Patent Application
20240199249
The present invention relates to methods for filling and sealing of pharmaceutical containers.
More particularly, the invention relates to methods for filling and sealing of pharmaceutical containers within a controlled environment chamber in a Ready-To-Use (RTU) format, e.g. in tubs and/or nests.
The invention also relates to filled and sealed pharmaceutical containers, e.g. vials, syringes, cartridges and the like, prepared by the method herein described.
Injectable pharmaceuticals are often packed in vials. Such vials are typically formed of glass and have a cylindrical neck with a flanged top. The neck is usually sealed by means of a closure, such as a rubber stopper and an aluminium seal, crimp cap or ferrule which is locked in place in order to permanently seal the pharmaceutical container, e.g. vial, syringe, cartridge, etc.
More recently alternative assemblies have been developed, including pre-sterilised ready-to-use nested containers examples of which include the Schott iQ® range: cartriQ® RTU cartridges; adaptiQ® RTU vials and syriQ® pre-fillable RTU syringes; and press-fit closures, examples of which include: West Daikyo's PLASCAP™ press-fit closure plus stopper; and ARaymond-Life RayDyLyo® press-fit closures; and nested stoppers for example Westar® nested stoppers.
The filling and sealing of such pharmaceutical containers usually requires that the entire operation is accomplished under sterile conditions.
However, the production of sterile pharmaceuticals is difficult, as it is essential to exclude any sources of contamination, such as microbial or viral contamination.
Furthermore, with increased drug potencies, some drugs can themselves be hazardous in the manufacturing environment and require any contact with the workforce in the manufacturing environment to be minimised in order to reduce occupational exposure.
Isolator technology, which provides a solid barrier between a process and the workforce, can be used in dosage manufacturing in order to minimise human contact. In addition, the use of automation is increasingly important in dosage manufacturing.
Historically, equipment for filling and sealing pharmaceutical containers, such as, e.g. vials, syringes, and the like, has been designed to process individual containers. Such processes typically used vibratory techniques for the supply of means for sealing the pharmaceutical containers, e.g. elastomeric closures, aluminium crimp caps, and the like.
Furthermore, conventional processing equipment for multiple pharmaceutical containers employ conveyor belts, and the like, which themselves present particular challenges to cleanability and sterility.
Furthermore, when processing pharmaceutical containers, such as vials, etc., the handling and feeding of closures, e.g. stoppers (usually elastomeric stoppers) and caps (usually aluminium crimp caps), can be problematic. Blockages are difficult to prevent at all times and often operator interventions may be required.
Such difficulties have led, inter alia, to the use of nested pharmaceutical containers.
Recent developments in filling pharmaceutical container filling techniques utilise nested containers and closures. However, generally, the processes comprise de-nesting the pharmaceutical containers for filling and sealing singularly. Such techniques are unsuited to the rapid fill and seal processes usually desired for pharmaceutical containers.
U.S. Pat. No. 10,196,161 describes a method for filling multiple containers with a pharmaceutical product is, which comprises a container nest holding the multiple containers and a closure nest holding multiple closures, aseptically filling the containers with the pharmaceutical product, and closing the containers with the multiple closures. The nests are configured to allow multiple closures and containers to be simultaneously aligned and closed simultaneously. Spring-loaded retaining structures on the closure nest allow it to releasably retain multiple closures above the corresponding multiple containers. However, the method and apparatus described therein is disadvantageous since, inter alia, all closures are applied at the same time, which means that there is generally a delay in filling the container and securing the closure; and on applying the closure, the force applied to each closure is uniform and cannot be tailored and measured easily to specific requirement for an individual container. The total load for closing all of the containers simultaneously can also be very large, typically 10,000 Newtons.
There is therefore a need for an improved method of filling pharmaceutical containers which overcomes or mitigates the disadvantages of prior art methods.
We have now developed a device that overcomes or mitigates the problems associated with the prior art devices. More particularly, we have developed a novel filling method and related apparatus which overcomes the aforementioned disadvantages.
Thus, according to a first aspect of the invention there is provided a method of aseptically filling a plurality of nested containers with a pharmaceutical product and applying closures to filled pharmaceutical containers, in an aseptically controlled environment, said method comprising:
The method of the invention may optionally include a step of decontaminating the plurality of nested containers and/or nested closures, e.g. by treating the plurality of nested containers and/or nested closures with a sterilising medium, for example, treating with e-beam or vaporised hydrogen peroxide. However, it will be understood by the person skilled in the art that the nested containers and/or nested closures may be pre-sterilised, in which case they may be subject to no-touch-transfer (NTT). NTT is essentially a protective aseptic transfer process where pre-sterilised nested containers, closures and tubs are packaged in bags so the contents remain sterile and are only exposed in an aseptic processing environment as they are removed from the in bags. A pre-requisite of NTT is that the pre-sterilised container primary packaging is sterile. It will be understood that when the method of the invention utilises pre-sterilised containers in an NTT environment, the decontamination step will generally not be required.
A variety of methods known in the art may be utilised in moving the sterile or decontaminated plurality of nested containers and/or nested closures from the transfer chamber or loading area into an aseptic cover removal zone. In a preferred embodiment of the invention the tubs containing a plurality of nested containers and/or nested closures may be loaded onto racks located on a moveable wall, turntable, and the like, such that the plurality of nested containers can be moved from the loading area to a covering removal zone.
In one aspect of the invention the transfer chamber or loading area and the covering removal zone will be separated by a moveable wall. The moveable wall may be provided with means, e.g. racks, for supporting the tubs housing the nested containers and/or the nested closures. The moveable wall may be provided with a means for supporting the tubs on both sides of the wall. Thus, the moveable wall may include means for supporting the tubs that is integral to the moveable wall.
In a preferred embodiment the means for supporting the tubs may comprise a plurality of shelving rods, such that a pair of shelving rods may act to support a tub. Such an arrangement allows for a library of nested containers and/or nested closures to be used. The plurality of shelving rods may be arranged such that the rods are located on both sides of the wall.
The arrangement of means for supporting the tubs on both sides of the moveable wall means that the nested containers and/or nested closures can be loaded onto both sides of the wall. The wall will be rotatable about an axis, e.g. a vertical axis, such that a tub of nested containers placed on the means for supporting tubs in the loading area may be transferred to the covering removal zone by rotation of the wall. Thus, a first side of the wall and its accompanying integral means for supporting tubs will be exposed to the loading area and upon rotation of the wall, the first side of the wall and its accompanying integral means for supporting tubs will be exposed to the covering removal zone, thus transferring any tubs of nested containers from the loading area to the covering removal zone. In use, the second side of the wall can be loaded and decontaminated whilst the first side, in the covering removal zone, is being unloaded.
The use of a rotatable wall and means for supporting tubs is novel per se.
The covering removal zone will generally be aseptic. Furthermore, in order to minimise any exposure to contamination, the covering removal zone will be a sealed aseptic zone and may be remotely operated or robotically operated.
In the aseptic covering removal zone a manipulator may be operated, e.g. robotically operated, to remove the tub of covered nested containers, or a tub of nested closures, from the wall; and to move the tub to a covering removal apparatus. For the avoidance of doubt, covering removal shall include removal of any covers and/or any liners that are in place on the nested containers.
The covering removal zone may include means for heating the tub, nested containers and/or nested closures. Covers over the tub, nested containers and/or nested closures are generally held on by an adhesive. Thus, it may be advantageous to pre-heat the adhesive in order to soften it. Softening the adhesive will generally, inter alia, make the cover easier to peel away; and may reduce particulate contamination introduction when breaking the seal created by the adhesive.
Once any covering has been removed, the nested containers and/or nested closures are removed from the uncovered tubs and moved to an aseptically controlled filling zone by a shuttle or such like. It is desirable that the nested containers and/or nested closures are removed from the tubs, as the tubs themselves can be a source of contamination. The shuttle is a linear transfer system or unit, or conveyor, capable of carrying multiple nests, typically two, in and out of the filling zone.
In the aseptically controlled filling zone the nested containers and nested closures are subsequently transferred onto second manipulator wherein the uncovered nested containers are positioned beneath a plurality of uncovered nested closures.
It will be understood that the term “beneath” should be interpreted broadly, in that, the nested containers need not be directly beneath the nested closures, but the nest of containers should be positioned lower than the nest of closures in order to facilitate the placement of the closures into the filled containers.
In one embodiment of the invention the uncovered nested containers are positioned beneath the plurality of uncovered nested closures. In another embodiment of the invention the uncovered nested containers are positioned alongside the plurality of uncovered nested closures.
In the filling zone the uncovered nested containers are each filled by a pharmaceutical product dispensing system. It will be understood that any conventionally known dispensing system may be utilised, however, a preferred dispensing system is a liquid filling needle dispensing system. The dispensing of the pharmaceutical product may comprise dispensing the pharmaceutical product from a single needle, i.e. filling a single container at a time. Preferably the dispensing system will comprise dispensing into a plurality of containers simultaneously from a corresponding plurality of dispensing needles. It will be understood that there is generally described herein a method of filling liquid pharmaceuticals into containers, it is within the scope of the present invention for the pharmaceutical to be in solid for, e.g. in powder form.
In a preferred embodiment, in order to be filled, the nested containers and closures will be transferred from the linear shuttle into a double or multi-nest holder. The nest holder will be mounted on or adjacent the manipulator. For example, the nest holder may be mounted directly onto the manipulator; alternatively, the manipulator may itself be provided with a platform, e.g. a turntable, a replicated tub, or the like, on which the nest holder may be positioned. Alternatively, the manipulator may grip the nest directly, e.g. by means of a fork arrangement.
Having both the container and closure nests in a multi-nest holder provides a very compact arrangement and avoids the need for separate, dedicated, manipulators for both containers and closures.
In the preferred embodiment the nests are arranged at multi-levels/different vertical positions to allow a closure cradle to pass under the nest of closures and over the containers. However, it will be understood that, depending upon, inter alia, the layout of the nests and closures, the closures may be dropped or pushed down from the nest into the closure cradle; or in another embodiment, the closures may be picked up or pushed up from the nest or tray into the cradle or cradles. It will be understood that the apparatus may include more than one cradle, but in use, the apparatus will use one cradle per closure, i.e. a cradle may manipulate one closure at a time repeatedly.
The nest transfers to the manipulator may be by a linear actuator or second articulating arm with a nest gripping head comprising typically of a matrix of suction cups that can hold the nest in position during a vertical transfer.
The manipulator moves the nested containers to predetermined positions such that they are aligned with the filling needle or needles.
The term “manipulator” as used herein will be understood by the person skilled in the art. Examples of manipulators shall include, but shall not be limited to, an articulating arm, a SCARA (Selective Compliance Assembly Robot Arm), a Cartesian robot, a six axis robot, and the like. As described herein, the method of aseptically filling a plurality of nested containers with a pharmaceutical product may comprise the use of more than one manipulator. When more than one manipulator is used the manipulators may be the same or different, for example all manipulators may comprise an articulating arm, or may comprise a mixture or combination of articulating arms, SCARAs, etc.
When positioned, the nests will be held stationary in a lateral dimension, e.g. stationary from side to side or backwards and forwards, whilst the containers are filled. Once filled, but the manipulator is capable of moving the nest in a lateral plane, e.g. from side to side or backwards and forwards, but, generally, not up or down, in order to move to the next container for filling to take place. The manipulator may optionally be capable of moving the nests vertically during filling and in between fills, but generally the manipulator will keep the nests stationary. The filling needles may be moved predominantly vertically by a manipulator.
A closure is allocated for each respectively filled container. Thus, a closure pusher, e.g. a push-rod exerts a force against a nested closure removing the closure from the nest and into a closure transfer device. The removal of the closure from the nest into the closure transfer device may occur separately, sequentially or simultaneously with the filling of the container.
The closure transfer device may be a transfer cradle or pocket adapted to carry the closure, or it may be a collector adapted to grasp and pick up the closure, such as a gripper or a suction cup.
According to one aspect of the invention the closure transfer device is a transfer cradle adapted to carry the closure.
According to another aspect of the invention the closure transfer device is a collector adapted to grasp and pick up the closure.
Alternatively vial closures, can be supplied in trays. In this instance a closure will be picked from a tray and placed into the transfer device before being pushed out of the transfer device into the pharmaceutical container. For this arrangement, the container nest and the closure nest are positioned adjacent to one another and positioned at a similar level vertically. The closures may either be pulled into the transfer device with an arm and suction cup arrangement or the closures may be picked and placed into the top of the arm. In both cases the arm sits above the tray, unlike the push through nests.
In a preferred embodiment the closures are picked from the tray with a push-rod with integrated gripper, grippers, suction cup or suction cups. This then allows the closures to be placed or pushed onto the container with the same device.
In one embodiment the closure cradle is held stationary whilst the nest holder, containing filled containers is moved by the manipulator to a position where a filled container is located beneath a closure transfer device in which a closure is housed. When the container and the closure transfer device are in position, a closure pusher is operated to remove the closure from the closure transfer device, being securely pushed into the filled container, thereby sealing the container.
In another embodiment the nest holder and the nest of closures are positioned alongside one another, i.e. in the same vertical plane, the nest holder and the nest of closures are moved laterally by the manipulator and the filling needle or needles and the closure transfer cradle are stationary in a substantially horizontal plane, but are capable of being manipulated in the vertical plane, i.e. up and down.
It is within the scope of the present invention for multiple containers to be filled and closed simultaneously. However, in one embodiment of the invention an array of containers, e.g. a selected group of containers, typically 2 or 5, in a nest holder is filled and closed before the next array of containers is filled. Such an arrangement is advantageous since, inter alia, there is generally no delay in filling the container and securing the closure. Furthermore, it is advantageous to apply a force to each closure separately from any surrounding closure, i.e. so that the force required can be tailored to any specific requirement for an individual container. This also allows the process to be seen by operators or by automatic inspection such as a vision system
The use of a closure transfer cradle is novel per se.
The method of the invention may further comprise returning the filled containers to the transfer chamber and terminating the spatial communication between the transfer chamber and the first controlled environment chamber.
It is within the scope of the present invention for the containers to be only partially closed by only partially inserting a closure into a container. Such partial closure allows for lyophilizing the pharmaceutical product in the container if desirables. Lyophilizing the pharmaceutical product may comprise lyophilizing the pharmaceutical product in a stoppering apparatus having an interior that may be isolated from the interior of the first controlled environment enclosure.
The partially closing of the first plurality of containers may comprise simultaneously partially closing at least a portion of the first plurality of containers. In another embodiment, partially closing the first plurality of containers may comprise partially closing all the containers in the container nest separately, sequentially or simultaneously.
Some or all of the plurality of the aseptic closures retained by the closure nest may be used to either fully or partially seal the pharmaceutical product into the containers. The plurality of containers may be equal in number to the number of aseptic closures releasably suspended by the closure nest. Two or more containers may be filled simultaneously.
The empty and filled containers may optionally be positioned on a weigh cell whilst in or out of the nest, so that the contents of the containers may be measured, e.g. operating under conditions of real time weight control.
According to a further aspect of the invention there is provided a sealed container filled with a pharmaceutical product using the method as herein described.
According to a further aspect of the invention there is provided an apparatus suitable for aseptically filling a plurality of nested containers with a pharmaceutical product in an aseptically controlled environment, said apparatus comprising:
In the apparatus of the invention means may be provided for locating the uncovered nested containers laterally adjacent to a plurality of nested closures on a shuttle, e.g. by use of a manipulator.
Means may be provided for transferring the uncovered nested containers and closures to a multi-nest holder e.g. by use of the manipulator herein described or by a second manipulator.
Means may be provided for locating the uncovered nested containers laterally adjacent to a plurality of nested closures in the multi-nest holder.
Generally, for removal of the covering a manipulator will collect the tub of nested containers and/or closures from the tub library and transfer the tub to the covering removal zone in order to have the covering removed. Once the covering is removed the tub is placed in a holding rack until a second manipulator removes any liner (if present, any lining is usually positioned underneath the covering). This second manipulator may also remove the nest from the tub, ready for moving into the filling zone. It is desirable for the tub not to be transferred into the filling zone in order to avoid any unnecessary risk of contamination.
As herein described, the use of a closure transfer cradle is novel per se. Therefore, according to a further aspect of the invention there is provided a filling mechanism, suitable for use with an apparatus as herein described, wherein the filling mechanism comprises manipulator suitable for holding a closure cradle in a stationary position whilst a nest holder, containing filled containers, is moved by the manipulator to a position where a filled container is located beneath a closure transfer cradle in which a closure is housed.
As herein described, the use of a rotatable wall and integral means for supporting tubs is novel per se.
Therefore, according to a further aspect of the invention there is provided a filling apparatus as herein described wherein the filling apparatus comprises:
The apparatus may optionally include means for decontaminating the plurality of nested containers and nested closures.
The invention will now be illustrated by way of example only and with reference to the accompanying figures in which:
In the figures herein the following numbering has been used:
Referring to
The loading zone (2) includes a rotatably mounted wall (5), wherein the wall (5) is provided with a plurality of shelving rods (6), wherein each pair of shelving rods (6) is capable of supporting a tub (7).
Each tub (7) will be filled with containers (for filling) or closures (not shown).
A first manipulator (8), e.g. an articulated robotic arm, collects the tubs (7), moving each tub (7) from the loading zone (2) to the covering removal zone (3).
In the covering removal zone (3) the first manipulator (8) operates to remove the tub (7) and transfers the tub (7) to a covering removal apparatus (9). The covering removal zone (3) may include means (not shown) for heating the tub (7). In the covering removal zone (3), covering removal apparatus (9) removes any covering from the tub (7), including any liner (not shown) to expose a nest of containers (10) or a nest of closures (11).
Once uncovered, the first manipulator (8) transfers an uncovered tub (7a) holding a nest of containers (10) or a nest of closures (11) to a shuttle (12), which transfers the uncovered tub (7a) into the filling zone (4).
Operations in the filling zone (4) are described in more detail below, with reference to
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| Number | Date | Country | Kind |
|---|---|---|---|
| 2104761.8 | Apr 2021 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2022/050817 | 3/31/2022 | WO |
