A Comparison of Routine [68Ga]Ga-PSMA-11 Preparation using Locametz and Illuccix Kits

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Wang, Luke J. Morrissette, Ka Kit Wong, Allen F. Brooks, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5363858/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Dec, 2024 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 1 posted 5 You are reading this latest preprint version Abstract Background Approval of Locametz and Illuccix kits for the manufacture of [ 68 Ga]Ga-PSMA-11 (gallium Ga68 gozetotide), a PET imaging agent for prostate cancer, as well as the corresponding therapeutic ([ 177 Lu]Lu-PSMA-617 Pluvicto), has led to a rapid increase in demand for [ 68 Ga]Ga-PSMA-11 PET imaging. Radiopharmaceutical manufacturers, using 68 Ge/ 68 Ga generators, may decide to adopt Locametz and/or Illuccix kits, which requires a comparison to select the most suitable kit for day-to-day use. The objective of this article is to compare both kits and provide guidance for selecting one for routine use, as well as evaluate labeling consistency of both kits during routine production. Additionally, we report our experience during 1.5 years of daily [ 68 Ga]Ga-PSMA-11 production at our facility using both kits. Results Locametz (n = 181) and Illuccix (n = 256) kits were prepared using non-silicone coated and silicone-coated needles with 68 Ga activities ranging from 0.53 to 3.16 GBq, with a failure rate of 1 in 128 runs for both kits. With Locametz, a 3.7 GBq generator and 10-min incubation at room temperature gave doses that passed quality control (QC) testing. Use of non-silicone coated needles in the process led to solution discoloration, and QC failure. Additionally, lack of vial inversion led to inconsistent labeling, which improved with subsequent vial agitation. For Illuccix, addition of the acetate buffer to the precursor vial prior to adding the [ 68 Ga]GaCl 3 simplifies the workflow. The maximum tolerated activity was 1.85 GBq. Lack of vial inversion led to failures, which were rectified by agitating the vial to properly incorporate the acetate solution with the generator eluate. Conclusions Both kits benefited from using a syringe pump to elute the 68 Ge/ 68 Ga generator, vial agitation, and longer length/smaller bore silicone coated needles. Both kits have similar workflows, comparable QC outcomes, and result in equivalent clinical images. Thus, the decision between kits will ultimately be determined on production preferences. Since radiopharmacies have an established “kit-based” workflow, Locametz kits with higher allowed activities and longer shelf-life may offer benefits. Conversely, more traditional PET manufacturing facilities might benefit from using Illuccix kits due to compatibility with cyclotron-produced [ 68 Ga]GaCl 3 allowing for kit batching. Ultimately, the commercial availability of 2 approved kits for production of [ 68 Ga]Ga-PSMA-11 PET has facilitated ready access to this important new imaging agent. Gallium-68 gozetotide Illuccix Locametz PET manufacturing prostate cancer PSMA-11 radiopharmacy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction According to the American Cancer Society and the NIH Surveillance, Epidemiology, and End Results (SEER) data set, one in every eight men will be diagnosed with prostate cancer in their lifetime, with the average age of first diagnosis at 66 years old (Siegel et al ., 2023). In the United States, prostate cancer is the second most common cancer type next to skin cancer, with estimates of about 288,000 new cases annually (Noone et al ., 2018; National Cancer Institute, 2024). High prevalence and diagnosis reliant on screening tests and symptoms, excluding a prostate biopsy which is the only true diagnosis but highly invasive, has led to the development of numerous imaging modalities to help diagnose and manage prostate cancer. These include transrectal ultrasound, magnetic resonance imaging, computerized tomography (CT) scans, and positron emission tomography (PET) (Zelefsky et al ., 2019; Niederhuber et al ., 2020; Taplin and Smith, 2023). In patients with high disease burden and associated metastases, use of PET/CT scans is beneficial in identifying the location of metastasized tumors. Use of the prostate-specific membrane antigen (PSMA) as a target in prostate cancer imaging is well established and the ligand [ 68 Ga]Ga-PSMA-11 (gallium Ga68 gozetotide), first reported by investigators at the German Cancer Research Center and Heidelberg University (Schäfer et al ., 2012; Eder et al ., 2013; Sachpekidis et al ., 2016) is established for the PET imaging of prostate cancer today (Barrio et al., 2016; Clore and Scott, 2024). Labeling bioactive molecules with gallium-68 is unique, as unlike other common PET isotopes such as carbon-11 or fluorine-18, there are two major production methods: cyclotron irradiation of a 68 Zn target (either liquid or solid), or elution of a germanium-68/gallium-68 ( 68 Ge/ 68 Ga) generator, to source the [ 68 Ga]GaCl 3 used in subsequent labeling steps. Both methods have their benefits and drawbacks. For instance, cyclotron-based production yields consistent supply and higher activity, but requires a more complicated purification process. In contrast, generator-based production allows straightforward access to 68 Ga-labeled tracers in facilities without a cyclotron, but requires careful management of generator decay. Both methods have been used to prepare [ 68 Ga]Ga-PSMA-11. For example, we and others produced [ 68 Ga]Ga-PSMA-11 for use in early clinical trials under an FDA-approved investigational new drug (IND) application via both a generator approach using a Scintomics synthesis module, and utilizing cyclotron-produced 68 Ga in conjunction with the GE FASTLab developer platform (Lin et al., 2018; Pandey et al., 2019; Rodnick et al ., 2020, 2022; Jackson et al . 2020; Thisgaard et al., 2021; Svedjehed et al ., 2022). Following successful completion of phase 3 clinical trials, the University of California Los Angeles (UCLA) and the University of California San Francisco (UCSF) submitted concomitant New Drug Applications for [ 68 Ga]Ga-PSMA-11 to the FDA for marketing authorization. This was granted in December 2020, making [ 68 Ga]Ga-PSMA-11 the first radiopharmaceutical for PET imaging of PSMA–positive lesions in men with prostate cancer approved in the US (Carlucci et al ., 2021). The pioneering efforts by UCSF and UCLA paved the way for commercial manufacturers to develop kits for the production of [ 68 Ga]Ga-PSMA-11. Cold kit labeling is expected to facilitate global access to 68 Ga-labeled radiopharmaceuticals including [ 68 Ga]Ga-PSMA-11 (Lepareur, 2022), and FDA approval of commercial kits for producing [ 68 Ga]Ga-PSMA-11 has altered the way many sites produce [ 68 Ga]Ga-PSMA-11 for routine clinical use. Illuccix, manufactured by Telix Pharmaceuticals, was approved in 2021, and Locametz, manufactured by Novartis, in 2022 (Novartis Pharmaceuticals Corporation, 2022; Telix Pharmaceuticals, 2023). These kits have also been approved by other regulatory agencies around the world. For traditional PET manufacturing facilities, approval of these kits has necessitated introduction of generator-based production into historically cyclotron-based workflows. In radiopharmacies and/or nuclear medicine departments already familiar with a kit-based workflow, approval of these kits has nevertheless increased the daily workload, and necessitated handling both PET ( 68 Ga) and SPECT (e.g. 99m Tc) radionuclides with different storage requirements and elution timing due to differences in generator age and kinetics. In either instance, manufacturers need to decide on adoption of Illuccix and/or Locametz kits in the formulary, depending on which is more appropriate for routine use at a given site. Approval of the Locametz and Illuccix kits with use of 68 Ge/ 68 Ga generators has enabled on demand access to [ 68 Ga]Ga-PSMA-11 in radiopharmacies and nuclear medicine departments. Since both Locametz and Illuccix kits contain the same precursor, PSMA-11, but with differences in formulation or excipients and labeling procedure, there are questions to consider when selecting one kit over (see: Supplementary Information, Table S1 ). The focus of this article is to compare both kits, provide guidance for radiopharmaceutical manufacturers to help select the most fitting kit for daily production of PSMA-11 at their own facility, and to provide guidance for switching from one kit to another. Additionally, we highlight some difficulties that were experienced during a year and a half of routine [ 68 Ga]Ga-PSMA-11 production at our facility, and solutions that we developed to overcome such issues. Methods Introduction Using E&Z GalliaPharm ® 68 Ge/ 68 Ga generators (Eckert and Zigler, 2021), Locametz (n=181) and Illuccix (n=256) kits were prepared at the University of Michigan from 2 nd June 2022 to 13 th September 2023. The workflow, variations in production batches, failure rates, and QC parameters were analyzed. QC tests were completed in accordance with kit package inserts, and according to standard procedures described in the United States Pharmacopeia (USP) (e.g. chapters , , , and ). Production of [ 68 Ga]Ga-PSMA-11 using Locametz Kits Overview: The procedure for producing [ 68 Ga]Ga-PSMA-11 using a Locametz kit in conjunction with an Eckert and Ziegler (E&Z) GalliaPharm ® 68 Ge/ 68 Ga Generator, as used at our facility, is described in the package insert (Novartis Pharmaceuticals Corporation, 2022). Briefly, [ 68 Ga]GaCl 3 is eluted from the generator using 5 mL of 0.1 M HCl directly into the Locametz vial fitted with a 0.2 μm sterile vent filter. The vial is then inverted once, placed upright, and left at room temperature (20-30 o C) for 5 minutes for labeling. The vial is then calibrated with a maximum allowable activity of 2.59 GBq and an expiration time of 6 hours is assigned. The dose in 5 mL can be further diluted to 10 mL with normal saline (0.9 % NaCl). Detailed Procedure: At our facility, production of Locametz kits requires the disposable and non-disposable items listed in Table S2 (see Supplementary Information). Production of Locametz occurs as follows: Take the Locametz vial from the kit and remove the flip-off cap from the top of the vial. Take a tear weight of the vial. In a segregated area with an ISO 5 primary engineering control (PEC), move and wipe the needed materials into the PEC using sterile 70% isopropyl alcohol. Using aseptic technique, pierce the Locametz dose vial with a 0.2 μm Millex-FG sterile air vent filter connected to a 0.8x50 mm (21Gx2”) needle. Then pierce the Locametz dose vial with a 0.22 μm Cathivex-GV sterile product filter connected to a 1.2x38 mm (18Gx1½”) silicone coated needle. Arrange the filters such that the bevel of the needle connected to the sterile air vent is positioned above the bevel of the needle connected to the product filter, and that both filters are in the top 1/3 of the Locametz vial ( Figure 1a ). This will minimize activity from being expelled out of the sterile vent filter during generator elution. Take the Locametz dose vial with the two filters out of the PEC and place it into a lead or tungsten shielded container suitable for PET isotopes. Connect the 1.85 GBq or 3.7 GBq E&Z generator outlet line to the Cathivex-GV filter and using a 10 mL organic syringe pull up 6.2 mL of 0.1 M Ultrapure sterile HCl from the three-way valve upstream of the inlet line minimizing air bubbles. Manually (or automatically if using a syringe pump), elute the generator at a rate no faster than 2 mL/min, ensuring that if there were air bubbles in the syringe they are not pushed into the generator. Once the elution is completed, note the time, as this is used to determine the expiration time. Remove the sterile air vent from the Locametz vial and discard in a shielded radioactive sharps bin. Remove the product filter from the Locametz vial and disconnect the filter from the generator outlet line and place it into a lead or tungsten shielded container. This will be used for the filter integrity test. Using tongs and behind appropriate shielding (e.g. lead L-block), invert the Locametz vial twice and agitate vigorously (shake up, down, and left, right) for 2 seconds then place the vial back into the vial shield. Alternatively, the entire vial shield (and vial) can be inverted and agitated. Let the vial sit at room temperature (20-25 o C) for 10 min for labeling to take place (Figure 1a) . QC Testing: For QC testing, the preferred method for determining radiochemical purity (RCP) is using an instant thin layer chromatography (TLC) method with a radiometric TLC (rTLC) plate scanner (see below). Production of [ 68 Ga]Ga-PSMA-11 using Illuccix Kits Overview: Production using Illuccix kits with E&Z generators (configuration A) is described in the corresponding Illucix package insert (Telix Pharmaceuticals, 2023). Briefly, [ 68 Ga]GaCl 3 is eluted from the generator using 5 mL of 0.1 M HCl into a sterile vacuumed reaction vial (vial 3) fitted with a 0.2 μm sterile vent filter to equalize pressure. With a 10 mL syringe connected to a needle, the acetate buffer (vial 2) is injected into the vial containing PSMA-11 (vial 1). Once combined, the mixture is swirled to dissolve the peptide in the buffer. Then, using a new 10 mL syringe, the buffer and ligand solution is added into the vial containing [ 68 Ga]GaCl 3 (vial 3). The resulting solution is left at room temperature (15-30 o C) for 5 min for labeling to occur. The vial is then calibrated, with a maximum allowable activity of 1.85 GBq, and an expiration time of 4 h is assigned. The dose will have a final volume of 7.5 mL. Detailed Procedure: At our facility, production of Illuccix kits requires the disposable and non-disposable items listed in Table S3 (see Supplementary Information). Production of Illuccix occurs as follow: Take vial 1 from the Illuccix kit and remove the blue flip-off cap from the top of the vial. Take a tear weight of the vial. In a segregated area with an ISO 5 PEC, move and wipe the needed materials into the PEC using sterile 70% isopropyl alcohol. Using aseptic technique, pierce vial 2 (acetate buffer vial) using a 5 mL organic syringe connected to a 1.2x38 mm (18Gx1½”) silicone coated needle and withdraw the entire contents of the vial (2.5 mL) minimizing the headspace in the syringe. Insert the syringe with the acetate buffer into vial 1 and inject the buffer solution into the vial. Vial 1 is under negative pressure (vacuum) and therefore does not need its pressure equalized. Remove the syringe and needle from vial 1 and agitate gently (side to side, not up and down) for 5 seconds. Then pierce vial 1 first with a 0.2 μm Millex-FG sterile air vent filter connected to a 0.8x50 mm (21Gx2”) needle, and second with a 0.22 μm Cathivex-GV sterile product filter connected to a 1.2x38 mm (18Gx1½”) silicone coated needle. Arrange the filters such that the bevel of needle connected to the sterile air vent is positioned above the bevel of the needle connected to the product filter and that both filters are in the top 1/3 of vial 1 ( Figure 1b ). This will minimize activity from being expelled out of the sterile vent filter during generator elution. Take vial 1 with the two filters out of the PEC and place into a lead or tungsten shield suitable for PET isotopes. Connect the 1.85 GBq E&Z generator (or a 3.7 GBq E&Z generator decayed to only producing at maximum of 1.85 GBq) outlet line to the Cathivex-GV filter and using a 10 mL organic syringe pull up 6.2 mL of 0.1 M Ultrapure sterile HCl from the three-way valve upstream of the inlet line minimizing air bubbles. Manually (or automatically when using a syringe pump), elute the generator at a rate no faster than 2 mL/min, ensuring that if there were air bubbles in the syringe it is not pushed into the generator. Once the elution is completed, note the time, as this is used to determine the expiration time. Remove the sterile air vent from vial 1 and discard in a shielded radioactive sharps bin. Remove the product filter from vial 1 and disconnect the filter from the generator outlet line and place it into a lead or tungsten shield. This will be used for the filter integrity test. Using tongs and behind appropriate shielding (e.g. lead L-block), agitate the vial (shake up, down, and left, right) for 2 seconds then place the vial back into the vial shielded container. Alternatively, the entire vial shield (and vial) can be agitated. Let the vial sit at room temperature (15-30 o C) for 5 minutes for labeling to take place (Figure 1b ). QC Testing: For QC, there are two methods for determining RCP, using a TLC method in conjunction with an rTLC scanner, or a cut and assay technique (see below). The cut and assay method requires the sample to be spotted at the 1 cm line (above the bottom of the plate), and to develop the plate a distance of 10 cm. The plate is then cut at the 6 cm mark (5 cm above the 1 cm demarcation). The percent incorporation (or radiochemical purity, RCP) is calculated by taking the activity counts in the top piece divided by the sum of activity counts in the top and bottom pieces multiplied by 100. Quality Control of [ 68 Ga]Ga-PSMA-11 using either Locametz or Illuccix QC of Locametz and Illuccix requires the same disposable and non-disposable items listed in Table S4 (see Supplementary Information). It is important to note that for Locametz or Illuccix preparation, the required QC procedures are the same, but there are some differences in the QC release criteria ( Table 1 ). Using tongs take a weight measurement and activity calibration of the dose vial, then with a 1 mL syringe connected to a 1.2x38 mm (18Gx1½”) silicone coated needle, insert into the dose vial and pull up ~ 0.1 mL for use in QC analysis. Ensure the pulling of activity is unidirectional, and the solution in the 1 mL syringe is not pushed back into the vial. Table 1: A comparison of the passing quality control criteria for PSMA-11 using Locametz or Illuccix kits. Release Criteria Locametz Illuccix Maximum Allowed Activity 2.59 GBq 1.85 GBq Shelf-life (after labeling) 6 hours 4 hours Target Volume 5.0 mL (can be diluted to 10 mL with normal saline) 7.5 mL Radiochemical purity by rTLC > 95% Impurity by rTLC ≤ 5% Retention factor (Rf) 0.8 – 1.0 0.6 – 1.0 pH 3.2 – 6.5 4.0 – 5.0 Appearance and Visual Inspection Clear, colorless, and free from particulates Clear, colorless to slight yellow, and free from particulates Filter Integrity Test [Cathivex®-GV] > 344.7 kPa (50 psi) Bacterial Endotoxin < 35 EU/mL < 23.3 EU/mL 68 Ge breakthrough (Radionuclidic purity) < 0.001% To analyze radiochemical purity by rTLC, using a 1-5 μL pipette, spot a 1 μL aliquot 1 cm above the bottom of a 7 cm TLC plate and place the plate into a TLC chamber with 6 mL of 1:1 (1 M) ammonium acetate solution (aqueous): methanol and cover the chamber (see Supplementary Information for details on preparation of this eluent). Develop the plate in the solution until the solvent front is 1 cm away from the top of the plate which will take about 8-12 minutes. Since the development time is quite slow, an optional 2 nd TLC plate can be developed concurrently to mitigate delays in the event of an invalid TLC test. Dry the developed plate on a hot plate to remove excess water and place the plate on a rTLC plate reader. Follow the package insert directions for passing criteria; briefly, for Locametz, a rTLC purity of > 95%, and a Rf of 0.8-1.0, and for Illuccix, a rTLC purity of > 95%, and a Rf of 0.6-1.0 (Novartis Pharmaceuticals Corporation, 2022; Telix Pharmaceuticals, 2023). To analyze for pH, using a 10-50 μL pipette with a pipette tip, a 17.5 μL aliquot is spotted onto a MQuant colorimetric pH indicator strip, the package insert directions for passing criteria are followed: for Locametz, a pH of between 3.2-6.5 is required, and for Illuccix, a pH of between 4.0-5.0. For visual inspection, the dose vial (and/or QC aliquot (~ 0.1 mL) depending on local practices) are inspected visually for color and particulates, and following the package insert directions for passing criteria: for Locametz, the vial should be clear, colorless, and free from particulates, and for Illuccix, the vial should be clear, colorless to slight yellow, and free from particulates (Novartis Pharmaceuticals Corporation, 2022; Telix Pharmaceuticals, 2023). To ensure that doses are sterile and free of bacterial endotoxins, three tests are conducted. First, the final product filter used to filter the [ 68 Ga]GaCl 3 into the final kit vial is tested for integrity. The filter is connected to an air line with a pressure regulator and placed into a jar containing Milli-Q water. The pressure regulator is slowly turned up to allow for increased pressure of air to the filter. When the filter is ruptured, determined by flow of air bubbles into the jar, this value is the filter integrity value which should be >344.7 kPa (50 psi) for the Cathivex®-GV filter, or the manufacturer’s specified pressure if a different filter is used. Second, bacterial endotoxins testing is performed using the Endosafe endotoxin PTS system. Using a 10-50 μL pipette with a pipette tip, 17.5 μL of the dose is added into a 5 mL falcon tube containing 3.9 mL of pre-measured LAL water. The sample is capped and vortexed for 5 seconds. Using a 1:300 dilution on the Endosafe endotoxin PTS cartridge reader with an Endosafe PTS cartridge, a 25 μL aliquot of the mixed LAL water is added to each of the four channels in the cartridge. The endotoxin test will take 650-800 seconds to complete. Following USP , the maximum allowable endotoxin limit is 175 endotoxin units (EU) per the maximum volume injected (United States Pharmacopeia, 2024a). Thus for Locametz the limit is 35 EU/mL, and for Illuccix the limit is 23.3 EU/mL. Lastly, sterility testing is performed. Due to the nature of PET radiopharmaceuticals, and in accordance with standard practice when working with PET drugs, the test is completed after the dose is released to the clinic for use and is administered to the patient. To determine if bacterial contamination has occurred, tubes of tryptic soy broth (TSB) and fluid thioglycolate medium (FTM) are each inoculated with 250 μL of the dose within 30 h of production. The TSB is incubated at room temperature (20-25 o C) and the FTM is incubated at 30-35 o C for 14 days during and, on days 5, 7, and 14 tubes are visually inspected for microbial growth. Following USP , the samples should be clear with no turbidity after 14 days (United States Pharmacopeia, 2024b). Finally, to ensure that the E&Z generators are not leaching long-lived germanium-68 ( 68 Ge, half-life 271 days) into batches of [ 68 Ga]Ga-PSMA-11, once a week the generators must be checked for germanium breakthrough by testing radionuclidic purity (RNP). This is accomplished by pushing 5 mL of 0.1 M ultrapure sterile hydrochloric acid through the generator into a shielded, vented 10 mL vial and transferring a 3 μL aliquot of the eluate into an HPLC vial (or equivalent small vial). The samples are read in a multi-channel analyzer (MCA) with a zoom window of 8-2048 keV for 20 minutes. The samples are read twice, with the first reading within 12 hours after elution and the second reading between 24-120 hours after elution. 68 Ge breakthrough is calculated by using the following equations: Following the E&Z GalliaPharm ® 68 Ge/ 68 Ga generator product description and Nuclear Regulatory Committee requirements, breakthrough values should be less than 0.001% of the total radioactivity (Tapp, 2016; Eckert and Zigler, 2021). Statistical Analysis Data is expressed as mean ± standard deviation, unless otherwise specified, and statistical analysis is conducted using Prism Version 9 software (GraphPad) with significance tested by comparing the 95% confidence interval (P < 0.05). The two main groups are production using Locametz kits, and production using Illuccix kits. The Locametz group is then further subdivided into production using 1.85 GBq E&Z or 3.7 GBq E&Z generators, either using regular needles (RN, 0.7x38 mm, 22Gx1½”) or non-metal leaching silicone coated needles (NMLN, 0.6x60 mm, 23Gx2⅜”). The Illuccix group is subdivided into production using 1.85 GBq E&Z generators or a decayed 3.7 GBq E&Z generator (producing less than 1.85 GBq), using either a syringe pump or manual elution, or using the two different sizes of NMLN silicone coated needles (0.6x60 mm (23Gx2⅜”) or 1.2x38 mm (18Gx1½”)). Results Using E&Z 68 Ge/ 68 Ga generators at our facility to produce [ 68 Ga]Ga-PSMA-11 for clinical use, we prepared Locametz kits (n = 181) from 2nd June 2022 to 9th February 2023, and prepared Illuccix kits (n = 256) from 17th October 2022 to 13th September 2023. Locametz Production Using the Locametz kits, the overall production success rate was 95.03% (172/181). For the doses that met (or exceeded) the established QC criteria (Table 1 ) and were released to the clinic for use in patients, the mean RCP by rTLC was 98.41 ± 0.47% (95% CI: 98.34–98.48) (Fig. 2 a). The activity at calibration ranged from 0.53–2.15 GBq across 5 different lots of 1.85 GBq E&Z generators and 1 lot of 3.7 GBq E&Z generator, with a mean time from end of elution to calibration of 11.28 ± 1.25 min (Fig. 2 b). The mean dose volume was 4.93 ± 0.14 mL and a mean pH of 3.9 (range 3.3–4.2) (Fig. 2 c). The time of synthesis was approximately 12 min. Including completion of the required paperwork and QC testing, the total time per production was approximately 35 min. For the subset of production using only non-silicone coated needles (RN, 0.7x38 mm, 22Gx1½”) for which generator produced [ 68 Ga]GaCl 3 was eluted into the Locametz vial (n = 52), the overall success rate was 84.62% (44/52). For the doses that passed and were released for use in patients, the mean RCP by rTLC was 98.38 ± 0.47% (95% CI: 98.24–98.53) (Fig. 2 a). The doses that used non-silicone coated RN needles, led to 8 failures which were not released for clinical use due to < 95% RCP, or minor discoloration (pink tinge) of the formulated dose approximately 15–20 minutes after the addition of [ 68 Ga]GaCl 3 (Fig. 3 ). Five of the failed batches had RCP < 95% (ranging from 45.71–91.55%), and the remaining 3 vials had passing RCP (ranging from 95.36–98.80%). All other QC parameters passed for these 8 batches. Vials with lower RCP appeared to discolor to a greater extent when re-examined after 1 year. In attempts to recreate the discoloration and identify the likely source for contamination, a variation of shaking and inverting, or not shaking and inverting, “heating” at 27 o C for 7 minutes or labeling at room temperature for 10 minutes, and the use of RN needles or silicone coated NMLN needles were tested. Ultimately, swapping the RN needles out for silicone coated NMLN needles led to doses that were clear, colorless, and free of particulates. All other variations (shaking and/or “heating” at 27 o C) using silicone coated NMLN led to passing QC parameters with no color changes. We hypothesize that the discoloration of failed batches was due to the leaching of metal ions from RN needles that could compete with 68 Ga during chelation. Silicone coated NMLN needles do not leach metal ions and were thus adopted for [ 68 Ga]Ga-PSMA-11 kit preparations going forward. For the subset of productions (n = 129) using silicone coated needles (NMLN, 0.6x60 mm, 23Gx2⅜”), the overall production success rate was 99.22% (128/129). For the doses that passed, the mean RCP by rTLC was 98.42 ± 0.47% (95% CI: 98.33–98.50) (Fig. 2 a). For these doses, only 1 failure was observed which was due to the lack of vial inversion and shaking leading to RCP of 91.55%. This issue was rectified by inverting and shaking the vial. Prior to the most recent package insert for Locametz, which changed the maximum allowed activity from 1.85 GBq to 2.59 GBq, we independently tested the compatibility of “high activity” with Locametz kits using a fractionation approach with a 3.7 GBq and a 1.85 GBq E&Z generator. Using the highest fractions of a 3.7 GBq E&Z generator corresponding to fractions 2 through 4 (the 2nd through 4th mL of 0.1 M HCl used to elute the generator) of the elution, combined with fractions 2 and 3 (the 2nd and 3rd mL of 0.1 M HCl) of an 1.85 GBq E&Z generator, we were able to add 3.16 GBq in 5 mL of 0.1 M HCl into the Locametz vial which, at calibration (11 minutes later), gave 2.9 GBq. The initial RCP was 97.22% (n = 2) and at 4 hours the RCP was 98.96% with all other QC parameters passing (see Supplementary Information, Figure S1 ab ). The RCP appears higher at 4 h when minor impurities decay below the rTLC limit of detection. A second attempt without fractionation was completed by eluting a 3.7 GBq generator with 6.2 mL of 0.1 M HCl through a 0.22 µm Cathivex-GV filter to give 2.22 GBq at calibration time, with RCP of 98.35% at calibration and 99.23% at 4 hours (see Supplementary Information, Figure S2 ab ). With the established “higher activity” Locametz, subdividing the group using NMLN needles (n = 129) into production using a 1.85 GBq generator (n = 81) and a 3.7 GBq generator (n = 48) showed no differences in product quality and no differences in failure rate. The RCP by rTLC were 98.49 ± 0.39% (95% CI: 98.40–98.58) and 98.29 ± 0.57% (95% CI: 98.13–98.46), respectively (Fig. 2 a). Illuccix Production Using Illuccix kits (n = 256), the overall production success rate was 99.22% (254/256). For the doses that met (or exceeded) established QC criteria (Table 1 ) and were released for use in patients, the mean RCP by rTLC was 97.81 ± 0.71% (95% CI: 97.73–97.90) (Fig. 2 a). The activity at calibration ranged from 0.611–1.79 GBq across 6 different lots of 1.85 GBq E&Z generators, and 1 lot of a decayed 3.7 GBq E&Z generator producing less than 1.85 GBq, with a mean time from end of elution to calibration of 6.19 ± 1.17 min (Fig. 2 b). To be able to use the decayed 3.7 GBq generator, it took 24 weeks of tri-weekly elution (and 68 Ge decay) to get to an activity below the 1.85 GBq threshold for use with Illucix kits. The mean dose volume was 7.25 ± 0.163 mL and the mean pH 4.24 (range 4.0–4.75) (Fig. 2 c). The time of synthesis was approx. 8 min. Including completion of required paperwork and QC testing, the total time per production was approximately 30 min. For the subset of productions (n = 34) using silicone coated needles (NMLN, 0.6x60 mm, 23Gx2⅜”) to transfer the acetate buffer from vial 2 to vial 1 and the elution of [ 68 Ga]GaCl 3 into vial 1, the production success rate was 100% (34/34). These doses had a mean RCP by rTLC of 98.04 ± 0.70% (95% CI: 97.80–98.29) and a mean volume of 7.37 ± 0.12 mL (95% CI: 7.33–7.41). These doses had a mean pH of 4.38 ± 0.17 (95% CI 4.325–4.440) (Fig. 2 a,c). For Illuccix kits (n = 222) prepared using silicone coated needles (NMLN, 1.2x38 mm, 18Gx1½”), the production success rate was 99.1% (220/222). For the doses that passed QC and were released for clinical use, the mean RCP by rTLC was 97.78 ± 0.70% (95% CI: 97.68–97.87) and a mean volume of 7.23 ± 0.16 mL (95% CI: 7.21–7.25). These doses had a mean pH of 4.21 ± 0.10 (95% CI: 4.199–4.225) (Fig. 2 a,c). In this subset of doses, there were three failures due to low pH (< 2.5), which we attribute to insufficient mixing of the kit components. After vigorously shaking the vial and leaving at room temperature for an additional 5 min, the doses were recalibrated, and a second aliquot was obtained for QC. All three doses had pH within normal range (4.2 and 4.4) and all other QC tests met (or exceeded) release criteria, allowing doses to be released for clinical use. Among all the Illuccix doses prepared (n = 256), the subset of doses using a 1.85 GBq generator (n = 157) had a success rate of 98.8% (155/157) with mean RCP by rTLC of 97.83 ± 0.73% (95% CI: 97.72–97.94) (Fig. 2 a). The doses using a decayed 3.7 GBq generator producing < 1.85 GBq (n = 99) were also used, which had a production success rate of 100% (99/99) and mean RCP by rTLC of 97.74 ± 0.68% (95% CI: 97.61–97.88) (Fig. 2 a). There were no major differences between the use of the different generators. Of all the Illuccix doses (n = 256), the subset of doses using a syringe pump to elute the generator by pushing 6.2 mL of 0.1 M HCl at 2 mL/min had a success rate of 96.9% (63/65), with mean RCP by rTLC of 97.92 ± 0.60% (95% CI: 97.77–98.07) and a mean volume of 7.20 ± 0.17 mL (95% CI: 7.15–7.24) (Fig. 2 c). The subset of doses manually eluted by pushing 6.2 mL of 0.1 M HCl at approx. 2 mL/min had a success rate of 100% (191/191) with mean RCP by rTLC of 97.77 ± 0.74% (95% CI: 97.67–97.87) and a mean volume of 7.26 ± 0.16 mL (95% CI: 7.24–7.29) (Fig. 2 c). Required weekly, breakthrough test was completed on all generators used. The breakthrough was below the limit of detection, which was determined to be < 0.0004% for all generators, meeting the established criteria. Discussion The time required to complete one synthesis of Locametz is around 12 minutes excluding QC testing (QC time is ~ 23 min); whereas for Illuccix it is around 8 minutes excluding QC testing (QC time is ~ 22 min). The success rates of production using Locametz and Illuccix kits were comparable, and no significant differences were observed. More importantly, when looking at the subset of productions using silicone coated needles (NMLN) for elution, the rates are the same (1 failure every 128 runs). This suggests that from a production standpoint both Locametz and Illuccix kits have very similar reliability, which makes the decision between which kit to use for routine production of [ 68 Ga]Ga-PSMA-11 more nuanced. Comparing our workflows, we assemble our final product vials in an ISO 5 PEC, following aseptic technique, and elute the generators in an ISO 8 hot cell (according to guidelines in USP ). When using Illuccix kits, we add the acetate vial (vial 2) into the PSMA-11 precursor vial (vial 1) in the ISO PEC, prior to the addition of the [ 68 Ga]GaCl 3 from the generator in the ISO 8 hot cell. This is a deviation from the package insert, which recommends adding the acetate and PSMA-11 solution into the [ 68 Ga]GaCl 3 . This order of events would require us to bring the eluted [ 68 Ga]GaCl 3 back to the ISO 5 PEC to add the acetate and PSMA-11 solution. This process becomes unnecessarily complicated, with higher radiation exposure rates to production staff, and therefore has not been adapted for routine production. This minor change to the process order has had no impact upon product quality. For Locametz, this is not an issue because a separate buffer (or pH adjusting) solution is not required. Excluding the eight failures related to using non-silicone coated needles (RN), we attribute the remaining failures (1 for Locametz, and 1 for Illuccix) to improper mixing. The Locametz package insert suggests the inversion of the dose vial to help with incorporation and mixing of the lyophilized buffer, but no agitation. Improper mixing of the Locametz vial led to a failure, which suggests that agitation of the vial increases the consistency of labeling by adequately mixing the buffer agent and HCl. Although the package insert suggests that labeling is complete within 5 minutes, it also recommends the vials be labeled at temperatures within 20°C to 30°C, which in colder climates may not always be possible (Novartis Pharmaceuticals Corporation, 2022). Extending the labeling time to 10 min further ensures consistency without the need to “heat” the reaction at 27°C to be within the allowed range. When labeling NetSpot ([ 68 Ga]Ga-DOTATATE), agitation of the vial is not recommended due to potential leaching of competing metals such as zinc from the vial septa leading to poor incorporation of 68 Ga(III), as Zn(II) can also form stable complexes with DOTA (Fang et al., 2020 ; Advanced Accelerator Applications USA Inc., 2021). The Locometz package insert recommends inversion of the vial to help with mixing but recommends against agitation or stirring (Novartis Pharmaceuticals Corporation, 2022). However, the affinity of HBED-CC for Ga(III) is higher than the affinity between HBED-CC and Zn(II) (Ma et al., 1994 ; Iudicello et al., 2021 ) and so we believe competing chelation of Zn is less likely to be an issue when preparing [ 68 Ga]Ga-PSMA-11 and this has borne out in our experience thus far. For Illuccix, the package insert does not specify the need to shake the vial after the addition of [ 68 Ga]GaCl 3 to the acetate buffered ligand solution (Telix Pharmaceuticals, 2023). However, with our production runs, we saw 3 instances where the lack of vial agitation led to poor incorporation of 68 Ga due to incorrect reaction pH (< 2.5). Our first low pH dose led to a failure, as we did not shake the vial on that occasion; however, with our second and third cases, the vial was shaken. In each case the vials were shaken again to ensure proper mixing of the [ 68 Ga]GaCl 3 and the acetate buffered ligand solution, and this led to appropriate incorporation (RCP ≥ 95%) and pH of ~ 4.2. Although the incorrect pH only contributed to 1.17% (3/256) of all Illuccix production runs, shaking the vial increases the consistency for efficient labeling, and is therefore recommended. When Locametz production was conducted using with non-silicone coated needles (RN, 0.7X38 mm, 22Gx1½”), several failures resulted (due to low incorporation of 68 Ga and/or discoloration of the product). We have not used Illuccix kits with these non-silicone coated needles, but the failed Locametz productions using these needles suggest that using silicone coated needles (NMLN) improves labeling and so they are also recommended for use with Illuccix. Although both Locametz and Illuccix kits contain the same “precursor”, the excipients and formulation of the kits are different (see Supllementary Information, Table S1 ). The QC criteria for appearance with Locametz requires “clear, colorless, particulate free” solutions (Novartis Pharmaceuticals Corporation, 2022), whereas Illuccix allows for “clear, colorless to slight yellow, particulate free” solutions (Telix Pharmaceuticals, 2023). The difference in QC appearance criteria is attributed to the differences in formulation. When looking at the components used to prevent radiolysis of PSMA-11, for Locametz, 1 mg of gentisic acid (radioprotectant) is used, while for Illuccix, 10 µg of D -mannose (a reducing sugar, acting as a radioprotectant) is used. The color change observed in Locametz kits could result from oxidation of gentisic acid, which is known to give a faint pinkish, yellowish color (Hosokawa et al., 2020 ). The purpose of gentisic acid in the dose vial is to prevent the oxidation of PSMA-11, acting as a sacrificial substrate for oxidative chemical reactions. The discoloration of Locametz is most likely attributed to gentisic acid’s radioprotective effects and therefore should not impact the RCP, and this is consistent with our findings. Nonetheless, by switching to needles that have a low potential for leaching metals that can catalyze oxidation, the discoloration is no longer observed, and therefore it is recommend that silicone coated needles (either 0.6x60 mm, 23Gx2⅜” or 1.2x38 mm, 18Gx1½”) be used to produce Locametz. The silicone coated needles (NMLN) used to label Locametz and Illuccix kits were from B. Braun (brand name Sterican®). We routinely use these needles with NetSpot kits to produce [ 68 Ga]Ga-DOTATATE) and thus we also selected them to label PSMA-11 and make our entire 68 Ga-labeling workflow more uniform. Originally, the 0.6x60 mm (23Gx2⅜”) needles were used, which provided sufficient length to pull up all the acetate buffer from Illuccix vial 2 without needing to invert the vial. Due to regulatory changes preventing us from obtaining these needles from a third-party, a new length of needles was used (1.2x38 mm, 18Gx1½”). Since these needles were shorter, and the bore larger, it made it very difficult to pull up all 2.5 mL of the acetate buffer from vial 2. The acetate buffer in vial 2 needed to be inverted, and because the needle was no longer as flexible as the 0.6x60 mm needles, required more manipulations to acquire an “accurate” volume. Ultimately, this change in needles led to minor differences in the final dose volume. Even with these volume changes, which presumably were due to the differences in acetate buffer added and not the HCl eluted through the generator, there were no significant differences in RCP or pH of the labeled product. This suggests that although the addition of 2.5 mL of acetate solution (vial 2) is recommended by the manufacturer in the package insert, a volume of ~ 2.2 mL is still tolerated by the kit. This is further demonstrated by the fact that the success rate was not significantly altered between the two sizes of needles (100% vs. 99.1%). If we exclude the 2 failures which were unrelated to the volume of acetate added, the success rate was 100% (failures were due to inadequate mixing and user error in operating the syringe pump). Although there are no differences in QC results between the two silicone coated needles, when selecting the length and bore size of the needles used for [ 68 Ga]GaCl 3 elution and QC sample draw, we recommend a longer length, smaller bore size needle, as this will make the assembly of the dose vial in an ISO 5 PEC more streamlined with fewer manipulations and hand exposure to radiation for staff. We demonstrated that adding higher amounts of 68 Ga to Locametz kits (> 1.85 GBq allowed by the paclage insert at the time) led to doses that still met all QC criteria at 4 h post-EOS. By using a fractionation approach we were able to demonstrate that up to 3.16 GBq (decay-corrected activity added to the vial = 3.5 GBq) was tolerated. Since a 3.7 GBq E&Z generator is expected to only produce 80% of its maximum activity, successful production using > 2.96 GBq of 68 Ga allows use a 3.7 GBq generator for producing Locametz throughout the generator’s lifetime. When comparing the Locametz lower activity ( 1.85 GBq) productions, there were no significant differences in RCP or other QC test results. In marked contrast, when > 1.85 GBq of 68 Ga were added to an Illuccix kit, rHPLC analysis showed 95%. This discrepancy requires further investigation but meant we did not use > 1.85 GBq of 68 Ga with Illuccix in this work. Use of a syringe pump to elute the 68 Ga generator when labeling Illuccix led to similar outcomes as manual elution, and we observed no major changes in RCP, volume, pH or other QC test results between the two approaches. A syringe pump can control the elution rate to a greater extent than manual elution, which tends to be faster than 2 mL/min and offers improved consistency of pressure applied. Since the use of a syringe pump is equivalent to manual elution, we recommend the use of a syringe pump to further decrease radiation hand exposure during generator elution. However, the use of a syringe pump can also increase the risk of user error, which led to one of our failures and careful checking of the setup is recommended. It is important to note that we used 6.2 mL of 0.1 M HCl to elute the generators because we wished to include a 0.22 µm Cathivex-GV filter in-line for terminal sterilization as part of the manufacturing process. The filter traps around 1.2 mL of solution (dead volume) which is lost and therefore accounted for by pushing more HCl through the generator. Since the generator elution is not homogenous, minimal activity is lost on the filter using a larger volume (Roesch and Riss, 2012 ). In a radiopharmacy or nuclear medicine department in an ISO 5 PEC in a clean room (ISO 7 secondary engineering control (SEC)), 5 mL of 0.1 M HCl can be used with or without a filter in-line into the vial. There are two methods for determining RCP using TLC, an iTLC method requiring the use of a radioTLC scanner / plate reader to scan the plate, and a “cutting” technique. Both methods are interchangeable, and therefore both methods can be used to determine RCP. Currently the Locametz package insert only specifies using the scanning method to analyze the TLC plates. On the other hand, the Illuccix package insert allows for either method for analysis. Since the “precursors” are the same, and the synthesis process is the same (free 68 Ga and [ 68 Ga]colloids will stay at the origin, and [ 68 Ga]Ga-PSMA-11 will move to the solvent front), both kits give similar results and thus we posit that either method can also be used for Locametz as well. It is worth noting that for the cutting method, because a dose calibrator is used to obtain the counts for subsequent calculations, a 5 µL spot on the TLC plate is recommended to have more activity and ensure sufficient counts in the dose calibrator. A summary of recommendations for the labeling of PSMA-11 using Locametz or Illuccix kits is presented in Table 2 . From a clinical perspective, PSMA-11 scans using Locametz or Illuccix kits are functionally the same. Figure 4 shows scans from a patient who received a [ 68 Ga]Ga-PSMA-11 PET scan using Locametz first, then a second [ 68 Ga]Ga-PSMA-11 PET scan using Illuccix 112 days after the first scan. The patient was not on treatment between scans, and was only taking dexamethasone. In both images, the patient has avid metastatic disease in the abdominal pelvic lymph nodes, thoracic and supraclavicular lymph nodes, and bones. These images, from the same patient, demonstrate the similarities of scans acquired using [ 68 Ga]Ga-PSMA-11 prepared using each kit. Table 2 A summary of recommendations for labeling PSMA-11 using Locametz or Illuccix kits. Locametz Kit Illuccix Kit Generator produced [ 68 Ga]GaCl 3 Can use E&Z, IRE EliT Galli EO, or ITM GeGant generators Can use E&Z with configuration A and IRE EliT Galli EO with configuration B Cyclotron produced [ 68 Ga]GaCl 3 Not allowed, not recommended Following package insert directions using GE GaCl 3 cassette with FASTLab synthesizer. Disregard our changes to the order of acetate solution addition Activity at calibration and expiration Up to 3.16 GBq for up to 4 hours or up to 2.59 GBq for up to 6 hours Up to 1.85 GBq for up to 4 hours Needles Silicone coated non-metal leaching needles, preferably needles with longer length and smaller bore size Addition of buffer solution not necessary, one vial formulation Add the acetate solution into the ligand vial first then add [ 68 Ga]GaCl 3 . There is approximately 0.3 mL of tolerance built into the amount of acetate solution added. Inversions after the addition of [ 68 Ga]GaCl 3 2 inversions no inversions Shaking the vial after addition of [ 68 Ga]GaCl 3 Vigorously (up, down, left, right) for 2 seconds Labeling Time at room temperature 10 minutes 5 minutes Quality Control, RCP by rTLC Either scanning or cutting method Use of a syringe pump Preferred to reduce hand exposure and increase elution rate consistency The labeling workflow for PSMA-11 with generator produced [ 68 Ga]GaCl 3 using Locametz or Illuccix kits are similar, and clinical images obtained using [ 68 Ga]Ga-PSMA-11 prepared with either kit are considered equivalent. This reinforces the notion that selection of a given kit is primarily dependent on production method preferences which are compared in Table 3 . The Locametz kit with a 1-vial formulation makes vial assembly easier and eliminates errors due to transfer between vials. Locametz kits allow the addition of more activity (3.16 GBq) when compared to Illuccix (1.85 GBq) and a longer shelf-life after labeling (6 h vs 4 h, respectively). Locametz kits can be used with more generators, including E&Z, IRE EliT Galli EO, and ITM GeGant, whereas the Illuccix kits can only be used with E&Z and IRE Elit Galli EO generators. Illuccix can be used with cyclotron-produced 68 Ga, whereas this is not included in the Locometz package insert. From a quality control perspective, both kits have similar release criteria, and either the scanning or cutting method for rTLC analysis can be used for both kits. The retention factor (Rf) cut-off for Locametz is tighter (0.8-1.0), whereas the Illuccix Rf cut-off is more accommodating (0.6-1.0), which also needs to be accounted for. Table 3 A comparison of production method and source of [ 68 Ga]GaCl 3 for Locametz and Illuccix Kits Locametz Kit Illuccix Kit Use with E&Z Generator Yes Yes, Configuration A only Use with IRE EliT Galli EO Generator Yes Yes, Configuration B only Use with ITM GeGant Generator Yes No Use with Cyclotron Produced [ 68 Ga]GaCl 3 No Yes, Configuration A only Vials in Kit Formulation 1 3 Dilution with normal saline Yes, to 10 mL No Maximum activity at calibration 3.16 GBq 1.85 GBq Shelf-Life after labeling 6 hours 4 hours Time for radiolabeling at room temperature 10 min 5 min Plate development time due to Rf criteria Longer time (tighter Rf criteria) Shorter time (looser Rf criteria) Finally, for facilities who are considering using either or both kits, due to cost, workflow or other reasons, the transition between kits is close to seamless. A similar list of non-consumable and consumable products are used which makes switching straightforward (see Supplementary Information, Tables S2 through S4 ). For radiopharmacies and nuclear medicine departments experienced with general nuclear medicine, the assembly and setup for Locametz is similar to the labeling of numerous 99m Tc kits (e.g. [ 99m Tc]MDP, [ 99m Tc]DTPA, [ 99m Tc]tetrofosmin (Myoview)) whereas the assembly and setup for Illuccix is closer to the labeling of other 99m Tc kits (e.g. [ 99m Tc]bicisate (Neurolite), [ 99m Tc]sulfur colloid without heating), or [ 68 Ga]Ga-DOTATATE (NetSpot). For facilities used to more traditional PET drug manufacturing like FDG, the use of Locametz or Illuccix kits may require new workflows and techniques as generator-based production has not traditionally been widely used at such sites, but this can readily be accomplished threough implementation of appropriate standard operating procedures. While this report has focused upon use of Locametz and Illuccix kits in conjunction with 68 Ge/ 68 Ga generators, such might also prefer Illuccix kits due to their compatibility with cyclotron-produced 68 Ga (Telix Pharmaceuticals, 2023). Conclusions In conclusion, preparation of [ 68 Ga]Ga-PSMA-11 using Locametz or Illuccix kits have comparable workflows and also provide equivalent PSMA PET images. Therefore, excluding cost and contracting considerations, selecting a kit for day-to-day use ultimately depends on the versatility of these kits and the preferred workflow at a given site. Both kits had comparable failure rates in our hands (1 in 128 vials), although we have observed that using silicone coated non-metal leaching needles, as well as vial agitation after the addition of [ 68 Ga]GaCl 3, leads to improved labeling consistency. Additionally, labeling Locametz kits at room temperature for 10 min (instead of 5 min) also improved consistency, without substantial delay in workflow. When comparing the two kits, traditional radiopharmaceutical facilities familiar with generator elution and a “kit-based approach” may prefer to use Locametz kits due to the similarities with the general 99m Tc workflow, whereas PET manufacturing facilities making FDG might prefer Illuccix kits due to the versatility of the gallium-68 source (generator or cyclotron). Overall, the commercial availability of 2 approved kits for production of [ 68 Ga]Ga-PSMA-11 PET has facilitated ready access to this important new prostate cancer imaging agent, and underpinned successful introduction of pluvicto radiotherapy. Abbreviations FTM fluid thioglycolate medium HPLC high pressure liquid chromatography iTLC instant thin layer chromatography LAL limulus amoebocyte lysate MCA multi–channel analyzer NMLN non–metal leaching silicone coated needles, either 0.6x60 mm (23G 2⅜”) needles or 1.2X38 mm (18G 1½”) needles PET positron emission tomography QC quality control RCP radiochemical purity Rf retention factor RN non–silicone coated, regular needles, or 0.7X38 mm (22G 1½”) needles RNP radionuclidic purity rTLC radio thin layer chromatography TSB tryptic soy broth Declarations Ethics approval and consent to participate Not applicable as this article does not contain any original research studies with human or animal subjects performed by any of the authors. Consent for publication Not applicable as this article does not contain any original research studies with human or animal subjects performed by any of the authors. Availability of Data and Materials Provided in the Supplementary Information is a list of Formulation, components of the Locametz and Illuccix kits ( Table S1 ), as well as a list of disposable and non-disposable items used in both the production of Locametz ( Table S2 ) and Illuccix ( Table S3 ). Additionally, required materials for quality control is also provided ( Table S4 ). Provided in an Excel sheet ( Appendix A ) is the raw data for all 437 PSMA-11 production batches reported and analyzed in this article. The preparer’s names have been replaced with generic names (Person A, Person B, etc.) in the Excel sheet, but reflect the actual radiochemists’s role for each batch. Competing Interests IEW, LJM, KKW, AFB and MD disclose no competing interests. PJHS holds equity in Novartis and Telix Pharmaceuticals. Given his role as Associate Editor, Peter J. H. Scott had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Funding Funding for this work from the University of Michigan (Department of Radiology and Support for Outstanding Academic Research, SOAR) is gratefully acknowledged. Authors’ contributions IEW labeled the Locametz and Illuccix kits, entered and analyze the data, and wrote the article; LJM labeled the Locametz and Illuccix kits, organized and entered the data, and helped with the initial analysis of the data; KKW provided clinical insight to the use of the labeled Locametz and Illuccix kits and provided PET scan images; AFB helped with the narrative of the article and provided edits for the article; MD provide regulatory oversight; PJHS provided supervision and funding, oversaw labeling of the kits, provided insight to the direction of the article, and final edits for the article. All authors read and approved the final manuscript. 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[Internet]. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215841s000lbl.pdf . Accessed 28-Oct-2024. Pandey MK, Byrne JF, Schlasner KN, Schmit NR, DeGrado TR. Cyclotron production of 68 Ga in a liquid target: Effects of solution composition and irradiation parameters. Nucl Med Biol. 2019;74–75:49–55. 10.1016/j.nucmedbio.2019.03.002 . Rodnick ME, Sollert C, Stark D, Clark M, Katsifis A, Hockley BG, et al. Cyclotron-based production of 68 Ga, [ 68 Ga]GaCl 3 , and [ 68 Ga]Ga-PSMA-11 from a liquid target. EJNMMI Radiopharm Chem. 2020;5(1):25. 10.1186/s41181-020-00106-9 . Rodnick ME, Sollert C, Stark D, Clark M, Katsifis A, Hockley BG, et al. Synthesis of 68 Ga-radiopharmaceuticals using both generator-derived and cyclotron-produced 68 Ga as exemplified by [ 68 Ga]Ga-PSMA-11 for prostate cancer PET imaging. Nat Protoc. 2022;17(4):980–1003. 10.1038/s41596-021-00662-7 . Roesch F, Riss J. The Renaissance of the 68 Ge/ 68 Ga Radionuclide Generator Initiates New Developments in 68 Ga Radiopharmaceutical Chemistry. Curr Top Med Chem. 2012;10(16):1633–68. 10.2174/156802610793176738 . Sachpekidis C, Kopka K, Eder M, Hadaschik BA, Freitag MT, Pan L, et al. Ga-PSMA-11 dynamic PET/CT imaging in primary prostate cancer. Clin Nucl Med. 2016;68(11):e473–9. 10.1097/RLU.0000000000001349 . Schäfer M, Bauder-Wüst U, Leotta K, Zoller F, Mier W, Haberkorn U, et al. A dimerized urea-based inhibitor of the prostatespecific membrane antigen for 68 Ga-PET imaging of prostate cancer. EJNMMI Res. 2012;2(1):1–11. 10.1186/2191-219X-2-23 . Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48. 10.3322/caac.21763 . Taplin M-E, Smith JA. Initial staging and evaluation of males with newly diagnosed prostate cancer – In UpToDate (Eds. Lee WR, Richie JP, Yushak M). Updated. 2023. https://www.uptodate.com/contents/initial-staging-and-evaluation-of-males-with-newly-diagnosed-prostate-cancer?search=prostatecancerdiagnosis&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2 . Accessed 28-Oct-2024. Tapp K, Eckert. and Ziegler GalliaPharm™ Germanium-68/Gallium-68 Pharmacy Grade Generator. NRC Licensing Guidance. 2016. Avaialble from: https://www.nrc.gov/docs/ML1625/ML16252A421.pdf . Accessed 28-Oct-2024. Telix Pharmaceuticals (US). ILLUCIX® (kit for the preparation of gallium Ga 68 gozetotide injection), for intravenous use. [Internet]. 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214032s001lbl.pdf . Accessed 28-Oct-2024. Thisgaard H, Kumlin J, Langkjær N, Chua J, Hook B, Jensen M, et al. Multi-curie production of gallium-68 on a biomedical cyclotron and automated radiolabelling of PSMA-11 and DOTATATE. EJNMMI Radiopharm Chem. 2021;6(1):1–11. 10.1186/s41181-020-00114-9 . United States Pharmacopeia. General Chapter, 〈85〉 Bacterial Endotoxins Test. USP-NF, 2024a. Rockville, MD: United States Pharmacopeia. https://doi.org/10.31003/USPNF_M98830_02_01 . Accessed 28-Oct-2024. United States Pharmacopeia. General Chapter, 〈71〉 Sterility Tests. USP-NF. 2024b. Rockville, MD: United States Pharmacopeia. https://doi.org/10.31003/USPNF_M98810_01_01 . Accessed 28-Oct-2024. Zelefsky M, Morris M, Eastham J. Chapter 70: Cancer of the Prostate. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2019. Supplementary Files SupplementalInformation1.docx SupplementalInformation2AppendixADataFile.xlsx Cite Share Download PDF Status: Published Journal Publication published 18 Dec, 2024 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 1 posted Editorial decision: Minor revision 12 Nov, 2024 Reviewers agreed at journal 03 Nov, 2024 Reviewers invited by journal 02 Nov, 2024 Editor assigned by journal 01 Nov, 2024 First submitted to journal 31 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5363858","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":373293501,"identity":"d1fed48b-761f-4d34-9e1c-6996d1710212","order_by":0,"name":"Ivan E. Wang","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Ivan","middleName":"E.","lastName":"Wang","suffix":""},{"id":373293502,"identity":"71d15524-9b56-47c5-aaa4-1dba319cc572","order_by":1,"name":"Luke J. Morrissette","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Luke","middleName":"J.","lastName":"Morrissette","suffix":""},{"id":373293503,"identity":"f1d36ed7-94ee-41fb-8b70-ca1e077ef5ba","order_by":2,"name":"Ka Kit Wong","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Ka","middleName":"Kit","lastName":"Wong","suffix":""},{"id":373293504,"identity":"48faa6c8-9344-4d6d-9b8e-d7c07252fb3c","order_by":3,"name":"Allen F. Brooks","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Allen","middleName":"F.","lastName":"Brooks","suffix":""},{"id":373293505,"identity":"20c717be-7bd7-43b1-af2b-c422de71ead9","order_by":4,"name":"Marianna Dakanali","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Marianna","middleName":"","lastName":"Dakanali","suffix":""},{"id":373293506,"identity":"6717a172-b726-4603-a937-14799240d620","order_by":5,"name":"Peter J. H. Scott","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYFCCMxCKH4gPMDaASOK0GEhINhCvhQeixQCkkigt5oxnD3/4UfGnzvhGduKBnzsY5PhuJODXYtlwLk2y54yBhNmN3A0He88wGEsS0mJw4IwZM2MbRMthxjaGxA1EaDH+DNJiPAOipZ4YLQbSIC0GEhAtCQaE/XLGDOgXY8kZZ94C/dImYTjzzAP8WswlzhgDQ0yOn789d/OHn2028nzHCTlM4gAKXwK/crAW/gbCikbBKBgFo2CEAwBMck0wPTKkOwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-6505-0450","institution":"University of Michigan","correspondingAuthor":true,"prefix":"","firstName":"Peter","middleName":"J. H.","lastName":"Scott","suffix":""}],"badges":[],"createdAt":"2024-10-31 00:44:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5363858/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5363858/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41181-024-00317-4","type":"published","date":"2024-12-18T15:58:22+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70378425,"identity":"6784dcde-807d-4421-af55-a301046317a2","added_by":"auto","created_at":"2024-12-02 15:38:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":141370,"visible":true,"origin":"","legend":"\u003cp\u003eVisual depiction of labeling process for Locametz and Illuccix kits\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea \u003c/sup\u003eThe assembly and components of Locametz (\u003cstrong\u003eA\u003c/strong\u003e) and Illuccix, \u003cem\u003econfiguration A\u003c/em\u003e (\u003cstrong\u003eB\u003c/strong\u003e) vials prior to the addition of generator produced [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e from an E\u0026amp;Z generator. Vial assembly occurs in a segregated area with an ISO 5 primary engineering control (PEC) with subsequent elution of a \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generator in an ISO 8 secondary engineering control (SEC). Non-metal leaching needles (NMLN) should be used to transfer the generator eluate into the dose vial. Abbreviations: NaOAc – anhydrous sodium acetate, NaOAc∙3H\u003csub\u003e2\u003c/sub\u003eO – Sodium Acetate Trihydrate.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5363858/v1/0800e867c985974984e7b253.png"},{"id":70378428,"identity":"6b6b3cad-c766-4746-9a2b-0638b654b72d","added_by":"auto","created_at":"2024-12-02 15:38:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":98987,"visible":true,"origin":"","legend":"\u003cp\u003eStatistical Analysis of RCP, activity, volume, and pH for the production of Locametz and Illuccix kits and their subgroups analysis.\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u003c/sup\u003e Displayed bars represents the 5-95% percentile of data except for “Activity Ranges between subgroups” which shows the mean ± standard deviation. Symbols are outliers. The radiochemical purity (RCP) by subgroups (generator size, needle type used), by kit (Locametz, Illuccix), and specific type of non-metal leaching needle (NMLN) (\u003cstrong\u003eA\u003c/strong\u003e). The activity ranges of the dose (at calibration) by subgroup (generator size, needle type used), and the time from end-of-elution (EOE) to end-of-synthesis (EOS) or calibration time (\u003cstrong\u003eB\u003c/strong\u003e). The volume ranges of the dose by subgroup (generator size, needle type used, and elution method), by kit (Locametz, Illuccix), and the subsequent pH of the subgroups (kit type, needle type) (\u003cstrong\u003eC\u003c/strong\u003e). Activities are not decay corrected by are compared at time of calibration. RCP were obtained using rTLC and the screening method using a plate reader. Doses that failed were not included (8 for Locametz, 2 for Illuccix) in this analysis. Analysis and figures generated using Prism Version 9 software (GraphPad).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5363858/v1/e5f64c866160d8a01a615d4f.png"},{"id":70379315,"identity":"bbab5682-0377-4c77-b644-94db4e97f387","added_by":"auto","created_at":"2024-12-02 15:46:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":433230,"visible":true,"origin":"","legend":"\u003cp\u003eFailed Locametz doses due to discoloration\u003csup\u003e c\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ec\u003c/sup\u003e\u003cstrong\u003e \u003c/strong\u003eFrom Left to Right: Locametz (LOC) lot 16 with 77.97% RCP, lot 19 with 83.16% RCP, lot 36 with 45.71% RCP, lot 50 with 98.8% RCP, lot 51 with 95.36% RCP, and control test using silicone coated non-metal leaching needles with 97.64% RCP. Image taken 1.5 years after synthesis and as a comparison lot 51 image taken day of synthesis (30 minutes after labeling). Doses with low RCP at end of synthesis had considerably greater color change after one year compared to doses that were passing but had minor discoloration. Comparing discoloration of lot 51 on the day of synthesis and control shows potential issues with using metal needles that are not coated in silicone.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5363858/v1/ce38f4d880b6c3fdb980b3f0.png"},{"id":70378424,"identity":"ed07f85c-fc39-49a2-a325-dd8df8ca13d9","added_by":"auto","created_at":"2024-12-02 15:38:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":270699,"visible":true,"origin":"","legend":"\u003cp\u003e[\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET Scan Using Locametz and Illuccix Kits\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ed\u003c/sup\u003e\u003cstrong\u003e \u003c/strong\u003e[\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET scan first using Locametz (\u003cstrong\u003eA\u003c/strong\u003e) then Illuccix (\u003cstrong\u003eB\u003c/strong\u003e) 112 days apart demonstrating avid metastatic disease in abdominal pelvic lymph nodes, thoracic and supraclavicular lymph nodes and bones. Patient was not on active treatment during the interval between scans. Image courtesy of Dr. Ka Kit Wong.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5363858/v1/c13c41d6aa39fe9e65aa3ed7.png"},{"id":72201991,"identity":"4e58c32d-0053-4621-8bc1-592183dccf63","added_by":"auto","created_at":"2024-12-23 16:13:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1717888,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5363858/v1/437baa5a-74d2-44fc-8dcc-0d0109846818.pdf"},{"id":70378427,"identity":"d95c3883-64ac-4cc7-9dd7-86b61a6ba132","added_by":"auto","created_at":"2024-12-02 15:38:49","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":827337,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalInformation1.docx","url":"https://assets-eu.researchsquare.com/files/rs-5363858/v1/5cbec27381fa60c3e5bea3c0.docx"},{"id":70378422,"identity":"8e7d5584-43c1-4c78-9268-541ddca91fe7","added_by":"auto","created_at":"2024-12-02 15:38:48","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":125102,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalInformation2AppendixADataFile.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5363858/v1/6adbc9be1ff09c5473b4bca2.xlsx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eA Comparison of Routine [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 Preparation using Locametz and Illuccix Kits\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAccording to the American Cancer Society and the NIH Surveillance, Epidemiology, and End Results (SEER) data set, one in every eight men will be diagnosed with prostate cancer in their lifetime, with the average age of first diagnosis at 66 years old (Siegel \u003cem\u003eet al\u003c/em\u003e., 2023). In the United States, prostate cancer is the second most common cancer type next to skin cancer, with estimates of about 288,000 new cases annually (Noone \u003cem\u003eet al\u003c/em\u003e., 2018; National Cancer Institute, 2024). High prevalence and diagnosis reliant on screening tests and symptoms, excluding a prostate biopsy which is the only true diagnosis but highly invasive, has led to the development of numerous imaging modalities to help diagnose and manage prostate cancer. These include transrectal ultrasound, magnetic resonance imaging, computerized tomography (CT) scans, and positron emission tomography (PET) (Zelefsky \u003cem\u003eet al\u003c/em\u003e., 2019; Niederhuber \u003cem\u003eet al\u003c/em\u003e., 2020;\u0026nbsp;Taplin and Smith, 2023). In patients with high disease burden and associated metastases, use of PET/CT scans is beneficial in identifying the location of metastasized tumors. Use of the prostate-specific membrane antigen (PSMA) as a target in prostate cancer imaging is well established and the ligand [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 (gallium Ga68 gozetotide), first reported by investigators at the German Cancer Research Center and Heidelberg University (Sch\u0026auml;fer \u003cem\u003eet al\u003c/em\u003e., 2012; Eder \u003cem\u003eet al\u003c/em\u003e., 2013; Sachpekidis \u003cem\u003eet al\u003c/em\u003e., 2016) is established for the PET imaging of prostate cancer today (Barrio et al., 2016; Clore and Scott, 2024).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Labeling bioactive molecules with gallium-68 is unique, as unlike other common PET isotopes such as carbon-11 or fluorine-18, there are two major production methods: cyclotron irradiation of a \u003csup\u003e68\u003c/sup\u003eZn target (either liquid or solid), or elution of a germanium-68/gallium-68 (\u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa) generator, to source the [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e used in subsequent labeling steps. Both methods have their benefits and drawbacks. For instance, cyclotron-based production yields consistent supply and higher activity, but requires a more complicated purification process. In contrast, generator-based production allows straightforward access to \u003csup\u003e68\u003c/sup\u003eGa-labeled tracers in facilities without a cyclotron, but requires careful management of generator decay. Both methods have been used to prepare [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11. For example, we and others produced [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 for use in early clinical trials under an FDA-approved investigational new drug (IND) application via both a generator approach using a Scintomics synthesis module, and utilizing cyclotron-produced \u003csup\u003e68\u003c/sup\u003eGa in conjunction with the GE FASTLab developer platform (Lin et al., 2018; Pandey et al., 2019; Rodnick \u003cem\u003eet al\u003c/em\u003e., 2020, 2022; Jackson \u003cem\u003eet al\u003c/em\u003e. 2020; Thisgaard et al., 2021; Svedjehed \u003cem\u003eet al\u003c/em\u003e., 2022). Following successful completion of phase 3 clinical trials, the University of California Los Angeles (UCLA) and the University of California San Francisco (UCSF) submitted concomitant New Drug Applications for [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 to the FDA for marketing authorization. This was granted in December 2020, making [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 the first radiopharmaceutical for PET imaging of PSMA\u0026ndash;positive lesions in men with prostate cancer approved in the US (Carlucci \u003cem\u003eet al\u003c/em\u003e., 2021).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe pioneering efforts by UCSF and UCLA paved the way for commercial manufacturers to develop kits for the production of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11. Cold kit labeling is expected to facilitate global access to \u003csup\u003e68\u003c/sup\u003eGa-labeled radiopharmaceuticals including [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 (Lepareur, 2022), and FDA approval of commercial kits for producing [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 has altered the way many sites produce [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 for routine clinical use. Illuccix, manufactured by Telix Pharmaceuticals, was approved in 2021, and Locametz, manufactured by Novartis, in 2022\u0026nbsp;(Novartis Pharmaceuticals Corporation, 2022; Telix Pharmaceuticals, 2023). These kits have also been approved by other regulatory agencies around the world. For traditional PET manufacturing facilities, approval of these kits has necessitated introduction of generator-based production into historically cyclotron-based workflows. In radiopharmacies and/or nuclear medicine departments already familiar with a kit-based workflow, approval of these kits has nevertheless increased the daily workload, and necessitated handling both PET (\u003csup\u003e68\u003c/sup\u003eGa) and SPECT (e.g. \u003csup\u003e99m\u003c/sup\u003eTc) radionuclides with different storage requirements and elution timing due to differences in generator age and kinetics. In either instance, manufacturers need to decide on adoption of Illuccix and/or Locametz kits in the formulary, depending on which is more appropriate for routine use at a given site.\u003c/p\u003e\n\u003cp\u003eApproval of the Locametz and Illuccix kits with use of \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generators has enabled on demand access to [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 in radiopharmacies and nuclear medicine departments. Since both Locametz and Illuccix kits contain the same precursor, PSMA-11, but with differences in formulation or excipients and labeling procedure, there are questions to consider when selecting one kit over (see: Supplementary Information, \u003cstrong\u003eTable S1\u003c/strong\u003e). \u0026nbsp;The focus of this article is to compare both kits, provide guidance for radiopharmaceutical manufacturers to help select the most fitting kit for daily production of PSMA-11 at their own facility, and to provide guidance for switching from one kit to another. Additionally, we highlight some difficulties that were experienced during a year and a half of routine [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 production at our facility, and solutions that we developed to overcome such issues.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUsing E\u0026amp;Z GalliaPharm\u003csup\u003e\u0026reg;\u003c/sup\u003e \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generators (Eckert and Zigler, 2021), Locametz (n=181) and Illuccix (n=256) kits were prepared at the University of Michigan from 2\u003csup\u003end\u003c/sup\u003e June 2022 to 13\u003csup\u003eth\u003c/sup\u003e September 2023. The workflow, variations in production batches, failure rates, and QC parameters were analyzed. QC tests were completed in accordance with kit package inserts, and according to standard procedures described in the United States Pharmacopeia (USP) (e.g. chapters \u0026lt;823\u0026gt;, \u0026lt;825\u0026gt;, \u0026lt;71\u0026gt;, and \u0026lt;85\u0026gt;).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProduction of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 using Locametz Kits\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverview: The procedure for producing [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 using a Locametz kit in conjunction with an Eckert and Ziegler (E\u0026amp;Z) GalliaPharm\u003csup\u003e\u0026reg;\u003c/sup\u003e \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa Generator, as used at our facility, \u0026nbsp;is described in the package insert (Novartis Pharmaceuticals Corporation, 2022). Briefly, [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e is eluted from the generator using 5 mL of 0.1 M HCl directly into the Locametz vial fitted with a 0.2\u0026nbsp;\u0026mu;m sterile vent filter. The vial is then inverted once, placed upright, and left at room temperature (20-30 \u003csup\u003eo\u003c/sup\u003eC) for 5 minutes for labeling. The vial is then calibrated with a maximum allowable activity of 2.59 GBq and an expiration time of 6 hours is assigned. The dose in 5 mL can be further diluted to 10 mL with normal saline (0.9 % NaCl).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDetailed Procedure: At our facility, production of Locametz kits requires the disposable and non-disposable items listed in \u003cstrong\u003eTable S2\u003c/strong\u003e (see Supplementary Information). Production of Locametz occurs as follows: Take the Locametz vial from the kit and remove the flip-off cap from the top of the vial. Take a tear weight of the vial. In a segregated area with an ISO 5 primary engineering control (PEC), move and wipe the needed materials into the PEC using sterile 70% isopropyl alcohol. Using aseptic technique, pierce the Locametz dose vial with a 0.2\u0026nbsp;\u0026mu;m Millex-FG sterile air vent filter connected to a 0.8x50 mm (21Gx2\u0026rdquo;) needle. Then pierce the Locametz dose vial with a 0.22\u0026nbsp;\u0026mu;m Cathivex-GV sterile product filter connected to a 1.2x38 mm (18Gx1\u0026frac12;\u0026rdquo;) silicone coated needle. Arrange the filters such that the bevel of the needle connected to the sterile air vent is positioned above the bevel of the needle connected to the product filter, and that both filters are in the top 1/3 of the Locametz vial (\u003cstrong\u003eFigure 1a\u003c/strong\u003e). This will minimize activity from being expelled out of the sterile vent filter during generator elution. Take the Locametz dose vial with the two filters out of the PEC and place it into a lead or tungsten shielded container suitable for PET isotopes. Connect the 1.85 GBq or 3.7 GBq E\u0026amp;Z generator outlet line to the Cathivex-GV filter and using a 10 mL organic syringe pull up 6.2 mL of 0.1 M Ultrapure sterile HCl from the three-way valve upstream of the inlet line minimizing air bubbles. Manually (or automatically if using a syringe pump), elute the generator at a rate no faster than 2 mL/min, ensuring that if there were air bubbles in the syringe they are not pushed into the generator. Once the elution is completed, note the time, as this is used to determine the expiration time. Remove the sterile air vent from the Locametz vial and discard in a shielded radioactive sharps bin. Remove the product filter from the Locametz vial and disconnect the filter from the generator outlet line and place it into a lead or tungsten shielded container. This will be used for the filter integrity test. Using tongs and behind appropriate shielding (e.g. lead L-block), invert the Locametz vial twice and agitate vigorously (shake up, down, and left, right) for 2 seconds then place the vial back into the vial shield. Alternatively, the entire vial shield (and vial) can be inverted and agitated. Let the vial sit at room temperature (20-25 \u003csup\u003eo\u003c/sup\u003eC) for 10 min for labeling to take place \u003cstrong\u003e(Figure 1a)\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eQC Testing: For QC testing, the preferred method for determining radiochemical purity (RCP) is using an instant thin layer chromatography (TLC) method with a radiometric TLC (rTLC) plate scanner (see below).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProduction of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 using Illuccix Kits\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverview: Production using Illuccix kits with E\u0026amp;Z generators (configuration A) is described in the corresponding Illucix package insert (Telix Pharmaceuticals, 2023). Briefly, [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e is eluted from the generator using 5 mL of 0.1 M HCl into a sterile vacuumed reaction vial (vial 3) fitted with a 0.2\u0026nbsp;\u0026mu;m sterile vent filter to equalize pressure. With a 10 mL syringe connected to a needle, the acetate buffer (vial 2) is injected into the vial containing PSMA-11 (vial 1). Once combined, the mixture is swirled to dissolve the peptide in the buffer. Then, using a new 10 mL syringe, the buffer and ligand solution is added into the vial containing [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e (vial 3). The resulting solution is left at room temperature (15-30 \u003csup\u003eo\u003c/sup\u003eC) for 5 min for labeling to occur. The vial is then calibrated, with a maximum allowable activity of 1.85 GBq, and an expiration time of 4 h is assigned. The dose will have a final volume of 7.5 mL.\u003c/p\u003e\n\u003cp\u003eDetailed Procedure: At our facility, production of Illuccix kits requires the disposable and non-disposable items listed in \u003cstrong\u003eTable S3\u003c/strong\u003e (see Supplementary Information). Production of Illuccix occurs as follow: Take vial 1 from the Illuccix kit and remove the blue flip-off cap from the top of the vial. Take a tear weight of the vial. In a segregated area with an ISO 5 PEC, move and wipe the needed materials into the PEC using sterile 70% isopropyl alcohol. Using aseptic technique, pierce vial 2 (acetate buffer vial) using a 5 mL organic syringe connected to a 1.2x38 mm (18Gx1\u0026frac12;\u0026rdquo;) silicone coated needle and withdraw the entire contents of the vial (2.5 mL) minimizing the headspace in the syringe. Insert the syringe with the acetate buffer into vial 1 and inject the buffer solution into the vial. Vial 1 is under negative pressure (vacuum) and therefore does not need its pressure equalized. Remove the syringe and needle from vial 1 and agitate gently (side to side, not up and down) for 5 seconds. Then pierce vial 1 first with a 0.2\u0026nbsp;\u0026mu;m Millex-FG sterile air vent filter connected to a 0.8x50 mm (21Gx2\u0026rdquo;) needle, and second with a 0.22\u0026nbsp;\u0026mu;m Cathivex-GV sterile product filter connected to a 1.2x38 mm (18Gx1\u0026frac12;\u0026rdquo;) silicone coated needle. Arrange the filters such that the bevel of needle connected to the sterile air vent is positioned above the bevel of the needle connected to the product filter and that both filters are in the top 1/3 of vial 1 (\u003cstrong\u003eFigure 1b\u003c/strong\u003e). This will minimize activity from being expelled out of the sterile vent filter during generator elution. Take vial 1 with the two filters out of the PEC and place into a lead or tungsten shield suitable for PET isotopes. Connect the 1.85 GBq E\u0026amp;Z generator (or a 3.7 GBq E\u0026amp;Z generator decayed to only producing at maximum of 1.85 GBq) outlet line to the Cathivex-GV filter and using a 10 mL organic syringe pull up 6.2 mL of 0.1 M Ultrapure sterile HCl from the three-way valve upstream of the inlet line minimizing air bubbles. Manually (or automatically when using a syringe pump), elute the generator at a rate no faster than 2 mL/min, ensuring that if there were air bubbles in the syringe it is not pushed into the generator. Once the elution is completed, note the time, as this is used to determine the expiration time. Remove the sterile air vent from vial 1 and discard in a shielded radioactive sharps bin. Remove the product filter from vial 1 and disconnect the filter from the generator outlet line and place it into a lead or tungsten shield. This will be used for the filter integrity test. Using tongs and behind appropriate shielding (e.g. lead L-block), agitate the vial (shake up, down, and left, right) for 2 seconds then place the vial back into the vial shielded container. Alternatively, the entire vial shield (and vial) can be agitated. Let the vial sit at room temperature (15-30 \u003csup\u003eo\u003c/sup\u003eC) for 5 minutes for labeling to take place \u003cstrong\u003e(Figure 1b\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eQC Testing: For QC, there are two methods for determining RCP, using a TLC method in conjunction with an rTLC scanner, or a cut and assay technique (see below). The cut and assay method requires the sample to be spotted at the 1 cm line (above the bottom of the plate), and to develop the plate a distance of 10 cm. The plate is then cut at the 6 cm mark (5 cm above the 1 cm demarcation). The percent incorporation (or radiochemical purity, RCP) is calculated by taking the activity counts in the top piece divided by the sum of activity counts in the top and bottom pieces multiplied by 100.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuality Control of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 using either Locametz or Illuccix\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQC of Locametz and Illuccix requires the same disposable and non-disposable items listed in \u003cstrong\u003eTable S4\u003c/strong\u003e (see Supplementary Information). It is important to note that for Locametz or Illuccix preparation, the required QC procedures are the same, but there are some differences in the QC release criteria (\u003cstrong\u003eTable 1\u003c/strong\u003e). Using tongs take a weight measurement and activity calibration of the dose vial, then with a 1 mL syringe connected to a 1.2x38 mm (18Gx1\u0026frac12;\u0026rdquo;) silicone coated needle, insert into the dose vial and pull up ~ 0.1 mL for use in QC analysis. Ensure the pulling of activity is unidirectional, and the solution in the 1 mL syringe is not pushed back into the vial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1:\u0026nbsp;\u003c/strong\u003eA comparison of the passing quality control criteria for PSMA-11 using Locametz or Illuccix kits.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eRelease Criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eLocametz\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eIlluccix\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMaximum Allowed Activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.59 GBq\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.85 GBq\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eShelf-life (after labeling)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 hours\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTarget Volume\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.0 mL (can be diluted to 10 mL with normal saline)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.5 mL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRadiochemical purity by rTLC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026gt; 95%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eImpurity by rTLC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026le; 5%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRetention factor (Rf)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8 \u0026ndash; 1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.6 \u0026ndash; 1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003epH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.2 \u0026ndash; 6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.0 \u0026ndash; 5.0\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAppearance and Visual Inspection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eClear, colorless, and free from particulates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eClear, colorless to slight yellow, and free from particulates\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFilter Integrity Test [Cathivex\u0026reg;-GV]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026gt; 344.7 kPa (50 psi)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBacterial Endotoxin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; 35 EU/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026lt; 23.3 EU/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003csup\u003e68\u003c/sup\u003eGe breakthrough (Radionuclidic purity)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\"\u003e\n \u003cp\u003e\u0026lt; 0.001%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTo analyze radiochemical purity by rTLC, using a 1-5\u0026nbsp;\u0026mu;L pipette, spot a 1\u0026nbsp;\u0026mu;L aliquot 1 cm above the bottom of a 7 cm TLC plate and place the plate into a TLC chamber with 6 mL of 1:1 (1 M) ammonium acetate solution (aqueous): methanol and cover the chamber (see Supplementary Information for details on preparation of this eluent). Develop the plate in the solution until the solvent front is 1 cm away from the top of the plate which will take about 8-12 minutes. Since the development time is quite slow, an optional 2\u003csup\u003end\u003c/sup\u003e TLC plate can be developed concurrently to mitigate delays in the event of an invalid TLC test. Dry the developed plate on a hot plate to remove excess water and place the plate on a rTLC plate reader. Follow the package insert directions for passing criteria; briefly, for Locametz, a rTLC purity of \u0026gt; 95%, and a Rf of 0.8-1.0, and for Illuccix, a rTLC purity of \u0026gt; 95%, and a Rf of 0.6-1.0 (Novartis Pharmaceuticals Corporation, 2022; Telix Pharmaceuticals, 2023).\u003c/p\u003e\n\u003cp\u003eTo analyze for pH, using a 10-50\u0026nbsp;\u0026mu;L pipette with a pipette tip, a 17.5\u0026nbsp;\u0026mu;L aliquot is spotted onto a MQuant colorimetric pH indicator strip, the package insert directions for passing criteria are followed: for Locametz, a pH of between 3.2-6.5 is required, and for Illuccix, a pH of between 4.0-5.0. For visual inspection, the dose vial \u0026nbsp;(and/or QC aliquot (~ 0.1 mL) depending on local practices) are inspected visually for color and particulates, and following the package insert directions for passing criteria: for Locametz, the vial should be clear, colorless, and free from particulates, and for Illuccix, the vial should be clear, colorless to slight yellow, and free from particulates (Novartis Pharmaceuticals Corporation, 2022; Telix Pharmaceuticals, 2023).\u003c/p\u003e\n\u003cp\u003eTo ensure that doses are sterile and free of bacterial endotoxins, three tests are conducted. First, the final product filter used to filter the [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e into the final kit vial is tested for integrity. The filter is connected to an air line with a pressure regulator and placed into a jar containing Milli-Q water. The pressure regulator is slowly turned up to allow for increased pressure of air to the filter. When the filter is ruptured, determined by flow of air bubbles into the jar, this value is the filter integrity value which should be \u0026gt;344.7 kPa (50 psi) for the\u0026nbsp;Cathivex\u0026reg;-GV filter, or the manufacturer\u0026rsquo;s specified pressure if a different filter is used.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSecond, bacterial endotoxins testing is performed using the Endosafe endotoxin PTS system. Using a 10-50\u0026nbsp;\u0026mu;L pipette with a pipette tip, 17.5\u0026nbsp;\u0026mu;L of the dose is added into a 5 mL falcon tube containing 3.9 mL of pre-measured LAL water. The sample is capped and vortexed for 5 seconds. Using a 1:300 dilution on the Endosafe endotoxin PTS cartridge reader with an Endosafe PTS cartridge, a 25\u0026nbsp;\u0026mu;L aliquot of the mixed LAL water is added to each of the four channels in the cartridge. The endotoxin test will take 650-800 seconds to complete. Following USP \u0026lt;85\u0026gt;, the maximum allowable endotoxin limit is 175 endotoxin units (EU) per the maximum volume injected (United States Pharmacopeia, 2024a). Thus for Locametz the limit is 35 EU/mL, and for Illuccix the limit is 23.3 EU/mL.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLastly, sterility testing is performed. Due to the nature of PET radiopharmaceuticals, and in accordance with standard practice when working with PET drugs, the test is completed after the dose is released to the clinic for use and is administered to the patient. To determine if bacterial contamination has occurred, tubes of tryptic soy broth (TSB) and fluid thioglycolate medium (FTM) are each inoculated with 250 \u0026mu;L of the dose within 30 h of production. The TSB is incubated at room temperature (20-25 \u003csup\u003eo\u003c/sup\u003eC) and the FTM is incubated at 30-35 \u003csup\u003eo\u003c/sup\u003eC for 14 days during and, on days 5, 7, and 14 tubes are visually inspected for microbial growth. Following USP \u0026lt;71\u0026gt;, the samples should be clear with no turbidity after 14 days (United States Pharmacopeia, 2024b).\u003c/p\u003e\n\u003cp\u003eFinally, to ensure that the E\u0026amp;Z generators are not leaching long-lived germanium-68 (\u003csup\u003e68\u003c/sup\u003eGe, half-life 271 days) into batches of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11, once a week the generators must be checked for germanium breakthrough by testing radionuclidic purity (RNP). This is accomplished by pushing 5 mL of 0.1 M ultrapure sterile hydrochloric acid through the generator into a shielded, vented 10 mL vial and transferring a 3 \u0026mu;L aliquot of the eluate into an HPLC vial (or equivalent small vial). The samples are read in a multi-channel analyzer (MCA) with a zoom window of 8-2048 keV for 20 minutes. The samples are read twice, with the first reading within 12 hours after elution and the second reading between 24-120 hours after elution. \u003csup\u003e68\u003c/sup\u003eGe breakthrough is calculated by using the following equations:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/58894_9946feeafa4c1df7/58894_custom_files/img1731606625.png\" width=\"783\" height=\"269\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eFollowing the E\u0026amp;Z GalliaPharm\u003csup\u003e\u0026reg;\u003c/sup\u003e \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generator product description and Nuclear Regulatory Committee requirements, breakthrough values should be less than 0.001% of the total radioactivity (Tapp, 2016;\u0026nbsp;Eckert and Zigler, 2021).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is expressed as mean \u0026plusmn; standard deviation, unless otherwise specified, and statistical analysis is conducted using Prism Version 9 software (GraphPad) with significance tested by comparing the 95% confidence interval (P \u0026lt; 0.05). The two main groups are production using Locametz kits, and production using Illuccix kits. The Locametz group is then further subdivided into production using 1.85 GBq E\u0026amp;Z or 3.7 GBq E\u0026amp;Z generators, either using regular needles (RN, 0.7x38 mm, 22Gx1\u0026frac12;\u0026rdquo;) or non-metal leaching silicone coated needles (NMLN, 0.6x60 mm, 23Gx2⅜\u0026rdquo;). The Illuccix group is subdivided into production using 1.85 GBq E\u0026amp;Z generators or a decayed 3.7 GBq E\u0026amp;Z generator (producing less than 1.85 GBq), using either a syringe pump or manual elution, or using the two different sizes of NMLN silicone coated needles (0.6x60 mm (23Gx2⅜\u0026rdquo;) or 1.2x38 mm (18Gx1\u0026frac12;\u0026rdquo;)).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eUsing E\u0026amp;Z \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generators at our facility to produce [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 for clinical use, we prepared Locametz kits (n\u0026thinsp;=\u0026thinsp;181) from 2nd June 2022 to 9th February 2023, and prepared Illuccix kits (n\u0026thinsp;=\u0026thinsp;256) from 17th October 2022 to 13th September 2023.\u003c/p\u003e\n\u003ch3\u003eLocametz Production\u003c/h3\u003e\n\u003cp\u003eUsing the Locametz kits, the overall production success rate was 95.03% (172/181). For the doses that met (or exceeded) the established QC criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and were released to the clinic for use in patients, the mean RCP by rTLC was 98.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47% (95% CI: 98.34\u0026ndash;98.48) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The activity at calibration ranged from 0.53\u0026ndash;2.15 GBq across 5 different lots of 1.85 GBq E\u0026amp;Z generators and 1 lot of 3.7 GBq E\u0026amp;Z generator, with a mean time from end of elution to calibration of 11.28\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25 min (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). The mean dose volume was 4.93\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14 mL and a mean pH of 3.9 (range 3.3\u0026ndash;4.2) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The time of synthesis was approximately 12 min. Including completion of the required paperwork and QC testing, the total time per production was approximately 35 min.\u003c/p\u003e \u003cp\u003eFor the subset of production using only non-silicone coated needles (RN, 0.7x38 mm, 22Gx1\u0026frac12;\u0026rdquo;) for which generator produced [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e was eluted into the Locametz vial (n\u0026thinsp;=\u0026thinsp;52), the overall success rate was 84.62% (44/52). For the doses that passed and were released for use in patients, the mean RCP by rTLC was 98.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47% (95% CI: 98.24\u0026ndash;98.53) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The doses that used non-silicone coated RN needles, led to 8 failures which were not released for clinical use due to \u0026lt;\u0026thinsp;95% RCP, or minor discoloration (pink tinge) of the formulated dose approximately 15\u0026ndash;20 minutes after the addition of [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Five of the failed batches had RCP\u0026thinsp;\u0026lt;\u0026thinsp;95% (ranging from 45.71\u0026ndash;91.55%), and the remaining 3 vials had passing RCP (ranging from 95.36\u0026ndash;98.80%). All other QC parameters passed for these 8 batches. Vials with lower RCP appeared to discolor to a greater extent when re-examined after 1 year. In attempts to recreate the discoloration and identify the likely source for contamination, a variation of shaking and inverting, or not shaking and inverting, \u0026ldquo;heating\u0026rdquo; at 27 \u003csup\u003eo\u003c/sup\u003eC for 7 minutes or labeling at room temperature for 10 minutes, and the use of RN needles or silicone coated NMLN needles were tested. Ultimately, swapping the RN needles out for silicone coated NMLN needles led to doses that were clear, colorless, and free of particulates. All other variations (shaking and/or \u0026ldquo;heating\u0026rdquo; at 27 \u003csup\u003eo\u003c/sup\u003eC) using silicone coated NMLN led to passing QC parameters with no color changes. We hypothesize that the discoloration of failed batches was due to the leaching of metal ions from RN needles that could compete with \u003csup\u003e68\u003c/sup\u003eGa during chelation. Silicone coated NMLN needles do not leach metal ions and were thus adopted for [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 kit preparations going forward.\u003c/p\u003e \u003cp\u003eFor the subset of productions (n\u0026thinsp;=\u0026thinsp;129) using silicone coated needles (NMLN, 0.6x60 mm, 23Gx2⅜\u0026rdquo;), the overall production success rate was 99.22% (128/129). For the doses that passed, the mean RCP by rTLC was 98.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47% (95% CI: 98.33\u0026ndash;98.50) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). For these doses, only 1 failure was observed which was due to the lack of vial inversion and shaking leading to RCP of 91.55%. This issue was rectified by inverting and shaking the vial.\u003c/p\u003e \u003cp\u003ePrior to the most recent package insert for Locametz, which changed the maximum allowed activity from 1.85 GBq to 2.59 GBq, we independently tested the compatibility of \u0026ldquo;high activity\u0026rdquo; with Locametz kits using a fractionation approach with a 3.7 GBq and a 1.85 GBq E\u0026amp;Z generator. Using the highest fractions of a 3.7 GBq E\u0026amp;Z generator corresponding to fractions 2 through 4 (the 2nd through 4th mL of 0.1 M HCl used to elute the generator) of the elution, combined with fractions 2 and 3 (the 2nd and 3rd mL of 0.1 M HCl) of an 1.85 GBq E\u0026amp;Z generator, we were able to add 3.16 GBq in 5 mL of 0.1 M HCl into the Locametz vial which, at calibration (11 minutes later), gave 2.9 GBq. The initial RCP was 97.22% (n\u0026thinsp;=\u0026thinsp;2) and at 4 hours the RCP was 98.96% with all other QC parameters passing (see Supplementary Information, \u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eab\u003c/b\u003e). The RCP appears higher at 4 h when minor impurities decay below the rTLC limit of detection. A second attempt without fractionation was completed by eluting a 3.7 GBq generator with 6.2 mL of 0.1 M HCl through a 0.22 \u0026micro;m Cathivex-GV filter to give 2.22 GBq at calibration time, with RCP of 98.35% at calibration and 99.23% at 4 hours (see Supplementary Information, \u003cb\u003eFigure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003eab\u003c/b\u003e). With the established \u0026ldquo;higher activity\u0026rdquo; Locametz, subdividing the group using NMLN needles (n\u0026thinsp;=\u0026thinsp;129) into production using a 1.85 GBq generator (n\u0026thinsp;=\u0026thinsp;81) and a 3.7 GBq generator (n\u0026thinsp;=\u0026thinsp;48) showed no differences in product quality and no differences in failure rate. The RCP by rTLC were 98.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39% (95% CI: 98.40\u0026ndash;98.58) and 98.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57% (95% CI: 98.13\u0026ndash;98.46), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eIlluccix Production\u003c/h2\u003e \u003cp\u003eUsing Illuccix kits (n\u0026thinsp;=\u0026thinsp;256), the overall production success rate was 99.22% (254/256). For the doses that met (or exceeded) established QC criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and were released for use in patients, the mean RCP by rTLC was 97.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71% (95% CI: 97.73\u0026ndash;97.90) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The activity at calibration ranged from 0.611\u0026ndash;1.79 GBq across 6 different lots of 1.85 GBq E\u0026amp;Z generators, and 1 lot of a decayed 3.7 GBq E\u0026amp;Z generator producing less than 1.85 GBq, with a mean time from end of elution to calibration of 6.19\u0026thinsp;\u0026plusmn;\u0026thinsp;1.17 min (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). To be able to use the decayed 3.7 GBq generator, it took 24 weeks of tri-weekly elution (and \u003csup\u003e68\u003c/sup\u003eGe decay) to get to an activity below the 1.85 GBq threshold for use with Illucix kits. The mean dose volume was 7.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.163 mL and the mean pH 4.24 (range 4.0\u0026ndash;4.75) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The time of synthesis was approx. 8 min. Including completion of required paperwork and QC testing, the total time per production was approximately 30 min.\u003c/p\u003e \u003cp\u003eFor the subset of productions (n\u0026thinsp;=\u0026thinsp;34) using silicone coated needles (NMLN, 0.6x60 mm, 23Gx2⅜\u0026rdquo;) to transfer the acetate buffer from vial 2 to vial 1 and the elution of [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e into vial 1, the production success rate was 100% (34/34). These doses had a mean RCP by rTLC of 98.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70% (95% CI: 97.80\u0026ndash;98.29) and a mean volume of 7.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12 mL (95% CI: 7.33\u0026ndash;7.41). These doses had a mean pH of 4.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17 (95% CI 4.325\u0026ndash;4.440) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea,c).\u003c/p\u003e \u003cp\u003eFor Illuccix kits (n\u0026thinsp;=\u0026thinsp;222) prepared using silicone coated needles (NMLN, 1.2x38 mm, 18Gx1\u0026frac12;\u0026rdquo;), the production success rate was 99.1% (220/222). For the doses that passed QC and were released for clinical use, the mean RCP by rTLC was 97.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.70% (95% CI: 97.68\u0026ndash;97.87) and a mean volume of 7.23\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16 mL (95% CI: 7.21\u0026ndash;7.25). These doses had a mean pH of 4.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10 (95% CI: 4.199\u0026ndash;4.225) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea,c). In this subset of doses, there were three failures due to low pH (\u0026lt;\u0026thinsp;2.5), which we attribute to insufficient mixing of the kit components. After vigorously shaking the vial and leaving at room temperature for an additional 5 min, the doses were recalibrated, and a second aliquot was obtained for QC. All three doses had pH within normal range (4.2 and 4.4) and all other QC tests met (or exceeded) release criteria, allowing doses to be released for clinical use.\u003c/p\u003e \u003cp\u003eAmong all the Illuccix doses prepared (n\u0026thinsp;=\u0026thinsp;256), the subset of doses using a 1.85 GBq generator (n\u0026thinsp;=\u0026thinsp;157) had a success rate of 98.8% (155/157) with mean RCP by rTLC of 97.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.73% (95% CI: 97.72\u0026ndash;97.94) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The doses using a decayed 3.7 GBq generator producing\u0026thinsp;\u0026lt;\u0026thinsp;1.85 GBq (n\u0026thinsp;=\u0026thinsp;99) were also used, which had a production success rate of 100% (99/99) and mean RCP by rTLC of 97.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68% (95% CI: 97.61\u0026ndash;97.88) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). There were no major differences between the use of the different generators.\u003c/p\u003e \u003cp\u003eOf all the Illuccix doses (n\u0026thinsp;=\u0026thinsp;256), the subset of doses using a syringe pump to elute the generator by pushing 6.2 mL of 0.1 M HCl at 2 mL/min had a success rate of 96.9% (63/65), with mean RCP by rTLC of 97.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60% (95% CI: 97.77\u0026ndash;98.07) and a mean volume of 7.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17 mL (95% CI: 7.15\u0026ndash;7.24) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The subset of doses manually eluted by pushing 6.2 mL of 0.1 M HCl at approx. 2 mL/min had a success rate of 100% (191/191) with mean RCP by rTLC of 97.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74% (95% CI: 97.67\u0026ndash;97.87) and a mean volume of 7.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16 mL (95% CI: 7.24\u0026ndash;7.29) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). Required weekly, breakthrough test was completed on all generators used. The breakthrough was below the limit of detection, which was determined to be \u0026lt;\u0026thinsp;0.0004% for all generators, meeting the established criteria.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe time required to complete one synthesis of Locametz is around 12 minutes excluding QC testing (QC time is ~\u0026thinsp;23 min); whereas for Illuccix it is around 8 minutes excluding QC testing (QC time is ~\u0026thinsp;22 min). The success rates of production using Locametz and Illuccix kits were comparable, and no significant differences were observed. More importantly, when looking at the subset of productions using silicone coated needles (NMLN) for elution, the rates are the same (1 failure every 128 runs). This suggests that from a production standpoint both Locametz and Illuccix kits have very similar reliability, which makes the decision between which kit to use for routine production of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 more nuanced. Comparing our workflows, we assemble our final product vials in an ISO 5 PEC, following aseptic technique, and elute the generators in an ISO 8 hot cell (according to guidelines in USP\u0026thinsp;\u0026lt;\u0026thinsp;825\u0026gt;). When using Illuccix kits, we add the acetate vial (vial 2) into the PSMA-11 precursor vial (vial 1) in the ISO PEC, prior to the addition of the [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e from the generator in the ISO 8 hot cell. This is a deviation from the package insert, which recommends adding the acetate and PSMA-11 solution into the [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e. This order of events would require us to bring the eluted [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e back to the ISO 5 PEC to add the acetate and PSMA-11 solution. This process becomes unnecessarily complicated, with higher radiation exposure rates to production staff, and therefore has not been adapted for routine production. This minor change to the process order has had no impact upon product quality. For Locametz, this is not an issue because a separate buffer (or pH adjusting) solution is not required.\u003c/p\u003e \u003cp\u003eExcluding the eight failures related to using non-silicone coated needles (RN), we attribute the remaining failures (1 for Locametz, and 1 for Illuccix) to improper mixing. The Locametz package insert suggests the inversion of the dose vial to help with incorporation and mixing of the lyophilized buffer, but no agitation. Improper mixing of the Locametz vial led to a failure, which suggests that agitation of the vial increases the consistency of labeling by adequately mixing the buffer agent and HCl. Although the package insert suggests that labeling is complete within 5 minutes, it also recommends the vials be labeled at temperatures within 20\u0026deg;C to 30\u0026deg;C, which in colder climates may not always be possible (Novartis Pharmaceuticals Corporation, 2022). Extending the labeling time to 10 min further ensures consistency without the need to \u0026ldquo;heat\u0026rdquo; the reaction at 27\u0026deg;C to be within the allowed range.\u003c/p\u003e \u003cp\u003eWhen labeling NetSpot ([\u003csup\u003e68\u003c/sup\u003eGa]Ga-DOTATATE), agitation of the vial is not recommended due to potential leaching of competing metals such as zinc from the vial septa leading to poor incorporation of \u003csup\u003e68\u003c/sup\u003eGa(III), as Zn(II) can also form stable complexes with DOTA (Fang et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Advanced Accelerator Applications USA Inc., 2021). The Locometz package insert recommends inversion of the vial to help with mixing but recommends against agitation or stirring (Novartis Pharmaceuticals Corporation, 2022). However, the affinity of HBED-CC for Ga(III) is higher than the affinity between HBED-CC and Zn(II) (Ma et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e1994\u003c/span\u003e; Iudicello et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) and so we believe competing chelation of Zn is less likely to be an issue when preparing [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 and this has borne out in our experience thus far.\u003c/p\u003e \u003cp\u003eFor Illuccix, the package insert does not specify the need to shake the vial after the addition of [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e to the acetate buffered ligand solution (Telix Pharmaceuticals, 2023). However, with our production runs, we saw 3 instances where the lack of vial agitation led to poor incorporation of \u003csup\u003e68\u003c/sup\u003eGa due to incorrect reaction pH (\u0026lt;\u0026thinsp;2.5). Our first low pH dose led to a failure, as we did not shake the vial on that occasion; however, with our second and third cases, the vial was shaken. In each case the vials were shaken again to ensure proper mixing of the [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e and the acetate buffered ligand solution, and this led to appropriate incorporation (RCP\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;95%) and pH of ~\u0026thinsp;4.2. Although the incorrect pH only contributed to 1.17% (3/256) of all Illuccix production runs, shaking the vial increases the consistency for efficient labeling, and is therefore recommended.\u003c/p\u003e \u003cp\u003eWhen Locametz production was conducted using with non-silicone coated needles (RN, 0.7X38 mm, 22Gx1\u0026frac12;\u0026rdquo;), several failures resulted (due to low incorporation of \u003csup\u003e68\u003c/sup\u003eGa and/or discoloration of the product). We have not used Illuccix kits with these non-silicone coated needles, but the failed Locametz productions using these needles suggest that using silicone coated needles (NMLN) improves labeling and so they are also recommended for use with Illuccix. Although both Locametz and Illuccix kits contain the same \u0026ldquo;precursor\u0026rdquo;, the excipients and formulation of the kits are different (see Supllementary Information, \u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). The QC criteria for appearance with Locametz requires \u0026ldquo;clear, colorless, particulate free\u0026rdquo; solutions (Novartis Pharmaceuticals Corporation, 2022), whereas Illuccix allows for \u0026ldquo;clear, colorless to slight yellow, particulate free\u0026rdquo; solutions (Telix Pharmaceuticals, 2023). The difference in QC appearance criteria is attributed to the differences in formulation. When looking at the components used to prevent radiolysis of PSMA-11, for Locametz, 1 mg of gentisic acid (radioprotectant) is used, while for Illuccix, 10 \u0026micro;g of \u003cb\u003eD\u003c/b\u003e-mannose (a reducing sugar, acting as a radioprotectant) is used. The color change observed in Locametz kits could result from oxidation of gentisic acid, which is known to give a faint pinkish, yellowish color (Hosokawa et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). The purpose of gentisic acid in the dose vial is to prevent the oxidation of PSMA-11, acting as a sacrificial substrate for oxidative chemical reactions. The discoloration of Locametz is most likely attributed to gentisic acid\u0026rsquo;s radioprotective effects and therefore should not impact the RCP, and this is consistent with our findings. Nonetheless, by switching to needles that have a low potential for leaching metals that can catalyze oxidation, the discoloration is no longer observed, and therefore it is recommend that silicone coated needles (either 0.6x60 mm, 23Gx2⅜\u0026rdquo; or 1.2x38 mm, 18Gx1\u0026frac12;\u0026rdquo;) be used to produce Locametz.\u003c/p\u003e \u003cp\u003eThe silicone coated needles (NMLN) used to label Locametz and Illuccix kits were from B. Braun (brand name Sterican\u0026reg;). We routinely use these needles with NetSpot kits to produce [\u003csup\u003e68\u003c/sup\u003eGa]Ga-DOTATATE) and thus we also selected them to label PSMA-11 and make our entire \u003csup\u003e68\u003c/sup\u003eGa-labeling workflow more uniform. Originally, the 0.6x60 mm (23Gx2⅜\u0026rdquo;) needles were used, which provided sufficient length to pull up all the acetate buffer from Illuccix vial 2 without needing to invert the vial. Due to regulatory changes preventing us from obtaining these needles from a third-party, a new length of needles was used (1.2x38 mm, 18Gx1\u0026frac12;\u0026rdquo;). Since these needles were shorter, and the bore larger, it made it very difficult to pull up all 2.5 mL of the acetate buffer from vial 2. The acetate buffer in vial 2 needed to be inverted, and because the needle was no longer as flexible as the 0.6x60 mm needles, required more manipulations to acquire an \u0026ldquo;accurate\u0026rdquo; volume. Ultimately, this change in needles led to minor differences in the final dose volume. Even with these volume changes, which presumably were due to the differences in acetate buffer added and not the HCl eluted through the generator, there were no significant differences in RCP or pH of the labeled product. This suggests that although the addition of 2.5 mL of acetate solution (vial 2) is recommended by the manufacturer in the package insert, a volume of ~\u0026thinsp;2.2 mL is still tolerated by the kit. This is further demonstrated by the fact that the success rate was not significantly altered between the two sizes of needles (100% vs. 99.1%). If we exclude the 2 failures which were unrelated to the volume of acetate added, the success rate was 100% (failures were due to inadequate mixing and user error in operating the syringe pump). Although there are no differences in QC results between the two silicone coated needles, when selecting the length and bore size of the needles used for [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e elution and QC sample draw, we recommend a longer length, smaller bore size needle, as this will make the assembly of the dose vial in an ISO 5 PEC more streamlined with fewer manipulations and hand exposure to radiation for staff.\u003c/p\u003e \u003cp\u003eWe demonstrated that adding higher amounts of \u003csup\u003e68\u003c/sup\u003eGa to Locametz kits (\u0026gt;\u0026thinsp;1.85 GBq allowed by the paclage insert at the time) led to doses that still met all QC criteria at 4 h post-EOS. By using a fractionation approach we were able to demonstrate that up to 3.16 GBq (decay-corrected activity added to the vial\u0026thinsp;=\u0026thinsp;3.5 GBq) was tolerated. Since a 3.7 GBq E\u0026amp;Z generator is expected to only produce 80% of its maximum activity, successful production using\u0026thinsp;\u0026gt;\u0026thinsp;2.96 GBq of \u003csup\u003e68\u003c/sup\u003eGa allows use a 3.7 GBq generator for producing Locametz throughout the generator\u0026rsquo;s lifetime. When comparing the Locametz lower activity (\u0026lt;\u0026thinsp;1.85 GBq) and higher activity (\u0026gt;\u0026thinsp;1.85 GBq) productions, there were no significant differences in RCP or other QC test results. In marked contrast, when \u0026gt;\u0026thinsp;1.85 GBq of \u003csup\u003e68\u003c/sup\u003eGa were added to an Illuccix kit, rHPLC analysis showed\u0026thinsp;\u0026lt;\u0026thinsp;95% RCP. In our hands, this did not align with rTLC test results, which showed RCP\u0026thinsp;\u0026gt;\u0026thinsp;95%. This discrepancy requires further investigation but meant we did not use\u0026thinsp;\u0026gt;\u0026thinsp;1.85 GBq of \u003csup\u003e68\u003c/sup\u003eGa with Illuccix in this work.\u003c/p\u003e \u003cp\u003eUse of a syringe pump to elute the \u003csup\u003e68\u003c/sup\u003eGa generator when labeling Illuccix led to similar outcomes as manual elution, and we observed no major changes in RCP, volume, pH or other QC test results between the two approaches. A syringe pump can control the elution rate to a greater extent than manual elution, which tends to be faster than 2 mL/min and offers improved consistency of pressure applied. Since the use of a syringe pump is equivalent to manual elution, we recommend the use of a syringe pump to further decrease radiation hand exposure during generator elution. However, the use of a syringe pump can also increase the risk of user error, which led to one of our failures and careful checking of the setup is recommended. It is important to note that we used 6.2 mL of 0.1 M HCl to elute the generators because we wished to include a 0.22 \u0026micro;m Cathivex-GV filter in-line for terminal sterilization as part of the manufacturing process. The filter traps around 1.2 mL of solution (dead volume) which is lost and therefore accounted for by pushing more HCl through the generator. Since the generator elution is not homogenous, minimal activity is lost on the filter using a larger volume (Roesch and Riss, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). In a radiopharmacy or nuclear medicine department in an ISO 5 PEC in a clean room (ISO 7 secondary engineering control (SEC)), 5 mL of 0.1 M HCl can be used with or without a filter in-line into the vial.\u003c/p\u003e \u003cp\u003eThere are two methods for determining RCP using TLC, an iTLC method requiring the use of a radioTLC scanner / plate reader to scan the plate, and a \u0026ldquo;cutting\u0026rdquo; technique. Both methods are interchangeable, and therefore both methods can be used to determine RCP. Currently the Locametz package insert only specifies using the scanning method to analyze the TLC plates. On the other hand, the Illuccix package insert allows for either method for analysis. Since the \u0026ldquo;precursors\u0026rdquo; are the same, and the synthesis process is the same (free \u003csup\u003e68\u003c/sup\u003eGa and [\u003csup\u003e68\u003c/sup\u003eGa]colloids will stay at the origin, and [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 will move to the solvent front), both kits give similar results and thus we posit that either method can also be used for Locametz as well. It is worth noting that for the cutting method, because a dose calibrator is used to obtain the counts for subsequent calculations, a 5 \u0026micro;L spot on the TLC plate is recommended to have more activity and ensure sufficient counts in the dose calibrator.\u003c/p\u003e \u003cp\u003eA summary of recommendations for the labeling of PSMA-11 using Locametz or Illuccix kits is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. From a clinical perspective, PSMA-11 scans using Locametz or Illuccix kits are functionally the same. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows scans from a patient who received a [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET scan using Locametz first, then a second [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET scan using Illuccix 112 days after the first scan. The patient was not on treatment between scans, and was only taking dexamethasone. In both images, the patient has avid metastatic disease in the abdominal pelvic lymph nodes, thoracic and supraclavicular lymph nodes, and bones. These images, from the same patient, demonstrate the similarities of scans acquired using [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 prepared using each kit.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eA summary of recommendations for labeling PSMA-11 using Locametz or Illuccix kits.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLocametz Kit\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIlluccix Kit\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenerator produced [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCan use E\u0026amp;Z, IRE EliT Galli EO, or ITM GeGant generators\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCan use E\u0026amp;Z with \u003cem\u003econfiguration A\u003c/em\u003e and IRE EliT Galli EO with \u003cem\u003econfiguration B\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyclotron produced [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNot allowed, not recommended\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFollowing package insert directions using GE GaCl\u003csub\u003e3\u003c/sub\u003e cassette with FASTLab synthesizer. Disregard our changes to the order of acetate solution addition\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActivity at calibration and expiration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUp to 3.16 GBq for up to 4 hours or\u003c/p\u003e \u003cp\u003eup to 2.59 GBq for up to 6 hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUp to 1.85 GBq for up to 4 hours\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeedles\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eSilicone coated non-metal leaching needles,\u003c/p\u003e \u003cp\u003epreferably needles with longer length and smaller bore size\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAddition of buffer solution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003enot necessary, one vial formulation\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdd the acetate solution into the ligand vial first then add [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e. There is approximately 0.3 mL of tolerance built into the amount of acetate solution added.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInversions after the addition of [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 inversions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eno inversions\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShaking the vial after addition of [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eVigorously (up, down, left, right) for 2 seconds\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLabeling Time at room temperature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 minutes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 minutes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuality Control, RCP by rTLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eEither scanning or cutting method\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse of a syringe pump\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePreferred to reduce hand exposure and increase elution rate consistency\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe labeling workflow for PSMA-11 with generator produced [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e using Locametz or Illuccix kits are similar, and clinical images obtained using [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 prepared with either kit are considered equivalent. This reinforces the notion that selection of a given kit is primarily dependent on production method preferences which are compared in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The Locametz kit with a 1-vial formulation makes vial assembly easier and eliminates errors due to transfer between vials. Locametz kits allow the addition of more activity (3.16 GBq) when compared to Illuccix (1.85 GBq) and a longer shelf-life after labeling (6 h vs 4 h, respectively). Locametz kits can be used with more generators, including E\u0026amp;Z, IRE EliT Galli EO, and ITM GeGant, whereas the Illuccix kits can only be used with E\u0026amp;Z and IRE Elit Galli EO generators. Illuccix can be used with cyclotron-produced \u003csup\u003e68\u003c/sup\u003eGa, whereas this is not included in the Locometz package insert. From a quality control perspective, both kits have similar release criteria, and either the scanning or cutting method for rTLC analysis can be used for both kits. The retention factor (Rf) cut-off for Locametz is tighter (0.8-1.0), whereas the Illuccix Rf cut-off is more accommodating (0.6-1.0), which also needs to be accounted for.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eA comparison of production method and source of [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e for Locametz and Illuccix Kits\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLocametz Kit\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIlluccix Kit\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse with E\u0026amp;Z Generator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes, Configuration A only\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse with IRE EliT Galli EO Generator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes, Configuration B only\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse with ITM GeGant Generator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUse with Cyclotron Produced [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYes, Configuration A only\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVials in Kit Formulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDilution with normal saline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes, to 10 mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum activity at calibration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.16 GBq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.85 GBq\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShelf-Life after labeling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 hours\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 hours\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime for radiolabeling at room temperature\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlate development time due to Rf criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLonger time (tighter Rf criteria)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eShorter time (looser Rf criteria)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFinally, for facilities who are considering using either or both kits, due to cost, workflow or other reasons, the transition between kits is close to seamless. A similar list of non-consumable and consumable products are used which makes switching straightforward (see Supplementary Information, \u003cb\u003eTables S2 through S4\u003c/b\u003e). For radiopharmacies and nuclear medicine departments experienced with general nuclear medicine, the assembly and setup for Locametz is similar to the labeling of numerous \u003csup\u003e99m\u003c/sup\u003eTc kits (e.g. [\u003csup\u003e99m\u003c/sup\u003eTc]MDP, [\u003csup\u003e99m\u003c/sup\u003eTc]DTPA, [\u003csup\u003e99m\u003c/sup\u003eTc]tetrofosmin (Myoview)) whereas the assembly and setup for Illuccix is closer to the labeling of other \u003csup\u003e99m\u003c/sup\u003eTc kits (e.g. [\u003csup\u003e99m\u003c/sup\u003eTc]bicisate (Neurolite), [\u003csup\u003e99m\u003c/sup\u003eTc]sulfur colloid without heating), or [\u003csup\u003e68\u003c/sup\u003eGa]Ga-DOTATATE (NetSpot). For facilities used to more traditional PET drug manufacturing like FDG, the use of Locametz or Illuccix kits may require new workflows and techniques as generator-based production has not traditionally been widely used at such sites, but this can readily be accomplished threough implementation of appropriate standard operating procedures. While this report has focused upon use of Locametz and Illuccix kits in conjunction with \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generators, such might also prefer Illuccix kits due to their compatibility with cyclotron-produced \u003csup\u003e68\u003c/sup\u003eGa (Telix Pharmaceuticals, 2023).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, preparation of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 using Locametz or Illuccix kits have comparable workflows and also provide equivalent PSMA PET images. Therefore, excluding cost and contracting considerations, selecting a kit for day-to-day use ultimately depends on the versatility of these kits and the preferred workflow at a given site. Both kits had comparable failure rates in our hands (1 in 128 vials), although we have observed that using silicone coated non-metal leaching needles, as well as vial agitation after the addition of [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3,\u003c/sub\u003e leads to improved labeling consistency. Additionally, labeling Locametz kits at room temperature for 10 min (instead of 5 min) also improved consistency, without substantial delay in workflow. When comparing the two kits, traditional radiopharmaceutical facilities familiar with generator elution and a \u0026ldquo;kit-based approach\u0026rdquo; may prefer to use Locametz kits due to the similarities with the general \u003csup\u003e99m\u003c/sup\u003eTc workflow, whereas PET manufacturing facilities making FDG might prefer Illuccix kits due to the versatility of the gallium-68 source (generator or cyclotron). Overall, the commercial availability of 2 approved kits for production of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET has facilitated ready access to this important new prostate cancer imaging agent, and underpinned successful introduction of pluvicto radiotherapy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFTM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efluid thioglycolate medium\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHPLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehigh pressure liquid chromatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eiTLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einstant thin layer chromatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLAL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003elimulus amoebocyte lysate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emulti\u0026ndash;channel analyzer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNMLN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon\u0026ndash;metal leaching silicone coated needles, either 0.6x60 mm (23G 2⅜\u0026rdquo;) needles or 1.2X38 mm (18G 1\u0026frac12;\u0026rdquo;) needles\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epositron emission tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eQC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003equality control\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradiochemical purity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRf\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eretention factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enon\u0026ndash;silicone coated, regular needles, or 0.7X38 mm (22G 1\u0026frac12;\u0026rdquo;) needles\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRNP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradionuclidic purity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003erTLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradio thin layer chromatography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTSB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etryptic soy broth\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable as this article does not contain any original research studies with human or animal subjects performed by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable as this article does not contain any original research studies with human or animal subjects performed by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProvided in the Supplementary Information is a list of Formulation, components of the Locametz and Illuccix kits (\u003cstrong\u003eTable S1\u003c/strong\u003e), as well as a list of disposable and non-disposable items used in both the production of Locametz (\u003cstrong\u003eTable S2\u003c/strong\u003e) and Illuccix (\u003cstrong\u003eTable S3\u003c/strong\u003e). Additionally, required materials for quality control is also provided (\u003cstrong\u003eTable S4\u003c/strong\u003e). Provided in an Excel sheet (\u003cstrong\u003eAppendix A\u003c/strong\u003e) is the raw data for all 437 PSMA-11 production batches reported and analyzed in this article. The preparer’s names have been replaced with generic names (Person A, Person B, etc.) in the Excel sheet, but reflect the actual radiochemists’s role for each batch.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIEW, LJM, KKW, AFB and MD disclose no competing interests. PJHS holds equity in Novartis and Telix Pharmaceuticals.\u0026nbsp;Given his role as Associate Editor, Peter J. H. Scott had no involvement in the peer-review of this article and has no access to information regarding its peer-review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for this work from the University of Michigan (Department of Radiology and Support for Outstanding Academic Research, SOAR) is gratefully acknowledged.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIEW labeled the Locametz and Illuccix kits, entered and analyze the data, and wrote the article; LJM labeled the Locametz and Illuccix kits, organized and entered the data, and helped with the initial analysis of the data; KKW provided clinical insight to the use of the labeled Locametz and Illuccix kits and provided PET scan images; AFB helped with the narrative of the article and provided edits for the article; MD provide regulatory oversight; PJHS provided supervision and funding, oversaw labeling of the kits, provided insight to the direction of the article, and final edits for the article. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge Dr. Melissa Rodnick for setting up the original \u003csup\u003e68\u003c/sup\u003eGa production processes at the University of Michigan; Dr. Melissa Rodnick, Laura Bruton, Karim Mahanna, Bradford Henderson, Dr. Jessica Gomez Lopez, Mara Clark and Jessica Clore for their help with day-to-day production of Locametz and Illuccix; and Mara Clark and Jessica Clore for their help with sterility testing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAdvanced Accelerator Applications USA Inc. 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Philadelphia, PA: Lippincott Williams \u0026amp; Wilkins; 2019.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gallium-68, gozetotide, Illuccix, Locametz, PET manufacturing, prostate cancer, PSMA-11, radiopharmacy","lastPublishedDoi":"10.21203/rs.3.rs-5363858/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5363858/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eApproval of Locametz and Illuccix kits for the manufacture of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 (gallium Ga68 gozetotide), a PET imaging agent for prostate cancer, as well as the corresponding therapeutic ([\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 Pluvicto), has led to a rapid increase in demand for [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET imaging. Radiopharmaceutical manufacturers, using \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generators, may decide to adopt Locametz and/or Illuccix kits, which requires a comparison to select the most suitable kit for day-to-day use. The objective of this article is to compare both kits and provide guidance for selecting one for routine use, as well as evaluate labeling consistency of both kits during routine production. Additionally, we report our experience during 1.5 years of daily [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 production at our facility using both kits.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eLocametz (n\u0026thinsp;=\u0026thinsp;181) and Illuccix (n\u0026thinsp;=\u0026thinsp;256) kits were prepared using non-silicone coated and silicone-coated needles with \u003csup\u003e68\u003c/sup\u003eGa activities ranging from 0.53 to 3.16 GBq, with a failure rate of 1 in 128 runs for both kits. With Locametz, a 3.7 GBq generator and 10-min incubation at room temperature gave doses that passed quality control (QC) testing. Use of non-silicone coated needles in the process led to solution discoloration, and QC failure. Additionally, lack of vial inversion led to inconsistent labeling, which improved with subsequent vial agitation. For Illuccix, addition of the acetate buffer to the precursor vial prior to adding the [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e simplifies the workflow. The maximum tolerated activity was 1.85 GBq. Lack of vial inversion led to failures, which were rectified by agitating the vial to properly incorporate the acetate solution with the generator eluate.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBoth kits benefited from using a syringe pump to elute the \u003csup\u003e68\u003c/sup\u003eGe/\u003csup\u003e68\u003c/sup\u003eGa generator, vial agitation, and longer length/smaller bore silicone coated needles. Both kits have similar workflows, comparable QC outcomes, and result in equivalent clinical images. Thus, the decision between kits will ultimately be determined on production preferences. Since radiopharmacies have an established \u0026ldquo;kit-based\u0026rdquo; workflow, Locametz kits with higher allowed activities and longer shelf-life may offer benefits. Conversely, more traditional PET manufacturing facilities might benefit from using Illuccix kits due to compatibility with cyclotron-produced [\u003csup\u003e68\u003c/sup\u003eGa]GaCl\u003csub\u003e3\u003c/sub\u003e allowing for kit batching. Ultimately, the commercial availability of 2 approved kits for production of [\u003csup\u003e68\u003c/sup\u003eGa]Ga-PSMA-11 PET has facilitated ready access to this important new imaging agent.\u003c/p\u003e","manuscriptTitle":"A Comparison of Routine [68Ga]Ga-PSMA-11 Preparation using Locametz and Illuccix Kits","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-02 15:38:35","doi":"10.21203/rs.3.rs-5363858/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2024-11-12T09:14:50+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-11-03T18:22:29+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-02T14:53:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-01T17:41:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Radiopharmacy and Chemistry","date":"2024-10-31T13:05:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-radiopharmacy-and-chemistry","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"erpc","sideBox":"Learn more about [EJNMMI Radiopharmacy and Chemistry](http://ejnmmipharmchem.springeropen.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/erpc/default.aspx","title":"EJNMMI Radiopharmacy and Chemistry","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2fdb00eb-9174-4b7d-a6b5-b41d4da49a44","owner":[],"postedDate":"December 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:05:25+00:00","versionOfRecord":{"articleIdentity":"rs-5363858","link":"https://doi.org/10.1186/s41181-024-00317-4","journal":{"identity":"ejnmmi-radiopharmacy-and-chemistry","isVorOnly":false,"title":"EJNMMI Radiopharmacy and Chemistry"},"publishedOn":"2024-12-18 15:58:22","publishedOnDateReadable":"December 18th, 2024"},"versionCreatedAt":"2024-12-02 15:38:35","video":"","vorDoi":"10.1186/s41181-024-00317-4","vorDoiUrl":"https://doi.org/10.1186/s41181-024-00317-4","workflowStages":[]},"version":"v1","identity":"rs-5363858","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5363858","identity":"rs-5363858","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}