SBIR-STTR Award

Positron Emission Tomography (PET) is a medical imaging modality widely used in cancer diagnostics. Oncological applications of PET include treatment planning, tumor staging and treatment efficacy evaluation. Availability of the procedure is limited by the supply of a short-lived radioactive contrast agent (18F-FDG). Trace-Ability is developing a solution that eliminates limitations in the supply of 18F-FDG and thus makes personalized medicine accessible for more cancer patients. The main focus of the proposed project is an automated platform for quality control of 18F-FDG. 18F-FDG production has to be performed daily due to the 2-hour half-life of 18F. Fourteen quality control tests are often the bottleneck of the production. Correct execution of this diverse set of procedures requires highly qualified and experienced facility personnel. Our approach is to develop a set of tests amenable for automation on commercially available hardware. This development concept is drastically different from the methods of our competitors, who rely on automation of existing tests and have to face the difficulties of the ground-up engineering, software development and hardware validation. Hardware platform chosen for this project include two analytical instruments: liquid chromatograph and plate reader. Combined with a liquid handling robot, this platform will be able to perform full QC testing if 18F- FDG. A single-use kit of reagents will enable GMP compliant operation of the platform. In this proposal we focus on proving feasibility of the last three tests never performed on a plate reader: radionuclide identity (half-life), radioactivity concentration and kryptofix concentration. Specific Aim 1: Establish feasibility of the radiation intensity measurement using the luminescence reading mode of a plate reader. We propose to use Liquid Scintillation Counting to measure 18F concentration and half-life. We hypothesize that due to the high energy of positrons emitted from 18F, a dedicated Liquid Scintillation Analyzer is not needed and that a plate reader in luminescence mode will be sensitive enough to accurately quantify 18F concentration. Therefore, the same plate reader used to quantify other QC parameters could be used to determine radionuclide identity and radioactivity concentration. Specific Aim 2: Establish feasibility of the kryptofix quantification using the absorbance reading mode of a plate reader. The current kryptofix test can hardly be automated: this is a multistep process and it relies on formation of a colored solid. We propose to develop a solution indicator that changes its color according to kryptofix concentration. We hypothesize that a "metal - metal ion indicator" complex can be used for this purpose. Formation of a metal+indicator complex will determine the absorption spectrum. Kryptofix can scavenge metal ions, increasing relative concentration of the free indicator. The resulting spectral shift wll be detected by the plate reader in the absorbance mode.

Public Health Relevance Statement:


Public Health Relevance:
Positron Emission Tomography (PET) is a unique diagnostic procedure critically important for accurate cancer diagnostics and treatment planning. Availability of PET is limited by labor intensive production of the radioactive contrast agent used in this procedure. Proposed project aims to alleviate this shortcoming by introducing an automated system for quality control of the contrast agent, resulting in expanded availability of PET to more cancer patients.

Project Terms:
absorption; analytical method; Automation; base; Cancer Diagnostics; Cancer Patient; cancer therapy; Chemicals; Clinical; Color; commercialization; Complex; Consult; Contracts; Contrast Media; Data; Development; Diagnostic Neoplasm Staging; Diagnostic Procedure; efficacy evaluation; Endotoxins; Engineering; experience; Face; Half-Life; Head; High Pressure Liquid Chromatography; Hour; Human Resources; Image; imaging modality; instrument; Ions; Legal patent; Life; Liquid substance; Literature; luminescence; Malignant Neoplasms; Manuals; Manufacturer Name; Measurement; Measures; Medical Imaging; Metals; Methods; Molecular; operation; Optics; Organic solvent product; personalized medicine; Phase; Positioning Attribute; Positron; Positron-Emission Tomography; Procedures; Process; Production; prototype; public health relevance; Qualifying; Quality Control; Radiation; Radioactive; Radioactivity; radiochemical; Radioisotopes; Reader; Reading; Reagent; Relative (related person); Reporting; Residual state; Robot; Sales; Sampling; Scintillation Counting; Signal Transduction; software development; Solid; Solutions; Stream; System; Technology; Testing; Tracer; Treatment Efficacy; treatment planning; tumor; Tumor stage; Validation; Visual

Positron Emission Tomography (PET) is regarded as a standard of care in the management of multiple types of cancer. Availability of this procedure relies on a steady supply of a radioactive contrast agent [F- 18]Fluoro-2-deoxy-d-glucose (FDG). Due to the inherent short half-life (110 min), multiple batches of FDG are typically produced at multiple sites on daily basis. Quality Control (QC) of FDG remains the most labor-, skill- and risk-intensive part of the production process. Reliance of QC on manual operation, subjectivity and untraceable records, limits the number of FDG batches that may be produced per day per facility, which in turn limits availability of PET imaging to cancer patients. Trace-Ability has taken an unconventional approach to QC automation (called Tracer-QC) which relies on optical measurements by a microplate reader for most of the QC tests. The innovation is in the disposable kit that enables multiple tests from a single sample on a single platform composed of a microplate reader and automated pipettor. Most of the QC tests have been already enabled by Trace-Ability relying on NCI Phase I SBIR and other funding. Radiochemical purity and chemical identity QC tests will be enabled during Phase II by integration of an HPLC component into the plate reader/pipettor system in a seamless way which allows the user to use a single sample to obtain a single report on 10 QC parameters. The integrated solution will then be validated for use in clinical FDG production. The second component of the Phase II project will focus on setting up reliable production of disposable Tracer-QC kits at commercial scale. Upon achievement of the above aims, Trace-Ability will be in position to offer FDG manufacturers a fully-automated QC solution that has been completely validated. This is critical since production of short- lived PET tracers has extremely low tolerance for failure. Optimized production processes will yield Tracer-QC kits that are not only optimized for reliability, but also for cost, maximizing the commercial potential of the Tracer-QC business that relies on recurring kit revenues from the growing install base. Finally, having an FDG QC solution with on-board HPLC enables expansion of Tracer-QC to any other PET tracers without further revisions of the stationary hardware, making it a true scalable platform. The impact in the field of Oncology will be manifested in increased availability of FDG scans and facilitation of new tracer development. Upon completion of the project Trace-Ability plans to use the new platform to develop QC methods for more PET tracers such as [F-18]FDOPA (brain tumors), [F-18]FLT (general oncological tracer), [C-11]Choline (prostate tumors), [Ga-68]DOTATOC (endocrine tumors).

Public Health Relevance Statement:
Project Narrative Trace-Ability is proposing automation of radio-pharmaceutical Quality Control. Successful completion of this project will enable dramatic improvements in efficiency of production of the most common radio- pharmaceutical in Positron Emission Tomography (PET) – Fludeoxyglucose F 18 (FDG). Resulting increase in supply of FDG will in turn increase availability of FDG PET, which is a standard of care in management of multiple types of cancer.

Project Terms:
Achievement; Aliquot; analytical method; Automation; base; Brain Neoplasms; Businesses; Cancer Control; Cancer Patient; cancer type; Chemicals; Choline; Chromatography; Clinical; clinical imaging; commercialization; Computer software; Contrast Media; cost; cost efficient; Data; Deoxyglucose; design; Development; Devices; Endocrine Gland Neoplasms; Evaluation; Failure; Freezing; Funding; glucose production; Goals; Half-Life; High Pressure Liquid Chromatography; Image; imaging modality; innovation; Manuals; Manufacturer Name; Measurement; Methods; Molecular; oncology; operation; Optics; Patients; Pharmacologic Substance; Phase; Positioning Attribute; Positron-Emission Tomography; Procedures; Process; Production; Prostatic Neoplasms; prototype; Quality Control; Radio; Radioactive; radiochemical; Reader; Records; Reporting; Risk; Sampling; Scanning; Site; skills; Small Business Innovation Research Grant; standard of care; System; Technology; Testing; Time; Tracer; tumor; United States National Institutes of Health; Validation; Visual