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Fully automated production of sodium [18F]fluoride on AllInOne and miniAllInOne synthesizers
Applied Radiation and Isotopes 102 (2015) 87–92
Contents lists available at ScienceDirect
Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Fully automated production of sodium [18F]fluoride on AllInOne and miniAllInOne synthesizers Charlotte Collet a,b, Muhammad Otabashi d, Fabrice Giacomelli e, Nicolas Veran a, Gilles Karcher a,b, Yves Chapleur a,b,c, Sandrine Lamandé-Langle b,c,n a
NancycloTEP, Plateforme d’imagerie expérimentale, F-54500 Vandoeuvre les Nancy, France Université de Lorraine, F-54500 Vandoeuvre les Nancy, France c CNRS, UMR 7565, F-54506 Vandoeuvre les Nancy, France d TRASIS SA, rue Gilles Magnée 90, 4430 Ans, Belgium e Cyclotron Research Centre, University of Liège, 4000 Liège, Belgium b
H I G H L I G H T S
A fully automated production of [18F]NaF on AllInOne and miniAllInOne synthesizers is reported. Radiochemical yields of 97% in less than 4 min were obtained. Radiochemical purity of more than 99% was achieved.
art ic l e i nf o
a b s t r a c t
Article history: Received 17 November 2014 Received in revised form 27 April 2015 Accepted 29 April 2015 Available online 14 May 2015
A fully automated production of the imaging agent sodium [18F]fluoride ([18F]NaF) on two different modules commercialized by Trasiss, the AllInOne and the miniAllInOne, is reported. Both modules allow to prepare [18F]NaF in good radiochemical yield (around 97%) in less than 4 min with the same specifications. Quality control of [18F]NaF produced by this way was performed according to the US and European Pharmacopeia monograph requirements. & 2015 Elsevier Ltd. All rights reserved.
Keywords: Sodium [18F]fluoride [18F]NaF Positron emission tomography Radiopharmaceutical
1. Introduction Sodium [18F]fluoride for injections ([18F]NaF) is a radiopharmaceutical of importance as a diagnostic agent for positron emission tomography (PET) in bone imaging. This isotonic preparation of 0.9% sodium chloride containing [18F]fluoride anion is used since 1960s (Blau et al., 1962) as a bone imaging agent in scintigraphy (Blau et al., 1972). With the development of modern positron emission tomography cameras it became a good imaging agent to give bone metabolism images (Weber et al., 1974). However it was not the most widely used due to the presence of a lowcost option for bone imaging such as 99mTc-methylene diphosphonate (99mTc-MDP) (Ogawa et al., 2011) used in single-photon emission computed tomography (SPECT) imaging. n Correspondence to: UMR 7565, Université de Lorraine, F-54506 Vandoeuvre les Nancy, France. Fax: þ 33 3 83 68 47 80. E-mail address: [email protected] (S. Lamandé-Langle).
http://dx.doi.org/10.1016/j.apradiso.2015.04.016 0969-8043/& 2015 Elsevier Ltd. All rights reserved.
Recent advances in PET technology and problems in the supply of Molybdenum-99 (Hockley et al., 2010; National Research Council, 2009) have renewed interest in the use of [18F]NaF. Furthermore, the use of [18F]NaF in PET imaging is more accurate than that of 99mTc-MDP in SPECT imaging for selective and specific detection of bone metastases in cancer patient (for example: Beheshti et al., 2009; Chakraborty et al., 2013; Even-Sapir et al., 2007, 2006; Iagaru et al., 2013, 2012; Krüger et al., 2009; Ota et al., 2014; Schirrmeister et al., 2001, 1999). The Food and Drug Administration (FDA) approved for [18F]NaF in 2011, a New Drug Approval from the National Cancer Institute as diagnostic agent for PET to image bone and localize altered osteogenic activity. Preparing PET radiopharmaceuticals in high quantity requires the use of a synthesizer. The production of [18F]NaF has been described on different synthesizers, i.e. the tracerlab FXFN (Hockley and Scott, 2010; Shao et al., 2011), the tracerlab MX FDG (Bicalho Silveira et al., 2010; Martinez et al., 2011) commercialized by General Electrics (GE) and on other modules (Kao et al., 2010;
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C. Collet et al. / Applied Radiation and Isotopes 102 (2015) 87–92
Nandy et al., 2007) but these synthesizers except tracerlab FXFN are no longer marketed. Today existing accredited techniques of this production are available on other modules like Modular-Lab PharmTracer from Eckert & Zieglers, FASTlab Multi-Tracer-Plattform from GEs and Synthera synthesis unit from IBAs. The quality control of this radiopharmaceutical has also been described (Li et al., 2011). Herein we describe an efficient automation of [18F]NaF on two recently introduced synthesizers by Trasiss namely AllInOne (AIO) and miniAllInOne (mAIO) both using disposable-cassettes and the same software. All steps of both productions are described and the use of both modules is compared. Quality control of [18F]NaF produced this way, was performed according to the US (US Pharmacopeia, 2014) and European Pharmacopeia (European Pharmacopeia, 2014) monograph requirements.
2. Materials and methods 2.1. Chemicals and materials 0.9% Sodium chloride (NaCl) solution for injections was purchased from Fresenius Kabis, sterile water for injections (WFI) Macoflex N from Macopharmas, Sterile Millex filters from Millipores and sterile product vials from Cis-Bio internationals (Tec-Elu-5). 18O-enriched water was supplied by CortecNets, Sep-Paks Accell Plus QMA cartridges from Waters Corporations and 20 mL BD luer lock syringes from Dutschers. All the reagents and materials were used as received. 2.2. Synthesizers 2.2.1. Description The AllInOne (AIO) is a very versatile module with which fluorine-18, carbon-11 and gallium-68 labeling could be performed. It is equipped with two arrays of eighteen rotary actuators having multiple positions, two heaters, seven radiation detectors, four pressure gas ports, four exhaust ports, five syringe drivers and two HPLC column positions.
The equivalent of the AIO but with less versatility is the miniAllInOne (mAIO) recently introduced by Trasiss. This module is ideal for easy and routine radiosyntheses and has the advantage to be compact and easy to operate. It includes two arrays of six rotary actuators having multiple positions, one heater, three radiation detectors, one pressure gas port, two exhaust ports and two syringe drivers. Both AIO and mAIO synthesizers are driven by the same intuitive and interactive software running under Windows. 2.2.2. Cassette Both the modules operate with single use cassettes and reagent sets: this facilitates GMP compliance, prevents cross-contamination and ensures reproducible low-bioburden results. The parts available in bulk allow the assembly of these cassettes for research purpose. These ones are structured around one or more rows of six rotating valves (in TPX and polyethylene) on which various components can be plugged: syringes (in polypropylene, isoprene and silicone as lubricant), several tubes or extension lines (in silicone), connectors (in polypropylene), water bag spike (in ABS) and gas filters (membrane made out of polytetrafluoroethylene and body of methylmethacrylate-butadienestyrene). All these materials are suitable for medical devices according to the class 6 USP (Biological tests of reactivity for elastomers, plastics and other polymer materials for a direct or indirect contact with the patient). A previous study (study report TE141751, Toxikon), based on a more complex process, demonstrated the absence of leachable in the final drug substance. 2.2.3. Synthesizer preparation The production of [18F]NaF was developed with the same sequence for both the modules. Before the activity reception, the machines perform the internal tests and the cassettes tests automatically. 2.3. Production Fluoride-18 was produced via the
Fig. 1. AIO layout for [18F]NaF production.
18
O(p,n)18F nuclear reaction
C. Collet et al. / Applied Radiation and Isotopes 102 (2015) 87–92
89
Fig. 2. mAIO layout for [18F]NaF production.
on a PET Trace cyclotron (GE). The bombardment was performed at 10 mA during 5 min to provide about 2 GBq of fluoride-18 delivered as a solution in 18O-enriched water (1.6 mL). The software reproduces the picture of the cassette layout (Fig. 1) for AIO and (Fig. 2) for mAIO and shows in real time all the movements of the machine during the [18F]NaF production. Both the automated processes are divided into three steps as follows: - Activity reception: the fluoride-18 solution is transferred into a 20 mL syringe body. - Synthesis: the fluoride-18 solution is passed through Sep-Paks Accell Plus QMA cartridge to trap the fluoride-18 and the liquid is collected in a separated vial. The QMA cartridge is washed with 7 mL of water for injections and then flushed with nitrogen gas flow. - Delivery: the fluoride-18 is eluted from the QMA cartridge with the desired volume (we normally used 3 mL) of 0.9% NaCl, passed through a sterile Millex-GS filter (0.22 mm) to the collection vial. This solution can be diluted by adding 1–10 mL of 0.9% NaCl through the filter. The activity of the prepared [18F]NaF was s measured in a Capintec CRC -25R ionization chamber and the product was then released for quality control.
2.4. Quality control procedure 2.4.1. Radionuclide purity Radionuclide purity and identity of [18F]F were determined by gamma-ray spectrometer (Canberras 802-2 2W and Osprey dtb) with NaI detector. Radionuclide identity was confirmed by the time-decay method measured on a Capintecs CRC-25R. 2.4.2. Radiochemical purity Radiochemical purity and identity of [18F]NaF was determined by an analytical high performance liquid chromatography (HPLC) system performed on a ICS3000 system (Dionexs) equipped with an autosampler AS50 (Dionexs). The UV detector was a 2996 model (Waters Corporations). The radioactivity detector was composed of CsF scintillation detector with associated electronics from Ortecs. The column used was a PA10 from Dionexs and the eluent 50 mM NaOH. 2.4.3. Chemical purity Chemical purity of [18F]NaF was determined by the HPLC system described before. The UV chromatogram with detection wavelength set at 220 nm permits to assess the fluoride content.
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2.4.4. pH The pH of the sodium [18F]fluoride dose was analyzed by applying a small amount of the dose to pH-indicator strips (0–14) and determined by visual comparison to the scale provided. The required pH range must be 5–8.5. 2.4.5. Bioburden Determination of bioburden was subcontracted to CisBio Internationals member of IBA moleculars and was performed according to the European Pharmacopeia monograph requirements (07/2010:20612, European Pharmacopeia, current edition) using inoculation test. The bioburden should be inferior to 1 CFU/mL (colony forming unit per mL) in order to be compatible with sterile filtration. 2.4.6. Sterility and endotoxins tests The sterility test of one part of [18F]NaF samples was performed according to the US and European Pharmacopeia monograph requirements, by direct inoculation of at least 1 mL of [18F]NaF with Resazurin Thioglycolate and Trypticase Soja media. Culture tubes were incubated at 32.5 °C for Resazurin Thioglycolate media and 22.5 °C for Trypticase Soja for 14 days and visually inspected daily. Analyses of endotoxin content in [18F]NaF were performed using a Sunrise microplate reader from Tecans according to a validated method and was performed with two controls: a negative water control and a positive product control.
3. Results and discussion 3.1. Automated production of [18F]NaF The production of sodium [18F]fluoride was successfully adapted to AIO and mAIO. For both the radiosynthesizers the sequence of steps is the same, only the composition of the cassette differs (Figs. 1 and 2). In the case of AIO (Fig. 1), after transfer into the plunger (v6), fluoride-18 was trapped on a Sep-Paks Accell Plus QMA cartridge by nitrogen gas flow (pressure 200 mbar; vacuum 300 mbar) during 10 s. [18O]H2O is collected into a recycling vial (v1). QMA cartridge was then flushed with nitrogen gas flow during 20 s (pressure 400 mbar; vacuum 300 mbar). Via syringe (SA1) on v3, 7 mL of water for injections (v11) was passed through the QMA cartridge (v4–v5; vacuum 300 mbar). The Sep-Paks Accell Plus QMA cartridge was then dried with a nitrogen gas flow (pressure 400 mbar; vacuum 300 mbar) during 10 s. Desired volume, 3 mL, of 0.9% NaCl (v7) was taken with syringe (SA1) on v3. Fluoride-18 was then eluted from the Sep-paks QMA cartridge
with these 3 mL of 0.9% NaCl to produce [18F]NaF and passed through a sterile filter into a sterile dose vial (v12). The residual [18F]NaF was then pushed into the same sterile dose vial through a sterile filter by nitrogen pressure ( pressure 500 mbar) during 10 s. With the mAIO (Fig. 2), after transfer into the plunger (v2), fluoride-18 was trapped on a Sep-paks Accell Plus QMA cartridge (v4–v5) by nitrogen gas flow (pressure 200 mbar; vacuum 300 mbar) during 10 s. [18O]H2O is collected into a recycling vial (v6). QMA cartridge was then flushed with nitrogen gas flow during 20 s (pressure 400 mbar, vacuum 300 mbar). Via syringe (SA2) on v3, 7 mL of water for injections (v9) was taken and passed through the QMA cartridge (v4–v5; vacuum 300 mbar). The Sep-Paks Accell Plus QMA cartridge was then dried with a nitrogen gas flow (pressure 400 mbar, vacuum 300 mbar) during 10 s. Desired volume, 3 mL, of 0.9% NaCl (v7) was taken with syringe (SA2) on v3. Fluoride-18 was then eluted from the Sep-paks QMA cartridge with these 3 mL of 0.9% NaCl to produce [18F]NaF and passed through a sterile filter into a sterile dose vial (v12). The residual [18F]NaF was then pushed into the same sterile dose vial through a sterile filter by nitrogen pressure (pressure 500 mbar) during 10 s. Typical preparation run started with 59.5 mCi (2.2 GBq) and produced in the average of 57 mCi (2.1 GBq) of 3 mL [18F]NaF solution in less than 4 min starting from activity reception. A high and reproducible decay corrected radiochemical yield in the average of 97%, was obtained on both synthesizers. There are no significant yield differences regardless of the module (AIO or mAIO). The final volume of [18F]NaF solution for injections could be easily changed according to need. This solution can be diluted by adding 1–10 mL of 0.9% NaCl. The differences between the two modules are the position of the constituent and the connection with two arrays of six rotary actuators (see Figs. 1 and 2), only the position of the plunger (20 mL syringe body) and the syringe was imposed by the module. Both the modules allowed us to produce [18F]NaF in good radiochemical yield in less than 4 min with the same specification. 3.2. Quality control of [18F]NaF Quality control of [18F]NaF is performed according to the US and European Pharmacopeia monograph requirements (USP 32 and EP 8.3). Results were presented (Table 1) for three repeatable batches. The visual appearance of [18F]NaF solution was free of particles and colorless. The pH value of the solution, measured using pH paper (0–14) by color determination in comparison to the scale provided, was in the average of 6.0–7.5, within the required pH range of 5–8.5.
Table 1 Quality control data for [18F]NaF. Trial
Appearance pH Radiochemical purity Radiochemical identity Chemical purity Radionuclidic identity Radionuclidic purity Bacterial endotoxin Sterility a b c
Reference USP 32, EP 8.3
Clear, colorless, free of particulates (4.5–8) USP, (5–8.5) EP 4 98.5% by HPLC RRTa ¼ 0.9–1.1 o 0.45 mg/mL T1/2b ¼ 105–115 min 499.9% o 17.5 EUc/mL Sterile
Relative retention time, rounded to the nearest 1/10. Semi-disintegration period. Endotoxin units (maximum recommended dose: 10 ml).
AIO
mAIO
Batch 1
Batch 2
Batch 3
Batch 1
Batch 2
Batch 3
Complies 6 Complies 1.0 o 0.45 108 Complies o 1 Sterile
Complies 7.5 Complies 1.0 o 0.45 110 Complies o 1 Sterile
Complies 6 Complies 1.0 o 0.45 109 Complies o 1 Sterile
Complies 7 Complies 1.0 o 0.45 108 Complies o 1 Sterile
Complies 6 Complies 1.0 o 0.45 108 Complies o 1 Sterile
Complies 7 Complies 1.0 o 0.45 110 Complies o 1 Sterile
C. Collet et al. / Applied Radiation and Isotopes 102 (2015) 87–92
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Fig. 3. HPLC of [18F]NaF. Top: radioactive detection. Bottom: UV detection, 220 nm.
Radionuclide identity was confirmed by measuring the half-life of fluorine-18, which must be included between 105 and 115 min according to the US and European Pharmacopeia monograph. A time decay of 109 71 min was obtained. The radionuclide purity was measured at release by gamma-ray spectrometer and showed the presence of one radionuclide, which had an energy of 511 keV. After decay the radionuclide purity was checked and showed no long-lived radioactive contaminants. High performance liquid chromatography (HPLC) of “cold” NaF standard (0.452 mg/mL) was performed and the system (cf. 2.4.2) showed good signal to noise ratio and NaF presented a retention time in the average of 10 min according to the criteria of the monograph. Identity and purity of [18F]NaF were determined by the same HPLC system. The only peak represented on the HPLC radiochromatogram (Fig 3) had the expected retention time, as the standard in these conditions. It was related to [18F]NaF and showed no impurities in the limit of detection (LOD o 0.2 MBq/ml). The radiochemical purity was more than 98.5% of the radioactivity. The UV HPLC-chromatogram of [18F]NaF (Fig. 3) showed no UV signal corresponding to NaF ( olimit of detection) in the average of 9 min. No significant quantity of 19F was found in the sample, the radiotracer was so produced in good chemical purity. Determination of bioburden was performed as described previously; it was inferior to 1 CFU/mL. The control of sterility was made and results were negative. The control of endotoxin content in [18F]NaF was carried out as explained before. Endotoxin content
of less than 1 EU/mL was obtained which is below the specifications (o175/volume max) in agreement with the US and European Pharmacopeia monograph.
4. Conclusion In conclusion, the first efficient automated production of [18F]NaF was developed on commercial Trasiss synthesizers. Both modules AIO and mAIO showed reproducible preparations with very good radiochemical yields. The small size and the easy manipulation of mAIO radiosynthesizer allows simple and fast [18F]NaF radiosynthesis. It could be easily used for routine cGMP productions in hot cells and could be connected to a dispenser unit.
Acknowledgments We thank the Région Lorraine and Grand Nancy for a postdoctoral fellowship to C. Collet.
References Beheshti, M., Langsteger, W., Fogelman, I., 2009. Prostate cancer: role of SPECT and PET in imaging bone metastases. Semin. Nucl. Med. 39, 396–407. Bicalho Silveira, M., Araugio Soares, M., Sarmento Valente, E., Soares Waquil1, S.,
92
C. Collet et al. / Applied Radiation and Isotopes 102 (2015) 87–92
Vidal Ferreira, G.A., Gouvêa dos Santos, R., Batista da Silva1, J., 2010. Synthesis, quality control and dosimetry of the radiopharmaceutical [18F]-sodium fluoride produced at the Center for Development of Nuclear Technology–CDTN. Braz. J. Pharm. Sci. 46 (3), 563–569. Blau, M., Ganatra, R., Bender, M.A., 1972. 18F-fluoride for bone imaging. Semin. Nucl. Med. 2, 31–37. Blau, M., Nagler, W., Bender, M.A., 1962. A new isotope for bone scanning. J. Nucl. Med. 3, 332–334. Chakraborty, D., Bhattacharya, A., Mete, U.K., Mittal, B.R., 2013. Comparison of 18F fluoride PET/CT and 99mTc-MDP bone scan in the detection of skeletal metastases in urinary bladder carcinoma. Clin. Nucl. Med. 38, 616–621. European Pharmacopoeia, 8th ed., 2014. Sodium Fluoride (18F) Injection. Even-Sapir, E., Metser, U., Mishani, E., Lievshitz, G., Lerman, H., Leibovitch, I., 2006. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar BS, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J. Nucl. Med. 47, 287–297. Even-Sapir, E., Mishani, E., Flusser, G., Metser, U., 2007. 18F-fluoride positron emission tomography and positron emission tomography/computed tomography. Semin. Nucl. Med. 37, 462–469. Hockley, B.G., Scott, P.J.H., 2010. An automated method for preparation of [18F]sodium fluoride for injection, USP to address the Technetium-99m isotope shortage. Appl. Radiat. Isot. 68, 117–119. Iagaru, A., Mittra, E., Dick, D.W., Gambhir, S.S., 2012. Prospective evaluation of (99m)Tc MDP scintigraphy, (18)F NaF PET/CT, and (18)F FDG PET/CT for detection of skeletal metastases. Mol. Imaging Biol. 14, 252–259. Iagaru, A., Young, P., Mittra, E., Dick, D.W., Herfkens, R., Gambhir, S.S., 2013. Pilot prospective evaluation of 99mTc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases. Clin. Nucl. Med. 38, 290–296. Kao, C.-H.K., Hsu, W.-L., Kao, P.-F., Lan, W.-C., Xie, H.-L., Lin, M.-C., Chao, H.-Y., 2010. An efficient and aseptic preparation of “sodium fluoride (18F) injection” in a GMP compliant facility. Ann. Nucl. Med. 24, 149–155. Krüger, S., Buck, A.K., Mottaghy, F.M., Hasenkamp, E., Pauls, S., Schumann, C., Wibmer, T., Merk, T., Hombach, V., Reske, S.N., 2009. Detection of bone metastases in patients with lung cancer: 99mTc-MDP planar bone scintigraphy, 18F-fluoride PET or 18F FDG PET/CT. Eur. J. Nucl. Med. Mol. Imaging 36, 1807–1812.
Li, C.-C., Farn, S.-S., Yeh, Y.-H., Lin, W.-J., Shen, L.-H., 2011. Development and validation of an anion-exchange HPLC method for the determination of fluoride content and radiochemical purity in [18F]NaF. Nucl. Med. Biol. 38, 605–612. Martinez, T., Cordero, B., Medin, S., Sanchez Salmon, A., 2011. Adaptation of the [18F]FDG module for the preparation of a sodium fluoride [18F] injection solution in agreement with the United States (USP 32) and European Pharmacopeia (PhEur 6). Rev. Esp. Med. Nucl. 30 (6), 351–353. Nandy, S.K., Rajan, M.G.R., Soni, P.S., Rangarajan, V., 2007. Production of sterile [F18] NaF for skeletal pet imaging. Indian J. Nucl. Med. 281, 16–23. National Research Council, 2009. Molybdenum-99/Technetium-99m supply reliability, Medical Isotope Production without Highly Enriched Uranium. The National Academies Press, Washington, DC, pp. 55–65. Ogawa, K., Saji, Hi, 2011. Advances in drug design of radiometal ?based imaging agents for bone disorders. Int. J. Mol. Imaging, 537687–537694. Ota, N., Kato, K., Iwano, S., Ito, S., Abe, S., Fujita, N., Yamashiro, K., Yamamoto, S., Naganawa, S., 2014. Comparison of 18F-fluoride PET/CT, 18F FDG PET/CT and bone scintigraphy (planar and SPECT) in detection of bone metastases of differentiated thyroid cancer: a pilot study. Br. J. Radiol. 87, 20130444. Schirrmeister, H., Glatting, G., Hetzel, J., Nüssle, K., Arslandemir, C., Buck, A.K., Dziuk, K., Gabelmann, A., Reske, S.N., Hetzel, M., 2001. Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer. J. Nucl. Med. 42, 1800–1804. Schirrmeister, H., Guhlmann, A., Elsner, K., Kotzerke, J., Glatting, G., Rentschler, M., Neumaier, B., Träger, H., Nüssle, K., Reske, S.N., 1999. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J. Nucl. Med. 40, 1623–1629. Shao, X., Hoareau, R., Hockley, B.G., Tluczek, L.J.M., Henderson, B.D., Padgett, H.C., Scott, P.J.H., 2011. Highlighting the versatility of the tracerlab synthesis modules. Part 1: fully automated production of [18F]labelled radiopharmaceuticals using a Tracerlab FXFN. J. Label. Compd. Radiopharm. 54, 292–307. United States Pharmacopeia 37th/The National Formulary 32th, 2014. Sodium Fluoride F 18 Injection. Weber, D.A., Keyes Jr., J.W., Landman, S., Wilson, G.A., 1974. Comparison of Tc99m polyphosphate and F18 for bone imaging. Am. J. Roentgenol. Radium Ther. Nucl. Med. 121, 184–190.
Contents lists available at ScienceDirect
Applied Radiation and Isotopes journal homepage: www.elsevier.com/locate/apradiso
Fully automated production of sodium [18F]fluoride on AllInOne and miniAllInOne synthesizers Charlotte Collet a,b, Muhammad Otabashi d, Fabrice Giacomelli e, Nicolas Veran a, Gilles Karcher a,b, Yves Chapleur a,b,c, Sandrine Lamandé-Langle b,c,n a
NancycloTEP, Plateforme d’imagerie expérimentale, F-54500 Vandoeuvre les Nancy, France Université de Lorraine, F-54500 Vandoeuvre les Nancy, France c CNRS, UMR 7565, F-54506 Vandoeuvre les Nancy, France d TRASIS SA, rue Gilles Magnée 90, 4430 Ans, Belgium e Cyclotron Research Centre, University of Liège, 4000 Liège, Belgium b
H I G H L I G H T S
A fully automated production of [18F]NaF on AllInOne and miniAllInOne synthesizers is reported. Radiochemical yields of 97% in less than 4 min were obtained. Radiochemical purity of more than 99% was achieved.
art ic l e i nf o
a b s t r a c t
Article history: Received 17 November 2014 Received in revised form 27 April 2015 Accepted 29 April 2015 Available online 14 May 2015
A fully automated production of the imaging agent sodium [18F]fluoride ([18F]NaF) on two different modules commercialized by Trasiss, the AllInOne and the miniAllInOne, is reported. Both modules allow to prepare [18F]NaF in good radiochemical yield (around 97%) in less than 4 min with the same specifications. Quality control of [18F]NaF produced by this way was performed according to the US and European Pharmacopeia monograph requirements. & 2015 Elsevier Ltd. All rights reserved.
Keywords: Sodium [18F]fluoride [18F]NaF Positron emission tomography Radiopharmaceutical
1. Introduction Sodium [18F]fluoride for injections ([18F]NaF) is a radiopharmaceutical of importance as a diagnostic agent for positron emission tomography (PET) in bone imaging. This isotonic preparation of 0.9% sodium chloride containing [18F]fluoride anion is used since 1960s (Blau et al., 1962) as a bone imaging agent in scintigraphy (Blau et al., 1972). With the development of modern positron emission tomography cameras it became a good imaging agent to give bone metabolism images (Weber et al., 1974). However it was not the most widely used due to the presence of a lowcost option for bone imaging such as 99mTc-methylene diphosphonate (99mTc-MDP) (Ogawa et al., 2011) used in single-photon emission computed tomography (SPECT) imaging. n Correspondence to: UMR 7565, Université de Lorraine, F-54506 Vandoeuvre les Nancy, France. Fax: þ 33 3 83 68 47 80. E-mail address: [email protected] (S. Lamandé-Langle).
http://dx.doi.org/10.1016/j.apradiso.2015.04.016 0969-8043/& 2015 Elsevier Ltd. All rights reserved.
Recent advances in PET technology and problems in the supply of Molybdenum-99 (Hockley et al., 2010; National Research Council, 2009) have renewed interest in the use of [18F]NaF. Furthermore, the use of [18F]NaF in PET imaging is more accurate than that of 99mTc-MDP in SPECT imaging for selective and specific detection of bone metastases in cancer patient (for example: Beheshti et al., 2009; Chakraborty et al., 2013; Even-Sapir et al., 2007, 2006; Iagaru et al., 2013, 2012; Krüger et al., 2009; Ota et al., 2014; Schirrmeister et al., 2001, 1999). The Food and Drug Administration (FDA) approved for [18F]NaF in 2011, a New Drug Approval from the National Cancer Institute as diagnostic agent for PET to image bone and localize altered osteogenic activity. Preparing PET radiopharmaceuticals in high quantity requires the use of a synthesizer. The production of [18F]NaF has been described on different synthesizers, i.e. the tracerlab FXFN (Hockley and Scott, 2010; Shao et al., 2011), the tracerlab MX FDG (Bicalho Silveira et al., 2010; Martinez et al., 2011) commercialized by General Electrics (GE) and on other modules (Kao et al., 2010;
88
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Nandy et al., 2007) but these synthesizers except tracerlab FXFN are no longer marketed. Today existing accredited techniques of this production are available on other modules like Modular-Lab PharmTracer from Eckert & Zieglers, FASTlab Multi-Tracer-Plattform from GEs and Synthera synthesis unit from IBAs. The quality control of this radiopharmaceutical has also been described (Li et al., 2011). Herein we describe an efficient automation of [18F]NaF on two recently introduced synthesizers by Trasiss namely AllInOne (AIO) and miniAllInOne (mAIO) both using disposable-cassettes and the same software. All steps of both productions are described and the use of both modules is compared. Quality control of [18F]NaF produced this way, was performed according to the US (US Pharmacopeia, 2014) and European Pharmacopeia (European Pharmacopeia, 2014) monograph requirements.
2. Materials and methods 2.1. Chemicals and materials 0.9% Sodium chloride (NaCl) solution for injections was purchased from Fresenius Kabis, sterile water for injections (WFI) Macoflex N from Macopharmas, Sterile Millex filters from Millipores and sterile product vials from Cis-Bio internationals (Tec-Elu-5). 18O-enriched water was supplied by CortecNets, Sep-Paks Accell Plus QMA cartridges from Waters Corporations and 20 mL BD luer lock syringes from Dutschers. All the reagents and materials were used as received. 2.2. Synthesizers 2.2.1. Description The AllInOne (AIO) is a very versatile module with which fluorine-18, carbon-11 and gallium-68 labeling could be performed. It is equipped with two arrays of eighteen rotary actuators having multiple positions, two heaters, seven radiation detectors, four pressure gas ports, four exhaust ports, five syringe drivers and two HPLC column positions.
The equivalent of the AIO but with less versatility is the miniAllInOne (mAIO) recently introduced by Trasiss. This module is ideal for easy and routine radiosyntheses and has the advantage to be compact and easy to operate. It includes two arrays of six rotary actuators having multiple positions, one heater, three radiation detectors, one pressure gas port, two exhaust ports and two syringe drivers. Both AIO and mAIO synthesizers are driven by the same intuitive and interactive software running under Windows. 2.2.2. Cassette Both the modules operate with single use cassettes and reagent sets: this facilitates GMP compliance, prevents cross-contamination and ensures reproducible low-bioburden results. The parts available in bulk allow the assembly of these cassettes for research purpose. These ones are structured around one or more rows of six rotating valves (in TPX and polyethylene) on which various components can be plugged: syringes (in polypropylene, isoprene and silicone as lubricant), several tubes or extension lines (in silicone), connectors (in polypropylene), water bag spike (in ABS) and gas filters (membrane made out of polytetrafluoroethylene and body of methylmethacrylate-butadienestyrene). All these materials are suitable for medical devices according to the class 6 USP (Biological tests of reactivity for elastomers, plastics and other polymer materials for a direct or indirect contact with the patient). A previous study (study report TE141751, Toxikon), based on a more complex process, demonstrated the absence of leachable in the final drug substance. 2.2.3. Synthesizer preparation The production of [18F]NaF was developed with the same sequence for both the modules. Before the activity reception, the machines perform the internal tests and the cassettes tests automatically. 2.3. Production Fluoride-18 was produced via the
Fig. 1. AIO layout for [18F]NaF production.
18
O(p,n)18F nuclear reaction
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Fig. 2. mAIO layout for [18F]NaF production.
on a PET Trace cyclotron (GE). The bombardment was performed at 10 mA during 5 min to provide about 2 GBq of fluoride-18 delivered as a solution in 18O-enriched water (1.6 mL). The software reproduces the picture of the cassette layout (Fig. 1) for AIO and (Fig. 2) for mAIO and shows in real time all the movements of the machine during the [18F]NaF production. Both the automated processes are divided into three steps as follows: - Activity reception: the fluoride-18 solution is transferred into a 20 mL syringe body. - Synthesis: the fluoride-18 solution is passed through Sep-Paks Accell Plus QMA cartridge to trap the fluoride-18 and the liquid is collected in a separated vial. The QMA cartridge is washed with 7 mL of water for injections and then flushed with nitrogen gas flow. - Delivery: the fluoride-18 is eluted from the QMA cartridge with the desired volume (we normally used 3 mL) of 0.9% NaCl, passed through a sterile Millex-GS filter (0.22 mm) to the collection vial. This solution can be diluted by adding 1–10 mL of 0.9% NaCl through the filter. The activity of the prepared [18F]NaF was s measured in a Capintec CRC -25R ionization chamber and the product was then released for quality control.
2.4. Quality control procedure 2.4.1. Radionuclide purity Radionuclide purity and identity of [18F]F were determined by gamma-ray spectrometer (Canberras 802-2 2W and Osprey dtb) with NaI detector. Radionuclide identity was confirmed by the time-decay method measured on a Capintecs CRC-25R. 2.4.2. Radiochemical purity Radiochemical purity and identity of [18F]NaF was determined by an analytical high performance liquid chromatography (HPLC) system performed on a ICS3000 system (Dionexs) equipped with an autosampler AS50 (Dionexs). The UV detector was a 2996 model (Waters Corporations). The radioactivity detector was composed of CsF scintillation detector with associated electronics from Ortecs. The column used was a PA10 from Dionexs and the eluent 50 mM NaOH. 2.4.3. Chemical purity Chemical purity of [18F]NaF was determined by the HPLC system described before. The UV chromatogram with detection wavelength set at 220 nm permits to assess the fluoride content.
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2.4.4. pH The pH of the sodium [18F]fluoride dose was analyzed by applying a small amount of the dose to pH-indicator strips (0–14) and determined by visual comparison to the scale provided. The required pH range must be 5–8.5. 2.4.5. Bioburden Determination of bioburden was subcontracted to CisBio Internationals member of IBA moleculars and was performed according to the European Pharmacopeia monograph requirements (07/2010:20612, European Pharmacopeia, current edition) using inoculation test. The bioburden should be inferior to 1 CFU/mL (colony forming unit per mL) in order to be compatible with sterile filtration. 2.4.6. Sterility and endotoxins tests The sterility test of one part of [18F]NaF samples was performed according to the US and European Pharmacopeia monograph requirements, by direct inoculation of at least 1 mL of [18F]NaF with Resazurin Thioglycolate and Trypticase Soja media. Culture tubes were incubated at 32.5 °C for Resazurin Thioglycolate media and 22.5 °C for Trypticase Soja for 14 days and visually inspected daily. Analyses of endotoxin content in [18F]NaF were performed using a Sunrise microplate reader from Tecans according to a validated method and was performed with two controls: a negative water control and a positive product control.
3. Results and discussion 3.1. Automated production of [18F]NaF The production of sodium [18F]fluoride was successfully adapted to AIO and mAIO. For both the radiosynthesizers the sequence of steps is the same, only the composition of the cassette differs (Figs. 1 and 2). In the case of AIO (Fig. 1), after transfer into the plunger (v6), fluoride-18 was trapped on a Sep-Paks Accell Plus QMA cartridge by nitrogen gas flow (pressure 200 mbar; vacuum 300 mbar) during 10 s. [18O]H2O is collected into a recycling vial (v1). QMA cartridge was then flushed with nitrogen gas flow during 20 s (pressure 400 mbar; vacuum 300 mbar). Via syringe (SA1) on v3, 7 mL of water for injections (v11) was passed through the QMA cartridge (v4–v5; vacuum 300 mbar). The Sep-Paks Accell Plus QMA cartridge was then dried with a nitrogen gas flow (pressure 400 mbar; vacuum 300 mbar) during 10 s. Desired volume, 3 mL, of 0.9% NaCl (v7) was taken with syringe (SA1) on v3. Fluoride-18 was then eluted from the Sep-paks QMA cartridge
with these 3 mL of 0.9% NaCl to produce [18F]NaF and passed through a sterile filter into a sterile dose vial (v12). The residual [18F]NaF was then pushed into the same sterile dose vial through a sterile filter by nitrogen pressure ( pressure 500 mbar) during 10 s. With the mAIO (Fig. 2), after transfer into the plunger (v2), fluoride-18 was trapped on a Sep-paks Accell Plus QMA cartridge (v4–v5) by nitrogen gas flow (pressure 200 mbar; vacuum 300 mbar) during 10 s. [18O]H2O is collected into a recycling vial (v6). QMA cartridge was then flushed with nitrogen gas flow during 20 s (pressure 400 mbar, vacuum 300 mbar). Via syringe (SA2) on v3, 7 mL of water for injections (v9) was taken and passed through the QMA cartridge (v4–v5; vacuum 300 mbar). The Sep-Paks Accell Plus QMA cartridge was then dried with a nitrogen gas flow (pressure 400 mbar, vacuum 300 mbar) during 10 s. Desired volume, 3 mL, of 0.9% NaCl (v7) was taken with syringe (SA2) on v3. Fluoride-18 was then eluted from the Sep-paks QMA cartridge with these 3 mL of 0.9% NaCl to produce [18F]NaF and passed through a sterile filter into a sterile dose vial (v12). The residual [18F]NaF was then pushed into the same sterile dose vial through a sterile filter by nitrogen pressure (pressure 500 mbar) during 10 s. Typical preparation run started with 59.5 mCi (2.2 GBq) and produced in the average of 57 mCi (2.1 GBq) of 3 mL [18F]NaF solution in less than 4 min starting from activity reception. A high and reproducible decay corrected radiochemical yield in the average of 97%, was obtained on both synthesizers. There are no significant yield differences regardless of the module (AIO or mAIO). The final volume of [18F]NaF solution for injections could be easily changed according to need. This solution can be diluted by adding 1–10 mL of 0.9% NaCl. The differences between the two modules are the position of the constituent and the connection with two arrays of six rotary actuators (see Figs. 1 and 2), only the position of the plunger (20 mL syringe body) and the syringe was imposed by the module. Both the modules allowed us to produce [18F]NaF in good radiochemical yield in less than 4 min with the same specification. 3.2. Quality control of [18F]NaF Quality control of [18F]NaF is performed according to the US and European Pharmacopeia monograph requirements (USP 32 and EP 8.3). Results were presented (Table 1) for three repeatable batches. The visual appearance of [18F]NaF solution was free of particles and colorless. The pH value of the solution, measured using pH paper (0–14) by color determination in comparison to the scale provided, was in the average of 6.0–7.5, within the required pH range of 5–8.5.
Table 1 Quality control data for [18F]NaF. Trial
Appearance pH Radiochemical purity Radiochemical identity Chemical purity Radionuclidic identity Radionuclidic purity Bacterial endotoxin Sterility a b c
Reference USP 32, EP 8.3
Clear, colorless, free of particulates (4.5–8) USP, (5–8.5) EP 4 98.5% by HPLC RRTa ¼ 0.9–1.1 o 0.45 mg/mL T1/2b ¼ 105–115 min 499.9% o 17.5 EUc/mL Sterile
Relative retention time, rounded to the nearest 1/10. Semi-disintegration period. Endotoxin units (maximum recommended dose: 10 ml).
AIO
mAIO
Batch 1
Batch 2
Batch 3
Batch 1
Batch 2
Batch 3
Complies 6 Complies 1.0 o 0.45 108 Complies o 1 Sterile
Complies 7.5 Complies 1.0 o 0.45 110 Complies o 1 Sterile
Complies 6 Complies 1.0 o 0.45 109 Complies o 1 Sterile
Complies 7 Complies 1.0 o 0.45 108 Complies o 1 Sterile
Complies 6 Complies 1.0 o 0.45 108 Complies o 1 Sterile
Complies 7 Complies 1.0 o 0.45 110 Complies o 1 Sterile
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Fig. 3. HPLC of [18F]NaF. Top: radioactive detection. Bottom: UV detection, 220 nm.
Radionuclide identity was confirmed by measuring the half-life of fluorine-18, which must be included between 105 and 115 min according to the US and European Pharmacopeia monograph. A time decay of 109 71 min was obtained. The radionuclide purity was measured at release by gamma-ray spectrometer and showed the presence of one radionuclide, which had an energy of 511 keV. After decay the radionuclide purity was checked and showed no long-lived radioactive contaminants. High performance liquid chromatography (HPLC) of “cold” NaF standard (0.452 mg/mL) was performed and the system (cf. 2.4.2) showed good signal to noise ratio and NaF presented a retention time in the average of 10 min according to the criteria of the monograph. Identity and purity of [18F]NaF were determined by the same HPLC system. The only peak represented on the HPLC radiochromatogram (Fig 3) had the expected retention time, as the standard in these conditions. It was related to [18F]NaF and showed no impurities in the limit of detection (LOD o 0.2 MBq/ml). The radiochemical purity was more than 98.5% of the radioactivity. The UV HPLC-chromatogram of [18F]NaF (Fig. 3) showed no UV signal corresponding to NaF ( olimit of detection) in the average of 9 min. No significant quantity of 19F was found in the sample, the radiotracer was so produced in good chemical purity. Determination of bioburden was performed as described previously; it was inferior to 1 CFU/mL. The control of sterility was made and results were negative. The control of endotoxin content in [18F]NaF was carried out as explained before. Endotoxin content
of less than 1 EU/mL was obtained which is below the specifications (o175/volume max) in agreement with the US and European Pharmacopeia monograph.
4. Conclusion In conclusion, the first efficient automated production of [18F]NaF was developed on commercial Trasiss synthesizers. Both modules AIO and mAIO showed reproducible preparations with very good radiochemical yields. The small size and the easy manipulation of mAIO radiosynthesizer allows simple and fast [18F]NaF radiosynthesis. It could be easily used for routine cGMP productions in hot cells and could be connected to a dispenser unit.
Acknowledgments We thank the Région Lorraine and Grand Nancy for a postdoctoral fellowship to C. Collet.
References Beheshti, M., Langsteger, W., Fogelman, I., 2009. Prostate cancer: role of SPECT and PET in imaging bone metastases. Semin. Nucl. Med. 39, 396–407. Bicalho Silveira, M., Araugio Soares, M., Sarmento Valente, E., Soares Waquil1, S.,
92
C. Collet et al. / Applied Radiation and Isotopes 102 (2015) 87–92
Vidal Ferreira, G.A., Gouvêa dos Santos, R., Batista da Silva1, J., 2010. Synthesis, quality control and dosimetry of the radiopharmaceutical [18F]-sodium fluoride produced at the Center for Development of Nuclear Technology–CDTN. Braz. J. Pharm. Sci. 46 (3), 563–569. Blau, M., Ganatra, R., Bender, M.A., 1972. 18F-fluoride for bone imaging. Semin. Nucl. Med. 2, 31–37. Blau, M., Nagler, W., Bender, M.A., 1962. A new isotope for bone scanning. J. Nucl. Med. 3, 332–334. Chakraborty, D., Bhattacharya, A., Mete, U.K., Mittal, B.R., 2013. Comparison of 18F fluoride PET/CT and 99mTc-MDP bone scan in the detection of skeletal metastases in urinary bladder carcinoma. Clin. Nucl. Med. 38, 616–621. European Pharmacopoeia, 8th ed., 2014. Sodium Fluoride (18F) Injection. Even-Sapir, E., Metser, U., Mishani, E., Lievshitz, G., Lerman, H., Leibovitch, I., 2006. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar BS, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J. Nucl. Med. 47, 287–297. Even-Sapir, E., Mishani, E., Flusser, G., Metser, U., 2007. 18F-fluoride positron emission tomography and positron emission tomography/computed tomography. Semin. Nucl. Med. 37, 462–469. Hockley, B.G., Scott, P.J.H., 2010. An automated method for preparation of [18F]sodium fluoride for injection, USP to address the Technetium-99m isotope shortage. Appl. Radiat. Isot. 68, 117–119. Iagaru, A., Mittra, E., Dick, D.W., Gambhir, S.S., 2012. Prospective evaluation of (99m)Tc MDP scintigraphy, (18)F NaF PET/CT, and (18)F FDG PET/CT for detection of skeletal metastases. Mol. Imaging Biol. 14, 252–259. Iagaru, A., Young, P., Mittra, E., Dick, D.W., Herfkens, R., Gambhir, S.S., 2013. Pilot prospective evaluation of 99mTc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases. Clin. Nucl. Med. 38, 290–296. Kao, C.-H.K., Hsu, W.-L., Kao, P.-F., Lan, W.-C., Xie, H.-L., Lin, M.-C., Chao, H.-Y., 2010. An efficient and aseptic preparation of “sodium fluoride (18F) injection” in a GMP compliant facility. Ann. Nucl. Med. 24, 149–155. Krüger, S., Buck, A.K., Mottaghy, F.M., Hasenkamp, E., Pauls, S., Schumann, C., Wibmer, T., Merk, T., Hombach, V., Reske, S.N., 2009. Detection of bone metastases in patients with lung cancer: 99mTc-MDP planar bone scintigraphy, 18F-fluoride PET or 18F FDG PET/CT. Eur. J. Nucl. Med. Mol. Imaging 36, 1807–1812.
Li, C.-C., Farn, S.-S., Yeh, Y.-H., Lin, W.-J., Shen, L.-H., 2011. Development and validation of an anion-exchange HPLC method for the determination of fluoride content and radiochemical purity in [18F]NaF. Nucl. Med. Biol. 38, 605–612. Martinez, T., Cordero, B., Medin, S., Sanchez Salmon, A., 2011. Adaptation of the [18F]FDG module for the preparation of a sodium fluoride [18F] injection solution in agreement with the United States (USP 32) and European Pharmacopeia (PhEur 6). Rev. Esp. Med. Nucl. 30 (6), 351–353. Nandy, S.K., Rajan, M.G.R., Soni, P.S., Rangarajan, V., 2007. Production of sterile [F18] NaF for skeletal pet imaging. Indian J. Nucl. Med. 281, 16–23. National Research Council, 2009. Molybdenum-99/Technetium-99m supply reliability, Medical Isotope Production without Highly Enriched Uranium. The National Academies Press, Washington, DC, pp. 55–65. Ogawa, K., Saji, Hi, 2011. Advances in drug design of radiometal ?based imaging agents for bone disorders. Int. J. Mol. Imaging, 537687–537694. Ota, N., Kato, K., Iwano, S., Ito, S., Abe, S., Fujita, N., Yamashiro, K., Yamamoto, S., Naganawa, S., 2014. Comparison of 18F-fluoride PET/CT, 18F FDG PET/CT and bone scintigraphy (planar and SPECT) in detection of bone metastases of differentiated thyroid cancer: a pilot study. Br. J. Radiol. 87, 20130444. Schirrmeister, H., Glatting, G., Hetzel, J., Nüssle, K., Arslandemir, C., Buck, A.K., Dziuk, K., Gabelmann, A., Reske, S.N., Hetzel, M., 2001. Prospective evaluation of the clinical value of planar bone scans, SPECT, and (18)F-labeled NaF PET in newly diagnosed lung cancer. J. Nucl. Med. 42, 1800–1804. Schirrmeister, H., Guhlmann, A., Elsner, K., Kotzerke, J., Glatting, G., Rentschler, M., Neumaier, B., Träger, H., Nüssle, K., Reske, S.N., 1999. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J. Nucl. Med. 40, 1623–1629. Shao, X., Hoareau, R., Hockley, B.G., Tluczek, L.J.M., Henderson, B.D., Padgett, H.C., Scott, P.J.H., 2011. Highlighting the versatility of the tracerlab synthesis modules. Part 1: fully automated production of [18F]labelled radiopharmaceuticals using a Tracerlab FXFN. J. Label. Compd. Radiopharm. 54, 292–307. United States Pharmacopeia 37th/The National Formulary 32th, 2014. Sodium Fluoride F 18 Injection. Weber, D.A., Keyes Jr., J.W., Landman, S., Wilson, G.A., 1974. Comparison of Tc99m polyphosphate and F18 for bone imaging. Am. J. Roentgenol. Radium Ther. Nucl. Med. 121, 184–190.