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Development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)N] Ammonia

BACKGROUND: [(13)N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [(13)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 [(13)...

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Autores principales: Yokell, Daniel L., Rice, Peter A., Neelamegam, Ramesh, El Fakhri, Georges
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221112/
https://www.ncbi.nlm.nih.gov/pubmed/32405797
http://dx.doi.org/10.1186/s41181-020-00097-7
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author Yokell, Daniel L.
Rice, Peter A.
Neelamegam, Ramesh
El Fakhri, Georges
author_facet Yokell, Daniel L.
Rice, Peter A.
Neelamegam, Ramesh
El Fakhri, Georges
author_sort Yokell, Daniel L.
collection PubMed
description BACKGROUND: [(13)N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [(13)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 [(13)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 [(13)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 [(13)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 [(13)N]ammonia assay can take several hours of instrument time. Since there are no mass limits on [(13)N]ammonia, a simplified TLC assay to determine radiochemical identity and purity could be developed to simplify and streamline QC. RESULTS: We have developed and validated a streamlined automated synthesis for [(13)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 [(13)N]ammonia and separate it from all known radiochemical impurities. CONCLUSIONS: The process for automated synthesis of [(13)N]ammonia simplifies and automates the purification and formulation of [(13)N]ammonia in a cGMP compliant manner needed for high-throughput manufacture of [(13)N]ammonia. The novel radio-TLC method has simplified [(13)N]ammonia quality control (QC) and now enables it to be tested using the same QC equipment as [(18)F]fludeoxyglucose (FDA/USP recognized name for 2-[(18)F]fluoro-2-deoxy-D-glucose). Both the streamlined automated synthesis of [(13)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 [(13)N]ammonia.
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spelling pubmed-72211122020-05-15 Development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)N] Ammonia Yokell, Daniel L. Rice, Peter A. Neelamegam, Ramesh El Fakhri, Georges EJNMMI Radiopharm Chem Methodology BACKGROUND: [(13)N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [(13)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 [(13)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 [(13)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 [(13)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 [(13)N]ammonia assay can take several hours of instrument time. Since there are no mass limits on [(13)N]ammonia, a simplified TLC assay to determine radiochemical identity and purity could be developed to simplify and streamline QC. RESULTS: We have developed and validated a streamlined automated synthesis for [(13)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 [(13)N]ammonia and separate it from all known radiochemical impurities. CONCLUSIONS: The process for automated synthesis of [(13)N]ammonia simplifies and automates the purification and formulation of [(13)N]ammonia in a cGMP compliant manner needed for high-throughput manufacture of [(13)N]ammonia. The novel radio-TLC method has simplified [(13)N]ammonia quality control (QC) and now enables it to be tested using the same QC equipment as [(18)F]fludeoxyglucose (FDA/USP recognized name for 2-[(18)F]fluoro-2-deoxy-D-glucose). Both the streamlined automated synthesis of [(13)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 [(13)N]ammonia. Springer International Publishing 2020-05-13 /pmc/articles/PMC7221112/ /pubmed/32405797 http://dx.doi.org/10.1186/s41181-020-00097-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Methodology
Yokell, Daniel L.
Rice, Peter A.
Neelamegam, Ramesh
El Fakhri, Georges
Development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)N] Ammonia
title Development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)N] Ammonia
title_full Development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)N] Ammonia
title_fullStr Development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)N] Ammonia
title_full_unstemmed Development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)N] Ammonia
title_short Development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)N] Ammonia
title_sort development, validation and regulatory acceptance of improved purification and simplified quality control of [(13)n] ammonia
topic Methodology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221112/
https://www.ncbi.nlm.nih.gov/pubmed/32405797
http://dx.doi.org/10.1186/s41181-020-00097-7
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