Liquid feeding device for the generation of droplets

Abstract

The present invention provides, inter alia, for a liquid feeding device for the generation of droplets, in particular for the use in a process line for the production of freeze-dried particles, with a droplet ejection section for ejecting liquid droplets in an ejection direction, the droplet ejection section comprising at least one inlet port for receiving a liquid to be ejected, a liquid chamber for retaining the liquid, and a nozzle for ejecting the liquid from the liquid chamber to form droplets, wherein the liquid chamber is restricted by a membrane on one side thereof, the membrane being vibratable by an excitation unit, wherein the longitudinal axis of the liquid chamber is tilted relative to the longitudinal axis of the nozzle, and/or the liquid feeding device further comprises a deflection section for separating the droplets from each other by means of at least one gas jet, wherein the deflection section gas jet intersects perpendicular with an ejection path of the liquid ejected from the liquid chamber.

Claims

1. A liquid feeding device for the generation of droplets, for the use in a process line for the production of freeze-dried particles for the pharmaceutical field, with a droplet ejection section for ejecting liquid droplets in an ejection direction, the droplet ejection section comprising at least one inlet port for receiving a liquid to be ejected, a liquid chamber for retaining the liquid, and a nozzle for ejecting the liquid from the liquid chamber to form droplets, wherein the liquid chamber is restricted by a membrane on one side thereof, the membrane being vibratable by an excitation unit, wherein the liquid feeding device further comprises a deflection section for separating the droplets from each other by means of at least one gas jet, and wherein the deflection section gas jet intersects perpendicular with an ejection path of the liquid ejected from the liquid chamber; wherein the excitation unit is configured to generate a controlled mechanical vibration of the membrane to eject equally sized liquid droplets from the nozzle.

2. The liquid feeding device according to claim 1, wherein the longitudinal axis of the liquid chamber is tilted relative to the longitudinal axis of the nozzle and wherein the membrane is a stainless steel membrane.

3. The liquid feeding device according to claim 1, wherein the deflection section comprises at least one deflection tube for emitting the gas jet, the at least one deflection tube protruding from a main body of the deflection section in the ejection direction of the liquid.

4. The liquid feeding device according to claim 3, wherein the deflection section comprises at least two deflection tubes arranged opposite to each other, and wherein the emitted gas jets meet each other at an ejection path of the liquid ejected from the liquid chamber, intersecting with the same.

5. The liquid feeding device according to claim 4, wherein the deflection section comprises four deflection tubes, and wherein the emitted gas jets meet each other at an ejection path of the liquid ejected from the liquid chamber, intersecting with the same.

6. The liquid feeding device according to claim 3, wherein each deflection tube comprises at least two gas jet outlet ports, and wherein the gas jet outlet port at the tip of the respective deflection tube connects with the tube interior at its edge.

7. The liquid feeding device according to claim 6, wherein each deflection tube comprises three gas jet outlet ports.

8. The liquid feeding device according to claim 1, wherein the droplets pass through a recess provided in a main body of the deflection section.

9. The liquid feeding device according to claim 8, wherein the recess is a central through-hole extending through the main body of the deflection section.

10. The liquid feeding device according to claim 1, wherein the droplet ejection section further comprises at least one outlet port.

11. The liquid feeding device according claim 10, wherein the longitudinal axis of the liquid chamber is tilted relative to the longitudinal axis of the nozzle in a way that the at least one outlet port is provided at the highest level of the liquid chamber.

12. The liquid feeding device according claim 10, wherein the at least one outlet port serves for drainage of excessive liquid to be ejected from the liquid chamber and/or serves for discharge of SiP fluid and/or CiP fluid introduced through the at least one inlet port of the droplet ejection section.

13. The liquid feeding device according to claim 10, wherein the at least one outlet port is arranged at an outer circumference of the liquid chamber.

14. The liquid feeding device according to claim 1, wherein the excitation unit comprises a combination of a permanent magnet separably attachable to the membrane opposite the liquid chamber and an electromagnetic coil for actuating the permanent magnet.

15. The liquid feeding device according to claim 14, wherein a damping element is provided around the permanent magnet.

16. The liquid feeding device according to claim 15, wherein the damping element is also provided between the permanent magnet and the electromagnetic coil.

17. The liquid feeding device according to claim 16, wherein the damping element is made out of silicone.

18. The liquid feeding device according to claim 1, wherein the membrane is a stainless steel membrane.

19. The liquid feeding device according to claim 1, wherein the droplet ejection section comprises an actuation portion and a nozzle portion, the actuation portion comprising at least the excitation unit, and the nozzle portion comprising at least the at least one inlet port, the liquid chamber, the nozzle and the membrane.

20. The liquid feeding device according to claim 19, wherein the nozzle portion comprises a nozzle portion main body and a nozzle body provided separately from the nozzle portion main body.

21. The liquid feeding device according to claim 20, wherein the nozzle body is permanently installed in a central through-hole in the nozzle portion main body.

22. The liquid feeding device according to claim 21, wherein the nozzle body is permanently installed in a central through-hole in the nozzle portion main body by laser welding.

23. The liquid feeding device according to claim 19, wherein the membrane is welded to the nozzle portion for airtightly closing the liquid chamber on one side.

24. The liquid feeding device according to claim 23, wherein the membrane is welded to the nozzle portion for airtightly closing the liquid chamber on one side by laser welding.

25. The liquid feeding device according to claim 1, further comprising a CiP/SiP section arranged between the droplet ejection section and the deflection section, for providing CiP fluid and/or SiP fluid to the parts of the liquid feeding device subsequent to the droplet ejection section.

26. The liquid feeding device according to claim 1, further comprising a droplet counting section for counting the droplets.

27. The liquid feeding device according to claim 26, wherein the droplet counting section for counting the droplets is provided before the deflection section in the ejection direction of the liquid.

28. A process line for the production of freeze-dried particles for the pharmaceutical field, comprising a liquid feeding device according to claim 1, for the generation of droplets, a freezing chamber for freeze-congealing droplets fed from the liquid feeding device, and a freeze-dryer for lyophilization of the frozen droplets.

29. A process for preparing a vaccine composition comprising one or more antigens in the form of freeze-dried particles comprising at least a step of generating liquid droplets of said vaccine composition with a liquid feeding device according to claim 1.

30. The process according to claim 29, wherein all the steps are carried out under sterile conditions.

31. The process according to claim 29, wherein the freeze-dried particles are sterile.

32. A process for preparing an adjuvant containing vaccine composition comprising one or more antigens in the form of freeze-dried particles comprising: at least a step of generating liquid droplets of said vaccine composition with the liquid feeding device according to claim 1, or at least the steps of generating liquid droplets of an antigen(s)-containing composition with the liquid feeding device according to claim 1, of generating liquid droplets of an adjuvant-containing composition with the liquid feeding device according to claim 1, freeze-drying the droplets to obtain freeze-dried particles, and blending the freeze-dried particles of antigen(s) with the freeze-dried particles of adjuvant.

33. The liquid feeding device for the generation of droplets for the use in a process line for the production of freeze-dried particles for the pharmaceutical field, with a droplet ejection section for ejecting liquid droplets in an ejection direction, the droplet ejection section comprising at least one inlet port for receiving a liquid to be ejected, a liquid chamber for retaining the liquid, and a fixed nozzle directed vertically for ejecting the liquid from the liquid chamber vertically to form droplets that travel along a vertical ejection path, wherein the liquid chamber is restricted by a membrane on one side thereof, the membrane being vibratable by an excitation unit, and wherein the longitudinal axis of the liquid chamber is tilted relative to the longitudinal axis of the nozzle.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

(1) Further aspects and advantages of the invention will become apparent from the following description of particular embodiments illustrated in the figures in which:

(2) FIG. 1 is a schematic illustration of a product flow in a process line comprising a liquid feeding device according to a preferred embodiment of the invention;

(3) FIG. 2 is a schematic illustration of a configurational mode of the process line as illustrated on FIG. 1;

(4) FIG. 3 shows an overall structure of a process line as illustrated in FIGS. 1 and 2;

(5) FIG. 4 shows a side view of the liquid feeding device according to the preferred embodiment of the invention;

(6) FIG. 5 is a cross-sectional view of the liquid feeding device of FIG. 4 along line A-A;

(7) FIG. 6 is a cross-sectional view of the liquid feeding device of FIGS. 4 and 5 along line B-B in FIG. 5;

(8) FIG. 7a is an enlarged view of detail “X” in FIG. 5;

(9) FIG. 7b is an enlarged view of detail “Y” in FIG. 6, illustrating one deflection tube of the liquid feeding device according to the preferred embodiment of the invention in cross-section;

(10) FIG. 8 is an enlarged view of the respective parts of an alternative structure of the actuation portion of the liquid feeding device according to the preferred embodiment of the invention, and

(11) FIG. 9 is an enlarged view of a deflection section of a liquid feeding device according to another preferred embodiment of the invention in cross-section.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

(12) As a general overview, FIG. 1 schematically illustrates a process line 100 for the production of freeze-dried particles in the form of pellets, wherein a product flow 102 is assumed to pass through the process line 100 under closed conditions 104, also referred to as enclosure 104. A liquid feeding device 200 in accordance with a preferred embodiment of the present invention feeds liquid to a freezing chamber 300, also known as prilling chamber or prilling tower, in the form of ejected droplets (see also droplets 103 in FIG. 3), where the liquid is subjected to freeze-congealing. Prilling is a method of producing reasonably uniform spherical particles from liquid solutions. It essentially consists of two operations, firstly producing liquid droplets and secondly solidifying them individually by cooling. The prilling technology is also known as “laminar jet break-up” technology. The resulting frozen droplets are then transferred via a first transfer section 400 to a freeze-dryer 500 in which the frozen droplets are lyophilized. After lyophilization, the thus produced pellets are transferred via a second transfer section 600 to a discharge station 700, which provides for a filling of the pellets under closed conditions into final recipients 106, typically in the form of IBCs (“Intermediate Bulk Containers”) which are then removed from the process line 100.

(13) Enclosure 104 is intended to indicate that the product flow 102 from entry to exit of process line 100 is performed under closed conditions, i.e., the product is kept under sterility and/or containment. The process line provides closed conditions without the use of an isolator, the role of which is indicated by dashed line 108 which separates line 102 from environment 110. Instead of the need of an isolator, enclosure 104 separates product flow 102 from the surrounding environment 110, wherein enclosure 104 is implemented individually for each of the devices 200, 300, 500, 700 and transfer sections 400, 600 of process line 100. Thus, the object of end-to-end protection of sterility and/or containment of the product flow 102 in the entire process line 100 is achieved without putting the entire process within one single device, such as an isolator as known from prior art. Instead, the process line 100 according to the invention comprises separate process devices, e.g., one or more prilling tower, freeze-dryer, discharge station, etc., which are connected as indicated in FIG. 1 by one or more transfer sections 400, 600 to form an integrated process line 100 enabling an interface-free end-to-end (or start-to-end) product flow 102.

(14) In an alternative view, FIG. 2 schematically illustrates the configuration of the process line 100 for the production of freeze-dried particles under closed conditions as shown in FIG. 1. Briefly, the product is flowing as indicated by arrow 102 and is preferably kept sterile and/or contained by accordingly operating each of the separate devices including liquid feeding device 200, freezing chamber 300, freeze-dryer 500 and first transfer section 400 under sterile conditions/containment, which is intended to be indicated by the respective enclosure parts 1042, 1043, 1045, and 1044 of enclosure 104. The discharge station 700, while not currently under operation in the shown state of process line 100, is also adapted for protecting sterility/providing containment by enclosure part 1047, and the second transfer section 600, while currently separating the devices 200, 300, 500 from the discharge station 700 in the shown state of process line 100, is also adapted for protecting sterility/providing containment by enclosure part 1046. Thus, in the exemplary configuration of the process line 100 as illustrated in FIG. 2, the first transfer section 400 is configured in an open state not to limit or interfere with the product flow 102, while the second transfer section 600 is configured to sealably separate the freeze-dryer 500 and discharge station 700, i.e., the second transfer section 600 operates to seal the freeze-dryer 500 and provide closed conditions 1046, 1047 in this respect.

(15) Each of the devices 200, 300, 500, 700 and the transfer sections 400, 600 are separately adapted and optimized for operation under closed conditions, wherein “operation” refers to at least one mode of operation including, but not limited to, production of freeze-dried particles, or maintenance modes. Here, a sterilization of a process device or transfer section naturally also requires that the device/section is adapted to maintain sterility/containment. For example, as symbolized by CiP/SiP system 105 in FIG. 2, cleaning and/or sterilization of a process device or transfer section may not require any mechanical or manual intervention in that it is performed automatically in place throughout the process line 100 or in parts thereof. Automatic control of respective valves or similar separating means provided in association with the transfer sections, preferably by remote access thereto, also contribute to configurability of the process line 100 for different operational configurations without mechanical and/or manual intervention.

(16) The details of how process devices such as freezing chambers or freeze-dryers can protect sterility and/or provide containment for the products processed therein depend on the specific application. For example, the sterility of a product is protected or maintained by sterilizing the involved process devices and transfer sections. It is to be noted that—after a sterilization process—a process volume confined within a hermetically closed wall will be considered sterile during a given time under particular processing conditions, such as, but not limited to, processing of the product under slight excess (positive) pressure compared to an environment 110. Containment can be considered to be achieved by processing the product under slightly lowered pressure compared to the environment 110. These and other appropriate processing conditions are known to the skilled person. As a general remark, transfer sections such as transfer sections 400, 600 depicted in FIGS. 1 and 2 have to ensure that product flow 102 through them is accomplished under closed conditions; this includes the aspect that closed conditions have to be ensured/maintained also for a transition of product into and out of the respective transfer section. In other words, an attachment or mounting of a transfer section to a device for achieving a product transfer has to preserve the desired closed conditions.

(17) FIG. 3 illustrates a process line 100 as basically known from, for example, EP 2 578 974 A1, following the principles as described in regard to FIGS. 1 and 2. The process line 100 as shown in FIG. 3 is designed for the production of freeze-dried pellets under closed conditions, and is adapted to apply the liquid feeding device 200 according to the preferred embodiment of the present invention. The process line 100 substantially comprises a prilling tower as a specific embodiment of a freezing chamber 300, a freeze-dryer 500, and a discharge station 700. Here, the freezing chamber 300 and the freeze-dryer 500 are permanently connected to each other via a first transfer section 400, while the freeze-dryer 500 and the discharge station 700 are permanently connected to each other via a second transfer section 600. Each transfer section 400, 600 provides for product transfers between the connected process devices.

(18) The liquid feeding device 200 indicated only schematically in FIG. 3 is for providing the liquid product along the product flow 102 to the freezing chamber 300. Droplet generation by the liquid feeding device 200 into the freezing chamber 300 is affected by flow rate, viscosity at a given temperature, and further physical properties of the liquid to be ejected, as well as by the processing conditions of the atomizing process, such as the physical conditions of the spraying equipment including frequency, pressure, etc. Therefore the liquid feeding device 200 is adapted to controllably deliver the liquid and to generally deliver the liquid in a regular and stable flow. To this end, the liquid feeding device 200 can be connected to one or more liquid pumps. Any pump may be employed which enables precise dosing or metering. Examples for appropriate pumps may include, but are not limited to, peristaltic pumps, membrane pumps, piston-type pumps, eccentric pumps, cavity pumps, progressive cavity pumps, Mohno pumps, etc. Such pumps may be provided separately and/or as part of control devices such as pressure damping devices, which can be provided for an even flow and pressure at the entry point into the liquid feeding device 200. Alternatively or additionally, the liquid feeding device 200 may be connected to a temperature control device, for example a heat exchanger, for cooling the liquid in order to reduce the freezing capacities required within the freezing chamber 300. The temperature control device may be employed to control the viscosity of the liquid and in turn, in combination with the feed rate, influence the droplet size and/or droplet formation rate. The liquid feeding device 200 can have one or more flow meters connected upstream thereof for sensing the liquid feed rate. One or more filtration components can also be provided upstream of the liquid feeding device 200. Examples for such filtration components include, but are not limited to, mesh-filters, fabric filters, membrane filters, and adsorption filters. The liquid feeding device 200 can also be connected to a means configured to provide for sterility of the liquid to be ejected; additionally or alternatively, the liquid can be provided to the liquid feeding device 200 in presterilized form.

(19) The freezing of the droplets 103 ejected and—thus—fed from the liquid feeding device 200 to the freezing chamber 300 may be achieved, for example, such that the diluted composition, i.e., the formulated liquid product, is prilled. “Prilling” may be defined as a frequency-induced break-up of a constant liquid droplet ejection jet into discrete droplets 103. Generally, the goal of prilling is to generate calibrated droplets 103 with diameter ranges for example from about 200 μm to about 1500 μm, with a narrow size distribution. For instance, the droplets may have a span equal or below about 1, preferably equal or below about 0.8, preferably equal or below about 0.7, preferably equal or below about 0.6, preferably equal or below about 0.4. The droplets 103 fall into the freezing chamber 300 in which a spatial temperature profile might be maintained with, for example a value of between −40° C. to −60° C., preferably between −50° C. and −60° C., in a top area and between −150° C. to −192° C., for example between −150° C. and −160° C., in a bottom area of the chamber 300. Lower temperatures may be reachable by cooling systems employing helium, for example. The droplets freeze during their fall in order to form preferably spherical, calibrated frozen particles, i.e. micropellets.

(20) Cooling the inner volume of the freezing chamber 300 sufficiently for freezing the falling droplets 103 can be achieved by means of cooling the inner wall surface of the chamber 300 via a cooling medium conducting tubing or the like, and providing the freezing chamber 300 with an appropriate height. Therefore, a counter- or concurrent flow of cooled gas in the chamber's internal volume or other measure for direct cooling of falling droplets 103 can preferably be avoided. By avoiding contact of a circulating primary cooling medium such as a counter- or concurrent flow of gas with the falling product 103, the requirement of providing a costly sterile cooling medium is avoided when sterile production runs are desired. The cooling medium circulating outside the chamber's inner volume, for example in tubing or the like, need not to be sterile. A cooling medium may be, for example, liquid nitrogen. In one embodiment, the freezing chamber 300 may comprise—with regard to the direction of the droplet flow—a counter-current flow or a concurrent flow of a cooling medium. In another embodiment, the freezing chamber 300 may be devoid of any counter-current or concurrent flow of cooling medium. In such a case, the congealing or freezing of the droplets is ensured by the cooling of the inner wall of the chamber. The droplets 103 are frozen on their gravity-induced fall within the freezing chamber 300 due to cooling mediated by the temperature-controlled wall chamber 300 and an appropriate non-circulating atmosphere provided within the internal volume, for example, an (optionally sterile) nitrogen and/or air atmosphere.

(21) As an example, in the absence of further cooling mechanisms, for freezing droplets 103 into substantially spherical micropellets with diameters in the range of 200-800 μm, an appropriate height of the prilling tower might be 1-2 m, while for freezing droplets into pellets with a size range up to 1500 μm, the prilling tower can have a height of about 2-3 m, wherein the diameter of the prilling tower can be between about 50-150 cm for a height of 200-300 cm. The temperatures in the prilling tower can optionally be maintained or varied/cycled throughout between about −50° C. to −190° C.

(22) The frozen droplets 103 reaching the bottom of the chamber 300 are then automatically transferred by gravity towards and into the first transfer section 400, from where the frozen droplets 103 are transferred into a rotary drum 501 of the freeze-dryer 500, in which sublimation of the frozen droplets 103 results in freeze-dried pellets under vacuum conditions generated by a vacuum pump for providing a vacuum in the internal volume of the freeze-dryer 500 and, thus, the internal volume of the drum 501. Afterwards, the freeze-dried pellets are transferred via the second transfer section 600 into the discharging station 700, in which the freeze-dried pellets are filled into vials 701 for shipping.

(23) FIG. 4 shows the liquid feeding device 200 according to the preferred embodiment of the invention, which liquid feeding device 200 comprises a droplet ejection section 210 with an actuation portion 220 and a nozzle portion 230, a CiP/SiP section 240, a droplet counting section 250 and a deflection section 260, in this order from top to bottom of the drawing. The order of the sections of the liquid feeding device 200 from top to bottom, i.e. from section 210 to section 260 coincides with the direction of product flow inside the liquid feeding device 200. In general, the actuation portion 220 of the droplet ejection section 210 serves for generating magnetic waves by alternating positive and negative magnetizations of a coil, which waves are used for effecting magnetic impulses resulting in an ejection of droplets from the nozzle portion 230 of the droplet ejection section 210. Here, an outlet port 235 of the nozzle portion 230 can also be gathered from FIG. 4, which outlet port 235 will be described later in further detail.

(24) The subsequently arranged CiP/SiP section 240 serves for cleaning and/or sterilizing the interior of the liquid feeding device 200, preferably by introducing steam into the liquid feeding device 200, thereby achieving steam pressure sterilization of the parts of the interior of the liquid feeding device 200 penetrable by the steam. Here, the steam can be introduced by inlet 241 into the CiP/SiP section 200 from the outside, wherein the inlet 241 can be connected to any kind of fluid delivering means, such as a steam pressure pump or the like for SiP procedures, or to a cleaning fluid pump or the like for CiP procedures. The droplet counting section 250 following the CiP/SiP section 240 serves for counting the generated droplets, wherein the CiP/SiP section 240 requires a predetermined length in order to provide sufficient travelling distance, such as 30 mm to 50 mm, for the ejected liquid jet to separate in an ejection direction into separate droplets.

(25) The droplet counting section 250 utilizes an optical device for optically registering the droplets passing through, such as a glass cylinder comprising light emitting optical fibers and light receiving optical fibers arranged opposite to each other across the area through which the droplets pass. Finally, the liquid feeding device 200 of the preferred embodiment comprises a deflection section 260 arranged subsequently to the droplet counting section 250, the deflection section 260 employing at least one gas jet 261 directed towards the droplet ejection path 211, wherein the gas jet 261 is discharged by deflection tubes 262, 263. The droplet counting section 250 can also be positioned at another location along the travel path of the droplets, as long as the necessary travelling distance of 30 to 50 mm required for the liquid jet to separate into droplets is maintained. The fluid for generating the gas jet 261 is introduced into the deflection section 260 and, thus, into the deflection tubes 262, 263 through a deflection gas inlet 267 which can be connected to any kind of gas delivering means, such as a gas pump or the like. The introduced gas can be air or alternatively any inert gas, such as any one of Nitrogen, Helium, Argon or Xenon, or the like. Here, a droplet ejection path 211 (see FIG. 7a) basically coincides with the longitudinal axis 201 of the liquid feeding device 200. In general, the CiP/SiP section 240, the droplet counting section 250 and the deflection section 260 each comprises a respective recess passing therethrough, wherein these recesses are connected with each other such that the droplets ejected from the droplet ejection section 210 can pass through the sections 240, 250 and 260 in order to exit the liquid feeding device 200 at its lower end, passing by the deflection tubes 262, 263 such that the droplets interact with the gas jet 261.

(26) The mounting of the entire liquid feeding device 200 needs to ensure that all of its sections 210, 240, 250 and 260 are in vertical alignment, in particular in order to achieve the intersection of the ejected droplets, i.e. the droplet ejection path with the at least one deflection gas jet 261. In practice, the different sections can be attached to each other by known means such as clamping components, screws or the like, and the transition areas between the different sections can be provided with known sealing elements, such as O-Rings or the like, in order to maintain closed conditions. The alignment of the different sections to each other can be achieved for example by known centering means, such as a combination of centering bores and respective centering protrusions at the transition areas of the single sections. In order to reduce the technical detail of the drawings, these known components (O-rings, screws, centering protrusions, etc.) have been omitted in the drawings for the sake of a clearer overview.

(27) FIG. 5 shows a cross-section of the liquid feeding device 200 along the line A-A in FIG. 4. Here, it can be gathered that the actuation portion 220 consists of an excitation unit 221 and a main body 222 consisting of antimagnetic material, such as plastic material (PTFE, i.e. Teflon, or the like), Aluminum, non-magnetic stainless steel or the like, wherein the excitation unit 221 basically consists of an electromagnetic coil 223 and a coil core arranged there inside, such as an iron core or the like. The combination of electromagnetic coil 223 and coil core act as a simple electromagnet for applying a magnetic force to a magnetic force receiving member, here in the form of a membrane 234 of the nozzle portion 230. The detailed structure of the nozzle portion 230 of the droplet ejection section 210 can be gathered from FIG. 7a, in which the detail “X” as indicated in FIG. 5 is shown in an enlarged view. From FIG. 7a, it can be gathered that the nozzle portion 230 comprises an inlet port 231, a liquid chamber 232 having a cross axis or lateral axis 2321 and a longitudinal axis 2322 and being arranged in an inclined manner, a nozzle 233 through which the liquid from the liquid chamber 232 is ejected, the mentioned membrane 234 constituting one side of the liquid chamber 232, the outlet port 235, also referred to as bypass or bypass port, and a main body 236 of the nozzle portion 230, in which the inlet port 231, the liquid chamber 232, the nozzle 233, the membrane 234 and the outlet port 235 are accommodated. Furthermore, the nozzle 233 is provided in a nozzle body 237 for manufacturing reasons, such that a nozzle orifice 2331 opens into a central through-hole provided in the CiP/SiP section 240, and the nozzle orifice 2331 is connected to the liquid chamber by a nozzle channel 2332. The nozzle 233 comprises a longitudinal axis 2333 proceeding coaxially to the droplet ejection path 211 and to the longitudinal axis 201 of the liquid feeding device 200. Here, the liquid chamber 232 is arranged in an inclined manner such that its longitudinal axis 2322 is tilted in regard to the longitudinal axis 2333 of the nozzle 233, preferably with an extend of 2-5°, further preferably 3°. The nozzle body 237 is permanently installed/inbuilt in a central through-hole 2361 provided in the main body 236, wherein the nozzle body can be attached to the main body 236 by laser-welding or the like.

(28) In FIG. 8, a further development of the actuation portion 220 can be gathered, which is applicable to the liquid infeed device 200 of the preferred embodiment. In the further developed actuation portion 220, the excitation unit 221 comprises a combination of a cylindrically shaped permanent magnet 224 separably attachable to the membrane 234 opposite the liquid chamber 232 and the above mentioned combination of electromagnetic coil 223 and coil core acting as a simple electromagnet. A damping element 225 in the form of an inverted U-shape, i.e. in the form of an inverted cup-shape, is provided around the permanent magnet 224 with its cup-bottom between the magnet 224 and the coil-coil core combination for achieving a damping effect between the magnet 224 and the coil 223, wherein the damping element 225 can be made out of silicone. The damping element 225 is provided basically in a cup-shaped manner in a way that the electromagnetic coil 223 and the magnet 224 all have defined positions in relation to each other. The damping element 225, also referred to as damper, can increase the displacement of the magnet 224, the damping element 225 covering the transversal circumference of the magnet 224, thereby arranging the magnet 224 inside the inner recess of the damping element 225 in a way that the magnet 224 can be just mounted centrically in regard to the damping element 225 and, thus, in regard to the electromagnetic coil 223, to avoid any tilting of the magnet 224 or its contact with the coil 223 or the coil core, resulting in the desired damping effect.

(29) The inlet port 231 opens into the liquid chamber 232 near the intersection between liquid chamber 232 and nozzle channel 2332. The outlet port 235 opens into the liquid chamber 232 at an outer circumference of the liquid chamber 232 at the highest possible position due to the tilting of the liquid chamber 232, such that liquid in the liquid chamber 232 may only exit the liquid chamber 232 through the outlet port 235 in case the liquid chamber 232 is entirely filled with liquid and the outlet port 235 enables a drainage of the liquid. The inlet port 231 can be connected to a liquid source, such as a pressurized liquid tank, a peristaltic pump or the like, wherein a pressurized liquid tank is a preferred option since no pressure fluctuations of the infed liquid occur due to the constant pressure inside the tank, wherein a peristaltic pump can exhibit pressure fluctuations of the infed liquid. The outlet port 235, on the other hand, can be connected to a drain tank, drain tubing, a liquid collection container or the like, wherein a blocking means can be provided subsequently to the outlet port 231, such as a check valve, a shut-off valve or the like. During droplet generation, i.e. droplet ejection into the freezing chamber 300, the liquid transferred through the liquid inlet port 231 into the liquid chamber 232 is the liquid to be ejected, such as, for example, antigens, adjuvants, vaccines, antibodies, APIs, ODTs, blood plasma components, or the like. However, since it is not or only insufficiently possible to provide CiP/SiP fluid from the CiP/SiP section 240 into the liquid chamber 232 through the nozzle orifice 2331 due to its minute inner diameter, the inlet port 231 can also be used to provide such CiP/SiP fluid through the inlet port 231 into the liquid chamber 232 and out of the outlet port 235, wherein the large diameters of the ports 231, 235 (large compared to the diameter of the nozzle orifice 2331) allow a substantial CiP/SiP fluid flow volume, resulting in excellent CiP/SiP results of the droplet ejection section 210 without the need of disassembling the liquid feeding device 200. Here, as an example of dimensions, the diameter of the liquid inlet port 231 can reside in a range of 0.9 mm to 1.3 mm, preferably 1.1 mm, and the diameter of the outlet port 235 can reside in a range of 0.8 mm to 1.2 mm, preferably 1.0 mm. Compared to an exemplary diameter of the nozzle orifice 2331 of about 300 μm, this results in a diameter ratio port/orifice of about 3:1 to 4:1.

(30) As can also be gathered from FIG. 7a in detail, besides the inlet 241, the CiP/SiP section 240 consists of a main body 242 sandwiched between the nozzle portion main body 236 as well as a main body 264 of the deflection section 260. In the CiP/SiP section main body 242, a central through-hole 243 as a transition zone for the droplets is provided as a straight bore hole in a cylindrical form. Furthermore, a fluid chamber 244 is provided in the main body 242, which fluid chamber 244 is arranged circumferentially around the through-hole 243, wherein the fluid chamber 244 is connected to the inside of the through-hole 243 by several fluid channels 245 for providing the CiP/SiP fluid coming from the inlet 241 into the through-hole 243 of the CiP/SiP section 240 and, thus, into the sections connected to the CiP/SiP section 240, such as the droplet counting section 250 and the deflection section 260. The fluid channels 245 are preferably provided in an inclined manner such that they open into the through-hole 243 with an angle, thereby providing any CiP/SiP fluid streamed into the through-hole 243 with a spin, resulting in an improved cleanability/sterilizability effect of the CiP/SiP section 240 and, thus, the other sections of the liquid feeding device 200 fluid-connected to the CiP/SiP section 240. Also, in addition, the inclined fluid channels 245 can be used to inject gas with the purpose of interfering with the ejected droplets on their ejection path 211 such that the separation of the droplets can be further promoted.

(31) In the direction of the droplet path 211, subsequently to the CiP/SiP section 240, the droplet counting section 250 is arranged, wherein the droplet counting section 250 comprises a main body 251 and an optical counting component 252. Here, the optical counting component 252 can be sandwiched between two parts of the main body 251 for the sake of simplified installation. The optical counting component 252 of the preferred embodiment can be a see-through glass tube with ports for fibre optics (not shown in detail), wherein the fibre optics serve for counting the droplets by means of an optical sender and an optical receiver, in between of which the ejected droplets pass through. In particular, the glass tube can be introduced as a glass cylinder integrated into a flange that carries opening ports to take up a light emitting sender and a respective receiver for registering the droplets passing through, the flange being sandwiched between the mentioned parts of the main body 251.

(32) As a further part of the liquid feeding device 200 which can be gathered from FIGS. 5 and 6, the deflection section 260 follows the droplet counting section 250 in an ejection direction 212 of the liquid and, thus, of the ejected droplets, wherein the deflection section 260 serves for spreading the droplets, i.e. separating the droplets from each other by means of the at least one gas jet 261 in order to avoid coalescence of the droplets prior to freezing and to improve the heat transfer. The at least one gas jet 261 of the deflection section 260 is provided by two deflection tubes, deflection tube 262 and deflection tube 263, which are arranged directly opposite to each other, with the droplet ejection path 211 proceeding in between. As already mentioned above, the fluid for generating the gas jet 261 is introduced into the deflection section 260 through a main body 264 and, thus, into the deflection tubes 262, 263 through the deflection gas inlet 266 which can be connected to any kind of gas delivering means, such as a gas pump or the like. The gas jet 261 is directed towards the droplet ejection path 211 such that the gas jet 261 or better the several gas jets 261 of the preferred embodiment impact on the ejected droplets on the ejection path 2111 with a right angle.

(33) Therefore, as can be gathered from FIG. 7b in detail, each deflection tube 262, 263 is hollow and comprises several gas jet outlet ports, i.e. the deflection tube 262 comprises three gas jet outlet ports 2621, 2622, 2623, and the deflection tube 263 comprises three gas jet outlet ports 2631, 2632, 2633. The outlet ports 2621, 2622, 2623 connect the hollow interior of tube 262 with the outside, and the outlet ports 2631, 2632, 2633 connect the hollow interior of tube 263 with the outside, i.e. with the interior of the freezing chamber 300. Here, the uppermost gas jet outlet port 2631 of deflection tube 263 is arranged directly opposite to the uppermost gas jet outlet port 2621 of deflection tube 262, the middle gas jet outlet port 2633 of deflection tube 263 is arranged directly opposite to the middle gas jet outlet port 2623 of deflection tube 262, and the lowest gas jet outlet port 2632 of deflection tube 263 is arranged directly opposite to the lowest gas jet outlet port 2622 of deflection tube 262, in an order from top to bottom in the ejection direction 212. The lowest gas jet outlet port 2622, 2632 of each deflection tube 262, 263 is arranged at its tip and connects with a respective interior of each tube 262, 263 at its edge, such that each deflection tube 262, 263 is self-draining, meaning that any fluid in each tube 262, 263 is drained therefrom through the respective lowest gas jet outlet port 2622, 2632 by means of gravity. In order to provide the gas jet fluid to the deflection tubes 262, 263, the hollow interior of each tube 262, 263 is fluid-connected with a fluid chamber 266 provided in the main body 264, which fluid chamber 266 is connected to the gas inlet 266 and is arranged circumferentially around a central through-hole 265 provided in the main body 264 for letting the droplets pass through the deflection section's main body 264.

(34) According to the preferred embodiment of the liquid feeding device 200 of the present invention, the main body 264 is an integral component. However, in accordance with a further embodiment, the main body 264 can also consist of several parts being mechanically connected, for example in the form of a clamping means, screws or the like, wherein the inside of the main body 264, i.e. the inside of the fluid chamber 266 needs to be fluid-tightly closed against the outside, for example by means of a sealing component such as an O-ring, a gasket or the like. Moreover, according to the preferred embodiment of the liquid feeding device 200 of the present invention, the central through-hole 265 as a transition zone for the droplets is provided in the form of a straight bore hole centrally extending throughout the main body 264 in a cylindrical form. However, in accordance with a further embodiment, the central through-hole 265 can also exhibit a conical shape, with an increasing diameter in the ejection 212 towards the deflection tubes 262, 263. Here, the opening of the diameter of the conical shape is preferably chosen to avoid any deposition of small droplets, so called satellites, in the area of the central through-hole.

(35) FIG. 9 shows a modification of the deflection section of the liquid feeding device according to the above described preferred embodiment of the invention, i.e. another preferred embodiment of the invention. In order to avoid redundancy, some of the components provided identical to the above described preferred embodiment are not shown or further described but are to be understood as having the same technical structure and functionality. Contrary to the above described embodiment of the liquid feeding device 200, the deflection section 260′ of the shown embodiment of the modified liquid feeding device 200′ comprises four deflection tubes, i.e. deflection tube 262′, deflection tube 263′, deflection tube 268 and a further deflection tube (not shown) instead of the two deflection tubes 262, 263 of the above described embodiment. Due to the cross-sectional view in FIG. 9, only three of the four deflection tubes of the present embodiment are shown in FIG. 9, i.e. deflection tubes 262′, 263′ and 268, whereas the fourth deflection tube is not shown. Similar to the above described deflection section 260, the deflection section 260′ is arranged subsequently to a droplet counting section of the liquid feeding device 200′, and the deflection section 260′ employs at least four gas jets generated from the four deflection tubes, which jets are directed towards a droplet ejection path. The fluid for generating the gas jets is introduced into the deflection section 260′ and, thus, into the deflection tubes through a deflection gas inlet 267′ which can be connected to any kind of gas delivering means, such as a gas pump or the like, which provides the introduced gas such as air or alternatively any inert gas, such as any one of Nitrogen, Helium, Argon or Xenon, or the like. Similarly to the deflection section 260, the deflection section 260′ serves for spreading the droplets, i.e. separating the droplets from each other by means of the at least one gas jet in order to avoid coalescence of the droplets prior to freezing and to improve the heat transfer. The four gas jets of the deflection section 260′ are provided by the four deflection tubes, wherein deflection tube 262′ and deflection tube 263′ are arranged directly opposite to each other, and wherein deflection tube 268 and the further deflection tube (not shown) are arranged directly opposite to each other, with the droplet ejection path proceeding in between at the cross section of the gas jets produced by the four deflection tubes. The fluid for generating the gas jets is introduced into the deflection section 260′ through a main body 264′ and, thus, into the deflection tubes through the deflection gas inlet 266′ which is connected to the deflection gas inlet 267′.

(36) The gas jets are directed towards the droplet ejection path such that the gas jets impact on the ejected droplets on the ejection path with a right angle to the longitudinal axis of the ejection section 260′. In order to be able to do so, each deflection is hollow and comprises one or several gas jet outlet ports which connect the hollow interior of each tube with the outside, i.e. with an interior of a freezing chamber of the process line. The gas jet outlet ports of each deflection tube can be provided similarly to the above described embodiment, i.e. with a number of one or several, e.g. three outlet ports for each deflection tube, the ports being arranged above each other on the same longitudinal axis. However, it is considered to be understood that the number of the outlet ports can be one, two, three, four etc., in each deflection tube, as desired, in order to provide as many gas jets as desired. Also, in the present embodiment, four deflection tubes are arranged in a way such that sets of two deflection tubes are arranged opposite to each other, resulting in a crosswise arrangement in the same plane, i.e. in an equiangular arrangement of 90° between two adjacent tubes. Thereby, the respective gas jets on each level of outlet ports meet each other at the droplet ejection path in a rectangular manner.

(37) As a modification thereof, only three tubes can also be provided, wherein the tubes are then to be arranged again in an equiangular manner, i.e. with 120° between two adjacent tubes. Moreover, five or more tubes could also be provided in an equiangular manner as a further modification, if desired. As a further alternative embodiment, it is conceivable that all provided gas jet outlet ports are directed to one and the same location on the droplet ejection path, thereby gathering the deflection force of all provided gas jets on the same spot.

(38) The products resulting from a process line 100 applying a liquid feeding device 200 or a liquid feeding device 200′ according to the invention can comprise virtually any formulation in liquid or flowable paste state that is suitable also for conventional (e.g., shelf-type) freeze-drying processes, for example, monoclonal antibodies, protein-based APIs, DNA-based APIs; cell/tissue substances; vaccines; APIs for oral solid dosage forms such as APIs with low solubility/bioavailability; fast dispersible oral solid dosage forms like ODTs, orally dispersible tablets, stick-filled adaptations, etc., as well as various products in the fine chemicals and food products industries. In general, suitable flowable materials for prilling include compositions that are amenable to the benefits of the freeze-drying process (e.g., increased stability once freeze-dried).

(39) The invention improves the generation of, for example, sterile lyophilized and uniformly calibrated particles, e.g., micropellets, as bulkware. The resulting product can be free-flowing, dust-free and homogeneous. Such products have good handling properties and can be easily combined with other components, wherein the components might be incompatible in liquid state or only stable for a short time period and thus otherwise not suitable for conventional freeze-drying.

(40) In order to support a permanently mechanically integrated system providing end-to-end sterility and/or containment, additionally, a specific cleaning concept for the liquid feeding device of the present invention is contemplated. In a preferred embodiment, a single steam generator, or a similar generator/repository for a cleaning and/or sterilization medium can be provided. The cleaning/sterilization system of the liquid feeding device of the present invention can be configured to perform automatic CiP/SiP for different sections of the device or of the entire device, which avoids the necessity of complex and time-consuming cleaning/sterilization processes requiring a disassembly of the liquid feeding device and/or which have to be performed at least in part manually.

(41) The products resulting from the use of the liquid feeding device according to the invention can comprise virtually any formulation in liquid or flowable paste state that is suitable also for conventional (e.g., shelf-type) freeze-drying processes, for example, monoclonal antibodies, protein-based APIs, DNA-based APIs, cell/tissue substances, vaccines, APIs for oral solid dosage forms such as APIs with low solubility/bioavailability, fast dispersible oral solid dosage forms like ODTs, orally dispersible tablets, stick-filled adaptations, etc., blood plasma components, as well as various products in the fine chemicals and food products industries.

(42) In general, suitable flowable materials for prilling include compositions that are amenable to the benefits of the freeze-drying process (e.g., increased stability once freeze-dried). The invention allows the generation of, for example, sterile lyophilized and uniformly calibrated particles, e.g., micropellets, as bulkware. The resulting product can be free-flowing, dust-free and homogeneous. Such products have good handling properties and can be easily combined with other components, wherein the components might be incompatible in liquid state or only stable for a short time period and thus otherwise not suitable for conventional freeze-drying. Freeze-drying in the form of particles, particularly in the form of micropellets allows stabilization of, for example, a dried vaccine product as known for mere freeze-drying alone, or it can improve stability for storage. The freeze-drying of bulkware (e.g., vaccine or fine chemical micropellets) offers several advantages in comparison to conventional freeze-drying; for example, but not limited to, the following: it allows the blending of the dried products before filling, it allows titers to be adjusted before filling, it allows minimizing the interaction(s) between any products, such that the only product interaction occurs after rehydration, and it allows in many cases an improvement in stability.

(43) In fact, the product to be bulk freeze-dried can result from a liquid containing, for example, antigens together with an adjuvant, the separate drying of the antigens and the adjuvant (in separate production runs, which can, however, be performed on the same process line according to the invention), followed by blending of the two ingredients before the filling or by a sequential filling. In other words, the stability can be improved by generating separate micropellets of antigens and adjuvant, for example. The stabilizing formulation can be optimized independently for each antigen and the adjuvant. The micropellets of antigens and adjuvant can subsequently be filled into the final recipients or can be blended before filling into the recipients. The separated solid state allows one to avoid throughout storage (even at higher temperature) interactions between antigens and adjuvant. Thus, configurations might be reached, wherein the content of the vial can be more stable than any other configurations. Interactions between components can be standardized as they occur only after rehydration of the dry combination with one or more rehydrating agents such as a suitable diluent (e.g., water or buffered saline).

(44) A subject-matter of the invention is relating to a process for preparing a vaccine composition comprising one or more antigens in the form of freeze-dried particles comprising at least a step of generating liquid droplets of said vaccine composition with a liquid feeding device 200, 200′ according to the invention. The obtained droplets are further subjected to a step of freeze-drying to obtain freeze-dried particles. The freeze-dried particles may optionally be filled into a recipient.

(45) A subject-matter of the invention is relating to a process for preparing a composition comprising one or more adjuvant(s) in the form of freeze-dried particles comprising at least a step of generating liquid droplets of said composition with a liquid feeding device 200, 200′ according to the invention. The obtained droplets are further subjected to a step of freeze-drying to obtain freeze-dried particles. The freeze-dried particles may optionally be filled into a recipient.

(46) In a further aspect, the invention is relating to a process for preparing an adjuvant containing vaccine composition comprising one or more antigens in the form of freeze-dried particles comprising at least a step of generating liquid droplets of said vaccine composition with a liquid feeding device according to the invention, or at least the steps of generating liquid droplets of an antigen(s)-containing composition with a liquid feeding device according to the invention, of generating liquid droplets of an adjuvant-containing composition with a liquid feeding device according to the invention, freeze-drying the droplets to obtain freeze-dried particles, and blending the freeze-dried particles of antigen(s) with the freeze-dried particles of adjuvant.

(47) Another subject-matter of the invention is relating to a process for preparing a vaccine composition comprising one or more antigens in the form of freeze-dried particles comprising at least the steps of generating liquid droplets of a liquid bulk solution comprising an adjuvant and one or more antigens with a liquid feeding device according to the invention, freeze-drying the obtained droplets, and, optionally, filling the freeze-dried particles obtained into a recipient.

(48) Alternatively when the one or more antigens and the adjuvant are not in the same solution, the process for preparing an adjuvant containing vaccine composition comprises at least the steps of generating liquid droplets of a liquid bulk solution comprising an adjuvant, generating liquid droplets of a liquid bulk solution comprising one or more antigens, wherein the liquid droplets generated at one of the steps before being generated with a with a liquid feeding device according to the invention, freeze-drying the obtained liquid droplets to obtain freeze dried particles of said one or more antigens and freeze dried particles of said adjuvant, blending the freeze dried particles of said one or more antigens with the freeze dried particles of said adjuvant, and, optionally, filling the blending of freeze-dried particles into a recipient.

(49) The liquid bulk solution of antigen(s) may contain for instance killed, live attenuated viruses or antigenic component of viruses like Influenza virus, Rotavirus, Flavivirus (including for instance dengue (DEN) viruses serotypes 1, 2, 3 and 4, Japanese encephalitis (JE) virus, yellow fever (YF) virus and West Nile (WN) virus as well as chimeric Flavivirus), Hepatitis A and B virus, Rabies virus. The liquid bulk solutions of antigen(s) may also contain killed, live attenuated bacteria, or antigenic component of bacteria such as bacterial protein or polysaccharide antigens (conjugated or non-conjugated), for instance from serotype b Haemophilus influenzae, Neisseria meningitidis, Clostridium tetani, Corynebacterium diphtheriae, Bordetella pertussis, Clostridium botulinum, Clostridium difficile. A liquid bulk solution comprising one or more antigens means a composition obtained at the end of the antigen production process. The liquid bulk solution of antigen(s) can be a purified or a non purified antigen solution depending on whether the antigen production process comprises a purification step or not. When the liquid bulk solution comprises several antigens, they can originate from the same or from different species of microorganisms. Usually, the liquid bulk solution of antigen(s) comprises a buffer and/or a stabilizer that can be for instance a monosaccharide such as mannose, an oligosaccharide such as sucrose, lactose, trehalose, maltose, a sugar alcohol such as sorbitol, mannitol or inositol, or a mixture of two or more different of these aforementioned stabilizers such as a mixture of sucrose and trehalose. Advantageously, the concentration of monosaccharide oligosaccharide, sugar alcohol or mixture thereof in the liquid bulk solution of antigen(s) ranges from 2% (w/v) to the limit of solubility in the formulated liquid product, more particularly it ranges from 5% (w/v) to 40% (w/v), 5% (w/v) to 20% (w/v) or 20% (w/v) to 40% (w/v). Compositions of liquid bulk solutions of antigen(s) containing such stabilizers are described in particular in WO 2009/109550, the subject-matter of which is incorporated by reference. When the vaccine composition contains an adjuvant it can be for instance:

(50) 1) a particulate adjuvant such as: liposomes and in particular cationic liposomes (e.g. DC-Choi, see e.g. US 2006/0165717, DOTAP, DDAB and 1,2-Dialkanoyl-sn-glycero-3-ethylphosphocholin (EthyIPC) liposomes, see U.S. Pat. No. 7,344,720), lipid or detergent micelles or other lipid particles (e.g. Iscomatrix from CSL or from Isconova, virosomes and proteocochleates), polymer nanoparticles or microparticles (e.g. PLGA and PLA nano- or microparticles, PCPP particles, Alginate/chitosan particles) or soluble polymers (e.g. PCPP, chitosan), protein particles such as the Neisseria meningitidis proteosomes, mineral gels (standard aluminum adjuvants: AlOOH, A1P04), microparticles or nanoparticles (e.g. Ca3(P04)2), polymer/aluminum nanohybrids (e.g. PMAA-PEG/AlOOH and PMAA-PEG/A1P04 nanoparticles) O/W emulsions (e.g. MF59 from Novartis, AS03 from GlaxoSmithKline Biologicals) and W/O emulsion (e.g. ISA51 and ISA720 from Seppic, or as disclosed in WO 2008/009309). For example, a suitable adjuvant emulsion for the process according to the present invention is that disclosed in WO 2007/006939;
2) a natural extracts such as: the saponin extract QS21 and its semi-synthetic derivatives such as those developed by Avantogen, bacterial cell wall extracts (e.g. micobacterium cell wall skeleton developed by Corixa/GS and micobaterium cord factor and its synthetic derivative, trehalose dimycholate);
3) a stimulator of Toll Like Receptors (TLR). It is particular natural or synthetic TLR agonists (e.g. synthetic lipopeptides that stimulate TLR2/1 or TLR2/6 heterodimers, double stranded RNA that stimulates TLR3, LPS and its derivative MPL that stimulate TLR4, E6020 and RC-529 that stimulate TLR4, flagellin that stimulates TLR5, single stranded RNA and 3M's synthetic imidazoquinolines that stimulate TLR7 and/or TLR8, CpG DNA that stimulates TLR9, natural or synthetic NOD agonists (e.g. Muramyl dipeptides), natural or synthetic RIG agonists (e.g. viral nucleic acids and in particular 3′ phosphate RNA).

(51) When there is no incompatibility between the adjuvant and the liquid bulk solution of antigen(s) it can be added directly to the solution. The liquid bulk solution of antigen(s) and adjuvant may be for instance a liquid bulk solution of an anatoxin adsorbed on an aluminium salt (alun, aluminium phosphate, aluminium hydroxide) containing a stabilizer such as mannose, an oligosaccharide such as sucrose, lactose, trehalose, maltose, a sugar alcohol such as sorbitol, mannitol or inositol, or a mixture thereof. Examples of such compositions are described in particular in WO 2009/109550, the subject-matter of which is incorporated by reference. The freeze-dried particles of the non adjuvanted or adjuvanted vaccine composition are usually under the form of spheric particles having a mean diameter between 200 μm and 1500 μm. Furthermore, the freeze-dried particles of the vaccine compositions obtained are sterile.

(52) While the current invention has been described in relation to its preferred embodiment, it is to be understood that this description is for illustrative purposes only. Accordingly, it is intended that the invention be limited only by the scope of the claims appended hereto.

(53) This application claims priority of European patent application EP 14 002 529.7-1351, the subject-matters of which are listed below for the sake of completeness:

(54) Item 1. Liquid feeding device for the generation of droplets, in particular for the use in a process line for the production of freeze-dried particles, with a droplet ejection section for ejecting liquid droplets in an ejection direction, the droplet ejection section comprising at least one inlet port for receiving a liquid to be ejected, a liquid chamber for retaining the liquid, and a nozzle for ejecting the liquid from the liquid chamber to form droplets, wherein the liquid chamber is restricted by a membrane on one side thereof, the membrane being vibratable by an excitation unit, wherein the longitudinal axis of the liquid chamber is tilted relative to the longitudinal axis of the nozzle, and/or the liquid feeding device further comprises a deflection section for separating the droplets from each other by means of a gas jet.

(55) Item 2. Liquid feeding device according to item 1, wherein the deflection section gas jet intersects with an ejection path of the liquid ejected from the liquid chamber.

(56) Item 3. Liquid feeding device according to item 1 or 2, wherein the deflection section comprises at least one deflection tube for emitting the gas jet, the at least one deflection tube protruding from a main body of the deflection section in the ejection direction of the liquid.

(57) Item 4. Liquid feeding device according to item 3, wherein the deflection section comprises two deflection tubes arranged opposite to each other, and wherein the emitted gas jets meet each other at an ejection path of the liquid ejected from the liquid chamber, intersecting with the same.

(58) Item 5. Liquid feeding device according to item 3 or 4, wherein each deflection tube comprises at least two gas jet outlet ports, and wherein the gas jet outlet port at the tip of the respective deflection tube connects with the tube interior at its edge, preferably wherein each deflection tube comprises three gas jet outlet ports.

(59) Item 6. Liquid feeding device according to any one of the preceding items, wherein the droplets pass through a recess provided in a main body of the deflection section, preferably wherein the recess is a central through-hole extending through the main body of the deflection section.

(60) Item 7. Liquid feeding device according to any one of the preceding items, wherein the droplet ejection section further comprises at least one outlet port, preferably wherein the at least one outlet port is arranged at an outer circumference of the liquid chamber.

(61) Item 8. Liquid feeding device according item 7, wherein the longitudinal axis of the liquid chamber is tilted relative to the longitudinal axis of the nozzle in a way that the at least one outlet port is provided at the highest level of the liquid chamber.

(62) Item 9. Liquid feeding device according item 7 or 8, wherein the at least one outlet port serves for drainage of excessive liquid to be ejected from the liquid chamber and/or serves for discharge of SiP fluid and/or CiP fluid introduced through the at least one inlet port of the droplet ejection section.

(63) Item 10. Liquid feeding device according to any one of the preceding items, wherein the excitation unit comprises a combination of a permanent magnet separably attachable to the membrane opposite the liquid chamber and an electromagnetic coil for actuating the permanent magnet, preferably wherein a damping element is provided around the permanent magnet, more preferably also between the permanent magnet and the electromagnetic coil, further preferably wherein the damping element is made out of silicone.

(64) Item 11. Liquid feeding device according to any one of the preceding items, wherein the membrane is a stainless steel membrane.

(65) Item 12. Liquid feeding device according to any one of the preceding items, wherein the droplet ejection section comprises an actuation portion and a nozzle portion, the actuation portion comprising at least the excitation unit, and the nozzle portion comprising at least the at least one inlet port, the liquid chamber, the nozzle and the membrane.

(66) Item 13. Liquid feeding device according to item 12, wherein the nozzle portion comprises a nozzle portion main body and a nozzle body provided separately from the nozzle portion main body, preferably wherein the nozzle body is permanently installed in a central through-hole in the nozzle portion main body, more preferably by laser welding.

(67) Item 14. Liquid feeding device according to item 12 or 13, wherein the membrane is welded to the nozzle portion for airtightly closing the liquid chamber on one side, preferably by laser welding.

(68) Item 15. Liquid feeding device according to any one of the preceding items, further comprising a CiP/SiP section arranged between the droplet ejection section and the deflection section, for providing CiP fluid and/or SiP fluid to the parts of the liquid feeding device subsequent to the droplet ejection section.

(69) Item 16. Liquid feeding device according to any one of the preceding items, further comprising a droplet counting section for counting the droplets, preferably provided before the deflection section in the ejection direction of the liquid.

(70) Item 17. Freezing chamber of a process line for the production of freeze-dried particles, preferably for the pharmaceutical field, comprising a liquid feeding device according to any one of the preceding items, for the generation of droplets to be fed into the freezing chamber.

(71) Item 18. Process line for the production of freeze-dried particles, comprising a freezing chamber according to item 17.

(72) Item 19. A process for preparing a vaccine composition comprising one or more antigens in the form of freeze-dried particles comprising at least a step of generating liquid droplets of said vaccine composition with a liquid feeding device according to anyone of items 1 to 16.

(73) Item 20. A process for preparing an adjuvant containing vaccine composition comprising one or more antigens in the form of freeze-dried particles comprising: at least a step of generating liquid droplets of said vaccine composition with a liquid feeding device according to anyone of items 1 to 16, or at least the steps of generating liquid droplets of an antigen(s)-containing composition with a liquid feeding device according to anyone of items 1 to 16, of generating liquid droplets of an adjuvant-containing composition with a liquid feeding device according to anyone of items 1 to 16, freeze-drying the droplets to obtain freeze-dried particles, and blending the freeze-dried particles of antigen(s) with the freeze-dried particles of adjuvant.

(74) Item 21. A process according to item 19 or 20, wherein all the steps are carried out under sterile conditions.

(75) Item 22. A process according to items 19 or 21, wherein the freeze-dried particles are sterile.