Practical [Y-90]DOTATOC manufacture for patient specific adaptive dose administration under cGMP.

495 Objectives To provide [90Y]DOTATOC that has been produced under an approved IND and is available with minimal chemist, radiopharmacist, and technologist manipulation for patient specific adaptive dose administration. The doses are prepared based on dosimetry from the patient’s previous injection to maximize tumor uptake versus limiting renal toxicity- all non-pediatric initial doses are 4.44 GBq (120 mCi). Methods All manufacturing operations and QC aliquoting were conducted in an iso-Class 5 isolator under cGMP. All materials entering the isolator and the inner isolator chamber were prepared under aseptic conditions. The synthesis was conducted using a single-use cassette specific for [90Y]DOTATOC manufacture and a Perspex shielded synthesis unit (Eckert & Zeigler). The procedure was designed to deliver the final product in ~ 100mL. Once the dose had been prescribed based on dosimetry, [90Y]YCl3 in 50mM HCl was ordered (typically 0.74 GBq more than called for in the final dose) to arrive the day before manufacture. Prior to synthesis, a freshly made solution of 50mg ascorbic acid in 100mL sterile saline was prepared; 84mL of this solution was passed through the final product sterilizing filter (FPSF) into a weighed vented product vial as diluent and to prevent product radiolysis. The amount of DOTATOC precursor (P) was scaled to the amount of activity received based on 115μg P in 1.0 mL ultrapure water (U-P H2O) for 7.4 GBq. For the initial dose of 4.44 GBq , 0.6mL of the precursor solution was used and the volume in the reaction vessel was constant by addition of 0.4mL of U-P H2O. Under computer control, the received [90Y]YCl3 (~500μL) was transferred to the reaction vessel (RV). The [90Y]YCl3 vial was then washed with a solution of 50mg ascorbic acid in 1.5mL U-P H2O and transferred to the RV. The RV was heated to 95oC for 25 min. The reaction mixture was transferred to and purified by trapping on a previously activated C-18 SPE cartridge, followed by a 2mL saline rinse of the RV. The product was eluted with 2.5 mL of 47.5% aqueous ethanol followed by 16 mL of saline into the final product vial to give ~100mL of [90Y]DOTATOC solution. The integrity of the FPSF was confirmed with a pressure test. Following thorough mixing, samples were aseptically removed for endotoxin and sterility tests. A further sample was removed for HPLC and pH determination. Results [90Y]DOTATOC was routinely produced in >98% radiochemical purity (HPLC) and >90% radiochemical yield after removal of QC samples. Having the final product in ~100 mL meant that only a small fraction was removed for QC. Conveniently, the dilution meant that the endotoxin test could be conducted without further dilution and sterility samples could be drawn and testing started immediately. Furthermore, the dilution in concert with the presence of ~1% ethanol and 50mg of ascorbic acid prevented any significant radiolysis (less than 10% after 3 days for 7.4 GBq runs). The final product vial was weighed to provide a contained volume and the radioactivity measured to give an accurate concentration. The use of a 100 mL vial with close to 100 mL contents made it easy to make consistently accurate Y-90 measurements. The adjustment of the amount of precursor used to provide a semi-quantitative way to maintain specific activity did not appear to affect yield. Only the quantity of [90Y]YCl3 needed to ensure a safety margin in product produced was purchased. Conclusions We are able to consistently provide a patient specific dose of [90Y]DOTATOC, up to 7.4 GBq, that has been based on the patient9s prior dosimetry. With 2 operators to facilitate transfer in and out of the isolator the entire process is completed in 3-3.5 hours. The procedure avoids purchasing and using excessive amounts of [90Y]YCl3 resulting in reduced costs, limiting exposure and disposal. Radiopharmacists can easily adjust the dose to that desired and the more dilute preparation avoids significant exposure to the administrating technologist, nurses, and accompanying family.