Microchip electrophoresis as basis for fully integrated, fully automated, low-cost radiopharmaceutical QC platform

PROJECT SUMMARY Positron emission tomography (PET) is an indispensable tool in research, drug development and clinical care, due to its very high sensitivity and quantitative nature. The complexity and high cost of producing PET tracers limits their use in research and their development and validation into quantitative in vivo biological assays. For

example, thousands of different PET tracers have been reported, but very few have been validated for use in animals or humans, and only a tiny fraction are approved for routine use in patients. New methods being developed for PET tracer manufacturing – especially microfluidics – have demonstrated

potential for vastly reduced tracer production cost and complexity through (i) reduction of expensive reagents, (ii) efficient production at preclinical and clinical scales, and (iii) compact instrumentation that can be operated with minimal infrastructure. As the quality control (QC) tests necessary to ensure radiopharmaceutical safety

must be performed after every synthesis, there have been some efforts to apply microfluidics in this area as well. DropletPharm, Inc. seeks to leverage microfluidic developments to create a tabletop radiopharmacy platform to eliminate the typical costly radiopharmacy infrastructure (i.e. hot cell, radiosynthesizer, stack

monitoring system, QC equipment), and replace it with a self-shielded benchtop device that performs both synthesis and analysis. In the current project, we seek to develop a microfluidics-based QC platform to automatically perform all necessary radiopharmaceutical QC tests, reducing costs and increasing throughput.

While many QC tests can be implemented as simple optical and radiation measurements (of aliquots pre-mixed with indicators), the (radio)chemical identity and purity tests are more challenging and require chemical separations. Recently, numerous research groups have used capillary electrophoresis for rapid

separation and analysis of radiopharmaceuticals labeled with various isotopes (incl. Tc-99m and F-18). The van Dam lab used [18F]FLT samples to demonstrate high-resolution and sensitivity can be achieved using microchip electrophoresis (MCE), where advantages of vastly reduced size, lower cost, and short analysis time

makes this technique highly attractive as a replacement for the gold standard techniques of radio-HPLC or radio-TLC for assessing radiochemical identity and purity as well as chemical purity and molar activity. To assess the technical feasibility to use this technology at the core of DropletPharm’s QC testing platform, this

proposal aims to address two limitations of the method published to date, and compare the analysis performance head-to-head with radio-HPLC or radio-TLC. Aim 1 will explore strategies to improve radiation detection sensitivity to enable the analysis of a wider range of clinical batches (i.e. those that are more dilute).

Aim 2 will explore radio-MCE separation of example radiotracers, including [18F]FLT and [68Ga]Ga-PSMA-11, and compare performance with the gold standard (radio-HPLC and radio-TLC). Successful completion of the milestones will indicate that Phase II commercial development into a full QC-testing module is warranted.