Abstract:
The present invention relates to methods for securing a distributor plate to a backing plate of a chromatography column without the need for releasable fixing means as screws or bolts. The invention also relates to chromatographic columns utilizing such methods. The method employs a negative pressure or vacuum that is generated internally within the column to affix the distributor to the backing plate.

Description:
TECHNICAL FIELD 
       [0001]    The present invention relates to chromatography columns and their component parts. In particular, the present invention relates to methods for securing a distributor plate to a backing plate of a chromatography column without the needs for bolts or screws. 
       BACKGROUND TO THE INVENTION 
       [0002]    Chromatography columns may be used in industrial processes to purify process liquids and separate substances of interest from process liquids; typical examples include large-scale preparative purification of fine chemicals and pharmaceuticals, together with biological products. 
         [0003]    Industrial-scale chromatography columns typically comprise a hollow, axially vertical tubular housing or tube including a liquid inlet at the upper end or lower end and through which the buffer and substances to be separated are dispensed to the media bed located within the cavity of the tube, and a liquid collecting system at the other end for collecting substances and buffer. The particulate chromatographic media or bed through which the buffer fluid and/or substances to be separated and purified percolates is located between the liquid inlet and collecting system. An adapter assembly is typically affixed to the upper end of the tubular housing and a base assembly to the lower end where it is bolted to the bottom flanges. Each of these assemblies typically comprises a strong backing plate and a distributor which further supports a bed support: a bed support is a layer of mesh, filter, sinter, screen or other fluid-permeable media-retaining material which permits process liquid flow into and out of the chromatography bed space or cavity while retaining the bed of particulate medium. To provide adjustability and control of the bed height and bed compression, the adapter assembly is typically made in the form of a piston or sliding adapter in the column tube interior. After the column is charged with bed media, typically through a nozzle, the adapter may be forced toward the bottom of the tube to compress or pressurize the media bed. Generally the base assembly is a fixed structure which is bolted against the bottom flange of the column tube but, in some instances, may also be in the form of a movably slidable piston or adapter. 
         [0004]    The backing plate of the base assembly generally acts as a support for the column, being itself supported on legs or some other stand arrangement which allows clearance for outlet pipe work projecting beneath the base assembly. However, in some columns clearance may not be sufficient for easy maintenance. 
         [0005]    Prior art adapter and base assemblies are formed by screwing or bolting the distributor plate into the backing plate by means of bolts or screws. As the distributor is made of inert nonmetallic materials, such as plastic, it may become distorted during the operation of the column when it is subjected to internal pressures ranging from −1 bar to +5 bar. To overcome this problem, the distributor is secured to the backing plate with many screws or bolts. This process typically requires helicoil threads being cut into the distributor plate, a process that can be costly and difficult to implement in high quality materials like stainless steel, polypropylene and other materials which are suitable for use in a GMP environment, and securing the distributor to the backing plate using appropriately threaded screws or bolts. 
         [0006]    A significant number of such bolts or screws are required (e.g. in 1 meter diameter column there would typically 20 to 40 screws or bolts and for a 2 meter diameter column approximately 100 to 150 screws or bolts) to secure the distributor to the backing plate as the resulting assembly must be able to withstand back compression pressures when, for instance, the column is being packed. The process of securing the distributor plate to the backing plate by the use of screws and/or bolts can be time consuming when the chromatography column is initially being set up for operation. Errors may occur in the set up process when screws or bolts of the wrong length or incorrect bore are used, resulting in a weaker seal between the component parts. 
         [0007]    Corrosion of the screws or bolts, and of the screw threads, can occur with time and repeated use of the column. Furthermore, the cleaning and/or maintenance of the column often necessitates the separation of the distributor plate from the backing plate. Once again, this process requires time to carefully unscrew or unbolt the distributor from the backing plate. 
         [0008]    There is therefore a need for chromatography columns which have a simpler, cost-effective means of securing the distributor plate to the backing plate to overcome the above mentioned problems encountered in the prior art. 
       SUMMARY OF THE INVENTION 
       [0009]    According to a first aspect of the present invention, there is provided a method of securing a distributor plate to a backing plate of a chromatography column by generating an internal vacuum therebetween. The term ‘internal vacuum’ as used herein means a vacuum or negative pressure which is produced in the course of operating the chromatography column, in contrast to a vacuum or negative pressure which is exerted by means of applying a negative pressure using a device such as a pump. Thus, for example, the movement of the component parts within a chromatography column can be configured to generate an internal vacuum. In one embodiment, the relative movement of the adapter assembly and the base assembly can be utilized to produce the internal vacuum. 
         [0010]    In one aspect, the chromatography column comprises an adapter assembly and/or a base assembly and movement of said adapter assembly and/or said base assembly generates said internal vacuum between said distributor plate and said backing plate. 
         [0011]    In another aspect, the method comprises the steps of:
       a) providing a chromatography column comprising:
           a tube in contact with an adapter assembly and a base assembly to define a cavity therebetween;   said cavity being in fluid connection with the exterior of the column via a closable adapter port and/or a closable base port;   the adapter assembly and/or the base assembly being movable within said cavity;   at least one of said adapter assembly and said base assembly comprising a backing plate in contact with a distributor plate to define an air pocket therebetween;   said air pocket being in fluid connection with the cavity via a closable passage in the distributor plate of the adapter assembly and/or the base assembly;   
           b) closing said passage in the adapter assembly and/or the base assembly;   c) moving the adapter assembly and/or the base assembly towards each other to remove air from the cavity;   d) closing the port in the adapter assembly and/or the base assembly;   e) opening the passage in the adapter assembly and/or the base assembly;   f) moving the adapter assembly and/or the base assembly away from each other to remove air from the air pocket; and   g) closing the passage in the adapter assembly and/or the base assembly to secure the distributor plate to the backing plate.       
 
         [0024]    In one aspect, the distributor plate is the adapter distributor plate and the backing plate is the adapter backing plate. Alternatively, the distributor plate may be the base distributor plate and the backing plate is the base distributor plate. It will be understood that the method of the invention may involve a column in which both the adapter assembly and the base assembly comprise a backing plate in contact with a distributor plate to define an air pocket therebetween. 
         [0025]    In another aspect, the face of the distributor plate in contact with the backing plate is reinforced, for example by ribbing, rods or other suitable forms of reinforcement. The purpose of the reinforcement is to prevent any distortion of the distributor plate when it is subjected to a vacuum or negative pressure. 
         [0026]    In one aspect, locating means are used to co-locate the backing plate and the distributor plate. 
         [0027]    In a further aspect, the method additionally comprises the step of allowing air to return to the air pocket to release the distributor plate from the backing plate. 
         [0028]    In yet another aspect, the method additionally comprises the step of securing the column tube to the base distributor plate by generating an internal vacuum therebetween. 
         [0029]    According to a second aspect of the present invention, there is provided a chromatography column comprising a movable adapter assembly and /or base assembly configured to generate an internal vacuum for securing a backing plate to a distributor plate. 
         [0030]    In one aspect, the chromatography column comprises:
       a tube in contact with an adapter assembly and a base assembly to define a cavity therebetween;   said cavity being in fluid connection with the exterior of the column via a closable adapter port and/or a closable base port;   the adapter assembly and/or the base assembly being movable within said cavity;   at least one of said adapter assembly and said base assembly comprising a backing plate in contact with a distributor plate to define an air pocket therebetween; and   each said air pocket being in fluid connection with the cavity via a closable passage in the distributor plate of the adapter assembly and/or the base assembly.       
 
         [0036]    In one aspect, the distributor plate is the adapter distributor plate and the backing plate is the adapter backing plate. Alternatively, the distributor plate may be the base distributor plate and the backing plate is the base distributor plate. It will be understood that both the adapter assembly and the base assembly may comprise a backing plate in contact with a distributor plate to define an air pocket therebetween. 
         [0037]    In another aspect, the port or the passage is controlled by manual, electrical or pneumatic means. 
         [0038]    In a further aspect, the face of the distributor plate in contact with the backing plate is reinforced, for example by ribbing, rods or other suitable forms of reinforcement. The purpose of the reinforcement is to prevent any distortion of the distributor plate when it is subjected to a vacuum or negative pressure. 
         [0039]    In one aspect, the column comprises locating means to co-locate the backing plate and the distributor. 
         [0040]    In another aspect, the column is additionally configured to generate an internal vacuum for securing the base distributor plate to the column tube. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0041]    The features and advantages of the invention will become apparent from the following description taken in connection with the accompanying drawings in which: 
           [0042]      FIG. 1  shows a sectional front view of a chromatography column known in the art in which a distributor plate is secured to a backing plate by screws. 
           [0043]      FIG. 2  is a schematic sectional front view of a different prior art chromatography column known in the art in which the distributor plate in which fixing means are used to secure a distributor plate to a backing plate. 
           [0044]      FIGS. 3   a - e  are schematic sectional view of a column according to the invention depicting the various stages of its operation in securing the base distributor plate to the base backing plate by generating an internal vacuum. 
           [0045]      FIG. 3   a  is a sectional front elevation of a column according to the invention with ports  311  and  321  open prior to expelling air from cavity  308 . 
           [0046]      FIG. 3   b  is a sectional front elevation of the column of  FIG. 3   a  having expelled air from cavity  308 . 
           [0047]      FIG. 3   c  is an inset of portion A of the column of  FIG. 3   b.    
           [0048]      FIG. 3   d  is a sectional front elevation of the column of  FIGS. 3   a  to c wherein the passages  315  and  313  are closed. 
           [0049]      FIG. 3   e  is an inset of portion a of the column of  FIG. 3   d.    
           [0050]      FIGS. 4   a  and  b  are schematic sectional front views of a column according to the invention depicting the various stages of its operation in securing the base distributor plate to the base backing plate and the column tube by generating an internal vacuum. 
           [0051]      FIG. 4   a  is a sectional front elevation of a column before a vacuum is applied and passage  415  is in an open configuration. 
           [0052]      FIG. 4   b  is a sectional front elevation of the column of  FIG. 4   a  after a vacuum has been applied. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0053]      FIG. 1  is a sectional front view of a chromatography column  100  known in the art. The column  100  is made of strong, inert materials such as stainless steel and other materials which are suitable for use in a Good Manufacturing Practice (GMP) environment typical of the pharmaceutical industry. The column  100  is supported on legs  102  having feet  104  which are adjustable in order to modify the height and/or the level of the column. The legs  102  support the column  100  which comprises a cylindrical housing or tube  106  defining a cavity  108 , for receipt of chromatographic media, separating a base assembly  110  at one end from an adapter assembly  120  at the other. The tube  106  may typically be made from stainless steel, or other strong, inert materials. Adjacent to the adapter assembly  120  is a dispersion system  130  comprising a nozzle  132  which includes a mobile phase pathway  134 , for the introduction of buffer or other suitable mobile phase liquids or chemicals/ materials to be separated, and a liquid inlet  136 . The adapter assembly  120  may be moveable within the cavity  108  of the tube  106  in an operational mode, for example, to pack or compress a bed of chromatographic media (not shown) present in the cavity  108  which is used to effect chromatographic separation of chemicals within the column. In the figure, the adapter assembly  120  comprises an adapter flange  122 , one or more distance pillars  124 , a backing plate  126  made typically of stainless steel, a distributor  128  made from inert, non-metallic material which may take the form of a plate having many channels to effect the even distribution of liquids, and a bed support  129  comprising a screen or mesh or filter and optionally a sealing ring (not shown). The bed support  129  may be made of an inert plastic or metal material such as stainless steel. The distributor  128  and bed support  129  are fastened to each other by releasable fixing means (not shown). Typical releasable fixing means  140  which secure the distributor  128  to the backing plate  126  include, but are not limited to, screws and bolts. Generally, the fixing means is a screw which is inserted through a threaded hole in the backing plate  126  into the distributor  128 . 
         [0054]    The fixing means  140  may be accessed and thus released from the exterior face of the distributor  128  or backing plate  126 , that is the face of the plate furthest away from the cavity  108 . Access may be gained from the exterior face of the backing plate or distributor to avoid unnecessary exposure of the operator to a suspended or supported load within the column. 
         [0055]    The base assembly  110  comprises a backing plate  112  and a distributor  114 , fastened to each other by releasable fixing means  140 , and a bed support  116 . The backing plate  112  is made typically of stainless steel while the distributor  114  may take the form of a plate having many channels to effect the even distribution of liquids. The bed support  116  comprises a screen or mesh or filter and optionally a sealing ring (not shown) and is attached to the distributor  114  by releasable fixing means (not shown). The bed support  116  may be made of an inert plastic or metal material such as stainless steel. The fixing means  140  can take the form of a screw or bolt inserted through corresponding holes around the perimeter of the components; typically the fixing means is a screw which is inserted through a hole in the backing plate  112  into a threaded aperture in the distributor  114 . In the example shown, access is obtained from the exterior face of the backing plate  112  to avoid operator exposure beneath a suspended load. 
         [0056]    It will be understood that separation of chemical or biological materials on the column, when the cavity  108  is full of chromatographic media, can be carried out in either a downward or upward flow. Thus, in a downward flow, liquid containing chemical or biological materials to be separated is introduced through nozzle  132  and moves in a downward direction through the bed of media, to be collected in the collection system at the base of the column through nozzle  152  of dispersion system  150  via an outlet port  154 . In upward flow mode, liquid containing materials to be separated is introduced via the bottom nozzle  152  and flows upwards through the media bed to be collected at the top of the column via nozzle  132  and inlet  136 . 
         [0057]      FIG. 2  is a sectional front view of a chromatography column  200  known in the art. The column  200  is made of strong, inert materials such as stainless steel and other materials which are suitable for use in a GMP environment typical of the pharmaceutical industry. The column  200  is supported on stand  202  having feet  204  which are adjustable in order to modify the height and/or the level of the column. The stand  202  supports the column  200  which comprises a cylindrical housing or tube  206  defining a cavity  208 , for receipt of chromatographic media, separating a base assembly  210  at one end from an adapter assembly  220  at the other. The tube  206  may typically be made from stainless steel, or other strong, inert materials. Adjacent to the base assembly  210  is a dispersion system  250  comprising a nozzle  252  which includes a mobile phase pathway  256 , for the introduction of buffer or other suitable mobile phase liquids or chemicals/ materials to be separated, and a liquid inlet  254 . The adapter assembly  220  may be moveable within a cavity  208  of the tube  206  in an operational mode, for example, to aspirate media, to prime the column, or to pack or compress the bed of chromatographic media used to effect chromatographic separation of chemicals within the column. 
         [0058]    In  FIG. 2 , the adapter assembly  220  comprises an adapter flange  222 , one or more distance pillars  224 , one or more connecting rod  260 , top plate  264 , a backing plate  226  made typically of stainless steel, drive system  262 , a distributor  228  made from inert, non-metallic material which may take the form of a plate having many channels to effect the even distribution of liquids, and a bed support  229  comprising a screen or mesh or filter and optionally a sealing ring (not shown). The bed support  229  may be made of an inert plastic or metal material such as stainless steel. The distributor  228  and bed support  229  are fastened to each other by releasable fixing means (not shown). Typical releasable fixing means  240  which secure the distributor  228  to the backing plate  226  include, but are not limited to, screws and bolts. Generally, the fixing means is a screw which is inserted through a threaded hole in the backing plate  226  into the distributor  228 . The fixing means  240  may be accessed and thus released from the exterior face of the distributor  228  or backing plate  226  that is the face of the plate furthest away from the cavity  208 . Access may be gained from the exterior face of the backing plate or distributor. 
         [0059]    The base assembly  210  comprises a backing plate  212  and a distributor  214 , fastened to each other by releasable fixing means  240 , and a bed support  216 . The backing plate  212  is made typically of stainless steel while the distributor  214  may take the form of a plate having many channels to effect the even distribution of liquids. The bed support  216  comprises a screen or mesh or filter and optionally a sealing ring (not shown) and is attached to the distributor  214  by releasable fixing means (not shown). The bed support  216  may be made of an inert plastic or metal material such as stainless steel. The fixing means  240  can take the form of a screw or bolt inserted through corresponding holes around the perimeter of the components; typically the fixing means is a screw which is inserted through a hole in the backing plate  212  into a threaded aperture in the distributor  214 . 
         [0060]    It will be understood that separation of chemical or biological materials on the column, when the cavity  208  is full of chromatographic media, can be carried out in either a downward or upward flow. Thus, in an upward flow, liquid containing chemical or biological materials to be separated is introduced through dispersion system  250  via inlet  256  and nozzle  252  and moves in an upward direction through the bed of media, to be collected in the collection system from the top of the column through dispersion system  230  via an outlet port  234 . In downward flow mode, liquid containing materials to be separated is introduced through dispersion system  230  via an outlet port  234  and flows downwards through the media bed to be collected at the bottom of the column through dispersion system  250  via nozzle  252  and port  254 . 
         [0061]      FIGS. 3   a - e  is a schematic sectional view of a column according to the invention depicting the various stages of its operation. The figure details the method of securing the distributor plate  314  to a backing plate  312  of the base assembly  310  by the generation of an internal vacuum between the components but it will be understood that the same principle would be applicable for securing the distributor plate  328  to the backing plate  326  of the adapter assembly  320 . It will also be understood that columns according to the invention may consist of a combination of adapter and base assemblies where one or both assemblies secure the distributor plate to the backing plate by means of an internally generated vacuum. 
         [0062]    The column  300  of  FIG. 3   a  comprises a base assembly  310  and an adapter assembly  320  in contact with a tube  306  to define a cavity  308 , which is filled with air, for containment of chromatographic media (not shown). The base assembly  310  comprises a backing plate  312  which is in contact with a distributor plate  314 ; the contacting surfaces of the plates  312  and  314  are configured such that a cavity or air pocket  313  is formed when they are in contact. The distributor plate  314  may reinforced, as for example by ribbing  314 ′, to prevent distortion when it is stressed. Furthermore, the base assembly  310  has a closable port  311  which is in fluid connection with the cavity  308  and the exterior of the column. With ports  311  and  321  open, passages  315  and  325  are closed and air is removed from the cavity  308  by moving the adapter assembly  320  and the base assembly  310  towards each other, typically by moving the adapter assembly  320  towards the base assembly  310 . 
         [0063]    Following removal of air from the cavity  308 , ports  311  and  321  are closed and one or both of the base assembly passage  315  and the adapter assembly passage  325  are opened. In the example given in  FIG. 3   b , both passages  315  and  325  are in the open configuration. 
         [0064]      FIG. 3   c  is an enlarged inset giving the detail of section A of the column  300 . While the inset shows how an actuator  317  controls the opening and closing of the passage  315  it will be understood that other means are available for controlling this process and that other embodiments of the invention are feasible (e.g. electrical /manual/pneumatic actuated or any other valves controlling the opening and closing of passage). The actuator  317  is free to move within the base backing plate  312 , air pocket  313  and passage  315 , shown here as a bore hole within the base distributor plate  314  and the base bed support  316 . A series of gaskets or o-rings  318  of different sizes provide air-tight seals between the component parts (e.g. between the baking plate  312  and the distributor plate  314 , between the bed support  316  and the distributor  314 ). In the figure, the actuator  317  is in the open position such that there is a fluid connection between the air pocket  313  and the cavity  308 . The actuator  317  will be in this open or resting position when there is no vacuum within the cavity  313 . The adapter  320  and base  310  assemblies are then drawn apart, typically by raising the adapter assembly  320  within the tube  306 , to draw air from the air pocket  313  via open passage  315 . As there is no differential pressure on either side of the distributor plate  314  the plate  314  will not become twisted or deformed in any way. 
         [0065]    The final step in the process of securing the distributor plate  314  to the backing plate  312  is depicted in  FIGS. 3   d  and  3   e . Passage  315  is closed and then port  311  and/or  321  is opened to give atmospheric pressure within the cavity  308  and a negative pressure within the pocket  313 , thus establishing a differential pressure across the distributor plate  314  ( FIG. 3   d ) which secures distributor plate  314  to the backing plate  312 . 
         [0066]      FIG. 3   e  is an enlarged inset giving the detail of section A of the column  300 , in which the component parts are identical to those described for  FIG. 3   c  above. In  FIG. 3   e , the actuator  317  has been drawn to form a seal with gasket/o-ring  315  and effectively close base passage  315  to the influx or efflux of air. 
         [0067]    The column may now be primed and filled with chromatographic media. 
         [0068]    To separate the base backing plate  312  from the distributor plate  314 , adapter  317  is retracted from its sealing position with gasket/o-ring  318  to open passage  315  and release the vacuum within the pocket  313 . Once the vacuum has been released, the backing plate  312  and the distributor plate  314  are no longer secured together. 
         [0069]      FIGS. 4   a  and  4   b  are schematic sectional views of a column according to the invention which has been modified to secure the base distributor plate to the backing plate and to the column tube by means of an internally generated vacuum. 
         [0070]      FIG. 4   a  shows a portion of a column, which is essentially identical to that shown in  FIG. 3   c  described above, except that the air pocket  413  between the base backing plate  412  and the distributor  414  has been extended  413 ′ to be in fluid communication with an air pocket or hollow  407  in the column tube  406  and that gaskets  418 ′ provide an air-tight seal between the base of the column tube  406  and distributor plate  414 . In the arrangement shown, with the adapter assembly  420  having removed air from cavity  408  (as described for  FIG. 3   a  above), actuator  415  is not in sealing contact with gasket/o-ring  418  such that the column cavity  408  is in fluid communication with air pocket  413  and hollow  407  via air pocket  413 ′. 
         [0071]    As described above, the actuator  417  will be in this open or resting position when there is no vacuum within the cavity  413 . The adapter  420  and base assemblies are then drawn apart, typically by raising the adapter assembly  420  within the tube  406 , to draw air from the air pocket  413 ,  413 ′ and hollow  407  via open passage  415 . 
         [0072]    The last step in the process of securing the distributor plate  414  to the backing plate  412  and the column tube  406  is shown in  FIG. 4   b . Passage  415  is closed when adapter  417  moves to form a seal with gasket/o-ring  418 . Port  311  and/or  321  is opened (see  FIG. 3   d ) to give atmospheric pressure within the cavity  408  and a negative pressure within the pocket  413 ,  413 ′ and hollow  407 . This establishes a differential pressure across the distributor plate  414 , which secures distributor plate  414  to the backing plate  412 , and between the distributor plate  414  and the column tube  406 . The distributor plate  414  is strengthened or reinforced by, for example, ribbing  414 ′ to prevent distortion of the plate when it is subjected to a differential pressure. 
         [0073]    To separate the distributor plate  414  from the backing plate  412  and the column tube  406 , adapter  417  is moved to open passage  415  and release the vacuum within pocket  413 ,  413 ′ and hollow  407 . 
         [0074]    Whilst the present invention has been described in accordance with various aspects and preferred embodiments, it is to be understood that the scope of the invention is not considered to be limited solely thereto and that it is the Applicant&#39;s intention that all variants and equivalents thereof also fall within the scope of the appended claims.