Yokell Daniel L, Rice Peter A, Neelamegam Ramesh, El Fakhri Georges
Department of Radiology, Gordon Center for Medical Imaging, Massachusetts General Hospital, 55 Fruit Street, Edwards 019B, Boston, MA, 02114, USA.
Department of Radiology, Harvard Medical School, Boston, MA, USA.
EJNMMI Radiopharm Chem. 2020 May 13;5(1):11. doi: 10.1186/s41181-020-00097-7.
[N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [N]ammonia cyclotron targets using a solution of 5 mM ethanol in water, there was a need to develop and validate an automated purification and formulation system for [N]ammonia to be in a physiological compatible formulation of 0.9% sodium chloride since there is no widely available commercial system at this time. Due to its short half-life of 10 min, FDA and USP regulations allow [N]ammonia to be tested in quality control (QC) sub-batches with limited quality control testing performed on the sub-batches for patient use. The current EP and the original USP method for the determination of the radiochemical purity and identity of [N]ammonia depended on an HPLC method using a conductivity detector and a solvent free of other salts. This HPLC method created issues in a modern cGMP high volume PET manufacturing facility where the HPLC is used with salt containing mobile phase buffers for quality control analysis of other PET radiopharmaceuticals. Flushing of the HPLC system of residual salt buffers which may interfere with the [N]ammonia assay can take several hours of instrument time. Since there are no mass limits on [N]ammonia, a simplified TLC assay to determine radiochemical identity and purity could be developed to simplify and streamline QC.
We have developed and validated a streamlined automated synthesis for [N]ammonia which provides the drug product in 8 mL of 0.9% sodium chloride for injection. A novel radio-TLC method was developed and validated to demonstrate feasibility to quantitate [N]ammonia and separate it from all known radiochemical impurities.
The process for automated synthesis of [N]ammonia simplifies and automates the purification and formulation of [N]ammonia in a cGMP compliant manner needed for high-throughput manufacture of [N]ammonia. The novel radio-TLC method has simplified [N]ammonia quality control (QC) and now enables it to be tested using the same QC equipment as [F]fludeoxyglucose (FDA/USP recognized name for 2-[F]fluoro-2-deoxy-D-glucose). Both the streamlined automated synthesis of [N]ammonia and the novel radio-TLC method have been accepted and approved by the US Food and Drug Administration (FDA) for the cGMP manufacture of [N]ammonia.
[N]氨是一种通过回旋加速器生产的心肌灌注显像剂。随着使用5 mM乙醇水溶液的高产率[N]氨回旋加速器靶的开发，由于目前尚无广泛可用的商业系统，因此需要开发并验证一种用于[N]氨的自动化纯化和制剂系统，使其成为0.9%氯化钠的生理相容性制剂。由于其半衰期仅10分钟，美国食品药品监督管理局（FDA）和美国药典（USP）的规定允许对[N]氨进行质量控制（QC）子批次测试，且对用于患者的子批次仅进行有限的质量控制测试。当前用于测定[N]氨放射化学纯度和鉴别的欧洲药典（EP）和原始USP方法依赖于使用电导检测器且溶剂不含其他盐的高效液相色谱（HPLC）方法。这种HPLC方法在现代的cGMP大容量正电子发射断层显像（PET）生产设施中产生了问题，在该设施中，HPLC用于含盐流动相缓冲液对其他PET放射性药物进行质量控制分析。冲洗可能干扰[N]氨测定的HPLC系统中的残留盐缓冲液可能需要数小时的仪器时间。由于对[N]氨没有质量限制，因此可以开发一种简化的薄层色谱（TLC）测定法来确定放射化学鉴别和纯度，以简化和优化质量控制。
我们开发并验证了一种简化的[N]氨自动化合成方法，该方法可提供8 mL 0.9%氯化钠注射液形式的药品。开发并验证了一种新颖的放射性TLC方法，以证明定量测定[N]氨并将其与所有已知放射化学杂质分离的可行性。
[N]氨的自动化合成过程以cGMP合规的方式简化并自动化了[N]氨的纯化和制剂过程，这是[N]氨高通量生产所必需的。这种新颖的放射性TLC方法简化了[N]氨的质量控制（QC），现在使其能够使用与[F]氟脱氧葡萄糖（2-[F]氟-2-脱氧-D-葡萄糖的FDA/USP认可名称）相同的QC设备进行测试。[N]氨的简化自动化合成和新颖的放射性TLC方法均已被美国食品药品监督管理局（FDA）接受并批准用于[N]氨的cGMP生产。
