U.S. patent application number 11/494671 was filed with the patent office on 2007-11-15 for serially linked containers for containing a sterile solution.
Invention is credited to Craig Johnson.
Application Number | 20070262076 11/494671 |
Document ID | / |
Family ID | 35457377 |
Filed Date | 2007-11-15 |
United States Patent
Application |
20070262076 |
Kind Code |
A1 |
Johnson; Craig |
November 15, 2007 |
Serially linked containers for containing a sterile solution
Abstract
The invention relates to a system which can be sterilized, for
preparing individual containers to be filled with a substantially
accurately predetermined volume of a sterile solution, which
comprises at least one string of containers comprising at least two
containers which are: serially linked or serially pre-attached to
one another to form a single tubing, predefined to regulate
individual container fill volume either by partial partition of
said single tubing or by specification which is indicative of the
boundaries of the individual containers, and made of a
substantially non-deforming material, one extremity of each of the
at least one string of containers comprising a single inlet for the
sterile solution and the other extremity comprising a single outlet
for air and/or for the sterile solution, said single tubing being
the exclusive flowing means for the sterile solution and for air,
when present, from the single inlet to the single outlet of the
string of containers.
Inventors: |
Johnson; Craig; (Mission
Viejo, CA) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET
2ND FLOOR
ARLINGTON
VA
22202
US
|
Family ID: |
35457377 |
Appl. No.: |
11/494671 |
Filed: |
July 28, 2006 |
Current U.S.
Class: |
220/4.13 |
Current CPC
Class: |
A61J 1/10 20130101; B65B
3/04 20130101; B65B 43/123 20130101; A61M 5/1413 20130101; A61J
1/12 20130101; A61J 1/1406 20130101; A61J 1/05 20130101; A61M
5/1411 20130101; A61J 1/1487 20150501; A61J 1/1418 20150501; A61M
5/162 20130101 |
Class at
Publication: |
220/004.13 |
International
Class: |
B65D 6/00 20060101
B65D006/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2005 |
EP |
05 291 613.7 |
Claims
1. A system which can be sterilized, for preparing individual
containers to be filled with a substantially accurately
predetermined volume of a sterile solution, which comprises at
least one string of containers comprising at least two containers
which are: serially linked or serially pre-attached to one another
to form a single tubing, predefined to regulate individual
container fill volume either by partial partition of said single
tubing or by specification which is indicative of the boundaries of
the individual containers, and made of a substantially
non-deforming material, one extremity of each of the at least one
string of containers comprising a single inlet for the sterile
solution and the other extremity comprising a single outlet for air
and/or for the sterile solution, said single tubing being the
exclusive flowing means for the sterile solution and for air, when
present, from the single inlet to the single outlet of the string
of containers.
2. The system of claim 1, further comprising means for air
displacement and connecting means, said means for air displacement
being connected to the single outlet of each of the at least one
string of containers via said connecting means.
3. The system of claim 2, wherein said means for air displacement
comprise at least one pre-sterilized venting bag or at least one
sterile barrier filter.
4. The system of one of claims 1 to 3, further comprising at least
one reservoir for sterile solution, said at least one reservoir of
sterile solution being optionally connected to the single inlet of
each of the at least one string of containers.
5. The system of claim 1 to 4, characterized in that, when the
sterile solution is present inside the system and in particular
when the reservoir for sterile solution is full, said system is
closed relative to the ambient environment, so that there is no
contact between the sterile solution and air, when present, inside
the system on the one hand and the ambient environment outside the
system on the other hand.
6. The system of one of claims 1 to 5, comprising a single string
of containers, means for air displacement and a single reservoir
for sterile solution, the means for air displacement being
connected to the single outlet of the single string of containers
via connecting means, and the single reservoir for sterile solution
being optionally connected via additional connecting means to the
single inlet of the single string of containers.
7. The system of one of claims 1 to 5, comprising at least two
strings of containers, means for air displacement and a single
reservoir for sterile solution, the at least two strings of
containers being placed in parallel, the means for air displacement
being connected to the outlets of all the strings of containers via
connecting means, and the single reservoir for sterile solution
being optionally connected to the inlets of all the strings of
containers via additional connecting means.
8. The system of one of claims 1 to 5, comprising N strings of
containers (N.gtoreq.2), N individual means for air displacement,
and a single reservoir for sterile solution, the N strings of
containers being placed in parallel and each of the N individual
means for air displacement being connected to the outlet of one
single string of containers among the N strings of containers via
connecting means, and the single reservoir for sterile solution
being connected to the inlets of the N strings of containers via
additional connecting means.
9. The system of one of claims 1 to 8 wherein said substantially
non-deforming material is a substantially rigid material.
10. The system of one of claims 1 to 8 wherein said substantially
non-deforming material is a flexible material whose deformation is
limited by applied forces such as framing means or an externally
applied mold which regulates the container volume.
11. The system of one of claims 1 to 10 wherein said substantially
non-deforming material is sufficiently non-deforming in order for
each container to be filled with a predetermined volume of said
sterile solution with a better accuracy than 20%, in particular
with a better accuracy than 10%, and in particular with a better
accuracy than 5%.
12. The system of one of claims 1 to 11, comprising at least one
reservoir for sterile solution and wherein said at least one
reservoir for sterile solution is made of a flexible material.
13. The system of one of claims 2 to 12, wherein the means for air
displacement comprise at least one venting bag and wherein said at
least one venting bag is made of a flexible material.
14. The system of one of claims 1 to 13 wherein all containers have
the same volume.
15. The system of one of claims 1 to 13 wherein at least some of
the containers have different volumes.
16. The system of one of claims 1 to 15 wherein the volume of each
individual container independently ranges from about 0.1 mL to
about 200 mL.
17. The system of one of claims 1 to 16 wherein the number of
individual containers per string of containers independently ranges
from 2 to about 100.
18. The system of one of claims 1 to 17 wherein the number of
strings of containers ranges from 1 to about 20.
19. The system of one of claims 1 to 18 wherein the containers are
selected among the group composed of vials, formed containers,
pouches, or bags.
20. The system of one of claims 1 to 19 wherein at least one of the
individual containers further comprises at least one individual
port per container for extracting sterile solution and optionally
at least one other individual port per container for letting in air
when sterile solution is extracted.
21. The system of one of claims 1 to 20 wherein the at least one
string of containers is made of a single tube of constant
cross-section, the containers being predefined by a specification
which is indicative of the boundaries of the individual containers,
each container optionally comprising one or two individual ports
such as capped ports and in particular such as capped female Luer
ports.
22. The system of one of claims 1 to 20 wherein the at least one
string of containers is made of a single tubing comprising portions
of tube alternated with flow-through couplings and in particular
male-female Luer connections, the containers being partly
predefined by a specification which is indicative of the boundaries
of the individual containers and by said flow-through couplings,
each container optionally comprising individual ports in particular
for attachment to a capped sterile vent.
23. The system of one of claims 1 to 20 wherein the at least one
string of containers is made of a single tubing comprising
alternated portions of tubing of respectively larger and smaller
cross-section, and wherein the individual containers are
substantially predefined by the alternation of said portions of
tubing and each individual container optionally comprises an
individual port such as a capped port.
24. The system of one of claims 1 to 20 wherein the at least one
string of containers is made of a substantially rigid material and
the individual containers are substantially predefined as strings
of formed containers by partial partition of the single tubing and
optionally comprise at least one individual port such as a capped
port.
25. The system of one of claims 1 to 24 wherein the containers are
designed with materials and shapes which are resistant to cracking
when cycled through freezing and thawing and which does not entrap
air pockets within the containers their access ports or the fill
ports.
26. A method for preparing individual containers to be filled with
a substantially accurately predetermined volume of a sterile
solution comprising the steps of: providing a system according to
any one of claims 1 to 25 comprising at least one reservoir for
sterile solution and additional connecting means, said at least one
reservoir for sterile solution being connected to the single inlet
of each of the at least one string of containers via said
additional connecting means; injecting the sterile solution from
said at least one reservoir filled with sterile solution into the
at least one string of containers via the single inlet of the at
least one string of containers, so as to provide individual
containers filled with a predetermined volume of sterile solution;
sealing the at least one string of containers by sealing means at a
plurality of positions, so as to provide filled, separate,
individual containers; and optionally detaching each individual
container from the at least one string of containers by detaching
means, so as to provide filled, separate, detached, individual
containers.
27. The method of claim 26, wherein the system remains closed
relative to the ambient environment during the steps of injecting
the sterile solution into the at least one string of containers and
of sealing the at least one string of containers, so that there is
no contact between the sterile solution and air, when present,
inside the system on the one hand and the ambient environment
outside the system on the other hand.
28. The method of claim 26, wherein the system remains open
relative to the ambient environment until the sealing of the at
least one string of containers, the sterility of the sterile
solution being maintained at all steps via at least one filtering
means.
29. The method of one of claims 26 to 28, wherein the system
comprises at least one venting bag for displaced air which is
connected to the outlets of the at least one string of containers
and which is mostly empty prior to injecting the sterile solution
into the at least one string of containers.
30. The method of one of claims 26 to 29, wherein the injection of
the sterile solution into the at least one string of containers is
made from the top to the bottom or from the bottom to the top by
means of hydrostatic pressure or of filling means such as a
peristaltic pump.
31. The method of one of claims 26 to 30, wherein the injection of
the sterile solution is made from the bottom to the top, whereby
air bubbles in the containers are substantially avoided.
32. The method of one of claims 26 to 31, wherein the sealing of
the containers of each of the at least one string of containers is
carried out by sealing means either after the filling of said
string of containers, or after the complete filling of all of the
at least one string of containers.
33. The method of one of claims 26 to 32, which comprises the
additional final step of freezing and optionally thawing the
sterile solution inside the containers, optionally more than once,
without stress fractures appearing on said containers.
34. The method of one of claims 26 to 33, wherein the individual
containers filled with a predetermined volume of sterile solution
obtained after the step of injecting the sterile solution or the
filled, separate, individual containers obtained after the step of
sealing or the filled, separate, detached, individual containers
obtained after the optional step of detaching are subsequently used
for cellular or clinical applications.
Description
[0001] The present invention relates to serially linked containers
for containing a sterile solution.
[0002] There are currently two types of systems for distributing
aliquots of sterile pharmaceuticals: [0003] open systems which are
implemented under tightly controlled environmental conditions, and
[0004] closed systems which require minimal environmental
controls.
[0005] Open systems are typically implemented in a biological
cabinet or laminar flow cabinet which passes highly purified air in
a defined direction across the work area. While this environment is
the traditional use, it is susceptible to exposure to occasional
viable particles, does not usually filter out many virus particles,
and is expensive to maintain. Nevertheless, many open systems are
currently in operation and use.
[0006] A first example of open system for distribution in
controlled environments is the pipette, in the case of small
volumes of bulk (less than about 20 ml). The pipette is not
designed to work as a closed system. Using a pipette, fluid may
reach the exit port and either plug the filter, be lost through the
exit port or become non sterile. The working tip of the pipette is
not connected in such a way that the incoming or exiting fluid is
shielded from the environment in which it is being used.
Furthermore, closure of the receptacle is usually manual. Thus,
this system relies heavily on the sterile environment around
it.
[0007] A second example of open system for distribution in
controlled environments is the syringe, still in the case of small
volumes of bulk (less than about 60 ml). The syringe or repeater
pipette could be used in a nearly closed environment. However, the
inside of the syringe barrel is exposed to the environment and the
plunger maintains a resistive but not fully sealed closure during
the draw of material into the barrel. Besides, the connection of
the syringe or repeater pipette to the source and receptacle is
typically done in an open manner. Moreover, closure of the
receptacle may be done manually. As an open process, this system
must be implemented in a tightly controlled environment in order to
maintain sterile aliquots.
[0008] Automated systems are yet another example of open systems.
These systems inject the material into an open vial which may then
be closed using any of several options. Again, because of the open
nature of the process, the fill must be completed in a tightly
controlled environment. Such systems typically do not allow for
single use sterile disposable sets. Thus cleaning and cleaning
validation may add risk to concerns about cross contamination of
products. Setup for these systems is also typically not practical
for small numbers of aliquots. Maintenance and validation of the
systems may also be relatively complicated for small volume
distributions.
[0009] Regarding closed systems, these have also been commonly used
in laboratories around the world. Usually, closed systems which are
in use in laboratories connect each aliquot in parallel to the
source. The connection may be made prior to sterilization or by
sterile connection of pre-sterilized sets.
[0010] U.S. Pat. No. 4,937,194, assigned to Baxter International,
discloses a typical closed system for the metering of nutrient
media into cell culture containers placed in parallel. U.S. Pat.
No. 4,021,283 discloses a method of making aseptic packaging,
consisting of forming a web of bags, filling them with a sterile
product and sealing them without exposing the sterile product to
the ambient air. Yet, although this system of interconnected bags
is closed by itself, it does not avoid the drawbacks of an open
system since the containers have to be filled by introducing a
filling pipe into the web of bags.
[0011] Canadian application No. 2,025,498 discloses another example
of a bag set design, method and apparatus for preparing bags of
sterile solution. This document provides for a long, tubular bag
element, which can be filled with a sterile solution through a
sterilized filter. A major inconvenience of this closed system is
that particular care has to be taken if the precision of the volume
of solution in each container is important: a weighing pan or a
flow meter has then to be used to meter a defined volume or weight
of the sterile solution.
[0012] International application No. WO 2005/030586 discloses a
container filling assembly for sterilely filling containers within
a closed system. This system includes a single inlet for supplying
a fluid to the containers, connecting means that branch out to each
individual container, and a vacuum source for driving the fluid
inside the containers. The use of a vacuum source proposed by this
document raises the problem of a possible leakage of ambient air
into the vials, compromising the sterility of one or more vials,
and a possible leakage of the fluid into the vacuum source.
Besides, if the whole set of containers cannot be entirely filled,
as is for instance the case when the reservoir of fluid is
insufficiently filled with fluid, several containers (and not just
one container) will then probably be only partially filled with
fluid, which will not enable to obtain a set of accurately filled
containers. This inconvenience is inherent in parallel container
filling assemblies, such as the hub and spoke container assembly of
WO 2005/030586, wherein all containers are to be filled essentially
simultaneously. Additionally, fluid losses in the tubing set will
be substantial for small volume fills and the sheer associated with
filling under vacuum may be disadvantageous to sheer sensitive
products such as cellular products.
[0013] Furthermore, a system for distributing aliquots of sterile
pharmaceuticals may need to be frozen for storage. In this respect,
the technical issue of providing a set of individual containers
liable to be filled with a sterile solution and then to be frozen
(down to the temperature of liquid nitrogen) and thawed, has not
been correctly addressed by prior art methods either. One standard
practice includes methods of injecting aliquots into open vials
which are then closed with screw on caps. The requirement for
manual manipulation makes this process unduly susceptible to errors
such as spilling, sterility breeches, cross contamination, and lot
mix-up prior to labeling. These systems are also susceptible to
contamination during storage in liquid nitrogen by transmission
through caps which may not be securely sealed. On occasion, such
containers may leak, crack, or explode upon thawing as internal
liquid phase nitrogen rapidly converts to the gas phase. A more
closed system is also commonly used which incorporates closed bags.
Such bags when filled commonly contain pockets of air which must be
removed manually to prevent leaking, splitting and explosion upon
thawing as described above. This system is also limited to volumes
greater than about 10 mL since for smaller volumes, accuracy and
losses become substantial.
[0014] In other terms, the technical issue of providing a system
for rapidly filling a number of containers with an accurately
predetermined volume of solution in sterile conditions, said
containers being optionally well adapted for subsequent freezing
and thawing, has not been satisfactorily addressed by prior
art.
DESCRIPTION OF THE INVENTION
[0015] One object of the invention is to provide a system with a
single use disposable set, for the sterile distribution of liquid
material (notably pharmaceuticals or biological products in a
sterile environment) into smaller aliquots, the volume of liquid
material in each aliquot being substantially accurately determined
by the controlled volume of receptacle containers without using any
metering device.
[0016] Another object of the invention is to provide a set of
containers filled from a single fill which may be stored in a
connected state if desired.
[0017] Another object of the invention is to provide a method for
rapidly filling many containers with fixed volumes in a
substantially closed environment with minimal if any waste.
[0018] Another object of the invention is to provide a method of
filling where air bubbles are substantially avoided and where
filled containers are well adapted for subsequent freezing
(potentially to cryogenic temperatures) and thawing.
[0019] Another object of the invention is to provide a method of
filling which can be implemented for example in a laboratory but
also on a commercial or even industrial scale, in the context of
preparing relatively large numbers of aliquots of sterile
solution.
[0020] The different objects of the invention are achieved by
providing a chain of aliquot containers pre-connected in a serial
fashion, the individual volume of which is pre-determined by
container design or by applied forces, and by filling the serially
connected containers via a single flow of sterile solution, in
particular opposite the direction of the gravitational or inertial
forces.
[0021] The invention relates to a system which can be sterilized,
for preparing individual containers to be filled with a
substantially accurately predetermined volume of a sterile
solution, which comprises at least one string of containers
comprising at least two containers which are: [0022] serially
linked or serially pre-attached to one another to form a single
tubing, [0023] predefined to regulate individual container fill
volume either by partial partition of said single tubing or by
specification which is indicative of the boundaries of the
individual containers, and [0024] made of a substantially
non-deforming material,
[0025] one extremity of each of the at least one string of
containers comprising a single inlet for the sterile solution and
the other extremity comprising a single outlet for air and/or for
the sterile solution,
[0026] said single tubing being the exclusive flowing means for the
sterile solution and for air, when present, from the single inlet
to the single outlet of the string of containers.
[0027] Examples of a sterile solution to be used according to the
invention are cellular suspensions, diagnostic particle
suspensions, and single access injectable pharmaceutical
products.
[0028] By "string" is also meant a chain or series or sequence; by
"containers" is also meant aliquots or receptacles, especially
those that are adapted for use in the context of the handling,
storage and subsequent use of a sterile solution, especially in the
medical or scientific context.
[0029] By "serially linked" is meant that the string of containers
is in fact only one continuous piece of tubular material without
internal connections, in which the individual containers are only
virtually delimited but not physically delimited.
[0030] By "serially pre-attached" is meant that the string of
containers is composed of physically distinct pieces of tubular
material which are serially attached or connected via
connections.
[0031] The serial nature of the linkage, respectively of the
pre-attachment, refers to a configuration in which each container
is linked, respectively pre-attached, to two neighboring containers
on two respective sides, except the two containers that are at the
respective extremities (inlet and outlet) of the string and that
are in contact with only one other container.
[0032] By "single tubing" is meant a single stretch of material or
materials forming a hollow vessel. The single tubing may be made
either of several serially linked tubes or of several serially
pre-attached tubes. If the single tubing is made of several
serially pre-attached tubes, there may be a longitudinal overlap
between some tubes, for instance if one extremity of a tube of
smaller diameter is embedded in the extremity of another tube of
larger diameter.
[0033] By "predefined to regulate individual container fill volume"
is meant that the dimensions and thus the volume of each container
of the string of containers, once filled, correspond to fixed and
predetermined values, even though: [0034] the string forms a single
tubing which may be made of only one piece of tube, the individual
containers being not necessarily physically delimited on the tubing
and [0035] the dimensions and/or volume of each individual
container not filled with sterile solution, i.e. in particular when
empty or partially or totally filled with air, may be undefined or
not accurately defined.
[0036] By "partial partition" of the tubing is meant either a
partial transversal sealing of the tubing or any other physical
delimitation of individual chambers or containers within the
tubing, such as successive transversal walls partially obstructing
the tubing.
[0037] By "specification which is indicative of the boundaries of
the individual containers" is in particular meant either one of the
following: [0038] marks on the outside of the tubing or in the
inside of the tubing (in case the tubing is made of an at least
partly transparent material); [0039] a predefined mold or fixture
applied to the tubing; [0040] a predetermined location or
dimension; [0041] a set of connections between different tube
portions serially connected to form the single tubing.
[0042] By "exclusive flowing means" is meant that the system is not
provided with any other flowing means for air and/or the sterile
solution than the serially linked containers. The single tubing is
the only flowing path for air and/or the sterile solution. In
particular, 10 there is no need for a fill tube to be inserted
inside the string of containers to fill them. It has to be noted
that the flow path which defines the direction of the air flow or
of the flow of sterile solution can be a straight line but also a
curved or a zigzag line according to particular configurations.
[0043] The tubing or its components can be made for instance of
rigid or flexible PVC (polyvinyl chloride), ABS (acrylonitrile,
butadiene, and styrene), PETG (polyethylene terephtalate glycol),
EVA (ethylene vinyl acetate), Teflon, polycarbonate, ABS
(acrylonitrile-butadiene-styrene) or other plastics, glass, metal
etc.
[0044] The system of the invention can be provided: [0045] empty;
or [0046] partially or totally full of air; or [0047] partially
filled with a sterile solution or in the course of a process of
filling with a sterile solution; or [0048] full of sterile solution
(possibly with bubbles of air).
[0049] It should be understood that all references that are made to
"air" in the present application usually relate to the ambient air
or atmospheric air but can also represent any other gas or
combination of gases if the system of the invention is placed in or
put in contact with another gas or combination of gases instead of
the ambient air.
[0050] It should also be understood that all references to a
"sterile solution" could also represent any non-sterile solution
that is sterilized once the system has been filled with said
solution.
[0051] In fact, in certain applications which involve filled
containers of sterile materials, the material prior to filling is
not sterile. In such applications, it is sometimes required to work
in an environment where the bio-burden is controlled but rigorous
aseptic technique is not required. In such applications, it is
possible to either sterilize just prior to filling or to fill first
and sterilize afterwards. Sterilization prior to filling can be
accomplished by filtering, heating, radiation, or other means.
Following sterilization, careful aseptic techniques and tight
environment control are required as described above for any open
processing steps in order to maintain sterility. Advantages of the
invention described herein for this situation have been discussed
above. Sterilization following filling can be accomplished by heat,
radiation, or other techniques. In such an instance, the filling is
done in a clean environment for the open steps to minimize the
bio-burden. Following the fill, sterilization is accomplished by
exposing the filled containers to heat or steam, radiation, or
other mechanisms. Thus, the invention described herein may apply to
such fills which are open or partially open during fill but which
are closed when sterilized, because of the advantages associated
with the clean and potentially biocompatible environment
provided.
[0052] The invention more particularly relates to the
above-mentioned system, further comprising means for air
displacement and connecting means, said means for air displacement
being connected to the single outlet of each of the at least one
string of containers via said connecting means.
[0053] The means for air displacement are in particular useful for
chasing air, if present, from the system at the time said system is
being filled with the sterile solution.
[0054] Examples of "connecting means" are pre-connection by various
weld or bonding methods, sterile connection devices such as the SCD
devices made by Terumo.RTM. or single use sterile connecting
devices.
[0055] In a particular embodiment, said means for air displacement
comprise at least one pre-sterilized venting bag or at least one
sterile barrier filter.
[0056] By "venting bag" is meant a container designed to be filled
with air chased from the system when filling the at least one
string of containers with the sterile solution.
[0057] By "sterile barrier filter" is meant a filter which is
typically available commercially and which allows the air chased
from the system when filling the at least one string of containers
with the sterile solution to pass from the system without either
exposing the sterile solution to environmental air contaminants or
exposing environmental air to the solution contents.
[0058] The above-mentioned system advantageously further comprises
at least one reservoir for sterile solution, said at least one
reservoir of sterile solution being optionally connected to the
single inlet of each of the at least one string of containers.
[0059] By "optionally connected" is meant that a system with a
reservoir for sterile solution connected to the at least one string
of containers as well as a system with a separate reservoir for
sterile solution to be subsequently connected to the at least one
string of containers are both within the scope of the present
invention.
[0060] The advantage of having the reservoir connected to the
system is that the connection step is not required at the time of
fill. However, the advantage of not having the reservoir
pre-connected, is that the reservoir may be handled separate from
the filling system as may be preferred in the case of culturing or
storage of the bulk sterile solution prior to fill.
[0061] Maintaining sterility during connection of reservoirs or
other components which are not pre-connected, may be accomplished
using devices such as spikes or interconnecting Luers in an aseptic
environment or by using closed connecting systems such as
heat-welded sterile connecting devices.
[0062] The system may comprise more than one reservoir for sterile
solution, in particular if the sterile solution is obtained by
mixing the contents of two or more reservoirs.
[0063] The system may comprise a sterilizing filter or other means
of fluid sterilization between the outlet of the reservoir and the
inlet of the at least one string of containers for sterilizing the
content of the reservoir during the fill step, in which case the
sterile solution is in fact considered sterile only once it has
been injected into the at least one string of containers.
[0064] Examples of reservoirs include bags, pouches, burettes
(optionally provided with an air filter), bottles etc.
[0065] Advantageously, when the sterile solution is present inside
the system and in particular when the reservoir for sterile
solution is full, the system is closed relative to the ambient
environment, so that there is no contact between the sterile
solution and air, when present, inside the system on the one hand
and the ambient environment outside the system on the other
hand.
[0066] Such a closed system can be typically provided with a
venting bag and reservoir such as defined above.
[0067] According to an advantageous embodiment, the above-mentioned
system comprises a single string of containers, means for air
displacement and a single reservoir for sterile solution, the means
for air displacement being connected to the single outlet of the
single string of containers via connecting means, and the single
reservoir for sterile solution being optionally connected via
additional connecting means to the single inlet of the single
string of containers.
[0068] The serial nature of this system implies a number of
advantages relative to currently available systems in terms of
filling the individual containers of the system with the sterile
solution. [0069] The filling process is quick. Little time is also
required to eliminate air from the containers. Speed of fill is a
particularly important factor when dealing with suspensions such as
cell suspensions which settle over time or where chemical or
biological degradation may occur. [0070] Losses and waste are
potentially minimized in the connecting pathways. [0071] Serial
connections make filling easy. In the case of serial connections,
the operation is like a classical production line: the operator
directs the sterile solution into a string of containers. This
string of containers is then managed as a single container as it is
filled. [0072] The system and method of the invention allow a
reduction in cost of the overall filling process.
[0073] Furthermore, the accuracy of the filling is based on the
volume of the containers and does not rely on any device for
metering the volume or weight of fluid to be injected.
[0074] According to another advantageous embodiment, the
above-mentioned system comprises at least two strings of
containers, means for air displacement and a single reservoir for
sterile solution, the at least two strings of containers being
placed in parallel, the means for air displacement being connected
to the outlets of all the strings of containers via connecting
means, and the single reservoir for sterile solution being
optionally connected to the inlets of all the strings of containers
via additional connecting means.
[0075] Alternatively, when two or more strings of containers are
present, using an analogy with components in an electric circuit,
any combination of parallel and serial associations of strings is a
possible configuration for the system of the invention.
[0076] The advantage of parallel strings includes the ability to
have a large number of containers in a short distance. For manual
manipulation, a large number of containers in a short distance may
be advantageous since the operator can reach each of the available
containers during the fill and closure of containers. Another
advantage may be the control of container volume particularly when
a mold or fixture is used.
[0077] According to a more particular embodiment, said system
comprises N strings of containers (N.gtoreq.2), N individual means
for air displacement, and a single reservoir for sterile solution,
the N strings of containers being placed in parallel and each of
the N individual means for air displacement being connected to the
outlet of one single string of containers among the N strings of
containers via connecting means, and the single reservoir for
sterile solution being connected to the inlets of the N strings of
containers via additional connecting means.
[0078] In this embodiment, multiple strings of serially linked
containers are connected in a parallel manner so that the multiple
strings of serially linked containers can be filled in a manner
similar to that described for a single string.
[0079] The parallel strings of serially linked containers can be
filled either simultaneously or at different times (for instance by
temporarily obstructing some of the strings while filling the
others).
[0080] More particularly the above-mentioned system can comprise N
strings of containers (N.gtoreq.2), wherein said connecting means
are branched connecting means which comprise N+1 extremities, one
of said N+1 extremities being connected to the means for air
displacement and each of the other N extremities being connected to
the outlet of a single one of the N strings of containers, and
wherein said additional connecting means are branched additional
connecting means which comprise N+1 extremities, one of said N+1
extremities being optionally connected to the single reservoir for
sterile solution and each of the other N extremities being
connected to the inlet of a single one of the N strings of
containers.
[0081] According to a preferred embodiment, the said substantially
non-deforming material is a substantially rigid material.
[0082] Examples of such "substantially rigid material" are the
following: ABS, polycarbonate, glass, or metal.
[0083] According to an alternative preferred embodiment, the
substantially non-deforming material is a flexible material whose
deformation is limited by applied forces such as framing means or
an externally applied mold which regulates the container
volume.
[0084] Examples of such "flexible material" are the following:
flexible PVC, thin sheets of Teflon, EVA.
[0085] The use of applied limiting structures renders the flexible
material "substantially rigid" by preventing or limiting its
deformation. More precisely the flexible material can be allowed to
expand up to a certain maximal volume, said maximal volume being
set by the framing means or externally applied mold. The use of
these externally applied limits is a major factor of volume
accuracy when filling the individual containers with the sterile
solution and sets the volume largely independent of filling
pressure.
[0086] Examples of such framing means or externally applied mold
are: externally applied frames or fixtures which limit deformation
from the outside of the container, framing which is integral to the
container walls which limit the deformation of the container such
as limitations imposed by the elastic nature of the wall material
itself or an integral mesh in the walls of the container which has
limiting elastic stretch, externally applied molds or tooling which
define and limit the shape of the filled container prior to the
final partitioning of the containers.
[0087] According to an advantageous embodiment, said substantially
non-deforming material is sufficiently non-deforming in order for
each container to be filled with a predetermined volume of said
sterile solution with a better accuracy than 20%, in particular
with a better accuracy than 10%, and in particular with a better
accuracy than 5%.
[0088] The accuracy that can be expected depends in particular on
the volume, shape, nature of materials, and assembly requirements
of the individual containers. Bigger volumes usually yield a
greater relative accuracy. Minimizing the complexity of shapes and
the number of connections may improve accuracy since fewer
variations are then introduced during assembly of the string of
containers. Tubular or spherical containers are more structurally
sound than containers with large broad flat surfaces made of
comparable materials. Thus, round containers tend to be less prone
to dimensional variance. Furthermore, round containers tend to have
less variance in volume for minor distortions than containers with
large broad flat surfaces. Making containers of a rigid material
may also favor accuracy due to the minimal deformation of rigid
containers. Moreover, assembly of the strings of containers usually
introduces variation. Thus, containers well adapted for minimal
manipulation will tend to have more accurate volumes.
[0089] According to an advantageous embodiment, the system
comprises at least one reservoir for sterile solution which is made
of a flexible material.
[0090] The use of a flexible reservoir for sterile solution
facilitates the obtaining of a completely closed system. Indeed the
reservoir for sterile solution filled with sterile solution can be
emptied by flowing the sterile solution into the at least one
string of containers without any need for a contact with the
ambient environment, owing to the ability of the reservoir to
deform.
[0091] According to an advantageous embodiment, the system
comprises means for air displacement which comprise at least one
venting bag, said at least one venting bag being made of a flexible
material.
[0092] For example the venting bag can be a flexible bag or pouch
initially substantially empty or collapsed, which is liable to
inflate upon filling of the system with the sterile solution as the
air is displaced.
[0093] According to a particular embodiment, all containers have
the same volume.
[0094] According to another particular embodiment of the
above-mentioned system, at least some of the containers have
different volumes.
[0095] According to a preferred embodiment of the above-mentioned
system, the volume of each individual container independently
ranges from about 0.1 mL to about 200 mL.
[0096] According to a preferred embodiment of the above-mentioned
system, the number of individual containers per string of
containers independently ranges from 2 to about 100.
[0097] According to a preferred embodiment of the above-mentioned
system, the number of strings of containers ranges from 1 to about
20.
[0098] According to a preferred embodiment of the above-mentioned
system, the containers are selected among the group composed of
vials, formed containers, pouches, or bags.
[0099] By "formed container" is meant a container which is made of
one or more pieces of a substantially rigid plastic, which are
preformed and if necessary assembled together, prior to filling.
Examples include thermoformed, or injection molded parts.
[0100] According to a particular embodiment of the above-mentioned
system, at least one of the individual containers further comprises
at least one individual port per container for extracting sterile
solution and optionally at least one other individual port per
container for letting in air when sterile solution is
extracted.
[0101] Such an individual port for extracting sterile solution may
be for instance used as an access port for a syringe.
[0102] According to a particular embodiment of the above-mentioned
system, the at least one string of containers is made of a single
tube of constant cross-section, the containers being predefined by
a specification which is indicative of the boundaries of the
individual containers, each container optionally comprising one or
two individual ports such as capped ports and in particular such as
capped female Luer ports.
[0103] Such a system minimizes assembly time, expense and error. It
also simplifies the design which may improve accuracy.
[0104] According to a particular embodiment of the above-mentioned
system, the at least one string of containers is made of a single
tubing comprising portions of tube alternated with flow-through
couplings and in particular male-female Luer connections, the
containers being partly predefined by a specification which is
indicative of the boundaries of the individual containers and by
said flow-through couplings, each container optionally comprising
individual ports in particular for attachment to a capped sterile
vent.
[0105] Flow through couplings facilitates filling with no air in
the filled containers or their access ports. This may be
particularly important for containers stored at cryogenic
temperatures.
[0106] According to a particular embodiment of the above-mentioned
system, the at least one string of containers is made of a single
tubing comprising alternated portions of tubing of respectively
larger and smaller cross-section, the individual containers are
substantially predefined by the alternation of said portions of
tubing and each individual container optionally comprises an
individual port such as a capped port.
[0107] The smaller cross section between containers provides a
segment of tubing for sealing which minimizes the losses in the
connections between containers.
[0108] According to a particular embodiment of the above-mentioned
system, the at least one string of containers is made of a
substantially rigid material and the individual containers are
substantially predefined as strings of formed containers by partial
partition of the single tubing and optionally comprise at least one
individual port such as a capped port.
[0109] Such a configuration can be accomplished by molding or
forming, such as thermoforming, the pieces of a string of
containers which are then sealed together leaving a flow path for
filling and for venting air.
[0110] In a first instance, such a system could be composed of a
formed strip which creates the primary container and flow path and
a second piece which provides one side of the container and
surfaces to seal the pieces together and to seal following the fill
to partition the chambers. By sealing the edges of such an
arrangement, a string of containers with flow path can be formed.
Such a system is inexpensive to make and assemble (see FIG. 5).
[0111] Another example of a string of formed containers can be
created by designing longitudinal strips of the strings or
containers which represent fractions of the string of containers. A
set of molds or forms can be used to make strips which when sealed
together, form complete strips of containers. A mold which forms
half of the string of containers, divided longitudinally, forms a
complete string of containers when two pieces are sealed together
along their edges. Such a design can pre-form additional access
ports into the system with minimal manual processing required. Such
a design is inexpensive to make and assemble, simple to use, and
very compact (see FIG. 9).
[0112] Another example of a strings of formed containers is a
string of molded containers connected together end to end or side
to side with a flow path from one container to the next. Such a
system is also inexpensive to make, simple to assemble, and
provides a flexible number of containers per string (see FIG.
7).
[0113] According to another particular embodiment of the
above-mentioned system, the at least one string of containers is
made of a flexible material which is rendered substantially
non-deforming by applied forces such as framing means or an
externally applied mold and the individual containers are
predefined as flexible pouches by a specification which is
indicative of the boundaries of the individual containers and/or by
partial partition of the single tubing and optionally comprise at
least one individual port such as a capped port.
[0114] According to this embodiment, the at least one string of
containers is made of a flexible material formed as a single tube
or pouch which is allowed to deform to the extent permitted by
structures or fixtures such as framing means or molds in a manner
which defines the volume of the individual containers which may be
further defined by optional partial partitions of the single tubing
and which optionally comprise at least one individual port such as
a capped port.
[0115] According to a particular embodiment of the present
invention, the containers are designed with materials and shapes
which are resistant to cracking when cycled through freezing and
thawing and which does not entrap air pockets within the containers
their access ports or the fill ports.
[0116] Said freezing may involve a temperature of less than
0.degree. C., and in particular a temperature below that of liquid
nitrogen.
[0117] Said thawing typically involves a temperature such as room
temperature (usually 20.degree. C.) or body temperature
(.about.37.degree. C.).
[0118] Examples of materials that are resistant to cracking include
EVA, polyethylene, polypropylene, Teflon, and more. Device designs
for applications frozen at very low temperatures should consider
using similar thicknesses of contacting materials, similar
coefficients of contraction of differing materials, materials with
low glass transition temperatures, and more.
[0119] Typical shapes which optimize the containers' resistance to
cracking are those which are well adapted to avoid the presence of
air bubbles in the containers, i.e. simple shapes with as few
corners, projections or cavities as possible. Containers with small
distances from wall to wall in the cross section facilitate uniform
freezing. Particularly, distance of 1/4 inch (6.25 mm) or less are
preferred.
[0120] The invention also relates to a method for preparing
individual containers to be filled with a substantially accurately
predetermined volume of a sterile solution comprising the steps of:
[0121] providing the above-mentioned system comprising at least one
reservoir for sterile solution and additional connecting means,
said at least one reservoir for sterile solution being connected to
the single inlet of each of the at least one string of containers
via said additional connecting means; [0122] injecting the sterile
solution from said at least one reservoir filled with sterile
solution into the at least one string of containers via the single
inlet of the at least one string of containers, so as to provide
individual containers filled with a predetermined volume of sterile
solution; [0123] sealing the at least one string of containers by
sealing means at a plurality of positions, so as to provide filled,
separate, individual containers; and [0124] optionally detaching
each individual container from the at least one string of
containers by detaching means, so as to provide filled, separate,
detached, individual containers.
[0125] By "sealing means" is for instance meant a dielectric
welding tubing sealer such as one made by Sebra.RTM., or a laser,
or a heat sealer.
[0126] By "detaching means" is meant means for breaking, cutting or
tearing away connections to or between the sealed containers.
[0127] This method for preparing individual containers to be filled
is advantageous relative to prior methods because it is quick,
easy, accurate, it minimizes the connecting pathways and enables
reduction in the costs of production.
[0128] According to a particular embodiment of the above-mentioned
method, the system remains closed relative to the ambient
environment during the steps of injecting the sterile solution into
the at least one string of containers and of sealing the at least
one string of containers, so that there is no contact between the
sterile solution and air, when present, inside the system on the
one hand and the ambient environment outside the system on the
other hand.
[0129] According to an alternative embodiment, the system remains
open relative to the ambient environment until the sealing of the
at least one string of containers, the sterility of the sterile
solution being maintained at all steps via at least one filtering
means.
[0130] In this embodiment the reservoir for sterile solution or the
means for air displacement or both are open or partially open to
the ambient environment and provided with a filtering means such as
a sterile barrier filter.
[0131] According to a particular embodiment of the above-mentioned
method, the system comprises at least one venting bag for displaced
air which is connected to the outlets of the at least one string of
containers and which is mostly empty prior to injecting the sterile
solution into the at least one string of containers.
[0132] The venting bag is then able to inflate and receive the air
that is chased upon filling with the sterile solution.
[0133] According to a particular embodiment of the above-mentioned
method, the injection of the sterile solution into the at least one
string of containers is made from the top to the bottom or from the
bottom to the top by means of hydrostatic pressure or of filling
means such as a peristaltic pump.
[0134] Filling by hydrostatic pressure is either achieved by
gravity of by the application of centripetal forces. Gravity can
push the sterile solution from the bottom of the at least one
string of containers to its top provided that the reservoir for
sterile solution is placed above the inlet to said at least one
string of containers.
[0135] Alternative filling means also include the application of a
vacuum at the single outlet of the string of containers or at one
of the possible additional ports.
[0136] According to a particular embodiment of the above-mentioned
method, the injection of the sterile solution is made from the
bottom to the top, whereby air bubbles in the containers are
substantially avoided.
[0137] Avoiding air trapping is advantageous because trapped air
may interfere with the volume accuracy and favor bursting of the
container upon freezing at a temperature below that of nitrogen
liquefaction and then thawing. According to the present invention,
the air is displaced with the fluid, so that manual manipulation to
express bubbles from the containers is generally not needed.
[0138] According to a particular embodiment of the above-mentioned
method, the sealing of the containers of each of the at least one
string of containers is carried out by sealing means either after
the filling of said string of containers, or after the complete
filling of all of the at least one string of containers.
[0139] The above-mentioned method advantageously comprises the
additional final step of freezing and optionally thawing the
sterile solution inside the containers, optionally more than once,
without stress fractures appearing on said containers.
[0140] By "freezing" is meant placing at a temperature below
0.degree. C. or at a temperature as low as that of liquid
nitrogen.
[0141] By "thawing" is in particular meant bringing to room
temperature (usually .about.20.degree. C.) or to body temperature
(.about.37.degree. C.)
[0142] By "stress fractures" is meant cracking or breaking due to
the stresses such as those associated with freezing, thawing, and
normal handling while frozen.
[0143] The system described herein is able to provide accurate
volume control without volume measurement, minimal losses for
smaller volumes, rapid fills, and reduced risk of air entrapment
with minimal manual manipulation. The containers are pre-connected
to each other to prevent mix-ups prior to fill and labeling and the
materials used may be designed to resist cracking when frozen and
thawed.
[0144] Materials that might be used in this application include
EVA, polyethylene, polypropylene, Teflon, and more. Device designs
for applications frozen at very low temperatures should consider
using similar thicknesses of contacting materials, similar
coefficients of contraction of differing materials, materials with
low glass transition temperatures, and more.
[0145] According to a particular embodiment of the above-mentioned
method, the individual containers filled with a predetermined
volume of sterile solution obtained after the step of injecting the
sterile solution or the filled, separate, individual containers
obtained after the step of sealing or the filled, separate,
detached, individual containers obtained after the optional step of
detaching are subsequently used for cellular or clinical
applications.
[0146] Such cellular or clinical applications may include cellular
vaccines, genetically altered cellular treatments, or viral gene
therapy products.
DESCRIPTION OF THE FIGURES
[0147] FIGS. 1 and 2 show two examples of small volume closed fill
freezing straws (closed system dispensing) according to the
invention. On the right (FIGS. 1B and 2B): a single string of
containers with a venting bag for air displacement attached at the
single outlet of the string. On the left (FIGS. 1A and 2A): an
individual sealed and detached container.
[0148] FIG. 3 shows an example of small volume closed fill freezing
vials according to the invention. FIG. 3B: a single string of
containers with a venting bag attached for air displacement (at the
outlet of the string) and a source bag or reservoir for sterile
solution attached at the other end (i.e. at the inlet of the
string). FIG. 3A: an individual sealed and detached vial.
[0149] FIG. 4 shows an example of a vial set assembly with several
strings of containers placed in parallel, for a closed system
dispensing according to the invention.
[0150] FIGS. 5A and 5B show an example of the string of formed
containers configuration according to the invention (FIG. 5B:
string of containers with venting bag attached; FIG. 5A: individual
sealed and detached container). FIG. 5C shows the filling process
of the string of containers in the string of formed containers
configuration.
[0151] FIG. 6 shows an example of a set of flexible pouches
according to the invention (FIG. 6B: string of containers with
means for air displacement attached; FIG. 6A individual sealed and
detached container).
[0152] FIG. 7 shows another example of the string of formed
containers configuration wherein the string is formed by two formed
pieces. FIG. 7A: top view (separated); FIG. 7B: isometric
cross-section of paired pieces (separated); FIG. 7C: side view of
paired pieces; FIG. 7D: individual container.
[0153] FIG. 8 shows another example of set of flexible pouches
according to the invention. The configuration is created by joining
two sheets of flexible plastic material together. FIG. 8A: top
view; FIG. 8B: view in perspective; FIG. 8C: side view FIG. 8D:
individual container.
[0154] FIG. 9A shows an example of set from FIG. 8 positioned on a
platen used for defining the volume capacity of each container.
FIG. 9B shows the opposite platen.
EXAMPLES
[0155] Serially Connected Vials
[0156] In the first instance of the system (1) according to the
invention shown in FIGS. 1A and 1B, a single string (2) of serially
connected vials is provided. This string is made of assembled
pieces of tubing and connectors to form a single tubing (3) and is
connected at its outlet to means for air displacement in the form
of a venting bag (4) via connecting means (5). After filling each
individual vial (6) can be delimited by two seals (7) performed
transversally on the tubing (3) at the specified sites. Each
individual vial (6) is provided with two Y connectors (8) that are
initially closed. After filling and sealing, one of the Y
connectors (8) can be opened (uncapped) to extract the sterile
solution from the vial (6), for instance via a syringe. The other Y
connector (8) can also be opened so as to provide air displacement
during extraction via the syringe. Each Y connector (8) also
provides a bubble trap to ensure that the sterile solution is not
up to the rim of the vial (6) when the cap is removed.
[0157] On FIGS. 2A and 2B is shown another system (1), where
individual containers (6) are pre-connected via male to female Luer
connections (9). Each individual container (6) is also provided
with a single Y connector (8) itself provided with a hydrophobic
capped sterile vent (10). Individual containers (6) are thus
delimited on the one hand by one of the Luer connections (9) and Y
connectors (8) and on the other hand by seals (7) performed
transversally on the tubing (3) after filling at the specified
sites. A venting bag (4) is connected to the string of individual
containers via another Luer connection.
[0158] On FIGS. 3A and 3B is shown yet another system (1) which is
additionally provided with a reservoir for sterile solution (11)
(or source bag) which is connected to the single inlet of the
string (2) of containers (6) via additional connecting means (12),
while a venting bag (4) is connected to the single outlet of said
string. The part (13) of the tubing (3) which makes up the
containers (6) is larger than the part (14) of the tubing (3) which
makes up the serial connections between containers (6). Like in
FIG. 2, individual containers (6) are delimited on the one hand by
a Y connector (8) (Luer connection) and on the other hand by a seal
(7) performed transversally on the tubing (3) after filling.
[0159] Set of Parallel Strings of Serially Linked Containers
[0160] FIG. 4 shows a system (1) according to the invention which
is provided with a set of four strings (2) of containers (6) such
as the one of FIG. 3 that are placed in parallel. These four
strings are connected at their outlet to a venting bag (4) via
connecting means (5) which comprise a common node with a 1 to 4
connector (15). They are also connected at their inlet to a
reservoir for sterile solution (not shown) via additional
connecting means (12) which typically comprise 30 inches sterile
weld compatible tubing as well as a common node with an additional
1 to 4 connector (16). The system is also provided with a drip
chamber (17) (or squeezable bubble trap) which helps prevent air
bubbles from forming in the line when the containers (6) are filled
and which works in conjunction with a clamp or check valve (17b) to
allow pumping when sufficient head pressure is not available to
clear the fluid from the line into the containers. The additional
connecting means to the reservoir include a spike (I 7a) which is
provided for connections when sterile welding is not possible or
desired. Various tubing clamps (17c) are also provided to
facilitate flow control into the string of containers which is not
blocked.
[0161] String of Formed Containers Configuration
[0162] In the example of FIGS. 5A and 5B, the string of individual
containers (6) is a string of formed containers with 2 parts:a
primary portion which forms multiple containers in a single stretch
(6b) and a cover piece (6a) which seals each container. A seal is
applied around the edge of the string of formed containers (21) and
the boundaries (18) between the containers (6) are either partially
sealed or not sealed at all to the cover piece. After filling, the
connecting boundaries (18) are completely sealed. Each container
(6) is provided with an access port (19). These ports may be
protected by a separate punch-through membrane or the container
material itself. This gives a sterile point for subsequently
accessing the content of each formed container (6). It is of note
that even though there may be partial seals (partial walls) between
individual containers at the location of connecting boundaries
(18), the serially linked containers are still made of a single
tubing (3) which is the exclusive flowing means for air and for the
sterile solution (20), as is shown on FIG. 5C.
[0163] Outer edges are pre-sealed. Partial partitioning seals which
further define the container may be completed prior to fill. Only a
small opening may be needed to pass fluid and gases into the linked
containers. The set is typically sterilized prior to dispensing.
During dispensing, the assembly is oriented with an incline
sufficient to fill lower units first (the direction of fill is
indicated by arrows on FIG. 5C). Air is vented out the top into the
bag (4). Alternatively, in case of a more open system, air could be
vented out through a sterile barrier filter. Seals between chambers
are sealed after filling. The shape of the chambers may be adjusted
to limit thickness if cryopreservation is required.
[0164] Flexible Pouches Configuration
[0165] On FIGS. 6A and 6B the individual containers (6) are
flexible pouches that are connected so that the outer edges of the
material are sealed and either part or none of the connecting
boundaries (18) are sealed prior to filling. During the fill, the
volume may be controlled by supplying sufficient pressure or by
external form fitting using vacuum if necessary. Once filled, the
boundaries (18) are sealed.
[0166] String of Formed Containers Configuration with 2 Formed
Parts
[0167] FIGS. 7A, 7B, 7C, and 7D illustrate a string of serially
linked containers created from 2 formed pieces (22a and 22b). The
two pieces shown could be thermoformed and cut from 2 sheets of
semi-rigid plastic.
[0168] After forming and cutting, pairs of parts are bonded
together along the edges (21) and along most of each boundary
between individual containers (18) while leaving the flow through
path unsealed. Alignment holes (23) are provided in order to
facilitate the bonding and to orient the string of containers
during filling. The assembly forms cavities as illustrated in the
expanded isometric cross section view (FIG. 7B). The bonded
surfaces (boundaries) are not emphasized but are represented by the
dark lines between the containers (18) on the side view (FIG. 7C).
These bonded regions can also be perforated to facilitate
separation of the parts after filling. The ports (19) can be
reinforced with a collar to hold them in place. The collar can be
designed to accommodate a closure (24) such as a threaded cap, an
access septum for needle access or needle free access, a tubing
spike, a slip connect cap, or tubing. The closure (24) is normally
added prior to sterilization. On FIG. 7C are also shown the
additional connecting means (12) which connect the string of
containers to a reservoir of sterile solution (not shown) and
connecting means (5) to a venting bag or filter (not shown). The
two seals (7) applied across the flow through path on a filled
individual container (6) are shown in FIG. 7D.
[0169] Note that the containers are linked with pass through
features which allow fluid to flow into the lower container and
through the high-point in the lower container into the adjacent
container above it. Having the ports oriented horizontally or
nearly horizontally (as illustrated), also minimizes the air
trapped in the ports.
[0170] During filling, the system can be positioned in a filling
fixture to hold the position but may allow manual access to
manipulate if needed. The fluid is added from the additional
connecting means (12). Each container is filled sequentially by
filling and then overflowing into the adjacent container as air is
pushed out of the port shown at the top of the drawing (connecting
means 5). The device may need to be rocked during filling to ensure
complete air removal. Following filling, the pass through ports are
sealed (7) and the vials are ready to separate into individual
containers (6). The ease of removal of air is important for
applications where freezing to temperatures near liquid nitrogen is
required.
[0171] Particular Flexible Pouch Configuration and Fixture
[0172] FIGS. 8A, 8B, 8C, and 8D illustrate a flexible pouch system
composed of a single string of serially-linked containers (6). This
configuration is created by laying two sheets of flexible plastic
material together and applying a tool that seals along the edges
(dark lines) (21) and along the boundaries between the individual
containers (18), perforating along the sealed boundaries between
the individual containers (18) to facilitate later separation, and
sealing and cutting the outline form of the bag along the edges
(21) from the sheets. This can be accomplished in a single
step.
[0173] Container access ports (19) are then inserted along the edge
of the bag as shown and bonded or welded in place. These ports can
be closed with threaded caps, septum's for needle or needle free
access, slip-lock closures, spike ports, or tubing. The fill tubing
(additional connecting means 12) is also bonded in place at one
extremity and a venting tubing (connecting means 5) at the other
extremity. The arrows indicate the direction for filling and
venting. On FIG. 8D is shown a filled and detached individual
container (6), with the flow through ports sealed (7).
[0174] Alignment holes (23) are provided which allow the bag to be
positioned to a tool such as that shown in FIGS. 9A and 9B to
improve the accuracy during filling and to control the final fill
volume.
[0175] When it is desired to fill the container to its full
capacity, container volume can be limited by the elastic nature of
the materials used which are limiting at low pressures. To fill the
container partially or when the container material is more elastic,
the container volume can be limited by applying a fixture that
controls the available space for filling.
[0176] FIG. 9A shows the set from FIGS. 8A, 8B, 8C and 8D
positioned on a platen which could be used to define the volume
capacity of the bag. The opposing platen is shown in FIG. 9B. On
the surface of these platens are guides (25) that align with the
alignment holes (23) in the part to hold the bags in position and
to line up the opposing platen. Optional embossed shapes (26)
across the surface of one platen line up with the mirror image
embossment on the opposing platen. When the platens are pressed
against each other with the bag in between them, the embossment
modifies the capacity of the containers. It is also possible to
control the container volume by using spacers between the platens
with or without the embossment. Access groves (27) are provided to
allow manual manipulation, clearance for ports or tubing, and for
access to seal the flow through ports between the containers (7).
If at least one of the platens is transparent, the progress of the
fluid and air can be easily monitored.
[0177] By orienting the bag with the vent end up and the input end
down, the fluid (20) fills the containers sequentially starting
from the bottom (see arrows). The fluid exits the lower container
at the high point and begins to fill the adjacent container. As the
device fills, the air is forced out of the venting port. Areas that
trap bubbles are minimal. However, rocking may be helpful to ensure
good air removal.
[0178] The tool may be applied prior to filling to restrict the
volume during the fill or it may be applied following the fill to
express excess fluid back out through the inlet port.
[0179] Once the containers are filled, the flow paths between the
containers are sealed (7), the system is removed from its fixture,
and containers are ready to be separated along the container
boundaries (18).
[0180] There are several distinct advantages of this design. [0181]
For a single bag design, containers of different volumes can be
created by changing the spacing or embossment of the tool. This is
particularly important in small volume production settings to
minimize device production costs. [0182] The design and the tool
can be easily adapted for thicker materials which are more
compatible with low temperature freezing or thinner materials which
are desirable when gas exchange is important. [0183] Device
production is inexpensive and repeatable even for small volumes.
[0184] In this design there is almost no waste of fill liquid in
connecting tubing. [0185] Filling is simple and quick. [0186] Air
removal is accomplished rapidly and reliably. The ease of removal
of air is important for applications where freezing to temperatures
near liquid nitrogen is required. [0187] It is possible to have a
thin cross section without giving up accuracy. Thin cross sections
also facilitates freezing in relevant applications. [0188]
Containers have additional capacity beyond that which is filled
during the fill.
[0189] This is important for applications where the contents must
be diluted or mixed with other fluids prior to extraction for
use.
[0190] Demonstration of Filling a Prototype and Using it in a
Cryopreserved State
[0191] Prototypes have been built according to the model of FIG.
3B. Vials were made of PVC tubing and polycarbonate Y
connectors.
[0192] The vials were filled from below and air was trapped in the
capped arm as expected but the vials could be easily filled from
the bottom up. Volumes were predictable based on internal diameter
and length of the tubing. By filling the vials to the top and then
starting to sealing from the top, less waste was observed.
[0193] To test the potential for use in a cryopreserved state, the
filled vials were sealed off and frozen in the -80.degree. C.
freezer over night. The following day, the vials were removed and
evaluated for stress fractures. None were observed.
* * * * *