Classifications

• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F26—DRYING
  • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
  • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
  • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
  • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
  • F26B5/065—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing the product to be freeze-dried being sprayed, dispersed or pulverised
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D1/00—Evaporating
  • B01D1/16—Evaporating by spraying
  • B01D1/18—Evaporating by spraying to obtain dry solids
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
  • B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
  • B01J2/04—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a gaseous medium
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
  • B01J2/18—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic using a vibrating apparatus

Definitions

• tray-based freeze-dryers comprise one or more trays or shelves within a (vacuum) drying chamber. Vials can be filled with the product and arranged on a tray, and then the tray with the filled vials is introduced into the freeze-dryer and the drying process is started.
• droplets need to be identifiable over a distance of preferably 200mnn, wherein a variation of about 500Hz should still be sufficient to provide droplets over the whole distance but of different droplet size, which indicates the robustness of the droplet formation by the respective nozzle design.
• the liquid feeding device of the present invention as described below fulfills these requirements.
• the liquid feeding device can comprise a deflection section for separating the droplets from each other by means of at least one gas jet.
• the liquid chamber can be tilted compared to the horizontal in a way such that the longitudinal axis of the liquid chamber is tilted relative to the longitudinal axis of the nozzle.
• the deflection section gas jet intersects perpendicular with an ejection path of the liquid ejected from the droplet ejection section resulting in separate droplets, also referred to as droplets ejected from the droplet ejection section.
• the liquid is introduced through the liquid infeed and urged through the liquid chamber and the nozzle by the generated vibrations, leaving the nozzle in form of a liquid jet which breaks apart into droplets due to the surface tension, thereby generating ejected droplets downstream the nozzle.
• a deflection section based on an electrostatic appliance or the like as an addendum or an alternative to the deflection section for separating the droplets from each other by means of a gas jet.
• Deflection sections based on electrostatic appliance or the like are known in the art.
• the ejection direction is to be understood as a direction in which the liquid or liquid jet and, further downstream, the droplets are ejected out of the nozzle, i.e. a direction along or parallel to the longitudinal axis of the nozzle body, and an ejection path is to be understood as the course that the liquid or, further downstream, the droplets travel downstream of the nozzle.
• the nozzle is directed vertically downwards towards the ground and the droplets are only affected by gravity, the ejection direction and the ejection path of the droplets coincide, both being directed towards the ground.
• the excitation unit preferably 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.
• a vertical adjustment of the electromagnetic coil support is necessary to avoid any tilting of the permanent magnet and to ensure a coherent contact to the membrane.
• a damping element can be provided around the permanent magnet and between the same and the electromagnetic coil for achieving a damping effect between the magnet and the coil, preferably wherein the damping element is made out of silicone, with such molds or shapes of the damping element that the electromagnetic coil and the magnet all have defined positions, and wherein the coil can be made out of copper.
• the deflection section comprises four deflection tubes, wherein each two of the four deflection tubes can be arranged opposite to each other.
• the deflection section comprises a main body and the four deflection tubes project from the main body of the deflection section parallel to the ejection direction of the droplets, i.e. the ejection path of the droplets, such that the deflection tubes are both basically provided collateral, i.e. parallel to the droplets ejection path such that the respective longitudinal axis of each two of the four deflection tubes arranged opposite to each other and the droplet ejection path are aligned in the same plane.
• the ejected droplets can pass through a recess provided in the main body of the deflection section in order to arrive in the vicinity of the deflection tubes.
• the recess can be a central through-hole of the main body of the deflection section, through which the droplets pass on their way to the intersection point with the gas jets.
• the central through hole also referred to as a transition zone for the droplets or pre-deflection zone, can be provided as a straight bore hole in a cylindrical form.
• turbulences may cause a deposition of droplets in horizontal or vertical areas that accumulate and coalesce into larger droplets, i.e.
• the droplet ejection section comprises at least one outlet port besides the at least one inlet port, the liquid chamber and the nozzle.
• the at least one outlet port also referred to as liquid outfeed
• the longitudinal axis of the liquid chamber can be tilted relative to the longitudinal axis of the nozzle, preferably in a way that the at least one outlet port is provided at the highest level of the liquid chamber, wherein the longitudinal axis of the liquid chamber thus coincides with the ejection direction of the liquid.
• the cross section of the outlet port is larger than the orifice of the nozzle, it becomes possible to feed a larger amount of SiP fluid or SiP fluid through the liquid chamber and thereby through the droplet ejection section, resulting in a faster and more effective way to clean or sterilize the droplet ejection section (i.e. the at least one inlet port, the liquid chamber, the at least one outlet port and the nozzle) compared to a structure where the nozzle is the only possibility for drainage of any fluid inside the liquid chamber.
• the provision of the outlet port allows higher cleaning liquid flows and higher sterilization fluid flows, for example saturated steam flows.
• the droplet ejection section can comprise an actuation portion and a nozzle portion, wherein the actuation portion comprises at least the excitation unit, and wherein the nozzle portion comprises at least the membrane, the at least one inlet port, the liquid chamber and the nozzle.
• the nozzle body in the form of an insert can be permanently installed in a central through-hole provided in the nozzle portion main body, wherein the liquid chamber and the outside of the droplet ejection section are connected by the nozzle channel.
• the installing of the nozzle body insert into the nozzle portion main body can be achieved by laser welding or the like.
• a nozzle function with a vertical droplet ejection jet can be achieved by the described two-part system consisting of nozzle body and nozzle portion main body.
• precise adjustment is necessary to ensure the vertical orifice.
• the positioning screw has to be designed such that the forces induced by the screw do not interfere with the strictly vertical alignment of all components, which can be the case in the known prior art.
• freeze-dried particles comprising such a freezing chamber.
• the liquid feeding device according to the invention is applicable for feeding droplets into different kinds of process lines for production of many formulations and/or compositions suitable for freeze-drying. This may include, for example, generally any hydrolysis-sensitive material.
• 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.
• 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
• 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.
• a central through-hole 243 as a transition zone for the droplets is provided as a straight bore hole in a cylindrical form.
• 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.
• 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.
• gas delivering means such as a gas pump or the like
• 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.
• 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.
• 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.
• 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).
• 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.
• 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.
• 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 ore more antigens and freeze dried particles of said adjuvant, blending the freeze dried particles of said one ore more antigens with the freeze dried particles of said adjuvant, and, optionally, filling the blending of freeze-dried particles into a recipient.
• 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.
• the liquid bulk solution comprises several antigens, they can originate from the same or from different species of microorganisms.
• 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 (EthylPC) liposomes, see US 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.
• 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 (EthylPC) liposomes,
• 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: AIOOH, A1 P04), microparticles or nanoparticles (e.g. Ca3(P04)2), polymer/aluminum nanohybrids (e.g. PMAA-PEG/AIOOH and PMAA- PEG/A1 P04 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
• 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);
• 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.
• aluminium salt alun, aluminium phosphate, aluminium hydroxide
• 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.
• 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
• 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.
• the deflection section gas jet intersects with an ejection path of the liquid ejected from the liquid chamber.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Item 18 Process line for the production of freeze-dried particles, comprising a freezing chamber according to item 17.

Landscapes

• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Life Sciences & Earth Sciences (AREA)
• Organic Chemistry (AREA)
• Epidemiology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Microbiology (AREA)
• Immunology (AREA)
• Mycology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Mechanical Engineering (AREA)
• Molecular Biology (AREA)
• General Engineering & Computer Science (AREA)
• Coating Apparatus (AREA)
• Nozzles (AREA)
• Medical Preparation Storing Or Oral Administration Devices (AREA)
• Glanulating (AREA)
• Drying Of Solid Materials (AREA)
• Vaporization, Distillation, Condensation, Sublimation, And Cold Traps (AREA)
• Medicinal Preparation (AREA)

Priority Applications (10)

Applications Claiming Priority (2)

Related Child Applications (3)

Publications (1)

Family

ID=51229796

Family Applications (1)

Country Status (10)

Cited By (2)

Families Citing this family (8)

Citations (5)

Family Cites Families (23)

• 2015
  • 2015-07-20 JP JP2017503599A patent/JP6166006B1/ja active Active
  • 2015-07-20 WO PCT/EP2015/066583 patent/WO2016012414A1/en not_active Ceased
  • 2015-07-20 DK DK15738385.2T patent/DK3171954T3/en active
  • 2015-07-20 EP EP15738385.2A patent/EP3171954B1/en active Active
  • 2015-07-20 BR BR112016031039-0A patent/BR112016031039B1/pt active IP Right Grant
  • 2015-07-20 AU AU2015293983A patent/AU2015293983B2/en active Active
  • 2015-07-20 CN CN201580039297.5A patent/CN107073350B/zh active Active
  • 2015-07-20 CA CA3000093A patent/CA3000093C/en not_active Expired - Fee Related
  • 2015-07-20 CA CA2955562A patent/CA2955562C/en not_active Expired - Fee Related
  • 2015-07-20 KR KR1020177003947A patent/KR101774203B1/ko active Active
  • 2015-07-20 US US15/328,068 patent/US10533800B2/en active Active
• 2020
  • 2020-01-08 US US16/736,832 patent/US11499777B2/en active Active

Patent Citations (5)

Also Published As

Similar Documents

Legal Events