U.S. patent application number 11/568882 was filed with the patent office on 2008-08-21 for apparatus for shell freezing a liquid content in a container.
This patent application is currently assigned to GLAXOSMITHKLINE. Invention is credited to Jacques Thilly, Pierre-Jacques Van Roy.
Application Number | 20080196437 11/568882 |
Document ID | / |
Family ID | 32526747 |
Filed Date | 2008-08-21 |
United States Patent
Application |
20080196437 |
Kind Code |
A1 |
Thilly; Jacques ; et
al. |
August 21, 2008 |
Apparatus for Shell Freezing a Liquid Content in a Container
Abstract
An apparatus for shell freezing a liquid content in a container,
comprising an endless loop conveyor having a conveying length
adapted to convey plural containers such as pharmaceutical vials,
incorporating plural rollers to spin the containers as they are
conveyed by the conveyor, and a return length, along at least part
of the return length the rollers are immersed in a cooling liquid
at a temperature below the freezing point of the liquid content of
the containers, and along the conveying length the rollers are
entirely above the surface of the cooling liquid. A preferred
cooling liquid is liquid nitrogen, the evaporating vapour of which
can be used to shield vials on the conveying length.
Inventors: |
Thilly; Jacques; (Les Isnes,
BE) ; Van Roy; Pierre-Jacques; (Brussels,
BE) |
Correspondence
Address: |
SMITHKLINE BEECHAM CORPORATION;CORPORATE INTELLECTUAL PROPERTY-US, UW2220
P. O. BOX 1539
KING OF PRUSSIA
PA
19406-0939
US
|
Assignee: |
GLAXOSMITHKLINE
RIXENSART
BE
|
Family ID: |
32526747 |
Appl. No.: |
11/568882 |
Filed: |
May 9, 2005 |
PCT Filed: |
May 9, 2005 |
PCT NO: |
PCT/EP05/05124 |
371 Date: |
January 15, 2008 |
Current U.S.
Class: |
62/374 |
Current CPC
Class: |
F25D 3/11 20130101; F26B
5/06 20130101 |
Class at
Publication: |
62/374 |
International
Class: |
F25D 3/11 20060101
F25D003/11 |
Foreign Application Data
Date |
Code |
Application Number |
May 10, 2004 |
GB |
0410382.6 |
Claims
1. An apparatus for shell freezing a liquid content in a container,
the apparatus comprising an endless loop conveyor having a
conveying length adapted to convey plural containers in a conveying
direction and incorporating plural rollers to spin the containers
as they are conveyed by the conveyor, and a return length,
characterised in that the return length of the conveyor is
configured such that along at least part of the return length at
least part of the rollers is immersed in a cooling liquid at a
temperature below the freezing point of the liquid content of the
containers, and the conveying length is configured such that along
the conveying length the rollers are entirely above the surface of
the cooling liquid.
2. Apparatus according to claim 1 characterised in that: the
conveyor is adapted to convey plural cylindrical vials containing a
liquid content which is an aqueous solution or suspension of a drug
compound or vaccine, in a horizontal conveying direction which is
perpendicular to their longitudinal cylindrical axis, the conveyor
incorporates plural rollers comprising part of the conveyor, which
are rotated about a rotation axis aligned horizontally across the
conveying direction as the conveyor conveys the vials, the rollers
adapted such that a conveyed vial rests on a pair of rollers which
are adjacent in the conveying direction such that the rotation of
the rollers imparts rotation to the vial resting thereon, the
rollers are cooled by their immersion in the cooling liquid such
that along the conveying length they are at a temperature below the
freezing point of the liquid content.
3. Apparatus according to claim 1 characterised in that the
conveyor is configured as an endless loop conveyor, having a
conveying length which is above the return length.
4. Apparatus according to claim 1 characterised in that the cooling
liquid is a liquefied gas.
5. Apparatus according to claim 4 characterised in that the cooling
liquid is liquid nitrogen.
6. Apparatus according to claim 4 characterised in that the
conveyor is configured that at least part of the rollers along the
conveying length are also exposed to cold gaseous nitrogen from
evaporating cooling liquid.
7. Apparatus according to claim 4 characterised in that a trough is
provided below the conveying length, the trough configured such
that the return length, or part at least of the rollers, dips into
the cooling liquid, and the trough is provided with upwardly
extending sidewalls of a height sufficient that cold vapour
evaporating from the cooling liquid forms a cloud around the upper
conveying length.
8. Apparatus according to claim 7 characterised in that the trough
is double walled with a void between the walls, and cold vapour
evaporating from the cooling liquid in the trough is able to flow
into this void between the walls.
9. Apparatus according to claim 1 characterised by a conveyor
constructed so that along the return length rollers are immersed
into the cooling liquid with their rotation axis vertical.
10. Apparatus according to claim 4 characterised by a downstream
end off-loading means to remove the containers, containing their
frozen content, and to deliver the containers to a receiving tray
wherein the receiving tray is kept cool at a temperature below the
freezing point of the liquid content so that the liquid content
remains frozen whilst the containers are waiting on the receiving
tray by means to expose the underside of the tray to cold vapour of
the evaporating cooling liquid.
Description
[0001] This invention relates to an apparatus for shell freezing
medicament products in vials in preparation for lyophilisation, and
to a method for shell freezing medicament products in vials in
preparation for lyophilisation which can be performed using this
apparatus.
[0002] Medicament products such as drugs and vaccines are often
lyophilised, i.e. an aqueous solution of the product is frozen,
then exposed in the frozen state to vacuum (herein the term
"vacuum" includes any sub atmospheric pressure sufficient to cause
evaporation of frozen liquid content) to evaporate off the water at
low temperature to leave a dry product for reconstitution. Often
this process is performed with the solution in a vial with an open
mouth or a stopper which allows water vapour to escape.
[0003] Numerous machines are known for performing lyophilisation or
various stages of the lyophilisation process. One such machine is
disclosed in WO-A-0812411, which uses shell freezing. EP-A-0048194
discloses the process of so called "shell freezing" in which the
vial is spun about its cylindrical axis to spread the liquid
content by centrifugal force around the vial sides in a thin layer
to create a large surface area before freezing. The large surface
area facilitates evaporation. In EP-A-0048194 vials in a horizontal
orientation are spun on a roller conveyor, and whilst on the
conveyor the vials are partly immersed in cold ethanol.
[0004] It is an object of this invention to provide an improved
apparatus, and process which can be performed by this apparatus,
for shell freezing, suitably as part of a lyophilisation process.
Other objects and advantages of the present invention will be
apparent from the following description.
[0005] According to this invention an apparatus for shell freezing
a liquid content in a container is provided, the apparatus
comprising an endless loop conveyor having a conveying length
adapted to convey plural containers in a conveying direction and
incorporating plural rollers to spin the containers as they are
conveyed by the conveyor, and a return length, characterised in
that the return length of the conveyor is configured such that
along at least part of the return length at least part of the
rollers is immersed in a cooling liquid at a temperature below the
freezing point of the liquid content of the containers, and the
conveying length is configured such that along the conveying length
the rollers are entirely above the surface of the cooling
liquid.
[0006] A preferred apparatus of this invention is adapted to convey
and spin conveyors being pharmaceutical vials containing a liquid
content which is an aqueous solution or suspension of a drug
compound or vaccine, to thereby spread the liquid content by
centrifugal force around the vial sides in a thin layer to create a
large surface area before freezing, and to shell freeze this liquid
content in preparation for lyophilisation, i.e. exposure in the
frozen state to vacuum to evaporate off the water at low
temperature to leave a dry product for reconstitution. Typically a
pharmaceutical vial has a cylindrical body and a cylindrical neck
region terminating at its mouth opening, with an internal step
between the body and the neck, so that when the vial is arranged
horizontally it can hold liquid content without it spilling out.
Suitable rotation speeds to spread the liquid content of a
container such as a vial into a thin layer around the interior of
the container by centrifugal force may be determined
experimentally.
[0007] This preferred form of the apparatus is preferably adapted
to convey plural vials of this generally cylindrical shape in a
conveying direction which is transverse, e.g. perpendicular, to
their longitudinal cylindrical axis. Preferably in this apparatus
this axis is horizontal i.e. the vials are conveyed horizontally
with their cylindrical axis aligned across the conveying
direction.
[0008] In this preferred form of the apparatus such vials are
preferably spun about their longitudinal cylindrical mouth-base
axis as a rotation axis, aligned horizontally across the conveying
direction to thereby form the liquid content into a layer around
the sides of the vial in a manner conventional in the art of shell
freezing.
[0009] Rollers are provided in the apparatus of this invention to
spin containers such as vials as they are conveyed by the conveyor
comprises plural rollers comprising part of the conveyor, which are
rotated about a rotation axis as the conveyor conveys the
containers, and which are in contact with the containers so as to
impart rotation to the containers. Preferably such rollers are
arranged with their axis of rotation aligned horizontally across
the conveying direction, preferably perpendicular to the conveying
direction. For example with the rollers arranged with their
rotation axes horizontal, a vial may rest on a roller, preferably
on a pair of rollers which are adjacent in the conveying direction,
with the rotation axis of the vial in a plane between the rotation
axes of the rollers, and the rotation of the rollers imparts
rotation to the vial resting thereon.
[0010] In the apparatus of the invention the containers and their
liquid content are cooled to below the freezing point of the liquid
content by contacting the containers, such as vials, with cold
rollers at a temperature below the freezing point of the liquid
content, and preferably having a high heat conductivity, e.g. cold
metal rollers. For example the rollers may be made of stainless
steel. As the cold rollers rotate in contact with the containers,
e.g. vials, to spin them, at the same time they withdraw heat from
the containers to cool them and their contents and to freeze the
liquid content.
[0011] Therefore a preferred construction of apparatus of this
invention comprises the features that:
[0012] the conveyor is adapted to convey plural cylindrical vials
containing a liquid content which is an aqueous solution or
suspension of a drug compound or vaccine, in a horizontal conveying
direction which is perpendicular to their longitudinal cylindrical
axis, the conveyor incorporates plural rollers comprising part of
the conveyor, which are rotated about a rotation axis aligned
horizontally across the conveying direction as the conveyor conveys
the vials, the rollers adapted such that a conveyed vial rests on a
pair of rollers which are adjacent in the conveying direction such
that the rotation of the rollers imparts rotation to the vial
resting thereon, the rollers are cooled by their immersion in the
cooling liquid such that along the conveying length they are at a
temperature below the freezing point of the liquid content, to
thereby withdraw heat from the containers to cool them and their
contents and to freeze the liquid content.
[0013] Some preferred features of construction of the apparatus of
this invention will now be described.
[0014] Construction of the Conveyor
[0015] Preferably the conveyor is configured as an endless loop
conveyor, having a conveying length which conveys the containers in
the conveying direction, and a return length along which the
conveyor moves in the opposite return direction to the conveying
direction.
[0016] Preferably the conveyor is configured so that the conveying
length is above the return length, and the return length may also
move horizontally below the conveying length. Such a configuration
conveniently enables a construction in which along the return
length the rollers are immersed in the cooling liquid, and the
conveying length is entirely above the surface of the cooling
liquid.
[0017] Such a conveyor may comprise an endless chain of linked
mountings for plural rollers upon which the rollers are rotatably
mounted. For example a roller may be provided with a spindle
extending in its rotation axis direction, and a mounting may
comprise a bearing upon which the spindles are rotatably mounted,
aligned transverse to the conveying direction. The spindle or
roller may be configured so that as it moves in the conveying
direction it engages with a track alongside the conveyor, so that
the engagement causes the spindle and hence the roller to rotate.
For example the spindle may be provided with a toothed pinion to
engage a toothed rack alongside the conveyor. Alternatively the
apparatus may be provided with means to drive the rollers to cause
them to spin, for example the spindle may be provided with a
toothed pinion, and a rack or a driven screw may be arranged
alongside the conveyor to engage and drive the pinion. Other ways
to cause such rollers to rotate will be apparent to those skilled
in the art. As mentioned above the rotation speed of such rollers
may be determined experimentally.
[0018] The conveyor may be supported at upstream and downstream
positions by guide wheels in a generally conventional manner, and
may be driven in a generally conventional manner so that the upper
conveying length moves in the conveying direction by rotating one
or more such guide wheels with a motor, typically an electric
motor. Such guide wheels are suitably rotatably mounted with their
rotation axis horizontal.
[0019] Cooling the Rollers.
[0020] A suitable cooling liquid is any substance which is liquid
at a temperature below the freezing point of the liquid content of
the containers, preferably the liquid being non-inflammable,
non-toxic and environmentally safe. Suitably the cooling liquid is
a liquid gas. A preferred cooling liquid is liquid nitrogen which
is typically at a temperature of -196.degree. C. Immersion in
liquid nitrogen can cool a metal roller to ca. -196.degree. C.
[0021] For example over at least part of the return length the
conveyor, or part at least of the rollers, may dip into the cooling
liquid such as liquid nitrogen. If the cooling liquid is a
liquefied gas such as liquid nitrogen, at least part of the
rollers, e.g. along the conveying length, may also exposed to cold
vapour from evaporating cooling liquid. For example a trough may be
provided below the conveying length, configured such that the
return length, or part at least of the rollers, may dip into
cooling liquid such as liquid nitrogen contained therein. Such a
trough may be elongate and may extend the entire length of the
conveyor. Such a trough may also be configured relative to the
conveying length of the conveyor so that cold vapour such as
gaseous nitrogen evaporating from liquid nitrogen in the trough
forms an atmosphere around the upper conveying length of the
conveyor. This configuration allows the vapour, e.g. gaseous
nitrogen to shield the conveying length of the conveyor from
environmental contamination, which is important if the vials
contain pharmaceutical products which are to be maintained sterile.
In particular such a shield of cold gaseous vapour can shield the
containers from moist ambient atmosphere, and thereby reduce the
likelihood of frost formation on and within the containers. This
may be achieved by providing the trough with upwardly extending
sidewalls of a height sufficient that cold vapour evaporating from
the cooling liquid forms a cloud around the upper conveying length.
To assist in maintaining sterility a flow of purified air, e.g.
Class A or higher may be directed around the conveying length of
the conveyor, suitably downwardly, in a well known manner.
[0022] Such a trough for containing the cooling liquid, especially
a liquefied gas such as liquid nitrogen needs to be insulated from
ambient temperature. Numerous methods of insulation are known. In a
preferred construction the trough may be double walled with a void
between the walls, and cold vapour evaporating from the cooling
liquid in the trough may be allowed to flow into this void between
the walls, to both provide insulation and provide a means of
removal of the vapour. For example such a double walled arrangement
may comprise an inner trough containing liquid nitrogen, and an
outer trough, with the void between the inner and outer trough, so
that nitrogen gas can spill over from the inner trough and descend
between the walls of the inner and outer troughs, and an outlet
means, e.g., an exhaust manifold may be provided in the outer
trough to remove the nitrogen gas.
[0023] In a preferred embodiment the conveyor is constructed so
that along the return length rollers are immersed into the cooling
liquid with their rotation axis vertical. This orientation of the
rollers can facilitate the use of a relatively deep but narrow
trough of cooling liquid, which can help to reduce evaporation loss
of the cooling liquid.
[0024] The construction described above provides an advantage over
for example EP-A-0048194 that the vials do not contact the cooling
liquid, and therefore the risk of contamination of the interior of
the vial is reduced. By the use of liquid nitrogen as a cooling
liquid the rollers can be made so cold that heat transfer from the
vial to the rollers is rapid without any need for the vial to
contact the cooling liquid. Further the use of a liquefied gas like
liquid nitrogen as cooling liquid enables the shielding of the
cooled vials from environmental moisture and other contamination by
the cloud of cold vapour.
[0025] On-Loading and Off-Loading.
[0026] The conveyor is preferably provided at an upstream end with
on-loading means to load containers such as vials onto the
conveyor, and at a downstream end with off-loading means to remove
the containers, containing their frozen content.
[0027] It is preferred that the on-loading means is configured to
load containers such as vials onto the conveyor in a vertical
orientation, i.e. with their mouth uppermost. Therefore in a
preferred construction of the apparatus the conveyor has an
on-loading position at which the plural rollers have their rotation
axis aligned vertically across the conveying direction, and means
to present plural vials to the conveyor, adapted such that a vial
presented to the conveyor is received between a pair of rollers
which are adjacent in the conveying direction. As the rollers move
downstream in the conveying direction from this on-loading position
the conveyor may be configured so that the rollers move, e.g.
rotate about a rotation axis parallel to the conveying direction
and perpendicular to their conveying length, so that their rotation
axis becomes aligned horizontally across the conveying direction as
described above. This may be achieved by mounting the rollers on
the conveyor such that the rollers can pivot about an axis parallel
to the conveying direction so that their rotation axis can pivot
between the vertical and horizontal alignments.
[0028] Whilst the rollers have their rotation axis other than
aligned horizontally across the conveying direction the rollers
need not rotate about their rotation axis, so that the containers
e.g. vials in contact with them do not consequently spin.
Preferably the rollers move in the conveying direction at a
sufficient speed that all or the bulk of the content of the
containers is still liquid by the time the rollers adopt their
horizontal orientation.
[0029] Whilst the rollers have their rotation axis other than
aligned horizontally across the conveying direction it may be
necessary to support containers such as vials in contact with the
rollers until gravity holds the containers down in contact with the
rollers when the rollers assume their horizontal alignment. The
apparatus may be provided with a suitable supporting means, such as
a rail adjacent to the conveyor.
[0030] Suitably containers such as vials may be loaded onto the
conveyor at this loading position by a conventional means,
preferably for example a rotating star wheel having notches in its
perimeter to receive containers such as vials in their vertical
orientation from for example a conventional loading tray, and to
rotate them into a position where they are adjacent to the conveyor
and received by the conveyor. Preferably two such star wheels may
be provided in series to receive vials from a loading tray and to
present them to the conveyor, i.e. comprising a first star wheel
which receives containers from a loading tray, and which presents
the containers to a second star wheel which in turn presents the
containers to the conveyor. In such an arrangement the second star
wheel may be mounted so as to be capable of some limited movement
relative to the conveyor so as to accommodate to any stresses
experienced by the containers as they are received by the conveyor,
so as to avoid breakage of fragile glass vials.
[0031] It is preferred that the off-loading means is also
configured to off-load containers such as vials from the conveyor
in a vertical orientation. Therefore in a preferred construction of
the apparatus the conveyor has an off-loading position at which the
plural rollers have their rotation axis aligned vertically across
the conveying direction, and means to receive plural vials from the
conveyor, adapted such that a vial is received from the conveyor
from a pair of rollers which are adjacent in the conveying
direction. As the rollers move upstream in the conveying direction
toward this off-loading position the conveyor may be configured so
that the rollers move, e.g. rotate about a rotation axis parallel
to the conveying direction, so that their rotation axis becomes
aligned vertically across the conveying direction as described
above. As with the on-loading position whilst the rollers have
their rotation axis other than aligned horizontally across the
conveying direction the rollers need not rotate about their
rotation axis, so that the containers e.g. vials in contact with
them do not consequently spin. Similarly as at the on-loading
position whilst the rollers have their rotation axis other than
aligned horizontally across the conveying direction it may be
necessary to support containers such as vials in contact with the
rollers, and the apparatus may be provided with a suitable
supporting means, such as a rail adjacent to the conveyor.
[0032] Suitably containers such as vials may be loaded off the
conveyor at this off-loading position by a conventional means,
preferably for example a rotating receiving star wheel having
notches in its perimeter to receive containers such as vials in
their vertical orientation from the conveyor and to deliver them to
a conventional receiving tray. Preferably a further star wheel is
provided on the opposite side of the conveyor from this receiving
star wheel, and having radially extending fingers which penetrate
between the rollers to push containers such as vials away from the
conveyor and into the notches of the receiving star wheel.
[0033] To assist continuous operation of the apparatus the
apparatus may be provided with plural receiving trays so that when
one is full it may be replaced by another. Preferably the receiving
tray is kept cool at a temperature below the freezing point of the
liquid content so that the liquid content remains frozen whilst the
containers are waiting on the receiving tray. Heat exchanger means
such as cooling tubes may be used to achieve this. When the
apparatus incorporates the above-mentioned trough of a cooling
liquid which is a liquid gas such as liquid nitrogen, a suitable
construction of cooling means comprises a tray upon which
containers such as vials may be received, and means to expose the
underside of the tray to cold vapour of the evaporating cooling
liquid. For example a plate may be situated underneath but in close
proximity to this tray so there is a narrow space between the tray
and the plate, and liquid nitrogen may be introduced into this
space to thereby cool the tray and maintain the tray at a
temperature below the freezing point of the liquid content.
[0034] The apparatus of the invention may comprise part of an
overall apparatus for lyophilisation of medicament in containers
such as vials, wherein the apparatus as described above is provided
in combination with a means to apply vacuum to cause evaporation of
frozen liquid content. Conventional known vacuum chambers may be
used.
[0035] The invention also provides a process for shell freezing a
liquid content in a container is provided, comprising the use of an
apparatus as described above. Suitably in this process plural
containers are conveyed on a conveyor adapted to convey plural
containers in a conveying direction, the apparatus incorporating
means to spin the containers as they are conveyed by the conveyor,
and the apparatus incorporating means to cool the containers and
their liquid content to below the freezing point of the liquid
content. Preferably the process is applied to vials as described
above, and preferred features of such an apparatus for use in the
process of the invention are as described above.
[0036] Preferably the process is one in which plural cylindrical
vials containing a liquid content which is an aqueous solution or
suspension of a drug compound or vaccine are conveyed by a conveyor
adapted to convey such vials in a conveying direction which is
transverse, e.g. perpendicular, to their longitudinal cylindrical
axis, and is horizontal,
[0037] the conveyor incorporating plural rollers comprising part of
the conveyor, which are rotated about a rotation axis aligned
horizontally across the conveying direction as the conveyor conveys
the vials, the rollers adapted such that a conveyed vial rests on a
pair of rollers which are adjacent in the conveying direction such
that the rotation of the rollers imparts rotation to the vial
resting thereon,
[0038] the rollers being at a temperature below the freezing point
of the liquid content, to thereby withdraw heat from the containers
to cool them and their contents and to freeze the liquid
content.
[0039] The invention will now be described by way of example only
with reference to the accompanying drawings in which:
[0040] FIG. 1 shows the overall schematic configuration of an
apparatus of this invention.
[0041] FIG. 2 shows the overall schematic configuration of an
apparatus of this invention with vials loaded on the conveyor.
[0042] FIG. 3 shows a cross section across the conveyor of FIG.
1
[0043] FIG. 4 shows how vials are loaded onto and transported on
the conveyor of FIGS. 1 and 2.
[0044] FIG. 5 shows a schematic plan view of the conveyor of FIGS.
1 and 2.
[0045] FIG. 6 shows the cooling of the rollers of the conveyor.
[0046] FIG. 7 shows in more detail the mounting of the rollers.
[0047] FIG. 8 shows in more detail the overall construction of the
conveyor.
[0048] FIG. 9 shows a rack and pinion system to spin the
rollers
[0049] FIG. 10 shows a more detailed plan view.
[0050] Parts shown in FIGS. 1-10 are identified below.
[0051] 100 conveyor 100 (generally)
[0052] 101 upper conveying length
[0053] 101A upstream end
[0054] 101B downstream end
[0055] 102 lower return length
[0056] 103, 104 guide wheels
[0057] 105 mountings
[0058] 106, 1061, 1062, 1063, 1064 plural rollers
[0059] 107 spindle
[0060] 108 toothed pinion gear
[0061] 109 rack
[0062] 1010 vial
[0063] 1011 liquid content
[0064] 1010A vial body
[0065] 1010B vial neck
[0066] 1010C vial mouth opening
[0067] 1010D internal step
[0068] 1011 liquid content
[0069] 1012 guide rail
[0070] 1013 guide rail
[0071] 200 trough
[0072] 201 liquid nitrogen
[0073] 202 side walls of trough
[0074] 203 gaseous nitrogen
[0075] 204 flow of purified air
[0076] 205 outer wall
[0077] 206 void
[0078] 207 exhaust manifold
[0079] 300 on-loading system
[0080] 301 loading table
[0081] 302 first star wheel
[0082] 303 second star wheel
[0083] 400 off-loading system
[0084] 401 receiving star wheel
[0085] 402 further star wheel
[0086] 403 receiving tray
[0087] 404 receiving tray
[0088] 405 plate
[0089] 1015 side plates
[0090] 1016 drive wheel
[0091] 1017 pivot axle
[0092] 1018-1022 motors
[0093] 1023, 1024 support wheels
[0094] Referring to FIGS. 1, 2 and 3, this shows an overall
perspective schematic view of the architecture of an apparatus of
this invention. FIGS. 1 and 2 show a longitudinal section, cut in
the conveying direction shown by the arrow, through the conveyor.
FIG. 3 shows a cross section through the conveyor cut across the
conveying direction at line III-III of FIG. 1. FIGS. 4 and 6 show
part sections cut across the conveying length at points IV-IV and
VI-VI respectively.
[0095] The apparatus comprises a conveyor 100 (generally) which is
an endless loop, having an upper conveying length 101 which moves
in the conveying direction shown by the arrow and a lower return
length 102 which returns in the opposite direction and is
positioned below the conveying length 101. At a respective upstream
end 101A and a downstream end 101B are guide wheels 103, 104
rotatably mounted with their rotation axles horizontal, and which
are driven in a generally conventional manner by electric motors
(not shown). Referring to FIG. 4 the conveyor 100 comprises a
series of linked mountings 105 for plural rollers 106 which are
rotatably mounted on the conveyor 100. Rollers 106 are generally
cylindrical and are arranged with their axis of rotation, i.e. the
longitudinal axis of their cylindrical shape, aligned horizontally
perpendicularly across the conveying direction. Each roller 106 is
integrally made with a spindle 107 extending in its rotation axis
direction, and each mounting 105 comprises a bearing through which
the spindles are rotatably threaded. These bearings are
lubricant-free but have considerable slack to reduce the
possibility of jamming. At an end of the spindle 107 opposite the
roller 106 is a toothed pinion gear 108 which engages a rack 109
which extends alongside the conveying length 101. Engagement of
this rack 109 with pinion 108 causes pinion 108, spindle 107 and
roller 106 to rotate.
[0096] FIGS. 1, 2 and 4 show two rollers 1061 and 1062 which are
adjacent in the conveying direction, looking in the direction along
the axis of rotation direction of the rollers 1061, 1062 which is
horizontal and perpendicular to the conveying direction. With the
rollers 1061, 1062 arranged in this way, as seen in FIGS. 2 and 4A,
a vial 1010, having a cylindrical body and viewed in FIG. 2 looking
in its cylindrical axis direction rests on the pair of rollers
1061, 1062 with its axis of rotation in a plane between the
rotation axes of the two rollers 1061, 1062. FIG. 2A shows more
clearly how the rotation of the rollers 1061, 1062 in the direction
as shown by arrows imparts corresponding rotation to the vial 1010
resting thereon, as the rollers 1061, 1062 and the vial 1010 are
conveyed in the conveying direction. This causes liquid content
1011 in the vial 1010 to form a thin layer around the sides of the
vial 1010. FIG. 4A shows the vial 1010 in a longitudinal section
and shows the cylindrical body 1010A and a cylindrical neck region
1010B terminating at a mouth opening 1010C, with an internal step
1010D between the body 1010A and the neck 1010B, so that when the
vial 1010 is arranged horizontally it can hold liquid content 1011
without it spilling out.
[0097] Rollers 106 are made of stainless steel and are at a
temperature below the freezing point of the liquid content 1010.
This causes the rollers 106, when they are in contact with the vial
1010 as shown in FIG. 2, to withdraw heat from the vial 1010 and
its liquid content 1010 to freeze the liquid content 1010. The
conveying length 101 of the conveyor and its speed in the conveying
direction are such that the vial 1010 remains in contact with the
cold rollers 106 for sufficient time that the liquid content 1010
is frozen by the time the vial reaches the downstream end
1010B.
[0098] The rollers 106 are cooled to the temperature below the
freezing point of the liquid content as follows. The conveyor 101
(shown schematically in FIG. 3) is mounted within a trough 200,
which is elongate in the conveying direction. Trough 200 contains
liquid nitrogen 201, and is configured such that along the return
length 102 of the conveyor the rollers 106 dip into the liquid
nitrogen 201. The trough extends the entire length of the conveyor
100. Conveyor 100 and trough 200 are configured so that the
conveying length 101 of the conveyor 100 is above the surface of
the liquid nitrogen 201, and the trough has upwardly extending
sidewalls 202 of a height sufficient that cold nitrogen gas
evaporating from the liquid nitrogen 201 forms a cloud 203 around
the upper conveying length 101 of the conveyor 100. This cloud of
gaseous nitrogen 203 shields the conveying length 101 of the
conveyor from environmental contamination, particularly from moist
ambient atmosphere, thereby reducing the likelihood of frost
formation on and within the vials 1010. To assist in maintaining
sterility a flow of purified air 204 of Class A or higher is
directed downwardly around the conveying length 101 of the conveyor
100 in a well known manner.
[0099] The trough 200 is double walled, having an outer wall 205
with a void 206 between the walls 204,205, and cold nitrogen gas
203 evaporating from the liquid nitrogen 201 in the trough 200
flows over the inner wall and into this void 206 between the walls
202,204, and an exhaust manifold 207 is provided to remove the
gaseous nitrogen. This double walled arrangement helps to insulate
the trough 200. Trough 200 is supported by a conventional stand
(not shown).
[0100] FIGS. 1, 4 and 5 show how vials 1010 are loaded onto the
conveyor 100. FIG. 4B shows a sectional view through the conveyor
100 at the line IV-IV of FIG. 1 looking opposite to the conveying
direction. As seen in FIG. 4B the mountings 105 are mounted
pivotally on the conveyor 100. In the on-loading position shown in
FIG. 4B the mountings are oriented, e.g. by use of guide cams or
ramp parts (not shown) positioned adjacent to the conveyor 100, so
that the rollers 106 have their cylindrical axis vertical, shown as
roller 1063. With the rollers 106 in this orientation, vials 1010
are presented to the rollers so that a vial 1010 presented to the
conveyor is received between a pair of rollers 1063, 1064 which are
adjacent in the conveying direction, with the vial 1010 in a
vertical configuration mouth uppermost as shown in FIG. 4B.
[0101] The rack 109 is located so that whilst the rollers 106 are
in this vertical orientation the rack 109 is not engaged with
pinion 108 so that the rollers do not rotate about their rotation
axis, and the vials 1010 in contact with them do not consequently
spin. Whilst in this vertical orientation the vials 1010 are
supported by a guide rail 1012 adjacent to the conveyor 100.
[0102] As the rollers 106 move downstream in the conveying
direction from this on-loading position the mountings 105 pivot so
that the rollers 106 move about a rotation axis parallel to the
conveying direction so that their rotation axis becomes aligned
horizontally across the conveying direction as seen in FIG. 4A,
i.e. along length 101C of the conveying length 1010 the vials swing
about an axis in the plane of the drawing until they are aligned
horizontally with the rollers 106 as in FIG. 4A, and identified as
rollers 1061,1062. This too may be achieved by suitably positioned
cam or ramp surfaces (not shown).
[0103] When the vials 1010 are in their horizontal orientation 1010
as seen in FIG. 4A in the region 101A of the conveying length of
the conveyor 100, the rack 109 is engaged with pinion 108 so that
the rollers rotate about their rotation axis, and the horizontal
vials 1010B in contact with them consequently spin.
[0104] FIG. 2 shows the liquid content 1011 of the vials 1010 in
three states: 1011A in a liquid state with the vial 1010 vertical,
1011B with the vial horizontal and spinning, with the liquid
content 1011B converting from a liquid to a frozen state as the
vial 1010 moves in the conveying direction, and 1011C in a frozen
state with the vial 1010 again vertical.
[0105] The plan view of FIG. 5 shows in schematic detail the
on-loading system 300 and off-loading system 400 of the conveyor
100. Vials 1010 are supplied in a vertical orientation onto a
conventional loading table 301, on which they are directed toward
the conveyor 100. The vials 1010 are loaded onto the conveyor 100
at this loading position by a first rotating notched star wheel 302
which receives vials 1010 in their vertical orientation from for
the loading table 301. First star wheel 302 transfers the vials
1010 to a second rotating notched star wheel 303 which on rotation
moves vials 1010 into a position where they are adjacent to the
vertically oriented rollers 106 of the conveyor and received by
these as described above. The star wheel 303 is synchronized with
the guide wheel 103 so that the vials in the notches of the star
wheel 303 are properly aligned with the rollers 106.
[0106] The plan view of FIG. 5 also shows the off-loading system
400 of the conveyor 100. Vials 1010 approach the downstream end
101B of the conveyor 100 in their horizontal orientation i.e. as
seen in FIG. 4B. As vials 1010 near the end 101B the mountings 105
pivot, e.g. under the action of cam or ramp surfaces (not shown) so
that the vials 1010 rotate into the vertical orientation 1010A as
shown in FIG. 4B but with their content 1011 in a thin frozen layer
around the walls of the vial 1010. Another guide rail 1013,
analogous to that 1012 is located at the downstream end 101B to
support the vials 1010 whist in their vertical orientation. At end
101B the vials 1010 are received by a rotating notched star wheel
401 which can receive vials 1010 in their vertical orientation from
the conveyor 101 in its notches. A further star wheel 402 is
rotatably mounted on the opposite side of the conveyor 101 from
star wheel 401 and has radially extending fingers which extend
between the rollers 106 in their vertical orientation to push vials
1010 into the notches of star wheel 401. As star wheel 401 rotates
it moves the vials 1010 into a position where they are in a
position to be delivered to an adjacent receiving tray 403. A guide
rail 1014 is provided to guide vials 1010 off the star wheel 401.
In a preferred form there are two receiving trays 403 and 404, so
that when one of these trays 403,404 is full it may be removed and
replaced by the other further vials 1010 may be diverted to the
other to thereby maintain continuous operation. The downward flow
of sterile air 204 is maintained over the entire area of the
conveyor 100 and the on and off loading areas 300, 400.
[0107] The receiving trays 403,404 are kept cool at a temperature
below the freezing point of the liquid content so that the liquid
content remains frozen whilst the containers are waiting on the
receiving tray 403. This is achieved by means of a plate 405
positioned beneath trays 403,404 with a narrow space (not shown)
vertically between the trays 403,404 and into which liquid nitrogen
is introduced. Alternatively there may be heat exchanger pipes
arranged beneath the trays 403,404. Additionally or alternatively
the trough 200 of liquid nitrogen may be configured so that cold
gaseous nitrogen evaporating from the trough 200 is directed into
contact with the underside of the tray 403, to cool and maintain
the tray at a temperature below the freezing point of the liquid
content 1011.
[0108] Thereafter the vials 1010 with their shell frozen content
may be taken away by an operator to a conventional vacuum chamber
(not shown) where they are exposed to a vacuum to evaporate the
frozen content in a conventional lyophilisation system.
[0109] FIG. 6 shows a part section cut across the return length 102
at points VI-VI. Here it is seen how the rollers 106 have pivoted
into a vertical configuration analogous to FIG. 4B but inverted. In
this configuration the rollers 106 are immersed in the liquid
nitrogen 201 in trough 200, and thereby cooled. As will be apparent
from FIG. 1 and 2, as the rollers 106 in their vertical orientation
at the downstream end 101B travel around the guide wheel 104 they
roll around the guide wheel 104 and enter the liquid nitrogen 201
in trough 200.
[0110] FIG. 7 shows a perspective view of the on-loading end 101A
of the conveyor 100, parts corresponding to FIGS. 1-6 being
numbered correspondingly. For clarity only some of the rollers 106
and their mountings 105 are shown. It is seen how guide wheel 103
is mounted between side plates 1015, and the conveyor 100 is driven
by drive wheel 1016. It can clearly be seen how rollers 106 swing
from a vertical orientation 1063 to a horizontal orientation
1061.
[0111] FIG. 8 shows an overall perspective view of the conveyor
100. It is seen how over most of the central part of the conveying
length 101 the rollers 106 are oriented horizontally. It can
clearly be seen how rollers 106 swing from a vertical orientation
1063 to a horizontal orientation 1061. Rollers 106 are also clearly
seen in their inverted orientation as shown in FIG. 6 on the return
length 102 of the conveyor 100.
[0112] FIG. 9 shows in a perspective view the mountings 105 of the
rollers 106, with spindles 107 and pinions 108. The mountings 105
are made of PTFE, being a low friction material, and they are
pivotally mounted at pivot axle 1018, about which the rollers 106
can pivot between vertical (see FIG. 4B) and horizontal (see FIG.
4A) orientations. In the construction shown in FIG. 10 the pinions
1020 are driven by means of the toothed rack 109 arranged adjacent
to the conveyor 100, with which pinions 108 engage as the pinions
108 move in the conveying direction.
[0113] FIG. 10 shows a more detailed plan view similar to FIG. 5.
In FIG. 10 two motors 1018, 1019 are shown used for driving the
conveyor 100 and the star wheels 302, 303, 401, 402 by appropriate
gearing. Two sets of star wheels 302, 303 and 401, 402 are
respectively used at the on- and off-loading positions 300, 400.
Motors 1020, 1021, and 1022 vibrate the on-loading and receiving
trays 301, 403, 404. Support wheels 103 (also seen in FIG. 8) are
rotatably mounted at points along the conveyor 100.
[0114] In the apparatus shown it is found that liquid content 1011
in vials 1010 freezes solid in 60-75 seconds, with an on- and
off-loading frequency of ca. 1 vial 1010 per second.
* * * * *