Abstract:
A chromatography column is normally filled with a slurry of media for operation. A piston normally compacts the slurry in the column. The piston moves through a cavity in communication with both a slurry inlet and slurry ports which are in communication with the interior of the chromatography column. A controller receiving inputs from at least one of position sensors and a pressure sensor directs movement of the plunger in an operational step selected from the group of a selected movement and up to a selected pressure.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     1. Field of the Invention  
         [0002]     The present invention relates an apparatus and method of operating a chromatography column and, more particularly, to such a chromatography column and a method for effectively packing media and/or ensuring that the top flow adapter remains within a tolerance of being level and/or automatically moving the top flow adapter to at least one predetermined position.  
         [0003]     2. Description of Related Art  
         [0004]     Chromatography is a process of separating the components of a mixture of chemical substances through the percolation of fluid through a body or bed of comminuted or porous rigid material, known as media. In the process, the various component are often resolved, or separated, by their selective retardation as they are transported through the bed by a moving fluid or buffer. A solution of the substances to be separated becomes the moving phase of the system passing through the interstices in the stationary or continuous phase which are finely divided particles, possibly in the form of a gel slurry.  
         [0005]     The substances in the moving phase are poured into the top of a chromatography column filled with the finely divided material, i.e., the media, that can absorb differentially the substances to be separated. The particular material used for the media varies widely with the substances to be separated. As the solution percolates down the column the components are separated from the buffer fluid which may be pumped back into the top of the column so as to again pass down through the bed as a carrier. The different substances as they travel down the column at different rates form bands of the different substances which are individually collected at the outlet.  
         [0006]     A chromatography column typically comprises a hollow vertically disposed cylindrical housing including a liquid dispensing section, also referred to as a top flow adapter or plunger in many embodiments, at the upper end and through which the buffer and substances to be separated are dispensed to the media bed, and a liquid collecting section at the lower end for collecting the substances and buffer individually. The media or bed through which the buffer fluid and mixture to be separated and purified percolates is located between these sections. The liquid dispensing section and liquid collecting section may each include a respective distribution plate and at least one of the plates may be connected in an assembly with an axially movable plunger-like body positioned within the housing. After the column is charged with the bed media, the plunger body is often forced toward the bottom to compress or pressurize the media bed which has been poured into the column.  
         [0007]     Prior art designs have allowed for the plunger to be moved with hydraulics manually controlled by an operator such as those shown and described in Applicant&#39;s U.S. Pat. No. 6,736,974, incorporated herein by reference. When the operator manually actuated the hydraulic controls of the prior art design, he or she would cause valves to open and shut to move the plunger up or down. There was no ability in this prior art design to have a controller move the plunger to a preset location. The operator had to attempt to stop at a preset location, which could be tricky. This is especially important during calibration steps. Also, there was no way to direct movement of one of the hydraulic cylinders independent of moving the other two in this prior art design.  
         [0008]     The hydraulics in the prior art design provided a single hydraulic pressure from a control valve to each of three cylinders which moved the plunger. There was no way to ensure that each of the three cylinders moved in a manner to ensure that the top flow adapter moved in a level manner. If one side of the plunger became temporarily lodged on the inside of the column, or on pack material, it was easy for the plunger to become somewhat canted within the column. This is undesirable. The calculations performed by the pharmaceutical companies are often done with the assumption that the media pack is uniform. A lack of uniformity could adversely affect a run of product thereby causing unintended problems and a poor quality batch of pharmaceutical product.  
         [0009]     The prior art packing technique involved an operator lowering a plunger until it stopped. If one of the cylinders encountered resistance, the other two could keep driving the plunger in a “canted” manner until they also stopped. A run of product could be performed with an unsatisfactory pack. This is believed to be undesirable.  
         [0010]     Accordingly, a need exists to improve the operational methods by providing an improved chromatography column.  
       SUMMARY OF THE INVENTION  
       [0011]     The present invention recognizes and addresses these needs and others.  
         [0012]     Consequently, it is an object of at least one embodiment of the present invention to provide a chromatography column capable of maintaining the top flow adapter at least within a predetermined tolerance of being level.  
         [0013]     It is another object of at least one embodiment of the present invention to provide a chromatography column capable of evenly packing media.  
         [0014]     It is another object of at least one embodiment of the present invention to provide a chromatography column with a controller which can move the top flow adapter to at least one predetermined position.  
         [0015]     Accordingly, the present invention provides a chromatography column having a cylinder defining a cavity for containing media therein. A top flow adapter or plunger is operatively coupled to a hydraulic piston moveable through at least a portion of the cavity within the cylinder during operation. A base is normally connected to the cylinder. The plunger may be operatively coupled to the hydraulic piston to adjust the height of the plunger above the base to provide a desired resin height between the plunger and the base for operation. The plunger may also be utilized to exert a force on the resin to “pack” the resin in the column.  
         [0016]     A controller is also provided which preferably at least assists in providing one of a number of operational capabilities not provided in the prior art. The controller receives an input relative to at least two of three of the hydraulic cylinders utilized in the preferred embodiment relating to at least one of position and/or pressure. These inputs can be utilized to move the top flow adapter relative to the column to at least one predetermined position, to pack the column to a particular pressure at each of at least some of the pistons, and/or to maintain the top flow adapter within a range of being level separate valves are used for each hydraulic cylinder in such an embodiment.  
         [0017]     The hydraulic system preferably includes at least one piston which is driven by at least one hydraulic cylinder. In the preferred embodiment, a plurality of hydraulic cylinders are utilized which are driven from a common hydraulic pressure source which is coupled to a controller. Unlike known prior art designs, the controller receives feedback related to each of the cylinders for increased performance capabilities. Upon receipt of a signal from a controller, the hydraulic cylinder(s) drive the hydraulic piston(s). Depending upon the configuration of the column, the piston(s) drive the plunger and/or the cylinder upwardly or downwardly. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0018]     The particular features and advantages of the invention as well as other objects will become apparent from the following description taken in connection with the accompanying drawings in which:  
         [0019]      FIG. 1  is a side plan view of a chromatography column according to the present invention in a first operational position; and  
         [0020]      FIG. 2  is a side plan view of the chromatography column illustrated in  FIG. 1  in a second operational position. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0021]     The present invention is concerned with a method and apparatus for permitting maintenance within a chromatography column which houses a slurry and/or media during operation.  FIGS. 1-2  depict one such chromatography column  10  with the slurry removed. The column  10  comprises an elongated hollow cylindrical housing  12 , or cylinder, having a dispersion section  14  at the top and a collecting section  16  at the bottom. The dispersion section  14  includes a cylindrical drum  18  having an upper cylindrical plunger head  20  formed at the lower end. The plunger  20  or top flow adapter is normally disposed within the upper portion of the housing  12  such as illustrated in the first operational position of  FIG. 1 . The plunger  20  may also be moved, such as with a drive system similar to the hydraulic arrangement illustrated to the second operational position of  FIG. 2 . The movement of the head  20  allows for the compression of media to “pack” resin and/or for the use of a particularly sized media column with the cavity  22  formed between the dispersion and collection sections  14 , 16  and/or between the plunger  20  and the base  64 .  
         [0022]     The dispersion section  14  may also include a product inlet  24  along with an inlet manifold  26  to distribute incoming fluid throughout a top portion of a resin column contained within the cavity  22 . An inlet screen  28  may be connected to the plunger head  20  by connectors such as TEFLON™ snaps (not illustrated) and/or an inner clamp nut  30 . The distributor plate  31  may be removable as well. A discussion of a distributor plate  31  design may be found in U.S. Pat. No. 6,190,560. A slurry fill valve  32  such as the valve taught in co-owned U.S. Pat. No. 6,190,560 may also be connected to the plunger head  20  and/or dispersion section  14 . The slurry fill valve  32  provides a way to fill the cavity  22  with resin without the need to lift the plunger  28  out of the cavity  22  within the cylinder  12 . Although a preferred dispersion section  14  is described, other dispersion sections designs could be utilized as well.  
         [0023]     In order to move the plunger head  20  in an operational mode from the first operational position shown in  FIG. 1  to the second operational position of  FIG. 2 , a drive system, illustrated as a hydraulic system is preferably utilized. Other systems, such as electric or pneumatic may be appropriate drive systems in other embodiments.  
         [0024]     The drive system is comprised of at least one, and preferably three or more, drive cylinders  34 . The drive cylinders  34  move drive pistons  36  which are coupled to the drum  18 . In the preferred embodiment, a portion of the drive pistons is a threaded portion  38  to allow for the drive piston  36  to connect or couple to connection arms  40  at specific locations relative to the drive piston  36  such as with nuts  42 , 44 . Guide rods  46  may be utilized in addition to the drive system to ensure linear movement of the drum  20  within the cavity  22  of the cylinder  12 .  
         [0025]     The drive system also includes a control unit  48  which may be operated to control movement of the plunger  20 . The control unit may have a hydraulic engine which provides fluid under pressure to operate the drive cylinders  34  or may be connected to a hydraulic supply. Controls  50  allow an operator to direct the movement of the plunger  20  within the cylinder  12 . Controls  50  may allow for operation of the hydraulic engine, or pump, a float switch, direction of movement selection and/or controlling valves. Gauges  52  allow for the operating parameters to be monitored. Gauges  52  may monitor air pressure, column pressure and/or drive system pressure, such as hydraulic pressure.  
         [0026]     The control unit  48  is also preferably equipped with a controller which is a hydraulic control unit (HCU)  54 . The HCU is preferably equipped with a touch screen  56  for operation of at least certain functions of the HCU  54 . As discussed below, some of the operations which can be performed and or assisted by the HCU include the movement of the top flow adapter through the movement of the plunger  20  up and down a predetermined amount, movement of the plunger to a preset height, movement of the plunger in a pack process, and an auto level movement of the plunger  20  as will be discussed in further detail below. It will be understood to one of ordinary skill in the art that as the plunger  20  moves, so does the top flow adapter in the preferred embodiment.  
         [0027]     The column  10 , unlike prior art configurations, utilizes sensors which provide input to the HCU  54  which can then vary signals to control operation of certain procedures in an improved manner as will be discussed below. The cylinders  34  preferably have sensors  58  in communication therewith which can sense a pressure. Sensors  58  provide an output which is received by the HCU  56  in the preferred embodiment. Sensors  60  which sense position are also employed which provide a position relative to each of the pistons  36 . Output from sensors  60  is also provided to the HCU  54 .  
         [0028]     Position sensors  60  in cooperation with the HCU  54  provide various capabilities which have not been achievable with prior art designs. First, an operator can select from one of a plurality of preset positions for the plunger  20  to be positioned relative to the cylinder  12 .  FIG. 1  and  2  show two of various positions of plunger  20  relative to cylinder  12  which could be pre-selected.  
         [0029]     In operation, the operator may utilize a touch screen  56 , or other input device, to input which of the predetermined positions the plunger  20 , and thus the top flow adapter, should be moved. The HCU  54  preferably then directs selective opening of valves  62  to each of the cylinders  36  to provide for the desired piston movement with the hydraulic system. Predetermined positions could be relative positions such as up or down six inches and/or to a set pre-pack position of providing the top flow adapter at two inches below the top of the column cylinder  12 .  
         [0030]     The HCU  54  also preferably normally operates in what is believed to be a new auto level configuration. Since each of the pistons  36  which control movement of the plunger  20  are equipped with position sensors  60 , the output from these sensors  60  received by the HCU  54  can be utilized. The elevation of each of the pistons  36  or other elevation corresponding to each of the lifting units connected to the plunger can be monitored. Should any particular elevation deviate from one of the other measured elevations, or any two deviate from the other in the preferred embodiment a correction can be made to place the elevations back within a tolerance range of one another. Corrections can include sounding an alarm and/or stopping at least one, if not two or more of the cylinders while one or more of the others level out.  
         [0031]     The HCU  54  can direct the selective opening and closing of at least some of the valves  62  which are in communication with respective cylinders  34  or other appropriate driver to ensure that the top flow adapter and the plunger  20  remain level within the chromatography cylinder  12 . By level, it will be understand that being within a predetermined tolerance range of level will be sufficient, such as within a centimeter for a two meter diameter cylinder  12 , or other appropriate first tolerance.  
         [0032]     If the plunger  20  somehow goes beyond a second tolerance (outside of the first tolerance), it may be preferable for the HCU  54  to secure any further movement of the plunger  20  and/or sound an alarm until the situation can be addressed. The HCU  54  in the preferred embodiment provides the ability for selected cylinders  34  to be controlled to correct such a situation.  
         [0033]     Another advantage of using the HCU  54  of the preferred embodiment is the ability to automate the packing process. The output from one or more pressure sensors  60  which could relate to back pressure on the cylinders  34  and/or pressure within the cavity  22 . By having the HCU downwardly direct the plunger  20  until reaching a predetermined backpressure as measured from the sensor, and preferably while employing the auto level feature, the HCU can secure downward movement upon reaching the set pressure and/or after a predetermined time after reaching the set pressure.  
         [0034]     The sensed pressure from one or more sensors  58  provide an input to the HCU  54  which then applies a pressure setpoint to determine a pressure error. This pressure error is applied with a damping factor to attempt to minimize overshoot of a desired pressure.  
         [0035]     The HCU may also provide the ability to stop movement of the plunger  20 , such as if the operator decided to terminate the automated packing process and/or to move the top flow adapter to a preset height.  
         [0036]     The HCU may also provide an ability to de-pressurize the hydraulic system. This can stop top flow adapter movement and reduce top flow adapter pressure. A pneumatic pump and/or system may be vented to depressurize the hydraulic system. Other venting or depressurizing techniques could also be utilized. This provides an advantage of using a controller  48  with multiple columns  10  (i.e., once a column is set up for operation, the controller  48  can then be moved to prepare another column for operation).  
         [0037]     The new controller  48  may now be utilized with various columns. The preferred embodiment of the controller  48  can identify the type and/or height of the column to which it is connected. This can be advantageous as different control parameters may be utilized with different sized columns. A PLC (or other computer) within the controller such as HCU, or otherwise, upon connection with a cable  64 , senses inputs which can be combined as binary numbers (such as the preset open or closed condition of two switches) to identify cylinder diameter and/or cylinder stroke and/or max bed height, etc. The switches provide inputs to the HCU  54  through cable  64  or otherwise.  
         [0038]     While the HCU  54  can provide a plurality of automated features, it is also anticipated that it can provide for manual operation including operation of separate valves  62  to respective cylinders (which was not an option in the prior art). Of course, any and potentially all of the automated features can be selected to be off through use of input such as touchscreen  56 .  
         [0039]     By using the inputs to HCU  54 , alarms can be provided such as if the plunger  20 , and/or top flow adapter is tilted past a predetermined tolerance, if the top flow adapter is lifted up past an upper height limit, if the column is disconnected (i.e., no top flow adapter is sensed), if the cable  64  is disconnected.  
         [0040]     The HCU preferably includes a PLC which is provided with the controller  48 . The PLC used in one operational version is an Allen-Bradley (A-B) MocroLogic  1500  Processor with I/O modules. This PLC monitors and controls the operation of three cylinders that support the plunger. The touchscreen  56  is an A-B PanelView  550 . Rockwell Automation Software including RSLogix  500  were utilized to develop the PLC programming, PanelBuilder 32  was utilized to develop a graphics interface and RSLink was utilized to communicate downloads to the PLC as well as interface with a PC and the touchscreen  56 . Other software and hardware as known in the art could also be utilized.  
         [0041]     The component parts, such as the drum  18 , the cylinder  12 , and the base are preferably constructed from stainless steel and/or high nickel alloy and/or acrylic. The drive system may be constructed out of appropriate materials including stainless steel. Three or more legs  76 , only two of which are illustrated, are connected to the base  64 . The drive cylinders  34  are connected to the rim  70  of the base.  
         [0042]     Numerous alternations of the structure herein disclosed will suggest themselves to those skilled in the art. However, it is to be understood that the present disclosure relates to the preferred embodiment of the invention which is for purposes of illustration only and not to be construed as a limitation of the invention. All such modifications which do not depart from the spirit of the invention are intended to be included within the scope of the appended claims.