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.
Highlights
Drug development is a process of high expense and high failure rate [1]
The results demonstrated high reliability and reproducibility in terms of specificity, linearity, precision, and repeatability with respect to both UV- and radio-detectors, as well as radioactivity recovery from the HPLC columns (Table 3)
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Summary
Drug development is a process of high expense and high failure rate [1]. Considerable improvement in drug development has occurred during recent years by shifting from empirical approaches to more mechanistic and predictive ones based on the achievements of molecular biology and imaging. Microdosing, positron emission tomography (PET) microdosing [2,3,4], is recognized by the EMEA and FDA, and the Exploratory Investigational New Drug (eIND) guidelines reduce the demand on toxicity studies and respective cost burden [5,6] This is possible because of the high sensitivity of PET and, the use of non-pharmacological radiopharmaceutical doses of pico-/nanomoles (nanograms-micrograms). PET-microdosing simplifies the initiation of clinical studies and accelerates the process of selection or rejection of a drug candidate based on pharmacokinetic studies in vivo in humans at a very early stage defined as a Phase 0 study It reduces the overall costs of drug development drastically. It is worth mentioning that adverse reactions to PET radiopharmaceuticals are extremely rare and with no serious or life-threatening events [7]
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