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 such as screws or bolts. The invention also relates to chromatographic columns utilizing such methods. The method employs a negative pressure or vacuum 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. 
       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. Industrial-scale chromatography columns typically comprise a hollow, axially vertical tubular housing or tube including a liquid inlet at the upper 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 lower 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. 
         [0003]    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. 
         [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 non metallic 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 backing plate, a process that can be costly and difficult to implement in high quality materials like stainless steel 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. 
         [0007]    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. 
         [0008]    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. 
         [0009]    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 
       [0010]    In a first aspect of the present invention, there is provide a method of securing a distributor plate to a backing plate of a chromatography column comprising the steps of:
       a) providing a chromatography column comprising:
           a liquid inlet and a liquid outlet;   a tube in contact with an adapter assembly and a base assembly to define a cavity therebetween,   said adapter assembly and said base assembly each comprising a backing plate and a distributor plate;   sealing means between said backing plate and said distributor plate of the adapter assembly and/or between the backing plate and the distributor of the base assembly, said sealing means defining an air pocket therebetween;   the backing plate of the adapter assembly and/or the backing plate of the base assembly having a passage in fluid connection with said air pocket and a vacuum pump; and   
           b) removing the air from the air pocket via said passage with said vacuum pump to secure the distributor plate to the backing plate.       
 
         [0018]    In one aspect, the vacuum pump is not an integral part of the column, thus providing more flexibility for its use. For example, the vacuum pump may be a separate entity to the column or a component part of a separate device such as a packing station for packing chromatography columns. 
         [0019]    In another aspect, both backing plates have a passage in fluid connection with an air pocket and the vacuum pump. In this embodiment, the distributor plate of both the adapter assembly and the base assembly would be secured to each other by means of a vacuum. 
         [0020]    In a further aspect, the sealing means is one or more O-rings. Other forms of sealing means which could be used to define an air pocket are possible. The sealing means are made from an inert, compressible material such as plastic, silicone or rubber (EPDM seals being preferable). The shape of the sealing means can vary, for example they may be circular, square, rectangular or oblong in shape. A circular or O ring shape is preferable. 
         [0021]    In one aspect, locating means can be used to co-locate the backing plate and the distributor plate. Examples of locating means include but are not limited to pins or studs which fit into corresponding holes or notches. 
         [0022]    In another aspect, air is allowed to return to the air pocket to release the distributor plate from the backing plate. 
         [0023]    In a second aspect of the present invention, there is provided a chromatography column comprising:
       a) a liquid inlet and a liquid outlet;   b) a tube connected to an adapter assembly and a base assembly to define a cavity therebetween,
           said adapter assembly and said base assembly each comprising a backing plate and a distributor plate;   
           c) sealing means between said backing plate and said distributor plate of the adapter assembly and/or between the backing plate and the distributor of the base assembly, said sealing means defining an air pocket therebetween;   d) the backing plate of the adapter assembly and/or the backing plate of the base assembly having a passage in fluid connection with said air pocket; and   e) a vacuum pump       
 
         [0030]    In one aspect, the vacuum pump not an integral part of the column thus providing more flexibility for its use. For example, the vacuum pump may be a separate entity to the column or a component part of a separate device such as a packing station for packing chromatography columns. 
         [0031]    In another aspect, both backing plates have a passage in fluid connection with an air pocket and the vacuum pump. In this embodiment, the distributor plate of both the adapter assembly and the base assembly would be secured to each other by means of a vacuum. 
         [0032]    In a further aspect, the sealing means is one or more O-rings. Other forms of sealing means which could be used to define an air pocket are possible. The sealing means are made from an inert, compressible material such as plastic, silicone or rubber (EPDM seals being preferable). The shape of the sealing means can vary, for example they may be circular, square, rectangular or oblong in shape. A circular or O ring shape is preferable. 
         [0033]    In one aspect, locating means can be used to co-locate the backing plate and the distributor plate. Examples of locating means include but are not limited to pins or studs which fit into corresponding holes or notches. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0034]    The features and advantages of the invention will become apparent from the following description taken in connection with the accompanying drawings in which: 
           [0035]      FIG. 1  shows a sectional front view of a chromatography column known in the art in which the distributor plate is secured to the backing plate by screws. 
           [0036]      FIG. 2  is a schematic sectional front view of an assembly of chromatography column in accordance with the invention. 
           [0037]      FIG. 3   a  is side perspective view of a column of the invention showing a partial sectional view of an adapter assembly. 
           [0038]      FIG. 3   b  is a front perspective view of the column shown in  FIG. 3   a  but without the partial, sectional view. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0039]      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 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 the bed of chromatographic media 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 . 
         [0040]    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. 
         [0041]    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, 
         [0042]    It will be understood that separation of chemical or biological materials on the column, when the tube  106  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 . 
         [0043]      FIG. 2  shows a schematic, front sectional view of an assembly of a chromatographic column in accordance with the invention. The assembly in the figure is an example of an adapter assembly but it will be understood by the skilled person that the same principle of operation would equally apply to a base assembly. Moreover, it will be further understood that a chromatography column in accordance with the present invention may comprise both an adapter assembly and base assembly. 
         [0044]    The adapter assembly  220  comprises a backing plate  226  and a distributor plate  228 . The backing plate  226  and distributor plate  228  have a circular configuration with a central hole therein ( 226   a  and  228   a ) for ease of alignment and location around the liquid inlet/ outlet (not shown). A small number of screws  240  are present which hold the distributor  228  to the backing plate  226  in a resting position and also serve to compress the sealing means or O ring  260  to create an air pocket  229  between the backing plate  226  and the distributor  228 . In a different embodiment (not shown) these screws can also be utilized to secure a bed support to the distributor plate. 
         [0045]    An air pocket  229  is formed between the backing plate  226  and the distributor plate  228  by sealing means  260 . The size of the air pocket may be governed by the size/dimensions of the sealing means and/or the configuration of the contacting surfaces of the backing plate  226  and the distributor plate  228 . For example, a section of one or both contacting surfaces of the backing plate  226  and/or distributor plate  228  may be recessed or inlaid to create a larger air pocket  229 , as defined by sealing means  260 , when the two surfaces come into contact. The sealing means  260  is made of an inert, compressible material such as plastic, silicone or rubber (EPDM seals being preferable), and may take the form of a ring, such as an O ring. The sealing means  260  forms an airtight seal to create air pocket  229 . Air is removed from the air pocket  229  via passage  270  by a vacuum pump exerting a negative pressure of typically 0.1 to 1.0 bar. The vacuum pump may be an integral part of the chromatography column or may be separate to the column, for example part of a packing station which is used to pack the column with chromatographic media. 
         [0046]      FIG. 3   a  is a side view of a column  300  according to the invention with a partial cut away or sectional view  321  of an adapter assembly  320  showing the internal arrangement of the backing plate  326 , distributor plate  328  and bed support  329 . The distributor plate  328  is secured to the backing plate  326  by means of a vacuum which is applied from a vacuum pump (not shown) which is external to the column  300 . The vacuum pump may be an integral part of the column or it may be a separate entity or part of another device (e.g. a packing station for packing the column with chromatographic media). Although not shown in the figure, an air pocket is created by sealing means, such as an O-ring, between the contacting surfaces of the backing plate  326  and distributor plate  328 . Air can be removed via a passage (not shown) in the backing plate  326  by application of a negative pressure. In operation, a vacuum of 0.1 to 1 bar is applied by a pump to remove air from the chamber and secure the distributor plate  328  to the backing plate  326 . Optionally, a base assembly (not shown) may be present in the column  300  which utilizes a vacuum to secure the backing plate to the distributor. 
         [0047]    A control box ( 390 ) on the top of the column  300  may for example employ red or green (flashing) lights  392  to highlight that a vacuum has been applied and that the column  300  is ready for use. 
         [0048]    The column is then operational and may be used for the separation and/or purification of chemicals and/or biomolecules. On completion of the separation and/or purification process, the vacuum is released and the backing plate may be removed from the distributor plate for cleaning purposes or inspection without the need to remove many screws or bolts. 
         [0049]      FIG. 3   b  is a front perspective view of the column shown in  FIG. 3   a  but without the partial cut away or sectional view. As can be seen, externally viewed the column is very similar to the column shown in  FIG. 1  and has the same component parts as described above for the prior art column. The column  300  is fabricated from strong, inert materials such as stainless steel, and is supported on legs  302  having feet  304  which may be adjustable. The column comprises a cylindrical housing or tube  306  which is also made of a strong, inert material suitable for GMP environments such as stainless steel. The tube  306  separates an adapter assembly  320  from a base assembly  310 . Adjacent to the adapter assembly is a dispersion system  330  for the introduction of buffer or other mobile phase liquids or chemicals/biological molecules to be separated and/or purified. As discussed in relation to the prior art column described in  FIG. 1  above, the adapter assembly  320  may be movable within the cavity of the tube  306  in an operational mode to pack or compress the bed of chromatographic media used in the chromatographic separation of chemicals and biological molecules. 
         [0050]    The significant difference in the column of  FIG. 3   b  to the prior art column of  FIG. 1  is that the distributor plate of the adapter assembly is secured to the backing plate by means of a negative pressure or vacuum (as described in  FIG. 3   a  above) rather than by many releasable fixing means such as screws or bolts. Optionally, and in addition to this feature, the base assembly may also be designed to utilize this same method to secure the backing plate to the distributor and thus obviate the need for many fixing means such as screws or bolts. 
         [0051]    This feature not only simplifies the design and manufacture of the adapter and backing assembly but also simplifies the workflow in setting up and cleaning the column, thus saving operator time and reducing potential errors. 
         [0052]    The skilled person will understand that either or both the adapter assembly and the base assembly may be configured to enable securing of the distributor to the backing plate. 
         [0053]    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.