Y-90 Microsphere measurement study N.Baird

Yttrium 90 Glass Microspheres: Dose Calibrator Measurement Performance Studies

N. Baird BSc. MLTRadiopharmaceutical Technical Support, Nordion, Ottawa Ontario Canada

Abstract

Yttrium-90 glass microspheres are commonly used in the treatment of unresectable hepatocellular carcinoma (HCC). The radiation measurement systems and methods used are critical to the accurate and repeatable assessment of various dose sizes during manufacture and prior to patient administration. Radionuclide dose calibrators provide an ion chamber based technology for the measurement of Y-90 microspheres that requires the measurement elements of precision, linearity and accuracy. This study of Y-90 microsphere radiation measurement across all dose sizes with multiple measurements in multiple dose calibrators is summarized.

Keywords: Yttrium-90, microspheres, hepatocellular carcinoma, radionuclide dose calibrator

1. Introduction

Theraspheres® are commercially available 10-35um Yttrium-90(Y-90) microspheres. Dose sizes are dispensed gravimetrically based on an initial specific activity assessment. Total radioactivity sizes from 3 Gigabecquerels (GBq) to 20GBq are manufactured. The radioactivity is calibrated to a 12:00 noon eastern calibration date. Y-90 microspheres are dispensed in 600uL of water for injection in a 2mL v-vial configuration and the sealed/crimped vial is encapsulated in a lucite shield (figure 1). Both the filled bare vial and the lucite configuration represent the product geometry for radioactive measurement. Y-90 is a high energy beta isotope (2.28MeV) and a 64.1 hour half life.

Radionuclide dose calibrators are gas filled ion chamber based detectors. In the case of Y-90, secondary electromagnetic radiation (Bremsstralung) is measured when it strikes the walls of the dose calibrator chamber. The specific ion chamber used, source holder, sample configuration and internal sleeve of dose calibrators are variables that add to the overall geometry profile of radiation measurement. Commercially available dose calibrators (Capintec®) as used in this study have consoles that receive the ion chamber signal and convert it by means of a gain setting to a usable value based on manufacturer’s standard measurements. The units in this study underwent routine day of use voltage, background and constancy tests. Semi-annual maintenance, accuracy and linearity checks were performed.

figure1: Final v-vial configuration of Y-90 microspheres encapsulated in lucite shielding. Picture printed with permission from Nordion.

2. Method Samples of 23, 15,10,5 and 3GBq Therasphere samples were gravimetrically dispensed and steam sterilized as per standard manufacturing procedures. The 23GBq was dispensed to reflect the top end activity measurement for linearity purposes. The samples were measured in triplicate in each of three defined dose calibrator configurations (figure 2). Two of the three configurations have known geometry factors with total activity confirmed annually by the National Institute of Standards Technology (NIST). NIST uses a Capintec® CRC-12 dose calibrator and provides reference measurements for total activity of Therasphere® (figure 3). Each configuration has a detailed installation and operational qualification with controlled drawings associated with the physical characteristics of the geometry. An example of the controlled dose calibrator configuration is captured in figure 4.

Yttrium-90 Glass Microspheres: Dose Calibrator Measurement Studies of Repeatability, Reproducibility, Linearity and Accuracy N.Baird

Device# Instrument Description

Gain Setting Geometry Factor (NIST Referenced)

Configuration

1 Capintec CRC-12 Radionuclide dose calibrator

47.5 10.1 Bare 2mL v-vial measured in ion chamber recessed in a nuclear cell in lead shielded castle with mechanical hoist (defined depth) and vial holder (defined dimensions)

2 Capintec CRC-12 Radionuclide dose calibrator

44.8 10.1 Lucite encapsulated v-vial measured in ion chamber recessed in a bench top in lead shielded castle with defined manual holder

3 Capintec CRC-35R Radionuclide dose calibrator

Y-90 (48 x10) defined by manufacturer

TBD Bare 2mL v-vial measured in ion chamber recessed in a nuclear cell in lead shielded castle with mechanical hoist (defined depth) and vial holder (defined dimensions)

Figure 2: Defined dose calibrator configurations used for measurement of Y-90 microspheres.

Reference Date March 21, 2010

Dose Calibrator

Dose size (GBq)

NIST Reference Measurement/Uncertainty

Manufacturer Measurement/Uncertainty

Manufacturer % Difference from Reference Value

1 3 3.01/±3.8% 3.01/±2.84% 0.0

1 20 19.5/±3.8% 19.7/±2.84% 1.03

2 3 3.11/±3.7% 3.12/±2.86% 0.32

2 20 20.2/±3.8% 20.3/±3.84% 0.50

Figure 3: National Institute of Standards Technology measurements of Y-90 microspheres in comparison to manufacturer values including specified geometry factor.

Repeatability: For the purposes of this study, repeatability was defined as the variation between three consecutive measurements performed by the same analyst by means of removing and replacing the source in the same measurement configuration and recording separate total activity data points. All dose sizes were measured in triplicate in all dose calibrators over five time points.

Reproducibility: For the purposes of this study, reproducibility was defined as the variation observed between decay corrected values when compared from completely separate measurement time points. Since the geometry is mechanically defined and restricted, analyst to analyst variation was not of practical concern. Decay corrected values incorporate a half-life calculation of measurements to a standard date and time and comparison of those measurements within each dose calibrator.

Accuracy: For the purposes of this study, accuracy was defined as “closeness to the reference value”. The reference value was defined as the NIST measurements depicted in figure 3.

Linearity: Linearity was defined in two ways. 1) Y-90 microspheres are dispensed gravimetrically from a homogeneous target ampoule of 2500mg. The 20GBq

(maximum 216mg) and 3GBq (minimum 22mg) have been defined as accurate measurements in dose calibrator configuration. Since the geometry factor has been defined as the same between (10.1) for all dose sizes measured in the NIST tested configurations, an assessment of a fractionation curve can be established. A 5-point standard curve represented by an R-Squared value will be calculated as a method to assess linearity.

2) Y-90 microspheres have a time decay curve consistent with the half-life of 64.1 hours. A time decay assessment over a period in excess of 14 days represents the Therasphere® product maximum manufacture to expiry shelf life and is a


representation of a combined product and dose calibrator linearity.


Further to the repeatability and reproducibility assessment, Table 8 summarizes the data from all vial measurements. A scan of the standard deviation column confirms that the variation from multiple measurements at the same time is negligible. Reproducibility measurements for the purposes of this study are reflected at different days in both the measured values and calibration values. The calibration values incorporate the geometry previously calculated from NIST comparisons (10.1) grown in to the date and time of manufacture. These values are a reflection of the variation of the Therasphere® product from a reportable result perspective. For example, the range of 3GBq is 3.0714 to 3.1505. The 3.1505 value is a measurement point grown in from a 14MBq measurement. At this level of measurement, small variation such as background, geometry variation or impurity ingress can affect the value. For example, suppose that a 1 MBq (27uCi) shift from 14MBq to a15GBq occurred. The value of 3.1505 would move to 3.36GBq. This would move the 3.1505GBq out of specification. The specification limit is of a 3GBq dose vial is 2.7-3.3GBq.

The product linearity was measured by an R-squared value. The 20GBq and 3GBq dose sizes are traceable to NIST as previously indicated. The multiple gravimetric vial dispensings of microspheres could be compared with counting beads. The values of certain activity values can be correlated to gravimetric values and vice versa. The perfect linear model has an R-square value of 1.00. The worst case R-square observed in this study was 0.9995. Linearity was also assessed by means of time decay. Figure 7 depicts the time decay linearity study of five dose vials of Therasphere®. Later on in this time decay curve at the day 15-16 time- point values appear to have higher differences from the expected day-0 value. As was observed in the case where low activity vials are more sensitive to variances such as background, geometry and impurity ingress the same thing could be suggested in time decay linearity.

figure4: Dose calibrator geometry configuration of a dose calibrator. The holder and pneumatic hoist ensures repeatable location of v-vials in a repeatable configuration. All items have controlled drawings to ensure physical dimensions. 3. Data Summary and Analysis Raw dose calibrator measurement data was collected over a 16-day period. The decay of Y-90 microspheres over that period of time resulted in a range of measurement from covering approximately six half-lives. The measured values were ≈ 6.06GBq to 0.014GBq. Since the dose calibrator measures secondary radiation, the raw data values are about 1/10th of the actual value. This is accounted for in the geometry factor of 10.1 as indicated in figure 2. The CRC-35R dose calibrator has a factory pre-set gain value for Y-90 of 48 x10. In this case the dose calibrator displays values 10 times greater than the CRC-12.Gage R&R Study Minitab version 15 statistical software was used to assess the repeatability and reproducibility of the activity data. Each time point was decay corrected to the date and time of manufacture in order to perform comparisons. All decay corrected values were calculated based on the identical 64.1 hour half- life. Each individual measurement system was assessed as per the example in figures 5. All three dose calibrator configurations showed similar results.


Figure 5: Gage R&R analysis of a dose calibrator configuration in the study. The major portion of the measurement variability is the individual parts (Therasphere vial) and a very small proportion is attributable to repeatability and reproducibility error.


Day 0Dose size (GBq)

Mass (mg)

Bare vial CRC-12 Dose cal #1 Ave. Std dev.

Activity at manufacture at cal Sun.

Lucite CRC-12 Dose cal # 2 Ave Std. dev

Grow in to manufacture at cal Sun.

Bare vial CRC-35R Dose Cal # 3 Ave Std. dev.

Grow in to manufacture at cal Sun.

1 22 181 6.0600 0.0000 6.0600 23.2522 5.0733 0.0115 6.2301 23.9089 49.3000 0.0000 61.1813 23.24992 15 123 4.0900 0.0000 4.0900 15.6933 3.4200 0.0000 4.1998 16.1173 33.3000 0.0000 41.3253 15.70433 10 75 2.5900 0.0000 2.5900 9.9378 2.1533 0.0058 2.6443 10.1479 21.2000 0.0000 26.3092 9.99794 5 40 1.3893 0.0006 1.3893 5.3309 1.1683 0.0015 1.4347 5.5060 11.3967 0.0153 14.1433 5.37475 3 23 0.8023 0.0006 0.8023 3.0785 0.6753 0.0006 0.8293 3.1826 6.5933 0.0208 8.1823 3.1094

R-sq 0.9998 0.9998 0.9997Day 5

1 22 181 1.7293 0.0015 6.0297 23.2616 1.8813 0.0015 6.2144 23.8447 18.7767 0.0115 61.4692 23.35212 15 123 1.1690 0.0010 4.0760 15.7244 1.2740 0.0010 4.2083 16.1471 12.7500 0.0173 41.7397 15.85693 10 75 0.7393 0.0006 2.5778 9.9449 0.8070 0.0010 2.6657 10.2282 8.0533 0.0058 26.3642 10.01584 5 40 0.3987 0.0006 1.3900 5.3625 0.4340 0.0000 1.4336 5.5007 4.3400 0.0000 14.2079 5.39765 3 23 0.2283 0.0006 0.7961 3.0714 0.2510 0.0000 0.8291 3.1813 2.5200 0.0058 8.2497 3.1341

R-sq 0.9998 0.9998 0.9998Day 8

1 22 181 0.8340 0.0000 6.0663 23.2765 0.8740 0.0000 6.2211 23.8704 8.1133 0.0058 61.2914 23.28462 15 123 0.5620 0.0000 4.0879 15.6851 0.5913 0.0006 4.2091 16.1503 5.5000 0.0000 41.5492 15.78453 10 75 0.3603 0.0006 2.6210 10.0567 0.3740 0.0010 2.6621 10.2146 3.4967 0.0058 26.4152 10.03514 5 40 0.1907 0.0006 1.3869 5.3214 0.2003 0.0006 1.4260 5.4714 1.8780 0.0017 14.1872 5.38975 3 23 0.1106 0.0001 0.8045 3.0868 0.1171 0.0002 0.8333 3.1973 1.0880 0.0020 8.2192 3.1225

R-sq 0.9995 0.9998 0.9997Day 12

1 22 181 0.2787 0.0006 6.0746 23.3082 0.3013 0.0006 6.2230 23.8775 3.0333 0.0058 61.3028 23.28892 15 123 0.1880 0.0000 4.0982 15.7247 0.2047 0.0006 4.2267 16.2177 2.0600 0.0000 41.6320 15.81603 10 75 0.1195 0.0001 2.6050 9.9952 0.1302 0.0001 2.6888 10.3170 1.3087 0.0012 26.4478 10.04754 5 40 0.0640 0.0001 1.3951 5.3531 0.0700 0.0001 1.4456 5.5468 0.7057 0.0012 14.2613 5.41795 3 23 0.0370 0.0001 0.8058 3.0920 0.0406 0.0001 0.8385 3.2171 0.4097 0.0006 8.2792 3.1453

R-sq 0.9997 0.9997 0.9998Day 15-16

1 22 181 0.1058 0.0001 6.1699 23.6738 0.1400 0.0000 6.2674 24.0480 1.3997 0.0021 61.9530 23.53602 15 123 0.0713 0.0001 4.1580 15.9541 0.0958 0.0001 4.2902 16.4615 0.9510 0.0000 42.0938 15.99143 10 75 0.0450 0.0001 2.6242 10.0692 0.0607 0.0001 2.7174 10.4265 0.6033 0.0006 26.7052 10.14534 5 40 0.02413 0.00006 1.40737 5.40008 0.03270 0.00010 1.46389 5.61693 0.32333 0.00289 14.31161 5.436985 3 23 0.01500 0.00002 0.87475 3.35640 0.01899 0.00000 0.85013 3.26194 0.19137 0.00127 8.47041 3.21791

R-sq 0.9998 0.9998 0.9998

Figure 6: Day 0 vs Day 15-16 data. R-squared values are derived from the mass and total activity values.

Dose calibrator #1 Activity Day 0 GBq day5 day5 % diff day8 day8% diff day12 day12% diff day16 day16 % diff23 6.060 6.030 0.501 6.066 -0.105 6.075 -0.241 6.170 -1.81315 4.090 4.076 0.343 4.088 0.052 4.098 -0.200 4.158 -1.66210 2.590 2.578 0.470 2.621 -1.197 2.605 -0.577 2.624 -1.322

5 1.389 1.390 -0.050 1.387 0.177 1.395 -0.417 1.407 -1.2993 0.802 0.796 0.773 0.804 -0.268 0.806 -0.436 0.821 -2.339

Dose calibrator #2 Activity Day 0 GBq day5 day5 % diff day8 day8% diff day12 day12% diff day15 day15 % diff23 6.230 6.214 0.251 6.221 0.143 6.223 0.113 6.267 -0.60015 4.200 4.208 -0.203 4.209 -0.223 4.227 -0.641 4.290 -2.15310 2.644 2.666 -0.809 2.662 -0.675 2.689 -1.684 2.717 -2.764

5 1.435 1.434 0.078 1.426 0.609 1.446 -0.759 1.464 -2.0343 0.829 0.829 0.025 0.833 -0.479 0.838 -1.102 0.850 -2.511

Dose calibrator #3 Activity Day 0 GBq day5 day5 % diff day8 day8% diff day12 day12% diff day15 day15 % diff23 61.181 61.469 -0.471 61.291 -0.180 61.303 -0.199 61.953 -1.26115 41.325 41.740 -1.003 41.549 -0.542 41.632 -0.742 42.094 -1.86010 26.309 26.364 -0.209 26.415 -0.403 26.448 -0.527 26.705 -1.505

5 14.143 14.208 -0.457 14.187 -0.310 14.261 -0.835 14.312 -1.1903 8.182 8.250 -0.824 8.219 -0.450 8.279 -1.184 8.470 -3.521

Figure 7: Time decay values for Therasphere® product measurement in three dose calibrators over 15 to 16 day period.



Conclusions:

Radionuclide dose calibrators have the capacity to measure Yttrium-90 microspheres to certain radioactivity levels provided appropriate controls are established. As defined in this study the devices are repeatable and reproducible for measurements from 6.06GBq to 14MBq. In order to achieve this capacity, each individual configuration must be maintained in terms on of geometry. Small variations at the low levels of activity can cause amplified grow in value differences. Due to the nature of Y-90, dose calibrators measure secondary radiation. In cases where older dose calibrators are used, factory multipliers may not be published in the manual as is the case with the CRC-12 models used in this study. In later models such as the CRC-35R, values for Y-90 are published as setting 48 x 10. Accuracy is achieved by comparison of measured vials to a reference as is the case with the NIST comparisons performed in this study. Once again, the overall geometry must be maintained in order to achieve accurate data.

Later in Y-90 microsphere time decay linearity analysis, measurements appear to lose correlation to the original measurement values. With Therasphere® this happens beyond expiry and may be attributable to the capability of the dose calibrator at low levels of measurement or radioactive impurity ingress. Time zero linear analysis can be performed by means of calculating an R-square value based on the gravimetric dispensing of specific amounts of beads versus the radioactivity measurement.

Dose calibrators are unique in terms of their capacity to deliver accurate and precise information. Each system must have a repeatable configuration in order to apply a reliable correction factor. Items such as vial configurations and volumes, location of the sample in the holder, dose calibrator sleeves, varying ion chambers with different consoles, contamination or background effects may affect results. Given the fact that these devices are used for critical measurements of patient doses it is recommended that all these elements be controlled.


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Y-90 Microsphere measurement study N.Baird