Abstract
Radiopharmaceuticals labeled with short-lived positron-emitting or gamma-emitting isotopes are injected into patients just prior to performing positron emission tomography (PET) or single photon emission tomography (SPECT) scans, respectively. These imaging modalities are widely used in clinical care, as well as in the development and evaluation of new therapies in clinical research. Prior to injection, these radiopharmaceuticals (tracers) must undergo quality control (QC) testing to ensure product purity, identity, and safety for human use. Quality tests can be broadly categorized as (i) pharmaceutical tests, needed to ensure molecular identity, physiological compatibility and that no microbiological, pyrogenic, chemical, or particulate contamination is present in the final preparation; and (ii) radioactive tests, needed to ensure proper dosing and that there are no radiochemical and radionuclidic impurities that could interfere with the biodistribution or imaging. Performing the required QC tests is cumbersome and time-consuming, and requires an array of expensive analytical chemistry equipment and significant dedicated lab space. Calibrations, day of use tests, and documentation create an additional burden. Furthermore, in contrast to ordinary pharmaceuticals, each batch of short-lived radiopharmaceuticals must be manufactured and tested within a short period of time to avoid significant losses due to radioactive decay. To meet these challenges, several efforts are underway to develop integrated QC testing instruments that automatically perform and document all of the required tests. More recently, microfluidic quality control systems have been gaining increasing attention due to vastly reduced sample and reagent consumption, shorter analysis times, higher detection sensitivity, increased multiplexing, and reduced instrumentation size. In this review, we describe each of the required QC tests and conventional testing methods, followed by a discussion of efforts to directly miniaturize the test or examples in the literature that could be implemented for miniaturized QC testing.
Highlights
Positron emission tomography (PET) and single photon emission tomography (SPECT) are real-time, 3D imaging techniques that have unparalleled specificity and sensitivity for visualizing biochemical processes in living subjects [1,2]
While the field is still far from achieving a fully-integrated microscale quality control (QC) testing platform, we highlight in this review the significant progress that has been made in developing microscale implementations suitable for several of the required QC tests for radiopharmaceuticals and pharmaceuticals
Using the positron emission tomography (PET) tracers [18F]FLT and [18F]FAC as model systems, our group explored the feasibility of using micellar electrokinetic chromatography (MEKC) to separate neutral tracers from neutral impurities, and showed comparable separation and limit of detection as high performance liquid chromatography (HPLC)/UV [82]
Summary
Positron emission tomography (PET) and single photon emission tomography (SPECT) are real-time, 3D imaging techniques that have unparalleled specificity and sensitivity for visualizing biochemical processes in living subjects [1,2]. PPrroodduuccttiioonnooffppoossitirtroonneemmisissioionntotommooggrarapphhyy(P(PEETT)/)/ssiinngle pphhoottoonn eemmiissssiioonn ttoommooggrraapphhyy ((SSPPEECCTT)) radiotracers for cclliinniiccaall iimmaaggiinnggininvvoolvlveessggenenereartaitoinonofofthteherardaidoiosoistotpoep(evi(avicayclyoctlrootnroonr ogrengernaetroart)o, rr),adraiodsiyonsythnetshiess, isp,upruifricifiatciaotnion(v(ivaiaHHPPLLCCoorr ssoolliidd--pphhaassee extractioonn)),, formulation ((vviiaa eevvaappoorraattiivvee oorr ssoolliidd--pphhaassee eexxttrraaccttiion mmeetthhoods), ffoollowed bby qquuaallity ccoonnttrrooll ((QQCC)) tteessttiinngg ttoo eennssuurree ssaaffeettyyoofftthheeffoorrmmuullaatteeddrraaddiioottrraacceerrpprriioorrttooiinnjejeccttiioonn Performing and documenting these required QC tests is cumbersome and time-consuming, and requires an array of expensive analytical chemistry equipment and significant dedicated lab space. The fabrication and material cost of many techniques used in microfluidic QC systems can be very low, potentially enabling tests to be implemented with a disposable fluid path. These advantages could be especially helpful in conjunction with emerging technologies that produce smaller batches of PET/SPECT tracers at a time (each requiring QC testing), including dose-on-demand approaches [29]. While the field is still far from achieving a fully-integrated microscale QC testing platform, we highlight in this review the significant progress that has been made in developing microscale implementations suitable for several of the required QC tests for radiopharmaceuticals and pharmaceuticals
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