Multifactorial Analysis of Radiochemical Purity in High-Activity 177Lu-Labeled Theranostics: Impact of Precursor Source, 177Lu Form, and Production Parameters

Multifactorial Analysis of Radiochemical Purity in High-Activity 177Lu-Labeled Theranostics: Impact of Precursor Source, 177Lu Form, and Production Parameters | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Multifactorial Analysis of Radiochemical Purity in High-Activity 177Lu-Labeled Theranostics: Impact of Precursor Source, 177Lu Form, and Production Parameters William Hunt, Mathew Long, Usama Kamil, Sunil Kellapatha, Wayne Noonan, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6763766/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jul, 2025 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 1 posted 5 You are reading this latest preprint version Abstract Background Lutetium-177 ( 177 Lu) theranostics have revolutionized personalized cancer treatment, particularly with FDA-approved therapies like [ 177 Lu]Lu-DOTATATE for neuroendocrine tumors and [ 177 Lu]Lu-PSMA for prostate cancer. Despite growing clinical adoption, there is limited understanding of how different production variables affect radiochemical purity, especially when scaling to high activities for multi-patient batches. This study evaluates the impact of precursor sources, 177 Lu forms (carrier-added (C.A.) vs. non-carrier-added (N.C.A.)), and radiochemical concentration on product quality. Results We analyzed 355 clinical batches of [ 177 Lu]Lu-DOTATATE (n = 101), [ 177 Lu]Lu-PSMA-617 (n = 169), and [ 177 Lu]Lu-PSMA-I&T (n = 85) produced with standardized protocols using lutetium-177 from multiple suppliers in both carrier-added and non-carrier-added forms. All radiopharmaceuticals demonstrated consistently high yields (≥ 98%) and met release criteria regardless of starting materials. [ 177 Lu]Lu-DOTATATE and [ 177 Lu]Lu-PSMA-617 maintained radiochemical purity above 90% throughout 24 hours, while [ 177 Lu]Lu-PSMA-I&T showed stability for 8 hours but fell below specifications at 24 hours. Negative correlations between bulk activity/concentration and radiochemical purity were observed across all preparations. The lutetium-177 products from various suppliers displayed notably distinct quality profiles. Some suppliers consistently provided higher radiochemical purities, irrespective of the carrier-added or non-carrier-added forms of lutetium-177. However, carrier-added formulations exhibited greater radiostability compared to non-carrier-added ones at elevated concentrations. Furthermore, differences in precursor quality among manufacturers were noted, with certain suppliers offering enhanced radiostability characteristics that may enhance product performance at high activity concentrations. Conclusion This comprehensive analysis reveals that hospital-based production can be automized resulting in high-quality and efficient multi-dose production. Small differences in radiochemical purity of 177 Lu -labeled theranostics depends on complex interactions between precursor source, 177 Lu supplier, and 177 Lu form, beyond simple activity-dependent radiolysis. These findings underscore the importance of optimizing production parameters for high-activity preparations and highlight the need to explore the various multifactorial variables that impact the quality of 177 Lu-theranostics. Lutetium-177 theranostics Radiochemical purity High-activity production Carrier-added lutetium-177 Non-carrier-added lutetium-177 DOTATATE PSMA-617 PSMA-I&T Radiolysis Quality control Figures Figure 1 Figure 2 Figure 3 Figure 4 BACKGROUND Theranostics is a combined approach that integrates targeted therapies with diagnostic agents to optimize patient treatment in personalized medicine. This rapidly evolving strategy has demonstrated remarkable effectiveness in treating metastatic cancer, achieving significant clinical results with relatively low toxicity ( 1 ). A key component of theranostics is the use of targeted ligands, often short peptides, which serve as vehicles for delivering radioactive payloads directly to cancer cells ( 2 ). These ligands can function as either diagnostic or therapeutic agents, depending on the specific radionuclide attached to them. Common diagnostic radionuclides include the positron emitters Gallium-68 ( 68 Ga) and Fluorine-18 ( 18 F), which are crucial for imaging and locating tumors. In contrast, the primary therapeutic radionuclide used is Lutetium-177 ( 177 Lu), a cytotoxic beta-emitting isotope that when incorporated into a targeted ligand destroys malignant cells. The precision with which targeted ligands deliver radioactive payloads is essential for enhancing treatment efficacy and improving patient outcomes in cancer therapy. The use of 177 Lu-labeled theranostics has surged over the past two decades, particularly with [ 177 Lu]Lu-DOTATATE for neuroendocrine tumors and [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T for prostate cancer ( 3 – 5 ). These therapies are increasingly being assessed for earlier lines of use, expanding their applicability beyond late-stage diseases ( 6 – 9 ), and in various combinations ( 10 , 11 ). In response to the growing global demand for 177 Lu-theranostics ( 12 ), FDA approval and commercialization of [ 177 Lu]Lu-PSMA-617 have enabled pharmaceutical companies to scale up manufacturing, allowing for the direct shipment of individual doses to hospitals for patient treatment in some parts of the world ( 13 ). Despite this progress, hospital-based batch production of 177 Lu-theranostics remains an option, particularly in regions where commercial supplies are unavailable or their supply is cost-prohibitive. Australia is one such region where hospital-based production has enabled implementation of theranostics including development of guidelines to support safe use ( 14 ). As demand for these therapies increases, hospitals often need to produce large multi-dose batches starting with high 177 Lu activities. However, there is a significant gap in our understanding of how these larger-scale preparations respond to radiolysis—the chemical decomposition caused by ionizing radiation. Literature on the production and stability of 177 Lu-theranostics at activities exceeding 40 GBq is scarce, if available at all ( 15 – 25 ). This knowledge gap is further exacerbated by variations in starting materials, such as carrier-added (CA) and non-carrier-added (NCA) 177 Lu, which are offered in different volumes (0.2 ml – 7 ml), radioactivity concentrations and formulations (0.04 M and 0.05 M HCl) from various suppliers (Table S1 summarizes the specifications of 177 Lu obtained from different sources). Literature reports often present these diverse sources of lutetium and their different forms as equivalent, overlooking their potential impact on the quality of the final product. Additionally, sourcing essential production consumables, including precursors, from multiple global suppliers further complicates the assessment of how these variables influence product quality. The literature on the production and quality control of [ 177 Lu]Lu-DOTA-TATE, [ 177 Lu]Lu-PSMA-617, and [ 177 Lu]Lu-PSMA-I&T cannot be meaningfully compared, even for the same agent, due to significant discrepancies in the source of starting materials, as well as in their production and quality control protocols. Table S2 provides a comprehensive, though not exhaustive, summary of key findings from various published reports, highlighting critical points of difference among them. Additionally, some of the reported production studies do not use well-established and comprehensively validated quality control methods, which calls into question the validity of their findings. For instance, S. Schmitl et al. reported an in-depth quality assurance investigation on [ 177 Lu]Lu-PSMA-I&T, revealing a likely overestimation of the radiochemical purity of this product, further complicating our ability to rely on published reports for accurate comparisons ( 25 ). The inherent differences in radioactive detector systems used across various laboratories also limit any direct comparison of results, making it extremely challenging to draw meaningful conclusions. The high cost of 177 Lu limits the ability to conduct large-scale, systematic comparative studies to evaluate the effects of various sources and forms of 177 Lu, as well as other reagents and precursors, on the quality of the final product. This is especially important when utilizing high starting activities of 177 Lu. Our center operates one of the largest hospital-based theranostic production and treatment facilities globally, which allows us to retrospectively collect significant data (n ≥ 350) on high-activity radiolabeling of [ 177 Lu]Lu-DOTA-TATE, [ 177 Lu]Lu-PSMA-617, and [ 177 Lu]Lu-PSMA-I&T, with starting activities reaching up to 90 GBq. By employing consistent production and quality control protocols, this data provides valuable and directly comparable insights into the effects of different sources and forms of 177 Lu, the impact of various precursor sources, and the significance of high-activity radiolabeling on the purity of the final product. This knowledge enhances our understanding of production processes and their implications for product quality, enabling us to better meet the needs of patients requiring these essential therapies. METHODS The production and quality control of [ 177 Lu]Lu-DOTA-TATE, [ 177 Lu]Lu-PSMA-617, and [ 177 Lu]Lu-PSMA-I&T were carried out using validated methods outlined in a detailed published protocol ( 26 ). Briefly, 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) and 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA) conjugated to their corresponding radiopharmaceutical precursor molecules were labelled in sodium acetate buffer (0.4 M, pH 5.0) containing [ 177 Lu]LuCl₃, 2,5-dihydroxybenzoic acid (4 mg), sodium L-ascorbate (20 mg), and heated to 80°C for 30 minutes (Fig. 1 ). The 177 Lu-labeled mixture was then directly formulated with the addition of an aqueous solution of sodium L-ascorbate (480 mg), pentetic acid (DTPA; 1 mg), and water for injection (10 ml). This process was automated using an iPHASE MultiSyn radiochemistry module with sterile kits affording sterile and apyrogenic 177 Lu-labeled radiopharmaceuticals in non-decay corrected yields > 95%. When necessary, the final product was diluted with saline to obtain radiochemical concentrations below 3.5 GBq/ml. Before clinical use the prepared 177 Lu-radiopharmaceutical underwent validated prerelease quality control tests including activity reconciliation, HPLC, TLC, and bubble point testing, meeting the release criteria outlined in Table S3. Results from all batches of [ 177 Lu]Lu-DOTA-TATE, [ 177 Lu]Lu-PSMA-617, and [ 177 Lu]Lu-PSMA-I&T in 2023 and 2024 were processed to obtain data used in the manuscript. Shelf-life stability assessment The remaining amounts of large batches (> 50 GBq) of [ 177 Lu]Lu-DOTA-TATE, [ 177 Lu]Lu-PSMA-617, and [ 177 Lu]Lu-PSMA-I&T, after patient doses were drawn, were resampled by extracting approximately 200 µL from the bulk dose vial, which was stored at room temperature. Resampling occurred at 4, 6, 8, and 24 hours after calibration. The material was then analyzed using the validated quality control methods detailed in our published protocol ( 26 ). Statistical analysis Analysis was conducted on batches of radiopharmaceuticals, defined by precursor and supplier, to determine the correlations between bulk activity and concentration with radiochemical purity (Table S4). Pearson's correlation coefficient was calculated along with bootstrapped confidence intervals (1000 replications). Means and standard deviations described the distribution of activity and concentration. This analysis was limited to products that comprised at least 10 batches with the same combination of precursor supplier, 177 Lu supplier, and 177 Lu form. RESULTS Production Yields and Activity Ranges of Clinical [ 177 Lu]Lu-Labeled Radiopharmaceuticals A total of 101 batches of [ 177 Lu]Lu-DOTATATE were produced, with formulated activities ranging from 8.3 to 65.3 GBq, among these, 14 (14%) batches exceeded 50 GBq. Radiochemical concentrations ranged from 0.74 to 3.02 GBq/ml. The yield for this radiopharmaceutical was 98% ± 3%. For [ 177 Lu]Lu-PSMA-617, 169 batches were produced, with formulated activities ranging from 5.2 to 88.9 GBq. Notably, 56 (33%) batches surpassed 50 GBq, while the radiochemical concentrations ranged from 0.43 to 2.96 GBq/ml, yielding 99% ± 5%. In the case of [ 177 Lu]Lu-PSMA-I&T, 85 batches were prepared, with activity levels ranging from 8.1 to 77.0 GBq. Seven (8.2%) batches exceeded 50 GBq and 28 (33%) batches fell between 30 and 50 GBq, with concentrations from 0.67 to 2.91 GBq/ml and a yield of 99% ± 3%. Some yields were reported to exceed 100% due to calibration discrepancies caused by varying wall thicknesses of vials supplied by different manufacturers compared to those used during the final formulation process. Importantly, all production batches passed the pre-release criteria outlined in Table S3 at the end of synthesis (EOS). 24-Hour Stability Profile of [ 177 Lu]Lu-DOTATATE, [ 177 Lu]Lu-PSMA-617, and [ 177 Lu]Lu-PSMA-I&T The stability of [ 177 Lu]Lu-DOTATATE (n=3; activity range: 34-65.3 GBq; concentration: 2.9-3.5 GBq/ml), [ 177 Lu]Lu-PSMA-617 (n=6; activity range: 17-88.9 GBq; concentration: 1.5-3.3 GBq/ml), and [ 177 Lu]Lu-PSMA-I&T (n=3; activity range: 34-77 GBq; concentration: 2.3-2.7 GBq/ml) were evaluated over a 24-hour period (Table 1). Due to the demands of clinical workflows and patient administration schedules, the mid-point sampling window was adjusted to accommodate a 6-8 hour timeframe rather than a fixed 8-hour timepoint. While additional stability data exists for other production batches at various individual timepoints, the results presented here represent only those batches where complete sampling profiles were achieved across all specified timepoints. All preparations maintained their physical appearance as clear and colorless solutions throughout the study period, with a stable pH of 6, well within the specified range of 4-8. Radiochemical identity was confirmed via HPLC at all time points. Radiochemical purity was evaluated using two complementary methods: HPLC and TLC. TLC analysis demonstrated consistent 100% purity across all compounds and time points. HPLC analysis revealed high radiochemical purity for [ 177 Lu]Lu-DOTATATE (93.7–95.5%) and [ 177 Lu]Lu-PSMA-617 (91.8–95.8%) throughout the 24-hour period. While [ 177 Lu]Lu-PSMA-I&T demonstrated acceptable radiochemical purity through the clinically relevant 0-8 hour window (91.0–94.3%), a decline to 85.5 ± 3.5% was observed at 24 hours, falling below the release specification of ≥90%. In our practice, this was not clinically relevant as radiopharmaceutical administration is given on the same as production. Table 1: 24-Hour Stability Profile and Quality Control Analysis of [ 177 Lu]Lu-DOTATATE, [ 177 Lu]Lu-PSMA-617, and [ 177 Lu]Lu-PSMA-I&T. [ 177 Lu]Lu-DOTATATE Activity range: 34–65.3 GBq, Concentration range: 2.9 – 3.5 GBq/ml; n=3 [ 177 Lu]Lu-PSMA-617 Activity range: 17–88.9 GBq, Concentration range: 1.5 – 3.3 GBq/ml; n=6 [ 177 Lu]Lu-PSMA-I&T Activity range: 34–77 GBq, Concentration range: 2.3 – 2.7 GBq/ml; n=3 Parameter Specification 0 hr 4 hr 6 – 8 hr 24 hr 0 hr 4 hr 6 – 8 hr 24 hr 0 hr 4 hr 6 – 8 hr 24 hr Appearance Clear and colourless Pass Pass Pass Pass Pass Pass Pass Pass Pass Pass Pass Pass pH 4 - 8 6 6 6 6 6 6 6 6 6 6 6 6 Radiochemical Identity (HPLC) Reference Std ±1 min Pass Pass Pass Pass Pass Pass Pass Pass Pass Pass Pass Pass Radiochemical Purity (HPLC) ≥90 95.2 ± 1.3 95.5 ± 0.5 94.7 ± 0.5 93.7 ± 0.9 95.8 ± 1.6 95.7 ± 2.2 95.0 ± 1.4 91.8 ± 1.2 94.3 ± 0.9 92.3 ± 0.9 91.0 ± 1.4 85.5 ± 3.5 Radiochemical Purity (TLC) ≥98 100 100 100 100 100 100 100 100 100 100 100 100 Table 2: Mean (SD) and Pearson Correlation Coefficient of bulk activity, radiochemical concentration with HPLC-derived radiochemical purity (%) in various radiopharmaceuticals. N Bulk Activity (GBq) Concentration (GBq/ml) Purity (%) Mean (SD) Correlation to HPLC RP % (95% CI) Mean (SD) Correlation to HPLC RP % (95% CI) Mean (SD) [ 177 Lu]Lu-PSMA-617 ABX – ANSTO N.C.A. 52 31.7 (18.0) -0.46 (-0.69 to -0.22) 1.99 (0.60) -0.20 (-0.45 to +0.04) 95.2 (1.3) ABX – Isotopia N.C.A. 18 47.8 (17.2) -0.63 (-0.97 to -0.28) 2.29 (0.27) -0.67 (-0.86 to -0.49) 95.7 (0.8) ABX – Isotopia C.A. 80 46.8 (21.4) -0.43 (-0.64 to -0.23) 2.23 (0.54) -0.44 (-0.64 to -0.24) 95.6 (1.3) ABX – ITM N.C.A. 19 30.9 (18.0) -0.42 (-0.76 to -0.07) 1.84 (0.60) -0.59 (-0.79 to -0.39) 96.1 (0.7) [ 177 Lu]Lu-PSMA I&T Huayi – ANSTO N.C.A 31 30.6 (17.2) -0.68 (-0.89 to -0.48) 1.78 (0.56) -0.60 (-0.77 to -0.42) 95.5 (1.8) Huayi – Isotopia N.C.A 13 29.7 (17.8) -0.70 (-0.99 to -0.41) 1.79 (0.55) -0.56 (-0.88 to -0.24) 96.3 (1.2) Pi Chem – ANSTO N.C.A 11 18.6 (7.9) -0.19 (-0.89 to +0.51) 1.53 (0.66) -0.17 (-0.87 to +0.54) 97.0 (1.3) Huayi – Isotopia C.A 12 24.6 (11.6) -0.63 (-0.90 to -0.36) 1.76 (0.72) -0.44 (-0.80 to -0.07) 96.4 (1.3) Huayi – ITM N.C.A 15 28.5 (12.8) -0.74 (-1.00 to -0.47) 1.92 (0.60) -0.80 (-1.00 to -0.59) 96.6 (0.9) [ 177 Lu]Lu-DOTATATE Huayi – ANSTO N.C.A 23 27.9 (18.5) -0.63 (-0.87 to -0.39) 1.71 (0.74) -0.61 (-0.87 to -0.34) 93.5 (1.8) Huayi – Isotopia N.C.A 14 31.0 (11.4) -0.27 (-0.92 to +0.37) 2.03 (0.43) -0.85 (-1.00 to -0.61) 95.6 (1.2) Huayi – Isotopia C.A 47 35.8 (14.7) -0.48 (-0.66 to -0.30) 2.12 (0.54) -0.40 (-0.59 to -0.22) 95.4 (1.3) Huayi – ITM N.C.A 11 24.2 (14.6) -0.63 (-1.00 to -0.06) 1.64 (0.70) -0.46 (-1.00 to +0.09) 95.3 (1.3) We examined the bulk activity and radiochemical concentration of the various [ 177 Lu]Lu-labeled theranostics, and their correlation to the radiochemical purity at the end of synthesis (EOS) (Table 2). This analysis highlights the impact of different precursor sources—such as ABX and Huayi —paired with various 177 Lu sources and forms including ANSTO N.C.A, ITM N.C.A, Isotopia C.A, and Isotopia N.C.A (Fig. 1–3). For [ 177 Lu]Lu-PSMA-617, the precursor was sourced entirely from ABX. By combining the ABX-sourced precursor with four different forms and sources of 177 Lu, moderate correlations were generally observed between bulk activity or concentration and radiochemical purity, with Pearson's correlation coefficients (ρ) ranging from -0.67 to -0.20 (Fig. 1). These were especially noted for the Isotopia supplied N.C.A product, (activity) r = -0.63 (95%CI: -0.97 to -0.28), (concentration) r = -0.67 (95%CI: -0.86 to -0.49) though the number of batches analysed was relatively few (n=18). Mean bulk activity was appreciably higher for the Isotopia products than the ANSTO or ITM N.C.A. products (mean difference: 15.5, 95%CI: 9.5 to 21.5). Five [ 177 Lu]Lu-PSMA-I&T variations were analyzed: four combining Huayi precursor with different forms of 177 Lu, and one using piChem precursor with ANSTO N.C.A 177 Lu. Generally more pronounced negative correlations with purity were observed between both bulk activity and concentration compared to [ 177 Lu]Lu-PSMA-617, with no bootstrapped confidence intervals crossing zero. In contrast, the product with a piChem precursor exhibited relatively weak correlation coefficients (r = -0.17, -0.19) with a considerably lower mean bulk activity (Fig. 2). There was numerically greater variation observed in measured purity with the ANSTO N.C.A. product (SD = 1.8) versus all others (SD: 0.9 to 1.3). For [ 177 Lu]Lu-DOTATATE, four variations were analyzed including precursor obtained from Huayi precursor in combination with different sources and forms of 177 Lu. In this instance, correlations generally ranged from moderate to strongly negative. Of note, the mean bulk activity and concentration was notably higher for the Isotopia 177 Lu (N.C.A) and (C.A.) batches (Fig. 3). Similar to [ 177 Lu]Lu-PSMA I&T, higher variation in purity was observed with the ANSTO N.C.A. 177 Lu and additionally for the [ 177 Lu]Lu-DOTATATE batches, the mean purity percentage for ANSTO N.C.A. was lower than the other three products, mean: 93.5% vs 95.4% (mean difference -1.9%; 95%CI: -2.6% to -1.2%). DISCUSSION Our standardized production protocol demonstrated significant versatility in the preparation of [ 177 Lu]Lu-DOTA-TATE, [ 177 Lu]Lu-PSMA-617, and [ 177 Lu]Lu-PSMA-I&T. This protocol successfully accommodated varying volumes (0.5–4.5 mL) of both carrier-added (CA) and non-carrier-added (NCA) [ 177 Lu] from multiple suppliers (ANSTO, Isotopia, and ITM) using a single cassette-based platform. The protocol's robustness is evidenced by consistently high radiochemical yields of ≥ 98% across all three radiopharmaceuticals and the successful preparation of over 300 high-activity batches for more than 2000 cycles of therapy. The 24-hour stability assessment revealed that both [ 177 Lu]Lu-DOTATATE and [ 177 Lu]Lu-PSMA-617 maintained high radiochemical purity (> 90%) throughout the study period, while [ 177 Lu]Lu-PSMA-I&T showed acceptable purity within the clinically relevant 0–8 hour window but declined below specification at 24 hours. This finding aligns with Schmitl et al.'s work, which employed a risk-based approach to establish 90% radiochemical purity thresholds, noting that heat-induced cyclization by-products known to occur in PSMA ligands ( 22 ) represented only a small fraction (2.87 ± 0.85%) of total radioactivity, while the main radiolysis products were activity concentration-dependent and comprised approximately 2.8 ± 0.1% of the samples ( 25 ). This confirms the suitability of our formulations for clinical use within standard administration timeframes, though with limitations for extended storage of [ 177 Lu]Lu-PSMA-I&T. Our analysis uncovers important insights into the relationship between bulk activity, radiochemical concentration, and radiochemical purity in various [ 177 Lu]Lu-labeled theranostics produced from different precursors and 177 Lu sources. A negative correlation between bulk activity/concentration and radiochemical purity was noted across the three radiopharmaceuticals ([ 177 Lu]Lu-PSMA-617, [ 177 Lu]Lu-PSMA-I&T, and [ 177 Lu]Lu-DOTATATE), which aligns with the expected increase in radiolytic breakdown of products at higher activities. However, the magnitude of this correlation varied considerably. The variability in precursor and 177 Lu sources produced nuanced results for each radiopharmaceutical, highlighting the complex interplay of factors that can affect the final product quality. A consistent pattern emerged across all three radiopharmaceuticals regarding the influence of 177 Lu source on product quality. When using identical precursor sources, ITM N.C.A. 177 Lu consistently delivered higher radiochemical purities compared to ANSTO's N.C.A. 177 Lu. Moreover, both C.A. and N.C.A. 177 Lu from Isotopia provided consistent purities across all formulations, closely matching the high-quality results achieved with ITM's N.C.A. 177 Lu. This consistent pattern points to inherent qualities in these 177 Lu sources that influence radiochemical stability regardless of which specific precursor is being labeled. Nevertheless, all sources and forms of 177 Lu led to products that passed acceptance testing and are therefore suitable for clinical use.. For [ 177 Lu]Lu-PSMA-I&T specifically, although a lower mean bulk activity was used with the PiChem precursor, it achieved slightly higher radiochemical purities and enhanced stability at elevated concentrations compared to the Huayi precursor. This may suggest critical differences in precursor quality/composition that impact radiostability. A particularly interesting finding emerged when comparing C.A. versus N.C.A. 177 Lu from Isotopia across different formulations. When using Isotopia's N.C.A. 177 Lu for both [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-DOTATATE, we observed steeper radiochemical degradation with increasing concentrations compared to formulations using C.A . 177 Lu. This suggests either that the higher amount of precursor typically used with C.A. 177 Lu or some intrinsic property of C.A. 177 Lu itself confers a protective effect against radiolytic degradation. This detailed analysis provides a unique evidence base that can inform 177 Lu suppliers, radiopharmaceutical manufacturers, and regulatory bodies investigating the precise composition and characteristics of their products to maintain or further improve the quality of their material for clinical applications. As global demand for radioligand therapy continues to rise, especially in regions with limited access to commercial supplies, the variability observed in our study offers vital evidence-based data for practitioners and regulatory authorities. This information supports the development of corresponding monographs that favor radiochemical purities of 90% or greater as the cut-off when utilizing high-activity, multi-dose productions involving the full range of precursor and 177 Lu sources and forms needed to meet the growing demand for radioligand therapy. While all products in our study maintained clinically acceptable quality, the subtle yet consistent variations based on supplier and formulation highlight the need for a nuanced approach to establishing regulatory standards that balances theoretical ideals with practical clinical realities. These insights are particularly valuable as international initiatives work to expand global access to radiopharmaceutical therapies, allowing for the development of realistic quality parameters that can support equitable access to these life-extending therapies while maintaining appropriate safety and efficacy standards across diverse healthcare settings ( 12 ). Hospital radiopharmaceutical production environments are often staffed by professionals with specialized academic and clinical expertise who are well positioned to investigate and interpret such subtle differences in radiopharmaceutical performance. The dismissive characterization of hospital-based radiopharmaceutical preparation as "home brew" or "ad hoc hospital-based compounding" is unfounded and disregards the foundational contributions these hospital-based departments have made to the field of nuclear medicine. While we recognize that certain practices in hospital-based theranostic production environments operate within evolving regulatory frameworks, we believe it’s essential to appreciate the significant, nuanced, and specialized contributions that these environments have made and continue to make to the advancement of the entire discipline. The most effective approach is for industry, academia, and clinical environments to collaborate and learn from each other, integrating pharmaceutical industry capabilities with hospital-based expertise to ensure equitable patient access and effectively address the complex logistical and technical challenges inherent in theranostic production. CONCLUSION Our comprehensive analysis of over 350 high-activity batches of 177 Lu-labeled theranostics reveals complex relationships between precursor sources, 177 Lu sources, and radiochemical purity. While precursor sources and 177 Lu sources influence measured radiochemical purity values, all preparations maintained quality standards sufficient for clinical release. However, the observed variations in radiochemical purity associated with different precursor- 177 Lu combinations highlight the importance of optimizing production parameters beyond simply considering radiolytic effects. The pronounced differences in stability profiles between C.A. and N.C.A. 177 Lu, along with precursor-specific effects on radiostability, emphasize that radiopharmaceutical quality depends on a complex interplay of factors not fully recognized previously in the literature. These findings warrant further mechanistic investigations to elucidate the chemical and physical characteristics of different 177 Lu sources, precursor molecules, and stabilizing agents, which could lead to enhanced production protocols that maximize both activity yields and radiochemical purity for optimal patient care. Abbreviations C.A. - Carrier-added; N.C.A – Non Carrier-added; DOTA - 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; DOTAGA - 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid; DTPA - Pentetic acid; EOS - End of synthesis; FDA - Food and Drug Administration; GBq – Gigabecquerel; HPLC - High-performance liquid chromatography; ITM - ITM Medical Isotopes; PSMA - Prostate-specific membrane antigen; SD - Standard deviation; TLC - Thin-layer chromatography; 18 F - Fluorine-18; 68 Ga - Gallium-68; 177 Lu - Lutetium-177. Declarations Professor Michael Hofman acknowledges philanthropic/government grant support from the Prostate Cancer Foundation (PCF), Peter MacCallum Foundation, and a NHMRC Investigator Grant. PSMA-617 supply was supported by Endocyte/Novartis. ETHICS APPROVAL AND CONSENT TO PARTICIPATE Not applicable CONSENT FOR PUBLICATION Not applicable AVAILABILITY OF DATA AND MATERIALS The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. COMPETING INTERESTS The authors declare that they have no competing interests. FUNDING Not applicable AUTHORS' CONTRIBUTIONS MBH developed and implemented the production protocol and was the major contributor in writing the manuscript. MSH assisted with setting the clinical specifications for the products and helped contribute to the writing of the paper. NP performed the statistical analysis and helped write the corresponding statistical sections of the paper. WH, ML, UK, SK, WN, PDR, and BE helped in the implementation of the protocol, data collection, and contributed to the writing of the paper. All authors read and approved the final manuscript. ACKNOWLEDGEMENTS Not applicable References Solnes LB, Werner RA, Jones KM, Sadaghiani MS, Bailey CR, Lapa C, et al. Theranostics: Leveraging Molecular Imaging and Therapy to Impact Patient Management and Secure the Future of Nuclear Medicine. J Nucl Med. 2020;61(3):311–8. Hall AJ, Haskali MB. Radiolabelled Peptides: Optimal Candidates for Theranostic Application in Oncology. Aust J Chem. 2022;75(2):34–54. Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [ 177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825–33. Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, et al. [ 177 Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797–804. Hofman MS, Emmett L, Sandhu S, Iravani A, Buteau JP, Joshua AM, et al. Overall survival with [ 177 Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 2024;25(1):99–107. Eapen RS, Buteau JP, Jackson P, Mitchell C, Oon SF, Alghazo O, et al. Administering [ 177 Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study. Eur Urol. 2024;85(3):217–26. Azad AA, Bressel M, Tan H, Voskoboynik M, Suder A, Weickhardt AJ, et al. Sequential [ 177 Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study. Lancet Oncol. 2024;25(10):1267–76. Emmett L, Subramaniam S, Crumbaker M, Nguyen A, Joshua AM, Weickhardt A, et al. [ 177 Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2024;25(5):563–71. Strosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, et al. 177 Lu-Dotatate plus long-acting octreotide versus high–dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752–63. Kostos L, Buteau JP, Yeung T, Iulio JD, Xie J, Cardin A, et al. AlphaBet: Combination of Radium-223 and [ 177 Lu]Lu-PSMA-I&T in men with metastatic castration-resistant prostate cancer (clinical trial protocol). Front Med (Lausanne). 2022;9:1059122. Kostos L, Buteau JP, Kong G, Tran B, Haskali MB, Fahey M et al. Clinical Trial Protocol for LuCAB: A Phase I-II Trial Evaluating Cabazitaxel in Combination with [ 177 Lu]Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer. J Nucl Med. 2025. Abdel-Wahab M, Giammarile F, Carrara M, Paez D, Hricak H, Ayati N, et al. Radiotherapy and theranostics: a Lancet Oncology Commission. Lancet Oncol. 2024;25(11):e545–80. Poschenrieder A, Taleska J, Schaetz L. 177 Lu-PSMA (R)Evolution in Cancer Care: Is It Really Happening? J Nucl Med. 2024;65(9):1340–2. Lee ST, Emmett LM, Pattison DA, Hofman MS, Bailey DL, Latter MJ, et al. The Importance of Training, Accreditation, and Guidelines for the Practice of Theranostics: The Australian Perspective. J Nucl Med. 2022;63(6):819–22. Aslani A, Snowdon GM, Bailey DL, Schembri GP, Bailey EA, Pavlakis N, et al. Lutetium-177 DOTATATE Production with an Automated Radiopharmaceutical Synthesis System. Asia Ocean J Nucl Med Biol. 2015;3(2):107–15. Di Iorio V, Boschi S, Cuni C, Monti M, Severi S, Paganelli G, et al. Production and Quality Control of [ 177 Lu]Lu-PSMA-I&T: Development of an Investigational Medicinal Product Dossier for Clinical Trials. Molecules. 2022;27(13):4143. Kraihammer M, Garnuszek P, Bauman A, Maurin M, Alejandre Lafont M, Haubner R, et al. Improved quality control of [ 177 Lu]Lu-PSMA I&T. EJNMMI Radiopharmacy Chem. 2023;8(1):7. Hooijman EL, Ntihabose CM, Reuvers TGA, Nonnekens J, Aalbersberg EA, van de Merbel JRJP, et al. Radiolabeling and quality control of therapeutic radiopharmaceuticals: optimization, clinical implementation and comparison of radio-TLC/HPLC analysis, demonstrated by [ 177 Lu]Lu-PSMA. EJNMMI Radiopharmacy Chem. 2022;7(1):29. Mukherjee A, Lohar S, Dash A, Sarma HD, Samuel G, Korde A. Single vial kit formulation of DOTATATE for preparation of 177 Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy. J Label Compd Radiopharm. 2015;58(4):166–72. Boasa CV, Diasa L, Matsudaa M, Araújoa E. Stability in the production and transport of 177 Lu labelled PSMA. Brazilian J Radiation Sci. 2021;9(1). Guleria M, Amirdhanayagam J, Sarma HD, Rallapeta RP, Krishnamohan VS, Nimmagadda A, et al. Preparation of 177 Lu-PSMA-617 in Hospital Radiopharmacy: Convenient Formulation of a Clinical Dose Using a Single-Vial Freeze-Dried PSMA-617 Kit Developed In-House. Biomed Res Int. 2021;2021(1):1555712. Martin S, Tönnesmann R, Hierlmeier I, Maus S, Rosar F, Ruf J, et al. Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [ 177 Lu]Lu-PSMA-617. J Med Chem. 2021;64(8):4960–71. Weineisen M, Schottelius M, Simecek J, Baum RP, Yildiz A, Beykan S, et al. 68 Ga- and 177 Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. J Nucl Med. 2015;56(8):1169–76. Sørensen MA, Andersen VL, Hendel HW, Vriamont C, Warnier C, Masset J, et al. Automated synthesis of 68 Ga/ 177 Lu-PSMA on the Trasis miniAllinOne. J Label Compd Radiopharm. 2020;63(8):393–403. Schmitl S, Raitanen J, Witoszynskyj S, Patronas E-M, Nics L, Ozenil M, et al. Quality Assurance Investigations and Impurity Characterization during Upscaling of [ 177 Lu]Lu-PSMAI&T. Molecules. 2023;28(23):7696. Hunt W, Long M, Kamil U, Kellapatha S, Noonan W, Roselt PD et al. A Scalable Protocol for the radiosynthesis of Clinical Grade Lutetium-177 labelled theranostic agents. Nat Protoc. 2025. Supplementary Files SuppLu177paper.docx Cite Share Download PDF Status: Published Journal Publication published 22 Jul, 2025 Read the published version in EJNMMI Radiopharmacy and Chemistry → Version 1 posted Editorial decision: Major revision 26 Jun, 2025 Reviewers agreed at journal 19 Jun, 2025 Reviewers invited by journal 29 May, 2025 Editor assigned by journal 29 May, 2025 First submitted to journal 28 May, 2025 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. 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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-6763766","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":463463600,"identity":"7ef81f35-bb20-4928-8699-ebcdcdbf603b","order_by":0,"name":"William Hunt","email":"","orcid":"","institution":"Peter Mac: Peter MacCallum Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Hunt","suffix":""},{"id":463463601,"identity":"462ee080-c352-4e01-9027-ff6160cd38c6","order_by":1,"name":"Mathew Long","email":"","orcid":"","institution":"Peter Mac: Peter MacCallum Cancer 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Centre","correspondingAuthor":false,"prefix":"","firstName":"Brittany","middleName":"","lastName":"Emmerson","suffix":""},{"id":463463608,"identity":"2dc8154f-46bb-4d0e-bfc2-abc5909824b3","order_by":8,"name":"Michael S Hofman","email":"","orcid":"","institution":"Peter Mac: Peter MacCallum Cancer Centre","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"S","lastName":"Hofman","suffix":""},{"id":463463609,"identity":"25278187-e69a-4082-a3ab-c123bbc11fc8","order_by":9,"name":"Mohammad B Haskali","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYHACNiBOYOBjZj5AohY2ZrYEEE2KFgYeA+K06LY3sD348SdNno2d59uDjz9s8nXbDz9g+LinFqcWszMH2A1723IM25h5txvOSEiz3HYmzYBxxrPjuLXcSGCT4G2oYARq2SbNk3DYwOxADgMzz4FjeLVI/vlTYd/GzPNM+k/CfwOz828Ia5HmYctJBGphk2ZIOGBgdgNsSw0evxxsk5ZtS0tuY2YzN+xJSwZqeWZwcMaBA7i1HG8+JvnmT7JtP//hZw9+2NgBHZb88MGHA3U4tTAwMDbAWGxwMaAVh/FoQQA2ZA4+W0bBKBgFo2CEAQBOF1R1TsxjEQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-3084-2084","institution":"Peter Mac: Peter MacCallum Cancer Centre","correspondingAuthor":true,"prefix":"","firstName":"Mohammad","middleName":"B","lastName":"Haskali","suffix":""}],"badges":[],"createdAt":"2025-05-28 03:36:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6763766/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6763766/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41181-025-00372-5","type":"published","date":"2025-07-22T15:57:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83812999,"identity":"20a37653-60cd-4cd1-a8d3-1907a2bfd960","added_by":"auto","created_at":"2025-06-03 07:16:43","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":68526,"visible":true,"origin":"","legend":"\u003cp\u003eGeneralized reaction scheme for the chelation of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTA-TATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6763766/v1/ab32f8ddab3be39bdbbbe24e.jpg"},{"id":83813003,"identity":"15108bd5-4ff9-4ccb-bdd5-4aa418cd28f8","added_by":"auto","created_at":"2025-06-03 07:16:43","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":148324,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of bulk activity (GBq) and radiochemical concentration (GBq/ml) versus radiochemical purity (%) in [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6763766/v1/c5a405caf836e8b8a24fabf2.jpg"},{"id":83813006,"identity":"f5395558-b382-4eb0-8e35-c5e4c946008f","added_by":"auto","created_at":"2025-06-03 07:16:43","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":148408,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of bulk activity (GBq) and radiochemical concentration (GBq/ml) versus radiochemical purity (%) in [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6763766/v1/2119d0c95870faa2d93e4731.jpg"},{"id":83814183,"identity":"f9d00b21-0fe5-4c46-8c46-55cbc3e7d769","added_by":"auto","created_at":"2025-06-03 07:24:43","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":140594,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of bulk activity (GBq) and radiochemical concentration (GBq/ml) versus radiochemical purity (%) in [\u003csup\u003e177\u003c/sup\u003eLu]Lu- DOTATATE.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6763766/v1/7efa563d413502e1c3e2cabb.jpg"},{"id":87756862,"identity":"eb4d6479-6ac9-47f3-9220-e0069b14a11c","added_by":"auto","created_at":"2025-07-28 16:09:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1300974,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6763766/v1/5f64b9df-5a3d-4bb9-ba5d-7f6b178e4276.pdf"},{"id":83812997,"identity":"364d2c1d-4bda-415d-b0e3-9bdc465af963","added_by":"auto","created_at":"2025-06-03 07:16:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":39585,"visible":true,"origin":"","legend":"","description":"","filename":"SuppLu177paper.docx","url":"https://assets-eu.researchsquare.com/files/rs-6763766/v1/574f9b43fdc6ff6c4dbd028b.docx"}],"financialInterests":"","formattedTitle":"Multifactorial Analysis of Radiochemical Purity in High-Activity 177Lu-Labeled Theranostics: Impact of Precursor Source, 177Lu Form, and Production Parameters","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eTheranostics is a combined approach that integrates targeted therapies with diagnostic agents to optimize patient treatment in personalized medicine. This rapidly evolving strategy has demonstrated remarkable effectiveness in treating metastatic cancer, achieving significant clinical results with relatively low toxicity (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). A key component of theranostics is the use of targeted ligands, often short peptides, which serve as vehicles for delivering radioactive payloads directly to cancer cells (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). These ligands can function as either diagnostic or therapeutic agents, depending on the specific radionuclide attached to them. Common diagnostic radionuclides include the positron emitters Gallium-68 (\u003csup\u003e68\u003c/sup\u003eGa) and Fluorine-18 (\u003csup\u003e18\u003c/sup\u003eF), which are crucial for imaging and locating tumors. In contrast, the primary therapeutic radionuclide used is Lutetium-177 (\u003csup\u003e177\u003c/sup\u003eLu), a cytotoxic beta-emitting isotope that when incorporated into a targeted ligand destroys malignant cells. The precision with which targeted ligands deliver radioactive payloads is essential for enhancing treatment efficacy and improving patient outcomes in cancer therapy.\u003c/p\u003e \u003cp\u003eThe use of \u003csup\u003e177\u003c/sup\u003eLu-labeled theranostics has surged over the past two decades, particularly with [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE for neuroendocrine tumors and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T for prostate cancer (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). These therapies are increasingly being assessed for earlier lines of use, expanding their applicability beyond late-stage diseases (\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), and in various combinations (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). In response to the growing global demand for \u003csup\u003e177\u003c/sup\u003eLu-theranostics (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), FDA approval and commercialization of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 have enabled pharmaceutical companies to scale up manufacturing, allowing for the direct shipment of individual doses to hospitals for patient treatment in some parts of the world (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite this progress, hospital-based batch production of \u003csup\u003e177\u003c/sup\u003eLu-theranostics remains an option, particularly in regions where commercial supplies are unavailable or their supply is cost-prohibitive. Australia is one such region where hospital-based production has enabled implementation of theranostics including development of guidelines to support safe use (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). As demand for these therapies increases, hospitals often need to produce large multi-dose batches starting with high \u003csup\u003e177\u003c/sup\u003eLu activities. However, there is a significant gap in our understanding of how these larger-scale preparations respond to radiolysis\u0026mdash;the chemical decomposition caused by ionizing radiation. Literature on the production and stability of \u003csup\u003e177\u003c/sup\u003eLu-theranostics at activities exceeding 40 GBq is scarce, if available at all (\u003cspan additionalcitationids=\"CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis knowledge gap is further exacerbated by variations in starting materials, such as carrier-added (CA) and non-carrier-added (NCA) \u003csup\u003e177\u003c/sup\u003eLu, which are offered in different volumes (0.2 ml \u0026ndash; 7 ml), radioactivity concentrations and formulations (0.04 M and 0.05 M HCl) from various suppliers (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e summarizes the specifications of \u003csup\u003e177\u003c/sup\u003eLu obtained from different sources). Literature reports often present these diverse sources of lutetium and their different forms as equivalent, overlooking their potential impact on the quality of the final product. Additionally, sourcing essential production consumables, including precursors, from multiple global suppliers further complicates the assessment of how these variables influence product quality.\u003c/p\u003e \u003cp\u003eThe literature on the production and quality control of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTA-TATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T cannot be meaningfully compared, even for the same agent, due to significant discrepancies in the source of starting materials, as well as in their production and quality control protocols. Table S2 provides a comprehensive, though not exhaustive, summary of key findings from various published reports, highlighting critical points of difference among them. Additionally, some of the reported production studies do not use well-established and comprehensively validated quality control methods, which calls into question the validity of their findings. For instance, S. Schmitl et al. reported an in-depth quality assurance investigation on [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T, revealing a likely overestimation of the radiochemical purity of this product, further complicating our ability to rely on published reports for accurate comparisons (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The inherent differences in radioactive detector systems used across various laboratories also limit any direct comparison of results, making it extremely challenging to draw meaningful conclusions.\u003c/p\u003e \u003cp\u003eThe high cost of \u003csup\u003e177\u003c/sup\u003eLu limits the ability to conduct large-scale, systematic comparative studies to evaluate the effects of various sources and forms of \u003csup\u003e177\u003c/sup\u003eLu, as well as other reagents and precursors, on the quality of the final product. This is especially important when utilizing high starting activities of \u003csup\u003e177\u003c/sup\u003eLu. Our center operates one of the largest hospital-based theranostic production and treatment facilities globally, which allows us to retrospectively collect significant data (n\u0026thinsp;\u0026ge;\u0026thinsp;350) on high-activity radiolabeling of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTA-TATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T, with starting activities reaching up to 90 GBq. By employing consistent production and quality control protocols, this data provides valuable and directly comparable insights into the effects of different sources and forms of \u003csup\u003e177\u003c/sup\u003eLu, the impact of various precursor sources, and the significance of high-activity radiolabeling on the purity of the final product. This knowledge enhances our understanding of production processes and their implications for product quality, enabling us to better meet the needs of patients requiring these essential therapies.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThe production and quality control of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTA-TATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T were carried out using validated methods outlined in a detailed published protocol (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Briefly, 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) and 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA) conjugated to their corresponding radiopharmaceutical precursor molecules were labelled in sodium acetate buffer (0.4 M, pH 5.0) containing [\u003csup\u003e177\u003c/sup\u003eLu]LuCl₃, 2,5-dihydroxybenzoic acid (4 mg), sodium L-ascorbate (20 mg), and heated to 80\u0026deg;C for 30 minutes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The \u003csup\u003e177\u003c/sup\u003eLu-labeled mixture was then directly formulated with the addition of an aqueous solution of sodium L-ascorbate (480 mg), pentetic acid (DTPA; 1 mg), and water for injection (10 ml). This process was automated using an iPHASE MultiSyn radiochemistry module with sterile kits affording sterile and apyrogenic \u003csup\u003e177\u003c/sup\u003eLu-labeled radiopharmaceuticals in non-decay corrected yields\u0026thinsp;\u0026gt;\u0026thinsp;95%. When necessary, the final product was diluted with saline to obtain radiochemical concentrations below 3.5 GBq/ml. Before clinical use the prepared \u003csup\u003e177\u003c/sup\u003eLu-radiopharmaceutical underwent validated prerelease quality control tests including activity reconciliation, HPLC, TLC, and bubble point testing, meeting the release criteria outlined in Table S3. Results from all batches of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTA-TATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T in 2023 and 2024 were processed to obtain data used in the manuscript.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eShelf-life stability assessment\u003c/h2\u003e \u003cp\u003eThe remaining amounts of large batches (\u0026gt;\u0026thinsp;50 GBq) of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTA-TATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T, after patient doses were drawn, were resampled by extracting approximately 200 \u0026micro;L from the bulk dose vial, which was stored at room temperature. Resampling occurred at 4, 6, 8, and 24 hours after calibration. The material was then analyzed using the validated quality control methods detailed in our published protocol (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAnalysis was conducted on batches of radiopharmaceuticals, defined by precursor and supplier, to determine the correlations between bulk activity and concentration with radiochemical purity (Table S4). Pearson's correlation coefficient was calculated along with bootstrapped confidence intervals (1000 replications). Means and standard deviations described the distribution of activity and concentration. This analysis was limited to products that comprised at least 10 batches with the same combination of precursor supplier, \u003csup\u003e177\u003c/sup\u003eLu supplier, and \u003csup\u003e177\u003c/sup\u003eLu form.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eProduction Yields and Activity Ranges of Clinical [\u003csup\u003e177\u003c/sup\u003eLu]Lu-Labeled Radiopharmaceuticals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 101 batches of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE were produced, with formulated activities ranging from 8.3 to 65.3 GBq, among these, 14 (14%) batches exceeded 50 GBq. Radiochemical concentrations ranged from 0.74 to 3.02 GBq/ml. The yield for this radiopharmaceutical was 98% \u0026plusmn; 3%.\u003c/p\u003e\n\u003cp\u003eFor [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, 169 batches were produced, with formulated activities ranging from 5.2 to 88.9 GBq. Notably, 56 (33%) batches surpassed 50 GBq, while the radiochemical concentrations ranged from 0.43 to 2.96 GBq/ml, yielding 99% \u0026plusmn; 5%.\u003c/p\u003e\n\u003cp\u003eIn the case of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T, 85 batches were prepared, with activity levels ranging from 8.1 to 77.0 GBq. Seven (8.2%) batches exceeded 50 GBq and 28 (33%) batches fell between 30 and 50 GBq, with concentrations from 0.67 to 2.91 GBq/ml and a yield of 99% \u0026plusmn; 3%. Some yields were reported to exceed 100% due to calibration discrepancies caused by varying wall thicknesses of vials supplied by different manufacturers compared to those used during the final formulation process. Importantly, all production batches passed the pre-release criteria outlined in Table S3 at the end of synthesis (EOS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e24-Hour Stability Profile of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe stability of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE (n=3; activity range: 34-65.3 GBq; concentration: 2.9-3.5 GBq/ml), [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 (n=6; activity range: 17-88.9 GBq; concentration: 1.5-3.3 GBq/ml), and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T (n=3; activity range: 34-77 GBq; concentration: 2.3-2.7 GBq/ml) were evaluated over a 24-hour period (Table 1). Due to the demands of clinical workflows and patient administration schedules, the mid-point sampling window was adjusted to accommodate a 6-8 hour timeframe rather than a fixed 8-hour timepoint. While additional stability data exists for other production batches at various individual timepoints, the results presented here represent only those batches where complete sampling profiles were achieved across all specified timepoints.\u003c/p\u003e\n\u003cp\u003eAll preparations maintained their physical appearance as clear and colorless solutions throughout the study period, with a stable pH of 6, well within the specified range of 4-8. Radiochemical identity was confirmed via HPLC at all time points. Radiochemical purity was evaluated using two complementary methods: HPLC and TLC. TLC analysis demonstrated consistent 100% purity across all compounds and time points. HPLC analysis revealed high radiochemical purity for [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE (93.7\u0026ndash;95.5%) and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 (91.8\u0026ndash;95.8%) throughout the 24-hour period. While [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T demonstrated acceptable radiochemical purity through the clinically relevant 0-8 hour window (91.0\u0026ndash;94.3%), a decline to 85.5 \u0026plusmn; 3.5% was observed at 24 hours, falling below the release specification of \u0026ge;90%. In our practice, this was not clinically relevant as radiopharmaceutical administration is given on the same as production.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1: \u003c/strong\u003e24-Hour Stability Profile and Quality Control Analysis of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T.\u0026nbsp;\u003c/p\u003e\n\u003ctable width=\"916\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" width=\"267\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"4\" width=\"209\"\u003e\n\u003cp\u003e\u003cstrong\u003e[\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eActivity range: 34\u0026ndash;65.3 GBq, Concentration range: 2.9 \u0026ndash; 3.5 GBq/ml; n=3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" width=\"223\"\u003e\n\u003cp\u003e\u003cstrong\u003e[\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eActivity range: 17\u0026ndash;88.9 GBq, Concentration range: 1.5 \u0026ndash; 3.3 GBq/ml; n=6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"5\" width=\"216\"\u003e\n\u003cp\u003e\u003cstrong\u003e[\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eActivity range: 34\u0026ndash;77 GBq, Concentration range: 2.3 \u0026ndash; 2.7 GBq/ml; n=3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u003cstrong\u003eSpecification\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"46\"\u003e\n\u003cp\u003e\u003cstrong\u003e0 hr\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e\u003cstrong\u003e4 hr\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003cstrong\u003e\u0026ndash;\u003c/strong\u003e\u003cstrong\u003e8 hr\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"51\"\u003e\n\u003cp\u003e\u003cstrong\u003e24 hr\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"4\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e\u003cstrong\u003e0 hr\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e\u003cstrong\u003e4 hr\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003cstrong\u003e\u0026ndash;\u003c/strong\u003e\u003cstrong\u003e8 hr\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e24 hr\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e0 hr\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e4 hr\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003cstrong\u003e\u0026ndash;\u003c/strong\u003e\u003cstrong\u003e8 hr\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e\u003cstrong\u003e24 hr\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003eAppearance\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003eClear and colourless\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"46\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"55\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003epH\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e4 - 8\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"46\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"55\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"54\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e6\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003eRadiochemical Identity (HPLC)\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003eReference Std \u0026plusmn;1 min\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"46\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"55\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003ePass\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003eRadiochemical Purity (HPLC)\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u0026ge;90\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"46\"\u003e\n\u003cp\u003e95.2 \u0026plusmn; 1.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e95.5 \u0026plusmn; 0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e94.7 \u0026plusmn; 0.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"55\"\u003e\n\u003cp\u003e93.7 \u0026plusmn; 0.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e95.8 \u0026plusmn; 1.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e95.7 \u0026plusmn; 2.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e95.0 \u0026plusmn; 1.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"54\"\u003e\n\u003cp\u003e91.8 \u0026plusmn; 1.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e94.3 \u0026plusmn; 0.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e92.3 \u0026plusmn; 0.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e91.0 \u0026plusmn; 1.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e85.5 \u0026plusmn; 3.5\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"123\"\u003e\n\u003cp\u003eRadiochemical Purity (TLC)\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"144\"\u003e\n\u003cp\u003e\u0026ge;98\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"46\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"55\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"55\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"58\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"54\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e100\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"54\"\u003e\n\u003cp\u003e100\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u003c/strong\u003e Mean (SD) and Pearson Correlation Coefficient of bulk activity, radiochemical concentration with HPLC-derived radiochemical purity (%) in various radiopharmaceuticals.\u003c/p\u003e\n\u003ctable width=\"935\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"312\"\u003e\n\u003cp\u003e\u003cstrong\u003eBulk Activity (GBq)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"283\"\u003e\n\u003cp\u003e\u003cstrong\u003eConcentration (GBq/ml)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u003cstrong\u003ePurity (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003eMean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003eCorrelation to HPLC RP %\u003c/p\u003e\n\u003cp\u003e(95% CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003eMean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003eCorrelation to HPLC RP %\u003c/p\u003e\n\u003cp\u003e(95% CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003eMean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e[\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eABX \u0026ndash; ANSTO N.C.A.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e31.7 (18.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.46 (-0.69 to -0.22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.99 (0.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.20 (-0.45 to +0.04)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e95.2 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eABX \u0026ndash; Isotopia N.C.A.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e47.8 (17.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.63 (-0.97 to -0.28)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e2.29 (0.27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.67 (-0.86 to -0.49)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e95.7 (0.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eABX \u0026ndash; Isotopia C.A.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e46.8 (21.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.43 (-0.64 to -0.23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e2.23 (0.54)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.44 (-0.64 to -0.24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e95.6 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eABX \u0026ndash; ITM N.C.A.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e19\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e30.9 (18.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.42 (-0.76 to -0.07)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.84 (0.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.59 (-0.79 to -0.39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e96.1 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e[\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA I\u0026amp;T\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHuayi \u0026ndash; ANSTO N.C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e30.6 (17.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.68 (-0.89 to -0.48)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.78 (0.56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.60 (-0.77 to -0.42)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e95.5 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHuayi \u0026ndash; Isotopia N.C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e29.7 (17.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.70 (-0.99 to -0.41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.79 (0.55)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.56 (-0.88 to -0.24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e96.3 (1.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003ePi Chem \u0026ndash; ANSTO N.C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e18.6 (7.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.19 (-0.89 to +0.51)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.53 (0.66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.17 (-0.87 to +0.54)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e97.0 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHuayi \u0026ndash; Isotopia C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e24.6 (11.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.63 (-0.90 to -0.36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.76 (0.72)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.44 (-0.80 to -0.07)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e96.4 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHuayi \u0026ndash; ITM N.C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e15\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e28.5 (12.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.74 (-1.00 to -0.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.92 (0.60)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.80 (-1.00 to -0.59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e96.6 (0.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003e\u003cstrong\u003e[\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHuayi \u0026ndash; ANSTO N.C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e27.9 (18.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.63 (-0.87 to -0.39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.71 (0.74)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.61 (-0.87 to -0.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e93.5 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHuayi \u0026ndash; Isotopia N.C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e14\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e31.0 (11.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.27 (-0.92 to +0.37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e2.03 (0.43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.85 (-1.00 to -0.61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e95.6 (1.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHuayi \u0026ndash; Isotopia C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e35.8 (14.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.48 (-0.66 to -0.30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e2.12 (0.54)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.40 (-0.59 to -0.22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e95.4 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"170\"\u003e\n\u003cp\u003eHuayi \u0026ndash; ITM N.C.A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"38\"\u003e\n\u003cp\u003e11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"113\"\u003e\n\u003cp\u003e24.2 (14.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"198\"\u003e\n\u003cp\u003e-0.63 (-1.00 to -0.06)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"104\"\u003e\n\u003cp\u003e1.64 (0.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"180\"\u003e\n\u003cp\u003e-0.46 (-1.00 to +0.09)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"132\"\u003e\n\u003cp\u003e95.3 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eWe examined the bulk activity and radiochemical concentration of the various [\u003csup\u003e177\u003c/sup\u003eLu]Lu-labeled theranostics, and their correlation to the radiochemical purity at the end of synthesis (EOS) (Table 2). This analysis highlights the impact of different precursor sources\u0026mdash;such as ABX and Huayi \u0026mdash;paired with various \u003csup\u003e177\u003c/sup\u003eLu sources and forms including ANSTO N.C.A, ITM N.C.A, Isotopia C.A, and Isotopia N.C.A (Fig. 1\u0026ndash;3).\u003c/p\u003e\n\u003cp\u003eFor [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, the precursor was sourced entirely from ABX. By combining the ABX-sourced precursor with four different forms and sources of \u003csup\u003e177\u003c/sup\u003eLu, moderate correlations were generally observed between bulk activity or concentration and radiochemical purity, with Pearson's correlation coefficients (\u0026rho;) ranging from -0.67 to -0.20 (Fig. 1). These were especially noted for the Isotopia supplied N.C.A product, (activity) r = -0.63 (95%CI: -0.97 to -0.28), (concentration) r = -0.67 (95%CI: -0.86 to -0.49) though the number of batches analysed was relatively few (n=18). Mean bulk activity was appreciably higher for the Isotopia products than the ANSTO or ITM N.C.A. products (mean difference: 15.5, 95%CI: 9.5 to 21.5).\u003c/p\u003e\n\u003cp\u003eFive [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T variations were analyzed: four combining Huayi precursor with different forms of \u003csup\u003e177\u003c/sup\u003eLu, and one using piChem precursor with ANSTO N.C.A \u003csup\u003e177\u003c/sup\u003eLu. Generally more pronounced negative correlations with purity were observed between both bulk activity and concentration compared to [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, with no bootstrapped confidence intervals crossing zero. In contrast, the product with a piChem precursor exhibited relatively weak correlation coefficients (r = -0.17, -0.19) with a considerably lower mean bulk activity (Fig. 2). There was numerically greater variation observed in measured purity with the ANSTO N.C.A. product (SD = 1.8) versus all others (SD: 0.9 to 1.3).\u003c/p\u003e\n\u003cp\u003eFor [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE, four variations were analyzed including precursor obtained from Huayi precursor in combination with different sources and forms of \u003csup\u003e177\u003c/sup\u003eLu. In this instance, correlations generally ranged from moderate to strongly negative. Of note, the mean bulk activity and concentration was notably higher for the Isotopia \u003csup\u003e177\u003c/sup\u003eLu (N.C.A) and (C.A.) batches (Fig. 3). Similar to [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA I\u0026amp;T, higher variation in purity was observed with the ANSTO N.C.A. \u003csup\u003e177\u003c/sup\u003eLu and additionally for the [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE batches, the mean purity percentage for ANSTO N.C.A. was lower than the other three products, mean: 93.5% vs 95.4% (mean difference -1.9%; 95%CI: -2.6% to -1.2%).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eOur standardized production protocol demonstrated significant versatility in the preparation of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTA-TATE, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T. This protocol successfully accommodated varying volumes (0.5\u0026ndash;4.5 mL) of both carrier-added (CA) and non-carrier-added (NCA) [\u003csup\u003e177\u003c/sup\u003eLu] from multiple suppliers (ANSTO, Isotopia, and ITM) using a single cassette-based platform. The protocol's robustness is evidenced by consistently high radiochemical yields of \u0026ge;\u0026thinsp;98% across all three radiopharmaceuticals and the successful preparation of over 300 high-activity batches for more than 2000 cycles of therapy.\u003c/p\u003e \u003cp\u003eThe 24-hour stability assessment revealed that both [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 maintained high radiochemical purity (\u0026gt;\u0026thinsp;90%) throughout the study period, while [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T showed acceptable purity within the clinically relevant 0\u0026ndash;8 hour window but declined below specification at 24 hours. This finding aligns with Schmitl et al.'s work, which employed a risk-based approach to establish 90% radiochemical purity thresholds, noting that heat-induced cyclization by-products known to occur in PSMA ligands (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) represented only a small fraction (2.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85%) of total radioactivity, while the main radiolysis products were activity concentration-dependent and comprised approximately 2.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1% of the samples (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). This confirms the suitability of our formulations for clinical use within standard administration timeframes, though with limitations for extended storage of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T.\u003c/p\u003e \u003cp\u003eOur analysis uncovers important insights into the relationship between bulk activity, radiochemical concentration, and radiochemical purity in various [\u003csup\u003e177\u003c/sup\u003eLu]Lu-labeled theranostics produced from different precursors and \u003csup\u003e177\u003c/sup\u003eLu sources. A negative correlation between bulk activity/concentration and radiochemical purity was noted across the three radiopharmaceuticals ([\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617, [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T, and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE), which aligns with the expected increase in radiolytic breakdown of products at higher activities. However, the magnitude of this correlation varied considerably. The variability in precursor and \u003csup\u003e177\u003c/sup\u003eLu sources produced nuanced results for each radiopharmaceutical, highlighting the complex interplay of factors that can affect the final product quality.\u003c/p\u003e \u003cp\u003eA consistent pattern emerged across all three radiopharmaceuticals regarding the influence of \u003csup\u003e177\u003c/sup\u003eLu source on product quality. When using identical precursor sources, ITM N.C.A. \u003csup\u003e177\u003c/sup\u003eLu consistently delivered higher radiochemical purities compared to ANSTO's N.C.A. \u003csup\u003e177\u003c/sup\u003eLu. Moreover, both C.A. and N.C.A. \u003csup\u003e177\u003c/sup\u003eLu from Isotopia provided consistent purities across all formulations, closely matching the high-quality results achieved with ITM's N.C.A. \u003csup\u003e177\u003c/sup\u003eLu. This consistent pattern points to inherent qualities in these \u003csup\u003e177\u003c/sup\u003eLu sources that influence radiochemical stability regardless of which specific precursor is being labeled. Nevertheless, all sources and forms of \u003csup\u003e177\u003c/sup\u003eLu led to products that passed acceptance testing and are therefore suitable for clinical use..\u003c/p\u003e \u003cp\u003eFor [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T specifically, although a lower mean bulk activity was used with the PiChem precursor, it achieved slightly higher radiochemical purities and enhanced stability at elevated concentrations compared to the Huayi precursor. This may suggest critical differences in precursor quality/composition that impact radiostability.\u003c/p\u003e \u003cp\u003eA particularly interesting finding emerged when comparing C.A. versus N.C.A. \u003csup\u003e177\u003c/sup\u003eLu from Isotopia across different formulations. When using Isotopia's N.C.A. \u003csup\u003e177\u003c/sup\u003eLu for both [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE, we observed steeper radiochemical degradation with increasing concentrations compared to formulations using C.A .\u003csup\u003e177\u003c/sup\u003eLu. This suggests either that the higher amount of precursor typically used with C.A. \u003csup\u003e177\u003c/sup\u003eLu or some intrinsic property of C.A. \u003csup\u003e177\u003c/sup\u003eLu itself confers a protective effect against radiolytic degradation.\u003c/p\u003e \u003cp\u003eThis detailed analysis provides a unique evidence base that can inform \u003csup\u003e177\u003c/sup\u003eLu suppliers, radiopharmaceutical manufacturers, and regulatory bodies investigating the precise composition and characteristics of their products to maintain or further improve the quality of their material for clinical applications. As global demand for radioligand therapy continues to rise, especially in regions with limited access to commercial supplies, the variability observed in our study offers vital evidence-based data for practitioners and regulatory authorities. This information supports the development of corresponding monographs that favor radiochemical purities of 90% or greater as the cut-off when utilizing high-activity, multi-dose productions involving the full range of precursor and \u003csup\u003e177\u003c/sup\u003eLu sources and forms needed to meet the growing demand for radioligand therapy. While all products in our study maintained clinically acceptable quality, the subtle yet consistent variations based on supplier and formulation highlight the need for a nuanced approach to establishing regulatory standards that balances theoretical ideals with practical clinical realities. These insights are particularly valuable as international initiatives work to expand global access to radiopharmaceutical therapies, allowing for the development of realistic quality parameters that can support equitable access to these life-extending therapies while maintaining appropriate safety and efficacy standards across diverse healthcare settings (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHospital radiopharmaceutical production environments are often staffed by professionals with specialized academic and clinical expertise who are well positioned to investigate and interpret such subtle differences in radiopharmaceutical performance. The dismissive characterization of hospital-based radiopharmaceutical preparation as \"home brew\" or \"ad hoc hospital-based compounding\" is unfounded and disregards the foundational contributions these hospital-based departments have made to the field of nuclear medicine. While we recognize that certain practices in hospital-based theranostic production environments operate within evolving regulatory frameworks, we believe it\u0026rsquo;s essential to appreciate the significant, nuanced, and specialized contributions that these environments have made and continue to make to the advancement of the entire discipline. The most effective approach is for industry, academia, and clinical environments to collaborate and learn from each other, integrating pharmaceutical industry capabilities with hospital-based expertise to ensure equitable patient access and effectively address the complex logistical and technical challenges inherent in theranostic production.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur comprehensive analysis of over 350 high-activity batches of \u003csup\u003e177\u003c/sup\u003eLu-labeled theranostics reveals complex relationships between precursor sources, \u003csup\u003e177\u003c/sup\u003eLu sources, and radiochemical purity. While precursor sources and \u003csup\u003e177\u003c/sup\u003eLu sources influence measured radiochemical purity values, all preparations maintained quality standards sufficient for clinical release. However, the observed variations in radiochemical purity associated with different precursor-\u003csup\u003e177\u003c/sup\u003eLu combinations highlight the importance of optimizing production parameters beyond simply considering radiolytic effects. The pronounced differences in stability profiles between C.A. and N.C.A. \u003csup\u003e177\u003c/sup\u003eLu, along with precursor-specific effects on radiostability, emphasize that radiopharmaceutical quality depends on a complex interplay of factors not fully recognized previously in the literature. These findings warrant further mechanistic investigations to elucidate the chemical and physical characteristics of different \u003csup\u003e177\u003c/sup\u003eLu sources, precursor molecules, and stabilizing agents, which could lead to enhanced production protocols that maximize both activity yields and radiochemical purity for optimal patient care.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eC.A. - Carrier-added; N.C.A \u0026ndash; Non Carrier-added; DOTA - 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid; DOTAGA - 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid; DTPA - Pentetic acid; EOS - End of synthesis; FDA - Food and Drug Administration; GBq \u0026ndash; Gigabecquerel; HPLC - High-performance liquid chromatography; ITM - ITM Medical Isotopes; PSMA - Prostate-specific membrane antigen; SD - Standard deviation; TLC - Thin-layer chromatography; \u003csup\u003e18\u003c/sup\u003eF - Fluorine-18; \u003csup\u003e68\u003c/sup\u003eGa - Gallium-68; \u003csup\u003e177\u003c/sup\u003eLu - Lutetium-177.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eProfessor Michael Hofman acknowledges philanthropic/government grant support from the Prostate Cancer Foundation (PCF), Peter MacCallum Foundation, and a NHMRC Investigator Grant. PSMA-617 supply was supported by Endocyte/Novartis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORS' CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMBH developed and implemented the production protocol and was the major contributor in writing the manuscript. MSH assisted with setting the clinical specifications for the products and helped contribute to the writing of the paper. NP performed the statistical analysis and helped write the corresponding statistical sections of the paper. WH, ML, UK, SK, WN, PDR, and BE helped in the implementation of the protocol, data collection, and contributed to the writing of the paper. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSolnes LB, Werner RA, Jones KM, Sadaghiani MS, Bailey CR, Lapa C, et al. Theranostics: Leveraging Molecular Imaging and Therapy to Impact Patient Management and Secure the Future of Nuclear Medicine. J Nucl Med. 2020;61(3):311\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHall AJ, Haskali MB. Radiolabelled Peptides: Optimal Candidates for Theranostic Application in Oncology. Aust J Chem. 2022;75(2):34\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [\u003csup\u003e177\u003c/sup\u003eLu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19(6):825\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, et al. [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797\u0026ndash;804.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHofman MS, Emmett L, Sandhu S, Iravani A, Buteau JP, Joshua AM, et al. Overall survival with [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 2024;25(1):99\u0026ndash;107.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEapen RS, Buteau JP, Jackson P, Mitchell C, Oon SF, Alghazo O, et al. Administering [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study. Eur Urol. 2024;85(3):217\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzad AA, Bressel M, Tan H, Voskoboynik M, Suder A, Weickhardt AJ, et al. Sequential [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study. Lancet Oncol. 2024;25(10):1267\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEmmett L, Subramaniam S, Crumbaker M, Nguyen A, Joshua AM, Weickhardt A, et al. [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2024;25(5):563\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrosberg JR, Caplin ME, Kunz PL, Ruszniewski PB, Bodei L, Hendifar A, et al. \u003csup\u003e177\u003c/sup\u003eLu-Dotatate plus long-acting octreotide versus high\u0026ndash;dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021;22(12):1752\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKostos L, Buteau JP, Yeung T, Iulio JD, Xie J, Cardin A, et al. AlphaBet: Combination of Radium-223 and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T in men with metastatic castration-resistant prostate cancer (clinical trial protocol). Front Med (Lausanne). 2022;9:1059122.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKostos L, Buteau JP, Kong G, Tran B, Haskali MB, Fahey M et al. Clinical Trial Protocol for LuCAB: A Phase I-II Trial Evaluating Cabazitaxel in Combination with [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer. J Nucl Med. 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbdel-Wahab M, Giammarile F, Carrara M, Paez D, Hricak H, Ayati N, et al. Radiotherapy and theranostics: a Lancet Oncology Commission. 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Nat Protoc. 2025.\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":"Lutetium-177 theranostics, Radiochemical purity, High-activity production, Carrier-added lutetium-177, Non-carrier-added lutetium-177, DOTATATE, PSMA-617, PSMA-I\u0026T, Radiolysis, Quality control","lastPublishedDoi":"10.21203/rs.3.rs-6763766/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6763766/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\u003eLutetium-177 (\u003csup\u003e177\u003c/sup\u003eLu) theranostics have revolutionized personalized cancer treatment, particularly with FDA-approved therapies like [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE for neuroendocrine tumors and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA for prostate cancer. Despite growing clinical adoption, there is limited understanding of how different production variables affect radiochemical purity, especially when scaling to high activities for multi-patient batches. This study evaluates the impact of precursor sources, \u003csup\u003e177\u003c/sup\u003eLu forms (carrier-added (C.A.) vs. non-carrier-added (N.C.A.)), and radiochemical concentration on product quality.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe analyzed 355 clinical batches of [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE (n\u0026thinsp;=\u0026thinsp;101), [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 (n\u0026thinsp;=\u0026thinsp;169), and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T (n\u0026thinsp;=\u0026thinsp;85) produced with standardized protocols using lutetium-177 from multiple suppliers in both carrier-added and non-carrier-added forms. All radiopharmaceuticals demonstrated consistently high yields (\u0026ge;\u0026thinsp;98%) and met release criteria regardless of starting materials. [\u003csup\u003e177\u003c/sup\u003eLu]Lu-DOTATATE and [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-617 maintained radiochemical purity above 90% throughout 24 hours, while [\u003csup\u003e177\u003c/sup\u003eLu]Lu-PSMA-I\u0026amp;T showed stability for 8 hours but fell below specifications at 24 hours. Negative correlations between bulk activity/concentration and radiochemical purity were observed across all preparations. The lutetium-177 products from various suppliers displayed notably distinct quality profiles. Some suppliers consistently provided higher radiochemical purities, irrespective of the carrier-added or non-carrier-added forms of lutetium-177. However, carrier-added formulations exhibited greater radiostability compared to non-carrier-added ones at elevated concentrations. Furthermore, differences in precursor quality among manufacturers were noted, with certain suppliers offering enhanced radiostability characteristics that may enhance product performance at high activity concentrations.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis comprehensive analysis reveals that hospital-based production can be automized resulting in high-quality and efficient multi-dose production. Small differences in radiochemical purity of \u003csup\u003e177\u003c/sup\u003eLu -labeled theranostics depends on complex interactions between precursor source, \u003csup\u003e177\u003c/sup\u003eLu supplier, and \u003csup\u003e177\u003c/sup\u003eLu form, beyond simple activity-dependent radiolysis. These findings underscore the importance of optimizing production parameters for high-activity preparations and highlight the need to explore the various multifactorial variables that impact the quality of \u003csup\u003e177\u003c/sup\u003eLu-theranostics.\u003c/p\u003e","manuscriptTitle":"Multifactorial Analysis of Radiochemical Purity in High-Activity 177Lu-Labeled Theranostics: Impact of Precursor Source, 177Lu Form, and Production Parameters","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-03 07:16:38","doi":"10.21203/rs.3.rs-6763766/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-06-26T10:11:52+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-19T09:08:32+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-29T07:20:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-29T05:12:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Radiopharmacy and Chemistry","date":"2025-05-28T18:10:40+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":"e22eb50d-0461-4ed4-9fd6-f6f7ddeee0af","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T16:05:45+00:00","versionOfRecord":{"articleIdentity":"rs-6763766","link":"https://doi.org/10.1186/s41181-025-00372-5","journal":{"identity":"ejnmmi-radiopharmacy-and-chemistry","isVorOnly":false,"title":"EJNMMI Radiopharmacy and Chemistry"},"publishedOn":"2025-07-22 15:57:38","publishedOnDateReadable":"July 22nd, 2025"},"versionCreatedAt":"2025-06-03 07:16:38","video":"","vorDoi":"10.1186/s41181-025-00372-5","vorDoiUrl":"https://doi.org/10.1186/s41181-025-00372-5","workflowStages":[]},"version":"v1","identity":"rs-6763766","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6763766","identity":"rs-6763766","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}