U.S. patent application number 15/898653 was filed with the patent office on 2019-02-21 for method for protecting and unprotecting the fluid path in a controlled environment enclosure.
The applicant listed for this patent is VANRX PHARMASYSTEMS INC.. Invention is credited to Marcin CICHY, Christopher PROCYSHYN.
Application Number | 20190056420 15/898653 |
Document ID | / |
Family ID | 59013756 |
Filed Date | 2019-02-21 |
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United States Patent
Application |
20190056420 |
Kind Code |
A1 |
PROCYSHYN; Christopher ; et
al. |
February 21, 2019 |
METHOD FOR PROTECTING AND UNPROTECTING THE FLUID PATH IN A
CONTROLLED ENVIRONMENT ENCLOSURE
Abstract
A controlled environment enclosure comprises a robotic arm
manipulation system used to protect and unprotect a fluid path and
a swab within the controlled environment enclosure. The apparatus
allows the fluid path to be protected against dangerous
decontamination vapors and chemicals before the controlled
environment enclosure is decontaminated. The apparatus allows the
fluid path to be unprotected without the use of gloves or other
means that degrade the integrity of the controlled environment
enclosure when decontamination is completed. The apparatus and
method allow for the protecting, unprotecting and decontaminating
sequences to be automated. In some embodiments the fluid path
comprises a fill needle that can removably and aseptically be
sealed with a disposable monolithic injection moulded polymeric
fill needle sheath. The apparatus and method further allow for the
use of a swab disposed in a swab holder that is aseptically and
removably sealable to a swab cap to protect the swab against
decontamination vapors.
Inventors: |
PROCYSHYN; Christopher;
(Surrey, CA) ; CICHY; Marcin; (Surrey,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VANRX PHARMASYSTEMS INC. |
BURNABY |
|
CA |
|
|
Family ID: |
59013756 |
Appl. No.: |
15/898653 |
Filed: |
February 18, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15375019 |
Dec 9, 2016 |
10067151 |
|
|
15898653 |
|
|
|
|
62265938 |
Dec 10, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01L 2400/0487 20130101;
G01N 2035/00148 20130101; A61J 1/14 20130101; B65B 3/003 20130101;
G01N 35/0099 20130101; A61J 1/12 20130101; G01N 35/10 20130101;
B01L 2300/0609 20130101; G01N 35/00029 20130101; B01L 2200/026
20130101; B65B 55/12 20130101; G01N 2035/00277 20130101; B01L
2200/141 20130101; B65B 3/04 20130101; B01L 1/04 20130101; B01L
3/02 20130101; B01L 2200/0689 20130101; A61J 1/20 20130101 |
International
Class: |
G01N 35/10 20060101
G01N035/10; B01L 1/04 20060101 B01L001/04; G01N 35/00 20060101
G01N035/00; B65B 3/04 20060101 B65B003/04; A61J 1/12 20060101
A61J001/12; B65B 3/00 20060101 B65B003/00; B65B 55/12 20060101
B65B055/12; B01L 3/02 20060101 B01L003/02; A61J 1/14 20060101
A61J001/14; A61J 1/20 20060101 A61J001/20 |
Claims
1. A fluid handling assembly for automatically carrying out a fluid
handling process in an aseptic environment, comprising: a first
sheath portion including: an implement portion disposed within the
first sheath portion for use in the process, a first locking
mechanism portion, a first sealing portion, and a first bearing
surface positioned at least generally normal to a locking axis, a
second sheath portion including: a second locking mechanism portion
configured to mate with the first locking mechanism portion when
the first and second locking mechanism portions are moved towards
each other along the locking axis, a second sealing portion
disposed to aseptically seal with the first sealing portion when
the first and second locking mechanism portions are mutually mated,
and a second bearing surface positioned at least generally normal
to the locking axis and facing toward the first bearing surface,
and wherein the first and second sheath portions define a sealed
cavity that aseptically encapsulates the implement portion when the
first and second locking mechanism portions are mutually mated.
2. A fluid handling assembly for automatically carrying out a fluid
handling process in an aseptic environment, comprising; a first
sheath portion including: a swab disposed within the first sheath
portion for use in the fluid handling process, and a first sealing
portion, a second sheath portion including: a second sealing
portion disposed to aseptically seal with the first sealing
portion, and wherein the first and second sheath portions define a
sealed cavity that aseptically encapsulates the swab when the first
and second sealing portions are mutually mated.
3. The fluid handling assembly of claim 2 wherein the first and
second sealing portions comprise clamping members.
4. The fluid handling assembly of claim 3 wherein the clamping
members include a spring loaded member.
5. The fluid handling assembly of claim 3 wherein the clamping
members include locating eyelets.
6. The fluid handling assembly of claim 3 further comprising a swab
package having a cap, wherein the first and second sheath portions
further includes a mating portion for engaging with the swab
package cap.
7. The fluid handling assembly of claim 6 wherein the clamping
members include clips configured to engage the swab package
cap.
8. The fluid handling assembly of claim 6 wherein the swab package
further includes a swab holder removably attached to the cap.
9. An apparatus for protection and unprotection of a fluid path
within a controlled environment enclosure, comprising: a. a fluid
path terminated by a fill needle with a removable sheath; b. a
remotely operated manipulation system for protection and/or
unprotection of the fluid path; and c. a removal station that
includes a surface operative to interact with part of the
sheath.
10. The apparatus of claim 9 wherein the remotely operated
manipulation system includes a robotic arm manipulation system.
11. The apparatus of claim 9 wherein the remotely operated
manipulation system includes a robot end tool including at least
one surface that is shaped to hold the fill needle.
12. The apparatus of claim 9 wherein the fluid path is a
pre-sterilized unit.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a Divisional Application of U.S.
patent application Ser. No. 15/375,019, filed Dec. 9, 2016, which
claims priority under 35 U.S.C .sctn. 119(e) to U.S. Provisional
Application 62/265,938 filed Dec. 10, 2015; and which claims
priority U.S. patent application Ser. No. 14/890,223, filed Jul.
27, 2016, which is a U.S National Phase Entry of PCT Application
PCT/US2012/047765, filed Jul. 20, 2012, which claims priority under
35 U.S.C .sctn. 119(e) to U.S. Provisional Application 61/510,780
filed Jul. 22, 2011. All of these applications are herein
incorporated by reference.
TECHNICAL FIELD
[0002] This document relates generally to apparatus and methods for
use in handling materials in controlled environment enclosures,
including apparatus and methods for aseptically filling
pharmaceutical containers using a fluid path that is protected and
unprotected.
BACKGROUND
[0003] Controlled environment enclosures are known in the art. Such
enclosures are used, for example, for containment of hazardous
materials. In other examples controlled environment enclosures are
used to provide controlled environments with limited numbers of
particulates.
[0004] In the art controlled environment enclosures are typically
fitted with ports for transfer of materials in and out of the
enclosure and the ports are fitted with gloves for manual
manipulation of equipment, parts or materials inside the enclosure.
Such gloves are subject to significant risk of puncture.
[0005] In some examples known in the art the controlled environment
enclosure is also used to limit exposure to viable particulates.
Such controlled environment enclosures may be required for aseptic
processing of cell cultures and for the manufacture of
pharmaceutical products, medical devices, food or food ingredients.
In these cases it is a requirement that the controlled environment
enclosure be decontaminated. This may be done thermally using steam
or chemically using chemical agents. Suitable chemical agents known
in the art include hydrogen peroxide, ozone, beta-propiolactone,
aziridine, formaldehyde, chlorine dioxide, ethylene oxide,
propylene oxide, and peracetic acid. In most cases the
decontamination and sterilization operations have to be preceded by
a cleaning process. Such cleaning processes have the function of
removing major contamination by simple mechanical and chemical
action.
[0006] In some examples in the prior art the controlled environment
also contains automated equipment. Such automated equipment
includes machines for filling of vials. The automated equipment
located in the controlled environment is typically of such a size
and complexity that it cannot be operated fully automatically
without human intervention. Such human intervention typically
requires the use of gloves with the associated risk of
puncture.
[0007] Fluid paths within the controlled environment enclosures may
be made from flexible tubing materials and can therefore have
significant gas permeability. Gases that naturally occur in air,
such as oxygen and carbon dioxide, as well as chemical
decontamination agents, are known to diffuse into these tubing
materials. Accumulation of these agents in flexible tubing and
subsequent delayed release can be a major contamination problem
during operation. This applies in particular to products or
solutions that are sensitive to exposure to alkylating agents,
oxidizers, radicals or carbon dioxide. A typical example of human
intervention involving the use of gloves is the installation of the
fluid path or multiple fluid paths after the completion of
decontamination.
[0008] In view of the above there remains a need for controlled
environments that do not require human intervention via the use of
gloves.
SUMMARY OF THE INVENTION
[0009] In one aspect of the invention there is provided a method
for installing a fluid path within a controlled environment
enclosure comprising, protecting the fluid path against an
environment external to the fluid path; introducing the fluid path
into the controlled environment enclosure; decontaminating the
controlled environment enclosure; and mechanically unprotecting the
fluid path within the controlled environment enclosure. The
mechanically unprotecting can be by a robotic arm manipulation
system. The decontaminating the controlled environment enclosure is
automatically done after the introducing the fluid path into the
controlled environment enclosure. The unprotecting is automatically
done after the decontaminating the controlled environment
enclosure.
[0010] In one aspect of the invention there is provided a method
for transferring within a controlled environment enclosure a fluid
along a fluid path to a destination within the controlled
environment enclosure, comprising protecting the fluid path against
an environment external to the fluid path; introducing the fluid
path into the controlled environment enclosure; decontaminating the
controlled environment enclosure; mechanically unprotecting the
fluid path within the controlled environment enclosure; and
transferring the fluid to the destination along the fluid path. The
mechanically unprotecting can be by a robotic arm manipulation
system. The fluid path can comprise a pre-sterilized tube. The
method can further comprise filtering the fluid in the fluid path
and the filtering can be sterile filtering. The destination can be
at least one of a culture of cells, a culture of tissue, an enzyme
solution, a suspension of immobilized enzymes, a mix of active
ingredients, and an excipient. The fluid can be an aseptic fluid.
The controlled environment enclosure can be an isolator. The
destination can be microwell plates or containers for
pharmaceutical products.
[0011] In one aspect of the invention there is provided a method
for uninstalling a fluid path from a controlled environment
enclosure, comprising mechanically protecting the fluid path within
the controlled environment enclosure; decontaminating the
controlled environment enclosure; opening the controlled
environment enclosure; and removing the fluid path from the
controlled environment enclosure. The mechanically protecting can
be by a robotic arm manipulation system. The decontaminating the
controlled environment enclosure can be done automatically after
the protecting the fluid path. The opening the controlled
environment enclosure can be done automatically after the
decontaminating the controlled environment enclosure.
[0012] In one aspect of the invention there is provided a method
for decontaminating a controlled environment enclosure having a
fluid path, the method comprising mechanically protecting by a
robotic action the fluid path within the controlled environment
enclosure; decontaminating the controlled environment enclosure;
and opening and closing the controlled environment enclosure. The
opening and closing the controlled environment enclosure can be
done before or after the decontaminating the controlled environment
enclosure. The mechanically protecting can be by a robotic arm
manipulation system. The decontaminating the controlled environment
enclosure can be done automatically after the mechanically
protecting the fluid path.
[0013] In one aspect of the invention there is provided an
apparatus for protection and unprotection of a fluid path within a
controlled environment enclosure that includes a fluid path
terminated by a fill needle with removable sheath, and a remotely
operated manipulation system for protection and/or unprotection of
the fluid path. The remotely operated manipulation system can
include a robotic arm manipulation system. The apparatus can
further include a tamper-evident device positioned to reveal a
breach of seal between the sheath and the fill needle. The
apparatus can further include a removal station that includes a
surface operative to interact with part of the sheath. The remotely
operated manipulation system can include a robot end tool including
at least one surface that is shaped to hold the fill needle. The
fluid path can be a pre-sterilized unit.
[0014] In one aspect of the invention there is provided an
apparatus for installing a fluid path within a controlled
environment enclosure that includes means for conveying the fluid,
and remotely operated means for protecting and/or unprotecting the
means for conveying the fluid.
[0015] The inventors envision that compact and well-designed
automated equipment can be operated inside closed controlled
environments without the use of any gloves, eliminating thereby the
risk of leaky gloves. The invention provides a method of installing
a fluid path inside a controlled environment enclosure without the
use of gloves. This requires the fluid path to be protected during
the decontamination process and to be unprotected prior to the use
of the fluid path. Furthermore the fluid path can be automatically
closed after use.
[0016] The closed fluid path can be re-opened and re-used at a
later time. This can be useful for continuing the use of the fluid
path after unplanned events that require breaking of the integrity
of the enclosed controlled environment. Additionally the closing of
the fluid path can be particularly useful in situations where the
fluid path has been in use for transfer of hazardous substances.
After closing of the fluid path, the enclosed environment can be
cleaned and decontaminated; after which the fluid path can be
removed.
[0017] In a first aspect of the invention a fluid handling assembly
is provided for automatically carrying out a fluid handling process
in an aseptic environment, the assembly comprising a first sheath
portion including an implement portion disposed within the first
sheath portion for use in the process, a first locking mechanism
portion, and a first sealing portion; a second sheath portion
including a second locking mechanism portion configured to mate
with positive detent with the first locking mechanism portion, and
a second sealing portion disposed to aseptically seal with the
first sealing portion when the first and second locking mechanism
portions are mutually mated, wherein the first and second sheath
portions define a sealed cavity that aseptically encapsulates the
implement portion when the first and second locking mechanism
portions are mutually mated. The assembly may be a fill assembly
and the implement portion comprises a proximal dispensing portion
of a fill needle, the fill needle including a fluid conduit that
extends through the first sheath portion to a distal fluid supply
end so that, when the first and second locking mechanism portions
are mutually mated, the proximal dispensing portion of the fill
needle is located inside the cavity and the distal fluid supply end
of the fluid conduit is located outside the cavity. The fluid
conduit may include a flexible tube in fluid communication with the
proximal dispensing portion of the fill needle. The assembly may be
a swab assembly with the implement portion comprising a swab
disposed inside the cavity when the first and second locking
mechanism portions are mutually mated.
[0018] The assembly may further comprise a controlled environment
enclosure configured to aseptically isolate the process and hold
the fluid handling assembly, and an articulated robot arm disposed
within the enclosure to manipulate the fluid handling assembly. The
first and second sheath portions may respectively comprise first
and second engagement portions. The assembly may further comprise a
robotic arm endpiece for the robotic arm, the endpiece configured
to bear the first sheath portion by engagement with positive detent
with the first engagement portion and a holding station comprising
a first holding fixture to hold the second sheath portion, the
fixture configured for engaging with the second engagement portion.
The holding station may comprise angled fingers disposed to engage
with the second engagement portion of the second sheath portion to
release the first sheath portion from the second sheath portion.
The holding station may comprise a second holding fixture
configured to suspend the mutually engaged first and second sheath
portions.
[0019] The first and second sheath portions may be separate
injection molded parts and wherein the locking mechanism portions
include at least one integrally molded spring member. The assembly
may further include a tamper indicator that is mechanically linked
to one of the locking mechanism portions and includes a portion
that is constructed to irreversibly tear in response to the
mechanical separation of the first and second sealing surfaces.
[0020] The first and second locking mechanism portions may be
configured to mutually mate when the first and second locking
mechanism portions are moved towards each other along a locking
axis. The first sheath portion may further include a first bearing
surface positioned at least generally normal to the locking axis,
and the second sheath portion may further include a second bearing
surface positioned at least generally normal to the locking axis
and facing the first bearing surface.
[0021] In a further aspect a method is provided for automatically
carrying out a fluid handling process in controlled environment
enclosure, the method comprising providing a first implement inside
a first sealed sheath, the first sheath sealed by a detent-based
sealing mechanism on the first sheath that keeps the first sheath
aseptically sealed around the first implement; placing the first
sheath in the controlled environment enclosure; decontaminating the
controlled environment enclosure around the first sheath after the
step of placing; actuating the sealing mechanism to open the first
sheath, and carrying out at least one step in the fluid handing
process with the implement in the controlled environment enclosure.
The step of providing may include providing a fill needle and
wherein the step of carrying out includes carrying out a fill
operation. The step of decontaminating amay take place before the
step of carrying out a fill operation, further including a step of
again actuating the sealing mechanism to seal the first sheath.
[0022] The method may further include an additional step of
decontaminating the controlled environment chamber after the steps
of carrying out a fill operation and again actuating the sealing
mechanism. The method may yet further include providing a swab
inside a second sealed sheath, providing a second detent-based
sealing mechanism on the second sheath that keeps the second sheath
sealed around the swab, placing the second sheath in the controlled
environment enclosure, wherein the step of decontaminating
decontaminates the outside of the second sheath, and swabbing the
fill needle after the step of carrying out a fill operation.
[0023] The method may further include the steps of removing the
first implement and the first sheath from the controlled
environment enclosure, discarding the first implement and the first
sheath, providing a second implement inside a second sealed sheath,
providing a second detent-based sealing mechanism on the second
sheath that keeps the second sheath sealed around the second
implement, placing the second sheath in the controlled environment
enclosure, decontaminating the controlled environment enclosure
around the second sheath, and carrying out at least one step in
another run of the fluid handing process with the implement in the
aseptic environment.
[0024] The steps of actuating the first sealing mechanism and
carrying out the filling operation amay be performed at least in
part by a robotic arm disposed within the controlled environment
enclosure. The method may further include the step of providing a
pre-sterilized tube aseptically sealed to the fill needle. The step
of carrying out a fill operation may include transferring fluid to
at least one of a culture of cells, a culture of tissue, an enzyme
solution, a suspension of immobilized enzymes, a mix of active
ingredients, and an excipient. The step of carrying out a fill
operation may include transferring fluid to at least one of
microwell plates and containers for pharmaceutical products.
[0025] In a further aspect, a method is provided for automatically
carrying out a fluid handling process in controlled environment
enclosure, comprising: providing a plurality of disposable
implements each aseptically sealed inside one of a plurality of
disposable sheaths, placing a first of the plurality of sealed
sheaths that contains a first of the plurality of implements in the
controlled environment enclosure, decontaminating the controlled
environment enclosure around the first sheath after the step of
placing the first sheath, opening the first sheath, carrying out at
least one step in the fluid handing process with the first
implement in the controlled environment enclosure, removing the
first sheath and the first implement from the controlled
environment enclosure, discarding the first implement and the first
sheath, placing a second of the plurality of sealed sheaths that
contains a second of the plurality of implements in the controlled
environment enclosure, decontaminating the controlled environment
enclosure around the second sheath after the step of placing the
second sheath, opening the second sheath, carrying out at least one
step in another run of the fluid handing process with the second
implement in the controlled environment, and repeating the steps of
placing, decontaminating, opening, removing, and discarding for
successive further ones of the plurality of disposable implements
and corresponding ones of the plurality of disposable sheaths. The
step of providing may provide a plurality of disposable implements
that each include an intact tamper indicator. The steps of placing
the first, second, and further sheaths may each include placing the
intact tamper indicator for the sheath being placed, and the steps
of opening the first, second, and further sheaths may each include
disrupting the tamper indicator for the sheath being opened.
[0026] In a further aspect, a fluid handling assembly is provided
for automatically carrying out a fluid handling process in an
aseptic environment, comprising: a first sheath portion including
an implement portion disposed within the first sheath portion for
use in the process, a first locking mechanism portion, a first
sealing portion, and a first bearing surface positioned at least
generally normal to a locking axis; a second sheath portion
including: a second locking mechanism portion configured to mate
with the first locking mechanism portion when the first and second
locking mechanism portions are moved towards each other along the
locking axis, a second sealing portion disposed to aseptically seal
with the first sealing portion when the first and second locking
mechanism portions are mutually mated, and a second bearing surface
positioned at least generally normal to the locking axis and facing
toward the first bearing surface, wherein the first and second
sheath portions define a sealed cavity that aseptically
encapsulates the implement portion when the first and second
locking mechanism portions are mutually mated.
[0027] In a further aspect, a fluid handling assembly is provided
for automatically carrying out a fluid handling process in an
aseptic environment, comprising: a first sheath portion including a
swab disposed within the first sheath portion for use in the
process, and a first sealing portion; and a second sheath portion
including a second sealing portion disposed to aseptically seal
with the first sealing portion, wherein the first and second sheath
portions define a sealed cavity that aseptically encapsulates the
swab when the first and second sealing portions are mutually
mated.
[0028] In a further aspect, a method is provided for automatically
carrying out a fluid handling process in controlled environment
enclosure, comprising: providing a swab inside a first aseptically
sealed sheath, placing the first sheath in the controlled
environment enclosure, decontaminating the controlled environment
enclosure around the first sheath after the step of placing,
opening the first sheath, and swabbing an implement used in the
fluid handing process with the swab in the controlled environment
enclosure.
[0029] Other features, elements, steps, characteristics and
advantages of the present invention will become more apparent from
the following detailed description of preferred embodiments of the
present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] In the drawings, which are not necessarily drawn to scale,
like numerals may describe similar components in different views.
Like numerals having different letter suffixes may represent
different instances of similar components. The drawings illustrate
generally, by way of example, but not by way of limitation, various
embodiments discussed in the present document.
[0031] FIG. 1 shows an apparatus for the protecting and
unprotecting of a fluid path in a controlled environment
enclosure.
[0032] FIG. 2 shows detail of an end piece of an apparatus for the
protecting and unprotecting of a fluid path in a controlled
environment enclosure
[0033] FIG. 3 shows detail of a robotic arm forming part of an
apparatus for the protecting and unprotecting of a fluid path in a
controlled environment enclosure
[0034] FIG. 4 is a flow chart for the typical prior art method.
[0035] FIG. 5 shows a method flow chart of an aspect of the
invention.
[0036] FIG. 6 shows a method flow chart of another aspect of the
invention.
[0037] FIG. 7 shows a method flow chart of another aspect of the
invention.
[0038] FIG. 8 shows a method flow chart of another aspect of the
invention.
[0039] FIG. 9a and FIG. 9b show isometric and sectional views
respectively of a combination of a fill needle and a fill needle
sheath, while FIG. 9c shows the combination of a fill needle and a
fill needle sheath with a tamper-indicator.
[0040] FIG. 10 shows a swab, swab sheath, and swab sheath cap for
use with the sheath removal station of FIG. 12 and robotic arm end
piece of FIG. 11.
[0041] FIG. 11 shows a robotic arm end piece according to one
embodiment of the invention for use with for use with the sheath
removal station of FIG. 12 and the fill needle and fill needle
sheath of FIG. 9a and FIG. 9b.
[0042] FIG. 12 shows a sheath removal station according to one
embodiment of the invention.
[0043] FIG. 13 shows the sheath removal station of FIG. 2 with a
swab package and fill needle package suspended on the sheath
removal station before use.
[0044] FIG. 14a shows the fill needle package of FIG. 9a and FIG.
9b held by the robotic arm end piece of FIG. 11.
[0045] FIG. 14b shows the fill needle package of FIG. 9a and FIG.
9b as well as the swab package of FIG. 10 held by the robotic arm
end piece of FIG. 11.
[0046] FIG. 15 shows a flow chart of (a) method for transferring
within a controlled environment enclosure a fluid along a fluid
path to a destination within the controlled environment enclosure
and (b) a method for installing a fluid path in the controlled
environment enclosure.
[0047] FIG. 16 shows a flowchart of a method for uninstalling from
a controlled environment enclosure a fluid path comprising a fill
needle.
DETAILED DESCRIPTION
[0048] FIG. 1 shows an embodiment of an apparatus for protecting
and unprotecting of a fluid path 404 in a controlled environment
enclosure 420. The term "fluid" as used herein denotes any liquid,
gas, liquid-gas mixtures and any mixture of solids in liquid that
has fluid attributes, such as flowability or having appreciable
fluidity at ambient temperature and pressure, including, without
limitation, a dispersion of a solid or solids in a liquid, an
emulsion, a slurry, a micro-emulsion, colloidal suspension, a
suspension, a suspension of liposomes, and a suspension of micelles
or the like. The term "fluid path" as used herein denotes any
single channel or multi channel tubing, rigid or flexible, for
transporting a fluid.
[0049] A fluid path 404 starts at a container 401. The term
"container" as used herein denotes any vessel suitable to hold a
fluid, including without limitation any vial, syringe, ampoule,
carpule, bottle, flask, beaker, bag, well in multi-well plates, or
tube. The container 401 is fitted with an air filter 402. The
container 401 can be equipped with optional sensors (not shown) to
measure volume, weight of fluid, or other parameters. In some
embodiments there can be multiple containers connected in parallel
or in series with one another. Along the fluid path 404 there can
be optional measuring devices (not shown) that measure properties,
including without limitation any one or more of pressure, flow,
temperature, density and conductivity. The fluid path 404 can be
fitted with a filter element 403. The filter element 403 can be
selected to be suitable for sterile filtration of fluids.
[0050] In FIG. 1 the fluid path 404 comprises flexible tubing 405
and enters the controlled environment enclosure 420 via a sealed
opening (not shown). The sealing can be, for example, via the use
of a suitable aseptically sealing flange (not shown), which may
seal by means of, for example without limitation, an aseptic
tri-clamp. The container 401 and air filter 402 can be located
outside the controlled environment enclosure 420, as shown in FIG.
1. In other embodiments of the invention the container 401 and air
filter 402 can be located inside the controlled environment
enclosure 420.
[0051] Controlled environment enclosure 420 is equipped with an
inlet filter 430, an inlet valve 431, a blower 432, an outlet
filter 433 and an outlet valve 434. The characteristics of blower
432, inlet filter 430 and outlet filter 433 are chosen to yield a
controlled environment inside controlled environment enclosure 420.
As understood by those skilled in the art, various other filter and
blower arrangements are possible to establish a controlled
environment inside controlled environment enclosure 420. A suitable
controlled environment can be obtained, for example without
limitation, by means of any one or more of turbulent airflow,
horizontal unidirectional airflow and vertical unidirectional
airflow.
[0052] The fluid from container 401 can be transferred through the
fluid path 404 by a number of different mechanisms, including
without limitation a peristaltic pump 410 as shown in FIG. 1, a
difference in pressure between the container 401 and the controlled
environment enclosure 420, a difference in static height of the
container 401 and the end of the fluid path 404, a gear pump, a
lobe pump, a membrane pump, a piston pump, or a syringe pump. In
FIG. 1, pump 410 is shown disposed inside controlled environment
enclosure 420. In other embodiments, pump 410 may be disposed
outside controlled environment enclosure 420.
[0053] The flexible tubing 405 of the fluid path 404 can terminate
with an end piece 414. A suitable end piece can be, for example
without limitation, a fill needle, a pipette dispensing system, a
syringe dispensing system, a valve dispensing system, quick
connectors, aseptic connectors, dispense tips and a needle for
piercing of elastomers. In FIG. 1 the end piece 414 is selected to
be a fill needle.
[0054] The end piece 414 can be manipulated inside the controlled
environment enclosure 420 by mechanical means, for example, a
robotic arm manipulation system 415. A suitable robotic arm
manipulation system 415 may be an articulated robotic arm. Suitable
robotic arm manipulation systems for mechanically manipulating end
piece 414 include, but are not limited to, 6-axis robotic arms,
Selective Compliant Articulated Robot Arm (SCARA) systems, r-theta
robots, or combinations of linear actuators and rotary
actuators.
[0055] Fluids are transferred along the fluid path 404 to a
destination, which can be containers such as the tray with vials
411 located on pedestal 412 in FIG. 1. The destination may be
microwell plates for pharmaceutical products.
[0056] The fluid path 404 may be employed for a variety of purposes
including without limitation the filling of empty containers,
washing and rinsing of containers, adding fluid to containers with
a freeze dried powder, adding fluids to containers containing
excipients and/or active ingredients, adding medium to cells,
tissue or microbes, inoculating cells or microbes, adding substrate
to enzyme solutions or suspensions of immobilized enzymes, adding
gases such as argon or nitrogen to create an inert head space in
containers, adding gases such as nitrogen, air or carbon dioxide to
cells and removing fluids out of containers by suction. The term
"excipient" as used herein denotes an inert substance used as a
diluent or vehicle for a drug.
[0057] Fluid path 404 may in some applications be required for
aseptic transfer of fluids. In such a case fluid path 404 can be
pre-sterilized before installation in the controlled environment
enclosure 420. The aseptic part of the fluid path 404 can start
with container 401 or with filter 403. Installation of the aseptic
fluid path 404 requires sealing of the end piece 414.
[0058] FIG. 4 is a flowchart showing the prior art method for
installing a fluid path in a prior art controlled environment
enclosure. The prior art method requires the steps in sequence of
decontaminating (100) the prior art controlled environment
enclosure; transferring (110) the fluid path into the prior art
controlled environment enclosure; and installing (120) by hand the
fluid path in the prior art controlled environment enclosure,
before using (130) the fluid path for the purpose for which it is
intended.
[0059] In an aspect of the invention there is provided a method for
installing a fluid path 404 in the controlled environment enclosure
420. Referring to the apparatus of FIG. 1 and the flow chart of
FIG. 5, the method comprises protecting (301) the fluid path 404
against an environment external to the fluid path 404, introducing
(302) the fluid path 404 into the controlled environment enclosure
420, decontaminating (303) the controlled environment enclosure
420, and mechanically unprotecting (304) the fluid path 404. In its
unprotected state fluid path 404 can then be used for transporting
(305) fluids to destination 411, which fluids can be aseptic or
sterile fluids. Such transporting (305) of fluids can comprise
filtering the fluid in the fluid path 404 using filter element 403
and the filtering can be sterile filtering. The terms "sterile" and
"aseptic" are used interchangeably in this specification. The term
"decontamination" as used herein denotes a process for removing or
inactivating contamination, including without limitation viruses,
bacteria, spores, prions, molds, yeasts, proteins, pyrogens and
endotoxins, to acceptable levels. "Decontamination" as used herein
includes both sterilization (that is, the destruction of all
microorganisms, including bacterial spores to a probability of
surviving organisms of typically less than 1:10.sup.6) and
disinfection (that is, the destruction and removal of specific
types of microorganisms).
[0060] In FIG. 2 a suitable arrangement for mechanically
unprotecting (304) fluid path 404 is shown, comprising end piece
414 of fluid path 404 in the form of a fill needle, together with a
fill needle sheath 503. The fill needle 414 comprises fill needle
tubing 501 and fill needle hub 502. Fill needle tubing 501 is in
fluid communication with fluid path 404 of FIG. 1 and is
aseptically joined to fluid path 404. When the fluid path 404 is
within controlled environment enclosure 420, the fill needle sheath
503 can be stored in a sheath removal station 413 of the controlled
environment enclosure 420 shown in FIG. 1.
[0061] The fill needle hub 502 and the fill needle tubing 501 can
be glued or welded together. In alternative embodiments the fill
needle hub 502 and the fill needle tubing 501 can be made as one
part out of solid material. The fill needle sheath 503 can be
manufactured using materials with different thermal expansion
coefficients to allow it to slide on and off the fill needle hub
502 after thermal expansion. Alternatively the fill needle sheath
503 can be designed to have a sliding fit on the fill needle hub
502 using porous PTFE or a steam permeable elastomeric
material.
[0062] Protecting (301) the fluid path 404 comprises sealingly
placing the fill needle sheath 503 over the fill needle 414 such
that the fill needle sheath 503 seals with the needle hub 502. The
fill needle sheath 503 and needle hub 502 can be equipped with one
or multiple of tamper evident features 504 that will provide
evidence of breaking the seal between needle hub 502 and fill
needle sheath 503. Possible tamper evident features 504 include but
are not limited to heat shrink bands, tape seals, breakable rings,
tear-off connectors and snap connect tear-off connectors.
Unprotecting (304) the fluid path 404 comprises removing the fill
needle sheath 503 from the fill needle 414, thereby exposing the
fill needle 414 to an environment within the controlled environment
enclosure 420. When the fill needle 414 is in use within the
controlled environment enclosure 420, the fill needle sheath 503 is
stored in the sheath removal station 413.
[0063] The mechanically unprotecting (304) the fill needle 414 when
it is within controlled environment enclosure 420 can comprise
using a robotic arm manipulation system 415 shown in FIG. 1. FIG. 3
illustrates part of the robotic arm manipulation system 415 of FIG.
1, wherein a forearm 601 is connected to a wrist 602, and the wrist
602 is connected to a tool flange 603. The end tool 604, shown in
FIG. 3 as being fork shaped, has a partially opened bore of such
diameter that the end tool 604 can slide around a narrow tubular
section of needle hub 502 and the end tool 604 can move upwards to
establish a precise locating fit to needle hub 502. For
unprotecting (304) the fill needle 414, the end tool 604 moves the
fill needle 414 with the fill needle sheath 503 and places the fill
needle 414 with the fill needle sheath 503 in sheath removal
station 413.
[0064] In one embodiment of the apparatus and method, the sheath
removal station 413 heats the fill needle sheath 503, which thereby
expands and releases its grip or seal to the needle hub 502.
Practitioners in the field will appreciate that there are many
different ways by which the fill needle sheath 503 can be removed
from the fill needle 414. The end tool 604, through the motion of
the robotic arm manipulation system 415, removes the fill needle
414 from the fill needle sheath 503. The fill needle sheath 503 can
remain in the sheath removal station 413 while the robotic arm
manipulation system 415 moves the fill needle 414 to the
destination. In one embodiment of the apparatus and method the
destination shown is the tray with vials 411 located on the
pedestal 412 in FIG. 1.
[0065] The end tool 604 and the needle hub 502 can have various
different other shapes allowing the use of various other closure
systems such as, for example without limitation, a plug, a cap with
sliding fit o-ring seal with minimal occluded surface area, a cap
with membrane peel-off seal, or a twist-off cap. As understood by
those skilled in the art, some closure systems will be more
suitable than other closure systems for use with particular
sterilization methods.
[0066] Materials of lesser permeability can be used in the
manufacture of the flexible tubing 405, but this is not always an
option. Tubing permeability can also be reduced by adding
additional layers to the tubing. Example methods for establishing
such additional layers around the flexible tubing 405 include, but
are not limited to, heat shrinking with non-permeable polymers such
as FEP, multilayer co-extrusion with non-permeable polymers,
creating a diffusion barrier by polymeric coating such as
poly(p-xylylene), encasing with layers of tape, and the fitting of
a sleeve.
[0067] In a further aspect of the invention there is provided a
method for uninstalling a fluid path 404 from the controlled
environment enclosure 420. Referring to the apparatus of FIG. 1 and
the flow chart of FIG. 6, the method comprises mechanically
protecting (306) the fluid path 404 within the controlled
environment enclosure 420 once the use of fluid path 404 has been
completed, decontaminating (303) the controlled environment
enclosure 420, and removing (307) the fluid path 404 from the
controlled environment enclosure 420. The mechanically protecting
(306) the fill needle 414 can comprise using the robotic arm
manipulation system 415 shown in FIG. 1.
[0068] The mechanically protecting (306) the fill needle 414 within
controlled environment enclosure 420 can comprise using the robotic
arm manipulation system 415 of FIG. 1. The end tool 604 (See FIG.
3) of robotic arm manipulation system 415 is used to move the fill
needle 414 to and place it in the fill needle sheath 503, which is
housed in the sheath removal station 413. The sheath removal
station 413 heats the fill needle sheath 503 until the fill needle
sheath 503 can slide over fill needle 414 to suitably seal to
needle hub 502 after cooling, to thereby protect (306) the fill
needle 414 within controlled environment enclosure 420. The robotic
arm manipulation system 415 can then further move the protected
fluid path 404 as may be required.
[0069] In a further aspect of the invention the mechanically
unprotecting (304) and the mechanically protecting (306) the fill
needle 414 using the robotic arm manipulation system 415 can be
done automatically. For example, a suitable controller 440 (see
FIG. 1), communicating control instructions with the controlled
environment enclosure 420 via a control line 450, can be programmed
to automatically unprotect (304) the fill needle 414 using the
robotic arm manipulation system 415 once the decontaminating (303)
the controlled environment enclosure 420 has been completed. Such
automation obviates human intervention in the step of mechanically
unprotecting (304) the fill needle 414. In an embodiment of the
method, the step of decontaminating (303) the controlled
environment enclosure 420 can also be managed by controller 440.
This allows the remainder of the steps of installing the fill
needle 414, beyond the step of introducing (302) the fluid path 404
into the controlled environment enclosure 420, to be automated
using controller 440, including the use of the fill needle for the
purpose for which it is installed, and the mechanically protecting
(306) the fill needle 414 after such use.
[0070] In a further aspect of the invention there is provided a
method for decontaminating the controlled environment enclosure 420
having a fluid path 404. The method comprises mechanically
protecting (306) the fluid path 404 within the controlled
environment enclosure by sealingly placing the fill needle sheath
503 over the fill needle 414 such that the fill needle sheath 503
seals with the needle hub 502; decontaminating (303) the controlled
environment enclosure 420; and opening (308) and closing (309) the
controlled environment enclosure 420. The opening (308) and closing
(309) the controlled environment enclosure 420 can be done after
the decontaminating (303) the controlled environment enclosure 420,
as may be the case when the fluid or the materials at the
destination 411 are dangerous. This is shown in FIG. 7.
Alternatively, the opening (308) and closing (309) the controlled
environment enclosure 420 can be done before the decontaminating
(303) the controlled environment enclosure 420. This is shown in
FIG. 8, as may be the case when the external environment holds
potential of contaminating the fluid or the materials at the
destination 411. The mechanically protecting (306) the fill needle
414 can comprise using the robotic arm manipulation system 415
shown in FIG. 1, as already described.
[0071] The protecting (306) the fill needle 414 using the robotic
arm manipulation system 415 can be done automatically via
controller 440 (see FIG. 1). Controller 440 can be programmed for
automatically mechanically protecting (306) the fill needle 414
using the robotic arm manipulation system 415, prior to opening
(308) and closing (309) the controlled environment enclosure 420.
The opening (308) and closing (309) the controlled environment
enclosure 420 can likewise be automated via controller 440.
[0072] We have described thus far herein an embodiment of a sheath
removal station 413 of FIG. 1 based on employing heat to secure or
release fill needle 414 from fill needle sheath 503. We now turn to
another embodiment of the subsystem comprising sheath removal
station 413', fill needle 414', fill needle sheath 503', and
robotic arm manipulation system 415 described at the hand of FIGS.
9a, 9b, 10 and 11. In this embodiment, we describe an alternative
sheath removal system and associated sheath removal station 413',
and provide more detail as regards fill needle 414', fill needle
sheath 503', and robotic arm manipulation system 415.
[0073] FIG. 9a and FIG. 9b provide isometric and sectional views
respectively of the fill needle sheath 503' and fill needle 414'
combination 900 of this embodiment. The term "aseptically sealed
fill needle package" 900 will be used in the present specification
to describe this combination of mutually aseptically sealed fill
needle sheath 503' and fill needle 414'. While FIG. 9a provides
perspective, the simplicity of FIG. 9b allows more elements to be
clearly indicated and numbered. Fill needle sheath 503' comprises a
substantially cylindrical vessel portion 910 configured to receive
the dispensing end of fill needle 414', and two clamping members
930a and 930b attached to vessel portion 910 by spring loaded
members 920a and 920b respectively. In one embodiment, shown in
FIG. 9a and FIG. 9b, the spring loading is established by means of
the natural elastic flexibility of members 920a and 920b. To this
end, fill needle sheath 503' may be manufactured from a polymeric
material with suitable inherent elasticity and that is compatible
with aseptic systems requirements. Locating eyelets 950a and 950b
are disposed in clamping members 930a and 930b respectively.
Clamping members 930a and 930b further comprise clamping clips 960a
and 960b respectively disposed to engage with filling needle 414'
as described in more detail below.
[0074] Filling needle 414' may be configured in many different
ways. In the present non-limiting exemplary embodiment, fill needle
414' comprises fill needle tubing 501' and fill needle hub 502'.
Fill needle 414' comprises a dispensing portion 506', being the
dispensing tip of fill needle 414'. Fill needle tubing 501' is in
fluid communication with fluid path 404 of FIG. 1 and is
aseptically joined to fluid path 404. Fill needle hub 502' mates
axially face-to-face with fill needle sheath 503' in an aseptic
pressure seal provided by elastically compressible O-ring 940. Fill
needle hub 502' further comprises locating ledges 508a' and 508b'
for engaging with clamping clips 960a and 960b of filling needle
414'. In manufacture, spring loaded members 920a and 920b are
fashioned to be spring loaded when clamping clips 960a and 960b are
engaged with locating ledge 508'. When filling needle 414' is
sheathed in fill needle sheath 503' with compressible O-ring 940
under suitable compression, clamping clips 960a and 960b are
engaged with locating ledge 508' and under a tension force
directing clips 960a and 960b towards each other. Under these
circumstances, the tension in fill needle sheath 503' is contained
in spring loaded members 920a and 920b. Other embodiments for
urging clips 960a and 960b towards each other when filling needle
414' is sheathed in fill needle sheath 503' are contemplated,
including embodiments in which discrete springs are employed to
render members 920a and 920b spring loaded.
[0075] Fill needle sheath 503' may be manufactured by injection
molding of a suitable polymeric material. In order to keep units
costs low it may specifically be injection molded as a single
monolithic unit. In the present specification the term "monolithic"
is employed to describe an object that is fashioned is a contiguous
whole from one piece of material without joints or seams, whether
by casting, molding, or deposition, or any other means. A single
mold in the art of injection molding generally produces a
monolithic product. The locking member portions of fill needle hub
502' and the fill needle sheath 503' may in particular be
integrally molded. This includes in particular spring loaded
members 920a and 920b.
[0076] Fill needle hub 502' comprises two engagement clips 510a'
and 510b' for engaging with robotic arm end piece 1100 of FIG. 11.
The operation of these will be described below at the hand of FIG.
11. Engagement clips 510a' and 510b' are able to flex such that
their top ends can be deflected closer together while engagement
clips 510a' and 510b' can push back in reaction against whatever
bodies are pushing them together. To this end engagement clips
510a' and 510b' may be spring loaded. In the embodiment of fill
needle hub 502' shown in FIGS. 9a and 9b, engagement clips 510a'
and 510b' are flexible by virtue of being manufactured from an
elastic material such as, for example without limitation, a
suitable polymeric material compatible with aseptic handling
requirements. Engagement clips 510a' and 510b' are shaped to both
clip over robotic arm end piece 1100 of FIG. 11 and be deflected
toward each other by end piece 1100.
[0077] In the embodiment shown in FIG. 9a and FIG. 9b, fill needle
hub 502' is shown as comprising several interior substructures.
This approach allows the same mold to be employed for the
manufacture by injection molding of all fill needle hubs, while the
interior substructures are then adapted to differently sized fill
needle tubing 501'. This allows costs to be kept low. Other
arrangements of substructures are also contemplated, including
without limitation embodiments wherein the entire fill needle hub
502' is one monolithic entity fashioned by injection molding of a
suitable polymeric material compatible with aseptic requirements.
Based on the above, fill needle package 900 comprises first and
second sheath portions that together define a sealed cavity that
aseptically encapsulates an implement portion when first and second
locking mechanism portions are mutually mated.
[0078] In view of the above, flow path 404 of FIG. 1, as supplied
for use in this embodiment, comprises flexible tubing 405, an
aseptically sealing flange for aseptically sealing the flow path
404 to the controlled environment chamber 420, and aseptically
sealed fill needle package 900.
[0079] Turning now to FIG. 9c, aseptically sealed fill needle
package 900 may have a tamper indicator 970 that is mechanically
linked to one of the locking mechanism portions of fill needle
package 900. In FIG. 9c tamper indicator 970 comprises a tearable
strip across spring loaded members 920a and 920b. When locating
eyelets 950a and 950b are forced apart, the portion of tamper
indicator 970 disposed across spring loaded members 920a and 920b
is torn irreversibly. Since the same act of separating locating
eyelets 950a and 950b also leads to the separation of sealing
surfaces between the fill needle hub 502' and the fill needle
sheath 503', the breaking of tamper indicator 970 is a direct
indicator of the breach of the aseptic seal between fill needle hub
502' and fill needle sheath 503'. The same tamper-evident
arrangement may be made for the swab system described below.
[0080] As part of the process of filling a pharmaceutical container
with a pharmaceutical product, a regulatory requirement may exist
in some cases for the dispensing tip of the fill needle 414,414' to
be swabbed with a suitable swab to collect potential contamination
species. Such swabs are then typically evaluated by a suitably
qualified laboratory in order to assess the aseptic state of the
pharmaceutical dispensing process. To this end, in another aspect
of the invention, an aseptically sealable/unsealable swab subsystem
is provided. In FIG. 10, swab subsystem 1000 comprises a swab
holder 1003 that may usefully be of the same design as fill needle
sheath 503' of FIG. 9a and FIG. 9b. Swab 1006 is mounted within
swab holder 1003 with the collection tip 1008 of swab 1006
protruding above the top of swab holder 1003. This arrangement
allows the dispensing tip of the fill needle 414,414' to be swabbed
by touching the dispensing tip to the collection tip 1008 of swab
1006. Swab holder 1003 may be a monolithic injection molded
polymeric swab holder.
[0081] Swab subsystem 1000 further comprises a swab holder cap 1002
that may usefully be of the same design as fill needle hub 502' of
FIG. 9a and FIG. 9b, with this modification that swab holder cap
1002 has no fill needle tube 502' and that swab holder cap 1002 is
instead permanently sealed at the top. As regards all other
mechanical operational aspects, fill needle sheath 503' and fill
needle 414' combination 900 and swab subsystem 1000 may be
identical. For this reason, the mechanical design aspects of swab
subsystem 1000 will not be further discussed here. We shall,
however, be referring below to engagement clips 1010a' and 1010b'
of swab holder cap 1002 as regards their engagement with robotic
arm end piece 1100 of FIG. 11. We shall also be referring below to
locating eyelets 1050a and 1050b disposed in clamping members 1030a
and 1030b respectively as regards their engagement with fingers.
The term "aseptically sealed swab package" 1000 will be used in the
present specification to describe this combination of mutually
aseptically sealed swab holder cap 1002 and swab holder 1003
containing swab 1006. The swab 1006 is supplied for use packaged in
the form of aseptically sealed swab package 1000. Based on the
above, swab package 1000 comprises first and second sheath portions
that together define a sealed cavity that aseptically encapsulates
an implement portion when first and second locking mechanism
portions are mutually mated. The locking member portions of f swab
holder cap 1002 and the swab holder 1003 may in particular be
integrally molded. This includes in particular spring loaded
members of the structure.
[0082] FIG. 11 shows one embodiment of an endpiece 1100 for robotic
arm 415 of FIG. 1 configured to engage with swab subsystem 1000 of
FIG. 10 and with fill needle sheath 503' and fill needle 414'
combination 900 of FIG. 9a and FIG. 9b. Flange 1110 is disposed and
shaped for attaching endpiece 1100 to robotic arm 415 of FIG. 1.
Openings 1120 and 1140 are disposed and shaped for holding fill
needle 414' and swab holder cap 1004 respectively. In the case of
fill needle 414', engagement clips 510a' and 510b' of fill needle
hub 502' engage with end piece engagement surfaces 1120a and 1120b
of endpiece 1100.
[0083] Procedurally, fill needle 414' is engaged as follows with
endpiece 1100. Endpiece 1100 is moved forward over the part of fill
needle tubing 501' that protrudes out of fill needle 414' and any
associated section of flow path 404 joined to fill needle tubing
501' until opening 1120 is directly above fill needle 414'. In this
process, opening 1120c allows endpiece 1100 to negotiate fill
needle tubing 501'. Endpiece 1100 may then be lowered such that the
bottom edges of engagement surfaces 1120a and 1120b engage with the
sloped portions of engagement clips 510a' and 510b'. When endpiece
1100 is lowered further, engagement clips 510a' and 510b' are both
flexibly deflected towards each other until engagement surfaces
1120a and 1120b pass the sloped portions of engagement clips 510a'
and 510b' and engagement clips 510a' and 510b' snap back to engage
their flat surfaces with engagement surfaces 1120a and 1120b of
endpiece 1100. This securely locates fill needle 414' in endpiece
1100. When fill needle 414' is engaged with endpiece 1100, clamping
members 930a and 930b are disposed in slots 1130a and 1130b
respectively so as to render locating eyelets 950a and 950b
accessible.
[0084] In the case of swab holder cap 1004, the engagement proceeds
in the same fashion, except that there is no fill needle tubing
501' requiring an opening similar to 1120c. Endpiece 1100 is simply
moved until opening 1140 is directly above swab holder cap 1004,
after which endpiece 1100 is lowered such that the flat surfaces of
engagement clips 1010a' and 1010b' engage with surfaces 1140a and
1140b of opening 1140 in a fashion similar to that described above
for engagement clips 510a' and 510b'. When swab holder cap 1004 is
engaged with endpiece 1100, clamping members 1030a and 1030b are
disposed in slots 1150a and 1150b respectively so as to render
locating eyelets 1050a and 1050b accessible.
[0085] When first using a fill needle 414, 414' and flow path 404,
the product to be dispensed into containers is first run through
the flow path 404 and fill needle 414, 414' to establish a steady
and reliable flow. This initial volume of product may be dispensed
into a priming bottle to be disposed of later. Grip 1160 on
endpiece 1100 may be employed as a general tool for handling, for
example, stoppers for such priming bottles and the like.
[0086] To describe the removal of fill needle sheath 503' from fill
needle 414', we turn now to FIG. 12, in which sheath removal
station 413' comprises sheath engagement fingers 1220a and 1220b
for engaging with locating eyelets 950a and 950b of fill needle
sheath 503'. When fill needle sheath 503', either with or without
fill needle 414' engaged with it, is forced onto sheath engagement
fingers 1220a and 1220b, the angled mutual orientation of sheath
engagement fingers 1220a and 1220b forces apart clamping members
930a and 930b of fill needle sheath 503'. This action forces
clamping clips 960a and 960b apart and disengages clamping clips
960a and 960b from locating ledge 508' of fill needle hub 502'.
O-ring 940 thereby is allowed to expand to its uncompressed state
and fill needle 414' is released from fill needle sheath 503'. Fill
needle sheath 503' is therefore removably sealable to fill needle
414'. When not in use, fill needle sheath 503' is aseptically
sealed to fill needle 414' and may be suspended from suspension
stubs 1240a and 1240b as shown in FIG. 13. As will be described
later, an operator may install flow path 404 in chamber 420. In
that process, fill needle sheath 503' with fill needle 414'
aseptically sealed to it, is positioned on suspension stubs 1240a
and 1240b.
[0087] Sheath removal station 413' also comprises sheath engagement
fingers 1230a and 1230b for engaging with locating eyelets 1050a
and 1050b of swab holder 1003. When swab holder 1003, either with
or without swab holder cap 1002 engaged with it, is forced onto
sheath engagement fingers 1230a and 1230b, the angled mutual
orientation of sheath engagement fingers 1230a and 1230b forces
apart clamping members 1030a and 1030b of swab holder 1003. This
action disengages swab holder cap 1002 from swab holder 1003. Swab
holder 1003 is therefore removably sealable to swab holder cap
1002. When not in use, swab holder 1003 aseptically sealed to swab
holder cap 1002 may be suspended from suspension stubs 1250a and
1250b as shown in FIG. 13. As will be described later, at the start
of the process of filling pharmaceutical containers with
pharmaceuticals in chamber 420, an operator may install swab holder
1003 aseptically sealed to swab holder cap 1002 on suspension stubs
1250a and 1250b as per FIG. 13.
[0088] FIG. 14a shows robotic arm endpiece 1100 holding aseptically
sealed fill needle package 900 by engagement clips 510a' and 510b'
of fill needle hub 502'. FIG. 14b shows robotic arm endpiece 1100
holding aseptically sealed swab package 1000 by engagement clips
1010a and 1010b of swab cap 1002.
[0089] In operation, fluid path 404 is sealed aseptically to
controlled environment enclosure 420 and fill needle package 900 is
suspended on suspension stubs 1240a and 1240b of sheath removal
station 413' as shown in FIG. 13. Swab package 1000 is introduced
into enclosure 420 and suspended on stubs 1250a and 1250b of sheath
removal station 413' as shown in FIG. 13. Controlled environment
enclosure 420 may now be decontaminated using any of the various
means previously described. Fluid path may now be unprotected by
unsealing fill needle 414' fill needle sheath 503'. This may be
done using robotic arm 415 as explained above at the hand of FIG.
12. This step leaves fill needle sheath 503' located on sheath
engagement fingers 1220a and 1220b and fill needle 414' located on
robotic arm endpiece 1100.
[0090] Swab holder cap 1002 may be similarly removed from swab
holder 1003 to expose swab 1006 to the environment in enclosure
420. The process leaves swab holder 1003 with swab 2006 located on
sheath engagement fingers 1230a and 1230b of sheath removal station
413'. Robotic arm 415 now may proceed to fill pharmaceutical vials
411 located on pedestal 412 in FIG. 1 with fluid via fill needle
414'. Fill needle 414' and swab holder cap 1002 remain resident on
robotic arm endpiece 1100 during the filling process.
[0091] When filling has been completed, robotic arm 415
automatically moves robotic arm endpiece 1100 with fill needle 414'
and swab holder cap 1002 to sheath removal station 413' to touch
the dispensing end 506' of fill needle 414' to the exposed tip 1008
of swab 1006.
[0092] Using robotic arm 415, eyelets 950a and 950b of fill needle
sheath 503' are engaged with sheath engagement fingers 1220a and
1220b to allow fill needle 414' to be aseptically sealed to fill
needle sheath 503', thereby protecting the fluid path 404. Eyelets
1050a and 1050b of swab holder 1003 may similarly engage with
sheath engagement fingers 1230a and 1230b of sheath removal station
413' to allow swab holder 1003 and swab holder cap 1002 to be
sealed aseptically to each other, thereby protecting the swab 2006.
Fluid path 404 and sealed swab package 1000 may now be removed from
controlled environment enclosure 420.
[0093] As shown in FIG. 14b, robotic arm endpiece 1100 has no
moving parts and is capable of simultaneously bearing both fill
needle package 900 and swab package 1000. Despite both robotic arm
endpiece 1100 and sheath removal station 413' having no moving
parts, they are jointly capable of opening and closing both fill
needle package 900 and swab package 1000. This is possible by
virtue of the interaction between the engagement fingers 1220a,
1220b, 1230a, 1230b of sheath removal station 413' and the eyelets
950a and 950b of fill needle sheath 503' and eyelets 1050a and
1050b of swab holder 1003, combined with the spring-loaded or
flexible nature of portions of fill needle sheath 503' and swab
holder 1003.
[0094] In one aspect of the invention, described at the hand of
FIG. 15, a method is provided for transferring (1500) within a
controlled environment enclosure a fluid along a fluid path to a
destination within the controlled environment enclosure, the method
comprising providing (1510) an aseptically sealed fluid path
comprising an aseptically sealed fill needle package, aseptically
sealing (1520) the fluid path to the controlled environment
enclosure, decontaminating (1530) the controlled environment
enclosure after aseptically sealing the fluid path to the
controlled environment enclosure, automatically unprotecting (1540)
the fluid path within the controlled environment enclosure,
transferring (1550) the fluid to the destination along the fluid
path after the automatically unprotecting, and disposing without
re-using (1570) of the fluid path after transferring the fluid to
the destination.
[0095] The automatically unprotecting (1540) may be by
automatically operating a robotic arm. The decontaminating (1530)
the controlled environment enclosure may automatically be done
after the sealing the fluid path to the controlled environment
enclosure. The providing an aseptically sealed fluid path (1510)
may comprise providing a fill needle removably and aseptically
sealed to a fill needle sheath and the sheath may be a monolithic
injection molded polymeric fill needle sheath. The providing an
aseptically sealed fluid path (1510) may comprise providing a
pre-sterilized tube aseptically sealed to the fill needle. The
transferring (1550) the fluid to a destination may comprise
transferring the fluid to at least one of a culture of cells, a
culture of tissue, an enzyme solution, a suspension of immobilized
enzymes, a mix of active ingredients, and an excipient. The
transferring (1550) the fluid may be transferring an aseptic fluid.
The transferring (1550) within a controlled environment enclosure
may be transferring within an isolator. The transferring the fluid
(1550) to a destination may comprise at least one of transferring
the fluid to microwell plates and to containers for pharmaceutical
products.
[0096] The method may further comprise automatically protecting
(1560) the fluid path after transferring the fluid to the
destination and before disposing of the fluid path. The
transferring (1550) the fluid may comprise filtering the fluid in
the fluid path. The filtering may be sterile filtering.
[0097] As part of the method described above, a method (1500a) is
provided for installing a fluid path within a controlled
environment enclosure comprising, providing (1510) an aseptically
sealed fluid path comprising an aseptically sealed fill needle
package, aseptically sealing (1520) the fluid path to the
controlled environment enclosure, decontaminating (1530) the
controlled environment enclosure after aseptically sealing the
fluid path to the controlled environment enclosure, and
automatically unprotecting (1540) the fluid path within the
controlled environment enclosure. The automatically unprotecting
may be by automatically operating a robotic arm. The
decontaminating the controlled environment enclosure may be
automatically done after the sealing the fluid path to the
controlled environment enclosure. The providing a fill needle may
comprise providing a fill needle removably and aseptically sealed
to a fill needle sheath. The providing a fill needle may comprise
providing a fill needle removably and aseptically sealed to a
monolithic injection molded polymeric fill needle sheath.
[0098] In a further aspect of the invention described at the hand
of FIG. 16, a method is provided for uninstalling (1600) from a
controlled environment enclosure a fluid path comprising a fill
needle, the method comprising automatically aseptically sealing
(1610) the fill needle to a monolithic injection moulded polymeric
fill needle sheath within the controlled environment enclosure,
decontaminating (1640) the controlled environment enclosure after
aseptically sealing (1610) the fluid path, opening (1650) the
controlled environment enclosure after the decontaminating (1640),
and removing (1660) the fluid path from the controlled environment
enclosure. The method may further comprise automatically swabbing
(1620) a dispensing end of the fill needle with a swab and
automatically aseptically sealing the swab (1630) in a swab package
before decontaminating (1640) the controlled environment, and
removing (1670) the swab package from the controlled environment
enclosure after opening the controlled environment enclosure.
[0099] The automatically aseptically sealing the fluid path (1610)
may be by automatically operating a robotic arm. The
decontaminating (1640) the controlled environment enclosure may be
done automatically after the sealing (1610) the fluid path. The
opening (1650) the controlled environment enclosure is done
automatically after the decontaminating (1640) the controlled
environment enclosure. The automatically swabbing (1620) may be by
automatically operating a robotic arm. The automatically
aseptically sealing (1610) the fluid path may be by automatically
operating the robotic arm. The decontaminating (1640) the
controlled environment enclosure may be done automatically after
the sealing the fluid path (1610) and sealing the swab (1630). The
swabbing (1620) may be with a swab disposed in a monolithic
injection molded polymeric swab holder.
[0100] As part of the above methods, a subsidiary method is
provided for decontaminating a controlled environment enclosure
containing a fluid path having a fill needle, the method comprising
automatically aseptically sealing (1610) the fill needle to a
monolithic injection molded polymeric fill needle sheath within the
controlled environment enclosure, and decontaminating (1620) the
controlled environment enclosure after aseptically sealing (1610)
the fluid path. The automatically aseptically sealing (1610) the
fluid path may be by automatically operating a robotic arm. A
subsidiary method is also provided for decontaminating a controlled
environment enclosure containing a swab disposed in a swab holder,
the method comprising automatically aseptically sealing the swab
holder to a swab holder cap (1630) within the controlled
environment enclosure, and decontaminating (1640) the controlled
environment enclosure after aseptically sealing the swab holder to
a swab holder cap. The automatically aseptically sealing (1630) the
swab holder to a swab holder cap may be by automatically operating
a robotic arm.
[0101] In the above-described embodiments, a pair of
injection-molded parts are snapped together using integrally molded
leaf spring members with clamping clips that engage with locating
ledges. This action provides a positive mechanical detent that
ensures that the implement is reliably sealed inside the sheath.
But one of ordinary skill in the art would recognize that a variety
of other types of mechanisms can be used to provide this type of
action, including but not limited to cam-based mechanisms,
ratcheting mechanisms, bistable linkages, spring-loaded balls,
snaps, and latch pins.
[0102] The mechanisms in the above-described embodiments are
presented in configurations that allow a concave sheath and
cover-like hub to be engaged with each other along a vertical axis,
but other geometric configurations can also be implemented. A pair
of concave sheath portions could both partly enclose an implement
in a downward-facing clamshell-type configuration, for example. And
while the sheath and its corresponding hub are preferably
manufactured as two completely separate parts as described above,
they could also be built as a compound unit, such as by connecting
them with a hinge or tether.
[0103] The above-described embodiments also provide bearing
surfaces on engagement clips and in eyelets that respectively
interact with an endpiece on a robot arm and protrusions on a
holding station, which allow a robot arm to automatically open and
close the sheath. But one of ordinary skill in the art would
recognize that many other combinations and arrangements of bearing
surfaces could also be employed.
ADDITIONAL NOTES
[0104] The above detailed description includes references to the
accompanying drawings, which form a part of the detailed
description. The drawings show, by way of illustration, specific
embodiments in which the invention can be practiced. These
embodiments are also referred to herein as "examples." All
publications, patents, and patent documents referred to in this
document are incorporated by reference herein in their entirety, as
though individually incorporated by reference. In the event of
inconsistent usages between this document and those documents so
incorporated by reference, the usage in the incorporated
reference(s) should be considered supplementary to that of this
document; for irreconcilable inconsistencies, the usage in this
document controls.
[0105] In this document, the terms "a" or "an" are used, as is
common in patent documents, to include one or more than one,
independent of any other instances or usages of "at least one" or
"one or more." In this document, the term "or" is used to refer to
a nonexclusive or, such that "A or B" includes "A but not B," "B
but not A," and "A and B," unless otherwise indicated. In the
appended claims, the terms "including" and "in which" are used as
the plain-English equivalents of the respective terms "comprising"
and "wherein." Also, in the following claims, the terms "including"
and "comprising" are open-ended, that is, a system, device,
article, or process that includes elements in addition to those
listed after such a term in a claim are still deemed to fall within
the scope of that claim. Moreover, in the following claims, the
terms "first," "second," and "third," etc. are used merely as
labels, and are not intended to impose numerical requirements on
their objects.
[0106] Method examples described herein can be machine or
computer-implemented at least in part. Some examples can include a
tangible computer-readable medium or machine-readable medium
encoded with instructions operable to configure an electronic
device to perform methods as described in the above examples. An
implementation of such methods can include code, such as microcode,
assembly language code, a higher-level language code, or the like.
Such code can include computer readable instructions for performing
various methods. The code can form portions of computer program
products. Further, the code can be tangibly stored on one or more
volatile or non-volatile computer-readable media during execution
or at other times. These computer-readable media can include, but
are not limited to, hard disks, removable magnetic disks, removable
optical disks (e.g., compact disks and digital video disks),
magnetic cassettes, memory cards or sticks, random access memories
(RAM's), read only memories (ROM's), and the like.
[0107] The above description is intended to be illustrative, and
not restrictive. For example, the above-described examples (or one
or more aspects thereof) may be used in combination with each
other. Other embodiments can be used, such as by one of ordinary
skill in the art upon reviewing the above description. The Abstract
is provided to comply with 37 C.F.R. .sctn. 1.72(b), to allow the
reader to quickly ascertain the nature of the technical disclosure.
It is submitted with the understanding that it will not be used to
interpret or limit the scope or meaning of the claims. Also, in the
above Detailed Description, various features may be grouped
together to streamline the disclosure. This should not be
interpreted as intending that an unclaimed disclosed feature is
essential to any claim. Rather, inventive subject matter may lie in
less than all features of a particular disclosed embodiment. Thus,
the following claims are hereby incorporated into the Detailed
Description, with each claim standing on its own as a separate
embodiment. The scope of the invention should be determined with
reference to the appended claims, along with the full scope of
equivalents to which such claims are entitled.
* * * * *