Abstract:
A container system is disclosed, where the container system includes a housing. A chromatography cartridge is disposed in the housing. A structural support in the housing is configured to retain the chromatography cartridge within the housing. The housing is configured to withstand a certain amount of pressure generated inside the chromatography cartridge. The chromatography cartridge is disposed in the housing either in horizontal or in vertical position.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a filing under 35 U.S.C. §371 and claims priority to international patent application number PCT/US2008/067338 filed Jun. 18, 2008, published on Dec. 31, 2008, as WO 2009/002780, which claims priority to U.S. provisional patent application No. 60/946,404 filed Jun. 27, 2007; the disclosure of which is incorporated herein by reference in its entirety. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to a system and method for assembling a large-scale chromatography structure. 
       BACKGROUND OF THE INVENTION 
       [0003]    Generally, purification by liquid chromatography is a process of separation of one or more liquid components from all other liquid components of a mixture. Large-scale liquid chromatography is currently the biotech industry&#39;s most widely utilized, if not the only, means of purification of biopharmaceuticals. Such purification is necessary in order to separate the therapeutic component of interest from all other impurities with which it coexists during the process of manufacture. 
         [0004]    Large-scale chromatography is carried out in cylindrical vessels, termed columns, which are packed with a chromatography medium itself comprising of porous microscopic spherical particles. In a typical purification procedure, the liquid mixture containing the therapeutic product of interest is pumped through the column where the therapeutic binds to and is retained by the chromatography medium while the undesirable impurities flow through and out of the column without binding. The therapeutic product is thus separated out of the mixture, i.e. it has been purified. The therapeutic product can later be unbound from the chromatography medium and extracted, or eluted, from the column. Normally, a large-scale purification process utilizes 3 or 4 different columns packed with different chromatography media in order to obtain the required high degree of purity. 
         [0005]    In the industry, when a packed bed of media contained within a column has been used several times to purify several batches of the therapeutic product, the chromatography medium may become incapable of performing the purification and therefore must be taken out and replaced. The process of removing the spent chromatography medium from the column is called unpacking Similarly, the process of filling the same column with new chromatography medium is called packing Therefore, the column itself can be viewed as a fixed piece of equipment whereas the chromatography medium is viewed as a consumable. 
         [0006]    Currently, the chromatography columns utilized by the industry need to be unpacked and repacked frequently. Such unpacking and repacking is always carried out on site and is performed by operators who are trained and highly skilled in the art. Also, these operators may require specialized training and a high skill level to unpack and repack chromatography columns. The packing of a column with chromatography medium is a critical and crucial process because it is the quality of the packed bed of medium that will determine how well the column will perform the separation. A poorly packed column will not perform the separation task assigned to it. Furthermore, a poorly packed column becomes unstable and its performance is unpredictable and inconsistent—a highly undesirable state of affairs. 
         [0007]    To ensure consistency and reproducibility of column performance, every newly packed column is subjected to an evaluation test, or a battery of tests, whose objective is to determine whether or not the column can perform the separation expected of it. There are two commonly used parameters for measuring a column&#39;s performance: 1) HETP (Height Equivalent to a Theoretical Plate) and 2) Asymmetry. HETP is, in essence, a measure for the efficiency with which the column can perform the separation. The asymmetry is in a way a measure of the uniformity of the packed medium, which in itself determines how evenly the process liquid will flow though the column. 
         [0008]    Due to the complexity of packing procedures and the skills required to perform the packing, newly packed columns in the biotech industry frequently fail the evaluation tests. Such columns need to be unpacked, repacked and tested. These three processes are lengthy and costly. More importantly, repeated packing and unpacking cause unnecessary delays in manufacturing of valuable therapeutic products. Ultimately, this results in reduced quantities of product manufactured annually and subsequently to a substantial revenue loss. Therefore, there is a need for a product, which can greatly reduce the uncertainties and failures from on site packing 
       SUMMARY OF THE INVENTION 
       [0009]    The present invention has been accomplished in view of the above-mentioned technical background, and it is an object of the present invention to provide a system and method for assembling a large-scale chromatography structure. 
         [0010]    In a preferred embodiment of the invention a container system is disclosed, where the container system includes a housing. A chromatography cartridge is disposed vertically in the housing. A structural support in the housing is configured to retain the chromatography cartridge within the housing. The housing is configured to withstand a certain amount of pressure generated inside the chromatography cartridge. 
         [0011]    In another preferred embodiment of the invention another container system is disclosed that includes a housing. A chromatography cartridge is disposed horizontally in the housing. A structural support in the housing is configured to retain the chromatography cartridge within the housing. The housing is configured to withstand a certain amount of pressure generated inside the chromatography cartridge. 
         [0012]    In yet another preferred embodiment of the invention, a method for assembling a chromatography structure is disclosed that includes: providing a housing, wherein the housing is configured to open, wherein the housing is configured to withstand a certain amount of pressure; inserting a cartridge into the housing; and securing the cartridge in the housing. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0013]    These and other advantages of the present invention will become more apparent as the following description is read in conjunction with the accompanying drawings, wherein: 
           [0014]      FIG. 1  illustrates a block diagram of a large scale chromatography cartridge in accordance with the invention; 
           [0015]      FIG. 2  illustrates a block diagram of a housing for the large-scale chromatography cartridge of  FIG. 1  in accordance with the invention; 
           [0016]      FIG. 3  illustrates a block diagram of another housing for the large-scale chromatography cartridge of  FIG. 1  in accordance with the invention; and 
           [0017]      FIG. 4  is a flow-chart that of how the large-scale chromatography cartridge of  FIG. 1  is inserted into the housing in accordance with the invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0018]    The presently preferred embodiments of the invention are described with reference to the drawings, where like components are identified with the same numerals. The descriptions of the preferred embodiments are exemplary and are not intended to limit the scope of the invention. 
         [0019]      FIG. 1  illustrates a block diagram of a chromatography cartridge  100 . The chromatography cartridge  100  includes a left tube wall  101   a,  a right tube wall  101   b,  a top distributor  102   a,  a bottom distributor  102   b,  a top bed support  103   a,  a bottom bed support  103   a,  an inlet port  104  and a packing device  105 . The inlet port  104  may also be a mobile phase inlet port. Packing device  105  may be a packing device nozzle. 
         [0020]    Cartridge  100  is a self-contained device or pre-packed disposable cartridge that is packed with typical chromatography media under controlled conditions, tested and certified it constitutes a ready-to-process disposable chromatography column. When in operation, this cartridge is contained in a suitable mechanical framework or housing that conforms to international pressure-vessel codes and standards. This cartridge is intended for industrial applications in the biopharmaceutical, food and beverage, and other industries where chromatography is utilized in conventional columns. The cartridge is manufactured in sizes representative of industry standards and ranging in diameter from 400 to 2000 MM. The cartridge  100  is placed in the housing  200  as shown in  FIG. 2 , and is positioned in a way which provides for a flow direction through the packed bed of chromatography media from top to bottom or bottom to top. When positioned in such a way, cartridge  100  is said to be in a horizontal position. Alternatively, the cartridge  100  is placed in the housing  300  as shown in  FIG. 3  and is positioned in a way, which provides for a flow direction through the packed bed of chromatography media from side to side, i.e. from left to right or from right to left. When positioned in such a way, cartridge  100  is said to be in a vertical position. The vertical position of the cartridge  100  is a desired position where the floor area is limited and lifting devices are unavailable as the cartridge  100  is rolled into position. 
         [0021]    Packing device  105  is a typical packing device or packing nozzle that sits on top of the cartridge  100 . This packing device  105  is a removable element that gives access to the interior of the cartridge  100  for the introduction of and packing of typical chromatography media between the top bed support  103   a  and bottom bed support  103   b . The distributors  102   a  and  102   b  are utilized to provide equal flow over the entire cross section of the packed cartridge  100 . Bottom bed support  103   a  and the top bed support  103   b  are sealed to the bottom distributor  102   a  and top distributor  102   b.  The purpose of the bottom bed support  103   a  and the top bed support  103   b  is to contain the chromatography medium within the cartridge  100  but allows the flow of liquid through. The bed supports  103   a  and  103   b  are made from woven material with controlled pore size made from either plastic or metal. 
         [0022]    These typical distributors  102   a  and  102   b  are fixed and sealed to the standard tube walls  101   a  and  101   b.  The tube walls  101   a    101   bs  are utilized to contain the packed chromatography media in the chromatography cartridge  100  and have the appropriate strength to contain the packed chromatography media. Also, the tube walls  101   a  and  101   b  may have a cylindrical, rectangular or any kind of shape and are made from acrylic, polypropylene, polyethylene, other suitable class VI plastics, metal, or other suitable materials accepted by the industry. Distributors  102   a  and  102   b  could be all or in part included within the cartridge  100  insert or as stand alone piece as can the bed supports  103   a  and  103   b    
         [0023]    When the cartridge  100  is filled with the packed chromatography media, then the packing device  105  can be removed and replaced with a mobile phase port similar to the inlet port  104 . The inlet port  104  is utilized to provide a pathway for pumping liquids into or out of the /cartridge via the bottom distributor  102   b  and the bed support  103   b.    
         [0024]      FIG. 2  shows a housing with the large scale chromatography cartridge of  FIG. 1 . Housing  200  includes a hinge  201 , a lid  202 , a first mobile phase port  203 , a second mobile phase port  205 , the large-scale chromatography cartridge  100 , rib  207   a,  rib  207   b , rib  207   c,  rib  207   d,  rib  207   e,  rib  207   f,  rib  207   g,  rib  209   a,  rib  209   b,  rib  209   c,  rib  209   d,  rib  209   e,  rib  209   f,  rib  209   g,  left leg  211   a  and right leg  211   b . Hinge  201  is utilized to open housing  200  to insert the chromatography cartridge  100  into the housing  200  and the hinge  201  is utilized to release the chromatography cartridge  100  from the housing  200 . Hinge  201  is utilized to open and close the lid  202  that retains the chromatography cartridge  100  in housing  200 . The first mobile phase port  203  is utilized to receive the pumped liquids into the chromatography cartridge  100  and the second mobile phase port  205  is for releasing the pumped liquids from the cartridge  100 . A nozzle or packing device (not shown) may be placed on top of the housing  200  to transfer chromatography media into the cartridge  100 . In another embodiment of the invention after packing the cartridge  100  with chromatography media, the first mobile phase port  203  or the second mobile phase port  205  may be attached to a disposable expansion device (not shown), which allows for any liquid expansion during transit of the cartridge  100 . Ribs  207   a - f  and ribs  209   a - g  are utilized to provide structural support for the cartridge  100  to retain the cartridge  100  in the housing  200 . Legs  211   a  and  211   b  are utilized as support to carry or stabilize the chromatography cartridge  100 . 
         [0025]    The housing  200  is constructed of a metal such as stainless steel or another suitable material or combination of suitable materials. This housing will conform to internationally accepted pressure level codes and standards and will be capable of containing the forces generated within the cartridge  100  during operation of the cartridge  100 . Housing  200  is capable of withstanding a pressure of less than 3 bar (45 psi). As shown in  FIG. 2 , the chromatography cartridge  100  is positioned inside the housing where the process liquids flow from the first mobile phase port  203  to the second mobile phase port  205 . In another embodiment of the invention, the process liquids may flow from the second mobile phase port  205  to the first mobile phase port  203 . Cartridge  100  is disposable whereas the housing  200  is not. When the cartridge  100  expires or has been used for a predetermined number of cycles, the lid of the housing  200  is opened. The cartridge  100  is then removed and a new cartridge is inserted into the housing  200 , then the lid is closed and the system is ready for operation. Since the housing  200  does not come into contact with the product (I.E. the biopharmaceutical or drug) it does not need to be made from materials which must meet relevant FDA regulations. 
         [0026]      FIG. 3  shows another housing with the large scale chromatography cartridge of  FIG. 1 . Housing  300  includes a central flange  301 , a first mobile phase port  303 , a second mobile phase port  305 , the large-scale chromatography cartridge  100 , rib  307   a,  rib  307   b,  rib  307   c,  rib  307   d,  rib  307   e,  rib  307   f,  rib  307   g,  rib  309   a,  rib  309   b,  rib  309   c,  rib  309   d,  rib  309   e,  rib  309   f,  rib  309   g,  left rail  311 , right rail  313 , left leg  315  and right leg  317 . Housing  300  is equivalent to housing  200  so a description of housing  300  will not be described herein. Central flange  301  is utilized to open housing  300  to insert the chromatography cartridge  100  into the housing  300  and the central flange  301  is utilized to release the chromatography cartridge from the housing  300 . The central flange  301  may be a bolt or clamp used to retain the cartridge  100  in housing  300 . 
         [0027]    The components first mobile phase port  303  and second mobile phase port  305  are equivalent to their counterparts first mobile phase port  203  and the second mobile phase port  205  described above so a description will not be included herein. Ribs  307   a,    307   b ,  307   c,    307   d,    307   e,    307   f  and  307   g  are equivalent to ribs  207   a,    207   b,    207   c,    207   d,    207   e ,  207   f  and  207   g  described above so a description will not be included herein. Ribs  309   a ,  309   b,    309   c,    309   d,    309   e,    309   f,    309   g  are equivalent to ribs  209   a,    209   b,    208   c,    209   d,    209   e ,  209   f  and  209   g  described above so the description will not be included herein. Rail  311  and rail  313  are utilized to allow the two sides of the housing, the left side and the right side, to slide away from each other and thus provide an opening through which cartridge  100  can be inserted and removed from the housing  300 . Legs  315  and  317  operate in the same manner as left leg  211   a  and right leg  211   b  to support the cartridge  100  in the respective housing  300  and housing  200 . 
         [0028]    For this housing  300 , the chromatography cartridge  100  is positioned in a vertical state. This positioning of the chromatography cartridge  100  enables the process liquids to flow from the first mobile phase port  303  to the second mobile phase port  305  in a left to right motion instead of a top down motion as the cartridge  100  in  FIG. 2 . Referring to  FIG. 3 , in another embodiment of the invention, the process liquids may flow in a right to left motion in the cartridge  100  in housing  300 . Housing  300  is constructed from the same materials as housing  200 . 
         [0029]    The advantages of using housing  300  are: 1. it occupies significantly less floor space; and does not require use of hoists or other lifting devices for removing and inserting cartridges. When the expired or used cartridge  100  needs to be removed, the center flange  301  is unbolted or unclamped, and then the two halves of the housing  300  slide open along the rails  311  and  313 . The old cartridge  100  is then rolled out and the new cartridge is rolled in. 
         [0030]      FIG. 4  shows a flow-chart of how the cartridge is inserted into the housing. At block  401 , a user opens the housing  200  ( FIG. 2 ). Housing  200  is opened when the user opens the lid  201 . In another embodiment of the invention, the user opens up the housing  300  ( FIG. 3 ) by unbolting or unclamping the center flange  301  and sliding the two halves along rails  311  and  313 . Referring to  FIG. 4 , when the housing  200  is open then the user at block  403  can insert the chromatography cartridge  100  into the housing  200 . Cartridge  100  typically includes a storage solution that is used for the prevention of bacterial growth in the cartridge when the cartridge  100  is in transit to the user. The storage solution may be 20% ethanol, an antimicrobial agent, weak benzyl alcohol solution or a weak caustic solution. The cartridge  100  is secured in the housing  200  by the multiple ribs  209   a - g  and  207   a - g  and then the housing is closed when the lid  201  is closed. In another embodiment of the invention, the housing  300  ( FIG. 3 ) is opened, and then the user inserts the chromatography cartridge  100  into the housing  300 . The cartridge  100  is secured in the housing  300  by the multiple ribs  309   a - g  and  307   a - g  and then the housing  300  is closed when the center flange  301  is bolted or clamped. 
         [0031]    At block  405 , the user connects the chromatography structure as shown  FIG. 2  or  FIG. 3 . to a liquid processing unit. The standard liquid processing unit includes: a skid, sanitary hoses, sanitary clamps and gaskets. Mobile phase ports  203  and  205  are connected to the standard skid. Housing  200  and cartridge  100  are designed in such a way that when the lid  201  is closed the mobile phase ports  203  and  205  will be accessible so the necessary connections to the liquid processing unit, i.e. the skid, can be easily made. At block  407 , the user washes a storage solution (20% ethanol) out of the cartridge  100  by utilizing a water or buffer that is transferred through the liquid processing unit and mobile phase port  203  through the cartridge  100  out of the mobile phase port  205 . In another embodiment of the invention, at block  407  the user washes the storage solution out of the cartridge  100  by utilizing a water or buffer that is transferred through the mobile phase port  303  through the cartridge  100  and out of the mobile phase port  305 . Optionally, the user may test the washed cartridge to verify test results provided by the manufacturer of the cartridge in the certificate of analysis. The cartridge  100  is ready for use by the user. 
         [0032]    Next, at block  409  the user determines if the cartridge  100  can be used again. If it is determined that it can be used again then the process returns to block  407 , if the cartridge  100  can not be used again then at block  411  the cartridge  100  is removed from the housing  200 . After the user removes cartridge  100  by taking the cartridge  100  out of housing  200  by opening the lid  201  and removing the cartridge  100 , then this process ends. In another embodiment of the invention, when the user removes the cartridge  100  from the housing  300  by unbolting or unclamping the central flange and removing the cartridge  100 , then the process ends. The user may insert a new cartridge in the housing  200 . In another embodiment of the invention, the user may insert a new cartridge in the housing  300 . 
         [0033]    This invention provides a system and method for assembling a large-scale chromatography structure. This large-scale chromatography structure provides the user with an immediately available and fully functioning cartridge that the user can use without worry about the complexity of packing it and using it. Thus, the user can avoid repeated packing and unpacking that cause unnecessary delays in manufacturing valuable therapeutic products. Also, this large-scale chromatography structure is able to withstand pressures that may be exerted on the cartridge as the cartridge undergoes testing. Thus, this invention provides the user with a simple product that can eliminate all failures and uncertainties of on-site column packing and testing. 
         [0034]    Although the present invention has been described above in terms of specific embodiments, many modification and variations of this invention can be made as will be obvious to those skilled in the art, without departing from its spirit and scope as set forth in the following claims.