U.S. patent application number 17/419196 was filed with the patent office on 2022-03-03 for cell processing device cell processing system and methods of use thereof.
The applicant listed for this patent is Oribiotech LTD. Invention is credited to Nicholas Brown, Simon Collings, Farlan Singh Veraitch.
Application Number | 20220064580 17/419196 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-03 |
United States Patent
Application |
20220064580 |
Kind Code |
A1 |
Veraitch; Farlan Singh ; et
al. |
March 3, 2022 |
CELL PROCESSING DEVICE CELL PROCESSING SYSTEM AND METHODS OF USE
THEREOF
Abstract
A cell processing device for use in performing one or more unit
processes in one or more of cell or gene therapy manufacturing,
comprising a cell processing platform fluidly coupled to at least
one auxiliary container and to at least one primary container, the
cell processing platform comprising a body portion comprising at
least one fluid inlet fluidly connected to a fluid outlet, and an
auxiliary container port fluidly coupled to the at least one fluid
inlet of the body portion, wherein the at least one auxiliary
container is received in sealing engagement with the auxiliary
container port such that the auxiliary container lumen is fluidly
connected with the at least one fluid inlet of the body portion,
and a primary container is received in sealingly engagement with
the primary container port such that the primary container lumen is
fluidly connected with the fluid outlet of the body portion.
Inventors: |
Veraitch; Farlan Singh;
(London, Greater London, GB) ; Collings; Simon;
(Datchet, Berkshire, GB) ; Brown; Nicholas;
(Datchet, Berkshire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Oribiotech LTD |
London, Greater London |
|
GB |
|
|
Appl. No.: |
17/419196 |
Filed: |
January 3, 2020 |
PCT Filed: |
January 3, 2020 |
PCT NO: |
PCT/GB2020/050009 |
371 Date: |
June 28, 2021 |
International
Class: |
C12M 1/00 20060101
C12M001/00; C12N 5/0783 20060101 C12N005/0783; A61K 48/00 20060101
A61K048/00; C12M 1/42 20060101 C12M001/42 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 4, 2019 |
GB |
1900107.2 |
Jan 4, 2019 |
GB |
1900108.0 |
Jan 4, 2019 |
GB |
1900109.8 |
Jan 4, 2019 |
GB |
1900111.4 |
Claims
1. A cell processing device for use in performing one or more unit
processes in one or more of cell or gene therapy manufacturing,
comprising: a cell processing platform fluidly coupled to at least
one auxiliary container and to at least one primary container, the
cell processing platform comprising a body portion comprising at
least one fluid inlet fluidly connected to a fluid outlet; and an
auxiliary container port fluidly coupled to the at least one fluid
inlet of the body portion, wherein the at least one auxiliary
container is received in sealing engagement with the auxiliary
container port to fluidly connect the auxiliary container lumen
with the at least one fluid inlet of the body portion, and a
primary container is received in sealingly engagement with the
primary container port to fluidly connect the primary container
lumen with the fluid outlet of the body portion.
2. The cell processing device according to claim 1, wherein the
auxiliary container port comprises a container receiving sleeve
connected to the body portion and being configured to surround at
least a portion of the auxiliary container, which portion comprises
the fluid outlet of the container.
3. The cell processing device according to claim 1, wherein the
cell processing platform comprises a plurality of auxiliary
container ports and wherein each one of a plurality of auxiliary
containers are received in sealing engagement with one of the
plurality of auxiliary container ports to fluidly couple the lumen
of each auxiliary container is fluidly coupled with a fluid inlet
of the body portion.
4. The cell processing device according to claim 3, wherein each
auxiliary container port is coupled to a separate fluid inlet of
the body portion.
5. The cell processing device according to claim 4, wherein each
separate fluid inlet of the body portion is fluidly connected to a
fluid outlet of the body portion.
6.-12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. The cell processing device according to claim 1, wherein the
auxiliary container port comprises a sterile connector end at one
or more of the fluid inlet or the fluid outlet of the auxiliary
container port, each sterile connector end configured to engage
with a further sterile connector end on a container or on the body
portion, respectively.
18. The cell processing device according to claim 1, wherein the
fluid outlet of the body portion comprises a sterile connector end
configured to engage with a further sterile connector end on the
primary container attachable to the body portion.
19. The cell processing device according to claim 1, comprising at
least one positional tracking device operable to indicate a set
location on the platform.
20. The cell processing device according to claim 19, wherein the
positional tracking device is one or more of: a magnet, an RFID
sensor, a light sensor or a cog operable to engage a further
cog.
21. (canceled)
22. (canceled)
23. A cell processing device according to claim 19, wherein the at
least one positional tracking device is located on the body portion
relative to the auxiliary container port.
24. (canceled)
25. The cell processing device according to claim 1, comprising a
sampling port in the body portion.
26. The cell processing device according to claim 1, comprising a
gas transfer port in the body portion.
27. The cell processing device according to claim 1, wherein the
auxiliary container port is configured to receive an auxiliary
container having a base section, a top section arranged
substantially in parallel with the base section and a wall element
arranged between the top section and the base section and defining
an internal lumen of the container, in which the wall element of
the container preferably is compressible with respect to the top
and base section and the wall element of the container is composed
of a flexible material.
28. The cell processing device according to claim 1, wherein the
primary container port is configured to receive a primary container
having a base section, a top section arranged substantially in
parallel with the base section and a wall element arranged between
the top section and the base section and defining an internal lumen
of the container, in which the wall element of the container
preferably is compressible with respect to the top and base section
and the wall element of the container is composed of a flexible
material.
29. The cell processing device according to claim 28, wherein the
primary container further comprises an attachment flange mounted to
the top section of the primary container and being configured to
sealingly engage and mount to the primary container port.
30. The cell processing device according to claim 1, wherein, the
at least one auxiliary container is compressible.
31. The cell processing device according to claim 1, wherein the at
least one auxiliary container is one of: a syringe or any shaped
container with a moving seal allowing variable volume
operations.
32. The cell processing device according to claim 1, wherein the at
least one auxiliary container is a bag retained in a frame and
moveable with respect to the frame.
33. The cell processing device according to claim 1, comprising one
or more auxiliary containers detachably connected to an auxiliary
container port of the cell processing platform.
34. The cell processing device according to claim 33, wherein one
or more of the auxiliary containers are connected to a respective
auxiliary container port with a sterile connector.
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a national phase entry under 35 U.S.C.
.sctn. 371 of International Patent Application PCT/GB2020/050009,
filed Jan. 3, 2020, designating the United States of America and
published as International Patent Publication WO 2020/141327 A1 on
Jul. 9, 2020, which claims the benefit under Article 8 of the
Patent Cooperation Treaty to United Kingdom Patent Application
Serial No. 1900109.8, filed Jan. 4, 2019, United Kingdom Patent
Application Serial No. 1900107.2, filed Jan. 4, 2019, United
Kingdom Patent Application Serial No. 1900108.0, filed Jan. 4,
2019, United Kingdom Patent Application Serial No. 1900111.4, filed
Jan. 4, 2019.
TECHNICAL FIELD
[0002] The disclosure relates to a cell processing device for
performing one or more unit operations in cell and/or gene therapy
manufacture and methods of use thereof.
BACKGROUND
[0003] Cell and gene therapy manufacturing processes are often
complex and include manual or semi-automated steps across several
devices. Equipment systems used in various steps (i.e., unit
operations) of cell-based therapeutic products (CTP) manufacturing
may include devices for cell collection, cell isolation/selection,
cell expansion, cell washing and volume reduction, cell storage and
transportation. The unit operations can vary immensely based on the
manufacturing model (i.e., autologous versus allogenic), cell type,
intended purpose, among other factors. In addition, cells are
"living" entities sensitive to even the simplest manipulations
(such as differences in a cell transferring procedure). The role of
cell manufacturing equipment in ensuring scalability and
reproducibility is an important factor for cell and gene therapy
manufacturing.
[0004] In addition, cell-based therapeutic products (CTP) have
gained significant momentum thus there is a need for improved cell
manufacturing equipment for various cell manufacturing procedures,
for example, but not limited to stem cell enrichment, generation of
chimeric antigen receptor (CAR) T cells, and various cell
manufacturing processes such as collection, purification, gene
modification, incubation/recovery, washing, infusion into patient
and/or freezing.
[0005] The culture or processing of cells typically requires the
use of a device to hold the cells, for example, in an appropriate
culture medium when culturing the cells. The known devices include
shaker flasks, roller bottles, T-flasks and bags. Such bottles or
flasks are widely used but suffer from several drawbacks. Chief
among the problems are the requirement for transfer of cells
without contamination when passaging or processing subsequently and
the sterile addition of supplements and factors. The existing cell
culture devices require re-supply of culture medium and oxygen for
continued cell growth. Gas permeable cell culture devices are
described in U.S. Pat. No. 8,415,144. However, such devices also
require transfer of medium and/or cells in and out of the
devices.
[0006] Collapsible cell processing devices for use in medicine are
known; see, for example, U.S. Pat. No. 4,867,172 concerning a blood
collector, or WO 2008/030597 concerning a canister liner for fluid
collection. However, such devices are not fabricated or constructed
for use in cell and/or gene therapy manufacturing unit operations
(i.e., steps).
[0007] A key limiting factor in the production of cells or gene
therapies for use in medicine is the absence of compact, automated
closed systems for performing unit operations without
contamination. For example, during cell culture, upstream or
subsequent processing of cells, there is a risk of contamination
when making additions to the culture vessel, or when removing cells
or removing liquid samples. The operating systems are largely
manual and hence expensive to operate. Multiple pieces of equipment
are typically required to cover all of the non-cell culture steps,
which involves many transfers, each of which is an opportunity for
operator errors and contamination to occur. Furthermore with
increasing manual operations comes increasing risk of manual errors
and therefore the current labor-intensive processes lack the
robustness required for the manufacture of clinical-grade
therapeutics.
[0008] There is therefore a need for cell processing devices (e.g.,
multistep cell processors), which permit such processing, which
avoids the requirement for constant movement of cells into fresh
devices. For example, it would be advantageous if scale-up of cells
in culture could be achieved without transfer of cells into a
larger device as the cell population for any given culture
increases.
[0009] Previous cell manufacturing devices use complex equipment,
which is large and difficult to assemble. The devices use complex
networks of tubing, valves and pumps to link elements of the
equipment together.
[0010] Provided is an improved cell and/or gene therapy processing
equipment, which combines the advantages of the cell culture
containers of the earlier applications (PCT/GB2016/051451 and
PCT/GB2017/053389) (i.e., avoiding the need for pumps and the
requirement for constant passaging of cells into fresh culture
devices, holding vessels, tubes etc.) with the advantages conferred
by having individually configurable cell and/or gene therapy
processing devices. Together with an improved, closed cell
processing unit, the improved device and container described herein
permit a variety of unit processes to be performed within a single
device or container having a smaller footprint and being less
complex than existing equipment, as will be explained in more
detail herein. Moreover, the cell processing containers described
herein may maintain an aseptic connection without the prerequisite
of a laminar flow cabinet, a glove box, or the like.
[0011] The earlier application (PCT/GB2016/051451) describes a cell
culture container in which the wall element, being composed of a
flexible material, is compressible with respect to its top and base
sections. The cell culture container described therein is
compatible with the cell processing unit and device described
herein.
[0012] In a further earlier application (PCT/GB2017/053389) an
improved version of a cell culture container is described, having
at least one inlet and further comprising one or more auxiliary
containers in fluid communication with the primary container. The
cell culture container described therein is improved so as to be
compatible with the cell processing unit and device described
herein. Moreover, a connection between the cell culture container
described therein and other components is improved, thereby
maintaining an aseptic environment through the connection. In the
earlier application (PCT/GB2017/053389), a laminar flow cabinet was
required in order to ensure an aseptic environment during cell
and/or gene therapy manufacture and/or processing. However, this
can increase costs and result in a more labor intensive process.
Thus, the present application also aims to provide an aseptic
connection between components, irrespective of the surrounding
environment or atmosphere.
BRIEF SUMMARY
[0013] It is an object of certain aspects of the disclosure to
provide an improvement over the above described techniques and
known art; particularly to provide a cell processing unit, a cell
processing platform, a cell processing device and a cell processing
container and systems that facilitate flexible, compact, low cost,
multistep cell processing while reducing the risk of
contamination.
[0014] In accordance with the disclosure there is provided a cell
processing device for use in one or more unit operations in cell
and/or gene therapy manufacture and a cell processing system and
method in accordance with the appended claims.
[0015] Also described is a cell processing unit for cell and/or
gene therapy manufacture and a cell processing system and
method.
[0016] Also described is a platform cell processing platform for
use in one or more unit operations in cell and/or gene therapy
manufacture and a cell processing system and method.
[0017] Also described is a cell processing container for use one or
more unit operations in cell and/or gene therapy manufacture, a
cell processing system comprising a cell processing container and a
multi-step method of performing one or more unit operations in cell
and/or gene therapy manufacture.
[0018] Cell Processing Device
[0019] According to an aspect of the disclosure there is provided a
cell processing device for use in performing one or more unit
operations in cell and/or gene therapy manufacture comprising a
cell processing platform according to the disclosure fluidly
coupled to at least one container.
[0020] The term "cell processing device" is used to define a cell
processing platform having at least one container coupled thereto.
The at least one container may be fluidly coupled thereto.
[0021] The term "cell processing platform" is used to define a
platform, or an interface, upon which one or more unit operations
in cell and/or gene therapy manufacture or processing may be
performed. The terms "cell processing platform," "liquid handling
platform," "platform," "cell processing interface" and "interface"
can be used synonymously. In some examples, the cell processing
platform serves as an interface between components, for example,
containers, bioreactors or the like, such that the user can
manipulate the cell processing platform thereby controlling one or
more unit operations in cell and/or gene therapy manufacture or
processing. The cell processing platform may provide a pathway, for
example, a fluid pathway, through conduits, seals, valves, septa or
the like to provide an interface between components, for example,
containers, bioreactors or the like.
[0022] In some examples, the cell processing platform may be
fluidly coupled to at least one container thereby allowing fluid
communication therebetween. That is, in some examples, the cell
process platform allows the introduction or extraction of one or
more fluids to or from the at least one container.
[0023] In certain embodiments, the cell processing platform is
fluidly coupled to at least one auxiliary container.
[0024] In certain embodiments, the cell processing platform is
fluidly coupled to at least one primary container.
[0025] Thus in certain embodiments there is provided a cell
processing device for use in performing one or more unit operations
in cell and/or gene therapy manufacture comprising a cell
processing platform fluidly coupled to at least one auxiliary
container and being fluidly coupled to at least one primary
container.
[0026] In certain embodiments the cell processing platform
comprises a body portion comprising at least one fluid inlet
fluidly connected to a fluid outlet, and an auxiliary container
port fluidly coupled to the at least one fluid inlet of the body
portion, wherein the at least one auxiliary container is received
in sealing engagement with the auxiliary container port such that
the auxiliary container lumen is fluidly connected with the at
least one fluid inlet of the body portion, and a primary container
is received in sealingly engagement with the primary container port
such that the primary container lumen is fluidly connected with the
fluid outlet of the body portion.
[0027] The primary container may be regarded as a first container.
The auxiliary container may be regarded as a second, or a
secondary, container. Any number of containers may be used.
[0028] The term "primary container" is used to define that a
container is connected to a first side, or surface, of the cell
processing platform. For example, the term "primary container" may
be used to define that the container is attached to a lower side,
or surface, of the cell processing platform. There may be any
number of primary containers.
[0029] The primary container may be a bellow-based container, for
example, a bellow-based bioreactor. That is, the container or
bioreactor may be based on a bellows, i.e., a container or
bioreactor including a wall element comprising a series of Z-folds,
or a wall element comprising, or forming, a concertina. The
bellow-based container or bioreactor may include a base section, a
top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container or
bioreactor. The wall element of the container or bioreactor
preferably is compressible with respect to the top and base
sections. The wall element of the container or bioreactor may be
composed of a flexible material. The wall element may comprise a
series of Z-folds. The wall element may comprise, or form, a
bellows. The container may take the form of a concertina.
[0030] The term "auxiliary container" or "secondary container" is
used to define that a container is connected to a second side, or
surface, of the cell processing platform. For example, the term
"auxiliary container" or "secondary container" may be used to
define that the container is attached to an upper side, or surface,
of the cell processing platform. There may be any number of
auxiliary containers.
[0031] The auxiliary container may be a bellow-based container, for
example, a bellow-based bioreactor. That is, the container or
bioreactor may be based on a bellows, i.e., a container or
bioreactor including a wall element comprising a series of Z-folds,
or a wall element comprising, or forming, a concertina. The
bellow-based container or bioreactor may include a base section, a
top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container or
bioreactor. The wall element of the container or bioreactor
preferably is compressible with respect to the top and base
sections. The wall element of the container or bioreactor may be
composed of a flexible material. The wall element may comprise a
series of Z-folds. The wall element may comprise, or form, a
bellows. The container may take the form of a concertina.
[0032] Generally, the term "container," or a "cell processing
container," is used to define a container, a receptacle, a volume,
a bioreactor, or the like in which one or more unit operations of
cell and/or gene therapy manufacture or processing may be
completed.
[0033] In certain embodiments, the body portion includes one, that
is, a single, fluid inlet, and one, that is, a single, fluid
outlet. In certain embodiments, the body portion includes one or
more fluid inlets, and one or more fluid outlets. In certain
embodiments, the body portion includes one, that is a single, fluid
inlet, and a plurality of fluid outlets. In certain embodiments,
the body portion includes a plurality of fluid inlets, and one,
that is, a single, fluid outlet. In certain embodiments, the body
portions includes a plurality of fluid inlets, and a plurality of
fluid outlets.
[0034] In certain embodiments, there may be provided one, that is,
a single, primary container and one, that is, a single, auxiliary
container. In certain embodiments, there may be provided one, that
is, a single, primary container and a plurality of auxiliary
containers. In certain embodiments, there may be provided a
plurality of primary containers and one, that is, a single,
auxiliary container. In certain embodiments, there may be provided
a plurality of primary containers and a plurality of auxiliary
containers.
[0035] In certain embodiments the at least one auxiliary container
is detachably connected to the auxiliary container port.
[0036] In certain embodiments the primary container is detachably
connected to the primary container port.
[0037] In certain embodiments, one or more auxiliary containers are
indirectly fluidly coupled to the auxiliary container port. More
specifically, one or more auxiliary containers may be connected to
one another in series. Thus, an auxiliary container may be in fluid
communication with a further auxiliary container, wherein the
further auxiliary container is not in direct fluid communication
with the auxiliary container port of the cell processing platform.
Additionally, or alternatively, the cell processing device may
further comprise one or more further containers, such as a
bioreactor, in direct fluid communication with the primary
container but not necessarily with the cell processing platform. In
this way, the cell processing device may provide a multistage
bioreactor operable to perform one or more unit processes in a cell
and/or gene therapy manufacturing process.
[0038] In certain embodiments the auxiliary container port
comprises a container receiving sleeve connected to the body
portion and being configured to surround at least a portion of the
auxiliary container, which portion comprises the fluid outlet of
the container.
[0039] In certain embodiments the container receiving sleeve
comprises insulation means configured to maintain the contents of
an auxiliary container received in the sleeve at a particular
temperature. More specifically, the insulation means is a thermal
sleeve. Accordingly, an auxiliary container port may be configured
to maintain the contents of an auxiliary container at an optimal
temperature. For example, the optimal temperature may be a cell
culture temperature (37 degrees Celsius), or room temperature (22
degrees Celsius), or refrigerated (e.g., around 4 degrees Celsius),
or below freezing (e.g., around minus 4 degrees Celsius or lower,
such as minus 20 degrees Celsius, or minus 80 degrees).
[0040] In certain embodiments, the cell processing device comprises
one or more auxiliary container ports configured to maintain a
variety of temperatures.
[0041] In certain embodiments the cell processing platform
comprises a plurality of auxiliary container ports and wherein each
one of a plurality of auxiliary containers are received in sealing
engagement with one of the plurality of auxiliary container ports
such that the lumen of each auxiliary container is fluidly coupled
with a fluid inlet of the body portion.
[0042] In certain embodiments, the auxiliary containers are
detachably mounted to the auxiliary container ports.
[0043] In certain embodiments each auxiliary container port is
coupled to a separate fluid inlet of the body portion.
[0044] In certain embodiments each separate fluid inlet of the body
portion is fluidly connected to a fluid outlet of the body
portion.
[0045] In certain embodiments the at least one fluid inlet and the
fluid outlet of the body portion are fluidly coupled to one another
by a fluid conduit.
[0046] In certain embodiments the fluid conduit comprises a valve
operable to open and close the fluid conduit.
[0047] In certain embodiments the valve is one of: a pinch valve, a
pressure sensitive valve, a clamp valve, a membrane valve, a
rupture disc, a venous valve and an aperture valve.
[0048] In certain embodiments each auxiliary container port
comprises a container filling port.
[0049] In certain embodiments the container filling port is fluidly
connected to a fluid inlet of the auxiliary container port.
[0050] In certain embodiments each container filling port comprises
a valve operatively coupled to the fluid inlet and a fluid outlet
of the auxiliary container port and operable to control fluid flow
direction through the auxiliary container port.
[0051] In certain embodiments the container filling port comprises
a valve operable, in an open position, to allow fluid to flow to
the fluid inlet of the auxiliary container port and not to the
fluid outlet of the auxiliary container port and, in a closed
position, to close the container filling port and to allow fluid to
flow from the fluid inlet of the auxiliary container port to the
fluid outlet of the auxiliary container port.
[0052] In certain embodiments the at least one auxiliary container
comprises a mating element configured to fluidly connect to a
corresponding mating element on the auxiliary container port.
[0053] In certain embodiments the mating element is one of: a
sterile connector end or a LUER-LOK.TM..
[0054] In certain embodiments the primary container port comprises
a mating element configured to fluidly connect to a corresponding
mating element on the primary container.
[0055] In certain embodiments the mating element comprises one of:
a sterile connector end or a LUER-LOK.TM..
[0056] In certain embodiments the auxiliary container port
comprises a LUER-LOK.TM. connector at the fluid inlet and/or the
fluid outlet of the auxiliary container port, each LUER-LOK.TM.
connector configured to engage with a further LUER-LOK.TM.
connector on a container and/or on the body portion, respectively.
More specifically, a male LUER-LOK.TM. connector is configured to
engage with a female LUER-LOK.TM. connector.
[0057] In certain embodiments the fluid outlet of the body portion
comprises a LUER-LOK.TM. connector configured to engage with a
further LUER-LOK.TM. connector on a primary container attachable to
the body portion.
[0058] In certain embodiments the auxiliary container port
comprises a sterile connector end at the fluid inlet and/or the
fluid outlet of the auxiliary container port, each sterile
connector end configured to engage with a further sterile connector
end on a container and/or on the body portion, respectively.
[0059] In certain embodiments the fluid outlet of the body portion
comprises a sterile connector end configured to engage with a
further sterile connector end on the primary container attachable
to the body portion.
[0060] In certain embodiments the cell processing device comprises
at least one positional tracking device operable to indicate a set
location on the cell processing platform. In this way, the position
of the platform may be tracked, for example, when the cell
processing device is mounted into a cell processing unit according
to the disclosure.
[0061] In certain embodiments the at least one positional tracking
device is a mechanical device.
[0062] In certain embodiments, the at least one positional tracking
device comprises a cog. In such embodiments, the mounting plate of
the cell processing unit may comprise a further cog operable to
engage the projections of the cog on the cell processing platform.
In this way, the cell processing device will need to be physically
inserted into the mounting plate of the cell processing unit in the
correct orientation. This, in turn, ensures the operator knows the
position of the device and thus containers mounted to the platform
in the cell processing unit.
[0063] In certain embodiments the positional tracking device is an
encoder. More specifically, the positional tracking device is one
or more of: a magnet, an RFID sensor, a light sensor or the
like.
[0064] In certain embodiments the cell processing device comprises
a plurality of positional tracking devices.
[0065] In certain embodiments the at least one positional tracking
device is located on the cell processing platform relative to the
auxiliary container port such that the location of the positional
tracking device is related to the position of the auxiliary
container port.
[0066] In certain embodiments the at least one positional tracking
device is located on the body portion of the cell processing
platform relative to the auxiliary container port.
[0067] In certain embodiments the system comprises a plurality of
positional tracking devices each located on the body portion of the
cell processing platform relative to an auxiliary container
port.
[0068] In certain embodiments the cell processing device comprises
a sampling port in the body portion of the cell processing
platform. Alternatively, the sampling port may be located in the
base section of the primary container.
[0069] In certain embodiments the cell processing device comprises
a gas transfer port in the body portion of the cell processing
platform. Alternatively, the gas transfer port may be located in
the wall of the primary container.
[0070] In certain embodiments the auxiliary container port is
configured to receive a container having a base section, a top
section arranged substantially in parallel with the base section
and a wall element arranged between the top section and the base
section and defining an internal lumen of the container, in which
the wall element of the container preferably is compressible with
respect to the top and base section and the wall element of the
container is composed of a flexible material.
[0071] In certain embodiments the primary container port is
configured to receive a primary container having a base section, a
top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container, in
which the wall element of the container preferably is compressible
with respect to the top and base section and the wall element of
the container is composed of a flexible material.
[0072] In certain embodiments the primary container further
comprises an attachment flange mounted to the top section of the
primary container and being configured to sealingly engage and
detachably mount to the primary container port.
[0073] In certain embodiments the at least one auxiliary container
is compressible. In this way, the container configuration is based
on a concertina (which can act as a pump) therefore there is no
need for separate pumps and complex sets of tubing/pipes to
transfer the contents of a container to another container in the
system. In turn this configuration reduces the space needed for a
cell and/or gene therapy manufacturing process.
[0074] In certain embodiments, the container is a container
described in the earlier patent application PCT/GB2016/051451.
[0075] In certain embodiments, the container is a container
described in the earlier patent application PCT/GB2017/053389.
[0076] Alternatively the container may comprise a syringe
arrangement allowing it to be re-filled or emptied.
[0077] In certain embodiments the at least one auxiliary container
is a syringe. In such a syringe arrangement, the container has an
arrangement analogous to a syringe having an element that is
moveable to either expel fluid from the container or draw it back
in.
[0078] In certain embodiments, the container may comprise any
shaped container with a moving seal allowing variable volume
operations.
[0079] In certain embodiments the at least one auxiliary container
is a bag retained in a frame and moveable with respect to the
frame. More specifically, the top section, the base section and
wall element of the at least one auxiliary container may form a
bag, which can be held within an external adjustable frame, or in
which the bag comprises an internal adjustable frame within the
material of the bag. Accordingly, one or more of the auxiliary
containers in fluid communication with a cell processing platform
of the disclosure may form a bag, which can be held within an
external adjustable frame, or in which the bag comprises an
internal adjustable frame within the material of the bag. Such a
bag may be configured to act, for example, as an intravenous drip
bag. It will therefore be understood the product(s) of any
reaction(s) carried out in a primary container or further container
of the cell processing device may be collected into the bag, which
can then be removed and transferred to an intravenous drip.
Alternatively, the product(s) of any reaction(s) can be directly
delivered to a patient from the lumen of the container,
[0080] In certain embodiments the cell processing device comprises
one or more auxiliary containers connected to an auxiliary
container port of the cell processing platform. More specifically,
the one or more auxiliary containers are detachably connected to an
auxiliary container port of the cell processing platform.
[0081] In certain embodiments one or more of the auxiliary
containers are connected to a respective auxiliary container port
with a sterile connector.
[0082] In certain embodiments one or more of the auxiliary
containers are connected to a respective auxiliary container port
with a LUER-LOK.TM. style connector.
[0083] In certain embodiments the at least one auxiliary container
is located on the top of the cell processing platform.
[0084] In certain embodiments the primary container is located on
the bottom of the cell processing platform.
[0085] According to a further aspect, the disclosure provides a
multi-step method of performing one or more unit operations in cell
and/or gene therapy manufacture using a cell processing device
according to the disclosure.
[0086] In certain embodiments the method comprises introducing a
cell population, for example, a cell population of interest, into
the primary container and sequentially adding one or more reagents
from one or more auxiliary containers into the primary container
via the cell processing platform in order to effect growth,
culturing and/or modification of the cells, for example, in order
to effect a desired growth, culturing and/or modification of the
cells.
[0087] In certain embodiments the auxiliary container is one of: a
reagent container, a cell culture container, a waste container, an
empty container or a bioreactor.
[0088] In certain embodiments the primary container is one of: a
cell culture container or a bioreactor, a reagent container, a
waste container, a filter, an electroporator, a purifier, a waste
container, a filter, an electroporator, a purifier, holding
container, apheresis/leukopheresis, differentiation chamber,
chromatography column, settling chamber, sieve, shaking/mixer, a
centrifuge and a magnetic bead separator or the like.
[0089] A container of the disclosure may be of circular, square,
rectangular, elliptical, or triangular cross section.
Alternatively, a container of the disclosure may comprise a number
of different sections or regions of a variety of cross sections,
such as, for example, a series of circular cross sections with
variable (increasing and /or decreasing) diameters.
[0090] Advanced blow molding techniques can be used to deposit a
second (or even third), external, coating or layer of plastic
impermeable to oxygen onto the wall, top and base of the auxiliary
container. In this way, shelf life of the container in storage can
be extended.
[0091] According to a yet further aspect the disclosure provides a
cell processing system comprising a cell processing device
according to an aspect of the disclosure and a cell processing unit
according to the disclosure.
[0092] Cell Processing Platform
[0093] According to an aspect of the disclosure there is provided a
cell processing platform for use in performing one or more unit
operations in cell and/or gene therapy manufacture, the platform
comprising a body portion comprising at least one fluid inlet
fluidly connected to a fluid outlet, and an auxiliary container
port fluidly coupled to the at least one fluid inlet of the body
portion, wherein the auxiliary container port is configured and
arranged to receive and sealingly engage with an auxiliary
container and to fluidly connect the auxiliary container lumen with
the at least one fluid inlet of the body portion, and a primary
container port configured and arranged to sealingly engage with a
primary container and to fluidly connect the primary container
lumen with the fluid outlet of the body portion.
[0094] The term "cell processing platform" is used to define a
platform, or an interface, upon which one or more unit operations
in cell and/or gene therapy manufacture or processing may be
performed. The terms "cell processing platform," "liquid handling
platform," "platform," "cell processing interface" and "interface"
can be used synonymously. In some examples, the cell processing
platform serves as an interface between components, for example,
containers, bioreactors or the like, such that the user can
manipulate the cell processing platform thereby controlling one or
more unit operations in cell and/or gene therapy manufacture or
processing. The cell processing platform may provide a fluid
pathway, through conduits, seals, valves, septa or the like to
provide an interface between components, for example, containers,
bioreactors or the like. The cell processing platform may provide
an aseptic fluid pathway through conduits, seals, valves, septa or
the like to provide an interface between components, for example,
containers, bioreactors or the like.
[0095] The primary container may be regarded as a first container.
The auxiliary container may be regarded as a second, or a
secondary, container. Any number of containers may be used.
[0096] The term "primary container" is used to define that a
container is connected to a first side, or surface, of the cell
processing platform. For example, the term "primary container" may
be used to define that the container is attached to a lower side,
or surface, of the cell processing platform. There may be any
number of primary containers.
[0097] The primary container may be a bellow-based container, for
example, a bellow-based bioreactor. That is, the container or
bioreactor may be based on a bellows, i.e., a container or
bioreactor including a wall element comprising a series of Z-folds,
or a wall element comprising, or forming, a concertina. The
bellow-based container or bioreactor may include a base section, a
top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container or
bioreactor. The wall element of the container or bioreactor
preferably is compressible with respect to the top and base
sections. The wall element of the container or bioreactor may be
composed of a flexible material. The wall element may comprise a
series of Z-folds. The wall element may comprise, or form, a
bellows. The container may take the form of a concertina.
[0098] The term "auxiliary container" or "secondary container" is
used to define that a container is connected to a second side, or
surface, of the cell processing platform. For example, the term
"auxiliary container" or "secondary container" may be used to
define that the container is attached to an upper side, or surface,
of the cell processing platform. There may be any number of
auxiliary containers.
[0099] The auxiliary container may be a bellow-based container, for
example, a bellow-based bioreactor. That is, the container or
bioreactor may be based on a bellows, i.e., a container or
bioreactor including a wall element comprising a series of Z-folds,
or a wall element comprising, or forming, a concertina. The
bellow-based container or bioreactor may include a base section, a
top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container or
bioreactor. The wall element of the container or bioreactor
preferably is compressible with respect to the top and base
sections. The wall element of the container or bioreactor may be
composed of a flexible material. The wall element may comprise a
series of Z-folds. The wall element may comprise, or form, a
bellows. The container may take the form of a concertina.
[0100] Generally, the term "container," or a "cell processing
container," is used to define a container, a receptacle, a volume,
a bioreactor, or the like in which one or more unit operations of
cell and/or gene therapy manufacture or processing may be
completed.
[0101] In certain embodiments, the body portion includes one, that
is, a single fluid inlet, and one, that is, a single, fluid outlet.
In certain embodiments, the body portion includes one or more fluid
inlets, and one or more fluid outlets. In certain embodiments, the
body portion includes one, that is a single, fluid inlet, and a
plurality of fluid outlets. In certain embodiments, the body
portion includes a plurality of fluid inlets, and one, that is, a
single, fluid outlet. In certain embodiments, the body portions
includes a plurality of fluid inlets, and a plurality of fluid
outlets.
[0102] In certain embodiments the auxiliary container port
comprises a sealable fluid inlet and/or a sealable fluid
outlet.
[0103] In certain embodiments, the auxiliary container port is
configured for sealing engagement with the fluid outlet of an
auxiliary container.
[0104] In certain embodiments, the primary container port is
configured for sealing engagement with the fluid inlet of a primary
container.
[0105] In certain embodiments the auxiliary container port
comprises a container receiving sleeve connected to the body
portion and being configured to surround at least a portion of the
auxiliary container, which portion comprises the fluid outlet of
the container.
[0106] In certain embodiments the container receiving sleeve
comprises insulation means configured to maintain the contents of
an auxiliary container received in the sleeve at a particular
temperature. More specifically, the insulation means is a thermal
sleeve. Accordingly, the auxiliary container receiving port may be
configured to maintain the contents of a container received within
the port at an optimal temperature. For example, the optimal
temperature may be cell culture temperature (37 degrees Celsius),
or room temperature (22 degrees Celsius), or refrigerated (e.g.,
around 4 degrees Celsius), or below freezing (e.g., around minus 4
degrees Celsius or lower, such as minus 20 degrees Celsius, or
minus 80 degrees).
[0107] In certain embodiments the cell processing platform may have
one or more auxiliary container ports configured to maintain a
variety of temperatures.
[0108] In certain embodiments the auxiliary container port
comprises a mating element configured to fluidly connect to a
corresponding mating element on an auxiliary container.
[0109] In certain embodiments the mating element is one of: a
sterile connector end or a LUER-LOK.TM.. When the mating element of
the auxiliary container port is a LUER-LOK.TM. the port may have a
male LUER-LOK.TM. connector, which will engage and couple with a
corresponding female LUER-LOK.TM. connector on the container or
vice versa.
[0110] In certain embodiments the primary container port comprises
a mating element configured to fluidly connect to a corresponding
mating element on a primary container.
[0111] In certain embodiments the mating element comprises one of:
a sterile connector end or a LUER-LOK.TM. When the mating element
of the primary container port is a LUER-LOK.TM., the port may have
a male LUER-LOK.TM. connector, which will engage and couple with a
corresponding female LUER-LOK.TM. connector on the container or
vice versa.
[0112] In certain embodiments the auxiliary container port
comprises a LUER-LOK.TM. connector at the fluid inlet and/or the
fluid outlet of the auxiliary container port, each LUER-LOK.TM.
connector configured to engage with a further LUER-LOK.TM.
connector on a container and/or on the body portion, respectively.
More specifically, a male LUER-LOK.TM. connector is configured to
engage with a female LUER-LOK.TM. connector.
[0113] In certain embodiments the fluid outlet of the body portion
comprises a LUER-LOK.TM. connector configured to engage with a
further LUER-LOK.TM. connector on a primary container attachable to
the body portion.
[0114] In certain embodiments the auxiliary container port
comprises a sterile connector end at the fluid inlet and/or the
fluid outlet of the auxiliary container port, each sterile
connector end configured to engage with a further sterile connector
end on a container and/or on the body portion, respectively.
[0115] In certain embodiments the fluid outlet of the body portion
comprises a sterile connector end configured to engage with a
further sterile connector end on a primary container attachable to
the body portion.
[0116] In certain embodiments the body portion is substantially
hollow.
[0117] In certain embodiments the at least one fluid inlet and the
fluid outlet of the body portion are fluidly coupled to one another
by a fluid conduit.
[0118] In certain embodiments the fluid conduit comprises a valve
operable to open and close the fluid conduit.
[0119] In certain embodiments the valve is one of: a pinch valve, a
pressure-sensitive valve, a clamp valve, a membrane valve, a
rupture disc, a venous valve and an aperture valve.
[0120] In certain embodiments the auxiliary container port
comprises a container filling port.
[0121] In certain embodiments the container filling port is fluidly
connected to a fluid inlet of the auxiliary container port.
[0122] In certain embodiments the container filling port comprises
a valve operatively coupled to the fluid inlet and a fluid outlet
of the auxiliary container port and operable to control fluid flow
direction through the auxiliary container port.
[0123] In certain embodiments the container filling port comprises
a valve operable, in an open position, to allow fluid to flow to
the fluid inlet of the auxiliary container port and not to the
fluid outlet of the auxiliary container port and, in a closed
position, to close the container filling port and to allow fluid to
flow from the fluid inlet of the auxiliary container port to the
fluid outlet of the auxiliary container port.
[0124] In certain embodiments the platform comprises a plurality of
auxiliary container ports each fluidly connected to a fluid inlet
of the body portion. In this way, each of the plurality of
auxiliary container ports is configured and arranged to receive and
sealingly engage with an auxiliary container and to fluidly connect
the container lumen with a fluid inlet of the body portion.
[0125] In certain embodiments each auxiliary container port is
coupled to a separate fluid inlet of the body portion.
[0126] In certain embodiments each separate fluid inlet of the body
portion is fluidly connected to a fluid outlet of the body
portion.
[0127] In certain embodiments the platform comprises at least one
positional tracking device operable to indicate a set location on
the platform. In this way, the position of the platform may be
tracked, for example, when the platform is mounted into a cell
processing unit according to the disclosure.
[0128] In certain embodiments the at least one positional tracking
device is a mechanical device.
[0129] In certain embodiments, the at least one positional tracking
device comprises a cog. In such embodiments, the mounting plate of
the cell processing unit may comprise a further cog operable to
engage the projections of the cog on the cell processing platform.
In this way, the cell processing platform will need to be
physically inserted into the mounting plate of the cell processing
unit in the correct orientation. This, in turn, ensures the
operator knows the position of the platform and thus containers
mounted to the platform in the cell processing unit.
[0130] In certain embodiments the positional tracking device is an
encoder. More specifically the positional tracking device is one or
more of: a magnet, an RFID sensor, a light sensor or the like.
[0131] In certain embodiments the platform comprises a plurality of
positional tracking devices.
[0132] In certain embodiments the at least one positional tracking
device is located relative to the (or each) auxiliary container
port such that the location of the positional tracking device is
related to the position of the auxiliary container port.
[0133] In certain embodiments the at least one positional tracking
device is located on the body portion relative to the auxiliary
container port.
[0134] In certain embodiments the platform comprises a sampling
port in the body portion.
[0135] In certain embodiments the platform comprises a gas transfer
port in the body portion.
[0136] In certain embodiments the auxiliary container port is
configured to receive a container having a base section, a top
section arranged substantially in parallel with the base section
and a wall element arranged between the top section and the base
section and defining an internal lumen of the container, in which
the wall element of the container preferably is compressible with
respect to the top and base section and the wall element of the
container is composed of a flexible material.
[0137] In certain embodiments, the auxiliary container port is
configured to receive a container described in International Patent
Application Number PCT/GB2016/051451.
[0138] In certain embodiments, the auxiliary container is
detachably mounted to the auxiliary container port.
[0139] In certain embodiments the primary container port is
configured to receive a primary container having a base section, a
top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container, in
which the wall element of the container preferably is compressible
with respect to the top and base section and the wall element of
the container is composed of a flexible material.
[0140] In certain embodiments, the auxiliary container port is
configured to receive a primary container described in
International Patent Application Number PCT/GB2016/051451 or
PCT/GB2017/053389.
[0141] In certain embodiments the primary container further
comprises an attachment flange mounted to the top section of the
primary container and being configured to sealingly engage and
mount to the primary container port.
[0142] In certain embodiments, the primary container is detachably
mounted to the primary container port.
[0143] Cell Processing Container
[0144] A critical step, and risk, in performing unit operations in
cell and/or gene therapy manufacture, is the sterile connection of
the components of the equipment to form a usable cell processing
device or the like.
[0145] At least this object and advantages that will be apparent
from the description have been achieved by a cell processing
container for use in one or more unit operations in cell and/or
gene therapy manufacture, the container having a base section, a
top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container, in
which the wall element of the cell culture container preferably is
compressible with respect to the top and base section and the wall
element of the cell culture container is composed of a flexible
material, wherein the cell processing container comprises at least
one sterile connector end configured to operatively couple with a
further sterile connector end so as to form a sterile connector
between the cell processing container and a further component to
which the cell processing container is to be fluidly connected.
[0146] A sterile connector when referred to herein shall at least
include a sterile connecting device configured to produce a sterile
connection or sterile welds between two elements, for example, two
containers or two pieces of compatible tubing. This procedure
permits sterile connection of a variety of containers and tubes of
varying diameters by maintaining a closed system as the two
portions of the sterile connecting device are mated with one
another. In this way, a sterile fluid pathway is maintained between
two elements, for example, containers, tubes or the like. Each
tube/container may have a sterile connector end embedded therein
and may have a removable membrane (e.g., paper) or valve barrier
for mating to another connector end embedded in a further
tube/container. Sterile connectors are designed to connect one
processing stream to another, such as a container to a sampling
line, media to a product vessel, or a filtration assembly to a
filling line. They become beneficial when no biocontainment hood is
available to make an aseptic connection as, owing to the aseptic
pathway created, a sterile connection can be achieved irrespective
of the environment of surroundings in which the connection is
made.
[0147] The line at the junction of the connection cannot be
disconnected without force because of safety mechanisms in place to
prevent this. Disconnection between connected sterile connector
ends may, for example, require a disconnection device, tube sealer,
or tube crimper.
[0148] The term "fluidly connected" is used to refer to a
connection between components to allow passageway of a fluid. The
term "fluid" is used to refer to gases and liquids, in addition to
solutions, suspensions, pastes and gels. Moreover, fluid may also
refer to granular particulates, or solids, such as powders. Such
particulates, solids or powders may or may not be suspended within
a liquid, as a solution, or the like.
[0149] In some examples, the wall element of the cell processing
container preferably, that is, optionally, is compressible with
respect to the top and base section. That is, the top section may
be compressed with respect to the base section, or the base section
may be compressed with respect to the top section, or the top
section and the base section may be compressed with respect to the
base section and the top section, respectively.
[0150] In other examples, the wall element of the cell processing
container is not compressible with respect to the top and base
sections. In some examples, the wall element of the cell processing
container may be flexible, such that a compression, or squeezing,
of the wall element inwardly toward a central longitudinal axis may
be achieved.
[0151] Generally, the term "container," or "cell processing
container," is used to define a container, a receptacle, a volume,
a bioreactor, or the like in which one or more unit operations of
cell and/or gene therapy manufacture or processing may
completed.
[0152] In certain embodiments the at least one sterile connector
end is a genderless sterile connector end configured to operatively
couple with a further genderless sterile connector end.
[0153] That is, the at least one sterile connector end may be
genderless in the sense that it includes neither a male portion nor
a female portion. In some examples, the genderless sterile
connector end may include one or more portions that cooperate with
a portion of a further genderless sterile connector end.
[0154] In certain embodiments the at least one sterile connector
end is a male sterile connector end configured to operatively
couple with a female sterile connector end.
[0155] In certain embodiments the at least one sterile connector
end is a female sterile connector end configured to operatively
couple with a male sterile connector end.
[0156] In certain embodiments the cell processing container
comprises a plurality of sterile connector ends each configured to
operatively couple with a separate further sterile connector end to
form a plurality of sterile connectors between the cell processing
container and at least one further component to which the cell
processing container is to be fluidly connected.
[0157] In certain embodiments the at least one further component is
one of: a further cell processing container, a cell processing
platform according to the disclosure, a tube or the like.
[0158] In certain embodiments the sterile connector ends are
embedded in the cell processing container.
[0159] In some examples, the sterile connector ends may form part
of the cell processing container. In some examples, the sterile
connector ends may form an integral part, or may be integrally
formed within, or as part of, the cell processing container.
[0160] In certain embodiments the sterile connector end is
operatively coupled to a pinch valve embedded in the cell
processing container.
[0161] In certain embodiments the cell processing container has a
circular, square, rectangular, elliptical, or triangular cross
section.
[0162] In certain embodiments, when the cell processing container
has a circular shape, the sterile connector end(s) is/are connected
to the top and/or base section of the cell processing container in
an essentially circular pattern.
[0163] According to an aspect of the disclosure there is provided a
cell processing system, comprising a cell processing container as
described above, further comprising one or more auxiliary
containers detachably connected to the cell processing
container.
[0164] In certain embodiments one or more of the auxiliary
containers comprises the further sterile connector end and is
connected to the cell processing container via the further sterile
connector end.
[0165] In certain embodiments one or more of the auxiliary
containers is located at or near the top section of the cell
processing container.
[0166] In certain embodiments, one or more of the auxiliary
containers is located on the top section of the cell processing
container.
[0167] In certain embodiments, one or more of the auxiliary
containers is located on the top section of the cell culture
container.
[0168] In certain embodiments one or more of the auxiliary
containers is located at or near the base section of the cell
processing container.
[0169] In certain embodiments one or more auxiliary containers is
located on the top section of the cell processing container.
[0170] In certain embodiments one or more of the auxiliary
containers is located on the base section of the cell culture
container.
[0171] In certain embodiments one or more containers may be
connected in series. For example, the cell processing system of the
disclosure may comprise an auxiliary container, which is in fluid
communication with a further auxiliary container, wherein the
further auxiliary container is not is direct fluid communication
with the cell processing container of the system.
[0172] In certain embodiments each container in a series of
containers comprises a sterile connector end in a top and in a base
section. In this way, it is possible to undertake one or more
processing steps in an auxiliary container before making a sterile
connection via the sterile connector ends in connected containers
in order to undertake one or more further processing steps in the
combined containers. In certain embodiments, the one or more
processing steps and the one or more further processing steps may
involve different cell processing units.
[0173] In certain embodiments the one or more auxiliary containers
have a base section, a top section arranged substantially in
parallel with the base section and a wall element arranged between
the top section and the base section and defining an internal lumen
of the container, in which the wall element of the auxiliary
container preferably is compressible with respect to the top and
base section and the wall element of the auxiliary container is
composed of a flexible material.
[0174] Advanced blow molding techniques can be used to deposit a
second (or even third), external, coating or layer of plastic
impermeable to oxygen onto the wall, top and base of the auxiliary
container. In this way, shelf life of the container in storage can
be extended.
[0175] According to a yet further aspect of the disclosure there is
provided a cell processing system operable to perform one or more
unit operations in cell and/or gene therapy manufacture. The cell
processing system comprises, a cell processing unit according to an
aspect of the disclosure, a cell processing device according to an
aspect of the disclosure comprising a cell processing platform
according to an aspect of the disclosure.
[0176] In certain embodiments, the cell processing system comprises
at least one cell processing container according to an aspect of
the disclosure.
[0177] According to a yet further aspect of the disclosure there is
provided a multi-step method of one or more unit operations in cell
and/or gene therapy manufacture using a cell culture system
according to the disclosure.
[0178] In certain embodiments the method comprises introducing a
cell population, for example, a cell population of interest, into
the cell processing container and sequentially adding one or more
reagents from one or more auxiliary containers into the cell
processing container in order to effect one or more unit operations
in cell and/or gene therapy manufacture, for example, desired one
or more unit operations in cell and/or gene therapy
manufacture.
[0179] Cell Processing Unit
[0180] According to an aspect of the disclosure there is provided a
cell processing unit for cell and gene therapy manufacture
comprising a housing defining an enclosure into which a cell
processing platform can be mounted, a platform mounting bracket
within the housing and configured and arranged to receive and
retain a cell processing platform, a drive apparatus configured and
arranged to operatively engage and act upon the cell processing
platform so as to move same with respect to the platform mounting
bracket, and an actuator configured and arranged to exert a force
on a container mounted into the cell processing platform so as to
expel a contents from the container.
[0181] The term "cell processing unit" is used to define a unit in
which one or more unit operations in cell and/or gene therapy
manufacture or processing may be performed. The cell processing
unit may serve as a housing for components used in such manufacture
and processing. The cell processing unit may take any suitable
shape or size. The cell processing unit may take the form of an
apparatus or the like. That is, the terms "cell processing unit,"
"cell processing apparatus" and "an apparatus for cell and/or gene
therapy manufacture or processing" may be used interchangeably.
[0182] The term "enclosure" is used to define an area or space in
which another component can be received, housed or enclosed, either
partially or fully. The enclosure may take the form of a chamber, a
receptacle, a volume of space or the like.
[0183] The term "cell processing platform" is used to define a
platform, or an interface, upon which one or more unit operations
in cell and/or gene therapy manufacture or processing may be
performed. The terms "cell processing platform," "liquid handling
platform," "platform," "cell processing interface" and "interface"
can be used synonymously. In some examples, the cell processing
platform serves as an interface between components, for example,
containers, bioreactors or the like, such that the user can
manipulate the cell processing platform thereby controlling one or
more unit operations in cell and/or gene therapy manufacture or
processing. The cell processing platform may provide a fluid
pathway, through conduits, seals, valves, septa or the like to
provide an interface between components, for example, containers,
bioreactors or the like.
[0184] The term "platform mounting bracket" is used to define a
mounting bracket for a cell processing platform as described
herein. The platform mounting bracket may take the form of one or
more components configured and arranged such that a cell processing
platform may be mounted thereto.
[0185] The term "actuator" is used to define an operable mechanism
that may cause actuation, or operation, of one or more components
of the cell processing unit or cell processing platform. In some
examples, the actuator may cause actuation, or operation, of one or
more containers. In some examples, the actuator may cause
actuation, or operation or compression, of one or more compressible
containers. In some examples, the actuator may cause actuation, or
operation, of one or more valves.
[0186] In certain embodiments the housing is accessible through a
door in a wall of the housing. More specifically, the door may be
hingedly connected to the wall of the housing. Yet more
specifically, the door is positioned in a front wall of the
housing. In this way, front loading of the cell processing unit is
possible.
[0187] In certain embodiments, the housing has a rectangular or
square footprint.
[0188] In certain embodiments the platform mounting bracket
comprises a mounting plate. More specifically, the mounting plate
is configured to receive a portion of a cell processing platform.
In this way, a cell processing platform is retained on the mounting
plate when in use.
[0189] In certain embodiments the platform mounting bracket
comprises a retaining flange spaced apart from the mounting plate
in order that a cell processing platform can be received and
retained in position in the housing between the mounting plate and
the retaining flange. More specifically, the retaining flange and
the mounting plate together provide a recess (slot) into which a
portion of a cell processing platform can be located and
retained.
[0190] In certain embodiments the mounting plate is substantially
C-shaped. Thus, a cell processing platform can be moved into
location on the mounting plate from a sideways (i.e., front)
loading position.
[0191] In certain embodiments the mounting plate is mounted to the
housing.
[0192] In certain embodiments, the mounting plate is adjustable.
More specifically, the distance between the base of the housing and
the mounting plate is adjustable. In this way, different cell
processing devices can be located in the housing.
[0193] In certain embodiments the mounting plate is positioned
within the housing to allow a cell processing device to be
supported by the plate without contacting the walls, top or base of
the housing. In this way, the mounting plate suspends a cell
processing device in the housing. The cell processing device is
therefore able to rotate in the housing.
[0194] In certain embodiments the drive apparatus is a rotational
drive apparatus configured and arranged to operatively engage and
act upon a cell processing platform so as to rotate same with
respect to the platform mounting bracket. Thus, the cell processing
platform, once positioned in the cell processing unit and engaged
with the rotational drive apparatus, can be indexed in its position
relative to the platform mounting bracket by operation of the
rotational drive apparatus. Thus, in certain embodiments the cell
processing unit is operable to move a cell processing platform
within it in an automatic process.
[0195] In certain embodiments the rotational drive apparatus
comprises a drive wheel, which is mounted on the platform mounting
bracket and is configured to engage a surface of a cell processing
platform and to impart rotational movement on it.
[0196] In certain embodiments the rotational drive apparatus
comprises a sprung wheel biased toward the drive wheel and spaced
apart from it and mounted on the platform mounting bracket.
[0197] In certain embodiments the rotational drive apparatus
comprises a hinged wheel biased toward the drive wheel and spaced
apart from it and mounted on the platform mounting bracket.
[0198] The term "hinged wheel" is used to define a wheel hingedly
mounted, that is, mounted upon a hinge, such that it may be
moveable between at least a first configuration and a second
configuration. The wheel may be hingedly mounted in any suitable
way, and may be moveable between any number of appropriate
configurations.
[0199] In certain embodiments the hinged wheel is moveable into an
open position in which a cell processing platform can be inserted
into and engaged with the platform mounting bracket and a closed
position in which the hinged wheel is engaged with a surface of the
cell processing platform in order to retain same in the cell
processing platform mounting bracket.
[0200] In certain embodiments the hinged wheel is moveable
manually.
[0201] In certain embodiments the hinged wheel is moveable
automatically. More specifically, the hinged wheel may be
operatively coupled to an actuator operable to move the hinged
wheel between the open position and the closed position.
[0202] In certain embodiments the hinged wheel is mounted to the
door of the housing.
[0203] In certain embodiments the door of the housing comprises a
platform engaging means. More specifically, the platform engaging
means is one of: a flange, a protrusion or a lug located on the
inside of the door (facing the inside of the housing) and being
operable to engage with the surface of a cell processing platform
when the door is closed. In this way, the platform engaging means
is operable to retain the cell processing platform in the mounting
bracket. The platform engaging means may also be operable to
maintain the cell processing platform in engagement with the drive
wheel of the rotational drive apparatus.
[0204] In certain embodiments the drive apparatus comprises a
three-point contact arrangement. In this way, a cell processing
platform in the cell processing unit is retained in the drive
mechanism around its full circumference.
[0205] In certain embodiments, the three elements of the drive
apparatus (e.g., the drive wheel, the sprung wheel and the hinged
wheel) are equally spaced from one another within the housing. Such
an arrangement facilitates the rotational movement of the cell
processing platform with the least number of drive wheels.
[0206] In certain embodiments the actuator is a linear
actuator.
[0207] The term "linear actuator" is used to define an actuator
that moves in a linear manner, that is, along an axis. In some
examples, the linear actuator may be operable along a longitudinal
axis.
[0208] In certain embodiments, the actuator comprises a lever, a
plunger or a series of levers, plungers or bellows configured to
compress a container mounted into the cell processing platform. In
certain embodiments the actuator is configured to compress the
primary container and/or the one or more auxiliary containers
mounted to the cell processing platform and located in the
housing.
[0209] In certain embodiments the linear actuator comprises a
plunger operatively coupled to a drive motor, wherein the plunger
is configured to engage a container in the cell processing platform
and to exert a compression force on the container.
[0210] In certain embodiments, the cell processing unit comprises a
plurality of actuators. In certain embodiments the apparatus
comprises a primary actuator configured and arranged to exert a
force on a primary container mounted to the cell processing
platform so as to expel a contents (e.g., a fluid, cells or the
like) from the container.
[0211] In certain embodiments the primary actuator is a linear
actuator.
[0212] In certain embodiments, the linear primary actuator
comprises a lever, a plunger or a series of levers, plungers or
bellows configured to compress the primary container.
[0213] In certain embodiments the primary actuator comprises a
plunger operatively coupled to a drive motor, wherein the plunger
is configured to engage a primary container mounted to the cell
processing platform and to exert a compression force on the primary
container.
[0214] It will be understood that any actuator should preferably be
capable not merely of compressing or collapsing a container mounted
to the cell processing platform but also of re-opening it where
this is required. In this way, the contents of the container can be
agitated by repeated compression/extension of the container.
[0215] In certain embodiments the apparatus comprises a valve
actuator operable to act upon a valve in the cell processing
platform so as to open and close same as force is applied to the
container. In certain embodiments the valve is a pinch valve.
[0216] In certain embodiments the valve actuator is a linear
actuator.
[0217] In certain embodiments the valve actuator comprises a
solenoid valve.
[0218] In certain embodiments the apparatus comprises a location
detecting sensor operable to detect the position of the cell
processing platform relative to the platform mounting bracket.
[0219] In certain embodiments the location detecting sensor is
operable to detect the rotational position of the cell processing
platform relative to the platform mounting bracket. In this way,
the location of container ports, and therefore the containers
mounted in the cell processing platform, are detectable as the cell
processing platform moves relative to the housing.
[0220] In certain embodiments the location detecting sensor
comprises one or more of: a Hall Effect sensor, an RFID sensor, a
light sensor or a cog operable to engage a further cog.
[0221] In certain embodiments the apparatus comprises a home
location detecting sensor operable to detect a home position of the
cell processing platform relative to the platform mounting
bracket.
[0222] The term "home position" is used to define a first, default
or original position of configuration of the cell processing
platform. The home position may be referred to as so with respect
to a predetermined position in relation to the platform mounting
bracket.
[0223] In certain embodiments the home location detecting sensor is
operable to detect a single rotational position of the cell
processing platform relative to the platform mounting bracket.
[0224] The term "a single rotational position" is used to define a
position within the path of rotation of the cell processing
platform. The single rotational position may be referred to as so
with respect to a position on the platform mounting bracket, for
example, a predetermined position.
[0225] In certain embodiments the home location detecting sensor
comprises one or more of: a Hall Effect sensor, an RFID sensor, a
light sensor or a cog operable to engage a further cog.
[0226] In certain embodiments the voltage detected by the Hall
Effect sensor is greater at the home position of the cell
processing platform relative to the platform mounting bracket than
at any other position during the rotation of the cell processing
platform relative to the platform mounting bracket.
[0227] In certain embodiments a container is mounted to the cell
processing platform to form a cell processing device as described
herein. More specifically, the container is compressible. In this
way, the container configuration is based on a concertina (which
can act as a pump) therefore there is no need for separate pumps
and complex sets of tubing/pipes to transfer the contents of a
container to another container in the system. In turn this
configuration reduces the space needed for a cell and/or gene
therapy manufacturing process.
[0228] In certain embodiments, the container is a container
described in the earlier patent application PCT/GB2016/051451.
[0229] In certain embodiments, the container is a container
described in the earlier patent application PCT/GB2017/053389.
[0230] In certain embodiments the container comprises a base
section, a top section arranged substantially in parallel with the
base section and a wall element arranged between the top section
and the base section and defining an internal lumen of the
container, in which the wall element of the container preferably is
compressible with respect to the top and base section and the wall
element of the container is composed of a flexible material.
Alternatively the container may comprise a syringe arrangement
allowing it to be re-filled or emptied. In such a syringe
arrangement, the container has an arrangement analogous to a
syringe having an element that is moveable to either expel fluid
from the container or draw it back in.
[0231] In certain embodiments, the container may comprise any
shaped container with a moving seal allowing variable volume
operations.
[0232] In certain embodiments the primary container is
compressible.
[0233] In certain embodiments the primary container comprises a
base section, a top section arranged substantially in parallel with
the base section and a wall element arranged between the top
section and the base section and defining an internal lumen of the
container, in which the wall element of the container preferably is
compressible with respect to the top and base section and the wall
element of the container is composed of a flexible material.
[0234] In certain embodiments the container(s) is one of: a reagent
container, a bioreactor, a cell culture container, a waste
container, a filter, an electroporator, a purifier, a waste
container, a filter, an electroporator, a purifier, holding
container, apheresis/leukopheresis, differentiation chamber,
chromatography column, settling chamber, sieve, shaking/mixer a
centrifuge and a magnetic bead separator or the like.
[0235] In certain embodiments the primary container is a cell
culture container.
[0236] In certain embodiments control of the cell processing unit
is automated.
[0237] The term "automated" is used to refer to operation of a
component without, or substantially without, user intervention.
[0238] In certain embodiments the cell processing unit comprises a
control system operable to activate the actuator and/or the drive
means. In this way, a cell processing device loaded into the unit
can be selectively moved to position a container in line with the
actuator and/or the actuator activated to act upon a container in
the housing so as to expel its contents.
[0239] In certain embodiments the control system is manually or
automatic. More specifically, the automatic control system may be
programmed to operate the actuator and/or the drive means in a
predetermined sequence.
[0240] In certain embodiments, the control system comprises a user
interface on the housing.
[0241] In certain embodiments, the control system comprises a user
interface operably linked to and remote from the housing.
[0242] In certain embodiments, the user interface is operable to
allow a user to program instructions into the control system.
[0243] In certain embodiments the cell processing unit comprises a
temperature control means. In this way, the temperature within the
housing can be controlled and selected.
[0244] According to another aspect the disclosure provides a cell
processing system comprising a cell processing unit according to
the disclosure.
[0245] According to a yet further aspect of the disclosure there is
provided a method of cell and/or gene therapy manufacture utilizing
a cell processing unit according to the disclosure.
[0246] As will be clear to the person skilled in the art, elements,
components, features and advantages of the cell processing unit,
cell processing platform, cell processing device, cell processing
container, sterile connector ends, and the methods of manufacture,
usage and components thereof may be applied equally to various
embodiments described herein. That is, where a feature is described
in relation to one embodiment, aspect or example, this is not
intended to preclude the inclusion of such a feature in relation to
another embodiment, aspect or example, as will be recognized by
those skilled in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0247] These and other aspects, features and advantages of which
embodiments of the disclosure are capable of, will be apparent and
elucidated from the following description of embodiments and
aspects of the disclosure, reference being made to the accompanying
drawings, in which:
[0248] FIG. 1 illustrates a perspective view of a cell processing
unit according to an embodiment of the disclosure with a cell
processing device partially loaded into the device;
[0249] FIG. 2 illustrates a side view of a cell processing device
according to an embodiment of the disclosure;
[0250] FIG. 3 illustrates a cross-sectional view of a part of the
cell processing device of FIG. 2;
[0251] FIGS. 4a and 4b illustrate a perspective view of the valve
means of the cell processing platform of the cell processing device
of FIG. 2;
[0252] FIG. 5 illustrates an isolated side view of one auxiliary
container port and auxiliary container of the cell processing
device FIG. 2;
[0253] FIG. 6 illustrates a perspective view of the mounting
bracket, actuators and frictional drive mechanism of the cell
processing unit of FIG. 1;
[0254] FIG. 7 illustrates a top view of the mounting plate and the
frictional drive mechanism of the partial cell processing unit of
FIG. 6;
[0255] FIG. 8 illustrates a perspective view of the underside of
the cell processing device of FIG. 2;
[0256] FIG. 9 illustrates a close up view of the cell processing
device and sensor arrangement of FIG. 8;
[0257] FIG. 10 illustrates a top view of the cell processing device
and sensor arrangement of FIG. 8;
[0258] FIG. 11 illustrates a Hall Effect Sensor of the cell
processing unit and a cell processing platform comprising at least
one magnet;
[0259] FIG. 12 shows a perspective view from the side of a
representation of one embodiment of a cell processing container
comprising a plurality of sterile connectors according to an
embodiment of the disclosure;
[0260] FIG. 13 shows a perspective view from the side of a
representation of one embodiment of the cell processing system of
the disclosure;
[0261] FIG. 14A shows a perspective view from the side of a
representation of one embodiment of the cell processing system of
the disclosure, where auxiliary containers are connected to the
cell processing container, leaving an empty auxiliary container
port for a further auxiliary container to be connected;
[0262] FIG. 14B shows a perspective view from the side of a
representation of one embodiment of the cell processing system of
the disclosure, where an auxiliary container has been connected to
the empty auxiliary container port of the cell processing
container;
[0263] FIGS. 15A, 15B, 15C and 15D show a known sterile connector
arrangement formed from two sterile connector ends;
[0264] FIGS. 16A, 16B, 16C and 16D show the formation of a sterile
connector from two known sterile connector ends;
[0265] FIG. 17A shows a perspective view from the side of a
representation of one embodiment of a cell processing container
comprising a sterile connector end embedded therein;
[0266] FIG. 17B shows a close view of the sterile connector end of
the cell processing container of FIG. 15A;
[0267] FIGS. 17C, 17d and 17E a perspective view from the side of a
representation of an auxiliary container for a cell processing
device and/or a cell processing system according to the disclosure
comprising a sterile connector end and being prepared for filling
with reagent;
[0268] FIG. 18A shows a perspective view from the side of a
representation of one embodiment of an auxiliary container
comprising a sterile connector end embedded in a base section and a
screw top cap in a top section;
[0269] FIG. 18B shows a perspective view from the side of a
representation of one embodiment of a cell processing container
comprising a plurality of sterile connector ends embedded in a top
and a bottom section;
[0270] FIG. 18C shows a schematic representation of a number of
prefilled auxiliary containers being connected to a cell processing
container to create a cell processing system according to the
disclosure having a sterile connector end in an auxiliary container
port for receiving a further auxiliary container containing patient
cells;
[0271] FIG. 18D shows a schematic representation of a number of
prefilled auxiliary containers being connected to a single use wave
container to create a cell processing system according to the
disclosure having a sterile connector end in an auxiliary container
port for receiving a further auxiliary container containing patient
cells; and
[0272] FIG. 18E shows a schematic representation of a number of
prefilled auxiliary containers being connected to a CSTR bioreactor
to create a cell processing system according to the disclosure
having a sterile connector end in an auxiliary container port for
receiving a further auxiliary container containing patient
cells.
DETAILED DESCRIPTION
[0273] Specific embodiments of the disclosure will now be described
with reference to the accompanying drawings. This disclosure may,
however, be embodied in many different forms and should not be
construed as limited to the embodiments set forth herein; rather,
these embodiments are provided so that this disclosure will be
thorough and complete, and will fully convey the scope of the
disclosure to those skilled in the art. The terminology used in the
detailed description of the embodiments illustrated in the
accompanying drawings is not intended to be limiting of the
disclosure. In the drawings, like numbers refer to like
elements.
[0274] The terminology used herein is for the purpose of describing
particular aspects of the disclosure only, and is not intended to
limit the disclosure. As used herein, the singular forms "a," "an"
and "the" are intended to include the plural forms as well, unless
the context clearly indicates otherwise.
[0275] In the drawings and specification, there have been disclosed
exemplary aspects of the disclosure. However, many variations and
modifications can be made to these aspects without substantially
departing from the principles of the present disclosure. Thus, the
disclosure should be regarded as illustrative rather than
restrictive, and not as being limited to the particular aspects
discussed above. Accordingly, although specific terms are employed,
they are used in a generic and descriptive sense only and not for
purposes of limitation, for example, definition of dimensions such
as width or breadth or height or length or diameter depends on how
exemplary aspects are depicted, hence, if depicted differently, a
shown width or diameter in one depiction is a length or thickness
in another depiction.
[0276] It should be noted that the word "comprising" does not
necessarily exclude the presence of other elements or steps than
those listed and the words "a" or "an" preceding an element do not
exclude the presence of a plurality of such elements. It should
further be noted that any reference signs do not limit the scope of
the claims, that the example aspects may be implemented at least in
part by means of both hardware and software, and that several
"means," "units" or "devices" may be represented by the same item
of hardware.
[0277] Features, integers, characteristics, compounds, chemical
moieties or groups described in conjunction with a particular
aspect, embodiment or example of the disclosure are to be
understood to be applicable to any other aspect, embodiment or
example described herein unless incompatible therewith. All of the
features disclosed in this specification (including any
accompanying claims, abstract and drawings), and/or all of the
steps of any method or process so disclosed, may be combined in any
combination, except combinations where at least some of such
features and/or steps are mutually exclusive. The disclosure is not
restricted to the details of any foregoing embodiments. The
disclosure extends to any novel one, or any novel combination, of
the features disclosed in this specification (including any
accompanying claims, abstract and drawings), or to any novel one,
or any novel combination, of the steps of any method or process so
disclosed.
[0278] In the drawings like reference numerals refer to like
parts.
[0279] Cell Processing Unit
[0280] FIG. 1 illustrates a cell processing unit 1 according to the
disclosure. The cell processing unit comprises a housing 2 formed
of four walls upstanding from a base wall and a top wall parallel
to the base wall and spaced apart from it by the length of the
walls. The housing 2 forming a chamber 3 with a hinged door 7 in
one wall for receiving a cell processing device 901 comprising cell
processing platform (CPP) 9. On the front panel of the cell
processing unit 1 is a control panel 5 to enable the user to
program and control various features positioned within the chamber
3, as well as their interactions with the cell processing device
901. Details of these features and the cell processing device 901
are set out in more detail below.
[0281] The cell processing unit 1 has a housing 2, which defines an
enclosed space, being chamber 3 in which one or more unit
operations (i.e., steps) of cell and/or gene therapy manufacturing
process can occur.
[0282] An automated cell processing system according to an
embodiment of the disclosure comprises cell processing unit 1 and a
cell processing device 901 as shown in FIG. 2. The cell processing
device 901 comprises a cell processing platform 9 and one or more
auxiliary containers 11 coupled to the platform 9. The platform 9
can be manipulated by the cell processing unit 1 to transfer
liquids between the auxiliary container 11 (e.g., feed bellows)
located on the top of the cell processing platform 9 and the
primary container 13 (e.g., reactor bellow) located on the bottom
of the cell processing platform 9. FIG. 1 shows an embodiment in
which the cell processing system has cell processing unit 1 and a
cell processing device 901 with five auxiliary containers 11
fluidly connected to the cell processing platform 9. The cell
processing unit 1 rotates the platform 9 using a friction drive
system. The cell processing unit 1 comprises a valve solenoid
micro-linear actuator (38, FIG. 6), which when activated, opens
pinch valves 27 in the cell processing platform 9 and presses the
auxiliary container 11 using a linear actuator (106, FIG. 6). The
cell processing platform 9 comprises a body portion comprising base
plate 15 onto which the primary container 13 (e.g., reactor bellow)
is fitted on the underneath into a primary container port (FIG. 2,
reference numeral 14) and the five auxiliary containers 11 (e.g.,
feed bellows) are fitted on top of the base plate 15 in auxiliary
container ports 19. The auxiliary containers 11 (e.g., feed
bellows) are mounted on top of the sleeves forming the auxiliary
container ports 19, which contain LUER-LOK.TM. fittings to connect
the auxiliary containers 11 to the tubing in the auxiliary
container ports 19. The tubing being fluidly connected to the
tubing in the base plate 15, through the base plate 15 and onto the
fluid outlet at the primary container port 14. Each auxiliary
container port 19 comprises a filling valve 31, which allows for
filling of the auxiliary container 11 fluidly coupled to the port
19. The base plate 15 of the cell processing platform 9 contains
normally closed pinch valves 27 acting on the tubing 29 between the
auxiliary containers 11 and the primary container 13. In this
embodiment, the cell processing system comprises a cell processing
device with five auxiliary containers. However, it should be
appreciated that in cell processing device may have a different
number of auxiliary containers according to the present disclosure.
It is further envisaged that the containers may have different
volumes according to the present disclosure.
[0283] The chamber 3 is not sterile, however the containers are
completely closed when loaded into the cell processing platform.
The containers in parallel and/or series in the cell processing
platform provide a single closed consumable unit (cell processing
device) for the entire manufacturing process. Filling the
containers occurs either aseptically (e.g., in a laminar flow hood)
or using sterile connections (e.g., tube welding or sterile
connections).
[0284] The housing 2 of the cell processing unit 1 allows for easy
insertion and removal of the cell processing device 901 through a
front opening door 7. With the door 7 open, the cell processing
device 901 comprising the cell processing platform 9 and attached
auxiliary containers 11 each comprising various cell processing
reagents can be placed down and slid into its final position. The
control panel 5 is located on the front of the housing 2, meaning
that all interactions with the cell processing unit 1 happen from
the front. In this way, multiple cell processing units 1 can be
placed close together, side by side or on top of each other. Having
rows of units or stacks of units, respectively, facilitates the
capacity for advanced manufacturing and processing. The depicted
embodiment is shown with five buttons, one for each feed actuation
in a test protocol for the system. The door 7 is transparent so
that the operations can be visible when demonstrating the function
of the apparatus. In alternative embodiments an opaque door could
be provided. In this way, the cells can be shielded from UV light
during processing.
[0285] Cell Processing Unit
[0286] FIG. 6 shows a portion 101 of cell processing unit 1 with
the housing 2 removed for ease of depiction. Inside the housing the
portion of the cell processing unit 101 comprises a linear actuator
103 for compression of the auxiliary container 11 feed bellows, a
linear actuator 106 for compression of the primary container 13
reactor bellow, a frictional drive mechanism (107, 109, 111)
mounted on mounting plate 104 and operable to rotate the cell
processing platform 9 and a micro linear actuator 38 for opening
the pinch valves, which are operable to open and close the tubing
in the platform. The internal structure of the apparatus is
machined from aluminum, the linear actuators 106, 103 are aluminum
and steel constructions with the lead screws hard coated in TFE dry
lubricant.
[0287] In addition to the mounting plate 104, the mounting bracket
comprises a mounting flange (not shown), located above the mounting
plate in such a way as to retain the cell processing platform by
frictional fit between the mounting plate 104 and the mounting
flange.
[0288] The layout of the actuators 38, 103, 106 allows them to be
hidden in the rear of the apparatus by a cover (not shown) through
which only the plungers 103a, 106a protrude to compress the bellows
of the auxiliary and primary containers respectively, helping to
give a clean and uncomplicated appearance, and provides an
apparatus that is simpler to clean and wipe down. A power supply
and the electronics for the actuators and the frictional drive
mechanism are mounted on the plate 112 below the mounting plate
104. The four risers 114 are adjustable in height and operable to
change the distance between the mounting plate 104 and the plate
112 housing the power supply and the electronics. In this way, the
apparatus can accommodation different sizes of primary
containers.
[0289] The housing 2 contains all of the actuators and electronics
necessary to manipulate the cell processing device. The feed bellow
plunger 103a and reactor plunger 106a operable to exert a
compression force on the auxiliary container and the primary
container respectively, attach to linear rails, each with a maximum
force of 100N. The motors driving the linear rails are bipolar
stepper motors. The valve actuator 38 is a linear actuator with a
maximum force of 45N.
[0290] The frictional drive mechanism (107, 109, 111) comprises a
drive wheel 107 located on mounting plate 104 and operable to
impart rotation on the cell processing device. The drive wheel 107
is a bipolar stepper motor. The actuator stepper motors on the
linear rails and the stepper motor in the frictional drive
mechanism are driven by a control system and associated power
supply (not shown).
[0291] FIG. 7 shows the elements of the frictional drive mechanism
(107, 109, 111) mounted to the mounting plate 104 of the mounting
bracket. To allow the cell processing device 901 comprising the
cell processing platform 9 and the auxiliary containers to be
inserted from front only, a drive method has been developed where
the cell processing platform 9 is held between three friction
wheels, one of which being driven 107, the other drive mechanism
109 and the third being a hinge wheel 111 within the door, which
opens to allow insertion of the platform 9 and closes to lock it in
place. The cell processing device 901 rotates on low friction PTFE
pads 116 on the mounting plate 104. The spring force of the sprung
friction wheel 109 will be such that there is no slip between the
drive wheel 107 and the outer face of the base plate 15 of the
platform 9. The driven wheel 107 is directly connected to a stepper
motor. The base plate 15 of the cell processing platform 9 is
fitted with a series of magnets 118 around its circumference so
that its position can be read by a Hall Effect sensor 120 mounted
on the mounting plate 104. The cell processing platform 9 therefore
acts like an encoder and gives closed loop position feedback
independent of any motor slip.
[0292] The Hall Effect sensor 120 mounted to the mounting plate 104
attached to the housing 2 is operable to detect the magnetic field
from the magnets 118 on a cell processing platform 9 mounted in the
housing 2. The Hall Effect sensor 120 is operable to detect the
position of the cell processing platform 9 relative to the mounting
bracket. As best seen in FIG. 8, each auxiliary container port 19
attached to the base plate 15 of the cell processing platform 9 has
a magnet 118 positioned in the base plate 15 adjacent the port 19.
In this way, the Hall Effect sensor 120 will detect a magnet 118
when an auxiliary container port 19 and its associated magnet 118
is in line with the sensor. Therefore the respective auxiliary
container port 19 is in a known position in the housing relative to
the mounting plate 104.
[0293] FIGS. 8, 9, 10 and 11 show the positional sensor array
operable to detect the position of the cell processing platform 9
of the cell processing device within the cell processing unit
1.
[0294] The sensor array comprises Hall Effect sensors 120 and a
series of magnets 118 on the base plate 15. The sensor array tracks
the position of the cell processing platform 9 using the Hall
Effect sensors 120. The Hall Effect sensors 120 produces a voltage
in response to magnetic fields produced by magnets 118. There are
two Hall Effect sensors 120 mounted to the mounting plate 104 in
the housing 2 and a series of magnets 118 embedded in the cell
processing platform 9. One of the Hall Effect sensors 120 is for
tracking rotation of the cell processing platform 9 relative to the
mounting plate 104 and the other Hall Effect sensor 120 is
dedicated to tracking a so-called home position of the cell
processing platform 9 relative to the mounting plate 104. The home
position is determined by having one magnet 118 on a different
pitch circle diameter to the other magnets 118 on the cell
processing platform 9, serving as an index or marker to count full
revolutions of the cell processing platform 9 in the housing 2.
Using the cell processing device as an encoder, rather than having
an encoder on the motor, means that there is a closed loop position
feedback on the cell processing device itself
[0295] To ensure there will be no slip between the drive mechanism
and the platform 9, the friction between the elastomeric driving
(friction) wheel 107 and the base plate 15 needs to be greater than
the friction between the PTFE pads 116 and the base plate 15. Using
the maximum force that will be transmitted between the drive wheel
107 and the base plate 15 of the platform 9, the normal force
required to ensure consistent drive can be calculated.
[0296] Cell Processing Device
[0297] The cell processing platform 9, as shown in FIGS. 2-5,
comprises a cell processing platform having an annular base plate
15 with a number of auxiliary container ports 19, in this case
five, arranged on the upper surface, and a single primary or
reaction container 13 mounted on its underside at a primary
container port 14. Each auxiliary container port 19 is adapted to
receive an auxiliary container 11, such as the types described
herein, or in the earlier publication WO2018087558. Each of the
auxiliary containers 11 in the example has a 45 ml maximum capacity
such that the total feed capacity of the five auxiliary containers
11 is 225 ml. The primary container 13 has a maximum capacity of
150 ml.
[0298] As shown in the cross-section of FIG. 3, the auxiliary
container 11 comprises a top section 21 and a base section 23 with
a collapsible bellows portion 17 located between them to define a
storage volume 20. The base section 23 includes fluid outlet 25
through which the contents of the storage volume 20 can be
transferred. With the auxiliary container 11 located into auxiliary
container port 19, the outlet 25 is in fluid communication with a
connector 26 located therein. In the example shown, the connector
26 comprises a 4-way stopcock described in more detail below.
[0299] The auxiliary containers 11 are formed of blow molded LDPE
while the auxiliary container ports 19 are formed of Nylon. The
base plate 15 is formed of machined HDPE and the primary container
13 is formed of blow molded HDPE bonded to a machined HDPE flange
being the primary container port 14. The base plate 15 is made up
of three pieces, which are screwed together. The primary container
13 is mounted to the base plate 15 by screws.
[0300] A flexible tubing 29 comprises a first end fitted to
connector 26, and a second end fitted to base plate outlet 33,
thereby forming a fluid communication conduit between the auxiliary
container 11 and the primary container 13. The flexible tubing 29
may comprise any appropriate length and cross section. In the
example show, the flexible tubing 29 is COLE-PARMER.RTM. Platinum
Cured Silicone Tubing with inner diameter (ID) 1/8'' and outer
diameter (OD) 3/16''. Aptly, the flexible tubing will be made from
a suitably non-leachable, resilient and biologically inert
material, in this case silicone, although other resilient materials
may be used.
[0301] Fluid flow through the fluid communication conduit, and
hence between an auxiliary container 11 and the primary container
13 is controlled by valve means 27, located within the base plate
15. In the example shown, the auxiliary container 11 is one of
several, each located in a corresponding auxiliary container port
19 on the base plate 15. Accordingly, each auxiliary container 11
is provided with a flexible tubing 29 to the primary container 13,
controlled by a separate valve means 27. In this way, the transfer
of the contents of each storage volume 20 may be precisely and
independently controlled.
[0302] One of the valve means 27 is shown in more detail in FIGS.
4a and 4b. The valve means 27 comprises a closure portion 37
slidably engaged within a radial channel located in the base plate
15 and defined between channel walls 41a and 41b. The closure
portion 37 is substantially a hollow rectangular shape with the
longer pair of opposing walls arranged parallel with the channel
walls 41a and 41b and the shorter pair of opposing walls arranged
at its inner and outer surfaces. An actuating portion 38 is
provided on the outer short wall and a compression portion 43 is
provided on the inner shorter wall.
[0303] The closure portion 37 is the located over a valve wall 39
fixed within the channel and spaced away from the channel walls 41a
and 41b. The closure portion 37 can thus be moved between two
extreme positions--a closed position (FIG. 4a) and an open position
(FIG. 4b)--by sliding past the valve wall 39 within the
channel.
[0304] The flexible tubing 29 is arranged to extend through the
valve means 27 such that a section of the tubing 29 sits between
the valve wall 39 and the compression portion 43. In the closed
position, the closure portion 37 is urged toward the outer
perimeter of the base plate 15 by a spring 35. The spring 35 is
positioned to act on the compression portion 43, urging it against
the flexible tubing 29 and pinching it against the valve wall 39.
Thus, in the closed position, the pinched section of tubing blocks
the fluid communication conduit and prevents fluid flow.
[0305] To unblock the conduit, the closure portion 37 is moved
toward the open position by pressing the actuating portion 38,
releasing the compression portion 43 from the valve wall 39 and
allowing the pinched section of the flexible tubing to revert to
its original shape and permitting fluid flow.
[0306] With the cell processing device installed in the cell
processing unit, the valve means 27 is actuated by actuator 38 and
opened while the auxiliary container 11 is compressed by plunger
103a. The actuator 38 may be configured so that the valve means 27
opens when the auxiliary container 11 is compressed. Alternatively,
actuation may occur as a separate step, for example, when the
auxiliary container 11 is received into the auxiliary container
port 19. The actuation may occur automatically in conjunction with
the compression of the auxiliary container 11, or may be controlled
to happen independently.
[0307] In the example shown, the valve actuation is carried out by
a linear actuator 38 located at the rear of the housing 2 of the
cell processing unit 1, which acts upon the closure portion 37 to
move it toward the open position. Thus, the valve means is normally
closed and actuated to open only when fluid needs to be delivered
to the primary container 13.
[0308] As shown in FIG. 3, each auxiliary container 11 is attached
to a filling valve connector 26 in the form of a 4-way stopcock.
The connector 26 comprises a LUER-LOK.TM. port for filling via
direct access to the auxiliary container 11. This port, which may
be used for manually inserting fluids into the auxiliary container,
does not have its own valve means 27 but is capped instead.
[0309] Two further capped LUER-LOK.TM. ports are provided on base
plate 15 for sampling/harvesting fluid, or gas exchange. A first
port leads to the head space of the primary container, while a
further port is connected to the base of the primary container
13.
[0310] FIG. 5 depicts the filling port 31 and lever 45 mounted on
the auxiliary container port 19. The lever 45 is provided in order
to fill the auxiliary container 11 without allowing material to
flow into the valve means 27 or primary container 13. The lever 45
is operatively connected to a 4-way stopcock, which forms the
connector 26 in the example described above. At the fill position
(lever pointing down), the filling port 31 is opened and flow of
material through the port 31 is directed into the auxiliary
container 11. Then, at the feed position (lever pointing up), the
filling port 31 is closed and flow is directed from the auxiliary
container 11 via the flexible tubing 29 and into the primary
container 13.
[0311] Sterile Connectors
[0312] FIG. 12 shows a cell processing container 200 according to
an embodiment of the disclosure. Cell processing container 200
comprises a base section 202, a top section 203 and a wall element
204 arranged between the top section 203 and the base section 2.
The wall element 204 is preferably composed of a flexible material.
The wall element 204 is preferably compressible with respect to the
top section 203 and the base section 202. The cell processing
container 200 may thereby have a "concertina" or "bellows
arrangement," e.g., it may have one or more z-folds in the wall
element 204 arrangement.
[0313] The cell processing container 200 may comprise 1 sterile
connector end and preferably comprises a plurality of connector
ends 205. The connector ends 205 are preferably sterile. The
sterile connector ends 205 are preferably located on the top
section 203 and/or on the base section 202 of the cell processing
container 200. The cell processing container 200 preferably
comprises at least 1, at least 2, at least 3, at least 4, or at
least 5 sterile connector ends 205. According to a preferred
embodiment, the sterile connector ends 205 are embedded in the cell
processing container 200. The sterile connector ends 205 enable an
easy and sterile connection of auxiliary containers 11 to the cell
processing container 200.
[0314] The cell processing container 200 may have any possible
shape. In a preferred embodiment the cell processing container 200
has a circular, square, rectangular, elliptical, or triangular
cross section.
[0315] In a preferred embodiment, when the cell processing
container 200 has a circular shape, the sterile connector ends 205
are preferably connected to the top 203 and/or base 202 section in
an essentially circular pattern. The cell processing container 200
also comprises a sterile connector end 205 in the center of the top
203 and the base 202. The sterile connector ends 205 are connected
to the top 203 and/or base 202 section essentially symmetrically
having essentially the same distance between the different
connector ends 205. This enables an easier and possibly automated
process of cell and/or gene therapy manufacturing. In an
alternative embodiment, when the cell culture container 200 has a
circular shape, a sterile connector end 205 are connected to the
center of the top section 203 and base section 202.
[0316] An embodiment of the disclosure is shown in FIG. 13 and
FIGS. 14A-14B, showing a cell processing system according to the
disclosure, comprising a cell processing container 200 as described
above together with one or more auxiliary containers 11 attached to
the cell processing container 200. The auxiliary containers 11 are
preferably connected to the cell processing container 200 via
sterile connector ends 205. The auxiliary containers 11 are
preferably connected to the cell processing container 200 on the
top section 203 and/or the base section 202. The auxiliary
containers 11 may also be cell processing containers according to
the disclosure comprising an embedded sterile connector end in a
base portion of the auxiliary container 11.
[0317] In further embodiments such as the one shown in FIG. 2, the
auxiliary containers 11 are fluidly coupled to the cell processing
container 13 through a body portion 15. The body portion forms part
of a cell processing platform 9. The auxiliary containers 11 each
comprise a sterile connector end embedded in the base section of
the auxiliary container 11. The embedded sterile connector end
interconnects and sealingly engages with a corresponding sterile
connector end in the body portion 15 of the cell processing
platform 9. The cell culture container 13, being a primary
container, is sealingly engaged with the bottom of the body portion
15 so as to form a fluid connection between the body portion 15 and
the cell culture container 13.
[0318] The fluid conduit (not shown) between the sterile connector
attaching the auxiliary container 11 to the body portion 15 and the
fluid outlet (not shown) of the body portion 15 to which the cell
processing container 13 is attached, comprises a pinch valve. The
pinch valve is operable to open and close the fluid conduit in
response to a valve actuator such that, as a compression force is
applied to the respective auxiliary container 11, the contents of
the auxiliary container can be transferred by the application of a
compression force to the container. In alternative embodiments, the
pinch valve may be replaced by a pressure-sensitive valve (e.g., a
burst valve) such that the valve opens as a compression force is
applied to the respective auxiliary container 11.
[0319] In the embodiment shown in FIGS. 14A and 14B, one or more of
feed bellows 11 are pre-attached to the primary cell processing
container 200 and prefilled with reagent (e.g., liquid) and stored
in a refrigerator. The cell processing system shown in FIGS. 14A
and 14B may be used for attaching heat labile components, such as
viruses or cells, which need to be stored in at -80 degrees Celsius
or in liquid nitrogen. Because, it is expensive to store the whole
cell processing system at these temperatures, the embedded sterile
connector end 205 in the feed bellows 11 and in the top of the cell
processing container 200 serve as a way to add the heat labile
component(s) without use of an aseptic laminar flow hood or sterile
tubing welders thus eliminating tube based connections and keeping
the system compact.
[0320] Advanced blow molding techniques can be used to deposit a
second (or even third), external, coating or layer of plastic
impermeable to oxygen onto the wall, top and base of the auxiliary
container. In this way, shelf life of the container in storage can
be extended.
[0321] FIGS. 15A to 15D show an exemplary sterile connection
between two sterile connector ends 400. The sterile connector ends
400 each have a mechanical connection (such as a screw thread) or
latch (not shown) arranged in an internal circumferential manner on
the sterile connector end 400. The internal circumferential latches
provide the proper orientation of sterile connector end 400
relative to the other to ensure that the opposedly aligned adhesive
members 40 attached to the sterile connector end 400 achieve a
sterile fluid connection. In FIG. 15B, two adhesive members 40 are
aligned so that the front second fold adhesive coating of each
adhesive member 40 mirror each other. This alignment is important
as the rolled member 40 may be withdrawn in only one linear
direction. Once the two front second fold adhesive coating surfaces
are in contact, as shown in FIG. 15C, the member pull grip 50 is
pulled away from the longitudinal axis of the sterile conduit 190
thereby exposing the conduit aperture (FIG. 15D). In FIGS. 15C and
15D, the rolled member 40 is completely withdrawn to an unfolded
configuration and the conduit apertures are aligned to form a
sterile corridor.
[0322] In FIG. 16A, two opposing sterile connector ends 150 are
aligned so that the front second fold adhesive coating 80 of each
rolled membrane of the sterile connector ends 150 mirror each
other. This alignment is important as the rolled membrane may be
withdrawn in only one linear direction. Once the two front second
fold adhesive coating 80 surfaces are in contact, as shown in FIG.
16B, the entire adhesive surface areas come into contact thereby
sealing each opposing sterile connector ends 150 together. In FIG.
16C, the membrane pull grip 50 is pulled away from the longitudinal
axis of the sterile corridor thereby exposing the conduit aperture
60. In FIG. 16D, the rolled member 40 is completely withdrawn to an
unfolded configuration and the conduit apertures 60 are aligned to
form a sterile corridor between each sterile connector end 150.
[0323] FIG. 17A shows a cell processing container 13 having a
sterile connector end 37 embedded in a top section of the container
wall. The sterile connector end 37 forms one half of a sterile
connector when the cell processing container 13 is fluidly
connected to the corresponding sterile connector end in an
auxiliary container 11. In alternative embodiments, the cell
processing container 13 is fluidly connected to the corresponding
sterile connector end in a body portion 15 of a cell processing
platform 9. The sterile connector end in a body portion 15 of a
cell processing platform 9 being part of a primary container port
of the platform.
[0324] FIG. 17B shows an exploded partial view of the sterile
connector end 37 of FIG. 17A. FIG. 17B shows a male sterile
connector end, being half of sterile connector, in a top wall of
cell culture container 13. The sterile connector end 37 comprises a
removable paper cap which, when engaged with the removable paper
cap of a further sterile connector end is removed, exposes the
sterile surfaces enclosed by a screw cap engaged with screw threads
of the sterile connector end 37 and creates a fluid connection
through to the cell processing container lumen. Specifically, the
removable paper cap is an anti-contamination pull tab, which is
initially folded over the sterile connector end 37 and has an end
protruding therefrom. The pull tab can then be pulled out to expose
the sterile surfaces to each other.
[0325] FIGS. 17C to 17E depict an auxiliary container 11 being
filled with media in a sterile process. The process can be manual
or automated. In FIG. 17D the sterile connector end 37 is removed
and media filled into the lumen of the auxiliary container 11. The
filling of the auxiliary container 11 is performed under sterile
conditions. In FIG. 17E, the sterile connector end 37 is replaced
and the auxiliary container 11 stored at the appropriate
temperature until it is needed for assembly of the cell processing
system. Once filled and ready for use, the auxiliary container 11
is inverted and the sterile connector end 37 mated and connected
with a corresponding sterile connector end on a primary container
such as a cell processing container.
[0326] In alternative embodiments such as the one depicted in FIG.
18A, the auxiliary container 11 has a screw cap 51 at one end and a
sterile connector end 37 at the other. In this way, the integrity
of the sterile connector end 37 can be maintained during storage of
the auxiliary container 11 by inverting the auxiliary container 11
such that the media sits at the end of the auxiliary container 11
having the screw cap 51 and the sterile connector end 37 is free
from any liquid contact.
[0327] The embedded sterile connector end 37 ensures that the
auxiliary container 11 can be readily connected to an auxiliary
container port of a cell processing platform 9 or directly to a
cell processing container 13 in a cell processing system according
to the disclosure.
[0328] FIG. 18A shows an auxiliary container 11 having a sterile
connector end 37 protected by in an end cap 151 in the base section
of the auxiliary container 11. The auxiliary container 11 also has
a screw cap 51 in the top section of the container to allow for
filling of the lumen of the container with media or the like. The
screw cap 51 is compatible with automated media filling techniques
and apparatus.
[0329] The sterile connector end 37 facilitates fluid connection
between the lumen of the auxiliary container and the contents in
it, with a cell processing container 13 having a corresponding
sterile connector end in a top section of the container 13. In
order to access the sterile connector end 37 in the base section of
the auxiliary container 11, the end cap 151 is removed, the sterile
connector end 37 can then be mated into sealing engagement with a
corresponding sterile connector end on the cell processing
container 13. In alternative embodiments, the sterile connector end
37 can be mated into sealing engagement with a corresponding
sterile connector end on a cell processing platform. More
specifically, the sterile connector end 37 can be mated into
sealing engagement with a corresponding sterile connector end in
the auxiliary container port 19 on a cell processing platform
9.
[0330] Advanced blow molding techniques can be used to deposit a
second (or even third), external, coating or layer of plastic
impermeable to oxygen onto the wall, top and base of the auxiliary
container. In this way, shelf life of the container in storage can
be extended.
[0331] FIG. 18B shows a cell processing container (reactor bellow)
13 comprising a plurality of bottom sterile connectors, being
embedded sterile connector ends 139, in the base section of the
cell culture container 13. In the depicted embodiments, the cell
processing container 13 (e.g., reactor bellow) is fitted with a
plurality of sterile connector ends 141 in a top section of the
container 13 for connection of a plurality of auxiliary containers
11. The auxiliary containers 11 may contain media and/or cell
nutrients required for cell culture. Alternatively, the auxiliary
containers may be for sampling or waste removal from cell
processing container 13. In a sampling arrangement, the cell
processing container (e.g., reactor bellow) 13 may be fluidly
connected via a pinch valve to a removable auxiliary container 11.
The pinch valve is opened and then the auxiliary container 11 is
expanded to take the sample from the cell processing container 13.
The pinch valve is then closed before detaching the sample
auxiliary container 11. The connection could be via LUER-LOK.TM. or
similar, which maintains a sterile barrier once the pinch valve is
closed. Thus, samples may be removed from the cell processing
container 13. The cell processing container 13 (e.g., reactor
bellow) is fitted with a plurality of sterile connector ends 139 in
a base section of the container 13 for connection to a plurality
subsequent collection/processing bellows (not shown). Pinch valves
127 are housed between the sterile connector ends 141 and the cell
culture container 13, which pinch valves 127 can be used to switch
on/off the flow of feeds from the auxiliary containers 11. Such
valve activation is useful/necessary, for example, if only partial
volumes are needed or feed needs to be added from a single
auxiliary container at two or more time points.
[0332] In alternative embodiments, pinch valves can be embedded in
the outlet tubing from each auxiliary container 11.
[0333] In yet further alternative embodiments, the pinch valves can
be pressure actuated to open when compression force is applied to
the respective auxiliary container 11.
[0334] FIG. 18C shows the use of prefilled auxiliary containers 311
in a cell processing system 300 according to the disclosure. Four
auxiliary containers 311 are prefilled with wash buffer and are
stored at room temperature. Four further auxiliary containers 311
are prefilled with growth media and are stored at 4 degrees
Celsius. Five auxiliary containers 311 are prefilled with
Lentivirus are stored at -80 degrees Celsius. Four further
auxiliary containers 311 are prefilled with media incorporating
magnetic beads and stored at 4 degrees Celsius. One each of the
prefilled auxiliary containers 311 are connected to the cell
processing container 313 via sterile connector ends embedded in the
base portion of each auxiliary container 311 and in the top of the
cell culture auxiliary container 311. An auxiliary container port
319 remains empty and ready for receiving a container including
patient cells. It should be appreciated that in alternative
embodiments, the cell processing system 300 comprises a different
number of prefilled auxiliary containers 311 according to the
present disclosure. For example, each set of prefilled auxiliary
containers 311 may comprise 10s or even 100s of auxiliary
containers 311.
[0335] The cell processing system including the auxiliary
containers 311 and the cell processing container 313 is now ready
for processing in a cell processing unit according to the
disclosure.
[0336] FIGS. 18D and 18E shows the prefilled auxiliary containers
311 housed on a conventional single use wave bioreactor 413 and
CSTR bioreactor 513.
[0337] The cell processing unit, cell processing platform, cell
processing device and cell processing container according to the
disclosure may be used in any chemical, biological or separation
process. Unit processes (e.g., steps) of such processes may be
undertaken. The cell processing device , in conjunction with the
cell processing unit and, optionally, at least one cell processing
container of the disclosure may be used in cell culture processes
(e.g., culturing, manipulating, expanding or storing cells) or in
gene modification processes (e.g., steps including purifying,
genetically modifying, recovery and wash processes). Other suitable
unit processes that can be performed in the cell processing unit,
platform, device and container of the disclosure include but are
not limited to purification (e.g., affinity, size), washing,
settling, centrifugation, filtration, chromatography, magnetic bead
processes, transduction, electroporation, novel hydrogels, shipping
and thawing, expansion of cells in culture, genetic modification
and cryopreservation.
[0338] A cell processing device and a cell processing container of
the disclosure are each suitable for cell culture and processing of
cells, including the use of the container in cell therapy, gene
therapy vector production and/or exosome production. A container or
device of the disclosure may be suitably sterilized prior to use
(e.g., by gamma irradiation or other means). Optionally, the
internal surface of the container may be coated with or comprise
biologically active agents, which can act on the cells in culture
and/or induce differentiation.
[0339] The cell processing equipment described herein may be used
in cell manufacturing and/or gene therapy manufacturing processes
involving any suitable cell or gene type. For example, the device
of the disclosure may be used to culture any prokaryotic or
eukaryotic cell, suitably an animal cell, e.g., a mammalian, cell.
The cells may be human or non-human. Examples of sources of
suitable non-human cells include, rodents such as mice, rats, and
guinea-pigs, as well as ungulate animals selected from ovine,
caprine, porcine, bovine and/or equine species, or non-human
primate species. However, the cells may be bacteria, yeast, fungi
or plant cell in origin also.
[0340] The cells may be of any type including somatic cells and
non-somatic cells. The cells may be stem cells derived from any
stage of development of the embryo, foetus or adult animal. The
cells may be genetically modified cells, such as chimeric antigen
receptor T-cells (CARTs). The cells may be from a deposited cell
line, such as genetically-modified Chinese Hamster Ovary (CHO)
cells to produce recombinant proteins.
[0341] For example, embryonic stem (ES) cells, including cells of
non-human origin. The cells may be derived from a deposited cell
line, such as an ES cell line. The ES cells may be derived from
means that do not necessitate the destruction of a human embryo
such as parthenogenetic activation, as described in WO 2003/046141.
The cells may be cells of a cancer or a hybridoma, which can be
caused to proliferate in culture and/or produce monoclonal
antibodies. The cells may also be derived from the result of
somatic cell nuclear transfer (SCNT) in which the nucleus of a
somatic cell is placed into an enucleated oocyte.
[0342] The cells may be pluripotent stem cells, for example,
primate pluripotent stem (pPS) cells, for example, human embryonic
stem (hES) cells. Where the cells are stem cells, the source may be
from any tissue of the body, including mesenchymal stem cells
(including umbilical cord derived stem cells), neural stem cells or
haematopoietic stem cells. Also included are induced pluripotent
stem (iPS) cells.
[0343] The disclosure therefore provides for the processing of
cells within a single device with multiple unit processes taking
place as desired within the cell processing device via
delivery/extraction of desired reagents, waste, cells, or product
into or from one or more auxiliary containers in fluid
communication with the primary container, thereby avoiding the risk
of contamination. The system is simpler to use and further avoids
the complexity of existing approaches. The disclosure provides for
the safer processing of cells with improved reproducibility and
ease of use.
[0344] The disclosure also provides for the extraction of cells
from a patient (biopsy, such as blood or bone marrow), separation
of cells, processing of cells (including cytokine stimulation
and/or genetic modifications), solid-liquid separations and loading
into a delivery device where the cells can be cultured in the same
device throughout the entire process.
[0345] In embodiments of the disclosure, cell processing containers
for performing unit operations in cell and/or gene therapy
manufacturing can be assembled in any configuration. In this way, a
cell processing system may be provided within which a wide variety
of processes (both biological, chemical and separations) can be
undertaken. Similarly, the cell processing system may comprise a
cell processing platform of the disclosure in conjunction with one
or more cell processing containers. In this way it is possible to
provide a multistage bioreactor operable to perform one or more
unit operations in cell and/or gene therapy manufacturing. Because
each cell processing container is based on a concertina arrangement
(which can act as a pump) there is no need for pumps and complex
sets of tubing/pipes. The system therefore shrinks the space needed
for any given manufacturing process. A cell processing system
according to the disclosure is particularly well suited for
autologous (patient specific) cell and gene therapy where one needs
to run a whole manufacturing run for each patient. Using
traditional manufacturing approaches is not feasible when scaling
up to over 5000 patients/year given the amount of space needed to
run so many parallel manufacturing runs.
[0346] Certain embodiments of the disclosure are described in the
following numbered clauses.
[0347] In certain embodiments, unless mutually incompatible, any
one or more of the features of one numbered clause may be combined
with any one or more of the features of any other one or more of
the numbered clauses. More specifically, any one of clauses 1 to 31
may be combined with one or more of clauses 32 to 47 unless
features are mutually incompatible. Further, any one of clauses 1
to 31 may be combined with one or more of clauses 48 to 76 unless
features are mutually incompatible. Yet further any one of clauses
32 to 47 may be combined with one or more of clauses 48 to 76
unless features are mutually incompatible.
[0348] In certain embodiments, unless mutually incompatible, any
one or more of the following numbered clauses may be combined with
any one or more of the appended claims.
[0349] 1. A cell processing unit for cell and gene therapy
manufacture comprising a housing defining an enclosure into which a
cell processing platform can be mounted, a platform mounting
bracket within the housing and configured and arranged to receive
and retain a cell processing platform, a drive apparatus configured
and arranged to operatively engage and act upon a cell processing
platform so as to move same with respect to the platform mounting
bracket, and an actuator configured and arranged to exert a force
on a container mounted into the cell processing platform so as to
expel a contents from the container.
[0350] 2. A cell processing unit according to clause 1, wherein the
platform mounting bracket comprises a mounting plate.
[0351] 3. A cell processing unit according to clause 2, wherein the
platform mounting bracket comprises a retaining flange spaced apart
from the mounting plate in order that a cell processing platform
can be received and retained in position in the housing between the
mounting plate and the retaining flange.
[0352] 4. A cell processing unit according to clause 2 or clause 3,
wherein the mounting plate is substantially C-shaped.
[0353] 5. A cell processing unit according to any one of the
preceding clauses, wherein the drive apparatus is a rotational
drive apparatus configured and arranged to operatively engage and
act upon a cell processing platform so as to rotate same with
respect to the platform mounting bracket.
[0354] 6. A cell processing unit according to clause 5, wherein the
rotational drive apparatus comprises a drive wheel, which is
mounted on the platform mounting bracket and is configured to
engage a surface of a cell processing platform and to impart
rotational movement on it.
[0355] 7. A cell processing unit according to clause 6, wherein the
rotational drive apparatus comprises a sprung wheel biased toward
the drive wheel and spaced apart from it and mounted on the
platform mounting bracket.
[0356] 8. A cell processing unit according to clause 6 or clause 7,
wherein the rotational drive apparatus comprises a hinged wheel
biased toward the drive wheel and spaced apart from it and mounted
on the platform mounting bracket.
[0357] 9. A cell processing unit according to clause 8, wherein the
hinged wheel is moveable into an open position in which a cell
processing platform can be inserted into and engaged with the cell
processing platform mounting bracket and a closed position in which
the hinged wheel is engaged with a surface of the cell processing
platform in order to retain same in the cell processing platform
mounting bracket.
[0358] 10. A cell processing unit according to any one of the
preceding clauses, wherein the actuator is a linear actuator.
[0359] 11. A cell processing unit according to clause 10, wherein
the linear actuator comprises a plunger operatively coupled to a
drive motor, wherein the plunger is configured to engage a
container in the cell processing platform and to exert a
compression force on the container.
[0360] 12. A cell processing unit according to any one of the
preceding clauses, comprising a primary actuator configured and
arranged to exert a force on a primary container mounted to the
cell processing platform so as to expel a fluid from the
container.
[0361] 13. A cell processing unit according to clause 12, wherein
the primary actuator is a linear actuator.
[0362] 14. A cell processing unit according to clause 13, wherein
the primary actuator comprises a plunger operatively coupled to a
drive motor, wherein the plunger is configured to engage a primary
container mounted to the cell processing platform and to exert a
compression force on the primary container.
[0363] 15. A cell processing unit according to any one of the
preceding clauses, comprising a valve actuator operable to act upon
a pinch valve in the cell processing platform so as to open and
close same as force is applied to the container.
[0364] 16. A cell processing unit according to clause 15, wherein
the valve actuator is a linear actuator.
[0365] 17. A cell processing unit according to clause 16, wherein
the valve actuator comprises a solenoid valve.
[0366] 18. A cell processing unit according to any one of the
preceding clauses, comprising a location detecting sensor operable
to detect the position of the cell processing platform relative to
the platform mounting bracket.
[0367] 19. A cell processing unit according to clause 18, wherein
the location detecting sensor is operable to detect the rotational
position of the cell processing platform relative to the platform
mounting bracket.
[0368] 20. A cell processing unit according to clause 18 or clause
19, wherein the location detecting sensor comprises a Hall Effect
sensor.
[0369] 22. A cell processing unit according to any one of clauses
18 to 20, comprising a home location detecting sensor operable to
detect a home position of the cell processing platform relative to
the platform mounting bracket.
[0370] 22. A cell processing unit according to clause 21, wherein
the home location detecting sensor is operable to detect a single
rotational position of the cell processing platform relative to the
platform mounting bracket.
[0371] 23. A cell processing unit according to clause 21 or clause
22, wherein the home location detecting sensor comprises a Hall
Effect sensor.
[0372] 24. A cell processing unit according to clause 23, wherein
the voltage detected by the Hall Effect sensor is greater at the
home position of the cell processing platform relative to the
platform mounting bracket than at any other position during the
rotation of the cell processing platform relative to the platform
mounting bracket.
[0373] 25. A cell processing unit according to any one of the
preceding clauses, wherein the container is compressible.
[0374] 26. A cell processing unit according to any one of the
preceding clauses, wherein the container comprises a base section,
a top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container, in
which the wall element of the container preferably is compressible
with respect to the top and base section and the wall element of
the container is composed of a flexible material.
[0375] 27. A cell processing unit according to any one of clauses
12 to 26, wherein the primary container is compressible.
[0376] 28. A cell processing unit according to any one of clauses
12 to 27, wherein the primary container comprises a base section, a
top section arranged substantially in parallel with the base
section and a wall element arranged between the top section and the
base section and defining an internal lumen of the container, in
which the wall element of the container preferably is compressible
with respect to the top and base section and the wall element of
the container is composed of a flexible material.
[0377] 29. A cell processing unit according to any one of the
preceding clauses where the container(s) is one of: a reagent
container, a bioreactor, a cell culture container, a waste
container, a filter, an electroporator, a purifier, holding
container, apheresis/leukopheresis, differentiation chamber,
chromatography column, settling chamber, sieve, shaking/mixer , a
centrifuge and a magnetic bead separator or the like.
[0378] 30. A cell processing unit according to any one of clauses
12 to 29, wherein the primary container is a cell processing
container.
[0379] 31. A cell processing unit according to any one of the
preceding clauses, wherein control of the device is automated.
[0380] 32. A cell processing container for use in one or more unit
operations in cell and/or gene therapy manufacture, the container
having a base section, a top section arranged substantially in
parallel with the base section and a wall element arranged between
the top section and the base section and defining an internal lumen
of the container, in which the wall element of the cell processing
container preferably is compressible with respect to the top and
base section and the wall element of the cell processing container
is composed of a flexible material, wherein the cell processing
container comprises at least one sterile connector end configured
to operatively couple with a further sterile connector end so as to
form a sterile connector between the cell processing container and
a further component to which the cell processing container is to be
fluidly connected.
[0381] 33. A cell processing container according to clause 32,
wherein the at least one sterile connector end is a genderless
sterile connector end configured to operatively couple with a
further genderless sterile connector end.
[0382] 34. A cell processing container according to clause 32,
wherein the at least one sterile connector end is a male sterile
connector end configured to operatively couple with a female
sterile connector end.
[0383] 35. A cell processing container according to clause 32,
wherein the at least one sterile connector end is a female sterile
connector end configured to operatively couple with a male sterile
connector end.
[0384] 36. A cell processing container according to any one of
clauses 32 to 35, comprising a plurality of sterile connector ends
each configured to operatively couple with a separate further
sterile connector end to form a plurality of sterile connectors
between the cell processing container and at least one further
component to which the cell processing container is to be fluidly
connected.
[0385] 37. A cell processing container according to any one of
clauses 32 to 36, wherein the sterile connector ends are embedded
in the cell processing container.
[0386] 38. A cell processing container according to any one of
clauses 32 to 37, wherein the sterile connector end is operatively
coupled to a pinch valve embedded in the cell processing
container.
[0387] 39. A cell processing container according to any one of
clauses 32 to 38, wherein the cell processing container has a
circular, square, rectangular, elliptical, or triangular cross
section.
[0388] 40. A cell processing container according to clause 39,
wherein, when the cell processing container has a circular shape,
the sterile connector end(s) is/are connected to the top and/or
base section of the cell processing container in an essentially
circular pattern.
[0389] 41. A cell processing system, comprising a cell processing
container according to any one of clauses 32-40, further comprising
one or more auxiliary containers detachably connected to the cell
processing container.
[0390] 42. A cell processing system according to clause 41, wherein
one or more of the auxiliary containers comprises the further
sterile connector end and is connected to the cell processing
container via the further sterile connector end.
[0391] 43. A cell processing system according to clause 41 or
clause 42 wherein one or more of the auxiliary containers is
located on the top section of the cell processing container.
[0392] 44. A cell processing system according to clause 41 or
clause 42, wherein one or more of the auxiliary containers is
located at or near the base section of the cell processing
container.
[0393] 45. A cell processing system according to any one of clauses
41 to 44, wherein the one or more auxiliary containers have a base
section, a top section arranged substantially in parallel with the
base section and a wall element arranged between the top section
and the base section and defining an internal lumen of the
container, in which the wall element of the auxiliary container
preferably is compressible with respect to the top and base section
and the wall element of the auxiliary container is composed of a
flexible material.
[0394] 46. A multi-step method of performing one or more unit
operations in cell and/or gene therapy manufacture using a cell
processing system according to clauses 41-45.
[0395] 47. The method according to clause 46, comprising
introducing a cell population of interest into the cell processing
container and sequentially adding one or more reagents from one or
more auxiliary containers into the cell processing container in
order to effect the desired one or more unit operations in cell
and/or gene therapy manufacture.
[0396] 48. A cell processing platform for use in one or more unit
operations in cell and/or gene therapy manufacture, the platform
comprising a body portion comprising at least one fluid inlet
fluidly connected to a fluid outlet, and an auxiliary container
port fluidly coupled to the at least one fluid inlet of the body
portion, wherein the auxiliary container port is configured and
arranged to receive and sealingly engage with an auxiliary
container and to fluidly connect the auxiliary container lumen with
the at least one fluid inlet of the body portion, and a primary
container port configured and arranged to sealingly engage with a
primary container and to fluidly connect the primary container
lumen with the fluid outlet of the body portion.
[0397] 49. A cell processing platform according to clause 48,
wherein the auxiliary container port comprises a container
receiving sleeve connected to the body portion and being configured
to surround at least a portion of the auxiliary container, which
portion comprises the fluid outlet of the container.
[0398] 50. A cell processing platform according to clause 48 or
clause 49, wherein the auxiliary container port comprises a mating
element configured to fluidly connect to a corresponding mating
element on an auxiliary container.
[0399] 51. A cell processing platform according to clause 50,
wherein the mating element is at least one of: a sterile connector
end or a LUER-LOK.TM..
[0400] 52. A cell processing platform according to any one of
clauses 48 to 51, wherein the primary container port comprises a
mating element configured to fluidly connect to a corresponding
mating element on a primary container.
[0401] 53. A cell processing platform according to clause 52,
wherein the mating element comprises at least one of: a sterile
connector end or a LUER-LOK.TM.
[0402] 54. A cell processing platform according to any one of
clauses 48 to 53, wherein the auxiliary container port comprises a
sterile connector end at the fluid inlet and/or the fluid outlet of
the auxiliary container port, each sterile connector end configured
to engage with a further sterile connector end on a container
and/or on the body portion, respectively.
[0403] 55. A cell processing platform according to any one of
clauses 48 to 54, wherein the fluid outlet of the body portion
comprises a sterile connector end configured to engage with a
further sterile connector end on a primary container attachable to
the body portion.
[0404] 56. A cell processing platform according to according to any
one of clauses 48 to 55, wherein the body portion is substantially
hollow.
[0405] 57. A cell processing platform according to according to any
one of clauses 48 to 56, wherein the at least one fluid inlet and
the fluid outlet of the body portion are fluidly coupled to one
another by a fluid conduit.
[0406] 58. A cell processing platform according to clause 57,
wherein the fluid conduit comprises a valve operable to open and
close the fluid conduit.
[0407] 59. A cell processing platform according to clause 58,
wherein the valve is one of: a pinch valve, a pressure-sensitive
valve, a clamp valve, a membrane valve, a rupture disc, a venous
valve and an aperture valve.
[0408] 60. A cell processing platform according to any one of
clauses 48 to 59, wherein the auxiliary container port comprises a
container filling port.
[0409] 61. A cell processing platform according to clause 60,
wherein the container filling port is fluidly connected to a fluid
inlet of the auxiliary container port.
[0410] 62. A cell processing platform according to clause 60 or
clause 61, wherein the container filling port comprises a valve
operatively coupled to the fluid inlet and a fluid outlet of the
auxiliary container port and operable to control fluid flow
direction through the auxiliary container port.
[0411] 63. A cell processing platform according to any one of
clauses 60 to 62, wherein the container filling port comprises a
valve operable, in an open position, to allow fluid to flow to the
fluid inlet of the auxiliary container port and not to the fluid
outlet of the auxiliary container port and, in a closed position,
to close the container filling port and to allow fluid to flow from
the fluid inlet of the auxiliary container port to the fluid outlet
of the auxiliary container port.
[0412] 64. A cell processing platform according to any one of
clauses 48 to 63, comprising a plurality of auxiliary container
ports each configured and arranged to receive and sealingly engage
with an auxiliary container and to fluidly connect the container
lumen with a fluid inlet of the body portion.
[0413] 65. A cell processing platform according to clause 64,
wherein each auxiliary container port is coupled to a separate
fluid inlet of the body portion.
[0414] 66. A cell processing platform according to clause 65,
wherein each separate fluid inlet of the body portion is fluidly
connected to a fluid outlet of the body portion.
[0415] 67. A cell processing platform according to any one of
clauses 48 to 66, comprising at least one positional tracking
device operable to indicate a set location on the platform.
[0416] 68. A cell processing platform according to clause 67,
wherein the positional tracking device is at least one of: a
magnet, an RFID sensor, a light sensor or a cog operable to engage
a further cog.
[0417] 69. A cell processing platform according to clause 67 or
clause 68, comprising a plurality of positional tracking
devices.
[0418] 70. A cell processing platform according to any one of
clauses 67 to 69, wherein the at least one positional tracking
device is located relative to the auxiliary container port such
that the location of the positional tracking device is related to
the position of the auxiliary container port.
[0419] 71. A cell processing platform according to any one of
clauses 67 to 70, wherein the at least one positional tracking
device is located on the body portion relative to the auxiliary
container port.
[0420] 72. A cell processing platform according to any one of
clauses 48 to 71, comprising a sampling port in the body
portion.
[0421] 73. A cell processing platform according to any one of
clauses 48 to 72, comprising a gas transfer port in the body
portion.
[0422] 74. A cell processing platform according to any one of
clauses 48 to 73, wherein the auxiliary container port is
configured to receive a container having a base section, a top
section arranged substantially in parallel with the base section
and a wall element arranged between the top section and the base
section and defining an internal lumen of the container, in which
the wall element of the container preferably is compressible with
respect to the top and base section and the wall element of the
container is composed of a flexible material.
[0423] 75. A cell processing platform according to any one of
clauses 48 to 74, wherein the primary container port is configured
to receive a primary container having a base section, a top section
arranged substantially in parallel with the base section and a wall
element arranged between the top section and the base section and
defining an internal lumen of the container, in which the wall
element of the container preferably is compressible with respect to
the top and base section and the wall element of the container is
composed of a flexible material.
[0424] 76. A cell processing platform according to clause 75,
wherein the primary container further comprises an attachment
flange mounted to the top section of the primary container and
being configured to sealingly engage and detachably mount to the
primary container port.
* * * * *