METHOD FOR FILLING CONTAINERS

Description

FIELD OF THE INVENTION

[0001] The present invention relates to a method for aseptically filling containers, in particular bottles, with a previously formed sterile composition. The present invention further relates to a filled container, in particular a filled bottle, resulting from the method according to the invention, in particular directly resulting from the method according to the invention. CONTEXT OF THE INVENTION

[0002] Automatic filling systems or filling lines for automatically filling containers, for example containers or bottles, with a pharmaceutical composition are known from the state of the art, for example FR 2 464 222 A1.

[0003] Empty containers are often purchased from an external company, which containers are pre-packaged and at least partially wrapped in a polymer wrapper or film. Typically, said bottles or containers all have their openings located on the same side of the wrapper. In order to be used and filled in the filling line, the containers must first be unwrapped. In particular, unwrapping consists of removing a polymer film at least partially wrapping a series of containers held together by this same polymer film.

[0004] Typically, the containers are completely or at least partially wrapped by a polymer film constituting a packaging in which the openings of the containers are all oriented on the same side and are covered by a part of said polymer film. During an unpacking step to access the containers by freeing them from the polymer film using a cutting tool, cutting the polymer film along the openings of the containers has the disadvantage that the edge of the opening of the latter can be damaged by the cutting tool. A damaged edge, for example an edge having a scratch or a notch due to the impact and / or the passage of the cutting tool, can compromise the ability of the containers to be hermetically closed according to the standards in force when carrying out aseptic fillings. In addition, the use of a tool to remove the packaging or the polymer film can give rise to additional contamination in the containers.

[0005] There is therefore a need to provide an aseptic container filling process that is reliable for supplying empty containers to a filling line, wherein the process of removing a series of containers from a package leaves the containers intact without giving rise to further contamination of the containers. SUMMARY OF THE INVENTION

[0006] The inventors have found that the method according to the present invention meets the above-mentioned needs and overcomes the above-mentioned drawbacks.

[0007] In the present invention, there is provided a method for aseptically filling containers, in particular bottles, with a previously formed sterile composition, said method comprising sequentially: a) a step of positioning a series of containers held together by a polymer film and each having an opening delimited by an edge as well as a bottom wall opposite said opening, on a laying surface of a first support located upstream of a washing and drying unit, said positioning step being carried out in such a way that the edge delimiting each opening of each container rests against said laying surface of said first support, a part of said polymer film being located between said laying surface of said first support and each opening of each container, b) a step of cutting said polymer film along the bottom walls of said containers, c) a step of pulling on said polymer film in such a way as to slide it downwards towards said laying surface of said first support,d) a step of placing a second support connected to the first support and resting against the bottom walls of each of said containers so that the latter are wedged between said first support and said second support, said second support and said first support forming an assembly, e) a step of rotating said assembly through an angle of 180° so that said containers wedged between said first support and said second support undergo a rotation of 180°, f) a step of releasing said first support so that said containers are no longer wedged between said first support and said second support, g) a step of completely removing said polymer film by releasing upwards to release said containers from said polymer film, h) a step of transferring said containers released from said assembly to said washing and drying unit,i) a step of washing and drying said containers by passing them through said washing and drying unit to obtain washed and dried containers, j) a step of transferring said washed and dried containers from said washing and drying unit to a depyrogenation unit, k) a step of depyrogenating said containers by passing them through said depyrogenation unit to obtain depyrogenized containers, l) a step of transferring said depyrogenized containers from said depyrogenation unit to a filling unit, m) a step of filling said depyrogenized containers by passing them through said filling unit, to obtain containers filled with said previously formed sterile composition, n) a step of placing a stopper in the opening of said filled containers,said step of placing said cap consisting of: either a complete insertion of said cap into said opening to achieve a hermetic closure of said filled containers, or a first partial insertion of a first part of said cap into said opening to achieve a non-hermetic closure of said filled containers in order to allow the performance of a freeze-drying step in a freeze-drying unit to obtain containers filled at least partially with a freeze-dried product, and a second subsequent insertion of a second part not yet inserted of said cap to achieve a hermetic closure of said containers filled at least partially with a freeze-dried product, o) a step of transferring said filled and hermetically closed containers to a crimping unit for said containers, to obtain crimped filled containers.

[0008] Advantageously, the method as proposed according to the present invention comprises all the steps necessary to ensure the filling of containers or bottles with a previously prepared composition, according to or in line with standard practices in the pharmaceutical industry. More particularly, the method according to the invention comprises a washing and drying step, a depyrogenation step, and further contains a step of hermetically sealing the container, optionally after lyophilization, by placing a stopper.

[0009] The method as proposed according to the present invention advantageously makes it possible to avoid any damage to the edge or rim of the containers. Indeed, during a step preceding the washing and drying steps, the depyrogenation step and the step of hermetically sealing the containers, the polymer film enveloping the series of containers is cut on the side where the bottoms or bases of the containers are located, said bottoms or bases of the containers preferably being oriented essentially upwards during this step. It has been found that carrying out such a cut on the side where the bottoms or bases of the containers are located, for example along the bottoms or bases of the bottles, does not cause serious damage compromising the performance of a subsequent step of hermetically sealing the containers.

[0010] This step of cutting the polymer film is then followed by a step of rotating the plurality of containers through an angle of 180°, or essentially through an angle of 180°. Such a rotation step not only allows the openings of the containers to be positioned in a suitable position before their transfer to a washing and drying unit but also allows for a complete shrinkage of the polymer film, all this while ensuring that the containers do not suffer damage, in particular at the edge of their opening. Therefore, according to the invention, no batch or series of containers, or at least only a small number of containers, need to be removed from the filling system. Furthermore, no monitoring is necessary to ensure the absence of damage at the edge part of the opening of the containers.

[0011] The method further has the advantage that the sequence of steps b) to f) avoids or at least reduces contamination of the interior of the container. FIGURES

[0012] There Figure 1 illustrates a series of containers, in particular a series of bottles, wrapped and held together by a polymer film. The Figures 2a-e are side views illustrating the principles of steps d) -f) according to one embodiment of the invention. DETAILED DESCRIPTION

[0013] The invention relates to a method for filling containers, in particular bottles, under aseptic conditions with a previously formed sterile composition.

[0014] It has been found that by using the method as described in the context of the present invention, the risk of damaging the containers, in particular the edge of the opening of the containers, as well as the risk of contamination of the containers during removal of the polymer film, can be significantly or even completely reduced.

[0015] For this purpose, a method for filling containers under aseptic conditions is proposed, said method comprising the following sequential steps: In a first step a) of the method according to the invention, a step of positioning a series of containers 1 held together by a polymer film 10 and each having an opening 2 delimited by an edge 3 as well as a bottom wall 4 opposite said opening 2, on a laying surface 20 of a first support 21 located upstream of a washing and drying unit, said positioning step being carried out in such a way that the edge 3 delimiting each opening 2 of each container 1 rests against said laying surface 20 of said first support 21, a part of said polymer film 10 being located between said laying surface 20 of said first support 21 and each opening 2 of each container 1.

[0016] For the purposes of the invention, the term "container" here refers to a receptacle or container suitable for storing / packaging compositions, in particular sterile compositions, in particular in a pharmaceutical context, such as bottles or flasks. Said container 1 has an opening 2 at one of its ends, which opening 2 allows said composition to be introduced and extracted from said container and which opening 2 is opposite the bottom of said container 1, more particularly a bottom wall 4 of said container 1, said bottom being located at another end of the container 1 and which bottom forms the base of the latter. The opening 2 is delimited by an edge 3. In particular embodiments, the edge 3 may relate to an edge inside the opening 2. According to such embodiments, the opening 2 may further have a second edge outside the opening.

[0017] Typically and with reference to the Figure 1, said containers 1 are sold grouped and / or packaged in a series or a plurality of containers 1, which may be held together, for example packaged or wrapped, by a film or a polymeric packaging 10. Usually, the plurality or series of containers 1 will be grouped in a rectangular or square shape, having a number of containers A in a first row in the x-direction, and a number of containers B in a second row in the y-direction, where A may be equal to B, resulting in a plurality of containers 1 packaged in a square shape; where A may be different from B, resulting in a plurality of containers 1 packaged in a rectangular shape. As a rule, the containers 1 will not be stacked on top of each other. On the Figure 1 , container series 1 has eight containers along an X axis, and four containers along a Y axis.

[0018] Typically, said polymer is a polyolefin, in particular polyethylene or polypropylene.

[0019] Typically, the openings 2 of the containers 1 will all be facing / oriented towards the same side in the wrapped / packaged configuration, so that a first flat area 11 of the polymer film 10 will be in contact with said openings 2 of the containers 1, while a second flat area 12 of the polymer film 10, opposite said first flat area 11 and substantially parallel thereto, will be in contact with said bottom walls 4 of said containers 1.

[0020] According to the method of the invention, the containers 1 held together by said polymer film 10, are arranged or positioned on a laying surface 20 of a first support 21, which first support 21 is located upstream of a washing and drying unit, in such a way that the openings 2 of the containers 1, in particular said edges 3 of each opening 2 of each container 1, face said laying surface 20 of said first support 21 and / or rest or rest against said laying surface 20 of said first support 21, a part of said polymer film 10 being located between said laying surface 20 of said first support 21 and the openings 2 of said containers 1.

[0021] In embodiments of the method, said laying surface 20 will be horizontal or essentially horizontal, and the series of containers 1 will be placed above said laying surface, with their openings 2 facing downwards or essentially downwards towards said laying surface 20.

[0022] The terms "essentially" or "substantially" with respect to a certain direction or rotation mean in this context that a deviation of at most 20°, preferably at most 15°, more preferably at most 10°, even more preferably at most 5°, and even more preferably at most 2° is always considered to be along said direction or rotation.

[0023] In a subsequent step b) of the method according to the invention, a step of cutting said polymer film 10 along the bottom walls 4 of said containers 1 is provided.

[0024] In embodiments of the method according to the invention, the step of cutting said polymer film 10 is carried out manually. Advantageously, the intervention of an operator makes it possible to avoid damaging the container bottoms 1, in particular the bottom walls 4, because this operator can avoid cutting the container bottoms 1 by cutting mainly in the empty space created between the container bottoms held together by said polymer film 10.

[0025] In alternative embodiments of the method according to the invention, the cutting of said film 10 is carried out in an automated manner.

[0026] Typically, this cutting step will result in the cutting of said second flat area 12 into at least two different parts.

[0027] In a subsequent step c) of the method according to the invention, a step of pulling on said polymer film 10 is provided so as to slide it downwards towards said laying surface 20 of said first support 21.

[0028] In preferred embodiments of the method according to the invention, the step of pulling on said film 10 is carried out manually. Advantageously, manual intervention makes it possible to pull and slide the polymer film 10 downwards or substantially downwards, without any container 1 falling to the side when it is positioned on said laying surface 20 of said first support 21.

[0029] In alternative embodiments of the method according to the invention, the step of pulling on said polymer film 10 is carried out in an automated manner.

[0030] In preferred embodiments of the method according to the invention, the step of pulling said polymer film 10 will result in a configuration according to which the polymer film 10 does not cover or no longer covers each of the bottom walls 4 of said series of containers 1, which means that the polymer film 10 is not or is no longer in contact with said bottoms of said containers 1, more particularly with each bottom wall 4 of each container 1. More particularly, said second flat area 12 of the polymer film 11, typically cut into at least two different parts following said cutting step b), can be slid downwards or substantially downwards, towards said laying surface 20 of said first support 21, so that all of the bottom walls 4 are no longer in contact with or are no longer covered by said second flat area 12 of the polymer film 10.

[0031] In a subsequent step d) of the method according to the invention and with reference to the Figure 2 , a step of placing a second support 31 connected to the first support 21 and resting against the bottom walls 4 of each of said containers 1 is provided in such a way that the latter are wedged between said first support 21 and said second support 31 ( Fig. 2a-2b ), said second support 31 and said first support 21 forming a whole.

[0032] In preferred embodiments of the method according to the invention, said second support 31 has a resting surface 30 which ensures contact with the bottom walls 4 of each of said containers 1, by resting against the bottom walls 4 of each of said containers 1. Thus, each of said containers 1 is wedged between a resting surface 20 of said first support 21 and a resting surface 30 of said second support 31. In particular, each of said bottom walls 4 of each of said containers 1 is in contact with said resting surface 30 of said second support 31 and each of the edges 3 delimiting said opening 2 of each of said containers 1 is in contact with or rests against said resting surface 20 of said first support 21, a part of said polymer film 10 being located between said resting surface 20 of said first support 21 and the openings 2 of said containers 1.

[0033] Preferably, said first support 21 and said second support 31 have the same dimension and / or shape.

[0034] In preferred embodiments of the method according to the invention, the step of placing a second support 31 is carried out without said second support 31 or said laying surface 30 of said second support 31, by pressing against the bottom walls 4 of each of said containers 1, touching said polymer film 10.

[0035] In embodiments of the method according to the invention, said second support 31 and said first support 21 form an assembly, in which said first support 21 and said second support 31 are connected in an articulated manner (not shown in the figure).

[0036] In embodiments of the method according to the invention, said second support 31 and said first support 21 form an assembly, in which said first support 21 and said second support 31 are essentially parallel, the distance between said supports 21, 31 being able to be modifiable, that is to say it can increase and / or decrease, without however substantially modifying the parallel nature of said supports 21, 31.

[0037] In a subsequent step e) of the method according to the invention, a step of rotating said assembly through an angle of essentially 180° or 180° ( Fig. 2c ) such that said containers 1 wedged between said first support 21 and said second support 31 undergo a rotation of essentially 180° or 180°.

[0038] In preferred embodiments of the method according to the invention, the assembly formed by said second support 31 and said first support 21 is rotated through an angle of 180°, relative to an axis which is essentially horizontal and around which said assembly rotates.

[0039] In preferred embodiments of the method according to the invention, step e) results in a positioning of the series of containers 1 essentially horizontal, the bottom wall 4 of each container 1 being oriented downwards, resting on the laying surface 30 of said second support 31.

[0040] In a subsequent step f) of the method according to the invention, a step of releasing said first support 21 is provided such that said containers 1 are no longer stuck between said first support 21 and said second support 31 ( Fig. 2d-2e ).

[0041] This step of releasing said first support 21 can be carried out by completely removing said first support 21 or by rotating the latter around an axis in order to raise it.

[0042] This step of releasing said first support 21 results in a break in the contact between said first support 21 and the edges 3 of the openings 2 of the containers 1.

[0043] This step of releasing said first support 21 is typically carried out by lifting or releasing said first support 21 to a higher position relative to the containers 1, preferably while maintaining the position of said first support 21 essentially parallel relative to said second support 31. Thus, this step results in the edges 3 delimiting each opening 2 of each container 1 no longer resting against said resting surface 20 of said first support 21. This step has the additional result that a space is created between the openings of the containers 1 and said first support 21, allowing the polymer film 10 covering the openings 2 of the containers 1 to be completely removed by upward release.

[0044] In a subsequent step g) of the method according to the invention, a step of total removal of said polymer film 10 by upward release is provided to release said containers 1 from said polymer film 10.

[0045] In embodiments according to the invention, said step of total removal of said polymer film 10 by upward release is carried out manually.

[0046] Advantageously, manual intervention makes it possible to remove the polymer film 10 by releasing it upwards, without any container 1 falling to the side.

[0047] In alternative embodiments of the method according to the invention, the removal of said polymer film 10 is carried out in an automated manner.

[0048] In preferred embodiments of the method according to the invention, step g) results in a positioning of the series of containers 1 essentially horizontal, placed on said placing surface 30 of said second support 31, in which the edges 3 of said openings 2 of the containers 1 are no longer in contact with the first support 21, and in which said polymer film 10 is completely removed and is no longer in contact with said containers 1.

[0049] In a subsequent step h) of the method according to the invention, a step of transferring said containers 1 released from said assembly to said washing and drying unit is provided.

[0050] In embodiments of the method according to the invention, said transfer of said containers 1 from said assembly to said washing and drying unit is carried out by means of a conveyor.

[0051] For the purposes of the present invention, the term "conveyor" designates any means or device for moving and / or transporting an element from a first location or a first zone to a second location or a second zone.

[0052] In embodiments of the method according to the invention, said openings 2 of the containers 1 are pointed upwards. This has the advantage that the containers 1 are easier to transport on the conveyor.

[0053] In a subsequent step i) of the method according to the invention, a step of washing and drying said containers 1 is provided by passing them through said washing and drying unit to obtain washed and dried containers 1.

[0054] In embodiments of the method according to the invention, said washing and drying unit comprises at least one of the following elements: a first inlet chamber, a washing chamber and a drying chamber.

[0055] In preferred embodiments of the method according to the invention, the washing and drying unit comprises means arranged to individually take charge of each container 1, preferably in or through said first inlet chamber, and to present each container 1, preferably in the washing chamber, to washing means, said containers 1 having their opening 2 preferably directed downwards.

[0056] In preferred embodiments of the method according to the invention, said washing means comprise a first upwardly directed nozzle, and preferably first means arranged to raise said upwardly directed nozzle so that it approaches or enters one of said containers 1 to supply a washing liquid and carry out the required washing while maintaining the container 1 in a fixed position.

[0057] In preferred embodiments of the method according to the invention, said washing liquid is purified water and said nozzle is provided for injecting said purified water into said containers 1. Typically, said purified water is distilled water.

[0058] Advantageously, according to the method according to the invention, additional washing is carried out by injection of water for injectable preparation.

[0059] In preferred embodiments, said purified water is injected at a temperature between 20°C and 30°C, and for a duration between 2 and 5 seconds per wash.

[0060] Preferably, according to the method according to the invention, three successive washes are carried out. Typically, each container 1 comprising at least a portion of said injected washing liquid is then dried by drying means, preferably after having been transferred into a drying chamber.

[0061] In preferred embodiments, said containers 1 have their opening 2 preferably directed downwards and said washing and drying unit comprises said drying means, said drying means comprising a second nozzle directed upwards, and preferably further means arranged to lower said second nozzle directed upwards, so that it approaches or enters one of said containers 1 to supply a dry gas into the container 1, typically by blowing said dry gas into the container 1 under high pressure, thereby expelling said washing liquid.

[0062] In preferred embodiments, said dry gas is dry air or a gas containing at least 95% nitrogen. Preferably, said dry gas is filtered compressed air.

[0063] In preferred embodiments, said gas has a temperature between 20°C and 30°C.

[0064] In preferred embodiments, said washing and drying unit comprises means for holding and fixing an individual container 1 in a determined position at least for part of the duration of step i).

[0065] In a subsequent step j) of the method according to the invention, a step of transferring said washed and dried containers 1 from said washing and drying unit to a depyrogenation unit is provided.

[0066] In embodiments according to the invention, said transfer of said washed and dried containers 1 from said washing and drying unit to a depyrogenation unit is carried out by a conveyor.

[0067] In embodiments according to the invention, said transfer of said washed and dried containers 1 is carried out in a closed space or in a closed tunnel, so that contamination of the washed and dried container can be reduced to a minimum.

[0068] In a subsequent step k) of the method according to the invention, a step of depyrogenation of said containers 1 is provided by passing through said depyrogenation unit to obtain depyrogenized containers.

[0069] The depyrogenation process herein relates to the process of deactivating and / or degrading pyrogens, said pyrogens including bacterial endotoxins, exotoxins and the bioburden of the surfaces of the bottles or containers. The bioburden herein relates to the amount of microbiological contamination of an unsterilized object or an unsterilized surface.

[0070] In preferred embodiments according to the invention, said depyrogenation step relates to depyrogenation by dry heat.

[0071] Typically, said depyrogenation unit comprises a batch furnace or a depyrogenation tunnel. Preferably, said depyrogenation unit consists of a depyrogenation tunnel.

[0072] In embodiments of the method according to the invention, said depyrogenation tunnel comprises at least one of the following elements: a second inlet chamber, a hot chamber and a cooling chamber.

[0073] In embodiments of the method according to the invention, the depyrogenation tunnel further contains a fourth chamber at the end of the tunnel, said fourth chamber being intended for additional cooling.

[0074] In preferred embodiments of the method according to the invention, the depyrogenation unit comprises means arranged to individually move said containers through at least one of said chambers.

[0075] Preferably, said depyrogenation unit, in particular said hot chamber, consists of at least a first dry heat depyrogenation zone, which comprises exposing the containers 1 to a temperature of at least 270°C for the duration of an imposed and predetermined residence time. Preferably, said containers 1 are exposed to a temperature of 280°C or higher, more preferably to a temperature of 300°C or higher, even more preferably to a temperature of 320°C or higher, and most preferably to a temperature of 340°C or higher, for a duration of an imposed and predetermined residence time.

[0076] In preferred embodiments of the method according to the invention, said residence time in said first depyrogenation zone may be at least 15 minutes, preferably at least 30 minutes. Preferably, said residence time will be between 15 minutes and 50 minutes, preferably between 20 minutes and 40 minutes.

[0077] In preferred embodiments of the method according to the invention, said cooling chamber operates at a temperature between 10°C and 20°C, preferably at a temperature of 18°C.

[0078] In preferred embodiments of the method according to the invention, a container 1 is subjected to a residence time in said cooling chamber of at least 15 minutes, preferably at least 30 minutes. Preferably, said residence time will be between 15 minutes and 50 minutes, preferably between 20 minutes and 40 minutes.

[0079] It has been found that the combination of residence time as described herein and temperature in the depyrogenation unit provides at least a 5 log, preferably a 6 log reduction of said biological load and pyrogens.

[0080] In a subsequent step l) of the method according to the invention, a step of transferring said depyrogenized containers 1 from said depyrogenation unit to a filling unit is provided.

[0081] In embodiments according to the invention, said transfer of said depyrogenized containers 1 from said depyrogenation unit to a filling unit is carried out by a conveyor.

[0082] In embodiments according to the invention, said transfer of said depyrogenized containers 1 from said depyrogenation unit to a filling unit is carried out in a closed space or a closed tunnel, so that contamination of the washed and dried container can be reduced to a minimum.

[0083] In a subsequent step m) of the method according to the invention, a step of filling said depyrogenized containers 1 by passing through said filling unit is provided, to obtain containers 1 filled with said previously formed sterile composition.

[0084] In embodiments of the method according to the invention, said filling unit comprises at least one of the following elements: a third intake chamber, and a filling chamber.

[0085] According to the invention, said containers 1 have their opening 2 preferably directed upwards in the filling unit.

[0086] In preferred embodiments of the method according to the invention, the filling unit comprises means arranged to individually move said containers 1 through at least one of said chambers.

[0087] In preferred embodiments of the method according to the invention, said filling unit comprises filling means, said filling means comprising a third downwardly directed nozzle or needle and preferably third means for lowering said third downwardly directed nozzle so that it approaches or enters one of said containers 1 to supply said preformed sterile composition into said container 1 while maintaining the container 1 in a fixed position.

[0088] In preferred embodiments of the method according to the invention, said sterile composition is injected using a peristaltic pump.

[0089] In preferred embodiments of the method according to the invention, a step of nitrogenizing said container 1 is provided before, during or after the filling step. For the purposes of the invention, the term "nitrogenizing said container" refers to a nitrogen treatment of said container.

[0090] In a subsequent step n) of the method according to the invention, a step of placing a stopper in the opening 2 of said filled containers 1 is provided, said step of placing said stopper consisting of: either by completely pushing said stopper into said opening 2 to achieve a hermetic closure of said filled containers 1, or by a first partial pushing of a first part of said stopper into said opening 2 to achieve a non-hermetic closure of said filled containers 1 in order to allow a freeze-drying step to be carried out in a freeze-drying unit to obtain containers 1 filled at least partially with a freeze-dried product, and by a second subsequent pushing of a second part of said stopper not yet pushed in to achieve a hermetic closure of said containers 1 filled at least partially with a freeze-dried product.

[0091] In embodiments according to the invention, said freeze-drying step is carried out in a freeze-drying unit, typically through three steps.

[0092] In a first freeze-drying step, said sterile composition is frozen (freezing step) by exposing it to a temperature of the order of -50°C to -60°C for a period of between 10 hours and 20 hours, at an ambient pressure of the order of 950 millibars.

[0093] According to the method according to the invention, a cooling slope of the order of 2°C per minute is observed.

[0094] At the end of said first freeze-drying step, said sterile composition is completely frozen and ready to undergo a sublimation step.

[0095] In a second freeze-drying step, the frozen composition is subjected to a low-pressure environment, inducing sublimation of the water in the composition. Typically, the composition is subjected to pressures of the order of 300 to 700 millibars for a period of between 5 hours and 3 days, at a temperature of at most -5°C.

[0096] In a third freeze-drying step, additional heat is added to the sublimated composition to remove any excess moisture: this is a desorption drying or secondary desiccation step.

[0097] At the end of said third freeze-drying step, said sterile composition has a moisture content of approximately 2%.

[0098] In embodiments according to the invention, said stopper is a closure, which may be a closure for injectables or for lyophilization.

[0099] In embodiments according to the invention, said stopper is produced from or contains rubber.

[0100] In a subsequent step o) of the method according to the invention, a step of transferring said filled and hermetically sealed containers 1 to a unit for crimping said containers is provided, to obtain crimped filled containers.

[0101] In embodiments according to the invention, the capsule intended to be crimped is made of aluminum, or contains aluminum.

[0102] According to a preferred embodiment, said step o) of the method according to the invention comprises a step of transferring said filled and hermetically sealed containers 1 from a first zone of said crimping unit to a second zone of said crimping unit, this transfer step being carried out using a scraper capable of performing movements in several directions and being arranged to push said filled containers towards said second zone of the crimping unit.

[0103] According to the method according to the invention, said first zone consists of a zone for receiving said filled and hermetically sealed containers.

[0104] According to the method according to the invention, said second zone may consist of an accumulation table which may be a rotating zone of the crimping unit making it possible to align the containers 1 to feed a third zone of the crimping unit where the actual crimping of the containers is carried out.

[0105] Preferably, said scraper is movable in rotation around an axis essentially facing upwards and / or movable in translation in an essentially horizontal plane, along an X axis and / or a Y axis.

[0106] In embodiments of the method according to the invention, the method further comprises a step of decontaminating the external surface of the containers 1, by using purified water.

[0107] Preferably, said decontamination step is carried out just before step i). Alternatively, said decontamination step is carried out as a final step after crimping.

[0108] In alternative embodiments, said decontamination step is carried out using a detergent sprayed by a nozzle onto the outer surface of the container.

[0109] Preferably, said decontamination step is followed by a drying step by blowing hot air or a hot gas onto the outer surface of the container.

[0110] In embodiments of the method according to the invention, the method further comprises a step of marking the containers 1.

[0111] Preferably, said step comprises marking the containers 1 with printing, preferably by UV or inkjet, said printing making it possible to identify the individual container 1 by a computer system.

[0112] Preferably, said printing is applied to the capsule or to the cap crimped onto the container 1.

[0113] In embodiments of the method according to the invention, the method further comprises a step of control via a camera.

[0114] Preferably, said camera allows the identification of individual containers by use of said fingerprint, as applied in the marking step described above.

[0115] In embodiments, a rejection area is provided, configured to receive containers, rejected based on the assessment provided by the camera. A container may be rejected if the marking is unclear or is at least partially illegible.

[0116] In embodiments of the method according to the invention, the method further comprises a step of inspection and / or visual control.

Claims

1. A method for aseptically filling containers 1, in particular vials, with a previously formed sterile composition, said method sequentially comprising: a) a step of positioning a series of containers (1) held together by a polymer film (10) and each having an opening (2) delimited by an edge (3) as well a bottom wall (4) opposite to said opening (2), on a laying surface (20) of a first support (21) located upstream of a washing and drying unit, said positioning step being performed so that the edge (3) delimiting each opening (2) of each container (1) rests against said laying surface (20) of said first support (21), a portion of said polymer film (10) being located between said laying surface (20) of said first support (21) and each opening (2) of each container (1), b) a step of cutting said polymer film (10) along the bottom walls (4) of said containers (1), c) a step of pulling on said polymer film (10) so as to cause it to slide downwards in the direction of said laying surface (20) of said first support (21), d) a step of placing a second support (31) connected to the first support (21) and bearing against the bottom walls (4) of each of said containers (1) so that the latter are wedged between said first support (21) and said second support (31), said second support (31) and said first support (21) forming an assembly, e) a step of rotating said assembly through an angle of 180° so that said containers (1) wedged between said first support (21) and said second support (31) are rotated through 180°, f) a step of releasing said first support (21) so that said containers (1) are no longer wedged between said first support (21) and said second support (31), g) a step of completely removing said polymer film (10) by upward disengagement to free said containers (1) from said polymer film (10), h) a step of transferring said containers (1) released from said assembly to said washing and drying unit, i) a step of washing and drying said containers (1) by passing through said washing and drying unit to obtain washed and dried containers (1), j) a step of transferring said washed and dried containers (1) from said washing and drying unit to a depyrogenation unit, k) a step of depyrogenating said containers (1) by passing them through said depyrogenation unit to obtain depyrogenated containers (1), l) a step of transferring said depyrogenated containers (1) from said depyrogenation unit to a filling unit, m) a step of filling said depyrogenated containers (1) by passing them through said filling unit, to obtain containers (1) filled with said previously formed sterile composition, n) a step of placing a plug in the opening of said filled containers (1), said step of placing said plug consisting of: - either pressing said plug completely into said opening (2) to hermetically seal said filled containers (1), - or a first partial depression of a first part of said plug into said opening (2) to achieve a non-hermetic closure of said filled containers (1) to enable a freeze-drying step to be carried out in a freeze-drying unit to obtain containers (1) filled at least partially with a lyophilisate, and in a subsequent second depression of a second, not yet depressed part of said plug to achieve hermetic closure of said containers (1) filled at least partially with a lyophilisate, o) a step of transferring said filled and hermetically sealed containers (1) to a unit for crimping said containers, to obtain crimped filled containers (1).

2. The method according to claim 1, wherein said step of positioning a series of containers is carried out on a horizontal or essentially horizontal laying surface (20) of a first support (21).

3. The method according to claim 1 or 2, wherein said step of releasing said first support (21) is performed by completely removing said first support (21) or by rotating the latter about an axis in order to raise it.

4. The method according to any one of claims 1 to 3, wherein said step of washing and drying said containers (1) by passing them through said washing and drying unit to obtain washed and dried containers (1), is carried out in a washing and drying unit comprising a first inlet chamber, a washing chamber and a drying chamber.

5. The method according to any one of claims 1 to 4, wherein said washing step is carried out with a washing liquid being purified water, in particular distilled water.

6. The method according to claim 5, wherein said purified water, in particular said distilled water, is injected at a temperature of between 20°C and 30°C, and for a time of between 2 and 5 seconds per washing.

7. The method according to any one of claims 1 to 6, wherein an additional washing step is carried out by injection of water for injectable preparation.

8. The method according to any one of claims 1 to 7, wherein said depyrogenating step is a dry heat depyrogenating step.

9. The method according to any one of claims 1 to 8, wherein said depyrogenating step comprises exposure of the containers (1) to a temperature of at least 270°C for a predetermined, imposed dwell time.

10. The method according to any one of claims 1 to 9, wherein said step of filling said containers (1) is carried out by injection of said previously formed sterile composition using a peristaltic pump.

11. The method according to any one of claims 1 to 10, wherein said step of transferring said filled and sealed containers (1) to a unit for crimping said containers comprises a step of transferring said filled and sealed containers (1) from a first zone of said crimping unit to a second zone of said crimping unit, this transferring step from said first zone to said second zone being carried out with the aid of a scraper capable of movements in several directions and being arranged to push said filled containers (1) towards said second zone of the crimping unit.

12. The method according to claim 11, wherein said first zone consists of a reception area for said filled and hermetically sealed containers (1).

13. The method according to claim 11 or 12, wherein said second zone consists of an accumulation table being a rotating zone of the crimping unit for aligning the containers (1) to feed a third zone of the crimping unit where the actual crimping of said containers (1) takes place.

14. The method according to any one of claims 1 to 13, wherein a step of marking the containers (1) is carried out.

15. The method according to claim 14, wherein said step of marking the containers (1) is carried out by printing, preferably by UV or inkjet printing, said printing enabling the individual container (1) to be identified by a computer system.