Method for filling containers in sterile conditions with a pharmaceutical product and related filling system

Abstract

The invention relates to a method for filling containers in sterile conditions with a pharmaceutical product, comprising the steps of: - supplying a plurality of sterile empty containers (1) into an infeed station, wherein each empty container comprises a cap assembly; - sequentially transferring the empty containers to a filling enclosure (55); - performing a filling cycle, comprising the sequential steps of a) introducing a group of empty container(s) into the filling enclosure (55); b) at least partially closing the filling enclosure (55); c) sterilizing an external surface of the empty container(s) by application of radiation; d) introducing a filling needle (75) through the fixed part (13) of the cap assembly and dispensing a pre-defined amount of pharmaceutical product into each container (1); e) opening the filling enclosure (55) and extracting the group of filled container(s); - repeating a filling cycle with a subsequent group of empty container(s). The invention is also directed to a related filling system.

Description

[0001] METHOD FOR FILLING CONTAINERS IN STERILE CONDITIONS WITH A PHARMACEUTICAL PRODUCT AND RELATED FILLING SYSTEM

[0002] Technical field

[0003] The present invention relates to methods for sterile filling of containers for pharmaceutical products, such as vials, and to related filling systems.

[0004] More specifically, the invention relates to methods wherein sterile empty containers, each closed by a cap assembly, are supplied and then filled with the pharmaceutical product in a filling station.

[0005] Background of the invention

[0006] 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.

[0007] 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.

[0008] 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.

[0009] 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.

[0010] 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, that includes the sterilization station, the filling station and the laser sealing station.

[0011] 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.

[0012] Summary of the Invention

[0013] According to a first aspect of the present invention, it is provided a method for filling containers in sterile conditions with a pharmaceutical product, comprising the steps of:

[0014] - supplying a plurality of sterile empty containers into an infeed station, wherein each empty container comprises a container body and a cap assembly sealingly closing an inner volume of the container body and having at least a fixed part;

[0015] - 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;

[0016] - 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 radiation; d) introducing a filling needle through the fixed part of the cap assembly and dispensing a pre-defined amount of pharmaceutical product through the filling needle into each container, 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).

[0017] 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.

[0018] Preferred embodiments of the invention may include one or several of the following features:

[0019] - the cap assembly further has a detachable part and the filling cycle further comprises the steps of

[0020] • after step b) and before step d), removing the detachable part of the cap assembly;

[0021] • 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;

[0022] - the detachable part of the cap assembly is a top part of the cap assembly, including a tamper evidence cap;

[0023] - 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;

[0024] - the sterile gas supplied in the filling enclosure is air.

[0025] Alternatively, the sterile gas supplied in the filling enclosure may be nitrogen or argon.

[0026] Preferred embodiments may further include one or several of the following features:

[0027] - the sterile gas flows unidirectionally through the filling enclosure, vertically from top to bottom;

[0028] - the empty containers are supplied to the infeed station sterile, packaged in sterile bags and debagged once inside the infeed station before being transferred to the filling enclosure;

[0029] - the infeed station is supplied with a sterile air flow;

[0030] - the method is carried out in a room defining a grade D space, the infeed station and the filling enclosure being located within said room. In a further aspect, it is provided a filling system for carrying out a method as described above, comprising:

[0031] - an infeed station designed to be supplied with a plurality of sterile empty containers, each empty container comprising a container body and a cap assembly sealingly closing an inner volume of the container body and having at least a fixed part;

[0032] - 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;

[0033] - a conveyor sub-system for sequentially transferring the empty containers from the infeed station to the filling enclosure;

[0034] - 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;

[0035] - a radiation sterilization sub-system for sterilizing an external surface of the empty container(s) within the filling enclosure by application of radiation;

[0036] - a delivery sub-system, including respective filling needle(s), for dispensing the pharmaceutical product through the fixed part of the cap assembly of each container of the group.

[0037] Preferably, the filling system of the invention may include one or several of the following features:

[0038] - the cap assembly further has 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;

[0039] - 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;

[0040] - the particle removal sub-system is designed such that said sterile gas flows unidirectionally through the filling enclosure, vertically from top to bottom;

[0041] - the empty containers are supplied into the infeed station sterile and packaged in sterile bags, and wherein the infeed station includes a debagging mechanism for debagging the sterile empty containers and transferring them to the conveyor sub-system. Brief Description of the Drawings

[0042] A preferred embodiment of the invention will now be described in more details, with reference to the following drawings wherein:

[0043] - Figure 1 is an elevation view of a vial adapted to be filled with a method according to the invention;

[0044] - Figure 1A is a cross-sectional view, in the vertical mid-plane A-A, of the vial of Figure 1 , filled with a pharmaceutical product;

[0045] - Figure 2 is a plan view of trays supporting multiple vials as shown on Figure 1 for supply to a filling system according to the invention;

[0046] - Figure 3 is a schematic plan view illustrating the layout of a filling line including multiple units each comprising a filling system according to the invention;

[0047] - Figure 4 is an enlarged detail view of a single unit represented on Figure 3;

[0048] - Figure 5 is an exploded perspective view of a filling system according to the invention;

[0049] - Figure 6 is a perspective view of the assembled filling system of Figure 5 in an initial step of a method according to the invention;

[0050] - Figure 7 is a front elevation view of the filling system of Figure 5, in the initial step represented on Figure 6, showing a group of in-line vials to be processed and a group of in-line vials after filling;

[0051] - Figure 8 is a perspective view of the assembled filling system of Figures 6 and 7 in a subsequent step of the method;

[0052] - Figure 9 is a front elevation view of the filling system of Figures 6 to 8 in a subsequent step of the method;

[0053] - Figures 10 to 13 are perspective views of the filling system of Figures 6 to 10 in respective subsequent steps of the method according to the invention.

[0054] Detailed Description of a Preferred Embodiment

[0055] Definitions

[0056] The following definitions will be used in the present description and claims:

[0057] - the term “sterile” means, referring to an environment or an object, free of any living microorganisms (or viable organisms); and - the term “grade” in combination with letters A, B, C, or D refers to the environmental classification defined in the European Commission Ell GMP document, Annex 1 , Vol. IV., “Manufacture of Sterile Medicinal Products” (effective 01 March 2009). The grades correspond to maximum numbers of particles permitted per m3and maximum permitted numbers of viable organisms expressed in CFU (Colony- Forming-Units) / m3.

[0058] The invention will now be further illustrated by the following preferred embodiment illustrated on the Figures.

[0059] Figures 1 and 1A illustrate a vial adapted to contain a pharmaceutical product and to be filled with a method of the invention. The vial 1 , represented in an upright position in a vertical plane, comprises a vial body 3 and a cap assembly 5.

[0060] While the invention is described for particular application to vials, it is applicable to other containers suitable for containing pharmaceutical products, such as bags, cartridges or syringes. In the case of cartridges or syringes, the cap assembly may be constituted by a stopper.

[0061] The vial body 3 is typically made from glass but may alternatively be made from any other material compatible with a pharmaceutical use. 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.

[0062] The cap assembly 5 comprises a fixed part and a detachable part respectively consisting of, in the illustrated embodiment, a stopper 13 and an outer cap 15.

[0063] 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 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.

[0064] 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.

[0065] In the illustrated embodiment, the stopper 13 has an external flange 21 , engaging an external surface of the neck portion 9 and defining therewith the snap-fit connection 17, and an inner 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 25 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.

[0066] The stopper 13 is preferably made from a relatively soft material such as rubber or TPE.

[0067] 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.

[0068] In the illustrated embodiment, 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.

[0069] The outer cap 15 is formed with a pair of opposing flat faces 27 that extend in planes parallel to the main axis X. The outer cap 15 is preferably made from a relatively hard material such as polypropylene or other plastic material.

[0070] 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.

[0071] With reference to Figure 2, vials of the type described in the foregoing are supplied for filling to a process line laid-out in trays 33, each vial 1 being inserted in a respective cavity 35 of the tray. The vials and the trays are sterile and thus packaged is sterile bags (not shown), for example made from polyethylene. The vials are empty and closed, the cap assembly 5 being sealingly attached to the vial body 3. The sterility of the vials, both inside and on the outside surface, is thus maintained due to isolation from the external environment by the sterile bags.

[0072] Referring to Figures 3 and 4, preferred layout of a process line 40 for implementing the method of the invention will now be described.

[0073] Trays 33 accommodating multiple sterile empty vials 1 are supplied, packed in the respective sterile bags, into a control room 41 . Pharmaceutical product in a liquid form (or drug product) for filling the vials, presented in large volume (e.g. 1000 L) bags 43 or vessels, is also supplied into the control room 41 . Bagged trays and drug product bags 43 can be manually handled by operators 45.

[0074] Adjacent to the control room 41 is a filling room 47, both rooms being separated by a wall 48. In the filling room 48, a plurality of identical filling systems 50 are provided (six in the represented example).

[0075] The process line 40 includes, extending through the wall 48 and within both rooms 41 , 47, a supply conveyor 51 for supplying the bagged trays 33 to the filling systems 50. The bagged trays 33 can thus be loaded onto the supply conveyor 51 by the operators 45 in the control room 41 and conveyed through the wall 48 into the filling systems 50 located in the filling room 47. Also, a door is provided in the wall 48 for the operators 45 to periodically enter the filling room 47 for replacing empty product bags 43 of the respective filing systems 50 with fresh ones when necessary (e.g. once a week).

[0076] While operators 45 are needed to work in the control room 41 , the filling room 47 is essentially run automatically. Human presence in the filing room 47 is only required, beyond maintenance operations, for changing the product bags 43 and is thus minimized.

[0077] As more apparent from Figure 4, each filling system 50 includes an infeed station 53 designed to be supplied with the sterile empty containers 1 arranged in trays 33 packaged in the sterile bags. The filling system 50 further includes a filling enclosure 55 and a conveyor sub-system 57.

[0078] The infeed station 53 includes a debagging mechanism (not shown) for debagging the sterile empty vials 1 and transferring them to the conveyor sub-system 57. Said conveyor sub-system is in turn designed for sequentially transferring the debagged empty vials 1 from the infeed station 53 to the filling enclosure 55. The infeed station 53 is preferably supplied with a sterile air flow.

[0079] Once processed within the filling enclosure 55, the vials 1 are re-arranged in trays 33 and conveyed by the conveyor sub-system 57 to a collection area 59 for automated return of the filled vials into the control room 41 .

[0080] The supply conveyor 51 and / or the conveyor sub-system 57 may be for example of the type known as XPIanar®, a technology available from the company Beckhoff Automation.

[0081] Both rooms 41 , 47 define a grade D space, whereby the method for filling the vials of the invention is carried out within a grade D space. It will be appreciated that, as soon as the vials are debagged in a non-sterile grade D space, their outer surface cannot be assumed to remain sterile. In contrast, the interior of the vials, which is closed by the cap assembly, is still maintained in sterile conditions.

[0082] With particular reference to Figures 5 and 6, the filling system 50 comprises a collecting sub-system including 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 cavity 71 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.

[0083] 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 the conveyor sub-system 57, introducing said vial into the filling enclosure 55, displacing it within the filling enclosure and, after filling, extracting it from the filling enclosure.

[0084] In the illustrated embodiment, the collecting sub-system is adapted to process only one single vial (that can be defined as a group of one vial) per cycle. It is however conceivable that the collecting sub-system may process simultaneously a group of several vials, using multiple pistons simultaneously operated for respective vials or using a single piston with multiple cavities for respective vials, for simultaneously displacing and processing multiple vials.

[0085] The filling system 50 further comprises a radiation sterilization sub-system 73, arranged next to the filling enclosure 55, for emitting a radiation such as e-beam radiation toward the filling enclosure 55 and sterilizing, by application of such radiation, an external surface of an empty vial 1 placed within the filling enclosure 55.

[0086] Furthermore, the filing system 50 includes a delivery sub-system, that comprises a filling needle 75, for dispensing pharmaceutical product through the stopper 13 of a vial 1 placed in the filling enclosure for being processed. The filling needle 75 is in fluid communication with the corresponding drug product bag 43. 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.

[0087] Also part of the filling system 50 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 communication with a sterile gas supply source (not shown). The particle removal sub- system 76 is designed such that, when supplied to the filling enclosure 55, the sterile gas flows unidirectionally therethrough, vertically from top to bottom.

[0088] 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.

[0089] The filling system 50 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. 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.

[0090] The filling enclosure 55 of the filling system 50 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.

[0091] 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.

[0092] 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 .

[0093] 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).

[0094] 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 .

[0095] As can be seen on Figure 8, 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 7 and 9). The exhaust duct 97 is preferably connected to a testing system for continuous or periodic control.

[0096] It will be noted that the filling enclosure 55, while never strictly closed, can be selectively open or at least partially closed. 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.

[0097] Reference will now be made to Figures 7 through 13 for describing a method according to a preferred embodiment of the invention.

[0098] 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 the infeed station 53, as described in the foregoing with reference to Figures 3 and 4. The empty vials are then sequentially transferred to the filling enclosure 55 for being sequentially processed by performing a filling cycle.

[0099] Figure 7 illustrates an initial configuration of the filling system 50 when performing a filling cycle, wherein a line of empty vials 1 (represented on the right-hand side of Figure 7) 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 33 and then being conveyed to the collection area 59, as described in the above. The conveyor sub-system is not represented on this Figure.

[0100] In this initial configuration, the piston 70 engages a vial to be processed whereby the vial is partly inserted in the cavity 71 of the piston and located outside and underneath the filling enclosure 55. With the piston 70 and the vial positioned outside the filling enclosure, the filling enclosure 55 is in an open configuration wherein the ambient, supposedly non- sterile, air of the room can freely flow into the filling enclosure 55. The filling cycle for the vial picked-up by the piston 70 can then start.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] This configuration is illustrated by Figure 8.

[0105] In a subsequent step of the filling cycle, illustrated by Figure 9, e-beam radiation is emitted by the radiation sterilization sub-system 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. The emission of e-beam radiation is then stopped once the sterilization has been achieved.

[0106] Referring to Figure 10, 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.

[0107] In the subsequent step illustrated on Figure 11 , 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.

[0108] As represented on Figure 12, 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 10 and, 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.

[0109] It will be noted that sterility is maintained within the filling enclosure 55 after the radiation sterilization until the filling enclosure is opened.

[0110] 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 13, with the piston 75 no longer projecting through the hole 91 , the filling enclosure 55 is returned into its open configuration.

[0111] 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.

[0112] As already mentioned, a filling method according to the invention may be carried out with a group of vials or containers simultaneously processed during the same filing cycle and within a single filling enclosure.

[0113] The method 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.

[0114] The method of the invention is adapted to supplies of containers pre-sterilized on a different site, thereby reducing the space required for sterile operations and providing flexibility to the production line.

Claims

CLAIMS1 . Method for filling containers in sterile conditions with a pharmaceutical product, comprising the steps of:- supplying a plurality of sterile empty containers (1 ) into an infeed station (53), 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) and having at least a fixed part (13);- 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 radiation; d) introducing a filling needle (75) through the fixed part (13) of the cap assembly (5) and dispensing a pre-defined amount of pharmaceutical product (30) through the filling needle (75) into each container (1 ), 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).

2. Method according to claim 1 , 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.

3. Method according to claim 2, wherein the detachable part (15) of the cap assembly (5) is a top part of the cap assembly, including a tamper evidence cap.

4. Method according to any one of claims 1 to 3, 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).

5. Method according to claim 4, wherein said sterile gas supplied in the filling enclosure (55) is air.

6. Method according to claim 4, wherein said sterile gas supplied in the filling enclosure (55) is nitrogen or argon.

7. Method according to any one of claims 4 to 6, wherein said sterile gas flows unidirectionally through the filling enclosure (55), vertically from top to bottom.

8. Method according to any one of claims 1 to 7, wherein the empty containers (1 ) are supplied to the infeed station (53) sterile, packaged in sterile bags and debagged once inside the infeed station before being transferred to the filling enclosure (55).

9. Method according to any one of claims 1 to 8, wherein the infeed station (53) is supplied with a sterile air flow.

10. Method according to any one of claims 1 to 9, wherein the method is carried out in a room (47) defining a grade D space, the infeed station (53) and the filling enclosure (55) being located within said room.

11. Filling system for carrying out a method according to any one of claims 1 to 10, comprising:- an infeed station (53) designed to be supplied with a plurality of 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) and having at least a fixed part (13);- 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 (57) for sequentially transferring the empty containers (1 ) from the infeed station (53) 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 (57), 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;- a radiation sterilization sub-system (73) for sterilizing an external surface of the empty container(s) within the filling enclosure (55) by application of radiation;- a delivery sub-system, including respective filling needle(s) (75), for dispensing the pharmaceutical product through the fixed part (13) of the cap assembly (5) of each container (1 ) of the group.

12. Filling system according to claim 11 , wherein the cap assembly (5) further has 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.

13. Filling system according to claim 11 or 12, 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).

14. Filling system according to claim 13, 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.

15. Filling system according to any one of claims 11 to 14, wherein the empty containers (1 ) are supplied into the infeed station (53) sterile and packaged in sterile bags, and wherein the infeed station (53) includes a debagging mechanism for debagging the sterile empty containers (1 ) and transferring them to the conveyor sub-system (57).

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