Wagner Michael, Doverfjord Johan G, Tillner Joachim, Antoni Gunnar, Haack Torsten, Bossart Martin, Laitinen Iina, Johansson Lars, Pierrou Stefan, Eriksson Olof, Velikyan Irina
R&D Research Platform, Integrated Drug Discovery, Sanofi, 65929 Frankfurt, Germany.
PET Center, Center for Medical Imaging, Uppsala University Hospital, 751 85 Uppsala, Sweden.
Pharmaceuticals (Basel). 2020 Jul 31;13(8):176. doi: 10.3390/ph13080176.
: [Ga]Ga-DO3A-VS-Cys-Tuna-2 (previously published as [Ga]Ga-DO3A-VS-Cys-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 [Ga]Ga-DO3A-VS-Cys-Tuna-2 was automated for clinical use to meet the radiation safety and good manufacturing practice (GMP) requirements. The automated synthesis platform (Modular-Lab PharmTrace, Eckert & Ziegler, Eurotope, Germany), disposable cassettes for Ga-labeling, and pharmaceutical-grade Ge/Ga 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-Cys-Tuna-2 (GMP-grade) was provided by Sanofi Aventis. The reproducible and GMP-compliant automated production of [Ga]Ga-DO3A-VS-Cys-Tuna-2 with on-line documentation was developed. The non-decay-corrected radiochemical yield was 45.2 ± 2.5% ( = 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% ( = 17) with the total amount of the peptide in the preparation of 48 ± 2 µg ( = 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. The fully automated GMP-compliant manufacturing process was developed and thoroughly validated. The resulting [Ga]Ga-DO3A-VS-Cys-Tuna-2 was used in a clinical study for accurate quantification of GCGR occupancy by a dual anti-diabetic drug in vivo in humans.
[镓]镓 - DO3A - VS - 半胱氨酸 - 金枪鱼 - 2（之前发表为[镓]镓 - DO3A - VS - 半胱氨酸 - S01 - GCG）在我们之前的研究中已显示出在大鼠和非人灵长类动物体内外对胰高血糖素受体（GCGR）具有高亲和力的特异性结合，证实了该示踪剂适用于人类药物开发应用。[镓]镓 - DO3A - VS - 半胱氨酸 - 金枪鱼 - 2的制造过程已实现自动化以供临床使用，以满足辐射安全和良好生产规范（GMP）要求。本研究中使用的自动化合成平台（Modular - Lab PharmTrace，德国埃克特&齐格勒公司，Eurotope）、用于镓标记的一次性试剂盒以及药用级锗/镓发生器（GalliaPharm）均购自埃克特&齐格勒公司。对时间、温度、前体浓度、自由基清除剂、缓冲液浓度和pH值等参数以及产品纯化步骤进行了研究和优化。针对产品质量和产量以及过程重现性进行了工艺优化。活性药物成分起始原料DO3A - VS - 半胱氨酸 - 金枪鱼 - 2（GMP级）由赛诺菲安万特公司提供。开发了具有在线记录功能的可重现且符合GMP标准的[镓]镓 - DO3A - VS - 半胱氨酸 - 金枪鱼 - 2自动化生产工艺。合成结束时，未进行衰变校正的放射化学产率为45.2±2.5%（ = 3，工艺验证），标记合成持续时间为38分钟，质量控制（包括放行程序）为20分钟。产品的放射化学纯度为98.9±0.6%（ = 17），制剂中肽的总量为48±2微克（ = 3，工艺验证）。放射性核素纯度、无菌性、内毒素含量、残留溶剂含量和无菌过滤器完整性测试均符合验收标准。该产品在室温下至少稳定2小时。开发并全面验证了完全符合GMP标准的自动化制造工艺。所得的[镓]镓 - DO3A - VS - 半胱氨酸 - 金枪鱼 - 2用于一项临床研究，以在人体内准确量化一种双抗糖尿病药物对GCGR的占有率。
