ENGLISH TRANSLATION VERIFICATION
CERTIFICATE u/r. 20(3)(b)
I, Mr. HIRAL CHANDRAKANT JOSHI, an authorized agent for the applicant,
FRAUNHOFER-GESELLSCHAFT ZUR FÖRDERUNG DER ANGEWANDTEN
FORSCHUNG E.V. do hereby verify that the content of English translated complete
specification filed in pursuance of PCT International application No.
PCT/EP2017/071879 thereof is correct and complete.
HIRAL CHANDRAKANT JOSHI
IN/PA No. 325 AGENT FOR
FRAUNHOFER-GESELLSCHAFT ZUR
FÖRDERUNG DER ANGEWANDTEN
FORSCHUNG E.V.
1
F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
INACTIVATION OF PATHOGENS IN BIOLOGICAL MEDIA
2. APPLICANT(S)
(a) NAME
(b) NATIONALITY
(c) ADDRESS
FRAUNHOFER-GESELLSCHAFT ZUR FÖRDERUNG
DER ANGEWANDTEN FORSCHUNG E.V.
GERMAN Company
HANSASTRASSE 27C,
80686 MUENCHEN,
GERMANY
3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL
The following specification describes invention
COMPLETE (√)
The following specification particularly describes the invention
and the manner in which it is to be performed
4. DESCRIPTION (Description shall start from next page)
5. CLAIMS (not applicable for provisional specification. Claims should start with the preamble – “I/We claim” on
separate page)
6. DATE AND SIGNATURE ( to be given on the last page of specification)
7. ABSTRACT OF THE INVENTION (to be given along with complete specification on the separate page)
Note:
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* Name of the applicant should be given in full, family name in the beginning
* Complete address of the applicant should be given stating with postal index no. / code, state and country
* Strike out the column which is/are not applicable
**This form is digitally signed.
2
The invention relates to the processing of fluid biological media, especially of
culture media or cell- or virus suspensions, potentially containing active
pathogens, with the aim of inactivating these pathogens and/or modifying
ingredients in these biological media by ionizing beta radiation.
As is known, pathogenic substances, including toxins or pathogens such as
viruses, virus particles, bacteria or other organisms, can be inactivated by
exposure to thermal or ionizing radiation - primarily UV, X-ray or gamma
radiation, as well as beta radiation. The pathogens are modified in such a way
that their pathogenic effect on an animal or human mechanism or a cell or
tissue culture is minimized or completely eliminated. Such thermal or ionizing
radiation - for example, with non-thermal electrons (beta radiation) - alters the
structural integrity of one or more structural or functional components of these
pathogens at the molecular level, thus leading to their inactivation. The
problem with this is that, according to a dose/effect correlation, a radiation
dose which is too low leads to incomplete or inadequate inactivation of the
pathogens; whereas a radiation dose which is too high can cause undesirable
structural changes and modifications in other components of the biological
medium. This is particularly problematic in the manufacture of vaccines from
suspensions of active pathogens - especially from virus suspensions. If, for
example, virus suspensions are irradiated with low-energy beta radiation in
order to deactivate the viruses, as described in DE 10 2013 012 455 A1, a
radiation dose which is too low leads to undesired, incomplete inactivation of
the viruses, whereas an excessive radiation dose leads to destruction or
partial denaturating of the virus or viral antigen structures, and thus to an
impairment of the immunogenic activity of the vaccine being produced. As
such, with too low or too high a radiation dose, the virus suspension cannot be
used as a vaccine.
However, irradiation with thermal or ionizing radiation can also be used for the
targeted modification - that is to say, the conversion, mutagenesis, stimulation,
3
transduction of cells or tissues - in cell research and in cell and tissue
production, in particular also for fragmentating cellular DNA to prevent cell
proliferation. In this case, control of the correct dose is highly important,
especially if dose/effect dependencies of such radiation-induced modifications
and effects on cells or tissues must first be determined scientifically.
In the context of the automation of biotechnological plants - in particular,
plants for the production of vaccines, as well as plants for cell and tissue
culturing - devices, methods, and means must be created which enable a
particularly continuous processing of biological media - especially pathogenic
suspensions, suspensions of cells or tissues, sterile media, etc. It is desirable
in such cases to furnish methods and means for the dose-controlled irradiation
of such biological media which are particularly fully automatic and
continuously operable and which can be "inserted" into the ongoing flow of
material in such plants. At the same time, it should be possible to clean,
sterilize, or exchange such means as required in the plant. Likewise, the
protection of personnel (from infection) and protection of products (from
contamination) must be ensured.
The invention was based on the technical problem of providing methods and
means for automated, continuous irradiation of fluid biological media,
particularly such as are suitable for subjecting a continuous fluid stream of the
biological medium to a controllable radiation dose in an automatic line for the
production or processing of such media. The invention must achieve an
improved - that is, particularly, a dose-controlled - irradiation exposure,
especially for the purpose of reliably inactivating pathogens or modifying
biological media in a targeted manner according to the radiation. At the same
time, an integral module should be furnished which is autonomously operable
within the automatic line and is interchangeable and easy to clean, while also
ensuring protection of personnel and protection of the product.
4
The technical problem is solved by a novel device for continuous
homogenization of a fluid medium to expose the homogenized medium to beta
radiation. According to the invention, a module is furnished for this purpose
which enables the generation of a continuous fluid film of continuously
supplied fluid, and which enables the irradiation of this fluid film, which has a
predeterminable thickness - that is, surface/volume ratio. The module is
designed according to the invention in the form of an exchangeable, integral
cassette. The cassette is sterilizable - particularly, separately from the
arrangement in which it can be utilized repeatedly for continuous, dosecontrolled
irradiation. The cassette according to the invention consists of a
module housing, having a tub for receiving the continuously supplied fluid, and
having a cylindrical roller which dips into this tub - particularly into the fluid
supplied and received therein - and which can rotate in the same along an
axis. In addition, the module has at least one inlet channel for supplying the
fluid into the tub. There is at least one wiper lip, which is in intimate contact
with the roller surface of the cylindrical roller - specifically, on the downwardrotating
side of the roller in the direction of rotation of the roll - to wipe off the
fluid film formed on the revolving roller surface of the fluid captured in the tub
during the rotation of the roller. There is also an outlet channel for receiving
and continuously discharging fluid which has been wiped off the roller surface
by this wiper lip.
According to the invention, there is an overflow channel on the tub for draining
excess supplied fluid from the tub, so as to define and maintain the level of
fluid in the tub.
According to the invention, the cassette is further made of a housing cover
which tightly seals the module housing to form the exchangeable cassette.
The housing cover has at least one radiation-permeable window (radiation
window) in the form of a metal window.
5
A preferred element of a first embodiment of the module housing of the
cassette according to the invention is a special gap-forming element which is
arranged on the side of the roller when the same runs into the fluid during
rotation, at the position where the supplied fluid runs out of the tub onto the
roller surface. The gap-forming element is distanced from the roller surface in
such a manner that a capillary gap is formed at that position. This capillary
gap extends at least to above the fluid level in the tub. According to the
invention, this gap-forming element serves to generate and homogenize the
fluid film formed on the roller surface.
The inventors have surprisingly found that the interaction of the elements
according to the invention can generate a very continuous fluid film from a
continuously supplied fluid, with a consistent thickness - and especially a
consistent surface/volume ratio - during continuous operation. The fluid level
in the tub, which is kept constant by the overflow channel included according
to the invention in the tub of the module housing can, particularly in
connection with the preferred specific gap-forming element which forms a
capillary gap in cooperation with the roller surface, said capillary gap
preferably extending to above this fluid level, result in a surprisingly uniform,
continuous fluid film on the roller. In one of these preferred embodiments, the
thickness of the fluid film can be adjusted within certain boundaries -
specifically, via the width of the capillary gap and/or via the height of the
portion of the capillary gap extending above the fluid level in the tub.
The type and quality of the fluid, its viscosity, and also the type and quality of
the wetted surfaces - particularly, the surface of the roller - as well as the
rotational speed of the roller also play a role in the formation of a suitable fluid
film.
In an alternative embodiment of the module housing of the cassette according
to the invention, such a special gap-forming element is omitted. This is
especially because, in certain variants, even without such a specially shaped
6
and arranged gap-forming element, it is possible to generate a continuous
fluid film on the rotating roller in a sufficiently reliable manner.
In a preferred embodiment, the height of the at least one overflow channel in
the tub, or the immersion depth, is variable, such that it is possible to set or
predetermine the fluid level in the tub.
In a preferred embodiment, in addition to the overflow channel, there is at
least one further means for fixing - that is, keeping constant - the fluid level in
the tub of the module. The constant maintenance of the fluid level in the tub
can preferably be improved by attaching a bubble detector or flow meter to the
overflow channel, which detects the flow rate and/or gas bubbles which may
arise. The type and quality of the flow at the overflow channel provides indirect
information about the fluid level in the tub of the module. The sensor signal
can be used to appropriately control the supply rate in the inlet channel.
Bubble detection is mainly used for "function control". Continuous flow without
bubbles at the overflow channel would suggest that the fluid in the inlet is in
danger of running into the inactivated fluid reservoir, which should be
prevented. In addition, the bubble detection during the start-up process can be
used to check whether the cassette has been connected properly with proper
tubing.
The pressure measurement is primarily used to check the tightness of the
closed system before or during operation. The inside of the module is
subjected to a slight overpressure or underpressure. If the module is leaking,
this is indicated by a pressure change.
In a further alternative embodiment, the fluid supply to the roller is embodied
as a so-called chambered doctor blade. The chamber is preferably sealed by
sealing lips on the roller. Alternatively, the chamber forms a sealing capillary
gap with the roller. The fluid is applied to the roller with regulated flow and/or
pressure.
7
In all embodiments, the wiper lip is preferably oriented on the downwardrotating
side of the roller against the downward-rotating direction of the
rotating roller. It works like a scraper directed counter to the direction of
rotation. Preferably, the wiper lip is pressed by the rotation onto the roller
surface and contacts the same with no gap, and preferably over its entire
width. Fluid wiped off the roller surface passes via the wiper lip preferably into
an outlet groove or outlet channel arranged on the anchoring of the wiper to
the module housing, and can be collected and discharged from the module
housing.
In an alternative, preferred variant, the wiper lip is arranged on the downwardrotating
side of the roller, in such a manner that it is oriented against the
downward-rotating direction of the rotating roller. It forms, together with the
surface of the roller, a transverse groove in which the fluid which is wiped off
can collect. From there, it can flow over passively and be collected in a
discharge groove arranged on the anchoring of the wiper, and be discharged
from the module housing. Alternatively and preferably, however, the outlet
channel at this position is embodied as at least one tube projecting into the
groove formed between the wiper lip and the downward-rotating side of the
roller. The fluid which is wiped off can preferably actively drain from the
groove via this tube - particularly preferably by suction applied by means of a
vacuum pump - and preferably a peristaltic pump - or alternatively by
expulsion via overpressure. However, this particularly requires a reservoir with
pressure compensation.
In a further alternative embodiment, the discharge of fluid from the roller
surface is facilitated via a double wiper lip. At least the trailing (lower) wiper lip
contacts the roller and is oriented counter to the downward-rotating direction
of the rotating roller. The two wiper lips, running in parallel, form a chamber
together with the roller surface in the manner of a chambered doctor blade.
The chamber forms the outlet channel.
8
In a preferred embodiment, at least one wiper, which is set at a distance from
the roller surface, is additionally arranged on the upward-rotating side of the
roller, and accordingly downstream of the capillary gap which is established.
The wiper serves to additionally homogenize the fluid film, and to set the film
height for particularly viscous media. In a preferred variant of this
embodiment, the distance of the wiper from the roller surface is adjustable, or
the wiper can be swapped out for accordingly differently-sized wipers in the
module so as to regulate the effect on the homogenization of the fluid film, and
on the thickness of the fluid film, and as required. In a special variant of this
embodiment, the wiper edge of the wiper has an arcuate or elliptical shape in
order to homogenize the fluid film between the central section and the
peripheral sections of the roller.
Preferred materials of the roller surface are selected from among: materials
which reflect electrons and/or heat rays - particularly preferably from among
metals of subgroup VIII (old IUPAC), and more preferably from among the
metals platinum (Pt), gold (Au), chromium (Cr), nickel (Ni) and iron (Fe), and
alloyed ferrous steels, especially chromium-nickel steel and other stainless
steels. Particularly preferred is a gold (Au) coating; alternatively a platinum
(Pt) coating is preferred. Alternatively or additionally, the roller surface is
hydrophilized by means of chemical or plasma processes, which are known
per se, in order to improve the formation of a closed fluid film on the surface.
Alternatively or additionally, the surface of the roller is structured.
In a preferred embodiment, the surface of the roller is temperature-controlled
by suitable measures - that is, in particular, cooled - to compensate for
radiation-induced heating, specifically to prevent unwanted adverse radiation
effects. In an alternative variant, the roller surface can be heated, particularly
in order to enhance the radiation effect in conjunction with the thermal action,
or to direct it specifically to thermally sensitive structures in the fluid medium.
Particularly for this purpose, there is an additional circulation for conveying a
9
cooling or heating fluid through the module, and particularly the roller. In an
alternative embodiment, the temperature of the roller surface is only controlled
by heat conduction via the module, which is temperature-controlled as a whole
from the outside. In an alternative embodiment, the supplied medium which
will be irradiated is tempered, preferably before it enters the module - and
alternatively or additionally during the irradiation.
According to the invention, at least one radiation window is included on the
housing cover of the cassette in order to seal the module housing in a gastight
and airtight manner. In a preferred embodiment, to protect the radiation
source, a radiation window is also included on the arrangement to which the
cassette can be coupled. The type and design of the radiation window
depends on the type and quality of the radiation. For irradiation with ionizing,
short-wave radiation, UV-C or soft X-rays, radiation windows made of plastic
or quartz glass can be used. However, according to the invention, metal
windows are used for irradiation with X-ray radiation or beta radiation. Metals
for the radiation windows are preferably selected from among titanium,
magnesium and aluminum, and alloys thereof.
Preferably, the module housing is cooled before or during operation - for
example, tempered to 4°C. In this case, fluid can condense on the radiation
window if there is ambient humidity. For this reason, in a preferred
embodiment, the radiation window can be washed with dry gas to prevent
condensation from forming on it. Preferably, the dry gas simultaneously
serves to cool the radiation window during the irradiation.
In a particular variant, the rotation of the roller in the module is generated via
the pressure and flow of the fluid supplied to the module for the purpose of
irradiation. In a first variant, the fluid which is supplied via the at least one inlet
channel drives the rotation of the roller in the primary fluid stream. That is, all
of the supplied fluid, which is "converted" to a continuous fluid film, serves to
drive the roller. In a preferred embodiment of this variant, a turbine element or
10
vaned wheel element is arranged on the roller axle or in the roller, and all of
the supplied fluid flows through the same. In a further such variant, the roller
surface is designed to be "adhesive" for the supplied fluid, in such a manner
that the fluid flowing over the gap-forming element onto the roller surface
generates movement in the roller with friction, due to the prevailing pressure
and gravity conditions.
In an alternative variant, a partial stream of the supplied fluid drives the roller.
In this case, a portion of the supplied fluid is "converted" into the continuous
fluid film, and another portion serves to drive the roller and flows back into the
tub. In this variant, a peripheral paddle wheel structure is preferably provided
at one or more positions along the outer surface of the roller. A partial stream
of the supplied fluid is directed to it and thereby causes the roller to rotate. In
this case, this portion of the supplied fluid particularly does not form a
continuous fluid film, and is not wiped by the wiping edge on the downwardrotating
side of the roller and discharged via the outlet channel of the module.
For this purpose, the wiper edge at the position of the rotating paddles has a
recess which prevents fluid at this position from being wiped off.
In alternative or additional embodiments, the roller of the module can be made
to rotate by an external drive. In a simple embodiment, the axle shaft of the
roller of the module is routed for this purpose out of the module housing to the
outside, where it can engage via a suitable mechanical coupling with an
external drive, such as a geared motor or step motor. In one embodiment, the
roller axis is directly routed on the module housing to the outside. In an
alternative embodiment, the drive shaft which leads out of the module housing
is coupled to the roller axle shaft inside the module housing via a transmission
- preferably a spindle gear, gears or toothed belts.
11
The shaft feedthrough of the drive shaft or roller axle is preferably designed as
a double shaft seal in the module housing, preferably with a flushable internal
space. The internal space can be rinsed with aseptic and/or disinfecting
rinsing medium.
In an alternative and preferred embodiment, the torque coupling between the
roller and the external drive element is a contactless magnetic coupling -
particularly via magnetic elements inserted into the roller, which form a
magnetic coupling together with a corresponding structure on the drive
element. In a preferred embodiment of this variant, the magnetic elements of
the roller can be brought into contact with an external electromagnetic drive -
particularly a stationary magnetic coil arrangement which is energized with
alternating current - thereby together forming an electric motor as a whole.
The interchangeable cassette according to the invention can be used in a
fixed apparatus - for example, within automatic lines - and can be exchanged
as needed for the purpose of cleaning or sterilization. It is envisaged that the
cassette comprises all the connections for the supply and discharge of the
biological fluid in this case. These can be configured with quick-change
adapters. In a preferred embodiment, the quick-change connections for the
fluid inlets and outlets are arranged on the module housing in such a way that
the fluid connections are established automatically upon the insertion or
plugging of the cassette into the sterilization arrangement. Such connections
can be CIP ("clean in place"), WIP ("wash in place") or SIP ("sterilization in
place") connections. Alternative connections known per se include valves and
sterile connectors such as Luer-Lock and related systems.
The interchangeable cassette according to the invention itself preferably has a
modular structure, such that elements within the module which determine the
formation, and particularly the thickness, of the desired fluid film can be
exchanged individually. For example, a plurality of differently sized gapforming
elements can be furnished; these can be exchanged in the module, in
12
the manner of a modular system, to adjust the thickness of the fluid film.
Likewise, the roller itself can be provided in different variants, the variants
differing substantially in the type and properties of the roller surface. Due to
the modular structure, particularly the design of the module as an
interchangeable and closed cassette, it is possible to operate a complete
system for the inactivation of dangerous pathogens even in lower-security
laboratories and automated lines. Due to the optional, fully enclosed design, it
is possible to configure and prepare the module as a whole, including the
necessary fluid inlets and outlets and the associated reservoirs in a first highsecurity
laboratory, and to then move this arrangement in a sterile, closed
configuration into the lower-security automatic line, where the radiation
treatment can be performed to inactivate the pathogenic agents. The fully
closed design of the module can prevent contamination of the other automatic
parts, particularly the radiation source, the drives of the roller, and the pumps.
At the same time, this results in, or improves, protection for personnel and the
product.
In a first variant, the module is open on one side and allows free projection of
the thermal or ionizing radiation onto the fluid film exposed on the roller
surface. In this case, this module is preferably inserted or plugged or
otherwise coupled into a fixed arrangement for operation, and is sealed to the
same. This fixed arrangement in turn contains at least the radiation source,
and preferably additionally contains means for transporting the fluid through
the module, and/or additionally contains means for driving the rotation of the
roller in the module.
In an alternative embodiment, the module is fully self-contained and is
preferably provided as an exchangeable, standardized cassette. There is
preferably a sealed housing cover for sealing the module housing, wherein the
housing cover particularly has a gas-tight and fluid-tight, but radiationtransparent
radiation window for the purpose of irradiation, through the
13
window, of the fluid film formed on the roller surface by means of an external
radiation source.
The invention also relates to a device for the continuous, dose-controlled
irradiation of fluid, particularly of a biological medium, for example for
inactivating pathogens in the medium or for modifying components of the
medium by means of ionizing or thermal radiation, which contains the module
according to the invention and additionally at least one radiation source,
wherein the module can particularly be coupled directly to the radiation
source. Furthermore, the device has at least one or more pumps for the
continuous active transport of this fluid through the module.
In a variant, there is additionally at least one reservoir containing the fluid to
be irradiated, and at least one collecting vessel for receiving the irradiated
fluid which flows out of the module. In a preferred embodiment, the purpose of
the reservoir is to continuously supply the module with this fluid through the
inlet, via a first supply line. The overflow of the module preferably opens into
the reservoir. The fluid is actively transported into the module, particularly by
the reservoir being pressurized - especially if the overflow does not return to
the reservoir - and/or by pump elements in the inlet. The fluid is passively
transported from the overflow of the module into the reservoir - particularly
facilitated by the negative pressure generated in the reservoir which arises
when the supply fluid is suctioned out of the reservoir, and/or gravity-assisted.
Alternatively and preferably, the fluid is actively transported via a pump -
particularly a peristaltic pump.
The collecting vessel for receiving the irradiated fluid is connected to the outlet
channel of the module. In a preferred embodiment, a pressure compensating
venting channel is additionally included, and connects the outlet side of the
module with the outlet vessel. The wiped, irradiated fluid is preferably
transported away passively - particularly gravity-assisted - or alternatively by
14
active transport, by the application of pressure or vacuum to the outlet vessel,
and/or by active pumping elements in the outlet branch of the module.
Preferably, this device additionally contains at least one mechanical or
electromagnetic drive element - optionally with suitable mechanical or
contactless coupling elements for driving the rotations of the roller in the
module.
The module according to the invention and the device according to the
invention are specifically suitable for homogenizing continuously supplied fluid
for the purpose of dose-controlled irradiation of the fluid. This primarily
functions, as described herein, to bring about the targeted inactivation of
pathogens in the fluid. Accordingly, a further object of the invention is a
method for inactivating pathogens in a biological fluid - which is particularly
carried out continuously. The method according to the invention comprises at
least the following steps: In step (a) the fluid, which potentially contains active
pathogens, is supplied, particularly actively, to the module according to the
invention. In step (b), the roller is rotated in the module according to the
invention, such that a continuous fluid film of a predeterminable thickness is
formed from the supplied biological fluid on the revolving roller surface. In step
(c), the fluid film formed and exposed on the roller surface is irradiated with a
pathogen-inactivating dose of ionizing radiation, the radiation dose being
determined by the radiation intensity of the radiation source passing through
the radiation-exposed volume of the fluid, which is determined by the radiation
window and the thickness of the fluid film which forms - and also preferably by
the flow velocity or flow rate of the fluid film, which can be determined by the
rotation speed of the roller. In step (d), the fluid irradiated after passing
through the radiation window and wiped off the roller surface is discharged
from the module and collected. This fluid contains pathogens which are
inactivated in a dose-dependent manner.
15
A method according to the invention also generally relates to the thermal or
ionizing irradiation of a fluid by means of the module according to the
invention, comprising the steps of (a): supplying the fluid to the module, (b)
rotating the roller in the module such that a continuous fluid film of
determinable thickness forms on the revolving roller surface, (c) irradiating the
fluid film on the roller surface with thermal or ionizing radiation; and (d)
collecting the irradiated fluid which can be discharged from the module.
Preferably, the radiation dose is determined by the radiation source and the
rotational speed. Since a dose gradient arises within the fluid, it is particularly
desirable in many cases for the layer of the fluid film on the roll to have the
least possible height. This advantageously results in minimal differences in the
radiation dose within the transported fluid. It may be desired to set the layer
height (greater than the least possible height) in instances where higher
throughput is desired - in the event that the dose gradient in the fluid is
acceptable. In this case, the thickness of the fluid film is preferably regulated
by adjusting the capillary gap on the outlet element of the module - optionally
in cooperation with an additionally-included wiping element. Alternatively, or
preferably additionally, the dose is determined and regulated by the rotation
speed of the roller, wherein the rotation speed decisively determines the
residence time of a specific volume of the medium in the irradiated area. The
rotational speed also optionally determines the thickness of the fluid film. In
addition, the dose and penetration depth can be determined by direct control
of the radiation source - for example the beta radiation source - in a manner
which is known per se.
A further object of the invention is the use of the module or device of this
invention for the continuous inactivation of pathogens in a fluid biological
medium, preferably a virus suspension, by means of ionizing radiation.
Finally, a further object of the invention is the use of the module or device of
this invention for modifying biological media by means of ionizing radiation.
16
The invention is explained in more detail by the following figures and
embodiments.
Figure 1 schematically shows the overall structure for continuous irradiation of
pathogen-containing fluids, for the purpose of inactivating the pathogens,
using the module according to the invention. A fluid medium 20 which
potentially contains pathogens has been furnished in a reservoir 21. The fluid
is actively conveyed into the tub 12 via the supply line 15 and the peristaltic
pump 94 via the inlet 14 on the module housing 10. An overflow 16 included in
the module housing returns excess fluid into the reservoir 21 via line 17, and
an optional peristaltic pump 96. The fluid level 24 in the tub 12 is kept
constant. The cylindrical roller 30 rotates in the fluid 20 in the tub 12. The gapforming
element 50 arranged according to the invention on the upwardrotating
side 34 of the roller forms a capillary gap 52 from the roller surface -
the capillary gap 52 also extending above the fluid level 24. Upon rotation of
the roller 30, the capillary gap 52 facilitates the formation and homogenization
of a fluid film 22 on the roller surface. The fluid film 22 which is formed is
guided past a radiation window 62 and is exposed at that point to the radiation
of a radiation source 80. After the irradiation on the upward-rotating side 36 of
the roller 30, the fluid film 22 is substantially completely removed or wiped off
by a wiping edge 40, which contacts and seals against the roller surface at
that position. The removed, irradiated fluid 26 is collected and removed into a
collecting vessel 27 via the outlet channel 18 via line 19 - optionally via
peristaltic pump 98. An optional pressure line 28 provides pressure
equalization. Figure 2 shows the principle routing of the fluid flow in the overall
arrangement analogous to Figure 1, on the basis of the schematic sectional
drawing of a specific embodiment of the module according to the invention.
Figure 3 shows a perspective, plan view of a specific embodiment of the
module 10 according to the invention, with the tightly-fitted cover 60 with the
radiation window 62. A drive element 90 with a coupling element 92 is shown
17
on the module, for driving the roller contained in the module. The roller is
driven in the module 10 in this case without contact, via magnetic elements in
the coupling element 92 and corresponding magnetic elements in the roller.
Figure 4 shows a perspective view of the module 10 according to Figure 3,
with the cover removed, and with a view of the rotatable cylindrical roller 30,
the wiping edge 40 in contact with the surface of the cylindrical roller 30 - in
this case in the form of a wiping plate compelled by spring force, and a
collecting channel 42 which opens into the outlet channel 18.
Figure 5 shows an alternative embodiment of a module 10 according to the
invention, with the cover 60 which in this case has an optically transparent
radiation window. The cylindrical roller 30 rotatable in the tub of the module
housing has at least one revolving paddle wheel ring with paddle elements 38
which are filled with fluid supplied by the module in order to cause the roller 30
to rotate. In this specific embodiment, the wiping edge 40 has a recess 44 at
the position of the revolving paddle elements 38 in order to not wipe off fluid
circulating at this position, which does not form a defined fluid film. Figure 6
shows a cutaway view of the specific embodiment of Figure 5. An inlet
channel 14 and an overflow channel 16 are formed on the tub 12 in which the
cylindrical roller 30 rotates. In the illustrated specific embodiment, the gapforming
element 50 is preferably constructed as a single piece together with
the cover 60 which can be placed on the module housing, to form the capillary
gap 52. On the downward-rotating side of the roller 30, the wiping edge 40 is
designed with a recess 44 in the form of a wiping plate compelled against the
roller surface by spring force. The fluid wiped off the roller surface is collected
in the collecting channel 42 and discharged from the module via the outlet
channel 18.
Figures 7A and 7B are schematic sectional views of a specific embodiment of
the module 10 according to Figure 2. Figure 7B shows a plan view of the
18
same module as a whole with a section line A included. This designates the
sectional plane in the corresponding Figures 7A, 6 and 2.
Figures 8A and 8B are schematic sectional views of portions of the
embodiments shown in Figures 4 and 5 and/or 9 and 10A and 10B. Figure 8A
shows a first embodiment and arrangement of the wiping edge 40 on the roller
30. The wiper 40 is oriented counter to the direction of rotation of the roller 30.
Figure 8B shows an embodiment and arrangement of the wiping edge 40 as
an alternative. The wiper 40 designed as a wiper lip is oriented in the direction
of rotation of the roller 30. In the case of the embodiment according to Figure
8A, the fluid wiped off the roller 30 with the wiper 40 can flow past the wiper
into the outlet 18 designed as a groove. In the case of the embodiment
according to Figure 8B, the fluid wiped off by the roller 30 with the wiper lip 40
can flow into a groove 19 formed between the roller surface and the wiper lip
40 and can be actively or passively removed therefrom via the outlet 18
designed as a cannula.
Figure 9B shows a schematic cross-sectional view of a further embodiment of
the cassette. The sectional plane of the view is located in the region of the
wiper lip 40. The module housing 10 is closed by the housing cover 60. The
radiation window 62 is situated in the housing cover 60. The wiper lip 40 in
front of the roller 30 in a preferred embodiment according to the invention has
an arcuate form, such that fluid wiped off of the roller 30 primarily collects, due
to gravity, in the region of the outlet tube 18, which is preferably arranged
centrally. In the illustrated embodiment, the rotation of the roller is facilitated
via an axially-disposed coupling 92, comprising the shaft passing through the
housing 10, and the drive unit 90. In the illustrated embodiment, the
immersion depth of the overflow tubes 16 which project into the tub 12 can
preferably and optionally be adjustable, such that the fluid level in the tub 12
can be preset.
19
Figures 10A and 10B show schematic sectional views of the embodiment of
Figure 9. The sectional plane of Figure 10A is shown as line "A" in Figure 9.
The sectional plane of Figure 10B is shown as line "B" in Figure 9. The
reference numbers apply accordingly. The fluid inlet 14 is located on the
underside of the tub 12. The outlet 18 projects into the groove formed
between the roller 30 and the wiper lip 40. The height of the overflow tube 16
can be varied to determine the fluid level in the tub 12.
20
WE CLAIM:
1. A cassette for generating a continuous fluid film (22) from supplied biological
fluid (20), suitable for irradiating the generated fluid film (22) and continuously
inactivating pathogens in the biological fluid in an arrangement for continuous,
dose-controlled irradiation,
having a module housing (10) comprising:
a tub (12) for holding the fluid (20),
an inlet channel (14) for supplying the fluid (20) to the tub (12),
an overflow channel (16) for discharging excess fluid from the tub (12)
to fix a fluid level (24) in the tub (12),
a cylindrical roller (30) which dips into the tub (12) and fluid (20) and is
rotatable in the same,
a wiper lip (40) on the downward-rotating side (36) of the roller (30),
which is in intimate contact with the roller surface (32) to wipe off the
fluid film (22) formed upon rotation of the roller (30) on the rotating
roller surface (32), and
an outlet channel (18) for receiving and discharging fluid (26) wiped off
by the wiper lip (40),
and having a housing cover (60) for tightly closing the module housing (10),
wherein the housing cover (60) has a gas-tight and fluid-tight metal window
(62) which is permeable for beta radiation,
21
wherein the cassette is sterilizable and interchangeable for repeated use in
the arrangement for continuous, dose-controlled irradiation.
2. The cassette according to claim 1, wherein the module housing (10) further
comprises:
a gap-forming element (50) on the upward-rotating side (34) of the roller (30),
for forming and homogenizing the fluid film (22) on the roller surface (32),
wherein the gap-forming element (50) on the upward-rotating side (34) of the
roller (30) is spaced from the roller surface (32) in such a manner that it forms
a capillary gap (52), wherein the capillary gap (52) extends to above the fluid
level (24).
3. The cassette according to claim 2, wherein the gap-forming element (50) can
be positioned at a variable distance from the roller surface (32), or can be
exchanged, to regulate the thickness of the fluid film (22) formed thereon.
4. The cassette according to claim 1, which does not contain a gap-forming
element (50) characterized in either of claims 2 or 3.
5. The cassette according to any one of the preceding claims, wherein the wiper
lip (40) on the downward-rotating side (36) of the roller (30) is oriented
counter to the downward-rotating direction of the rotating roller.
6. The cassette according to any one of the claims 1 to 4, wherein the wiper lip
(40) on the downward-rotating side (36) of the roller (30) is oriented in the
downward-rotating direction of the rotating roller.
22
7. The cassette according to claim 6, wherein the outlet channel (18) is designed
as at least one tube projecting into the groove (58) formed between the wiper
lip (40) and the downward-rotating side (36) of the roller (30).
8. The cassette according to any one of the preceding claims, wherein the
module housing (10) has a coupling (92) to drive the rotation of the roller (30)
externally via a drive unit (90) which can be coupled and is arranged outside
the module housing (10).
9. The cassette according to claim 8, wherein the roller (30) has magnetic
elements for driving the rotation of the roller (30) externally via a mechanical
or electromagnetic drive unit (90) which is arranged outside the module
housing (10) and which can be magnetically coupled to the roller (30) via the
coupling (92).
10. An arrangement for the continuous, dose-controlled irradiation of biological
fluid (20) for the continuous inactivation of pathogens in the biological
fluid (20), comprising:
the exchangeable cassette according to any one of the preceding
claims, and
a source (80) for beta radiation,
wherein the cassette is directly coupled to the radiation source (80).
23
11. The arrangement according to claim 10, further comprising one or more
pumps (94, 96) for the continuous, active transport of the fluid (20, 26)
through the module housing (10).
12. The arrangement according to claim 10 or 11, further comprising a
mechanical or electromagnetic drive unit (90) for driving the rotation of the
roller (30) in the module (10).
13. A method for inactivating pathogens in a biological fluid (20), comprising the
steps of:
a) supplying the biological fluid (20) potentially containing active
pathogens to the cassette according to any one of the claims 1 to 9,
b) rotating the roller (30) in the module housing (10) of the cassette such
that a continuous fluid film (22) of the biological fluid (20), of
predeterminable thickness, is formed on the revolving roller surface
(32),
c) irradiating the fluid film (22) on the roller surface (32) with ionizing beta
radiation in a dose which causes inactivation of the pathogens of the
biological fluid (20),
d) collecting the irradiated fluid (26) with inactive pathogens from the roller
surface (32).
24
14. The use of the cassette according to any one of the claims 1 to 9 for the
continuous inactivation of pathogens in a biological fluid by means of ionizing
beta radiation.