Abstract:
A filling apparatus for, a filling system for and a method of introducing into a container a suspension or solution of a substance, in particular a pharmaceutical substance, in a propellant under pressure, the filling apparatus comprising: a main body ( 4 ) including a passageway ( 20 ) having an inlet opening ( 21 ) and first and second outlet openings ( 25, 22 ), the first outlet opening ( 25 ) communicating, in use, with a valve stem ( 144 ) extending from a head ( 141 ) of a body ( 139 ) of a container ( 138 ); a fill actuator ( 7 ) in communication with the inlet opening ( 21 ) of the passageway ( 20 ) comprising a filling valve assembly ( 29 ) for selectively introducing propellant under pressure containing a substance in a suspension or solution into the passageway ( 20 ); an exhaust actuator ( 10 ) in communication with the second outlet opening ( 22 ) of the passageway ( 20 ) comprising an exhaust valve assembly ( 48 ) for selectively exhausting propellant under pressure containing substance from the passageway ( 20 ) and including at least one exhaust gas conduit ( 84, 92, 93 ) having an outlet ( 86, 94, 95 ) configured so as, in use, to provide a flow of exhaust gas substantially aligned with a flow of propellant containing substance from the second outlet opening ( 22 ) of the passageway ( 20 ); and a container-engaging body ( 16 ) for receiving, in use, the head ( 141 ) of the body ( 139 ) of the container ( 138 ) which includes the valve stem ( 144 ).

Description:
This application is a continuation of application Ser. No. 09/818,671, filed Mar. 28, 2001, which is a continuation of Ser. No. 09/355,026, filed Jul. 23, 1999, both now abandoned, the entire content of which is hereby incorporated by reference in this application. 
    
    
     The present invention relates to a filling apparatus for, a filling system for and a method of introducing into a container a suspension or solution of a substance, in particular a pharmaceutical substance, in a propellant under pressure. Most particularly, the present invention relates to a filling head included in a line in which a propellant under pressure containing a substance in a suspension or solution is circulated, with the filling head being brought into and out of communication with containers to be filled. 
     BACKGROUND OF THE INVENTION 
     Containers for holding a suspension or solution of a pharmaceutical substance in a propellant under pressure are well known. One such known container comprises a body which defines a storage chamber, a valve stem which extends from a head of the body and a metering chamber which is selectively communicatable by the valve stem with the atmosphere and the storage chamber; the valve stem providing, via an L-shaped conduit which extends between the free end and the side wall thereof, the outlet of the container through which metered doses of propellant containing pharmaceutical substance are delivered. The valve stem is axially displaceable between a first, extended position in which the metering chamber, and hence the container, is closed to the atmosphere since the L-shaped conduit is disposed wholly outside the metering chamber, and a second, depressed position, in which the metering chamber is in communication with the outlet provided by the L-shaped conduit in the valve stem and through which a metered dose of propellant containing pharmaceutical substance is delivered. The container is filled with the valve stem in the depressed position, with the propellant containing pharmaceutical substance being forced downwardly through the L-shaped conduit in the valve stem, through the metering chamber and into the storage chamber defined by the body of the container. 
     EP-A-0419261 discloses a filling system for introducing into a container a suspension or solution of a pharmaceutical substance in a propellant under pressure, which filling system includes a filling apparatus that prevents the escape of pharmaceutical substance into the atmosphere. In this filling system the filling apparatus is configured to be flushed by a volume of high pressure propellant while still in fluid communication with the container so that the propellant under pressure containing pharmaceutical substance which is remaining in the filling apparatus after filling the container with the same is flushed through into the container prior to withdrawal of the filling apparatus from the container. This configuration does, however, require additional propellant to be introduced into the container to achieve the flush. Moreover, following the flushing action, propellant under pressure present in the valve stem can escape to the atmosphere. 
     SUMMARY OF THE INVENTION 
     The present invention in at least one preferred aspect aims to provide an improved filling apparatus which at least partially overcomes the above-mentioned problems. 
     The present invention also aims to provide a method and filling system which are configured to fill a container without requiring the release of propellant alone or propellant containing pharmaceutical substance directly to the atmosphere. 
     The present invention provides a filling apparatus for introducing into a container a suspension or solution of a substance, in particular a pharmaceutical substance, in a propellant under pressure, comprising: a main body including a passageway having an inlet opening and first and second outlet openings, the first outlet opening communicating, in use, with a valve stem extending from a head of a body of a container; a fill actuator in communication with the inlet opening of the passageway comprising a filling valve assembly for selectively introducing propellant under pressure containing a substance in a suspension or solution into the passageway; an exhaust actuator in communication with the second outlet opening of the passageway comprising an exhaust valve assembly for selectively exhausting propellant under pressure containing substance from the passageway and including at least one exhaust gas conduit having an outlet configured so as, in use, to provide a flow of exhaust gas substantially aligned with a flow of propellant containing substance from the second outlet opening of the passageway; and a container-engaging body for receiving, in use, the head of the body of the container which includes the valve stem. 
     Preferably, the exhaust actuator includes a plurality of first exhaust gas conduits, the respective outlet openings of which define an array surrounding the second outlet opening of the passageway. 
     More preferably, the outlet openings of the first exhaust gas conduits are disposed downstream, with respect to the direction of flow, of the second outlet opening of the passageway. 
     More preferably, the array of outlet openings of the first exhaust gas conduits define a circular array. 
     Preferably, the exhaust actuator includes a first chamber with which the first exhaust gas conduits commonly communicate and a conduit in communication with the first chamber through which exhaust gas is delivered. 
     In a preferred embodiment the exhaust actuator includes a plurality of second exhaust gas conduits, the respective outlet openings of which are downstream, with respect to the direction of flow, of the outlet openings of the first exhaust gas conduits and define an array surrounding the second outlet opening of the passageway. 
     Preferably, the array of outlet openings of the second exhaust gas conduits define a circular array. 
     Preferably, the exhaust actuator includes a second chamber with which the second exhaust gas conduits commonly communicate and a conduit in communication with the second chamber through which exhaust gas is delivered. 
     Preferably, the exhaust valve assembly includes an exhaust valve body which is configured selectively to be seated on or unseated from a valve seat disposed at the second outlet opening of the passageway and a substantially annular chamber which surrounds the exhaust valve body through which, in use, flows propellant containing substance and exhaust gas when the exhaust valve body is unseated from the valve seat. 
     More preferably, the annular chamber is conical in shape, increasing in diameter from the second outlet opening of the passageway. 
     The present invention also extends to a filling system for introducing into a container a suspension or solution of a substance, in particular a pharmaceutical substance, in a propellant under pressure incorporating the above-described filling apparatus. 
     The present invention further provides a method of introducing into a container a suspension or solution of a substance, in particular a pharmaceutical substance, in a propellant under pressure, comprising the steps of: providing a container comprising a body defining a storage chamber and a valve stem extending from the body; communicating the valve stem of the container with a first outlet opening of a passageway in a main body of a filling apparatus, the filling apparatus comprising a fill actuator comprising a filling valve assembly for selectively introducing into an inlet opening of the passageway propellant under pressure containing a substance in a suspension or solution and an exhaust actuator comprising an exhaust valve assembly for selectively exhausting propellant under pressure containing substance from a second outlet opening of the passageway and including at least one exhaust gas conduit having an outlet configured so as, in use, to provide a flow of exhaust gas substantially aligned with a flow of propellant containing substance from the second outlet opening of the passageway; opening the filling valve assembly thereby to fill the storage chamber of the container with propellant under pressure containing substance in a suspension or solution; closing the filling valve assembly; providing exhaust gas through the at least one exhaust gas conduit; and opening the exhaust valve assembly to enable propellant under pressure containing substance in the passageway and the valve stem of the container to exhaust, whereby the exhausted propellant containing substance is entrained in the exhaust gas. 
     Preferably, the exhaust actuator includes a plurality of first exhaust gas conduits, the respective outlet openings of which define an array surrounding the second outlet opening of the passageway. 
     More preferably, the outlet openings of the first exhaust gas conduits are disposed downstream, with respect to the direction of flow, of the second outlet opening of the passageway. 
     More preferably, the array of outlet openings of the first exhaust gas conduits define a circular array. 
     Preferably, the exhaust actuator includes a first chamber with which the first exhaust gas conduits commonly communicate and a conduit in communication with the first chamber through which exhaust gas is delivered. 
     In a preferred embodiment the exhaust actuator includes a plurality of second exhaust gas conduits, the respective outlet openings of which are downstream, with respect to the direction of flow, of the outlet openings of the first exhaust gas conduits and define an array surrounding the second outlet opening of the passageway. 
     Preferably, the array of outlet openings of the second exhaust gas conduits define a circular array. 
     Preferably, the exhaust actuator includes a second chamber with which the second exhaust gas conduits commonly communicate and a conduit in communication with the second chamber through which exhaust gas is delivered. 
     Preferably, the exhaust valve assembly includes an exhaust valve body which is configured selectively to be seated on or unseated from a valve seat disposed at the second outlet opening of the passageway and a substantially annular chamber which surrounds the exhaust valve body through which, in use, flows propellant containing substance and exhaust gas when the exhaust valve body is unseated from the valve seat. 
     More preferably, the annular chamber is conical in shape, increasing in diameter from the second outlet opening of the passageway. 
     Preferably, the exhaust gas is heated to a temperature of at least about 35° C. 
     Preferably, the ratio of the mass flow rate of the exhaust gas to the exhausted propellant containing substance is at least 10:1. 
     Preferably, the exhaust gas has a mass flow rate of from 0.1 to 10 grams/second. 
     Preferably, the exhaust gas comprises pressurised air. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     A preferred embodiment of the present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which: 
     FIG. 1 illustrates a part-sectional side view of a filling head in accordance with a preferred embodiment of the present invention; 
     FIG. 2 illustrates a vertical sectional view (along section A—A) of the filling head of FIG. 1; 
     FIG. 3 illustrates a horizontal sectional view (along section B—B) of the filling head of FIG. 1; 
     FIG. 4 illustrates an underneath plan view of the filling head of FIG. 1; 
     FIG. 5 illustrates an end view of the filling head of FIG. 1, illustrated with part of the housing of the exhaust actuator removed; 
     FIG. 6 illustrates a schematic representation of a filling system in accordance with a preferred embodiment of the present invention for introducing into a container a suspension or solution of a pharmaceutical substance in a propellant under pressure, with the system incorporating the filling head of FIG. 1; and 
     FIGS. 7 to  13  illustrate enlarged part-sectional side views of part of the filling head of FIG. 1 in a series of respective positions representing successive sequential steps in a container filling operation. 
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     FIGS. 1 to  5  illustrate a filling head  2  in accordance with a preferred embodiment of the present invention. 
     The filling head  2  comprises a main body  4  which includes a downwardly-extending part  5  that extends from a lower surface  6  thereof, a fill actuator  7  disposed to one lateral side of the main body  4  and an exhaust actuator  10  disposed to the opposite lateral side of the main body  4 . The filling head  2  further comprises an actuating mandrel  14  disposed to and above the main body  4  by which the filling head  2  is moved vertically. The filling head  2  still further comprises a slide body  16  for receiving a container to be filled which is mounted to the downwardly-extending part  5  of the main body  4  so as to be vertically movable relative thereto. 
     The main body  4  includes a vertically-oriented passageway  20  which is located substantially centrally therein and includes first and second horizontally-opposed openings  21 ,  22  at the upper end  24  thereof and a third opening  25  at the lower end  26  thereof which is located in the downwardly-extending part  5 . The first and second openings  21 ,  22  communicate respectively with the fill actuator  7  and the exhaust actuator  10 . 
     The fill actuator  7  comprises a housing  28  and a filling valve assembly  29  which is movably disposed thereto. The filling valve assembly  29  comprises a filling valve stem  30  which is slideably disposed within an annular chamber  31  in the main body  4  and includes a valve sealing end  32  which seals against a valve seat  33  that defines the first opening  21  of the passageway  20  in the main body  4 . The chamber  31  includes an inlet conduit  34  and an outlet conduit  35  formed in the main body  4  on opposing lateral sides of the chamber  31 . The filling valve assembly  29  further comprises a reciprocally movable filling valve member  36  which is axially coupled to the filling valve stem  30  and is sealingly disposed within an annular chamber  37  defined in the housing  28 . The filling valve member  36  includes a radially outwardly-extending part  38  which sealingly divides the chamber  37  into first and second chamber parts  39 ,  40 , the first chamber part  39  being near to the filling valve stem  30  and the second chamber part  40  being remote from the filling valve stem  30 . The housing  28  includes a conduit  41  which communicates with the second chamber part  40  of the chamber  37  and is for connection to a source of a pressurised fluid. The filling valve assembly  29  yet further comprises biasing means  42 , in this embodiment a compression spring, for biasing the filling valve member  36  and hence the filling valve stem  30  into the chamber  31  in the main body  4 . The application/withdrawal of fluid pressure via the conduit  41  introduces/withdraws fluid from the second chamber part  40  of the chamber  37 , thereby causing sliding movement of the filling valve member  36  in the chamber  37 , and thereby sliding movement of the filling valve stem  30  in the chamber  31 . In this way, the valve sealing end  32  of the filling valve stem  30  can be moved into and out of engagement with the valve seat  33  that communicates with the first opening  21  of the passageway  20  in the main body  4 . The chamber  31  is sealed at the end thereof remote from the valve seat  33  and at the junction of the filling valve member  36  and the filling valve stem  30  by a flexible annular seal  43  that surrounds the filling valve stem  30 . 
     The exhaust actuator  10  comprises a valve block  44  which is disposed in a cavity  45  in the main body  4 , a housing  46  which is connected to the valve block  44  and an exhaust valve assembly  48  which is movably disposed within the housing  46 . 
     The housing  46  comprises an annular support sleeve  49  and the exhaust valve assembly  48  comprises an exhaust valve stem  50  which includes a valve sealing end  51  and is slideably disposed in the support sleeve  49 . The exhaust valve stem  50  is generally conical in shape, and increases in diameter away from the valve sealing end  51 . In this embodiment the exhaust valve stem  50  includes a peripheral ridge  52  which acts to reduce the retention of substance thereon. The exhaust valve assembly  48  further comprises a reciprocally movable exhaust valve member  54  which is axially coupled to the exhaust valve stem  50  and is sealingly disposed within an annular chamber  56  in the support sleeve  49 . The exhaust valve member  54  includes a radially outwardly-extending central part  58  which sealingly divides the chamber  56  into first and second chamber parts  60 ,  62 , the first chamber part  60  being near to the exhaust valve stem  50  and the second chamber part  62  being remote from the exhaust valve stem  50 . The support sleeve  49  includes first and second conduits  64 ,  66  for connection to a source of a pressurised fluid, each conduit  64 ,  66  communicating with a respective one of the first and second chamber parts  60 ,  62  of the chamber  56 . Application of fluid pressure via one of the conduits  64 ,  66  introduces fluid into a respective one of the first and second chamber parts  60 ,  62  of the chamber  56 , thereby causing sliding movement of the exhaust valve member  54  in the chamber  56 , and thereby sliding movement of the exhaust valve stem  50  in the support sleeve  49 . In this way, the valve sealing end  51  of the exhaust valve stem  50  can be moved into and out of engagement with an exhaust valve seat  67  provided by the valve block  44 . The housing  46  further includes a generally annular chamber  70  in which the support sleeve  49  and the exhaust valve stem  50  are located, with the part of the chamber  70  surrounding the generally conical exhaust valve stem  50  also being generally conical. The housing  46  yet further comprises an exhaust tube  71  which is disposed to a side thereof remote from the valve block  44  and communicates with the chamber  70 . 
     The valve block  44  includes a conical recess  72  which is an extension of the chamber  70  in the housing  46  and at the bottom of which is the exhaust valve seat  67 . The valve block  44  further includes a fluid passageway  73  therein which includes a first, inlet opening  74  which communicates with the second opening  22  of the passageway  20  in the main body  4  and a second, outlet opening  75  at the exhaust valve seat  67 . 
     In order to provide the required mounting for the support sleeve  49 , the chamber  70  in the housing  46  is divided into three arcuate chamber parts  78 ,  80 ,  82  in the vicinity of the mounting of the exhaust valve assembly  48  (as illustrated in FIG.  5 ). In this embodiment the three arcuate chamber parts  78 ,  80 ,  82  are substantially equal in circular length. 
     The chamber  70  is configured principally to be exhausted with an exhaust gas passing from the valve block  44 . In this embodiment the valve block  44  includes a plurality of first exhaust gas inlet passages  84  which surround the outlet opening  75  at the exhaust valve seat  67 . The first exhaust gas inlet passages  84  include respective outlets  86  which define an array, preferably a circular array, around the exhaust valve seat  67 , with the array being axially centred on a common axis of the exhaust valve stem  50 , the exhaust valve seat  67  and the passageway  73 . At least those portions of the first exhaust gas inlet passages  84  which define the outlets  86  are parallel to the passageway  73 . In this embodiment the outlets  86  are formed in the surface of the conical recess  72  in the valve block  44  and are located downstream, with reference to the direction of flow through the chamber  70 , of the outlet opening  75  of the passageway  73 . The valve block  44  further includes an annular chamber  88  in an outer surface thereof which commonly connects the first exhaust gas inlet passages  84  and which is in communication with a conduit  90  in the main body  4  for supplying a source of an exhaust gas thereto. In this embodiment the conduit  90  is directed radially to the annular chamber  88 , but in an alternative embodiment could be directed tangentially. 
     The chamber  70  is further configured to be exhausted with an exhaust gas passing through the housing  46 . In this embodiment the housing  46  includes a plurality of second and third exhaust gas inlet passages  92 ,  93  downstream of the first exhaust gas inlet passages  84 . The second and third exhaust gas inlet passages  92 ,  93  include respective outlets  94 ,  95  which define an array, preferably a circular array, around the exhaust valve seat  67  and communicate with the chamber  70 . At least those portions of the second and third exhaust gas inlet passages  92 ,  93  which include the outlets  94 ,  95  are parallel to the first exhaust gas inlet passages  84 , and thus also parallel to the passageway  73  in the valve block  44 . The housing  46  includes an annular chamber  96  which commonly connects the second and third exhaust gas inlet passages  92 ,  93  and a conduit  98  in communication with the chamber  96  for supplying a source of an exhaust gas thereto. 
     The slide body  16  is mounted for vertical sliding movement relative to the main body  4  by first and second spaced biasing elements  100 , in this embodiment compression springs, disposed therebetween. Each of the biasing elements  100  is mounted on a respective threaded member  102 , both of which threaded members  102  connect the slide body  16  to the main body  4 . In the normal or inoperative configuration, the slide body  16  is biased by the biasing elements  100  downwardly away from the main body  4  so as to be separated therefrom by a gap  103 . 
     The slide body  16  includes a bore  104  for slideably receiving in mating relationship the downwardly-extending part  5  of the main body  4 . The slide body  16  further includes a projection  105  on the upper surface  106  thereof which is complementary to a corresponding recess  107  formed in the lower surface  6  of the main body  4  around the downwardly-extending part  5 . The bore  104  includes an annular seal  109  which surrounds the downwardly-extending part  5  so as to form a fluid tight seal therebetween. The lower, distal end  110  of the downwardly-extending part  5  is provided thereunder with an annular valve stem seal  112  which includes a central opening  113  which is aligned with the passageway  20  in the main body  4 , the inner and outer diameters of the valve stem seal  112  substantially corresponding respectively to the inner diameter of the third opening  25  in the passageway  20  and the inner diameter of the bore  104 . The bore  104  defines a chamber  116  which is configured to have an inner diameter that is larger than the outer diameter of the valve stem of the container to be filled. The chamber  116  includes a main, upper section  122  and lower section  123  which is of slightly smaller diameter than the upper section  122  and defines an opening  124  through which the valve stem of the container to be filled extends. The slide body  16  yet further includes a conduit  126  which is in communication with the chamber  116 . The slide body  16  further comprises an annular head seal  131  which is located below and surrounds the opening  124  to the chamber  116 . The head seal  131  is retained in a central opening  133  in a seal retaining block  132  which provides the lower part of the slide body  16 . The seal retaining block  132  includes a downwardly-extending recess  134  in a lower surface  135  thereof for receiving the head of a container to be filled. 
     As illustrated in FIG. 7, in this embodiment a container  138  to be filled by the filling head  2  comprises a body  139  which defines a storage chamber  140  for holding a suspension or solution of a pharmaceutical substance in a propellant under pressure. The body  139  includes a head  141  which includes a peripheral housing  142  that defines a metering chamber  143  and a valve stem  144  that is movably disposed in the housing  142  and extends from the head  141 . The valve stem  144  is movable between an extended position (as illustrated in FIG. 7) and a depressed position (as illustrated in FIG.  8 ), the valve stem  144  normally being biased by a compression spring  145  into the extended position. The valve stem  144  includes an L-shaped conduit  146  which extends between a first, outlet opening  147  located at the distal end of the valve stem  144  and a second, inlet opening  148  located in the lateral wall of the valve stem  144 . The valve stem  144  further includes a U-shaped conduit  151  in that part thereof which is always disposed within the container  138 . The U-shaped conduit  151  includes first and second axially-spaced openings  153 ,  155  located in the lateral wall of the valve stem  144  and enables communication between the metering chamber  143  and the storage chamber  140  of the container  138  via bores  156  in the housing  142 . 
     When the valve stem  144  is in the extended position (as illustrated in FIG.  7 ), the inlet opening  148  of the L-shaped conduit  146  is located outside the body  139  of the container  138 , and in particular remote from the metering chamber  143  within the container  138 . Thus, when the valve stem  144  is in the extended position, the container  138  is closed since there is no communication path between the storage chamber  140  and the L-shaped conduit  146  in the valve stem  144 . In the extended position, the U-shaped conduit  151  communicates via the first opening  153  and the bores  156  in the housing  142  with the storage chamber  140  and via the second opening  155  with the metering chamber  143 . In this position, with the container  138  inverted, the metering chamber  143  is filled. 
     When the valve stem  144  is in the depressed position (as illustrated in FIG.  8 ), that is, one of either a fill position or a discharge position, the valve stem  144  is pushed down against the biasing action of the biasing element  145 , thereby to move the inlet opening  148  of the L-shaped conduit  146  into communication with the metering chamber  143  and the U-shaped conduit  151  out of communication with the metering chamber  143  and solely in communication with the storage chamber  140  via the bores  156  in the housing  142 . In a filling operation, a solution or suspension of a pharmaceutical substance in a propellant under pressure is forced downwardly through the L-shaped conduit  146 , through the metering chamber  143  and into the storage chamber  140  of the container  138  by being forced past an annular seal  166  which surrounds the valve stem  144  at the bottom of the metering chamber  143 . During the discharge of a metered volume of a suspension or solution of a pharmaceutical substance in propellant under pressure from the container  138 , the metered volume of suspension or solution present in the metering chamber  143  is permitted to flow outwardly through the L-shaped conduit  146  by the provision of a communication path between the metering chamber  143  and the inlet opening  148  of the L-shaped conduit  146 . In the discharge operation, the seal  166  prevents any further of the suspension or solution in the storage chamber  140  from entering the metering chamber  143  so that a precise volume is discharged. 
     In this embodiment the principal structural components of the filling head  2  are typically composed of stainless steel and the seals are typically composed of nitrile rubber. The only exceptions are the diaphragm seals and the seals which come into contact with propellant which typically are composed of PTFE and the valve block  44  and the exhaust valve stem  50  which are typically composed of hardened stainless steel. 
     FIG. 6 illustrates a filling system which incorporates the above-described filling head  2  for filling a container  138  with a metered volume of a suspension or solution of a pharmaceutical substance in a propellant under pressure. 
     The filling head  2  is included in a circulatory line, designated generally by reference sign  170 , in which a propellant under pressure containing a pharmaceutical substance in a suspension or solution is circulated. The circulatory line  170  includes a mixing vessel  172  which holds propellant containing pharmaceutical substance in a suspension or solution. The mixing vessel  172  is pressurised, as is the remainder of the circulatory line  170 , so that the propellant is not only under pressure, but is also maintained as a liquid where the boiling point of the propellant is lower than the ambient temperature. A line  176  connects an outlet  174  of the mixing vessel  172  to a pump  178 , which pump  178  is provided to pump propellant around the circulatory line  170 . Another line  180  connects the pump  178  to the inlet side of an inlet valve  182 . A further line  183  connects the outlet side of the inlet valve  182  to a metering chamber  184 . The metering chamber  184  is configured to receive a metered volume of the propellant containing pharmaceutical substance in a suspension or solution on opening of the inlet valve  182 . The metered volume corresponds to the volume which is required to be introduced into the container  138  by the filling head  2 . A yet further line  186  connects the metering chamber  184  to the filling head  2 , specifically the inlet conduit  34  in the main body  4  of the filling head  2 . As described hereinabove, the inlet conduit  34  communicates with the chamber  31  surrounding the filling valve stem  30  and thence with the outlet conduit  35 . A still further line  188  connects the filling head  2 , specifically the outlet conduit  35  in the main body  4  of the filling head  2 , to the inlet side of an outlet valve  190 . A still yet further line  192  connects the outlet side of the outlet valve  190  to an inlet  194  of the mixing vessel  172 , thereby completing the circulatory line  170 . The filling system further includes a bypass valve  196  which is provided in a line  198  connected between the inlet side of the inlet valve  182  and the outlet side of the outlet valve  190 . 
     The operation of the filling head  2  in filling a container  138  with a metered volume of a suspension or solution of a pharmaceutical substance in a propellant under pressure and subsequently exhausting residual propellant under pressure containing pharmaceutical substance will now be described hereinbelow with reference to FIGS. 6 to  13 . 
     In a first step, as illustrated in FIG. 7, the head  141  of a container  138  to be filled is located within the downwardly-extending recess  134  in the seal retaining block  132  of the slide body  16 . In this position, the head  141  of the container  138  bears against the head seal  131  and the distal end of the valve stem  144  of the container  138  bears against the valve stem seal  112 , with the valve stem  144  being urged into the extended position by the biasing element  145 . In this way, the chamber  116  is sealed by the valve stem and head seals  112 ,  131 . Although not illustrated, it will be understood that the bottom of the container  138  is supported and urged upwardly. Further, in this position, the biasing elements  100  urge the slide body  16  away from the main body  4  so as to provide the gap  103  therebetween, and both the filling valve assembly  29  and the exhaust valve assembly  48  are closed. 
     In a second step, as illustrated in FIG. 8, the actuating mandrel  14  is operated upon to move the main body  4  and both the fill actuator  7  and the exhaust actuator  10  disposed thereto downwardly relative to the slide body  16  against the bias of the biasing elements  100 . This movement causes the projection  105  to pass into the recess  107  and the gap  103  to be closed. Additionally, the downwardly-extending part  5  of the main body  4  is urged via the valve stem seal  112  against the distal end of the valve stem  144  of the container  138 , thereby to push the valve stem  144  downwardly to the depressed open position in which the inlet opening  148  of the L-shaped conduit  146  in the valve stem  144  is in communication with the metering chamber  143  of the container  138  and the U-shaped conduit  151  in the valve stem  144  is located solely in communication with the storage chamber  140  of the container  138  and out of communication with the metering chamber  143 . 
     In a third step, as illustrated in FIG. 9, the filling valve assembly  29  is opened by retracting the valve sealing end  32  of the filling valve stem  30  from the valve seat  33 . A metered volume of propellant containing pharmaceutical substance in suspension or solution present in the metering chamber  184  is then introduced through the inlet conduit  34 , through the annular chamber  31 , through the passageway  20 , through the L-shaped conduit  146  in the valve stem  144 , through the metering chamber  143  of the container  138  and finally past the seal  166  into the storage chamber  140  of the container  138  via the bores  156  in the housing  142 . 
     Prior to opening of the filling valve assembly  29 , the inlet valve  182  and the outlet valve  190  in the circulatory line  170  are closed. When the inlet valve  182  and the outlet valve  190  are closed, the line  183  connecting the inlet valve  182  to the metering chamber  184 , the metering chamber  184 , the line  186  connecting the metering chamber  184  to the filling head  2  and the line  188  connecting the filling head  2  to the inlet side of the outlet valve  190  are full of propellant containing pharmaceutical substance in suspension or solution. When the metering chamber  184  is emptied a volume of propellant under pressure containing pharmaceutical substance corresponding to that metered by the metering chamber  184  is passed through the line  186  and into the filling head  2  through the inlet conduit  34 . In this way, a precisely metered volume of propellant containing pharmaceutical substance in suspension or solution is introduced into the container  138 . In order that the pump  178  can continue to operate continuously, thereby continuing to circulate the propellant containing pharmaceutical substance around the circulatory line  170 , when the inlet valve  182  and the outlet valve  190  are closed, the bypass valve  196  is open. 
     In a fourth step, as illustrated in FIG. 10, after a metered volume of propellant containing pharmaceutical substance in suspension or solution has been introduced into the container  138 , the filling valve assembly  29  is closed by biasing the valve sealing end  32  of the filling valve stem  30  against the valve seat  33 . Thereafter, two separate operations are commenced in order to obviate the inadvertent release of propellant containing pharmaceutical substance into the atmosphere at the end of the filling operation. 
     In a first operation a pressurized fluid is supplied to the conduit  126  in the slide body  16 . This fluid provides a sealing jacket in the chamber  116  and the space  167  defined between the inner circumference of the head seal  131  and the lateral wall of the valve stem  144  of the container  138 . This fluid is supplied at a pressure higher than the vapour pressure of the propellant under pressure containing pharmaceutical substance which remains in the passageway  20  in the main body  4  and the valve stem  144  of the container  138 . In a preferred embodiment the fluid is a gas. Preferably, the gas is one of air or nitrogen. 
     In a second operation an exhaust gas, preferably one of air or nitrogen, is introduced under pressure into the chamber  70  in the exhaust actuator  10  via the first, second and third exhaust gas inlet passages  84 ,  92 ,  93 . The exhaust gas is preferably heated to a temperature of at least about 35° C., more preferably from 35 to 50° C., in order to prevent any of the propellant containing pharmaceutical substance which is exhausted through the chamber  70  from re-liquefying therein. Typically, where air is used as the exhaust gas, the mass flow rate is in the range of from 0.1 to 10 grams/second, preferably around 2 grams/second. 
     In a fifth step, as illustrated in FIG. 11, the actuating mandrel  14  is partially raised thereby partially releasing the valve stem  144  of the container  138  to an intermediate position between the extended closed position (as illustrated in FIG. 7) and the depressed open position (as illustrated in FIG.  8 ). In this intermediate position, the inlet opening  148  of the L-shaped conduit  146  in the valve stem  144  of the container  138  is raised so as not to be in communication with the metering chamber  143  of the container  138  but with the space  167  defined between the inner circumferential surface of the head seal  131  and the lateral wall of the valve stem  144  of the container  138  and the chamber  116  in communication therewith. The propellant under pressure containing pharmaceutical substance which is present in the L-shaped conduit  146  in the valve stem  144  and the passageway  20  in the main body  4  is prevented from escaping therefrom via the inlet opening  148  in the valve stem  144  as a result of the overpressure of the fluid supplied via the conduit  126 . Thus, following the filling operation, and while the valve stem  144  of the container  138  is still in communication with the filling head  2 , the provision of a sealing jacket of a pressurised fluid around the part of the valve stem  144  which includes the L-shaped conduit  146  prevents the propellant under pressure containing pharmaceutical substance which remains in the L-shaped conduit  146  in the valve stem  144  and the passageway  20  in the main body  4  from escaping through the inlet opening  148  in the valve stem  144 , which propellant containing pharmaceutical substance would otherwise be subsequently released to the atmosphere following the removal of the container  138  from the filling head  2 . 
     When the valve stem  144  is in this intermediate position, the metering chamber  143  of the container  138  is closed to the atmosphere since the L-shaped conduit  146  in the valve stem  144  does not communicate with the metering chamber  143  but rather only to the outside of the container  138 , and in particular with the space  167  defined between the inner circumferential surface of the head seal  131  and the lateral wall of the valve stem  144  and the chamber  116  in communication therewith. By providing the valve stem  144  in this intermediate position, propellant under pressure containing pharmaceutical substance present in the metering chamber  143  cannot escape therefrom and therefore only the propellant containing pharmaceutical substance present in the L-shaped conduit  146  in the valve stem  144  and the passageway  20  in the main body  4  need be exhausted. The provision of a sealing jacket of overpressure fluid about the part of the valve stem  144  which includes the inlet opening  148  following the filling operation and during the exhaust operation further advantageously provides that when the container  138  is ultimately removed from the filling head  2  (in the final step following the step as illustrated in FIG.  13 ); no residual propellant containing pharmaceutical substance can escape from the L-shaped conduit  146  in the valve stem  144  or the passage way  20  in the main body  4  prior to exhaustion thereof through the exhaust actuator  10 . 
     In a sixth step, as illustrated in FIG. 12, the exhaust valve assembly  48  is opened by retraction of the valve sealing end  51  of the exhaust valve stem  50  from the exhaust valve seat  67 . In this way, a communication path is provided between the L-shaped conduit  146  in the valve stem  144 , the passageway  20  in the main body  4  and the chamber  70  in the exhaust actuator  10 . The release of pressure from the propellant containing pharmaceutical substance on opening of the exhaust valve assembly  48  causes the propellant to boil off as a gas and escape through the passageway  73  in the valve block  44  into the chamber  70 . In this way, both the propellant and the pharmaceutical substance contained therein escape from the L-shaped conduit  146  in the valve stem  144  and the passageway  20  in the main body  4  into the chamber  70 . The provision of exhaust gas flows through the first, second and third exhaust gas inlet passages  84 ,  92 ,  93  create parallel flows to the gas escaping from the passageway  73  in the valve block  44 . This configuration creates substantially aligned flows between on the one hand the now gaseous propellant entraining pharmaceutical substance escaping from the passageway  73  in the valve block  44  and on the other hand the exhaust gas flows through the first, second and third exhaust gas inlet passages  84 ,  92 ,  93  downstream thereof. This configuration provides a uniform flow of gas in the chamber  70  which entrains the propellant and the pharmaceutical substance that escapes from the passageway  20  in the main body  4  and the L-shaped conduit  146  in the valve stem  144 . Preferably, the mass flow rate of the exhaust gas is at least 10 times the peak mass flow rate of the gaseous propellant flowing into the chamber  70  when the propellant boils off. In a preferred embodiment a vacuum pump incorporating a filter is connected to the exhaust tube  71  so as to collect the escaping pharmaceutical substance. 
     In a seventh step, as illustrated in FIG. 13, the exhaust valve assembly  48  is closed by urging the valve sealing end  51  of the exhaust valve stem  50  against the exhaust valve seat  67 , the fluid supplied to the conduit  126  in the slide body  16  to provide a sealing jacket around the part of the valve stem  144  which includes the inlet opening  148  is terminated and the exhaust gas supplied to the first, second and third exhaust gas inlet passages  84 ,  92 ,  93  is terminated. The actuator mandrel  14  is raised, thereby to raise again the filling head  2  relative to the container  138  so that the slide body  16  is spaced by the normal gap from the main body  4 . In this way, the valve stem  144  is raised from the intermediate position to the extended position, thereby to provide the metering chamber  143  of the container  138  in communication via the U-shaped conduit  151  in the valve stem  144  with the storage chamber  140  of the container  138 . 
     In a final step the container  138  is removed from the filling head  2  without inadvertent leakage of propellant and pharmaceutical substance to the atmosphere. The filling head  2  is then ready for the next filling cycle for a subsequent container. 
     Finally, it will be understood by a person skilled in the art that the present invention has been described in its preferred embodiment and can be modified in many different ways without departing from the scope of the invention as defined in the appended claims.