WO2025233795A1

WO2025233795A1 - Method for sterilizing and filling containers for pharmaceutical product and related filling system

Info

Publication number: WO2025233795A1
Application number: PCT/IB2025/054662
Authority: WO
Inventors: Terrence Edward HOLLIS; Robert Merrill SMITH; Frank SURACE
Original assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Current assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Priority date: 2024-05-07
Filing date: 2025-05-05
Publication date: 2025-11-13
Anticipated expiration: 2026-11-07

Abstract

The invention relates to a method for sterilizing containers and filling said containers in sterile conditions with a pharmaceutical product, comprising the steps of: - providing a plurality of internally sterile empty containers (1); - performing a filling cycle, comprising the sequential steps of o introducing a group of empty container(s) (1) into a filling enclosure (55); o sterilizing an external surface of the empty container(s) (1) by application of electron beam radiation emitted by an electron beam emitter (73); o introducing a filling needle (75) into each container body (3) and dispensing pharmaceutical product through the filling needle (75); o extracting the group of filled container(s) (1); - repeating a filling cycle with a subsequent group of empty container(s), The power of the electron beam radiation is modulated during the filling cycle between a maximum value and a minimum value, different from the maximum value and different from zero, whereby a plurality of filling cycles are carried out without switching off the electron beam emitter (73). The invention is also directed to a related filling system.

Description

METHOD FOR STERILIZING AND FILLING CONTAINERS FOR PHARMACEUTICAL PRODUCT AND RELATED FILLING SYSTEM

Technical field

The present invention relates to methods for sterilizing and filling of containers for pharmaceutical products, such as vials, and to related filling systems.

More specifically, the invention relates to methods wherein sterile empty containers, each closed by a cap assembly, are supplied and then externally sterilized and filled with the pharmaceutical product in a filling station.

Background of the invention

In the pharmaceutical field, the filling operation must be carried out in strictly sterile conditions that are monitored to prevent any viable particles from contaminating the interior of the container and the product.

Conventional filling methods are typically carried out in sterile isolators, wherein empty, open container bodies, such as vials, are supplied, sterilized, filled and closed with sterile caps. The caps are separately supplied and sterilized before final assembly to the container bodies. All of these steps are performed in one isolator chamber.

To reduce the number of steps performed in the isolator, and thus reduce the challenges associated with obtaining and maintaining sterility of the components during the whole filling process, it has been proposed to perform the sterilization of containers before supply to the filling line.

In such methods, known for example from WO 2004/000100, sealed, empty vials are sterilized prior to being loaded into the filling equipment (or isolator), whereby the interior of the vials is made and remains sterile while they are transported to the filling equipment. The vials, once loaded into the filing equipment, are then sterilized again by radiation, whereby sterility of the external surface of the vials is obtained or restored before the filling step. The filling step is carried out in-line, by introducing a filling needle through the cap (or stopper), the stopper being resealed after completion of the filling step by applying laser energy to the penetrated surface of the stopper.

While such methods may have certain advantages, it is still challenging to maintain strict sterility and ensure compliance with the applicable manufacturing standards. This is due to the large volume required to be sterile.

It is desirable to reduce the size of the sterile space within the filling equipment, more generally within the filling line, to achieve and better control sterility of the filling step.

Also, for obtaining or restoring sterility of the vials (or, more generally, of the containers), it has been proposed to use electron beam (also referred to as “e-beam”) radiation that can be produced by an electron beam emitter and directed towards the vials during a part of the filling process.

It was found that, while e-beam radiation could advantageously be used for such purpose, the practical implications of using an e-beam emitter in a filling equipment had some downsides. In particular, it was found that the lifetime of an e-beam emitter used in an intermittent mode (power on for the sterilization phase only and power off during the rest of the filling process) was too low for use at a large volume production scale.

It is an objective of the invention to achieve sterilization by e-beam radiation in filling systems for large volume production, without involving unreasonable costs of maintenance and/or replacement parts.

Summary of the Invention

According to a first aspect of the present invention, it is provided a method for sterilizing containers and filling said containers in sterile conditions with a pharmaceutical product, comprising the steps of: - providing a plurality of internally sterile empty containers, wherein each empty container comprises a container body and a cap assembly sealingly closing an inner volume of the container body;

- sequentially transferring the empty containers to a filling enclosure that can be selectively opened, for introducing therein or removing therefrom a group of container(s), or at least partially closed;

- performing a filling cycle, comprising the sequential steps of a) introducing a group of empty container(s) into the filling enclosure; b) at least partially closing the filling enclosure; c) sterilizing an external surface of the empty container(s) within the filling enclosure by application of electron beam radiation emitted by an electron beam emitter; d) introducing a filling needle into each container body and dispensing a predefined amount of pharmaceutical product through the filling needle, thereby obtaining a group of filled container(s); e) opening the filling enclosure and extracting the group of filled container(s) from the filling enclosure;

- repeating a filling cycle with a subsequent group of empty container(s), wherein the power of the electron beam radiation is modulated during the filling cycle between a maximum value and a minimum value, different from the maximum value and different from zero, whereby a plurality of filling cycles are carried out without switching off the electron beam emitter.

The filling enclosure can thus have a reduced size adapted for accommodating one or small number of container(s) and be isolated from the rest of the environment, making it possible to create, maintain and control sterile conditions more easily and during only a limited period of time corresponding to a part of the filling cycle. Achieving sterility during this limited period of time is sufficient to ensure that the filling step itself, which is the most critical phase requiring no risk of contamination, is performed in sterile conditions.

Since the power of the e-beam emitter is modulated at a continuously positive value, instead of being repeatedly switched on and off, the lifetime of the emitter is significantly increased. Also, excessive dosing of the container with electrons, that could damage the mechanical properties of the container, is prevented. Preferred embodiments of the invention may include one or several of the following features:

- the power of the electron beam radiation is set at the maximum value during step c) and at a lower value during the rest of the filling cycle;

- the power of the electron beam radiation, during the filling cycle and before step c), is set at the minimum value;

- the power of the electron beam radiation, during the filling cycle and after the completion of step c), is set at the minimum value;

- the containers have a main axis, the electron beam emitter being arranged next to the filling enclosure for emitting e-beam radiation toward the containers in a direction substantially radial to their main axis, and wherein the containers are rotated about their main axis during step c);

- the cap assembly has at least a fixed part and the step d) of introducing the filling needle into the container body is carried out by introducing the filling needle through the fixed part of the cap assembly;

- the cap assembly further has a detachable part and the filling cycle further comprises the steps of

• after step b) and before step d), removing the detachable part of the cap assembly;

• after step d) and before step e), replacing the detachable part of the cap assembly onto the container body for sealingly closing the thus filled container;

- the detachable part of the cap assembly is a top part of the cap assembly, including a tamper evidence cap;

- the containers have a main axis, the electron beam emitter being arranged next to the filling enclosure for emitting e-beam radiation toward the containers in a direction substantially radial to their main axis, and wherein the containers are rotated about their main axis during the whole filling cycle except during the steps of removing and replacing the detachable part of the cap assembly;

- the filling cycle further includes supplying a continuous sterile gas flow in the filling enclosure for preventing any particle potentially present on the external surface of the container(s) from remaining in or reaching an area in the vicinity of the cap assembly.

According to a preferred embodiment, said sterile gas supplied in the filling enclosure is air. Alternatively, said sterile gas supplied in the filling enclosure may be nitrogen or argon.

Preferably, said sterile gas flows unidirectionally through the filling enclosure, vertically from top to bottom.

In a further aspect, it is provided a filling system for carrying out a method as described above, comprising:

- an infeed station designed to be supplied with a plurality of internally sterile empty containers, each empty container comprising a container body and a cap assembly sealingly closing an inner volume of the container body;

- a filling enclosure that can be selectively opened, for introducing therein or removing therefrom a group of container(s), or at least partially closed, for sterile filling of the containers;

- a conveyor sub-system for sequentially transferring the empty containers from the infeed station to the filling enclosure;

- a collecting sub-system for, in each filling cycle, picking up a group of empty container(s) from the conveyor sub-system, introducing said group of empty container(s) into the filling enclosure, closing the filling enclosure and, after filling, extracting said group of container(s) from the filling enclosure;

- an electron beam emitter for sterilizing an external surface of the empty container(s) within the filling enclosure by application of electron beam radiation;

- a delivery sub-system, including respective filling needle(s), for dispensing the pharmaceutical product through the cap assembly of each container of the group, wherein the electron beam emitter is suitable for emitting electron beam radiation with a power that can be modulated between a maximum value and a minimum value, different from the maximum value and different from zero, whereby a plurality of filling cycles can be carried out without switching off the electron beam emitter.

Preferably, the filling system of the invention may include one or several of the following features:

- the containers have a main axis, the electron beam emitter being arranged next to the filling enclosure for emitting e-beam radiation toward the containers in a direction substantially radial to their main axis, and wherein the collecting sub- system is suitable for rotating the containers about their main axis during at least a part of the filling cycle;

- the cap assembly has a fixed part, through which the filling needle can be introduced for dispensing the pharmaceutical product into the container, and a detachable part, the filling system further including a wrench mechanism for, within the at least partially closed filling enclosure, removing said detachable part before filling and replacing said detachable part onto each container body for sealingly closing the container once filled;

- the filling system further comprises a particle removal sub-system for continuously supplying sterile gas flow in the at least partially closed filling enclosure and thus preventing any particle potentially present on the external surface of the container(s) from remaining in or reaching an area in the vicinity of the cap assembly; and

- the particle removal sub-system is designed such that said sterile gas flows unidirectionally through the filling enclosure, vertically from top to bottom.

Brief Description of the Drawings

Preferred embodiments of the invention will now be described in more details, with reference to the following drawings wherein:

- Figure 1 is perspective view of a vial according to a first embodiment of the invention;

- Figure 1 A is a schematic cross-sectional view, in the vertical mid-plane A-A, of the vial of Figure 1 , filled with a pharmaceutical product;

- Figure 1 B is a perspective enlarged detail view of the vial of Figures 1 and 1A, showing the cavity formed at the bottom end thereof;

- Figure 2 is an exploded perspective view of a filling system according to a particular embodiment of the invention;

- Figure 3 is a perspective view of the assembled filling system of Figure 2 in an initial step of a filling method carried out with the filling system;

- Figure 4 is a front elevation view of the filling system of Figure 2, in the initial step represented on Figure 3, showing a group of in-line vials to be processed and a group of in-line vials after filling;

- Figure 5 is a perspective view of the assembled filling system of Figures 3 and 4 in a subsequent step of the filling method; - Figure 6 is a front elevation view of the filling system of Figures 3 to 5 in a subsequent step of the filling method;

- Figures 7 to 10 are perspective views of the filling system of Figures 3 to 6 in respective subsequent steps of the filling method;

- Figure 11 is a partial perspective view of a filling system according to an alternative embodiment of the invention, showing in an initial step the wrench mechanism and the piston of the collecting sub-system supporting a vial to be filled; and

- Figure 12 is a partial perspective view of the filling system of Figure 12 in a subsequent step of the filling method.

Detailed Description of Preferred Embodiments

In the present description and claims, the term “sterile” means, referring to an environment or an object, free of any living microorganisms (or viable organisms).

The invention will now be further illustrated by the following preferred embodiments illustrated on the Figures.

Figures 1 and 1A illustrate a container, more specifically a vial, adapted to contain a pharmaceutical product and to be filled with a method of the invention.

The vial 1 , represented on Figure 1A in an upright position in a vertical plane, comprises a vial body 3 and a cap assembly 5. The terms “top”, “up”, “upper”, “bottom”, “down” and any orientation- or position-related terms shall be understood in relation to the position of the vial as shown on Figure 1A.

The vial body 3 is typically integrally made from glass but may alternatively be made from any other material compatible with a pharmaceutical use. In particular, the main body may be integrally made from a molded plastic material.

The vial body 3 is formed with a substantially cylindrical wall 7 extending along a main axis X, a bottom wall 8 closing the cylindrical wall 7 at the bottom end thereof, and a neck portion 9 coaxially extending from the cylindrical wall 7 at the upper end thereof and open at its upper end. As visible on Figure 1 A, the cap assembly 5 comprises a fixed part fixedly attached to the neck portion 9 and a detachable part detachably attached to the neck portion 9 and/or the fixed part. The fixed part and the detachable part respectively consist of, in the illustrated embodiments, a stopper 13 and an outer cap 15.

The terms “fixed” and “detachable”, when used as qualifiers for the parts of the cap assembly 5, are referring to the connection of said parts of the cap assembly 5 to the vial body 3 during the time of carrying out the method of the invention. In particular, even though the connection of the cap assembly 5 can be released by a user, such that the whole cap assembly 5 can be removed by a user from the vial body 3 for access to the content of the vial 1 , the stopper 13 remains attached to the vial body 3 during the filling of the vial 1 with the method carried out with the filling system of the invention, as will be seen in the following. In contrast, the outer cap 15 is removed from the vial body 3 before performing the filling of the vial 1 .

The neck portion 9 of the vial body 3 and the cap assembly 5 are formed with respective mutually engaging connecting means for releasably attaching the parts of the cap assembly 5 onto the vial body 3. In this example, a bayonet-type connection is provided for releasable attachment of the outer cap 15 to the vial body 3 and a snap-fit connection 17 is provided for attachment of the stopper 13 to the neck portion 9 of the vial body 5.

In the illustrated embodiments, the stopper 13 has an internal flange 21 , engaging an internal surface of the neck portion 9 and defining therewith the snap-fit connection 17, and an inner plugging portion 23 for plugging the neck portion 9 and thereby closing the inner volume 24 of the vial body 3. The inner portion 23 comprises two contacting lips that are closed in a rest position but can be opened for introducing a canula or needle in the vial to fill it or extract product therefrom.

The stopper 13 is preferably made from a relatively soft material such as rubber or TPE.

In an alternative embodiment (not represented), the stopper may have a permanent hole for introducing a canula or needle, that could be closed off by the outer cap after filling. In a further alternative embodiment (also not represented), the stopper may be pierceable by a filling needle and resealable after filling e.g. by application of radiation. In the illustrated embodiments, the outer cap 15 is designed as a top part of the cap assembly 5 that covers the external flange 21 and, when attached to the vial body 5, axially bears onto the stopper 13, whereby the stopper 13 and the outer cap 15 together sealingly close the inner volume 24 of the vial body 3. The detachable part of the cap assembly 5 preferably includes a tamper evidence cap that is, in the illustrated embodiment, made integral with the outer cap 15, but could be conceived as a separate piece.

As visible on Figure 1 , the outer cap 15 is formed with a pair of opposing flat faces 27 that extend in planes parallel to the main axis X. Those flat faces 27 are provided for engagement by a wrench mechanism for removing and/or replacing the outer cap 15 from/onto the vial body 3.

The outer cap 15 is preferably made from a relatively hard material such as polypropylene or other plastic material.

On Figure 1A, the vial 1 is represented filled with a pharmaceutical product 30 in a liquid form. In the present description and claims, the term “fill”, “filled” or “filling” are referring to the introduction into or the presence in the vial of a certain amount of product, generally corresponding to a partial fill of the inner volume. In other words, those terms should not be interpreted as limited to obtaining vials full of product.

As shown on Figures 1 , 1 A, 1 B, the vial body 3 further includes at the bottom end thereof a flange 33 defining a cavity 35 with a non-cylindrical shape. This cavity 35 is designed to be engaged matingly engaged by a male connecting piece (as will be described in the following) such that relative rotation of the vial 1 about the main axis X is prevented.

In the present description and claims, the term “non-cylindrical” shall refer, in relation to the main axis X, to a non-circular shape.

In this first embodiment, the flange 33 axially and downwardly projects from the bottom wall 8. The flange 33 has an external surface that is formed as an axial extension of an external surface of the cylindrical wall 7, both the flange 33 and the cylindrical wall thus having the same external diameter. The cavity 35 has a substantially circular shape with two opposing flats 37 formed on an inner surface of the flange 33.

In other (not illustrated) embodiments the flange may have alternative shapes, for example a frustoconical shape i.e. downwardly projecting from the bottom wall 8 but inclined with respect to the main axis X.

Also visible on Figures 1 and 1 B, markings are provided on the external side of the bottom wall 8 in the form of three dots 39 indicative of the position and orientation of the vial 1 about the main axis X for an optical reader.

With reference to Figures 2 to 10, a particular embodiment will be described of a filling system for processing vials of the invention.

It will be appreciated that the invention (filling system and method), while described for a vial, is also applicable to other containers typically used in the pharmaceutical field. In case the invention is applied to a container different from a vial, terms such as “vial body” used in the following description should be understood as more generally referring to “container body”.

Referring particularly to Figures 2 and 3, the filling system comprises a filling enclosure 55 and a collecting sub-system including an automated support in the form of a cylindrical piston 70, that is extending and is displaceable in a vertical direction. At its top free end, the piston 70 is provided with a piston head 71 designed for coaxially accommodating a vial 1 and holding it in an upright position. The collecting sub-system also comprises a motorized and automated mechanism for displacing the piston 70.

The piston head 71 has a projecting male connecting piece 72 for matingly engage the cavity 35 of the vial 1 , whereby the orientation of the vial 1 about its main axis X corresponds to the orientation of the support 70 and whereby relative rotation about the main axis X is prevented.

The piston 70 is rotatable about axis X, whereby the vials 1 can be rotated the collecting sub-system about their main axis X during at least a part of the filling cycle. io As it will be described in more details in the following, for each filling cycle, the collecting sub-system is designed for the piston 70 to pick up an empty vial 1 from a conveyor, holding and introducing said vial into the filling enclosure 55 and placing it in a predetermined orientation about its main axis X, displacing it within the filling enclosure and, after filling, extracting it from the filling enclosure.

In the illustrated embodiment, the collecting sub-system is adapted to process only one single vial per cycle. It is however conceivable that the collecting sub-system may process simultaneously a group of vials, using multiple pistons simultaneously operated for respective vials or using a single piston with multiple heads for respective vials, for simultaneously displacing and processing multiple vials.

The filling system further comprises a radiation sterilization sub-system 73, arranged next to the filling enclosure 55. The radiation sterilization sub-system 73 is more specifically an electron beam emitter suitable for emitting an electron beam (e-beam) radiation toward the filling enclosure 55 and a vial contained therein in a direction substantially radial to their main axis X and sterilizing, by application of such radiation, an external surface of the empty vial 1 . The e-beam emitter 73 is suitable for emitting the e-beam radiation with a power that can be modulated between a maximum value and minimum value, in particular a strictly positive minimum value.

Furthermore, the filing system includes a delivery sub-system, that comprises a filling needle 75, for dispensing pharmaceutical product through the stopper 13 into the vial body 3 of a vial 1 placed in the filling enclosure for being processed. The filling needle 75 is in fluid communication with a corresponding drug product bag. In the case of an alternative embodiment wherein multiple vials are processed simultaneously within the filling enclosure, it will be appreciated that a corresponding number of needles would be provided for simultaneously delivering pharmaceutical product into the respective vials.

Also part of the filling system is a particle removal sub-system 76 provided for continuously supplying sterile gas flow in the filling enclosure 55 and thus preventing any particle potentially present on the external surface of the vial from remaining in or reaching an area in the vicinity of the cap assembly 5. The particle removal sub-system 76 includes a sterile gas supply tube 77 provided at the top of the filling enclosure 55 and a filter 78 for filtering said gas thus supplied to the filling enclosure. The tube 77 is in fluid n communication with a sterile gas supply source (not shown). The particle removal subsystem 76 is designed such that, when supplied to the filling enclosure 55, the sterile gas flows unidirectionally therethrough, vertically from top to bottom.

The sterile gas is preferably air but could alternatively be an inert gas such as nitrogen and/or argon, in case such cover gas is required to be present in the filled vials.

The filling system further includes a wrench mechanism 79 for, when a vial 1 is being processed within the filling enclosure 55, removing the outer cap 15 before filling of the vial 1 and replacing said outer cap 15 onto the vial body 3 for sealingly closing the vial once filled. The wrench mechanism 79 has a wrench head 80 that fits the flat faces 27 of the outer cap 15 of a vial 1 placed in the filling enclosure 55. In this particular embodiment, it is motorized and automated for selectively and controllably removing the outer cap 15 from vial body 3 or replacing it onto the vial body 3.

The filling enclosure 55 of the filling system comprises a first 81 and a second 82 vertical hollow cylinders, and a casing 83 encasing both hollow cylinders. Each hollow cylinder 81 , 82 is provided with a lateral through hole forming a passage 84 between the inner volumes of both hollow cylinders. The first hollow cylinder 81 defines a chamber for receiving the vials to be filled.

Each hollow cylinder 81 , 82 is open at both ends and the casing 83 comprises a horizontal top wall 85, with the filter 78 interposed between the top wall 85 and the top end of the hollow cylinders 81 , 82, whereby the top end of the hollow cylinders 81 , 82 are closed by the filter 78 and the top wall 85.

The top wall 85 is provided with a through hole wherein the needle 75 is inserted and fixedly attached by a sealed connection, such that the tip of the needle 75 (the end to be inserted in the vials for filling) projects into the first hollow cylinder 81 .

The top wall 85 is also provided with a sterile gas inlet 86 connected to tube 77 for the supply of sterile gas through the filter 78 into the hollow cylinders 81 , 82 and circulation of said sterile gas from the top to the bottom of the hollow cylinders 81 , 82. The hollow cylinders 81 , 82 and the casing 83 are radiation-permeable in the sense that they do not constitute barriers for the radiation applied for sterilization of the vials (e-beam radiation in the preferred embodiment).

The filling enclosure 55 further comprises a horizontal bottom plate 87, arranged at the bottom end of the hollow cylinders 81 , 82 and formed with a first 91 and a second 92 through holes, fittedly engaged by the bottom end of the respective hollow cylinders 81 , 82. The through holes 91 , 92 define exhaust holes for the sterile gas supplied to the filling enclosure 55. The first through hole 91 , corresponding to the first cylinder 81 , also defines an opening in the filling enclosure 55 for the insertion of the piston 70 and thus of a vial to be filled in the first cylinder 81 .

As can be seen on Figure 5, when inserted in the filling enclosure 55 through the hole 91 , the piston 70 partially closes the bottom end of the first cylinder 81 and thus partially closes the filling enclosure 55. In such an inserted position of the piston 70, a thin annular gap 95 is radially formed between the piston 70 and the bottom plate 87, whereby the sterile gas can exhaust into an exhaust duct 97 (visible for example on Figures 4 and 6). The exhaust duct 97 is preferably connected to a testing system for continuous or periodic air monitoring.

It will be noted that the filling enclosure 55, while never strictly closed, can be selectively open (for introducing or removing the vial) or at least partially closed (for sterile filling of the vial). The filling enclosure 55 is open when the piston 70 is in a lower position wherein it does not project through the hole 91 and partially closed by the piston 70 when the piston 70 in one of its higher positions projects through the hole 91. The piston 70 is driven from a lower to a higher position for introducing a vial to be processed (filled) into the filling enclosure 55, or from a higher position to the lower position for removing a filled vial therefrom.

Reference will now be made to Figures 4 through 10 for describing a method according to a preferred embodiment of the invention.

In a first step of the method for filling vials (or more generally containers) in sterile conditions with a pharmaceutical product, a plurality of sterile empty vials 1 are supplied into an infeed station. The empty vials are then sequentially transferred to the filling enclosure 55 for being sequentially processed by performing a filling cycle.

When transferred into the filling enclosure, the vials are internally sterile but presumed externally non-sterile as the vials are conveyed from the infeed station to the filling enclosure in a non strictly sterile environment. Hence the need for sterilizing the external surface the vials or restoring sterility thereof in the filling enclosure before the filling operation.

Figure 4 illustrates an initial configuration of the filling system when performing a filling cycle, wherein a line of empty, internally sterile, vials 1 (represented on the right-hand side of Figure 4) are being conveyed toward the filling enclosure 55 and in stand-by for subsequent filling cycles. A line of filled vials (represented on the left-hand side) are being conveyed from the filling enclosure 55 to a station for rearrangement into trays and then being conveyed to a collection area.

In this initial configuration, the piston 70 engages a vial to be processed whereby the cavity 35 of the vial 1 is engaged by the connecting piece 72 and located outside and underneath the filling enclosure 55. The filling cycle for the vial picked-up by the piston 70 can then start.

A first step of the filling cycle for the selected empty vial consists in introducing the empty vial 1 into the filling enclosure 55 through the hole 91 by driving the piston 70 upwards, such that the vial 1 is brought into a position underneath and spaced from the tip of the needle 75, thus without contacting the needle.

As explained in the foregoing, with the piston 70 projecting through the hole 91 into the first hollow cylinder 81 of the filling enclosure 55, the filling enclosure is partially closed.

Then the wrench head 80 is brought into engagement with the flat faces 27 of the outer cap 15, by lateral displacement of the wrench mechanism 79 though the passage 84.

This configuration is illustrated by Figure 5. During the filling cycle, as illustrated by Figure 6, e-beam radiation is emitted by the e- beam emitter 73 toward the filling enclosure 55, thus sterilizing the interior of the filling enclosure 55 and more specifically the external surface of the vial 1 within the filling enclosure. E-beam radiation is continuously emitted and modulated over the whole filling cycle, as will be described in more details in the following, in particular not stopped during the step of filling the vial.

Referring to Figure 7, a subsequent step of the filling cycle is illustrated, wherein the outer cap 15 (detachable part of the cap 5) is removed from the rest of the vial by the wrench mechanism 79, leaving the stopper 13 (fixed part of the cap 5) in place on the vial body 3. The wrench head 80 holds the outer cap 15 in the second hollow cylinder 82, spaced from the vial such that it does not interfere with any displacement of the vial and the piston during the subsequent step of the cycle.

It will be appreciated that, due to the engagement of the male connecting piece 72 in the cavity 35 of the vial 1 , the position of the vial on the piston 70 and its angular orientation about the main axis are maintained against the torque or twisting effort exerted by the wrench head 80, when the wrench head 80 is rotated relative to the vial for removing the outer cap 15.

In the subsequent step illustrated on Figure 8, the piston 70 is driven upwards, thus moving the vial 1 without its outer cap 15 towards the tip of the needle 75 and then causing the filling needle 75 to be introduced in the vial through the stopper 13. A pre-defined amount of pharmaceutical product is then dispensed through the filling needle 75 into the vial 1 , thereby obtaining a filled vial.

As represented on Figure 9, the piston 75 with the filled vial is then, in a subsequent step of the filling cycle, driven downwards back to the vertical position shown on Figure 7. In this position, the outer cap 15 is replaced onto the vial body 3 by the wrench mechanism 79 for sealingly closing the filled vial.

It will be noted that sterility is maintained within the filling enclosure 55 after the radiation sterilization until the filling enclosure is opened. Then, as a final step of the filling cycle, the piston 79 is driven further downward and extracted from the filling enclosure 55 through the hole 91 , thus also extracting the filled vial from the filling enclosure. In this position, as represented on Figure 10, with the piston 75 no longer projecting through the hole 91 , the filling enclosure 55 is returned into its open configuration.

During the filling cycle, while the filling enclosure 55 is partially closed, sterile air (or gas) flow is continuously supplied in the filling enclosure particle removal sub-system 76, vertically downwards directed, and discharged through the holes 91 , 92. This an additional safety measure that prevents any particle potentially present in the filling enclosure 55 from migrating into the vicinity of the cap assembly and into the vial. This also helps maintaining sterility within the filling enclosure as it prevents air from the room, considered as non-sterile, from entering into the filling enclosure 55. Sterility is thus maintained until the filled vial is sealingly closed and extracted from the filling enclosure.

Once the filled vial has been moved onto the conveyor sub-system, the piston 75 picks up the next empty vial in the stand-by line and the filling cycle is repeated.

As already mentioned, a filling method may be carried out with a group of vials simultaneously processed during the same filing cycle and within a single filling enclosure.

As also previously mentioned, e-beam radiation is continuously emitted by the e-beam emitter 73 and modulated over the whole filling cycle. In particular, the e-beam radiation is modulated during the filling cycle between a maximum value and a minimum value, different from the maximum value and different from zero, whereby a plurality of filling cycles are carried out without switching off the electron beam emitter 73.

During the filing cycle, the power of the e-beam radiation is modulated and the vials are rotated about their axis (by controlled rotation of the piston 70 about axis X) as outlined below.

As a vial 1 enters the filling enclosure 55, the vial exterior and the filling enclosure are presumed unsterile. The vial interior is sterile because the vials are assembled, closed, and previously sterilized. The electron beam emitter 73 is on and operating at low power, more specifically at the minimum value. The vial 1 is rotating to promote uniform electron dosing of the exterior and prevent the vial surfaces facing the e-beam emitter 73 from being excessively dosed with electrons. Excessive dosing with electrons could damage the vial’s mechanical properties.

Once the vial 1 is completely inside the filling enclosure 55 and centered in front of the electron beam emitter 73, the emitter’s power level is increased to high, more specifically to the maximum value. The vial 1 continues rotating. With the e-beam emitter 73 operating at high power, the vial 1 rotates at least one revolution about axis X. This sterilizes the vial exterior and the filling enclosure 55.

After that sterilization step, the e-beam emitter’s power level is reduced to low, more specifically to the minimum value. The vial 1 continues rotating.

The vial 1 is then moved into a position to be opened. During this step, the emitter’s power level remains low, more specifically at the minimum value, and the vial 1 continues rotating.

In order to proceed to removing the detachable part 15 of the cap assembly 5, rotation of the vial 1 is stopped, whereby the vial 1 can go through the motion to remove the detachable part 15. During this step, the e-beam emitter’s power level remains low (minimum value).

Once the detachable part 15 has been removed, the vial 1 resumes rotating. The detachable part 15 of the cap assembly 5 is protected from direct radiation exposure because it is recessed in a pocket.

The vial 1 is then moved to the filling position and filled. During this step, the vial 1 is rotating, and the e-beam emitter 73 continues operating at low power (minimum value).

The vial 1 is then moved into position to be closed, by replacing the detachable part 15 onto the vial body 3. During this step, the e-beam emitter’s power level remains low (minimum), and the vial 1 continues rotating.

The vial 1 then stops rotating to go through the motion required to close it and the vial 1 is then closed. During this step, the e-beam emitter’ power level remains low (minimum). The vial 1 is then moved out of the filling enclosure 55. The vial 1 continues rotating until it is out of the filling enclosure 55. Once out, rotation of the vial 1 can stop. The emitter’s power level remains low (minimum) during that step.

The filling cycle is now complete. The filled vial moves on to be weighed and the next empty vial (or set of empty vials) enters the filling enclosure to be filled.

As outlined in the foregoing, the power of the electron beam radiation is preferably set at the maximum value only during the sterilization step itself i.e. once the filling enclosure 55 has been partially closed with the vial 1 inside and before the detachable part 15 of the cap assembly 5 is removed for introducing the filling needle into the vial body 3. The electron beam radiation is set at a lower value, preferably at the minimum value, during the rest of the filling cycle.

As also outlined in the foregoing, the vials are rotated about their main axis X during the whole filling cycle except during the steps of removing and replacing the detachable part 15 of the cap assembly 5.

A method carried out with the filling system of the invention makes it easier to create, maintain and control sterility, as the sterility is achieved for a short period corresponding to a part of a filling cycle and within a reduced space corresponding to a specific operation of the processing line.

The method is adapted to supplies of vials pre-sterilized on a different site, thereby reducing the space required for sterile operations and providing flexibility to the production line.

In an alternative embodiment of the filling system according to the invention, illustrated on Figures 11 and 12, the filling system includes a wrench mechanism 179 having a wrench head 180 and essentially differs from the embodiment illustrated on Figures 2 to 10 in that the wrench head is stationary within the filling enclosure. It is more specifically rigidly fixed to a fixed upright arm 181 arranged within the filling enclosure. The piston 70 supporting the vial 1 is therefore not only vertically displaceable but also laterally displaceable in a controlled and automated manner. The piston 70 is further rotatable about the main axis X of the vial. It will be appreciated that the engagement of the male connecting piece 72 within the cavity 35 of the vial prevents any relative rotation of the vial 1 with respect to the piston 70 about the axis X.

For removing the detachable part of the cap 5 from the vial body 3, the movements of the piston 70 are controlled such that the flat faces 27 of the cap 5 are (i) appropriately oriented with respect to the wrench 180 (as illustrated by Figure 11 ) and (ii) brought into engagement with the corresponding contact surfaces of the wrench 180 (as shown on Figure 12).

The piston 70 is then rotated about the common axis X of the piston and the vial, such that the bayonet-type connection of the detachable part of the cap is released.

The movements of the piston 70 are then controlled to displace the vial 1 within the filling enclosure at a suitable location for insertion of the filling needle, while the outer cap is retained by the wrench mechanism 179. Once filled, the vial 1 is then moved back to the wrench 180 and suitable displacements of the piston 70 are executed in a controlled and automated manner, such that the outer cap is replaced onto the vial body 3 and then the filled vial is extracted from the filling enclosure.

It will be appreciated that the invention, as described in the foregoing, allows for proper sterilization of vials using an e-beam radiation emitter in an automated filling equipment suitable for large scale production, without damaging the emitter due repetition of cycles at a high speed.

Claims

1 . Method for sterilizing containers and filling said containers in sterile conditions with a pharmaceutical product, comprising the steps of:

- providing a plurality of internally sterile empty containers (1 ), wherein each empty container (1 ) comprises a container body (3) and a cap assembly (5) sealingly closing an inner volume (24) of the container body (3);

- sequentially transferring the empty containers (1 ) to a filling enclosure (55) that can be selectively opened, for introducing therein or removing therefrom a group of container(s), or at least partially closed;

- performing a filling cycle, comprising the sequential steps of a) introducing a group of empty container(s) (1 ) into the filling enclosure (55); b) at least partially closing the filling enclosure (55); c) sterilizing an external surface of the empty container(s) (1 ) within the filling enclosure (55) by application of electron beam radiation emitted by an electron beam emitter (73); d) introducing a filling needle (75) into each container body (3) and dispensing a pre-defined amount of pharmaceutical product (30) through the filling needle (75), thereby obtaining a group of filled container(s); e) opening the filling enclosure (55) and extracting the group of filled container(s) (1 ) from the filling enclosure;

- repeating a filling cycle with a subsequent group of empty container(s), wherein the power of the electron beam radiation is modulated during the filling cycle between a maximum value and a minimum value, different from the maximum value and different from zero, whereby a plurality of filling cycles are carried out without switching off the electron beam emitter (73).

2. Method according to claim 1 , wherein the power of the electron beam radiation is set at the maximum value during step c) and at a lower value during the rest of the filling cycle.

3. Method according to claim 2, wherein the power of the electron beam radiation, during the filling cycle and before step c), is set at the minimum value.

4. Method according to claim 2 or 3, wherein the power of the electron beam radiation, during the filling cycle and after the completion of step c), is set at the minimum value.

5. Method according to any one of claims 1 to 4, wherein the containers have a main axis, the electron beam emitter being arranged next to the filling enclosure (55) for emitting e-beam radiation toward the containers in a direction substantially radial to their main axis, and wherein the containers are rotated about their main axis during step c).

6. Method according to any one of claims 1 to 5, wherein the cap assembly (5) has at least a fixed part (13) and the step d) of introducing the filling needle (75) into the container body (3) is carried out by introducing the filling needle (75) through the fixed part (13) of the cap assembly (5).

7. Method according to claim 6, wherein the cap assembly (5) further has a detachable part (15) and the filling cycle further comprises the steps of

• after step b) and before step d), removing the detachable part (15) of the cap assembly (5);

• after step d) and before step e), replacing the detachable part (15) of the cap assembly (5) onto the container body (3) for sealingly closing the thus filled container.

8. Method according to claim 7, wherein the detachable part (15) of the cap assembly (5) is a top part of the cap assembly, including a tamper evidence cap.

9. Method according to claim 7 or 8, wherein the containers have a main axis, the electron beam emitter being arranged next to the filling enclosure (55) for emitting e-beam radiation toward the containers in a direction substantially radial to their main axis, and wherein the containers are rotated about their main axis during the whole filling cycle except during the steps of removing and replacing the detachable part (15) of the cap assembly (5).

10. Method according to any one of claims 1 to 9, wherein the filling cycle further includes supplying a continuous sterile gas flow in the filling enclosure (55) for preventing any particle potentially present on the external surface of the container(s) (1 ) from remaining in or reaching an area in the vicinity of the cap assembly (5).

11. Method according to claim 10, wherein said sterile gas supplied in the filling enclosure (55) is air.

12. Method according to claim 10, wherein said sterile gas supplied in the filling enclosure (55) is nitrogen or argon.

13. Method according to any one of claims 10 to 12, wherein said sterile gas flows unidirectionally through the filling enclosure (55), vertically from top to bottom.

14. Filling system for carrying out a method according to any one of claims 1 to 13 comprising:

- an infeed station designed to be supplied with a plurality of internally sterile empty containers (1 ), each empty container comprising a container body (3) and a cap assembly (5) sealingly closing an inner volume (24) of the container body (3);

- a filling enclosure (55) that can be selectively opened, for introducing therein or removing therefrom a group of container(s), or at least partially closed, for sterile filling of the containers;

- a conveyor sub-system for sequentially transferring the empty containers (1 ) from the infeed station to the filling enclosure (55);

- a collecting sub-system (70) for, in each filling cycle, picking up a group of empty container(s) (1 ) from the conveyor sub-system, introducing said group of empty container(s) into the filling enclosure (55), closing the filling enclosure (55) and, after filling, extracting said group of container(s) from the filling enclosure;

- an electron beam emitter (73) for sterilizing an external surface of the empty container(s) within the filling enclosure (55) by application of electron beam radiation;

- a delivery sub-system, including respective filling needle(s) (75), for dispensing the pharmaceutical product through the cap assembly (5) of each container (1 ) of the group, wherein the electron beam emitter is suitable for emitting electron beam radiation with a power that can be modulated between a maximum value and a minimum value, different from the maximum value and different from zero, whereby a plurality of filling cycles can be carried out without switching off the electron beam emitter (73).

15. Filling system according to claim 14, wherein the containers have a main axis, the electron beam emitter being arranged next to the filling enclosure (55) for emitting e-beam radiation toward the containers in a direction substantially radial to their main axis, and wherein the collecting sub-system is suitable for rotating the containers about their main axis during at least a part of the filling cycle.

16. Filling system according to claim 14 or 15, wherein the cap assembly (5) has a fixed part (13), through which the filling needle (75) can be introduced for dispensing the pharmaceutical product into the container, and a detachable part (15), the filling system (50) further including a wrench mechanism (79) for, within the at least partially closed filling enclosure (55), removing said detachable part (15) before filling and replacing said detachable part (15) onto each container body (3) for sealingly closing the container (1 ) once filled.

17. Filling system according to any one of claims 14 to 16, further comprising a particle removal sub-system (76) for continuously supplying sterile gas flow in the at least partially closed filling enclosure (55) and thus preventing any particle potentially present on the external surface of the container(s) (1 ) from remaining in or reaching an area in the vicinity of the cap assembly (5).

18. Filling system according to claim 17, wherein the particle removal sub-system (76) is designed such that said sterile gas flows unidirectionally through the filling enclosure, vertically from top to bottom.