KR20200066667A - Apparatus and method for monitoring and controlling the filling of a container with fluid medicine in a sterile environment - Google Patents

Abstract

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

Description

Apparatus and method for monitoring and controlling the filling of a container with fluid medicine in a sterile environment

The present invention relates to the field of medicine exemplified by IPC classification A61, and more particularly, for administrative reasons, including the transfer of a drug to a medical or veterinary patient, a device for sterilization and sterilization of a container for pharmaceutical substances and drugs And linked methods. In one aspect, the present invention relates to the programmed and automated operation of such devices configured and arranged to fill a medicament container with a predetermined amount of liquid or other material.

The subject of filling pharmaceuticals into pharmaceutical containers is a major aspect of the pharmaceutical industry. The above tasks are strictly controlled by various government agencies and public institutions in various countries. Technically, the challenge is challenging in that pharmaceutical products need to be filled into containers under very strict aseptic conditions. Very specific procedures are specified for these operations, to the extent that the treatment of pharmaceuticals is very different, especially compared to the treatment of other industrial products, including semiconductors, which also require extreme and consistent environmental conditions. In fact, the parallels between handling semiconductors in semiconductor "clean rooms" and treating medicines in aseptic isolators are superficial. It is common for all of them to use a "clean room", but there are no inherent sterility requirements associated with semiconductor manufacturing.

The filling of the medicine container with a fluid medicine requires special treatment of both the container and the fluid medicine itself aseptically. This results in complex mechanisms and procedures, many of which can be automated to one degree or another. Often, manufacturing equipment for fluid pharmaceutical processing is bulky and expensive. This leads to problems related to smaller jobs, especially small production and development environments. As technology in the related art advances, the need for smaller and more compact devices, especially for filling and compounding fluids, becomes clear.

The prior art is usually characterized by the use of vibratory bowls and escapements. In addition, many prior art systems employ gloves used by the operator to allow access to the interior of the chamber.

In one overall aspect, the present 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 provides a filling system comprising a sterile chamber capable of maintaining sterile 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 a. The method also includes transporting at least one container tub inside the chamber, wherein the at least one container tub is sealed by a container tub cover and has multiple medicinal containers. It also includes a container nest, aseptically sealing the chamber, and establishing aseptic conditions inside the chamber. The container nest having a plurality of medicinal containers is transported inside the destination reference positioning structure, the container nest is held in place by the restraining surface, and both the rotating stage and the filling station are operated, A fluid pharmaceutical substance is dispensed into the interior of at least some of the pharmaceutical containers.

In certain embodiments, operating the charging station may include rotating the charging station. The step of dispensing the fluid medicinal material may include dispensing the fluid medicinal material inside the container on an iterative and serial basis. Providing a filling system includes providing a filling device including at least one cover removal station inside the chamber, and transferring the container nest into a destination reference positioning structure comprises: the rotating stage And operating 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 transferring the at least one container tub into the chamber comprises removing the cover And attaching to the container tub cover, and operating the at least one cover removal station can include fastening the fastening tool with the cover removal fixture.

The method may further include conveying a container closed tub into the chamber that is sealed by a container closed tub cover and includes at least one container closed nest having multiple medicinal container closures. The method comprises disposing one of the at least one closed nest among the at least one closed nest to align the closure within the at least one closed nest with the corresponding container in the container nest, and rotating the rotating stage, The method may further include conveying the nest of the aligned closure and the container to a ramming station, and forcing the closure into the corresponding container. The step of disposing one closed nest among at least one closed nest may include obtaining image information for one closed nest among the at least one closed nest, and among the at least one closed nest based on the image information. And disposing one closed nest.

Disposing one of the at least one closed nest among the at least one closed nest may include applying a vacuum to the sucker cup, elevating the container closed nest using the sucker cup, and operating the rotating stage. It may include. The step of transferring the container nest to the interior of the destination positioning opening includes applying a vacuum to the sucker cup, lifting and lowering the container nest using the sucker cup, and operating the rotating stage. It can contain. Dispensing the fluid medicament material may include operating the rotating stage and the filling station simultaneously and/or continuously, wherein removing the container tub cover comprises rotating the stage and at least one cover removal station. It may include the step of operating simultaneously and / or continuously.

In another overall aspect, the present invention features a system comprising a sterile chamber capable of maintaining sterile conditions as a system for filling a nested medicinal container with a fluid medicinal material. The chamber is a destination reference position including a filling station and a constraining surface having a shape and arranged to receive and fix a medicine container nest having a plurality of medicine containers as a plane rotation stage having a rotation stage rotation axis. And a planar rotating stage comprising a setting structure.

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

The at least one cover removal station may rotate about a cover removal rotation axis parallel to the rotation stage rotation axis, and in combination with rotation of the rotation stage, the container tub cover from the at least one container tub, It can be arranged and configured to remove the container closed tub cover from the container closed tub. The at least one cover removal station can include a fastening tool, and the fastening tool can be arranged and configured to engage a fastening fixture pre-attached to the container tub cover and the container closed tub cover.

The system further includes at least one camera and a controller arranged to acquire image information for at least one of the container nest and the closed nest, and the chamber is arranged to engage with the container nest and the container closed nest. And at least one vacuum pick-up system including a sucker cup, wherein the at least one vacuum pick-up system, under the control of the controller, in combination with the rotation of the rotating stage is the at least one second starting reference positioning The medicine container nest is lifted from a medicine container tub fixed to one of the openings, and the medicine container is deposited in the destination-based positioning opening in combination with the rotation of the rotating stage, and the first origin reference The medicine container closing nest is lifted from the medicine container closing tub fixed to the positioning opening, and the container closing nest can be deposited on 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, and the controller is configured to rotate the rotating stage so as to place the closure in the closed nest corresponding to a container in the container nest. It can operate to control the rotation. The system may further include a ram system configured to force the closure into the interior of the corresponding container.

The system includes at least one rotary cover removal station having a cover removal station rotation axis parallel to the rotation stage rotation axis, and the container on the container nest so that the closure portion of the container closure nest corresponds to a container in the container nest. And at least one vacuum pickup system for placing the closed nest, and a ram system for forcing the closure into the interior of the container, wherein the filling station rotates a filling station parallel to the rotating stage rotation axis. It may be a rotary filling station having an axis and including a fluid dispensing head. The system may further include a controller including at least one camera, a memory, and a processor for acquiring at least one image information from the container nest and the closed nest. The controller instructs the rotating stage to rotate to an angular position that is one of the preset and based on the image information, and works in conjunction with the rotating stage to remove the at least one cover removal station and the charging station. , To control the at least one vacuum pickup system and the ram system.

In another overall aspect, the present invention is a system for filling a nested medicinal container with a fluid medicinal substance, a means for establishing and maintaining sterile conditions in the chamber, a container nest having multiple medicinal containers in the chamber And means for transporting the container nest from the container tub to the restraining means in the chamber. The system may also be configured to rotate the means for constraining within the chamber, and while the container nest is constrained by the means for constraining, the container nest to the interior of at least some of the medicament containers from among multiple medicament containers. And means for dispensing the fluid medicinal substance.

In another aspect, a system for filling a nested medicinal container with a fluid medicinal material is provided, the system comprising a sterile chamber capable of maintaining sterile conditions, the chamber comprising a rotating stage A planar rotation stage having an axis of rotation, and a plurality of locating structures disposed with respect to the rotation stage at different positions about the axis of rotation of the rotation stage, different from the rotation stage axis of rotation Positioning structure for holding the nest of pharmaceutical container parts at a position, and while the medicine container part is fixed in the nest in one positioning structure among the positioning structures, filling the medicine container part It includes a container filling station having a dispensing head for doing so. The positioning structure comprises a surface associated with first tub-holing openings in the rotating stage to grip a first tub comprising at least one nest of the container portion, To grip a second tub comprising at least one nest of closures, to grip a surface associated with a second tub grip opening in the rotating stage, and to grip at least one nest, the And a surface associated with the destination nest-phage opening in the rotating stage.

The chamber may further include at least one vacuum pickup system including a sucker cup disposed to engage the container nest and the container closing nest fixed on the rotating stage, wherein the at least one pickup system is the rotating Configured to in combination with the rotation of the stage, elevating the medication container nest from the medication container tub, and in combination with the rotation of the rotation stage to deposit the medication container nest in the destination opening, medication The medicine container closing nest is lifted from the container closing portion, and the medicine container closing nest is deposited on top of the medicine container nest.

At least one positioning structure among the positioning structures may include a reconfigurable positioning structure having one or more adjustable positioning surfaces for placing the tub relative to the rotating stage. The reconfigurable positioning structure is configured to preset a tub comprising at least one pair of reconfigurable stopping members and opposite ends across the opening in the rotating stage, the tub including at least one nest. It may include a restraining member that is precisely placed in a first predetermined position. The stopping member may be adjusted to stop the tub at the first preset position by rotary adjustment, and the restraining member may restrain the tub within the preset first position Can be deployed.

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

At least one reconfigurable positioning structure among the reconfigurable positioning structures faces at least a first pair of defining a positioning surface that faces each other along a first positioning axis that is at least entirely parallel to a surface of the rotating stage. At least a second pair of opposing positions defining a positioning element and a mutually opposite positioning surface along a second positioning axis at least entirely perpendicular to the first positioning axis and parallel to a surface of the rotating stage Decision elements may be included. At least one of the positioning elements in each of the first and second pair of positioning elements has a rotation axis parallel to a surface of the rotating stage and comprises a number of different positioning surfaces It may include a rotating positioning element.

The system may further include a reconfigurable vacuum pick-up system, wherein the reconfigurable vacuum pick-up system includes: a first set of sucker cups arranged in a first pattern and a second pattern different from the first pattern. The first set of sucker cups or the second set of sucker cups while two sets of sucker cups and at least one nest among the nests of the medicine container portion are fixed by one of the plurality of positioning structures It may include a selection mechanism (operative to position) that is arranged to engage with at least one of the nests of the medicine container portion (operative to position). The selection mechanism of the reconfigurable vacuum pick-up system may include a rotary mechanism operative to place the first set of sucker cups or the second set of sucker cups in a fastened position.

The system further comprises at least one cover removal station arranged to remove the cover from a tub containing at least one nest made of a pharmaceutical packaging material fixed within one of the positioning structures. It can contain. The at least one cover removal station can rotate about a rotation axis of the cover removal station parallel to the rotation stage rotation axis, thereby removing the tub cover in combination with rotation of the rotation stage. The at least one cover removal station may include an engagement tool that is disposed and configured to engage with the cover removal fixture on the tub cover.

The filling station can rotate about a filling station rotation axis parallel to the rotation stage rotation axis, so that the plurality of medicine containers held by one positioning structure among the positioning structures in combination with rotation of the rotation stage Dispensing head is placed on top of any one of the pharmaceutical containers.

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

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

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

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

In another aspect, a method for filling a nested medicinal container with a fluid medicinal material is provided, the method comprising providing a filling system comprising a sterile chamber capable of maintaining sterile conditions, wherein The chamber includes a filling station and a plane rotating stage having a destination positioning structure; Transferring at least one container tub, sealed by a container tub cover, including a container nest having a plurality of medicinal containers, into the chamber; Aseptically sealing the chamber; Establishing sterile conditions in the chamber; Fixing the container nest by transferring the container nest having the plurality of medicine containers into the destination positioning structure; And operating the rotating stage and the filling station to dispense the fluid medicinal substance into the interior of at least a portion of the medicament container among the plurality of medicinal containers. Operating the charging station may include rotating the charging station. The dispensing of the fluid medicinal material may include dispensing the fluid medicinal material into the container in a repetitive and continuous manner.

Providing the filling station includes providing a filling device including at least one cover removal station inside the chamber, and transferring the container tub into the destination positioning structure comprises: rotating And operating the 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. Providing the filling system may include providing at least one cover removal station having a fastening tool inside the chamber, and transferring at least one container tub inside the chamber may include providing a container tub cover. And attaching the cover removal fixture, and operating the at least one cover removal station can include fastening the fastening tool to the cover removal fixture.

The method may further include conveying the container closure tub containing at least one container closure nest sealed with a container closure tub cover and having a plurality of medicinal container closures into the chamber. The method comprises disposing one of the at least one closed nest among the at least one closed nest, and rotating the rotating stage so that the closure in the at least one closed nest and the corresponding container in the container nest are aligned. , Transporting the nest of the aligned closure and the container to a ramming station, and forcing the closure to the interior of the corresponding container. The method may further include adjusting the tub positioning structure to accommodate the size of the closed nest tub. The step of arranging one closed nest among the at least one closed nest may include obtaining image information of one closed nest among the at least one closed nest, and the at least one closed nest based on the image information. It may include the step of disposing one of the closed nest. Disposing one of the at least one closed nest among the at least one closed nest may include applying a vacuum to the sucker cup, elevating the container closed nest using the sucker cup, and operating the rotating stage. It may include.

The step of transferring the container nest to the interior of the destination positioning opening includes applying a vacuum to the sucker cup, lifting and lowering the container nest using the sucker cup, and operating the rotating stage. It can contain. The method may further include the step of selecting one sucker cup among the plurality of sets of sucker cups, and applying a vacuum to the sucker cup may be performed on the selected set of sucker cups. The step of selecting the one sucker cup may include rotating one sucker cup from the plurality of sets of sucker cups to an into position. The method may further include 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 two at least entirely orthogonal directions. The method may further include adjusting the tub positioning structure to accommodate the size of the container nest tub.

In yet another overall aspect, the present invention features a container assembly for gripping a nested medicinal container portion. The container assembly includes a container, the container comprising a bottom, a top lip providing a horizontal top sealing surface having a peripheral outline, and the bottom And a side wall located between the upper lip. The container assembly also includes a peelable container cover made of 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 peelable container cover may include a portion that extends outwardly of the peripheral contour of the upper sealing surface of the container, and 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 peelable container cover extending to. The container is rectangular, and may include four side walls. The cover removal fixing part may include an appendage that enables the cover removal fixing part to be fastened by a fastening tool. The cover removal fixing part may include a ballshaped appendage that enables the cover removal fixing part to be fastened by a fastening tool. The peelable container cover is heat sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination. The peelable container cover is sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using a chemical agent. The peelable container cover is sealed to the sealing surface of the upper lip of the rectangular container to seal the contents of the container against decontamination using irradiation. The peelable container cover is sealed on 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 polymer membrane. The cover removal fixing part may be clipped to a portion of the peelable container cover that extends outwardly of the peripheral contour of the upper sealing surface of the container. The sealed container can accommodate a sterile pharmaceutical container or closure.

In another aspect, there is provided a method for removing a container cover from a sealed container in a controlled environment enclosure, wherein the sealed container is sealed by the container cover, the method comprising: Providing the cover sealed to the sealing surface of the lip of the container, so as to seal the container's contents against decontamination within the enclosure, the cover having a cover removal fixture; Decontaminating the sealed container, in 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 step may include fastening the cover removal fixing part with a fork-shaped fastening tool. The fastening step may include fastening a ball-shaped appendage on the cover removal fixing part.

The providing step may include providing a sterilized medicinal container or closure in a sealed container prior to the step of removing the contamination. The attaching step can be performed before the container is placed in the controlled environment enclosure. Decontamination of the sealed container within the controlled environment enclosure may be performed prior to removing the cover. The step of removing the cover may include moving the fastening tool relative to the container. The step of 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 in the controlled environment enclosure.

In another aspect, a method for removing a cover from a tub sealed with a cover in a sterile environment is provided, the method comprising providing a sterile chamber capable of maintaining sterile conditions, the chamber comprising: Including a droplet monitoring system comprising a fluid medication dispensing head and a digital imaging unit configured to generate droplets of fluid medication; Establishing sterile conditions inside the sterile chamber; Providing a sterile medicinal container inside the sterile chamber; Moving at least one of the dispensing head and the container to place an opening of the container under the dispensing head to accommodate 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 among the plurality of droplets along the droplet path from the imaging unit; And determining the volume of the fluid medicine 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.

Determining the volume of the fluid medicament dispensed into the container from the plurality of images may include determining a volume of at least one of the plurality of droplets. Determining the volume of at least one droplet from a plurality of droplets comprises: the first and second entire portions of the at least one droplet appearing on the left and right sides of the droplet path respectively in at least one image of the at least one droplet ( first and second total portions), and first and second whole portions of the droplets passing through the circumference around the droplet path are respectively mathematically rotated to first and second of at least one droplet among a plurality of droplets. And calculating a second volume and equating the volumes of at least one of the plurality of droplets to the average of the first and second volumes.

Acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit may include obtaining a plurality of images above a set portion of the droplet path. Optionally, acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit comprises: determining a portion of the droplet path from which the droplets have a stable shape; When the droplet is located in a part of the droplet path where the droplet has a stable shape, it may include the step of selecting from at least one image of the at least one droplet from among the images of the taken droplet.

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

The method may further include disposing at least one of the dispensing head and the container to place an opening of the container under the dispensing head receiving the droplet along the droplet path. The step of moving the container may include operating the robot arm. The step of moving the dispensing head may include operating the robot arm, which may be an articulated robot arm.

In another aspect, a system for aseptic dispensing of a fluid medicament into a container is provided, the system comprising: a sealable sterile chamber capable of maintaining sterile conditions; A fluid medication dispensing head configured to generate droplets of the fluid medication inside the chamber; A droplet monitoring system including a digital imaging unit disposed in the chamber to acquire a droplet image dispensed by the fluid medicine dispensing head; A controller comprising a memory and a processor, comprising: a controller in communication with the fluid medication dispensing head and the digital imaging unit; And software for controlling the dispensing of the fluid medicine droplet by the fluid medicine dispensing head. Includes configured software.

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

The system and method according to the invention need not employ vibratory bowls or escapes. In addition, the system and method do not require gloves. Accordingly, the system and method according to the present invention have a small space occupancy for fluid medicine, and can cope with the demand for small-scale filling and compounding.

By referring to the following description of the embodiments of the present invention together with the accompanying drawings, features and objects different from the above-described features and objects of the present invention, and the accompanying methods will be more clear, and the present invention itself is better Will be understood.
1A is a view showing an apparatus for filling a medicine container with a pharmaceutical fluid product. For clarity, some surfaces are shown with the inside visible, while others are shown transparently.
1B is a plan view of one chamber constituting the apparatus shown in FIG. 1A.
1C shows the rotating stage of the device shown in FIGS. 1A and 1B.
1D is a side view showing a part of the device shown in FIGS. 1A and 1B.
FIG. 1E shows a state in which the medicine container tub cover seated on the rotating stage of FIGS. 1A to 1E is removed.
1F shows a medicament container filled with a fluid medicinal material in the device of FIGS. 1A-1E.
1G is a view illustrating in more detail the cover removal component of the device shown in FIGS. 1A, 1B-1E.
2A and 2B combine to form a flow chart showing a method for aseptically filling a medicament container with a pharmaceutical fluid substance in a space-constrained environment.
3A is a diagram illustrating a subsystem according to another embodiment of an apparatus for filling a medicament container with a pharmaceutical fluid product.
FIG. 3B is a view showing a part of FIG. 3A in more detail.
4A is a diagram showing a subsystem according to another embodiment of an apparatus for filling a medicine container with a fluid medicine.
4B is a view showing a part of FIG. 4A in more detail.
5A is a diagram showing a subsystem according to another embodiment of an apparatus for filling a medicine container with a fluid medicine.
FIG. 5B is a view showing a part of FIG. 5A in more detail.
6 shows a flow chart of another method for filling a nested medicinal container with a fluid medicinal material.
7A is a diagram illustrating a subsystem according to another embodiment of an apparatus for filling a medicine container with a fluid medicine, based on the systems of FIGS. 5A and 5B.
7B is a diagram of a droplet monitoring system.
8 is a view showing a subsystem of another embodiment of an apparatus for filling a medicine container with a fluid medicine.
9 is a view showing a subsystem of another embodiment of an apparatus for filling a medicine container with a fluid medicine.
10 is a diagram showing a subsystem of another embodiment of an apparatus for filling a medicine container with a fluid medicine.
11 shows a flow chart of a method for sterile dispensing of a fluid medicament into a container.
In various drawings, corresponding reference numbers refer to corresponding parts. Although the drawings represent embodiments of the invention, the drawings are not necessarily drawn to scale, and certain features may be exaggerated to better illustrate and illustrate the invention. The flowchart is also representative in nature, and actual embodiments of the invention may include other features or steps not shown in the drawings. Although 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 in the precise form disclosed in the detailed description that follows. Rather, embodiments are selected and described so that those skilled in the art can use the teachings disclosed in the embodiments.

The present invention relates to an apparatus and method for filling a medicament container with a fluid medicinal substance in a spatially constrained environment. In FIG. 1A, the filling system 1000 includes a sealable chamber 100 in communication with the surrounding environment, wherein the sealable chamber 100 has an aseptic environment established therein. ), and maintain the sterile condition therein. The interior of the hermetic chamber 100 can be sterile by one or more of many treatment methods, including sterilizing agents such as steam, hydrogen peroxide, vapor, ozone, nitrogen dioxide and ethylene oxide. (sterilant) treatment. The structure and mechanism 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 separated from the sealing chamber 100 by the upper wall 110 and the lower wall 120, respectively, and it is not required to be able to maintain a sterile environment therein. Communication with the surrounding environment of the sealable chamber 100 may be performed through an appropriate aseptically sealable door 102 schematically indicated by broken lines in FIG. 1A. Suitable sealable doors and ports are well known in the art and will not be considered in more detail herein. For example, the surrounding environment may be a clean room that is tailored to handle medication while manufacturing the medication. In such a space-limited clean environment, space is valuable (at a premium), and there is a great advantage in reducing the so-called “footprint” of equipment that must be housed in this clean environment.

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

When introducing sterile conditions into the chamber, the sterile conditions present inside the chamber are compromised due to items whose surfaces are not properly sterilized. Conversely, even if sterile or sterilized items are introduced into a chamber that does not have aseptic conditions therein, the chamber interior does not become aseptic. Indeed, the sterile conditions of the surface of the introduced item are only damaged. Likewise, even if filtered air that filters out all biological entities enters the non-sterile chamber, it does not somehow sterilize the chamber or make the chamber sterile to the extent acceptable to the pharmaceutical industry. The reason is that the inner surface of the chamber is not sterilized by this inflow of air. What is achieved is that only filtered air is contaminated, with active biological species present on the inner surface of the non-sterile chamber.

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

In some prior art systems, containers introduced into the chamber for the purpose of filling with medicament are routed through a sterilizing subsystem. This kills biological species on the container. When the sterile container is introduced into the chamber when the chamber itself is not sterile, the container loses sterile conditions because biological species defined within the chamber will be deposited on the sterile container in advance.

"Class 100", "Class 10", or even when applying a laminar flow hood or a high efficiency Particulate Air (HPPA) filter or ULPA (Ultra Low Particulate Air) filter of any quality Medicine or semiconductor clean rooms of any quality level, including "Class 1", do not have the means to ensure that the surfaces of those clean rooms are sterile or sterile, so these clean rooms cannot constitute sterile chambers. It should also be mentioned. Standards for clean rooms exist from both the US federal government and the International Standards Organization (ISO). They define, as another standard, the allowable particle content in the cubic volume of air in such a clean room in great detail. None of these standards are examining the problem of biological species present on the surface in the cleanroom. This helps in arguing that the chamber cannot be sterile just by managing the atmosphere or air flow 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" written by Rutala et al. of the Centers for Disease Control and Prevention lists a summary of mechanisms and methods related to sterilization. Our interest in this specification is particularly to sterilize both of these mechanisms for sterilizing the interior of the chamber, ie the interior surface and atmosphere of the chamber. 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 sterile gases and vapors. In one suitable method suitable for the present invention, sterilization is carried out with hydrogen peroxide vapor and then flushed with ozone before the chamber is applied to fill the medicament container.

Subsystems of the device 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 the device 1000, certain components and subsystems are omitted in the drawings of FIGS. 1B-1C for the sake of brevity, and are most relevant to the text supported herein. The focus is on the components and subsystems. The planar rotary stage 130 can be rotated completely in full 360 degrees in a horizontal plane parallel to the lower wall 120 about the rotation stage rotation axis 131, and bellows feed-through , 190). Since the bellows feedsurr is used, the chamber 100 can maintain sterile conditions while the rotating stage 130 is operating. An appropriate engine and gearing system 320 may be accommodated inside 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 are described herein. Is not discussed further in.

As shown in FIG. 1C, the rotating stage 130 is provided with at least three fiducial locating openings 132, 134, 136. The reference positioning opening 132 includes a container tub 530 that holds the sterilized pharmaceutical container 510 pre-packed in a predetermined pattern within the container nest 500. It is applied to accommodate. The container barrel 530 is usually substantially rectangular, and is sealed with a peelable cover 520. Suppliers of pharmaceutical containers provide their products to users of the devices herein in this format. The reference positioning opening 134 is configured to receive container closure tubs 630 that hold the pre-packed sterile medicinal container closure 610 in a predetermined pattern in the container closure nest 600. Is applied. The container closing tube 630 is usually substantially rectangular, and is sealed with a peelable tub cover not shown in FIGS. 1A to 1G. The peelable cover of the container closing tub 630 is functionally the same as the peelable cover 520. Suppliers of pharmaceutical containers provide products of this type to users of the devices herein. For occupying a small space of the system 1000, the rectangular axis of the reference positioning openings 132, 134, 136, the rotating stage, so as to ensure an appropriately small radius relative to the rotating 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 the peelable tub cover 620 is described in United States Patent Application Publication US 2016/0200461, published on July 14, 2016, the disclosure of which is fully incorporated herein. Alternative cover gripping arrangements for removing a tub cover from a tub are disclosed in United States Published Patent Application US 2016 published September 1, 2016, the details of which are fully incorporated herein. /0251206 is also described. Removal of the tub cover can be controlled and monitored by the subsystems and methods described in PCT International Publication No. WO2018/049516 A1, published March 22, 2018, the disclosure of which is fully incorporated herein.

For clarity, FIGS. 1A-1G and related text to be described below indicate the use of a single tub 530 of the medication container 510 along a single tub 630 of the container closure 610. Indeed, a container closure 610 is provided as multiple nests 630 for one container closure tub 630. For this purpose, the rotating stage 130 has more than one, each of which receives each container tub among the container tubs 530 that receive the pre-packed sterile medicinal container 510 in the container nest 500. It may include a reference positioning opening (132). In other embodiments, there may be more than one nest 530 of containers 510 within a single medication container tub 530.

A reference positioning opening 136 is specially arranged to accommodate a container nest 500 having a medication container 510. The container tub 530 and the container closing tub 630 are naturally located in the reference positioning openings 132, 134, while suspended within their openings 132, 134 by their own rims. , The medicine container 510 is precisely positioned in the opening 136 and is retained in position by some other mechanism. For this purpose, the reference positioning opening 136 includes four fiducial retaining guides 137. As a loose component of the system 1000, the base plate 138 is located within the reference positioning opening 136 and seats in a horizontal area at the bottom of each of the four reference point fixation 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, the cover 520 is peeled from the container tub 530 in the reference positioning opening 132 (not visible) to expose the container nest 510 having the pharmaceutical container 530, but the reference positioning opening 136 ) Indicates an empty state. At this point when the system 1000 is operating, a cover similar to the cover 520 at the reference positioning opening 134 (not visible) is already peeled off from the closed container tub 630, having a container closure 610. The nest 600 is exposed. 1G shows a detailed view of an enlarged state in which the cover 520 is peeled off. The cover removal station 140 is rotatable about a rotation axis 144 of the cover removal station parallel to the rotation stage rotation axis 131, and includes an engagement tool 142. The fastening mechanism is fork-shaped to be fastened with a cover removal fixture 540 attached to the cover 520 in this particular embodiment. Before the container tub 530 is transferred 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 ball-shaped so that it can be fastened by a fastening mechanism 142. shaped appendage). Other combinations of cover removal fixtures and fasteners can be contemplated, and the system 1000 is not limited to a specific combination of cover removal fixtures and fasteners shown in FIGS. 1A, 1E, and 1G. For example, the cover removal fixture 540 can be manufactured as an integral part of the cover 520 for use in a charging system such as the charging system 1000. Alternatively, the cover removal fixing mechanism is disposed while being placed inside the tub 530 of the nest 500 having the container 530 and while being placed inside the tub 630 of the nest 600 having the container closure 610. The clip can be fixed to the cover 520.

The rotating stage 130 may be lowered to help obtain a less acute angle between the cover 520 and the tub 530. If it is too sharp, the cover 520 may be torn. With respect to removing the cover 520 due to the combined movement of the cover removal station 140 and the rotation stage 130, the cover removal station 140 may be rotated while the rotation stage 130 is rotating. By providing a path with less stress, the possibility that the cover 520 is torn is limited. In particular, when the container tub 530 is disposed within the reference positioning opening 132 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 can be rotated to guarantee.

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

In FIGS. 1A, 1B and 1F, a filling station 170 for filling the medicine container 510 with a pharmaceutical fluid product is applied to a fluid medicine dispensing head 174 (see FIG. 1F ). It contains a fluid medicine feed line (172) to be supplied. The charging station 170 can rotate about a charging station rotation axis 176 parallel to the rotation stage rotation axis 131. When the nest 500 is seated in the reference positioning opening 136, the filling station 170 is able to place the dispensing head 174 over the opening of any selected container 510 in the nest 500. The rotating stage 130 may rotate simultaneously or sequentially. Due to this, by the medicine dispensing head 174, all the containers 510 in the nest 500 can be filled with a fluid medicine. If the filling station is not engaged with the filling container 510, the filling station 170 can rotate to swing the dispensing head 174 in a direction away from the reference positioning opening 136, Accordingly, as the container closing portion 610 is disposed immediately above the opening of all the containers 510 present in the reference positioning opening 136, the nest 600 having the container closing portion 610 is nested ( 500).

Another term employed to describe the dispensing head 174 is "filling needle". Suitable filling needles and protective sheathing arrangements for such filling needles are disclosed in U.S. Patents, the disclosure of which is fully incorporated herein and published on December 1, 2016 and August 31, 2017, respectively. It is described in applications US 2016/0346777 and US 2017/0121046.

1A and 1B show two vacuum pickup systems 150 and 160, each of which includes a plurality of suction cups 152, 162 and FIG. 1B. The vacuum pickup system 150 is arranged to pick up the nest 500 of the containers 510 by the sucker cup 152, and the vacuum pickup system 160 is provided by the sucker cup 162 of the containers 610. It is arranged to pick up the nest 600. The vacuum pickup system 160 can be raised or lowered such that the sucker cup 162 can be engaged with another nest 600 of the container closure 610 contained within the tub 630 at different depths. Have it. For this purpose, the vacuum pick-up system 160 may include a bellows feedsurer capable of vertical movement while maintaining aseptic integrity of the chamber 100. An appropriate vacuum pump or vacuum line from a vacuum source outside the system 1000 can be connected to the vacuum pickup systems 150, 160 and ensure adequate vacuum in the sucker cups 152, 162.

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

The container closing ram system 180 shown in FIGS. 1A, 1B, and 1D is an upper ram plate 182 disposed above the rotating stage 130 inside the chamber 100. ), a lower ram plate (184) disposed under the rotating stage (130) inside the chamber (100), and a ram drive (310) located inside the chamber (300). . The ram driving unit 310 is arranged to drive the lower ram plate 184 through the bellows feed-through 186 toward the upper ram plate 182 in the vertical direction. When the loose base plate 138 of the reference positioning opening 136 is positioned above the lower ram plate 184 by the appropriately rotating rotating stage 130, the loose base plate 138 is the lower ram plate 184 ), and guided by a reference point fixing guide (137, see FIG. 1D) in the process. When the closing portion 610 in the closing nest 600 is finally pushed against the upper ram plate 182, the closing portion is forced into the openings of the container 510 in the nest 500. Due to this, a sandwich nest of the closed container 510 is generated. As shown in FIG. 1D, in the process, the nests 500 and 600 are pressed together, thereby creating a compound nest 500/600.

The controller 400 shown in FIGS. 1A and 1B can communicate with the rest of the components of the system 1000 through the control communication line 410, or physically inside the system 1000, for example inside the chamber 200. Can be included as The controller 400 may have a processor that includes appropriate memory and appropriate software programming instructions, which are intermittent for supplying fluid medication to the dispensing head 174 when loaded in memory executed by the processor. In addition to controlling on-and-off valving, movement of the ram system 180, vertical movement and rotation of the rotating stage 130, application of vacuum to the vacuum pickup systems 150, 160 , Controls any rotation or vertical movement required by the imaging operations by the cameras 210 and 220, vertical movement of the vacuum pickup system 160, cover removal station 140 and charging station 170. Appropriate valves and pumps, especially peristaltic pumps, required for the supply of fluid medicines to the dispensing head 174 are well known in the art and can be accommodated within the chamber 200 or located outside the system 1000. You 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 can typically be accommodated within the chamber 200 of the system 1000. When executed by the processor, the software pre-determined or instructs the rotating stage to rotate to an angular position based on image information obtained from the camera, and in particular with the rotating stage (in conjunction with) ) Control the cover removal station, filling station, vacuum pick-up system and ram system, so that they can work.

Now, with reference to the flow chart shown in FIG. 2A and the subsequent flow chart in FIG. 2B, a method for filling an enclosed medicinal container with a fluid medicament based on the system 1000 will be described. The method comprises providing a filling device 1000 comprising a sterile chamber 100 capable of maintaining sterile conditions ([2010]), wherein the chamber comprises at least a destination reference positioning opening 136. Rotation stage 130 with two source reference positioning openings 132, 134, charging station 170, at least one cover removal station 140, and horizontally oriented And including a container ramming system 180 and at least one vacuum pickup system (eg, 150 and/or 160). The method includes at least two container tubs 530 sealed with a container tub cover 520 and including a container nest 500 having a plurality of medicinal containers 510, at least two origin reference positioning openings 132 , 134) transferring at least the inside of the first opening ([2020]); And a container closed tub 630 sealed with a closed tub cover and including at least one container closed nest 600 having a plurality of medicinal container closures 610. ), the step of transferring to the inside of the second opening ([2025]).

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 includes removing at least one container tub cover 520 from at least one container tub 530 and removing at least one cover removal station 140 from the closed tub 630 so as to remove the closed nest 600. Operating the rotating stage 130 ([2040]); A rotating stage 130 and at least one vacuum pick-up system (e.g., 150 and/or) so that the container nest 500 having multiple medicament containers 510 can be transported to the destination reference positioning opening 136 Operating 160 ([2050]); And operating the rotating stage 130 and the filling station 170 to dispense fluid medicinal substances into the interior of at least some of the medicament containers of the multiple medicament containers 510 on an iterative and serial basis. The dispensing step ([2060]) is further included. Contrary to simultaneously, the term "repetitive and continuous" herein is used to describe the fact that the same operating steps are repeatedly used to fill various containers and that the containers are filled one after another. "Is adopted. In some embodiments, multiple containers can be filled simultaneously, using a filling station with multiple dispensing heads.

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

Operating the at least one cover removal station 140 ([2040]) includes a fastening tool (eg, tool 142) and a cover removal fixture (eg, high) pre-attached to the cover being removed. Government 540). Operating the at least one vacuum pickup system ([2050]) may include contacting the container nest 500 with multiple sucker cups 152 while applying vacuum to the sucker cup 152. have. Dispensing the fluid medicinal substance into the interior of at least some of the plurality of medicine containers ([2060]) is filled in an iterative and continuous manner over the opening of at least some of the medicine containers among the plurality of medicine containers 510 And disposing on the dispensing head 174 of the fluid product of the station 170. Operating the rotating stage 130 and one of the at least one vacuum pickup system ([2050]) acquires image information of the container nest 500 having a plurality of pharmaceutical containers 510, and the container nest 500 ) Operating the camera 210 to position one of the at least one vacuum pickup system on top.

The method operates at least one of the vacuum pick-up systems (eg, 150 and/or 160) and the rotating stage 130 to at least one container closure nest having multiple medicinal container closures 610 ( 500) to transfer one of the container closing nest to the destination reference positioning opening 136, and to arrange at least one closing nest 160 so that the closing portion 610 can align with the container 510 Step ([2070]); Operating the rotating stage 130 to place the aligned container nest 500 and the closed nest 600 together in the ramming system 180 ([2080]); And operating the ramming system to force the plurality of container closures 610 inside the plurality of containers 510 ([2090]).

Operating one of the at least one vacuum pickup system ([2070]) comprises contacting the container closing nest 600 with multiple sucker cups 162 while applying vacuum to the sucker cup 162. It can contain. Operating the ramming system ([2090]) may include driving a plurality of medication containers 510 toward the upper ram plate of the ramming system 180.

Operating one of the rotating stage 130 and the at least one vacuum pickup system ([2070]) comprises closing one of the containers from at least one container closure nest 600 having multiple medicinal container closures 610. Operating the camera 220 so as 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 closure nest 600. have.

The step of providing a charging device ([2010]) may further include a controller 400 and a software program that can be executed 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 one of the at least one vacuum pickup system 150 and/or 160 ([2070]); Operating a charging station; Any one or more of the steps of operating the ramming system 180 ([2090]) may be automatically executed by a software program in the controller.

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

In another embodiment, a plurality of steps of removing a container tub cover from at least one container tub 530; Removing the container tub cover from at least one container closure tub (630); Transferring the container nest 500 to a destination-based positioning opening 136; Dispensing a fluid medicinal substance into the interior of the medicine container 510; Transferring one of the at least one container closing nest (600) to the destination reference positioning opening (136); And arranging the container nest 500 and the closed nest 600 aligned with the ramming system 180 may include rotating the rotating stage having the container nest and the container closed nest.

In a general embodiment, removing the container tub cover from at least one container tub 9530; Removing the container tub cover from at least one container closure tub (630); Transferring the container nest 500 to a destination-based positioning opening 136; Dispensing a fluid medicinal substance into the interior of the medicine container 510; Transferring one of the at least one container closing nest (600) to the destination reference positioning opening (136); And arranging the container nest 500 and the closing nest 600 aligned with the ramming system 180, at least one of the steps may include rotating the rotating stage having the container nest and the container closing nest.

It should be noted that the filling system 1000 and the methods associated therewith do not need to employ vibrating vessels and escapements that are characteristic of the prior art. Unlike many prior art systems, the filling system 1000 also does not require the use of gloves for use by users accessing the interior of the chamber.

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

The system described above also employs fiducial openings defined on a rotating stage that accommodates multiple tubs and nests, but the system has sufficient constraining surfaces to accommodate tubs and nests. ) Other types of reference structures, including other configurations, may also be applied. For example, a notched post mounted on a rotating stage can receive a tub and/or nest 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 charging system according to the present invention may be identical in all respects to the embodiments described above with reference to FIGS. 1A and 1B, except for the vacuum pickup system(s) 150 or 160. 3A and 3B show part of a charging system as described above. In particular, FIG. 3B focuses on one entire area of the vacuum pickup system, 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 can likewise be replaced with a reconfigurable vacuum pickup system 160' having the same arrangement as the vacuum pickup system 150'. For clarity, the vacuum pickup system 160' is not shown in FIGS. 3A and 3B. In another embodiment, a single reconfigurable vacuum pick-up system 150' can be employed to pick up both the container nest and the container closed nest. The vacuum pickup system 150 ′ can access the container nest and the container closing nest by rotation of the rotating 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 the sucker cups 152a', 152b'. Further, the vacuum pickup system 150' may be arranged to lift the nest 600 of the container closure portion 610 by sucker cups 152a' and 152b'. As with the vacuum pickup system 150, the sucker cups 152a', 152b' can be fastened to other nests 600 of the container closure 610 contained while having different depths inside the tub 530. , The vacuum pickup system 150 ′ may 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', which are arranged linearly. Each set of 152a', 152b') is arranged at a different angle perpendicular to the longitudinal axis of the rotating arms 154a', 154b'. Due to this arrangement, the rotating arms 154a', 154b' can rotate around their transverse axes, and a different set of linearly arranged sucker cups 152a', 152b' can be placed on the other nest 500 of the container 510. It can be oriented to be fastened with (oriented). Due to this arrangement, the set of sucker cups 152a', 152b' can be individually selected for use. The rotation of the rotating arms 154a' and 154b' can be performed manually. In another embodiment, the rotation 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.

A different set is selected from the sucker cups 152a' and 152b' that are linearly arranged through rotation of the rotating arms 154a' and 154b', so that the sucker cups 152a' and 152b' of that set are the containers 510. It may be arranged to be fastened with another container nest 500 having a container closure container 600 having a container closure portion 610.

3A and 3B show the vacuum pickup system 150' as including two rotating arms, ie rotating arms 154a' and 154b'. In other embodiments, more than one arm may be employed, all of which share the concept of a selectable configuration of a sucker cup. The selection of the sucker cup configuration in FIGS. 3A and 3B is made for the rotation of the arms 154a' and 154b' having the corresponding sucker cups 152a' and 152b', while in other embodiments the selection of the sucker cup configuration is different. It may be performed on the basis of, another example of such a configuration, so that the container nest or the container closing nest and the other set of sucker cups can be fastened, the sucker-cup in a plane parallel to the rotating surface of the rotating stage 130. Branches include, but are not limited to, lateral translation of the cancer. In Figures 3a and 3b the sucker cups are arranged in a linear set. In other embodiments, a non-linear arrangement of sucker cups can be employed.

Turning now to FIG. 3B in particular, the members 149, 139 are examined in more detail. In one embodiment, the reconfigurable stopping member 149 is shown having two different ends, which rotate the rotating axis 141 of the stopping member to a set position. By properly rotating the reconfigurable stopping member 149 to the center, the first end can be employed for use. At the set position, the reconfigurable stopper member 149, along the direction parallel to the transverse axis of the rotating arms 154a', 154b', with respect to the proximal end of the container 530 It provides a hard stop against the selected end of the topping member 149. In this embodiment, to stop the container 530, the reconfigurable stopping member 149 can be rotated 180 degrees completely so that the second end of the reconfigurable stopping member 149 can be disposed. Reconfigurable stopping member 140 so that the proximal end of container 530 can be stopped at a point different from the point where the first end of reconfigurable stopping member 149 stops the proximal end of container 530 The second end of can be configured.

The restraining member 139 is configured to push against the distal end of the container 530. Other mechanisms may be provided to secure the pushing action of the constraining member, but one particularly suitable means is to provide suitable spring loading to the constraining member to rotate about its axis 143. By the above-described operation, the reconfigurable stopping member 149 and the restraining member 130 together place the container 530 in the correct position parallel to the transverse axis of the rotating arms 154a', 154b'. By selecting the appropriate end of the reconfigurable stopping member 149 so that the container 530 can be stopped, a particularly accurate position can be selected. Due to this arrangement, containers 530 having different dimensions parallel to the transverse axis of the rotating arms 154a', 154b' are placed in the correct predetermined position with respect to the multiple sets of sucker cups 152a', 152b'. Can be.

A particular set of sucker cups 152a', 152b' can be selected to match the selection of a particular end of the reconfigurable stopper member 149. In this way, the vacuum pick-up system 150' can be set up in a configuration that can ensure that the containers 530 of the selected size are correctly placed, such that the container nest 500 inside the containers 530 is a specific set of It can be fastened by the sucker cup (152a', 152b'). Accordingly, the vacuum pickup system 150' can be reconfigured to be fastened to a nest having a different size in a container having a different size.

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 rotation plane of the rotation stage 130, the The dimensions of a container perpendicular to one dimension are considered to be the same. In this arrangement, the reference positioning openings 132 and 134 are sized to constrain the container 530 within the perpendicular dimension, within the plane of rotation of the rotating stage 130.

In another embodiment, in addition to the arrangement of FIGS. 3A and 3B, other reconfigurable stopping and restraining members are provided to cope with placing the container 530 in the vertical direction within the rotational plane of the rotating stage 130. Can be added. In order to allow the container 530 to be disposed in this vertical direction, the reference positioning openings 132 and 134 do not have a size capable of constraining the container in any direction within the rotation plane of the rotation stage 9130.

In the above-described embodiment, the reconfigurable stopping member 149 rotates the reconfigurable stopping member 149 around the stopping member rotating shaft 141 to use either end at any one time. It has been described as having two ends selected. In other embodiments, the reconfigurable stopping member 149 may have or be configured with a shape having more than two ends, the ends of which are reconfigurable stopping members around the rotating axis 141 of the stopping member. It can be selected by appropriate rotation of (149). In one embodiment, when the reconfigurable stopping member has a very large number of stopping ends, the reconfigurable stopping member may have a shape of a cam, the shape of which cam rotates appropriately. It represents a very large number of possible stopping ends that can be selected through rotation of the reconfigurable stopping member around 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 mobility platform that includes a reference positioning opening 132, a reconfigurable stopping member 149 and a restraining member 139. For the system shown in Figures 3A and 3B, the mobility platform is a rotating stage 130. Other mobility platforms are also contemplated, as described below. For example, any system that fiducially locates the tub 530 is also essential, as long as the tub 530 constrains and positions the nest 500 within the tub 530 spatially. Nest 530 is positioned inherently as a reference.

All of the various embodiments contemplated include a reconfigurable vacuum pickup system, which can be configured to engage its sucker cup with a corresponding area on the medication container nest. Containers in the container nest can be closed by a corresponding container closure suspended in the container closure nest. The planar surface of the container closing nest can have an outline, which passes through the perimeter of the sucker cup so that the sucker cup can penetrate and engage the container nest. It 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 closing nest can have an appropriate opening inside its plane, which can function as a through hole through which the sucker cup can penetrate and engage the container nest. The proposed vacuum pick-up system is constructed and arranged to lift a combination of containers nested by a container nest and its closure, as opposed to by a closed nest.

In a general embodiment, the nest handling subsystem includes a reconfigurable vacuum pickup system for lifting the container nest, and/or the container closing nests will include one or more arms with 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 with a particular container nest or container closing nest. This selection can be made based on one of the size and shape of the nest or both of the size and shape of the nest. The nest processing system is disposed adjacent to the opposite end of the reference positioning opening 132 for gripping the tub 530 containing the container nest 500 with the container 510, such that the opposite end of the tub 530 And fastening, may further include at least one pair of reconfigurable stopping member 149 and the restraining member 139. The stopping member and the restraining member are arranged to place the tub 530 in a predetermined position that can ensure that the selected set of sucker cups can be engaged with the container nest and/or container closing 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 a member 145 and a constraining member, in this case a member 135 Can be functional. In the same way that the reconfigurable stopping member 149 and the restraining member 139 actuated for any tub in the opening 132, the reconfigurable stopping member 140 and the restraint bonsai 135 are opened 134 It works 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 vacuum pickup systems 150 and 160 are described as part of the medication filling system 1000. However, the vacuum pickup systems 150', 160 can also be employed in other devices of its own right, which are not limited to the charging systems shown in Figures 1A-1E, in fact. Applications of some other embodiments include, but are not limited to, lyophilizing systems. It can be applied to a suitable nest of arbitrary objects arranged in a predetermined pattern. In addition, the system 1000 shown in FIGS. 1A-1E employs a rotating stage 130, but the reconfigurable pickup system 150 ′ can employ any suitable mobility platform including a suitable reference positioning opening. .

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

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

The step of transferring ([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 ( And operating the at least first constraining member 139 to constrain 530.

The step of conveying ([2025]) operates at least the second reconfigurable stopping member 145 to stop the container closing tub 630 at a predetermined closing tub position, and the container tub to the predetermined closing tub position And operating the at least second constraining member 135 to constrain the 630.

Operating the at least one vacuum pickup system 150', 160' ([2050]) comprises at least one reconfigurable vacuum pickup system 150', 160' arranged to engage the container nest 500. And configuring to select a predetermined first set of sucker cups.

Operating one of the at least one vacuum pickup system 150', 160' ([2070]) is arranged such that at least one vacuum pickup system 150', 160' is engaged with the container closing nest 600. And selecting a predetermined second set of sucker cups.

The method includes at least one predetermined set of sucker cups designed to simultaneously remove the container nest 500 and the container closing nest 600 from the ramming system 180 in engagement with the container nest 500. And operating the vacuum pickup systems 150', 160' [2095].

As an alternative embodiment of the arrangement of the vacuum pickup systems 150, 160 shown in FIG. 1A, it has the form of vacuum pickup systems 150', 160'; Embodiments taking the form of elements 135, 45, 139, 149 in a batch arrangement associated with starting openings 132, 134 are considered in FIGS. 3A and 3B. Attention is now directed to an alternative embodiment regarding 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 other embodiments in an arrangement around destination opening 136. To place the nest 500 in the opening 136 and the nest 600 above the nest 500 in the opening 136, along with the rotation of the controller 400 and the rotating stage 130, FIG. 1A Although the cameras 210 and 220 of can be employed, the adjustable destination reference positioning system of FIGS. 4A and 4B, including rotary positioning elements 164a and 164b, includes nests 600, 500) can be alternatively or additionally employed to accurately position.

Conventional industrial container nests are not manufactured according to a dimensional standard, and as a result, any system for filling and closing the container 510 of the nest structure may have a different size nest having a container 510 ( 500) must have a mechanism that can be accurately placed. For this purpose, the rotating placement elements 164a, 164b can have different sets of paired placement surfaces 167a, 167b; 163a, 163b, and thus, have specific dimensions between the paired placement surfaces. Eggplant nests 500 may be fitted accurately. In FIG. 4B, the nest 500 is adapted such that the two opposite ends having a first dimension contact the mutually opposing surfaces 167a, 167b of the rotating placement elements 164a, 164b, respectively. By counter-rotating the rotational placement elements 164a, 164b around each axis 166a, 166b, the surfaces 167a, 167b can face each other, and accordingly the first dimension Nests of different lengths can be precisely placed between these surfaces.

4B, when the surfaces 167a and 167b face each other, the nests that are stably disposed between these surfaces, respectively, are the surfaces 165a and 165b of the rotational placement elements 164a and 164b, respectively. By resting on the image, it can be maintained in an accurately set vertical position. When the surfaces 163a, 163b face each other, other nests that are stably placed on these surfaces are seated on the surfaces 16a, 161b of the rotating placement elements 164a, 164b, respectively, to be maintained in precisely set vertical positions. Can. The rotating arrangement elements 164a, 164b can be manually rotated about the axes 166a, 166b, respectively. In some embodiments, rotation of the rotational placement elements 164a, 164b may be performed automatically by a motorized drive controlled by the controller 400 and appropriate control software. Such control can be based on predetermined dimensional data for the nest placed between the surfaces of the rotating placement elements 164a, 164b. In addition, such control may be based on input data derived from imaging data obtained from cameras 210 and/or 220. In addition, as the surfaces rotate towards positions facing each other, rotational placement elements 164a, 164b, which are intended to engage the opposite ends of the nest 500 along the first dimension, are closed horizontally on the nest 500. This rotation may occur as the nest 500 descends into a position functioning as a grip). In this embodiment, the horizontal and vertical placement of the nest between the rotating placement elements 164a, 164b is not mutually independent.

4A and 4B, another arrangement for the first dimension of the nest 500 can also be established for the second dimension of the nest 500 perpendicular to the first dimension. Due to this, any nest 500 disposed in the opening 136 can be accurately positioned to a preset position by the setting of the rotational arrangement elements 164a and 164b.

Another embodiment of the rotating arrangement element is shown in FIGS. 5A and 5B. Unlike the embodiments of FIGS. 4A and 4B just described above, the horizontal and vertical arrangements of the nests between the two mutually rotatable elements 164a' and 164b' in FIGS. 5A and 5B are independent of each other. Works. This action, for each of the two mutually perpendicular planar dimensions processed in the embodiment just described, a pair of fixed opposite planar tabs that place the nest 500 within the vertical dimension. or fixed opposing planar tabs 165a', 165b') and a pair of rotating placement elements 164a', 164b' that place the nest 500 within the first horizontal dimension. In this embodiment, the rotating placement elements 164a', 164b' are two rotating elements ganged on the axles 166a', 166b' to rotate in unison, respectively, and bosses, respectively. , 169a', 169b'), and a mutual alignment ether side of the flat tabs 165a' and 165b'. The set of rotating elements 164a', 164b', each separated into two simultaneous acting elements, is nested within horizontal dimensions in the same manner as rotating elements 164a, 164b in the embodiments of Figures 4A and 4B just described above. Contribute to limiting (500).

Although the rotating elements 164a', 164b' can be designed with more complex shapes, the surfaces 167a' of the rotating elements 164a' and the surface 167b' of the rotating elements 164b' in FIGS. 5A and 5B are designed. It shows a very simple implementation that contributes to placing the nest 500 within this first horizontal dimension. The element 164a' coupled to the mandrel 166a' is rotated counter-clockwise within the boss 169a', and the element 164b' coupled to the mandrel 166b' within the boss 169b'. Rotating clockwise, the surfaces 163a', 163b' can face each other, and nests of different lengths within the first horizontal dimension are disposed between the rotating elements 164a', 164b' to be accurately positioned. You can.

The synchronously acting elements 164a' and 164b' can be manually rotated about the axes of the axles 166a' and 166b' inside the bosses 169a' and 169b', respectively. In some embodiments, rotation of the elements 164a', 164b' may be performed automatically by a motorized drive controlled by the controller 400 and suitable control software. This control can be based on certain dimensional data associated with the nest placed between the elements 164a', 164b' surfaces. In addition, such control may be based on input data derived from imaging data obtained from cameras 210 and/or 220. In addition, a specific surface of the rotating placement elements 164a', 164b', which are intended to engage the opposite ends of the nest 500 along the first dimension, while the specific surfaces of the placement element rotate toward opposite positions, the specific surface of the nest 500 ) As the nest 500 descends to function as a closing horizontal grip from above, this rotation may occur.

5A and 5B show a rotational arrangement element that can rotate opposite to each other in a pair of different sets, and this rotational arrangement element is not given reference numerals for clarity, and rotational elements 164a' and 164b' ), ganged together and arranged to accurately position the nest 500 independently of the first vertical dimension and the second planar dimension of the nest 500 perpendicular to the first dimension.

In another aspect, with reference to FIG. 6, a method for filling a nested medicinal container 510 with a fluid medicinal material is provided, wherein the sterile chamber 100 is capable of maintaining sterile conditions As a step ([6010]) of providing a charging system 1000 including a chamber, the chamber 100 has a charging station 170 and a destination positioning structure 136, 164a, 164b, 164a', 164b'. Including a plane rotation stage 130; Transferring at least one container tub (530) containing a container nest (500) sealed in a container tub cover (5320) and having a plurality of medicinal containers (510) inside the chamber ([6020]); Aseptically sealing the chamber 100 ([6040]); Establishing aseptic conditions inside the chamber 100 ([6050]); To the interior of the destination positioning openings 136, 164a, 164b, 164a', and 164b', a container nest 500 having a plurality of pharmaceutical containers 510 is transported to hold the container nest 500 (is held) in place) ([6060]); And operating the rotating stage 130 and the filling station 170 to dispensing the fluid medicinal substance into the interior of at least some of the plurality of medicinal containers 510 (6060). Operating the charging station 170 may include rotating the charging station 170. The step of injecting the fluid pharmaceutical substance may include the step of injecting the fluid pharmaceutical substance into the container 510 in an iterative and continuous manner.

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

The method includes transferring a container closed tub 630 containing at least one container closed nest having a plurality of medicinal container closures 610 sealed with a container closed tub cover into the chamber ([6030] ) May be further included. The method arranges one of the at least one container nest 600 so as to align the closure 510 in the at least one closing nest 600 with the corresponding container 510 in the container nest 500. Step ([6080]); Rotating the rotating stage 130 to transfer the nests 500 and 600 of the aligned closure 610 and the container 510 to the ramming station ([6090]); And forcing the closing portion 610 into the corresponding container 510 ([6100]). The method may further include adjusting the tub positioning structures 135 and 145 to accommodate the size of the closed nest tub 630. Placing one of the at least one closed nest 600 ([6080]) includes: obtaining image information on one of the closed nests 600; And disposing one closed nest among at least one closed nest based on the image information. Placing one of the at least one closed nest ([6080]) comprises: applying a vacuum to the sucker cups 162, 152a, 152b, 152a', 152b'; Elevating the container closing nest 600 using a sucker cup; And operating the rotating stage 130.

Transferring the container nest 500 to the interior of the destination positioning opening ([6020]) includes applying a vacuum to the sucker cup; Elevating the container nest 500 using a sucker cup; And operating the rotating stage 130. The method may further include the step of selecting a set of sucker cups among the plurality of sets of sucker cups, and applying a vacuum to the sucker cup is performed on the selected set of sucker cups. The step of selecting may include rotating one set of sucker cups in-position among a plurality of sets of sucker cups. 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 step can be performed in two at least entirely orthogonal directions. The method may further include adjusting the tub positioning structures 139 and 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 that is, for example, a tub 530 or tub 630 within a controlled environment enclosure (see FIG. 1G ), The sealed container is sealed by a container cover that is, for example, a cover 520, and the method lips the container to seal the contents of the container against decontamination in a controlled environment enclosure. Providing a container having a cover 520 sealed on a sealing surface of a lip, the cover 520 having a cover removal fixture 540 and sealed within a controlled environmental enclosure 100 And removing the contamination of the container, fastening the cover removal fixture 540 with the fastening tool 142, and removing the cover from the container using the fastening tool 142. The fastening step may fasten the cover removal fixture 540 with a fork-shaped fastening tool 142. The fastening step may fasten a ball-shaped appendage on the cover removal fixture 540.

Providing includes providing a sterilized medicinal container 510 or closure 610 in a sealed container, for example, a tub 530 or tub 630, prior to the step of removing contamination. can do. The attaching step can occur before the container is provided in a controlled environmental enclosure 100. Decontamination of the sealed container within the proposed 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. The step of 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 in a controlled environment enclosure.

FIG. 7A is a subsystem diagram of another embodiment of an apparatus for filling a medicament container with a fluid medicament, based on the subsystems shown in FIGS. 1A, 1C, 1F, 5A, and 5B. For clarity, the sterile seal chamber 100 of FIG. 1 only; The rotating stage 130 of Figures 1a and 1c; As a container nest 500 having a medication container 510, some subsystems have been omitted so that only the nest 500 held in position by the arrangement shown in FIG. 5B can be represented. In FIG. 7A, the filling arm 170 of FIG. 1A is replaced with a joint robot filling arm 170 ′. Due to the alternative reference placement, the nest 500 may be provided if the openings of each container 510 can be known properly, accurately and accurately in order to reliably dispense droplets of fluid medicament into the container 510. Any alternative reference arrangement for fixing can 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 is an illuminating imager system 252, mirror 254. And a retroreflector (256). The droplet monitoring subsystem 250 can be controlled by the controller 400, with the end controller 400 communicating with the 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 articulating robot filling arm 170 ′ supplies fluid medication via the fluid medication delivery line 172. In FIG. 7A, the filling medication 170 ′ is equipped with a fluid medication dispensing head 174 ′. The dispensing head 174' is positioned and configured to produce a droplet of fluid medicament, within a limited range of constant volume and droplet shapes that can move down along the droplet path 710. For this purpose, a suitable nozzle may be provided on the dispenser head 174'. The controller 400 may control the dispensing behavior of the dispenser head 174', wherein the end controller 400 pumps fluid to the dispenser head 174' or the dispenser head 174' Can communicate with. The imaging system 252 can include a telecentric lens, whereby the imaging system 252 is capable of measuring a constant size of the droplet produced by the dispenser head 174'. It becomes possible.

The illumination imaging unit system 252 illuminates the retroreflective portion 254, is dispensed by the dispenser head 174', and moves along the droplet path 710 into the arbitrary container 510, the droplet 700 It is arranged and arranged to obtain high-speed images. 7A and 7B, the a-a' line represents a light beam path. Since the rotating stage 130 moves all the containers 510 along a circular path around the rotational axis of the rotating stage 130, the articulating robot filling arm 170' operates, and the droplet monitoring system 250 ) Moving 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 articulating robot filling arm 170' operate to place any container 510 so that it can be filled by the dispenser head 174'. In addition to the operation of the rotating stage 130, any operation of the charging arm 170 ′ can 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 adjust the movement of the charging arm 170' and the rotating stage 130.

When executed by the processor, it is loaded into the memory of the controller 400, controls the dispensing of the fluid medication droplet by the fluid medication dispensing head 174', and the fluid medication droplet 700 along the fluid path 710 Software may be provided to collect images of the. The software also allows 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", which incorporates an alternative droplet monitoring system 250' into the other articulating robotic filling arm. Two mirrors 245' and 258' are employed along the illumination imager system 252' and the retroreflector 256', and we reserve the same reference number, i.e. 174 for the dispenser head. ', for the fluid medicine delivery line is 172. The illumination imaging unit system 252' illuminates the retroreflective unit 256' and dispenses by the dispenser head 174' through the mirrors 254', 258'. Is arranged and arranged to obtain a high-speed image of the droplet 700 moving into any container 510 along the droplet path 710. In this particular embodiment, filling by the dispenser head 174' For arranging any container 510 fixed to the nest 500, only the articulating robot filling arm 170" needs to be operated, and filling of all the containers 510 fixed to the nest 500 is required. During deployment, the rotating stage 130 can be held stationary. In a more general case, both the rotating stage 130 and the articulating robot filling arm 170" operate, so that any container 510 can be placed for filling by the dispenser head 174'. In addition to the operation of 130, any operation of charging arm 170" can be controlled through controller 400. For this purpose, the controller 400 can communicate with both the charging arm 170" and the rotating stage 130. The imaging unit system 252' may include a telecentric lens, and accordingly the imaging unit 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 the 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 adopts a robot arm that grips the container by a suitable 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 disclosed in United States Patent Application Publication No. 2017/121046 A1, United States Patent Application Publication No. 2016/0200461 A1, United States Patent Application Publication No. 2016/0184986 A1, the disclosure of which is entirely incorporated herein by reference. United States Patent Publication No. 2016/0346777 A1 and United States Patent Publication No. 2014/0196411 A1. We describe below embodiments of the droplet monitoring system of the present invention for use with joint arms of the type described in more detail in these four lists of published patents.

FIG. 9 shows the filling of a medicament container with a sterile sealing chamber 100 ′ in which a container nest 500 having a medicament container 510 therein is secured by an end-effector 810 of the articulated arm 800. The droplet monitoring system 250 of FIGS. 7A and 7B, implemented in a system, is shown. The joint arm 800 may be a robot joint arm. In some embodiments, the articulated robot arm 800 can 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 public patent of the above list, and may be in a form of being incorporated for reference. For example, the controller 400' may be a controller 440 used by the charging system described in FIG. 1 of United States Patent Application Publication No. 2016/0346777 A1 or a controller 13 of FIG. 1 of United States Patent Application Publication No. 2017/121046 A1. ), but is not limited thereto. For example, the joint arm 800 is the joint arm 200 of FIG. 2 of United States Patent Application Publication No. 2016/0184986 A1, the joint arm 22 of FIG. 1 of United States Patent Application Publication No. 2016/0200461 A1, or the United States Publication Patent It may be the joint arm 30 of FIG. 2 of 2017/121046 A1, but is not limited thereto. In addition, the controller 400' can be used to control the droplet monitoring system 250, for this purpose the controller communicates with the droplet monitoring system 250.

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

In another embodiment of the system, the dispensing head 174' and container(s) 510 are both robot arms 170, 170' on the one hand and robot arms 800 on the other hand. It can be moved by cancer. Either one or two robotic arms may be articulated robotic arms of the type described in the United States Published Patents merged above. In another embodiment, the dispensing head 174' and the container 510 can be placed 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 retroreflective portions 256 and 256' that are projected from a light source housed in the illuminated digital imaging system 252. In other embodiments, the droplet 700 can be backlit or illuminated from any other angle. In this embodiment, the imaging unit system may not require an integrated illuminator, and the lighting unit may be disposed elsewhere from the imaging unit.

Now we return to a method for aseptically dispensing a fluid medicament into a medicine container 510, described by the flow chart of FIG. 11, wherein the method comprises a sterile chamber 100, 100' capable of maintaining sterile conditions. As a step of providing ([3010]), the chamber comprises a fluid medicine dispensing head 174' and a digital imaging unit 252, 252' configured to generate a droplet of fluid medicine 700. 250, 250'); Establishing sterile conditions inside the sterile chambers 100, 100' ([3020]); Providing a sterile medicinal container 510 inside the sterile chambers 100, 100' ([3030]); Dispensing multiple droplets 500 of the fluid medicament from the dispensing head 174' into the container 510 along the droplet path 710 ([3040]); Acquiring a plurality of images of at least one droplet among the plurality of droplets 700 along the droplet path 710 from the imaging unit ([3050]); And determining a volume of the fluid medicine dispensed inside the container 510 from a plurality of images ([3060]).

In some embodiments, the method may further include stopping the dispensing of the fluid medicament ([3070]) based on the volume of the fluid medicament strung into the container 510. In other embodiments, the step of stopping may be based on the length of the dispensing time of the fluid medicament inside the container 510, or based on weighting the amount of fluid medicament dispensed inside the container 510. have. Therefore, the droplet information obtained from the imaging unit is one method for controlling the fluid pharmaceutical dispensing process, just as when monitoring the fluid pharmaceutical 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 may include: at least one droplet shown on the left and right sides of the droplet path 710 in at least one image of the at least one droplet 700 ( Identifying first and second total portions of 700); At least one liquid among the plurality of droplets 700 by mathematically rotating the first and second entire portions of the droplets 700 separately through the circumference around the droplet path 710. Calculating the first and second volumes of the enemy (calculating); And equating the volume of at least one of the plurality of droplets 700 to the average of the first and second volumes. The term “total portion” is used herein to describe the entire side-on planar view of the droplet relative to the left or right side of the droplet path 710. The two whole parts of the droplet will generally not be completely identical. The entire two plane parts, i.e. approximately'halves' are then taken and rotated separately in software with respect to the droplet path 710 to obtain two "drop volumes", followed by two droplets The volume is averaged to obtain an estimated volume of droplets.

Obtaining a plurality of images of at least one droplet 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. The branch may include acquiring multiple images above the predetermined portion of the droplet path. In this specification, the shape of the droplet, if 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 (shape) can be regarded as "stable", the shape of which can be variously changed within the periphery of the setting.

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

In another embodiment, determining the volume of the fluid medicament dispensed into the container from multiple images ([3060]) includes determining a representative volume of the droplet 700 and the container 510 inside. Counting the total number of droplets dispensed with (counting), and may then include the step of multiplying the representative volume of the droplets by the total number of droplets. Determining the representative volume of the droplet 700 may include only measuring the first droplet and estimating it as a representative. In another embodiment, determining the representative volume of droplet 700 may include measuring multiple droplets and calculating an average droplet volume across the entire multiple droplets.

Acquiring multiple images of one droplet among the plurality of droplets 700 along the droplet path 710 from the imaging units 252 and 252' ([3050]) is performed by the retroreflective units 256 and 256'. It may include the step of acquiring a plurality of images by adopting the light reflected by the image portion. Acquiring a plurality of images of at least one droplet among the plurality of droplets 700 along the droplet path 710 from the image units 252 and 252 ′ includes obtaining a plurality of images by using a telecentric lens. It can contain. The telecentric lens may be integrated in the imaging units 252 and 252'. Providing sterile fluid medicine inside the sterile chambers 100 and 100 ′ may include providing sterile fluid medicine inside the container nest 500.

The method moves at least one of the dispensing head 174' and the container 510, so that the container (below the dispensing head 174') can receive the droplet 700 along the droplet path 710. The step of disposing the opening of 510 ([3035]) may be further included. The step of moving the container may include operating the robot arm 800. Moving the container 510 may include moving the container nest 500 that holds the container 510. The step of operating the robot arm 800 may include operating the joint robot arm. The step of moving the dispensing head 174' may include operating the robot arms 170', 170". The step of moving the dispensing head 174' is a joint robot arm 170', 170").

In the embodiments of Figures 7A, 7B, 8, 9, and 10, the controllers 400, 400' also communicate with the dispensing head 174', or a pump that supplies fluid medication to the dispensing head, whereby the controller The 400 and 400' controls the flow of droplets through the dispensing head 174' and turns the flow on or off. For clarity, these lines of communication are not shown in FIGS. 7A, 7B, 8, 9 and 10.

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

Claims (29)

In a device specially adapted to bring the medicament into a particular physical or administering forms, aseptic dispensing the fluid medicament predetermined in the medicament container 510 using a processor. As a way,
Providing a sterile chamber (100) capable of maintaining sterile conditions, the chamber configured to produce droplets (700) of a fluid medicament (medical dispensing head (174) 174'), and comprising a droplet monitoring system (250, 250') comprising a digital imaging unit (252, 252') and an associated processor (400);
Establishing sterile conditions inside the sterile chamber;
Providing a sterile medicinal container inside the sterile chamber;
Initiating dispensing of a plurality of fluid medicinal droplets from the dispensing head along the droplet path 710 into the interior of the container;
Acquiring a plurality of images of at least one of the plurality of droplets along the droplet path from an imager; And
The processor comprising the steps of determining whether the fluid medicine of the set volume is dispensed into the container from the plurality of images, and stopping dispensing when the fluid medicine of the set volume is dispensed into the container. Method for sterile dispensing of fluid medicine into a medicine container. According to claim 1,
The above method,
A step of providing a sterile chamber 100 capable of maintaining sterile conditions, the chamber comprising a fluid medication dispensing head 174 configured to generate droplets of fluid medication, and digital imaging units 252 and 252' Including the droplet monitoring system (250, 250');
Establishing sterile conditions inside the sterile chamber;
Providing a sterile medicine container (510) inside the sterile chamber;
Dispensing a plurality of fluid medicinal droplets from the dispensing head along the droplet path 710 into the container;
Acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit; And
And determining a volume of the fluid medicine dispensed into the container from the plurality of images. The method according to claim 1 or 2,
The step of determining the volume of the fluid medicament dispensed into the container from the plurality of images includes determining at least one droplet volume among the plurality of droplets. In any one of the preceding claims,
Determining the volume of the at least one droplet among the plurality of droplets,
Identifying first and second total portions of the at least one droplet that are respectively displayed on the left or right side of the droplet path within at least one image among the at least one droplet;
The first and second whole portions of the droplets, respectively, passing through a circumference around the droplet path, are separately mathematically rotated, so that the first and second droplets of at least one droplet among the plurality of droplets Calculating the volume; And
And equalizing at least one droplet volume among the plurality of droplets with an average of the first and second volumes. In any one of the preceding claims,
Acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit comprises: obtaining a plurality of images above a predetermined portion of the droplet path Way. In any one of the preceding claims,
Acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the image unit,
Determining a part of the droplet path from which the droplets have a stable shape, from the plurality of images;
And when the droplet is a part of a droplet path having a stable shape, selecting at least one image from the at least one droplet among the acquired droplet images. In any one of the preceding claims,
The step of determining 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. In any one of the preceding claims,
The step of stopping the dispensing of the fluid medicament based on the volume of the fluid medicament dispensed into the container is to stop dispensing of the fluid medicament when the total amount of the fluid medicament dispensed into the container is equal to the set volume. Method comprising steps. In any one of the preceding claims,
Acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit adopts light reflected by the retroreflector (retroreflector, 256, 256') to the imaging unit And obtaining the plurality of images. In any one of the preceding claims,
Acquiring a plurality of images of at least one droplet among the plurality of droplets along the droplet path from the imaging unit comprises: obtaining the plurality of images using a telecentric lens. Way. In any one of the preceding claims,
The step of moving the container includes operating the robot arm 800. In any one of the preceding claims,
And moving at least one of the dispensing head and the container to place the opening of the container under the dispensing head to accommodate the droplet along a droplet path. In any one of the preceding claims,
The method of operating a robotic arm includes the step of operating a jointed robotic arm. In any one of the preceding claims,
The step of moving the container includes moving the container nest 500 holding the container. The method according to any one of claims 12 to 14,
The step of moving the dispensing head includes operating the robot arms 170', 170". The method according to any one of claims 12 to 15,
The step of operating the robot arm includes the step of operating the joint robot arm. In any one of the preceding claims,
The step of providing a sterile medicament container inside the sterile chamber includes providing the sterile medicament container inside a container nest. In any one of the preceding claims,
And stopping the dispensing of the fluid medicament based on the volume of the fluid medicament dispensed inside the container. A system 1000 for sterile dispensing of fluid medicaments inside a container 510, the system comprising:
A sealable sterile chamber 100 capable of maintaining sterile conditions;
A fluid medication dispensing head (174, 174') configured to create droplets of the fluid medication inside the chamber;
A droplet monitoring system (250, 250') including a digital imaging unit (252, 252') disposed inside the chamber to obtain an image of a droplet (700) dispensed by the fluid medication dispensing head;
A controller (400, 400') comprising a memory and a processor, comprising: a controller in communication with the fluid medication dispensing head and the digital imaging unit; And
Software for controlling dispensing of the fluid medicine droplet by the fluid medicine dispensing head, configured to collect an image of the fluid medicine droplet along a droplet path when the software is loaded into a memory and executed by the processor System containing software. The method of claim 19,
Further comprising at least one of a fluid dispensing head placement system 170 and a container placement system (130, 150, 160) in communication with the controller, the software, the fluid dispensing head placement system and the container placement system A system configured to further control at least one. The method of claim 20,
The fluid dispensing head placement system comprises a robot arm (170', 170"). The method according to any one of claims 20 to 21,
The fluid dispensing head placement system comprises a joint robot arm. The method according to any one of claims 20 to 22,
The fluid dispensing head placement system comprises a joint robot arm hermetically sealed in the chamber. The method according to any one of claims 20 to 23,
The container placement system comprises a robot arm (800). The method according to any one of claims 20 to 24,
The robotic arm includes an end effector arranged to hold the container nest 500. The method according to any one of claims 20 to 25,
The container placement system comprises a joint robot arm. The method according to any one of claims 20 to 26,
The container placement system comprises a joint robot arm sealed in the chamber. The method according to any one of claims 19 to 27,
The droplet monitoring system includes a retroreflective portion (256, 256') arranged to reflect the light passing through the droplet to the digital image unit. The method according to any one of claims 19 to 28,
The digital imaging unit comprises a telecentric lens system.

Images