Note: Descriptions are shown in the official language in which they were submitted.
CA 02256621 1998-11-25
WO 97/47377 PCT/US97/09821
TITLE OF THE INVENTION
DISPOSABLE STORAGE, TRANSPORT AND RESUSPENSION
SYSTEM
BACKGROUND OF THE INVENTION
The present invention relates to a system for the transport,
storage, mixing and resuspension of sterile and non-sterile liquids. In
particular, it relates to a system for use with suspensions used in the
pharmaceutical industry.
Ln the chemical industry, and in particular the
pharmaceutical industry, there is a need for a system capable of holding
liquids and mixtures of liquids and solids where a sterile environment
can be maintained while providing means for stirring, mixing,
resuspending, sampling and complete delivery of the contents. To date,
the industry has relied upon stainless steel storage vessels with associated
stirring devices, ports and mixers. These associated pieces of equipment
require special seals in order to assure that the sterile conditions
established within the device are maintained during mixing and
pumping.
Due to the weight of these stainless steel devices, they are
difficult to maneuver, which leads to increased production times. These
stainless steel systems often require special handling equipment. When
these stainless steel devices are used to transport bulk product,
significantly higher shipping costs result due to the weight of the
container and the added cost of returning the empty system for future
use.
Since the stainless steel systems are not disposable, they
must be cleaned and resterilized before being reused. This may involve
chemical cleaning with agents such as perchlorate solution, and the
attendant disposal problems associated with disposal of such products.
After cleaning, the systems must be inspected and tested to assure that all
foreign matter has been removed. Since new products will be
introduced, validation of the cleaning and resterilization procedures as
CA 02256621 1998-11-25
WO 97/47377 PCT/US97/09821
-2-
well as tests to assure efficacy must be completed. This also adds to the
costs and complication of using the stainless steel systems.
Since the stainless steel systems are expensive, it is not cost
effective to maintain several different sizes of the vessels. As a result,
vessel size is usually set to the largest expected batch of material. When
small batches are prepared, they are stored in oversized containers with
the attendant costs and problems which have been previously described.
One of the primary uses for this type of vessel is the
storage and transportation of sterile suspensions of alum in an aqueous
medium for use in the production of vaccines. In practice, a sterile
alum suspension is prepared in the vessel and shipped to the area where
inoculation with the bulk virus or bacteria stock will occur. Since the
suspension may be prepared well in advance of inoculation, the system
must also serve as a storage container.
Prior to inoculation, the alum must often be resuspended.
In many instances, uniform particle size and the preparation of a
homogeneous suspension of the alum are critical to the success of the
final product. Once resuspension has been assured, the suspension may
be pumped into a vessel where inoculation will occur or inoculation may
be carried out in the storage container.
It is apparent that certain production, shipping and storage
problems exist with the current systems.
It is therefore the object of this invention to replace the
stainless steel container with a plastic system which is lighter, less
expensive, disposable, affords a procedure to resuspend any materials
that may settle over time, maintains sterility, and provides a means of
obtaining samples of the contents so that uniformity can be assured.
It is a further object to provide a system that can be used
where a sterile environment is not necessary.
In order to provide such a system the device must be
capable of assuming any needed volume. It must alsci be capable of
being sterilized and maintaining the sterile environment for extended
periods of time. Additionally, the surface of the device which comes in
contact with the vaccine suspension must not interact with the product.
CA 02256621 1998-11-25
WO 97/47377 PCT/US97/09821
-3-
That is, it must not absorb protein, adjuvants or other ingredients from
the suspension. Additionally, all fittings and connections to the device
must be sterilizable and must be capable of maintaining the sterility of
the product during storage.
In order to be practical in an environment including sterile
vaccines, the new system must be capable of resuspending alum within a
two hour period of time. More conveniently, the resuspension should
be possible within 30 minutes.
The product must also be capable of being shipped by
regular carrier over great distances or moved by conventional carts
inside a manufacturing area.
Since the uniformity of the suspension is critical to the
uniformity of the final vaccine product, the device must allow
dispensing of product with no apparent settling during the dispensing
period. In addition, the system must be designed to deliver as much of
the suspension as possible so that only a minimal amount of material is
retained within the system once dispensing is complete.
The device of this invention provides for a light weight,
sterilizable system capable of mixing, storing, resuspending, shipping
and dispensing solutions or suspensions. The instant device of this
invention has demonstrated the ability to overcome tile problems
discussed above and provide reliable, homogeneous suspensions for the
manufacture, mixing, storage and dispensing of aqueous suspensions.
SUMMARY OF THE INVENTION
A disposable transport, storage and resuspension system
for use in the manufacture of sterile and non-sterile liquids and
suspensions is presented comprising a collapsible container and a
support device, the collapsible container having means for ingress and
egress of fluids and solids into the container and means for mixing and
resuspending the contents of the container.
CA 02256621 2004-03-12
- 3a -
In accordance with one aspect of the invention, there is provided a system
for use in the manufacture of sterile and non-sterile liquids and suspensions
comprising:
a collapsible container and a support device,
the collapsible container having means for ingress and egress of fluids and
solids into the container, and
means for mixing and resuspending the contents of the container,
wherein the collapsible container comprises a flexible plastic container
having a top, bottom and sides which enclose a volume of space, the bottom of
the
container having a mixing block being weldably affixed inside the container.
In accordance with another aspect of the invention, there is provided a
collapsible container and a support device for use in the manufacture of
sterile and
non-sterile liquids and suspensions, the collapsible container having means
for
ingress and egress of fluids and solids into the container, and means for
mixing
and resuspending the contents of the container; the egress, mixing and
resuspending means comprising a closed loop mixing manifold which is external
to the container and a mixing block located inside the collapsible container.
CA 02256621 2004-03-12
WO 97147377 PCT/US97/098~21
-4-
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a cross section of the preferred embodiment of the system
which includes the collapsible container and the support device.
Figure 2 is a schematic diagram of the enclosed mixing system.
Figure 3(a) is a top view of the mixing block.
Figure 3(b) is an isometric view of the front of the mixing block.
Figure 4 is a side view of the mixing arms.
DETAILED DESCRIPTION QF THE INVENTION
There is disclosed a disposable transport, storage and
mixing system for use in the manufacture of sterile and non-sterile
liquids and suspensions comprising a collapsible container and a support
device, the collapsible container having means for ingress and egress of
fluids and solids into the container and means for mixing and
resuspending the contents of the container.
For the purpose of this invention, a "transport, storage and
mixing system" is a device which can be used to hold a volume of liquid
or liquid and solid in a manner which is suitable for shipping either
locally or over great distances, having the capacity to provide for
agitation of the contents. In one preferred embodiment of this
invention, the system is configured to provide for the storage, transport
and mixing of liquids or liquids and solids which are sterile. In a
further preferred embodiment of this invention, the system provides for
storage, transport and mixing of a suspension useful in the preparation
of a vaccine. In the most preferred embodiment of this invention, the
system provides for storage, transport and mixing of an alum suspension
that may be inoculated to produce a vaccine.
. The following description of .this invention is provided to
enable any person skilled in the art to make and use the present
invention and sets for the best mode contemplated by the inventor for
carrying out this invention. Various modifications, however, will
remain readily apparent to those skilled in these arts.
CA 02256621 1998-11-25
WO 97/47377 PCT/US97109821
-S-
While the present invention is described herein in the
context of a system for the storage, transportation and mixing of a
suspension of alum for use in the production of a vaccine, artisans will
understand that the present invention is not so limited. The present
invention has equal application to other fluids that require mixing,
sterile or non-sterile conditions, portability and ease of disposal.
Referring to Figure 1, a preferred version of the
collapsible container ( 1 ) and a support device {2) are shown. The
collapsible container ( 1 ) in the drawing includes means for ingress ( 15)
and egress ( 13) of fluids and solids into and out of the container and
means for mixing and resuspending ( 10, 11 and 12) the contents of the
container.
The collapsible container may be fabricated from any
suitable material that will function within the desired temperature range
and will not adversely impact the substance to be contained. By
"collapsible container" is meant that the container ( 1 ) will not support
its own weight. Therefore, when the container is empty, it collapses
upon itself. Since one of the primary functions of the container is for
use in the preparation of alum based vaccines, it is further preferred
that the collapsible container be designed to withstand sterilization using
Gamma irradiation or other suitable techniques which are known in the
art.
In a preferred embodiment of the invention, the collapsible
container is initially evacuated of air before being treated with Gamma
radiation. The collapsible container may then be shipped in its most
compact state and stored in this manner until needed. When a liquid is
added to the collapsible container, the container expands as needed in
response to the added volume of fluid. As a result of this feature, the
head space, or air volume, within the container is held to a minimum.
In a preferred embodiment of this device, a polymeric
material, such as linear low density polyethylene is used to produce the
collapsible container. This material meets the requirements set forth
above in that it will not interact with aqueous solutions or suspensions,
does not absorb the media or innoculum used to produce a vaccine and
CA 02256621 2004-03-12
wo ~~ia~~~ Pc~ertrs~~ro9am
_6_
is useful between about 1 °C to about 60° C. Other polymeric
materials
which meet the requirements of this device may also be used to
construct the collapsible container.
In the most preferred embodiment of the collapsible
container, the container comprises three layers, the inner most layers
comprising blown film polyethylene and the outer layer is a co-extruded
EVOH nylon.
The collapsible container ( 1 ) has means for ingress ( 15) and
egress (13) of fluids and solids into and out of the container. That is,
liquids, suspensions and mixtures of liquids and solids may be added to
the collapsible container through inlet means such as tube (15). The
chemical integrity and sterility of the collapsible container is assured
through the incorporation of valve means such as the hose clamps (14)
shown in Figure 1. Since the collapsible container is initially evacuated
before use, when clamp ( 14) of tube ( 15) is opened and fluid flows in,
the container expands and take the shape of the support device (2) or if a
support device is not present, the collapsible container expands to the
limits of its own shape.
The support device (2) allows for long distance transport of
the container ( 1 ). Additionally, the angle of the bottom of the support
device is crucial for both the suspension of the alum and for complete
draining of the container.
The collapsible container (l~ is also equipped with means
for mixing and resuspending the contents of the container. This is
accomplished in the preferred embodiment of the invention using a
short dip tube (10) and a full length dip tube (11) and a return tube
( 12), which are connected to a mixing block (60) which is fitted with a
plurality of mixing arms.
The mixing b-lock may be fabricated from low ~of high
density polyethylene. The tubing connected thereto may be any type of
flexible tubing suitable for the operation of the system.
Addition of tubing and various fittings is accomplished
using thermal welding. This may be accomplished using a Vertrod~Heat
Sealing Machine or other suitable device.
* trade-mark
CA 02256621 1998-11-25
WO 97/47377 PCT/US97/09821
_7_
With reference to Figure 2, the preferred means for mixing
and resuspending the contents of the container are shown
diagramatically in this view of the preferred device. In this preferred
embodiment, material from inside the collapsible container may be
withdrawn through the short dip tube ( 10) or the full length dip tube
( 11 ) depending upon the open or closed state of the snapper clamps ( 14)
attached to dip tubes ( 10) and ( 11 ). The material may be withdrawn
using, for example a peristaltic pump (32) and returned to the
collapsible container through return tube ( 12}. In practice, a piece of
tubing is included between the "Y" connector (30} and the pump (32)
and a second piece of tubing is included between the pump (32) and
return tube ( 12). This configuration results in a closed loop system for
mixing and resuspending the contents of the collapsible container which
maintains sterility and assures proper mixing.
Referring again to Figure 1, the short dip tube ( 10) may
protrude from about 1 % to about RO% of the distance from top of the
collapsible container to the bottom, when the container is full of liquid.
Using this tube, the liquids and solids contained within the collapsible
container are drawn from an area above the mixing block (60).
Additionally, the full length dip tube ( 11 ) may be used to withdraw
material from the container. This tube is connected to the mixing block
(60) and communicates the inside of the mixing block (60) with the
closed loop system.
A top view of the mixing block (60) is shown in Figure 3
(a). This block may be machined from a single piece of suitable plastic,
or in the alternative it may be molded either as one piece or as multiple
pieces which are then affixed using welding, gluing, mechanical
attachment or any other form of attachment known in the art. Port (61 )
is used to connected the full length dip tube ( 11 ) to the mixing block.
Port (62) receives the return tube ( 12). The material which is pumped
back through the return tube (12) is diverted in the mixing block and
channeled to the spray arms (66) which are shown in Figure 1, and are
attached to the mixing block at ports (64). The contents of the
collapsible container may be evacuated through egress tube (13) which
CA 02256621 1998-11-25
WO 97/47377 PCT/LJS97/09821
is connected to the mixing block (60) at port (63). As indicated in
Figure 3(b), the bottom of the mixing block has openings (65) which
communicate the inside of the container with the full length dip tube
( 11 ). Therefore, when the contents of the container ( 1 ) are circulated
using full length dip tube ( 11 ), mixing from the bottom of the container
is assured.
A side view of the spray arms is shown in Figure 4. Each
spray arm consists of a hollow tube which is open at the end which fits
within port (64) of the mixing block and is closed at the opposite end.
Each of the spray arms contains a plurality of apertures which
communicate the inside of the collapsible container ( 1 ) with the inside of
the mixing block (60). In practice, material from within the tank is
circulated through the closed loop and pumped back Into the mixing
block (60) where it is channeled into the spray arms {66) and exits
through orifice (70). The position of the various orifices {70) relative
to the base of the container is as follows:
The mixing arm has a primary set of holes drilled
longitudinally along the bottom of the arm (71 ) which allows fluid to
sweep the region of the container under the arm. A secondary set of
holes, useful in mixing and resuspending material within the container,
is drilled along the side of the arm. Beginning at a point closest to the
block, the first hole is drilled at an angle of 0°. The subsequent
holes
along the side of the arm are set at increasing angles up to 45°. The
fluid exiting from these secondary holes creates a swirling vortex flow
pattern that sweeps the side of the barrel and lifts any sediment towards
the upper regions of the bag.
In the preferred embodiment, the mixing tubes are
positioned within the mixing block (60) using locator rods (68) as
shown in Figure 4. This allows for accurate and reproducible
positioning of the orifices during manufacture.
The mixing arms are machined with a set of longitudinal
slots (67) in the fitted end. One slot is larger than the others so as to
accommodate a locator pin. The main body of the mixing block is
machined with holes designed to receive the fitted ends of the arms.
CA 02256621 1998-11-25
WO 97/47377 PCT/US97/09821
-9-
The hole design uses a barbed interference fit. The locator pin is
inserted into a small pilot hole inside the block. The arms are inserted
into the block with the larger slot sliding over the locator pin. The
locator pins are situated in the same place on each block to ensure that
the arms are properly oriented during manufacture.
The most preferred embodiment of this device is a system
for use in the manufacture of vaccines which comprises: a collapsible
container and a support device, the collapsible container being flexible
and having a top, bottom and sides which enclose a volume of space, the
bottom of the container having a mixing block being weldably affixed
inside the container, the mixing block having a top, bottom and sides,
the mixing block further having a plurality of recirculation outlets; the
mixing block having a plurality of openings which communicate the
inside of the mixing block to the inside of the container; the sides of the
mixing block having a plurality of spray arms, the spray arms being
directed from the bottom of the container to the sides and top of the
container, the spray arms being hollow and attached to the mixing
block, the top end of the spray arms being sealed, the spray arms having
a plurality of holes which communicate the inside of the container with
the inside of the spray arms; the top of the container having an inlet tube
which provides for ingress of fluids and solids into the container, the
top of the container further having a long dip tube which extends from
outside the top of the container through the top of the container and
inside the container where it terminates in the mixing block, the long
dip tube being hollow and communicating the inside of the container, at
the bottom of the mixing block, with the outside of the container, the
portion of the long dip tube which extends outside the top of the
container terminating in a "Y" fitting; the top of the container further
having a short dip tube which extends from outside the top of the
container, through the top of the container and inside the container to a
distance from about 1 % to about 80% of the length of the container, the
portion of the short dip which extends outside the top of the container
terminating in the other arm of the "Y" fitting that is connected to the
long dip tube; the top of the container further having a recirculating dip
CA 02256621 1998-11-25
WO 97/47377 PCT/US97/09821
- 10-
tube which extends from outside the top of the container to the mixing
block, the portion of the recirculation dip tube which extends outside the
top of the container terminating in a valve, such that when the valve is
open, the recirculation dip tube communicates the outside of the
container with the inside of the inside of the mixing block; an external
recirculation loop being attached to the leg of the "Y" fitting connected
to the long dip tube and to short dip tube, the recirculation loop having
means for pumping the liquid from the short dip tube or the long dip
tube, depending upon the positions of the snapper clamps attached to the
long and short dip tubes, to the recirculation dip tube, the liquid then
moving out the mixing block and through the spray arms; the top of the
container further having a pump out tube which extends from outside
the top of the container to the mixing block, the portion of the pump out
dip tube which extends outside the top of the container terminating in a
valve, such that when the valve is open, the pomp out dip tube
communicates the outside of the container with the inside of the mixing
block;the outside of the container having tabs which allow the container
to be fastened to the support device; the support device being a rigid
frame capable of holding the container in position when in use; wherein,
a solution or suspension is introduced into the container through the
inlet tube and mixed or resuspended by pumping the contents from the
container through the short or long dip tube, through the recircuiating
loop and back into the container through the recirculating dip tube; the
solution or suspension may be pumped out of the container using the
pump out tube.
The closed loop mixing feature has been shown to be
particularly effective in resuspending alum which has settled from a
suspension. In the preferred embodiment of the invention, the pump has
a flow capacity of from about 0.5 L/min to about 50 L/min. The most
preferred flow velocity is about 20 L/min. In a series of studies, 200 L
of an alum suspension was introduced into the collapsible container and
allowed to stand. At the end of one week, the resuspension of this
material was examined using nephlometric measurements of the
suspended alum as a function of mixing time. The pump was operated
CA 02256621 2004-03-12
~l~'~ ~Tt4'1~'fy ~~'~'~18~T/09~1~
-iI°°
at 20 L/min and samples were taken after first bacl~ flushing the system for a
period of 15 minutes. A homogeneous suspension was achieved after mixing
for about 30 minutes. In a similar study, where the suspension was allowed to
settle for one month, a homogeneous suspension was again reached in about
30 minutes.
The etosed locip rniXing system also provides a- means for
maintaining homogeneity during delivery of the suspension. after
resuspending material which had settled, the concentration of alum in
pg/ml of the suspension was determined during the emptying of the
System. Suspensions that stood for one week
or one month, both maintained homogeneity during the emptying
operation.
Since it is often necessary to sample the material within the
collapsible container, sampling means, such as removable tubes (40)
may be included within the loop. This is shown schematically in Figure
2. The sampling tubes consists of an elastomeric tubing with a sterile
plug in the end. This tubing is connected via a sterile welder to another
piece of elastomeric tubing connected to the sampling vessel.
In this disclosure, there is shown and described only the
preferred embodiment of the invention; but, as aforementioned, it is to
be understood that the invention is capable of changes or modification
within the scope of the inventive concept as expressed herein.
