4. THE CLEANROOM

According to GMP rules the production of FDG is done in a cleanroom. The cleanroom has grade C (class ISO 7 according ISO 14644-1) (2), and moreover is properly shielded using concrete in their walls for radiological protection. The air supplied to the cleanroom has three step of filtration: Previous (Viledon P-15/500; efficiency 92%), intermediate (Luwa FP-95; EU-8; efficiency 95%), and final (Luwa CR-ST; EU-14; efficiency 99.999%). Environmental conditions are: temperature 22ºC ± 2, and relative humidity < 60%. The lighting level is 500 lux. Clean areas have overpressure of 10 Pa respect to adjacent rooms

The entry of personnel and materials are carried out through airlocks: a changing room grade D (class ISO 8 according ISO 14644-1) (2) for personnel and several airlocks for materials. Surfaces inside the cleanroom are smooth, non-porous, impervious and free from cracks, without uncleanable recesses and a minimum of projecting ledges, shelves, and cupboards. Ceilings are sealed to prevent ingress of air bearing particles. Floor is non-porous, slip-resistant, abrasion-resistant, and conductive. All exposed materials are suitable for effective and frequent cleaning and disinfection. Personnel wear the required clothing for grade C (hair, bear and moustache -where relevant- are covered and a single trouser suit, gathered at the wrist and with high neck and appropriate shoes or overshoes are worn).

Component preparation, synthesis and filling are carried out in separate areas inside the cleanroom: a laminar air flow work station AV 30-70 (*2) for component preparation, two airtight hot cells B4(*3) of 75 mm lead thickness for synthesis, where the air input pass through a HEPA filter, and an airtight dispensing hot cell AB (*4) of 75 mm lead thickness for filling, with a laminar flow unit (*5) . All the extracted air from these equipments pass through a filter EU-13 (efficiency 99.97%) and activated carbon, and through different dose rate meters before go out.

5. PRODUCTION

Production of FDG is done using an automatic synthesiser (photo 2). CADPET has installed two double synthesisers for FDG (*6) . This synthesiser are a closed system where the evacuation is performed via a cooling trap with liquid nitrogen, so the volatile radioactive substances are trapped. Nevertheless, the radioactive exhaust gas can be collected separately to decay. The synthesiser receives the [F-18] fluoride in [O-18] H2O by a shielded line from the cyclotron, and after separation of [F-18] fluoride, occurs a stereospecific aminopolyether mediated nucleophilic substitution employing 1,3,4,6,-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-b-D-mannopyranose as a precursor, and basic hydrolysis with a typical radiochemical yield of 50%. Technical data are shown in table 3. After the synthesis, an automatic cleaning program can be started. The reaction vial will be autoclaved after the cleaning program.

Photo 2

The FDG solution is filled in vials using an automatic dispenser (*7) (photo 3) that works with terminal sterilisation inside the vial. At the beginning, the operator defines the number of sample vials and each activity and volume for a reference time. The solution is aseptically dispensed through a sterile filter into evacuated vials in a grade A (class ISO 5 according ISO 14644-1) (2). After filling the desired number of vials (up to 12 vials in one cycle), an automated autoclaving process is carried out (134 ºC for 5 minutes). Finally the dispensed activity in each vial is determined using a dose calibrator CRC 35R (*8) before ejection into the lead container. With the help of a lift with an airlock the container is moved outside the hot cell ready to ship.

Photo 3

6. QUALITY CONTROL AND QUALITY ASSURANCE

After the synthesis, an aliquot of FDG are tested in the Quality Control Laboratory according the European Pharmacopoeia (3). In this laboratory we have installed the equipments for test pH measurements, chemical and radiochemical purity, residual kryptofix, residual solvents, radionuclidic purity, sterility and pyrogens. CADPET has a quality assurance program, with personnel responsible for technical direction, quality assurance, quality control and production. There are written procedures about personnel, documentation, suppliers, storage, equipments, production, filling, quality control, and self inspection. Records are kept of all results obtained during the production of a lot of FDG

7. SHIPPING

After the quality control, a multidose vial is prepared inside a type A container. We use two kind of containers:

A) Containers with 3 cm lead thickness (*9) to ship by road. This container is a 12 L steel container, with wall thickness of 0.5 mm, closed by a sliding ring. External dimensions are 23 x 32 cm. Inside there is a 1 L white drum, closed by a sliding ring, for the collection of radioactive liquids in a vial. This vial is inside a lead container of 30 mm wall thickness. The intervening space is filled up with the absorbing material vermiculite. The white drum is held in the centre by a styropor insert. The total weight of the packing is 10.3 Kg.

B) Containers with 5 cm lead thickness (*10) to ship by road or airplane. This container has a design similar to the above with external dimensions 38 x 54 cm. The vial is inside a lead container of 30 mm wall thickness, and the remaining lead thickness is in the external container.

8. CONCLUSION

CADPET has license to do a maximum of 4 bombardments per day to produce up to 111 GBq of 18F-fluoride EOB per bombardment, and to ship until 44.4 GBq of FDG per bombardment. In Spain there were only two cyclotrons working, one in the center (Madrid), and the other one in the north (Pamplona). Recently, two new cyclotrons have been installed (in Madrid and in Barcelona), but also are in the center or in the north of Spain, so the distribution to the south was very complicated. The creation of this regional distribution centre in Andalucía, where there are five PET cameras working will help to the spreading of Clinical Applications of Positron Emission Tomography in Andalucía and nearby regions in Spain.

9. BIBLIOGRAPHY

(1) Manufacture of sterile medicinal products. Annex I of the EU guide to Good Manufacturing Practice 1997.

(2) International Standard ISO 14644-1. Cleanroom and associated controlled environments. Part 1: Classification of airborne particulates.

(3) Fludeoxyglucose (18F) injection. European Pharmacopoeia - Supplement 2000.

Notas

*1. GEMS PET Systems, UPPSALA, Sweden
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*2 Telstar, Tarrasa, Spain
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*3 Von Gahlen, Didam, Holland
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*4 Von Gahlen, Didam, Holland
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*5 Interflow, Wieringerwerf, The Netherlands
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*6 Nuclear Interface, Münster, Germany
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*7 Nuclear Interface, Münster, Germany
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*8 Capintec, New Jersey, USA
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*9 Von Gahlen, Didam, Holland
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*10 Medical Radioprotección, Vizcaya, Spain.
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