18
Schmitz F., Van Gansbeke B., Monclus M., Van Naemen J., Kadiata M., Ekelmans D., Goldman S.
1 PET/Biomedical Cyclotron Unit, ULB-Hospital Erasme, Route de Lennik, 808, B-1070, Brussels, Belgium
Introduction
Radiopharmaceuticals labeled with short-lived radioisotopes, especially positron emitters, are classically purified in a final step by using a sterilization filter (e.g. GS-0.22
µm from Millipore). Because of technical and physical considerations, sterility of the final solution as well as absence of pyrogen are checked after the radiopharmaceutical has been administered to patients. With the widespread clinical use of this type of tracers, especially [ 18 F]-FDG 1 , the need for classical sterilization of the final product into an autoclave is envisioned and is discussed in this abstract. Such a treatment applied to [ 18 F]-FDG has been evaluated in this work.
Materials and methods
At the end of the synthesis, the [ 18 F]-FDG radioactivity concentration is at about 30 mCi/ml. The [ 18 F]-FDG is automatically produced in a “Coincidence” module. We usually collect 2133+/-81 mCi (n=43) in 17 ml of a citrate buffered solution which is poured in a physiological solution of 51 ml. The radiochemical purity of the product is checked at the end of the synthesis following the
European Pharmacopea guidelines. The pH of the final solution is at 6.5+/-0.5. Aliquots of 10+/-1 mCi of the [ 18 F]-FDG solution routinely produced are poured into vials which are closed afterwards with Teflon septum. The vials have been heated during 20 minutes at 140 °C. To estimate the influence of the autoclaving process on the radiochemical purity, this parameter is measured on a
TLC scanner and compared to the radiochemical purity of the non-heated product. Some batches were also evaluated in parallel on an HPLC system to validate the accuracy of the measurement done on the TLC scanner. No mismatch between the two techniques
(HPLC/TLC) has been observed.
Results
The radiochemical purity of [ 18 F]-FDG routinely produced has been first evaluated over different periods of time to match the goal that all the batches are characterized by a radiochemical purity higher than 95 % at any time before autoclaving. The measurements were done during 12 hours on three different batches as described in table 1. A first screening has also been performed on the different synthesizers available on the market (IBA, Nuclear Interface, Coincidence). Autoclaving of [ 18 F]-FDG coming out of these boxes brings the radiochemical purity below 95 % whatever the type of reaction used 2,3,4 .
It should be noted that for some processes, hydrolysis conditions (HCl 1.0 M/130 °C/10 minutes/closed vial) are, for some aspects, as drastic as autoclave conditions for the final product. As described in table 2, we have tried to reduce the degradation of the product during autoclaving by adding
“stabilizers” which are essentially acidic species, such as tartaric acid, citric acid, HCl, ... These added products certainly play a favourable role during the autoclaving process by strongly reducing the amount of the by-product. This by-product is identified as fluoride-18. As described in table 3, we have not detected a major influence of the amount of stabilizer regarding the degradation of the final product after autoclaving.
Conclusion
It is well known that autoclaving an [ 18 F]-FDG solution after distribution and capping of the final vial sterilizes the product. It now appears essential to add an acidic stabilizer in the solution to maintain the radiochemical purity after this treatment.
Table 1 : stability of [ 18 F]-FDG over time after EOS Table 2 : influence of added products on [ 18 F]-FDG stability
8
9
6
7
10
11
12
4
5
2
3
0
1
Time after
EOS
(hours)
Radiochemical purity 1
(%)
97.5
97.6
97.8
98.7
96.3
96.1
97.4
97.8
97.9
95.8
98.7
95.4
95.7
Radiochemical purity 2
(%)
97.0
96.7
96.9
95.8
97.2
97.2
97.1
98.1
98.1
97.5
98.1
96.5
95.8
Radiochemical purity 3
(%)
97.6
97.7
97.8
96.9
96.7
96.7
96.8
98.2
98.3
97.9
97.5
97.6
97.3
Table 3 : influence of concentration of added products on [ 18 F]-FDG stability
Added product
Nothing
(pH 6.5)
HCl
(pH 6.0)
HCl
(pH 4.5)
Ethanol
(3%)
Ascorbic acid
(pH 4.5)
Citric acid
(pH 4.5)
Phosphate buffer
(pH 4.5)
Acetic acid
(pH 4.5)
Sulfate buffer
(pH 4.5)
Radiochemical purity (%)
88+/-10 (n=5)
88+/-11 (n=5)
97+/-1 (n=5)
93+/-4 (n=5)
97+/-2 (n=5)
96+/-1 (n=5)
96+/-2 (n=5)
96+/-1 (n=5)
97+/-1 (n=5)
Phosphate buffer concentration
Radiochemical purity (%)
1.0 M (pH 4.5)
0.5 M (pH 4.5)
96+/-1 (n=5)
96+/-2 (n=5)
0.1 M (pH 4.5) 97+/-1 (n=5)
0.01 M (pH 4.5) 96+/-1 (n=5)
0.001 M (pH 4.5) 95+/-1 (n=5)
References :
1. European Pharmacopea, third edition addendum 2001, 853-855, ISBN 92-871-4316-1
2. Hamacher, K., et al, Efficient stereospecific synthesis of no-carrier-added 2-

18F

-fluoro-2-
deoxy-D-glucose using aminopolyether supported nucleophilic substitution, J Nuc Med, 1986.
27 (2): p. 235-238.
3.
Füchtner, F., et al, Basic hydrolysis of 2- 
18F

-fluoro-1,3,4,6-tetra-O-acetyl-D-glucose in the preparation of 2-

18F

-fluoro-2-deoxy-D-glucose, Int J Appl Rad Isots, 1996. 47(1): p. 61-66.
4. Lemaire, C., et al, Fast [18F]FDG synthesis by alkaline hydrolysis on a low polarity solid phase
support, J. Label. Comp. Rad., 2002. 45: p.435-447.