Note: Descriptions are shown in the official language in which they were submitted.
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FREEZE-DRYING PROCESS AND APPARATUS
The present invention relates to a novel freeze-drying
(lyophilisation) process. This process is particularly
advantageous for freeze-drying pharmaceutical products. The
invention also includes the lyophilised products produced by
the process.
Freeze-drying or lyophilisation, is used generally to
increase the stability and hence storage life of materials.
As such it is particularly useful where a material is known
to be unstable or less stable in aqueous solution, as is
often the case with pharmaceutical materials.
In its simplest form freeze-drying consists of freezing
the aqueous material in a vial and then subjecting the
material to a vacuum and drying.
The conventional method of freeze-drying is to load
magazines full of vials onto chilled shelves in a sealed
freeze-drying chamber. The shelf temperature is then reduced
to freeze the product. At the end of the freezing period,
the aqueous material is frozen as a plug at the bottom of the
vial. The pressure in the chamber is then reduced and
simultaneously the shelves are heated thereby causing the
frozen water to sublime leaving a freeze-dried plug in the
bottom of the vial (Figure 4A). The whole lyophilisation
cycle normally can take 20 to 60 hours, depending on the
product and size of vial.
The disadvantages of this conventional method are as
follows:
a) the time taken to freeze-dry a product;
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b) the freeze-drying process is batch rather than
continuous;
c) except in very sophisticated automated installations,
there must necessarily be human operators to load the
trays of vials into the freeze-drying chamber, which
leaves the product open to contamination;
d) the process is energy intensive when the power
consumption of the clean room is taken into account;
e) the freeze-drying apparatus is very expensive and takes
up a large area of space, which is necessarily very
expensive because it must be maintained_clean or sterile
to a high standard; and
f) the vials are subjected to a number of discontinuous
handling operations such as high-speed in line filling,
transfer to holding tables, and transfer to and from
trays.
These operations risk vial damage or contamination,
create particles in the clean area, and require operator
supervision.
European patent EP-A-0048194 discloses a method of
"shell-freezing" material such that the resulting lyophilised
product forms a relatively thin coat or "shell" in the vial.
In this method, the aqueous material is placed a vial which
is then rotated slowly on its side in a freezing bath. The
shell-frozen product is then loaded into a conventional
lyophilisation chamber and dried over a six hour cycle (page
7).
However, although this method allegedly results in a =
"shell frozen" material, distribution can be non-uniform.
Also relatively long lyophilisation times may still be
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required. The above rolling method also suffers from other
disadvantages, including:
a) it limits the amount of liquid that can be placed in the
vial since above a certain limit some liquid would pour
out;
b) there is a risk of spillage in any event during the
rolling process;
c) rolling in a liquid coolant may result in contamination
by the coolant;
d) such a rolling process may result in a less uniform
shell (giving a longer drying time); and
e) a rolling process may result in a longer freezing time
(compared to the present invention).
U.S. Patent No. 3952541 describes an apparatus for a
freezing aqueous solution or suspension which comprises a
refrigerated tank which has at least one plate, which carries
the materials to be frozen, mounted on a shaft to rotate at
about 10 to 20 revolutions per minute around the base of the
tank. The tank is adjustable to tilt at (for example) a 450
angle, and a fan mounted inside the roof of the tank blows
cold air around the refrigerated tank. Once the product is
frozen, it appears that the vials would have to be
transferred to a separate drying chamber, for approximately
llM hours. The whole lyophilisation cycle takes 12 hours and
the product obtained is of an internally concave paraboloid
form.
The disadvantages of this process is that the time is
still long (12 hours), the process must be operated batchwise
and it is not capable of handling a large throughput of
vials. Furthermore, when transferring the frozen open
product from the refrigerated tank to a drying chamber, there
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must apparently be human operator contact and the product must be
maintained in a frozen stage until transferred.
British patent no. 784784 discloses a freeze-drying process
in which vessels containing liquid material are subjected to a
centrifugal force at a low vacuum. The low vacuum causes the
water to be released and the effect of centrifuging helps suppress
the formation of bubbles and froth as the liquid boils under
reduced pressure. Both this step and the drying step involve
subjecting the vessel to traumatic operations which can cause
particles in the clean area of the process, and disrupt the final
product.
DE-C-967120 relates to a continuous freeze-drying process.
Each vial is carried in a guide capsule where it is rotated
rapidly under vacuum conditions to freeze the substance in the
vial. Thereafter the guide capsule releases the vial into a
drying chamber and returns to collect another vial. The drying
chamber is composed of a long winding heated conduit in which the
vials are rolled down under gravity in abutting fashion.
Disadvantages of this process, however, is firstly that the vials
undergo a very traumatic journey in the drying chamber and will
bang together generating contaminating particles and disrupting
the frozen product. Secondly, the throughput of the process is
limited in that only one vial at a time can enter the drying
chamber when another vial exits. Thirdly as the guide capsules
are continually recycled, they can result in a source of
contamination.
In US-A-3203108, liquid in a vial is frozen into the form of
a shell by rotating the vial at high speed. However the heater
for drying the product is attached to the spinner. Therefore both
the freezing and drying operations take place within the same
chamber which limits the throughput of the process.
AMENDED SHEET
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In FR-A-1259207 a bottle containing a liquid is rotated
quickly under vacuum, and the liquid frozen as a shell. There is
no mention of how or where the product is subsequently dried.
In_US-A-3195547 a bottle containing liquid_is rotated quickly
in a bath of freezing liquid thereby freezing the liquid in the
bottle as a shell. There is no mention of how or where the
product is subsequently dried.
In US-A-244512 a series of containers with a shell of frozen
material are received into drying cabinets which emit infra-red
rays to dry the shell of frozen material. The drying cabinets are
housed in a dryer and the process is batch process in that the
whole dryer must be loaded and unloaded after drying. This limits
the throughput of the dryer.
Further freeze-drying processes are described in British
patent nos. 1199285 and 1370683, and US patent no. 3769717.
It is an object of the present invention to obviate or
mitigate at least some of the aforesaid disadvantages.
It is a further object of the invention to provide a
lyophilisation process and apparatus with shorter cycle times than
the aforementioned prior process and apparatus.
It is yet a further object of the invention to provide
lyophilisation apparatus which can be housed in a smaller space
than the conventional freeze-drying apparatus and preferably also
negates the need for human operator contact at critical parts of
the process so as to minimise human contamination of the product.
According to a first aspect of the present invention there is
provided a process for carrying out freeze-drying which includes a
freezing step of rotating about the longitudinal axis the vessel
containing the liquid material to be freeze-dried at a speed not
less than that require to maintain the liquid in a shell of
substantially uniform thickness against the inner walls of the
vessel by the action
AIAENDED SHEET
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of centrifugal force while subjecting the liquid material
to freezing conditions sufficient to freeze the liquid
material into the form of said shell.
Preferably the vials are rotated about their axes
5 while held in the substantially horizontal position. This
aids the achievement of an even distribution of liquid
around the interior of the vessel.
Thus, in one embodiment of the process aspect of the
invention, there is provided a continuous or semi-
continuous process for carrying out freeze drying of liquid
material in one or more vessels in which the vessels are
loaded at one end of the process and moved automatically
through the various stages up to and including being
subjected to vacuum drying conditions, characterised in
that the process comprises the steps of:
a) loading racks or magazines with vessels to be
filled, such that said vessels are held apart in individual
locations in the racks or magazines;
b) washing the vessels and racks or magazines, said
vessels being in the inverted position so that washing
water will drain therefrom through an open neck of said one
or more vessels;
c) sterilising the vessels and the racks or
magazines;
d) filling the vessels through the necks thereof
with the liquid material to be frozen;
e) rotating each of the vessels containing the
liquid material to be frozen about its longitudinal axis,
whilst held in a substantially horizontal position, at a
speed not less than that required to maintain the liquid in
a shell of substantially uniform thickness against the
inner walls of the vessel by the action of centrifugal
force while subjecting the liquid to freezing conditions
sufficient to freeze the material into the form of said
shell, wherein vessels are removed from the racks or
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magazines and are rotated remote from the racks or
magazines and after a preset time to complete freezing, the
rotation is stopped and the vessels are returned to the
racks or magazines; and
f) moving the racks or magazines with unsealed
vessels containing the frozen material held at individual
locations into and through a vacuum drying chamber to dry
the frozen material.
The apparatus for carrying out the process of the
first aspect of the invention, forms the second aspect of
the invention. Accordingly, there is provided apparatus
for quick freezing of a liquid material contained in a
sterilized vessel for subsequent drying in such a manner
that said liquid material forms a shell of substantially
uniform thickness on the inner walls of said vessel; said
apparatus comprising: rotatable gripping means for holding
the vessel and rotating it about its longitudinal axis and
capable of rotating at high speeds so as to maintain the
liquid material against the inner walls of the vessel by
centrifugal force; filling means for introducing the liquid
material into the vessel; freezing means for freezing the
liquid in the form of a shell of substantially uniform
thickness against the inner walls of the vessel; and
conveying means to move the next vessel or vessels into
position for filling and freezing.
By gripping means we mean a means to hold the vessel
steadfast while it is rotated about its longitudinal axis.
Thus, in one embodiment of the apparatus aspect of the
invention, there is provided an apparatus for a continuous
or semi-continuous freeze-drying process of a liquid
material contained in one or more sterilised vessels in
such a manner that said liquid material forms a shell of
substantially uniform thickness on the inner walls of said
vessels and in which vessels loaded at one end of the
process are moved automatically through various stages of
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the process up to and including being subjected to vacuum
drying conditions; characterised in that said apparatus
comprises:
conveying means to move the vessels through the
apparatus as the continuous or semi-continuous freeze-
drying process is performed;
racks or magazines which include individual locations
for locating vessels such that they are held apart and
which are moved by the conveying means through the
apparatus;
a washer for washing and a steriliser for sterilising
the vessels prior to filling;
filling means for introducing the liquid material into
each vessel through a neck thereof;
rotatable gripping means for removing the vessels from
the racks or magazines, holding each vessel and rotating
said vessel about its longitudinal axis at a high speed so
as to maintain the liquid material against the inner walls
of the vessel by centrifugal force and returning the vessel
to the racks or magazines;
freezing means for freezing the liquid in the form of
a shell of substantially uniform thickness against the
inner walls of the vessels; and
a vacuum drying chamber containing heating means for
drying the frozen material.
Preferably the liquid material is aqueous. By aqueous
material we mean aqueous solutions, suspension or the like
preferably of pharmaceutical products such an antibiotics
vaccine, organic chemical drugs, enzymes or serum. The
invention, however, can be used for freeze-drying material
dissolved or suspended in a solvent other than water.
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By substantially uniform thickness of shell we mean
whereby the thickness varies less than about 50 of the
average thickness from the upper to the lower and of the
vessel. By this we mean to include the average thickness of
the shell measured at the mid-point between any local peaks
or troughs in the shell surface caused by e.g. fluid dynamic
interactions between the liquid and freezing gas during the
freezing process.
The invention (of the first and second. aspects) can be
applied to large vessels of liquid material, but preferably
the vessels are vials or other such small vessels, such as
about 10 to 40 mm in diameter and a plurality of these vials
are filled and frozen simultaneously. This is the type of
vessel used in the pharmaceutical industry to carry at least
one unit dose of drug. The drug is then reconstituted with
water before administering to the patient.
The uniformity of the shell thickness is a function of
the angle of the vessel and the speed of rotation. It is
preferable to rotate the vessel up to about 45 off the
horizontal, most preferably in a substantially horizontal
position.
When the liquid material is introduced to the vessel
while it is simultaneously rotating substantially about the
horizontal (or up to about 45 of f the horizontal), a shell
frozen product is obtained with substantially no frozen
product on the base of the vessel. This appears to be the
first time that this type of shell has been achieved, and it
forms a third aspect of the invention. All shell dried product obtainable by
the process and apparatus of the
inventions also form this further aspect of the invention.
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The speed of rotation of the vessel should be controlled
to maintain the liquid material in a shell on the inner walls
of the vessel by the action of centrifugal force. If the
speed of rotation is too low the liquid material will not be
held as a shell on the walls of the vessel. The speed of
rotation is a design consideration depending on the density
of the liquid material to be frozen and the size of the
vessel and preferably about 2500 to 3500 revolutions per
minute. Typically it will be about 3000 revolutions per
minute for a vial of about 10 to 40 mm diameter.
It has also been found that if the liquid material is
advantageously introduced into the vessel while it is
simultaneously rotating at an angle at or near the
horizontal, then a greater quantity of material can be
introduced. That is, if a greater than the normal "fill"
quantity of material is introduced when the vessel is
stationary and horizontal, some material will run out. This
is less likely to happen if the vessel is simultaneously
rotating when it is filled.
The liquid material is frozen into the form of a shell
by subjecting it to freezing conditions. In one preferred
embodiment of the invention this is achieved by injecting a
controlled flow of freezing inert gas such as nitrogen into
the vessel while it is simultaneously rotating the vessel.
2S The flow of freezing gas is controlled in the sense that if
injected at too high a pressure it may disrupt the shell of
= aqueous material or may cause it to overflow.
Injecting freezing gas into the interior of the rotating
vessel has the advantage of speeding up the freezing step.
Freezing gas could also, however, be circulated around the
outside of the vessel, but with such a process it is
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important to minimise the points of contact between the
gripping means and outer walls of the vessel so as to
minimise any insulation of the liquid material by such
contact.
The method of the present invention readily lends itself
to incorporation in a continuous or semi-continuous freeze
drying process. In such a process the vessels are held in
racks or magazines and are moved automatically through the
various stages up to and including being subjected to the
vacuum drying conditions.
A process for carrying out freeze-drying according
to the first aspect of the invention includes a freezing
step, said process including the following steps:
a) loading one or more racks or magazines with the
vessels to be filled;
b) washing the vessels, and racks or magazines;
c) sterilising the vessels, and racks or magazines;
d) filling the vessel with the liquid material to be
frozen;
e) freezing the liquid material according to the first
aspect of the invention;
f) subjecting the vessels containing the frozen material
to vacuum conditions;
g) drying the frozen material;
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h) plugging the vessels; and
i) unloading the vessel and optionally capping and
labelling the vessels.
In steps a) to c) and optionally in steps f) to h), the
vessels can optionally be held in an inverted position e.g.
in the racks or magazines. The vessels must be inverted in
step b) so that washing water will drain. Furthermore, in a
preferred embodiment of the invention where the vessels are
held by the base and gas injected in through the:ir open
necks, then having the vessels already inverted at step c)
saves an additional handling step.
It will be readily appreciated that the vessels could be
unloaded prior to plugging.
A fourth aspect of the invention relates to the process
for drying a shell dried material, and the fifth aspect
relates to the apparatus for carrying out this drying
operation.
Accordingly in a fourth aspect of the invention there is
provided a process for freeze-drying a liquid material frozen
in the form of a shell on the inner walls of the body of a
vessel, which includes the drying step of applying heat for a
time interval radially inwardly from a heating means to the
shell in a vacuum chamber over a substantial surface area of
the shell so as to dry the shell frozen material.
In a fifth aspect of the invention there is provided
apparatus for drying a liquid material frozen in the form of
a shell on the inner walls of the body of a vessel, said
apparatus comprising:
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a vacuum chamber,
heating means within the vacuum chamber designed to
direct heat radially inwardly from the heating means to the
shell frozen material, and conveying means to convey the
5 vessel through the vacuum chamber.
The advantage of heating the vessel radially inwards
from the heating means is that the drying cycle time is
greatly reduced as compared with conventionally drying
methods. Here the base of the vessel is heated, such as on a
10 heated shelf, and the heat transfer is axially upwards
through the glass walls of the vessel. This causes a
temperature differential along the length of the vessel
walls, thereby causing a'drying front' in the shell frozen
material. As a result the drying cycle time is typically 30
hours for plug-frozen material compared to a drying cycle
time in accordance with the invention of 3 hours.
Preferably the heating means is in close proximity to
the wall of the vessel, such as 5mm or less, advantageously 3
mm or less. In a preferred embodiment of the invention
(heating blocks) the distance between the wall of the vessel
and the heating means is about lmm.
Preferably also the heating means extends round
substantially the whole circumference of the vessel, and
advantageously also extends substantially to the same height
as the shell. In a particularly preferred embodiment the
heating means includes a heating chamber into which the
vessel is received.
Since the drying time is greatly reduced, the throughput
of the vacuum drier is increased. Therefore a similar
production capacity can be achieved with a much smaller
vacuum drier than that used conventionally.
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It will be appreciated that although the first, second
or the fourth and fifth aspects of the invention can be used
independently with conventional freezing or drying apparatus,
it is advantageous to use them together. Thus as a
consequence of the decreased freezing time achieved by the
first and second aspects of the invention together with the
decreased drying time of the fourth and fifth aspects of the
invention, the production capacity of the conventional
freeze-drying apparatus can be achieved with much smaller
apparatus according to the invention. In fact the apparatus
of the invention can be mobile, whereas conventional freeze-
drying apparatus is much too large and bulky to be mobile.
With all the aspects of the invention used together, an
automated continuous or semi-continuous process can also be
designed with minimal or no human operator contact. In this
respect the conveying means is preferably the arrangement of
rollers described hereafter. The magazine is also preferably
of the design defined in the sixth aspect of the invention
Accordingly in a sixth aspect of the invention there is
provided a magazine comprising a magazine comprising a tray
having an upper and lower surface and having equispaced
location apertures extending through the tray for locating
the necks of the vials, each set of at least three locating
apertures defining an area therebetween in which an air flow
aperture has been cut away, and one or more abutments
adjacent each aperture which trace the circumference of the
base of a vessel about the vertical axis of the locating
aperture to form a locating flange on which the vessel can be
located in the upright position.
Preferably the location apertures are arranged in rows
and columns and each set of four location apertures define
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substantially the corners of a square, in which an airflow
aperture is provided.
All aspects of the invention will now be described by
way of example with reference to the following drawings, in
which:
Figure 1 is a schematic cross-sectional side view
showing the series of steps carried out in the continuous
lyophilisation process of the invention, including the
filting and freezing of aqueous material in a vial carried in
a magazine and the drying of the material;
.Figure 2 is a schematic cross-sectional side view
showing another embodiment of the process of the invention;
Figure 3 is a top and side perspective view of the
apparatus shown schematically in Figure 1;
Figure 4A is a cross-sectional view through a vial having
a conventionaJplug.of lyophilised material at its base.
Figure 4B is a cross-sectional view through a vial having
a shell of lyophilised material on the inner walls of the vial
in accordance with the invention;
Figure 5 is a top perspective view of a magazine used in
the process of Figures 1 and 2;
Figure 6 is a fragmented plan view showing a corner
portion of the magazine displayed in Figure 5;
Figure 7 is a cross-sectional view through a portion of
the magazine of Figures 5 and 6 but showing a vial in
position and a section of a roller conveyor below the
magazine;
Figure 8 is a top and side perspective view of automated
apparatus including an automated arm carrying grippers for
carrying out the filling and freezing steps D and B shown in
Figures 1 and 2 (i.e. in the Fill-Spin-Freeze (FSF) chamber);
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Figure 9 is a side view of the roller conveying means
for carrying the magazines and vials throughout the process;
Figure 10 is a plan view of part of the filling and
freezing apparatus shown in Figure 8;
Figure 11" is a cross-sectional view of the grippers
carried by the arm (not shown) of Figure 8;
Figure 12 is a schematic side view of the arm and
grippers, but additionally showing a driving means for
rotating the grippers;
Figure 13 is a schematic cross-sectional vieia of a
portion of the arm and grippers;
Figure 14 is a cross-sectional view through a vial
showing a nozzle inserted into the vial;
Figure 15 is a schematic longitudinal cross-sectional
view of the FSF chamber shown in Figure 8;
Figure 16 is another schematic plan view of a part of
the filling and freezing apparatus of Figure 8, but
additionally showing a check weigh station;
Figure 17 is a top and side perspective view of the
automated drying apparatus for the drying step (H and I)
shown in Figure 1;
Figure 18 is a cross-sectional plan view through a
portion of a heating block used for drying the frozen
material in the vials;
Figure 19 is a cross-sectional plan view through heating
walls which are an alternative embodiment to the blocks of
Figure 15 for drying the frozen material in the vials; and
Figure 20 is a plan view of the drying vacuum tunnel
housing the drying apparatus.
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Referring to the process of Figures 1 and 2, the steps
of an embodiment of the process and apparatus of the
invention are as follows below.
Loading step (A): Vials (1) are loaded upside-down into
a magazine (2), such that the neck of each vial locates in an
aperture (3) of the magazine (2). This loading step (A)
takes place in a non-sterile environment and the vials (1)
can be manually or automatically loaded. The vial (1) are
carried through the whole process in the magazine (2), which
is in turn carried through the process on conveyor means in
the form of roller conveyors (not shown in Figures 1 and 2,
but shown in Figure 7). This is different from prior freeze-
drying processes where the vials are placed loosely on metal
trays. The specifically designed magazines (2) are shown
more particularly in Figures S to 7.
Washing step (B) and Sterilising step (C): The vials
(1) are then washed both inside and outside by injecting
washing solution into the inverted vials (1) through their
necks and spraying washing solution onto the outside of the
vials (1). The vials (1) are then hot air sterilised (Step
C) by passing them into a sterilising chamber (4 - see Figure
3)) where hot air is blown onto the vials (1). The
sterilised magazines (2) full of vials (1) are then carried
by the_conveying means onto a Fill-Spin-Freeze (FSF) section
(5) where the filling (D) and freezing (E) steps take place.
The apparatus for carrying out these steps is shown more
particularly in Figures 8 to 16.
Filling step (D) and Freezing step (E): In a filling and freezing operation,
the vials (1) and magazines (2) enter
the FSF section (5) and are allowed to cool to the FSF
internal temperature (typically about -50 C) . Vials (1) are
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removed from the magazines (2) one row at a time, (or
feasibly two rows at a time) these being picked up by a robot
arm (not shown in Figures 1 and 2) carrying a plurality of
rotatable gripping means in the form of multi-fingered
5 gripper (6). 'I'he vials (1) are rotated to horizontal and the
robot arm swings 900 to the side of the FSF chamber. The
vials (1) are rapidly rotated and filled with the required
dose of aqueous material, particularly a drug material such
as a vaccine. Optionally the_ vials may be firstly filled
10 then spun, but preferably the filling occurs while
simultaneously spinning the vial (1). The speed of rotation
or spinning should be not less than that required to maintain
the aqueous material in a shell (7) of substantially uniform
thickness against the inner walls of the vial (1). The vials
15 (1) are then moved over nozzles from which is blown cold gas
(typically - nitrogen at about -150 C) to expose the spinning
aqueous material to freezing conditions sufficient to freeze
the material into the shell (7). The frozen shell (and later
the dried shell) will be of a substantially uniform thickness
- i.e. the thickness of the shell measured at any position
along the axis of the vial will not vary more than about 50
providing that the thickness is measured as the average
between any surface peaks or troughs which may result from
fluid dynamics during the freezing process. After a preset
time to complete freezing, the spinning is stopped and the
vials (1) returned to the magazine (2). The temperature of
the interior of the enclosure is maintained sufficiently cold
so that the shells do not melt.
Weighing Step (F) : Whilst a row of vials (1) is being
filled and frozen, other vials (1) are weighed by indexing
the magazine (2) back and forward over the weigh load cells
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(8 - Figure 1) This allows all vials (1) to be weighed
before and after filling to check the correct dosage has been
dispensed. The weigh load cells (8) are shown more
particularly in Figure 16.
Turn over of vials (Step G): After filling and
freezing, the vials (1) are (optionally) turned over from
upside-down to the correct way up (see Figure 1). This is
achieved by picking up the vials (1) (one row at a time) from
one magazine (2) and transferring them to the magazine in
front. A transfer arm (9) holding sufficient grippers for a
row of vials holds the vials (1) around their centre and
rotates 1800 about a horizontal axis across the direction of
movement of the magazine (2). The vials (1) are then
released the correct way up on the magazine in front (2).
This optional step demands that there is always the
equivalent of an empty magazine in the process, which is
loaded at the start of production. In the process of Figure
2, this turn over step does not occur and the vials are
loaded inverted back into the magazine (2) before being
conveyed onto the drying section of the process.
Vacuum Tunnel - Entry air Lock (Step H): Once the
material in the vial (1) has been frozen, it is ready for
drying. The magazine (2) enters an air lock chamber (l0a)
between the FSF chamber (4) and a vacuum drying chamber (111.
The outer door (12a) of the airlock (l0a) then closes and the
air pressure is reduced to the same as the vacuum chamber
(11). The inner door (13a) then opens and the magazine (2)
enters the vacuum chamber (11). The outer door (12a) is then
opened ready for the next magazine (2).
The magazines (2) in the vacuum tunnel (11) move by
conveyor means in an indexing motion one complete magazine
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length at' a time, typically every 10 mins. When the
magazines (2) have been indexed to the new stations heater
blocks (14) lower over the vials (1). These direct heat
substantially radially inwards to the vial over substantially
the whole surface area of the shell frozen material (7) and
thereby provide the energy to sublime off the water and
freeze dry the material (7). Immediately prior to the
magazines (2) indexing the heater blocks are raised to their
first position to allow the magazine (2) and vials (1) to
pass underneath and move one magazine (2) length to the next
heater block (14). The heater blocks (14) are each set to a
different temperature, so giving the temperature profile
necessary to achieve the correct drying conditions for the
particular drug material being handled. The freeze-dried
shell material (7) produced according to the invention is
shown more clearly in Figure 4b. The conventional plug dried
product is shown in Figure 4A.
At the end of the vacuum tunnel there is a second air-
lock. This works in a similar way to the input air lock,
allowing the vials out whilst maintaining the vacuum in the
r.ain tunnel.
Plugging (Step J): There are two options for plugging.
One is to carry out plugging in the outlet air lock (lOb).
In this case the plugs (15) would enter the air lock (l0a) as
a magazine (2) exits. The plugs (15) would be pushed into
the vials (1) before opening the outer door (12b) ; this
allows plugging at any desired pressure and in any chosen
gas. The second option is to plug after the air lock (lOb)
in a sterile plugging area (16) (see Figure 3).
Conventional equipment could be used here but the size of the
sterile area (16) would increase as a result.
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18
Capping (Step K): The crimping of caps (17) onto the
plugs (15) could use standard equipment and be carried out in
a clean (but not necessarily sterile) area.
The whole freeze-drying process is operated from a
central control station more particularly shown in Figure3.
Figures 5 to 7 show a magazine (2) used for carrying the
vials (1) through the whole freeze-drying process. The
magazine (2) of Figure 5 comprises a tray (18) having an
upper and lower surface and having eight rows of eight
equispaced location apertures (19) extending through the tray
(18) for locating the necks of the vials. Each set of four
locating apertures (19) defines the four corners of a square
in which an air flow aperture (20) has been cut away. A
concave abutment (21) adjacent each aperture trace the
circumference of the base of a vial (1) about the vertical
axis of the locating aperture (19) to form a locating flange
(22) on which vial (1) can be located in the upright
position.
The vials (1) are preferably held in an inverted
position as shown in Figure 7. This Figure also shows that
the top surface of the vial neck preferably does not contact
the magazine (2) so that any particles which may be produced
by fretting between vial (1) and magazine (2) at point A are
unlikely to contaminate the inside of the vial (1).
The vial is supported on its neck at point B. This
design depends upon the diameter of the vial (1) being
greater than the diameter of the neck of the vial.
The location aperture (19) in the magazine (2) is
preferably castellated as shown in Figure 6. The
castellations (23) allow water to be jetted between vial (1)
and magazine (2) during the washing process to remove any
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particles that may have been trapped in the gap. The open
area of the air-flow aperture (20) allows the free passage of
air through the magazine during hot air sterilisation and for
cold laminar air flow in the FSF section (5) ~see Figure 15).
Locating 'holes (24) towards the outer edge of the
magazine are preferably provided for precise positioning.
The holes are circular on one side and elongated on the other
side to allow for position location without overconstraint.
As shown more particularly in Figures 8'and 9, the means
for conveying the magazines through the lyophilisation
process preferably comprises a plurality of parallel rollers
(25) axially mounted near both ends of corresponding
rotatable shafts (26) which in turn are suspended between two
long parallel side supports (27). Referring to figure 7,
each roller has an outwardly and circumferentially extending
flange (28) on which the magazine rests and is moved along.
Also mounted on the rotatable shaft (26) adjacent the roller
is a toothed drive gear wheel (29). The underside of the
magazine (2) has a rack with teeth (30) to engage with the
teeth of the drive gear (29) and index the magazine (2)
along.
Through the whole process the magazine (2) is supported
on a series of these rollers (25), not all of which have
drive teeth. Furthermore not all of the drive teeth will
move at the same time, thereby giving controlled indexing of
the magazine throughout the process. For example within the
FSF chamber (5), the magazine (2) is preferably indexed by
one row at a time, typically one row per minute. it will
also move back and forward by one or two rows (as described
hereafter) above the check weighing cells (8). In the drying
chamber (11), however the magazine (2) is preferably indexed
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by a whole magazine length at a time, one index every 8
minutes for example. Therefore the rollers in the FSF
chamber (5) would not be directly linked to those in the
drying chamber (11). The conveying rollers are however
5 synchronised where necessary to provide a smooth transfer
between different roller sections.
Figure 9 shows a side view of the drive roller
arrangement transporting magazines (2) through the process.
More particularly, the figure represents the movement from
10 the FSF region (5) to the airlock(10a) and the vacuum chamber
(11) through air lock doors (12a and 13). In order to move a
magazine from region to region, each set of rollers needs to
be driven independently. The rollers (25) are connected
together in groups by drive shafts (31,32,33) and are driven
15 by independent drive motors (34,35 and 36). Each motor (34
to 36) is position controlled by central software to provide
the necessary movements and to synchronise movement between
adjacent groups during magazine transfer from group to group.
The transfer of magazine (2) and vials (1) throughout
20 the process on the preferred roller conveyor arrangement (25
to 36) of the invention has a number of advantages for use
particularly in a continuous freeze-drying process. This is
especially so in comparison with conventional drives which
might be for example flat bed conveyors, chain link
conveyors, other conveyor types or trays as used in
conventional freeze drying. These are as follows:
1. There is no vial-to-vial contact. This reduces the
amount of particle generation caused by fretting and
reduces the chances of a vial fracture.
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2. The magazine design is very open for the washing and
sterilising process. Washing is better because the
exact vial location is known hence wash jets can be
directed at key parts of the vial. The open spaces of
the magazine allow the hot air of sterilisation to pass
freely through the magazine.
3. The open structure also allows good airflow in the FSF
region where downwards laminar air flow is needed to
maintain very low particle levels in the region of the
vials. The layout of the supporting rollers is also
clean and simple and hence helps air flow.
4. The magazines and rollers themselves constitute a
greatly reduced source of particles in comparison with
conventional conveyors which tend to have large numbers
of fretting surfaces.
5. Since the magazines preferably pass through the whole
process (rather than short lengths of conveyors in each
section) there is only a minimum of mechanical handling
of the vials. There is no need for any vial handling
stage between the steriliser and the FSF chamber for
example, nor between the FSF and the drying chamber.
6. Since the magazines preferably pass through the whole
process (rather than short lengths of conveyors in each
section) they are repeatedly cleaned i.e. they are
cleaned and sterilised on each path through, whereas a
conveyor contained within any one machine element would
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not be cleaned and hence would have the possibility to
cause vial-to-vial contamination.
7. The separate nature of the magazines allows them to pass
through the air lock doors on entry to and exit from the
tunnel. This is possible because the air lock (sliding)
doors can be located between two parallel rollers.
8. Since each vial is located in its individual location in
the magazine, the vials can be readily located when
necessary e.g. for gripping for the FSF process, for
heating in the drying chamber and for plugging.
Conventional vial transport generally requires a
separate mechanism for vial alignment prior to handling
stages.
9. Since each vial is located in its individual location in
the magazine it can be individually tracked through the
process for development purposes- or to identify a
particular vial in the event of a process failure such
as poor filling. A vial which is identified by the
check weigh system as faulty, can therefore be
subsequently retrieved at any convenient stage in the
process.
Referring to Figure 8 the magazines (2) and vials (1)
are moved through the FSF chamber (5) in the direction of the
arrow from the rear to the front end thereof and then into
the continuous vacuum drying tunnel(consisting of the air
locks (lOa,lOb) and drying chamber (11)).
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A robotic handler (37) is fixedly located towards the
front end of the FSF chamber (5) and alongside the roller
conveyor (25 to 36).
An arm (38) carrying a plurality of rotatable equispaced
gripper means (39) extends perpendicularly from the upper end
of the robotic handler (37) and is controlled thereby.
A filling (40) and freezing station (41) are both
located in the chamber (5) alongside the roller conveyor (25
to 36) and rearwardly of the robotic handler (37). The
filling station (40) consists of a row of needle nozzles (42)
which each has a connector (43) for connecting outside the
FSF chamber to a reservoir of the aqueous material to be
lyophilised (44 - see Figure(1O). The freezing station (41)
also contains a row of needle nozzles (45) which also each
has an adapter (46) for connecting to a supply of freezing
nitrogen gas (44) also outside the FSF chamber. The nozzles
(45) of the freezing station (41) are located directly below
the nozzles (42) of the filling station (41) and both sets of
nozzles (42,45) are mounted on a casing (47) at approximately
the same height as the arm (38). The filling and gas
reservoirs (44) are conveniently located outside the FSF
chamber (5) so that the FSF chamber (5) can be maintained as
clean as possible (see Figure 9). The filling needles (42)
is provided with either heating means or thermal insulation
to prevent the liquid material freezing inside the needle
(42) during filling.
Figure 11=shows the rotatable vial gripper means (6) in
cross-section. The vial (1) is held in concentrically moving
fingers (48) which are designed to hold the vial (1) with its
axis accurately concentric with the axis of rotation of the
gripper (6). The fingers (48) are housed and are axially
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movable within an outer casing (49) and have outwardly
extending projections (50) which are slidably receivable
into complimentary recesses (51) in the outer casing (49) or
visa versa. The vial (1) is spun to produce a shell (7) of
the liquid drug inside the vial (1). The vial (1) is then
transferred to a position enclosing the freezing gas nozzle
to freeze the shell (7). This ensures that the frozen shell
(7) has a substantially uniform wall thickness, and is an
improvement over rolling while freezing. The fingers (48)
are controlled by a push rod (52) extending axially along the
gripper shaft (53) connected between the base of the fingers
and a flange (55). The fingers are opened by the movement of
an actuator frame (54) (which is mounted within the robot arm
(37)) in the direction of the arrows against the
flange(55)therby compressing a spring (56) against the
flange(55) and a second flange (not shown). In the open
position the fingers (48) are pushed axially out of the
outer casing (49) by the push rod (52) such that the
projections (50) slide into the complimentary recesses (51)
thereby allowing the fingers to open. In the closed position
the force of the spring (56) pulls the fingers (42) axially
into the casing(49) and the projections (50) slide out from
the recesses (51) thereby forcing the fingers (48) to close,
as with a collet. This arrangement has the advantage that in
the event of power failure to the flange actuator (54) the
fingers (48) will remain clamped shut. In the open position,
the frame actuator(54) abuts the flange(55), but in the
closed position they are spaced apart allowing free rotation
of the whole gripping arrangement(6).
Each rotatable gripping means (6) is designed with a
sufficient chamfered lead-in (57) that even a poorly shaped
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vial (1) located poorly in a magazine will still move
smoothly into the gripper means (6) when it is lowered over
the magazine.
Figure 12 shows the drive arrangement (58,59) by which
5 the gripping means (6) are all rotated. There is a single
drive motor (58) linked to each gripper shaft (53) by a
toothed timing belt (59).
As shown more particularly in Figure 13, since the FSF
atmosphere is at about -50 C, the robot arm (37) is covered
10 by outer sleeve (60) which has internal insulation (61). The
arm (37) is held at room temperature by thermostatically
controlled heater element (62). The outer sleeve (60)
contains a sliding seal (63) to allow rotation and the robot
handler (37) is provided with flexible bellows (64) to allow
15 vertical motion relative to magazine (2). This arrangement
means that the insulated outer sleeve (60,61) provides
thermal insulation between the cold atmosphere and the
relatively warm mechanical components of the arm (38).
The outer sleeve (60) and insulation (61) of the arm (37)
20 serve at least two purposes.
1. To allow the arm mechanisms to operate at room
temperature while the arm is mounted within the FSF
enclosure.
2. To protect the clean FSF environment from any particles
25 which are generated by movable parts such as the
spinning gripper shafts (53) or the drive belt (59).
Air which is contained inside the enclosure will be
extracted from the enclosure via vent aperture (64) and does
not require any fan for extraction since the enclosure will
be positively pressurised. This extraction will cause
relatively high air velocity in the narrow aperture (65)
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26
between the spinning gripping means (6) and the outer arm
casing (60), which will tend to carry any particles generated
in the vicinity of the gripping means (6) together with any
particles generated within the interior atmosphere of the
robot arm ( 3 7)'towards the vent aperture (64) and hence away
from the clean area of the vials (1).
In a fill, spin, freeze cycle, the arm (37) is lowered
vertically from a first position in which the gripping means
(6) are disposed perpendicular to the roller conveyor (25 to
36) and spaced above the vials (1) carried thereon, and a
second position in which each gripping means (6) grips the
base of a vial (1). Typically one row of vials (1) are
removed simultaneously from the magazine (2). The arm (37)
is then raised to the first position and rotated through 900
to a third position in which the gripping means are
substantially parallel to the roller conveyor (25 to 36) and
the vials (1) are held substantially horizontally. The arm
(37) then swings through 90 in a horizontal plane in front
of the filling means so that a nozzle (42) of the filling
station (40) extends in through the neck of a corresponding
vial (1)_ The vials are then rotated at a high speed of
about 3000 rpm and a measured dose of aqueous material is
simultaneously injected into the vial (1), causing the
material to be maintained in a shell (7) against the inner
walls of the vial (1) by the action of centrifugal force.
The vials (1) are then withdrawn from the nozzles (42) of the
filling station (40) and the arm (38) lowered to the height
of the freezing station (41) and moved towards it so that the
nozzles (45) thereof are inserted into the vials (1) and a
controlled jet of cold nitrogen gas (typically of a
temperature of about -50 C) is injected into the vial (1)
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27
whilst it is simultaneously rotating to freeze the aqueous
material into a shell (7) against the inner walls of the vial
(1). After a preset time to allow freezing (typically
between 30 to 60 seconds) the rotation is stopped and the
vials (1) returned to the magazine (2).
One major advantage deriving from the very short
freezing cycle time is that the throughput capacity of a
conventional freeze-drying apparatus can be accommodated on a
much smaller scale of apparatus. As a result the process can
be more easily automated and continuous thereby excluding
human operators from the process and thus maximising the
sterility of the process. To achieve this, the interior of
the process line must be isolated from the exterior by
'isolation technology'. This requires both a barrier to the
ingress of dirt or bacteria and also means internally so that
the chamber (4) can be cleaned and sterilised automatically -
i.e. it must be cleared when sealed closed and it must remain
sealed throughout the whole production of a batch. Therefore
preferably the whole freeze-drying process of the invention
is designed for reliable mechanical handling. That is if a
vial (1) is dropped or is broken during the process then it
is very hard to continue without an operator going inside the
isolator to tidy up. If this is necessary then sterility is
lost, product in the area must be discarded and the procedure
for cleaning and sterilisation must be repeated before
production can continue. This would be a time consuming and
costly delay, and hence reliable mechanisms are important.
Figure 15 shows how a sterile barrier is arranged in the
FSF area (5). The figure is a cross section of the
production line, looking in the direction of product flow.
The barrier itself (66) is shown as a thick wall because of
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28
the necessity for thermal insulation (internal temperature
may be -50 C). The internal gas is circulated round by fan
(67) in the direction of the various arrows. As the air
passes through filter ('HEPA' filter) (68) fine particles and
micro-organisms are removed and the flow is also evened out
so that the flow in the region below the filter (68) is
laminar, downwards. The downwards flow of clean air ensures
that the filling process and the waiting vials (1) are in
clean air and that any particles shed in these or other
regions are carried downwards and clear of the vials.
The injection of the freezing gas to form the shell is
shown more particularly in Figure 14. Preferably the
freezing nozzle (45) has a plurality of ports (69) along its
length through which the freezing gas is injected.
The substantially horizontal orientation of the vial (1)
mitigates the problem of producing a parabolic surface to the
shell and helps form a shell of substantially uniform
thickness. The rate of heat transfer from gas to product is
increased by increasing the temperature difference (by having
colder gas) and by increasing relative velocity between gas
and liquid. very high gas velocity however will disrupt the
liquid shell and cause an uneven frozen shape. The pattern
of ports (69) in the side of the nozzle (45) (Figure 14)
mitigates this problem by reducing any local peaks in gas
velocity.
Since the vial (1) can be simultaneously spun and filled
it is possible to fill the vial beyond the limit where the
aqueous material would spill over the neck if the vials were
not spinning. For sensitive drugs, it may be advantageous to
do the filling at a lower rotational speed than the freezing,
to minimise the effect of shear.
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It is advantageous to be able to weigh every vial (1) so
that the weight of filled product in each vial can be checked
and any process deviations noted and corrected. This means
for example that if one of the filling pumps was tending to
fill slightly'less than target fill weight then the pump
could be adjusted to keep the fill weight under control. Any
total filling failure for example caused by a blockage would
be instantly recognised.
The weigh cells (8) are located in the FSF area (5)
under one row of vials adjacent to the robot arm (37) (Figure
16). The weigh cells (8) are mounted on a frame (8A) such
that when the frame (8A) is raised then all the vials (1) in
that row are lifted by the weigh cells (8) clear of the
magazine (2) and their individual weights can be determined.
The direction of magazine indexing is shown by the arrow.
The sequence of filling and weighing is as follows:
Row 1 is indexed over the weigh cells and is weighed,
empty.
The robotic arm (38) then picks row 1, spin-fills and
freezes it.
During this time the magazine (2) moves so that row 2 is
indexed over the weigh cells (8) and is weighed, empty.
Row 1 is then returned to the magazine (2).
The robotic arm (38) then picks row 2, spin-fills and
freezes it.
During this time the magazine (2) moves so that row 3 is
indexed over the weigh cells (8) and is weighed, empty and
then row 1 is indexed over the weigh cells (8) and is
weighed, full.
Row 2 is then returned to the magazine (2).
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The robotic arm (38) then picks row 3, spin-fills and
freezes it.
During this time the magazine moves so that row 4 is
indexed over the weigh cells (8) and is weighed, empty and
5 then row 2 is indexed over the weigh cells (8) and is
weighed, full.
Row 3 is then returned to the magazine (2). This
process is repeated until all vials (1) in the magazine (2)
have been weighed and filled. The next magazine (2) is then
10 indexed forward.
It is preferable that each vial (1) is weighed before
and after filling as described because the difference
between fill weights that must be detected is less than the
likely difference in vial (1) weights. Preferably also each
15 vial is weighed each time on the same weigh cell (8) so that
variations between weigh cells (8)_will have no effect on the
accuracy of the measurement.
Drying (Step I): The apparatus for drying the shell
frozen material (7) is more particularly shown in Figures 17
20 to 20.
The 'viais (1) pass through the vacuum tunnel
(l0a,10b,11) from the rear to the front. The vacuum tunnel
(l0a,l0b,i1) comprises a sealed vacuum drying chamber (11)
and airlock chambers (lOa,lOb) at the rear and front end of
25 the drying chamber (11). Each airlock (lOa,lOb) has an inner
(13a,13b) and outer (12a,12b) door. The magazine (2) enters
the front air lock (l0a) between the FSF chamber (5) and a
vacuum drying chamber (11). The outer door (12a) of the
first airlock (10a) then closes and the air pressure is
30 reduced to the same as the vacuum drying chambers (11). The
inner door (13a) of the front airlock (10a) then opens and
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the magazine (2) enters the vacuum drying chamber (il). The
inner door (13a) is then closed, the outer door (12a) of the
front airlock (l0a) then opens ready for the next magazine
(2).
A conveyo"r means (not shown) preferably of the same
roller conveyor arrangement (25 to 36) in the FSF chamber (5)
is provided for moving the magazines (2) of vials (1) through
the vacuum tunnel (10a,10b,11). A series of heater blocks
(70) are spaced along the length of the vacuum chamber (11)
above the conveyor means (25 to 36) and magazines (2) As
shown more particularly in Figure 18 (which shows the plan
view of a portion of a heater block (70) and vials), the
heating blocks (70) comprise a plurality of tubular heating
chambers (71) corresponding to the number of vials (1) in
each magazine (2). Each chamber (71) is defined by a tubular
wall (72) which extends to a height just above the top of the
vial (1), and the heating chamber (71) is optionally provided
with a top (72) which optionally may have an aperture (73)
communicating with the drying chamber (11), to release water
vapour from the chamber (71) (Figure 1). In the embodiment of
Figure 2, there is no aperture in the top of each heating
chamber (71) but the vial (1) is inverted and water vapour
escapes through the locating aperture (3) of the magazine
(2). The lower end of each heating chamber is open to
receive the vial (1). The heating blocks (70) are moveable
vertically from a first position above the magazines (2) to
a second position in which they are lowered so that the base
of the heating block (70) rests on or near to the upper
surface of the magazine (2) such that each vial (1) fits
snugly into a heating chamber (71) In the embodiment of
Figure 18, a small space is left between the body of each
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vial (1) and the inner walls (72) of the corresponding
heating chamber (71). In this position heat can pass
radially inwards from the heating block to the shell frozen
material (7) over a substantial area of the shell (7) in the
direction of the arrows (Figure 18). The heat is transferred
by radiation and by conduction and convection through the
residual gas which exists in the (vacuum) heating chamber
(71). The vacuum space between the heating chamber wall (72)
and the body of the vial is important in that it has an
effect on how efficient heat is transferred to the shell (7)
of material. Preferably the proximity of the heating wall
and vial (1) is about 5mm or less, more preferably about 3mm
or less. In the embodiment shown the proximate distance is
about imm.
The heater block (70) is constructed of a good thermally
conducting material. Aluminium, for example, is suitable
providing it is treated to prevent the production of
particles caused by surface oxidation for example by
anodising. The temperature of the heater block (70) can be
maintained by the passage of heating fluid through an element
or pipe (73) attached to, or a conduit (73) running through
the heating block (70).
Although the heating block (70) passes heat into the
vials (1), it will sometimes be necessary for the block (70)
to be cooled in order to maintain correct temperature (if for
example the heat gain from ambient to the block (70) is
greater than the heat lost from the block (70) to the vials
(1). (Cooling is also needed at the start of a batch). For
this reason the blocks (70) are controlled by a fluid which
can be heated or cooled and not just by an electrical heater
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element. In particular during primary drying the vials (1)
may be at -50 C and the heater blocks at -20 C.
Figure 19 shows an alternative heating means to the
heating blocks (70) of Figure 18. In this embodiment long
heating walls' (74) are provided running in parallel along
each side of and down the middle (longitudinally) of the
conveyor means (25 to 36) on which the magazines (2) rest.
Each wall (74) is approximately the same height as the vials
(1) when they are resting on the magazine (2)_ As with the
heating blocks, the heating walls are preferably controlled
by circulating a thermal liquid through an element (73)
running through or attached to the walls (74). The walls
(74) consist of separate sections, the temperature of which
progressively increases along the vacuum chamber (11) in the
direction of the large arrow such that the temperature
experienced by the shell frozen material (7) in each vial (1)
progressively increases as it moves axially along the drying
chamber (11). The thermal pathway for heat transfer is again
radially inwards (as shown) by the arrows from the heating
walls to the shell frozen material (3) over a substantial
a:fea of the shell, thereby drying the shell (7) much quicker
than previous methods in the art. Again the heat transfer
will be by a combination of conduction or convection and
radiation in the vacuum space between the heating walls (74)
and the vials (1). As before the proximity between the
heating walls (74) and body of the vials is preferably 5mm or
less, more preferably about 3mm or less.
The difference between the heating embodiments of
Figures 16 and 17 is that the vial (1) is passed between two
heating walls (74) instead of being received into a heating
chamber (70). As a consequence, it is no longer necessary to
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lift the heating blocks to allow the vials (1) to move and
therefore the embodiment of Figure 19 lends itself to a more
simplified design. The disadvantage, however, is the longer
thermal pathway and less efficient heat transfer from the
heating walls (74) to the shell (7). By substantially
enclosing the vial with the heating means, such as with the
heating chamber (71) of the heating block (7), a faster
drying time is achieved.
With both the heating block (70) and heating walls (74),
because the heaters are individually temperature controlled,
product passing along the tunnel are exposed to a drying
cycle, such as for example: 1 hour at -25 C, 34 hour at +S C,
;~ hour at +5 C, 34 hour at +40 C, and % hour at +40 C.
Figure 20 shows in plan view the arrangement of vacuum
pumps and condensers on the side'of the vacuum chamber (11)
and air locks (lOa,lOb). There is a separate vacuum pump
(75) and condenser (76) for each air lock (10a,10b) and
multiple vacuum pumps (75) are disposed along the length of
the tunnel. The vacuum will become progressively higher
along the length of the tunnel (10a,lOb,ll) as the product
becomes progressively more dry. Isolating doors (77) can
therefore be provided at intermediate positions in the tunnel
to isolate a vessel, if it is found that product is sensitive
to the degree of vacuum which is applied during secondary
drying.
The condensers (76) will become progressively covered
with ice as more product passes down the tunnel. For the
purpose of defrosting, the product on run can be interrupted
but preferably there should be a surplus of condensing
capacity such that each condenser (76) can be isolated by
means of the valve (78) for defrosting after which time it
CA 02215748 2003-03-12
WO 96/29556 PC7/GB96/00597
can be put back into service without interruption of
production.
In both of the illustrated embodiments (Figures 18 and
19) of the heating means (i.e. using the heating blocks (70)
5 and heating walls (74)), the heat passes radially inwards
from the heating means to the shell frozen material in each
vial. As a result the product is dried much quicker than
conventional drying apparatus where the vial rests on a
heated shelf (and thus only the base is heated directly). In
10 this case heat passes axially upwards from the base through
the glass walls causing a temperature gradient that increases
the time required to dry the shell (7). Furthermore, because
of the efficient heat transfer conditions, the drying process
and apparatus of the invention is less energy demanding than
15 the previous process.
