Liquid Feeding Device for the Generation of Droplets
Technical Field
The invention relates to the generation of droplets, in particular to be used for the
production of freeze-dried pellets as bulkware, wherein a liquid feeding device is
applied for the generation of droplets for the production of freeze-dried particles by
means of a respective process line for droplet generation and freeze congealing of
liquid droplets to form pellets.
Background of the Invention
The production method generally referred to as freeze-drying, also known as
lyophilization, is a process for drying high-quality products such as, for example,
pharmaceuticals, biotechnology materials such as proteins, enzymes,
microorganisms, and in general any thermo- and/or hydrolysis-sensitive material.
With freeze-drying, the frozen product is usually dried via the sublimation of ice
crystals into water vapor, i.e. via the direct transition of water content from the solid
phase into the gas phase. Freeze-drying is often performed under vacuum conditions
but works generally also under atmospheric pressure.
Application examples for freeze-drying processes in the pharmaceutical area
comprise drying drugs or APIs (Active Pharmaceutical Ingredients), API formulations,
hormones, peptide-based hormones, monoclonal antibodies, blood plasma products
or derivatives, vaccines or other injectables and in general substances which
otherwise would not be stable over a required time span. Removing the water prior to
sealing the product in vials or other appropriate containers for preserving sterility
results in that the product can be stored and shipped, and permits that the product
can later be reconstituted by dissolving the product in an appropriate medium, such
as water or the like, prior to administration, e.g., by intradermal or intramuscular
injection.
Design principles for freeze-dryer devices are well-known in the present technical
field. For example, 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.
Process systems combining spray-freezing and freeze-drying are also well-known in
the present technical field. For instance, US 3,601 ,901 describes a highly integrated
device comprising a vacuum chamber with a freezing compartment and a drying
compartment. The freezing compartment comprises a spray nozzle on top of an
upwardly projecting portion of the vacuum chamber. The sprayed liquid is atomized
and rapidly frozen into a number of small frozen particles which fall downwardly
within the freezing compartment to arrive at a conveyor assembly. The conveyor
advances the particles progressively for freeze-drying in the drying compartment.
When the particles reach a discharge end of the conveyer, they are in freeze-dried
form and fall downwardly into a discharge hopper.
As another example, WO 2005/1 05253 describes a freeze-drying apparatus for fruit
juice, pharmaceuticals, nutraceuticals, tea, and coffee. A liquid substance is
atomized through a high-pressure nozzle into a freezing chamber and reduced in
temperature to below its eutectic temperature, thereby inducing a phase change of
liquids in the liquid substance. A co-current flow of cold air freezes the droplets. The
frozen droplets are then pneumatically conveyed by the cold air stream via a vacuum
lock into a vacuum drying chamber and are further subjected to an energy source
therein to assist sublimation of liquids as the substance is conveyed through the
chamber.
Many products to be freeze-dried are compositions comprising two or more different
input agents or components which are mixed prior to freeze-drying. Thus, a
composition is mixed with a predefined ratio and is then freeze-dried and filled into
vials for shipping. A change in the mixing ratio of the composition after filling into the
vials is practically not feasible. The mixing, filling and drying processes therefore
cannot normally be separated.
WO 2009/1 09550 A 1 discloses a process for stabilizing an adjuvant containing a
vaccine composition in dry form. It is proposed to separate if desirable the drying of
the antigen from the drying of the adjuvant, followed by blending of the two before the
filling or by sequential filling. Specifically, separate micropellets comprising either the
antigen or the adjuvant are to be generated. The antigens micropellets and the
adjuvants micropellets are then blended before filling into vials, or are directly filled to
achieve the desired mixing ratio only at the time of blending or filling. Further it is
possible to improve the overall stability, as the stabilizing formulations can be
optimized independently for each component. The separated solid states allow to
avoid interactions between the different components throughout storage, even at
higher temperature.
Products such as to be found in the pharmaceutical or biotechnology area often have
to be manufactured under closed conditions, i.e., they have to be manufactured
under sterile conditions and/or under containment. Thus, a process line intended for
a production under sterile conditions has to be adapted such that no impurities can
enter and contaminate the product. Further, a process line adapted for a production
under containment has to be adapted such that neither the product, elements
thereof, nor auxiliary material can leave the process line and enter the environment.
Here, one of the critical components for such a process line, in particular for the
sterile manufacture of lyophilized microspheres, is the nozzle device serving to
generate droplets to be freeze-dried, sometimes also referred to as spray nozzle or
prilling nozzle. In particular, the nozzle can define in a very early stage of the process
parameters of the product quality like particle size and particle size distribution. Due
to this, the nozzle is a very important component of the bulk freeze drying process
and a specific development area due to the number of parts of the nozzle, which are
influencing the product quality significantly.
The detailed description of an example of such a prilling nozzle can be found in US
6,458,296 B , in which a nozzle is provided inside a reactor and consists of a carrier
plate with a depression defined by a circular peripheral wall a bore extending from
the center point of its bottom. The bore opens in a recess for accommodating a
nozzle. Associated with the depression is a pressure ring fixing a diaphragm made of
silicone and a seal, such that a pulsation chamber is provided by the diaphragm and
the depression. The diaphragm carries a disk magnet which is fixed to the
diaphragm, for example by gluing, and an electrical coil is suspended at a spacing
with respect to the disk magnet, wherein alternating current flows passing through
the coil generate alternately positive and negative magnetizations. The thus
generated magnetic waves act on the disk magnet and cause it to vibrate together
with the diaphragm, resulting in a resonant excitation of the same. In the pulsation
chamber, a liquid is introduced and urged through 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, which is known as so
called "laminar jet break up". As long as no resonance frequency is initiated, the
droplet size distribution is broad. The resonance frequency, however, leads to
monosized droplets. Thereafter, the droplets pass through a central aperture of a
metal ring connected to a high-voltage source, wherein the ejected droplets
penetrate into an electrical field which is built up between the metal ring and the
nozzle such that a charge flux occurs in the direction of the nozzle, providing the
separated droplets with a similar electrostatic charge causing mutual repulsion of the
droplets for separating the droplets from each other.
However, the solution as proposed in US 6,458,296 B 1 exhibits certain undesired
disadvantages, such as a lack of suitability for CiP ("Cleaning in Place") and/or SiP
("Sterilization in Place") requirements, a weak fixing of the magnet on the diaphragm,
leading to easy separation of the magnet, for example caused by heat, a high
flexibility of the membrane resulting in the need to stabilize the membrane during
sterilization, difficult mounting of the entire structure, a nozzle design intended for
sterilization in an autoclave after disassembling the entire structure, no possibility of
deaeration, i.e. gas-ventilation, without removing the nozzle, or sticking of the
electrostatically charged droplets at the reactor walls or other components inside the
reactor, resulting in undesired waste product. Therefore, there is a need for a
redesigned prilling nozzle device resolving the cited disadvantages of the known prior
art, focusing on improved reproducibility of droplet generation, improved design for
CiP and SiP requirements, use of defined GMP ("Good Manufacturing Practice")
compatible materials, improved integration of droplet counting, and improved
deflection system, i.e. preferably avoiding electrostatic charging that puts an
impediment to further particle handling.
As further known prior art in regard to nozzle technique and droplet generation, EP 1
550 556 A 1 describes a inkjet recording apparatus for jetting a droplet to a base
member, wherein the apparatus comprises in some embodiments a liquid solution
supplying section with a liquid solution chamber. Inside the chamber, a piezo element
is arranged, and a driving voltage power source is provided for applying a driving
voltage for changing the shape of the piezo element in order to achieve the jetting of
a droplet to the outside of the chamber through a nozzle.
Now, in order to evaluate if a certain nozzle design provides useable nozzle
functionality, 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.
Summary of the Invention
In view of the above, the present invention provides a liquid feeding device for the
generation of droplets, in particular for the use in a process line for the production of
bulkware of freeze-dried particles. In detail, the present invention provides such a
liquid feeding device comprising a droplet ejection section for ejecting liquid droplets
in an ejection direction, wherein the droplet ejection section comprises at least one
inlet port for receiving a liquid to be ejected, also referred to as liquid infeed, a liquid
chamber for retaining the liquid, and a nozzle for ejecting the liquid or liquid jet from
the liquid chamber to form droplets. Here, the liquid chamber is restricted by a
membrane on one side thereof, wherein the membrane is vibratable by an excitation
unit. The liquid feeding device can comprise a deflection section for separating the
droplets from each other by means of at least one gas jet. Further or alternatively, 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. Moreover, 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. With such a structure of the liquid feeding device, 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. Here, it is to be noted that, in certain embodiments, one may implement 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. It is to be noted that 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. In the
case that 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. Now, by means of the
at least one gas jet of the deflection section, the droplets can be separated from each
other in order to avoid coalescence of the droplets prior to freezing and to improve
the heat transfer by spreading the droplets. The gas jet can exit a gas access port
provided in the deflection section, wherein the gas used for the gas jet is preferably
sterile filtered gas.
In order to achieve the vibrations of the membrane, 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. Here, 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 damping element, also referred to as damper, can
increase the displacement of the magnet, wherein the damping element preferably
accommodates the magnet in a way that it can be just mounted centrically to the
electromagnetic coil to avoid any tilting of the magnet. Preferably, medium sized
magnets are to be used.
Now, as to the function of the excitation unit, the electrical frequency applied to the
electromagnetic coil is transformed into mechanical vibration of the magnet, wherein
the applied frequency preferably ranges from 800Hz to 10.000Hz, more preferably
from .300Hz to 3.500Hz. The mechanical vibration of the magnet then needs to be
transferred further to the membrane, which is in direct contact with the liquid out of
which droplets have to be generated. Here, the magnet preferably needs to be in
contact with the membrane, for example by means of a magnetic contact or the like.
In this regard, it is preferable that the membrane is a stainless steel membrane, i.e.
made of the type of stainless steel that has magnetic properties, such as .4028 steel
or AM 350 steel, preferably GMP compatible, with a preferred thickness of about
I OOmiti . A stainless steel membrane, for example welded on a flange, provides
enough flexibility in order to achieve a precise vibration inside the liquid jet. With the
vibrating membrane, a controlled intrinsic vibration can be provided to the liquid jet,
such that the liquid jet leaving the nozzle is broken into equally sized droplets by a
superimposed mechanical vibration. As an alternative, the mechanical vibration
transferred to the membrane may also be generated by other kinds of excitation
units, such as units applying a piezo actuator, a mechanical eccentric wheel, or the
like. A vertical adjustment of a support of the electromagnetic coil can be
advantageous to avoid any tilting of the magnet and to ensure a coherent contact
between the magnet and the membrane.
Further, the deflection section can comprise at least one deflection tube for emitting
the at least one gas jet, wherein the at least one deflection tube protrudes from a
main body of the deflection section in the ejection direction of the droplets. Here, the
deflection section comprises a main body and the at least one deflection tube which
projects 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 tube is
basically provided collateral to the droplets ejection path such that the longitudinal
axis of the deflection tube and the droplet ejection path are aligned in the same
plane. Further, the at least one gas jet emitted from the deflection tube is provided in
a manner such that the gas jet is directed towards the droplets, thereby intersecting
with the droplet ejection path, preferably perpendicular, i.e. at an angle of about 90°.
Moreover, in view of the droplet ejection path, 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 tube. Here, the recess can be a central through-hole the
main body of the deflection section, extending through the same, through which the
droplets pass on their way to the intersection point with the gas jet.
Alternatively or additionally, the deflection section comprises at least two deflection
tubes arranged opposite to each other. Here, the deflection section comprises a main
body and the two 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 the
deflection tubes and the droplet ejection path are aligned in the same plane. Further,
the at least one gas jet emitted from each of the two deflection tubes is provided in a
manner such that the respectively emitted gas jet is directed towards the droplets,
thereby intersecting with the droplet ejection path, preferably perpendicular, i.e. at an
angle of about 90°.
Due to the arrangement of the two deflection tubes opposite to each other across the
droplet ejection path, preferably with the same distance to the droplet ejection path,
the emitted gas jets meet each other right at the droplet ejection path of the droplets
ejected from the droplet ejection section, thereby intersecting with the same.
Alternatively or additionally, the deflection section comprises four deflection tubes,
wherein each two of the four deflection tubes can be arranged opposite to each
other. Here again, 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. Further, the at least one gas jet emitted from each of the
four deflection tubes is provided in a manner such that the respectively emitted gas
jet is directed towards the droplets, thereby intersecting with the droplet ejection path,
preferably perpendicular, i.e. at an angle of about 90°. Thereby, the at least four gas
jets preferably intersect with each other at the droplet ejection path. This allows that
the ejected droplets might also enter the deflection section de-centered from the
longitudinal or vertical axis, i.e. the droplet ejection path, which makes a droplet
deflection function more robust, resulting in that a higher resistance against vertical
deviations can be achieved.
Moreover, in view of the droplet ejection path, 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. Here, 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. However, with a straight transition zone, it becomes
possible that turbulences may cause a deposition of droplets in horizontal or vertical
areas that accumulate and coalesce into larger droplets, i.e. so called dripping, which
deteriorates product quality and yield. Alternatively, the central through-hole can be
provided as a conical through-hole, with an increasing diameter in the direction
towards the deflection tubes. 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 pre-deflection zone. After leaving the conical zone, the droplets get separated
from each other by deflection gas jets. In the main body of the deflection section, the
gas for the gas jets is guided in a chamber inside the main body around the transition
zone, from where it is finally transferred into the vertical deflection tubes.
The precision requirements for the deflection gas jets are high since they have to
meet exactly in the center between each other where the droplets fall downwards.
Thus, since the emitted gas jets from the two deflection tubes being arranged
opposite to each other meet exactly at the droplet ejection path, a separation of the
droplets from each other is achieved, resulting in a desired distribution of the
monosized droplets without the risk of droplets interfering with each other, for
example by merging into one undesired combined droplet of twice the mass and size.
In order to achieve an optimum droplet distribution, each deflection tube comprises at
least two gas jet outlet ports in the form of lateral openings in the deflection tubes,
preferably three gas jet outlet ports, for example with a diameter of about 0,4mm.
Furthermore, each deflection tube has an inclined tip end, wherein the gas jet outlet
port at the tip of the respective deflection tube, i.e. the lowest deflection opening is
positioned in the lowest position and connects with the tube interior at its edge in
order to drain the entire deflection tube during CiP and SiP processes. Here again,
the precision requirements for the gas jet outlet ports are high since the gas jets have
to meet in the center at the droplet ejection path. In general, the deflection by gas
uses preferably 0.1 m3/h - 0.3m3/h, further preferably 0.2m3/h of deflection gas per
outlet port.
In accordance with a further preferred implementation of the present invention, the
droplet ejection section comprises at least one outlet port besides the at least one
inlet port, the liquid chamber and the nozzle. Preferably, the at least one outlet port,
also referred to as liquid outfeed, is arranged at an outer circumference of the liquid
chamber, contrary to the at least one inlet port, which is preferably arranged near the
center of the liquid chamber in the vicinity of the nozzle. Here, as mentioned above,
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. This means that the
liquid chamber which generally has a larger lateral dimension than longitudinal
dimension is provided in an inclined manner such that the liquid chamber will be filled
by liquid entering from the at least one inlet port until it reaches the at least one outlet
port at the higher level or higher position, thereby ensuring that sufficient liquid is
provided to the nozzle for ejection. In order to avoid waste of excessive liquid in the
liquid chamber by releasing the same through the outlet port or in order to avoid a
breach of sterile conditions, a blocking means can be provided subsequently to the
outlet port, such as a check valve, a shut-off valve or the like. With the described
inclination of the entire liquid chamber, the liquid carrying cavity is self draining and
self-venting, i.e. self-deaerating, in order to avoid any gas bubbles that would change
the vibration properties. Hereto, it is to be noted that liquids are non compressible,
whereas gas bubbles are compressible, therefore the existence of gas bubbles inside
the liquid chamber would be highly disadvantageous since the vibration work would
be absorbed by the gas bubbles.
The at least one outlet port, which can also be referred in functional term to as a
bypass opening, however, can not only serve for drainage of excessive liquid to be
ejected from the liquid chamber but can primarily serve for discharge of SiP fluid
and/or CiP fluid introduced through the at least one inlet port into the liquid chamber.
Here, it is to be noted that the drainage of excessive liquid to be ejected can
compromise a sterile application of the liquid feeding device in that an open outlet
port might violate sterile conditions of the same. Therefore, a drainage function of the
liquid chamber by means of the outlet port might be only relevant or desired when
using the liquid feeding device of the invention not under sterile conditions. In regard
of the discharge function of SiP fluid and/or CiP fluid, it is noted that, since 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. In
other words, the provision of the outlet port allows higher cleaning liquid flows and
higher sterilization fluid flows, for example saturated steam flows.
In accordance with the present invention, 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.
Furthermore, in accordance with above, the nozzle portion can further comprise the
at least one outlet port. Moreover, the nozzle portion can comprise a nozzle portion
main body and a nozzle body which is provided separately from the nozzle portion
main body. In doing so, it is possible to manufacture the nozzle portion main body
and the nozzle body separate from each other, i.e. it becomes possible to establish
the nozzle channel in the nozzle body separately from the nozzle portion main body,
for example by the means of drilling the orifice channel into the nozzle body
centrically on a turning lathe or the like. Thereby, high precision requirements of the
drilling of the nozzle channel can be achieved, which is necessary for implementing
straight droplet ejection jet from the orifice and for preventing a tilted droplet ejection
jet. After the drilling of the orifice channel, 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. Here, the installing of the nozzle body insert into
the nozzle portion main body can be achieved by laser welding or the like. Thus, 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. Here,
precise adjustment is necessary to ensure the vertical orifice. The length of the orifice
channel is preferably between 0.5mm to 2.0mm, more preferably between 0,5mm to
1.0mm, and the diameter of the nozzle orifice preferably lies within a range of 10Omiti
to I OOOmhh , further preferably within a range of 120mhh to QOOmhh , more preferably
about 300mhh . Here, since half of the desired droplet diameter can be assumed as
the corresponding nozzle orifice diameter, a desired pellet size of approx. 600 miti
should be achieved by an orifice diameter of approx. 300mhh . The deaeration
connection as described above avoids that gas bubbles are sticking in the nozzle.
In order to be able to provide an airtight closure of the liquid chamber on the side of
the membrane, the same is welded to the nozzle portion of the droplet ejection
section, preferably by laser welding or the like. Here, the membrane can also be
welded into a separate flange which is provided separately from the nozzle portion in
order to be able to disassemble and inspect all the single components. The welding
of the membrane is reproducible and will lead to the same displacement even with a
different product. In general, in view of the above described structure of the actuation
portion comprising the excitation unit with a combination of the permanent magnet
separably attachable to the membrane, the electromagnetic coil and the damping
element, the mounting of the entire design needs to ensure that all these
components are in close contact. In practice, this is achieved by putting all the
components in a suspended, higher position and fixating them by means of at least
one positioning screw, then loosening the positioning screw and allowing the
components to have magnetic contact. By this, a sufficiently defined allocation of
forces is achieved. 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.
In accordance with a further preferred implementation of the present invention, the
liquid feeding device further comprises a CiP/SiP section being 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. In this section, a lateral access for cleaning liquid and steam is provided.
Here again, the section is provided with a central through-hole for allowing the
ejected droplets still in the form of a droplet ejection jet to pass through, wherein the
droplet ejection jet leaving the nozzle orifice transforms by means of the resonance
frequency vibrations from the membrane into separate, discrete liquid sections which
take the shape of a perfect sphere due to superficial tension of the ejected liquid. The
height of the CiP/SiP section, i.e. the length of the through-hole therein is preferably
in the range of 20mm to 50mm, more preferably 30mm to 40mm. Only after the
CiP/SiP section, separate droplets are available.
As to the further structure of the liquid feeding device of the present invention, the
liquid feeding device preferably further comprises a droplet counting section for
counting the ejected droplets, wherein the droplet counting section can be provided
before the deflection section in the ejecting direction of the droplets, i.e. in between
the CiP/SiP section and the deflection section. The droplet counting section
preferably comprises a droplet counting means, for example an optically counting
means, which can be implemented by a glass segment or glass tube and ports for
fibre optics or the like, wherein the fibre optics serve for counting of the droplets by
means of an optical sender and an optical receiver. 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 droplets that
pass there in-between. The droplet counting section allows to count each single
droplet and, thereby, to evaluate if the counted number corresponds to the estimated
ejected droplets generated by the frequency of the vibration of the membrane. If this
is the case, it can be determined that the droplet generation is as intended, whereas
a deviating result can be taken as a signal for a malfunction, resulting in an alarm or
the like.
In general, in view of the above described structure of the liquid feeding device of the
present invention, including all the different sections, the mounting of the entire
design needs to ensure that all these sections are in vertical alignment, in particular
in order to achieve the intersection of the ejected droplets with the deflection gas jets.
In practice, this is achieved by different centering means, for example by means of
centering bores and respective centering protrusions at the single sections.
According to a further aspect of the invention, a freezing chamber of a process line
for the production of freeze-dried particles is provided, preferably for the
pharmaceutical field, which freezing chamber comprises a liquid feeding device as
described above for the generation of droplets to be fed into the freezing chamber.
Further, according to another aspect of the invention, a process line for the
production of freeze-dried particles is provided by the present invention, comprising
such a freezing chamber.
The above mentioned particles can comprise, for example, pellets and/or granules.
The term "pellets" as used herein may be understood as preferably referring to
particles with a tendency to be spherical. Pellets with sizes in the micrometer range
are called micropellets. Accordingly, micropellets obtained with a nozzle in
accordance with the invention may have a substantial spherical shape with an aspect
ratio close to 1, preferably ranging from 0.8 to 1. According to one example, the liquid
feeding device of the present invention can be used for the production of essentially
or predominantly spherical freeze-dried micropellets with a mean value for the
diameters thereof chosen from a range of about 200mhh to about 1500mhh , or from
about 400mhh to about I OOOmhh, and more preferably from about 500mhh to about
dqqmiti . The micropellets obtained with a nozzle according to the invention have a
narrow distribution around a mean value. Preferably, they also have a substantial
symmetric or normal distribution around a mean value. The span which represents
the narrowness of distribution of particles around a mean value is calculated
according to the formula: (D9o-Dio)/D5owhere D90, D 0 and D5o represent,
respectively, the diameters of 90% or less, 10% or less, and 50% or less of the
particles. The micropellets obtained with a nozzle in accordance with the invention
may have a span equal or below about 1, preferably equal or below about 0.8, further
preferably equal or below about 0.7, further preferably equal or below about 0.6,
further preferably equal or below about 0.4, and even further preferably equal or
below about 0.2. According to one embodiment, when using a nozzle in accordance
with the invention having a diameter of 30Ό mhh , the span of the obtained particles
may be equal or below about 0.8, preferably equal or below about 0.7, and more
preferably equal or below about 0.6. The measure of the size of micropellets
obtained with a nozzle in accordance with the invention may be made by laser
granulometry (or laser-diffraction scattering) using, for example, a Malvern
Mastersizer 2000 apparatus. For example, a sample of micropellets (e.g. of a volume
of 50 ml) may be prepared under nitrogen flushing. The sampler used may be a
SCIROCCO 2000a with a large hopper. The measure is performed using the
Fraunhofer method, with a measure of the background noise for 10 seconds, a
measuring time of 60 seconds, pressure of 0.8 bar, vibration at 50% and obscuration
between 0.5% and 40%.
The term "bulkware" can be broadly understood as referring to a system or plurality
of particles which contact each other, i.e., the system comprises multiple particles,
microparticles, pellets, and/or micropellets. For example, the term "bulkware" may
refer to a loose amount of pellets constituting at least a part of a product flow, such
as a batch of a product to be processed in a process device or a process line,
wherein the bulkware is loose in the sense that it is not filled in vials, containers, or
other recipients for carrying or conveying the particles / pellets within the process
device or process line. Similar holds for use of the substantive or adjective "bulk."
The bulkware as referred to herein will normally refer to a quantity of particles
(pellets, etc.) exceeding a (secondary, or final) packaging or dose intended for a
single patient. Instead, the quantity of bulkware may relate to a primary packaging;
for example, a production run may comprise production of bulkware sufficient to fill
one or more intermediate bulk containers, so called IBCs.
Flowable materials suitable for the liquid feeding device of the present invention
include liquids and/or pastes which, for example, have a viscosity of less than about
300mP*s . As used herein, the term "flowable materials" is interchangeable with the
term "liquids" for the purpose of describing materials being fed by the present liquid
feeding device to the subsequent devices or sections. Any material may be suitable
for use with the techniques according to the invention in case the material is flowable,
and can be atomized and/or prilled. Further, the material must be congealable and/or
freezable.
The terms "sterility" or "sterile conditions" and "containment" or "contained conditions"
are understood as required by the applicable regulatory requirement for a specific
case. For example, "sterility" and/or "containment" may be understood as defined
according to GMP requirements.
Embodiments of the liquid feeding device may comprise any device adapted for a
droplet generation from a liquid as described above. Freezing can be achieved by
gravity fall-down of the droplets in a chamber, tower, or tunnel. Exemplary freezing
chambers include, but are not limited to prilling chambers or towers, atomization
devices such as atomization chambers, nebulization/atomization and freezing
equipment, etc.
In particular embodiments, the entire liquid feeding device (or sections thereof) can
be adapted for CiP and/or SiP. Access points for introduction of a cleaning medium
and/or a sterilization medium, including, but not limited to use of nozzles, steam
access points, etc., can be provided throughout the sections of the device. For
example, steam access points can be provided for steam-based SiP. In some of
these embodiments, all or some of the access points are connected to one cleaning
and/or sterilization medium repository/generator. For example, in one variant, all
steam access points are connected to one or more steam generator in any
combination.
Advantages of the Invention
Various embodiments of the present invention provide one or more of the
advantages discussed hereafter. For example, with the liquid feeding device as
presented herein, it is possible to avoid all disadvantages of the known prior art. In
particular, with the liquid feed device of the present invention, it becomes possible to
achieve the desired product quality like particle size and particle size distribution in a
very early stage of the production process.
Furthermore, with the stainless steel membrane of the presented liquid feeding
device, receiving an FDA certificate may be facilitated compared to the known PTFE
membranes or the like.
Moreover, mounting of the inner structure of the liquid feeding device is simplified,
wherein it becomes possible to remove the magnet without difficulty compared to the
known prior art in which the head of the nozzle with fixing of the electromagnetic coil
has to be screwed together with the membrane flange and the nozzle body, such that
a removal of the magnet during sterilization becomes impossible (heating reduces
the permanent magnetic properties). Also, since the magnet as provided in the
devices as known from the above cited prior art is glued to the membrane, fixing of
the magnet on the membrane is weak such that, during disassembling and cleaning,
the magnet it is often separated from the membrane and has to be glued again onto
the membrane; also, a separation of the magnet from the membrane is facilitated by
hot surfaces, which will be the case during sterilization. The thus heat sensitive
magnet, however, needs to be in position all the time.
As a further advantage of the present invention, deaeration of the nozzle is possible
with the structure of the liquid feeding device of the present invention, which is
necessary for a clear droplet formation.
Also, it has not been possible with the known drilled nozzles of the prior art to
achieve straight vertical droplet jets. All known stainless steel nozzle tips directly
processed into a stainless steel nozzle main body showed an undesired tilted liquid
droplet jet. Only by providing the nozzle body separate from the main body during
drilling and fixating the same into the main body afterwards, an improved nozzle
channel has been generated which results in an improved straight droplet jet.
Furthermore, with a liquid feeding device as presented herein, in particular by
providing the liquid chamber with an outlet port, it becomes possible to achieve
sufficient steam throughput for sterilization, and thus, it becomes possible to equip a
process line for the production of freeze-dried particles with the possibility to maintain
closed conditions at all times, even during sterilization procedures. Therefore, sterile
and/or contained product handling is enabled while avoiding the necessity of putting
the entire process line into a separator or isolator. In other words, a process line
provided with a liquid feeding device according to the invention adapted for example
for an operation under sterile conditions can be operated in an unsterile environment.
Costs and complexity related to using an isolator can therefore be avoided while still
conforming to sterile and/or containment requirements, for example GMP
requirements. For example, there may be an analytical requirement of testing in
regular time intervals (e.g., every hour or every few hours) whether sterile conditions
are still maintained inside an isolator. By avoiding such costly requirements,
production costs can be considerably reduced.
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. Suitable liquid formulations include, but are not limited
to, antigens, adjuvants, vaccines, antibodies (e.g., monoclonal), antibody portions
and fragments, other protein-based Active Pharmaceutical Ingredients (APIs) (e.g.,
DNA-based APIs, and cell/tissue substances), APIs for oral solid dosage forms (e.g.,
APIs with low solubility/bioavailability), fast dispersible or fast dissolving oral solid
dosage forms (e.g., ODTs, orally dispersible tablets), and stick filled presentations,
etc.
Also, with the deflection section for separating the droplets from each other by means
of at least one gas jet of the liquid feeding device, some disadvantages which may
occur further to the droplet separation by electrostatic charge of the droplets or the
like may be avoided, such as the undesired sticking of the charged droplets to
surfaces of a freeze-dryer.
Description of the Figures
Further aspects and advantages of the invention will become apparent from the
following description of particular embodiments illustrated in the figures in which:
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;
Fig 2 is a schematic illustration of a configurational mode of the process line
as illustrated on Fig. 1;
Fig 3 shows an overall structure of a process line as illustrated in Figs. 1 and
2;
Fig 4 shows a side view of the liquid feeding device according to the
preferred embodiment of the invention;
Fig 5 is a cross-sectional view of the liquid feeding device of Fig. 4 along line
A-A;
Fig. 6 is a cross-sectional view of the liquid feeding device of Figs. 4 and 5
along line B-B in Fig. 5;
Fig. 7a is an enlarged view of detail "X" in Fig. 5;
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;
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
Fig. 9 is an enlarged view of a deflection section of a liquid feeding device
according to another preferred embodiment of the invention in crosssection.
Detailed Description of Embodiments
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.
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.
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.
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 Figs. 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.
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.
Fig. 3 illustrates a process line 100 as basically known from, for example, EP 2 578
974 A 1, 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.
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.
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 200mhh to about 1500mhh , 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.
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 noncirculating
atmosphere provided within the internal volume, for example, an
(optionally sterile) nitrogen and/or air atmosphere. 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 - dqqmhh, an appropriate height of the
prilling tower might be 1 - 2m, while for freezing droplets into pellets with a size
range up to 1500mhh , the prilling tower can have a height of about 2 - 3m, wherein
the diameter of the prilling tower can be between about 50 - 150cm for a height of
200 - 300cm. The temperatures in the prilling tower can optionally be maintained or
varied/cycled throughout between about -50°C to - 190°C.
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 freezedried
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.
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
2 10 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 2 10 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 2 10 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 2 10 . 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.
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 30mm to 50mm, for the ejected liquid jet to separate in an ejection direction
into separate droplets.
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 2 1, 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 50mm 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 2 11 (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 .
The mounting of the entire liquid feeding device 200 needs to ensure that all of its
sections 2 10, 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 alignnnent 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.
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 2 10 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
2 11 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.
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.
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 0.9mm to 1.3mm, preferably 1.1mm, and the diameter of
the outlet port 235 can reside in a range of 0.8mm to 1.2mm, preferably 1.0mm.
Compared to an exemplary diameter of the nozzle orifice 2331 of about 300mhh, this
results in a diameter ratio port/orifice of about 3:1 to 4:1 .
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 2 11 such that
the separation of the droplets can be further promoted.
In the direction of the droplet path 2 11, 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 .
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 2 12 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 2 11 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 2 11 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 2 111 with a right angle.
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 2 12 . 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.
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 2 12 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 throughhole.
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'.
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.
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.
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, proteinbased
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).
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.
In order to support a permanently mechanically integrated system providing end-toend
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.
The products resulting from the use of the liquid feeding device according to the
invention can comprise virtually any formulation in liquid o 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.
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.
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).
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.
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.
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.
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.
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
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 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 nonconjugated),
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
2009/1 09550, the subject-matter of which is incorporated by reference. When the
vaccine composition contains an adjuvant it can be for instance:
1) a particulate adjuvant such as: liposomes and in particular cationic liposomes (e.g.
DC-Choi, see e.g. US 2006/01 6571 7, DOTAP, DDAB and 1 ,2-Dialkanoyl-snglycero-
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.
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,
A 1P04), 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
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 o 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).
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
2009/1 09550, the subject-matter of which is incorporated by reference. The freezedried
particles of the non adjuvanted or adjuvanted vaccine composition are usually
under the form of spheric particles having a mean diameter between 200mhh and
1500mhh . Furthermore, the freeze-dried particles of the vaccine compositions
obtained are sterile.
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.
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:
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
Item 11. Liquid feeding device according to any one of the preceding items, wherein
the membrane is a stainless steel membrane.
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.
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.
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 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.
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.
Item 18 . Process line for the production of freeze-dried particles, comprising a
freezing chamber according to item 17 .
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 .
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.
Item 2 1. A process according to item 19 or 20, wherein all the steps are carried out
under sterile conditions.
Item 22. A process according to items 19 or 2 1, wherein the freeze-dried particles are
sterile.

We Claim :
1. Liquid feeding device for the generation of droplets, in particular for the use in 5 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 10 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. 15
2. 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.
3. Liquid feeding device for the generation of droplets, in particular for the use in 20 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 25 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.
4. Liquid feeding device according to any one of the preceding claims, wherein the 30 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.
41
5. Liquid feeding device according to claim 4, 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
6. Liquid feeding device according to claim 5, 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.
10
7. Liquid feeding device according to any one of claims 4 to 6, 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. 15
8. Liquid feeding device according to any one of the preceding claims, 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. 20
9. Liquid feeding device according to any one of the preceding claims, 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. 25
10. Liquid feeding device according claim 9, 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.
30
11. Liquid feeding device according claim 9 or 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.
35
42
12. Liquid feeding device according to any one of the preceding claims, 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 5 permanent magnet and the electromagnetic coil, further preferably wherein the damping element is made out of silicone.
13. Liquid feeding device according to any one of the preceding claims, wherein the membrane is a stainless steel membrane. 10
14. Liquid feeding device according to any one of the preceding claims, 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 15 the membrane.
15. Liquid feeding device according to claim 14, 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 20 installed in a central through-hole in the nozzle portion main body, more preferably by laser welding.
16. Liquid feeding device according to claim 14 or 15, wherein the membrane is welded to the nozzle portion for airtightly closing the liquid chamber on one side, 25 preferably by laser welding.
17. Liquid feeding device according to any one of the preceding claims, 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 30 liquid feeding device subsequent to the droplet ejection section.
18. Liquid feeding device according to any one of the preceding claims, further comprising a droplet counting section for counting the droplets, preferably provided before the deflection section in the ejection direction of the liquid. 35
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19. 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 claims, for the generation of droplets,
a freezing chamber for freeze-congealing droplets fed from the liquid feeding 5 device, and
a freeze-dryer for lyophilization of the frozen droplets.
20. 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 10 generating liquid droplets of said vaccine composition with a liquid feeding device according to anyone of claims 1 to 18.
21. A process for preparing an adjuvant containing vaccine composition comprising one or more antigens in the form of freeze-dried particles comprising: 15
at least a step of generating liquid droplets of said vaccine composition with a liquid feeding device according to anyone of claims 1 to 18, or
at least the steps of generating liquid droplets of an antigen(s)-containing composition with a liquid feeding device according to anyone of claims 1 to 16, of generating liquid droplets of an adjuvant-containing composition with a liquid 20 feeding device according to anyone of claims 1 to 18, 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.
22. A process according to claim 20 or 21, wherein all the steps are carried out 25 under sterile conditions.
23. A process according to any one of claims 20 to 22, wherein the freeze-dried particles are sterile.