Patent Description:
The present invention relates to multi-column chromatography systems and, more specifically, to multi-column chromatography systems having rotational valve assemblies embedded within a panel for controlling fluid flow throughout the system.

Column chromatography systems are used in the separation of mixtures. For example, a feed stream that comprises a variety of different types of molecules can be flowed down through a chromatography column. A matrix housed within the column is specifically engineered to capture or slow the flow a particular molecule of interest while the remainder of the mixture can more freely flow through and out of the column. For example, the matrix can be a resin or type of filter. Once the molecule of interest has been captured within the column and the remainder of the mixture removed, an eluting fluid can be passed down the column which releases the molecule of interest from the matrix. The molecule of interest then flows out of the column for collection and subsequent processing. In some embodiments, a washing fluid followed by a regeneration fluid can then be passed down through the column so as to restore the original properties of the matrix which can then again be used to collect the molecule of interest from a feed stream.

Multi-column chromatography systems are designed to enable a continuous processing of the feed stream. For example, once a first column is filled with a molecule of interest, the feed stream is then transferred to a second column and then to subsequent other columns as needed. While the feed stream is being delivered to the other columns, the first column can be eluted, washed and restored. Once the first column is restored, the feed stream can then be returned to the first column. The same circular process is also performed with the other columns. Accordingly, as a result of using a multi-column system, the rate of processing of the feed stream is increased, relative to the use of a single column, because there is no downtime in processing of the feed stream.

Although multi-column chromatography systems are effective, they have a number of shortcomings. For example, multi-column chromatography systems can be very complex. Specifically, to ensure proper fluid flow into and out of each column, it is not uncommon for a large scale, multi-column chromatography system to be formed from over a hundred different tubes that are interconnected in a complex layout. In addition, each tube has a separate pinch valve mounted thereon for controlling the flow of fluid through the tube. Such systems are expensive to build, control, operate, and maintain.

Furthermore, such systems typically have a relatively large void volume. The void volume includes the volume insides the tubes and other conduits that are used to transfer fluids to, from, and between the columns. Having a large void volume can make it difficult to process smaller quantities of a feed stream and can result in larger waste of unprocessed or uncollected fluids that remain with the void volume of the tubing and conduits.

In addition, the operation of multi-column chromatography systems relies heavily on the use of sensors to determine when to switch between different fluid flows and when to switch flows to different locations. Such sensors can change depending on the feed source and the molecule of interest to be collected. In conventional systems, it can be difficult or impossible to switch out or replace sensors. Furthermore, the sensors are often positioned remote from the chromatography columns. As such, there can be a significant delay in determining properties of the fluid flowing out of the chromatography columns which can reduce performance and delay optimal switching between columns. A multi-column chromatography system is known from <CIT>.

Accordingly, what is needed in the art are multi-column chromatography systems that solve all or some of the above-identified shortcoming or other deficiencies know in the art.

According to independent claim <NUM>, a chromatography system includes:.

In an alternative embodiment, the first valve is rotatably disposed within the first cavity, and wherein rotating the first valve to different positions produces isolated fluid communication between the inlet fluid channel and each of the plurality of first outlet fluid channels.

In another embodiment, the first plate has a bottom surface and the second plate has a top surface, an elongated channel groove being recessed into the bottom surface of the first plate or the top surface of the second plate, the channel groove comprising at least a portion of the inlet fluid channel.

In another embodiment, the first plate and the second plate are secured together by an adhesive or welding.

In another embodiment, a gasket disposed between the first plate and the second plate, the gasket at least partially bounding the inlet fluid channel.

In another embodiment, the panel is comprised of a polymer and has a thickness of at least <NUM>, <NUM>, <NUM>, <NUM>, or <NUM>.

In another embodiment, the panel is sufficiently rigid that it cannot bend over an angle of at least <NUM>°, <NUM>°, or <NUM>° without plastic deformation.

In another embodiment, the panel comprises a first plate overlying and being secured to a second plate, each of the plurality of first outlet fluid channels being at least partially bounded between the first plate and the second plate.

In another embodiment, the panel comprises a first plate, a second plate, and a third plate secured together, the second plate being sandwiched between the first plate and the third plate.

In another embodiment, at least one of the plurality of first outlet fluid channels is at least partially bound between the first plate and the second plate and wherein the inlet fluid channel is at least partially bounded between the second plate and the third plate.

In another embodiment, the inlet fluid channel passes through the second plate so as to communicate with the first plate and the second plate.

In another embodiment, a second valve is rotatably disposed within the second cavity.

In another embodiment, the first one of the plurality of chromatography columns houses a matrix that is designed for capturing a molecule of interest, the inlet fluid channel being in communication with:.

In another embodiment, an actuator is coupled with the first valve, the actuator being configured to selectively move the first valve.

In another embodiment, an actuator is coupled with the first valve, the actuator being configured to selectively rotate the first valve.

In another embodiment, the actuator is further configured to selectively depress and release the first valve.

In another embodiment, a central processing unit (CPU) is in electrical communication with the actuator and is programmed to automatically control operation of the actuator.

In another embodiment, a sensor block is removably mounted on the panel and is in fluid communication with an outlet of the first one of the plurality of chromatography columns, the sensor block comprising one or more sensors configured to detect properties of a fluid.

In another embodiment, the sensor block comprises at least one of a conductivity sensor, ultraviolet light (UV) sensor, pressure sensor or temperature sensor.

In another embodiment, at least a portion of the first cavity extends entirely through the panel between the top face and the opposing bottom face.

In an example not forming part of the present invention, a chromatography system includes:.

In an alternative example not forming part of the present invention, the first valve is rotatably disposed within the first cavity, wherein rotating the first valve to different positions produces isolated fluid communication between the inlet fluid path and each of the plurality of first outlet fluid channels.

In another example not forming part of the present invention, the sensor block is removably received within a slot formed on the top surface of the panel.

In another example not forming part of the present invention, a connector is removably securing the sensor block the panel.

In another example not forming part of the present invention, the sensor block is in direct fluid communication with the inlet fluid channel bounded within the panel.

In another example not forming part of the present invention, the sensor block comprises at least one of a conductivity sensor, ultraviolet light (UV) sensor, pressure sensor or temperature sensor.

In another example not forming part of the present invention, the panel comprises a first plate overlying and being secured to a second plate, the inlet fluid channel being at least partially bounded between the first plate and the second plate.

In another example not forming part of the present invention, the panel comprises a first plate, a second plate, and a third plate secured together, the second plate being sandwiched between the first plate and the third plate.

In another example not forming part of the present invention, at least one of the plurality of first outlet fluid channels is at least partially bound between the first plate and the second plate and wherein the inlet fluid channel is at least partially bounded between the second plate and the third plate.

Another example not forming part of the present invention further includes:.

Another example not forming part of the present invention, further includes:.

Various embodiments of the present invention will now be discussed with reference to the appended drawings.

Before describing the present disclosure in detail, it is to be understood that this disclosure is not limited to particularly exemplified apparatus, systems, methods, or process parameters that may, of course, vary. It is also to be understood that the terminology used herein is only for the purpose of describing particular embodiments of the present disclosure and is not intended to limit the scope of the disclosure in any manner.

The term "comprising" which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

It will be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a "partition" includes one, two, or more partitions.

As used in the specification and appended claims, directional terms, such as "top," "bottom," "left," "right," "up," "down," "upper," "lower," "proximal," "distal" and the like are used herein solely to indicate relative directions and are not otherwise intended to limit the scope of the disclosure or claims.

Where possible, like numbering of elements have been used in various figures. Furthermore, multiple instances of an element and or sub-elements of a parent element may each include separate letters appended to the element number. For example, two instances of a particular element "<NUM>" or two alternative embodiments of a particular element may be labeled as "10a" and "10b". In that case, the element label may be used without an appended letter (e.g., "<NUM>") to generally refer to all instances of the element or any one of the elements. Element labels including an appended letter (e.g., "10a") can be used to refer to a specific instance of the element or to distinguish or draw attention to multiple uses of the element. Furthermore, an element label with an appended letter can be used to designate an alternative design, structure, function, implementation, and/or embodiment of an element or feature without an appended letter. Likewise, an element label with an appended letter can be used to indicate a sub-element of a parent element. For instance, an element "<NUM>" can comprise sub-elements or surfaces "12a" and "12b.

Various aspects of the present devices and systems may be illustrated by describing components that are coupled, attached, and/or joined together. As used herein, the terms "coupled", "attached", and/or "joined" are used to indicate either a direct connection between two components or, where appropriate, an indirect connection to one another through intervening or intermediate components. In contrast, when a component is referred to as being "directly coupled", "directly attached", and/or "directly joined" to another component, there are no intervening elements present. Furthermore, as used herein, the terms "connection," "connected," and the like do not necessarily imply direct contact between the two or more elements.

Various aspects of the present devices, systems, and methods may be illustrated with reference to one or more exemplary embodiments. As used herein, the term "embodiment" means "serving as an example, instance, or illustration," and should not necessarily be construed as preferred or advantageous over other embodiments disclosed herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure pertains. Although a number of methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, the preferred materials and methods are described herein.

Depicted in <FIG> and <FIG> are schematic drawings of a chromatography system <NUM> incorporating features of the present disclosure. In general, chromatography system <NUM> is designed to separate a mixture so as to isolate and collect a molecule(s) of interest from the mixture. <FIG> is a top plan view of chromatography system <NUM> while <FIG> is an elevated side view thereof. In general, chromatography system <NUM> comprises a stand <NUM> having an upper end <NUM> and an opposing lower end <NUM>. Secured to upper end <NUM> of stand <NUM> is a panel <NUM> having a top surface <NUM> and an opposing bottom surface <NUM>. In one embodiment, stand <NUM> comprises a tubular column having an interior surface <NUM> that bounds a channel <NUM> that extends at least partially along the length thereof. In this embodiment, stand <NUM> can centrally extend through panel <NUM> so that panel <NUM> radially outwardly projects from stand <NUM> to an annular perimeter edge <NUM>. Stand <NUM> can be configured to independently support panel <NUM> and can have an enlarged base <NUM> secured to lower end <NUM>. Base <NUM> can comprise an enlarged platform, a cart, or some other stabilizing structure. In alternative embodiments, stand <NUM> can comprise at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> spaced apart columns that connect to and support panel <NUM>. In such other embodiments, stand <NUM> or the columns thereof need not centrally extend through panel <NUM> but could be secured at perimeter edge <NUM> or at other locations of panel <NUM>. In the depicted embodiment, stand <NUM> is shown as being horizontally disposed. In alternative embodiments, stand <NUM> can be angled relative to horizontal and in other embodiments can vertically disposed, i.e., angled <NUM>° relative to horizontal.

Chromatography system <NUM> further comprises a plurality of chromatography columns <NUM>. In the depicted embodiment, the plurality of chromatography columns <NUM> comprises chromatography columns 30a, 30b, 30c, and 30d. In alternative embodiments, chromatography system <NUM> can comprise other numbers of chromatograph columns such as at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> separate chromatograph columns or in a range between any two of the foregoing numbers. Each chromatography column <NUM> has an upper end <NUM> where an inlet is located and an opposing lower end <NUM> where an outlet is located. Each chromatography column <NUM> also has an interior <NUM> in which a chromatography matrix <NUM> is disposed.

As is known in the art, chromatography matrix <NUM> can have a variety of different compositions and/or configuration and is selected or engineered for each use to capture or slow a molecule of interest from a mixture within a feed steam while the remainder of the feed stream can more freely pass through chromatography matrix <NUM>. By way of example and not by limitation, chromatography matrix <NUM> can comprise a resin or type of filter, such as a porous membrane, that are designed to bind the molecule of interest. In more specific embodiments, chromatography matrix <NUM> can comprise an ion exchange resin or membrane or a hydrophobic or hydrophilic resin or membrane. In alternative embodiments, as discussed further below, chromatography matrix <NUM> can be selected so that only the molecule of interest and a related carrier fluid can pass through column <NUM> while the remaining contaminates within the feed stream are retained within column <NUM>.

In one embodiment, each of chromatography column 30a-30d can comprise the same matrix <NUM>. In other embodiments, one or more of chromatography columns 30a-30d can have a different matrix <NUM> than the other columns. In one embodiment, chromatography columns 30a-30d are vertically orientated along a longitudinal axis and are disposed below panel <NUM>. More, specifically, chromatography columns 30a-30d can be disposed between panel <NUM> and base <NUM> and can be supported by panel <NUM>, stand <NUM> and/or base <NUM>. Although not required, in one embodiment, chromatography columns 30a-30d can be vertically aligned with perimeter edge <NUM> of panel <NUM> and be equally spaced apart around perimeter edge <NUM>.

With continued reference to <FIG>, chromatography system <NUM> further comprises a feed line <NUM>, a load waste line <NUM>, an elute/wash line <NUM>, a product line <NUM>, a regeneration line <NUM>, and a regeneration waste line <NUM>. Feed line <NUM>, elute/wash line <NUM> and regeneration line <NUM> are examples of delivery lines that deliver a fluid through panel <NUM> to a corresponding chromatography column <NUM>. In contrast, load waste line <NUM>, product line <NUM>, and regeneration waste line <NUM> are examples of return lines that receive a fluid from panel <NUM> after the fluid has passed through one or more of chromatography columns <NUM>.

Chromatography system <NUM> also comprises a plurality of fluid channels that are bound within panel <NUM> and a plurality of valve assemblies that are rotatably disposed on panel <NUM>. In part, the fluid channels function to: <NUM>) deliver fluid from a delivery line to a chromatography column <NUM>, <NUM>) transfer fluid between different chromatography columns <NUM>, and/or <NUM>) transfer fluid from a chromatography column <NUM> to a return line. The valve assemblies function to control the flow of fluid through the fluid channels. For example, as depicted in <FIG>, panel <NUM> comprises a first plate <NUM>, a second plate <NUM>, and a third plate <NUM> with second plate <NUM> being sandwiched between first plate <NUM> and third plate <NUM>. First plate <NUM> has top surface <NUM> and an opposing bottom surface <NUM>. Second plate <NUM> has a top surface <NUM> and an opposing bottom surface <NUM>. Likewise, third plate <NUM> has a top surface <NUM> and opposing bottom surface <NUM>. Although not required, in one embodiment, the top surface and bottom surface of each of plates <NUM>, <NUM>, and <NUM> are planar and are disposed in parallel alignment. Furthermore, each plate <NUM>, <NUM>, and <NUM> can have a thickness extending between corresponding top surface and bottom surface that is at least or less than. <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> or in a range between any two of the foregoing.

Each of the different plates can have the same thickness or a different thickness. In addition, the thickness of each plate can very, especially dependent upon surface features formed thereon. Plates <NUM>, <NUM>, and <NUM> are commonly made from a substantially rigid polymer, co-polymer, polymeric material, such as polycarbonate, Poly(methyl methacrylate), polypropylene, or polyvinylidene fluoride (PVDF). Other polymers can also be used. In one embodiment, a coating can be applied to the plates. For example, the plates can be coated with polytetrafluoroethylene (PTFE). Common polymers that are use are thermoplastics. In alternative embodiments, other materials can be used such as glass, metal, or composites. It is commonly desired to form plates <NUM>, <NUM>, and <NUM> from a translucent material so that the flow of fluid through the fluid channels bound therein can be easily inspected. However, opaque materials can also be used, such as for processing liquids that are light sensitive.

The fluid channels bound within panel <NUM> can be formed in a variety of different ways. For example, as depicted in <FIG>, a fluid channel 176a can be formed by forming an elongated channel groove 178a on bottom surface <NUM> of first plate <NUM> and then securing bottom surface <NUM> of first plate <NUM> to top surface <NUM> of second plate <NUM>, thereby bounding channel groove 178a between plates <NUM> and <NUM> so as to form fluid channel 176a. In this embodiment, plates <NUM> and <NUM> are bound together so as to form a liquid tight seal therebetween. For example, plates <NUM> and <NUM> can be bound together by an adhesive, welding or through other conventional techniques. Although channel groove 178a is formed having a semi-circular transverse cross section, other configurations having a desired cross-sectional area can also be used.

In an alternative embodiment, a fluid channel 176b can be formed by forming an elongated channel groove 178b on top surface of second plate <NUM>. Bottom surface <NUM> of first plate <NUM> is then secured to top surface <NUM> of second plate <NUM>, as discussed above, thereby bounding channel groove 178b between plates <NUM> and <NUM> so as to form fluid channel 176b. In yet another alternative embodiment, elongated channel grooves 178a and 178b can be aligned to form a fluid channel. For example, elongated channel groove 178a can be formed on bottom surface <NUM> of second plate <NUM> while elongated channel groove 178b can be formed on top surface <NUM> of third plate <NUM>. Bottom surface <NUM> of second plate <NUM> is then secured to top surface <NUM> of third plate <NUM>, as discussed above, so that channel grooves 178a and 178b are aligned, thereby forming a fluid channel 176c. The channel grooves can be formed by cutting the grooves into the plates or by initially forming the plates so as to have the channel grooves formed thereon, such as by molding or <NUM>-D printing the plates with the channel grooves.

Turning to <FIG>, in a further alternative embodiment to fluid channel 176a-176c, the alternative channel grooves 178a and 178b can be formed as shown in <FIG>. However, in this embodiment, a first gasket 182a is positioned between first plate <NUM> and second plate <NUM> while a second gasket 182b is positioned between second plate <NUM> and third plate <NUM>. Gaskets <NUM> form a sealed engagement between plates <NUM>, <NUM>, and <NUM> and thereby prevent leaking of fluid channels <NUM>. Gaskets <NUM> are typically made from a material that is different from the material used to form plates <NUM>, <NUM>, and <NUM>. In one embodiment, gaskets <NUM> are formed from a material having a greater elasticity than the material used to form plates <NUM>, <NUM>, and <NUM> and in one embodiment is made from an elastomeric material. Other materials that will not leach into the fluid flowing through the fluid channels and can form the desired seal can also be used.

Turning to <FIG>, in another alternative embodiment, fluid channels can be formed without the need to recess channel groves into one or more of the plates. For example, a fourth plate <NUM> can be sandwiched between two of the other plates, such as between first plate <NUM> and second plate <NUM>. Fourth plate <NUM> has an elongated slot <NUM> that extends along fourth plate <NUM> and passes between a top surface <NUM> and an opposing bottom surface <NUM> thereof. First plate <NUM> is secured to top surface <NUM> of fourth plate <NUM>, such as by welding or adhesive, while second plate <NUM> is secured to bottom surface <NUM> of fourth plate <NUM>, thereby bounding slot <NUM> between first plate <NUM> and second plate <NUM> so as to form a fluid channel 176d. In this embodiment, fourth plate <NUM> can be made of the same material as the other plates. <FIG> also such a further alternative where a gasket <NUM> having an increased thickness is disposed between second plate <NUM> and third plate <NUM>. Gasket <NUM> bounds a slot <NUM> that extends along gasket <NUM> and passes between a top surface <NUM> and an opposing bottom surface <NUM> thereof. Gasket <NUM> is sandwiched between second plate <NUM> and third plate <NUM> so as to bound slot <NUM> between second plate <NUM> and third plate <NUM> and thereby form a fluid channel 176e. In this embodiment, gasket <NUM> can be made from a different material than the other plates <NUM>, <NUM>, and/or <NUM> and can be made of material such as previously discussed with regard to gaskets <NUM>.

Turning to <FIG>, in another alternative embodiment, it is appreciated that panel <NUM> need not be made of separate plates that are secured together. Rather, panel <NUM> can be formed as a single, integral, unitary structure that bounds any number or layout of fluid channels such as fluid channels 176f and <NUM>. Panel <NUM> shown in <FIG> can be formed using conventional <NUM>-D printing techniques. Independent of the method or structure used to form the fluid channels within panel <NUM>, in one alternative embedment, a coating can be applied to the interior surfaces of panel <NUM> that are bounding the fluid channels. The coating can be designed to inhibit the molecule of interest from binding on the interior surface of panel <NUM>, thereby improving collection yield of the molecule of interest. For example, in one embodiment the interior surfaces of panel <NUM> that are bounding the fluid channels can be coated to polytetrafluoroethylene (PTFE). Other applicable coatings can also be used.

Although the primary embodiments disclosed within the present application show forming panel <NUM> using plates <NUM>, <NUM>, and <NUM>, it is appreciated that panel <NUM> and the related fluid channels can be formed using any of the configuration or techniques disclosed herein or any combination of the foregoing. Furthermore, as discussed below in more detail, panel <NUM> is formed in one embodiment from three stacked plates <NUM>, <NUM>, and <NUM> because it permits fluid channels to be formed long two horizontal planes that are vertically spaced apart. This permits a greater concentration of the fluid channels and a greater versatility in path layout. However, in alternative embodiments, depending in part and the desired flow path and the number of chromatograph columns being used, panel <NUM> can be formed with any desired number of stacked plates. For example, panel <NUM> be made with at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> stacked plates or have a range between any two of the foregoing numbers. For example, as depicted in <FIG>, panel <NUM> can be made with five stacked plates <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> and bounding fluid channel <NUM>. As depicted, fluid channel <NUM>, along with the other fluid channels disclosed herein can be bound to extend horizontally between any two desired plates and can extend vertically up and/or down so as to transition between any other two adjacently disposed plates.

In one embodiment, the final panel <NUM> typically has a thickness extending between top surface <NUM> and bottom surface <NUM> that is at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> or is in a range between any two of the foregoing values. Furthermore, panel <NUM> is sufficiently rigid so that it cannot be bent over an angle of greater than <NUM>°, <NUM>°, <NUM>° without plastic deformation.

Returning to <FIG>, the fluid channels and valve assemblies can be organized and placed in a variety of different ways/locations on panel <NUM>. The number and organization depends, in part, upon the number of chromatography columns <NUM> being used and the desired processing through chromatography columns <NUM>. However, in the depicted embodiment, each delivery line <NUM>, <NUM>, and <NUM> is fluid coupled in series to two delivery valve assemblies and each return line <NUM>, <NUM>, <NUM> is fluid couple in series to two return valve assemblies.

For example, feed line <NUM> fluid couples upstream to a feed source housing a feed liquid. The feed liquid comprises a mixture that includes a molecule(s) of interest. In one embodiment, the feed liquid can comprise a clarified cell broth, buffer, cell culture media or the like in which the molecule of interest and, typically, other undesired components are disposed. Another example of a feed liquid can include a lysate or an Adeno-Associated Virus (AAV) in liquid suspension. The molecule of interest commonly comprises a protein, although other molecules can also be selected.

In one embodiment, feed line <NUM> travels up through channel <NUM> within stand <NUM> and passes out of stand <NUM> such as through an opening <NUM> shown in <FIG>. In alternative embodiments, feed line <NUM> and the other lines discussed herein as passing through channel <NUM> can travel outside of stand <NUM>, such as along the outer surface thereof, so as to facilitate easy replacement between different runs. As shown in <FIG>, a terminal end of feed line <NUM> then fluid couples with a fluid channel 210a of panel <NUM> through a connector 212a. Feed line <NUM> is typically comprised of a flexible conduit, such as a flexible, polymeric tubing. In one embodiment, such tubing can be bent over an angle at least <NUM>° without plastic deformation. Other conduits, such as rigid conduits, can also be used. With reference to <FIG> and <FIG>, fluid channel 210a extends from connector 212a to a first delivery valve assembly 214a. The configuration and operation of the valve assemblies will be discussed below in greater detail. A fluid channel 216a within panel <NUM> extends from first delivery valve assembly 214a to a second delivery valve assembly 218a. In turn, a fluid channel 220a extends from second delivery valve assembly 218a and is fluid coupled with an inlet end <NUM> of chromatography column 30a. More specifically, fluid channel 220a extends to a connector 224a disposed on panel <NUM>, such as on perimeter edge <NUM>. A conduit 226a, disposed outside of panel <NUM>, extends from connector 224a to inlet end 222a of chromatography column 30a. Conduit 226a can comprise a flexible conduit, such as a flexible, polymeric tubing. In one embodiment, such tubing can be bent over an angle at least <NUM>° without plastic deformation. Other conduits, such as rigid conduits, can also be used.

Turning now to <FIG> and <FIG>, a conduit 228a has a first end fluid coupled with an outlet end 230a of chromatography column 30a and an opposing second end fluid coupled with a fluid channel 232a of panel <NUM>. This fluid coupling can be through a connector 234a on panel <NUM>. Connector 234a can be disposed at perimeter edge <NUM> of panel <NUM> or at other locations. Fluid channel 232a couples with an inlet of a sensor block 236a. A fluid channel 233a within panel <NUM> couples with an outlet end of sensor block 236a and extends to a first return valve assembly 240a. Conduit 228a, along with other conduits disclosed herein, can be made of the same materials and have the properties as conduit 226a, as discussed above. In some embodiments, all conduits of the inventive systems can be made of the same material while in other embodiments, some conduits made be made of different material, depending on their intended use.

Sensor block 236a is typically designed to be removably coupled to panel <NUM>. For example, in one embodiment, sensor block 236a is received within a slot 238a formed on top surface <NUM> of panel <NUM>, such as through a snap fit connection, so as to form a fluid coupling with fluid channels 232a and 233a. Alternatively, sensor block 236a may simply be removably mounted to top surface <NUM> of panel <NUM> through a connector such as a clamp, tri-clamp, fastener, spring or the like, so as to fluid couple with fluid channels 232a and 233a. In one embodiment, the fluid coupling can be achieved through aseptic connections. In another alternative embodiment, as depicted in <FIG>, sensor block 236a couples to panel <NUM> either through a connector 242a or by being secured within slot 238a as shown in <FIG>. However, in this embodiment, fluid channel 232a extends to a fluid coupler 244a on panel <NUM>, such as on top surface <NUM>, and a conduit 246a extends from fluid coupler 244a to the inlet of sensor block 236a. In turn a conduit 248a extends from an outlet of sensor block <NUM> and is fluid coupled with fluid channel 233a through a fluid coupler 250a disposed on panel <NUM>. Conduits 246a and 248a can be made of the same alternative materials as conduit 228a, as previously discussed. In one further alternative embodiment, the second end of conduit 228a (<FIG>) can be directly coupled to the inlet end of sensor block 236a so as to eliminate the need for fluid channel 232a.

As shown in <FIG>, sensor block 236a comprises one or more sensors 252a that detect properties of the fluid exiting chromatography column 30a including detecting the presence of the molecule of interest. For example, sensors 252a can comprise a conductivity sensor, ultraviolet light (UV) sensor, pressure sensor, temperature sensor, pH sensor, multiple UV sensors or other sensors. In one embodiment, sensor block 236a can comprise at least <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> separate sensors or in a range between any two of the foregoing numbers. Sensor block 236a is typically designed to be removably mounted to panel <NUM> so that sensor block 236a can be easily removed and replaced with a new sensor block for each new run. The new sensor block 236a can have the same sensor(s) 252a or can have one of more different sensors 252a depending on the intended use. Likewise, prior to use, a sensor block 236a can be selected from a plurality of different sensors blocks 236a, such as at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, where each sensor block has one or more different sensors than the other sensors blocks. The selected sensor block can then be easily mounted to panel <NUM> for operation. In view of the foregoing, the disclosed sensor blocks thus provide the advantage that they are easily replaced, easily secured, provide improved versatility in use, minimize void space, are proximate to the chromatography column outflow for efficient and timely processing and movement of the fluid and have other advantages. However, in alternative embodiments where there is no need to replace the sensors 252a, one or more of sensors 252a can be permanently mounted on panel <NUM>. For example, some sensor 252a, such as reusable sensors, may be permanently mounted on panel <NUM> while other sensors 252a are removably mounted on panel <NUM>.

Turning to <FIG> and <FIG>, a fluid channel 256a within panel <NUM> extends from first return valve assembly 240a to a second return valve assembly 258a. In turn, a fluid channel 260a extending from second return valve assembly 258a fluid couples with load waste line <NUM> through a fluid coupler 262a. Load waste line <NUM> can comprise the same type of conduit as feed line <NUM> and can, in one embodiment, extend down channel <NUM> of stand <NUM> where it eventually couples with a receptacle for receiving load waste.

The same conduits, fluid channels, valve assemblies, sensor block, and alternative for the above described circuit extending from feed line <NUM> to load waste line <NUM> can be used to form a circuit extending from elute/wash line <NUM> to product line <NUM> and from regeneration line <NUM> to regeneration waste line <NUM>. Like elements of the circuits extending between lines <NUM> and <NUM>, between lines <NUM> and <NUM> and between lines <NUM> and <NUM> are all identified by like reference characters except that the reference characters for the elements of the circuit extending between lines <NUM> and <NUM> include the suffix letter "b" and the elements of the circuit extending between lines <NUM> and <NUM> include the suffix letter "c. " For example, with reference to <FIG>, elute/wash line <NUM> fluid couples with chromatography column 30b through first delivery valve assembly 214b and second delivery valve assembly 218b while the fluid exiting chromatography column 30b passes through sensor block 236b, first return valve assembly 240b and second return valve assembly 258b before communicating with product line <NUM>. Elute/wash line <NUM> can pass through channel <NUM> of stand <NUM> and fluid couple upstream with a source of eluting fluid and with a washing fluid. Eluting fluids typically comprise a buffer or purified water. One common example of a buffer used as an eluting fluid is <NUM> acetic acid. Other buffers can also be used. Examples of washing fluids can include phosphate and NaCl solutions, more specifically, <NUM> phosphate and <NUM> NaCl. Other fluids, such as buffers, that will not detrimentally alter the matrix material can also be used. Product line <NUM> can extend down through channel <NUM> of stand <NUM> and fluid couple with a container for collecting the product, i.e., the molecule(s) of interest, or with a further processing instrument for processing the product.

Similar to the above, regeneration line <NUM> fluid couples with chromatography column 30c through first delivery valve assembly 214c and second delivery valve assembly 218c while the fluid exiting chromatography column 30c passes through sensor block 236c, first return valve assembly 240c and second return valve assembly 258c before communicating with regeneration waste line <NUM>. Regeneration line <NUM> can pass through channel <NUM> of stand <NUM> and fluid couple upstream with a source of regeneration fluid. The regeneration fluid can comprise any fluid that will restore the matrix material to its desired properties. One example of the regeneration fluid can comprise a NaOH solution such as <NUM> NaOH. Regeneration waste line <NUM> can extend down through channel <NUM> of stand <NUM> and fluid couple with a container for collecting the regeneration waste fluid.

As will be discussed below in greater detail, additional fluid channels are formed within panel <NUM>. In part, such fluid channels enable fluid to pass to or between any combination of chromatograph columns <NUM>. Regulation of the flow through the fluid channels is controlled by the valve assemblies. The number of valve assemblies mounted on panel <NUM> can very based on the number of chromatography columns being used and the desired processing steps. In one embodiment, the number of valve assemblies mounted on panel <NUM> can comprise at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> or in a range between any two of the foregoing.

The configuration and operation of one embodiment of the valve assembly will now be discussed. Depicted in <FIG> is first delivery valve assembly 214a. In general, valve assembly 214a comprises a valve 40a rotatably mounted to panel <NUM>, a support 41a that upstands from top surface <NUM> of panel <NUM> adjacent to valve 40a, an actuator 42a disposed on support 41a, and a stem 43a that extends between valve 40a and actuator 42a. Although support 41a is shown as being U-shaped so as to extend over valve 40a, it is appreciated that support 41a can have a variety of different configurations that will support actuator 42a.

For reasons as will be discussed below in greater detail, actuator 42a can function to selectively depress and raise, or at least release, portions of valve 40a and can function to selectively rotate portions of valve 40a in opposite directions. As such, in one embodiment, actuator 42a can comprise a solenoid 270a that selectively depresses and raises/releases stem 43a and a motor 274a, such as a stepper motor, that selectively rotates stem 43a in opposite directions. Other electric or pneumatic mechanism that can achieve the above functions can also be used as actuator 42a. Actuator 42a is in electrical communication with and is controlled by a programmable, central processing unit (CPU) <NUM>. CPU <NUM> communicates with memory <NUM>, such as non-transitory memory, in which programming and relevant data can be stored. CPU <NUM> and memory <NUM> can be positioned remotely and connect with actuator 42a either wirelessly through a transmitter and receiver or they can be hardwired together. In other embodiments, CPU <NUM> and memory <NUM> can be positioned on panel <NUM>, stand <NUM>, and/or base <NUM>.

Depicted in <FIG> is a perspective view of valve 40a encircled by a cutaway portion of panel <NUM>. With reference to the exploded view in <FIG>, valve 40a generally comprises a cover <NUM>, coupler <NUM>, directional component <NUM>, spring <NUM> and alignment member <NUM>. Panel <NUM> is specifically configured to receive and engage with valve 40a so that no fluid couplings, such as through separate conduits, are required. More specifically, valve 40a is configured for selectively changing a flow path of fluid between combinations of an input fluid channel <NUM> formed in panel <NUM> and communicating with valve 40a and one of a plurality of output fluid channels <NUM> formed in panel <NUM> and communicating with valve 40a, or alternatively blocking the fluid from flowing to any of output fluid channels <NUM> from input fluid channel <NUM>. As better depicted in <FIG>, in the illustrated embodiment, the plurality of output fluid channels <NUM> comprises five output fluid channels 282a-e. However, in other embodiments, valve 40a can be formed having a variety of different numbers of output fluid channels including at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> or a range between any two of the forgoing numbers. The number of output fluid channels depends, in part, on the number of chromatography columns <NUM> being used and the desired processing. In the embodiment illustrated in <FIG>, fluid channel 210a corresponds to input fluid channel <NUM> in <FIG> while fluid channel 216a corresponds to one of output fluid channels 282a-e.

With continued reference to <FIG>, panel <NUM> has an inner surface <NUM> that bounds a cavity <NUM>. Cavity <NUM> extends between an upper end <NUM> and an opposing lower end <NUM>. Input fluid channel <NUM> and output fluid channels 282a-e are spaced apart and extend radially away from inner surface <NUM>. Although input fluid channel <NUM> and output fluid channels 282a-e are shown as arranged around cavity <NUM> in a particular arrangement, the relative positions of input fluid channel <NUM> and output fluid channels 282a-e can be rearranged as desired. For convenience in identification hereinafter, output fluid channels 282a-e can be referred to as a first output channel 282a, a second output channel 282b, a third output channel 282c, a fourth output channel 282d, and a fifth output channel 282e. Input fluid channel <NUM> functions to interface with and receive liquid from an input source, such as from a conduit, valve, or delivery line. Similarly, each of output fluid channels 282a-e function to interface with and transmit liquid to an output, such as conduit, valve, or return line.

Input fluid channel <NUM> and each output fluid channels 282a-e has an inner opening <NUM> on inner surface <NUM> of panel <NUM>. Inner opening <NUM> of input fluid channel <NUM> can herein be referred to as an inlet opening while each opening <NUM> of output fluid channels 282a-e can herein be referred to as an outlet opening. As shown in <FIG>, a central axis of each of output fluid channels 282a-e extends along a first plane Pi and a central axis of input fluid channel <NUM> extends along a second plane P<NUM>. The second plane P<NUM> can be spaced from the first plane Pi and extend substantially parallel to the first plane Pi. Though the second plane P<NUM> is depicted as positioned below the first plane Pi, the first and second planes Pi and P<NUM>, and thus the input fluid channel <NUM> and output fluid channels 282a-e, can be repositioned, e.g. switched, as desired. In the depicted embodiment, first plane Pi is disposed at the intersection between first plate <NUM> and second plate <NUM> while second plane P<NUM> is disposed at the intersection between second plate <NUM> and third plate <NUM>.

Panel <NUM> is also formed to include a ledge <NUM> that extends radially inward from inner surface <NUM> and extends partially around the outer circumference of cavity <NUM>. As shown in <FIG>, ledge <NUM> is prevented from extending entirely around the outer circumference of cavity <NUM> by a flow stop rib <NUM> that extends upward from ledge <NUM> and outward from inner surface <NUM>. When valve 40a is fully assembled, ledge <NUM> defines a lower limit of the flow of fluid flowing through valve 40a and flow stop rib <NUM> prevents fluid from flowing in a counter-clockwise direction after it enters input fluid channel <NUM>, as will be discussed further below.

Inner surface <NUM> of panel <NUM> extends upward to an annular shoulder <NUM> at upper end <NUM>. A stop member <NUM> upstand from shoulder <NUM>. In one embodiment, the terminal top of stop member <NUM> is disposed flush with top surface <NUM> of panel <NUM>. Stop member <NUM> can be a solid tab that extends vertically upward from shoulder <NUM>, as well as circumferentially around the top of upper end <NUM> of cavity <NUM>. As shown, stop member <NUM> can extend about <NUM> degrees around upper end <NUM>. However, stop member <NUM> can be alternatively shaped and sized as desired. Stop member <NUM> is configured to interact with a stop member <NUM> located on cover <NUM> (<FIG>) for limiting the rotational range of directional component <NUM> relative to panel <NUM>. The interaction between stop member <NUM> of panel <NUM> and stop member <NUM> of the cover <NUM> will be described further below.

Turning to <FIG>, panel <NUM> is also formed so as to include a bottom ledge <NUM> that extends inward from inner surface <NUM> at the lower end <NUM>. Bottom ledge <NUM> can be substantially ring-shaped, and can define a top surface 35a (<FIG>), a bottom surface 35b opposite top surface 35a, and a central bore <NUM> that extends vertically through bottom ledge <NUM> from top surface 35a to bottom surface 35b. Central bore <NUM> is open to cavity <NUM>, but defines a substantially smaller diameter than cavity <NUM>. Bottom ledge <NUM> includes at least one alignment bore <NUM> that extends from top surface 35a to bottom surface 35b. In the depicted embodiment, bottom ledge <NUM> includes eight alignment bores <NUM> equidistantly spaced circumferentially around bottom ledge <NUM>, as well as equidistantly spaced radially from the center of central bore <NUM>. However, it is contemplated that different numbers of alignment bores <NUM> can be included, and that the relative positions of alignment bores <NUM> can vary. For example, bottom ledge <NUM> can include at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> alignment bores, or more than eight alignment bores. Bottom ledge <NUM>, and particularly alignment bores <NUM>, function to rotationally lock directional component <NUM> relative panel <NUM> in particular positions, as will be described below.

With reference to <FIG>, <FIG>, valve 40a includes directional component <NUM> configured to be received within cavity <NUM> of panel <NUM>. Directional component <NUM> includes a sidewall <NUM> that has an outer surface 44a, an inner surface 44b opposite outer surface 44a, an upper end 47a, and a lower end 47b opposite the upper end 47a. Directional component <NUM> can be formed of an elastomeric material, such as urethane or silicone. Directional component <NUM> can also include a central cavity <NUM> that extends through directional component <NUM> from upper end 47a to lower end 47b, central cavity <NUM> being defined by inner surface 44b. As a result, directional component <NUM> can be substantially shaped as a hollow cylinder, with sidewall <NUM> having a small thickness relative to the diameter of central cavity <NUM>. Sidewall <NUM> can have a substantially consistent thickness throughout, such that the shape of inner surface 44b of directional component <NUM> generally mirrors the shape of outer surface 44a. Outer surface 44a can also be referred to as an engagement sealing surface, as outer surface 44a is configured to contact inner surface <NUM> of panel <NUM> (<FIG>). Directional component <NUM> can include at least one rib <NUM> that extends radially inward from inner surface 44b and is configured to engage a corresponding slot <NUM> defined by coupler <NUM> (<FIG>), which will be discussed below. Though five ribs <NUM> are depicted, directional component <NUM> can include more or less ribs <NUM> as desired. For example, directional component <NUM> can include at least <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> ribs or a range between any two of the foregoing.

Directional component <NUM> can include a transfer channel <NUM> that extends from the outer surface 44a into sidewall <NUM> and partially around a circumference of directional component <NUM>. When directional component <NUM> is disposed within cavity <NUM> of panel <NUM> and outer surface 44a contacts inner surface <NUM> of panel <NUM>, the transfer channel <NUM> can be configured to receive a flow of liquid from input fluid channel <NUM> and direct the flow of liquid to one of output fluid channels 282a-e. In this embodiment, the transfer channel <NUM> is a single, continuous channel that is formed across a majority of the circumference of directional component <NUM>, though it is noted that transfer channel <NUM> is not formed across the entire circumference.

In the depicted embodiment, transfer channel <NUM> can be understood as comprising two portions-a horizontal portion 52b and a vertical portion 52a that extends from horizontal portion 52b. The width and depth of transfer channel <NUM> can be selected in order to provide an adequate and constant fluid flow or to satisfy any other functional considerations. Horizontal portion 52b can extend substantially around a majority of the circumference of directional component <NUM>, while vertical portion 52a can extend upward from horizontal portion 52b and terminate at a location below the top of directional component <NUM>. Horizontal portion 52b can define a similar width and depth as vertical portion 52a, though these dimensions may differ as desired. When directional component <NUM> is disposed within cavity <NUM> of panel <NUM> (<FIG>), the first plane Pi can extend through vertical portion 52a of the transfer channel <NUM>, such that a part of vertical portion 52a is horizontally aligned with output fluid channels <NUM>. Likewise, when directional component <NUM> is disposed within cavity <NUM> of panel <NUM>, second plane P<NUM> can extend through horizontal portion 52b of transfer channel <NUM>, such that a part of horizontal portion 52b is horizontally aligned with input fluid channel <NUM>. As a result, in various rotational positions horizontal portion 52b can receive a liquid flow from the input fluid channel <NUM> and direct the liquid flow to the vertical portion 52a, which then directs the liquid flow to one of output fluid channels 282a-e.

Horizontal portion 52b of transfer channel <NUM> is prevented from extending completely around the circumference of directional component <NUM> by a blocking extension <NUM> (<FIG>) that extends downwardly from sidewall <NUM> on the outer surface 44a. Blocking extension <NUM> divides horizontal portion 52b such that horizontal portion 52b substantially forms a C-shape around the circumference of the directional component <NUM>. Effectively, blocking extension <NUM> prevents liquid from flowing completely around the entire circumference of directional component <NUM> when valve 40a is fully assembled. Blocking extension <NUM> can define a variety of widths, depending on the intended length of horizontal portion 52b of transfer channel <NUM>. Regardless of the width of blocking extension <NUM>, blocking extension <NUM> can contact the inner surface <NUM> of panel <NUM> like the rest of outer surface 44a of directional component <NUM> that does not define transfer channel <NUM>. In certain rotational positions, blocking extension <NUM> can align with inner opening <NUM> (<FIG>) of input fluid channel <NUM>, such that liquid is prevented from flowing into transfer channel <NUM> from input fluid channel <NUM>. This rotational position will be discussed further below.

Now referring to <FIG> and <FIG>, valve 40a can include coupler <NUM>. Coupler <NUM> can include a sidewall <NUM> that defines an outer surface 64a, an inner surface 64b opposite the outer surface 64a, an upper end 65a, and a lower end 65b opposite upper end 65a. Like panel <NUM> and the directional component <NUM>, coupler <NUM> can be formed of a substantially rigid polymer, co-polymer, or other plastic. Coupler <NUM> can also include a central cavity <NUM> defined by the inner surface 64b that extends through directional component <NUM> from upper end 65a to lower end 65b. Sidewall <NUM> can include at least one slot <NUM> that extends from outer surface 64a of coupler <NUM> radially into sidewall <NUM>. In the depicted embodiment, coupler <NUM> is shown as including five slots <NUM>. However, coupler <NUM> can include more or less slots <NUM> as desired, though the number of slots <NUM> will generally correspond to the number of ribs <NUM> included in directional component <NUM>. This is because when valve 40a is assembled, slots <NUM> can each receive a corresponding rib <NUM> of directional component <NUM> to align and secure directional component <NUM> and coupler <NUM> in relation to each other. Likewise, as coupler <NUM> can be disposed within central cavity <NUM> of directional component <NUM>, outer surface 64a of coupler <NUM> can substantially match the shape of inner surface 44b of directional component <NUM> to ensure a tight fit. Coupler <NUM> can also include a plurality of recesses <NUM> that extend from upper end 65a and inner surface 64b into the sidewall <NUM>. Though four recesses <NUM> are shown, and recesses <NUM> are shown as being spaced equidistantly around coupler <NUM>, more or less recesses <NUM> can be included, and recesses <NUM> can be differently spaced. As will be discussed further, recesses <NUM> are configured to engage a portion of cover <NUM> for rotationally fixing cover <NUM> relative to coupler <NUM>.

The coupler <NUM> can further include a bottom ledge <NUM> that extends inward from inner surface 64b at lower end 65b. Bottom ledge <NUM> can be substantially ring-shaped and can define a top surface 67a and a bottom surface 67b opposite top surface 67a. A plurality of ribs <NUM> can extend upward from the top surface 67a of bottom ledge <NUM> to a central support <NUM> positioned above the bottom ledge <NUM>. Though four ribs <NUM> are depicted, valve 40a can include more or less than four ribs <NUM> as desired. The central support <NUM> can be substantially ring-shaped and can define a bore <NUM> that extends centrally through. The bore <NUM> can be open to the central cavity <NUM> and can define a substantially smaller cross-section than the central cavity <NUM>. When valve 40a is fully assembled, the central support <NUM> can support the bottom end of a spring <NUM>, (<FIG>) which will be described further below.

A plurality of extensions <NUM> can extend downward from the bottom surface 67b of the bottom ledge <NUM>. Each of the extensions <NUM> can include a lip <NUM> that extends radially outward from the downward end of the extension <NUM>, where each lip <NUM> defines a substantially planar upper surface 80a. Though four extensions <NUM> are shown, the coupler <NUM> can include more less than four extensions as desired. For example, the coupler <NUM> can include one extension, two extensions, or more than four extensions. Further, though the extensions <NUM> are depicted as spaced substantially equidistantly around the bottom ledge <NUM>, it is contemplated that the spacing of the extensions <NUM> can be altered. In the assembled configuration, when the coupler <NUM> is disposed within the central cavity <NUM> of the directional component <NUM> and the directional component <NUM> is disposed within cavity <NUM> of panel <NUM>, extensions <NUM> can extend through central bore <NUM> of panel <NUM> and engage the bottom ledge <NUM>. Specifically, the upper surface 80a of each respective lip <NUM> can engage the bottom surface 35b of the bottom ledge <NUM> of panel <NUM>. This engagement axially secures both coupler <NUM> and directional component <NUM> relative to panel <NUM>, while still allowing the coupler <NUM> and the directional component <NUM> to rotate relative to panel <NUM>.

Now referring to <FIG>, <FIG>, <FIG> and <FIG>, valve 40a further includes cover <NUM>. Cover <NUM> includes a body <NUM> that has an upper surface 87a, a lower surface 87b opposite upper surface 87a, and a rim <NUM> that extends downward from lower surface 87b. Cover <NUM> can be formed of a substantially rigid polymer, co-polymer, or other plastic. A knob <NUM> can extend upwards from the upper surface 87a, where knob <NUM> is configured to be gripped for manual rotation of cover <NUM>. and rotationally connected components. Knob <NUM> is depicted as having a greater diameter and height than body <NUM> for easier manual actuation, though knob <NUM> can be differently sized or shaped as desired. Stem 43a is shown upstanding from knob <NUM>. In an alternative embodiment, knob <NUM> can be eliminated and stem 43a can upstand from body <NUM>.

Cover <NUM> can also include a shaft <NUM> that extends downward from an upper end 96a attached to lower surface 87b of body <NUM> to a lower end 96b axially spaced from body <NUM>. Shaft <NUM> can define a bore <NUM> that extends from lower end 96b to upper end 96a and can include a plurality of fluted ribs <NUM> that extend radially outward from shaft <NUM>. However, bore <NUM> can extend to any extent through shaft <NUM>. In addition to shaft <NUM>, knob <NUM> can also be substantially hollow and define a recess <NUM> that is in communication with bore <NUM>. When valve 40a is fully assembled, shaft <NUM> can extend through bore <NUM> defined by central support <NUM> (<FIG>) of coupler <NUM>, and lower surface 87b of cover <NUM> can be configured to contact an upper end of spring <NUM>. As a result, spring <NUM> contacts lower surface 87b of cover <NUM> at its upper end, extends over shaft <NUM> and fluted ribs <NUM>, and contacts the central support <NUM> of the coupler <NUM> at its lower end.

Cover <NUM> can include a plurality of alignment tabs <NUM> extending downward from lower surface 87b of body <NUM>. Each of alignment tabs <NUM> can be configured as hollow and substantially trapezoidal and can be received in a corresponding recess <NUM> of coupler <NUM> when valve 40a is fully assembled. As noted above, interaction between alignment tabs <NUM> and recesses <NUM> can serve to rotationally couple coupler <NUM> to cover <NUM>. As a result, directional component <NUM> is also rotationally coupled to cover <NUM>. As depicted, cover <NUM> can include four alignment tabs <NUM> equidistantly spaced circumferentially around shaft <NUM>. However, the orientation and number of alignment tabs <NUM> can very as desired. For example, cover <NUM> can include one, two, or more than four alignment tabs, and alignment tabs <NUM> can be unequally spaced circumferentially around shaft <NUM>. However, the spacing and number of the alignment tabs <NUM> will generally correspond to the spacing and number of recesses <NUM> of coupler <NUM>. In an embodiment, one of alignment tabs <NUM> can include an extended rib 95a that can be received by a respective one of recesses <NUM>. The inclusion of the extended rib 95a in one of alignment tabs <NUM> ensures that cover <NUM> can be attached to the other components of valve 40a in only one orientation. Cover <NUM> can also include first and second radial ribs 91a, 91b, where each of the first and second radial ribs 91a, 91b extends between adjacent ones of alignment tabs <NUM>. The first and second radial ribs 91a, 91b are configured to engage the outer side of the spring <NUM> when valve 40a fully assembled.

Cover <NUM> can also include a stop member <NUM> that extends inward from the inner surface of rim <NUM>. As depicted, stop member <NUM> includes two circumferentially spaced stops: a first stop 94a and a second stop 94b. Each of the first and second stops 94a, 94b can be configured as hooked extensions extending from the inner surface of rim <NUM>, though other configurations are contemplated. Alternatively, stop member <NUM> can define a single, monolithic stop that extends inward from the inner surface of rim <NUM>. During operation of valve 40a, stop member <NUM> can be utilized to limit rotation of cover <NUM>, and thus coupler <NUM> and directional component <NUM>, relative to panel <NUM>. This occurs due to the contact between stop member <NUM> and stop member <NUM> that projects from upper end 19a of panel <NUM>.

Referring to <FIG>, <FIG>, valve 40a can further include an alignment member <NUM> attached to lower end 96b of shaft <NUM> of cover <NUM>. Like the other components of valve 40a, alignment member <NUM> can be formed of a substantially rigid polymer, co-polymer, or other plastic. Alignment member <NUM> can include a substantially annular body <NUM> and a plurality of legs <NUM> extending inward from the inner surface of body <NUM>. Each of legs <NUM> can include a first leg 110a and a second leg 110b separate from die first leg 110a, and can extend from body <NUM> to a central ring <NUM> concentrically positioned with respect to body <NUM>. Though each of legs <NUM> is shown as including first and second legs 110a, 110b, each of legs <NUM> can be alternatively configured. For example, in other embodiments, each of the legs <NUM> can define a substantially monolithic body. The positioning of body <NUM>, legs <NUM>, and central ring <NUM> provides alignment member <NUM> with a substantially wheel and spoke shaped configuration. Central ring <NUM> defines a bore <NUM> that extends through central ring <NUM> and can be centered with respect to body <NUM> and central ring <NUM>. Central ring <NUM> can be configured to receive lower end 96b of shaft <NUM> of cover <NUM> in order to axially and rotationally couple cover <NUM> to alignment member <NUM>. For example, central ring <NUM> can be attached to lower end 96b of shaft <NUM> through ultrasonic welding, though other attachment means are contemplated. Alignment member <NUM> can further include a plurality of protrusions <NUM> that extend from the upper surface of body <NUM>. Though protrusions <NUM> are depicted as substantially cylindrical and equidistantly spaced about body <NUM>, protrusions <NUM> can be alternatively configured as desired. Additionally, though eight protrusions <NUM> are depicted, alignment member <NUM> can include different numbers of protrusions <NUM> in different embodiments. For example, alignment member <NUM> can include one, two, or more than eight protrusions, where each protrusion is equidistantly spaced or non-equidistantly spaced about body <NUM>. As shown in <FIG>, each of protrusions <NUM> is sized and configured to be received in a respective alignment bore <NUM> of panel <NUM> for rotationally coupling and decoupling cover <NUM> relative to panel <NUM>, as will be described below.

Now referring to <FIG>, the method of rotating components of valve 40a and the various flow paths that can be achieved will be described. When valve 40a is fully assembled, cover <NUM> and alignment member <NUM> are axially movable together relative to panel <NUM>. Without any external forces applied to valve 40a, cover <NUM> is initially in a first vertical position. This position is maintained by spring <NUM>, which applies a biasing force to lower surface 87b of cover <NUM>, thus pushing cover <NUM> upwards. As alignment member <NUM> is rotationally and axially coupled to cover <NUM>, spring <NUM> biasing cover <NUM> upwards also biases alignment member <NUM> upwards, such that in the first vertical position protrusions <NUM> of alignment member <NUM> are disposed within respective alignment bores <NUM> of panel <NUM>. The interaction between protrusions <NUM> and panel <NUM> in the first vertical position causes cover <NUM>, and thus coupler <NUM> and directional component <NUM>, to be rotationally fixed relative to panel <NUM>. Alignment bores <NUM> can be designed such that when cover <NUM> and alignment member <NUM> are in the first vertical position, directional component <NUM> is in one of a finite number of predetermined positions, where each predetermined position defines a unique flow path through input fluid channel <NUM> and output fluid channels 282a-e.

To rotate directional component <NUM> and alter the flow path through valve 40a, a downward force can be applied to cover <NUM> to overcome the upward force of the spring <NUM>, thus moving the cover <NUM> and attached alignment member <NUM> downward relative to panel <NUM>. With enough force, alignment member <NUM> can be moved sufficiently downward such that protrusions <NUM> are spaced downward relative to alignment bores <NUM>. For example, such as a downward force can be produced by actuator 42a (<FIG>) pushing downward on cover <NUM> through stem 43a. In one embodiment, an annular groove <NUM> is recessed on top surface of panel <NUM> and encircles cavity <NUM> (<FIG>). Groove <NUM> provides room for the perimeter edge of cover <NUM> to be downwardly depressed. In other embodiment, the perimeter edge of cover <NUM> can be cut back or cover <NUM> can be elevated so that groove <NUM> is not required.

Because protrusions <NUM> are no longer constrained by the alignment bores <NUM> when cover <NUM> and alignment member <NUM> are in the second vertical position, cover <NUM> and alignment member <NUM>-along with directional component <NUM> and coupler <NUM>-can be freely rotated relative to panel <NUM>. For example, such rotation can be produced by actuator <NUM> rotating cover <NUM> and alignment member <NUM> through stem 43a. Cover <NUM> and alignment member <NUM> can be rotated in both a first rotational direction R<NUM> and a second rotational direction R<NUM> that is opposite the first rotational direction R<NUM>. In the depicted embodiment, the first rotational direction R<NUM> is a counter-clockwise direction, and the second rotational direction R<NUM> is a clockwise direction. Operation of valve 40a can thus rotate cover <NUM> to obtain the desired fluid flow path when cover <NUM> and alignment member <NUM> are in the second vertical position. Once the desired flow path has been achieved, the downward force can be released from cover <NUM>, thus allowing spring <NUM> to bias cover <NUM> and alignment member <NUM> upward again into the first vertical position, and protrusions <NUM> to again be received in respective ones of alignment bores <NUM>. As noted above, in the first vertical position, cover <NUM>, alignment member <NUM>, directional component <NUM>, and coupler <NUM> will again be rotationally fixed relative to panel <NUM>. Additionally, the extent to which cover <NUM> and rotationally coupled components can be rotated in the first rotational direction R<NUM> is limited by the interaction between stop member <NUM> of cover <NUM> and stop member <NUM> of panel <NUM>.

Continuing with <FIG>, various rotational positions of valve 40a will be discussed. Referring to <FIG>, in a first rotational position a first flow path F<NUM> is defined through valve 40a. In the first rotational position, input fluid channel <NUM> receives a flow of fluid from an input, which then flows through input fluid channel <NUM>, through transfer channel <NUM>, and to second output channel 282b. Between input fluid channel <NUM> and second output channel 282b, the flow of fluid is contained by transfer channel <NUM>, the inner surface <NUM> of panel <NUM>, and ledge <NUM> (<FIG>), each of which prevents the fluid from escaping transfer channel <NUM> and migrating to any of the other output fluid channels <NUM>. Due to the presence of blocking extension <NUM>, the fluid is prevented from flowing within transfer channel <NUM> entirely around the complete circumference of directional component <NUM> in the second rotational direction R<NUM>. Likewise, flow stop rib <NUM> prevents the fluid from flowing around the circumference of directional component <NUM> in the first rotational direction R<NUM> after entering the valve 40a through input fluid channel <NUM>.

To alter the fluid flow path, a force is applied to cover <NUM>, as previously described, to move cover <NUM> and alignment member <NUM> from the first vertical position to the second vertical position. When the cover <NUM> and alignment member <NUM> are in the second vertical position, cover <NUM> can be rotated in the second rotational R<NUM> to a second rotational position, as shown in <FIG>. Cover <NUM> can be prevented from rotating in the second rotational direction R<NUM> from the first rotational position to the second rotational position by the interaction of stop member <NUM> of cover <NUM> and the stop member <NUM> of panel <NUM>. However, in other embodiments the rotational movement of cover <NUM> from the first rotational position to the second rotational position can be reversed. Stop member <NUM> of cover <NUM> and stop member <NUM> of panel <NUM> can be configured such that the second rotational position depicted in <FIG> is the furthest cover <NUM> and the rotationally coupled components can be rotated relative to the panel <NUM> in the first rotational direction R<NUM>. In the second rotational position, blocking extension <NUM> of directional component <NUM> is positioned circumferentially between input fluid channel <NUM> of panel <NUM> and first output channel 282a. As a result, a second flow path F<NUM> is defined in the second rotational position, in which the blocking extension <NUM> and flow stop rib <NUM> prevent the flow of fluid from exiting valve 40a through any of output fluid channels 282a-e. The second flow path F<NUM> thus only extends from the input to the end of the vertical portion 52a of transfer channel <NUM>. Because of this, the second rotational position can be referred to as an off position for valve 40a, as no fluid will be transferred through the valve 40a from input fluid channel <NUM> to any of output fluid channels 282a-e.

After cover <NUM>, and thus directional component <NUM>, is in the second rotational position, cover <NUM> and alignment member <NUM> can be axially moved from the first vertical position to the second vertical position to allow cover <NUM> to be rotated in the second rotational direction R<NUM> to a third rotational position, as shown in <FIG>. In the third rotational position, a third flow path F<NUM> is defined through valve 40a. In the third rotational position, input flow channel <NUM> receives a flow of fluid from an input, which then flows through the input flow channel <NUM>, through transfer channel <NUM>, and to first output channel 282a. Between input flow channel <NUM> and first output channel 282a, the flow of fluid is contained by transfer channel <NUM>, inner surface <NUM> of panel <NUM>, and ledge <NUM>, each of which prevents the fluid from escaping the transfer channel <NUM> and migrating to any of the other output fluid channels 282a-e. While rotation of cover <NUM> and directional component <NUM> is only described from the first rotational position to the second and third rotational positions, rotation between any combination of these rotational positions, as well as other rotational positions that direct fluid to any of output fluid channels 282a-e, can be performed as desired. Also, while rotation may be described with reference to only certain components, such as cover <NUM> and directional component <NUM>, rotation of cover <NUM> also causes rotation of the alignment member <NUM>, coupler <NUM>, and directional component <NUM> relative to panel <NUM>.

In view of the forgoing, valve assembly 214a, including valve 40a thereof, is able to receive a fluid through input fluid channel <NUM> and then direct the fluid to any select one of output fluid channels 282a-e. Valve 40a and portions of valve assembly 214a incorporate features of but are modified relative to the multi-port valve disclosed in <CIT>. However, the disclosure, operation, and alternatives of the multi-port valve disclosed in <CIT> are also relevant to valve 40a and valve assembly 214a. In alternative embodiments, it is appreciated that other types of valve assemblies/valves that perform the same function can also be used as valve 40a and/or at least portions of valve assembly 214a. Examples of such valve assemblies/valves are disclosed in <CIT> and <CIT>.

Turing to <FIG>, a further top plan view of chromatography system <NUM> is shown. However, in this view a plurality of additional fluid channels are formed within panel <NUM> that extend between different valve assemblies. These additional fluid channels can be disposed between first plate <NUM> and second plate <NUM> and/or between second plate <NUM> and third plate <NUM> and/or between any other combinations of plates forming panel <NUM> as previously discussed and are herein referred to as fluid channels <NUM>. Although fluid channels <NUM> can connect to each of the different valve assemblies in a variety of different configurations depending on the configuration and desired processing of chromatography system <NUM>, in the depicted embodiment, each of first delivery valve assemblies 214a, 214b, and 214c are fluid coupled to each of second delivery valve assemblies 218a, 218b, and 218c through separately formed fluid channels <NUM> bound in panel <NUM>. Likewise, each of first return valve assemblies 240a, 240b, and 240c are fluid coupled to each of second return valve assemblies 258a, 258b, and 258c through separately formed fluid channels <NUM> bound in panel <NUM>.

Furthermore, as depicted in <FIG>, chromatography system <NUM> also comprises a valve assembly <NUM> and a valve assembly <NUM> rotatably mounted on panel <NUM> and having the same configuration and alternatives as valve assembly 214a disclosed herein. Valve assembly <NUM> is fluid coupled to an inlet of a pump <NUM> through a fluid channel <NUM> of panel <NUM> extending from valve assembly <NUM> and a conduit <NUM> disposed outside of panel <NUM> extending from fluid channel <NUM> to the inlet of pump <NUM>. In turn, valve assembly <NUM> is fluid coupled to an outlet of pump <NUM> through a fluid channel <NUM> of panel <NUM> extending from valve assembly <NUM> and a conduit <NUM> disposed outside of panel <NUM> and extending from fluid channel <NUM> to the outlet of pump <NUM>. Returning to <FIG>, each first return valve assembly 240a, 240b, and 240c is also fluid coupled to valve assembly <NUM> through separately formed fluid channels <NUM> while each second delivery valve assembly 218a, 218b, and 218c is fluid coupled to valve assembly <NUM> through separately formed fluid channels <NUM>. As discussed below, pump <NUM> can be used to assist in transferring the liquid feed between chromatography columns <NUM>.

Finally, <FIG> also shows valve assemblies that are operably coupled with chromatography column 30d. Specifically, fluid can flow from a delivery valve assembly 214d to delivery valve assembly 218d an into chromatography column 30d. Fluid can then flow out of chromatography column 30d, through sensor 236d, return valve assembly 240d and return valve assembly 258d. Delivery valve assembly 214d is also fluid coupled with each of delivery valve assemblies 218a, 218b, and 218c through separately formed fluid channels <NUM> bound in panel <NUM> (<FIG>). Likewise, first return valve assemblies 240d is fluid coupled to each of second return valve assemblies 258a, 258b, and 258c through separately formed fluid channels <NUM> bound in panel <NUM>. Valve assemblies 258d and 214d are also fluid coupled together through a pump <NUM>.

Give the above configuration of chromatography system <NUM>, one example of a method of use will now be discussed. It is understood that the liquid flowing from, to, or between lines, valve assemblies, chromatography columns, sensor blocks, and pumps, as discussed below, is passing through the related fluid channels within panel <NUM> and/or through corresponding conduits, as previously discussed herein, and thus for purposes of simplicity the corresponding fluid channels and conduits are not specifically referenced. Initially a stream of the feed liquid containing a molecule(s) of interest is passed from feed line <NUM>, through valve assemblies 214a and 218a into chromatography column 30a. The matrix e.g., resin or filter, within chromatography column 30a is designed to capture or slow the molecule(s) of interest while the remaining feed liquid passes therethrough. The fluid exiting chromatography column 30a passes into sensor block 236a where a sensor therein, such as a UV sensor, detects whether the molecule of interest is present. If not, the fluid flows through valve assemblies 240a and 258a and out through load waste line <NUM>. Once the molecule of interest is detected by sensor block <NUM>, valve assembly 240a is rotated so that the fluid exiting chromatography column 30a now travels through valve assembly 240a, valve assembly <NUM>, pump <NUM>, valve assembly <NUM>, valve assembly 218b and into chromatography column 30b. The fluid exiting chromatography column 30b passes through sensor block 236b. If the molecule of interest is not detected, the fluid passes through valve assembly 240b, valve assembly 258a and again out through load waste line <NUM>.

To optimize the use of the matrix within chromatography column 30a, the feed liquid continues to flow into chromatography column 30a, as discussed above, until sensor block 236a detects that chromatography column 30a is saturated with the molecule(s) of interest. Valve assembly 214a is then rotated so that the feed liquid no passes through valve assembly 214a, valve assembly 218b and into chromatography column 30b.

Concurrent with the rotation of valve assembly 214a, valve assembly 240a is rotated so that the fluid exiting chromatography column 30a will now pass through valve assembly 240a, valve assembly 258b and out through product line <NUM>. An eluting fluid is dispensed through elute/wash line <NUM> which passes through valve assembly 214b, valve assembly 218a and into chromatography column 30a. The eluting fluid releases the molecule of interest from the matrix within chromatography column 30a which now passes through sensor block 236a, valve assembly 240a, valve assembly 258b and out through product line <NUM> as noted above. The eluting fluid continues to flow until sensor block 236a no longer detects the molecule of interest. Once sensor block 236a no longer detects the molecule of interest, the flow of the eluting fluid is switched upstream to a washing fluid which now follows the same path from elute/wash line <NUM> to chromatography column 30a. The washing fluid washes the eluting fluid from chromatography column 30a which exits by passing through sensor block 236a, valve assembly 240b, valve assembly 258a and again out through load waste line <NUM>.

Once chromatography column 30a is washed, the regeneration liquid is then feed into regeneration line <NUM> where it passes through valve assembly 214c, valve assembly 218a an into chromatography column 30a. When sensor block 236a detects the regeneration liquid leaving chromatography column 30a, the valve assemblies are adjusted so that the exiting fluid flows through valve assembly 240a, valve assembly 258c and exits out through regeneration waste line <NUM>. The regeneration liquid continues to flow until it is determined that the matrix within chromatography column 30a has been fully regenerated to its original state. For example, this can be determined by flowing a specific quantity of regeneration liquid through chromatography column 30a and/or by flowing regeneration liquid for a predefined time. In some embodiments, it can also be determined by sensor block 236a detecting changes in properties of the regeneration liquid. Other methods known in the art can also be used. Flow of the regeneration liquid can then be stopped, and the valve assemblies turned so that feed line <NUM> can again deliver a new stream of feed liquid containing the molecule of interest into chromatography column 30a through valve assemblies 214a and 218a. The process can then be repeated as discussed above.

It is understood by those skilled in the art that the above processes being performed with regard to chromatography column 30a can also be performed with one or more of the other chromatography columns. For example, when sensor block 236b detects the presence of the molecule of interest, the flow leaving chromatography column 30b can be delivered to chromatography column 30c. Once chromatography column 30b is saturated with the molecule of interest, the eluting fluid and washing fluid from elute/wash line <NUM> can be passed down through chromatography column 30b. For example, the eluting and washing of chromatography column 30b may occur concurrently with the regeneration of chromatography column 30a. Finally, chromatography column 30b can be regenerated, such as while chromatography column 30a is again receiving the initial feed liquid. In view of the forgoing, it is appreciated that all of chromatography columns <NUM> or any desired combination thereof can be used for processing the feed liquid in a continuous flow process. That is, by progressively switching the stream of feed liquid to different chromatography column as a prior chromatography column becomes saturated, the feed liquid can continuously flow until processing of the feed liquid is completed. Accordingly, the number and volume of chromatography columns used is dependent upon the processing being performed. Furthermore, one or more of the chromatography columns being used in a single run can be designed to perform a different function, e.g., collect different molecules of interest.

It is appreciated that embodiments of the disclosed chromatography system have a number of advantages. For example, panel <NUM> bounding the various fluid channels can be easily and inexpensively fabricated. More specifically, panel <NUM> can be produced quicker and at a lower cost than conventional systems where large numbers of separate tubing sections must be manually fluid connected together. In addition, in contrast to conventional systems that incorporate a separate pinch valve for each tube to control fluid flow, the present design uses a single rotatable valve to control the operation of several fluid channels. As a result, the void volume of the present design is substantially less than for conventional systems of comparable production capacity. As a result, smaller volumes of a feed liquid can be more efficiently processed and there is less fluid waste. Likewise, panel <NUM> and the conduits used therewith can be economically produced as single-use items that are disposed of and replace after each run, thereby avoiding the need for cleaning or sterilization.

Claim 1:
A chromatography system (<NUM>) comprising
a plurality of chromatography columns (30a-30d);
a panel (<NUM>) having a top face (<NUM>) and an opposing bottom face (<NUM>), a first cavity (<NUM>) being formed on the panel (<NUM>) so as to pass through the top face (<NUM>), the first cavity (<NUM>) being encircled by an inner surface, the panel (<NUM>) bounding:
an inlet fluid channel (<NUM>) having a first end and an opposing second end, the second end of the inlet fluid channel (<NUM>) terminating at an inlet opening formed on the inner surface encircling the first cavity (<NUM>) so that the inlet fluid channel (<NUM>) communicates with the first cavity (<NUM>); and
a plurality of first outlet fluid channels (282a-e) each of the plurality of first outlet fluid channels (282a-e) having a first end and an opposing second end, the first end of each of the plurality of first outlet fluid channels (282a-e) terminating at an outlet opening formed on the inner surface encircling the first cavity (<NUM>) so that each of the plurality of first outlet fluid channels (282a-e) communicate with the first cavity (<NUM>), a first one of the plurality of first outlet fluid channels (282a-e) being in fluid communication with a first one of the plurality of chromatography columns (30a-30d); and
a first valve (40a) movably disposed within the first cavity (<NUM>), wherein moving the first valve (40a) to different positions produces isolated fluid communication between the inlet fluid channel (<NUM>) and each of the plurality of first outlet fluid channels (282a-e), the chromatography system being characterized in that the panel (<NUM>) comprises a first plate (<NUM>) overlying and being secured to a second plate (<NUM>), the inlet fluid channel (<NUM>) being at least partially bounded between the first plate (<NUM>) and the second plate (<NUM>).