Specific activity—
Mobile phase, Standard solution, Test solution, and Chromatographic system—
Proceed as directed in the test for Radiochemical purity.
Procedure—
Separately inject equal volumes (about 50 µL) of the
Standard solution and the
Test solution into 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
C is the concentration of the
Standard solution; and
rU and
rS are the peak responses of the
Test solution and the
Standard solution, respectively. Determine the concentration of fluorodopa F 18, in mCi per mL, as directed in the
Assay for radioactivity. Calculate the
Specific activity by dividing the result from the
Assay (in mCi per mL) by the concentration (in mg per mL): it is not less than 0.463 mCi per mg of
L-fluorodopa (3.7 × 10
3 MBq [100 mCi] per mmol).
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
Labeling under
Injections 
1
: the time and date of calibration; the amount of
18F as 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
18F is 109.7 minutes. The label also includes the statement “Do not use if cloudy or if it contains particulate matter.”
Radionuclidic identification (see Radioactivity 821)—
A:
Its half-life, determined using a suitable detector system, is between 105 and 115 minutes.
B: Radiochemical identity—
The retention time of the major peak in the chromatogram of the Test solution corresponds to that in the chromatogram of the Standard solution, as obtained in the test for Radiochemical purity.
Bacterial endotoxins 85:
not more than 175/
V USP Endotoxin Unit per mL of Injection, in which
V is the maximum administered total dose, in mL, at the expiration time.
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 USP L-Fluorodopa RS in 10 mmol of pH 4.5 sodium acetate buffer, and dilute quantitatively, and stepwise if necessary, with the same buffer to obtain a solution having a known concentration of about 0.1 mg per mL.
Test solution—
Use the Injection diluted with water such that it provides a count rate of about 5 × 105 counts per minute.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a 4.6-mm × 30-cm column that contains packing L1, a radioactivity detector, and a variable wavelength UV detector operating in the range of 260 to 290 nm. The flow rate is about 0.8 mL per 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 solution and the Standard solution and inject about 50 µL into 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 solution corresponds to that in the chromatogram of the Standard solution. [NOTE—The typical retention time for fluorodopa is about 6 minutes. Retention times are very sensitive to the pH of the solvent.]
Radionuclidic purity—
Using a suitable gamma-ray spectrometer (see
Selection of a Counting Assembly under
Radioactivity 821), 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 F 18 emissions. Not less than 99.5% of the gamma emissions should correspond to the 0.511 MeV, 1.022 MeV, or Compton scatter peaks of F 18, with no individual impurity peaks present above 0.1%.
Chemical purity—
The methods and limits described in this section relate to potential impurities associated with commonly used methods of synthesis for Fluorodopa F 18 Injection. 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 5 µmol solution of morin in a mixture of toluene, acetic acid, methanol, and acetonitrile (91:5:2:2).
Standard solution—
Prepare a mixture of 10 mmol each of dimethyltin dibromide and trimethyltin bromide in alcohol.
Test solution—
Use the Injection.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph is equipped with a fluorescence detector (excitation at 420 nm and detection at 500 nm) and a 4.6-mm × 25-cm column that contains packing L32. The flow rate is about 1 mL per minute.
Procedure—
Separately inject equal volumes (about 50 µL) of the
Standard solution and the
Test solution into the chromatograph, record the chromatograms, and measure the peak responses. The volume of Injection in the
Standard solution and the
Test solution may 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
C is the concentration, in µg per mL, of the relevant organotin compound in the
Standard solution; and
rU and
rS are the peak responses obtained from the
Test solution and the
Standard solution, respectively: not more than 0.5 µg per mL of 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. A bypass 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 0.1 M potassium permanganate and dilute sulfuric acid (1 in 10).
]
Apparatus—
Use a flameless atomic absorption spectrophotometer for measuring radiation at 253.7 nm emitted by mercury vapor.
Stannous chloride suspension—
Add 25 g of stannous chloride to 250 mL of 0.5 N sulfuric acid. This mixture is a suspension and is to be stirred continuously during use.
Sodium chloride–hydroxylamine hydrochloride solution—
Dissolve 12 g of sodium chloride and 12 g of hydroxylamine hydrochloride in water, dilute with water to 100 mL, and mix.
Mercury stock solution—
Dissolve 135.4 mg of mercuric chloride, accurately weighed, in 75 mL of water. Add 10 mL of nitric acid, dilute with water to 100.0 mL, and mix. Each mL of this solution contains 1 mg of mercury.
Mercury standard solution—
Before using, make successive dilutions of the Mercury stock solution with water to obtain a Mercury standard solution containing 0.1 µg per mL.
Calibration—
To six 300-mL glass-stoppered bottles, transfer, respectively, 0-, 0.5-, 1.0-, 2.0-, 5.0-, and 10.0-mL aliquots of the
Mercury standard solution containing 0 µg to 1.0 µg of mercury. To each bottle add water to make 100 mL, mix, and add 5 mL of sulfuric acid and 2.5 mL of nitric acid. Add 15 mL of potassium permanganate solution (1 in 20). Allow to stand for 15 minutes. Add 8 mL of potassium persulfate solution (1 in 20), and heat in a water bath at 95
for 2 hours. Cool, and add 6 mL of
Sodium chloride–hydroxylamine hydrochloride solution to reduce the excess permanganate. When the solution has been decolorized, wait for 30 seconds and add 5 mL of
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 1 L per minute, is allowed to run continuously. The absorbance will increase and reach a maximum within 30 seconds. As soon as the recorder pen levels off, in about 1 minute, 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 1.0 mL of Injection to a 300-mL glass-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 preparation from the standard curve: not more than 0.5 µg is found.
Enantiomeric purity—
Mobile phase—
Prepare a filtered and degassed mixture of 100 mmol of monobasic potassium phosphate and 2 mmol of cupric sulfate (1:1). Adjust to a pH of 4.6. Make adjustments if necessary (see
System Suitability under
Chromatography 621).
Standard solution—
Use the Standard solution as directed under Radiochemical purity.
Test solution—
Use the Injection.
Chromatographic system (see Chromatography 621)—
The liquid chromatograph as directed under
Radiochemical purity is equipped with a 4.6-mm × 25-cm column that contains packing L32. The flow rate is about 1 mL per 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 2.1 and 7.3, respectively.
Procedure—
Prepare a mixture of the Test solution and the Standard solution, and inject about 50 µL into 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%.
Other requirements—
It meets the requirements under
Injections 1, except that the Injection may be distributed or dispensed prior to completion of the test for
Sterility 71; the latter being started within 24 hours 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 821, determine the radioactivity, in MBq (or mCi) per mL, of Injection.
