Language selection

Search

Patent 2362108 Summary

Third-party information liability

Some of the information on this Web page has been provided by external sources. The Government of Canada is not responsible for the accuracy, reliability or currency of the information supplied by external sources. Users wishing to rely upon this information should consult directly with the source of the information. Content provided by external sources is not subject to official languages, privacy and accessibility requirements.

Claims and Abstract availability

Any discrepancies in the text and image of the Claims and Abstract are due to differing posting times. Text of the Claims and Abstract are posted:

  • At the time the application is open to public inspection;
  • At the time of issue of the patent (grant).
(12) Patent: (11) CA 2362108
(54) English Title: ACCESS VALVE DEVICES, THEIR USE IN SEPARATION APPARATUS, AND CORRESPONDING METHODS
(54) French Title: DISPOSITIFS DE SOUPAPE D'ACCESS LEUR UTILISATION DANS UN APPAREIL DE SEPARATION ET METHODES ASSOCIEES
Status: Expired
Bibliographic Data
(51) International Patent Classification (IPC):
  • B01D 15/08 (2006.01)
(72) Inventors :
  • DAVIS, JOHN (United Kingdom)
  • HOFMANN, MARTIN JOHN (United Kingdom)
(73) Owners :
  • GE HEALTHCARE BIO-SCIENCES AB (Sweden)
(71) Applicants :
  • AMERSHAM PHARMACIA BIOTECH AB (Sweden)
(74) Agent: ROBIC
(74) Associate agent:
(45) Issued: 2006-12-05
(22) Filed Date: 1995-10-03
(41) Open to Public Inspection: 1996-04-11
Examination requested: 2001-11-16
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
941 9888.4 United Kingdom 1994-10-03

Abstracts

English Abstract

The separation process is for separating a target component from a liquid incorporating the target component with other components. It comprises the steps of providing a bed of particulate packing medium; flowing liquid upwardly through the bed of particulate packing medium; through a restricted-permeability element and through a process outlet, to expand the bed in the bed space and effect separation of the target component from the liquid through retention by the particulate packing medium; opening a clearing outlet communicating directly with the bed space, at or adjacent the restricted-permeability element; and forcing a clearing flow of fluid relative to the restricted permeability element to disturb the particulate matter which has accumulated against it, and causing said matter to pass out of the bed space through the clearing outlet.


French Abstract

Procédé de séparation pour séparer un composant cible d'un liquide incorporant le composant cible avec d'autres composants. Le procédé comprend les étapes de fourniture d'un lit de liquide de couverture de particules ; l'écoulement vers le haut du liquide à travers le lit de liquide de couverture de particules ; à travers un élément de perméabilité restreinte et à travers une sortie de traitement, pour étendre le lit dans l'espace de lit et effectuer la séparation du composant cible du liquide par la rétention par le liquide de couverture de particules ; l'orifice de sortie de dégagement communiquant directement avec l'espace de lit, au niveau de ou adjacent à l'élément de perméabilité restreinte ; et le forçage d'un écoulement de dégagement de liquide relatif à l'élément de perméabilité restreinte pour agiter les particules de matière qui s'y sont accumulées, et provoquer le passage de ladite matière hors de l'espace de lit par l'orifice de sortie de dégagement.

Claims

Note: Claims are shown in the official language in which they were submitted.




24


CLAIMS:


1. A separation process for separating a target
component from a liquid incorporating the target
component with other components, the separation process
comprising
providing a bed of particulate packing medium, said
medium being adapted to retain the target component and
said bed thereof being enclosed in a bed space defined by
a column housing, said housing having a process outlet
and a restricted permeability element between the process
outlet and bed space to retain the particulate packing
medium in the bed space;
flowing liquid upwardly through the bed of
particulate packing medium, through the restricted-
permeability element and through the process outlet, to
expand the bed in the bed space and effect separation of
the target component from the liquid through retention by
the particulate packing medium;
said other components of the liquid comprising
particulate matter, said particulate matter accumulating
against the restricted-permeability element during the
flowing of the liquid, and the process further comprising
opening a clearing outlet communicating directly
with the bed space, at or adjacent the restricted-
permeability element, and
forcing a clearing flow of fluid relative to the
restricted permeability element to disturb the
particulate matter which has accumulated against it, and
causing said matter to pass out of the bed space through
the clearing outlet.




25


2. A separation process as claimed in claim 1, in which
the liquid comprises unclarified or partially-clarified
cell culture broth, and the target component is a protein
product in the culture broth.

3. A separation process as claimed in claim 1 in which
the clearing flow comprises a reverse flow forced back
through the restricted permeability element.

4. A separation process as claimed in claim 1 in which
a said clearing flow is forced through at least one
nozzle at the bed space side of the restricted-
permeability element.

5. A separation process as claimed in claim 4 in which
a said nozzle is on a conduit at the centre of the
restricted-permeability element, and the clearing flow
radiates from the nozzle.

6. A separation process as claimed in claim 1 in which
the column housing has a housing wall and an access valve
is provided through the housing wall and restricted-
permeability element to enable communication of first and
second fluid flow conduits directly into the bed space,
said access valve being adjustable between a closed
condition in which said conduits are isolated from the
bed space and an open condition in which said conduits
are open to the bed space;
said access valve being adjusted in the process to
the open position whereupon said second fluid flow
conduit provides the clearing outlet and a said clearing
flow of fluid is introduced through the first fluid flow
conduit.



26


7. A separation process as claimed in claim 1 in which
the column housing has an inlet-side restricted-
permeability element and said flowing comprises pumping
liquid medium through the inlet-side restricted-
permeability element to expand the bed, and an inlet-side
access valve movable between open and closed conditions
is provided to communicate directly with the bed space, a
material containing said target component being
introduced directly into the bed space through said
inlet-side access valve in its open condition.

8. A separation process as defined in claim 7 in which
said material comprises an unclarified or partially-
clarified culture broth, and the target component is a
protein product in the culture broth.

9. A separation process as claimed in claim 7 in which
the inlet-side access valve opens at the centre of the
inlet-side restricted permeability element.

Description

Note: Descriptions are shown in the official language in which they were submitted.


., v ,
CA 02362108 2001-11-16
ACCESS VALVE DEVICES, THEIR USE IN SEPARATION APPARATUS,
AND CORRESPONDING METHODS
FIELD OF THE INVENTION
This specification relates to methods and apparatus
for_ the control of fluid flow, e.g in chromatography, i.e.
apparatus and methods for separating substances by passing
a mobile phase through a stationary or retained phase to
cause separation of mobile phase components.
BACKGROUND
Chromatography is a well-established and valuable
technique in both preparative and analytical work as well
as in purification generally. Typical industrial
chromatography apparatus has an upright housing in which a
bed of packing material, usually particulate, rests
against a permeable retaining layer. Fluid mobile phase
enters through an inlet e.g at the top of the column,
usually through a porous, perforated, mesh or other
restricted-permeability layer, moves through the packing
bed and is taken out at an outlet, typically below a
restricted-permeability layer.
Changing the bed of packing material, because it is
spent or in order to run a different process, is an
arduous task particularly with big industrial columns
which can be hundreds of litres in volume. The existing
bed has usually become compacted and difficult to remove.
The housing must be dismantled, the compacted pac~;ing mass
disrupted and then removed. Furthermore, the new bed must
be very evenly packed if the column is to be effective:

CA 02362108 2001-11-16
2
the fresh material must be added carefully while
maintaining a flow of liquid. Usually the apparatus must be
kept clean, particularly with biological products where
high system sterility may be needed for weeks or even
months. One small contamination can be disastrous.
Conventionally, many hours have been needed to
change the spent packing in a big column.
GB-A-2258415 describes a column which can be
packed and unpacked without taking it apart, using special
supply and discharge valves in the top and bottom plates of
the housing. The packing supply valve has a spray nozzle
which can be retracted into the top plate, with the spray
openings closed by a seal on the plate, or advanced to
project into the column bed space, freeing the openings for
a slurry of packing material to be pumped in. The discharge
valve has an advanceable nozzle with radially-directed
spray openings at its enlarged head, positioned coaxially
within a wider bore of the bottom plate. When retracted the
head fits in the bore to seal itself and the bore. To empty
the column, the nozzle is advanced and buffer liquid pumped
through it. The advanced nozzle head breaks up the packed
medium and the pumped-in buffer carries it out through the
larger bore, now opened.
There are difficulties in maintaining long-term
sanitary conditions with these valve assemblies.

CA 02362108 2001-11-16
3
THE INVENTION
The process is a separation process in which a
liquid incorporating components to be separated is caused
to flow upwardly through a bed of particulate stationary
phase (packing medium) enclosed in a bed space of a column
housing, for example at a rate which expands or fluidises
the bed. After passing through the bed the liquid passes a
restricted-permeability element (typically a mesh, or a
porous or other perforated layer which will retain the
packing medium particles) and out of the column housing
through a process outlet.
Preferably, the liquid may incorporate parti
culate or cohesive matter which will not pass, or not
freely pass, the restricted-permeability element.
Biological culture products are an important example of
this. For instance, expanded bed separation is used to
remove a target protein, by adsorption onto the bed
particles, from an unclarified or partially-clarified
culture broth containing cells, cell debris, lipid
particles and/or the like.
As separation proceeds, such materials accumulate
against the restricted-permeability element used to prevent
escape of packing material through the process outlet. In
time, the accumulated matter prevents effective operation.
Processing must be stopped, the column housing opened and
the accumulated matter cleared before restarting.

CA 02362108 2001-11-16'
4
Our proposal is to remove such accumulated matter
from the bed space, e.g. from time to time as the process
proceeds, and optionally without cutting off the input of
feed stock liquid.
According to the present invention, there is
provided a separation process for separating a target
component from a liquid incorporating the target component
with other components, the separation process comprising:
providing a bed of particulate packing medium, said
medium being adapted to retain the target component and
said bed thereof being enclosed in a bed space defined by
a column housing, said housing having a process outlet
and a restricted permeability element between the process
outlet and bed space to retain the particulate packing
medium in the bed space;
flowing liquid upwardly through the bed of
particulate packing medium, through the restricted-
permeability element and through the process outlet, to
expand the bed in the bed space and effect separation of
the target component from the liquid through retention by
the particulate packing medium
said other components of the liquid comprising
particulate matter, said particulate matter accumulating
against the restricted-permeability element during the
flowing of the liquid, and the process further comprising
opening a clearing outlet communicating directly
with the bed space, at or adjacent the restricted-
permeability element, and
forcing a clearing flow of fluid relative to the

CA 02362108 2005-04-15
restricted permeability element to disturb the
particulate matter which has accumulated against it, and
causing said matter to pass out ~of the bed space through
the clearing outlet.
So, the separation process may continue with
reduced or eliminated interruptions for clearance of
accumulated matter from the bed space.
Preferably, the clearing flow may be provided by
forcing a reverse flow through the restricted-permeability
element, e.g. back through the process outlet, or through
other conduits penetrating the impermeable wall behind the
restricted-permeability element. Additionally or alternati-
vely the clearing flow may come through one or more nozzles
on the bed space side of the element by pumping fluid out
of them e.g. at the centre of the element, and desirably
with a clearing flow radiating from a conduit penetrating
the housing wall.
20 According to the present invention, there is
provided a separation process for separating a target
component from a liquid incorporating the target component
with other components, the separation process comprising:
providing a bed of particulate packing medium, said
medium being adapted to retain the target component and
said bed thereof being'enclosed in a bed space defined by
a column housing, said housing having a process inlet, an
inlet-side restricted-permeability element separating the
bed space from the process inlet, a process outlet, an
outlet-side restricted-permeability element separating

CA 02362108 2005-04-15
6
the bed space from the process outlet, said restricted-
permeability elements retaining the~particulate packing
medium in the bed space;
introducing a flow of liquid through the process
inlet and upwardly through the inlet-side restricted-
permeability element, through the bed of particulate
packing medium to expand the bed in the bed space,
through the outlet-side restricted-permeability element
and through the process outlet, and
introducing a mobile phase material containing the
target component directly into the bed space through a
valued input opening.
Preferably, introduction is through an access
valve device opening through the restricted-permeability
element.
In this way a mobile phase incorporating
particulate matter, or other matter which might clog the
restricted-permeability element, can be introduced conve-
niently into the bed for processing.
By combining the above proposals, the introduced
particulate or other matter can then conveniently be
cleared from the bed space.

CA 02362108 2001-11-16
7
BRIEF DESCRIPTION OF THE DRAWINGS
Embodiments of our proposal are now described in
detail, with reference to the accompanying drawings in
which:
Figure 1 is a cross-sectional schematic side view
of a chromatography column showing the basic features
thereof;
Figure 2 is an axial cross-section showing an end
plate construction in more detail;
Figure 3 shows enlarged, in axial cross-section,
the construction of an access valve;

CA 02362108 2001-11-16
8
Figure 4 is an axial cross-section corresponding to
Fig. 2 with the access valve in a part-open position;
Figure 5 is an axial cross-section corresponding to
Fig. 2 but with the access valve in a fully-open position;
Figure 6 is an axial cross-section of the end plate
illustrating a medium packing operation;
Figure 7 is a view corresponding to Fig. 6, with the
column in operation and the access valve being cleaned;
Figure 8 is an axial cross-section corresponding to
Fig. 6 illustrating the process of unpacking a packing
medium f rom the column;
Figure 9 is an axial cross-section of the top end
plate of a chromatography column undergoing expanded-bed
chromatography, illustrating a clearing operation;
Figure 10 is an axial cross-section of a column end
which is a variant of that in Figs 2 to 8; and
Figure 11 is a schematic view of a second version of
the access valve.
DETAILED DESCRIPTION OF EMBODIMENTS
Figure 1 shows schematically the general components
of a chromatography column The column has a
cylindrical fluid-impermeable side wall 11, e.g. of
stainless steel or a high-strength/reinforced polymeric
material which may be translucent. The open top and
bottom ends of the side wall 11 are closed by top and
bottom end assemblies 12,13. Each end assembly has a
fluid-impermeable end plate 3 fitting sealingly to plug
the opening of the cylindrical wall 11, and preferably of

CA 02362108 2001-11-16
9
stainless steel or high-strength engineering plastics
material, e.g polypropylene. The end plates are backed up
by metal retaining plates 2 bearing against their outer
surfaces and projecting radially beyond the side wall as
retaining flanges 22 through which adjustable tension rods
14 are secured. These link the top and end assemblies
12,13 and help the construction to withstand high fluid
pressures.
Each end plate 3 has a central through-opening 31 for
communication between the exterior of the column and the
packing bed space 9 defined by the side wall 11 and end
assemblies 12, 13. Access through the opening 31 is sub-
divided into separate conduits, connected externally
through a connection manifold 8.
A filter layer 4, typically of filtered or woven
plastics or steel, extends across the area of the bed
space 9 at the inner surface of the end plate 3. The
inner surface 35 of the end plate 3 is recessed behind the
filter layer 4, e.g. conically as illustrated, and
preferably with the use of support ribs (not indicated)
supporting the filter layer 4 from behind, to define
between them a filtration space 34. One of the
conununication conduits, a mobile phase conduit 33, opens
inwardly into this filtration space 34, as well as
outwardly to a mobile phase connector 81 of the manifold
2~ 8.
From the manifold 8, an access valve device 5
projects inwardly through the end plate opening 31 and

CA 02362108 2001-11-16
1
sealingly through a central orifice 41 of the filter layer
4. The access valve 5, embodiments of which are described
in more detail below, governs the communication of one or
more conduits from the manifold 8 directly to the bed
space 9, i.e. bypassing the filter layer 4. Indicated
here are first and second valued conduits 51, 61 governed
by the valve 5, and connected externally through
connectors 82 of the manifold 8.
In a typical operation of the column, a packed bed of
particulate stationary phase material fills the bed space
9 between the top and bottom filter layers 4. The valve
devices 5 being closed, a mobile phase is fed in through
mobile phase connector 81 (arrow "A"), passes through
conduit 33 into the filtration space 34 and through the
filter layer 4 to elute down through the packed bed,
effecting separation of its components. Liquid eluate
passes thought the filter layer 4 of the bottom end
assembly 13 and out through the mobile phase connector 81
thereof (arrow "B") for collection as appropriate.
Figure 1 and the above explanation are to illustrate
general relationships of components and a typical mode of
operation. The skilled person knows, and it will also
appear from the following description, that other specific
constructions and modes of operation may be appropriate
for different kinds of process.
A more detailed embodiment of an end plate and valve
construction is now described with reference to Figures 2
and 3.

CA 02362108 2001-11-16
11
A manifold 8 is provided as a machined metal or
plastics block fired sealingly over the central opening 31
of the end plate 3 by threaded connectors 88, and recessed
into a central aperture 23 of an outer metal retaining
plate 2 which is fixed to the end plate 3 by bolts 21 or
other suitable fasteners. The periphery of the end plate
3 seals against the column side wall 11 with an annular
polymeric seal member 32 which also overlaps the filter
layer 4 to retain its periphery. This seal member may
have an internal rigid reinforcement. Unlike a
conventional O-ring it eliminates dead space by sealing
with a cylindrical surface and mounting in a shape-fitting
groove of the end plate.
The manifold 8 has a central bore 91 coaxial with the
plate opening 31 and having inwardly and outwardly
directed threaded connection openings 83, 89. The
cylindrical barrel 6 of a spool valve S is screwed into
the inward connection 83, to extend coaxially inwardly
through the central plate opening 31 and out through a
central circular orifice 41 of the filter layer 4,
terminating in an outward flange 65 which overlaps the
filter layer 4. A cylindrical outer sleeve 66 fits snugly
around the barrel 6, its outward edge resting against the
inward face of the manifold block through a polymeric
sealing ring 662 and its inner edge resting against the
outer surface of the filter layer 4 through another
polymeric sealing ring 661, trapping the layer 4 between
the sleeve 66 and barrel flange 65. Since the barrel's

CA 02362108 2001-11-16
12
outer diameter corresponds to that of the layer orifice
41, it is possible in the illustrated condition to remove
the barrel by unscrewing it and withdrawing it inwardly,
without disturbing the filter layer 4. This is an
advantage for column maintenance.
One or more flow conduits 33 are created by clearance
between the barrel assembly (barrel and sleeve) and the
plate opening 31. Thus, the plate opening 31 may have a
plurality of axially-extending channels distributed around
it to form the conduits 33, intervening surfaces of the
opening 31 fitting against the barrel assembly. Or, a
full annular clearance may be provided. Or, these
conduits may be provided away from the barrel assembly,
defined only through the material of the plate 3. The
inner ends of the conduits 33 communicate into the
filtration space 34. Their outer ends align sealingly (by
virtue of polymeric sealing rings 662,663) with connection
conduits 811 of the manifold block, connected in common to
a threaded or otherwise connectable port 81. This
establishes direct fluid communication between filtration
space 34 and the port 81, while communication between the
bed space 9 and port 81 is necessarily through the filter
layer 4. Ribs provided on the inner plate surface 35 (in
known manner) assist even distribution or collection of
fluid to or from the space 34.
A bore 61 extends axially through the barrel 6 from
one end to the other. The bore's outward end merges
sealingly (by polymeric sealing ring 664) and without

CA 02362108 2001-11-16
13
change of diameter into the central manifold bore 91. The
inward end of the bore 6 is on the bed space side of the
filter layer 4, and constitutes a mouth opening 611. The
bore 61 has a uniform cylindrical cross-section except for
a radially-enlarged portion near but outward of the mouth
611. The enlarged portion 612 has a central cylindrical
part bordered on either side by tapering surfaces 613.
These are angled at not more than 45" from axial.
A central probe element acts in the bore 61, to
give the function of a spool valve. The probe element
has an elongate tube 72 with an open internal bore 73,
extending axially from adjacent the barrel mouth 611 out
through the outward end of the barrel 6 and the coaxial
ball 91 of the manifold 8. Outwardly of_ the outer barrel
end, a tapered sealing ring 665 seals between the tube 72
and surrounding manifold bore 91: a plug collar 87 is
screwed into the outer connection 89 of the manifold to
hold the tapered seal 665 effectively in place.
At its inward end, the probe has a solid head 71
with a pointed tip 74, terminating the bore 73. The head
71 has a cylindrical sealing surface 711, of the same
diameter as the barrel bore 61, and which as shown can
seal against an inward sealing surface 64 at the mouth 611
of the barrel bore 61, assisted by a flush-recessed
polymeric sealing ring 641.
The probe bore 73 opens at a set (Fig. 4) of spray
openings 75 opening through and distributed
circurnferentially around the tube 72. The tip sealing

CA 02362108 2001-11-16
14
surface 711 stands radially proud of these openings 75.
Immediately outwardly of the openings the probe head 71
has another radially-enlarged portion or land 76 which
presentsla cylindrical sealing surface 761 bordered by
tapering portions 762 angled at not more than 45" from the
axial.
Outwardly of this second enlargement 76 the tube
exterior 72 is a plain cylinder.
The diameter of the sealing surface 761 on the second
enlargement 76 is the same as that 711 on the first
enlargement 71.
The tube 72 being narrower than the barrel ball 61,
an annular-section clearance 51 is defined between them.
This constitutes an outer valve conduit extending out
through the outer end of the barrel 6 into the manifold
bore 91 up to the seal 665, where it diverts to a threaded
or otherwise connectable manifold port 82.
Beyond the manifold 8, the outer end of the probe
tube 72 is connected to means for advancing or retracting
it axially relative to the barrel 6, with sliding through
the seal 665. These means may be motor or servo
activated, e.g. advancing the probe by rotating a fixed
drive member which engages the tube 72 via a screw thread,
e.g. as proposed in GB-A-2258415. Additionally or
alternatively, a manual control is provided for. the axial
adj us tmen t .
The spool valve effect of the valve 5 is as follows.
Figs 2 and 3 show a first, closed condition in which.

CA 02362108 2001-11-16
the head sealing land 711 seals with the mouth sealing
surface 64 of the barrel, isolating both the valve
conduits 51, 73 from the bed space 9. The filtration
conduits 33 are not affected by the valve. The nozzle
openings 75 and the second sealing land 76 register
5 axially with the radially-enlarged portion 612 of t:he
barrel bore 61. This puts the nozzle openings 75 into
communication with the outer valve conduit 51, creating a
continuous sealingly-enclosed flow path between the probe
tube bore 73 and the manifold port 82. This path has no
10 unswept areas or dead spaces. Within the valve device 5,
none of its boundary surfaces deviates from the local
central flow axis/layer by more than 45°, assisting
effective sweeping. In the manifold the path likewise has
no dead ends.
15 Consequently, when the chromatography column is
running (see also Fig. 7) the valve device and its
associated connections can be cleaned in place by.feeding
a cleaning solution (e. g. aqueous alkali, or other
suitable cleaning medium known to the art) through that
fully-sweepable cleaning path. It is particularly
envisaged to feed the cleaning solution in through the
probe tube 72.
Figure 4 illustrates a second, partially-open
condition of the valve 5. The probe tube 72 is advanced
sufficiently to bring the second sealing land 76 into
register with the bore mouth 611, where their respective
sealing surfaces 761, 64 effect a sliding seal. This also

CA 02362108 2001-11-16
16
brings the nozzle openings 75 to outside the mouth 611,
communicating with the bed space 9. Accordingly the inner
valve conduit constituted by the bore 73 is put into
direct communication with the bed space, bypassing the
filter layer 4, while the outer valve conduit 51 remains
isolated from the bed space 9.
Figure 6 illustrates an application of this in
creating a new bed of packing material. The packing
itself can be as described in GB-A-2258415. Specifically
a flowable flurry of packing material particles in carrier
liquid is pumped in through the tube 72 and sprays out
radially in circumferentially-distributed directions from
the openings 75. As packing material accumulates in the
bed space 9 excess carrier fluid escapes through the
filter layer 4 and away through the filtration conduits 33
and manifold port 81, to which a connecting tube is
fastened. This is continued until sufficient packing
material has been introduced.
Figure 5 illustrates a third condition of the valve.
Here the probe tube 72 has been advanced further inwardly
to bring the second sealing land 76 clear of the mouth
seal 64, which now opposes the smaller-diameter outer
surface of the tube 72 to create a clearance, opening the
outer valve conduit 51 to the bed space 9 through the
mouth 611.
Figure 8 shows how to exploit this third condition to
unpack material from a column bed. It should be noted
that, as disclosed in GB-A-2258415, the advanced pointed

CA 02362108 2001-11-16
17
head 71 of the probe is apt to disrupt existing bed
material, which is often a hard compacted mass, and
thereby help to initiate unpacking. A carrier liquid such
as a buffer is pumped in through the probe bore 73 and out
through the nozzle openings 75; its high nozzle velocity
helps to disrupt and entrain the packed material. The
particulate packing material cannot pass the filter layer
4, but it can respond to the pumping in of liquid by
escaping as a slurry through the mouth 611 of the valve
and along the outer valve conduit 51 to the manifold port
82 for discharge along a connected tube.
So, for the first time a single column wall
installation enables both packing and unpacking of a
column. This can give much greater flexibility in column
operation. Note that the packing and unpacking operations
can be effected entirely from outside the column housing,
without needing to dismantle or remove the end assemblies.
Furthermore the valve which can do this can itself'be
cleaned in place, even when the column is running by
introducing a mobile phase onto the bed through the
filtration conduits 33 as shown in Fig. 7. So, even this
relatively sophisticated wall installation does not
introduce a risk of contaminants accumulating and
leaching into a long-running process perhaps with
disastrous results. In the terminology of the skilled
person in this field, this valve device is a "sanitary"
installation.
Furthermore the valve is easily dismantled for

CA 02362108 2001-11-16
18
maintenance because the probe can be entirely withdrawn
inwardly from the barrel bore 61.
Further modes of use, in relation to expanded-bed
separation processes, are explained with reference to
Figs. 9 and 10. Expanded bed adsorption is a recently-
developed separation technique, particularly for reducing
or eliminating the need to clarify biological cultures
before eluting them through a packing to separate out a
desired component',. The packing bed is expanded by an
upflow of liquid medium so that even particulate material
in the sample can~,work its way through the bed to the
outlet above the bed. For expansion the bed must rest on
a permeable layer' through which the liquid up-flow is
established. Introduction of the sample must therefore
generally be done'. as a single pass, which sample batch
then elutes through the bed. Usually desired materials
are adsorbed onto. the bed particles, and in a subsequent
step are recovered by stopping the liquid up-flow~
compressing the bed by moving down the upper plate and
then percolating through the bed a liquid that desorbs the
target substance from the bed particles.
A column for this can have top and bottom retaining
assemblies which each have an impermeable plate interior
filter layer and a central valve device as shown in the
previous Figures. The normal filtration conduits and
means for establishing up-flow of a mobile phase are also
provided.
A first feature here is that a sample e.g.

CA 02362108 2001-11-16
19
unclarified broth, can conveniently be introduced into the
expanded bed, bypassing the lower filter mesh, by
injecting it though the inner valve conduit 73 of the
lower valve in its second, partially open condition.
Where sample is injected intermittently the lower valve is
returned to its fully-closed first condition in between.
Our new valve construction therefore provides a convenient
way of introducing such a sample past a mesh required for
maintaining an up-flow.
A second and very significant feature is explained in
relation to Fig. 9, which shows in more detail a top end
assembly for the expanded-bed process.
During normal running of the process the mobile phase
passes through the filter layer 4', through the filtration
conduits 33' and out. There is a gradual accumulation of
particulate debris and other matter reluctant to pass the
filter 4', e.g. lipids. This therefore accumulates in an
upper bed space region 91 adjacent to filter layer 4'. In
time it hinders the maintenance of proper flow.
By moving the upper valve device 5' to its third,
fully-open condition for a short period of time, while
creating a clearing flow of liquid adjacent the filter
layer 4' to disturb the accumulated matter, this matter
can be caused to follow the clearing flow out of the bed
space via the outer valve conduit 51. One method of
achieving a clearing flow is to provide a short blast of
suitable liquid, e.g. a buffer, through the probe bore 73'
and out through the nozzle openings 75' which are near the

CA 02362108 2001-11-16
filter layer 4'. Alternatively or additionally, the
normal flow direction (arrow "X") of buffer out of the
system can temporarily be reversed and buffer pumped back
in through the filtration conduits 33' (arrow "Y").
thereby creating a temporarily downward flow through the
S filter layer 4' (arrow "Z"), disrupting the accumulated
material so that it can accompany the escape of the
temporary liquid pressure wave out through the valve
conduit 51. This may be done either with or without cut-
off of the supply of sample at the bottom of the column.
Thus, the process can be run as long as the
absorption proceeds efficiently, without needing to stop
for other reasons. This is a highly advantageous
procedure.
Fig 10 shows a variant end plate construction for a
15 chromatography column. The differences from the previous
embodiment include the following.
The filter layer 4 is formed integrally with.inner
and outer annuli 41,42, in one piece in plastics material.
The inner annulus 41 forms a flush termination for the
20 barrel 6 of the central valve 5, and has an inwardly-
facing surface to form the seal with the valve's central
probe_ This flush one-piece construction further reduces
the risk of contamination at the point of access. It also
enables the filter layer's inner periphery to self-trap in
2; a groove of the valve barrel 6, enabling that barrel 6 to
be one component rather than two. The end cell and valve
components may be of polypropylene.

CA 02362108 2001-11-16
21
The filter layer's outer annulus 42 is used to hold
the filter layer in place by trapping between the wall 11
of the column and the end plate 3 of the cell, which in
this version is a one-piece polypropylene construction.
The connection manifold 8 has the mobile phase
inlet/outlet port S1 and the waste slurry outlet port 82
inclined outwardly, rather than perpendicularly as in the
previous embodiment, to improve flow. A further
significant feature in this embodiment is that the filter
layer 4 is concave, by virtue of the support ribs on the
end plate 3 being formed with inclined rather than
slightly radial edges. We find that this slight conicity
improves drainage from the column during clearing.
Fig 11 shows schematically a different embodiment
valve which however embodies similar concepts. Here the
central movable probe is a simple armature rather than a
fluid-carrying nozzle. Its enlarged head 171 is carried
on actuating rod 272 and has a flat end surface 17J.2, a
first outer sealing land 1711, a conical convergence 1613
to a narrow recess or waist 1612, and a smaller
enlargement 176 with a second sealing surface 1761.
The mobile phase conduit 33 is provide outside the
valve barrel 6 as before. Inside the valve barrel the
central fluid conduit 173 is defined not through the probe
272,171 but rather by an inner conduit wall 172
surrounding the probe shaft 272 and having an opening with
an inwardly-directed seal 174, recessed back from r_he main
opening through the filter layer 4, which has its own

CA 02362108 2001-11-16
2z
inwardly-directed seal 141 at the mouth of the.oucer
conduit defined between the outer barrel wall 6 and the
inner conduit wall 172.
Fig'11 shows the valve fully open, with the central
probe fully advanced to open both conduits e.g for
unpacking and column. Unpacking liquid is pumped in
through the inner conduit 173 and squirts out around the
armature head 171; waste slurry flows back and out through
the outer conduit.
In the partially open position, e.g for packing a
column, the armature is partially retracted so that second
sealing surface 1761 seals off the inner conduit, the
outer conduit remaining open. Slurry can be pumped in
through the outer conduit. This shears the slurry less
than the spray nozzle of the first embodiment.
Full retraction of the armature brings its front
surface 1712 flush with the filter layer 4 and its first
head sealing surface 1711 into sealing engagement~with the
central filter opening seal 141, closing off the outer
conduit. At the same time the second sealing land 176
drops below the inner conduit seal 174 which then opposes
the recess 1612 to permit a circulating, clean-in-place
flow through the inner and outer conduits.
Note that in the open conditions the conical portion
1613 of the head 171 can be axially adjusted to alter the
direction of liquid pumped in. This embodiment
illustrates how two separate seals on the fixed part of
the valve can provide the same effect as previously if

CA 02362108 2001-11-16
23
their spacing is different from that of the corresponding
sealing portions of the movable part.

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date 2006-12-05
(22) Filed 1995-10-03
(41) Open to Public Inspection 1996-04-11
Examination Requested 2001-11-16
(45) Issued 2006-12-05
Expired 2015-10-05

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Request for Examination $400.00 2001-11-16
Registration of a document - section 124 $50.00 2001-11-16
Registration of a document - section 124 $50.00 2001-11-16
Application Fee $300.00 2001-11-16
Maintenance Fee - Application - New Act 2 1997-10-03 $100.00 2001-11-16
Maintenance Fee - Application - New Act 3 1998-10-05 $100.00 2001-11-16
Maintenance Fee - Application - New Act 4 1999-10-04 $100.00 2001-11-16
Maintenance Fee - Application - New Act 5 2000-10-03 $150.00 2001-11-16
Maintenance Fee - Application - New Act 6 2001-10-03 $150.00 2001-11-16
Maintenance Fee - Application - New Act 7 2002-10-03 $150.00 2002-09-26
Maintenance Fee - Application - New Act 8 2003-10-03 $150.00 2003-09-25
Registration of a document - section 124 $100.00 2004-04-14
Maintenance Fee - Application - New Act 9 2004-10-04 $200.00 2004-09-22
Maintenance Fee - Application - New Act 10 2005-10-03 $250.00 2005-09-22
Registration of a document - section 124 $100.00 2006-04-03
Final Fee $300.00 2006-08-07
Maintenance Fee - Application - New Act 11 2006-10-03 $250.00 2006-09-20
Maintenance Fee - Patent - New Act 12 2007-10-03 $250.00 2007-09-17
Maintenance Fee - Patent - New Act 13 2008-10-03 $250.00 2008-09-17
Maintenance Fee - Patent - New Act 14 2009-10-05 $250.00 2009-09-18
Maintenance Fee - Patent - New Act 15 2010-10-04 $450.00 2010-09-17
Maintenance Fee - Patent - New Act 16 2011-10-03 $450.00 2011-09-19
Maintenance Fee - Patent - New Act 17 2012-10-03 $450.00 2012-09-17
Maintenance Fee - Patent - New Act 18 2013-10-03 $450.00 2013-09-17
Maintenance Fee - Patent - New Act 19 2014-10-03 $450.00 2014-09-29
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
GE HEALTHCARE BIO-SCIENCES AB
Past Owners on Record
AMERSHAM BIOSCIENCES AKTIEBOLAG
AMERSHAM PHARMACIA BIOTECH AB
DAVIS, JOHN
EUROFLOW (UK) LIMITED
HOFMANN, MARTIN JOHN
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
Documents

To view selected files, please enter reCAPTCHA code :



To view images, click a link in the Document Description column. To download the documents, select one or more checkboxes in the first column and then click the "Download Selected in PDF format (Zip Archive)" or the "Download Selected as Single PDF" button.

List of published and non-published patent-specific documents on the CPD .

If you have any difficulty accessing content, you can call the Client Service Centre at 1-866-997-1936 or send them an e-mail at CIPO Client Service Centre.


Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Claims 2001-11-16 4 150
Abstract 2001-11-16 1 25
Description 2001-11-16 23 841
Drawings 2001-11-16 10 356
Representative Drawing 2002-01-11 1 9
Cover Page 2002-02-15 1 43
Claims 2005-04-15 3 104
Description 2005-04-15 23 840
Representative Drawing 2006-11-08 1 10
Cover Page 2006-11-08 2 47
Assignment 2006-04-03 7 637
Correspondence 2001-11-29 1 42
Assignment 2001-11-16 3 113
Correspondence 2002-01-07 1 13
Correspondence 2002-01-17 2 106
Correspondence 2002-02-14 1 42
Assignment 2002-02-01 2 50
Correspondence 2002-03-20 1 13
Fees 2002-09-26 1 32
Assignment 2004-04-14 4 178
Prosecution-Amendment 2004-11-02 2 58
Prosecution-Amendment 2005-04-15 5 144
Correspondence 2006-08-07 1 31
Assignment 2006-08-03 3 75
Correspondence 2006-09-15 1 2
Assignment 2006-10-23 1 32
Correspondence 2006-11-21 1 2
Assignment 2006-12-01 3 89
Correspondence 2010-08-10 1 49