Fluorodopa F18Injection
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»Fluorodopa F18Injection is a sterile USP28aqueous solution,suitable for intravenous administration of 6-[18F]fluorolevodopa in which a portion of the molecules are labeled with radioactive 18F(see Radiopharmaceuticals for Positron Emission Tomography—Compounding á823ñ).It contains not less than 90.0percent and not more than 110.0percent of the labeled amount of 18Fexpressed in MBq (or mCi)per mLat the time indicated in the labeling.It may contain suitable preservatives and/or stabilizing agents.
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Specific activity—
Mobile phase,Standard solution,Test solution,andChromatographic system— Proceed as directed in the test for Radiochemical purity.
Procedure— Separately inject equal volumes (about 50µL)of the Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure the responses for the major peaks.Calculate the concentration of L-fluorodopa found,in mg per mL,in the Injection by the formula:
C(rU/rS),
in which Cis the concentration of the Standard solution;and rUand rSare the peak responses of the Test solutionand the Standard solution,respectively.Determine the concentration of fluorodopa F18,in mCi per mL,as directed in the Assay for radioactivity.Calculate the Specific activityby dividing the result from the Assay(in mCi per mL)by the concentration (in mg per mL):it is not less than 0.463mCi per mg of L-fluorodopa (3.7×103MBq [100mCi]per mmol).USP28
Packaging and storage— Preserve in single-dose or multiple-dose containers that are adequately shielded.
Labeling— Label it to include the following,in addition to the information specified for Labelingunder Injections á1ñ:the time and date of calibration;the amount of 18Fas fluorodopa expressed as total MBq (or mCi)per mL,at time of calibration;the expiration time and date;the name and quantity of any added preservative or stabilizer;and the statement “Caution—Radioactive Material”.The labeling indicates that in making dosage calculations,correction is to be made for radioactive decay.The radioactive half-life of 18Fis 109.7minutes.The label also includes the statement “Do not use if cloudy or if it contains particulate matter.”
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USP Reference standards á11ñ— USP Endotoxin RS.USPL-Fluorodopa RS.USP28
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Radionuclidic identification (see Radioactivity á821ñ)—
A: Its half-life,determined using a suitable detector system,is between 105and 115minutes.
B:Radiochemical identity— The retention time of the major peak in the chromatogram of the Test solutioncorresponds to that in the chromatogram of the Standard solution,as obtained in the test for Radiochemical purity.USP28
Bacterial endotoxins á85ñ: not more than 175/VUSP Endotoxin Unit per mLof Injection,in which Vis the maximum administered total dose,in mL,at the expiration time.
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pHá791ñ: between 4.0and 5.5.USP28
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Radiochemical purity—
Mobile phase— Prepare a filtered and degassed mixture of 0.1%acetic acid and methanol (97:3).
Standard solution— Dissolve an accurately weighed quantity of USPL-Fluorodopa RSin 10mmol of pH4.5sodium acetate buffer,and dilute quantitatively,and stepwise if necessary,with the same buffer to obtain a solution having a known concentration of about 0.1mg per mL.
Test solution— Use the Injection diluted with water such that it provides a count rate of about 5×105counts per minute.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a 4.6-mm ×30-cm column that contains packing L1,a radioactivity detector,and a variable wavelength UVdetector operating in the range of 260to 290nm.The flow rate is about 0.8mLper minute.Chromatograph the Test solution,and record the peak responses as directed for Procedure:the relative standard deviation for replicate injections is not more than 2.0%.
Procedure— Prepare a mixture of the Test solutionand the Standard solutionand inject about 50µLinto the chromatograph,record the chromatograms,and measure the areas for both the radioactive and nonradioactive peaks.The ratio and injected volume may be adjusted to obtain suitable detection system sensitivity.The radioactivity of the major peak is not less than 90%of the total radioactivity measured,and no individual radiochemical impurity is more than 2%.The retention time of the major peak in the chromatogram of the Test solutioncorresponds to that in the chromatogram of the Standard solution.[NOTE—The typical retention time for fluorodopa is about 6minutes.Retention times are very sensitive to the pHof the solvent.]USP28
Radionuclidic purity— Using a suitable gamma-ray spectrometer (see Selection of a Counting Assemblyunder Radioactivity á821ñ),count an appropriate aliquot of Injection for a period of time sufficient to obtain a gamma spectrum.The resultant gamma spectrum should be analyzed for the presence of identifiable photopeaks which are not characteristic of F18emissions.Not less than 99.5%of the gamma emissions should correspond to the 0.511MeV,1.022MeV,or Compton scatter peaks of F18,with no individual impurity peaks present above 0.1%.
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Chemical purity— The methods and limits described in this section relate to potential impurities associated with commonly used methods of synthesis for Fluorodopa F18Injection.If methods of synthesis are used that may result in different impurities,the presence of unlabeled ingredients,reagents,and by-products specific to the process must be controlled and then potential for physiological or pharmacological effects must be considered.
LIMIT OF ORGANOTIN(to be determined if tin-containing starting materials or reagents are used in the synthesis)—
Mobile phase— Prepare a filtered and degassed 5µmol solution of morin in a mixture of toluene,acetic acid,methanol,and acetonitrile (91:5:2:2).
Standard solution— Prepare a mixture of 10mmol each of dimethyltin dibromide and trimethyltin bromide in alcohol.
Test solution— Use the Injection.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph is equipped with a fluorescence detector (excitation at 420nm and detection at 500nm)and a 4.6-mm ×25-cm column that contains packing L32.The flow rate is about 1mLper minute.
Procedure— Separately inject equal volumes (about 50µL)of the Standard solutionand the Test solutioninto the chromatograph,record the chromatograms,and measure the peak responses.The volume of Injection in the Standard solutionand the Test solutionmay be adjusted to obtain suitable detection system sensitivity.Calculate the concentration,in µg per mL,of dimethyltin and trimethyltin in the portion of Injection taken by the formula:
C(rU/rS),
in which Cis the concentration,in µg per mL,of the relevant organotin compound in the Standard solution;and rUand rSare the peak responses obtained from the Test solutionand the Standard solution,respectively:not more than 0.5µg per mLof dimethyltin and trimethyltin is found.
LIMIT OF MERCURY(to be determined if mercury-containing starting materials or reagents are used in the synthesis)— [Caution—Because of the toxic nature of mercury vapor,great care must be taken to avoid inhaling it.Abypass has been included in the system,therefore,either to vent the mercury vapor into an exhaust hood or to pass the vapor through some absorbing media such as a solution containing equal volumes of 0.1Mpotassium permanganate and dilute sulfuric acid (1in 10). ]
Apparatus— Use a flameless atomic absorption spectrophotometer for measuring radiation at 253.7nm emitted by mercury vapor.
Stannous chloride suspension— Add 25g of stannous chloride to 250mLof 0.5Nsulfuric acid.This mixture is a suspension and is to be stirred continuously during use.
Sodium chloride–hydroxylamine hydrochloride solution— Dissolve 12g of sodium chloride and 12g of hydroxylamine hydrochloride in water,dilute with water to 100mL,and mix.
Mercury stock solution— Dissolve 135.4mg of mercuric chloride,accurately weighed,in 75mLof water.Add 10mLof nitric acid,dilute with water to 100.0mL,and mix.Each mLof this solution contains 1mg of mercury.
Mercury standard solution— Before using,make successive dilutions of the Mercury stock solutionwith water to obtain a Mercury standard solutioncontaining 0.1µg per mL.
Calibration— To six 300-mLglass-stoppered bottles,transfer,respectively,0-,0.5-,1.0-,2.0-,5.0-,and 10.0-mLaliquots of the Mercury standard solutioncontaining 0µg to 1.0µg of mercury.To each bottle add water to make 100mL,mix,and add 5mLof sulfuric acid and 2.5mLof nitric acid.Add 15mLof potassium permanganate solution (1in 20).Allow to stand for 15minutes.Add 8mLof potassium persulfate solution (1in 20),and heat in a water bath at 95for 2hours.Cool,and add 6mLof Sodium chloride–hydroxylamine hydrochloride solutionto reduce the excess permanganate.When the solution has been decolorized,wait for 30seconds and add 5mLof Stannous chloride suspension.Immediately attach the flask to the aeration apparatus to form a closed system.Allow the sample to stand without manual agitation.The circulating pump,previously adjusted to a rate of 1Lper minute,is allowed to run continuously.The absorbance will increase and reach a maximum within 30seconds.As soon as the recorder pen levels off,in about 1minute,open the bypass valve and continue the aeration until the absorbance returns to its minimum value.Close the bypass valve,remove the stopper and frit from the bottle,and continue the aeration.Plot a standard curve of the peak height versus micrograms of mercury.
Test preparation— Transfer 1.0mLof Injection to a 300-mLglass-stoppered bottle,and proceed as directed under Calibration,beginning with “To each bottle add water”.Measure the absorbance of the solution,and determine the quantity,in µg,of mercury in the Test preparationfrom the standard curve:not more than 0.5µg is found.
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Enantiomeric purity—
Mobile phase— Prepare a filtered and degassed mixture of 100mmol of monobasic potassium phosphate and 2mmol of cupric sulfate (1:1).Adjust to a pHof 4.6.Make adjustments if necessary (see System SuitabilityunderChromatography á621ñ).
Standard solution— Use the Standard solutionas directed under Radiochemical purity.
Test solution— Use the Injection.
Chromatographic system (see Chromatography á621ñ)— The liquid chromatograph as directed under Radiochemical purityis equipped with a 4.6-mm ×25-cm column that contains packing L32.The flow rate is about 1mLper minute.Chromatograph the Standard solution,and record the peak responses as directed for Procedure:the capacity factors,k¢,for the D-and L-isomers are not less than 2.1and 7.3,respectively.
Procedure— Prepare a mixture of the Test solutionand the Standard solution,and inject about 50µLinto the chromatograph,record the chromatograms,and measure the areas for both the radioactive and nonradioactive peaks.The ratio and injected volume may be adjusted to obtain suitable detection system sensitivity.The radioactivity of the L-isomer is not less than 95%.USP28
Other requirements— It meets the requirements under Injections á1ñ,except that the Injection may be distributed or dispensed prior to completion of the test for Sterility á71ñ;the latter being started within 24hours of final manufacture,and except that it is not subject to the recommendation on Volume in Container.
Assay for radioactivity— Using a suitable calibrated system as directed under Radioactivity á821ñ,determine the radioactivity,in MBq (or mCi)per mL,of Injection.
Auxiliary Information— Staff Liaison:Andrzej Wilk,Ph.D.,Senior Scientific Associate
Expert Committee:(RMI)Radiopharmaceuticals and Medical Imaging Agents
USP28–NF23Page 847
Pharmacopeial Forum:Volume No.30(2)Page 486
Phone Number:1-301-816-8305