Abstract:
A system allows for the safe, rapid, efficient recovery of a drug solution from sealed vials. The system is closed so that highly potent compounds can later be recovered and reworked without large investment in further engineering controls.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims priority to U.S. Provisional Patent Application No. 60/877,873, filed Dec. 29, 2006 and entitled “Recovery System,” the entire contents of which are incorporated herein by reference. 
     
    
     BACKGROUND 
       [0002]    The invention generally relates to methods of recovering material from containers. 
         [0003]    The products of the chemical, biotechnological, and pharmaceutical industries can be the result of immense investments of money, time, and effort. Occasionally a manufacturing or human error can create a problem. For example an unsafe contaminant could accidentally be introduced into the product, or a batch of the product could be accidentally packaged into non-sterile containers, where sterility of the product is required for safety. It may be desirable to recover as much of the product as possible, and then purify or sterilize it as appropriate. 
       SUMMARY 
       [0004]    In the embodiments described here, liquid can be recovered from stoppered vials by providing the vials upside down in a holding cassette over upwardly extending hollow needles. The needles puncture the stoppers in the vials and draw the liquid through a manifold to a vessel. The cassette with multiple vials can be manually provided in a holder and manually removed from the holder after the liquid is removed. The recovery process can be initiated with a safety feature that requires two simultaneous actions, such as two buttons to be pushed by two hands to prevent inadvertent actuation. The system preferably uses a peristaltic pump, which is preferably operated with a foot pedal actuation. 
         [0005]    Other features and advantages will become apparent from the following detailed description, drawings, and claims. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0006]      FIG. 1  is a schematic diagram showing the components of a recovery system. 
           [0007]      FIG. 2  is a detailed diagram of a vial holder and needle assembly. 
           [0008]      FIG. 3  is a schematic diagram showing the components of an automated recovery system including a flip cap remover and conveyor belt. 
           [0009]      FIG. 4  is a detailed diagram of a vial positioner. 
           [0010]      FIGS. 5A and 5B  show perspective views of an optional flip cap remover. 
           [0011]      FIG. 6  is a schematic diagram showing the components of an automated recovery system including a flip-cap remover, conveyor belt, and reconstitution subsystem. 
           [0012]      FIG. 7  is a detailed diagram of a reconstitution and recovery valve assembly. 
       
    
    
     DETAILED DESCRIPTION 
       [0013]    The systems described here are directed to methods of recovering expensive or dangerous materials from sealed containers safely, nearly completely, and with high throughput. They can be used with benign materials or with materials that are unsafe for human contact; it could be toxic, explosive, mutagenic, or carcinogenic, for example, such that human involvement in the recovery process should be kept to a minimum. 
         [0014]      FIG. 1  is a schematic diagram showing components of an embodiment of a recovery system. The system has three main components: recovery device  100  that holds sealed vials containing a solution, a peristaltic pump  170  that pumps the solution out of the vials, and a recovery tank  190  that receives the pumped solution. In recovery device  100 , vial holder cassette  110  holds solution-containing vials  120  upside down, so the solution flows to the bottom. Vials  120  can be made of any sturdy material, such as glass or plastic, which is preferably transparent so that recovery of the material can be monitored. 
         [0015]    Caps or stoppers seal vials  120 , preventing the solution from leaking during normal storage and transportation. The stoppers are made of a material that can be pierced with a needle to allow the solution to be withdrawn without removing the stopper. The stopper preferably “re-seals” after being punctured. Rubber is an example of a useful stopper material. These features of the stopper reduce the risks of human contact with a dangerous material, of further contamination, and of losing material during recovery process. 
         [0016]    A needle holder  130  securely holds a row of needles  140  directly beneath vials  120 . The needles  140  have a hollow bore, and are sufficiently strong to pierce the stoppers of vials  120  without breaking. If a needle does break it can be replaced easily by twisting it off and twisting a new one on. When a user presses two cylinder push buttons  160 , an air cylinder  150  raises needle holder  130 , preferably to a height where the tips of the needles  140  barely puncture the vial stoppers. This way as solution is drawn out of the vial, the tips of the needles  140  stay immersed in the solution until nearly all of the solution is withdrawn. 
         [0017]    Tubing  180  connects each of the needles  140  to peristaltic pump  170  and then to recovery tank  190 . Pump  170  is designed such that the solution does not come in contact with internal pump components, but is transmitted via continuous tubing  180  into recovery tank  190 . Using such a pump allows the tubing  180  to be sterilized or discarded after the recovery process is completed, and also minimizes the risk of human exposure, contamination of the solution by the pump, contamination of the pump by the solution, and loss of the material into the pump. Recovery tank  190  has a vent filter  195  that allows gases, but not the liquid, to escape, and stores the solution until the user is ready to further process or purify it. In some embodiments, the liquid is reprocessed or purified by any needed means including by heating, filtering, disinfecting light, mixture with other materials, or any other desired process. 
         [0018]      FIG. 2  illustrates in greater detail the components of recovery device  100 , with the rest of the system as shown in  FIG. 1 . Vial holder cassette  110  holds the vials  120  stopper side down. A user locks cassette  110  into place in the device, where it is securely held in all three dimensions. Side rails  118  hold cassette  110  in place in the horizontal plane. Vial stop  115  and side rail adjustments  112  hold cassette  110  in place vertically. Vial stop  115  also prevents vials  120  from moving upwardly when the needles puncture the stoppers. Cassette  110  is easily interchangeable, allowing recovery of solution from a large number of vials in a short amount of time. While the cassette is shown with one row of 10 vials, it could be used with other plural numbers of vials in other two-dimensional arrays. The cassette can be manually provided with no system and fixed in place without a carousel or other moving device, although automated moving systems could be used. The vials can have a narrower neck and wider body, unlike a test tube, thereby creating a shoulder that can rest in the cassette. 
         [0019]    As described previously, needle holder  130  securely mounts needles  140  to be used for solution recovery. Holder  130  approximately centers each needle tip  145  on the stopper of corresponding vial  120 . The device holds needle holder  130  in place in all three dimensions. Guide rods  135  hold needle holder  130  in place in the horizontal plane. The vertical position of air cylinder  150  determines the vertical position of needle holder  130 . To adjust the vertical height of  130 , i.e. to controllably puncture the vial stoppers with needles  140 , the user simultaneously pushes two push buttons  160 . Two buttons are provided as a safety measure, in order to keep the user&#39;s hands away from the moving needles  140  and to prevent accidental starting. Other safely methods could be used, preferably including two simultaneous actions to start the process. Needle holder  130  stays raised as long as both buttons  160  are pressed, and then lowers when buttons  160  are released. When the user presses buttons  160 , a valve (not shown) opens, allowing compressed air at about 100 psi to raise air cylinder  150  to a pre-set height appropriate to the size of vials  120 . Once needles  140  pierce the stoppers at the appropriate height, the user activates peristaltic pump  170  with a foot switch (not shown). The needles  140  connect to manifold  155  with tubing  180 , which connects to pump  170  via additional tubing  180  as illustrated in  FIG. 1 . 
         [0020]    In one use, mass balances were used to monitor the yield of solution recovery, by weighing the vials before and after recovery, and it was found that the system recovered more than 95% of the material from 2 mL vials. Each cassette holds 10 vials, and by interchanging cassettes the device can be used to recover material from about 2000 vials per hour. The cassette is not limited to this size, and can be made as large or as small as needed to hold the desired size and number of vials. 2 mL is only provided as an example vial size, since it is commonly used for doses of drug solutions. Vials would not need to be used at all, but any container with a section that could be punctured without breaking or leaking could be used. 
         [0021]    In the described system the user locks the cassettes into place and controls the needle height, but an automated system for exchanging cassettes and controlling the needle height could be implemented and would allow for even faster throughput of vials. Also, while the described recovery system moves the needles to puncture the vials, the needles could also be held fixed and the vials moved downwardly instead. 
         [0022]    A solution is not the only material that can be recovered from sealed vials with the described system. If the vial contains a solid, or a liquid that is too viscous to pump out, the system can be used to introduce into the vial an appropriate solvent that dissolves the material. This is done by switching the recovery tank with a container of the solvent, and setting the pump to operate in reverse. The cassette holds the vials as usual, and the user presses the push buttons to raise the needles up to puncture the stoppers. Then the user activates the pump, which pumps solvent into the vials. This creates a solution suitable for recovery as usual. The user releases the pump and lowers needles, and then switches the system back to its original configuration, and operates it as described above. The switching can be automated. 
         [0023]    The needles  140 , manifold  155 , tubing  180 , and recovery tank  190  are the only components that come in contact with the material, and are preferably non-reactive with the material. If the system is used to recover different materials, the tubing, manifold, needles, and tank should be changed for use with each different material to avoid cross-contamination and also potential reactivity. The pump itself does not need to be peristaltic, but any pump that has the functionality of isolating the solution from contamination in the pump could be used. 
         [0024]    The systems described here can be used with any liquid that should be recovered, including liquids that are expensive and/or potentially harmful, such as anti-cancer drugs. 
         [0025]    The system can also be fully or partially automated in order to enhance the ease of use of the system.  FIG. 3  is a schematic diagram showing components of an embodiment of a recovery system similar to the one described above, but including additional features that automate certain aspects of the operation. Like the system illustrated in  FIG. 1 , the automated system of  FIG. 3  includes three main components: a recovery device  300 , recovery peristaltic pump  370 , and recovery tank  390 . In order to automate certain aspects of the system&#39;s operation, the system of  FIG. 3  also includes an accumulation area  322  for holding a plurality of vials to be processed, an optional flip-cap remover  323  for removing flip-caps from vials, a vial positioner  337  that positions the vials appropriately for liquid recovery, and a conveyor belt  325  for transporting the vials through the different features of the system. The system also includes a programmable logic controller (not shown) that is in communication with various components of the system including recovery device  300 , vial positioner  337 , recovery peristaltic pump  370 , and conveyor belt  325 , and that coordinates the motion of these components so that the system automatically transports the vials through the different components of the system, and recovers liquid from the vials. 
         [0026]    In operation, the user manually loads vials  320 , e.g., from cases or boxes, into accumulation area  322 . Nearby load table  321  provides a supportive surface for holding the cases or boxes while the user loads the vials  320  into the accumulation area  322 . The user need not carefully arrange the vials  320  within the accumulation area, as the automated components of the system position the vials  320  throughout the system, as needed. The user initiates the system by entering an appropriate command to the logic. 
         [0027]    Under control of the programmable logic controller, conveyor belt  325  transports the vials  320  from the accumulation area  322  to the optional flip-cap remover  323 . Vials  320  optionally include flip-caps that cover and provide durable protection to the caps or stoppers during normal storage or transportation, but can be relatively easily removed by the user. The flip-caps prevent the caps or stoppers from becoming contaminated by dirt, fingerprints, or other environmental contaminants during transportation, so that when the needles puncture the caps or stoppers in order to recover the solution from the vials, those contaminants do not end up on the needle and thus taint the solution. Optional flip-cap remover  323  can be included in the system when vials having flip-caps are to be processed, so that a user need not manually remove the flip-caps from the vials. 
         [0028]      FIG. 5B  shows a detailed side view of optional flip-cap remover  323 . Conveyor belt  325  routes the vials  320  through flip-cap remover  323 . A gripper belt  528 , which is driven by a small DC fractional horse power motor  523  (or other appropriate driving device) that is in communication with and controlled by the programmable logic controller, grips and advances the vial past a set of wedge-shaped flip-cap removal tools  529  that pry the flip-cap off of the vial and into catch tray  324 . The incline of the tool, as can be seen in  FIG. 5B , removes the flip cap as the vial passes by.  FIG. 5A  shows a front view of flip-cap remover  323 . As the gripper belt  528  advances the vial  320  past the flip-cap removal tools  529 , the upper surfaces  531  of the tools contact the ends of the flip cap, and pry the cap off as the vial advances past the tools, while the lower surfaces  532  of the tools prevent the vial from lifting. A small, continuous compressed gas stream blows the removed flip-cap into the catch tray  324 . 
         [0029]    Referring again to  FIG. 3 , after optional flip-cap removal, conveyor belt  325  then transports the vials  320  to the recovery device  300  under control of the programmable logic controller. Recovery device  300  is similar to that illustrated in  FIG. 2 , but includes additional features that automate the recovery of solution from vials  320 . Recovery device  300  includes needle holder  330 , which holds a row of needles  340  relative to vials  320 , and air cylinder  331 , which moves the needles  340  so that they puncture the vial stoppers, as opposed to moving the vials as shown in  FIG. 2  (more below). Tubing (not shown) connects the needles  340  to recovery manifold  350 , recovery peristaltic pump  370 , and recovery tank  390 , which are substantially as described above for the system illustrated in  FIGS. 1 and 2 . 
         [0030]    In order to automate recovery of solution from the vials, recovery device  300  further includes vial positioner  337  that is in communication with the programmable logic controller. As discussed in greater detail below, the programmable logic controller instructs vial positioner  337  to correctly align an appropriate number of vials relative to the row of needles  340 . Then, the programmable logic controller actuates the air cylinder  331 , which translates needle holder  330  downwards so that needles  340  puncture the vial stoppers, preferably to a height were the tips of needles  340  are near the bottoms of vials  320 . This way as solution is drawn out of the vial, the tips of the needles  340  stay immersed until nearly all of the solution is withdrawn. After moving needle holder  330 , the logic then starts recovery peristaltic pump  370 , which pulls the solution out of the vials, through recovery manifold  350 , through pump  370 , and into recovery tank  390 . Recovery tank  390  has a vent filter  395  that allows gases, but not the liquid, to escape. Once the solution is recovered from the vials, conveyor belt  325  transports the substantially empty vials for disposal in empty vial collection bin  327 . 
         [0031]      FIG. 4  shows a detailed top view of vial positioner  337  relative to conveyor belt  325 . The other features of recovery device  300  are omitted for clarity, but their position relative to vial positioner  337  can be seen in  FIG. 3 . Vial positioner  337  includes vial counter  450 , stop cylinder  434 , vial locator  432 , vial locator cylinder  435 , and vial stop  433 , and is designed to correctly position a predetermined number of vials at a time, e.g., ten vials, relative to a corresponding number of needles  340 . 
         [0032]    In order to correctly position and subsequently withdraw liquid from vials  320 , the programmable logic controller first actuates stop cylinder  434  into the path of the vials, which prevents conveyor belt  325  from transporting the vials out of recovery device  300  before the device recovers solution from them. Vial counter  450 , e.g., a commercially available LED-based vial counter, counts the number of vials that conveyor belt  325  transports into recovery device  300 , and relays that information to the programmable logic controller. When the vial count equals the predetermined number of vials, the programmable logic controller stops conveyor belt  325  so as to not transport excess vials into recovery device  300 . At this time, the predetermined number of vials is positioned loosely between vial stop  433  and vial locator  432  along conveyor belt  325 . 
         [0033]    Next, the programmable logic controller actuates vial locator cylinder  435 , which positions vial locator  432  relative to vial stop  433  so as to firmly hold the vials in place between them. Vial locator  432  includes a number of grooves, each of which is sized and shaped so as to position a corresponding vial stopper center  436  beneath a corresponding needle (not shown) when cylinder  435  positions vial locator  432  relative to vial stop  433 . The grooves go around the neck of the vials, which prevents the vials from lifting beyond a certain point when needles are withdrawn from them; the upward force caused by the withdrawn needles presses the shoulder of the vial against the lower surface of the vial locator. The grooves are also appropriately spaced from each other to provide a sufficient amount of space between the vials, as well as to position them correctly relative to the needles. “V” grooves are useful because they can center vials of a variety of sizes relative to the needles. For example, in some embodiments the grooves are sized to center vials between the sizes of about 5 mL and 30 mL, without needing to change the tool. In other embodiments, semicircular grooves that are sized for one particular vial size, e.g., 5 mL, can be used. The number, size, and spacing of the grooves can be selected according to the size of the vials to be processed. The vial locator  432 , vial stop  433 , and/or needle holder  330  can be readily removed and replaced with vial locators, vial stops, and needle holders of different sizes, spacings, and shapes, so that the system can readily recover solution from vials of many different sizes and shapes, for example between about 5 mL and 500 mL. 
         [0034]    As discussed above, the programmable logic controller then actuates air cylinder  331  so that the needles pierce the vial stoppers to an appropriate height, and starts recovery peristaltic pump  370  to withdraw solution from the vials. The pump operates for a desired time. This time can correspond to the amount of time needed to withdraw the solution from the vials, which depends on the volume of solution in the vials as well as the rate at which recovery peristaltic pump  370  pulls solution from the vials via needles  340 , tubing (not shown), and recovery manifold  350 . The programmable logic controller stops peristaltic pump  370 , raises air cylinder  331  to withdraw needles  340  from the vials, and actuates vial locator cylinder  435  to position vial locator  432  away from vial stop  433 , so that the vials are no longer held in place. Then, the programmable logic controller actuates stop cylinder  434  out of the path of the vials and re-starts conveyor belt  325 , which transports the substantially empty vials for disposal in empty vial collection bin  327 . The motion of conveyor belt  325  brings a new set of vials into recovery device  300 , and the programmable logic control repeats the process of recovering solution from the new vials as described above, beginning with actuating stop cylinder  434  into the path of the new vials. 
         [0035]    Note that the vials in the system illustrated in  FIG. 3  are kept cap-side up, and are not turned cap-side down as shown in  FIG. 2 . Although the cap-side up position potentially allows for recovery of slightly less liquid than does the cap-side down position, because a small amount of liquid may remain at the bottom of the vial, the overall throughput of the system can be improved by leaving the vials cap-side up. Specifically, while the recovery system can be modified to include an appropriate component that turns the vials cap-side down (either individually or some number at a time) before recovering solution from them, it can be faster and mechanically simpler to simply leave the vials cap-side up, with possibly a small reduction in the amount of solution ultimately recovered from the vials. 
         [0036]    If the vials instead contain a solid or viscous liquid to be recovered, the system can be modified to introduce a solvent into the vial to dissolve the solid or viscous liquid, and subsequently recover the resulting solution.  FIG. 6  is a schematic diagram showing components of an embodiment of an automated recovery system similar to that illustrated in  FIG. 3 , but that further includes a subsystem for introducing a solvent to the vial in order to dissolve a material that would not otherwise be easily recoverable. The recovery system of  FIG. 6  includes loading area  621 , accumulation area  622 , conveyor belt  625 , optional flip cap remover  623 , vial positioner  637 , needle holder  630 , needles  640 , air cylinder  631 , recovery manifold  650 , vial counter  655 , recovery peristaltic pump  670 , recovery tank  690 , filter  695 , and a programmable logic controller (not shown), which are substantially the same as those described with reference to  FIG. 3 . The system of  FIG. 6  also includes a solvent subsystem that includes solvent tank  790  with filter  795 , solvent manifold  750 , and solvent peristaltic pump  770  in communication with the programmable logic controller. Referring also to  FIG. 7 , recovery device  600  is modified to include reconstitution and recovery Y-valve assemblies  730 , each of which is associated with a needle  640  and is in communication with the programmable logic controller. Tubing (not shown) connects each of the Y-valve assemblies  730  to solvent manifold  750 , solvent peristaltic pump  770 , and solvent tank  790 , and separately connects Y-valve assemblies  730  to recovery manifold  650 , recovery peristaltic pump  670 , and recovery tank  690 . 
         [0037]      FIG. 7  shows a detailed view of a Y-valve assembly  730  as connected to a portion of needle holder  630  and needle  640 . Assembly  730  includes tubing that connects to solvent manifold  750  and tubing that connects to recovery manifold  650 . The small arrows indicate the direction of fluid flow within the tubing (into the assembly for the solvent, and out of the assembly for the solution of solvent plus dissolved material from the vial). Between the needle  740  and the tubing connected to the manifolds, assembly  730  also includes pinch valves  744  and  644  that are in communication with the programmable logic controller and independently operable. The controller opens and closes these valves in order to keep the solvent, and its associated tubing isolated from the solution, and its associated tubing. 
         [0038]    Referring again to  FIG. 6 , after the user loads the vials into accumulation area  622 , the programmable logic controller transports the vials to optional flip-cap remover  623 , and then to recovery device  600 . At recovery device  600 , the programmable logic controller instructs vial positioner  637  to correctly align vials  620  relative to needles  640 , and then actuates air cylinder  631  to translate needle holder  630  downwards to an appropriate height, substantially as described above. 
         [0039]    Referring also to  FIG. 7 , the programmable logic controller then pumps an appropriate volume of solvent into the vials. Specifically, the controller opens pinch valve  744 , closes pinch valve  644  to keep solvent from inadvertently going up the tubing towards manifold  650 , and then turns on solvent peristaltic pump  770 . Pump  770  pumps solvent out of solvent tank  790  via tubing  780 , into manifold  750 , through the open pinch valve  744  of valve  730 , and through needle  640  into vial  620 . After a pre-determined time corresponding to the amount of time needed to pump the appropriate volume of the solvent into the vials, which depends on the desired volume as well as the rate at which solvent peristaltic pump  770  pumps solution into the vials via needles  640 , tubing, and manifold  750 , the programmable logic controller turns off the solvent peristaltic pump  770 . The solvent dissolves the material in the vials, thus forming a solution capable of being recovered substantially as described above. 
         [0040]    To recover the solution, the programmable logic controller opens pinch valve  644  and closes pinch valve  744 , in order to prevent the solution from inadvertently going up the tubing towards manifold  750 , and then turns on recovery peristaltic pump  670 . At this point, recovery proceeds substantially as described with reference to  FIG. 3 . After a predetermined time corresponding to the amount of time needed to substantially withdraw the solution from the vials, the programmable logic controller stops recovery peristaltic pump  670 , raises air cylinder  631  to withdraw needles  640  from the vials, and instructs vial positioner  637  to release substantially empty vials  620 . Then the programmable logic controller re-starts conveyor belt  625 , which transports the substantially empty vials for disposal in empty vial collection bin  627 . The motion of conveyor belt  625  brings a new set of vials into recovery device  600 , and the programmable logic repeats the process of pumping solvent into the new vials and subsequently recovering solution from the vials. 
         [0041]    Note that the needle height when pumping solvent into the vials, and when pumping solution out of the vials, need not be the same. In some circumstances, it may be preferable to first lower needle holder  630  to a height where the tips of needles  640  barely puncture the vial stoppers when pumping solvent into the vials, and then to lower needle holder  640  to a height where the tips of needles  640  are substantially at the bottom of the vials when pumping the solution out of the vials. Note also that while the described embodiment uses pinch valves to control the flow of solvent and solution to and from the vials, other kinds of valves can be used, for example check valves, or other kinds of valves that can be controlled by the programmable logic controller. Pinch valves are useful because they can provide an adequate seal while the pumps turn off and on. 
         [0042]    Although the programmable logic controller turns on and off the peristaltic pumps in order to start and stop flow to and/or from the vials, in general the flow can be controlled in other appropriate ways, for example by opening or closing a valve that is inline between the pump and the manifold. 
         [0043]    While the controller has been described primarily as a “programmable logic controller”, it should be understood that a broad range of controllers could be used, including various combinations of hardware and software in application-specific or general purpose devices. The controller could thus include small specific purpose controllers, or appropriate programmed microprocessors, or be part of larger computer systems that control other functions as well. The controller can be in communication with various components of the systems with wired or wireless connections. 
         [0044]    Other aspects, modifications, and embodiments are within the scope of the following claims.