CN111201007A

CN111201007A - Device and method for monitoring and controlling the filling of containers with pharmaceutical liquids in a sterile environment

Info

Publication number: CN111201007A
Application number: CN201880066525.1A
Authority: CN
Inventors: 卡洛斯·阿贝多·迪亚兹·格雷洛
Original assignee: VanRx Pharmasystems Inc
Current assignee: VanRx Pharmasystems Inc
Priority date: 2017-10-10
Filing date: 2018-09-26
Publication date: 2020-05-26
Anticipated expiration: 2038-09-26
Also published as: EP3694465A4; KR102366435B1; KR102520045B1; CN111201007B; BR112020007069A2; TW201929827A; KR20200066667A; BR112020007069B1; WO2019071339A1; EP3694465A1; KR20230052987A; KR20220025287A; CA3077526A1

Abstract

The present invention relates to a system and method for monitoring and controlling the aseptic dispensing of a pharmaceutical liquid into a container (510); the system (1000) provides a pharmaceutical liquid dispensing head (174, 174') for dispensing drops (700) of pharmaceutical liquid into the container along a drop path (710); and a drop monitoring system (250, 250') for monitoring drops generated and dispensed. The volume of at least one droplet is determined based on an image of a droplet falling along the droplet path. The volume of the drug liquid dispensed is determined by the volume of the droplet. The pharmaceutical liquid dispensing head and the drop monitoring system may be integrated with each other and used in systems that use different mechanisms including a rotating table system (130) and robotic arms (170', 170 ", 800) for moving containers.

Description

Device and method for monitoring and controlling the filling of containers with pharmaceutical liquids in a sterile environment

Technical Field

The present invention relates to the medical field as exemplified by IPC class a61, and more particularly to an apparatus and associated method for the sterilization and aseptic processing of pharmaceutical materials and containers for pharmaceuticals, including the administration of pharmaceutical forms to medical or veterinary patients. In one aspect, the present invention relates to the programming and automation of a device configured and arranged for filling a predetermined amount of liquid or other substance into a medicament container.

Background

The problem of filling pharmaceutical containers with drugs is a major aspect of the pharmaceutical industry. This subject is subject to strict control by governments and authorities of various countries. Technically, this problem is a challenge, since the drug needs to be filled into the container under very strict aseptic conditions. Very specific procedures are prescribed for this task, so that the handling of drugs differs greatly in extent from the handling of any other industrial product, including in particular semiconductors, which also requires extreme and consistent environmental conditions. In fact, the similarities between semiconductor processing in a semiconductor "clean lab" and pharmaceutical processing in a sterile isolator are crude. They have used this "clean lab" together, but the sterility requirements from raw are not relevant to semiconductor manufacturing.

Filling of drug containers with liquid drugs in particular requires sterile handling of the containers and the liquid drug itself, which leads to complex mechanisms and procedures, many of which can be automated to one degree or another. In general, production equipment for liquid drug processing is bulky and expensive, which poses problems for small scale operations, particularly in small scale production and development environments. With the development of this field, in particular in the filling and mixing of liquid medicaments, the need for smaller, more compact devices has become apparent.

The prior art is characterized by the use of a vibrating bowl and ratchet arrangement. Many prior art systems also use gloves for the operator to access the interior of the chamber.

Disclosure of Invention

In one general aspect, the invention features a method for filling nested drug containers with a pharmaceutical liquid substance, such as a liquid, solution, or suspension having therapeutic properties. The method includes providing a filling system comprising a sterilizable chamber capable of maintaining sterility, wherein the chamber includes a filling station and a planar rotation stage having a target datum positioning structure including a limiting surface. The method further comprises delivering at least one container barrel sealed by a container barrel lid into the chamber and containing a container nest carrying a plurality of medicament containers; aseptically sealing the chamber; and forming a sterile condition within the chamber. A container nest carrying a plurality of drug containers is transferred into a target indexing structure such that the container nest is held in place by the restraining surface and a drug liquid substance is dispensed into at least a portion of the plurality of drug containers by operating the rotary table and the filling station.

In particular embodiments, operating the filling station may include rotating the filling station. Dispensing the pharmaceutical liquid substance may include dispensing the pharmaceutical liquid substance into the container in a repetitive and continuous manner. Providing a filling system may include providing a filling apparatus including at least one lid removal station within the chamber, while transferring the container nest to the target datum structure includes removing the container lid from the container bucket by operating the rotary table and the at least one lid removal station. Operating the at least one cap removal station may include rotating the at least one cap removal station. Providing a filling system may include providing at least one cap removal station having an engagement tool within the chamber; transferring at least one container barrel into the chamber may comprise attaching a cap removal fixture to the container barrel cap; and operating at least one cap removal station may comprise engaging the engagement means with the cap removal fixture.

The method may further comprise transferring a container closure pail into the chamber, the container closure pail being sealed by a container closure lid and containing at least one container closure nest carrying a plurality of medicament container closures. The method may further include positioning one of the at least one closure nest to align a closure in the at least one closure nest with a corresponding container in the container nest; transferring the aligned nests of closures and containers to a punching station by rotating the rotary table; and forcing the closure into the corresponding container. Positioning one of the at least one enclosure nest may comprise: acquiring image information about one of the at least one enclosure nest; and locating one of the at least one enclosure nest based on the image information.

Positioning one of the at least one enclosure nest may comprise: applying a vacuum to the chuck; raising a container closure nest with the suction cups; and operating the turntable. Conveying the container nest into the targeting opening can include: applying a vacuum to the chuck; raising the container nest with the suction cup; and operating the turntable. Dispensing the pharmaceutical liquid substance may include: operating the rotating table and the filling station synchronously and/or continuously; and removing the container lid may comprise operating the rotary table and the at least one lid removal station synchronously and/or continuously.

In another general aspect, the invention features a system for filling a nested drug-liquid substance into a drug-container, including: a sterilizable chamber capable of maintaining a sterile condition. The chamber includes: a filling station; and a planar turntable having a turntable axis of rotation and including a target datum locating feature comprising a restraining surface arranged and shaped to receive and retain a medicament container nest carrying a plurality of medicament containers.

In a particular embodiment, the filling station may comprise: a liquid product dispensing head; while the filling station is configured to be rotatable about a filling station axis of rotation parallel to the rotational stage axis of rotation to position the dispensing head over any of the plurality of drug containers in the container nest held in the target datum-locating structure as the rotational stage rotates. The chamber may further comprise: at least one cap removal station; and the rotating table may further include: a first source datum locating structure comprising a limiting surface arranged and shaped to receive and retain a medicament container closure barrel sealed by a container closure barrel lid and to receive at least one medicament container closure nest carrying a plurality of medicament container closures; and at least one second source-referenced positioning opening configured and shaped to receive and retain a drug container barrel sealed by a container barrel lid and to receive a drug container nest carrying a plurality of drug containers.

The at least one lid removal station may be arranged and configured to be rotatable about a lid removal station axis of rotation parallel to the rotational table axis of rotation to remove the container lid from the at least one container pail and the container closure lid from the container closure pail with rotation of the rotational table. At least one cap removal station may comprise an engagement tool arranged and configured to engage engagement fasteners pre-attached to the container lid and the container closure lid.

The system may further comprise: at least one camera positioned to acquire image information about one of the container nest and the closure nest; and a controller; meanwhile, the chamber further includes: at least one vacuum pick system including suction cups arranged to engage the container nests and the container closure nests, the at least one vacuum pick system being configured to lift a medicament container nest from a medicament container drum held in at least one second source datum alignment opening as the rotary table rotates, and to place the medicament container nest into a target datum opening and lift a medicament container nest closure from a medicament container closure drum held in a first source datum alignment opening as the rotary table rotates, and to place the container closure nest on top of the medicament container nest under control of the controller.

The controller is operable to command the at least one camera to provide the image information to the controller, and the controller is operable to control rotation of the rotating table to place the closures in the closure nest into corresponding containers in the container nest. The system may further include a punch system configured to force the closures into the respective containers.

The system may further comprise: at least one rotatable lid removal station having a lid removal station axis of rotation parallel to the turntable axis of rotation; at least one vacuum pick-up system for placing container closure nests on the container nests as closures in the closure nests correspond to containers in the container nests; and a ram system for forcing the closure into the container; also, the filling station is a rotatable filling station having a filling station axis of rotation parallel to the turntable axis of rotation and including a liquid product dispensing head. The system may further comprise: 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 operable to command the turntable to rotate to one of predetermined angular positions based on the image information, and to control the at least one lid removal station, the filling station, the at least one vacuum pickup system, and the stamping system to operate with the turntable.

In a further general aspect, the invention features a system for filling a nested drug container with a pharmaceutical liquid substance, including: means for establishing and maintaining a sterile condition in a chamber; means for confining a container nest carrying a plurality of medicament containers within the chamber; and means for transferring a container nest to the means for restraining the container bucket in the chamber. The system also includes: means for rotating the means for restraining in the chamber; and means for dispensing a pharmaceutical liquid substance into at least a portion of the plurality of pharmaceutical containers in the container nest when the container nest is restrained by the means for restraining.

In a further aspect, there is provided a system for filling a nested drug container with a pharmaceutical liquid substance, the system comprising: a sterilizable chamber capable of maintaining a sterile condition, the chamber comprising: a planar turntable having a turntable axis of rotation; a plurality of positioning structures provided corresponding to the rotary table at different positions around the rotary table rotation axis for holding nests of the medicament container components at different positions around the rotary table rotation axis; and a container filling station having a dispensing head for filling the containers while the containers are held in a nest of one of the positioning structures. The positioning structure may include: a surface associated with a first tub holding opening in the rotating table for holding a first tub of nests containing at least one container; a surface associated with a second barrel holding opening in the rotary table for holding a second barrel of nests containing at least one closure; and a surface associated with a target nest holding opening in the rotary table for holding at least one nest.

The chamber may further comprise: at least one vacuum pick system including suction cups arranged to engage container nests and container closure nests held on the rotary table, the at least one vacuum pick system being configured in conjunction with rotation of the rotary table to lift a medicament container nest from a medicament container drum and to locate the medicament container nest in the target opening and to lift a medicament container closure nest from a medicament container closure drum and to locate the medicament container closure nest on top of the medicament container nest as the rotary table rotates.

At least one of the positioning structures may comprise: a reconfigurable positioning structure having one or more adjustable seating surfaces to seat a barrel relative to the turntable. The reconfigurable positioning structure may include: at least one pair of reconfigurable stop members and a restraining member, the reconfigurable stop members and the restraining member being disposed in opposed relation to one another across an opening in the carousel to accurately position a bucket containing at least one nest in a first predetermined position. The stop member may be adjustable to stop the barrel at the first predetermined position by a rotational adjustment, and the restricting member may be configured to restrict the barrel at the first predetermined position.

At least a first one of the reconfigurable positioning structures may include: a rotational positioning assembly having an axis of rotation parallel to the plane of the rotary table, and comprising: a plurality of different positioning surfaces selectable by rotating the rotational positioning assembly. At least one of the reconfigurable positioning structures may include a pair of opposing rotational positioning assemblies, each rotational positioning assembly having an axis of rotation parallel to the plane of the rotary table, and each may include: a plurality of different positioning surfaces can be selected by rotating the rotary positioning component to adapt to different nest widths.

At least one of the reconfigurable positioning structures may include: at least one first pair of opposed positioning elements defining mutually opposed positioning surfaces along a first positioning axis at least substantially parallel to the plane of the rotary table; and at least one second pair of opposed positioning elements defining mutually opposed positioning surfaces along a second positioning axis at least substantially parallel to the plane of the rotary table and at least substantially perpendicular to the first positioning axis. At least one of the first pair of positioning assemblies and the second pair of positioning assemblies may comprise a rotary positioning assembly having an axis of rotation parallel to the plane of the rotary table and comprising a plurality of distinct positioning surfaces.

The system may further include a reconfigurable vacuum pick-up system comprising: a first set of suction cups arranged in a first configuration; a second set of suction cups arranged in a second configuration different from the first configuration; and a selection mechanism operable to position the first set of suction cups or the second set of suction cups to engage at least a first one of the nests of the medicament container component when the at least the first one of the nests is retained by one of the plurality of positioning structures. The selection mechanism of the reconfigurable vacuum pick-up system may include a rotation mechanism to operatively position the first set of suction cups or the second set of suction cups in an engaged position.

The system may further comprise: at least one lid removal station arranged to remove a lid from a tub containing at least one nest of pharmaceutical packaging material held in one of the locating formations. The at least one lid removal station may be rotatable about a lid removal station axis of rotation parallel to the turntable axis of rotation to remove lid lids as the turntable rotates. The at least one lid removal station may comprise an engagement tool arranged and configured to engage with a lid removal fixture on the lid.

The filling station may be configured to be rotatable about a filling station axis of rotation parallel to the carousel axis of rotation to position the dispensing head over any of the plurality of medicament containers held by one of the positioning structures as the carousel rotates.

The system may further comprise: at least one camera arranged to acquire image information about at least one nest of the medicament container component. The system may further include a punch system configured to force the nested closures into the corresponding nested containers.

The system may further comprise: at least one rotatable lid removal station having a lid removal station axis of rotation parallel to the turntable axis of rotation; at least one vacuum pick-up system for placing the container closure nest on a container nest with the closures in the closure nest corresponding to the containers in the container nest; and a ram system for forcing the closure into the container; and wherein the filling station is a rotatable filling station having a filling station axis of rotation parallel to the turntable axis of rotation and including a liquid product dispensing head.

The system may further comprise: at least one camera for acquiring image information about at least one of the container nest and the closure nest; a controller comprising a memory and a processor, wherein the controller is operable to command the turntable to rotate to one of predetermined angular positions based on the image information and to control the at least one lid removal station, the filling station, the at least one vacuum pickup system, and the stamping system to operate with the turntable.

In another aspect, there is provided a system for filling a nested drug container with a pharmaceutical liquid substance, comprising: means for establishing and maintaining a sterile condition in a chamber; means for confining a container nest carrying a plurality of medicament containers within the chamber; means for transferring a container nest to the means for restraining the container bucket in the chamber; means for rotating the means for restraining in the chamber; and means for dispensing a drug liquid substance into at least a portion of the plurality of drug containers in the container nest when the container nest is restrained by the means for restraining.

In a further aspect, there is provided a method for filling a nested drug container with a pharmaceutical liquid substance, the method comprising: providing a filling system comprising a sterilizable chamber capable of maintaining sterility, the chamber including a filling station and a planar rotation table having a target positioning structure; transferring at least one container drum into the chamber, the container drum being sealed by a container drum lid and containing a container nest carrying a plurality of medicament containers; aseptically sealing the chamber; establishing sterility within the chamber; transferring the container nest carrying the plurality of drug containers into the targeting structure such that the container nest remains in place; and dispensing the pharmaceutical liquid substance into at least a portion of the plurality of pharmaceutical containers by operating the rotary table and the filling station. The operation of the filling station may include rotating the filling station. The dispensing the pharmaceutical liquid substance may include dispensing the pharmaceutical liquid substance into the container on a repeated and continuous basis.

The providing a filling system may include: providing a filling apparatus comprising at least one lid removal station within the chamber, and wherein said transferring the container bucket to the targeting structure comprises: removing the container lid from the container bucket by operating both the rotary table and the at least one lid removal station. Said operating the at least one cap removal station may comprise rotating the at least one cap removal station. The providing the filling system may include: providing at least one lid removal station having an engagement tool within the chamber; said transferring at least one container barrel into the chamber may comprise: attaching a lid removal fixture to the container lid; and wherein said operating the at least one cap removal station comprises: the engagement tool is engaged with the cap removal fixture.

The method may further comprise: a container closure drum is transferred into the chamber, the container closure drum being sealed by a container closure lid and containing at least one container closure nest carrying a plurality of medicament container closures. The method may further comprise: positioning one of the at least one closure nest to align a closure in the at least one closure nest with a corresponding container in the container nest; transferring the aligned nests of closures and containers to a punching station by rotating the rotary table; and forcing the closure into the corresponding container. The method may further comprise adjusting a bucket positioning structure to accommodate the size of the closure nest. Said positioning one of the at least one enclosure nest may comprise: acquiring image information about one of the at least one enclosure nest; and locating one of the at least one enclosure nest based on the image information. Said positioning one of the at least one enclosure nest may comprise: applying a vacuum to the chuck; raising the container closure nest with the suction cups; and operating the turntable.

Said conveying the container nest into the targeting opening may comprise: applying a vacuum to the suction cups to raise the container nest with the suction cups; and operating the turntable. The method may further comprise: selecting one of the plurality of sets of suction cups, and wherein applying vacuum to the selected set of suction cups is performed. The selecting may include rotating one of the plurality of sets of suction cups into position. The method may further comprise: the target positioning structure is adjusted to accommodate the size of the container nest. The adjustment may be performed in two at least substantially orthogonal directions. The method may further comprise: a bucket positioning structure is adjusted to fit the size of the container nest bucket.

In another general aspect, the invention features a container assembly for holding nested drug containers, including: a container, comprising: a bottom portion; a top lip providing a horizontal top sealing surface having a peripheral contour; and a sidewall between the bottom and top lips. The container assembly further comprises: a peelable container lid formed from a sheet of flexible material sealed to the sealing surface of the top lip of a rectangular container to seal the contents of the container; and a lid removal fixture on the container lid.

The sealed peelable container lid may include: extending to a portion of the outside of the peripheral contour of the top sealing surface of the container, and the lid removal fixture may extend on the portion of the peelable container lid that is outside of the peripheral contour of the top sealing surface of the container. The container may be rectangular and include four sidewalls. The cap removal fixture may include an attachment to allow it to be engaged by an engagement tool. The cap removal fixture may include a ball attachment to allow it to be engaged by an engagement tool. The peelable container lid can be heat sealed to the sealing surface of the top lip of the rectangular container to seal the contents of the container without requiring sterilization. The peelable container lid can be sealed to the sealing surface of the top lip of the rectangular container using a chemical medium to seal the contents of the container without requiring sterilization. The peelable container lid can be sealed to the sealing surface of the top lip of the rectangular container using radiation to seal the contents of the container without requiring sterilization. The peelable container lid can be sealed to the sealing surface of the top lip of the rectangular container using plasma to seal the contents of the container without the need for sterilization. The peelable lid may be made of a plastic material. The peelable lid may be made of a water impermeable metal film. The peelable lid may be made from a polymeric film. The lid-removal fixture can be clamped to a portion of the peelable container lid extending outside the peripheral contour of the top sealing surface of the container. The sealed container may hold a sterilized medicament container or closure.

In another aspect, there is provided a method of removing a container lid from a sealed container in a controlled environment enclosure, the sealed container being sealed by the container lid, the method comprising: providing the container in the controlled environment enclosure with the lid sealed to a sealing surface of a lip of the container to seal the contents of the container without requiring sterilization, the lid having a lid removal fixture; sterilizing the sealed container in the controlled environment enclosure; engaging the cover removal fixture with a bonding tool; and removing the lid from the container using the engagement tool. The engagement may engage the cap removal fixture with a fork-shaped engagement tool. The engagement may engage a ball attachment on the cap removal fixture.

The providing may include: a sterilized medicament container or closure is provided in the sealed container prior to sterilization. The attachment may be made before the container is in the controlled environment enclosure. Sterilizing the sealed container in the controlled environment enclosure may be performed prior to removing the lid. Removing the cap may comprise moving the engagement means relative to the container. Removing the cap may comprise moving the container and the engagement means. The method may further comprise attaching the lid removal fixture to the lid prior to providing the container in the controlled environment enclosure.

In a further aspect, there is provided a method of aseptically filling a pharmaceutical liquid into a container, the method comprising: providing a sterilizable chamber capable of maintaining sterility, the chamber including a pharmaceutical liquid dispensing head configured to generate drops of a pharmaceutical liquid, and a drop monitoring system including a digital imager; establishing a sterile condition within the sterilizable chamber; providing a sterile drug container within the sterilizable chamber; moving at least one of the dispensing head and the container to position an opening of the container below the dispensing head to receive the droplet along a droplet path; dispensing a plurality of droplets of the liquid from the dispensing head along a droplet path into the container; acquiring a plurality of images of at least one of the plurality of droplets along the droplet path from the imager; and determining the volume of liquid dispensed into the container; the method may further include stopping the dispensing of the liquid based on the volume of liquid dispensed into the container.

Determining from the plurality of images the volume of liquid dispensed into the container may include: a volume of at least one of the plurality of droplets is determined. The determining the volume of at least one of the plurality of droplets may include: identifying a first total portion and a second total portion of the at least one drop appearing on the left and right sides of the drop path, respectively, in the at least one image of the at least one drop; calculating a first volume and a second volume of at least one drop of the plurality of drops by mathematically rotating the first total portion and the second total portion of the drop, respectively, through 2 π around the drop path; and equating the volume of at least one of the plurality of droplets to an average of the first volume and the second volume.

Said acquiring images of at least one of the plurality of droplets along the droplet path from the imager may comprise: the plurality of images are acquired over a predetermined portion of the drop path. Alternatively, said acquiring from the imager a plurality of images of at least one of the plurality of droplets along the droplet path may comprise: determining a portion of the drop path from the plurality of images, wherein the drop has a stable shape; and selecting at least one image of the at least one droplet from the acquired images of the droplet when the droplet is in a portion of the droplet path where the droplet has a stable shape.

Determining from the plurality of images the volume of liquid dispensed into the container may include: the volume of each droplet dispensed into the container is determined. The stopping of the dispensing of the liquid based on the volume of the liquid dispensed into the container may include: the dispensing of the liquid is stopped when the total amount of liquid dispensed into the container equals a predetermined volume. Said acquiring images of at least one of the plurality of droplets along the droplet path from the imager may comprise: a plurality of images are acquired using light reflected by the retro-reflector to the imager. Said acquiring images of at least one of the plurality of droplets along the droplet path from the imager comprises: a plurality of images are acquired by a telecentric lens. Said providing a sterile drug container within the sterilizable chamber comprises: the sterile drug container is provided in a container nest.

The method may further comprise: moving at least one of the dispensing head and the container to position an opening of the container below the dispensing head to receive the drop along a drop path. Moving the container may include: operating a robot arm. Operating the robot arm may include: operating a joint robot. Moving the dispensing head may include: operating a robot, which may be a joint robot.

In a further aspect, there is provided a system for aseptically dispensing a pharmaceutical liquid into a container, the system comprising: a sealable and sterilizable chamber capable of maintaining sterility; a drug liquid dispensing head disposed in the chamber for generating droplets of the drug liquid; providing a droplet monitoring system comprising a digital imager in the chamber to acquire images of droplets dispensed by the liquid dispensing head; a controller including a memory and a processor, the controller communicatively coupled to the liquid dispensing head and the digital imager; and software configured to control the dispensing of the drops of the pharmaceutical liquid through the liquid dispensing head and collect images of the drops of the pharmaceutical liquid along a drop path when the software is loaded into the memory and executed by the processor.

The system may further comprise: at least one of a liquid dispensing head positioning system and a container positioning system communicatively coupled to the controller, the software further configured to control at least one of the liquid dispensing head positioning system and the container positioning system. The liquid dispensing head positioning system may include a robot arm, which may be a jointed robot arm; the jointed robot arm may be hermetically sealed to the chamber. The container positioning system may include a robotic arm. The robotic arm used in the container positioning system may include an end actuator configured to hold a container nest. The robot used in the container positioning system may comprise a jointed robot, which in some embodiments may be hermetically sealed to the chamber. The drop monitoring system may include a retro-reflector configured to reflect light through the drop to the digital imager. The digital imager may include a telecentric lens.

Systems and methods according to the present invention do not require the use of a vibrating bowl or ratchet device; the system or method also does not require the use of gloves. The system and method according to the present invention can meet the needs for compact, small-scale filling and liquid drug compounding.

Drawings

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

FIG. 1A is a diagram of an apparatus for filling a pharmaceutical liquid product in a pharmaceutical container; for clarity, some surfaces are shown in cross-section, while others are shown as transparent;

FIG. 1B is a plan view of one chamber of the device of FIG. 1A;

FIG. 1C shows a rotary table of the apparatus of FIGS. 1A and 1B;

FIG. 1D is a side view showing a portion of the apparatus of FIGS. 1A and 1B;

fig. 1E shows the drug container lid being removed when placed in the rotational stage of fig. 1A-1D;

FIG. 1F is a view showing a drug container filled with a drug liquid substance in the device of FIGS. 1A-1E;

FIG. 1G is a more detailed diagram providing a cover removal feature of the device of FIGS. 1A, 1B and 1E;

fig. 2A and 2B are flow diagrams that collectively form a method for aseptically filling a pharmaceutical liquid substance into a pharmaceutical container in a space-constrained environment;

FIG. 3A is a view of a subsystem of another embodiment of an apparatus for filling a pharmaceutical liquid product into a pharmaceutical container;

FIG. 3B shows a portion of FIG. 3A in greater detail;

FIG. 4A is a view of a subsystem of another embodiment of an apparatus for filling a pharmaceutical liquid product into a pharmaceutical container;

FIG. 4B shows a portion of FIG. 4A in greater detail;

FIG. 5A is a view of a subsystem of yet another embodiment of an apparatus for filling a pharmaceutical liquid product into a pharmaceutical container;

FIG. 5B shows a portion of FIG. 5A in greater detail;

FIG. 6 is a flow diagram showing another method for filling a nested drug container with a pharmaceutical liquid substance;

FIG. 7A is a view of a subsystem of another embodiment of an apparatus for filling a pharmaceutical liquid product into a pharmaceutical container based on the system of FIGS. 5A and 5B;

FIG. 7B is a view of a droplet monitoring system;

FIG. 8 is a view of a subsystem of another embodiment of an apparatus for filling a pharmaceutical liquid product into a pharmaceutical container;

FIG. 9 is a view of a subsystem of yet another embodiment of an apparatus for filling a pharmaceutical liquid product into a pharmaceutical container;

FIG. 10 is a view of a subsystem of yet another embodiment of an apparatus for filling a pharmaceutical liquid product into a pharmaceutical container; and

fig. 11 is a flow chart of a method of aseptically dispensing a pharmaceutical liquid into a container.

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

Detailed Description

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

The present invention relates to a device and a method for filling a pharmaceutical liquid substance into a pharmaceutical container in a space-limited environment. In fig. 1A, the filling system 1000 includes a sealable chamber 100 in communicative connection with an atmospheric environment, the sealable chamber 100 capable of having a sterile environment formed within and capable of maintaining the sterile environment within its interior. The interior of the sealable chamber 100 may be sterilized by any one or more of a variety of treatments, including but not limited to treatment with a sterilant, such as steam, hydrogen peroxide vapor, ozone, nitrogen dioxide, and ethylene oxide. The structure and mechanisms for performing such a sterilization step are well known in the art and are not shown in FIG. 1A.

Chambers

200 and 300 are separated from chamber 100 by upper wall 110 and lower wall 120, respectively, and need not be capable of maintaining a sterile environment within the interior thereof. The chamber 100 is communicatively connected to the atmosphere via a suitable sterile-sealed access door 102, shown schematically in phantom outline in FIG. 1A. Suitable sealable doors and interfaces are well known in the art and will not be discussed further in this specification. For example, the atmospheric environment may be a clean room adapted to handle the drug during production. Since space is of great importance in such a clean environment where space is limited, there are many advantages in reducing the so-called "footprint" of the device to be placed in the clean environment.

The terms "sterile" and "sanitize" and derivatives thereof are to be understood as follows for the purpose of this specification. The formation of a sterile state in the interior of the chamber is understood to mean that the state is formed over the entire internal ambient environment of the chamber and over substantially all exposed internal surfaces of the chamber. This would include surfaces exposed to all items, containers, subsystems, etc. within the ambient environment of the interior of the chamber. Very tight gaps or micro-cracks may be present in the chamber interior, so that the sterilization gas or vapour may not penetrate completely into these tight areas, e.g. the degree of sterilization may not be complete under certain practical circumstances. This is recognized in both the industry and industry standards. The effects of establishing a sterile state within a chamber and "sterilizing the interior of the chamber" have the same meaning in this specification.

Introducing items with surfaces that are not properly sterilized into a sterile chamber interior in a sterile state can disrupt the sterility of the chamber interior. Conversely, introducing a sterile or disinfected item into a chamber that does not have a sterile condition inside does not make the inside of the chamber sterile. In fact, all that is done is to destroy the sterility of the surface of the introduced article. Similarly, the introduction of filtered air, even if all of the organisms are filtered out, into an unsterilized chamber may not sterilize the chamber in any way or to an acceptable degree for the pharmaceutical industry. The reason for this is that the inner surfaces of the chamber are not disinfected by such introduced air. All this occurs as a result of the filtered air being contaminated with biological species present on the interior surfaces of the unsterilized chamber.

For clarity and completeness, the technical term "sterilization" which may also be mentioned is sometimes also used in connection with the introduction of a medicinal liquid along a sterile tube into a controlled chamber body. In this case, the term in the art relates to the state within the catheter or the fact that the drug liquid can be filtered to a suitable degree. This makes it absolutely impossible to sterilize or sterilize the interior of the chamber. The sterility in this case is limited by the interior of the conduit carrying the drug stream. Such drug streams are often filtered to a high degree, but such filtering only affects the interior of a particular catheter and does not sterilize the interior of the chamber in any way.

In some prior art systems, containers introduced into the chamber for the purpose of filling with drugs are passed through a sterilization subsystem, thereby killing biological species on the containers. Such sterilized containers lose their sterility when introduced into the chamber when the chamber itself is not sterile, as the biological species contained within the chamber will deposit on the previously sterile containers.

It should also be noted that any quality pharmaceutical or semiconductor clean room, including "class 100", "class 10" or "class 1", cannot construct a sterile chamber even when using laminar flow hoods or the like or any quality HEPA (high efficiency particulate air) filters or ULPA (ultra low particulate air) filters, because they cannot provide a reliable means to disinfect or sterilize the interior surfaces. The standard for clean rooms is from the federal government and ISO (international organization for standardization) in the united states. Which specifies the allowable particle content of a cubic volume of air in such a clean room facility. None of these standards directly address the problem of biological species present on indoor surfaces. This means that the chamber cannot be rendered sterile by mere management of its air or airflow. Instead, the chamber may be sterilized by merely sterilizing its interior surfaces.

The Rutala et al manuscript from the centers for disease control, "guide for disinfection and sterilization of health care facilities in 2008", lists the outline of the disinfection mechanism and method. In this description we will particularly focus on the mechanical means for sterilizing the interior of the chamber; i.e. to sterilize its inner surface and the surrounding environment within the chamber. Steam-alkali processes are most suitable for this task, taking into account the requirements. These include, but are not limited to, treatment with heated water vapor, hydrogen peroxide vapor, ozone, nitrogen dioxide, ethylene oxide, glutaraldehyde vapor, or other suitable sterilizing gases and vapors. In one suitable method for use in the present invention, sterilization is by means of hydrogen peroxide vapor, followed by flushing with ozone before the chamber is used for filling of the drug container.

The subsystems of the apparatus 1000 including the sealable chamber 100 will be illustrated in FIGS. 1A-1G. Due to the simplicity and density of the components and subsystems of the device 1000, certain components and subsystems are omitted from the drawings of fig. 1B-1G for clarity, and emphasis is placed on the components and subsystems most relevant to the text supported in this specification. The planar rotation stage 130 may be fully rotated 360 degrees about the rotation stage rotation axis 131 in a horizontal plane parallel to the lower wall 120 and may be raised and lowered by a bellows feed-through 190. The use of a bellows feed-through 190 allows the chamber 100 to maintain sterility during movement of the rotary table 130. A suitable engine and transmission 320 may be housed within the chamber 300. Motors, such as stepper motors, and drive systems adapted to accurately and repeatably rotate the rotary table 130 at a suitable angle are well known in the art and are not discussed further in this specification.

As shown in fig. 1C, at least three

fiducial positioning openings

132, 134, and 136 are provided in the rotary stage 130. The datum alignment opening 132 is adapted to receive a container barrel 530, the container barrel 530 adapted to hold sterile medication containers 510 prepackaged in a predetermined configuration in the container nest 500. The container tub 530 is generally rectangular and is sealed with a peelable lid 520. In this form, the supplier of the medicament container provides its product to the user of the device of the present specification. The datum alignment opening 134 is adapted to receive a container-closure bucket 630, the container-closure bucket 630 being adapted to hold sterile drug container closures 610 pre-packaged in a predetermined configuration in a container-closure nest 600. The container-closure bucket 630 is generally rectangular and is sealed with a peelable lid not shown in fig. 1A-1G. The peelable lid of the tub 630 is functionally identical to the peelable lid 520. In this form, the supplier of the medicament container provides its product to the user of the device of the present specification. For simplicity of the system 1000, the rectangular axes of the

fiducial positioning openings

132, 134 and 136 may be oriented at an angle relative to the radial direction of the rotary table 130 to determine a suitable small radius for the rotary table 130.

Suitable container nests 500 and container closure nests 600 are described in U.S. patent application No. 2016/0200461, published 2016, 7, 14; container pail 530 and container closure pail 630; and a peelable lid 520, the entire contents of which are incorporated herein by reference. An alternative lid gripping device for removing a lid of a pail from the pail is also described in us patent application No. 2016/0251206 published on 1/9/2016, the entire contents of which are incorporated herein. The removal of the lid may be controlled and monitored by the subsystems and methods described in PCT international publication No. WO 2018/049516 a1, published 3, 22, 2018, the entire contents of which are incorporated herein by reference.

For clarity, the use of a single barrel 530 of the medicament container 510 and a single barrel 630 of the container closure 610 will be described below with reference to fig. 1A-1G and the associated text to be described. In practice, the container closures 610 of each container-closure pail 630 are provided as a plurality of nests 600. To this end, the rotational stage 130 may include one or more datum alignment openings 132, each of which receives a container barrel 530 holding sterile drug containers 510 prepackaged in one of the container nests 500. In other embodiments, more than one nest 500 of containers 510 may be present in a single drug container barrel 530.

The datum alignment opening 136 is specifically configured to receive a container nest 500 carrying a medicament container 510. While the

buckets

530 and 630 naturally sit in the

datum alignment openings

132 and 134 and hang in the

openings

132 and 134 by their own edges, the container 510 sits correctly in the opening 136 and is held in place by some other mechanism. To this end, the fiducial positioning opening 136 includes four fiducial holding guides 137. The bottom plate 138 is located in the fiducial positioning opening 136 to serve as a release member of the system 1000, and is supported on a horizontal portion of the bottom of each of the four fiducial holding guides 137 (refer to fig. 1C and 1D). This configuration allows the bottom plate 138 to be guided by the reference holding guide 137 to move freely. When we discuss the closing of a container with a container closure we will return to this configuration.

Fig. 1E shows the fiducial positioning openings 136 empty and the cover 520 being peeled away from the container barrel 530 in the fiducial positioning openings 132 (not visible) to expose the nest 500 carrying the drug containers 510. At this point in the operation of the system 1000, a lid similar to the lid 520 has been peeled away from the tub 630 in the datum alignment opening 134 (not visible) to expose the nest 600 carrying the container closures 610. Fig. 1G shows a close-up detailed view of the peeling of the lid 520. The lid removal station 140 is rotatable about a lid removal station axis of rotation 144 parallel to the rotation stage axis of rotation 131 and comprises an engagement tool 142, which in this particular embodiment is fork-shaped for engagement with a lid removal fixture 540 attached to the lid 520. The lid removal fixture 540 is pre-attached to the lid 520 prior to transferring the tub 530 into the system 1000 through the door 102 (see fig. 1A). In the embodiment shown in fig. 1E and 1G, cap removal fixture 540 is clamped to cap 520 and has a ball attachment to allow it to be engaged by engagement tool 142. Other combinations of cap removal fixtures and bonding tools are contemplated, and the system 1000 is not limited to the specific combination of cap removal fixtures and bonding tools shown in fig. 1A, 1E, and 1G. For example, cap-removal fixture 540 may be made an integral part of cap 520 for use in a filling system, such as filling system 1000. Or it may be clamped to the lid 520 during insertion of the nest 500 carrying containers 510 into the tub 530 and during insertion of the nest 600 carrying container closures 610 into the tub 630.

The rotational stage 130 may be lowered to help achieve a smaller acute angle between the lid 520 and the tub 530. An excessively acute angle may cause tearing of the cover 520. The lid removal station 140 may rotate while the rotary stage 130 rotates, such that the combined motion of the lid removal station 140 and the rotary stage 130 provides a low stress path for removing the lid 520, limiting the chances of tearing of the lid 520. In particular, when the container bucket 530 is placed into the datum alignment opening 132 or removed from the datum alignment opening 132, the lid removal station 140 may be rotated to ensure that the engagement tool 142 does not appear above the datum alignment opening 132.

In some embodiments, the system 1000 includes a single lid removal station 140 to sequentially remove lids from the

tubs

530 and 630. In other embodiments, the system 1000 may be equipped with two or more lid removal stations 140 for specifically removing lids from the

buckets

530 and 630, as well as other additional buckets. In some embodiments, the lids are removed from the

tubs

530 and 630 and from the other tubs simultaneously, all of the removal process benefiting from a single rotational movement of the rotational stage 130.

In fig. 1A, 1B and 1F, a filling station 170 for filling pharmaceutical liquid products into pharmaceutical containers 510 comprises: a pharmaceutical liquid product supply line 172 (see fig. 1F) that supplies pharmaceutical liquid product to a pharmaceutical liquid product dispensing head 174. The filling station 170 is rotatable about a filling station axis of rotation 176 that is parallel to the rotary table axis of rotation 131. When a nest 500 is located in the datum alignment opening 136, the filling station 170 and the rotary table 130 may be rotated simultaneously or sequentially to place the dispensing head 174 over any selected container 510 in the nest 500. This allows the containers 510 in each nest 500 to be filled with the pharmaceutical liquid product via the product dispensing head 174. When the filling containers 510 are not engaged, the filling station 170 can be rotated to swing the dispensing head 174 completely out of the datum-locating opening 136, thereby allowing the nest 600 carrying the container closures 610 to be placed on top of the nest 500 as the closures 610 are placed directly on top of the openings of each container 510 residing in the datum-locating opening 136.

Another term used to describe the dispensing head 174 is a "fill needle". Suitable filling needles and protective sheath configurations for such filling needles are described in published U.S. patent applications 2016-0346777 and 2017-0121046, the entire contents of which are incorporated herein by reference.

Fig. 1A and 1B show two vacuum pick-up

systems

150 and 160, each comprising a plurality of

suction cups

152 and 162, respectively (see fig. 1B). Vacuum pick-up system 150 is configured to pick up nest 500 of containers 510 via suction cups 152, and vacuum pick-up system 160 is configured to pick up nest 600 of containers 610 via suction cups 162. The vacuum pick-up system 160 can be raised and lowered to allow the suction cups 162 to engage nests 600 of different container closures 610 contained at different depths within the bucket 630. To this end, the vacuum pick-up system 160 may include a telescoping feed-through tube that allows vertical movement while maintaining the sterile integrity of the chamber 100. Suitable vacuum pumps or vacuum lines from a vacuum source external to system 1000 may be connected to

vacuum pickup systems

150 and 160 and ensure a suitable vacuum at

suction cups

152 and 162.

Cameras

210 and 220 are provided to view and record the positioning of

suction cups

152 and 162 on

nests

500 and 600, respectively. In the embodiment shown in FIG. 1A,

cameras

210 and 220 are disposed within chamber 200, respectively, and

nests

500 and 600 are viewed through sealed

windows

112 and 122, respectively. In other embodiments,

cameras

210 and 220 may be disposed within chamber 100 and view nests directly from within chamber 100.

As shown in fig. 1A, 1B and 1D, the container closure stamping system 180 includes: an upper punch plate 182 disposed above the rotary table 130 within the chamber 100; a lower punch 184 disposed below the rotary table 130 in the chamber 100; and a punch driver 310 located inside the chamber 300. The punch driver 310 is arranged to drive the lower punch 184 vertically towards the upper punch 182 via the telescopic feed tube 186. The released bottom plate 138 of the fiducial positioning opening 136 is pushed up by the lower punch 184 while being located above the lower punch 184 by appropriately rotating the rotary table 130 and guided in the process by the fiducial holding guide 137 (see fig. 1D). When the closures 610 in the closure nest 600 are eventually pushed against the upper punch 182, they are forced into the openings of the containers 510 within the nest 500. This creates a sandwich nesting of closed containers 510 each closed by a corresponding closure 610. As shown in fig. 1D,

nests

500 and 600 are forced together to form composite nest 500/600.

The controller 400 shown in fig. 1A and 1B may be communicatively connected to the rest of the system 1000 via a control communication line 410, or may be physically contained within the system 1000, such as within the chamber 200. The controller 400 may have a suitable memory and a processor containing suitable software program instructions that, when loaded into the memory by the processor, control: the movement of the punch system 180, the vertical movement and rotational action of the rotary table 130, the application of vacuum to the vacuum pick-up

systems

150 and 160, the imaging by the

cameras

210 and 220, the vertical movement of the vacuum pick-up system 160, any rotational or vertical movement required from the cap removal station 140 and the filling station 170, and the on-off valve for the pharmaceutical liquid product supplied to the dispensing head 174. Suitable valves and pumps, typically peristaltic pumps, required for supplying the pharmaceutical liquid product to the dispensing head 174 are well known in the art and may be housed in the chamber 200 or may be located external to the system 1000. Various mechanical drives for the above subsystems are known in the art and will not be discussed in detail herein. These may be generally housed in the chamber 200 of the system 1000. When the processor executes the software, the software instructs the rotary table to rotate to a predetermined or angular position based on image information from the camera and controls the lid removal station, the filling station, the vacuum pick-up system and the stamping system to operate exclusively in cooperation with the rotary table.

A method based on a system 1000 for filling a nested pharmaceutical container with a pharmaceutical liquid product is now described under the flow chart shown in fig. 2A and subsequently in fig. 2B. The method comprises the following steps: providing a filling apparatus 1000, the filling apparatus 1000 comprising a sterilizable chamber 100 capable of maintaining a sterile state, the chamber comprising a rotary table 130 having a target fiducial positioning opening 136 and at least two source fiducial positioning openings (132 and 134); a filling station 170; at least one cap removal station 140; a vertically oriented container punch system 180; and at least one vacuum pickup system (e.g., 150 and/or 160) [ step 2010 ]. The method further comprises the following steps: transferring at least one container tub 530 sealed by a container tub cover 520 into at least a first of the at least two source fiducial locating openings (132 and 134), the container tub 530 containing a container nest 500 carrying a plurality of drug containers 510[ step 2020 ]; and transferring the container-closure bucket 630, sealed by the closure bucket lid, into a second of the at least two source-referenced registration openings (134 and 132), the container-closure bucket 630 housing at least one container-closure nest 600 carrying a plurality of drug container closures 610 [ step 2025 ].

The method further comprises the following steps: aseptically sealing the chamber 100[ step 2030 ]; and forming a sterile condition within the chamber 100 step 2035. Forming a sterile condition within the chamber 100 step 2035 may include treating the interior of the chamber 100 using any one or more of steam, hydrogen peroxide steam, ozone, nitrogen dioxide, and ethylene oxide.

The method further comprises the following steps: operating the at least one lid removal station 140 and rotating the rotating table 130 to remove the container lid 520 from the at least one container pail 530 and remove the closure lid from the closure pail 630 step 2040; operating one of the rotary table 130 and the at least one vacuum pick-up system (e.g., 150 and/or 160) to transfer the container nest 500 carrying the plurality of drug containers 510 to the target fiducial positioning opening 136[ step 2050 ]; and dispensing the pharmaceutical liquid material into at least a portion of the plurality of pharmaceutical containers 510 in a repeated and continuous manner by operating the rotational stage 130 and the filling station 170 [ step 2060 ]. The term "repeat and continue" as used in this specification is intended to describe the fact that the same operational steps are repeated for filling the various containers and the containers are filled one after the other, rather than simultaneously. In some embodiments, multiple containers may be filled simultaneously using a filling station having multiple dispense heads.

Steps

2040, 2050 and 2060 each involve rotating the rotary table 130 and operating another device, respectively the lid removal station 140, one of the at least one vacuum pick-up systems (e.g. 150 and/or 160) and the filling station 170. The acts involved may be simultaneous in some cases or embodiments, and sequential in other cases or embodiments. In some embodiments, some actions may be simultaneous, while other actions may be sequential.

Operating the at least one cap removal station 140 step 2040 may include: an engagement tool (e.g., tool 142) is engaged with a cap removal fixture (e.g., fixture 540) that is pre-attached to the removed cap. Operating one of the at least one vacuum pickup systems [ step 2050] may include: the container nest 500 is brought into contact with the plurality of suction cups 152 while a vacuum is applied to the suction cups 152. Dispensing a drug-liquid substance to at least a portion of the plurality of drug containers step 2060 may comprise: the liquid product dispensing head 174 of the filling station 170 is positioned over the opening of at least a portion of the plurality of medication containers 510 in a repetitive and sequential manner. Operating one of the rotary table 130 and the at least one vacuum pick-up system may comprise: the camera 210 is operated to obtain image information of a container nest 500 carrying a plurality of drug containers 510 and to position one of the at least one vacuum pickup systems above the container nest 500.

The method further comprises the following steps: operating one of the at least one vacuum pick-up systems (e.g., 150 and/or 160) and the rotary table 130 to transfer one of the at least one container closure nest 600 carrying the plurality of drug container closures 610 to the target datum alignment opening 136 and to position the at least one closure nest 600 to align the closures 610 with the containers 510[ step 2070 ]; operating the rotary table 130 to co-locate the aligned container nest 500 and closure nest 600 in the stamping system 180[ step 2080 ]; and operating the stamping system 180 to force the plurality of container closures 610 into the plurality of containers 510 step 2090.

Operating one of the at least one vacuum pickup systems [ step 2070] may comprise: the container closure nest 600 is brought into contact with the plurality of suction cups 162 while applying vacuum to the suction cups 162. Operating the stamping system 180[ step 2090] may include: the plurality of drug containers 510 are driven toward the upper platen 182 of the stamping system 180.

Operating the rotary table 130 and one of the at least one vacuum pick-up system [ step 2070] may comprise: camera 220 is operated to obtain image information of one of the at least one container closure nest 600 carrying the plurality of drug container closures 610 and one of the at least one vacuum pickup systems is positioned over one of the at least one container closure nest 600.

Providing a filling device step 2010 may include: a filling apparatus is provided which further comprises a controller 400 and a software program executable by the controller 400. This may be done automatically by executing a software program in the controller 400: any one or more aseptically sealed chambers 100[ step 2030 ]; creating a sterile condition within the chamber 100 step 2035; operating the rotating table 130; operating at least one cap removal station 140; operating one of the at least one vacuum pick-up systems (150 and/or 160) [ step 2070 ]; operating the filling station 170; and operating the stamping system 180 step 2090.

In the embodiment shown in fig. 1A-1F, each of

steps

2040, 2050, 2060, 2070, and 2080 includes a rotary table, such as rotary table 130, that rotates the carrying container nest and the container closure nest.

In other embodiments, multiple steps of removing the container lid from the at least one container pail 530; removing the container lid from the at least one container-closure pail 630; transferring the container nest 500 to the target fiducial locating opening 136; dispensing a drug liquid substance into the drug container 510; transferring one of the at least one container closure nest 600 to the target datum alignment opening 136; and positioning the aligned container nests 500 and closure nests 600 in the stamping system 180 includes rotating a rotary table that rotatably carries the container nests and the container closure nests.

In a general embodiment, at least one of the steps of removing the container lid from the at least one container pail 530; removing the container lid from the at least one container-closure pail 630; transferring the container nest 500 to the target fiducial locating opening 136; dispensing a drug liquid substance into the drug container 510; passing one of the at least one container closure nest 600 to the target datum alignment opening 136; and positioning the aligned container nests 500 and closure nests 600 in the stamping system 180 includes rotating a rotary table that rotatably carries the container nests and the container closure nests.

It is noted that neither the filling system 1000 nor the associated method requires the use of a vibratory bowl or escapement mechanism typical of the prior art. Unlike many prior art systems, the filling system 1000 also does not require the use of gloves for the operator to access the interior of the chamber.

The above system is described as using a controller running stored software running on a general purpose computer platform, but may also be implemented in whole or in part using dedicated hardware.

The system described above also employs a datum opening defined in the rotating table to hold the buckets and nests, but other types of datum structures may be employed including other configurations of restraining surfaces sufficient to hold the buckets and nests in place. For example, a brace having a notch mounted on the rotating platform may secure a bucket and/or nest above the rotating platform. Further datum locating structures for holding a bucket for a nest of containers or container closures are described below in fig. 3A, 3B, 4A and 5A.

In all respects other than the vacuum pick-up

system

150 or 160, another embodiment of the filling system according to the invention may be identical to the embodiment described above from that shown in fig. 1A and 1B. Fig. 3A and 3B show a portion of the filling system as described above. Fig. 3B specifically focuses on the general area of one of the vacuum pick-up systems, e.g., vacuum pick-up system 150. In this alternative embodiment, the vacuum pick-up system 150 is replaced by a reconfigurable vacuum pick-up system 150'. The vacuum pick-up system 160 of fig. 1A and 1B may similarly be replaced by a reconfigurable vacuum pick-up system 160 'configured the same as the vacuum pick-up system 150'. For clarity, the vacuum pick-up system 160' is not shown in fig. 3A or 3B. In other embodiments, a single reconfigurable vacuum pick-up system 150' may be used to pick up both container nests and container closure nests. The vacuum pick-up system 150' may enter the container nest and the container closure nest by rotation of the rotary table 130.

The vacuum pick-up system 150' includes two rotating arms 154a ' and 154b ', which in turn include a plurality of suction cups 152a ' and 152b ', respectively. A vacuum pick-up system 150' is provided to pick up nests 500 of containers 510 via suction cups 152a ' and 152b '. The vacuum pick-up system 150' may also be configured to pick up the nest 600 of container closures 610 via the suction cups 152a ' and 152b '. As with the vacuum pick-up system 150, the vacuum pick-up system 150' may be raised and lowered to allow the suction cups 152a ' and 152b ' to engage different nests 600 of container closures 610 contained at different depths within the bucket 630.

The suction cups 152a 'and 152b' are arranged on the rotating arms 154a 'and 154b' as sets of linearly arranged suction cups 152a 'and 152b', each set of linearly arranged suction cups 152a 'and 152b' being arranged at a different angle perpendicular to the longitudinal axis of the rotating arms 154a 'and 154 b'. This arrangement allows the swivel arms 154a 'and 154b' to swivel about their longitudinal axes in order to engage different sets of linearly arranged suction cups 152a 'and 152b' with different nests 500 of the container 510. This allows the sets of suction cups 152a 'and 152b' to be individually selectable for use. The rotation of the rotating arms 154a 'and 154b' may be performed manually. In other embodiments, rotation of the rotating arms 154a ' and 154b ' may be accomplished by a suitable motorized drive combined in the vacuum pick-up system 150' and controlled by the controller 400 shown in fig. 1A.

With the selection of different sets of linearly configured suction cups 152a 'and 152b' via rotation of the rotating arms 154a 'and 154b', the suction cup sets 152a 'and 152b' can be arranged to engage with different container nests 500 carrying containers 510 or container closure nests 60 carrying container closures 610.

Fig. 3A and 3B show a vacuum pick-up system 150' comprising two rotating arms, namely rotating arms 154a ' and 154B '. In other embodiments, one or more arms may be employed, all sharing the concept of alternative configurations of suction cups. The selection of the suction cup configuration in fig. 3A and 3B is by rotation of the arms 154a 'and 154B' supporting the suction cups 152a 'and 152B', and in other embodiments the selection may be made on the basis of different configurations, including, for example, but not limited to, lateral translation of the suction cup support arms in a plane parallel to the plane of rotation of the rotary table 130, to engage different sets of suction cups with container nests or container closure nests. In fig. 3A and 3B, the suction cups are arranged in a straight line group. In other embodiments, non-linear configurations of suction cups may be employed.

Turning now to fig. 3B. In particular, we consider

members

149 and 139 in more detail. In one embodiment, the illustrated reconfigurable stop member 149 has two distinct ends, a first end of which may be selected for use by appropriate rotation of the reconfigurable stop member 149 about the stop member rotation axis 141 to a default position. In this set position, the reconfigurable stop member 149 provides a secure stop for the proximal end of the container bucket 530 to abut against a selected end of the reconfigurable stop member in a direction parallel to the longitudinal axis of the rotating arms 154A 'and 154 b'. In this embodiment, the reconfigurable stop member 149 may be rotated 180 degrees to position the second end of the reconfigurable stop member 149 to stop the container barrel 530. The second end of the reconfigurable stop member 149 may be configured to stop the proximal end of the container bucket 530 at a different point than the first end of the reconfigurable stop member 149 stops the proximal end of the container bucket 530.

The restraining member 139 is configured to push against the distal end of the container barrel 530. While different mechanisms may be envisaged to ensure the urging action of the restraining member 139, one particularly suitable arrangement involves the restraining member 139 being provided with a suitable spring load to rotate about the axis 143. Through the above-described operation, the reconfigurable stop member 149, together with the restraining member 139, allows the container bucket 530 to be positioned at a precise location parallel to the longitudinal axes of the rotating arms 154a 'and 154 b'. The specific precise location is selectable by selecting the appropriate end of the reconfigurable stop member 149 to stop the container barrel 530. This configuration allows different sizes of container buckets 530 parallel to the longitudinal axis of the rotating arms 154a 'and 154b' to be located in precise predetermined positions and correspond to the suction cup sets 152a 'and 152 b'.

The particular suction cup sets 152a 'and 152b' may be selected to match the particular ends of the selected reconfigurable stop members 149. In this manner, the vacuum pick system 150' may be set to a configuration that ensures that the selected container tub 530 dimensions are accurately positioned to allow the container nest 500 within the container tub 530 to be engaged by a particular set of suction cups 152a ' and 152b '. Thus, the vacuum pick-up system 150' is reconfigurable to engage nests of different sizes within containers of different sizes.

For clarity, the foregoing description and fig. 3A and 3B show configurations that allow accurate positioning of the container tub 530 along only one dimension in the plane of rotation of the rotary table 130, the dimension of the containers perpendicular to the one dimension being considered the same. In this configuration, the

datum alignment openings

132 and 134 are sized to constrain the container barrel 530 in a vertical dimension in the plane of rotation of the rotary table 130.

In another embodiment, another reconfigurable stop member and limit member may be added to the configuration in fig. 3A and 3B to account for the positioning of the container bucket 530 in a vertical direction within the rotational plane of the rotational table 130. To allow for positioning of the container tub 530 in this vertical direction, the dimensions of the

datum alignment openings

132 and 134 do not constrain the containers in any direction within the plane of rotation of the rotary table 130.

In the above described embodiment, the reconfigurable stop member 149 has been described as having two ends, one of which is selected to be used at any time by rotating the reconfigurable stop member 149 about the stop member rotational axis 141. In other embodiments, the reconfigurable stop member 149 may be shaped or configured to have more than two stop ends, the ends being selectable by appropriate rotation of the reconfigurable stop member 149 about the stop member rotation axis 141. In an embodiment wherein the reconfigurable stop member has a very large number of stop ends, the reconfigurable stop member may be considered in the shape of a cam, representing a large number of possible stop ends that may be selected by rotation of the reconfigurable stop member about a suitable stop member rotation axis.

Generally, the system described in figures 3A and 3B includes a reconfigurable reference nest positioning system. The reconfigurable reference nest positioning system includes a movable platform that includes reference positioning openings 132, reconfigurable stop members 149, and restraining members 139. In the case of the systems of fig. 3A and 3B, the movable platform is a rotary table 130. Other movable platforms are also contemplated, as explained later. For example, to the extent that a bucket 530 is positionally restrained and a nest 500 is positioned within a bucket 530, any system that references positions a bucket 530 also references positions a nest 500 at the same time.

Various embodiments contemplated include a reconfigurable vacuum pick-up system that may be configured to engage its suction cups with corresponding areas on a drug container nest. The containers in the container nests may be closed by respective container closures suspended in the container closure nests. The planar surface of the container closure nest may have a profile that leaves a perforation at its periphery for the suction cup to pass to engage the container nest. For example, in fig. 3A, the perforations 602 are shown on the perimeter of the closure nest 600. Alternatively or additionally, the container closure nest may have suitable openings in its planar interior to provide a passage for the suction cups to pass through to engage the container nest. Contemplated vacuum pick-up systems are further configured and arranged to pick up a nested combination of containers and their closures through the container nest, rather than through the closure nest.

In a general embodiment, a nest of processing subsystems includes: a reconfigurable vacuum pick-up system for picking up a container nest and/or a container closure nest may comprise one or more arms carrying groups of suction cups. By reconfiguring the vacuum pick-up system, a selected set of suction cups from the plurality of sets of suction cups may be selected, the selected set of suction cups being predisposed to engage a particular container nest or container closure nest. The selection may be based on one or both of the size and shape of the nest. The nest processing system may further include at least one pair of reconfigurable stop members 149 and restraining members 139 disposed proximate opposite ends of the datum alignment opening 132 for holding a bucket 530 containing a container nest 500 of carrier containers 510 for engagement with opposite ends of the bucket 530. The stop and limit members are provided to position the bucket 530 in a predetermined position that ensures that a selected set of suction cups can engage the container nest and/or container closure nest.

As with opening 132, opening 134 of fig. 3A may also be used with at least one set of a reconfigurable stop member (in this case member 145) and a restraining member (in this case member 135). The reconfigurable stop member 145 and restraining member 135 act against any bucket in opening 134 as do the reconfigurable stop member 149 and restraining member 139 against any bucket in opening 132.

In accordance with the various embodiments described above with respect to fig. 1A-1E and 3A and 3B, the vacuum pick-up

system

150, 160 is described as part of a drug filling system 1000. However, the vacuum pick-up systems 150', 160' may also be used in other devices on their own right, and are not limited to the filling systems of fig. 1A-1E, or indeed in general filling systems. Some other example applications include, but are not limited to, freeze-drying systems. It can be applied to a suitable nest of any objects arranged in a predetermined configuration. Furthermore, although the system 1000 of fig. 1A-1E employs the rotary stage 130, the reconfigurable vacuum pick-up system 150' may employ any suitable movable platform that includes suitable fiducial locating openings.

The method described above in fig. 2A and 2B can now also be described in more detail with reference to fig. 3A and 3B. Providing at least one vacuum pick-up system as part of the step of providing a filling apparatus step 2010 may include: at least one reconfigurable vacuum pick-up system 150 'is provided, the at least one reconfigurable vacuum pick-up system 150' including a plurality of sets of suction cups 152a 'and 152 b'.

Providing a filling device step 2010 may include: a rotary table 130 is provided having a target datum alignment opening 136 and at least two source

datum alignment openings

132, 134, each having at least one pair of reconfigurable stop members 149 and limit members 139.

The transmitting [ step 2020] may comprise: the at least first reconfigurable stop member 149 is operated to stop the container bucket 530 in a predetermined container bucket position and the at least first restraining member 139 is operated to restrain the container bucket 530 in the predetermined container bucket position.

The transmitting [ step 2025] may include: the at least second reconfigurable stop member 145 is operated to stop the container-closure bucket 630 in a predetermined closure-bucket position, and the at least second restraining member 135 is operated to restrain the container-closure bucket 630 in the predetermined closure-bucket position.

Operating the at least one vacuum pickup system 150', 160' [ step 2050] can include: at least one reconfigurable vacuum pick-up system 150', 160' is configured to select a first predetermined set of suction cups that are configured to engage the container nest 500.

Operating one of the at least one vacuum pickup systems 150', 160' [ step 2070] may include: at least one reconfigurable vacuum pick-up system 150', 160' is configured to select a second predetermined set of suction cups that are configured to engage the container closure nest 600.

The method may further include operating at least one vacuum pick system 150', 160' with a first predetermined set of suction cups selected to engage the container nest 500 and collectively removing the container nest 500 and the container closure nest 600 from the stamping system 180[ step 2095 ].

We consider in fig. 3A and 3B an alternative embodiment of the configuration of the vacuum pick-up

systems

150 and 160 of fig. 1A in the form of vacuum pick-up systems 150 'and 160'; and a positioning arrangement associated with

source openings

132 and 134 in the form of

assemblies

135, 145, 139 and 149. We now turn our attention to an alternative embodiment of the configuration of fig. 1A and 3A around the target opening 136. Fig. 4A and its close-up view in fig. 4B show different embodiments of the system of fig. 3A having a configuration surrounding target opening 136. While the

cameras

210 and 220 of fig. 1A may be used in conjunction with the rotation of the controller 400 and the rotation stage 130 to position the nest 500 at the opening 136 and to position the nest 600 above the nest 500 at the opening 136, the adjustable target fiducial positioning system of fig. 4A and 4B, including the rotational positioning components 164A and 164B, may alternatively or additionally be used to accurately position the

nests

600 and 500.

Typical industrial container nests are not manufactured to size standards, and therefore any system for filling and closing nested containers 510 must have a mechanism to accurately position differently sized nests 500 that carry containers 510. To this end, the

rotational positioning members

164a and 164b may have different sets of paired

positioning surfaces

167a, 167b and 163a, 163b, allowing a nest 500 of a particular size to fit precisely between such paired positioning surfaces. In fig. 4B, the nest 500 is assembled such that two opposing ends in a first dimension contact the mutually facing surfaces 167a and 167B of the rotational positioning components 164a and 164B, respectively. By rotating the

components

164a and 164b in opposite directions to each other about the

axes

166a and 166b, respectively, the

surfaces

167a and 167b can face each other and thereby allow their precise positioning between nests of different lengths in the first dimension.

As is apparent from fig. 4B, when the surfaces 167a and 167B face each other, the nest snugly positioned therebetween can be held in a precise and predetermined vertical position by bearing against the surfaces 165a and 165B of the rotational positioning members 164a and 164B, respectively. When the

surfaces

163a and 163b are facing each other, the alternate nest snuggly therebetween can be held in a precise and predetermined vertical position by resting against the

surfaces

161a and 161b of the

rotational positioning members

164a and 164b, respectively. The

rotational positioning assemblies

164a and 164b may be manually rotated about

axes

166a and 166b, respectively. In some embodiments, rotation of the

rotational positioning assemblies

164a and 164b may be accomplished automatically by motorized drives controlled by the controller 400 and appropriate control software. The control may be based on predetermined dimensional data relating to nests located between the surfaces of the

elements

164a and 164 b. It may also be based on input data derived from imaging data obtained from cameras 210 and/or 220. In addition, the nest 500 can be rotated as it is lowered into position so that particular surfaces of the

components

164a and 164b designated to engage opposite ends of the nest 500 along a first dimension can act as closed horizontal clips on the nest 500 when the surfaces are rotated to a position where they face each other. In this embodiment, the horizontal and vertical positioning of the nest between the

rotational positioning components

164a and 164b are not independent of each other.

Another configuration of a first dimension of the nest 500 shown in fig. 4A and 4B can also be established for a second planar dimension of the nest 500 perpendicular to the first dimension. This allows any nest 500 placed at the opening 136 to be accurately positioned in a selected predetermined position by virtue of the arrangement of the

rotational positioning members

164a and 164 b.

Fig. 5A and 5B illustrate another embodiment of a rotational positioning assembly. In contrast to the embodiment of fig. 4A and 4B described immediately above, the horizontal and vertical positioning of the nest between the two mutually counter-rotatable elements 164A 'and 164B' in fig. 5A and 5B are positioning actions that are independent of one another. This is accomplished by positioning the nest 500 in the vertical dimension using a pair of fixedly opposed planar tabs 165a 'and 165b' and a pair of rotational positioning assemblies 164a 'and 164b' to position the nest 500 in the first horizontal dimension in each of the two mutually perpendicular planar dimensions described in the immediately above embodiment. In this embodiment, each rotational positioning assembly 164a 'and 164b' includes a set of two rotatable assemblies coupled to shafts 166a 'and 166b', respectively, to rotate in unison and in alignment with each other on either side of planar tabs 165a 'and 165b' within projections 169a 'and 169b', respectively. The sets of rotating assemblies 164A 'and 164B' except that each is divided into two ganged assemblies are used to confine the nest 500 in the horizontal dimension in the same manner as the rotating positioning assemblies 164A and 164B in the embodiment of figures 4A and 4B just described.

Although the rotational positioning members 164a 'and 164B' may be designed in more complex shapes, a very simple embodiment is shown in figures 5A and 5B, wherein the surface 167a 'of the rotational positioning member 164a' and the surface 167B 'of the rotational positioning member 164B' are used to position the nest 500 in the first horizontal dimension. By turning the rotational positioning component 164a 'connected by the shaft 166a' and the rotational positioning component 164b 'connected clockwise by the shaft 166b' within the projection 169b 'counterclockwise within the projection 169a', the surfaces 163a 'and 163b' can be made to face each other so that nests of different lengths in the first horizontal dimension can be positioned and precisely located between the rotational positioning components 164a 'and 164 b'.

The linked rotational positioning components 164a 'and 164b' may be manually rotated within the projections 169a 'and 169b' about the axis of the shafts 166a 'and 166b', respectively. In some embodiments, rotation of the rotational positioning assemblies 164a 'and 164b' may be accomplished automatically by motorized drives controlled by the controller 400 and appropriate control software. This control may be based on predetermined dimensional data about nests positioned between the surfaces of the rotational positioning components 164a 'and 164 b'; it may also be based on input data derived from imaging data obtained from cameras 210 and/or 220. In addition, the rotation can be performed when the nest 500 is lowered into position so that particular surfaces of the rotational positioning components 164a 'and 164b' designated to engage opposite ends of the nest 500 along a first dimension can act as closed horizontal clips on the nest 500 when the surfaces are rotated to their position facing each other.

Figures 5A and 5B show another set of paired relatively rotatable rotational positioning assemblies, not numbered for clarity, grouped similarly to the rotational positioning assemblies 164a 'and 164B', and arranged to precisely position the nests 500 independently in the vertical dimension and in the second planar dimension of the nests 500 perpendicular to the first dimension.

In another aspect illustrated in fig. 6, there is provided a method for filling a nested drug container 510 with a pharmaceutical liquid substance, the method comprising: providing a filling system 1000 comprising a sterilizable chamber 100 capable of maintaining a sterile state, the chamber 100 comprising a filling station 170 and a planar rotation stage 130 having

target positioning structures

136, 164a, 164b, 164a ', 164b' [ step 6010 ]; transferring at least one container tub 530 into the chamber, the container tub 530 being sealed by a container tub cover 520 and housing a container nest 500 carrying a plurality of drug containers 510 step 6020; aseptically sealing the chamber 100 step 6040; creating a sterile condition within the chamber 100 step 6050; transferring the container nest 500 carrying the plurality of drug containers 510 into the targeting

structure

136, 164a, 164b, 164a ', 164b' such that the container nest 500 is held in place step 6060; and dispensing the pharmaceutical liquid substance into at least a portion of the plurality of pharmaceutical containers 510 by operating the rotational stage 130 and the filling station 170 step 6070. Operating the filling station 170 may include rotating the filling station 170. Dispensing the pharmaceutical liquid substance may include dispensing the pharmaceutical liquid substance into the container 510 in a repeated and continuous manner.

Providing a filling system 1000 step 6010 may include providing a filling apparatus including at least one lid removal station 140 within the chamber 100, and wherein transferring the pod 530 to the target positioning structure includes removing the pod lid 520 from the pod 530 by operating the rotary table 130 and the at least one lid removal station 140. Operating the at least one cap removal station 140 may include rotating the at least one cap removal station 140. Providing a filling system 1000 step 6010 may include providing at least one lid removal station 140 having an engagement tool 142 within the chamber 100, transferring at least one container tub 530 into the chamber 100 step 6020 may include attaching a lid removal fixture 540 to the container tub lid 520; and wherein operating the at least one cap removal station 140 comprises engaging the engagement tool 142 with the cap removal fixture 540.

The method may further include transferring a container-closure bucket 630 into the chamber 100, the container-closure bucket 630 being sealed by a container-closure bucket lid and containing at least one container-closure nest 600 carrying a plurality of drug container closures 610 [ step 6030 ]. The method may further comprise: positioning one of the at least one closure nest 600 to align a closure 610 in the at least one closure nest 600 with a corresponding container tub 530 in the container nest 500 step 6080; transferring the aligned

nests

500, 600 of closures 610 and containers 510 to a punching station by rotating the rotating table 130 step 6090; and forcing the closures 610 into the respective containers 510 step 6100. The method may further include adjusting the

drum positioning structures

135, 145 to accommodate the size of the container-closure drum 630. Positioning one of the at least one closure nest 600 step 6080 may include: obtaining image information about one of the at least one closure nest 600; and locating one of the at least one enclosure nest 600 based on the image information. Positioning one of the at least one closure nest 600 step 6080 may include: applying a vacuum to

suction cups

162, 152a, 152b, 152a ', 152 b'; raising the container closure nest 600 with the suction cups; and operating the rotating table 130.

Transferring the container nest 500 into the target positioning opening [ step 6020] may include: applying vacuum to the suction cup; raising the container nest 500 with the suction cups; and operating the rotating table 130. The method may further comprise selecting one of the plurality of sets of suction cups and wherein applying vacuum to the suction cups is performed on the selected set of suction cups. The selection may include rotating one of the sets of suction cups into position. The method may further include adjusting the targeting

structure

136, 164a, 164b, 164a ', 164b' to accommodate the size of the container nest 500. The adjustment may be performed in two at least substantially orthogonal directions. The method may further include adjusting the

bucket positioning structures

139, 149 to accommodate the size of the container nest bucket 530.

In another aspect, a method (see fig. 1G) for removing a container lid from a sealed container, such as a

drum

530 or 630, sealed by the container lid (e.g., lid 520), in a controlled environment enclosure is provided, the method comprising: providing a lid 520 sealed to the sealing surface of the lip of the container to the container in the controlled environment enclosure 100 to seal the contents of the container without requiring sterilization, the lid 520 having a lid removal fixture 540; sterilizing the sealed container in the controlled environment enclosure 100; engaging the cap removal fixture 540 with the engagement tool 142; and removing the cap from the container using the engagement tool 142. The engagement may engage the cap removal fixture 540 using a fork engagement tool 142. A ball attachment that can engage on the cap removal fixture 540 is engaged.

Providing may include providing the sterilized medication container 510 or closure 610 in a sealed container, such as a

tub

530 or 630, prior to sterilization. The attachment may be made before the container is in the controlled environment enclosure 100. Sterilizing the sealed container in the controlled environment enclosure 100 may be performed prior to removing the lid 520. Removing the lid 520 may include moving the engagement tool 142 relative to the container barrel 530. Removing the lid 520 may include moving the container barrel 530 and the engagement tool 142. The method may further include attaching a lid removal fixture 540 to the lid 520 prior to providing the container tub 530 in the controlled environment enclosure.

Fig. 7A is a view of a subsystem showing a further embodiment of filling a pharmaceutical liquid product in a pharmaceutical container based on the subsystems shown in fig. 1A, 1C, 1F, 5A and 5B. For the sake of brevity, several subsystems are omitted to show only the sterile sealable chamber 100 of FIG. 1A; the rotary table 130 of fig. 1A and 1C;

openings

132, 134, and 136 of FIG. 1C; there is a container nest 500 carrying medicament containers 510, the container nest 500 being held in place by the arrangement shown in figure 5B. In fig. 7A, the fill arm 170 of fig. 1A is replaced with an articulated mechanical fill arm 170'. Any reference configuration to hold nest 500 may be substituted so long as it allows the opening of each container 510 to be known with suitable accuracy and precision for reliably dispensing the pharmaceutical liquid into the container 510.

A drop monitoring subsystem 250 incorporating the previously described components of fig. 7A is shown separately in fig. 7B, and includes: an illuminated imager system 252, a reflector 254, and a retro-reflector 256. The droplet monitoring subsystem 250 may be controlled by a controller 400, with the end controller 400 being communicatively coupled to the droplet monitoring subsystem 250. The controller 400 may include a memory and a processor. As in the case of fill arm 170 in fig. 1A and 1F, articulated mechanical fill arm 170' supplies drug liquid through drug liquid feed line 172. In fig. 7A, a mechanical fill arm 170 'is equipped with a pharmaceutical liquid product dispensing head 174'. The dispensing head 174' is configured and arranged to produce drops of the same volume of the pharmaceutical liquid and move along the drop path 710 within a limited range of drop shapes. For this purpose, the dispensing head 174' may be equipped with suitable nozzles. The controller 400 may control the dispensing action of the dispensing head 174'; the end controller 400 may be communicatively coupled to the dispensing head 174 'or a pump may provide the dispensing head 174' with the pharmaceutical liquid. The imager system 252 may include a telecentric lens to enable the imager system 252 to make consistent size measurements of the droplets produced by the dispensing head 174'.

Illuminated imager system 252 is configured and arranged to illuminate retro-reflector 256 and acquire high-speed images of drops 700 dispensed by dispensing head 174' moving along drop path 710 into any receptacle 510. The line a-a' in fig. 7A and 7B represents the beam path. As the rotary stage 130 moves each container 510 along a circular path about the rotational axis of the rotary stage 130, the articulated mechanical fill arm 170' is operated to move the dispensing head 174' along a linear trajectory of the imaging path a-a ' of the drop monitoring subsystem 250. Thus, in this embodiment, both the rotary table 130 and the articulated mechanical fill arm 170 'are operated to position any receptacle 510 for filling by the dispense head 174'. Any operation of the filling arm 170' may be controlled by the controller 400, in addition to the operation of the rotary table 130. To this end, the controller 400 is communicatively connected with the fill arm 170 'and the rotary table 130 to allow the controller 400 to coordinate the movement of the fill arm 170' and the rotary table 130.

Software may be loaded into the memory of controller 400 and, when executed by the processor, configured to control the dispensing of droplets 700 of drug liquid through liquid dispensing head 174', and to collect images of droplets 700 of drug liquid along the droplet path. The software may also allow the controller 400 'to control the mechanical fill arm 170' and the rotational stage 130.

An alternative embodiment shown in FIG. 8 shows another articulated mechanical fill arm 170 "in which an alternative drop monitoring subsystem 250' is integrated. This particular embodiment employs two mirrors 254 'and 258' with an illuminated imager system 252 'and a retro-reflector 256'. The same numbering is retained here, namely 174' as the dispensing head of the pharmaceutical liquid product feed line 172. Illuminated imager system 252' is configured and arranged to illuminate retro reflector 256' and acquire high-speed images of droplets 700 dispensed by dispensing head 174' to enter any of containers 510 along droplet path 710 via mirrors 254' and 258 '. In this particular embodiment, it is only necessary to operate the articulated mechanical fill arm 170 "to position any containers 510 received in the nest 500 for filling by the dispensing head 174', and the rotary table 130 may remain stationary during the fill positioning with all containers 510 remaining in the nest 500. In a more general case, both the rotary table 130 and the articulated mechanical fill arm 170 "may be operated to position any receptacle 510 for filling by the dispense head 174'. Any operation of the fill arm 170 "may be controlled by the controller 400, in addition to the operation of the rotary table 130. To this end, the controller 400 is communicatively connected to the fill arm 170 "and the rotary table 130. The imager system 252' may include a telecentric lens to enable the illuminated imager system 252' to make consistent size measurements of the droplets produced by the dispensing head 174 '.

The use of the drop monitoring subsystem of the present invention is not limited to the rotary table drug filling system of fig. 1-8. They may also be used in any system for dispensing a liquid drop-wise into a container, whether nested or not. A set of filling systems suitable for filling a drug container with a drug liquid in an aseptic chamber using the drop monitoring system of the present invention employs a robotic arm to hold the container by a suitable end actuator. The robot may be a jointed robot and may be hermetically sealed to the chamber 100. Suitable examples of such systems are provided in U.S. patent publication No. 2017/121046a1, U.S. patent publication No. 2016/0200461a1, U.S. patent publication No. 2016/0184986a1, U.S. patent publication No. 2016/0346777a1, and U.S. patent publication No. 2014/0196411a1, the disclosures of which are incorporated herein by reference in their entirety. The following describes embodiments of the drop monitoring subsystem of the present invention for use in conjunction with a jointed arm of the type described in more detail in these four listed publications.

Fig. 9 shows the drop monitoring system 250 of fig. 7A and 7B implemented in a drug container filling system having a sterile sealable chamber 100', wherein a container nest 500 carrying drug containers 510 is held by an end actuator 810 of an articulated arm 800. The jointed arm 800 may be a jointed robot arm. In some embodiments, the jointed arm robot 800 may be controlled by a suitable controller 400'. To this end, as shown in fig. 9, the controller 400' is communicatively coupled to the robot arm 800. The robotic arm 800 may be of the type described in detail in the aforementioned published data and is incorporated by reference. The controller 400' may be, for example, but not limited to, the controller 440 used by the filling system described in U.S. patent publication No. 2016/0346777a1 with respect to fig. 1 or the controller 13 of U.S. patent publication No. 2017/121046a 1. The jointed arm 800 may be, for example, but not limited to, the jointed arm 200 of FIG. 2 of U.S. patent publication No. 2016/0184986A1, the jointed arm 22 of FIG. 1 of U.S. patent publication No. 2016/0200461A1, or the jointed arm 30 of FIG. 2 of U.S. patent publication No. 2017/121046A 1. The controller 400' may also be used to control the droplet monitoring system 250 so that it is communicatively connected to the droplet monitoring system 250.

Fig. 10 shows the drop monitoring system 250' of fig. 8, which employs the same drug container filling system as described in fig. 9. The controller 400' may also be used to control the droplet monitoring system 250', for which purpose it is communicatively connected to the droplet monitoring system 250 '.

In other embodiments of the system, both the dispensing head 174 'and the container 510 may be moved by a robotic arm, on the one hand, the robotic arms 170', 170 ", on the other hand 800. Either or both of the robotic arms may be a jointed robot arm of the type described in the previously listed incorporated U.S. patent publications. In still further embodiments, both the dispensing head 174' and the containers 510 may be in fixed positions, with these particular embodiments involving, for example, filling a single container 510 at a time.

The embodiments shown in fig. 7A, 7B, 8, 9 and 10 all employ a retro-reflector 256, 256 'illuminated by a light source housed in an illuminated digital imager system 252, 252'. In other embodiments, the drop 700 may be backlit, or may be illuminated from any other angle. In such embodiments, the imager system need not incorporate an integral light emitter, and the light emitter may be located elsewhere separate from the imager.

Turning now to the method described with respect to the flowchart in fig. 11. To aseptically dispense a pharmaceutical liquid into the pharmaceutical container 510, the method comprises: providing a sterilizable chamber 100, 100 'capable of maintaining a sterile condition, the chamber including a drug liquid dispensing head 174' configured to generate droplets 700 of a drug liquid, and a droplet monitoring system 250, 250 'including a digital imager 252, 252' [ step 3010 ]; establishing a sterile condition within the sterilizable chamber 100, 100' [ step 3020 ]; providing a sterile drug container 510 within the sterilizable chamber 100, 100' [ step 3030 ]; dispensing a plurality of drops 700 from a dispensing head 174' into a container 510 along a drop path 710 step 3040; acquiring a plurality of images of at least one of the plurality of droplets 700 along the droplet path 710 from the imager 252, 252' [ step 3050 ]; and determining a volume of liquid dispensed into the container 510 from the plurality of images [ step 3060 ].

In some embodiments, the method may further comprise: the dispensing of liquid is stopped based on the volume of liquid dispensed into the container 510 step 3070. In other embodiments, the stopping may be based on the amount of time the drug liquid is dispensed into the container 510 or on the weighing of the amount of drug liquid dispensed into the container 510. Thus, the drop information from the imager may be used only to monitor the drug liquid dispensing process, as when it forms the basis for the stop, or as a way of controlling the liquid dispensing process step 3070.

Determining the volume of liquid dispensed into the container 510 from the plurality of images [ step 3060] may include: the volume of at least one of the plurality of droplets 700 is determined. Determining the volume of at least one of the plurality of droplets 700 may include: identifying a first total portion and a second total portion of the at least one drop 700 that appear to the left and right, respectively, of the drop path 710 in the at least one image of the at least one drop 700; calculating a first volume and a second volume of at least one drop of the plurality of drops 700 by 2 π around drop path 710 by mathematically rotating the first total portion and the second total portion of drop 700, respectively, individually; and equating the volume of at least one of the plurality of droplets 700 to an average of the first volume and the second volume. The term "total portion" is used herein to describe all side plan views of a droplet to the left or right of the droplet path 710. The two total portions of the droplet will generally not be equal. Then, the total or approximate "half" of the two planes are taken and rotated around drop path 710 in software to obtain two "drop volumes," respectively, which are then averaged to obtain the assumed volume of the drop.

Acquiring multiple images of at least one of the plurality of droplets 700 along the droplet path from the imagers 252, 252' step 3050 may comprise: a plurality of images are acquired over a predetermined portion of the droplet path where the droplet 700 has a stable shape. In this description, the shape of the drop may be considered "stable" when it is significantly separated from the dispensing head 174', and is limited to a predetermined perimeter when viewed by the imager, which allows variation within the predetermined perimeter.

Determining the volume of liquid dispensed into the container 510 from the plurality of images [ step 3060] may include: the volume of each drop 700 dispensed into the container 510 is determined. Stopping the dispensing of the liquid based on the volume of liquid dispensed into the container 510 may include: the dispensing of the liquid is stopped when the total amount of liquid dispensed into the container 510 equals the predetermined volume. The predetermined volume may be, for example, but not limited to, the volume of a single adult dose of the pharmaceutical liquid. Other predetermined volumes may be integer multiples of the dose or volume specified by the health authority, regulatory agency, or chemical safety specification, MSDS, of the pharmaceutical liquid.

In other embodiments, determining the volume of liquid dispensed into the container 510 from the plurality of images [ step 3060] may include: determine a representative volume of the drop 700, calculate the total number of drops dispensed into the vessel 510, and then multiply the representative drop volume by the number of drops. Determining a representative volume of droplet 700 may include: only the first drop was measured and assumed to be representative. In other embodiments, determining a representative volume of droplet 700 may include: a plurality of droplets is measured and an average droplet volume of the plurality of droplets is calculated.

Acquiring multiple images of at least one of the plurality of droplets 700 along the droplet path 710 from the imagers 252, 252' [ step 3050] can include: a plurality of images are acquired by light reflected to the imager by the retro-reflectors 256, 256'. Acquiring a plurality of images of at least one of the plurality of droplets 700 along the droplet path 710 from the imager may include: a plurality of images are acquired through a telecentric lens. The telecentric lens may be included in the imager 252, 252'. Providing a sterile drug container 510 within the sterilizable chamber 100, 100' may include: a sterile drug container 510 is provided within container nest 500.

The method may further comprise: at least one of the dispensing head 174 'and the container 510 is moved to position the opening of the container 510 below the dispensing head 174' to receive the droplet 700 along the droplet path 710 step 3035. Moving the container may include: the robot arm 800 is operated. Moving the container 510 may include: the container nest 500 holding the containers 510 is moved. Operating the robot 800 may include: operating a joint robot. Moving the dispensing head 174' may include: the robot arms 170', 170 "are operated. Moving the dispensing head 174' may include: the articulated robot arms 170', 170 "are operated.

In the embodiment shown in fig. 7A, 7B, 8, 9 and 10, the controller 400, 400 'is also in communication with the dispensing head 174', or is provided with a pump, allowing the controller 400, 400 'to regulate and turn on or off the flow of droplets through the dispensing head 174'. For clarity, the communication lines are not shown in fig. 7A, 7B, 8, 9, and 10.

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

Claims

1. A method of aseptically dispensing a predetermined quantity of a pharmaceutical liquid into a pharmaceutical container (510) using a processor in a device (1000) particularly adapted for introducing pharmaceutical products into specific physical or administration forms, characterized in that the method comprises:

providing a sterilizable chamber (100) capable of maintaining a sterile state, the chamber including a pharmaceutical liquid dispensing head (174, 174') configured to generate droplets (700) of the pharmaceutical liquid; and a drop monitoring system (250, 250') including a digital imager (252, 252') and an associated processor (400);

establishing a sterile condition within the sterilizable chamber;

providing a sterile drug container within the sterilizable chamber;

initiating dispensing of a plurality of drops of the liquid from the dispensing head into the container along a drop path (710);

acquiring a plurality of images of at least one of the plurality of droplets along the droplet path from the imager; and

the processor determines from the plurality of images whether a predetermined volume of the liquid is dispensed into the container and stops dispensing droplets when a predetermined volume of the liquid is dispensed into the container.

2. A method of aseptically dispensing a pharmaceutical liquid into a pharmaceutical container (510), the method comprising:

providing a sterilizable chamber (100) capable of maintaining a sterile state, the chamber including a pharmaceutical liquid dispensing head (174) configured to generate droplets (700) of the pharmaceutical liquid; and a drop monitoring system (250, 250') including a digital imager (252, 252');

establishing a sterile condition within the sterilizable chamber;

providing a sterile drug container (510) within the sterilizable chamber;

dispensing a plurality of droplets of the liquid from the dispensing head into the container along a droplet path (710);

determining a volume of liquid dispensed into the container from the plurality of images.

3. The method of claim 1 or 2, wherein determining from the plurality of images a volume of liquid dispensed into the container comprises determining a volume of at least one of the plurality of droplets.

4. The method of any preceding claim, wherein said determining the volume of at least one of the plurality of droplets comprises:

identifying a first total portion and a second total portion of the at least one drop appearing on the left and right sides of the drop path, respectively, in the at least one image of the at least one drop;

calculating a first volume and a second volume of at least one drop of the plurality of drops by 2 pi around the drop path by mathematically rotating the first total portion and the second total portion of the drop, respectively, individually; and

a volume of at least one of the plurality of droplets is made equal to an average of the first volume and the second volume.

5. The method of any preceding claim, wherein acquiring images of at least one of the plurality of droplets along the droplet path from the imager comprises acquiring the images over a predetermined portion of the droplet path.

6. The method of any preceding claim, wherein said acquiring from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises:

determining a portion of the drop path from the plurality of images, wherein the drop has a stable shape; and

at least one image of the at least one droplet is selected from the acquired images of the droplet when the droplet is in a portion of the droplet path where the droplet has a stable shape.

7. The method of any preceding claim, wherein determining from the plurality of images the volume of liquid dispensed into the container comprises determining the volume of each droplet dispensed into the container.

8. The method of any one of the preceding claims, wherein stopping the dispensing of the liquid based on the volume of liquid dispensed into the container comprises stopping the dispensing of the liquid when the total amount of liquid dispensed into the container equals a predetermined volume.

9. The method of any preceding claim, wherein acquiring from the imager a plurality of images of at least one of the plurality of droplets along the droplet path comprises acquiring the plurality of images with light reflected to the imager by a retro-reflector (256, 256').

10. The method of any preceding claim, wherein acquiring the plurality of images of at least one of the plurality of droplets along the droplet path from the imager comprises acquiring the plurality of images via a telecentric lens.

11. The method of any preceding claim, wherein moving the container comprises operating a robotic arm (800).

12. The method of any of the preceding claims, further comprising moving at least one of the dispensing head and the container to position an opening of the container below the dispensing head to receive the droplets along the droplet path.

13. The method of any of the preceding claims, wherein operating a robot comprises operating a jointed robot.

14. The method of any of the preceding claims, wherein moving the container comprises moving a container nest (500) holding the container.

15. The method of any of claims 12 to 14, wherein moving the dispensing head comprises operating a robotic arm (170', 170 ").

16. The method of any of claims 12 to 15, wherein operating a robot comprises operating a jointed arm robot.

17. The method of any of the preceding claims, wherein providing a sterile drug container within the sterilizable chamber comprises providing the sterile drug container within a container nest.

18. The method of any preceding claim, further comprising stopping the dispensing of the liquid based on the volume of liquid dispensed into the container.

19. A system (1000) for aseptically dispensing a pharmaceutical liquid into a container (510), the system comprising:

a sealable and sterilizable chamber (100) capable of maintaining sterility;

a drug liquid dispensing head (174, 174') in the chamber configured to generate droplets of the drug liquid;

a drop monitoring system (250, 250') in the chamber, including a digital imager (252, 252') configured to acquire images of drops (700) dispensed by the liquid dispensing head;

a controller (400, 400') including a memory and a processor, the controller communicatively coupled to the liquid dispensing head and the digital imager; and

software configured to control the dispensing of the drops of the pharmaceutical liquid through the liquid dispensing head and collect images of the drops of the pharmaceutical liquid along a drop path when the software is loaded in the memory and executed by the processor.

20. The system (1000) of claim 19, further comprising at least one of a liquid dispensing head positioning system (170) and a container positioning system (130, 150, 160) communicatively coupled to the controller, the software further configured to control at least one of the liquid dispensing head positioning system and the container positioning system.

21. The system (1000) of claim 20, wherein the liquid dispensing head positioning system comprises a robotic arm (170', 170 ").

22. The system (1000) of claim 20 or 21, wherein the liquid dispensing head positioning system comprises a jointed robot arm.

23. The system (1000) of any of claims 20-22, wherein the liquid dispensing head positioning system comprises a jointed robot arm hermetically sealed to the chamber.

24. The system (1000) of any of claims 20 to 23, wherein the container positioning system comprises a robotic arm (800).

25. The system (1000) of any of claims 20 to 24, wherein the robotic arm comprises an end actuator (810) configured to hold a container nest (500).

26. The system (1000) of any of claims 20 to 25, wherein the container positioning system comprises a jointed robot arm.

27. The system (1000) of any of claims 20-26, wherein the container positioning system comprises a jointed robot arm hermetically sealed to the chamber.

28. The system (1000) of any of claims 19 to 27, wherein the drop monitoring system comprises a retro-reflector (256, 256') arranged to reflect light through the drops to the digital imager.

29. The system (1000) of any of claims 19 to 28, wherein the digital imager comprises a telecentric lens.