Patent Description:
Reconnectable fluid tubing couplings i.e. those couplings that can be removed and replaced multiple times and yet still provide a fluid seal at each reconnection for flexible tubing such as garden hoses and plastics plumbing are known. However, their ease of connection and/or hygiene are questionable particularly if the same designs were to be employed with chromatography systems, where sanitary couplings are required and where, often, much higher fluid pressure is encountered, for example up to <NUM> Bar or above. Typical plumbing fittings used in chromatography systems have multiple components comprising metal springs and O-rings and so have resultant dead-ends or O-ring grooves, which can harbour unwanted contaminants, for example pathogens, in use. These dead-ends and grooves are difficult to sanitise. Further, the use of metal parts is problematic when gamma irradiation is attempted to sanitise such a coupling assembly. In additional the use of screw threads or special tools is undesirable where speed and ease of connection or disconnection is sought.

One prior art barb lock tubing coupling arrangement is shown in <CIT>, but that coupling requires tooling for assembly and is not intended to be readily releasable.

Liquid chromatography is a well-known procedure for separating mixtures of molecules, for example separating proteins in liquid samples. For example, modular multiple column chromatography cartridges such as those described in <CIT> may be used for such a purpose. The proteins may typically be suspended in a fluid, and driven through a chromatography separation medium along with a buffer solution. The various sample molecules of the mixture travel at different speeds through a chromatography medium, causing them to separate. This separation may be completed by a fractionation step where the mobile phase may be directed to different containers, e.g. by an outlet valve of the chromatography system.

Also, in chromatography system, particularly benchtop experimental equipment it is often necessary to cleanse the equipment comprising interconnecting tubing in use, and then tear down the tubular set-up, in order to remake the tubing in a different configuration, to accommodate a different experiment. Thus, special sanitisation equipment is inconvenient, and speedy cleaning is needed, along with fast disconnection and reconnection. One such piece of equipment is disclosed in U88821718, where interchangeable modular
components of a chromatography system are interconnectable by external fluid conduits, and which would benefit from an improved means of such interconnection.

The present invention is directed to the chromatography system of claim <NUM>. The dependent claims refer to preferred embodiments.

An object of embodiments is to provide chromatography system, particularly.

Another object of embodiments is to provide an easily cleanable coupling
with no, or limited, dead-ends or other spaces where contaminants can accumulate. Another object of embodiments is to provide a coupling which can be connected and released quickly without the use of tools if needed.

More advantages and benefits of the present invention will become readily apparent to the person skilled in the art in view of the detailed description below.

The invention will now be described in more detail with reference to the appended drawings, wherein:.

Good Manufacturing Practice (GMP) sets out guidelines for bioprocessing procedures, which if followed require cleanliness standards. Advantageously, the standards are easier to achieve with the proposed apparatus, for example where fluid paths in the system have, in one configuration at least, a continuous flow path with no substantive stagnant portions, thereby providing complete cleaning without the need to break down the fluid conduits. Embodiments of the proposed system provide a sanitary small-scale chromatography system suitable for both GMP and non-GMP work. Functionally wide flow and pressure ranges of the system makes it fit for both production of technical batches and scale-up studies as well as small-scale production of GMP-grade material. The high accuracy and flow range of the pumps enables precise gradient formation, covering a large range of chromatography column sizes and more repeatable results.

In embodiments, a modular construction provides increased functionality, for different uses. Interactive control software allows changes to be made in real-time and unexpected deviations to be quickly identified. The small, bench-top size frees up lab space. The system allows in-situ column packaging, i.e. the ability to compress chromatography media in the column, or each column where two or more columns are used, whilst being connected to the system, and without having to then disconnect any fluid conduits prior to performing chromatographic procedures.

<FIG> shows an exploded view of an embodiment of a releasable coupling <NUM> according to one embodiment. The coupling <NUM> comprises two parts: a cylindrical inner component, in the form of a collet <NUM> for accepting a fluid tubing; and a cylindrical locking collar <NUM> having and internal through-aperture <NUM> for slideably accepting the collet <NUM>. A fluid tubing (not shown) will extend in use along an axis T, and within a central bore <NUM> within the collet <NUM> of a size which snuggly fits around the tubing. The collet <NUM> has a collet flange <NUM>, formed on a cylindrical mid portion <NUM> and plural resiliently deflectable and circumferentially arranged fingers <NUM> extending from the mid portion <NUM> to a distal end <NUM> of the collet <NUM>.

The collet <NUM> is a sliding fit in a through-aperture <NUM> of the collar <NUM>, and the collar <NUM> is thereby mountable over and around the fingers <NUM> and mid portion <NUM> of the collet <NUM>. The collar <NUM> can be manipulated along the fingers <NUM> and mid portion <NUM> to selectively deflect or relax the fingers <NUM>, which deflection causes gripping of the tubing, as described in more detail below. Manipulation of the collar <NUM> is assisted by a collar flange <NUM> at a distal end of the collar, extending from a body <NUM> of the collar which can be pulled or pushed manually. The collar has a distal end <NUM>. The fingers <NUM> flare outwardly toward the distal end <NUM> of the collet, thus it will be appreciated that if the aperture <NUM> is of a generally constant internal diameter, then sliding of the collar <NUM> in a direction from the collet flange <NUM> to the distal end <NUM> of the collet <NUM> will cause the internal diameter of the aperture <NUM> to abut outer surfaces of the fingers <NUM> and force them inwardly to provide a tubing clamping action.

<FIG> shows the coupling <NUM> of <FIG> in section, arranged in a tubing clamping position. Here, the distal end <NUM> of the collar <NUM> and the distal end <NUM> of the collet <NUM> are have been manipulated into alignment by means of manual repositioning of the collar flange <NUM> relative to the collet flange <NUM>. In that position the inner surface of aperture <NUM> and an outer surface of the fingers form complementary surfaces which abut and thereby cause deflection of the fingers <NUM> inwardly toward the axis T for inwardly urging an adjacent portion of a tubing (not shown) inside the collet, for example to compress, or squeeze or clamp the tubing. Release of the coupling is achieved manipulating the collar and its flange in the direction of arrows R.

<FIG> shows the coupling <NUM> again in section and arranged, but in a tubing releasing position. Here, the collar <NUM> has been slid in the direction R toward a distal end of the collet, but it is prevented from sliding off the collect by the collet flange <NUM> and/or a step <NUM> in both the aperture <NUM> and the bore <NUM>, one or each of which form a stop. In that position, the fingers <NUM> are relaxed and spring resiliently outwardly to cease or reduce any urging/compressing/clamping action on the tubing. The position shown in <FIG> is achieved by manipulation of the collar <NUM> and its flange <NUM> in the direction of arrow R (<FIG>) relative to the collet <NUM>.

<FIG> shows a section through a coupling assembly <NUM> comprising a male part, in this case in the form of a connector spigot <NUM>, the male part having a widening, e.g. a sealing ridge, a bead or a barb, <NUM> which is positionable inside a flexible fluid tubing <NUM> beyond an open end of the tubing <NUM> as a push fit. The tubing <NUM> is held to the spigot <NUM> by compression of the tubing <NUM> onto the spigot <NUM>. The coupling <NUM> surrounds the tubing <NUM> and provides the releasable compression of the tubing onto the spigot <NUM>, in the manner described above principally in relation to <FIG>, for releasably holding the tubing <NUM> to the spigot <NUM>. In this Figure, it is clear that the fingers <NUM> compress the tubing <NUM> behind the widening <NUM>, thereby assisting the holding of the tubing to the spigot, and effectively locking the tubing to the spigot <NUM>. The coupling assembly <NUM> can supply fluid to or remove fluid from a module <NUM> which in this embodiment is a chromatography system which requires a releasable fluid coupling that can be cleaned easily and that will not harbour contamination. In another embodiment, the fluid pressure at the module <NUM> could be measured or adjusted via the fluid tubing <NUM>, and so only fluid communication is needed. It follows that fluid flow within in the tubing <NUM> is not essential.

<FIG> shows the same section as in <FIG>, but in this view having the coupling assembly <NUM> in a releasing position, as shown in <FIG>. In use, the coupling <NUM>, positioned according to <FIG> will clamp the tubing <NUM> in place on the spigot <NUM>, and when the collar flange <NUM> is pulled in the direction of arrows R, the compression on the tubing is released. That release allows the collar flange <NUM>, the collar <NUM> and the collet <NUM>, to be withdrawn along the tubing in the direction of arrow R in <FIG>. As described above the collet has a stop or stops (collet flange <NUM> and/or step <NUM>), which prevent the collar from coming off the collet, and thereby allow the collet to be withdrawn with the flange <NUM>. In that withdrawn position, the tubing <NUM> can be pulled off the spigot <NUM> with ease. Connection or reconnection of the tubing <NUM> onto the spigot is carried out by reversing the above mentioned steps. the tubing <NUM> is fitted over the spigot <NUM>, the collet flange <NUM> is pushed in the opposite direction to arrow R, and once the distal end <NUM> of the collet is firmly seated against the module <NUM>, the collar flange <NUM> is pushed home to deflect the fingers <NUM> against an outer surface of the tubing for clamping the tubing onto the spigot <NUM>.

The coupling <NUM> is preferably formed from just two plastics material mouldings. From the drawings, it can be seen that the outer surface of the collar <NUM> is smooth, i.e. the collar flange <NUM> is a continuous annular formation upstanding from the annular body <NUM>, and the collar flange and an outer surface of the collar on which the collar flange is formed has a continuously curved profile with no sudden changes in direction. Thereby, the chances of contamination of the coupling in use are reduced and the coupling can be easily cleaned. Additionally, two fingers of a user can be used, one on each side of the collar body <NUM> to hold each side of the collar flange to pull it in the direction of arrow R (<FIG>). At the same time the user's thumb can be used to react such a pulling force by resting the thumb against the collet flange <NUM> opposing the two fingers.

It is important to ensure that the tubing <NUM> is substantially fully fitted over the spigot <NUM>. To that end the collet <NUM> and collar <NUM> can be formed from transparent plastics. Additionally, the spigot can be a different colour to the tubing to provide a visual colour indication where the tubing is not fully overlapping the spigot if any of the spigot's colour can be viewed. One modification of the embodiment shown in <FIG> is shown in <FIG> wherein: <FIG> shows a modified spigot <NUM>' which has resilient projections <NUM>, eg. resilient arms, extending outwardly; <FIG> shows a tubing <NUM> pushed fully home onto the spigot <NUM>'. When the tubing is fully home on the spigot, the arms <NUM> move inwardly, only then allowing the collet fingers <NUM> to be pushed over the tubing as shown in <FIG>, ready for the collar <NUM> to be forced over the fingers for clamping the tubing in place as described above. Without the spigot <NUM>' being fully inserted into the tubing <NUM>, the collect <NUM> will not pass the arms <NUM>.

<FIG>, <FIG> and <FIG> show a modification <NUM> of the coupling assembly in section, which do not have all features recited by claim <NUM>. In this embodiment, the collar <NUM> of <FIG> has been replaced by a locking plate <NUM> which has plural through-apertures <NUM>, each of which accepts a collet <NUM>. The locking plate comprises projections <NUM> which serve in place of the flange <NUM> illustrated in the previous figures. The centres of the through-apertures are aligned with the centres of plural male parts projecting from a module <NUM>, so that plural connections can be made in one operation.

In <FIG> the locking plate <NUM> can be seen offered up to the module <NUM> with collets <NUM> assembled in the through-apertures <NUM> and, inside the collets <NUM>, tubings <NUM> already fitted over male parts, such as spigots <NUM>. <FIG> shows the same coupling assembly as shown in <FIG>, but with the locking plate <NUM> and the collets <NUM> pushed in the direction of arrow R up to a front face of the module <NUM>, such that the collets overlie the spigots <NUM> and the ends of the tubings <NUM>. <FIG> shows another view of the coupling assembly of <FIG>, but now with the locking plate <NUM> pushed even further in the direction of arrow R in <FIG>. In <FIG>, the locking plate acts to clamp the fingers <NUM> of the collets <NUM> around the tubings <NUM>, in a manner as described above.

<FIG> shows yet another modification of the coupling assembly, where locking collars <NUM>'are each mounted to a locking plate <NUM> by means of a flexible mount, in this case a spherically formed mount <NUM> which allows each collar <NUM>'to rotate about a centre point of the mount <NUM> and thereby provides tolerance for a degree of misalignment or dimensional error in the male parts on the module. The locking plate could of course be formed from a flexible material to provide a similar tolerance. Two couplings are illustrated in <FIG>, but other linear arrays or two dimensional arrays of couplings could be employed, to match a configuration of male parts <NUM>, for example an array of <NUM> couplings could be used to match the square male part arrangement shown in <FIG>. The couplings need not be in the same plane. The couplings need not have generally parallel axes, if some degree flexibility is afforded, for example as described with reference to <FIG>. For ease of use tubing <NUM> may have a single coupling <NUM> at one end, and may come together at an opposite end in a multiple coupling <NUM>, in the manner of a manifold.

<FIG> shows a chromatography system <NUM> comprising a support <NUM>, which comprises conventional fluid processing modular components, in the form of interchangeable modules such as:.

Other modules could be employed. The modules can be connected in any suitable manner using a fluid tubing <NUM> which has couplings <NUM> at each end, only one of which is shown for convenience. The couplings <NUM> could be replaced by multiple tubing and couplings <NUM> of the type shown in <FIG>, <FIG>, <FIG> or <FIG>, to speed up connection and release of the couplings. For convenience, each of the valves <NUM> has the same male part configuration, meaning that the same configuration of locking plate <NUM> could be used for each valve.

<FIG> shows a release tool <NUM> which has a forked end <NUM> suitable for engagement with each side of a flange <NUM>,or projection <NUM>,to pull the same outwardly away from a module <NUM> or <NUM> to <NUM>, or to push it, where there is no room for fingers to pull.

An alternative embodiment of the coupling <NUM> is shown in <FIG>, <FIG> and <FIG>. In that embodiment a locking collar <NUM> (<FIG>) surrounds a cylindrical inner component, in the form of a collet <NUM> having fingers <NUM> of the type described above, which fingers in turn surround the fluid tubing <NUM>. To a large extent the coupling <NUM> is operable in the same manner as the couplings <NUM> and <NUM> described above, in that, to make a fluid-tight coupling, the tubing <NUM> is pushed over a male part <NUM> protruding from a module <NUM>, then the collet is slid over the tubing until its distal end <NUM> is adjacent to, or abuts the module <NUM>, and then the collar is moved toward the module to initiate the clamping of the fingers <NUM> of the collet <NUM>. That position is shown in <FIG>.

It will be noted that the distal end <NUM> comprises a pair of bayonet type openings for accepting complementary locking pins <NUM> which are supported by a boss <NUM> extending from the module <NUM> about the male part <NUM>. In this embodiment, the final locking position of the collar <NUM> is not achieved until it is pushed further toward the module <NUM>, into the finally locked position shown in <FIG>, by means of manipulating, in a linear and rotational manner, a distal end <NUM> of the collar over, and along the boss <NUM> such that the bayonet openings <NUM> accept the pins <NUM>. Thereby the fingers <NUM> are further clamped to the tubing <NUM> and the collar <NUM> (and coupling <NUM>) is secured to the module <NUM>, held in place by the pins <NUM>.

The embedment shown in <FIG>, <FIG> and <FIG> relies on the substantially linear locking movement of a locking collar mentioned immediately above, i.e. where some twisting is employed to secure the collar <NUM> in place and to apply a clamping force. That twisting can be made easier by the use of wings <NUM> extending from the collar <NUM>, instead of the flange mentioned above.

<FIG> show portions of another collet <NUM> and collar <NUM> in detail, which could be employed with the couplings <NUM>, <NUM>, or <NUM>. In this variant, the clamping of the fingers, fingers <NUM> in this case, can be brought about by twisting of the collar <NUM> about the collet <NUM>, either as an alternative to the sliding motion of the collar <NUM>, in the manner described above, or as well as said sliding motion.

In more detail an inner surface of the collar <NUM> has detents <NUM>, which act tapering portions <NUM> of the fingers <NUM> as the collar is twisted relative to the fingers. The circumferential ramps <NUM> each act as a cam, being forced inwardly toward the tubing <NUM> by respective detents in use as the collar is twisted, in this example, in the direction of arrow R. Thereby the fingers <NUM> are compressed around the tubing <NUM> in use, from the position shown in <FIG> to the clamping position shown in <FIG> where at the detents come to rest in complementary recesses <NUM>. The amount of twisting used for locking is <NUM> degrees or less, and preferably about <NUM> degrees or less if three or more circumferentially arranged fingers are employed.

Experiments have shown that the couplings <NUM>, <NUM>, and <NUM> described above, for use with a tubing having an outside diameter of around <NUM> to <NUM> are capable of sealing the tubing at the coupling, with internal fluid pressures of at least <NUM> Bar or higher like <NUM>, <NUM>, <NUM> or <NUM> Bar or more, as will be discussed more in detail embodiments of the couplings have been successfully verified by extensive leak testing at <NUM> Bar. Said couplings provide a fluid-tight connection of a tubing around a male part which is connectable and releasable by substantially linear only motion of the locking collar <NUM> or locking plate <NUM>, without the need for twisting or threading of parts. Thus, the couplings can be spaced closer together than conventional threaded couplings because room for twisting is avoided. Herein substantially linear means <NUM> degrees or less of rotation, for example <NUM> degrees or less, less than <NUM> degrees, less than <NUM> degrees, less than <NUM> degrees , less than <NUM> degrees or almost no rotation.

Collar elements have been described in different embodiments each having the same functionality in the releasable coupling, namely the described features: locking collar <NUM>, locking plate <NUM>, locking collar <NUM>', locking collar <NUM> and collar <NUM>. One is non-cylindrical (locking plate <NUM>) and the others are shaped cylindrically. The collar element comprises at least one projection, e.g. a collar flange <NUM> or wings <NUM>, extending outwardly away from the aperture of a size allowing manual manipulation of the collar between the first and second positions.

The inner component has been described as a collet <NUM> in connection with <FIG> which may be provided with a stop portion, such as a collet flange <NUM> and/or step <NUM>. The collet flange <NUM> extends outwardly and is of a size which assists the manual manipulation of the coupling Furthermore, resiliently deflectable portion is a term that is equivalent to deflectable fingers <NUM> described in connection with <FIG>, and fingers <NUM> described in connection with <FIG>.

<FIG> shows a chromatography apparatus <NUM> according to an aspect of the invention. The apparatus comprises, but it not limited to, individual modular components <NUM> to <NUM> as listed below, at least some of which are demountable from an apertured front panel <NUM> of a support <NUM> of the apparatus <NUM> and mounted thereon in one generally vertical plane, such that the liquid connections required between modular components can be made only at the front face <NUM>. In practice the demountable modular components have no more than two standard sizes which can, if needed, be repositioned on the panel <NUM> to suit a different procedure. Each modular component has a serial bus communication connection and power connection so that its physical position is immaterial to a controller for example located in the support <NUM>, or located remotely. Thereby, the modular components can be regarded as modular and thereby repositionable and/or interchangeable.

The chromatography apparatus shown in <FIG> has the following modular component:.

Modular components can be omitted or repositioned as explained above. It will be apparent that some modular components can be replaced with other modular components or the space left by an omitted modular component can be filled with a blanking plate (see e.g. <NUM> <FIG>). More than one of the same numbered modular components can be used where necessary.

Fluid interconnections between the fluid manipulating modular components of the apparatus i.e. all the modular components listed above except modular components <NUM>, <NUM>, <NUM> and <NUM>, and external modular components for example sample input reservoirs, buffer fluid reservoirs, chromatograph column(s) and fraction collection equipment, all not shown in <FIG>, are made via fluid conduits in this case in the form of flexible plastics tubing, which can be readily coupled and uncoupled to corresponding ports of the fluid manipulating modular components, in any desired configuration, for example using a coupling as previously described.

<FIG> shows one possible liquid interconnection configuration between the main modular components of the chromatography apparatus <NUM>, connected in this case to two chromatography columns <NUM> and <NUM>, although the apparatus allows any workable interconnection between modular components and additional parts such as multiple columns, and liquid reservoirs. Reconfigurable liquid interconnections are denoted by short chain dotted lines <NUM>.

At the heart of the apparatus <NUM> is the column valve unit <NUM>, which in this case has a construction as disclosed in the pending application <CIT> and is incorporated herein by reference. The value unit <NUM> provides multiple switching of flow for allowing flow in one or both columns <NUM>/<NUM> in either direction (up or down in the drawing). The user can select upflow or downflow, or select to bypass one or both columns. The flow can be directed to waste or to the next component in the flow path. The columns can also be connected in series, each column comprising a chamber of changeable volume for housing chromatographic separation media and an adapter moveable to increase or decrease each said volume, and wherein the column valve unit <NUM> is in fluid communication with each adapter and is selectively operable to move independently or collectively each adapter by means of fluid pressure changes to consequently change each volume and in use to cause compression or relief from compression of media within each column volume.

The column valve unit <NUM> comprises pre-column and post-column pressure sensors and further comprises a fluid inlet <NUM> configured to receive an input fluid. The input fluid may e.g. be a chemical sample suspended in a buffer composition. The column valve unit <NUM> further comprises a fluid outlet <NUM> configured to provide an output fluid from the valve unit. The provided output fluid may typically be the resulting fluid after passing the received input fluid through one or more columns of the chromatography apparatus <NUM>. The valve unit <NUM> further comprises a first pair of fluid ports <NUM> and <NUM> configured to be coupled to a first column <NUM> and a second pair of fluid ports <NUM> and <NUM> configured to be coupled to a second column <NUM>. The valve unit <NUM> further comprises a coupling valve assembly configured to direct fluid between a selection of the fluid inlet <NUM>, the fluid outlet <NUM>, the first pair of fluid ports <NUM> and <NUM> and the second pair of fluid ports <NUM> and <NUM> in response to one or more control signals.

In addition the valve has a port <NUM> which can be used to change the volume of hydraulic cylinders <NUM> and <NUM> which are part of the columns <NUM> and <NUM>, for example to provide compression of the columns' contents, also known as column packing. That packing procedure can be automated. With such a system column diameters of between about <NUM> and <NUM> have been found to be packable in this way. The columns can be pre-packed, but rinsed and re-consolidated with the aid of pressure sensors in the value unit <NUM> measuring back-pressure resulting from pressure within the columns and in accordance with to known protocols, for example as described in <CIT>, which disclosure is incorporated herein by reference.

<FIG>, <FIG> and <FIG> show the system connected with tubing for various configurations, where only some of the modular components referenced in <FIG> remain in place in these figures, and the apertures left by removed modular components are blanked off with blanking plates <NUM>, screwed into place over the aperture to prevent accidental liquid ingress into the support <NUM>.

In <FIG> a system <NUM>' with a configuration of modular components suitable for regulated environments where systems are custom-built in a factory. The system is delivered mounted, calibrated, and performance tested and suitable for work in GMP environments. <FIG> shows one system <NUM>" with some modular components removed, and Figure <NUM> shows a system <NUM>‴ with more modular components in place, similar to Figure <NUM>, and showing typical tubular interconnections <NUM>.

In use, modular components are easily removed or added to the system and installation finalized through a one-click activation in software which can recognize each modular component. The software can provide comprehensive and customizable operational control as well as pre-emptive maintenance. In addition to the modular components described above, input-output communication modular components can be used to interface with analogue and/or digital external sensors or other equipment such as automatic fraction collecting devices. The wide flow rate and pressure ranges enables more than <NUM>-fold scaling in the range <NUM> to <NUM> internal diameter columns. This wide range makes the apparatus suitable to bridge the transition into GMP environments.

The packing (and re-packing) of chromatography columns, using the system described above is controllable fully by the controller <NUM> initiated by the control panel <NUM>. The controller <NUM> is able to drive the display screen <NUM> (<FIG>) to aid visualisation of the packing process and progress. The control software comprises an accessible column packing record. Columns packing records can therefore be defined, created, and updated from the software for traceability and quality assurance purposes. In addition, the record can be used to monitor column performance and provide statistics for usage, separation performance, and packing intervals.

The display screen can provide a process visualization which quickly gives an operator an overview of the system's function, progress through operational steps and alarms, only providing the desired amount of information at each step. The active flow path is always displayed in the process visualisation to minimize user errors. Real time changes can be made by selecting the appropriate process on the visualization screen, e.g. selecting or dragging icons on the screen. Control, graphical interfaces are provided for specific sections, such as the column valve unit <NUM>.

Preprogramed steps are employed but these can be modified and saved as user-defined steps for added customization.

The system described and illustrated above is designed for sanitary environments. For example, the support <NUM> is flat or curved without joints, gaps or significant concavities, other than at the edges of the faces, which makes it easy to wipe down and reduces the chance of dust and liquid trapping. The pH monitor <NUM> has in-line calibration and the column valve unit <NUM> provides in-process column packing, so a closed flow path through operations can be employed, meaning that no breaks in the fluid path need be made throughout one or more chromatography column packing/regeneration stages and throughout the separation operation,.

<FIG> illustrates a prior art modular component <NUM> provided with four ports <NUM> each adapted to be connected to a prior art fluid connection <NUM>. Due to the size of the coupling <NUM> required to secure the fluid connection <NUM> to the port <NUM>, the couplings have to be arranged at different heights. This is a bulky solution and also requires that space is provided around the modular component to facilitate mounting/dismounting of fluid connections <NUM> to the respective port <NUM>.

<FIG> illustrates a modular component <NUM> having four ports <NUM>, each having a tubing <NUM>, which at a first end thereof is provided with a releasable coupling <NUM> (as described in connection with <FIG>), connected to each respective port <NUM>. A second end of one of the tubing is connected to a converter <NUM> with another releasable coupling <NUM>, to provide attachment of a fluid connection not suitable to be connected directly to the port <NUM>. The converter <NUM> is described in more detail in connection with <FIG>. The result of using releasable couplings when connecting fluid connection to the modular component is a less bulky design since the ports may be positioned more closely to each other. Also the releasable coupling is easier to sanitize, to mount/dismount and replace if needed.

<FIG> shows a cross-sectional view of a converter <NUM>, having a body <NUM>, a flange <NUM>, a through-hole <NUM> and a spigot <NUM> integrated with the body <NUM>. The converter <NUM> is in this embodiment made from a single piece of material, such as plastic, metal, etc. The flange <NUM> is in this example adapted to be used in a Tri Clamp (TC) coupling, and the spigot <NUM> is adapted to receive a tubing provided with a resealable coupling <NUM> (not shown).

<FIG> shows a cross-sectional view of an alternative converter <NUM>' similar to the converter described in connection with <FIG> with one exception. The converter <NUM>' comprises two parts, wherein the body <NUM> and flange <NUM> are made from a single piece of material, e.g. plastic, and the spigot <NUM>' is made from another material, e.g. metal.

<FIG> shows a prior art modular component <NUM> with three threaded holes as ports <NUM>. Tubing <NUM>, each provided with a treaded connector <NUM> is secured to the respective ports <NUM>. <FIG> shows a threaded connector <NUM> comprising an end flange <NUM>, secured to a frist end of the tubing <NUM> and adapted to provide sealing when arranged in the threaded hole <NUM>, and a body having a threaded portion <NUM> and a grip portion <NUM> designed to be used when securing the threaded connector <NUM> to the modular component <NUM>. Due to the space needed to secure the threaded connectors <NUM> to the modular component <NUM>, the design is rather bulky compared to when a releasable coupling is used, as shown i <FIG>.

When a fluid tubing is connected to a port using a threaded connector, there is an unintentional turning of the fluid tubing (approximately <NUM>-<NUM> turns) when securing the threaded connector to a threaded hole. This is in particular a drawback when securing short fluid tubing, e.g. <NUM>-<NUM> long, where the tubing experience a kinking behaviour. Furthermore, a separate O-ring may be needed to create the desired pressure and fluid sealing.

In order to benefit from the advantages provided by the resealable coupling <NUM>, adaptors may be introduced in the threaded holes of the modular component <NUM>.

<FIG> shows a cross-sectional view of an adaptor <NUM>, having a body <NUM>, a threaded portion <NUM>, a through-hole <NUM> and a spigot <NUM> integrated with the body <NUM>. The adaptor <NUM> is in this embodiment made from a single piece of material, such as plastic, metal, etc. The threaded portion <NUM> is in this example adapted to be introduced in the threaded hole of a modular component using the body <NUM> as a grip portion, and the spigot <NUM> is adapted to receive a tubing provided with a resealable coupling <NUM> (not shown).

<FIG> shows a cross-sectional view of an alternative adaptor <NUM>' similar to the adaptor described in connection with <FIG> with one exception. The converter <NUM>' comprises two parts, wherein the body <NUM> and threaded portion <NUM> are made from a single piece of material, e.g. plastic, and the spigot <NUM>' is made from another material, e.g. metal.

<FIG> shows a cross-sectional view of an alternative converter <NUM>, having a body <NUM>, a portion with a threaded hole931, a through-hole <NUM> and a spigot <NUM> integrated with the body <NUM>. The converter <NUM> is in this embodiment made from a single piece of material, such as plastic, metal, etc. The threaded hole <NUM> is in this example adapted to receive a threaded connector as described in connection with <FIG>. The spigot <NUM> is adapted to receive a tubing provided with a resealable coupling <NUM> (not shown). It should be noted that the spigot may be separately manufactured in a different material compared to the body and portion with the threaded hole.

An advantage of the releasable coupling assembly <NUM> is no thread which means sanitizable and less maintenance need. A simple widening <NUM> (i.e. sealing ridge, barb or bead) on a spigot <NUM> extending from the front of a panel is much easier to sanitize compared to a conventional screw on connector with very limited access into the threaded hole as illustrated in <FIG>.

Another advantage is that no flange, in contrast to what is illustrated in connection with <FIG>, is required, and it is therefore possible to cut the tubing manually before connecting it using the releasable coupling <NUM>. Thus, it is easy to exchange tubing when needed due to the fact that the resting size of the inner diameter of the tubing is in the same range as the outer diameter of the sealing ridge <NUM> on the spigot <NUM>, the resting size of the inner diameter of the tubing is preferably less than ±<NUM>% of the outer diameter of the spigot.

Another advantage is that no O-ring or gasket is required, which means less maintenance and more robust solution compared to prior art solutions. Sealing is achieved using the tubing material in direct sealing engagement with the sealing ridge <NUM>. However, this requires the tubing to have some degree of flexibility and deformation properties. The resealable coupling provides minimum number of connections/joints between different materials and parts which improves the possibility to sanitize the fluid connection if needed. Another advantage is that the resealable coupling assembly is easy to attach, e.g. one hand snap fitting for low pressure applications.

Converter connectors, as described in connection with <FIG> and <FIG>, may be used to provide connections to other connectors, e.g. TC connectors. Threaded adapters, as described in connection with <FIG>, may be used to upgrade old equipment with threaded holes (see <FIG>) to connectors adapted to use the releasable coupling when attaching tubing.

As described above, spigots <NUM> may be arranged closer together than if screw type connectors or TC connectors were provided. This would enable shorter internal flow paths in the modular components, e.g. valves, whereby the use of releasable coupling assemblies may reduce the size of fluidic components with internal flow paths. This will in turn affect the whole chromatography system with reduced footprint in relation to the flow capacity.

<FIG> show a cross-sectional view of a spigot without and with mounted tubing. It should be emphasized that the dimensions of the tubing (inner diameter D1) and the spigot (outer diameter D2) are important to create proper sealing and avoiding creating pockets between the tubing <NUM> and the open end <NUM> of the spigot <NUM>, in which pockets deposition of residues from biological material may be caught. The elastic modulus of the tubing will provide the necessary deformation of the tubing to pass over the sealing ridge <NUM> provided in close proximity to the open end <NUM>. The shape of the sealing ridge is important to achieve the desired functionality with key aspects:.

As mentioned above, other parameters of importance are:.

In some of the embodiments, the sealing ridge has a rounded design with radius R and a height h from centre of spigot. The radius extends to the open end of the spigot and provides an angle for allowing the tubing to slide over the sealing ridge onto the spigot using a force low enough for a normal operator and that the tubing does not bend under the pressure when sliding over the sealing ridge. the rounded section may start at a radius which is similar to the inner radius of the tubing. the height is determined by the elastic modulus of the tubing and pressure limits for the connector.

Other shapes of the sealing ridge are shown in <FIG>. Arrows F1-F3 in <FIG> schematically indicates the forces involved in sealing and locking the tube end <NUM> on the spigot <NUM>. In one embodiment, e.g. as exemplified by connector <NUM> above, the collet is arranged to apply the tubing clamping pressure at the spigot side of the midpoint of the sealing ridge as indicated by F2 in <FIG>. In one embodiment, essentially the fluid sealing force F1 between the tubing and the front end of the sealing ridge close to the open end of the spigot is achieved primarily by the elasticity of the tubing. The sealing is achieved without any pockets when positioning the sealing ridge in close proximity to the open end, i.e. no flat section at the open end of the spigot.

By applying the locking pressure essentially F2 behind the midpoint of the sealing ridge, essentially all available clamping force is used to keep the tubing on the sealing ridge. The pressure limit is dependent on the height of the sealing ridge, the clamping force, the slope of the sealing ridge and the friction coefficient between the tubing and the spigot. However, all surfaces should be as smooth as possible in order to be sanitizable. In alternative embodiments, parts of the available clamping force may be applied at the end section <NUM> of the spigot <NUM> in order to further secure the seal between the spigot and the tube. In the disclosed embodiment <NUM>, the fingers <NUM> of the collet <NUM> are designed such that they only apply a clamping force in proximity to the sealing ridge <NUM> but leaves a space to the tube at the lower end of the spigot when in the clamping position. In this way the clamping force is less dependent of dimensional variations in the different components (spigot, tube, collet and collar) since the clamping force will involve spring loading of the fingers <NUM> about the clamping position. In the disclosed embodiment the available clamping force is determined by the force applied by the operator when pushing the collar <NUM> over the collet <NUM> into the tubing clamping position whereby the fingers <NUM> are displaced to abut the tube, the force needed for locking the clamp by pushing the collar <NUM> should be adapted to be a reasonable force for the user, while at the same time avoiding the need for a too high release force for releasing the clamp.

<FIG> shows a situation when the fluid tubing <NUM> is mounted over the sealing ridge <NUM> and the length of the spigot <NUM>, and schematically indicates the locking pressure on the tubing applied to the spigot side of the midpoint of the sealing ridge. The fluid sealing force F1 between the tubing and the front end of the sealing ridge close to the open end of the spigot is achieved by the elasticity of the tubing. The sealing is achieved without any pockets when positioning the sealing ridge in close proximity to the open end, i.e. no flat section at the open end of the spigot.

By applying the locking pressure F2 behind the midpoint of the sealing ridge, essentially all available clamping force is used to keep the tubing on the sealing ridge. The pressure limit is dependent on the height of the sealing ridge, the clamping force, the slope of the sealing ridge and the friction coefficient between the tubing and the spigot. However, all surfaces should be as smooth as possible in order to be sanitizable. Furthermore, sharp corners may unintentionally create pockets where biological material may be trapped, and sharp corners therefore should be avoided in order to be sanitizable.

It may be desirable to provide an additional sealing force F3 at the base of the spigot (reverse side to the open end) to increase the sealing pressure limit. In one embodiment, at least <NUM>% of the clamping force is applied behind the midpoint of the sealing ridge (indicated with F2). In one embodiment, abutment or a smaller pressure applied at or near the base of the spigot to stabilize the connection.

The clamping force may be provided using a releasable coupling as described above. Other types of couplings are possible, provided they provide suitable amount of clamping force as described above, e.g. hose clamps, eccentric couplings. The length of the selected connector has to be selected based on the length of the spigot to avoid leverage.

<FIG> show cross-sectional views of alternative sealing ridge configurations. In <FIG> shows a spigot <NUM> having a first alternative sealing ridge <NUM> provided with a non-uniform contour. The rear edge <NUM> of the sealing ridge drops more rapidly from the midpoint of the sealing ridge to the outer surface of the spigot. This improves the pressure limit of the connection. Furthermore, the front end of the sealing ridge <NUM> is in line with the open end of the spigot as indicated by reference numeral D3. This will increase the force needed to mount the fluid tubing (not shown) compared to the spigot described in connection with <FIG>.

<FIG> shows a spigot <NUM> having a second alternative sealing ridge <NUM> provided with a non-uniform contour. The rear edge <NUM> of the sealing ridge is curved with a radius r2 from the midpoint of the sealing ridge to the outer surface of the spigot. The contour from the midpoint of the sealing ridge to the open end of the spigot is curved with a radius r1, r1 is greater than r2.

Furthermore, the front end of the sealing ridge <NUM> is in line with the open end of the spigot as indicated by reference numeral D4, which in this example is greater than D3. which indicate that the force needed to mount the fluid tubing (not shown) compared to the spigot described in connection with <FIG>.

In general terms the present invention relates to a novel connector concept for chromatography systems, where the conventional threaded fluidic connectors as exemplified in <FIG> may be replaced by a considerably more convenient connector of spigot type, where the tube for interconnecting components in the chromatography system simply is pushed onto a spigot and then secured thereon by a releasable clamp applying a radial clamping force on the outer periphery of the tube. As mentioned, the spigot is preferably provided with a sealing ridge in order to enable the connector concept to be used at the pressure ranges needed. It has surprisingly been verified that it is possible to design such a connector to provide a leak proof fluid connection at internal pressures exceeding the required ranges in liquid chromatography of <NUM> Bar and even up to above <NUM> Bar, while still significantly improving ease of use for the operator. The procedure for connecting a tube to a port in a chromatography system according to embodiments hereof simply involves the steps of pushing the tube end over the spigot, positioning the releasable connector clamp around the tube end and applying a locking force by actuating the connector clamp. Similarly, the procedure for disconnecting a tube from a port in a chromatography system according to embodiments hereof simply involves the steps of deactuating the connector clamp to release the locking force, optionally removing the releasable connector clamp from the tube end and pulling the tube end free from the spigot. One major benefit of the disclosed embodiments is that the steps of pushing and applying locking clamp does not require twisting motion that may transfer rotational motion to the tube whereby the tube is not rotated with respect to the male part during the step of applying. As mentioned this prevents the tube from getting twisted and from forming kinks that may restrict fluid flow or even destroy the tube segment. Further, compared to conventional chromatography systems with connectors that require flanged tubing, e.g. tubing with an inner diameter of <NUM> to <NUM>, the present system provides the benefit of allowing customization of the fluid path by adding the step of cutting the tube segment to an optimal length before interconnecting the path.

Embodiments of the present connector/chromatography system have been verified to provide leak proof connections over the desired pressure range for liquid chromatography. In one embodiment, the chromatography system upper pressure limit for operation is at <NUM> Bar, and in order to verify proper sealing at <NUM> Bar the connectors have regularly been leak tested at <NUM> Bar. In the testing, the limit determining a leak was set to 1µl/min at <NUM> Bar per connector in the tested flow path. Successful tests were performed under the following conditions:.

As previously mentioned it was surprisingly found that this was possible to achieve while providing such improved ease of use compared to conventional connections.

In addition to the above leak tests, Salt Creep Tests were performed by circulating a mobile phase of <NUM> (NH4)2SO4 in the system overnight (approximately <NUM> hours), with a backpressure of <NUM> MPa. Thereafter the system is visually inspected for salt creeping around the connectors, the valves and the other modules. It was verified that the connectors and the chromatography system passed the test without visible salt creep.

<FIG> Shows the interaction between the spigot <NUM>, the tube <NUM> and the collet <NUM> and its fingers <NUM> in accordance with one embodiment. In <FIG> the tube end <NUM> is shown above the spigot wherein the dashed lines indicate the relationship between the inner diameter of the tube and the spigot elements. As can be seen, the spigot base is slightly wider than the tube inner diameter, and the sealing ridge <NUM> is significantly wider, but with a rounded front edge for allowing the tube to be pushed onto the spigot. In <FIG>, the tube end has been pushed onto the spigot (beyond the drawn part) and the collet <NUM> has been applied around the tube end and actuated in a locked position for clamping the tube. The collet <NUM> is disclosed in geater detail in <FIG> where it can be seen that the fingers <NUM> are provided with a clamping section <NUM> for clamping the tube at the region o the center of the sealing ridge <NUM> of the spigot <NUM>. In one embodiment the tube inner diameter is <NUM> and the outer diameter <NUM> whereas the spigot base diameter is <NUM> and the sealing ridge <NUM> which together with the locking force from the clamp <NUM> provides a leak free connection. The tubes used in liquid chromatography systems of this type generally has tubes of sufficiently rigid material in order to comply with the pressures involved and may e.g. be made of Fluorinated EtenPropen (FEP) plastic.

According to one embodiment, a component <NUM>-<NUM>; <NUM>; <NUM> for a chromatography system <NUM> is disclosed. The component (wich may be modular) comprises one or more ports, each port is accessible via a spigot <NUM>; <NUM>, <NUM>' for receiving a first end of a fluid tubing <NUM>; <NUM>; <NUM>. The first end being sealable around the spigot by a releasable coupling <NUM>, <NUM>, <NUM> external to the tubing end and the coupling having a releasable clamping action actuatable by sliding motion of a collar element <NUM>, <NUM>, <NUM>', <NUM>, <NUM> of the coupling along the end of the fluid tubing.

The spigot (<NUM>) may be an integral part of the component <NUM>-<NUM>. Furthermore, the spigot <NUM>; <NUM>' may be provided on an adaptor <NUM>; <NUM>' configured to be connected to the port of the component <NUM>. In some embodiments, the port is a threaded hole <NUM> and the adaptor <NUM>, <NUM>' comprises a corresponding threaded portion <NUM>, body <NUM> and spigot <NUM>; <NUM>'.

In some embodiments, the adaptor <NUM> is made from a single piece of material, wherein the single piece of material may be plastic or metal.

In some embodiments, the spigot <NUM>' is made from a first material, and the body <NUM> and the threaded portion <NUM> are made from a second material, wherein the first material may be a metal and the second material may be plastic.

According to one embodiment, a releasable coupling <NUM> configured to hold a fluid tubing to a spigot is disclosed. The coupling comprises:.

The collar element comprises at least one projection extending outwardly away from the aperture of a size allowing manual manipulation of the collar between the first and second positions.

In some embodiments, the inner component <NUM> further comprises a stop portion <NUM>; <NUM> co-operable with the collar element to prevent or inhibit the sliding of the collar element off the inner component in at least one direction.

In some embodiments, the collar element is slideable on the inner component from the first position where the deflection is provided, to the second position where the collar element abuts the stop portion.

In some embodiments, the collar flange <NUM> is formed at one end of the collar element, wherein the stop portion is formed at one end of the inner component. The collar flange <NUM> and stop portion can be brought into proximity by manual manipulation to the second position, and the collar element can be further slid by manual manipulation to the first position whereat the collar flange <NUM> is spaced from the stop portion.

In some embodiments, the portion is a collet flange <NUM> extending outwardly and of a size which assists the manual manipulation of the coupling. In some embodiments, the collar flange <NUM> is a continuous annular formation upstanding from the body <NUM> of the collar.

In some embodiments, the collar flange <NUM> and an outer surface of the collar element on which the collar flange is formed has a continuously curved profile with no sudden changes in direction.

In some embodiments, the resiliently deflectable portion <NUM>; <NUM> of the inner component <NUM>; <NUM>; <NUM> comprises plural circumferentially arranged fingers which are deflectable inwardly toward the tubing in use. In some embodiments, the collar element <NUM> further comprises bayonet openings <NUM> cooperating with complementary locking pins <NUM> for releasably securing the coupling to a module <NUM>.

According to one embodiment, a converter <NUM>; <NUM>'; <NUM> for connecting an end of a first fluid tubing <NUM> to an end of a second fluid tubing is disclosed. The converter comprises a spigot <NUM>; <NUM>'; <NUM> for receiving the end of the first fluid tubing <NUM>, wherein the end of the first fluid tubing being sealable around the spigot by a releasable coupling <NUM>, <NUM>, <NUM> external to the tubing end. The coupling has a releasable clamping action actuatable by sliding motion of a collar element <NUM>, <NUM>, <NUM>', <NUM>, <NUM> of the coupling along the end of the fluid tubing.

In some embodiments, the converter <NUM>; <NUM>' further comprises a body <NUM> and a flange <NUM>, or a body <NUM> and a portion with a threaded hole <NUM>, configured to be connected to the end of the second fluid tubing.

In some embodiments, the converter <NUM> is made from a single piece of material, wherein the single piece of material may be plastic or metal.

In some embodiments, the spigot <NUM>' is made from a first material, and the body <NUM> and the flange <NUM>, or the body <NUM> and the portion with the threaded hole <NUM>, are made from a second material. The first material may be a metal and the second material may be plastic.

According to one embodiment a chromatography system <NUM> comprising plural components <NUM>-<NUM>; <NUM>; <NUM> as described above, fluidically interconnectable by fluid tubing <NUM> is disclosed. The components comprises one or more spigots <NUM> for receiving a respective end of the fluid tubing <NUM>, the fluid tubing end being sealable around the spigot by a releasable coupling <NUM>, <NUM>, <NUM> as described above, the coupling having a releasable clamping action actuatable by sliding motion of a collar element <NUM>, <NUM>, <NUM>', <NUM>, <NUM> of the coupling along the end of the fluid tubing.

In some embodiments, the sliding motion is motion generally toward a respective component, and the clamping action is releasable by the motion away from said component.

In some embodiments, the plural components <NUM>-<NUM> are modular components positionably rearrangeable on a support <NUM>, and the fluid tubing <NUM> comprises multiple lengths of fluid tubing each having opposed ends provided with one said coupling <NUM>, <NUM>, <NUM> at each end, in use together allowing for generally sealed fluid flow or fluid communication between respective modular components.

In some embodiments, the sliding motion is linear motion only, or is substantially linear motion with a twisting motion of <NUM> degrees or less.

In some embodiments, the chromatography system is a chromatography system formed from the plural components.

In some embodiments, the chromatography system further comprises a converter as described above.

According to one embodiment there is provided a chromatography system comprising plural fluid handling components fluidically interconnectable by fluid tubing <NUM> to form a chromatography fluid flow path, said fluid handling components comprising one or more fluid ports with a spigot extending from a component face and for receiving a respective end of the fluid tubing such that the fluid tubing end sealingly embraces the spigot and for receiving a releasable locking clamp for applying a radial locking force on an outer surface of the tubing end for locking the fluid tube end on the spigot, wherein the interconnection is leak proof at an internal of pressure at least <NUM> Bar preferably <NUM>, <NUM>, <NUM> or <NUM> Bar.

Claim 1:
A chromatography system (<NUM>) comprising plural fluid handling components (<NUM>-<NUM>; <NUM>) fluidically interconnectable by fluid tubing (<NUM>; <NUM>) to form a bioprocess fluid flow path, said fluid handling components comprising one or more fluid ports with a spigot (<NUM>; <NUM>'; <NUM>; <NUM>; <NUM>) extending from a component face and for receiving a respective end of the fluid tubing (<NUM>; <NUM>) such that the fluid tubing end sealingly embraces the spigot (<NUM>; <NUM>'; <NUM>; <NUM>; <NUM>) and for receiving a releasable locking clamp (<NUM>; <NUM>) comprised in the chromatography system for applying a radial locking force on an outer surface of the tubing end for locking the end of the fluid tubing (<NUM>; <NUM>) on the spigot (<NUM>; <NUM>'; <NUM>; <NUM>; <NUM>), characterised in that the interconnection withstands at least <NUM> bar, and wherein the releasable locking clamp (<NUM>; <NUM>) comprises:
a cylindrical inner component (<NUM>; <NUM>; <NUM>) for accepting the fluid tubing (<NUM>; <NUM>), said inner component including a resiliently deflectable portion (<NUM>; <NUM>; <NUM>) arranged to urge an outer surface of the fluid tubing (<NUM>; <NUM>) toward a respective spigot (<NUM>; <NUM>'; <NUM>; <NUM>; <NUM>); and
a cylindrical collar element (<NUM>; <NUM>'; <NUM>; <NUM>) having an internal through-aperture (<NUM>) for accepting the inner component (<NUM>; <NUM>; <NUM>), the through-aperture (<NUM>) and resiliently deflectable portion (<NUM>, <NUM>; <NUM>) having complementary surface formations which in a first position of the collar element (<NUM>; <NUM>'; <NUM>; <NUM>) mounted to the inner component (<NUM>; <NUM>; <NUM>) provide for resilient deflection in use, and which in a second different position do not cause said deflection.