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Analytical and Bioanalytical Chemistry

, Volume 410, Issue 9, pp 2423–2436 | Cite as

Toward miniaturized analysis of chemical identity and purity of radiopharmaceuticals via microchip electrophoresis

  • Jimmy Ly
  • Noel S. Ha
  • Shilin Cheung
  • R. Michael van Dam
Research Paper

Abstract

Miniaturized synthesis of positron emission tomography (PET) tracers is poised to offer numerous advantages including reduced tracer production costs and increased availability of diverse tracers. While many steps of the tracer production process have been miniaturized, there has been relatively little development of microscale systems for the quality control (QC) testing process that is required by regulatory agencies to ensure purity, identity, and biological safety of the radiotracer before use in human subjects. Every batch must be tested, and in contrast with ordinary pharmaceuticals, the whole set of tests of radiopharmaceuticals must be completed within a short-period of time to minimize losses due to radioactive decay. By replacing conventional techniques with microscale analytical ones, it may be possible to significantly reduce instrument cost, conserve lab space, shorten analysis times, and streamline this aspect of PET tracer production. We focus in this work on miniaturizing the subset of QC tests for chemical identity and purity. These tests generally require high-resolution chromatographic separation prior to detection to enable the approach to be applied to many different tracers (and their impurities), and have not yet, to the best of our knowledge, been tackled in microfluidic systems. Toward this end, we previously explored the feasibility of using the technique of capillary electrophoresis (CE) as a replacement for the “gold standard” approach of using high-performance liquid chromatography (HPLC) since CE offers similar separating power, flexibility, and sensitivity, but can readily be implemented in a microchip format. Using a conventional CE system, we previously demonstrated the successful separation of non-radioactive version of a clinical PET tracer, 3′-deoxy-3′-fluorothymidine (FLT), from its known by-products, and the separation of the PET tracer 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-cytosine (D-FAC) from its α-isomer, with sensitivity nearly as good as HPLC. Building on this feasibility study, in this paper, we describe the first effort to miniaturize the chemical identity and purity tests by using microchip electrophoresis (MCE). The fully automated proof-of-concept system comprises a chip for sample injection, a separation capillary, and an optical detection chip. Using the same model compound (FLT and its known by-products), we demonstrate that samples can be injected, separated, and detected, and show the potential to match the performance of HPLC. Addition of a radiation detector in the future would enable analysis of radiochemical identity and purity in the same device. We envision that eventually this MCE method could be combined with other miniaturized QC tests into a compact integrated system for automated routine QC testing of radiopharmaceuticals in the future.

Graphical abstract

Miniaturized quality control (QC) testing of batches of radiopharmaceuticals via microfluidic analysis. The proof-of-concept hybrid microchip electrophoresis (MCE) device demonstrated the feasibility of achieving comparable performance to conventional analytical instruments (HPLC or CE) for chemical purity testing.

Keywords

Capillary electrophoresis Microchip electrophoresis Positron emission tomography Chemical purity analysis Microfluidics Quality control testing Radiopharmaceuticals 

Notes

Funding

This work was supported in part by the Department of Energy Office of Biological and Environmental Research (DE-SC0001249), the National Institute on Aging (R21AG049918), and the National Cancer Institute (U54 CA151819A, i.e., the Caltech/UCLA Nanosystems Biology Cancer Center).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

216_2018_924_MOESM1_ESM.pdf (514 kb)
ESM 1 (PDF 514 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jimmy Ly
    • 1
    • 2
    • 3
  • Noel S. Ha
    • 1
    • 2
  • Shilin Cheung
    • 2
    • 4
  • R. Michael van Dam
    • 1
    • 2
  1. 1.Department of Bioengineering, Henry Samueli School of Engineering and Applied ScienceUniversity of California Los AngelesLos AngelesUSA
  2. 2.Crump Institute for Molecular Imaging and Department of Molecular and Medical Pharmacology, David Geffen School of MedicineUniversity of California Los AngelesLos AngelesUSA
  3. 3.Bioengineering and Therapeutic Sciences, UCSFSan FranciscoUSA
  4. 4.Trace-ability, Inc.Culver CityUSA

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