Automated GMP-Compliant Production of [68Ga]Ga-DO3A-Tuna-2 for PET Microdosing Studies of the Glucagon Receptor in Humans

Michael Wagner; Johan G Doverfjord; Joachim Tillner; Gunnar Antoni; Torsten Haack; Martin Bossart; Iina Laitinen; Lars Johansson; Stefan Pierrou; Olof Eriksson; Irina Velikyan

doi:10.3390/ph13080176

Automated GMP-Compliant Production of [⁶⁸Ga]Ga-DO3A-Tuna-2 for PET Microdosing Studies of the Glucagon Receptor in Humans

Pharmaceuticals (Basel). 2020 Jul 31;13(8):176. doi: 10.3390/ph13080176.

Authors

Affiliations

¹ R&D Research Platform, Integrated Drug Discovery, Sanofi, 65929 Frankfurt, Germany.
² PET Center, Center for Medical Imaging, Uppsala University Hospital, 751 85 Uppsala, Sweden.
³ Translational Medicine, Sanofi, 65929 Frankfurt, Germany.
⁴ Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
⁵ Global Imaging, Sanofi, 65929 Frankfurt, Germany.
⁶ Antaros Medical AB, 431 83 Mölndal, Sweden.
⁷ Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.

Abstract

Introduction: [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 (previously published as [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-S01-GCG) has shown high-affinity specific binding to the glucagon receptor (GCGR) in vitro and in vivo in rats and non-human primates in our previous studies, confirming the suitability of the tracer for drug development applications in humans. The manufacturing process of [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 was automated for clinical use to meet the radiation safety and good manufacturing practice (GMP) requirements. Methods: The automated synthesis platform (Modular-Lab PharmTrace, Eckert & Ziegler, Eurotope, Germany), disposable cassettes for ⁶⁸Ga-labeling, and pharmaceutical-grade ⁶⁸Ge/⁶⁸Ga generator (GalliaPharm^®) used in the study were purchased from Eckert & Ziegler. The parameters such as time, temperature, precursor concentration, radical scavenger, buffer concentration, and pH, as well as product purification step, were investigated and optimized. Process optimization was conducted with regard to product quality and quantity, as well as process reproducibility. The active pharmaceutical ingredient starting material DO3A-VS-Cys⁴⁰-Tuna-2 (GMP-grade) was provided by Sanofi Aventis. Results: The reproducible and GMP-compliant automated production of [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 with on-line documentation was developed. The non-decay-corrected radiochemical yield was 45.2 ± 2.5% (n = 3, process validation) at the end of the synthesis with a labeling synthesis duration of 38 min and a quality controlincluding release procedure of 20 min. The radiochemical purity of the product was 98.9 ± 0.6% (n = 17) with the total amount of the peptide in the preparation of 48 ± 2 µg (n = 3, process validation). Radionuclidic purity, sterility, endotoxin content, residual solvent content, and sterile filter integrity tests met the acceptance criteria. The product was stable at ambient temperature for at least 2 h. Conclusion: The fully automated GMP-compliant manufacturing process was developed and thoroughly validated. The resulting [⁶⁸Ga]Ga-DO3A-VS-Cys⁴⁰-Tuna-2 was used in a clinical study for accurate quantification of GCGR occupancy by a dual anti-diabetic drug in vivo in humans.

Keywords: GMP; Gallium-68; automation; diabetes; glucagon receptor; radiopharmaceuticals.