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DRUG MASTER FILE: [11C]Acetate
1. Name of Radiopharmaceutical (active ingredient)
[11C]Acetate
2. Indicate the chemical structure for low molecular weight drug molecules
(not required for antibodies, proteins, or polymeric agents)
CH3COOH
3. Has an Investigational New Drug (IND) application been filed for this
radiopharmaceutical?
NO:
YES:
If Yes:
IND #
Institution:
4. State specific details of techniques to analyze and quantify the compound
(ex: spectrophotometer – make, settings, sample dilutions, etc.)
Acetate is a naturally occurring compound from which no hazard to the patient would
reasonably be expected, especially as this will be administered as a tracer at a tracer dose.
Therefore, as acetate is a non-toxic, endogenous molecule, no assay of quantity or specific
activity is performed.
4a. Active Ingredient and Quantity (milligrams) to be administered.
The only active ingredient will be acetate. The carbon-11 acetate will be dissolved in sterile
aqueous isotonic solution of sodium chloride (0.141 mEq/mL) and sodium bicarbonate
(0.016 mEq/mL). pH 4.5-8.5.
4b. Indicate the minimum detectable mass of the drug by HPLC analysis.
No assay of quantity or specific activity is performed.
5. Radioisotopes
Carbon-11
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5b. Total activity of each isotope per administration (injection, IV, oral, etc.)
The quantity of acetate molecules per 40 mCi dose will be in the range of 80-400 mcg.
However, as acetate is a non-toxic, endogenous molecule, no assay of quantity or specific
activity is performed.
6. Method of assaying radioisotope activity prior to administration
(ex: Capintec ion chamber, gamma counter, or liquid scintillation counter; include details of
make, setting, type of standard, etc.)
Capintec dosimeter in radiopharmacy, calibrated against daily NBS traceable standards (Cs137) immediately prior to injection.
7. Radionuclidic Purity
(in %)
>99%
8. Significant radionuclidic impurities and means of assay
There are no significant radionuclidic impurities. The nuclear reaction which produces the
carbon-11 (collected initially as 11CO2) is the 14N(p,α)11C reaction with nitrogen gas
containing a trace of oxygen as the target material. When this target gas is irradiated with
18 MeV protons during the cyclotron run, the only radionuclide produced other than carbon11 is trace levels of 13N produced by the 16O(p,α)13N reaction. The 13N is in the form of
molecular nitrogen, which is not trapped by the cold trap used to collect the 11CO2. Thus, no
radionuclide impurities are expected to be present in the 11CO2 used to synthesize the
carbon-11 acetate. Radionuclidic purity is nevertheless checked quarterly by decay rate.
To date results are >99% carbon-11.
9. Radiochemical Purity
(in %)
>95%
10. Significant radiochemical impurities and means of assay
(ex: Chromatographic techniques and procedure for analyzing radiochromatogram).
The radiochemical impurity possible in the synthesis of carbon-11 acetate is carbon-11
acetone and carbon-11 bicarbonate. These can be separated from the carbon-11 acetate
using anion-exchange radio-HPLC (10 mM KH2PO4 at pH 3.85 on a 10 µm 4.6 mm x 250
mm Partisil SAX column, flow rate 2.0 mL/minute). Each synthesis batch is analyzed by
radio-HPLC prior to delivery for administration. Radiochemical purity is typically >98%.
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11. Provide evidence that the tracer will be stable over period of storage prior to
administration.
(Give details of storage conditions and on-going quality assurance procedures for sterility,
apyrogenicity, and radiochemical purity.)
The 20-min half-life of carbon-11 requires that the radiopharmaceuticals be administered to
the patient within 40 min (maximum) of synthesis. Repeated injections of the drug product
onto the analytical HPLC have demonstrated that the product is stable at room temperature
for this period of time. The radiopharmaceuticals will be stored at room temperature prior to
patient administration. Over this time under the conditions of storage there has been no
chromatographic evidence of chemical decomposition of the acetate, a stable naturally
occurring compound.
12. What, if any, toxic or pharmacological effects may occur?
(Attach pharmacological dose calculations based on data available from published literature or
from other valid human studies).
(NOTE: If study is being performed under 9C, evidence must be presented that there will be no
pharmacological effect in human subjects. In addition, references for pharmacological dose
data must be listed below)
Acetate is a naturally occurring compound from which no hazard to the patient would
reasonably be expected, especially as this will be administered as a tracer at a tracer dose.
13. Route(s) of Administration
Intravenous injection
14. Provide detailed information on how the pharmaceutical quality of the radioactive
drug will be assured at the time of administration.
Include the following:
 pH
 Sterility
 Apyrogenicity
 Identify (chemical and radiochemical purity)
 Concentration
a. pH
A drop of the final preparation is spotted on Merck pH strips. The acceptable pH range is
4.5-8.5.
b. Sterility/Apyrogenicity
A 1.0 mL aliquot is inoculated into each of the appropriate sterility test media and incubated
according to U.S.P recommendations:
i. Fluid Thioglycollate Media (BBL, Division of Becton-Dickinson Co., Cockeysville, MD): 14
days at 30-35° C.
ii. Soybean Casein Broth (BBL, Division of Becton-Dickinson Co., Cockeysville, MD): 14
days at 20-25° C.
Positive growth is indicated by cloudiness in the culture media. Results will be compared to
positive and negative controls.
Pyrogen testing will be performed on each batch utilizing the Limulus Lysate Amoebacyte
(LAL) Test with positive and negative water controls. All LAL test reagents utilized for
bacterial endotoxin detection will be appropriately licensed by the FDA.
Testing of sterility and apyrogenicity will be performed “after the fact” on uninjected aliquots
of every tenth batch of the radiopharmaceutical solution using the aforementioned tests. If a
positive result is obtained, appropriate review of preparation procedures will be undertaken
and the source of the contamination will be identified and eliminated. Following the
incorporation of corrective procedures, necessary sterility and pyrogen testing will be
completed to assure that identified problems have been corrected.
c. Identify (chemical and radiochemical purity)
The identity of the radiopharmaceutical will be confirmed as [11C]acetate based
chromatographic retention time of the 11C product to the retention time of authentic sample
of acetate according to the chromatographic methods given below:
HPLC Column:
Solvent:
Flow rate:
Detectors:
Partisil-10 SAX (anion ex) 4.6x150 mm.
10 mM potassium phosphate; pH = 3.85
2 mL/min
Ultraviolet (214 nm) and Radiation (NaI scintillation)
d. Concentration
The concentration of carbon-11 acetate (in mcg/mL) in the final product solution will be in
the range of 80-400 mcg/mL. However, as acetate is a non-toxic, endogenous molecule, no
assay of quantity or specific activity is performed.
e. Specific Activity (activity per mass of drug)
Not applicable
For questions or concerns, contact:
Scott E. Snyder, Ph.D.
Assistant Research Scientist
Division of Nuclear Medicine
(734) 763-0902
Fax: (734) 764-0288
Email: [email protected]