the lower ram plate (184) toward the upper ram plate (182) through a bellows feedthrough (186). When the loose base plate (138) of the reference positioning opening (136) is positioned above the lower ram plate (184) by the appropriately rotating rotary stage (130), the loose base plate (138) is pushed upward by the lower ram plate (184) and guided by the reference point fixing guide (137, see FIG. 1d) in the process. When the closing portion (610) in the closed nest (600) is finally pushed against the upper ram plate (182), the closing portion is forced into the openings of the containers (510) in the nest (500). This creates a sandwiched nest of closed containers (510). As shown in FIG. 1d, the nests (500, 600) are forced together in the process, creating a compound nest (500/600).

The controller (400) illustrated in FIGS. 1A and 1B may communicate with the remaining components of the system (1000) via a control communication line (410), or may be physically contained within the system (1000), for example, within the chamber (200). The controller (400) may have a processor including suitable memory and suitable software programming instructions which, when loaded into the memory and executed by the processor, control the on-and-off valving for the supply of fluid medication to the dispensing head (174), as well as the movement of the ram system (180), the vertical movement and rotational operation of the rotation stage (130), the application of vacuum to the vacuum pick-up system (150, 160), the imaging by the cameras (210, 220), the vertical movement of the vacuum pick-up system (160), and any rotational or vertical movement required by the cover removal station (140) and the filling station (170). Suitable valves and pumps, particularly peristaltic pumps, required for supplying the fluid medication to the dispensing head (174) are well known in the art and may be housed within the chamber (200) or located external to the system (1000). Various mechanical drives for the subsystems described above are well known in the art and will not be discussed in further detail herein. These drives may typically be housed within the chamber (200) of the system (1000). When executed by the processor, the software commands the rotation stage to rotate to angular positions based on predetermined or image information obtained from the cameras, and controls the cover removal station, the filling station, the vacuum pick-up system, and the ram system to operate specifically in conjunction with the rotation stage.

Now, referring to the flow chart shown in FIG. 2a and continued in FIG. 2b, a method for filling a pharmaceutical container contained therein with a fluid pharmaceutical product based on the system (1000) will be described. The method comprises the steps of providing a filling device (1000) comprising a sterile chamber (100) capable of maintaining sterile conditions ([2010]), the chamber comprising a rotational stage (130) having a destination reference positioning opening (136) and at least two source reference positioning openings (132, 134), a filling station (170), at least one cover removal station (140), a horizontally oriented container ramming system (180), and at least one vacuum pick-up system (e.g., 150 and/or 160). The method further includes the step of transporting at least one container tub (530) sealed with a container tub cover (520) and including a container nest (500) having a plurality of pharmaceutical containers (510) into the interior of at least a first opening among at least two origin reference positioning openings (132, 134) ([2020]); and the step of transporting the container closure tub (630) sealed with a closure tub cover and including at least one container closure nest (600) having a plurality of pharmaceutical container closures (610) into the interior of a second opening among at least two origin reference positioning openings (134, 132) ([2025]).

The method further includes a step of aseptic sealing the chamber (100) ([2030]) and a step of establishing aseptic conditions inside the chamber (100) ([2035]). The step of establishing aseptic conditions inside the chamber (100) ([2035]) may include a step of treating the interior of the chamber (100) with one or more of water vapor, hydrogen peroxide vapor, ozone, nitrogen dioxide, and ethylene oxide.

The method further comprises the steps of: operating at least one cover removal station (140) and a rotation stage (130) to remove a container tub cover (520) from at least one container tub (530) and to remove a closure nest (600) from a closure tub (630) ([2040]); operating the rotation stage (130) and at least one vacuum pick-up system (e.g., 150 and/or 160) to transfer a container nest (500) having a plurality of medication containers (510) to a destination reference positioning opening (136) ([2050]); and operating the rotation stage (130) and the filling station (170) to dispense a fluid medication into the interior of at least some of the medication containers (510) on an iterative and serial basis ([2060]). The term "repeatedly and sequentially" is adopted herein to describe the fact that the same operational steps are repeatedly used to fill the different containers, as opposed to simultaneously, and that the containers are filled sequentially (one after another). In some embodiments, multiple containers may be filled simultaneously, using a filling station having multiple dispensing heads.

Steps [2040], [2050] and [2060] are each associated with rotating the rotation stage (130) and operating other devices, each of which is a cover removal station (140), at least one vacuum pick-up system (e.g., 150 and/or 160), and a charging station (170). The associated motions may be concurrent in some cases or embodiments, and sequential in other cases or embodiments. In some embodiments, some of the motions may be concurrent and others may be sequential.

The step of operating at least one cover removal station (140) ([2040]) can include the step of engaging a fastening tool (e.g., tool 142) and a cover removal fixture (e.g., fixture 540) pre-attached to the cover to be removed. The step of operating at least one vacuum pick-up system ([2050]) can include the step of contacting the container nest (500) with the plurality of suction cups (152) while applying a vacuum to the suction cups (152). The step of dispensing a fluid pharmaceutical substance into the interior of at least some of the plurality of pharmaceutical containers ([2060]) can include the step of repeatedly and continuously disposing a fluid product dispensing head (174) of the filling station (170) over the openings of at least some of the plurality of pharmaceutical containers (510). The step of operating the rotating stage (130) and at least one vacuum pick-up system ([2050]) may include the step of operating the camera (210) to obtain image information of a container nest (500) having a plurality of pharmaceutical containers (510) and positioning at least one of the vacuum pick-up systems above the container nest (500).

The method further comprises the steps of operating the rotation stage (130) and at least one vacuum pick-up system (e.g., 150 and/or 160) to transfer one of the at least one container closure nest (500) having a plurality of pharmaceutical container closures (610) to the destination reference positioning opening (136) and positioning the at least one closure nest (160) such that the closure (610) is aligned with the container (510) ([2070]); operating the rotation stage (130) to position the aligned container nest (500) and closure nest (600) together with the ramming system (180) ([2080]); and operating the ramming system to force the plurality of container closures (610) within the plurality of containers (510) ([2090]).

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

The step of operating the rotating stage (130) and at least one vacuum pick-up system ([2070]) may include the step of operating the camera (220) to acquire image information of at least one container closure nest (600) having a plurality of pharmaceutical container closures (610), and to place at least one of the vacuum pick-up systems on top of one of the container closure nests (600).

The step of providing a charging device ([2010]) may further include a controller (400) and a software program executable by the controller (400). Any one or more of the steps of aseptic sealing the chamber (100) ([2030]); establishing aseptic conditions within the chamber (100) ([2035]); operating the rotation stage (130); operating at least one cover removal station; operating at least one of the vacuum pick-up systems (150 and/or 160) ([2070]); operating the charging station; and operating the ramming system (180) ([2090]) may be automatically executed by the software program in the controller.

In the embodiments described with reference to FIGS. 1A to 1F, steps [2030], [2050], [2060], [2070] and [2080] each include a step of rotating a rotation stage, for example, a rotation stage (130), having a container nest and a container closure nest.

In another embodiment, 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 a container nest (500) to a destination reference positioning opening (136); dispensing a fluid pharmaceutical substance into an interior of a pharmaceutical container (510); transferring one of the at least one container closure nests (600) to the destination reference positioning opening (136); and arranging the container nests (500) and closure nests (600) aligned with the ramming system (180) can include rotating a rotation stage having the container nests and the container closure nests.

In a typical embodiment, at least one of the steps of removing a container tub cover from at least one container tub (9530); removing a container tub cover from at least one container closure tub (630); transferring a container nest (500) to a destination reference positioning opening (136); dispensing a fluid pharmaceutical substance into an interior of a pharmaceutical container (510); transferring one of the container closure nests (600) to the destination reference positioning opening (136); and arranging the container nests (500) and closure nests (600) aligned with a ramming system (180) can include rotating a rotation stage having the container nests and the container closure nests.

It should be noted that the filling system (1000) and associated methods do not require the use of vibrating containers and escapements, which are characteristic of the prior art. Unlike many prior art systems, the filling system (1000) also does not require the use of gloves for use by a user accessing the interior of the chamber.

Although the above system has been described as employing a controller executing stored software running on a general-purpose computer platform, the system may also be implemented, in whole or in part, using special-purpose hardware.

While the system described above also employs fiducial openings defined on the rotational stage that accommodate a plurality of tubs and nests, the system may also employ other forms of fiducial structures that include other configurations of constraining surfaces sufficient to accommodate tubs and nests. For example, a notched post mounted on the rotational stage could accommodate tubs and/or nests above the rotational stage. Another fiducial positioning structure for accommodating tubs or nests for containers or container closures is described below with reference to FIGS. 3a, 3b, 4a, and 5a.

Another embodiment of a charging system according to the present invention may be identical in all respects to the embodiments described above with reference to FIGS. 1A and 1B , except for the vacuum pick-up system(s) (150 or 160). FIGS. 3A and 3B illustrate a portion of a charging system as described above. In particular, FIG. 3B focuses on an entire area of one of the vacuum pick-up systems, for example the vacuum pick-up system (150). In this alternative embodiment, the vacuum pick-up system (150) is replaced with a reconfigurable vacuum pick-up system (150'). The vacuum pick-up system (160) of FIGS. 1A and 1B may likewise be replaced with a reconfigurable vacuum pick-up system (160') having the same arrangement as the vacuum pick-up system (150'). For clarity, the vacuum pick-up system (160') is not illustrated in FIGS. 3A and 3B . In another embodiment, a single reconfigurable vacuum pick-up system (150') may be employed to pick up both the container nest and the container closed nest. The vacuum pick-up system (150') can access the container nest and the container closed nest by rotation of the rotation stage (130).

The vacuum pick-up system (150') includes two rotating arms (154a', 154b'), each of which includes a plurality of suction cups (152a', 152b'). The vacuum pick-up system (150') is arranged to lift a nest (500) of containers (510) by the suction cups (152a', 152b'). Additionally, the vacuum pick-up system (150') may be arranged to lift a nest (600) of container closures (610) by the suction cups (152a', 152b'). Similar to the vacuum pick-up system (150), the vacuum pick-up system (150') can be raised or lowered so that the suction cups (152a', 152b') can be fastened to different nests (600) of the container closure (610) having different depths inside the tub (530).

The suction cups (152a', 152b') are arranged on a rotary arm (154a', 154b') as a plurality of sets of linearly arranged suction cups (152a', 152b'), each set of linearly arranged suction cups (152a', 152b') being arranged at a different angle perpendicular to the longitudinal axis of the rotary arm (154a', 154b'). This arrangement allows the rotary arm (154a', 154b') to rotate about its transverse axis and to be oriented such that different sets of linearly arranged suction cups (152a', 152b') can engage different nests (500) of the container (510). Due to this arrangement, the sets of suction cups (152a', 152b') can be individually selected for use. The rotation of the rotary arms (154a', 154b') can be performed manually. In another embodiment, the rotary arms (154a', 154b') can be rotated by a suitable motorized drive integrated into the vacuum pick-up system (150') and controlled by the controller (400) illustrated in FIG. 1a.

By rotating the rotary arm (154a', 154b'), another set of linearly arranged suction cups (152a', 152b') can be selected, and the suction cups (152a', 152b') of that set can be arranged to be connected to another container nest (500) having a container (510) or a container closure nest (600) having a container closure portion (610).

FIGS. 3A and 3B illustrate a vacuum pick-up system (150') comprising two rotating arms, namely rotating arms (154a', 154b'). In other embodiments, more than one arm may be employed, all embodiments sharing the concept of selectable configurations of suction cups. While in FIGS. 3A and 3B selecting a suction cup configuration is understood to be accomplished by rotation of the arms (154a', 154b') having the corresponding suction cups (152a', 152b'), in other embodiments selection of the suction cups may be performed on the basis of other configurations, examples of which include but are not limited to lateral translation of the arms having the suction cups in a plane parallel to the rotational plane of the rotational stage (130) such that other sets of suction cups may engage a container nest or a container closure nest. In FIGS. 3A and 3B the suction cups are arranged in a linear set. In other embodiments, a non-linear arrangement of the suction cups may be adopted.

Turning now specifically to FIG. 3b, the members (149, 139) will now be examined in more detail. In one embodiment, the reconfigurable stopping member (149) is shown as having two different ends, the first end of which can be adopted for use by suitably rotating the reconfigurable stopping member (149) about its axis of rotation (141) to a set position. In that set position, the reconfigurable stopping member (149) provides a hard stop against the selected end of the reconfigurable stopping member (149) along a direction parallel to the transverse axis of the rotating arm (154a', 154b') with respect to the proximal end of the container (530). In this embodiment, the reconfigurable stopping member (149) can be rotated a full 180 degrees so that the second end of the reconfigurable stopping member (149) can be positioned to stop the container (530). The second end of the reconfigurable stopping member (140) can be configured so that the proximal end of the container (530) can be stopped at a different point than the point at which the first end of the reconfigurable stopping member (149) stops the proximal end of the container (530).

The restraining member (139) is configured to push against the distal end of the container (530). While other mechanisms may be contemplated to ensure the pushing action of the restraining member, one particularly suitable means is to provide suitable spring loading to the restraining member to rotate it about its axis (143). By the operation described above, the reconfigurable stopping member (149) and the restraining member (130) together position the container (530) in a precise position parallel to the transverse axis of the pivot arm (154a', 154b'). By selecting a suitable distal end of the reconfigurable stopping member (149) to stop the container (530), a particularly precise position can be selected. This arrangement allows containers (530) having different dimensions parallel to the transverse axis of the rotary arms (154a', 154b') to be positioned at precise predetermined positions relative to multiple sets of suction cups (152a', 152b').

A specific set of suction cups (152a', 152b') can be selected to match the selection of a particular end of the reconfigurable stopping member (149). In this manner, the vacuum pick-up system (150') can be configured to ensure that a container (530) of a selected size is accurately placed, so that a container nest (500) inside the container (530) can be engaged by the specific set of suction cups (152a', 152b'). Accordingly, the vacuum pick-up system (150') can be reconfigured to engage nests of different sizes within containers of different sizes.

For clarity, FIGS. 3a and 3b and the description above illustrate an arrangement in which a container (530) can be precisely positioned along only one dimension within the rotational plane of the rotational stage (130), with the dimension of the container perpendicular to that one dimension being considered identical. In such an arrangement, the reference positioning openings (132, 134) are sized to constrain the container (530) within the perpendicular dimension within the rotational plane of the rotational stage (130).

In another embodiment, in addition to the arrangement of FIGS. 3A and 3B, other reconfigurable stopping members and restraining members may be added to accommodate positioning the container (530) in the vertical direction within the rotational plane of the rotational stage (130). To accommodate positioning the container (530) in this vertical direction, the reference positioning openings (132, 134) are not sized to restrain the container in any direction within the rotational plane of the rotational stage (9130).

In the above-described embodiment, the reconfigurable stopping member (149) is described as having two ends, either of which may be selected for use at any one time by rotating the reconfigurable stopping member (149) about the stopping member rotation axis (141). In other embodiments, the reconfigurable stopping member (149) may be shaped or configured to have more than two ends, which ends may be selected by appropriate rotation of the reconfigurable stopping member (149) about the stopping member rotation axis (141). In one embodiment, where the reconfigurable stopping member has a very large number of stopping ends, the reconfigurable stopping member may have the shape of a cam, the shape of which cam represents a very large number of possible stopping ends that may be selected by rotation of the reconfigurable stopping member about an appropriate stopping member rotation axis.

In general, the system described with reference to FIGS. 3a and 3b comprises a fiducial nest positioning system. The fiducial nest positioning system comprises a movable platform comprising a fiducial positioning aperture (132), a reconfigurable stopping member (149), and a restraining member (139). In the case of the system illustrated in FIGS. 3a and 3b, the movable platform is a rotational stage (130). As described below, other movable platforms are also contemplated. For example, to the extent that the tub (530) positionally restrains and positions the nest (500) within the tub (530), any system that fiducially locates the tub (530) also inherently fiducially locates the nest (530).

All of the various embodiments described herein include a reconfigurable vacuum pick-up system, which can be configured to engage suction cups with corresponding regions on a pharmaceutical container nest. Containers within the container nest can be closed by corresponding container closures suspended from the container closure nest. The planar surface of the container closure nest can have an outline that leaves pass-throughs in its perimeter through which suction cups can pass to engage with the container nest. As an example, a pass-through (602) is illustrated in the perimeter of the closure nest (600) in FIG. 3A . Alternatively or additionally, the container closure nest can have suitable openings within its planar surface that can function as pass-throughs through which suction cups can pass to engage with the container nest. The vacuum pick-up system being pursued is constructed and arranged to lift a combination of containers nested by a container nest and their closures, as opposed to a closed nest.

In a typical embodiment, the nest handling subsystem comprises a reconfigurable vacuum pick-up system for picking up a container nest and/or the container closure nests can include one or more arms having a plurality of sets of suction cups. The vacuum pick-up system can be reconfigured so that a set of suction cups from the plurality of sets of suction cups can be selected, and the selected set of suction cups can be pre-arranged to engage with a particular container nest or container closure nest. This selection can be based on one or both of the size and shape of the nest or the size and shape of the nest. The nest handling system can further include at least one pair of reconfigurable stopping members (149) and restraining members (139) positioned adjacent to opposite ends of a reference positioning opening (132) for gripping a tub (530) containing a container nest (500) having a container (510) and engaging the opposite ends of the tub (530). The stopping member and the restraining member are positioned to place the tub (530) in a predetermined position to ensure that the selected set of suction cups can engage with the container nest and/or container closure nest.

As with the opening (132), the opening (134) of FIG. 3a can also be functioned by at least one set of reconfigurable stopping members, in this case members (145), and restraining members, in this case members (135). In the same manner that the reconfigurable stopping members (149) and restraining members (139) function for any tub within the opening (132), the reconfigurable stopping members (140) and restraining members (135) function for any tub within the opening (134).

The various embodiments described above have been described with respect to FIGS. 1A-E and FIGS. 3A and 3B, in which the vacuum pick-up system (150, 160) is described as part of a pharmaceutical filling system (1000). However, the vacuum pick-up system (150', 160) may also be employed in other devices in its own right, including but not limited to the filling systems illustrated in FIGS. 1A-1E, i.e., filling systems in general. Applications of some other embodiments include, but are not limited to, lyophilizing systems. Any suitable nest of objects arranged in a predetermined pattern may be applied. Furthermore, while the system (1000) illustrated in FIGS. 1A-1E employs a rotating stage (130), the reconfigurable pick-up system (150') may employ any suitable movable platform including a suitable reference positioning aperture.

Now, the method described above with reference to FIGS. 2a and 2b can be further described with reference also to FIGS. 3a and 3b. As part of the step of providing a charging device ([2010]), the step of providing at least one vacuum pick-up system can include the step of providing at least one reconfigurable vacuum pick-up system (150'), wherein the at least one reconfigurable vacuum pick-up system (150') comprises a plurality of sets of suction cups (152a', 152b').

The step of providing a charging device ([2010]) may include the step of providing a rotation stage (130) having a destination reference positioning opening (136) and at least two origin reference positioning openings (132, 134), each origin reference positioning opening including at least one pair of reconfigurable stopping members (149) and a restraining member (139).

The transferring step ([2020]) may include operating at least a first reconfigurable stopping member (149) to stop the container tub (530) at a predetermined container tub location, and operating at least a first restraining member (139) to restrain the container tub (530) at the predetermined container tub location.

The transferring step ([2025]) may include operating at least a second reconfigurable stopping member (145) to stop the container closing tub (630) at a predetermined closing tub position, and operating at least a second restraining member (135) to restrain the container tub (630) at the predetermined closing tub position.

The step of operating at least one vacuum pick-up system (150', 160') ([2050]) can include configuring at least one reconfigurable vacuum pick-up system (150', 160') to select a first set of suction cups arranged to engage with the container nest (500).

The step of operating at least one of the vacuum pick-up systems (150', 160') ([2070]) can include configuring the at least one vacuum pick-up system (150', 160') to select a second set of suction cups arranged to engage the container closure nest (600).

The method may further include the step [2095] of operating at least one vacuum pick-up system (150', 160') having a first set of suction cups designed to simultaneously remove the container nest (500) and the container closure nest (600) from the ramming system (180).

An alternative embodiment to the arrangement of the vacuum pick-up system (150, 160) illustrated in FIG. 1a is considered in FIGS. 3a and 3b, having the form of a vacuum pick-up system (150', 160'); and having elements (135, 45, 139, 149) in an arrangement in connection with the source opening (132, 134). Attention is now turned to an alternative embodiment with respect to the arrangement for the destination opening (136) illustrated in FIGS. 1a and 3a. The close-up drawings in FIGS. 4a and 4b show the system of FIG. 3a having a different embodiment in the arrangement around the destination opening (136). To place a nest (500) in an opening (136) and place a nest (600) above the nest (500) in the opening (136), the camera (210, 220) of FIG. 1a may be employed together with the rotation of the controller (400) and the rotation stage (130), but an adjustable destination reference positioning system of FIGS. 4a and 4b, including rotary positioning elements (164a, 164b), may alternatively or additionally be employed to accurately place the nests (600, 500).

Conventional industrial container nests are not manufactured to dimensional standards, and as a result, any system for filling and closing containers (510) of a nested structure must have a mechanism for accurately positioning nests (500) of different sizes having containers (510). For this purpose, the rotating positioning elements (164a, 164b) may have different sets of paired positioning surfaces (167a, 167b; 163a, 163b), such that nests (500) of specific dimensions can be accurately fitted between these paired positioning surfaces. In FIG. 4b, the nest (500) is adapted such that two opposite ends having a first dimension each contact mutually facing surfaces (167a, 167b) of the rotating positioning elements (164a, 164b). By counter-rotating the rotational arrangement elements (164a, 164b) about their respective axes (166a, 166b), the surfaces (167a, 167b) can face each other, thereby allowing nests with different lengths in the first dimension to be accurately positioned between these surfaces.

As is clear from FIG. 4b, when the surfaces (167a, 167b) face each other, a nest snugly positioned between these surfaces can be maintained in a precisely set vertical position by resting on the surfaces (165a, 165b) of the rotational arrangement elements (164a, 164b), respectively. When the surfaces (163a, 163b) face each other, another nest snugly positioned on these surfaces can be maintained in a precisely set vertical position by resting on the surfaces (16a, 161b) of the rotational arrangement elements (164a, 164b), respectively. The rotational arrangement elements (164a, 164b) can each be manually rotated about an axis (166a, 166b). In some embodiments, the rotation of the rotational positioning elements (164a, 164b) may be performed automatically by a motorized drive controlled by the controller (400) and appropriate control software. This control may be based on predetermined dimensional data for the nest disposed between the surfaces of the rotational positioning elements (164a, 164b). Such control may also be based on input data derived from imaging data obtained from cameras (210 and/or 220). In addition, the rotation may occur as the nest (500) is lowered into a position where the rotational positioning elements (164a, 164b) intended to engage opposite ends of the nest (500) along the first dimension serve as a closing horizontal grip on the nest (500) while the surfaces rotate toward a position where they face each other. In this embodiment, the horizontal and vertical arrangements of the nests between the rotating arrangement elements (164a, 164b) are not mutually independent.

As shown in FIGS. 4a and 4b, another arrangement for the first dimension of the nest (500) can also be established for the second dimension of the nest (500) perpendicular to the first dimension. This allows any nest (500) placed in the opening (136) to be precisely positioned at a preset position by setting the rotational positioning elements (164a, 164b).

Another embodiment for the rotational arrangement elements is illustrated in FIGS. 5a and 5b. Unlike the embodiment of FIGS. 4a and 4b just described above, in FIGS. 5a and 5b the horizontal and vertical arrangement of the nest between the two mutually oppositely rotatable elements (164a', 164b') act independently of each other. This is achieved by employing a pair or fixed opposing planar tabs (165a', 165b') for positioning the nest (500) within the vertical dimension, and a pair of rotational arrangement elements (164a', 164b') for positioning the nest (500) within the first horizontal dimension, in each of the two mutually perpendicular planar dimensions addressed in the embodiment just described above. In this embodiment, the rotating arrangement elements (164a', 164b') each comprise two rotating elements ganged together on a mandrel (166a', 166b') to rotate in unison, and mutual alignment ether side of planar tabs (165a', 165b') within bosses (169a', 169b', respectively). The set of rotating elements (164a', 164b'), each separated into two co-moving elements, contribute to confining the nest (500) within the horizontal dimension in the same manner as the rotating elements (164a, 164b) in the embodiments of FIGS. 4a and 4b just described above.

While the rotating elements (164a', 164b') may be designed with more complex geometries, a very simple implementation is shown in FIGS. 5a and 5b where the surface (167a') of the rotating element (164a') and the surface (167b') of the rotating element (164b') contribute to positioning the nest (500) within the first horizontal dimension. By rotating the element (164a') coupled to the mandrel (166a') counterclockwise within the boss (169a'), and rotating the element (164b') coupled to the mandrel (166b') clockwise within the boss (169b'), the surfaces (163a', 163b') are made to face each other, allowing nests having different lengths within the first horizontal dimension to be positioned precisely between the rotating elements (164a', 164b').

The co-operating elements (164a', 164b') can each be manually rotated about the axis of the mandrel (166a', 166b') within the boss (169a', 169b'). In some embodiments, the rotation of the elements (164a', 164b') can be performed automatically by a motorized drive controlled by the controller (400) and suitable control software. Such control can be based on predetermined dimensional data associated with the nest disposed between the surfaces of the elements (164a', 164b'). Additionally, such control can be based on input data derived from imaging data obtained from cameras (210 and/or 220). Additionally, this rotation may occur as the nest (500) is lowered such that certain surfaces of the rotating placement elements (164a', 164b') that are intended to engage with the opposite ends of the nest (500) along the first dimension function as a closing horizontal grip over the nest (500) while rotating toward a position where certain surfaces of the placement elements face each other.

FIGS. 5a and 5b show a pair of mutually counter-rotatable rotating arrangement elements, which are not labeled for clarity, forming another set, ganged together with the rotating elements (164a', 164b') and positioned to accurately position the nest (500) independently in a first vertical dimension and a second planar dimension of the nest (500) perpendicular to the first dimension.

In another aspect, and with reference to FIG. 6, a method for filling nested pharmaceutical containers (510) with a fluid pharmaceutical substance is provided, the method comprising the steps of: providing a filling system (1000) comprising a sterile chamber (100) capable of maintaining sterile conditions ([6010]), the chamber (100) comprising a filling station (170) and a planar rotation stage (130) having a destination positioning structure (136, 164a, 164b, 164a', 164b'); transferring, within the chamber, at least one container tub (530) containing a container nest (500) having a plurality of pharmaceutical containers (510) and sealed with a container tub cover (5320); aseptically sealing the chamber (100) ([6040]); A step of establishing an aseptic condition inside the chamber (100) ([6050]); a step of transporting a container nest (500) having a plurality of pharmaceutical containers (510) into the interior of the destination positioning openings (136, 164a, 164b, 164a', 164b') so as to hold the container nest (500) in place ([6060]); and a step of operating both the rotation stage (130) and the filling station (170) so as to dispense a fluid pharmaceutical substance into the interior of at least some of the plurality of pharmaceutical containers (510) ([6070]). The step of operating the filling station (170) may include the step of rotating the filling station (170). The step of dispensing the fluid pharmaceutical substance may include the step of dispensing the fluid pharmaceutical substance into the interior of the containers (510) in a repetitive and continuous manner.

The step of providing a charging system (1000) ([6010]) may include the step of providing a charging device including at least one cover removal station (140) within the chamber (100), and the step of transferring the container tub (530) within the destination positioning structure may include the step of operating both the rotation stage (130) and the at least one cover removal station (140) to remove the container tub cover (520) from the container tub (530). The step of operating the at least one cover removal station (140) may include the step of rotating the at least one cover removal station (140). The step of providing a charging system (1000) ([6010]) may include the step of providing at least one cover removal station (140) having a fastening tool (142) within the chamber (100), the step of transferring at least one container tub (530) into the chamber (100) may include the step of attaching a cover removal fixture (540) to a container tub cover (520), and the step of operating the at least one cover removal station (140) may include the step of fastening the fastening tool (142) to the cover removal fixture (540).

The method may further include a step ([6030]) of transferring a container closure tub (630) containing at least one container closure nest, the container closure tub being sealed with a container closure tub cover and having a plurality of pharmaceutical container closures (610), into the chamber. The method may further include a step ([6080]) of arranging one of the at least one container nest (600) so as to align the closure (510) within the at least one closure nest (600) with a corresponding container (510) within the container nest (500); a step ([6090]) of rotating the rotation stage (130) to transfer the aligned closure (610) and the nest (500, 600) of containers (510) to a ramming station; and a step (6100) of forcing the closure (610) into the corresponding container (510). The method may further include a step of adjusting the tub positioning structure (135, 145) so as to accommodate the size of the closed nest tub (630). The step of placing one of the at least one closed nest (600) ([6080]) may include a step of acquiring image information about one of the at least one closed nest (600); and a step of placing one of the at least one closed nest based on the image information. The step of placing one of the at least one closed nest ([6080]) may include a step of applying a vacuum to the suction cups (162, 152a, 152b, 152a', 152b'); a step of elevating the container closed nest (600) using the suction cups; and a step of operating the rotation stage (130).

The step of transferring the container nest (500) into the interior of the destination positioning opening ([6020]) may include the steps of applying a vacuum to the suction cups; elevating the container nest (500) using the suction cups; and operating the rotation stage (130). The method may further include the step of selecting one set of suction cups from the plurality of sets of suction cups, and the step of applying the vacuum to the suction cups is performed with respect to the selected set of suction cups. The step of selecting may include the step of rotating one set of suction cups from the plurality of sets of suction cups into position. The method may further include the step of adjusting the destination positioning structure (136, 164a, 164b, 164a', 164b') so as to accommodate the size of the container nest (500). The step of adjusting may be performed in at least two generally orthogonal directions. The above method may further include a step of adjusting the tub positioning structure (139, 149) to accommodate the size of the container nest tub (530).

In another aspect, a method is provided for removing a container cover from a sealed tub, for example a tub (530) or a tub (630), within a controlled environment enclosure (see FIG. 1g), wherein the sealed container is sealed by a container cover, for example a cover (520), the method comprising the steps of providing a container having a sealed cover (520) on a sealing surface of a lip of the container so as to seal contents of the container against decontamination within the controlled environment enclosure, the cover (520) having a cover removal fastener (540), decontaminating the sealed container within the controlled environment enclosure (100), engaging the cover removal fastener (540) with an engaging tool (142), and removing the cover from the container using the engaging tool (142). The fastening step may fasten the cover removal fixture (540) with a fork-shaped fastening tool (142). The fastening step may fasten a ball-shaped appendage onto the cover removal fixture (540).

The providing step can include providing a sterilized pharmaceutical container (510) or closure (610) within a sealed container, for example a tub (530) or tub (630), prior to the decontaminating step. The attaching step can occur prior to the container being provided within the controlled environment enclosure (100). The decontaminating step of the sealed container within the suggested environmental enclosure (100) can occur prior to the step of removing the cover (520). The step of removing the cover (520) can include moving the fastening tool (142) relative to the container (530). The step of removing the cover (520) can include moving both the container (530) and the fastening tool (142). The method can further include attaching a cover removal fixture (540) to the cover (520) prior to the step of providing the container (530) within the controlled environment enclosure.

FIG. 7a is a diagram illustrating subsystems of another embodiment of a device for filling a pharmaceutical container with a fluid pharmaceutical, based on the subsystems illustrated in FIGS. 1a, 1c, 1f, 5a and 5b. For clarity, several subsystems are omitted so that only the sterile sealable chamber (100) of FIG. 1; the rotation stage (130) of FIGS. 1a and 1c; and the container nest (500) having a pharmaceutical container (510) held in position by the arrangement illustrated in FIG. 5b are illustrated. In FIG. 7a, the filling arm (170) of FIG. 1a is replaced with an articulated robotic filling arm (170'). Any alternative reference arrangement for securing the nest (500) may be adopted, provided that the opening of each container (510) is known with adequate accuracy and precision to reliably dispense a droplet of a fluid medication into the container (510).

In addition to the components mentioned above in FIG. 7a, a droplet monitoring subsystem (250) is added, which is illustrated separately in FIG. 7b, comprising an illuminating imager system (252), a mirror (254), and a retroreflector (256). The droplet monitoring subsystem (250) can be controlled by a controller (400), wherein the distal controller (400) communicates with the droplet monitoring subsystem (250). The controller (400) can include memory and a processor. As with the filling arm (170) of FIGS. 1a and 1f, the articulated robotic filling arm (170') supplies the fluid medication via a fluid medication delivery line (172). In FIG. 7a, the filling arm (170') is provided with a fluid medication dispensing head (174'). The dispensing head (174') is positioned and configured to produce a droplet of a fluid medicament within a limited range of droplet shapes that can travel down a consistent volume and droplet path (710). For this purpose, the dispenser head (174') may be provided with a suitable nozzle. A controller (400) may control the dispensing behavior of the dispenser head (174'), wherein the distal controller (400) may be in communication with the dispenser head (174'), or a pump that supplies the fluid medicament to the dispenser head (174'). The imaging system (252) may include a telecentric lens, whereby the imaging system (252) is capable of making consistent size measurements of the droplets produced by the dispenser head (174').

The illumination imaging system (252) is arranged and positioned to illuminate the retroreflective section (254) and acquire high-speed images of droplets (700) dispensed by the dispenser head (174') and moving along the droplet path (710) into an arbitrary container (510). In FIGS. 7A and 7B, the line a-a' represents the light beam path. Since the rotation stage (130) moves all the containers (510) along a circular path around the rotation axis of the rotation stage (130), the articulated robot charging arm (170') operates to move the dispenser head (174') along a linear trajectory following the imaging path (a-a') of the droplet monitoring system (250). Thus, in this embodiment, both the rotation stage (130) and the articulated robot filling arm (170') are operable to place any container (510) so that it can be filled by the dispenser head (174'). In addition to the operation of the rotation stage (130), any operation of the filling arm (170') can be controlled via the controller (400). For this purpose, the controller (400) communicates with both the filling arm (170') and the rotation stage (130), such that the controller (400) can coordinate the movements of the filling arm (170') and the rotation stage (130).

Software may be provided that, when executed by the processor, is loaded into the memory of the controller (400) and controls dispensing of a fluid medication droplet by the fluid medication dispensing head (174') and collects images of the fluid medication droplet (700) along the fluid path (710). The software also enables the controller (400) to control the robotic filling arm (170') and the rotation stage (130).

An alternative embodiment illustrated in FIG. 8 shows a different articulated robot filling arm (170") with an alternative droplet monitoring system (250') integrated into the different articulated robot filling arm. This particular embodiment employs two mirrors (245', 258') along with an illumination imaging system (252') and a retroreflector (256'). We reserve the same reference numerals, i.e., 174' for the dispenser head and 172 for the fluid drug delivery line. The illumination imaging system (252') is arranged and positioned to acquire high-speed images of a droplet (700) being dispensed by the dispenser head (174') via the retroreflector (256') and moving along the droplet path (710) into any container (510). In this particular embodiment, the droplet monitoring system (700) is positioned along the droplet path (710) along the dispensing head (174'). Only the articulated robot charging arm (170") needs to be operated to place any container (510) secured to the nest (500) for charging, and the rotation stage (130) can be held stationary while placing any container (510) secured to the nest (500) for charging. In a more general case, both the rotation stage (130) and the articulated robot charging arm (170") can be operated to place any container (510) for charging by the dispenser head (174'). In addition to operation of the rotation stage (130), any operation of the charging arm (170") can be controlled via the controller (400). For this purpose, the controller (400) can communicate with both the filling arm (170") and the rotation stage (130). The imaging system (252') can include a telecentric lens, thereby enabling the imaging system (252') to obtain a constant size measurement of the droplets produced by the dispenser head (174').

The use of the droplet monitoring system of the present invention is not limited to the rotary stage drug filling systems of FIGS. 1A to 8. They may also be employed in any system in which any fluid, whether nested or not, is dispensed dropwise into the container. One group of filling systems suitable for filling a drug container with a fluid drug within a sterile chamber using the droplet monitoring system of the present invention employs a robotic arm that grasps the container by means of a suitable end effector. The robotic arm may be an articulated robotic arm and may be hermetically sealed to the chamber (100). Suitable examples of such systems are provided in U.S. Patent Publication Nos. 2017/121046 A1, 2016/0200461 A1, 2016/0184986 A1, 2016/0346777 A1, and 2014/0196411 A1, the disclosures of which are all incorporated herein by reference in their entirety. We describe below embodiments of the droplet monitoring system of the present invention for use with joint arms of the type described in more detail in the publications in each of these four lists.

FIG. 9 illustrates the droplet monitoring system (250) of FIGS. 7A and 7B implemented in a pharmaceutical container filling system having a sterile sealable chamber (100') in which a container nest (500) having a pharmaceutical container (510) therein is secured by an end-effector (810) of an articulated arm (800). The articulated arm (800) may be a robotic articulated arm. In some embodiments, the articulated robotic arm (800) may be controlled by a suitable controller (400'). For this purpose, as shown in FIG. 9, the controller (400') communicates with the robotic arm (800). The robotic arm (800) is described in detail in the published patents listed above, which are incorporated by reference in their entirety. For example, the controller (400') may be, but is not limited to, the controller (440) used by the charging system described in FIG. 1 of U.S. Patent Publication No. 2016/0346777 A1 or the controller (13) of FIG. 1 of U.S. Patent Publication No. 2017/121046 A1. For example, the articulating arm (800) may be, but is not limited to, the articulating arm (200) of FIG. 2 of U.S. Patent Publication No. 2016/0184986 A1, the articulating arm (22) of FIG. 1 of U.S. Patent Publication No. 2016/0200461 A1, or the articulating arm (30) of FIG. 2 of U.S. Patent Publication No. 2017/121046 A1. Additionally, the controller (400') can be used to control the droplet monitoring system (250), for which purpose the controller communicates with the droplet monitoring system (250).

FIG. 10 illustrates the droplet monitoring system (250') of FIG. 8, which is adopted in the same pharmaceutical container filling system described in FIG. 9. The controller (400') may also be used to control the droplet monitoring system (250'), for which purpose the controller communicates with the droplet monitoring system (250').

In another embodiment of the above system, both the dispensing head (174') and the containers (510) can be moved by robotic arms, which are, on the one hand, the robotic arms (170, 170') and, on the other hand, the robotic arm (800). Either or both robotic arms can be articulated robotic arms of the type described in the incorporated U.S. patent applications listed above. In yet another embodiment, the dispensing head (174') and the containers (510) can be positioned in fixed positions, for example, these particular embodiments relate to filling a single container (510) at a time.

The embodiments illustrated in FIGS. 7a, 7b, 8, 9 and 10 all employ a retroreflector (256, 256') that is illuminated from a light source housed in the illumination digital imaging system (252). In other embodiments, the droplet (700) may be backlit or illuminated from any other angle. In such embodiments, the imaging system may not require an integrated illuminator, and the illuminator may be located elsewhere, separate from the imaging system.

We now return to the method for aseptic dispensing of a fluid medication into a medication container (510), described by the flowchart of FIG. 11, comprising the steps of: providing a sterile chamber (100, 100') capable of maintaining sterile conditions ([3010]), the chamber including a fluid medication dispensing head (174') configured to generate droplets (700) of the fluid medication and a droplet monitoring system (250, 250') including a digital imaging unit (252, 252'); establishing sterile conditions within the sterile chamber (100, 100') ([3020]); providing a sterile medication container (510) within the sterile chamber (100, 100') ([3030]); The method comprises the steps of: dispensing a plurality of droplets (500) of a fluid medicine from a dispensing head (174') along a droplet path (710) into a container (510) ([3040]); acquiring a plurality of images of at least one droplet among the plurality of droplets (700) along the droplet path (710) from an imaging unit ([3050]); and determining a volume of the fluid medicine dispensed into the container (510) from the plurality of images ([3060]).

In some embodiments, the method can further include a step ([3070]) of stopping the dispensing of the fluid medication based on a volume of the fluid medication dispensed into the container (510). In other embodiments, the step of stopping can be based on a length of time for the fluid medication to be dispensed into the container (510), or based on a weighting of the amount of fluid medication dispensed into the container (510). Thus, the droplet information obtained from the imaging unit can be used as one method for controlling the fluid medication dispensing process, either when simply monitoring the fluid medication dispensing process, or when forming the basis for the stopping step ([3070]).

The step of determining a volume of a fluid medicament dispensed into the container (510) from the plurality of images ([3060]) may include the step of determining a volume of at least one droplet among the plurality of droplets (700). The step of determining the volume of at least one droplet among the plurality of droplets (700) may include the steps of: identifying first and second total portions of at least one droplet (700) shown on the left and right sides of a droplet path (710) in at least one image of at least one droplet (700); calculating the first and second volumes of the at least one droplet among the plurality of droplets (700) by separately mathematically rotating the first and second total portions of the droplet (700) through 2π about the droplet path (710); and may include a step of equating the volume of at least one droplet among the plurality of droplets (700) to the average of the first and second volumes. The term "total portion" is used herein to describe an entire side-on planar view of the droplet to the left or right of the droplet path (710). The two total portions of the droplet will typically not be completely identical. Two planar total portions, i.e., approximately 'halves', are then taken and separately rotated by software about the droplet path (710) to obtain two "droplet volumes", which are then averaged to obtain an assumed volume of the droplet.

The step ([3050]) of acquiring multiple images of at least one of the multiple droplets (700) along the droplet path from the imaging unit (252, 252') may include the step of acquiring multiple images above a predetermined portion of the droplet path, above which the droplet (700) has a stable shape. In the present specification, a shape of a droplet may be considered "stable" if the droplet is distinctly detached from the dispensing head (174') and is assumed to have a shape limited to a predetermined perimeter as seen by the imaging unit, wherein the shape may vary within the predetermined perimeter.

The step of determining a volume of the fluid medication dispensed into the container (510) from the plurality of images ([3060]) may include the step of determining a volume of each droplet (700) dispensed into the container (510). The step of stopping dispensing the fluid medication based on the volume of the fluid medication dispensed into the container (510) may include the step of stopping dispensing the fluid medication when a total amount of the fluid medication dispensed into the container (510) is equal to a set volume. For example, the set volume may be, but is not limited to, a single adult human dosage volume of the fluid medication. Other set volumes may be dosages or integer multiplies of dosages specified by a health authority, regulatory agency, or MDDS sheet for the fluid medication.

In another embodiment, the step of determining a volume of the fluid medication dispensed into the container from the plurality of images ([3060]) can include the steps of determining a representative volume of the droplets (700), counting a total number of droplets dispensed into the container (510), and then multiplying the droplet representative volume by the total number of droplets. The step of determining the representative volume of the droplets (700) can include the steps of measuring only a first droplet and estimating it as representative. In another embodiment, the step of determining the representative volume of the droplets (700) can include the steps of measuring a plurality of droplets and computing an average droplet volume across the plurality of droplets.

The step of acquiring multiple images of one droplet among the plurality of droplets (700) along the droplet path (710) from the imaging unit (252, 252') ([3050]) may include the step of acquiring multiple images by taking light reflected by the retroreflective unit (256, 256') to the imaging unit. The step of acquiring multiple images of at least one droplet among the plurality of droplets (700) along the droplet path (710) from the imaging unit (252, 252') may include the step of acquiring multiple images by using a telecentric lens. The telecentric lens may be integrated into the imaging unit (252, 252'). The step of providing a sterile fluid medication inside the sterile chamber (100, 100') may include the step of providing a sterile fluid medication inside the container nest (500).

The method may further include a step ([3035]) of moving at least one of the dispensing head (174') and the container (510) so as to place an opening of the container (510) below the dispensing head (174') so as to receive a droplet (700) along the droplet path (710). The step of moving the container may include a step of operating a robot arm (800). The step of moving the container (510) may include a step of moving a container nest (500) that holds the container (510). The step of operating the robot arm (800) may include a step of operating an articulated robot arm. The step of moving the dispensing head (174') may include a step of operating the robot arm (170', 170"). The step of moving the dispensing head (174') may include a step of operating an articulated robot arm (170', 170").

In the embodiments of FIGS. 7a, 7b, 8, 9 and 10, the controller (400, 400') is also in communication with the dispensing head (174'), or a pump supplying fluid medicament to the dispensing head, such that the controller (400, 400') can control the flow of droplets through the dispensing head (174') and turn that flow on or off. For clarity, these communication lines are not shown in FIGS. 7a, 7b, 8, 9 and 10.

While the present invention has been described as having an exemplary design, the invention may be further modified within the spirit and scope of the present disclosure. This patent application is therefore intended to cover any variations, uses, and modifications of the invention using its overall principles. Furthermore, this patent application is intended to cover such departures from the present disclosure as are known or come within common practice in the art to which the invention pertains.

Claims (10)

A device specifically modified for aseptically dispensing a predetermined amount of pharmaceutical fluid into a pharmaceutical container using a processor, said device comprising:
A sterile chamber capable of maintaining sterile conditions, the chamber comprising a sterile chamber including a fluid medication dispensing head configured to generate a plurality of droplets of a fluid medication, and a droplet monitoring system including a digital imaging unit and a processor;
The dispensing head is positionable over a sterile pharmaceutical container within the chamber, such that the dispensing head can dispense a plurality of droplets of a fluid pharmaceutical from the dispensing head along a droplet path into the interior of a container within the chamber;
The processor is configured to acquire, from a digital imaging unit, a plurality of images of at least one droplet among the plurality of droplets dispensed from the dispensing head along the droplet path, to determine from the plurality of images whether a set volume of the fluid medicament has been dispensed from the dispensing head by determining a volume of at least one droplet among the plurality of droplets, and is further configured to stop dispensing of the droplet if the set volume of the fluid medicament has been dispensed from the dispensing head;
The processor is configured to identify first and second entire portions of at least one droplet, each of which is displayed on the left and right sides of the droplet path, within at least one image of the at least one droplet, and to separately mathematically rotate the first and second entire portions of the droplet, respectively, passing through a circle around the droplet path, thereby computing first and second volumes of the at least one droplet among the plurality of droplets, and thereby determining the volume of the at least one droplet among the plurality of droplets by equating the volume of the at least one droplet among the plurality of droplets to an average of the first and second volumes.
A device wherein the set amount of the fluid medication is selected from one of a single adult human dose of the fluid medication and a dose of an integer multiple of the fluid medication. In the first paragraph,
A device wherein the imaging unit is configured to acquire multiple images of at least one droplet among multiple droplets dispensed from the dispensing head along the droplet path by acquiring the multiple images above a set portion of the droplet path. In the second paragraph,
The device is configured such that the processor determines from the plurality of images a portion of a droplet path in which the droplet has a stable shape, and, if the droplet is in a portion of the droplet path in which the droplet has a stable shape, selects from the acquired images at least one image of at least one droplet among the plurality of droplets dispensed from the dispensing head along the droplet path. In the first paragraph,
A device wherein the processor is configured to determine the volume of each droplet dispensed from the dispensing head to the lower container. In the first paragraph,
A device further comprising a retroreflector arranged to reflect light to the imaging portion when acquiring multiple images of at least one droplet among the plurality of droplets along the droplet path. In the first paragraph,
A device further comprising a telecentric lens for acquiring multiple images of at least one droplet among the plurality of droplets along the droplet path. In the first paragraph,
A device further comprising means for moving at least one of the dispensing head and the container to position an opening of the container beneath the dispensing head to receive a droplet dispensed along the droplet path. In Article 7,
A device further comprising an articulated robotic arm for moving at least one of the dispensing head and the container. In Article 8,
A device wherein the sterilization chamber is configured to provide a sterile pharmaceutical container within the container nest. In Article 9,
A device wherein the chamber is configured to include a container nest for holding the container, and the articulated robot arm is configured to move the container nest for holding the container.