Patent Publication Number: US-7581367-B2

Title: Compact system for packaging injectable liquid products into containers in a sterile environment

Description:
This application is the US national phase of international application PCT/EP2006/000167 filed 11 Jan. 2006 which designated the U.S. and claims benefit of IT BO2005A000010, dated 12 Jan. 2005, the entire content of which is hereby incorporated by reference. 
   The present invention forming a part of the technical field relating to the packaging of pharmaceutical products in a protected environment. 
   In particular, the invention refers to a complete and compact system for sterile packaging with integrated washing, sterilising/depyrogenating and subsequent filling of containers with liquids, in particular injectable liquids for use in the- biotechnological field, to which the following disclosure will refer explicitly without thereby losing in generality. Specifically, the packaging system in object operates in a zone provided with an insulating arrangement suitable for preventing contamination coming from outside and between different parts of the system, and for furthermore preventing contamination of the external environment by the system. 
   In general, packaging systems are known, each of which is defined by a plurality of operating machines connected together, such as example a washing operating machine for washing the containers that is connected to a sterilising tunnel machine for sterilising the containers that is connected to a filling machine for filling the containers with liquids, in turn connected to a capping/sealing machine for sealing the filled containers. 
   A packaging system of the aforementioned type generally provides for installing of auxiliary devices such as conveyors or sections of connector between consecutive operating machines and furthermore comprises micro filtrating apparatuses and laminar air-flow generating apparatuses in addition to structures suitable for isolating the system from the external environment. 
   Furthermore, in the same system connections are provided for supplying the liquid product to be packaged, the replacement air and any materials used for periodic sterilising of the system. 
   Currently, such a constructional set-up has the drawback of occupying very important productive spaces and with great overall dimensions, not only because of the significant dimensions of the various operating machines connected together but also because the respective connectors and connecting and conveying devices are often of significant dimensions, also because they have to adapt to the conformation of the various operating machines. 
   Furthermore, with a system that is structured in such a way and with such significant dimensions, the usual and complex validation tests, that are designed to test the suitability of the system for treating pharmaceutical products for which the system has been designed in compliance with all current legislation, need to be conducted several times. 
   In fact, an initial validation phase is conducted on the premises of the manufacturer where the machines forming part of the system were assembled together for an initial testing phase. 
   Once this first validation phase has been completed, the system then has to be disassembled and conveyed by blocks to the operating working premises of the system, where the system is reassembled. 
   Once reassembling has been carried out it is then necessary to repeat anew, in addition to the in situ testing operations, all the validation tests that are necessary in order to deliver to the end user a perfectly functioning system and which conforms to regulations. 
   As can be easily intuitable, this involves very great waste of resources in terms of use highly specialised technicians in addition to a generally very high installation cost. 
   Such significant drawbacks are particularly evident and felt above all in the pharmacological industry, and in particular in the field of so-called “biotechnology”, where on the other hand the need has currently emerged to package large volumes of batches of product at reduced costs and for relatively limited periods. 
   In fact, these products are generally new drugs being clinically tested, or drugs intended for limited diffusion, and are packaged by companies that in most cases are structured as research laboratories. The dimension of the logistic structures is generally limited, whereas the number of products being tested/in production and the frequency of alternating thereof on the production lines are particularly high. 
   An object of the present invention is thus to provide a system for packaging in a sterile environment liquid products, in particular injectable liquids, in containers, which is free of the drawbacks of the prior art disclosed above. 
   In particular, an object of the present invention is to provide a packaging system structure for liquid products in a protected environment of compact type and which is able to meet all the productive needs set out above. 
   A further object of the invention is to provide a particularly efficient packaging system and which is able to optimise energy consumption on the production site. 
   According to the present invention a compact system is provided for packaging in a sterile environment liquid products, in particular injectable pharmaceutical liquids, into suitable containers, the system comprising a plurality of operative packaging stations connected together and arranged in succession along an advancing path of the said containers; said plurality of stations comprising at least a washing station intended for cleaning and decontaminating each of the said containers, at least a sterilising station for sterilising the containers exiting said washing station, and at least a filling and sealing station for filling said containers with said liquids and for sealing the containers; wherein said stations and a connecting arrangement thereof are mounted in an operating configuration on a sole work platform; said washing station and said sterilising station being arranged parallel to one another and placed alongside and connected together by a first conveyor of the containers arranged transversely to the washing station and the sterilising station to define a first substantially “U”-shaped portion of the said path; said filling and sealing station being arranged aligned on said washing station and connected, in a staggered position, to said sterilising station by a second conveyor of said containers arranged transversely to the sterilising station, to define a second substantially “L”-shaped portion of said advancing path. 

   
     The technical features of the invention according to the aforementioned objects are clearly ascertainable by the contents of the claims set out below, and the advantages thereof will be clearer in the detailed disclosure that follows, with reference to the attached drawings, that show an embodiment thereof purely by way of non-limitative example, in which: 
       FIG. 1  illustrates schematically a partially sectioned plan view and with some parts removed for clarity, of an embodiment of a compact packaging system according to the present invention; 
       FIGS. 2   a ,  2   b  are schematic frontal and section views of an operating station of the system of  FIG. 1  in two different respective functional positions; 
       FIG. 3  schematically illustrates a frontal and section view of another operating station of the packaging system of  FIG. 1 ; and 
       FIGS. 4 and 5  illustrate two respective section views according to IV-IV and respectively according to V-V of the same operating station of  FIG. 3 , illustrated in two respective different functional positions. 
   

   With reference to the attached  FIG. 1 ,  1  indicates overall a compact and automatic system particularly designed for packaging, in a protected environment, liquid pharmaceutical products for use in the biotechnological field inside suitable containers  2  and similar, for example, vial, syringes or bottles  2 , according to an embodiment of the invention. 
   The system  1  comprises a plurality of operating stations  100 ,  200  and  300  connected together and integrated and arranged consecutively in relation to an advancing conveying plane path A of the bottles  2  to be filled, according to a particular configuration, as will be disclosed in detail below. 
   In particular, all the operating stations  100 ,  200 ,  300  and corresponding, connecting members  10 ,  20  of the system  1  are mounted and arranged on a single platform  3  dimensioned in such a way as to occupy a rectangular area the same as the area of a loading plane of a standard road transport vehicle, so as to be compatible with the loading and conveying of the entire system  1  mounted on the plane, the system  1 , thus all the aforementioned operating stations that compose the latter, is furthermore managed and controlled by a sole control unit (known and not illustrated). 
   In the embodiment illustrated in  FIG. 1 , the system  1  comprises a washing station  100  of empty bottles  2  intended for washing and decontaminating each empty bottle  2  of any organic or inorganic residue present inside the bottle  2  before filling with the liquid product. 
   The washing station  100  extends longitudinally on the platform  3 , and has particularly compact dimensions. 
   According to what has been illustrated in  FIGS. 2   a  and  2   b , the washing station  100 , that is specifically the object of a separate patent application filed together with the current application by the same applicant, comprises a conveying plane  50  suitable for defining the inlet of the entire system  1  and on which the empty bottles  2  are deposited to be supplied in an orderly manner along the path A with their open inlets facing upwards, to a conveyor  51  of the belt  52  type wound in a loop and moveable in step mode around a corresponding pulley  53  and supporting a plurality of grasping grippers  54 . 
   According to what has been illustrated in  FIG. 2   b , during step movement of the belt  52  around the pulleys  53  (direction K in  FIGS. 2   a  and  2   b ), at a lower operating position R 1  the grippers  54  temporarily arranged on the lower branch  52   a  of the belt  52  are each suitable for grasping by the neck a corresponding bottle  2  from the plane  50  and advancing a corresponding group of bottles  2  until the bottles  2  of the group are turned 180° in relation to the position taken on the plane  50 , namely with their open inlet facing downwards. 
   In this configuration (upper branch  52   b  of the belt  52 ), the entire conveyor  51  is suitable for moving by means of a known moving arrangement and which is not illustrated and for example applied to the aforementioned pulleys  53 , vertically downwards (arrows F 1  in  FIGS. 2   a  and  2   b ) reaching a second operating position R 2  in which each nozzle  55  of a bank  56  of washing nozzles  55  is suitable for being inserted through the open inlet inside a corresponding bottle  2  overturned in such a way as to be able to spray the inside of the bottle  2  with a sterilising washing liquid. 
   As can be observed in  FIG. 2   b , owing to the structure of the conveyor  51  that is movable with reciprocating motion in a vertical direction, the removing and grasping position R 1  of a first group of bottles  2  from the plane  50 , and the inserting position R 2  of the nozzles  55  into the bottles  2  of a subsequent group of bottles  2  arranged on the upper branch  52   b  and therefore with the washing of the bottles  2  of the this subsequent group, are achieved simultaneously with great simplification of movements and overall dimensions. In other words, during use, the grasping of the aforementioned first group of bottles  2  from the plane  50  by means of the grippers  54  supported by the belt  52  in the position R 1  is achieved during inserting of the nozzles  55  inside the bottles  2  of the subsequent group at the operating position R 2 . 
   Lastly, the station  100  comprises an outlet  57 , at which the washed bottles  2  are unloaded from the conveyor  51  with grippers  54  to be deposited on a connecting conveyor  10  arranged transversely to the plane  50 . 
   In a version that is not illustrated, the conveyor  51  is provided fixed in relation to the bank  56  of nozzles  55 , whilst the latter are fitted movable with reciprocating motion from and to the bottles  2  to be inserted inside the bottles  2  and to achieve the washing thereof. 
   According to what has been illustrated in  FIG. 1  and in  FIG. 3 , the system  1  furthermore comprises a sterilising station  200 , defined by a two-stage sterilising unit  200 , which is also arranged longitudinally on the platform  3  intended for receiving the bottles  2  exiting the station  100  and advanced by the conveyor  10  to carry out the sterilising/depyrogenating of the bottles  2 . 
   Still according to what has been illustrated in  FIG. 1 , the station  200  extends substantially parallel to the washing station  100  and is conveniently arranged in a position laterally alongside the washing station  100 , such that the advancing directions of the bottles  2  along a “U” section of the path A at the two stations  100  and  200  alongside one another are opposite one another. 
   The sterilising unit  200 , that is the specific subject of a separate patent application filed at the same time as this application by the same applicant, comprises in an embodiment illustrated in  FIGS. 1 and 3 , a pair of sterilising modules, respectively a first module  210  and a second module  250 , arranged consecutively and communicating together by means of an intermediate passage  203 . 
   These modules  210  and  250  of the station  200  are activatable independently of one another according to hot and/or cold sterilising modes of the bottles  2 . 
   In other words, by suitably activating in relation to one another the modules  210  and  250 , as will be explained better below, it is possible to achieve excellent sterilisation of the bottles  2  with the following four alternative operating modes: hot-cold, hot-hot, cold-cold, or, lastly, cold-hot. 
   The entire unit  200  is enclosed within an insulated covering structure  290  intended for preventing significant heat loss to the external environment. 
   The unit  200  furthermore provides a belt conveyor  205 , arranged at the bottom part thereof between a loading inlet  201 , made in the first sterilising module  210 , and an unloading outlet  202 , made in the second sterilising module  250 . 
   According to what has been illustrated in  FIGS. 1 and 3 , the conveyor  205  is intended for supporting the bottles  2  on an upper branch  206  thereof to convey the bottles  2  inside and through the first and second module  210  and  250  according to sequences that will be more fully detailed below. 
   The loading inlet  201  and the unloading outlet  202  are provided with corresponding gate valves  201   a ,  202   a  ( FIG. 3 ), suitable for enabling the opening and closing thereof for the respectively passage of the entering and exiting bottles  2 . 
   In the first sterilising module  210  a sterilising chamber  212  is obtained, the lower part of which is crossed by the aforementioned conveyor  205 . 
   As better illustrated in  FIG. 3 , in the upper part of the first module  210  by means of suitable conduits and separating baffles an air flow F 2  is created that is intended for being blown towards the bottles  2  according to the modes disclosed below to define two different heating or cooling paths of the alternately selectable bottles  2 . 
   This flow F 2  flows, above the conveyor  205 , into a bell  230 , below which a filtering element  220  is provided, defined for example by a HEPA filter of suitable class for obtaining the desired degree of air purity. 
   In the first module  210  a generating device  215  of the aforementioned air flow F 2  is also provided. 
   The first  210  and second  250  sterilising modules can have a substantially identical structure: thus, similarly to the first module  210 , also the second module  250  is suitable for defining a corresponding sterilising chamber  252  crossed in the lower part thereof by the aforementioned conveyor  205 , and is provided with a flow generating device  255  for generating an air flow F 3  traversing and flowing into a bell  270 , with a filtering element  260  or HEPA filter. 
   Accordingly, in the illustrated embodiment, the two modules  210  and  250  are arranged specularly so that the aforementioned intermediate passage  203  ( FIG. 1 ) consists of corresponding openings made in the modules  210 ,  250  made to match each other. 
   Further openings made at the opposite ends of the modules  210 ,  250  respectively form the aforementioned loading inlet  201  and unloading outlet  202  of this sterilising unit  200 . 
   As already mentioned above, both the first module  210  and the second module  250  may both operate as hot or cold sterilisers, as can now be seen in  FIGS. 4 and 5 . 
   According to what has been illustrated in the first of the above figures,  FIG. 4 , with which for simplicity and clarity it is intended for disclosing the first module  210  suitable for operating in hot-sterilising mode, in the first module  210  the sterilising chamber  212  is obtained, that is crossed in the lower part thereof by the aforementioned conveyor  205 . 
   In the upper part of the first module  210  a path is made for an air flow F 3  intended for being blown towards the bottles  2  in the manner disclosed below and comprising two heating and cooling branches  218  and  219  of the bottles  2  that are selectable alternately. 
   This path leads, above the conveyor  205 , into the bell  230 , below which the aforementioned filtering element  220  or HEPA filter is fixed. 
   Within the heating branch  218  a heating device  211  is located, substantially defined by a coil resistor intended for heating the aforementioned air flow to a preset sterilising/depyrogenating temperature of the bottles  2 . 
   In the first module  210  the aforementioned generating device  215  of the aforementioned air flow is also provided. 
   The generating device  215  comprises an inlet fan  216 , arranged at an air intake  213  and suitable for sucking in air from the external environment, and a main fan  217 , arranged above the aforementioned bell  230  and suitable for conveying the air flow to the bottles  2  through the HEPA filter  220  in a substantially laminar mode. 
   The first sterilising module  210  furthermore comprises a refrigerating unit  225 , that is selectively activatable and intended for rapidly cooling the air flow entering the aforementioned first module  210 , when the latter is arranged in the cooling operating mode. 
   At the inlet of the aforementioned heating  218  and cooling  219  branches flow-switching members  221  are provided. 
   These substantially comprise a pair of butterfly switches  222 ,  223 , that are switchable in push-pull mode between open and closed positions to connect or disconnect corresponding heating branches  218  and cooling branches  219  of the air flow F 2  path. 
   In the upper part of the first module  210  an evacuation fan  224  is provided that is intended for conveying part of the circulating air flow to the external environment. 
   With this fan  224  a mixing valve  225   a  is associated that is arrangeable in different opening degrees intended for mixing in suitable proportions air coming from the external environment with the part of the air flow that enters the evacuation fan  224 , to lower the temperature of the exiting air. 
   With reference now to  FIG. 5 , with which for simplicity and clarity it is intended for disclosing the second module  250  suitable for operating in cold mode, the second module  250  defines the sterilising chamber  252 , crossed in the lower part thereof by the aforementioned conveyor  205 . 
   In the upper part of the second module  250  a path for an air flow F 3  is made comprising two heating  258  and cooling  259  branches. This path leads, above the conveyor  205 , into the bell  270 , below which the aforementioned HEPA filter  260  is fixed. 
   Inside the heating branch  258  a heating device  251  is arranged, that can be defined by a coil resistor and that is intended for heating the air flow to the aforementioned preset sterilising and depyrogenating temperature of the bottles  2 . 
   In the second module  250  a generating device  255  above the aforementioned air flow F 3  is also provided. 
   The generating device  255  comprises an inlet fan  256 , arranged at an air intake  253  and suitable for sucking in air from the external environment, and a main fan  257 , arranged above the aforementioned bell  270 . 
   A refrigerating unit  265  is furthermore present that is selectively activatable and is intended for rapidly cooling the air flow F 3  entering thereof the second module  210 , when the latter is arranged in the cooling operating mode. 
   At the inlet of the aforementioned heating  258  and cooling  259  branches flow-switching members  261  are provided. 
   These substantially comprise a pair of butterfly switches  262 ,  263 , that are switchable in push-pull mode as already disclosed previously. 
   In the upper part of the second module  250  an evacuation fan  264  is provided that is intended for conveying part of the flow of circulating air to the external environment. 
   With this fan  264  a corresponding mixing valve  265   a  is associated that is arrangeable for different degrees of opening to lower the temperature of the exiting air. 
   According to what is illustrated in  FIG. 1 , as already mentioned, between the aforementioned washing  100  and sterilising  200  stations a first conveyor  10  is provided, that can be of the known belt type and intended for removing bottles  2  from the outlet of the washing station  100 , already washed and decontaminated, and for conveying the bottles  2  to the inlet  201  of the sterilising station  200 . 
   Owing to the respective side-by-side arrangement of the aforementioned stations  100  and  200 , the aforementioned first conveyor  10  is arranged transversely to the orientation of the system  1 , thus defining part of the “U” portion of the aforementioned path A. 
   Still according to what is illustrated in  FIG. 1 , the system  1  furthermore comprises a filling and sealing station  300  for filling the bottles  2  with liquid substances and subsequent for sealing the bottles  2  with corresponding caps, the station  300  is arranged downstream of the aforementioned sterilising station  200  in relation to the path A; this filling and sealing station  300  is substantially aligned on the washing station  100  and is staggered in relation to the outlet line of the sterilising station  200 , defining, together with a second transverse conveyor  20 , a second “L”-shaped portion connected to the aforementioned “U”-shaped portion of the advancing path A of the bottles  2 . 
   Such an arrangement enables a particularly compact system configuration to be obtained that makes it possible to contain the external dimensions within the limits set by the work plane of standard means of road transport, as shown above. 
   The filling and sealing station  300  is of the known type with linear development and overall comprises a filling unit  301  having a bank  302  of filling nozzles (known and not illustrated in  FIG. 1 ), and a sealing cap-supplying and applying device  303  (not shown) arranged along a step-mode filling line defined between two conveyors  304  of the known star type and also provided with two successive weighing device for weighing bottles  2  and with a locking unit  306  of the bottles  2 . 
   The filling station  300  can be structurally shaped in a manner similar to the Filling/Capping/Locking machine called “STERIFILL F200” designed and marketed by the same applicant. 
   The aforementioned filling and sealing station  300  is directly connected to the sterilising station  200  by the aforementioned second conveyor  20 , of a type similar to the aforementioned first conveyor  10  and it is also transversely arranged. 
   The system  1  lastly comprises a sterile chamber  5  that extends above, by covering it, the portion of the system  1  situated downstream of the sterilising station  200 , and namely the second conveyor  20  and the entire filling and sealing station  300 . 
   In view of the particular arrangement thereof, the sterile chamber  5  therefore has an “L” shape with a first branch  5   a  arranged transversely and against the sterilising station  200  to enclose the second conveyor  20 , and a second branch  5   b  arranged longitudinally at the outlet of the aforementioned filling and sealing station  300 , and therefore of the outlet of the system  1 . 
   The sterile chamber  5  is made with substantially known techniques by means of suitable isolating joint panels and is provided with suitable means for providing the regular sterilisation thereof, which is not shown for simplicity as it is completely known. 
   Substantially, the system  1  is assembled as a single and compact body, with sufficient structural rigidity to enable the packaging and conveying thereof without having to dismantle any part. 
   This aspect makes the managing of the system easier for the entire productive life thereof. 
   The system  1  can in fact be subjected to validation tests directly in the factory, as soon as assembled and then be directly packaged and conveyed to the production site. 
   As nothing of the component units thereof has been removed in the meantime, it is unnecessary to conduct new validation tests once in the packaging place. 
   It is in fact sufficient to conduct the switch-on of the so-called utilities (electric power supply, compressed air, supply line of the liquid product to be packaged etc.) by means of suitably placed inlets, then to conduct a normal operating test and conduct the necessary calibrating and synchronising operations in addition to an operation of first sterilisation of the sterile chamber  5 . 
   The aforementioned procedure can also be applied whenever it is necessary to move the system  1  to another production site, for example in order to package a different product. 
   What has been set out above makes clear the great versatility of the this system and the simplicity with which the system can be set up to package different products, also on different operating sites. 
   All this makes the system particularly suitable both for packaging a single product in not particularly great quantities for a long period and for packaging batches of different products for short periods. 
   The configuration of the system therefore fully meets the needs of the modern pharmacological industry and in particular of the companies operating in the biotechnology field. 
   It is understood that everything disclosed above has been disclosed purely by way of non-limitative example. Possible modifications to and variations on the invention are therefore considered to fall within the extent of the protection accorded to this technical solution as disclosed above and claimed below.