A Rapid and Specific HPLC Method to Determine Chemical and Radiochemical Purity of [68&gt;Ga]Ga-DOTA-Pentixafor (PET) Tracer: Development and Validation

Migliari, Silvia; Sammartano, Antonino; Scarlattei, Maura; Baldari, Giorgio; Ruffini, Livia

doi:10.2174/1874471013666200929125102

Cited by 7 publications

(6 citation statements)

References 26 publications

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“…We produce Ga-68 in the daily routine to prepare pharmaceutically acceptable radiopharmaceuticals for clinical and research purpose [27][28][29][30], with flexible response to patient needs and optimized planning of batch utilization.…”

Section: Discussionmentioning

confidence: 99%

Performance and long-term consistency of five Galliform 68Ge/68Ga generators used for clinical Ga-68 preparations over a 4 year period

Sammartano

Migliari

Scarlattei

et al. 2022

Nuclear Medicine Communications

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Background Gallium-68 is a positron emitter for PET applications that can be produced without cyclotron by a germanium (Ge-68) chloride/gallium (Ga-68) chloride generator. Short half-life (67.71 min) of Ga-68, matching pharmacokinetic properties of small biomolecules, facilitates isotope utilization in compounding radiopharmaceuticals for PET imaging. The increasing cost of good manufacturing practice-compliant generators has strengthened the need for radionuclide efficient use by planning specific radiopharmaceutical sessions during the week, careful maintenance of the generator and achievement of high labeling yield and radiochemical purity (RCP) of the radiolabeled molecules. Methods The aim of this study was to evaluate the annual performance of five consecutive 68Ge/68Ga generators used for small-scale preparations of 68Ga-radiopharmaceuticals. To assess the long-term efficiency of isotope production we measured the weekly elution yield. To assess process efficiency we measured elution yield, labeling yield and RCP of four radiopharmaceutical preparations (68Ga-DOTATOC, 68Ga-PSMA-HBED-CC, 68Ga-PENTIXAFOR and 68Ga-DOTATATE). Results The annual mean elution yield of the generators was 74.7%, higher than that indicated by the manufacturer, and it never went below 65%. The Ge-68 level in the final products was under the detection limits in all the produced batches (mean value 0.0000048%). The RCP of radiopharmaceuticals determined by high-performance liquid chromatography was 98 ± 0.22%. The mean yield of radiolabelling was 64.68, 68.71, 57 and 63.68% for 68Ga-DOTATOC, 68Ga-PSMA-HBED-CC, 68GaPENTIXAFOR and 68Ga-DOTATATE. Conclusion The ability to prepare in the hospital radiopharmacy high-purity and pharmaceutically acceptable 68Ga-radiolabeled probes on a routine basis facilitates patient access to precision imaging for clinical and research aims.

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Section: Discussionmentioning

confidence: 99%

Performance and long-term consistency of five Galliform 68Ge/68Ga generators used for clinical Ga-68 preparations over a 4 year period

Sammartano

Migliari

Scarlattei

et al. 2022

Nuclear Medicine Communications

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“…Many studies have already been published on the validation of analytical methods applied to radiopharmacy, in particular on the assessment of the radiochemical purity of specific radiopharmaceuticals. However, to date, none of these studies have combined an evaluation by HPLC and TLC [ 15 , 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of Analytical Methods for Radiochemical Purity of 177Lu-PSMA-1

et al. 2022

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Prostate Specific Membrane Antigen (PSMA) is a highly relevant target in nuclear medicine due to its overexpression in prostate cancer. The 68Ga/177Lu-PSMA-1 combination is a theranostic agent for the detection and treatment of tumors overexpressing the PSMA target. Specifically, 177Lu-PSMA-1 is used in the treatment of castration-resistant prostate cancer that is ineffective or intolerant to the latest generation of chemotherapy and/or hormone therapy. This radiopharmaceutical is manufactured in a radiopharmaceutical synthesizing unit and must pass a quality control where the radiochemical purity (RCP) is assessed prior to release of the batch. RCP evaluation is performed by high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). Since there is no monograph for 177Lu-PSMA-1 in the European Pharmacopoeia, we validate the analytical methods according to the EANM recommendations adapted from ICH Q2. Specificity, linearity, accuracy, precision, intermediate precision, limit of quantification (LOQ) and robustness were described for HPLC and TLC in this study. The results obtained demonstrated the robustness and reliability of the HPLC and TLC analytical methods for the evaluation of the RCP of 177Lu-PSMA-1.

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“…For the development of a feasible UV-HPLC method to detect HEPES, its chemical and physical properties need to be considered, such as a UV/vis absorption wavelength that is below 200 nm, or 220 nm for [ 68 Ga]Ga-radiopharmaceuticals [ 21 , 22 , 23 , 24 , 25 , 26 ]. We started from a ‘‘mother’’ solution with the highest concentration (250 μg/mL) of HEPES, obtained by dissolving the analyte in phosphate buffer solution (PBS) with 10% ethanol and serial dilutions (100, 80, 60, 40, 20, 10, 5, 3 μg/mL).…”

Section: Methodsmentioning

confidence: 99%

“…We have synthesized PET radiopharmaceuticals such as [ 68 Ga]Ga-DOTATOC, [ 68 Ga]Ga-HBEDD-CC-PSMA [ 21 ]; [ 68 Ga]Ga-DOTATATE [ 22 ]; [ 68 Ga]Ga-DOTA-Pentixafor [ 23 , 24 ]; and [ 68 Ga]Ga-NODAGA-Exendin-4 [ 25 , 26 ] using the automated synthesis module Scintomics GRP TM (Scintomics GmbH, Fürstenfeldbruck, Germany) and tested them to assess all release criteria with a validated QCs system.…”

Section: Introductionmentioning

confidence: 99%

A Specific HPLC Method to Determine Residual HEPES in [68Ga]Ga-Radiopharmaceuticals: Development and Validation

et al. 2022

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Background: Nowadays, in Nuclear Medicine, clinically applied radiopharmaceuticals must meet quality release criteria such as high radiochemical purity and radiochemical yield. Many radiopharmaceuticals do not have marketing authorization and have no dedicated monograph within European Pharmacopeia (Ph. Eur.); therefore, general monographs on quality controls (QCs) have to be applied for clinical application. These criteria require standardization and validation in labeling and preparation, including quality controls measurements, according to well defined standard operation procedures. However, QC measurements are often based on detection techniques that are specific to a certain chromatographic system. Several radiosyntheses of [68Ga]Ga-radiopharmaceuticals are more efficient and robust when they are performed with 2-[4-(2-hydroxyethyl)piperazin-1-yl] ethanesulfonic acid (HEPES) buffer, which is considered as an impurity to be assessed in the QC procedure, prior to clinical use. Thus, Ph. Eur. has introduced a thin-layer chromatography (TLC) method to quantify the HEPES amount that is present in [68Ga]Ga-radiopharmaceuticals. However, this is only qualitative and has proven to be unreliable. Here we develop and validate a new high-performance liquid chromatography (UV-Radio-HPLC) method to quantify the residual amount of HEPES in 68Ga-based radiopharmaceuticals. Method: To validate the proposed UV-Radio-HPLC method, a stepwise approach was used, as defined in the guidance document that was adopted by the European Medicines Agency (CMP/ICH/381/95 2014). The assessed parameters are specificity, linearity, precision (repeatability), accuracy, and limit of quantification. A range of concentrations of HEPES (100, 80, 60, 40, 20, 10, 5, 3 μg/mL) were analyzed. Moreover, to test the validity and pertinence of our new HPLC method, we analyzed samples of [68Ga]Ga-DOTATOC; [68Ga]Ga-PSMA; [68Ga]Ga-DOTATATE; [68Ga]Ga-Pentixafor; and [68Ga]Ga-NODAGA-Exendin-4 from different batches that were prepared for clinical use. Results: In the assessed samples, HEPES could not be detected by the TLC method that was described in Ph. Eur. within 4 min incubation in an iodine-saturated chamber. Our developed HPLC method showed excellent linearity between 3 and 100 μg/mL for HEPES, with a correlation coefficient (R2) for calibration curves that was equal to 0.999, coefficients of variation (CV%) < 2%, and percent deviation value of bias from 100% to 5%, in accordance with acceptance criteria. The intra-day and inter-day precision of our method was statistically confirmed and the limit-of-quantification (LOQ) was 3 μg/mL, confirming the high sensitivity of the method. The amount of HEPES that was detected with our developed HPLC method in the tested [68Ga]Ga-radiopharmaceuticals resulted well below the Ph. Eur. limit, especially for [68Ga]Ga-NODAGA-Exendin-4. Conclusions: The TLC method that is described in Ph. Eur. to assess residual HEPES in [68Ga]-based radiopharmaceuticals may not be sufficiently sensitive and thus unsuitable for QC release. Our new HPLC method was sensitive, quantitative, reproducible, and rapid for QCs, allowing us to exactly determine the residual HEPES amount in [68Ga]Ga-radiopharmaceuticals for safe patient administration.

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A Rapid and Specific HPLC Method to Determine Chemical and Radiochemical Purity of [68>Ga]Ga-DOTA-Pentixafor (PET) Tracer: Development and Validation

Cited by 7 publications

References 26 publications

Performance and long-term consistency of five Galliform 68Ge/68Ga generators used for clinical Ga-68 preparations over a 4 year period

Performance and long-term consistency of five Galliform 68Ge/68Ga generators used for clinical Ga-68 preparations over a 4 year period

Development and Validation of Analytical Methods for Radiochemical Purity of 177Lu-PSMA-1

A Specific HPLC Method to Determine Residual HEPES in [68Ga]Ga-Radiopharmaceuticals: Development and Validation

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