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Application of response surface methodology and quality by design to [68Ga]Ga-PSMA-11 preparation

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Abstract

In this study, the optimum conditions for the synthesis of [68Ga]Ga-PSMA-11 were determined for the first time using the Quality by Design (QbD). The response surface methodology was used to estimate the effect of input variables (PSMA-11 concentration, time, reaction temperature, and pH) on the responses calculated as the percentage of the radiochemical purity and the RR configuration. Since using QbD principles in the production of radiopharmaceuticals is not common, this study will help increase the number of applications in this field and ensure quality in radiopharmaceutical manufacturing, allowing decreased cost and the number of experiments.

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References

  1. Evangelista L, Maurer T, van der Poel H et al (2022) [68Ga]Ga-PSMA versus [18F] PSMA positron emission tomography/computed tomography in the staging of primary and recurrent prostate cancer. A systematic review of the literature. Eur Urol Oncol 5(3):273–282

    Article  PubMed  Google Scholar 

  2. Rasul S, Haug AR (2022) Clinical applications of PSMA PET examination in patients with prostate cancer. Cancers (Basel) 14:3768. https://doi.org/10.3390/cancers14153768

    Article  PubMed  Google Scholar 

  3. Lenzo NP, Meyrick D, Turner JH (2018) Review of gallium-68 PSMA PET/CT imaging in the management of prostate cancer. Diagnostics 8:16

    Article  PubMed  PubMed Central  Google Scholar 

  4. Eiber M, Weirich G, Holzapfel K et al (2016) Simultaneous (68)Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer. Eur Urol 70:829–836. https://doi.org/10.1016/j.eururo.2015.12.053

    Article  CAS  PubMed  Google Scholar 

  5. Kesch C, Kratochwil C, Mier W et al (2017) 68Ga or 18F for prostate cancer imaging? J Nucl Med 58:687–688

    Article  PubMed  Google Scholar 

  6. Lindenberg L, Choyke P, Dahut W (2016) Prostate cancer imaging with novel PET tracers. Curr Urol Rep 17:1–8

    Article  Google Scholar 

  7. Schwarzenboeck SM, Rauscher I, Bluemel C et al (2017) PSMA ligands for PET imaging of prostate cancer. J Nucl Med 58:1545–1552

    Article  CAS  PubMed  Google Scholar 

  8. Eder M, Neels O, Müller M et al (2014) Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC: a new PET tracer for imaging of prostate cancer. Pharmaceuticals 7:779–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nanabala R, Anees MK, Sasikumar A et al (2016) Preparation of [[68Ga]PSMA-11 for PET–CT imaging using a manual synthesis module and organic matrix based 68Ge/68Ga generator. Nucl Med Biol 43:463–469

    Article  CAS  PubMed  Google Scholar 

  10. Calderoni L, Farolfi A, Pianori D et al (2020) Evaluation of an automated module synthesis and a sterile cold kit–based preparation of 68Ga-PSMA-11 in patients with prostate cancer. J Nucl Med 61:716–722

    Article  CAS  PubMed  Google Scholar 

  11. Beheshti M, Paymani Z, Brilhante J et al (2018) Optimal time-point for 68Ga-PSMA-11 PET/CT imaging in assessment of prostate cancer: feasibility of sterile cold-kit tracer preparation? Eur J Nucl Med Mol Imaging 45:1188–1196

    Article  CAS  PubMed  Google Scholar 

  12. Yu LX (2008) Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res 25:781–791. https://doi.org/10.1007/s11095-007-9511-1

    Article  CAS  PubMed  Google Scholar 

  13. Guideline ICHHT (2009) Pharmaceutical development. Q8 (2R) as revised august

  14. International Council for Harmonisation (2015) ICH guideline Q10 on pharmaceutical quality system. Eur Med Agency 44:1–20

    Google Scholar 

  15. ICH (2005) ICH guideline Q9 on quality risk management. Regul ICH 44:1–20

    Google Scholar 

  16. Gundogdu E, Demir ES, Özgenç E et al (2020) Applying quality by design principles in the development and preparation of a new radiopharmaceutical: technetium-99m-imatinib mesylate. ACS Omega 5:5297–5305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lange R, Ter Heine R, Van Der Gronde T et al (2016) Applying quality by design principles to the small-scale preparation of the bone-targeting therapeutic radiopharmaceutical rhenium-188-HEDP. Eur J Pharm Sci 90:96–101

    Article  CAS  PubMed  Google Scholar 

  18. Beg S, Chaudhary V, Sharma G et al (2016) QbD-oriented development and validation of a bioanalytical method for nevirapine with enhanced liquid–liquid extraction and chromatographic separation. Biomed Chromatogr 30:818–828

    Article  CAS  PubMed  Google Scholar 

  19. Bezerra MA, Santelli RE, Oliveira EP et al (2008) Response surface methodology (RSM) as a tool for optimization in analytical chemistry. Talanta 76(5):965–977

    Article  CAS  PubMed  Google Scholar 

  20. Mourabet M, El Rhilassi A, El Boujaady H et al (2017) Use of response surface methodology for optimization of fluoride adsorption in an aqueous solution by Brushite. Arab J Chem 10:S3292–S3302

    Article  CAS  Google Scholar 

  21. Politis SN, Colombo P, Colombo G, Rekkas DM (2017) Design of experiments (DoE) in pharmaceutical development. Drug Dev Ind Pharm 43:889–901

    Article  CAS  Google Scholar 

  22. Yousry C, Farrag NS, Amin AM (2023) Radiolabeling of statistically optimized nanosized atorvastatin suspension for liver targeting and extensive imaging of hepatocellular carcinoma. J Drug Deliv Sci Technol 80:104171

    Article  CAS  Google Scholar 

  23. Pehlivanoglu H, Ocak M, Caglar-Andac S (2022) Development and validation of a UV-Radio-HPLC method to assess chemical and radiochemical purity of [[68Ga]Ga-PSMA-11. Appl Radiat Isot 190:110487. https://doi.org/10.1016/j.apradiso.2022.110487

    Article  CAS  Google Scholar 

  24. Schultz MK, Mueller D, Baum RP et al (2013) A new automated NaCl based robust method for routine production of gallium-68 labeled peptides. Appl Radiat Isot 76:46–54

    Article  CAS  PubMed  Google Scholar 

  25. Mueller D, Breeman WAP, Klette I et al (2016) Radiolabeling of DOTA-like conjugated peptides with generator-produced 68Ga and using NaCl-based cationic elution method. Nat Protoc 11:1057–1066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Velikyan I (2015) 68Ga-based radiopharmaceuticals: production and application relationship. Molecules 20:12913–12943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Amor-Coarasa A, Schoendorf M, Meckel M et al (2016) Comprehensive quality control of the ITG 68Ge/68Ga generator and synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical imaging. J Nucl Med 57:1402–1405

    Article  CAS  PubMed  Google Scholar 

  28. Maruk AY, Larenkov AA (2020) Determination of ionic 68Ga impurity in radiopharmaceuticals: major revision of radio-HPLC methods. J Radioanal Nucl Chem 323:189–195

    Article  CAS  Google Scholar 

  29. Rathore AS, Winkle H (2009) Quality by design for biopharmaceuticals. Nat Biotechnol 27:26–34

    Article  CAS  PubMed  Google Scholar 

  30. Kaur P, Garg T, Rath G et al (2016) Development, optimization and evaluation of surfactant-based pulmonary nanolipid carrier system of paclitaxel for the management of drug resistance lung cancer using box-behnken design. Drug Deliv 23:1912–1925

    CAS  PubMed  Google Scholar 

  31. Sharma D, Maheshwari D, Philip G et al (2014) Formulation and optimization of polymeric nanoparticles for intranasal delivery of lorazepam using box-behnken design: in vitro and in vivo evaluation. Biomed Res Int 2014:156010

    Article  PubMed  PubMed Central  Google Scholar 

  32. Luurtsema G, Pichler V, Bongarzone S et al (2021) EANM guideline for harmonisation on molar activity or specific activity of radiopharmaceuticals: impact on safety and imaging quality. EJNMMI Radiopharm Chem 6:34. https://doi.org/10.1186/s41181-021-00149-6

    Article  PubMed  PubMed Central  Google Scholar 

  33. Eppard E, Homann T, de la Fuente A et al (2017) Optimization of labeling PSMAHBED with ethanol-postprocessed 68Ga and its quality control systems. J Nucl Med 58:432–437

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Istanbul University-Cerrahpasa, Nuclear Medicine Department for the support in obtaining the 68Ga radionuclide and Modular-Lab Standard module (Eckert & Ziegler).

Funding

This study was supported by the Research Fund of Istanbul University with Project No: TYL-2019–33814.

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Authors and Affiliations

  1. Institute of Graduate Studies in Health Sciences, Istanbul University, Istanbul, Turkey

    Huseyin Pehlivanoglu

  2. Department of Nuclear Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Huseyin Pehlivanoglu

  3. Molecular Imaging and Theranostics Center, University of Missouri, 1514 Research Park Drive, Columbia, MO, 65211, USA

    Meltem Ocak

  4. Department of Analytical Chemistry, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey

    Sena Caglar-Andac

Authors
  1. Huseyin Pehlivanoglu
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  2. Meltem Ocak
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  3. Sena Caglar-Andac
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Correspondence to Sena Caglar-Andac.

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Pehlivanoglu, H., Ocak, M. & Caglar-Andac, S. Application of response surface methodology and quality by design to [68Ga]Ga-PSMA-11 preparation. J Radioanal Nucl Chem 333, 43–51 (2024). https://doi.org/10.1007/s10967-023-09246-z

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  • DOI: https://doi.org/10.1007/s10967-023-09246-z

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