Stock solution preparation
The radionuclides were obtained from various suppliers: [99mTc]-NaTcO4, [123I]-NaI and [131I]-NaI from GE Healthcare (Eindhoven, The Netherlands), [124I]-NaI from BV Cyclotron VU (Amsterdam, The Netherlands), [177Lu]-LuCl3 from IDB Holland (Baarle-Nassau, The Netherlands), and [111In]-InCl3 and [90Y]-YCl3 from Curium (Petten, The Netherlands).
[177Lu]-LuCl3, [111In]-InCl3, [90Y]-YCl3, [131I]-NaI and [124I]-NaI stock solutions and samples were prepared within 24 hours of the first day of the intercomparison measurements, which took place over three consecutive days. Due to their shorter half-life, [99mTc]-NaTcO4 and [123I]-NaI solutions were prepared at each measurement day. For each radionuclide, a stock solution was prepared with approximately 10 MBq·mL-1 on the first measurement day. Stock solutions were prepared using sterile water (Baxter, Netherlands) in a borosilicate glass container and immediately after preparation dispensed into samples to avoid precipitations.
Evaluation of radionuclidic impurities
Each stock solution was checked for radionuclidic impurities by high-resolution gamma-ray spectrometry using a high-purity germanium detector (GR1018; Mirion Technologies, Georgia, USA) as described in the supplemental material. No short- or long-lived radionuclidic impurities were found for 99mTc, 111In and 90Y. For 123I, 124I and 131I, trace amounts of 125I were observed with a maximum radionuclidic impurity of 0.030%, 0.037% and 0.039%, respectively. For 177Lu, trace amounts of 177mLu were observed with a maximum radionuclidic impurity of 0.017%.
Determination of reference activity
The reference (true) activity concentration of each stock solution was determined by the Belgian Nuclear Research Centre SCK CEN (Mol, Belgium) in collaboration with the Joint Research Centre (Geel, Belgium), which is specialized in primary and secondary standardization of radioactivity [12]. Reference activity measurements were performed using two secondary standard ionization chambers: a Fidelis (Southern-Scientific, Henfield, UK) and an ISOCAL-III (Vinten Instruments, UK). Both systems use calibration factors traceable to the primary standards of activity of the UK National Physical Laboratory (NPL).
From each stock solution, three 10-mL Type 1+ Schott vials (SCHOTT AG Pharmaceutical Systems, Mainz, Germany) were filled with 4 mL of solution, and their activities were assayed in both reference chambers. With the exception of 90Y, the reference activity of each Schott vial was determined from the mean of the activities measured with both the Fidelis and the ISOCAL, and the gravimetrically-determined mass of stock solution in the vial. All activity measurements were corrected for background signal and for radioactive decay to a common reference time using the half-life values reported in Publication 107 of the International Commission on Radiological Protection [13]. Additionally, before determination of the average value, the activity measurements were corrected for linearity, radionuclide impurities (significant only for (177mLu/)177Lu measurements) and for deviations in response against the NPL master chamber (see supplementary Table S1). For the latter correction, radionuclide- and chamber-dependent correction factors were estimated from the NPL acceptance testing data of each system (corrections < 1.1% for the gamma emitters and 14.5% for the 90Y Fidelis measurements).
With the exception of 90Y, the Fidelis and ISOCAL systems agreed within ±0.7% in Schott vial activity measurements. For 90Y, however, a difference in response of approximately 10% was observed between both systems. On the basis of this discrepancy and the lack of experimental data to correct the response of the ISOCAL against the NPL master chamber for pure beta emitters, the reference activity concentration of the 90Y stock solution was derived from activity measurements with the Fidelis only.
The reference activity concentration of the radionuclide stock solution was then determined as the mean of the activity concentrations from the three Schott vials. The expanded uncertainty (95% confidence level) in the reference activity concentrations of the stock solutions was: 2.0% for 99mTc, 1.7% for 111In, 2.2% for 123I, 2.0% for 124I, 1.1% for 131I, 1.2% for 177Lu and 6.9% for 90Y, see supplementary Table S2.
Sample preparation
From each stock solution, a set of four samples comprising two different clinical containers each with two filling volumes were prepared: two 3-mL Luer-lock syringes (Terumo Europe, Leuven, Belgium) filled with 1 mL and 3 mL of solution, and two 11-mL TechneVial glass vials (Curium, Petten, The Netherlands) filled with 1 mL and 10 mL of solution. Each syringe was sealed with a combi-stopper (Braun, The Netherlands). The content mass of each sample was verified gravimetrically, by weighing the sample before and after filling with an analytical balance (XS105DU/M; Mettler-Toledo, Tiel, The Netherlands). The reference activity (Aref) of each sample was calculated by multiplying the content mass with the stock solution reference activity concentration. As the uncertainty in sample mass measurements was negligible compared to the uncertainty in radioactivity concentration, the relative uncertainty of the sample reference activity (uref) was approximately equal to the relative uncertainty of the stock solution activity concentration.
Due to transport logistics, for one hospital separate sets of samples (a 3-mL syringe filled with 3 mL and a TechneVial filled with 10 mL of stock solution) were prepared for all radionuclides.
Clinical activity measurements
Sample measurements were performed on a total of 32 radionuclide calibrator systems of 8 university hospitals located in the Netherlands, Belgium and Germany. Of all systems, 4 were manufactured by Capintec Inc (Florham Park, USA), 11 by former MED Nuklear-Medizintechnik (now Nuvia Instruments, Dresden, Germany), 1 by PTW-Freiburg (Freiburg, Germany), and 16 by former Veenstra Instruments (now Comecer Netherlands, Joure, Netherlands) (see supplemental Table S3).
If applicable, measurements were performed using hospital-specific calibration settings and sample geometry corrections. Otherwise, standard factory settings were used (see supplemental Tables S4-S10). Each sample was measured three times (n=3) keeping the sample in unchanged position. The sample activities at the moment of clinical measurements were almost always above 6 and 10 MBq for respectively diagnostic and therapeutic radionuclides. Each measurement was corrected for background signal and radioactive decay. For each measurement triplet the average net activity (Ām) and standard deviation (SD) were calculated. The statistical measurement uncertainty (um) was estimated at the 95% confidence level (coverage factor k=4.30 for a t-distribution with two (n-1) degrees of freedom), as follows:
This statistical uncertainty (um) was within 0.7% for the large majority (> 75%) of the activity datasets, indicating a good short-term measurement reproducibility.
Evaluation of performance
Individual radionuclides
The radionuclide calibrator measurement accuracy was determined as the percentage deviation of the average measured activity Ām with respect to the sample reference activity Aref.
For each radionuclide and sample geometry, the typical accuracy and reliability of activity measurements was described in terms of the median and the inter-quartile range (IQR) values of the measurement percentage deviations of all systems pooled together. Similarly, these metrics were used to assess the manufacturer dependence of measurement accuracy and inter-system variability.
Theranostic pairs
Finally, since patient tissue doses are proportional to the amount of therapeutic activity administered and in a theranostic approach the amount of therapeutic activity is based on diagnostic imaging, the combined systematic percentage deviation (bias) that would be associated to therapeutic doses (ED) was calculated for the theranostic pairs 131I/123I, 131I/124I, 177Lu/111In, 90Y/99mTc and 90Y/111In, as follows: