Abstract
The invention relates to a device for freeze-drying a liquid-containing composition, including but not limited to injectable compositions, in particular pharmaceutical compositions, biological compositions, cosmetic compositions or medical nutritional products. In particular, the present disclosure relates to a device suitable for freeze-drying liquid-containing compositions in a continuous process and to methods therefore. The device for freeze-drying a liquid containing composition in a continuous process comprises one or more, preferably three or more, of a spinner, a transportation mechanism, a vial handler, a vacuum door, and a stoppering system.
Claims
1. A transportation mechanism for use in a device for freeze-drying a liquid-containing composition in a continuous process, the transportation mechanism comprising: two or more platforms for receiving vials; and a walking beam, said walking beam comprising an elongated member having an at least partly open bottom surface, and wherein a cross-sectional shape of the elongated member comprises two lateral projections on opposing sides of the at least partly open bottom surface, said projections being arranged to engage with a neck portion of the vial, said walking beam being arranged to move along a first vertical axis and along a second axis parallel to the elongated member to move at least one vial between the two or more platforms.
2. The transportation mechanism of claim 1, wherein the lateral projections extend along the entire length of the elongated member.
3. The transportation mechanism of claim 1, wherein the at least partly open bottom surface is defined by a recess of the elongated member extending over the entire length of the elongated member.
4. The transportation mechanism of any one of claim 1, wherein the elongated member comprises two openings on opposing ends of the elongated member, suitable for admitting at least the to be engaged neck portion of the vial.
5. The transportation mechanism of claim 4, wherein the two openings are formed in the bottom surface and/or at least one of a side surface of the elongated member.
6. The transportation mechanism of claim 1, wherein the lateral projections are provided with a chamfered top surface.
7. The transportation mechanism of claim 1, wherein the elongated member is further provided with at least one opening on a top surface, such that an passage is defined through the elongated member.
8. The transportation mechanism of claim 1, wherein the platforms are provided with an upwardly directed rim along the periphery of the platform.
9. The transportation mechanism of claim 1, wherein the walking beam comprises two or more elongated members provided substantially parallel to each other.
10. The transportation mechanism of claim 1, wherein the movement of the elongated member along the first vertical axis is actuated by one or more lift motors; and/or wherein the movement of the elongated member along the second axis is actuated by a crankshaft mechanism.
11. The transportation mechanism of claim 1, wherein the platforms are rotating platforms for rotating vials.
12. The transportation mechanism of claim 11, wherein the rotating platforms are coupled to drive disks, wherein said drive disks are actuated by a belt; and/or wherein said drive disks are actuated by magnetic couplings to rotate the rotating platforms.
13. A module, wherein the module is a sublimation and/or desorption module, comprising the transportation mechanism according to claim 1, wherein the module comprises an array of infrared radiators along a length of the module.
14. A device for freeze-drying a liquid containing composition in a continuous process, said device comprising a transportation mechanism according to claim 1.
15. A method for transporting a plurality of vials, each vial being respectively transported at the same time from a start platform for that vial to an end platform for that vial, wherein the start platforms are different for each vial and wherein the end platforms are different for each vial; the method comprising: engaging with a neck portion of each vial at its start platform; performing an upward vertical movement of each vial; performing a horizontal movement of each vial, such that each vial is above its end platform; performing a downward vertical movement of each vial so that each vial is placed on its end platform; and disengaging with the neck portion of each vial at its end platform.
Description
BRIEF DESCRIPTION OF DRAWINGS
[0112] Embodiments will now be described, by way of example only, with reference to the accompanying schematic drawings in which corresponding reference symbols indicate corresponding parts, and in which:
[0113] FIG. 1 illustrates a perspective view of an embodiment according to the invention showing the device for freeze-drying a liquid-containing composition;
[0114] FIG. 2A-2D shows a spinner according to an embodiment of the invention provided in four stages wherein:
[0115] FIG. 2A shows a perspective view illustrating the stage where a vial is positioned on the support;
[0116] FIG. 2B shows a perspective view illustrating the vial after being positioned on the support;
[0117] FIG. 2C shows a frontal view illustrating the position the spinner and the vial at the start of rotation; and
[0118] FIG. 2D shows a frontal view illustrating the position of the spinner and the vial at the end of rotation;
[0119] FIG. 3A-3D shows a transportation mechanism according to an embodiment of the invention illustrating five steps of the transportation mechanism, in which:
[0120] FIG. 3A shows a frontal view illustrating the starting position of the transportation mechanism;
[0121] FIG. 3B shows a frontal view illustrating the upward vertical movement a walking beam, lifting the vials;
[0122] FIG. 3C shows a frontal view illustrating the horizontal forward movement of the walking beam bringing the vials to the next position;
[0123] FIG. 3D shows a frontal view illustrating the downward vertical movement, putting the vials on the rotating platforms; and
[0124] FIG. 3E shows a frontal view illustrating the horizontal backwards movement of the walking beam while leaving the vials in place;
[0125] FIG. 4 shows a transportation mechanism according to an embodiment of the invention, illustrating a drive mechanism generating a movement of the transport mechanism; where
[0126] FIG. 4A shows a top view illustrating the drive mechanism to move the lift frame in a horizontal direction; and
[0127] FIG. 4B shows a side view illustrating the drive mechanism which allows horizontal and vertical displacement of the transportation mechanism;
[0128] FIG. 5 shows a perspective view of the transportation mechanism according to an embodiment of the invention illustrating the free flow of vapour from vials provided in the transport mechanism;
[0129] FIG. 6 shows a side view of the transportation mechanism according to an embodiment of the invention illustrating self-alignment of the vial provided in the transport mechanism; where
[0130] FIG. 6A shows a side view illustrating the vial aligning itself along a vertical axis;
[0131] FIG. 6B shows a side view illustrating the vertically aligned vial in lifted position; and
[0132] FIG. 6C shows a side view illustrating the vial positioned on the rotating platform;
[0133] FIG. 7 shows a perspective view of a vacuum door according to an embodiment of the invention where:
[0134] FIG. 7A shows a perspective view showing the vacuum door;
[0135] FIG. 7B shows a cut-away view of the vacuum door, illustrating the inner parts of the vacuum door assembly;
[0136] FIG. 7C shows a cut-away view of the vacuum door, illustrating the process conditions during the cleaning process;
[0137] FIG. 8 shows a cross-sectional view of a vacuum door coupled to a load lock according to an embodiment of the invention where:
[0138] FIG. 8A illustrates a vacuum door coupled to a chamber having a higher pressure than the adjacent module; and
[0139] FIG. 8B illustrates a vacuum door coupled to a chamber having a pressure equal to the adjacent module;
[0140] FIG. 9 shows a perspective view of a vial handler according to an embodiment of the invention where:
[0141] FIG. 9A illustrates the vial handler in a retracted position; and
[0142] FIG. 9B illustrates the vial handler in an extended position;
[0143] FIG. 10 shows a side view of a vial handler according to an embodiment of the invention where:
[0144] FIG. 10A shows the vial handler in a retracted position without vertical displacement;
[0145] FIG. 10B shows the vial handler in an extended position without vertical displacement;
[0146] FIG. 10C shows the vial handler in a retracted position with downward vertical displacement;
[0147] FIG. 10D shows the vial handler in an extended position with downward vertical displacement;
[0148] FIG. 10E shows the vial handler in a retracted position with upward vertical displacement; and
[0149] FIG. 10F shows the vial handler in a retracted position with upward vertical displacement.
[0150] FIG. 11 shows a blow-out view of a gripper of the vial handler according to an embodiment of the invention, where:
[0151] FIG. 11A shows the gripper having a design with positions for two vial types;
[0152] FIG. 11B shows the gripper having a small vial in an engaged position; and
[0153] FIG. 11C shows the gripper having a large vial in an engaged position;
[0154] FIG. 12 shows a side view of a gripper of the vial handler according to an embodiment of the invention, where:
[0155] FIG. 12A shows the gripper having a large vial in an engaged position; and
[0156] FIG. 12B shows the gripper having a small vial in an engaged position;
[0157] FIG. 13 shows a perspective view of a stoppering system according to an embodiment of the invention, where:
[0158] FIG. 13A shows a feed of stoppers to a stopper holder in a receiving position;
[0159] FIG. 13B shows a rotation of the stopper holder from a receiving position to a stoppering position;
[0160] FIG. 13C shows the stopper holder in the stoppering position;
[0161] FIG. 14 shows a blow-out view of a stoppering system according to an embodiment of the invention, where:
[0162] FIG. 14A shows a stopper holder positioning a stopper near the neck of a vial;
[0163] FIG. 14B shows a stopper being pushed into the neck of a vial;
[0164] FIG. 14C shows the vial with the stopper being released from the stopper holder;
[0165] FIG. 15A-C shows spinners according to embodiments of the invention, comprising a lock and/or a shield; and
[0166] FIG. 16 shows the shield that covers the seal/bearing of the axle of the spinner.
[0167] The figures are intended for illustrative purposes only, and do not serve as restriction of the scope or the protection as laid down by the claims.
Detailed Description of Illustrative Embodiments
[0168] Hereinafter, certain embodiments will be described in further detail. It should be appreciated, however, that these embodiments may not be construed as limiting the scope of protection for the present disclosure.
[0169] Referring to FIG. 1, a perspective view of an embodiment according to the invention is illustrated, showing the device for freeze-drying a liquid-containing composition. The shown embodiment shows an overview of the complete freeze-drying line from the stage where the vials are filled until the stage where the vials are stoppered. The illustrated embodiment shows an infeed and filling module 71, a spin-freezing module 72, a vial handler 73, a load-lock 74, a stoppering module 75, a desorption module 76, a sublimation module 77 and a vacuum pump 78. The infeed and filling module 71 is arranged to provide vials to the device for freeze-drying. Vials are provided to the infeed table of the infeed and filling module 71 and filled with an appropriate amount of liquid-containing composition. A vial handler 73 picks up the vials and introduces the vials into the spin-freeze module 72. The spin-freeze module 72 preferably comprises at least one module in accordance with an embodiment described herein and above under (i). In the spin-freeze module 72 the temperature is reduced to freeze the liquid-containing composition. When this process is finished, the vials are transferred into a load lock 74. The load lock 74 preferably comprises a transportation section and two vacuum doors. The pressure in the load lock 74 is at a pressure of the spin-freeze module 72. The first vacuum door is then opened, allowing the vials to be provided to the transportation section by the vial handler 73. The first vacuum door then closes, and the pressure inside the load lock is brought to substantially the same (reduced) pressure as the next module, which is the sublimation module 77. The vials are transported through the transportation section to the second vacuum door, and when the pressure in the load lock 74 is the same as the pressure in the sublimation module 77, the gate opens and the vials are moved into the sublimation module 77 by a vial handler 73. Preferably, the pressure inside the sublimation module 77 is a vacuum. For example, the pressure inside the sublimation module 77 below 100 Pa, preferably below 60 Pa, more preferably below 40 Pa, still more preferably below 10 Pa. After sublimation in the sublimation module 77, where the temperature of the vials is increased under a low pressure, the vials are transferred to a second load lock 74 in a similar manner as described above to move them to a desorption module 76. The pressure of the load lock 74 is adjusted in accordance with the pressure in the sublimation module 77, the vials are provided to the transportation section of the second load lock by the vial handler 73, the pressures are adjusted in accordance with the pressure of the desorption module 76. After proper adjustment of the vacuum pressure, the vials are provided to the desorption module 76 through the second load lock by the vial handlers 73. Generally, the pressure in the desorption module 76 is vacuum. For example, the pressure inside the desorption module 76 below 100 Pa, preferably below 60 Pa, more preferably below 40 Pa, still more preferably below 10 Pa. A transportation mechanism according to any of the embodiments described herein is preferably provided in the sublimation module 77 and/or the desorption module 76. When the desorption process of the liquid-containing composition is finished, the vials are transferred to a third load lock 74 to move them to a stoppering module 75. Again, the pressure in the load lock 74 is adjusted based on the desorption module 76 and the stoppering module 75 while moving the vials through the third load lock. In the stoppering module 75, the vials are provided with a stopper to seal the vial from the outer environment. After stoppering the process is finished.
[0170] Now referring to FIG. 2A-2D, a spinner according to an embodiment of the invention is shown provided in four stages wherein FIG. 2A shows a perspective view illustrating the stage where a vial 1 is positioned on the support 2.
[0171] The spinner is preferably incorporated in the spin freezing module 72. In the shown embodiment of FIG. 2A, the vial 1 is being positioned on the support 2. The support comprises two fixed arms 3 connected to the support. A rotating arm 4, also coupled to the support 2, is shown in an outward position to allow the vial 1 to be brought into the support platform from the side. The two fixed arms 3 and the rotating arm 4 form a clamping mechanism. In the shown embodiment of FIG. 2B, the vial 1 is positioned onto the support 2, while the rotating arm 4 is in an open position. The rotating arm 4 is rotationally coupled to the support 2 via a hinge. The rotating arm 4 comprises a top portion, which is moved outwardly in the shown embodiment, and a bottom portion having a counterweight 5. The hinge is provided between the top portion and the bottom portion of the rotating arm 4. In the shown embodiment, the spinner further comprises a rotational axis 6, around which the spinner is rotated, and a sealed ball bearing 7, which is arranged to allow rotation of the spinner while sealing the spin-freeze module 72 from the outer environment. In the embodiment shown in FIG. 2C, the rotation 8 of the vial 1 is started through a drive, which is not shown, of the rotational axis 6. As shown, the centrifugal force acting on the counterweight 5 of the rotating arm 4 tilts the top portion of the rotating arm 4 inwards to clamp the vial. As shown in FIG. 2C, the centrifugal forces acts on the centre of gravity of the rotating arm 4, which is preferably positioned below the hinge. If the centre of gravity of the rotating arm 4 is positioned below the hinge, an increase of rotational velocity of the spinner will increase the gripping force on the vial. As shown, the counterweight 5 of the rotating arm 4 is pushed outward due to centrifugal force, resulting in the top portion of the rotating arm 4 to be pushed inwards. This leads to a force acting on the vial 1, pushing it towards, the fixed arms 3. The drive of the rotary axis 6, which is not shown, is located outside of the spin-freezing module 72 and the connection is made through a shaft with a sealed ball bearing 7. In FIG. 2D, the rotation of the spinner has stopped. The gravitational forces acting on the counterweight 5 lead the top portion of the rotating arm 4 to move away from the vial 1, thereby releasing it for further processing.
[0172] FIG. 15A-C shows a related embodiment where the top portion 4A of the one or more rotating arms 4 are slanted away when the spinner is stationary and the bottom parts 4B are slanted towards the support 2. In this stationary situation the vial 1 is easily removed and placed. To avoid undesired release of the vial 1 during ramp up of the rotation speed, a lock 9A can be added to the support that forces the counterweights in an outward direction prior to ramp up of the rotation speed. The lock 9A can comprise a slidable element with a slanted top surface, that can slide upwards in the direction of the support, such that the slanted top surface engages the bottom parts 4B. For example, as shown in FIG. 15A, the slidable element can move upwards along the axis of rotation 6 underneath the support 2 of the vial 1. Because of the slanted top surface of the slidable element, the bottom parts 4B are engaged at their resting position. Due to the upward sliding movement of the slidable element, the bottom parts 4B can be pushed in an outward direction towards a position slanted away from the rotation axis of the support such that the top portion of the one or more rotating arms engages or engages more with the vial. This position is shown in FIG. 15B. As an example, an optional lever 16 with fingers 17 can achieve the sliding movement of the slidable element or lock 9A. This sliding movement takes place during the stationary situation of the spinner. Before the spinning starts, the lever 16 is moved downwards to disengage with the sliding element, thus allowing the free rotation of the spinner axle. This position is shown in FIG. 15C. To prevent the slidable element from moving downwards at that point, the position of this slidable element is kept by frictional, magnetic or spring force (not shown). After spinning is finished, the lever 16 will engage with the sliding element while moving downward.
[0173] In a yet further preferred embodiment shown in FIG. 16, the section near the drive mechanism is shielded such that the flow of air cannot convectively disperse the generated particles. The shield 9B can for example be formed from stainless steel, PTFE, UHMPE and/or PEEK. Preferably, the shield has a rounded shape, e.g., a dome shape or umbrella shape, to achieve optimal flow of air least disturbed by the fast rotation of the axle. The dimensions of the shield can be such that the shield well extends over the dimensions of the particle source, for example the seal or bearing 19 that covers the direct air flow from the drive mechanism towards the support 2, such that the shield covers the direct air flow from the drive mechanism and the particle source towards the support 2. This further reduces the risk of particles ending up in the contents of the vial 1.
[0174] This shield 9B can be conveniently combined with the embodiment as described above where e.g. a lock 9A comprising a slidable element is used to engage the counterweights in a manner that the vial 1 is clamped in e.g. a stationary situation. For example, the shield provides a resting position for the slidable element when the slidable element does not engage the bottom parts 4B of the one or more rotating arms 4. In another embodiment, the slidable element can be configured in such a manner that the bottom surface of the slidable element forms the shield. The shield can be effective during the rotation of the spinner. After the rotation has started, the combined sliding element and shield can be moved towards the lower position. This means that the lever (16) as indicated in FIG. 15 can be moved downwards also, with minimal friction to the sliding element. This minimal friction can be achieved by making use of point contacts or by a choice of low-friction materials such as PTFE. This also can be achieved by rolling contacts such as small bearings.
[0175] Now referring to FIG. 3A-3D, a transportation mechanism according to an embodiment of the invention is shown illustrating five steps of the transportation mechanism. The figures show the starting position of the transportation mechanism, the upward vertical movement of a walking beam, lifting the vials, the horizontal forward movement along the second axis of the walking beam bringing the vials to the next position, the downward vertical movement, putting the vials on the rotating platforms, and the horizontal backwards movement along the same second axis of the walking beam while leaving the vials in place. This shows the cyclic movement of the transport mechanism, which indexes the vials to their next position. The transportation mechanism is preferably provided in the sublimation module 77 and/or the desorption module 76.
[0176] In the shown embodiments, the transport mechanism comprises a walking beam 12, a plurality of rotating platforms 2, and a horizontal guiding mechanism 13. The transport mechanism further comprises drives to execute movements, which are not shown in this figure. The walking beam 12 comprises an elongated member having a recess extending over the entire length of the elongated member, wherein said recess defines two openings on opposing ends of the elongated member, and said recess further defining an open bottom surface of the elongated member, and wherein a cross-sectional shape of the elongated member comprises two lateral projections on opposing sides of the open bottom surface, said projections being arranged to engage with a neck portion of the vial 1, said walking beam 12 being arranged to move along a first vertical axis and along a second axis parallel to the elongated member to move at least one vial between the two or more rotating platforms.
[0177] FIG. 3A shows the starting position of the transportation mechanism. Here, the walking beam 12 is provided such that the neck portion of the vial 1 is provided in the recess of the walking beam through one of the two openings on opposing ends of the elongated member. In this position, the vials 1 rest on the rotating platforms 2, and are rotated so that they are heated in a substantially homogeneous manner. The rotating tables 2 are driven by a belt 11 provided underneath the rotating tables 2. This belt 11 connects all rotating platforms 2 to rotate the rotating platforms 2 at the same rotational velocity. To this end, the rotating platforms 2 are coupled to drive disks which are actuated by the belt 11. Preferably, the drive disks comprise a peripheral recess for receiving the belt 11 such that the belt 11 does not slip from the drive disks.
[0178] FIG. 3B shows the upward vertical movement 14 along the first vertical axis of a walking beam 12, lifting the vials 1. As the walking beam 12 is raised in a vertical movement 14, the lateral projections engage with the neck of the vial 1 to lift the vial 1 from the rotating platform 2. The vials 1 then stop rotating as they are lifted from the rotating platforms 2 and are engaged by the recess defined in the elongated member of the walking beam 12.
[0179] FIG. 3C shows the horizontal forward movement 15 along the second axis of the walking beam 12 bringing the vials 1 to the next position. Once the vials 1 are raised, the walking beam 12 may move the vials to the next position such that the vials 1 are moved from a first rotating platform 2 to a second rotating platform 2. The engagement of the vials with the lateral projections around the neck portion of the vial increases the stability of the vial during movement.
[0180] FIG. 3D shows the downward vertical movement 16, putting the vials 1 on the rotating platforms 2. Once the walking beam 12 positions the vials 1 above their required position, they may be lowered onto the rotating platforms 2. In an embodiment, the last vial 1 held by the elongated member of the walking beam 2 is positioned on a final platform which does not rotate. Alternatively, the last vial 1 is positioned on a final rotating platform where it will be retrieved by a vial handler 73 in accordance with any of the embodiments herein.
[0181] FIG. 3E shows the horizontal backwards movement 17 of the walking beam 12 while leaving the vials 1 in place. Once the vials 1 are positioned on their respective rotating platforms 2, the walking beam 12 is brought back into its original position, as shown in FIG. 3A. In the meanwhile, a new vial 1 may have been placed on the first rotating platform 2. In the shown embodiment of FIG. 3E, this has not been done to show the relative movement of the walking beam 12 more clearly. Since the downward vertical movement 16 shown in FIG. 3D releases the engagement of the vials 1 with the elongated member of the walking beam 12, the vials 1 can rotate freely on the rotating platforms 2. The elongated member of the walking beam 12 may then be brought back to its original position by moving along the horizontal backwards movement 17 along the second axis. This allows a vial handler 73 to pick the last vial 1 for further processing. As shown on the right side of FIG. 3E, the final vial is now no longer positioned in the recess of the elongated member such that it may be picked up from the platform for further processing.
[0182] Now referring to FIG. 4, a transportation mechanism according to an embodiment of the invention is shown, illustrating a drive mechanism generating a movement of the transport mechanism. In particular, FIG. 4A shows a top view illustrating the drive mechanism to move the lift frame along the second axis, in two opposing horizontal directions 15, 17. The drive mechanism comprises a crankshaft mechanism to move the walking beam 12 along the second axis. The crankshaft mechanism comprises two rods, coupled to a rotating shaft. The rotation 21 of the shaft actuates the rods and moves the walking beam 12 backwards and forwards along the second axis.
[0183] FIG. 4B shows a side view illustrating the drive mechanism which allows horizontal and vertical displacement of the transportation mechanism. The movement of the elongated member of the walking beam 12 along the first vertical axis in a vertical direction 14, 16 is actuated by lift motors. The lift motors comprise a rotational drive 19 and a spindle mechanism 18 to actuate the walking beam 12 in a vertical direction 14, 16. The guide frame 13 transmits the movement along the first vertical axis to the walking beam 12 while simultaneously allowing for movement along the second axis in the horizontal directions 15, 17.
[0184] FIG. 5 shows a perspective view illustrating the free flow of vapour 63 from vials provided in the transport mechanism. The shown embodiment shows the transportation mechanism having two parallel elongated members to form the walking beam 12. The elongated members are provided with at least one opening 68 on a top surface, such that a passage is defined which extends through the elongated member. By providing such an opening 68 defining a passage, sublimed vapour from the liquid-containing substance can flow 68 upward during sublimation or desorption, without being trapped in the elongated member. In the shown embodiment, the opening 68 on the top surface is an elongated opening, extending over a width of a plurality of vials 1. Another benefit of the provision of such openings 68 to the walking beam 12 is that the risk of particles falling into the vial 1 during the transportation process is reduced.
[0185] Now referring to FIG. 6, a side view is shown, illustrating self-alignment of the vial 1 provided in the transport mechanism. In particular, FIG. 6A shows a side view illustrating the vial aligning itself along a vertical axis. As the vial 1 is lifted from the rotating platform 2, it may be out of alignment with the centre of the recess provided in the elongated member of the walking beam 12. As the vial 1 is lifted from the rotating platform 2, a vertical centreline of the vial 1 may thus be out of alignment with a vertical centreline of the recess provided in the elongated member of the walking beam 12. As the vial 1 is lifted, the lateral projections, which engage with the neck portions of the vial 1, will straighten the vial 1. In the shown embodiment, the lateral projections have a chamfered top surface, which allows the vial 1 to attain a balanced position within the recess of the elongated member of the walking beam 12. The chamfered top surface of the lateral projections allows a raised portion of the neck portion of the vial 1 to slide down, while allowing a lowered portion of the neck portion of the vial to move upwards from the position shown in FIG. 6A. As such, the vial 1 is rotated such that the centreline of the vial 1 is aligned with a centreline of the recess of the elongated member of the walking beam 12 as shown in FIG. 6B. As the vial is positioned on the rotating platform 2, as shown in FIG. 6C, the alignment of the vial 1 reduces the risk on friction between the elongated member of the walking beam 12 and the vial 1. That is, the lateral projections of the elongated member to not touch the neck portion of the vial 1 while the vial 1 is rotating.
[0186] FIG. 7 shows a perspective view of a vacuum door according to an embodiment of the invention. In particular, FIG. 7A shows a perspective view of the vacuum door having a first panel 27, and a second opposing panel. A space is defined between the first 27 and the second panel. The two opposing panels have at least one opening 25, the opening 25 of the first panel 27 being located opposite the opening of the second panel, such that a vial 1 can be passed through the openings 25 to move through the vacuum door, wherein at least one sealing door 26 is provided in the space defined by the opposing panels 27, said sealing door 26 being moveable between a first position wherein the sealing door 26 is positioned in front of the openings 25, and a second position, wherein the sealing door 26 is positioned away from the openings 25, the vacuum door further comprising an actuation mechanism 33 for actuating the sealing door, said actuation mechanism 33 being arranged to move the sealing door 26 towards the first opening 25 or towards the second opening, when the sealing door 26 is in the first position. During transport of vials 1 from one module to another, the vials pass through the gate openings 25. The vacuum doors are preferably used in a load lock 74 for transporting the vials 1 between e.g. the infeed and filling module 71 and the spin-freezing module 71, and/or between the spin-freeze module 71 and the sublimation module 77, and/or between the sublimation module 77 and the desorption module 76 and/or between the desorption module 76 and the stoppering module 75.
[0187] FIG. 7B shows a cut-away view of the vacuum door, illustrating the inner parts of the vacuum door assembly wherein the sealing doors 26 are shown in the second position, such that they are positioned away from the openings 25. The sealing doors 26 are moved between the first and second positions by use of a pneumatic cylinder 28, said pneumatic cylinder 28 further comprising a bellows 29 provided around at least a part of a rod, said rod being attached to the sealing door 26. The pneumatic cylinder 28 is arranged to move the sealing doors 26 between the first and second positions by actuation of the rod. The bellows 29 provides separation of the clean area and the outer environment. This further reduces the risk of contamination of the liquid-containing composition in the vials 1.
[0188] Once the sealing doors 26 are in the first position, in front of the openings 25, the sealing doors may be moved towards the first opening or towards the second opening by an actuation mechanism 33. In the shown embodiment, this actuation mechanism is a bellows which is arranged to engage with an extended portion of the rod to push the doors towards the opening in the first or the second opposing panels to seal the vacuum door.
[0189] FIG. 7C shows a cut-away view of the vacuum door, illustrating the process conditions during the cleaning process. Once the sealing doors 26 are in the first position in front of the openings 25 in the panels, the vacuum doors may be cleaned. In the cleaning process, water with cleaning agents, or another liquid, is sprayed through nozzles and jets 30 to clean the space of the vacuum door. The water with cleaning agents is supplied through inlet ports 31.
[0190] The shown embodiment of the vacuum door further comprises two cleaning drains 32, which are arranged to allow a cleaning agent to be removed from the space of the vacuum door during cleaning.
[0191] The vacuum door is preferably used in a load lock 74. In such an embodiment, the load lock 74 comprises a transportation section comprising at least two vacuum doors, a first vacuum door being provided on a first side of the transportation section and a second vacuum door being provided in a second side of the transportation section, and said load lock further comprising at least two vial handlers 73, said vial handlers 73 being arranged to move vials 1 through the vacuum doors.
[0192] Now referring to FIG. 8 a cross-sectional view of a vacuum door coupled to a chamber 34 is shown. In particular, FIG. 8A illustrates a vacuum door coupled to a chamber 34 having a higher pressure than the adjacent module. The chamber 34 may be the transportation section of a load lock 74 but may also be e.g. the sublimation module 77, the desorption module 76, the stoppering module 75, the spin-freeze module 72 and/or the infeed and filling module 71.
[0193] As shown in FIG. 8A, the vacuum door comprises a space defined by two opposing panels having opposing openings 25 provided therein. The sealing door 26 is in the first position, in front of the openings 25. In the shown embodiment, the sealing door 26 is pressed towards a panel by the actuation mechanism 33 which is provided in the form of a bellows which is arranged to engage with an extended portion of the rod to push the doors towards the opening in the first panels to seal the vacuum door. The bellows is driven by pneumatics which forces the bellows 33 to move the sealing door 26 to snugly fit to the opening 25 and assure proper closure. In the event that the chamber 34 has a higher pressure than the adjacent module, the relative overpressure provides a further force on the sealing of the sealing door 26 and the opening 25. By controlling the positions of the bellows 33, the sealing doors 26 can be moved in the direction where closure is required. In the shown embodiment, the bellows 33 comprise a flexible membrane which is pneumatically actuated to move outwardly when pressurized.
[0194] The sealing door 26 comprises two peripheral seals 62 provided on a first and a second side of the sealing door 26, said peripheral seals 62 being arranged to engage with an seat region of the openings 25 provided around the periphery of the openings. These seals 62 are preferably flexible.
[0195] As shown in FIG. 8B, when the chamber 34 attains the same pressure as an adjacent module, and the bellows 33 does not engage with the rod to actuate the sealing door 26, the sealing door is positioned in the centre of the space defined by the opposing panels. In this configuration, the sealing door 26 can move up and down through the connection with a rod mechanism 63 without touching the opening 25. Further, FIG. 8B shows one sealing door 26 in the first position, in front of the opening 25 and one sealing door 26 in the second position where the opening 25 is free and a vial 1 may be moved through the door.
[0196] Now referring to FIG. 9 a perspective view of a vial handler 73 is shown according to an embodiment of the invention. In particular, FIG. 9A shows a vial handler 73 in a retracted position and FIG. 9B shows the vial handler 73 in an extended position. The vial handler 73 is arranged to transfer vials 1 from one location or module to another or from one module into a load lock and visa-versa. In an advantageous embodiment, the vial handler 73 is coupled to load locks 74 to transport vials 1 from one module to the next through a load lock 74. For example, the vial handler 73 may be used to transport vials 1 from the sublimation module 77 to the desorption module 76 through a load lock 74. A first vial handler 73 removes the vials 1 from the sublimation module 77 and into the transportation section of the load lock 74. A second vial handler 73 then moves the vials 1 from the transportation section of the load lock 74 to the desorption module 76. The vial handlers 73 are arranged to move the vials 1 both in horizontal and vertical way.
[0197] The horizontal translation of the vial handler 73 is shown in FIG. 9 whereas the vertical translation is shown in FIG. 10, which shows a side view of a vial handler according to an embodiment of the invention. In particular, FIG. 10A shows the vial handler in a retracted position without vertical displacement, FIG. 10B shows the vial handler in an extended position without vertical displacement, FIG. 10C shows the vial handler in a retracted position with downward vertical displacement, FIG. 10D shows the vial handler in an extended position with downward vertical displacement, FIG. 10E shows the vial handler in a retracted position with upward vertical displacement, FIG. 10F shows the vial handler in a retracted position with upward vertical displacement.
[0198] As shown in FIG. 9 and FIG. 10, the vial handler 73 comprises an elongated arm defining a distal end and a proximal end. The vial handler 73 further comprises a gripper 45 arranged to engage with a neck portion of a vial 1. The gripper 45 is provided on the distal end of the elongated arm. The elongated arm is provided through a barrier defining a pivot point 44, said pivot point 44 being positioned between the distal end and the proximal end of the elongated arm such that actuation in a plane orthogonal to the elongated arm of the proximal end of the elongated arm on a first side of the barrier translates to an opposite movement of the distal end of the arm on a second side of the barrier.
[0199] A plurality of actuators move the proximal end of the elongated arm. The movement between the retracted position and the extended position is effectuated by a linear guiding 42, actuated by a motor drive 43. The vials 1 are picked up and held by their neck portion in the gripper 45. The gripper 45 is mounted on the distal end of the elongated arm, which is surrounded by bellows 47 to protect the sterile environment from the outer environment.
[0200] The vertical movement of the distal end of the elongated arm is achieved by actuation of the proximal end of the elongated arm, on the other side of the barrier. The vertical movement is effectuated by another motor drive 43 with an eccentric wheel 48, which is coupled to the elongated arm. As the eccentric wheel 48 is driven by the motor drive, the proximal end of the elongated arm may be raised or lowered. As a result, the distal end and the gripper 45 are raised and/or lowered.
[0201] As shown in FIG. 10C and FIG. 10D, the eccentric wheel 48 is rotated such that the proximal end of the elongated arm is raised, leading to the lowering of the distal end of the elongated arm and the gripper 45. As shown, the effect of the movement of the proximal end of the elongated arm is dependent on the level of horizontal extension of the elongated arm.
[0202] The drives 43 arranged to actuate the horizontal and vertical movement of the elongated arm are provided on a frame 46. In a preferred embodiment, the frame is coupled to the barrier. The pivot point 44 comprises a leaf spring to allow the movement of the elongated arm while the bellows 47 remains coupled to the barrier. The bellows 47 is coupled to the barrier on one end and to the distal end of the elongated arm on the other end. As such, while the arm extends, the bellows 47 remains positioned around the distal end of the elongated arm to prevent the ingress of particles into the sterile environment from the outer environment.
[0203] Now referring to FIG. 11, a blow-out view is shown, illustrating a gripper 45 of the vial handler 73 according to an embodiment of the invention. In particular, FIG. 11A shows the gripper having a design with positions for two vial types. The gripper 45 is shown attached to the distal end of the elongated arm of the vial handler 73. The distal end of the elongated arm has a bellows 47 provided around the elongated arm. The gripper 45 of the shown embodiment comprises two portions in stepped relation to one another. A proximal portion 49 is arranged to receive a small vial 1 neck, where a distal portion 50 is arranged to receive a large vial 1 neck. FIG. 11B shows the gripper 45 having a small vial 1A in an engaged position and FIG. 11C shows the gripper 45 having a large vial 1B in an engaged position. If a vial 1 is too small to be engaged by the distal portion 50, it will pass through and be engaged by the proximal portion 49. As such, the two positions cover a large range of applicable vials 1, thus reducing the requirement for change-over when different vial sizes are applied. The distal portion 50 and the proximal portion 49 contain a rim 51 which prevents vials to fall off when horizontal and vertical movements are effectuated.
[0204] FIG. 12 shows a side view of the gripper 45 of the vial handler 73 where FIG. 12A shows the gripper 45 having a large vial 1B in an engaged position and FIG. 12B shows the gripper 45 having a small vial 1A in an engaged position. As shown in FIG. 12A, the large vial 1B is engaged by the distal portion 50 of the gripper 45 since it cannot move further into the gripper 45. The large vial 1B is supported by the rim 51. In FIG. 12B, the small vial 1A is engaged by the proximal portion 49 of the gripper 45 since it moved through the space defined by the distal portion 50 of the gripper 45.
[0205] Now referring to FIG. 13, a perspective view of a stoppering system according to an embodiment of the invention is shown. In the shown embodiment, the stoppering system comprises a stopper holder 55 being rotatably attached to a substantially horizontal actuation axis at a first end. The horizontal actuation axis is driven by a rotation motor 57. The stopper holder 55 is rotationally moveable between a receiving position and a stoppering position by the actuation axis, which is driven by the rotation motor 57. The second end of the stopper holder 55 comprises a slot 60 at an edge region for receiving a stopper 53. The slot 60 has a lateral shape to receive the stopper 53 from the stopper feed. Upon receiving the stopper 53, it is contained in the slot 60 on a first side of the edge (slot 60 is shown in FIG. 14). The slot further defines an opening for engaging the stopper 53 with a vial 1 on a second side of the edge, wherein in the receiving position the opening is directed upwards, and wherein in the stoppering position the opening is directed downwards. The slot 60 is formed such that the stopper 53 is held in the slot 60 in the stoppering position.
[0206] In FIG. 13A, a feed of stoppers 53 is shown which lead to the slot 60 in the stopper holder 55 when it is in a receiving position. Through a controlled movement control system, which is not shown, stoppers 53 are only pushed when the stopper holder 55 in the receiving position and is not provided with a stopper 53. In the meanwhile, a vial 1 is positioned on a support platform 52, waiting for the stoppering to occur.
[0207] FIG. 13B shows the rotation of the stopper holder 55 from a receiving position to a stoppering position. Once the stopper 53 is provided in the opening 60 of the stopper holder 55, the stopper holder 55 may be rotated 56 around the actuation axis. This brings the stopper 53 towards the vial 1.
[0208] FIG. 13C shows the stopper holder 55 in the stoppering position. In this position, the stopper holder 55 exerts a force on the vial 1 which is standing on a the support platform 52. To allow for different vial sizes the stopper holder 55 can be exchanged by dismounting the stopper holder from the actuation axis using the knob 61.
[0209] Now referring to FIG. 14, a blow-out view of a stoppering system according to an embodiment of the invention is shown, where FIG. 14A shows a stopper holder 55 positioning a stopper 53 near the neck of a vial 1, FIG. 14B shows a stopper 53 being pushed into the neck of a vial 1, and FIG. 14C shows the vial 1 with the stopper 53 being released from the stopper holder 55.
[0210] In the shown embodiment, a flexible plate 59 is provided on the stopper holder 55. The flexible plate 59 is arranged over the opening defined by the slot 60. The flexible plate 59 has an opening corresponding with the opening defined by the slot 60 but the opening on the flexible plate 59 is smaller than the opening defined by the slot 60. As a result, the stopper 53 is maintained in the slot 60 and rests on the flexible plate 59 when the stopper holder 55 is in the stoppering position. By providing a flexible plate 59, the stopper 53 is kept in place during the movement of the stopper holder 55 from the receiving position to the stoppering position.
[0211] The use of such a flexible plate 59 allows slight deformation to press the stopper 53 into the vial 1 to an increased extent. As shown in FIG. 14B, the flexible plate 59 is deformed as the stopper 53 is pressed into the vial 1. As the stoppers 53 are pressed into the vial 1 further, the quality of the primary closure is increased.
[0212] As shown in FIG. 14C, once the stopper 53 is pressed into the vial 1, the vial may be removed from underneath the stopper holder 55.
[0213] The figures are intended for illustrative purposes only, and do not serve as restriction of the scope or the protection as laid down by the claims.
[0214] Two or more of the above embodiments may be combined in any appropriate manner as is also shown in FIG. 1.
[0215] The invention is further exemplified by the following clauses.
[0216] Clause 1: A transportation mechanism for use in a device for freeze-drying a liquid-containing composition in a continuous process, the transportation mechanism comprising: two or more rotating platforms for receiving and rotating vials; and a walking beam, said walking beam comprising an elongated member having a recess extending over the entire length of the elongated member, wherein said recess defines two openings on opposing ends of the elongated member, and said recess further defining an open bottom surface of the elongated member, and wherein a cross-sectional shape of the elongated member comprises two lateral projections on opposing sides of the open bottom surface, said projections being arranged to engage with a neck portion of the vial, said walking beam being arranged to move along a first vertical axis and along a second axis parallel to the elongated member to move at least one vial between the two or more rotating platforms.
[0217] Clause 2: The transportation mechanism of clause 1, wherein the lateral projections are provided with a chamfered top surface, preferably wherein the lateral projections extend continuously along the entire length of the elongated member, preferably wherein the elongated member is further provided with at least one opening on a top surface, such that an passage is defined through the elongated member.
[0218] Clause 3: The transportation mechanism of any of clauses 1-2, wherein the rotating platforms are provided with an upwardly directed rim along the periphery of the rotating platform, preferably wherein the rotating platforms are coupled to drive disks, said drive disks preferably being actuated by a belt, more preferably wherein a single belt extends over all drive disks to rotate all rotating platforms at the same rotational velocity.
[0219] Clause 4: A vial handler for use in a device for freeze-drying a liquid-containing composition in a continuous process, said vial handler comprising: an elongated arm defining a distal end and a proximal end; and a gripper arranged to engage with a neck portion of a vial, said gripper being provided on the distal end of the elongated arm, wherein the elongated arm is provided through a barrier defining a pivot point, said pivot point being positioned between the distal end and the proximal end of the elongated arm such that actuation of the proximal end of the elongated arm in a plane orthogonal to the elongated arm on a first side of the barrier translates to an opposite movement of the distal end of the arm on a second side of the barrier.
[0220] Clause 5: The vial handler of clause 4, the gripper comprises two forwardly projecting legs, said legs having a reducing thickness moving away from the distal end of the arm, such that the legs have an increasing width moving away from the distal end of the arm, preferably wherein the reach of the elongated arm, along the direction of the elongated arm, during extension of the elongated arm, is at least about 150 mm, preferably at least about 200 mm, more preferably at least about 250 mm, still more preferably at least about 300 mm.
[0221] Clause 6: The vial handler of clause 4 or 5, containing at least 2 grippers, preferably at least 5 grippers, more preferably at least 10 grippers.
[0222] Clause 7: A vacuum door for use in a device for freeze-drying a liquid-containing composition in a continuous process, said vacuum door comprising: a first panel; and a second opposing panel, defining a space therebetween, said two opposing panels having at least one opening, the opening of the first panel being located opposite the opening of the second panel, such that a vial can be passed through the openings to move through the vacuum door, wherein at least one sealing door is provided in the space defined by the opposing panels, said sealing door being moveable between a first position wherein the sealing door is positioned in front of the openings, and a second position, wherein the sealing door is positioned away from the openings, the vacuum door further comprising an actuation mechanism for actuating the sealing door, said actuation mechanism being arranged to move the sealing door towards the first opening or towards the second opening, when the sealing door is in the first position.
[0223] Clause 8: The vacuum door of clause 7, wherein the sealing door comprises two peripheral seals, preferably flexible seals, provided on a first and a second side of the sealing door, said peripheral seals being arranged to engage with an seat region of the openings provided around the periphery of the openings.
[0224] Clause 9: The vacuum door of clause 7 or 8, wherein the vacuum door further comprises a pneumatic cylinder provided in the space defined by the two opposing panels, said pneumatic cylinder comprising a bellows provided around at least a part of a rod, said rod being attached to the sealing door, wherein the pneumatic cylinder is arranged to move the sealing doors between the first and second position, preferably wherein the actuation mechanism comprises at least one bellows actuator, provided in the first or second panel, said bellows actuator being arranged to engage with the rod to move the sealing door towards the opening in the first or the second panel, more preferably wherein the bellows actuator comprises a circular membrane, having an engagement surface provided in the middle of the membrane, wherein the membrane is arranged to project outwardly such that the engagement surface is moved outwardly.
[0225] Clause 10: A load lock for use in a device for freeze-drying a liquid-containing composition in a continuous process, said load lock comprising: a transportation section; and a first and a second vacuum door according to any of clauses 7-9; the first vacuum door being provided on a first side of the transportation section and the second vacuum door being provided in a second side of the transportation section, and said load lock further comprising at least two vial handlers, preferably vial handlers according to any of clauses 4-6, said vial handlers being arranged to move vials through the vacuum doors.
[0226] Clause 11: A spinner for use in a device for freeze-drying a liquid-containing composition in a continuous process, said spinner comprising: a support for supporting a vial; and a clamping mechanism connected to the support, wherein the clamping mechanism comprises at least two arms coupled to the support, wherein at least one of the arms is a rotating arm being rotationally coupled to the support via a hinge, wherein the rotating arm comprises a top portion and a bottom portion having a counterweight, said hinge being provided between said top portion and said bottom portion.
[0227] Clause 12: The spinner according to clause 11, wherein the gravitational centre of the rotating arm is positioned below the hinge, preferably wherein the moment of the bottom portion is more than 10% larger than the moment of the top portion, preferably between 20-100% larger than the moment of the top portion, more preferably between about 20-50% larger than the moment of the top portion.
[0228] Clause 13: The spinner according to clause 11 or 12, wherein the rotating arm has a balanced position, when the spinner is stationary, and wherein the bottom portion is slanted towards the support, while the top portion is slanted away from the support.
[0229] Clause 14: A stoppering system for use in a device for freeze-drying a liquid-containing composition in a continuous process, said stoppering system comprising: a stopper holder; and a horizontal actuation axis, said stopper holder being rotatably attached to the horizontal actuation axis at a first end, said stopper holder being moveable between a receiving position and a stoppering position by the actuation axis, wherein the second end of the stopper holder comprises a slot at an edge region for receiving a stopper, said slot having a lateral shape to receive the stopper such that the stopper may be contained in the slot on a first side of the edge, and an opening for engaging the stopper with a vial on a second side of the edge, wherein in the receiving position the opening is directed upwards, and wherein in the stoppering position the opening is directed downwards, wherein the slot is formed such that the stopper is held in the slot in the stoppering position.
[0230] Clause 15: The stoppering system according to clause 14, wherein a flexible plate is provided on the stopper holder, said flexible plate being arranged over the opening defined by the slot, and said flexible plate having an opening corresponding with the opening defined by the slot, the opening on the flexible plate being smaller than the opening defined by the slot, such that the stopper is maintained in the slot.
[0231] Clause 15: A device for freeze-drying a liquid containing composition in a continuous process, said device comprising one or more, preferably three or more, of: a transportation mechanism according to any of clauses 1-3; a vial handler according to any of clauses 4-6; [0232] a vacuum door according to any of clauses 7-9, preferably wherein the vacuum door forms part of a load lock according to clause 10; a spinner according to any of clauses 11-13; and a stoppering system according to any of clauses 14-15, preferably wherein the device comprises at least the transportation mechanism, the vial handler, and the vacuum door, more preferably wherein the device is able to process at least about 5000 vials per day.
