Abstract:
Stackable planar adsorption devices include a plurality of layers of adsorptive media provided in a web format. The layers are stacked in contiguous fashion, sealed and include fluid passageways to provide a range of scalable chromatography devices suitable for large scale manufacturing applications.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 61/297,896, filed Jan. 25, 2010, which is incorporated by reference in its entirety. 
    
    
     TECHNICAL FIELD 
     The field of this invention is related to absorptive devices and processes, of which chromatography is an example. More specifically, this invention relates to planar adsorptive processes and devices having planarly cohesive adsorptive media. 
     BACKGROUND OF THE INVENTION 
     Adsorptive processes and devices are widely used in the analysis and purification of chemicals, including synthetic and naturally-derived pharmaceuticals, blood products and recombinant proteins. 
     Chromatography is a general separation technique that relies on the relative affinity or distribution of the molecules of interest between a stationary phase and a mobile phase for molecular separation. The stationary phase typically comprises a porous media imbibed with solvent. The mobile phase comprises a solvent, which can be aqueous or organic, that flows through the interstitial space that exists between the spaces occupied by the stationary phase. 
     Columns with associated end caps, fittings and tubing are the most common configuration, with the media packed into the tube or column. The mobile phase, is pumped through the column. The sample is introduced at one end of the column, the feed end, and the various components interact with the stationary phase by any one of a multitude of adsorptive phenomena. The differential adsorptive interaction between the components and media leads them to traverse the column at different velocities, which results in a physical separation of the components in the mobile phase. The separated components are collected or detected at the other end of the column, the eluent end, in the order in which they travel in the mobile phase. In one type of adsorptive process, referred to as capture and release process, the process involves multiple steps, first to load the media, then to wash it, and then to elute it. 
     Chromatographic methods include among other methods, gel chromatography, ion exchange chromatography, hydrophobic interaction chromatography, reverse phase chromatography, affinity chromatography, immuno-adsorption chromatography, lectin affinity chromatography, ion affinity chromatography and other such well-known chromatographic methods. 
     Adsorptive media comes in many forms, most typically in the form of beads. The beads are conventionally packed into columns, with the column walls and ends imbolizing the beads into a fixed adsorptive bed, a bed being a porous 3 dimensional structure containing the stationary phase (in this case the beads) and the pore space through which the mobile phase flows/permeates (the space between the beads). Adsorptive media may also be formed into cohesive beds that retain their shape by virtue of the cohesion in the media; just like beds made with beads, these beds have two distinct regions, one occupied by the stationary phase and another occupied by the mobile phase; this type of media are referred to as monolithic media, or simply as monoliths. Media may also be formed in the shape of fabrics or webs, which can be stacked to form an adsorptive bed. Beds made of monoliths are cohesive in 3 dimensions, whereas beds made of webs are cohesive only in 2 dimensions; beds made of beads alone have no cohesion, requiring the column to maintain its shape. The processes and devices of this invention require that the beds be (at least) planarly cohesive—i.e. cohesive in 2 dimensions—enabling the formation of planarly cohesive adsorptive blocks. 
     Planar adsorptive processes and devices have been in use. Examples of planar adsorptive processes are paper chromatography and thin layer chromatography. In these processes, the adsorptive bed has a planar geometry in contrast to the cylindrical geometry of conventional chromatography beds. The mobile phase typically flows through the stationary phase by virtue of the capillarity of the porous medium, which draws the solvent into the porous space of the media. These processes do not require that the fluid pressure be contained since the fluid is not being pumped. More recently, a form of planar chromatography has been developed in which the fluid is pumped; this process is referred to as over-pressure planar chromatography (OPPC). OPPC requires that the media be contained in apparatus that maintains the shape of the bed in spite of the pressures used. In all cases, the planar adsorptive beds used in these processes are very thin, usually no thicker than a millimeter, making them suitable for analytical applications. 
     Membrane-based adsorptive devices have been developed. In these devices the adsorptive media is either supported by or embedded into a flat micro-porous membrane, which is then fabricated into filtration devices. Two or more of these membranes may be stacked to form an adsorptive bed with a longer flow path; however, the number of layers that can be stacked is limited by the low hydraulic permeability of microfiltration membranes. Such filtration devices are characterized by the fact that the fluid being treated flows through the adsoprtive media in a direction substantially perpendicular to the planar dimension of the media. The virtue of membrane adsorbers is their fast kinetics, enabling them to have short bed depths and high feed rates. However, the same attributes that confer them with fast kinetics severely and limit their capacity. Additionally, the intrinsic geometry of existing membrane adsorbers limit their scalability, the largest ones typically being no larger than 5 liters. 
     Furthermore, the bed depth, or absorptive path length, important in purification steps requiring resolution, is limited in membrane-based devices due to the low hydraulic permeability of microporous membranes. Membrane absorptive media is expensive, because the high cost of the membrane substrate and the challenges of functionalizing the membrane surface with absorptive chemistry. Finally, membrane-based adsorptive devices inherently have low capacity, as a result membrane adsorption devices have found applicability primarily in “polishing” steps—e.g. virus and DNA removal—where the adsorptive load is negligible, rather than in the core capture/purification steps. 
     Conventional chromatographic devices require that beads must be packed into a column. The quality of this packing determines the performance of the adsorbing bed. This adds another source of variability to the chromatographic process and must be validated before use. Furthermore, beds packed with beads are prone to voiding, a phenomenon whereby the beads settle into a denser structure resulting in the creation of voids and in nonhomogeneities in the packing density of the bed, all of which results in a deterioration of performance. This is especially true in columns packed with soft beads. 
     SUMMARY 
     The special demands imposed on pharmaceutical manufacturing processes make it highly desirable that such processes be easily scaled-up. In particular, there are many advantages to processes that can be scaled-up without having to reset or redevelop the processing conditions. Such processes are referred to in the industry as linearly-scalable processes; in essence, the parameters that define the separation process and operating conditions remain unchanged as the process moves from the laboratory bench (i.e., discovery), where the column can be as small as several milliliters, to the process development laboratory (e.g., columns of several liters), to clinical manufacturing, to large-scale manufacturing, where the chromatography column can be as large as several hundred liters. Existing chromatographic devices are not linearly scaleable, their design and geometry requiring significant alterations as the device size increases, thereby introducing uncertainties and unwanted risks as processes evolve from drug discovery, to clinical trials, to small-scale and then to large-scale manufacturing. 
     It is the object of this invention to design an adsorptive device suitable for chromatography that is linearly-scalable over a large dynamic range. It is a further object of this invention to make it easy for end-users to increase the capacity of a system without having to upgrade the whole system by simply stacking the same adsorptive devices. It is a further object of this invention to design adsorptive devices with adsorptive media that is rigid, will resist the compression of the hydraulic pressures and that will not void, enabling the use of soft stationary phases, e.g. agarose, at high pressures. It is a further object of this invention to design devices that are easy to load and unload on the equipment in which the devices are being used, and to make the attachment simple and reliable to prevent operational problems. These and other features of the invention will become apparent in the detailed description below. 
     An adsorptive device, according to one embodiment, includes at least one block comprising planarly cohesive, substantially isotropic adsorptive media, the block including a first end; a second end; a first substantially planar surface; a second substantially planar surface; at least one sidewall substantially perpendicular to the first and second planar surfaces; a first plurality of distribution passageways disposed within the at least one block, adjacent the first end and substantially perpendicular to the first and second planar surfaces; a second plurality of distribution passageways disposed within the at least one block adjacent the second end and substantially perpendicular to the first and second planar surfaces; and a peripheral seal encapsulating the at least one sidewall. Such a device can be linearly scaled to operate from the process development laboratory scale, to clinical manufacturing, to large-scale manufacturing. 
     Aspects of the present invention relate to absorptive devices that have the high capacity of beads but the operational advantages of webs, and in particular webs that have the properties of native agarose in rigid form. Other aspects of the present invention relate to linearly scalable devices and absorptive devices that provide the flexibility to develop new purification processes beyond the conventional batch chromatography processes. 
     Embodiments of the invention include media in web form (as compared to beads) producing significant fabrication and structural benefits. In one embodiment the webs are stacked in cassette devices to form beds of significant thickness, exceeding several millimeters, and as large as tens of centimeters to create adsorptive devices in the form of a “cassette”. These adsorptive beds capable of being formed into beds of significant thicknesses are herein referred to as adsorptive blocks or blocks. Since the cassettes have significant thickness, the webs include distributor passageways in the height dimension (i.e. in the “stacking” dimension for the case of webs). In this embodiment, the webs have impermeable edges adhered to them. This feature allows the webs to support themselves against the tensile stresses generated by the pressure within the cassette on the sidewalls, requiring no additional structure to support the sidewalls of the cassettes. 
     In another embodiment, an adsorptive device for processing a fluid includes a pair of end plates, each plate including a feed end, a feed inlet disposed at the feed end, an eluent end, and an eluent outlet disposed at the eluent end, a plurality of cassettes in a stacked configuration, each cassette includes planarly cohesive, substantially isotropic adsorptive media; a first substantially planar surface, a second substantially planar surface substantially parallel to the first substantially planar surface, a first plurality of distribution passageways within each of the plurality of cassettes, the passageways fluidly coupled to the feed inlet, a second plurality of distribution passageways within each of the plurality of cassettes, the passageways fluidly coupled to the eluent outlet; the planar surfaces of each of the plurality of cassettes having the same shape; a peripheral seal encapsulating a sidewall of each of the plurality of cassettes to contain the fluid under operating pressures; wherein cassette geometry and location of the passageways induce substantially uniform lateral flow from the feed end to the eluent end within the block, the uniform lateral flow being parallel to the first and second substantially planar surface; and one of the pair of endplates is adjacent to a first surface of the block and a second one of the pair of endplates is adjacent to a second surface of the block. Such a device enables processing much larger volumes of fluids with a single device. 
     A method of forming a planarly cohesive, substantially isotropic adsorptive media block, according to one aspect of the invention, includes providing a plurality of planarly cohesive, substantially isotropic webs having an edge, a first end and a second end; cutting the webs to a predetermined dimension; stacking the webs to form a stack of webs; forming a peripheral edge seal adjacent to the web edges; and forming distributor passageways at a first end and at an opposite second end. Such a technique enables the manufacture of scalable chromatography devices. Another aspect of the invention is related to an integrated assembly of cassettes, hereby referred to as a “multiplexed cassette”, particularly suitable for SMBC (Simulated Moving Bed Chromatography). 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
       The foregoing and other aspects, embodiments, objects, features and advantages of the present teachings can be more fully understood from the following description in conjunction with the accompanying drawings. In the drawings, like reference characters generally refer to like features and structural elements throughout the various figures. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the present teachings. The following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of the invention as encompassed by the claims. 
         FIG. 1A  is a schematic diagram of a perspective top view of an adsorptive device according to an aspect of the invention; 
         FIG. 1B  is a schematic diagram of a bottom view of the adsorptive device of  FIG. 1 ; 
         FIGS. 2A and 2B  are schematic diagrams of cross sectional views (along section  2 A- 2 A) of the device of  FIG. 1A ; 
         FIG. 3A  is a schematic diagram of a side view of an adsorptive device for processing a fluid according to an aspect of the invention; 
         FIGS. 3B and 3C  are schematic diagrams of cross sectional views (along section  3 B- 3 B and along section  3 C- 3 C) of the device of  FIG. 2A  showing details of the end plates and manifolds; 
         FIG. 4  is an elevation view of a stack of cassettes hydraulically in parallel forming a composite cassette; 
         FIG. 5  is an elevation view of a stack of cassettes hydraulically in series forming a composite cassette; 
         FIGS. 6A-6C  are schematic diagrams showing flow profiles in cassettes according to an aspect of the invention; 
         FIGS. 7-11  are schematic diagrams showing alternative geometries, media types and flow profiles of cassettes according to other aspects of the invention; 
         FIGS. 12-13  are schematic diagrams showing alternative fabrication methods of devices according to the invention; 
         FIG. 14  is a schematic diagram showing a cassette assembly according to an aspect of the invention; 
         FIGS. 15-16  are schematic diagrams showing the multiplexed cassettes according to aspects of the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     This invention specifically relates to devices and processes suitable for preparative and manufacturing processes, and more specifically to processes used in the manufacture in the pharmaceutical industry for the production of medicinal or therapeutic products. 
     In contrast to conventional devices, applicants have discovered a way to support adsorptive media in a configuration that is linearly scalable and self supporting. Embodiments of the invention utilize planarly cohesive media. A web of adsorptive media, as for example, Macro-IPN media, is planarly cohesive. The media retains its shape even when pulled apart by a tensile force. A monolith is also planarly cohesive, except that it is much thicker than a bed. The cohesion plane of planarly cohesive media is oriented in parallel to the planar surfaces of the adsorptive device. The cohesiveness of the media along the cohesion plane enables the fabrication of adsorptive media blocks as described below. 
     The term adsorptive media, chromatography media, and media are herein used interchangeably to refer to the stationary phase of an adsorptive device; media can also refer a single type of medium. As used herein, intimate contact generally refers to the scale of the void space left between adjacent layers, and means that these void spaces are of the same order of magnitude as the scale of the interstitial space occupied by the mobile phase within the beds. The term solvent and mobile phase are used herein interchangeably to refer to the mobile phase. The term lateral flow means fluid flow within the media along the cohesion plane; for example, in web-based adsorptive media lateral flow means flow along the plane of the web, in contrast to flow that is perpendicular to the plane of the web. The term adsorptive block and adsorptive device and cassette are used interchangeably to refer to the planarly cohesive beds of adsorptive media used in devices of this invention. The term isotropic means that the porous media through which the fluid flows has a homogenous porous structure perpendicular to the direction of flow, such that the specific resistance to flow is independent of the location within the media in planes perpendicular to the direction of flow; the importance of isotropic media is elaborated upon further below. By substantially it is meant that the deviations of the values of the property being described are sufficiently small to enable the adsorptive device to perform as expected. 
     Referring to  FIGS. 1A-1B , an adsorptive device  10  includes at least one block  20  comprising planarly cohesive, substantially isotropic adsorptive media  21 , the block has a first end  12 , a second end  16 , a first substantially planar surface  22 , a second substantially planar surface  23 , at least one sidewall  26  substantially perpendicular to the first and second planar surfaces  22 ,  23 . The block further comprises a first plurality of distribution passageways  14   a - 14   n  (collectively referred to as distribution passageway  14 ) disposed within the at least one block  20 , adjacent the first end  12  and substantially perpendicular to the first and second planar surfaces  22  and  23 , a second plurality of distribution passageways  18   a - 18   n  (collectively referred to as distribution passageway  18 ) disposed within the at least one block  20  adjacent the second end and substantially perpendicular to the first and second planar surfaces  22  and  23 , and a peripheral edge seal  28  encapsulating the at least one sidewall  26  having a planar surface portion  24 . 
     The alignment and location of the distribution passageways  14  and  18  with respect to each other and the geometrical shape of the first and second planar surfaces  22  and  23  (also referred to as the footprint) are designed to induce substantially uniform lateral flow of fluid within the block  20  from the first end  12  to the second end  16 . The block  20  may have a variety of footprints, for example, rectangular, circular, trapezoidal, etc. The shape of the footprint in conjunction with the location of the distribution passageways  14  and  18  are the design factors responsible for inducing the desired uniform flow. 
     The block  20  is a three-dimensional device characterized by a length  32 , a height  30  and a width  34 . The direction of fluid flow is aligned with the length coordinate; the width of the planar surfaces  22  and  23  defines the width  34  and the height  30  of the block  20  is the dimension perpendicular to the planar surfaces  22  and  23 . 
     In operation, fluid is introduced and distributed into distribution passageways  14  and collected and removed from distribution passageways  18 . The adsorptive device  10  is rendered “self-supporting” by the encapsulation of the sidewall  26  defined by the cohesion planes, parallel to the planar surfaces  23  and  23 , of the planarly cohesive, substantially isotropic adsorptive media  21 . The blocks  20  of adsorptive device  10  do not require additional support structures to contain the hydraulic pressures generated in use, enabling the blocks  20  to be easily loaded and unloaded between end plates shown below in conjunction with  FIG. 3A . This attribute additionally allows the stacking of blocks  20  without a change of the end plates enabling very easy scale-up. 
     It is understood that in an adsorptive device  10  there are numerous possible paths, or streamlines, between the distribution passageways  14  and  18 . The fluid in each streamline takes a certain amount of time to complete the trajectory from the first end  12  to the second end  16 , this time being typically referred to as the residence time. High performance adsorptive devices require that the variation in the residence time of all the streamlines be as small as possible. To achieve this performance attribute, adsorptive blocks should have adsorptive media that is substantially isotropic along planes perpendicular to the direction of flow, in addition to having streamlines that have substantially uniform length. Flow uniformity is the net result of this combination of properties. 
     In one embodiment the layers of adsorptive media are formed from web-based adsorption media, for example, macroporous IPN media produced in a web and cut to fit the block  20 . Macroporous IPN media is described in PCT application PCT/US2010/024804 entitled POROUS INTERPENETRATING POLYMER NETWORKS WITH IMPROVED PROPERTIES, filed Feb. 19, 2010, which is incorporated by reference in its entirety. In other embodiments the layers of adsorptive media might comprise Empore discs (3M Corp., St. Paul, Minn.), or Whatman Chromatography Paper (GE Life Sciences, Westborough Mass.). 
       FIG. 2A  shows a magnified section view (through Section  2 A-Section  2 A of  FIG. 1A ) of distribution passageways  14  on the first end of block  20 .  FIG. 2A  shows a cross section of block  20  having four layers of web  29 .  FIG. 2B  shows a block  20 ′ having more layers of web  29  and therefore a higher height than the block  20  shown in  FIG. 1A . Block  20  can include multiple web layers  29   a - 29   n  (collectively referred to as web layer  29 ) of the planarly cohesive, substantially isotropic adsorptive media  21 . 
     The feed stream (not shown) is distributed along the width of the block  20  by manifold  120  (shown below in conjunction with  FIG. 3B ) entering each one of several passageways  14   a - 14   n  as a feed sub-stream, which is further distributed and turned forming lateral flow streams within each web layer  29 . In contrast to filtration devices, lateral streams  8  flow along the plane that defines web layer  29  (i.e., these flow laterally rather than perpendicularly to the plane of web layer  29 ). 
       FIG. 2B  shows adsorptive device  10 ′ which includes additional web layers  29  as compared to adsorptive device  10  of  FIG. 2A . 
     Now referring to  FIGS. 3A-3C , an adsorptive device  100  for processing a fluid includes a pair of end plates  102   a  and  102   b  (also referred to as end plate  102 ). Each end plate  102  has a feed end  105  and an eluent end  107 . At least one of the pair of end plates  102  has a feed inlet  106  disposed at the feed end  105 , and at least one of the pair of end plates  102  has an eluent outlet  108  disposed at the eluent end  107 . The adsorptive device  100  further includes a plurality of cassettes  200  in a stacked configuration (shown here as a single cassette  200 , stacked configurations described below in conjunction with  FIGS. 3 ,  4  and  5 ). 
     Each cassette  200  is similar to the block  20  of  FIG. 1A . As described above, the cassette  200  geometry and location of the passageways induce substantially uniform lateral flow from the feed end  105  to the eluent end  107  within the block, the uniform lateral flow being parallel to the first and second substantially planar surface. Here, one of the pair of end plates  102   a  is adjacent to the first surface  22  of the cassette  200  and a second one of the pair of end plates  102   b  is adjacent to a second surface  23  of the cassette  200 . 
     Still referring to  FIGS. 3A-3C , cassette  200  further comprises peripheral edge seal  28  forming an impermeable seal of web  29  (also called “seal” and “peripheral edge seal”) using a sealant. In one embodiment a thermoset resin is used and in another embodiment a thermoplastic resin is used to form the seal. Other sealants known in the art can also be used. Peripheral edge seal  28  is adhered to web  29  forming a structural boundary to include the elevated pressures present inside the cassette. Cassette  200  further comprises passageways  14  and  18  distributed along its width at both the feed and eluent ends, respectively, and are used for the introduction of the feed stream and collection of the eluent stream along the width of cassette  200 . Passageways  14  (also referred to as distribution passageways) penetrate cassette  200  along its height from top to bottom, enabling the distribution of fluid along the height H. 
       FIG. 3B  shows a sectional side view of a manifold  120   a  disposed in end plate  102   a . Manifold  120   a  is used to introduce the feed stream  130   a , whereas manifold  120   b  disposed on the opposite end of end plate  102   a  is used to recover the eluent stream  130   b , as shown in  FIG. 3C . Flow passages  124   a  inside manifold  120   a  are used to distribute the feed stream to distribution passageways  14  in cassette  200 . Flow passages  124   b  inside manifold  120   b  are used to collect the eluent stream from distribution passageways  18  in cassette  200 . It is understood that there are several different operational configurations of the manifold  120   a  and  120   b  in the end plates  102   a  and  102   b.    
     In certain embodiments, cassettes  210   a - 210   n  are stacked such that they are hydraulically in parallel as shown in  FIG. 4  (hereafter referred to as a “parallel configuration”). In this case cassettes  210  form a composite cassette  250  whose height is equal to the sum of the heights of each cassette  210 . Manifolds  120   a  and  120   b  ( FIG. 3A ) are used to support stacked cassettes  210  by means of support structure (not shown), which can be made of tie rods or of some sort of external press), and include passageways (not shown) to distribute the feed stream into the distribution passageways on the feed end and to collect the eluent stream from the eluent end of cassettes  210 . Manifolds  120  have a feed and an eluent end to match the feed and eluent ends of cassettes  210 . 
     Feed and eluent distribution passageways  14  and  18  can be configured in several positions in the end plates. Both can be located only in the top manifold, or only in the bottom manifold. Alternatively, feed distribution passageways can be located only on the top end plate with eluent distribution passageways only on the bottom end plate or any combinations thereof, as long as there is at least one set of feed distribution passageways and one set eluent distribution passageways in either the top or bottom manifolds disposed within the end plates. Gaskets  110  may be used to obtain a reliable seal between adjacent cassettes  210  and between cassettes  210  and manifolds. Gaskets  110  may be integrated (and adhered) into each cassette  210 , or may be a separate component that is added as part of a stack of cassettes  210  to form a block. To enable cassettes  210  to be stacked in the fashion shown in  FIG. 4 , these must be approximately of the same length and width, and the distribution passageways need to be similarly located so that they line up and are in fluid communication; however, it should be understood that while  FIG. 4  shows cassettes  210  of the same height, cassettes can be of different heights. 
     Alternatively in other embodiments, cassettes are stacked such that they are hydraulically in series as shown in  FIG. 5 . In this case cassettes  310   a - 310   n  form a composite cassette  350  whose hydraulic length is equal to the sum of the lengths of each cassette  310  by virtue of flow diverter plate  320 . Manifolds (not shown) are used to support stacked cassettes  310  by means of support structure (not shown), and include distribution to distribute the feed stream into the distribution passageways  314  on the feed end and to collect the eluent stream from the eluent end of cassettes  310 . End plates have a feed and an eluent end to match the feed and eluent ends of cassettes  310 . In contrast to the parallel configuration shown in  FIG. 4 , feed and eluent passageways must be located in separate manifolds. Gaskets  110  may be used to obtain a reliable seal between adjacent cassettes  310 , between cassettes  310  and flow diverter plates  320 , and between cassettes  310  and end plates. Gaskets  110  may be integrated (and adhered) into each cassette  310 , or may be a separate component that is added as part of a stack of cassettes to form a block. To enable cassettes  310  to be stacked in the fashion shown in  FIG. 5 , these must be approximately of the same length and width, and the distribution passageways need to be similarly located so that they line up and are in fluid communication. However, it should be understood that while  FIG. 5  shows cassettes  310  of the same height, cassettes can be of different heights; furthermore, two or more cassettes can be placed in series. 
     It is understood that it is possible to create composite cassettes utilizing combinations of parallel and series configurations as shown in  FIGS. 4 and 5  by introducing flow diverter plates  320  at desired locations within a stack of cassettes  310 . 
       FIG. 6A  shows a magnified section view (through Section  2 A on  FIG. 1B ) of distribution passageway  14   f  on the feed end of block  20 , showing the flow profile of the feed stream within each web  21   a - 21   n . The feed stream (not shown) is distributed along the width of the block by the manifold (not shown) entering each one of several distribution passageways  14  as feed sub-stream  17 , which is further distributed and turned forming lateral streams  25   a - 25   n  within each web layer. In contrast to filtration devices, lateral streams  25   a - 25   n  flow along the plane that defines web  21  (i.e., these flow laterally rather than perpendicularly to the plane of web  21 ).  FIG. 6B  shows the flow streamlines  21   a - 21   n  in plan view on web  21 , showing the fluid traveling from the feed end towards the eluent end.  FIG. 6C  shows a magnified section view (through Section  2 A on  FIG. 1B ) of distribution passageway  18   f  on the eluent end of block  20 , further showing how lateral streams  33   a - 33   n  within each web layer  21  are collected to form eluent sub-stream  39  within distribution passageway  18   f . There are multiple eluent sub-streams  39  that are collected along the width of the cassette by the manifold (not shown) forming the complete eluent stream (not shown) from block  20 . 
       FIG. 7  shows another embodiment of this invention, where the cassette is configured in a circular geometry instead of a rectangular geometry as shown in  FIG. 1A . Circularly shaped web  412  has a peripheral edge seal  410  with distribution passageways  404   a - 404   n . In this case the feed distribution passageways  404  are located in the periphery of web  412 , whereas the eluent distribution passageway  402  may be a single channel in the center of web  412  (it should be understood that the distribution passageway  402  in the center of the circular web may also comprise two or more distribution passageways  402 ). Alternatively, the passageway  402  in the center is the feed distributor whereas the passageways  404  near the periphery are the eluent distributors. In this case the fluid flow path is radial, making the length of the flow path approximately equal to the radius of the circularly shaped web  412 . 
       FIG. 8  shows another embodiment of a circularly shaped cassette including ribs  408   a - 408   n  that force the fluid to flow in a spiral trajectory forming a longer flow path than that on the embodiment shown in  FIG. 7 . 
       FIG. 9  shows another embodiment of a cassette  440  whose webs  452  are approximately in the shape of a “pie slice” or a trapezoid. Any shape is possible as long as webs  452  are flat, have peripheral edge seal  448  and distribution passageways  444  and  446 , the application dictating which shape is most beneficial. Also, in general it should be understood that ribs (not shown) can be utilized in any geometry, circular, rectangular or otherwise, to channel the fluid in trajectories which may be different from the natural trajectory that a fluid would travel within the webs  452 . 
       FIG. 10  shows a cassette  500  according to one embodiment of this invention made with an adsorptive media in the form of a monolith  522  instead of multiple web layers, the key difference being that monolith  522  is much thicker than a web, such that a single monolith creates a substantial height (only possible with multiple layers when using webs). According to this embodiment monolith  522  comprises peripheral edge seal  506  and distribution passageways  508 ,  FIG. 8B  showing a cassette made with a monolith thinner than that shown in  FIG. 8C . Just as has been described in  FIGS. 1 through 7 , cassettes of the same geometries and possibilities can be made with monoliths  522  as long as these have flat top and bottom surfaces and have sufficient tensile and compressive strength to support the hydraulic forces generated in use. Monoliths create the option of adding a seal to the flat top and bottom surfaces capable of restraining the hydraulic forces generated in use. In this case the top and bottom plates become optional since the cassette is self-supporting; furthermore, the end plates only need to attach to the feed and eluent distributors in cassette  500 . 
       FIG. 10  shows a cassette  500 ′ according to one embodiment of this invention made with an adsorptive media in the form of a monolith  522  instead of multiple web layers, the key difference being that monolith  522  is much thicker than a web, such that a single monolith creates a substantial height (only possible with multiple layers when using webs). According to this embodiment monolith  522  comprises peripheral edge seal  506  and distribution passageways  508 ,  FIG. 10B  showing a cassette made with a monolith thinner than the cassette  500 ′ shown in  FIG. 10C . Just as has been described in  FIGS. 1 through 7 , cassettes of the same geometries and possibilities can be made with monoliths  522  as long as these have flat top and bottom surfaces and have sufficient tensile and compressive strength to support the hydraulic forces generated in use. Monoliths create the option of adding a seal to the flat top and bottom surfaces capable of restraining the hydraulic forces generated in use. In this case the top and bottom plates become optional since the cassette is self-supporting; furthermore, the end plates only need to attach to the feed and eluent distributors in cassettes  500  and  500 ′. 
       FIG. 11A  shows a plan view of another embodiment of a rectangularly-shaped cassette in which the cassette is “double-sided.” In this embodiment the cassette includes another set of center distribution passageways  516  at the center point of the length dimension of web  512  in addition to the set of distribution passageways  504  and  508  at the two ends of the cassette  500 . Referring to  FIG. 11A  cassette  550  comprises webs  512  with peripheral edge seal  513  having a set of center distribution passageways  516  at the center point of the length dimension of web  512 , and two sets of distribution passageways  504  and  508  at the two ends of web  512 . In this particular embodiment center distribution passageways  516  distribute the feed stream, while end passageways  504  and  508  collect the eluent stream. Flow profiles for this embodiment are shown in  FIG. 11B . In an alternative embodiment of a double-sided cassette (not shown), distribution passageways  504  and  508  distribute the feed streams while center passageways  506  collect the eluent streams. 
       FIGS. 12A-12E  represents in schematic manner an exemplary process to fabricate the cassette shown in  FIG. 1A . A plurality of webs  600  are cut to a desired dimension as shown  FIG. 12A  and stacked as shown in  FIG. 12B . A peripheral edge seal  606  is created by one of many methods known to those skilled in the art (e.g., thermoset resins or thermoplastic resin or other sealants known to those skilled in the art can also be used) as shown in  FIG. 12C . Once cured, the stack of webs  600  is perforated (by drilling, die cutting, laser cutting or other methods known to those skilled in the art) to form substantially straight distribution passageways  604  and  608  in the height dimension as shown in  FIG. 12D , resulting in finished cassette  620  of  FIG. 12E . 
     There are many variations to this fabrication method. For example, the distribution passageways may be perforated on each individual web  650  before these are stacked; this method allows the formation of distribution passageways that are not identically located in each web  650 , which is acceptable as long as the distribution passageways  654  and  658  have some overlap enabling fluid communication when adjacent webs  650  and  660  are stacked, as shown in  FIGS. 13A and 13B . Referring to  FIG. 13A , web  650  is perforated with oblong distribution passageways  654 , which are not centered in the width dimension but are closer to one edge of web  650  than the other edge, whereas web  660  shown in  FIG. 13B  is perforated with the same oblong distribution passageways  658  which are also not centered (according to offset  655 ), but displaced towards the opposite edge of web  660 . When adjacent webs  650  and web  660  are stacked, the distribution passageways  654  and  658  do not line up perfectly on top of each other, but do overlap to still create a distributor that is in fluid communication. It should be appreciated that perforating the web  650  with distribution passageways  654  and  658  before stacking the webs provides a large flexibility in the formation of the distributors which may be of advantage in some applications. Likewise it may be advantageous to add peripheral edge seal  662  to each web individually before these are stacked. 
     Distributors may add to band spreading, a phenomenon that deteriorates the effectiveness of chromatographic separation, a deterioration that increases as the hold-up volume of distributors becomes larger relatively to the volume in the separation medium. Therefore, distributors should be designed to have the lowest volume. However, this needs to be balanced with the pressure drop generated by a distributor, which becomes larger the smaller the diameter of the distribution passageways. In many cases, it is possible to maintain the distributor volume to be small relative to the rest of the adsorptive medium, and in such cases, the exact distribution pattern of the feed and eluent streams within the distributor has little impact on the separation performance of the devices. In such cases, it is of little consequence where the fluid enters and exits the cassette. 
     Another approach to reduce the deterioration produced by distributors is to design them such that the bands are not distorted, even when the distributor volume is not small. This requires that every streamline within the separation device (the separation media and the distributor, including the flow passages/distributors contained within the end plates) have the same residence time. For devices of this invention, wherein the feed stream comes from a point source and the eluent stream goes back to a point source, the location of entry and exit of the feed and eluent streams, respectively, may be important, leading to preferred embodiments for the distributor design. In the case of rectangular devices of this invention (e.g. as shown in  FIGS. 1 through 4 ), to maintain the residence time at every streamline as uniform as possible in the presence of significant hold-up volume in the distributors the design principle that should be followed is this: there should be mirror image symmetry in the flow pattern of the feed and eluent streams as they enter and exit the cassette along any plane bisecting the cassette in any of its dimensions. Specifically, this means two things: first, the feed and eluent streams should be located in opposing end plates, and secondly, the feed stream should enter the top (or bottom) end plate on the side opposite to that in which the eluent stream exits the opposite end plate. 
       FIGS. 14A ,  14 B and  14 C show a device  700  comprising a cassette assembly according to one aspect of this invention with end plates designed according to the design principle described in the previous paragraph.  FIG. 14A  shows a sectional side view of cassette assembly  700 , with top end plate  706   a , a first gasket  705   a , cassette  702 , a second gasket  705   b , and bottom end plate  706   b . In this schematic diagram, top end plate  706   a  is used to introduce the feed stream, whereas bottom end plate  706   b  is used to recover the eluent stream. Flow passages  716   a  inside top end plate  706   a  is used to distribute the feed stream to distributor passageways  704   a  in cassette  702 . Flow passages  716   b  inside bottom end plate  706   b  are used to collect the eluent stream from distributor passageways  704   b  in cassette  702 .  FIG. 14B  is a front view of a cassette assembly  700  taken along section  14 B in  FIG. 14A . Referring to  FIG. 14B , feed stream  707  enters end plate  706   a  at feed port  717 , and then is further distributed along the width of the device utilizing flow passages  716   a . Referring now to  FIG. 14C , eluent stream  709  exits end plate  706   b  at eluent port  719 , after having been collected along the width of the device utilizing flow passages  716   b .  FIGS. 14A ,  14 B and  14 C clearly show that feed and eluent flow passages in end plates  706   a  and  706   b  are in mirror image symmetry one to the other as described in the previous paragraph, representing a preferred embodiment whenever the volume of the distributor passageways  704   a  and  704   b  in the devices of this invention lead to decreased separation performance. It should be further noticed that in this embodiment the flow direction of the feed and eluent streams is the same at every point within cassette assembly  702 . 
       FIGS. 15A and 15B  show another embodiment of this invention, according to which multiple cassettes  810   a - 810   n  are integrated into a single multiplexed cassette  800 . Block  822  has peripheral edge seal  823  and further partitioned into multiple cassettes  810   a - 810   n  by means of inter-cassette seals  825 . Distribution passageways  824  are perforated along the height of block  822  on both ends of block  822  in the manner shown in  FIG. 15A . In this embodiment block  822  of multiplexed cassette  800  is built from a stack of multiple layers of web (not shown). Peripheral edge seals  823  and inter-cassette seals  825  are adhered to webs such that these can sustain the internal pressures present in cassettes  810   a - 810   n  during use. In another embodiment the media used to form the adsorptive block  822  may be in the form of a monolith (not shown) instead of webs. 
       FIG. 16A  is an elevation view of a multiplexed cassette  800  in combination with end plates  926   a  and  926   b  forming multi-cassette assembly  900 .  FIG. 16B  is a schematic flow diagram of multiplexed cassette assembly  900 . End plate  926   a  includes multiple passageways  934   a  for introducing multiple feed streams  930   a - 930   n  and an array of valves  935   a - 935   n  for diverting each feed stream into the manifold  924   a  of each one of cassettes  910   a - 910   n  (corresponding to cassettes  810   a - 810   n  of  FIG. 16A . End plate  926   b  includes multiple passageways for collecting multiple eluent streams  934   b  from each one of cassettes  810   a - 810   n  and an array of valves  935   b  for diverting each eluent stream from the eluent distributors  924   b  into either a product stream  931 , a waste stream  932 , or possibly, a feed stream  933   a - 933   n  into another one of cassettes  910   a - 910   n . The passageways and valves are included within the end plate, thereby liberating the user from having to make individual connections to each individual cassette  910   a - 910   n . The process design dictates which valves are opened and closed, with a control system (not shown) that opens and close the valves accordingly. In some embodiments the end plates  926   a  and  926   b  are reusable. In other embodiments end plates  926   a  and  926   b  may be integrated with the cassette to form a completely disposable assembly  900 , in which case valves  935   a  and  935   b  may be pneumatically actuated, with the pneumatic streams actuated by an array of reusable valves (not shown) connected to the disposable cassette assembly  900  by simple, quick-connect means known to those skilled in the art. This embodiment would be suitable for applications where cross-contamination between batches can&#39;t be tolerated, or where the cost of cleaning and validating the cleaning cycle is cost or time prohibitive, or when the safety of operating personnel demands that there be no exposure to the fluid streams. 
     In other embodiments a planarly cohesive adsorptive block is formed with a planarly cohesive scaffold packed with bead-based media. In one example, the planarly cohesive scaffold comprises bi-planar plastic netting, e.g. Vexar plastic netting (Conweb Plastics, Minneapolis Minn.). Plastic netting of this type is made of a biplanar array of polymer monofilaments forming a planarly cohesive net with open cells, typically square or rectangular cells. These nets can be stacked into a block with sidewalls perpendicular to the planar surfaces, which are then encapsulated with a suitable thermoset resin to form a planarly cohesive scaffold. The block comprising the empty scaffold is then packed with bead-based media. In this embodiment the scaffold renders the adsorptive media block planarly cohesive even though the beads are not. In still another embodiment, molded plates with open cells of similar size and orientation as those of plastic netting and edge seals are stacked and fusion bonded by methods known to those skilled in the art, forming a scaffold. 
     It is understood that although the embodiments described herein relate specifically to bio-molecular applications, the principles, practice and designs described herein are also useful in other applications, including the manufacture of vaccines and biopharmaceuticals. All literature and similar material cited in this application, including, patents, patent applications, articles, books, treatises, dissertations and web pages, regardless of the format of such literature and similar materials, are expressly incorporated by reference in their entirety. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including defined terms, term usage, described techniques, or the like, this application controls. 
     The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described in any way. While the present invention has been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present invention encompasses various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. While the teachings have been particularly shown and described with reference to specific illustrative embodiments, it should be understood that various changes in form and detail may be made without departing from the spirit and scope of the teachings. Therefore, all embodiments that come within the scope and spirit of the teachings, and equivalents thereto are claimed. The descriptions and diagrams of the methods of the present teachings should not be read as limited to the described order of elements unless stated to that effect. 
     The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made without departing from the scope of the appended claims. Therefore, all embodiments that come within the scope and spirit of the following claims and equivalents thereto are claimed.