Abstract:
Undesirable metal cation contaminants, including hafnium, can be reduced from a solution containing Lutetium-177 on a bed of an anion exchange resin. The thus purified solution can be stored and transported in a polypropylene vial, to prevent the possibility of hafnium entering the solution from a glassware wall and of Lutetium from being lost from the solution by chemically reacting with a glassware wall. The vial can be sealed with a rubber stopper which has a polytetrafluoroethylene coating facing the solution to prevent the possibility of contaminants which could interfere with later uses of the Lutetium-177 from leaching into the solution from the rubber stopper. Recipients of the Lutetium-177-containing vial can be provided with a prepackaged column of the anion exchange resin to enable such recipients to remove the hafnium which accumulated in the solution as a product of radioactive decay during shipment.

Description:
BACKGROUND OF THE INVENTION 
     In one aspect, this invention relates to a chemical purification process. In another aspect, the invention relates to a container for chemicals. In another aspect, the invention relates to a clean-up kit for use with radioisotopes prior to the manufacture of radiopharmaceutical products with such radioisotopes. 
     Lutetium-177 is a radioisotope which is used for radio-diagnostic and radio-therapeutic purposes. Lutetium-177 (atomic number 71) has a half-life of about 6.71 days and decays by emission of an electron to form hafnium-177 (atomic number 72). The short half-life is beneficial from the standpoint of quickly breaking down when administered to a patient, but is problematic from the standpoint of requiring extremely prompt (and careful) handling of the material between the producer of the radioisotope and the patient. Delays between the time of production of the material and its incorporation into a pharmaceutical material, and its administration to a patient result in a decrease in the amount of Lutetium-177, with a resultant decrease in radioactive potency (curies/volume), and a concomitant increase in the concentration of the hafnium decay product (mass/volume). 
     Lutetium-177 is typically received for the preparation of a radiopharmaceutical in a small glass vial which contains a specific dose of Lutetium-177 chloride in hydrochloric (HCl) acid solution. The dose is typically measured by the radioactive output of the vial, typically in millicuries. The radioactive output is typically a calculated value for a specific time and day. In order to deliver the calculated dose to a target site, it is necessary to transfer all of the Lutetium-177 in the vial to the target site at the indicated time. 
     Delivery is typically accomplished by incorporating the Lutetium-177 into a radiopharmaceutical product. This is typically done by reacting the Lutetium-177 with an organic moiety, such as a peptide or chelator, which will seek the target site when introduced into the patient. The stoichiometries of the reactions between the Lutetium-177 and the organic moiety, and the radiopharmaceutical and the target site, however, is complicated by the presence of the hafnium, and may be further complicated by the presence of further impurities commonly found in Lutetium-177 solution, such as iron, lead, zinc, aluminum, copper and calcium. 
     The hafnium competes with the Lutetium-177 for reaction with the organic moiety, and the hafnium-pharmaceutical competes with the Lutetium-177 radiopharmaceutical for binding with the target site. The efficacy with which a given radioactive dose of Lu-177 can be converted into a target-seeking form and delivered to the target site is thus highly dependent on the Lu/Hf ratios at each stage of the process. Stoichiometry is also complicated by the fact that a significant portion of the Lutetium-177 cannot be easily removed from the vial. Apparently, a portion of the lutetium can become chemically bound to the glass. Further, the amount of hafnium which is present can be greater than the amount calculated as being present from the decay of the Lutetium-177. Apparently, hafnium, as well as other impurities which are inherent to the glass, can be leached out by the solution from the inside of the glass vial. 
     The glass wall of the vial causes a further complication in delivering a prescribed radioactive dose to the target site. The actual output of the radioactive material in the vial is often different from the measured radioactive output from the vial, due to attenuation or radioactive shielding by the glass wall of the vial, and can be as much as 50% higher. 
     Simple techniques for removing the hafnium from the Lutetium-177 solution and for getting all of the Lutetium-177 from the vial would be very desirable, as this would enable higher quantities of ultra-pure Lutetium-177 to be delivered to the target site. 
     Techniques for providing ultra-pure Lutetium-177 to the end user, and for enabling the end user to better assess the potency of the dose of Lutetium-177 to be administered would also be desirable. 
     SUMMARY OF THE INVENTION 
     It has been found that undesirable metal cation contaminants, including hafnium, can be removed from a solution containing Lutetium-177, on a bed of an anion exchange resin. 
     It has been further found that a polypropylene vial containing a sterile solution of Lutetium-177 chloride in dilute HCl is easily emptied of Lutetium-177 as the solution does not adhere to the plastic wall of the vial. The solution furthermore does not pick up environmental hafnium from the vial, or other metals, since these materials are not found in polypropylene. 
     With a glass vial, as much as 20% of the Lutetium-177 remains behind when the vial is emptied. With a polypropylene vial, more than 99% of the Lutetium-177 is easily emptied from the vial. With a glass vial, the measured radioactivity of the vial is up to 50% less than the actual radioactivity of the Lutetium-177 in the vial. With a polypropylene vial, the measured activity through the wall of the vial is much closer to actual levels. The use of a polypropylene vial thus results in less waste of Lutetium-177, a more pure form of Lutetium-177, and a more easily measured amount of Lutetium-177. 
     It has been further found that providing a rubber stopper to seal the vial which has a polytetrafluoroethylene coating facing the solution will prevent contaminants which could interfere with the stoichiometries mentioned previously from leaching from the rubber and into the solution. The stopper is preferably formed from vinyl butyl rubber and the coating is preferably Teflon® brand polytetrafluoroethylene. 
     It is further proposed to provide a column containing a strong anion exchange resin to recipients of an HCl solution of Lutetium-177, to enable such recipients, prior to further use of the solution, to remove the hafnium which accumulated, due to radioactive decay of the Lutetium-177, in the solution during shipment. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a cross-sectional view illustrating certain features of a vial according to one embodiment of the invention. 
         FIG. 2  is a pictorial view illustrating certain features of a kit including a column, a filter, and a vial according to another embodiment of the invention. 
         FIG. 3  is a cross sectional view of a stopper well adapted for use with the vial shown in  FIG. 2 . 
         FIG. 4  is a cross sectional view of a radiation protection shield in accordance with certain aspects of the invention containing a kit similar to that shown in  FIG. 2  in dashed lines. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     One embodiment of the invention provides a process for purifying a solution of Lutetium-177 which contains undesirable metal cation contaminants. The process is carried out by contacting the solution with a bed of an anion exchange resin under conditions that retain the undesirable metal cation contaminants on the bed. 
     The process is effective to remove hafnium from the solution, as well as certain other metal contaminants such as zinc and/or iron. The solution susceptible to treatment in accordance with this aspect of the invention is generally a dilute solution of a strong acid, usually HCl. The bed of resin which is employed in this aspect of the invention is most preferably contained in the form of a strong anion exchange resin in a column and the contacting occurs by flowing the solution through the column. The most preferred resin comprises a strongly basic anion exchange resin which is about 8% cross linked. 
     Good results have been obtained where the column has been prepped by first flowing an HCl solution through the column to form an HCl-treated column, then flowing an NaCl solution through the HCl treated column to form an NaCl treated column, and then flowing sterile water through the NaCl-treated column. These preparative steps assist in eluting a sterile, nonpyrogenic product. 
     The anion exchange resin is preferably in a powdered form, generally comprising particles having a particle size predominantly in the range of about to 100 to about 200 mesh. To speed solution flow though the column, it is preferred to employ a sterile gas pressure enhanced head on the column. This can be carried out by injecting a sterile gas, preferably air, into an upper end of the column to push the solution of Lutetium 177 through the column. 
     With reference to  FIG. 1 , there is provided in accordance with certain aspects of the invention a polypropylene vial  2  containing a sterile solution  4  of Lutetium-177 chloride in dilute HCl solution. Generally speaking, the vial will contain in the range of from about 0.1 to about 1000 mCi, usually from about 1 to about 500 mCi, of Lutetium-177 and essentially no hafnium. The volume of the solution will generally range from about 0.05 mL to about 50 mL, usually in the range of from about 0.1 to about 10 mL. The pH will generally range from about 0.1 to about 2.0, usually in the range of from about 0.5 to about 1.5. 
     Preferably, a rubber stopper  6  seals the vial  2 . The rubber stopper  6  preferably forms a pierceable septum and has a polytetrafluoroethylene coating  8  facing the solution  4 . A metal band  10 , generally formed from aluminum, positions the stopper in reliable sealing engagement with the vial. 
     Generally speaking, the container portion of the invention shown in  FIG. 1  is known. It is the use of a container of this type to contain the just described solution of Lutetium-177 which constitutes this aspect of the invention. 
       FIG. 2  illustrates a column system  12  for removing hafnium from an HCl solution of Lutetium-177. The column system  12  comprises a column  14  having an upper end  16  and a lower end  18 . The lower end defines a column outlet. The upper end is generally sealed by a pierceable cap  17 . The column preferably tapers from the upper end to the lower end. A bed  20  of a powdered strong anion exchange resin, which can be as previously described, is positioned in the column  14 . The bed is positioned so as to define a gas head space  22  in the upper end of the column beneath the septum  17 . A support means  24  for supporting the bed is positioned inside of the column near the lower end thereof. A disk-shaped frit forms a suitable support means  24 . 
     The system preferably further comprises a filter means  26  having an upper inlet  28  and a lower outlet  30 . The upper inlet  28  is sealingly engageable with the column outlet  18 . The filter preferably removes any particles greater than 0.22 microns in size and promotes product sterility. A first annular flange  32  is preferably positioned on an outer surface of the column near the lower end thereof. A second annular flange  34  is preferably positioned on an outer surface of the filter near the upper inlet end thereof. The flanges facilitate attaching their respective items to support apparatus and to each other. 
       FIG. 4  illustrates in cross sectional view a radiation protection shield system  50  containing a column system  12 ′ similar to that described above. To provide adequate shielding for Lutetium-177, it is preferred that the wall thickness of at least those portions of the shield between the fluid in the column system and the user constitute at least one inch of lead. The system  50  as shown is generally cylindrical in shape, and has a bottom end closure  52  and a top end closure  54 . Preferably, the system  50  comprises a lower portion  56  which forms a receptacle for receiving the vial, a tubular extension  58  mounted on an upper end of the lower portion  50  to shield the column, and an upper portion  60  which provides a top streaming shield. The portions of the shield system can be provided with alignment guides such as a tongue and groove structure  62  as illustrated in  FIG. 4  to provide additional structural stability and to eliminate a potential radiation leakage path if desired. 
     The items shown in  FIGS. 1-4  provide a kit which can be used by an end user to remove hafnium which has accumulated in a solution of Lutetium-177 as a product of radioactive decay. The kit would preferably be used immediately prior to utilizing the solution in the preparation and/or labeling of a Lutetium-177-based radiopharmaceutical. The kit comprises a vial, a column, a filter, a polypropylene receptacle, and a stopper. As used, the kit preferably further comprises a radioactive shield and a sterile air supply. 
     A suitable vial is exemplified by the sealed vial  2  as shown in  FIG. 1 . The vial  2  contains a sterile HCl solution  4  of Lutetium-177. 
     A suitable column is exemplified by is the column  14  as shown in  FIG. 2 . The column  14  contains a bed of a powdered strong anion exchange resin to remove the hafnium from the solution upon passage of the solution through the column. 
     A suitable filter is exemplified by the filter  26  as shown in  FIG. 2 . The filter  26  removes small particles from the solution after passage of the solution through the bed of powdered strong anion exchange resin and promotes sterility. 
     A suitable polypropylene receptacle is exemplified by the sterile polypropylene vial  36  shown in  FIG. 2 . The vial receives the solution after passage through the filter and has a volume sufficient to accommodate the filtered solution. 
     A suitable stopper is exemplified by the stopper  38  shown in  FIG. 3 . This stopper is for sealing the vial  36  of filtered solution, after the removal of the filter  26  and the column  14 . The stopper  38  has a polytetrafluoroethylene coating  40  and seals the vial with a crimp. 
     Certain aspects of the invention are further illustrated by the following example. 
     EXAMPLE 
     General 
     Care should be taken to insure that the work environment including the reagents, column with anion exchange resin, and process equipment such as glassware, if used, and plasticware be essentially hafnium-free. It is preferred to avoid glassware, as well as metals of any type, including syringe needles. 
     Extremely pure water and acids having a hafnium content of well below 1 ppb should be used. Handling should be carried out in a sterile flow hood. Glassware, if used, should be acid washed and plasticware, preferably polypropylene, should be metal free. Gloves should be used in handling the equipment and test tubes and containers should be kept covered to prevent airborne contamination. 
     Analysis for hafnium may be done by atomic absorption technique such as by electrothermal atomic absorption spectrophotometry (ETAAS). The principle of this technique is based upon the absorption of light at element-specific wavelengths (resonance line) for neutral atoms in the ground state. Solutions suspected of containing hafnium are placed onto a piece of pyrolytically coated graphite and dried. The graphite is heated very quickly by passing an electrical current across it. When the temperature of the graphite reaches the boiling point of the element (or salt), the element forms a gaseous cloud in the light path. The amount of light that is absorbed is proportional to the quantity of ground state neutral atoms formed from the element deposited on the graphite. Preferred ETAAS equipment is provided with a deuterium background correction. 
     Preferably, analysis for hafnium is carried out by Inductively Coupled Plasma (ICP) technique, more preferably ICP coupled with Optical Emission Spectroscopy (OES). ICP-OES uses a high temperature plasma discharge to generate positively charged ions. The sample in liquid form is pumped into the spray chamber and nebulizer. It comes out as an aerosol into the base of the plasma flame. As it passes through the plasma flame the liquid sample is transformed to a vaporized, atomized and ionized gaseous form and its outer electrons are excited to the next higher energy state. Upon de-excitation, each element in the sample emits specific-wavelength photons of light which are detected and quantifiable to extremely low levels against calibration standards. 
     The following information describes the process by which Lu-177 chloride is purified. 
     Step 1: Receipt of Bulk Lu-177 Chloride Solution from Radionuclide Production Facility 
     The bulk Lu-177 chloride solution is received from the supplier 72 hours or greater after production. The solution consists of the Lu-177 chloride in a solution of 0.05 N HCl. Activity is 830 mCi/mL. Exemplary metal levels which have been actually measured in the starting material as analyzed from a 10 microliter sample are as follows: 
     Ca: 2.33 ng/mCi 
     Fe: 0.16 ng/mCi 
     Zn: 1.6 ng/mCi 
     Pb: 0.11 ng/mCi 
     Hf: 19.5 ng/mCi. 
     Step 2: Purification of Bulk Lu-177 Chloride Solution 
     Purification of the bulk Lu-177 chloride solution is performed using column chromatography with a strong anion exchange resin. The strong anion exchange resin was purchased from Aldrich, catalog #21742-5, Dowex 1X8-200 ion exchange resin (Dowex-1-chloride, strongly basic anion, 8% crossing, 100-200 dry mesh). 
     A. The column is prepared by adding between 0.1 and 2.0 g of the anion exchange resin to the Biorad column (731-1550). Next, 10 mL of 0.1 N HCl is eluted through the column. After the addition of the 0.1 N HCl, 10 mL of 0.9% NaCl for injection is eluted through the column. Finally, 10 mL of sterile water for injection is eluted through the column. 
     B. The column is blown dry and then the entire volume of the bulk Lu-177 chloride solution is applied to the top of the column resin. The solution is passed through the column by application of a stream of air through a sterile syringe attached to the top of the column. The eluted purified solution is collected through a 0.22 mμ filter and into a 10-mL sterile polypropylene plastic vial. If more than 20% of the initial radioactivity remains on the column after elution, the column is rinsed with approximately 0.5 mL 0.05 N HCl through the same 0.22 ml filter. Both elutions are then pooled into the same sterile polypropylene plastic vial and assayed. 
     Step 3: Test to Determine Hafnium Content 
     A. A 20 μL sample is withdrawn from the sterile plastic vial (Step 2B) and diluted with 2980 μL of 1% nitric acid to yield a 1:300 dilution in a volume of 3 mL. 
     B. The diluted solution is analyzed for hafnium using an atomic absorption graphite furnace or ICP. 
     Step 4: Results 
     The product from Step 2 is a sterile, pyrogen-free radiochemical solution presently approved for investigational use only. The active ingredient is Lu-177 chloride in 0.05 N (+/−0.01 N) HCl (pH &lt;2.0), typically shipped 0.5 mL per vial. Radionuclide purity is 99.9% (min.) Lu-177, others 0.1% (max.). Chemical purity is: 
     Ca: 0.6 ng/mCi 
     Fe: 0.03 ng/mCi 
     Zn: 0.389 ng/mCi 
     Pb: 0.04 ng/mCi 
     Hf: 0.198 ng/mCi. 
     Hafnium concentration is highly dependent on the amount of time which has passed since the last purification. In an exemplary embodiment, hafnium concentration is reduced from 16,222 μg/L to 164 μg/L, which means the inventive process removed 99% of the hafnium. The concentration of hafnium quickly increases, so it is preferred that the Lu-177 solution be used very promptly after purification in accordance with the invention because after 6.74 days, the concentrations of Lu-117 and hafnium will be equal. 
     While certain preferred embodiments of the invention have been described herein, the invention is not to be construed as being so limited, except to the extent that such limitations are found in the claims.