KR102366435B1 - Apparatus and method for monitoring and controlling the filling of containers with fluid medicaments in an aseptic environment - Google Patents

Abstract

The present invention relates to a system and method for monitoring and controlling the aseptic dispensing of a fluid medicament into a container (510). The system 1000 includes a fluid medicament dispensing head 174 , 174 ′ for dispensing a droplet 700 of a fluid medicament along a droplet path 710 inside a container, and droplet monitoring to monitor the generated, dispensed droplet. Systems 250 and 250' are employed. Based on the image of a droplet falling along the droplet path, at least one droplet volume is determined. The volume of fluid medicament dispensed is determined from the droplet volume. The fluid medicament dispensing head and droplet monitoring system can be integrated with each other, use different mechanisms to move the container, and be used in a system including a rotating stage system 130 and robotic arms 170', 170", 800. can

Description

Apparatus and method for monitoring and controlling the filling of containers with fluid medicaments in an aseptic environment

The present invention relates to the field of medicine exemplified by IPC Class A61, and more particularly to an apparatus for the sterilization and sterilization processing of pharmaceutical substances and containers for medicinal products, including the transport of the medicinal products to a medical or veterinary patient for administrative reasons. and associated methods. In one aspect, the present invention relates to the programmed and automated operation of such a device constructed and arranged to fill a medicament container with an amount of liquid or other substance.

The subject of filling pharmaceuticals into pharmaceutical containers is a major aspect of the pharmaceutical industry. The above tasks are tightly controlled by various government agencies and public bodies in various countries. Technically, this challenge is challenging in that pharmaceutical products need to be filled into containers under very stringent aseptic conditions. Very specific procedures are specified for these operations, particularly to the extent that they make the processing of pharmaceuticals very different compared to the processing of other industrial products, including semiconductors, which also require extreme and consistent environmental conditions. In fact, the parallels between processing semiconductors in a semiconductor "clean room" and processing medicaments in an aseptic isolator are superficial. Although they all share the use of a "clean room", they do not have the inherent sterility requirements associated with semiconductor manufacturing.

The filling of a medicament container with a fluid drug specifically requires aseptic handling of both the container and the fluid medicament itself. This results in complex mechanisms and procedures, many of which can be automated to one degree or another. Often, manufacturing equipment for processing fluid medicaments is bulky and expensive. This has caused problems with smaller operations, particularly small-scale production and development environments. As the art advances, the need for smaller and more compact devices is becoming clearer, particularly for filling and compounding fluid medicaments.

The prior art is typically characterized by the use of vibratory bowls and escapements. Additionally, many prior art systems employ gloves used by the operator to provide access to the chamber interior.

In one overall aspect, the invention features a method for filling a nested medicinal container with a pharmaceutical fluid substance, such as a liquid, solution or suspension, having therapeutic properties. The method comprises providing a filling system comprising a sterile chamber capable of maintaining aseptic conditions, the chamber comprising a filling station and a destination fiducial locating structure comprising a constraining surface; and providing a charging system comprising a planar rotating stage having The method also includes transferring at least one container tubs into the chamber, wherein the at least one container tub is sealed by a container tub cover and having a plurality of medicament containers. It also includes the steps of including a container nest, aseptically sealing the chamber, and establishing aseptic conditions within the chamber. A container nest having a plurality of medicament containers is transported into a destination reference positioning structure, so that the container nest is held in place by the constraining surface, actuating both the rotation stage and the filling station, so that the multiple A fluid medicinal substance is dispensed into the interior of at least some of the medicine containers of the medicine container.

In certain embodiments, operating the charging station may include rotating the charging station. Dispensing the fluid medicinal substance may include dispensing the fluid medicinal substance inside the container on an iterative and serial basis. Providing a filling system includes providing a filling device comprising at least one cover removal station within the chamber, wherein transporting the container nest into a destination reference positioning structure comprises: the rotating stage and operating all of the at least one cover removal station to remove the container tub cover from the container tub. Operating the at least one cover removal station may include rotating the at least one cover removal station. Providing a filling system includes providing at least one cover removal station having a fastening tool into the chamber, and wherein transferring the at least one container tub into the chamber comprises a cover removal fixture. attaching to the container tub cover, and operating the at least one cover removal station may include engaging the fastening tool with the cover removal fixture.

The method may further comprise transferring into the chamber a container closure tub sealed by a container closure tub cover and comprising at least one container closure nest having a plurality of medicament container closures. The method comprises: positioning a closure nest 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; rotating the rotation stage; The method may further include transferring the aligned closure and nest of containers to a ramming station, and forcing the closure into the interior of the corresponding container. The disposing of one closed nest among the at least one closed nest includes: acquiring image information for one closed nest among the at least one closed nest; and, based on the image information, among the at least one closed nest disposing one closure nest.

Placing one closed nest among the at least one closed nest includes: applying a vacuum to a sucker cup; elevating and lowering the container closing nest using the sucker cup; and operating the rotating stage. may include The step of transferring the container nest to the inside of the destination positioning opening includes the steps of applying a vacuum to a sucker cup, elevating the container nest using the sucker cup, and operating the rotation stage. may include The dispensing of the fluid medicinal substance may comprise simultaneously and/or serially operating the rotating stage and the filling station, wherein removing the container tub cover comprises the rotating stage and the at least one cover removal station. may include simultaneously and/or sequentially operating the

In another overall aspect, the present invention features a system for filling a nested medicinal container with a fluid medicinal substance, the system comprising a sterile chamber capable of maintaining aseptic conditions. The chamber includes a filling station and a planar rotational stage having a rotational stage axis of rotation, the destination reference position comprising constraining surfaces shaped and arranged to receive and secure a medicine container nest having a plurality of medicine containers. and a planar rotation stage including a setting structure.

In certain embodiments, the filling station may include a fluid product dispenser head, the filling station being capable of rotating about a filling station rotation axis parallel to the rotation stage rotation axis, such that the rotation In combination with rotation of the stage, the dispensing head is placed on top of any one of a plurality of medicament containers held within a container nest within the reference positioning structure. The chamber may further include at least one cover removal station, wherein the rotating stage is a medicine container closing tub sealed with a container closure tub cover and comprising at least one medicine container closure nest having a plurality of medicine container closures. A medicament container tub comprising a medicament container nest sealed with a container closure tub cover, the medicament container nest having a first origin reference positioning structure comprising a constraining surface having a shape and disposed to receive and grip the medicament. and at least one second origin reference positioning structure arranged and shaped to receive and grip.

the at least one cover removal station is rotatable about a cover removal rotation axis parallel to the rotation stage rotation axis, the container tub cover being removed from the at least one container tub in combination with rotation of the rotation stage; It may be arranged and configured to be able to remove the container closing tub cover from the container closing tub. The at least one cover removal station may include a fastening tool, the fastening tool being arranged and configured to engage a fastening fixture pre-attached to the container tub cover and the container closure tub cover.

The system further comprises at least one camera arranged to acquire image information on at least one of the container nest and the closure nest, and a controller, wherein the chamber is arranged to engage with the container nest and the container closure nest. at least one vacuum pick-up system comprising a sucker cup configured to elevating a medicament container nest from a medicament container tub fixed to one of the openings, depositing the medicament container in the destination reference positioning opening in combination with rotation of the rotation stage, the first origin reference The medicine container closure nest can be lifted from the medicine container closing tub fixed to the positioning opening, and the container closing nest can be deposited on the top of the medicine container nest.

the controller is operative to instruct the at least one camera to provide the image information to the controller, the controller operable to place the closure in the closure nest corresponding to a container in the container nest, the rotating stage can operate to control the rotation of The system may further include a ram system configured to force the closure into the interior of the corresponding container.

The system comprises at least one rotatable cover removal station having a cover removal station axis of rotation parallel to the axis of rotation of the stage of rotation; at least one vacuum pickup system for positioning the closure nest and a ram system for forcing the closure into the interior of the container, wherein the filling station rotates parallel to the rotation stage axis of rotation. It may be a rotatable filling station having a shaft and including a fluid drug dispensing head. The system may further include at least one camera for acquiring image information of at least one of the container nest and the closed nest, and a controller including a memory and a processor. the controller instructs the rotating stage to rotate to an angular position, one of which is preset and based on the image information, and works in conjunction with the rotating stage for the at least one cover removal station, the charging station , to control the at least one vacuum pickup system and the ram system.

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

In another aspect, there is provided a system for filling a nested medicinal container with a fluid medicinal substance, the system comprising a sterile chamber capable of maintaining aseptic conditions, the chamber comprising: a rotating stage A planar rotation stage having an axis of rotation, and a plurality of locating structures arranged with respect to the rotation stage at different positions about the rotation stage axis of rotation, a positioning structure for holding a nest of pharmaceutical container parts in position, and filling the medicine container part while the drug container part is held in the nest in one of the positioning structures and a container filling station having a dispensing head for dispensing. The positioning structure comprises: a surface associated with first tub-holing openings in the rotation stage for gripping a first tub comprising at least one nest of the container portion; for gripping a second tub comprising at least one nest of a closure, a surface associated with a second two-tub gripping opening in the rotation stage, and for gripping at least one nest, the and a surface associated with the destination nest-grass opening in the rotation stage.

The chamber may further include at least one vacuum pickup system comprising a sucker cup arranged to engage with the container nest and container closure nest fixed on the rotation stage, the at least one pickup system comprising the rotational stage. configured to in combination with rotation of a stage to elevate the medicament container nest from the medicament container tub, deposit the medicament container nest within the destination opening in combination with rotation of the rotation stage, and The medicament container closure nest is lifted from the container closure, and the medicament container closure nest is deposited on top of the medicament container nest.

At least one of the positioning structures may include a reconfigurable positioning structure having one or more adjustable positioning surfaces that position the tub relative to the rotation stage. The reconfigurable positioning structure includes at least a pair of reconfigurable stopping members and disposed opposite to each other across an opening in the rotation stage to provide a preset first tub comprising at least one nest. It may include a restraining member precisely positioned in a first predetermined position. The stopping member may be adjusted to hold the tub in the first preset position by means of a rotary adjustment, and the restraining member may be adapted to restrain the tub in the first preset position. can be placed.

At least a first reconfigurable positioning structure among the reconfigurable positioning structures may include a rotary positioning element having an axis of rotation parallel to a plane of the rotation stage, and rotating the rotational positioning element It includes a number of different positioning surfaces that can be selected by way of At least one of the reconfigurable positioning structures includes a pair of opposing rotational positioning elements, each rotational positioning element having an axis of rotation parallel to the face of the rotational stage; , a number of different locating surfaces that can be selected by rotating the rotating locating element to accommodate different nest widths.

At least one of the reconfigurable positioning structures comprises at least a first pair of opposing positioning surfaces defining mutually opposing positioning surfaces along a first positioning axis that is at least generally parallel to the face of the rotation stage. a positioning element and at least a second pair of opposing positions defining mutually opposing positioning surfaces along a second positioning axis at least generally parallel to the face of the rotation stage and at least generally perpendicular to the first positioning axis Determining factors may be included. At least one of the positioning elements in each of the first pair and the second pair of positioning elements has an axis of rotation parallel to the plane of the rotation stage and includes a plurality of different positioning surfaces. It may include a rotating positioning element.

The system may further include a reconfigurable vacuum pickup system, the reconfigurable vacuum pickup system comprising: a first set of sucker cups arranged in a first pattern; and a second set of sucker cups arranged in a second pattern different from the first pattern. the first set of sucker cups or the second set of sucker cups, while at least one nest of two sets of sucker cups and nests of the medicament container portion is fixed by one of the plurality of positioning structures It may include a selection mechanism (selection mechanism) for engaging (operative to position) to engage with at least one nest of the nest of the medicament container portion. The selection mechanism of the reconfigurable vacuum pickup system may include a rotary mechanism operative to place the first set of sucker cups or the second set of sucker cups in an engaged position.

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

The filling station is rotatable about a filling station rotation axis parallel to the rotation stage rotation axis, such that the plurality of medicament containers are gripped by one of the positioning structures in combination with the rotation of the rotation stage. A dispensing head is placed on the top of any one of the medicament containers.

The system may further include at least one camera arranged to obtain image information about at least one nest of the nests of the medicine container unit. The system may further comprise a ram system configured to force the nested closure into the interior of the corresponding nested container.

The system comprises: at least one rotatable cover removal station having a cover removal station rotation axis parallel to the rotation stage axis of rotation; at least one vacuum pickup system for placing the container closure on the container nest such that the closure in the closure nest corresponds to a container in the container nest; and a ram system for forcing the closure within the container, the filling station having a filling station rotation axis parallel to the rotation stage rotation axis, the filling station having a fluid product dispenser head; It is a rotating charging station.

The system may further include at least one camera for acquiring image information of at least one of the container nest and the closed nest, and a controller including a memory and a processor, wherein the controller is preset and instructs the rotation stage to rotate to an angular position, one of which is based on image information, so that the at least one cover removal station, the charging station, the at least one vacuum pickup system and the ram system It operates to control to work in conjunction with the rotating stage.

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

In another aspect, there is provided a method for filling a nested medicinal container with a fluid medicinal substance, the method comprising the steps of providing a filling system comprising a sterile chamber capable of maintaining aseptic conditions, the method comprising: the chamber comprising a filling station and a planar rotating stage having a destination positioning structure; transferring at least one container tub sealed by a container tub cover and including a container nest having a plurality of medicine containers into the chamber; aseptically sealing the chamber; establishing aseptic conditions within the chamber; transferring the container nest having the plurality of medicine containers into the destination positioning structure to fix the container nest; and operating both the rotation stage and the filling station to dispense the fluid medicinal substance into at least some of the plurality of medicine containers. Operating the charging station may include rotating the charging station. The dispensing of the fluid medicinal substance may include dispensing the fluid medicinal substance into the interior of the container in an iterative and continuous manner.

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

The method may further comprise transferring into the chamber a container closure tub containing at least one container closure nest sealed with a container closure tub cover and having a plurality of medicament container closures. The method comprises the steps of: positioning one closure nest 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 closure and nest of containers to a ramming station, and forcing the closure into the interior of the corresponding container. The method may further include adjusting the tub positioning structure to accommodate a size of the closed nested tub. The step of arranging one closed nest among the at least one closed nest includes: obtaining image information about one closed nest among the at least one closed nest; and, based on the image information, the at least one closed nest disposing one of the closed nests. Placing one closed nest among the at least one closed nest includes: applying a vacuum to a sucker cup; elevating and lowering the container closing nest using the sucker cup; and operating the rotating stage. may include

The step of transferring the container nest to the inside of the destination positioning opening includes the steps of applying a vacuum to a sucker cup, elevating the container nest using the sucker cup, and operating the rotation stage. may include The method may further include selecting one sucker cup from among the plurality of sets of sucker cups, and applying a vacuum to the sucker cups may be performed on the selected set of sucker cups. The step of selecting the single sucker cup may include rotating one of the plurality of sets of sucker cups into an into position. The method may further comprise adjusting the destination positioning opening to accommodate the size of the container nest. The step of adjusting the destination positioning structure may be performed in at least two generally orthogonal directions. The method may further include adjusting the tub positioning structure to accommodate the size of the container nest tub.

In another overall aspect, the present invention features a container assembly for gripping a nested medicament container portion. The container assembly includes a container, the container comprising: a top lip providing a bottom and a horizontal top sealing surface having a peripheral outline; and a sidewall positioned between the upper lip. The container assembly also includes a releasable container cover comprising a sheet of flexible material sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container, and a cover removal fixture on the top of the container cover. .

The sealed releasable container cover may include a portion extending out of the peripheral contour of the upper sealing surface of the container, and wherein the cover removal fixture is outside the peripheral contour of the upper sealing surface of the container. It may be located on the portion of the releasable container cover extending to. The container is rectangular and may include four sidewalls. The cover removal fixing unit may include an appendage that enables the cover removal fixing unit to be fastened by a fastening tool. The cover removal fixture may include a ballshaped appendage that enables the cover removal fixture to be fastened by a fastening tool. The releasable container cover is heat sealed to the sealing surface of the upper lip of the rectangular container, thereby sealing the contents of the container against decontamination. The releasable container cover is sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using a chemical agent. The releasable container cover is sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using irradiation. The releasable container cover is sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using plasma. The peelable cover may be made of a plastic material. The peelable cover may be made of an impermeable laminated foil. The peelable cover may be made of a polymeric membrane. The cover removal fixture may be clipped to a portion of the releasable container cover extending out of the peripheral contour of the upper sealing surface of the container. The sealed container may contain a sterile medicament container or closure.

In another aspect, there is provided a method for removing a container cover from a sealed container within a controlled environment enclosure, wherein the sealed container is sealed by the container cover, the method comprising: providing the container in an enclosure with the cover sealed to a sealing surface of a lip of the container to seal the contents of the container against decontamination, the cover having a cover removal fixture; decontaminating the sealed container within a controlled environment enclosure; fastening the cover removal fixing part with a fastening tool; and removing the cover from the container using the fastening tool. The fastening may include fastening the cover removal fixing part with a fork-shaped fastening tool. The fastening may include fastening a ball-shaped accessory on the cover removal fixing part.

The providing step may include, prior to the decontaminating step, providing a sterile medicament container or closure in a sealed container. The attaching may be performed before the container is placed within the controlled environment enclosure. Decontaminating the sealed container within the controlled environment enclosure may be performed prior to removing the cover. Removing the cover may include moving the fastening tool relative to the container. Removing the cover may include moving both the container and the fastening tool. The method may further include attaching the cover removal fixture to the cover prior to providing the container within the controlled environment enclosure.

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

The determining of the volume of the fluid medicine dispensed into the container from the plurality of images may include determining the volume of at least one droplet among the plurality of droplets. The step of determining the volume of the at least one droplet from the plurality of droplets includes: first and second entire portions of the at least one droplet appearing on the left and right sides of the droplet path, respectively, in the at least one image of the at least one droplet ( first and second total portions) and separately mathematically rotating first and second total portions of the droplet passing around a circumference around the droplet path to obtain first and second portions of at least one of the plurality of droplets. It may include calculating a second volume, and equating the volume of at least one droplet among the plurality of droplets to an average of the first and second volumes.

The acquiring, from the imaging unit, a plurality of images of at least one droplet from among a plurality of droplets along the droplet path may include acquiring a plurality of images above a set portion of the droplet path. Optionally, the acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from the imaging unit includes: determining a portion of a droplet path in which the droplets have a stable shape from the plurality of images; When the droplet is located in a part of the droplet path having a stable shape, the method may include selecting at least one image of the at least one droplet from among taken droplet images.

Determining the volume of the fluid medicament dispensed into the container from the plurality of images may include determining the volume of each droplet dispensed into the container. The step of stopping dispensing of the fluid medicament based on the volume of the fluid medicament dispensed into the container may include stopping dispensing of the fluid medicament when the total amount of the fluid medicament dispensed into the container is the same as the set volume. there is. Acquiring a plurality of images of at least one droplet from among a plurality of droplets along a droplet path from the imaging unit may include acquiring a plurality of images by adopting light reflected to the imaging unit by a retroreflector. there is. Acquiring the plurality of images of at least one droplet from among the plurality of droplets along the droplet path from the imaging unit may include acquiring the plurality of images by a telecentric lens. Providing a sterile medicament container within a sterile chamber includes providing a sterile medicament container within a container nest.

The method may further include moving at least one of the dispensing head and the container to position an opening in the container below the dispensing head for receiving the droplet along the droplet path. Moving the container may include operating a robotic arm. Moving the dispensing head may include actuating a robotic arm, which may be an articulated robotic arm.

In another aspect, a system for aseptically dispensing a fluid medicament into a container is provided, the system comprising: a sealable sterile chamber capable of maintaining aseptic conditions; a fluid medicament dispensing head configured to generate a droplet of the fluid medicament within the chamber; a droplet monitoring system including a digital imaging unit disposed inside the chamber to acquire an image of a droplet dispensed by the fluid medicament dispensing head; A controller comprising a memory and a processor, comprising: a controller communicating with the fluid medicament dispensing head and the digital imaging unit; and software for controlling dispensing of the fluid medicament droplet by the fluid medicament dispensing head, wherein when the software is loaded into a memory and executed by the processor, to collect an image of the fluid medicament droplet along a droplet path Includes software configured.

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

Systems and methods in accordance with the present invention need not employ vibratory bowls or escapements. Also, the system and method do not require gloves. Thus, the system and method according to the present invention can meet the requirements for compact, small-scale filling and compounding for fluid medicaments.

By referring to the following description of the embodiments of the present invention together with the accompanying drawings, the features and objects other than the above-mentioned features and objects of the present invention, and the manners accompanying them will become clearer, and the present invention itself will be better understood will be understood
1A is a diagram illustrating a device for filling a medicament container with a pharmaceutical fluid product. For clarity, some surfaces are shown with the interior visible and others are shown transparent.
Fig. 1B is a plan view of one chamber constituting the apparatus shown in Fig. 1A;
Fig. 1c shows the rotational stage of the apparatus shown in Figs. 1a and 1b.
1D is a side view of a portion of the device shown in FIGS. 1A and 1B ;
Figure 1e shows a state in which the medicine container tub cover seated on the rotation stage of Figures 1a to 1e is removed.
1F shows a medicament container filled with a fluid medicinal substance in the device of FIGS. 1A-1E .
1G is a more detailed view of a cover removal component of the apparatus shown in FIGS. 1A, 1B-1E ;
2A and 2B are taken together to form a flow chart illustrating a method for aseptically filling a medicament container with a pharmaceutical fluid substance in a spatially limited environment.
3A is a diagram illustrating a subsystem according to another embodiment of a device for filling a medicament container with a pharmaceutical fluid product.
3B is a view showing a part of FIG. 3A in more detail.
4A is a diagram illustrating a subsystem according to another embodiment of a device for filling a medicament container with a fluid medicament.
FIG. 4B is a view showing a part of FIG. 4A in more detail.
5A is a diagram illustrating a subsystem according to another embodiment of a device for filling a medicament container with a fluid medicament.
5B is a view showing a part of FIG. 5A in more detail.
6 shows a flowchart of another method for filling a nested medicament container with a fluid medicament substance.
7A is a diagram illustrating a subsystem according to another embodiment of a device for filling a medicament container with a fluid medicament, based on the system of FIGS. 5A and 5B ;
7B is a diagram of a droplet monitoring system.
8 is a diagram illustrating a subsystem of another embodiment of a device for filling a medicament container with a fluid medicament.
9 is a diagram illustrating a subsystem of another embodiment of a device for filling a medicament container with a fluid medicament.
10 is a diagram illustrating a subsystem of another embodiment of a device for filling a medicament container with a fluid medicament.
11 shows a flow chart of a method for aseptically dispensing a fluid medicament into a container.
Corresponding reference numbers in the various drawings refer to corresponding parts. While the drawings represent embodiments of the invention, the drawings are not necessarily drawn to scale, and certain features may be exaggerated so as to better illustrate and explain the invention. The flowcharts are also representative in nature, and actual embodiments of the invention may include other features or steps not shown in the drawings. While the examples set forth herein represent embodiments of the invention in one or more forms, these examples should not be construed as limiting the scope of the invention in any way.

The embodiments disclosed below are illustrative, and are not intended to limit or limit the invention to the precise form disclosed in the detailed description that follows. Rather, the embodiments are chosen and described so that those skilled in the art may use the teachings disclosed in the embodiments.

The present invention relates to an apparatus and method for filling a medicament container with a fluid medicament substance in a spatially constrained environment. 1A , a filling system 1000 includes a sealable chamber 100 in communication with an ambient environment, the sealable chamber 100 having an aseptic environment established therein. ) and can maintain the aseptic conditions therein. The interior of the hermetic chamber 100 may be sterilized by one or more of many processing methods, such as steam, hydrogen peroxide, vapor, ozone, sterilizing agents such as nitrogen dioxide and ethylene oxide. (sterilant), but is not limited thereto. Structures and mechanisms capable of performing such a sterilization step are well known in the art, and are not shown in FIG. 1A.

The chambers 200 and 300 are respectively separated from the hermetic chamber 100 by an upper wall 110 and a lower wall 120, respectively, and it is not required to be able to maintain a sterile environment therein. Communication of the sealable chamber 100 with the surrounding environment may be accomplished through a suitable aseptically sealable door 102 schematically indicated by dashed lines in FIG. 1A . Suitable hermetic doors and ports are well known in the art and will not be considered in more detail herein. For example, the ambient environment may be a clean room adapted to handle medicaments while they are being manufactured. In such a spatially limited clean environment, since space is at a premium, reducing the so-called "footprint" of equipment that must be housed in such a clean environment is a great advantage.

The terms “aseptic” and “sterilize” are to be understood as follows for the purposes of this specification. It should be understood that establishing sterile conditions within a chamber means establishing such conditions throughout the interior atmosphere of the chamber as well as substantially all interior surfaces of the chamber. This should include all surfaces, such as all items, containers, and subsystems, that are exposed to the chamber's internal atmosphere. For example, there may be extremely tight crevices or microscopic crevices inside the chamber so that sterilizing gas or sterilizing vapor cannot completely penetrate inside such dense area. To this extent, the degree of sterilization in practical cases may not be complete. This is recognized both by industry and by standards established for that industry. Establishing aseptic conditions within the interior of the chamber, and “sterilizing the interior of the chamber” operations will have the same meaning herein.

When aseptic conditions are introduced into the chamber, the existing aseptic conditions inside the chamber are compromised by items whose surfaces are not properly sterilized. Conversely, even if sterile or sterilized items are introduced into the interior of the chamber that does not have aseptic conditions therein, the interior of the chamber does not become sterile. In practice, the sterility condition of the surface of the introduced item will only be compromised. Likewise, introducing filtered air from all biological entities into a non-sterile chamber does not somehow sterilize the chamber or render the chamber as sterile as is acceptable to the pharmaceutical industry. This is because the interior surfaces of the chamber are not sterilized by this inlet of air. What is achieved is only the contamination of the filtered air, with active biological species present on the interior surfaces of the non-sterile chamber.

For the sake of clarity and completeness, it is noted that the term "sterile" is also commonly used in the art in relation to the introduction of a fluid agent along a sterile tube into the interior of a body inside a controlled chamber. Dots should also be recorded. In this case, the term in the art refers to the fact that the conditions or fluid medicament inside the tube can be filtered to an appropriate degree. This does not sterilize or sterilize the interior of the chamber in question. Aseptic conditions in this case are confined to the interior of the tube with the pharmaceutical stream. These streams are often filtered to a high degree, but such filtration only affects the interior of a particular tube and does not sterilize the interior of the chamber at all.

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

“Class 100”, “Class 10” or “Class 10”, even when applying a laminar flow hood or applying any quality High Efficiency Particulate Air (HPPA) or Ultra Low Particulate Air (ULPA) filter. Because a pharmaceutical or semiconductor cleanroom of any quality level, including "Class 1," does not have the means to ensure that the surfaces of that cleanroom are sterile or sterile, such a cleanroom cannot constitute a sterile chamber. It should also be mentioned. Standards for cleanrooms exist from both the US federal government and the International Standards Organization (ISO). These are other standards that specify in great detail the allowable particulate content in a cubic volume of air in such a clean room. None of these standards address the issue of biological species present on surfaces within the cleanroom. This helps the argument that a chamber cannot be sterile by merely managing the atmosphere or airflow in the chamber. Conversely, the chamber cannot be sterile by sterilizing only the surface inside the chamber.

The text "Guideline for Disinfection and Sterilization in healthcare Facilities, 2008" by Rutala et al. of the Centers for Disease Control and Prevention lists an overview of mechanisms and methods related to sterilization. Our interest in this specification is specifically to sterilize these mechanisms for sterilizing the interior of the chamber, namely both the interior surface of the chamber and the atmosphere. Given the requirements given, steam-based methods are best suited for the task at hand. These methods 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 gas and vapor. In one suitable method suitable for the present invention, the sterilization treatment is performed by hydrogen peroxide vapor followed by flushing with ozone before the chamber is applied to fill the medicament container.

The subsystems of the apparatus 1000 included in the hermetic chamber 100 will now be described with reference to FIGS. 1A-1G . Due to the compactness and density of the components and subsystems of apparatus 1000, certain components and subsystems have been omitted from the drawings of FIGS. 1B-1C for the purpose of brevity, and are most relevant to the supporting text herein. The focus is on the components and subsystems that exist. The planar rotary stage 130 is capable of full 360 degree rotation in a horizontal plane parallel to the lower wall 120 about the rotary stage axis of rotation 131 , and a bellows feed-through , 190) can be raised and lowered. Because the bellows feed water is used, the chamber 100 can maintain aseptic conditions while the rotating stage 130 is operating. A suitable engine and gearing system 320 may be accommodated in the chamber 300 . Engines and gear systems, for example stepper motors, suitable for rotating the rotating stage 130 , with suitable angular precision and repeatability, are well known in the art and described herein. is no longer discussed in

As shown in FIG. 1C , the rotation stage 130 is provided with at least three fiducial locating openings 132 , 134 , 136 . The reference positioning opening 132 accommodates a container tub 530 holding a sterile medicament container 510 pre-packed in a predetermined pattern within the container nest 500 . applied to accept it. Container bin 530 is typically substantially rectangular and is sealed with a peelable cover 520 . Suppliers of medicament containers provide their products in this format to users of the devices herein. The fiducial positioning opening 134 is configured to receive container closure tubs 630 that grip the sterile medicament container closure 610 pre-packed in a predetermined pattern in the container closure nest 600 . is applied. Container closure bin 630 is typically substantially rectangular and is sealed with a peelable tub cover not shown in FIGS. 1A-1G . The peelable cover of the container closing tub 630 is functionally the same as the peelable cover 520 . The supplier of the medicament container provides a product in this form to the user of the device herein. For the small space occupancy of the system 1000 , the rectangular axis of the reference positioning apertures 132 , 134 , 136 is a rotation stage so as to ensure an appropriately small radius with respect to the rotation stage 130 . It may be oriented at an angle with respect to the radial direction of 130 .

suitable container nest 500 and container closure nest 600; a container tub 530 and a container closing tub 603 ; and releasable tub cover 620 is described in US Patent Application Publication No. US 2016/0200461, published July 14, 2016, the disclosure of which is incorporated herein in its entirety. Alternative cover gripping arrangements for removing a tub cover from a tub are described in US Patent Application Publication No. US 2016, published September 1, 2016, the details of which are incorporated herein in their entirety. /0251206 also described. Removal of the tub cover may be controlled and monitored by the subsystems and methods described in PCT International Publication No. WO2018/049516 A1, published Mar. 22, 2018, the disclosure of which is hereby fully incorporated herein.

For clarity, FIGS. 1A-1G , and related text to be described below, refer to the use of a single tub 530 of the medicament container 510 along with a single tub 630 of the container closure 610 . In practice, the container closure 610 is provided as multiple nests 630 for one container closure tub 630 . For this purpose, the rotating stage 130 includes more than one, each receiving a respective container tub, of the container tubs 530 containing the pre-packed sterile medicament containers 510 in the container nest 500 . and a reference positioning aperture 132 that In other embodiments, there may be more than one nest 530 of containers 510 within a single medicament container tub 530 .

A reference positioning opening 136 is specifically arranged to accommodate a container nest 500 having a medicament container 510 . Container tub 530 and container closure tub 630 are naturally located in reference positioning openings 132, 134, and are suspended by their rims within corresponding openings 132, 134 whereas , the medicament container 510 is precisely positioned in the opening 136 and retained in position by some other mechanism. For this purpose, the fiducial positioning aperture 136 includes four fiducial retaining guides 137 . As a loose component of system 1000, baseplate 138 is positioned within fiducial positioning apertures 136 and rests in a horizontal portion underneath each of four fiducial anchoring guides 137 (Fig. 1c and 1d). Due to this arrangement, while the base plate is guided by the reference point fixing guide 137 , the base plate 138 can move freely. We will return to this arrangement when discussing container closures using container closures.

1E shows that at the reference positioning opening 132 (not shown) the cover 520 has been peeled away from the container tub 530 to expose the container nest 510 with the medicament container 530 , but the reference positioning opening 136 . ) indicates an empty state. At this point in time system 1000 is operating, a cover similar to cover 520 at the reference positioning opening 134 (not visible) has already been peeled off from the closed container tub 630 , having a container closure 610 . The nest 600 is exposed. 1G shows an enlarged detailed view of a state in which the cover 520 is peeled off. A cover removal station 140 is rotatable about an axis of rotation of the cover removal station 144 parallel to an axis of rotation of the stage of rotation 131 and includes an engagement tool 142, The fastening mechanism is fork-shaped to engage a cover removal fixture 540 attached to the cover 520 in this particular embodiment. Before the container tub 530 is transported into the system 1000 through the door 102 (see FIG. 1A ), the cover removal fixture 540 is pre-attached to the cover 520 . In the embodiment shown in FIGS. 1E and 1G , the cover removal fixture 540 is clipped to the cover 520 and is capable of being fastened by a fastening mechanism 142 with a ball-shaped accessory. It has a shaped appendage). Other combinations of cover removal fasteners and fasteners are contemplated, and system 1000 is not limited to the particular combination of cover removal fasteners and fasteners shown in FIGS. 1A, 1E, and 1G . For example, cover removal fixture 540 may be manufactured as an integral part of cover 520 for use in a charging system such as charging system 1000 . or during placement into the tub 530 of the nest 500 with the container 530, and during placement into the tub 630 of the nest 600 with the container closure 610, the cover removal fastener may be The cover 520 may be clip-fixed.

The rotation stage 130 may be lowered to help obtain a less acute angle between the cover 520 and the tub 530 . If the angle is excessively acute, the cover 520 may be torn. The cover removal station 140 may be rotated while the rotation stage 130 rotates, such that in connection with removing the cover 520 due to the combined movement of the cover removal station 140 and the rotation stage 130 . By providing a low-stress path, the likelihood of the cover 520 being torn is limited. In particular, when the container tub 530 is placed in or removed from the reference positioning opening 132 , the fastening mechanism 142 is not present on top of the reference positioning opening 132 . The cover removal station 140 may be rotated to ensure that.

In some embodiments, system 1000 includes a single cover removal station 140 for continuously removing covers from tubs 520 , 620 . In another embodiment, system 1000 may be equipped with two or more cover removal stations 140 for dedicated removal of cover from tubs 520 , 620 and other additional tubs. In some embodiments, the cover is simultaneously removed from the tubs 520 , 620 and other tubs, with all removal processes benefiting from a single rotational movement of the rotary stage 130 .

1A , 1B and 1F , a filling station 170 for filling a medication container 510 with a pharmaceutical fluid product dispenses the fluid medication into a fluid medication dispenser head 174 (see FIG. 1F ). It contains a fluid drug feed line 172 to supply. The charging station 170 may rotate about a charging station rotation axis 176 parallel to the rotation stage rotation axis 131 . Charging station 170 , such that when nest 500 is seated in reference positioning opening 136 , dispensing head 174 can be placed over the opening of any selected container 510 within nest 500 . And the rotation stage 130 may rotate simultaneously or sequentially. This allows the medication dispensing head 174 to fill all containers 510 in the nest 500 with the fluid medication. When the filling station is not engaged with the filling container 510 , the filling station 170 can rotate to swing the dispensing head 174 completely away from the reference positioning opening 136 , Accordingly, the nest 600 having the container closure 610 is nested while the container closure 610 is disposed immediately above the openings of all containers 510 residing in the reference positioning opening 136 . 500) may be disposed on the top.

Another term employed to describe the dispensing head 174 is “filling needle”. Suitable filling needles and protective sheathing arrangements for such filling needles, the disclosures of which are incorporated herein in their entirety, are disclosed in U.S. Patent Publications, December 1, 2016 and August 31, 2017, respectively. Applications US 2016/0346777 and US 2017/0121046 are described.

1A and 1B show two vacuum pickup systems 150 and 160, each comprising a plurality of suction cups 152 and 162 (see FIG. 1B). The vacuum pickup system 150 is arranged to pick up the nest 500 of containers 510 by means of a sucker cup 152 , and the vacuum pickup system 160 is configured to pick up the nests 500 of containers 510 by means of a sucker cup 162 . arranged to pick up the nest 600 . The vacuum pickup system 160 can be raised or lowered so that the sucker cup 162 can engage with other nests 600 of the container closure 610 contained at different depths within the tub 630 . let there be For this purpose, the vacuum pickup system 160 may include a bellows feedsur capable of vertical movement while maintaining the aseptic integrity of the chamber 100 . A suitable vacuum pump or vacuum line from a vacuum source external to system 1000 may be connected to vacuum pickup system 150 , 160 , and may ensure adequate vacuum in sucker cups 152 , 162 .

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

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

The controller 400 shown in FIGS. 1A and 1B may communicate with the rest of the components of the system 1000 via a control communication line 410 , or may be physically located inside the system 1000 , eg, inside the chamber 200 . can be included as The controller 400 may have a processor comprising suitable memory and appropriate software programming instructions, which, when loaded into memory executed by the processor, intermittently for dispensing fluid medication to the dispensing head 174 . Control of on-and-off valving, as well as movement of ram system 180 , vertical movement and rotational operation of rotary stage 130 , and application of vacuum to vacuum pickup systems 150 , 160 . , controlling the image operation by the cameras 210 , 220 , the vertical movement of the vacuum pickup system 160 , any rotation or vertical movement required from the cover removal station 140 and the charging station 170 . Appropriate valves and pumps, particularly peristaltic pumps, required for the delivery of fluid medication to the dispensing head 174 are well known in the art and may be housed within the chamber 200 or located outside the system 1000 . can Various mechanical drives for the subsystems described above are well known in the art and will not be discussed in more detail herein. These drives may typically be housed within the chamber 200 of the system 1000 . When executed by the processor, the software instructs the rotary stage to rotate to an angular position either predetermined or based on image information obtained from the camera, and in conjunction with the rotary stage. ) to operate, control the cover removal station, filling station, vacuum pickup system and ram system.

A method for filling a nested medicament container with a fluid medicament based on the system 1000 will now be described with reference to the flowchart shown in FIG. 2A and continuing in FIG. 2B . The method comprises providing ([2010]) a filling device (1000) comprising a sterile chamber (100) capable of maintaining aseptic conditions, said chamber having a destination reference positioning opening (136) and at least A rotating stage 130 with two source reference positioning openings 132 , 134 , a charging station 170 , at least one cover removal station 140 , and horizontally oriented including a container ramming system 180 and at least one vacuum pickup system (eg, 150 and/or 160 ). The method comprises at least one container tub 530 sealed with a container tub cover 520 and containing a container nest 500 having a plurality of medicament containers 510 with at least two origin reference positioning openings 132 . , 134) of at least transferring to the inside of the first opening ([2020]); and at least one container closure nest 600 sealed with a closure tub cover and having a plurality of medicament container closures 610 . ) further comprising the step of transferring ([2025]) to the inside of the second opening.

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

The method comprises at least one cover removal station 140 and at least one cover removal station 140 to remove the container tub cover 520 from the at least one container tub 530 and remove the closing nest 600 from the closing tub 630 . operating the rotation stage 130 ([2040]); A rotating stage 130 and at least one vacuum pickup system (eg, 150 and/or actuating 160) ([2050]); and operating the rotation stage 130 and the filling station 170 to dispense, on an iterative and serial basis, the fluid medicinal substance into the interior of at least some of the plurality of medicament containers 510 . It further comprises a dispensing step ([2060]). In order to describe the fact that the same operating steps are used repeatedly to fill various containers, as opposed to simultaneously, and that containers are filled one after another, the term "repeated and continuously "This is adopted. In some embodiments, multiple containers may be filled simultaneously using a filling station with multiple dispensing heads.

Steps [2040], [2050], and [2060] each rotate the rotation stage 130 , the other device, the cover removal station 140 , respectively, the at least one vacuum pickup system (eg, 150 and/or 160 ) ), and other devices that are charging stations 170 . The related motions may be concurrent in some instances or embodiments and may be continuous in other instances or embodiments. In some embodiments, some of the operations may be concurrent and others may be continuous.

Actuating the at least one cover removal station 140 ([2040]) comprises a fastening tool (eg, tool 142) and a cover removal fixture (eg, a high and concluding a government 540). Operating the at least one vacuum pickup system ([2050]) may include contacting the container nest 500 with a plurality of sucker cups 152 while applying a vacuum to the sucker cups 152. there is. The step of dispensing the fluid medicinal substance into the interior of at least some of the plurality of medicine containers ([2060]) is filled in a repeating and continuous manner at the top of the opening of at least some of the plurality of medicine containers 510. disposing on the fluid product dispensing head 174 of the station 170 . The step of operating one of the rotation stage 130 and the at least one vacuum pickup system ([2050]) acquires image information of the container nest 500 having a plurality of medicine containers 510, and the container nest 500 ) operating the camera 210 to position one of the at least one vacuum pickup system thereon.

The method comprises operating a rotating stage 130 with one of at least one vacuum pickup system (eg, 150 and/or 160 ) to operate at least one container closure nest having a plurality of medicament container closures 610 ( 500) to transfer one container closing nest among the destination reference positioning openings 136, and disposing at least one closing nest 160 so that the closing part 610 can align with the container 510 step ([2070]); actuating the rotation stage 130 to place the aligned container nest 500 and closure nest 600 together in the ramming system 180 ([2080]); and actuating the ramming system to force the plurality of container closures 610 into the plurality of containers 510 ([2090]).

Operating one of the at least one vacuum pickup system ([2070]) includes contacting the container closure nest 600 to the plurality of sucker cups 162 while applying a vacuum to the sucker cups 162 . may include Actuating the ramming system ([2090]) may include driving a plurality of medicament containers 510 toward an upper ram plate of the ramming system 180 .

Actuating one of the rotating stage 130 and the at least one vacuum pickup system ([2070]) comprises closing one of the at least one container closure nest 600 having a plurality of medicament container closures 610. operating the camera 220 to obtain image information of the nest and to place one of the at least one vacuum pickup system on top of one of the at least one container closed nests 600 there is.

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

In the embodiment described with reference to FIGS. 1A-1F , the steps [2030], [2050], [2060], [2070] and [2080] each have a container nest and a container closure nest, for example a rotating stay and rotating the rotating stage, which is the gin 130 .

In another embodiment, a plurality of steps of removing the container tub cover from the at least one container tub (530); removing the container tub cover from the at least one container closing tub (630); transporting the container nest (500) to the destination reference positioning opening (136); dispensing a fluid medicinal substance into the medicine container 510; transferring one of the at least one container closure nests (600) to the destination reference positioning opening (136); and placing the aligned container nest 500 and the closure nest 600 on the ramming system 180 may include rotating a rotation stage having the container nest and the container closure nest.

In a general embodiment, removing the container tub cover from the at least one container tub 9530; removing the container tub cover from the at least one container closing tub (630); transporting the container nest (500) to the destination reference positioning opening (136); dispensing a fluid medicinal substance into the medicine container 510; transferring one of the at least one container closure nests (600) to the destination reference positioning opening (136); and disposing the container nest 500 and the closure nest 600 aligned to the ramming system 180 , at least one may include rotating a rotation stage having the container nest and the container closure nest.

It should be noted that the filling system 1000 and its associated methods need not employ the vibrating container and escapement characteristic of the prior art. Unlike many prior art systems, the filling system 1000 also does not require the use of gloves for use by a user accessing the interior of the chamber.

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

While the system described above also employs fiducial openings defined in the rotating stage to accommodate a number of tubs and nests, the system provides sufficient constraining surfaces to receive tubs and nests. ), other types of reference structures, including other configurations of For example, notched posts mounted on the rotating stage may receive tubs and/or nests above the rotating stage. Another reference positioning structure for receiving a tub or nest for a container or container closure will be described below with reference to FIGS. 3A, 3B, 4A and 5A.

Other embodiments of the filling system according to the present invention may be identical in all respects to the embodiment described above with reference to FIGS. 1A and 1B , with the exception of the vacuum pickup system(s) 150 or 160 . 3a and 3b show part of a charging system as described above. In particular, FIG. 3b focuses on the entire area of one of the vacuum pickup systems, for example, the vacuum pickup system 150 . In this alternative embodiment, the vacuum pickup system 150 is replaced with a reconfigurable vacuum pickup system 150'. The vacuum pickup system 160 of FIGS. 1A and 1B may likewise be replaced with a reconfigurable vacuum pickup system 160' having the same arrangement as the vacuum pickup system 150'. For the sake of clarity, the vacuum pickup system 160' is not shown in FIGS. 3A and 3B. In another embodiment, a single reconfigurable vacuum pickup system 150' may be employed to be able to pick up both the container nest and the container closure nest. The vacuum pickup system 150 ′ may access the container nest and the container closure nest by rotation of the rotation stage 130 .

The vacuum pickup system 150' includes two rotating arms 154a', 154b', each of which includes a plurality of sucker cups 152a', 152b'. The vacuum pickup system 150' is arranged to lift the nest 500 of the container 510 by means of sucker cups 152a', 152b'. Further, the vacuum pickup system 150' may be arranged to lift the nest 600 of the container closure 610 by means of sucker cups 152a', 152b'. Similar to the vacuum pickup system 150 , the sucker cups 152a ′, 152b ′ can be fastened to different nests 600 of the container closure 610 contained while having different depths inside the tub 530 . , the vacuum pickup system 150' can be raised or lowered.

The sucker cups 152a', 152b' are arranged on the rotating arms 154a', 154b' as a plurality of sets of linearly arranged sucker cups 152a', 152b'. Each set of 152a', 152b' is arranged at a different angle perpendicular to the longitudinal axis of the rotary arms 154a', 154b'. This arrangement allows the swivel arms 154a', 154b' to rotate about their transverse axis and a different set of linearly arranged sucker cups 152a', 152b' to the other nests 500 of the container 510. It can be oriented to be fastened with (oriented). This arrangement allows sets of sucker cups 152a', 152b' to be individually selected for use. Rotation of the rotating arms 154a', 154b' may be performed manually. In another embodiment, the rotary arms 154a', 154b' are rotated by a suitable motorized drive integrated into the vacuum pickup system 150' and controlled by the controller 400 shown in FIG. 1A. can do.

Another set of linearly arranged sucker cups 152a', 152b' is selected through rotation of the rotary arms 154a', 154b', so that the very set of sucker cups 152a', 152b' is transformed into a container 510. It may be arranged to be fastened with another container nest 500 having a , or a container closure nest 600 having a container closure part 610 .

3A and 3B show the vacuum pickup system 150' as including two rotating arms, ie, rotating arms 154a', 154b'. In other embodiments, more than one arm may be employed, all of which share the concept of selectable configurations of sucker cups. While the selection of the sucker cup configuration in FIGS. 3A and 3B is construed as rotation of the arms 154a', 154b' with the corresponding sucker cups 152a', 152b', in other embodiments the selection of the sucker cup may be of a different configuration. An example of such a different configuration is a sucker-cup in a plane parallel to the rotational surface of the rotational stage 130 so that a container nest or container closure nest and another set of sucker cups can engage. Branching includes, but is not limited to, lateral translation of the cancer. 3a and 3b the sucker cups are arranged in a linear set. In other embodiments, a non-linear arrangement of sucker cups may be employed.

Turning now specifically to FIG. 3B , members 149 , 139 are discussed in greater detail. In one embodiment, a reconfigurable stopping member 149 is shown having two different ends, which rotate the axis of rotation 141 of the stopping member into a set set position. By properly rotating the reconfigurable stopping member 149 about its center, the first end may be employed for use. In its set position, the reconfigurable stopping member 149 moves, relative to the proximal end of the container 530 , along a direction parallel to the transverse axis of the rotary arms 154a', 154b', It provides a hard stop against the selected end of the topping member 149 . In this embodiment, the reconfigurable stopping member 149 may be rotated a full 180 degrees such that the second end of the reconfigurable stopping member 149 may be disposed to stop the container 530 . reconfigurable stopping member 140 , such that the first end of reconfigurable stopping member 149 can stop the proximal end of container 530 at a point different from the point at which it stops the proximal end of container 530 . The second end of the can be configured.

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

A particular set of sucker cups 152a ′, 152b ′ may be selected to match the selection of a particular end of the reconfigurable stopping member 149 . In this way, the vacuum pickup system 150' can be set up in a configuration that can assure that containers 530 of a selected size are placed correctly, so that the container nests 500 inside the containers 530 can be placed in a specific set of It can be fastened by sucker cups 152a', 152b'. Accordingly, the vacuum pickup system 150 ′ may be reconfigured to be fastened with nests having different sizes in containers having different sizes.

For clarity, FIGS. 3A and 3B and the foregoing description show an arrangement that allows the container 530 to be accurately positioned along only one dimension in the plane of rotation of the rotation stage 130 , which Dimensions of containers perpendicular to one dimension are considered equal. In this arrangement, the fiducial positioning apertures 132 , 134 are sized to constrain the container 530 within the vertical dimension, within the plane of rotation of the rotation stage 130 .

In other embodiments, other reconfigurable stopping members and constraining members are provided in addition to the arrangement of FIGS. 3A and 3B to cope with disposing the container 530 in the vertical direction within the plane of rotation of the rotation stage 130 . can be added In order for the container 530 to be positioned in this vertical direction, the reference positioning openings 132 , 134 are not sized to constrain the container in any direction inside the rotation plane of the rotation stage 9130 .

In the embodiment described above, the reconfigurable stopping member 149 rotates the reconfigurable stopping member 149 about the stopping member rotation axis 141 so that either end is used at any one point in time. It has been described as having two ends that are selected for In other embodiments, the reconfigurable stopping member 149 may be shaped or configured to have more than two distal ends, the distal ends of the reconfigurable stopping member 149 about the stopping member rotation axis 141 . It can be selected by an appropriate rotation of (149). In one embodiment, where the reconfigurable stopping member has a very large number of stopping ends, the reconfigurable stopping member may have the shape of a cap, the shape of which is the appropriate stopping member rotation. It represents a very large number of possible stopping ends that can be selected through rotation of a reconfigurable stopping member about an axis.

Overall, the system described with reference to FIGS. 3A and 3B includes a reconfigurable fiducial nest positioning system. The reconfigurable reference nest placement system includes a movable platform comprising a reference positioning aperture 132 , a reconfigurable stopping member 149 and a restraining member 139 . For the system shown in FIGS. 3A and 3B , the mobile platform is a rotating stage 130 . As discussed below, other mobility platforms are also contemplated. For example, to the extent that the tub 530 spatially constrains and positions the nest 500 within the tub 530 , any system that fiducially locates the tub 530 is also essentially The nest 530 is positioned relative to the (inherently) nest 530 .

All of the various embodiments contemplated include a reconfigurable vacuum pickup system, which may be configured to engage the sucker cup with a corresponding area on the medicament container nest. Containers within a container nest may be closed by a corresponding container closure suspended from the container closure nest. The planar surface of the container closure nest may have an outline, the outline having pass-throughs in its perimeter such that the sucker cup may pass therethrough and engage the container nest. is passing through (leave). As an example, a through hole 602 is shown in the periphery of the closed nest 600 in FIG. 3A . Alternatively or additionally, the container closure nest may have suitable openings within its plane, so that it may function as a through hole through which the sucker cup may engage with the container nest. A liftable vacuum pickup system is constructed and arranged to be able to lift a combination of containers and their closures nested by a container nest, as opposed to by a closed nest.

In a general embodiment, the nest handling subsystem may include a reconfigurable vacuum pickup system for lifting container nests and/or the container closure nests may include one or more arms having multiple sets of sucker cups. can By reconfiguring the vacuum pickup system, a set of sucker cups can be selected from multiple sets of sucker cups, and the selected set of sucker cups can be pre-arranged to engage a specific container nest or container closure nest. This selection may be made based on either the size and shape of the nest or both the size and shape of the nest. The nest handling system is disposed adjacent an opposite end of a reference positioning opening 132 for gripping a tub 530 containing a container nest 500 having a container 510 , the opposite end of the tub 530 . It may further include at least one pair of reconfigurable stopping members 149 and constraining members 139 for engaging with. The stopping member and constraining member are arranged to position the tub 530 in a predetermined position that can ensure that a selected set of sucker cups can engage a container nest and/or a container closure nest.

As in the case of the opening 132 , the opening 134 in FIG. 3A is also provided by at least one set of reconfigurable stopping members, in this case member 145 , and a constraining member, in this case member 135 . can function. In the same way that the reconfigurable stopping member 149 and the constraining member 139 acted on any tub in the opening 132 , the reconfigurable stopping member 140 and the constraining bonsai 135 act as the opening 134 . ) functions for any tub in

The various embodiments described above have been described with respect to FIGS. 1A-E and FIGS. 3A and 3B , in which the vacuum pickup systems 150 , 160 are described as part of the medicament filling system 1000 . However, the vacuum pick-up system 150', 160 may also be employed in other devices of its own right, which are not limited to the filling system shown in FIGS. Applications of some other embodiments include, but are not limited to, lyophilizing systems. It can be applied to any suitable nest of any objects arranged in a predetermined pattern. Further, while the system 1000 shown in FIGS. 1A-1E employs a rotating stage 130, the reconfigurable pickup system 150' may employ any suitable mobility platform including suitable fiducial positioning apertures. .

The method described above with reference to FIGS. 2A and 2B can now be described in more detail with reference to FIGS. 3A and 3B as well. Providing at least one vacuum pickup system as part of providing a charging device ([2010]) may comprise providing at least one reconfigurable vacuum pickup system 150', wherein the at least one Reconfigurable vacuum pickup system 150' includes multiple sets of sucker cups 152a', 152b'.

Providing a charging device ([2010]) may include providing a rotating stage 130 having a destination reference positioning opening 136 and at least two origin reference positioning openings 132 , 134 . and each origin reference positioning opening includes at least one pair of reconfigurable stopping members 149 and constraining members 139 .

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

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

The actuating ([2050]) at least one vacuum pick-up system 150', 160' comprises at least one reconfigurable vacuum pick-up system 150', 160' arranged to engage with the container nest 500. configuring to select a first predetermined set of sucker cups.

Actuating one of the at least one vacuum pick-up system 150', 160' ([2070]) arranges the at least one vacuum pick-up system 150', 160' to engage the container closure nest 600. and configuring to select a predetermined second set of sucker cups.

The method comprises at least one comprising a first set of sucker cups engaged with a container nest (500) and designed to simultaneously remove the container nest (500) and container closure nest (600) from the ramming system (180). operating [2095] the vacuum pickup systems 150', 160').

As an alternative embodiment to the arrangement of the vacuum pickup system 150, 160 shown in Fig. 1a, it has the form of a vacuum pickup system 150', 160'; An embodiment having the form of elements 135 , 45 , 139 , 149 in a disposition arrangement associated with a departure opening 132 , 134 is considered in FIGS. 3A and 3B . Attention is now directed to an alternative embodiment with respect to the arrangement for the destination opening 136 shown in FIGS. 1A and 3A . The close-up views in FIGS. 4A and 4B show the system of FIG. 3A with another embodiment in an arrangement around the destination opening 136 . 1A with rotation of the controller 400 and the rotation stage 130 to place the nest 500 at the opening 136 and the nest 600 on top of the nest 500 at the opening 136 , FIG. 1A . Although the cameras 210 and 220 of FIG. 4 may be employed, the adjustable destination reference positioning system of FIGS. 4A and 4B, including rotary positioning elements 164a, 164b, may include nests 600, 500) can be employed alternatively or in addition to accurately positioning.

Conventional industrial container nests are not manufactured to a dimensional standard, and as a result, any system for filling and closing a nested container 510 will not contain a nest of a different size with a container 510 ( 500) must have a mechanism that can accurately place it. For this purpose, rotational placement elements 164a, 164b may have different sets of paired placement surfaces 167a, 167b; 163a, 163b, such that certain dimensions are provided between such paired placement surfaces. Branch nests 500 can be precisely fitted. In FIG. 4B , nest 500 is adapted such that its two opposite ends having a first dimension may contact mutually opposing surfaces 167a and 167b of rotationally disposed elements 164a and 164b, respectively. Counter-rotating the rotationally positioning elements 164a , 164b about their respective axes 166a , 166b so that the surfaces 167a , 167b can face each other, thus providing a first dimension This allows nests of different lengths to be precisely placed between these surfaces.

As is clear from FIG. 4B , when surfaces 167a and 167b face each other, nests snugly disposed between these surfaces are, respectively, surfaces 165a and 165b of rotationally positioned elements 164a and 164b. By resting, it can be maintained in a precisely established vertical position. When surfaces 163a, 163b face each other, the other nests stably disposed on these surfaces will be seated on surfaces 16a, 161b of rotationally disposed elements 164a, 164b, respectively, to be maintained in precisely established vertical positions. can Rotational positioning elements 164a and 164b may be manually rotated about axes 166a and 166b, respectively. In some embodiments, rotation of rotational positioning elements 164a , 164b may be performed automatically by a motorized drive controlled by controller 400 and appropriate control software. This control may be based on predetermined dimensional data for a nest disposed between the surfaces of the rotationally disposed elements 164a, 164b. Such control may also be based on input data derived from imaging data obtained from cameras 210 and/or 220 . In addition, while rotating towards a position in which the surfaces face each other, rotationally positioning elements 164a , 164b destined for engagement with opposite ends of the nest 500 along a first dimension are provided on the nest 500 with a closing horizontal grip. This rotation may occur as the nest 500 descends into the interior of the position functioning as a grip). In this embodiment, the horizontal and vertical placement of the nests between the rotationally positioning elements 164a and 164b are not mutually independent.

As shown in FIGS. 4A and 4B , another arrangement with respect to the first dimension of the nest 500 may also be established for a second dimension of the nest 500 perpendicular to the first dimension. This allows any nest 500 disposed in the opening 136 to be accurately positioned in a preset position by the setting of the rotational positioning elements 164a and 164b.

Another embodiment for a rotating positioning element is shown in FIGS. 5A and 5B . Unlike the embodiment of Figures 4a and 4b just described above, in Figures 5a and 5b the horizontal and vertical placement of the nest between the two mutually anti-rotatable elements 164a', 164b' is arranged independently of each other. works This action is, for each of the two mutually perpendicular planar dimensions processed in the embodiment just described above, a pair of fixed opposing planar tabs that place the nest 500 within the perpendicular dimension. or fixed opposing planar tabs, 165a', 165b'), and a pair of rotating positioning elements 164a', 164b' that position the nest 500 in a first horizontal dimension. In this embodiment, rotationally positioning elements 164a', 164b' each have two rotatable elements ganged on mandrels 166a', 166b' to rotate in unison, respectively, and a boss. , 169a', 169b') with a mutual alignment ether side of the planar tabs 165a', 165b'. The set of rotating elements 164a', 164b', each separated into two co-operating elements, nest within the horizontal dimension in the same manner as the rotating elements 164a, 164b in the embodiment of FIGS. 4A and 4B just described above. (500) contributes to localization.

Although the rotating elements 164a', 164b' can be designed with more complex shapes, the surface 167a' of the rotating element 164a' and the surface 167b' of the rotating element 164b' in Figs. It shows a very simple implementation that contributes to placing the nest 500 within this first horizontal dimension. Rotate element 164a' coupled to mandrel 166a' counter-clockwise within boss 169a' and rotate element 164b' coupled to mandrel 166b' within boss 169b'. By rotating clockwise, the surfaces 163a', 163b' are made to face each other, and nests having different lengths within the first horizontal dimension are positioned between the rotating elements 164a', 164b' to be precisely positioned. can

Simultaneous elements 164a', 164b' may be manually rotated about the axes of mandrels 166a', 166b' inside bosses 169a', 169b', respectively. In some embodiments, rotation of elements 164a', 164b' may be performed automatically by a motorized drive controlled by controller 400 and suitable control software. Such control may be based on predetermined dimensional data relating to nests disposed between surfaces of elements 164a', 164b'. Further, such control may be based on input data derived from imaging data obtained from cameras 210 and/or 220 . Further, certain surfaces of the rotating positioning elements 164a', 164b' destined for engagement with opposite ends of the nest 500 along a first dimension along a first dimension rotate toward a position in which the specific surfaces of the positioning elements face each other. ), this rotation may occur as the nest 500 descends to function as a closing horizontal grip from above.

5a and 5b show another set of paired, mutually anti-rotatable rotationally positioning elements, which have not been referenced for clarity and have rotated elements 164a', 164b' ) and are arranged to precisely position the nest 500 independently in a first vertical dimension and a second planar dimension of the nest 500 perpendicular to the first dimension.

In another aspect, described with reference to FIG. 6 , a method is provided for filling a nested medicament container 510 with a fluid medicament substance, the method comprising a sterile chamber 100 capable of maintaining aseptic conditions. providing ([6010]) a charging system 1000 comprising: a chamber 100 having a charging station 170 and destination positioning structures 136, 164a, 164b, 164a' including a planar rotation stage 130; transferring ([6020]) at least one container tub 530 containing a container nest 500 sealed with a container tub cover 5320 and having a plurality of medicament containers 510 inside the chamber; aseptically sealing the chamber 100 ([6040]); establishing aseptic conditions inside the chamber 100 ([6050]); Transfer the container nest 500 having a plurality of medicament containers 510 into the interior of the destination positioning openings 136 , 164a , 164b , 164a ′, 164b ′, thereby holding the container nest 500 . in place) step ([6060]); and operating both the rotation stage 130 and the filling station 170 to dispense ([6070]) the fluid medicinal substance into at least some of the plurality of medicine containers 510. Operating the charging station 170 may include rotating the charging station 170 . The injecting of the fluid medicinal substance may include injecting the fluid medicinal substance into the container 510 in a repetitive and continuous manner.

Providing the charging system 1000 ( [6010]) may include providing a charging device comprising at least one cover removal station 140 within the chamber 100, the destination positioning structure The step of transferring the container tub 530 to the inside includes removing the container tub cover 520 from the container tub 530 by operating both the rotation stage 130 and the at least one cover removing station 140 . do. Operating the at least one cover removal station 140 may include rotating the at least one cover removal station 140 . Providing the filling system 1000 ([6010]) may include providing at least one cover removal station 140 having a fastening tool 142 inside the chamber 100, the chamber ( 100) The step of transferring the at least one container tub 530 to the inside may include attaching the cover removal fixture 540 to the container tub cover 520, and the at least one cover removal station 140 is installed. Actuating includes fastening the fastening tool 142 to the cover removal fixture 540 .

The method comprises the steps of transferring, into the chamber, a container closure tub 630 containing at least one container closure nest sealed with a container closure tub cover and having a plurality of medicament container closures 610 ([6030] ) may be further included. The method places one of the at least one container nests 600 such that the closures 510 in the at least one closing nest 600 and the corresponding containers 510 in the container nest 500 can be aligned. to ([6080]); rotating the rotating stage 130 to transfer the nests 500 and 600 of the aligned closure 610 and container 510 to the ramming station ([6090]); and forcing the closure 610 into the corresponding container 510 ([6100]). The method may further include adjusting the tub positioning structures 135 , 145 to accommodate the size of the closed nest tub 630 . The step of arranging one of the at least one closed nests 600 ([6080]) includes: obtaining image information about one closed nest among the at least one closed nests 600; and arranging one closed nest among at least one closed nest based on the image information. Placing one of the at least one closed nest ([6080]) includes: applying a vacuum to the sucker cups 162, 152a, 152b, 152a', 152b'; elevating the container closure nest (600) using a sucker cup; and operating the rotation stage 130 .

Transferring the container nest 500 into the interior of the destination positioning opening ([6020]) includes applying a vacuum with a sucker cup; elevating the container nest 500 using a sucker cup; and operating the rotation stage 130 . The method may further include selecting a set of sucker cups from among the plurality of sets of sucker cups, wherein applying a vacuum to the sucker cups is performed on the selected set of sucker cups. The selecting may include rotating a set of sucker cups from among the plurality of sets of sucker cups into position. The method may further include adjusting the destination positioning structures 136 , 164a , 164b , 164a ′, 164b ′ to accommodate the size of the container nest 500 . The adjusting may be performed in two at least generally orthogonal directions. The method may further include adjusting the tub positioning structures 139 , 149 to accommodate the size of the container nest tub 530 .

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

Providing includes providing a sterile medicament container 510 or closure 610 in a sealed container, eg, tub 530 or tub 630 , prior to decontamination. can do. The attaching step may occur before the container is provided within the controlled environment enclosure 100 . Decontamination of the sealed container within the suggested environmental enclosure 100 may occur prior to removing the cover 520 . Removing the cover 520 may include moving the fastening tool 142 relative to the container 530 . Removing the cover 520 may include moving both the container 530 and the fastening tool 142 . The method may further include attaching the cover removal fixture 540 to the cover 520 prior to providing the container 530 within the controlled environment enclosure.

7A is a diagram illustrating a subsystem of another embodiment of a device for filling a medicament container with a fluid medicament, based on the subsystems illustrated in FIGS. 1A , 1C , 1F , 5A and 5B ; For clarity, only the sterile hermetic chamber 100 of FIG. 1 ; the rotation stage 130 of FIGS. 1A and 1C ; As the container nest 500 with the medicament container 510 , several subsystems have been omitted so as to represent only the nest 500 held in position by the arrangement shown in FIG. 5B . In FIG. 7A , the charging arm 170 of FIG. 1A has been replaced by an articulated robotic charging arm 170 ′. Due to the alternative reference arrangement, nest 500 can be used if the opening of each container 510 can be known with adequate precision and precision in order to reliably dispense a droplet of fluid medicament into the container 510 . Any alternative reference arrangement for fixation may be employed.

In addition to the components mentioned above in FIG. 7A , a droplet monitoring subsystem 250 , shown separately in FIG. 7B , is added, which includes an illuminating imager system 252 , a mirror 254 . and a retroreflector 256 . Droplet monitoring subsystem 250 may be controlled by controller 400 , which distal controller 400 communicates with droplet monitoring subsystem 250 . The controller 400 may include a memory and a processor. As in the case of the filling arm 170 of FIGS. 1A and 1F , the articulated robotic filling arm 170 ′ supplies the fluid medication via the fluid medication delivery line 172 . In Figure 7A, a filling arm 170' is equipped with a fluid medication dispensing head 174'. The dispensing head 174 ′ is positioned and configured to dispense droplets of a fluid medicament that are within a limited range of a consistent volume and droplet shape capable of moving down along a droplet path 710 . For this purpose, the dispenser head 174' may be equipped with a suitable nozzle. The controller 400 may control the dispensing behavior of the dispenser head 174', wherein the dispensing controller 400 is the dispenser head 174', or a pump that supplies the fluid medicament to the dispenser head 174'. can communicate with The imaging system 252 may include a telecentric lens, such that the imaging system 252 provides constant size measurements of the droplets produced by the dispenser head 174'. it becomes possible

Illuminated imager system 252 illuminates retroreflector 254 , and droplet 700 that is dispensed by dispenser head 174 ′ and travels along droplet path 710 into any container 510 . arranged and arranged to acquire high-speed images of 7A and 7B, the line a-a' represents a light beam path. Since the rotation stage 130 moves all containers 510 along a circular path around the rotation axis of the rotation stage 130 , the articulated robotic filling arm 170 ′ operates, causing the droplet monitoring system 250 to operate. ) moves the dispenser head 174' along a linear trajectory following the imaging path a-a'. Thus, in this embodiment, both the rotating stage 130 and the articulated robotic filling arm 170' operate to position any container 510 so that it can be filled by the dispenser head 174'. In addition to the operation of the rotary stage 130 , any operation of the charging arm 170 ′ may be controlled via the controller 400 . For this purpose, the controller 400 communicates with both the charging arm 170 ′ and the rotating stage 130 , so that the controller 400 can coordinate the motion of the charging arm 170 ′ and the rotating stage 130 .

When executed by the processor, loaded into the memory of the controller 400 , controlling the dispensing of the fluid medicament droplet by the fluid medicament dispensing head 174 ′, and along the fluidic path 710 , the fluid medicament droplet 700 . Software may be provided to collect images of The software also enables the controller 400 to control the robot charging arm 170 ′ and the rotating stage 130 .

The alternative embodiment shown in Figure 8 shows another articulated robotic filling arm 170" into which an alternative droplet monitoring system 250' is integrated. This particular embodiment includes: It employs two mirrors 245', 258' along an illumination imaging system 252' and a retroreflector 256' We reserve the same reference number, ie, 174 for the divider head. ', 172 for fluid medication delivery lines. Illuminated imaging system 252' illuminates retroreflector 256' and dispenses by dispenser head 174' via mirrors 254', 258'. and arranged to acquire a high-speed image of a droplet 700 moving along a droplet path 710 and into any container 510. In this particular embodiment, filling by the dispenser head 174' In order to place any container 510 fixed to the nest 500 for this purpose, only the articulated robot charging arm 170 " needs to be operated, and the filling of all containers 510 fixed to the nest 500 is performed. During deployment, the rotating stage 130 may be held stationary. In a more general case, both the rotating stage 130 and the articulated robot filling arm 170" are operative to place any container 510 for filling by the dispenser head 174'. The rotating stage ( In addition to the operation of 130 , any operation of charging arm 170 ″ may be controlled via controller 400 . For this purpose, the controller 400 may communicate with both the charging arm 170" and the rotating stage 130. The imaging system 252' may include a telecentric lens, and thus the imaging System 252' may enable constant size measurement of droplets produced by dispenser head 174'.

The use of the droplet monitoring system of the present invention is not limited to the rotating stage medicament filling system of FIGS. 1A-8 . They can also be employed in any system in which any fluid, whether nested or not, is dispensed dropwise into a container. One group of filling systems suitable for filling a medicament container with a fluid medicament in a sterile chamber using the droplet monitoring system of the present invention employs a robotic arm that grips the container by an appropriate end-effector. do. The robot arm may be an articulated robot arm, and may be hermetically sealed in the chamber 100 . Suitable examples of such systems are, for example, US Patent Publication No. 2017/121046 A1, US Patent Application Publication No. 2016/2000461 A1, US Patent Application Publication No. 2016/0184986 A1, the disclosures of which are all incorporated herein by reference, in their entirety. US Patent Publication No. 2016/0346777 A1 and US Patent Application Publication No. 2014/0196411 A1. We describe below an embodiment of the droplet monitoring system of the present invention for use with a joint arm of the type described in more detail in these four listed published patents.

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

FIG. 10 shows the droplet monitoring system 250 ′ of FIG. 8 , which is employed in the same medicament container filling system described in FIG. 9 . The controller 400' may also be used to control the droplet monitoring system 250', for this purpose the controller communicates with the droplet monitoring system 250'.

In another embodiment of the system, both the dispensing head 174 ′ and the container(s) 510 are robotic arms 170 , 170 ′ on the one hand and robotic arms 800 on the other hand. It can be transmitted by cancer. Either or both robotic arms may be articulated robotic arms of the type described in the incorporated United States Patent Publications listed above. In another embodiment, the dispensing head 174 ′ and the container 510 may be disposed in a fixed position, for example, these particular embodiments relate to filling a single container 510 at a time.

The embodiments shown in FIGS. 7A, 7B, 8, 9 and 10 all employ retroreflectors 256 , 256 ′ illuminated from a light source housed in an illuminated digital imager system 252 . In other embodiments, droplet 700 may be backlit or illuminated from any other angle. In such embodiments, the imaging unit system may not require an integrated illuminator, and the illuminator may be located elsewhere separate from the imaging unit.

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

In some embodiments, the method may further include stopping dispensing of the fluid medicament based on the volume of the fluid medicament struggled into the container 510 ([3070]). In other embodiments, the step of stopping may be based on the length of time of dispensing of the fluid medicament into the container 510 , or based on weighting the amount of the fluid medicament dispensed into the container 510 . there is. Accordingly, the droplet information obtained from the imaging unit is used as a method for controlling the fluid drug dispensing process, such as when only monitoring the fluid drug dispensing process, or when forming the basis for the stopping step ([3070]), can be used

Determining the volume of the fluid medicine dispensed into the container 510 from the plurality of images ([3060]) may include determining the volume of at least one droplet among the plurality of droplets 700. The step of determining the volume of at least one droplet among the plurality of droplets 700 includes at least one droplet ( identifying first and second total portions of 700; At least one of the plurality of droplets 700 by mathematically rotating the first and second entire portions of the droplet 700 through 2π about the droplet path respectively separately calculating first and second volumes of the enemy; and equating the volume of at least one droplet among the plurality of droplets 700 with an average of the first and second volumes. To describe the entire side-on planar view of a droplet to the left or right of the droplet path 710 , the term “total portion” is used herein. The two overall portions of a droplet will generally not be completely identical. Two planar whole parts, approximately 'halves', are then taken and rotated separately in software about droplet path 710 to obtain two "droplet volumes", which are then The volumes are averaged to obtain the estimated volume of the droplet.

In the step of acquiring a plurality of images of at least one droplet from among the plurality of droplets 700 along the droplet path from the imaging units 252 and 252' ([3050]), the droplet 700 has a stable shape at the top thereof. and acquiring a plurality of images over a predetermined portion of the droplet path. Herein, when the droplet is distinctly detached from the dispensing head 174' and is assumed to be a shape defined by a predetermined perimeter as seen by the imaging unit, the shape of the droplet is (shape) can be considered "stable", the shape of which can vary widely within the perimeter of that setting.

Determining the volume of the fluid medicine dispensed into the container 510 from a plurality of images ([3060]) may include determining the volume of each droplet 700 dispensed into the container 510. . In the step of stopping dispensing of the fluid medicament based on the volume of the fluid medicament dispensed into the container 510, the total amount of the fluid medicament dispensed into the container 510 is the same as the set volume. It may include stopping dispensing of the medicament. For example, the set volume may be, but is not limited to, a single adult human dosage volume of the fluid medicament. Other established volumes may be doses or integer multiplies of doses specified by the health authority, regulatory body, or MDDS sheet of the fluid medicament in question.

In another embodiment, determining the volume of the fluid medicament dispensed into the container from a plurality of images ([3060]) includes determining a representative volume of the droplet 700 and the container 510 interior counting the total number of droplets dispensed into Determining a representative volume of droplet 700 may include merely measuring the first droplet and estimating it representative. In other embodiments, determining the representative volume of droplet 700 may include measuring a plurality of droplets and calculating an average droplet volume across the plurality of droplets.

The step ([3050]) of acquiring a plurality of images of one droplet from among the plurality of droplets 700 along the droplet path 710 from the imaging units 252 and 252' is to the retroreflectors 256 and 256'. and acquiring a plurality of images by adopting the light reflected by the image unit. Acquiring a plurality of images of at least one droplet from among the plurality of droplets 700 along the droplet path 710 from the imaging units 252 and 252 ′ includes acquiring a plurality of images by using a telecentric lens. may include A telecentric lens may be integrated into the imaging sections 252 and 252'. The step of providing the sterile fluid medicament inside the sterile chambers 100 and 100 ′ may include providing the sterile fluid medicament inside the container nest 500 .

The method includes moving at least one of the dispensing head 174' and the container 510 to receive the droplet 700 along the droplet path 710 by moving the container ( It may further include disposing the opening of 510 ( [3035]). Moving the container may include operating the robot arm 800 . Moving the container 510 may include moving the container nest 500 holding the container 510 . Actuating the robotic arm 800 may include operating the articulated robotic arm. Moving the dispensing head 174' may include operating the robot arms 170', 170". Moving the dispensing head 174' may include the articulated robotic arm 170', 170").

7A, 7B, 8, 9 and 10, the controller 400, 400' is also in communication with the dispensing head 174', or a pump that supplies fluid medicament to the dispensing head, such that the controller 400, 400' controls the flow of droplets through the dispensing head 174', and may turn the flow on or off. For the sake of clarity, these lines of communication are not shown in Figures 7a, 7b, 8, 9 and 10.

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

Claims (29)

A method for aseptically dispensing a predetermined amount of a fluid medicament into a medicament container using a processor in a device specially adapted for bringing the medicament into particular physical or administering forms ,
providing a sterile chamber capable of maintaining aseptic conditions, the chamber comprising: a fluid medicament dispensing head configured to produce droplets of the fluid medicament; a digital imaging unit and a processor; comprising a droplet monitoring system comprising a;
establishing aseptic conditions within the sterile chamber;
providing a sterile medicament container within the sterile chamber;
initiating dispensing of a plurality of fluid medicament droplets from the dispensing head to the interior of the container along a droplet path;
acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from an imager; and
Determining whether a fluid medicament of a set volume has been dispensed into the container from the plurality of images, including the step of the processor determining the volume of at least one droplet among a plurality of droplets; stopping dispensing when a volume of fluid medicament has been dispensed into the container;
Determining the volume of at least one droplet among the plurality of droplets includes:
identifying first and second total portions of the at least one droplet displayed on the left or right side of the droplet path, respectively, within the at least one image for the at least one droplet;
first and second portions of at least one of the plurality of droplets by separately mathematically rotating the first and second entire portions of the droplet through 2π about the droplet path, respectively. calculating the volume;
equating a droplet volume of at least one of the plurality of droplets to an average of the first and second volumes. The method of claim 1,
Acquiring the plurality of images of at least one of the plurality of droplets along the droplet path from the imaging unit includes acquiring the plurality of images over a predetermined portion of the droplet path How to. 3. The method of claim 2,
Acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from the imaging unit,
determining, from the plurality of images, a portion of the droplet path in which the droplet has a stable shape;
and selecting at least one image of the at least one droplet from an acquired droplet image when the droplet is in a part of a droplet path having a stable shape. The method of claim 1,
The determining of the volume of the fluid medicament dispensed into the container from the plurality of images includes determining the volume of each droplet dispensed into the container. The method of claim 1,
The step of acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from the image unit may include: A method comprising the step of obtaining. The method of claim 1,
Acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from the imaging unit includes acquiring the plurality of images using a telecentric lens method. The method of claim 1,
disposing an opening in the container under the dispensing head to move at least one of the dispensing head and the container to receive the droplet along a droplet path. 8. The method of claim 7,
wherein moving at least one of the dispensing head and the container comprises actuating an articulated robotic arm. 8. The method of claim 7,
Wherein moving the container comprises moving a container nest holding the container. The method of claim 1,
The step of providing a sterile medicament container inside the sterile chamber comprises providing the sterile medicament container inside a container nest. A method for aseptically dispensing a fluid medicament into a medicament container, the method comprising:
providing a sterile chamber capable of maintaining aseptic conditions, the chamber comprising: a fluid medicament dispensing head configured to produce droplets of the fluid medicament; and a digital imaging unit; comprising a droplet monitoring system;
establishing aseptic conditions within the sterile chamber;
providing a sterile medicament container within the sterile chamber;
initiating dispensing of a plurality of fluid medicament droplets from the dispensing head to the interior of the container along a droplet path;
acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from an imager; and
determining the volume of the fluid medicament dispensed into the container from the plurality of images by determining the volume of at least one droplet among the plurality of droplets,
Determining the volume of the fluid medicament dispensed into the container comprises:
identifying first and second total portions of the at least one droplet displayed on the left or right side of the droplet path, respectively, within the at least one image for the at least one droplet;
first and second portions of at least one of the plurality of droplets by separately mathematically rotating the first and second entire portions of the droplet through 2π about the droplet path, respectively. calculating the volume;
equating a droplet volume of at least one of the plurality of droplets to an average of the first and second volumes. 12. The method of claim 11,
Acquiring the plurality of images of at least one of the plurality of droplets along the droplet path from the imaging unit includes acquiring the plurality of images over a predetermined portion of the droplet path How to. 12. The method of claim 11,
Acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from the imaging unit,
determining, from the plurality of images, a portion of the droplet path in which the droplet has a stable shape;
and selecting at least one image of the at least one droplet from an acquired droplet image when the droplet is in a part of a droplet path having a stable shape. 12. The method of claim 11,
The determining of the volume of the fluid medicament dispensed into the container from the plurality of images includes determining the volume of each droplet dispensed into the container. 12. The method of claim 11,
In the step of stopping dispensing of the fluid medicament based on the volume of the fluid medicament dispensed into the container, when the total amount of the fluid medicament dispensed into the container is the same as the set volume, dispensing of the fluid medicament A method comprising the step of aborting. 12. The method of claim 11,
The step of acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from the image unit may include: A method comprising the step of obtaining. 12. The method of claim 11,
Acquiring a plurality of images of at least one droplet from among the plurality of droplets along the droplet path from the imaging unit includes acquiring the plurality of images using a telecentric lens method. 12. The method of claim 11,
disposing an opening in the container under the dispensing head to move at least one of the dispensing head and the container to receive the droplet along a droplet path. 19. The method of claim 18,
wherein moving the container comprises actuating a robotic arm. 20. The method of claim 19,
wherein actuating the robotic arm comprises actuating the articulated robotic arm. 19. The method of claim 18,
Wherein moving the container comprises moving a container nest holding the container. 19. The method of claim 18,
wherein moving the dispensing head comprises actuating a robotic arm. 23. The method of claim 22,
wherein actuating the robotic arm comprises actuating the articulated robotic arm. 12. The method of claim 11,
The step of providing a sterile medicament container inside the sterile chamber comprises providing the sterile medicament container inside a container nest. 12. The method of claim 11,
and stopping dispensing of the fluid medicament based on the volume of the fluid medicament dispensed into the container. delete delete delete delete

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