Abstract:
By treating potable water at a temperature of at least 250° C. (482° F.) and at a pressure of at least 4 Mpa (570 psia), can produce pyrogen-free water using treatment times of 0.05 to 5 seconds or less. The addition of an oxidant, in the form of a gas, a liquid, or a solid, further decreases the required treatment time to less than 0.05 second. The reduction in equipment size achieved with this rapid treatment time allows the utilization of treatment units small enough to be easily transported to remote locations or installed in the restricted space environment existing in ships and submarines.

Description:
[0001]    This application is a non-provisional application claiming priority from provisional application Ser. No. 60/180,278, filed Feb. 4, 2000. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    The present invention relates to a process and apparatus for producing sterile water for injection from potable water.  
         BACKGROUND OF THE INVENTION  
         [0003]    Sterile and pyrogen-free water for injection (WFI) is an essential material for field medical operations requiring parenteral procedures. Producing, transporting, and storing sufficiently large amounts of WFI is a key logistical problem. This challenge necessitates the development of a compact, reliable, and automatic system that can continuously produce sterile and pyrogen-free WFI from potable water sources. Furthermore, sterile and pyrogen-free WFI can be used to produce intravenous (IV) fluids and reconstitute freeze-dried blood products. Such devices are particularly useful for ocean vessels to reduce shipboard WFI storage burdens.  
           [0004]    The elimination of all living microorganisms (sterilization) and fever-causing agents (depyrogenation) from water can be accomplished by physical methods (heat), chemical agents (ethylene oxide, formaldehyde, alcohol, ozone), radiation, or mechanical methods (filtration). Steam and dry heat are widely used means of sterilization, which can be achieved at temperatures of 121° C. (15 min.) and 180° C. (20 min.), respectively.  
           [0005]    On the other hand, pyrogens, or bacterial endotoxins, are either metabolic products of living microorganisms or the constituents of dead microorganisms. Chemically, pyrogens are lipopolysaccharides (LPS) with molecular weights ranging from 15,000 to several million. Both dry pyrogen extracts and pyrogenic aqueous solutions lose little or their activity over years. Therefore, depyrogenation requires satisfactorily high temperatures and long holding times. Some of the reported data indicate that 180° C. for 3 to 4 hours, 250° C. for 30 to 45 minutes, or 650° C. for 1 minute will destroy pyrogens.  
           [0006]    In addition to sterilization and depyrogenation, injectable water must also be virtually free from particulate matter, oxidizable substances, dissolved gases, and metals. Currently, the only acceptable ways of manufacturing WFI are distillation and reverse osmosis (RO). However, both methods have limitations when intended for field deployment.  
           [0007]    Although distillation is the oldest and most effective method to remove LPS, the distillation still operated under low pressures is bulky and heat recovery is limited. Distillation and reverse osmosis physically separate pyrogen from water but neither destroys the pyrogens. The pyrogens concentrated in the distillation still residues or reverse osmosis retentate must be purged continuously or intermittently from the system. To ensure consistent production of pyrogen-free water, the equipment must be periodically sterilized to destroy the residual pyrogens that would accumulate on the walls of the equipment.  
           [0008]    As for RO, typically 99.5% to 99.9% of endotoxin load can be removed in a single pass, and RO filters are not absolute. To produce WFI, both of these methods require additional treatment steps, typically involving active carbon filters, deionizers, and ultrafiltration filters. There is currently a lack of a final heat sterilization method, which is currently required for FDA approval.  
         SUMMARY OF THE INVENTION  
         [0009]    The present invention includes a fully continuous process to convert treated potable water to sterile and pyrogen-free water for injection (WFI) by integrating:  
           [0010]    Hydrothermal processing (HTP) for sterilization and depyrogenation  
           [0011]    Multi-stage flash evaporation for salt removal and heat recovery  
           [0012]    In-situ filtration for particulate removal  
           [0013]    The key feature of this approach is to expose both feed water and process equipment to high temperatures. During the HTP stage of the process, the system is maintained at sufficient pressures to prevent water from evaporating. This high-temperature water environment results in extremely short treatment times required for sterilization and depyrogenation, hence enabling the development of a compact and efficient system. To remove electrolytes, the pressure of the system is reduced stepwise to achieve unit operations similar to that of a multi-stage flash evaporation process. By incorporating the microchannel technology into the evaporator design, effective heat recovery can be achieved. The entire system including filters is under high heat sterilization conditions so that the possible buildup of bacteria and/or pyrogens during normal operations can be eliminated.  
           [0014]    Since the destruction of pyrogens by HTP is the most critical step among the three basic processing steps, initial efforts were made to prove the proposed HTP concept. To this end, a laboratory-scale HTP system was designed, constructed, and operated with a design capacity of treating 35 gram/min water at temperatures up to 600° C. (1,112° F.) and pressures up to 31 Mpa (4,500 psig). Variations of the reactor residence time were achieved by adjusting either the feed flow rate (i.e., pump stroke length and/or frequency) or reactor volume, or both. The feed flow rate typically ranged from 2 ml/min to 30 ml/min. Three reactor assemblies were used to cover a wide range of reactor volumes. Dimensions of these reactor assemblies, reflecting two orders of magnitude reactor volume variation from 29.3 ml (¼-in reactor assembly) to 0.4 ml ({fraction (1/16)}-in reactor assembly).  
           [0015]    Using this HTP system, the destruction of an endotoxin ( E. coli  O113:H10) reached six-orders of magnitude within less than one second of exposure time. Results derived from these proof-of-concept experiments are given in Tables 1 to 2.  
           [0016]    Furthermore, a simplified process of the present invention includes stacked microchannel chambers consisting of at least two repeat modules. Each of the microchannel modules consists of independently integrated heat exchanger and evaporator components. These modules are connected in series.  
           [0017]    As the water leaves the HTP reactor and passes through the pressure letdown device, the pressure of the water is reduced. As a result, a portion of the water flashes off in the evaporator section. The vapor portion goes through heat exchange with the incoming feed stream and after pressure reduction is collected as WFI product. The liquid portion of the water from the evaporator section goes through the pressure letdown device and enters the next microchannel module. The liquid fraction of the last module, which contains the accumulated electrolytes, is discarded as waste stream (reject).  
           [0018]    Sterile, pyrogen-free water is an essential material for medical operations requiring parenteral procedures, for producing intravenous (IV) fluids and reconstituted freeze-dried blood products for injection. The process of the invention allows the continuous production of pyrogen-free water for injection (WFI) from potable water under field conditions. The very short treatment time required to produce WFI using the process of the invention allows the use of compact, reliable, automated equipment easily deployable in remote locations where simplicity of operation, reliability, and small space requirement are critical. This process will be particularly useful aboard ships, in combat support medical units, during humanitarian relief operations following natural disasters and in rural hospitals.  
           [0019]    The process of the invention, by treating potable water at a temperature of at least 250° C. (482° F.) and at a pressure of at least 4 Mpa (570 psia), can produce pyrogen-free water using treatment times of 0.05 to 5 seconds or less. The addition of an oxidant, in the form of a gas, a liquid, or a solid, further decreases the required treatment time to less than 0.05 second. The reduction in equipment size achieved with this rapid treatment time allows the utilization of treatment units small enough to be easily transported to remote locations or installed in the restricted space environment existing in ships and submarines.  
           [0020]    Furthermore, the total destruction of pyrogens achieved, eliminates the need for periodic heat sterilization of the equipment. This ensures the production of reliable, consistent WFI quality and simplifies operations. The application of multiple effect flash evaporation coupled with heat exchange insures a high level of heat economy while producing water essentially free of dissolved solids from the condensation of the flashed steam. The dissolved solids are concentrated in the residual water that is discarded. The need for a de-ionizer unit as required in conventional WFI production facilities is therefore eliminated. Because of the high temperature used in the reactor, it is expected that solids (e.g.; salts, hydroxides, oxides) may deposit on the wall of the reactor and in the multiple effect flash evaporator. This condition will increase in severity when temperatures and pressures in excess of the critical temperature (374.15° C.) and pressure (22.13 Mpa) of water are selected because the solubility of salts decreases significantly in supercritical water.  
           [0021]    The process of the invention will remedy this problem by providing an automatically controlled purged cycle whereby the temperature in the reactor is decreased periodically to a temperature selected in the range of 100 to 200° C. to dissolve the deposited solids while maintaining sterility of the equipment. The water produced during the purge cycle will be discarded and the cycle terminated automatically when the conductivity of the water exiting the process is equal to the conductivity of the feed water. The process of the present invention therefore combines pyrogen removal, sterilization, and demineralization in one simple unit operation where prior art processes required three separate unit operations.  
           [0022]    These and other objects of the invention, as well as many of the intended advantages thereof, will become more readily apparent when reference is made to the following description taken in conjunction with the accompanying drawings. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0023]    [0023]FIG. 1 is a schematic illustration of a system for producing sterile and pyrogen-free water for injection.  
         [0024]    [0024]FIG. 2 is a process flow diagram of a laboratory scale hydrothermal processing system.  
         [0025]    [0025]FIG. 3 is a process flow diagram of a hydrothermal processing system according to the present invention. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0026]    In describing a preferred embodiment of the invention illustrated in the drawings, specific terminology will be resorted to for the sake of clarity. However, the invention is not intended to be limited to the specific terms so selected, and it is to be understood that each specific term includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.  
         [0027]    With reference to the drawings, in general in FIG. 1 in particular, the system for producing sterile and pyrogen-free water for injection embodying the teachings of the subject invention is generally designated at  10 . With reference to FIG. 1, the system includes an inlet  12  for potable water. The water passes into a heated enclosure, generally designated as  14 , as represented by arrow  16 . The water passes through a series of microchannel chambers  18  as indicated by dotted arrow line  20 .  
         [0028]    Some of the water passing through microchannel chambers  18 , as indicated by arrow  32  passes to a hydrothermal processing reactor  34 . This water, as indicated by arrow  36  returns to the microchannel chambers  18  for further processing. Some of the water as represented by arrow  22 , then passes into filters  24 . Water exiting from the filters  22  passes, as indicated by arrow  26 , into a temperature conditioner as generally designated by reference numeral  28 . Sterile, pyrogen-free water for injection is produced as indicated by arrow  30 . Waste water as indicated by arrow  38  leaves the microchannel chambers and passes through an outlet port as indicated by arrow  40  for proper disposal.  
         [0029]    A power supply  42  powers the operation contained in the heated enclosure, including heating the enclosure to a temperature of at least 250° C. while maintaining a pressure of at least 4 MPa. The time for producing pyrogen-free water can be as little as 0.05 to 5 seconds or less.  
         [0030]    In FIG. 2, a laboratory scale hydrothermal processing system is shown. A 100 ml glass bottle  50  as available from Associates of Cape cod, as a LAL Reagent Water Bottle, is positioned on an electronic scale  52  as available from Denver Instruments, model XS-410, 410 g maximum, 0.01 g readability. Water flows through ⅛ inch outside diameter polyethylene tubing  54  to an air driven pump  56  such as is available from Williams Instruments, model P250 V225-CRTC.  
         [0031]    Another section of ⅛ inch outside diameter X 0.035 inch wall thickness, stainless steel 316 tubing  58  conveys water to a fluidized sand bed  60  after passing a pressure indicator  62  such as is available from 3-D instruments, 6000 PSI full scale, 20 PSI divisions. In the fluidized sand bed is a coiled preheater and a coiled reactor made of stainless steel 316 tubing. Thermocouples  64 , such as are available from Omega Engineering, model number CAIN-116U-24, {fraction (1/16)} inch outer diameter, inconel 600, type K, are used.  
         [0032]    Connecting the fluidized sand bed with an ice water bath  66  is another section  68  of ⅛ inch outer diameter stainless steel 316 tubing. In the ice/water bath is a coiled cooler  70  of ⅛ inch outer diameter × 0.035 inch wall thickness stainless steel 316 tubing.  
         [0033]    From the ice/water bath, is connected a capillary pressure restrictor  72  of {fraction (1/16)} inch stainless steel 316 tubing, leading to a 10 milliliter sterilized sample vial  74  as is available from American Pharmaceutical Partners, Lot 392462 or Procession Glide Needle B-D 22G1 1/2 (Becton Dickinson). Also extending from the ice/water bath is a back pressure regulator  76  as available from Whitney, Model SS 4R3A. The regulator leads, by a section  78  of ¼ inch outside diameter × 0.049 inch wall thickness stainless steel 316 tubing, to a 1,000 milliliter glass bottle  80  used as an effluent container. The data obtained from the use of this system is found in Tables 1 and 2.  
         [0034]    In FIG. 3, a process flow diagram of a hydrothermal processing system  82  is shown. Potable water introduced at arrow  84  is passed into low temperature filters  86 . Waste or rejected water is passed in the direction of arrow  88 .  
         [0035]    The treated potable water moves in the direction of arrow  90  to a pump  92 . The pump water is then passed in a direction of arrow  94  into stacked microchannel chambers  96  which each include a heat exchanger section  98 , an evaporator section  100  and pressure letdown devices  102 . In the stacked microchannel chambers, multi-effect flash evaporation is coupled with heat exchange.  
         [0036]    For pyrogen destruction, sterilization and particulate removal, the water is passed through high temperature filters  104  and electric heaters  106 . Ultimately, rejected water is passed in the direction of arrow  108  whereas sterile, pyrogen free water for injection is passed in the direction of arrow  110 .  
         [0037]    The foregoing description should be considered as illustrative only of the principles of the invention. Since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and, accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.  
                                                                                                                                                                           TABLE 1                                       Run   Feed   Sample   Feed   Rxr   Rxr   Specific   Q       Pyrogen Conc.**               Time   Wt.   Duration   Rate   Temp   Pressure   Volume   at TP   RT*   (pg/ml)   PDE            Description   (min)   (g)   (min)   (g/min)   (C.)   (psi)   (ml/g)   (ml/min)   (min)   Feed   Effluent   (%)                    reactor effluent of Sample #5   3.67   100    2   27.27   388.8   3500   5.6   152.7   0.02   2500000   &lt;6.0   99.9998       reactor effluent of Sample #6   4.5   95   2   21.11   303   1700   1.4037   29.6   0.10   2500000   &lt;6.0   99.9998       reactor effluent of Sample #4   7   81   3   11.57   302   1700   1.4037   16.2   0.18   2500000   &lt;6.0   99.9998       reactor effluent of RO water**   23       2   12.33   200    300   1.1564   14.3   0.21   N/A   &lt;6.0       reactor effluent of Sample #3   5   67   2   13.40   200    300   1.1564   15.5   0.19   2500000   &lt;6000   99.8       reactor effluent of Sample #2   3.5   96   2   27.43   196.7    300   1.1564   31.7   0.09   2500000   &gt;6000   &lt;99.8       reactor effluent of Sample #1   3   95   2   31.67   151.3    300   1.1   34.8   0.09   2500000   &gt;6000   &lt;99.8                                                          
 
         [0038]    [0038]                                                                                                                                                                           TABLE 2                                       Run   Feed   Sample   Feed   Rxr   Rxr   Specific   Q at TP       Pyrogen Conc.**               Time   Wt.   Duration   Rate   Temp   Pressure   Volume   (ml/   RT   (pg/ml)   PDE            Description   (min)   (g)   (min)   (g/min)   (C.)   (psi)   (ml/g)   min)   (min)   Feed   Effluent   (%)                    reactor effluent of Sample #1   6   80.4   2   13.4   397.4   3500   5.6   75.0   0.0053   2500000   &lt;6.0   99.9998       (100 ml solution + 1 ml 3% H202)       reactor effluent of Sample #2   4   62   1.5   15.50   395   3500   5.6   86.8   0.0046   2500000   &lt;6.0   99.9998       reactor effluent of Sample #3   3   96.6   1   32.20   299.8   1700   1.4037   45.2   0.0088   2500000   &lt;6.0   99.9998       (100 ml solution + 1 ml 3% H202)       reactor effluent of Sample #4   2   64.4   1   32.20   300   1700   1.4037   45.2   0.0088   2500000   &lt;6.0   99.9998       reactor effluent of Sample #2 + 4   2.5   80   1   32.00   250.7    700   1.1564   37.0   0.011   2500000   &lt;6.0   99.998       reactor effluent of RO water***   12   356   2   29.67   251    700   1.1564   34.3   0.012   N/A   &lt;6.0       reactor effluent of Sample #5   8   97   4   12.13   204.3    400   1.1   13.3   0.030   2500000   &gt;6000   &lt;99.8       (100 ml solution + ml 3% H202)       reactor effluent of Sample #6   4.86   93   2   19.13   299.8   1700   1.4037   26.8   0.0149   2500000   &lt;6.0   99.9998       reactor effluent of Sample #7   3.28   95   1   29.00   296.6   1700   1.4037   40.7   0.0098   2500000   &lt;6.0   99.9998       (100 ml solution + 1 ml 3% H202)