Evaluation of the Efficacy and Safety of the ITM

68Ge/68Ga Generator After its Recommended Shelf-life

Tossaporn Sriprapa, M.Sc.*, Thanete Doungta, M.Sc.**, Nopparath Sakulsamart, B.Sc.***, Nilmanee Taweewatthanasopon, B.Sc.*, Lanyawat Madputeh, B.Sc.*, Pitima Ragchana, M.Sc.*, Napamon Sritongkul, M.Sc.*, Malulee Tantawiroon, M.Sc.*, Somlak Kongmuang,****, Benjapa Khiewvan, M.D.*, Shuichi Shiratori, Ph.D.*

*Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, **Thailand Institute of Nuclear Technology,

Bangkok, Thailand, ***Bachelor of Pharmacy, Department of Pharmacy, Mahidol University, ****Department of Pharmaceutical Technology, Department of Pharmacy, Silpakorn University, Thailand.

ABSTRACT

Objective: 68Ga can be routinely produced by a 68Ge/68Ga generator without the need for a cyclotron. It is recommended to replace the 68Ge/68Ga generator after 250 elutions or 12 months of shelf-life whichever endpoint is reached first. However, a 68Ge/68Ga generator that has gone past its recommended lifespan can still be further used as a 68Ga source for 68Ga-labeled radiopharmaceuticals for use in animal experiments. To ensure the quality of 68Ga eluates, we aimed to evaluate the efficacy and safety of the ITM (Isotope Technologies München) 68Ge/68Ga generator in our institute after its recommended shelf-life.

Materials and Methods: A 21-month-old ITM 68Ge/68Ga generator was eluted using 4.0 ml of 0.05 M HCl. The 68Ga elution yields were calculated, and 68Ge breakthrough was measured at least 48 h after elution in an aliquot amount using a multichannel analyzer (MCA) with a high-purity germanium probe. Metal impurities in the 68Ga eluates were analyzed by ICP-MS.

Results: The elution yield of 68Ga was 35.2 ± 8.1%; n = 5 (decay corrected). 68Ge breakthrough from the ITM 68Ge/68Ga generator was below the detectable level. The average amounts of the metallic ions 57Fe, 66Zn, 203Pb, 60Ni, and 63Cu were 18.60, 9.86, 2.42, 0.52, and 0.47 µg/GBq, respectively.

Conclusion: The ITM 68Ge/68Ga generator demonstrated consistent and reliable 68Ga elution profiles with an absence of either 68Ge breakthrough or other metal contaminants in the eluent samples as verified by the manufacturer. The use of the ITM 68Ge/68Ga generator could be extended past its recommended shelf-life to prepare 68Ga radiopharmaceuticals that are considered safe and suitable for use in animal experimentation and other applications.

Keywords: 68Ge/68Ga Generator; 68Ge Breakthrough; 68Ge/68Ga Generator impurities; Gallium-68, 68Ge/68Ga Generator shelf-life. (Siriraj Med J 2023; 75: 752-758)

INTRODUCTION

68Ga is a positron-emitting isotope of gallium with a half-life of 68 min. Over the past two decades, 68Ga-labeled tracers have increasingly attracted more attention in diagnostic molecular imaging and clinical

research. Due to the nearly ideal nuclear properties of radiometals for positron emission tomography (PET) and chelation chemistry using a bifunctional chelating approach (BFCA)1, various classes of 68Ga-labeled tracers have been developed, including 68Ga-DOTA-Bombesin2,

Corresponding Author: Shuichi Shiratori E-mail: Shuichi.shi@mahidol.ac.th

Received 21 July 2023 Revised 25 August 2023 Accepted 9 September 2023 ORCID ID:http://orcid.org/0000-0003-4560-0803 https://doi.org/10.33192/smj.v75i10.264289

All material is licensed under terms of the Creative Commons Attribution 4.0 International (CC-BY-NC-ND 4.0) license unless otherwise stated.

68Ga-NOTA-RGD3, 68Ga-albumin4,5, and 68Ga-DOTA-

hEGF (human epidermal growth factor).6 Moreover, 68Ga was integrated with 177Lu as a twin radiometal for use in a novel theranostic concept.7 As part of precision medicine, tailor-made 68Ga-based radiopharmaceuticals have been robustly employed in diagnostic prostate cancer imaging, including 68Ga-PSMA-HBED-CC (68Ga-PSMA-11®)8,9 and 68Ga-PSMA I&T10,11, and in diagnosing neuroendocrine tumor imaging, including 68Ga-DOTATATE12,13, 68Ga- DOTATOC14,15, and 68Ga-DOTANOC.16,17 Recently, both 68Ga-PSMA-HBED-CC and 68Ga-DOTATATE

were approved by the US FDA for the clinical imaging of prostate cancer and a rare neuroendocrine tumors, respectively. Moreover, a new class of radiotracers based on fibroblast-activation-protein inhibitors (FAPIs) labeled with 68Ga, such as 68Ga-FAPI-0418 and 68Ga-FAPI-4619, have demonstrated high tumor-to-background ratios for PET imaging of a wide array of cancers.

68Ga can be produced in an ionic form of the chemically active 68GaCl3 by two methods: via a medium-energy cyclotron and a 68Ge/68Ga generator. Cyclotron-produced 68Ga is obtained via 68Zn(p,n)68Ga activation using either a target foil or plate in a solid target20 or solution in a liquid target.21 68Ga production utilizing a solid target results in significantly higher yields. However, the target needs manipulating for the production, including for transferring the solid target into the target holder in the cyclotron. Also, after the bombardment, the solid target has to be removed manually or removed via an automated target transfer system to be dissolved in a hot cell. This manipulating and post-processing can put the personnel at a higher risk of radioactive exposure above the risk they already experience in the cyclotron facility, besides being time-consuming during short half-life 68Ga production. On the other hand, the solution in the liquid target approach can be conveniently loaded into the target holder in the same way as done in 18F production. Also, similar to the solid-target approach, 68Ga must be purified from the remaining 68Zn contaminants in the solution, which leads to a lower yield of 68Ga production.

To overcome these limitations, the 68Ge/68Ga generator is used as an alternative approach and indeed is the most common method to produce 68Ga in clinical use, especially in non-cyclotron medical centers. Commercially available, compact-sized 68Ge/68Ga generators, which reflect the efforts of six decades of development22, can provide an acidic solution of 68GaCl3 that is suitable for routine labeling with BFCA through forming an octahedral coordination complex. A typical generator consists of a small chromatographic column, where 68Ge is immobilized with selected absorbents, such as TiO2,

SnO2, pyrogallol-derivatized SiO2, and a mixed matrix, situated in a shielding lead container. 68Ge, a parent radionuclide, spontaneously decays in the column to give 68Ga, with typical yields of 70%–80% in the elution. Secular equilibrium, where both 68Ge and 68Ga have equal radioactivity, in the 68Ge/68Ga generator occurs due to the half-life of 68Ge (270 d) being over 100 times longer than that of 68Ga (68 min). Theoretically, 68Ga accumulated from previous elutions means the system can reach secular equilibrium in around 14 h. Almost 100% 68Ga can be produced after 6 h post elution. Most manufacturers suggest that the 68Ga production cycle for clinical use can be repeated up to 2–3 times a day depending on the generator-loaded radioactivity and the age of the generator.

The first 68Ge/68Ga generator was launched worldwide beginning in the late 1990s. Some of its many advantages that deserve mentioning include the stable column matrices, easy elution, long shelf-life of 1–2 years, effective shielding container, and compact size. Each 68Ge/68Ga generator manufacturer offers various parameters in terms of different types of column matrix, molarity of the HCl eluent, 68Ga volume of elution, 68Ge breakthrough and impurity amount, and weight of the generator, as shown in Table 1.

Although it is necessary to replace a new 68Ge/68Ga generator for clinical use after its recommended shelf-life, the “expired” 68Ge/68Ga generator can actually continue to be employed to elute 68Ga to label certain 68Ga-based radiopharmaceuticals for research purposes, especially for animal experimentation. In the present study, the essential parameters of an over-lifespan ITM 68Ge/68Ga generator (i.e., used past its recommended lifespan) were evaluated to ensure its efficacy and safety for continuing 68Ga elution.

MATERIALS AND METHODS

A SiO2-based 68Ge/68Ga generator was purchased from Isotope Technologies München (ITM) Medical Isotopes GmbH, Germany (previously, Isotope Technologies Garching (ITG)). All the solvents and reagents were purchased from commercial suppliers and used without further purification. 0.05 M HCl (GMP) was purchased from ABX Advanced Biochemical Compounds.

The 68Ga activity was measured with a dose calibrator (CRC25R, Capintec, USA). The 68Ge activity was measured by gamma-ray spectrometry using a multichannel analyzer, A multichannel analyzer (MCA) integrated gamma spectrometer system (Ortec DSPEC jr 2.0) coupled with a high-purity germanium probe (HPGe probe, Ortec Gem20P4-70) was used in the experiments. The

TABLE 1. Characteristics of some commercially available 68Ge/68Ga generators.

Generator specifications

Company

Column

material

Eluent

68Ge

breakthrough

Elution

volume

Metallic

impurities

Weight of

generator

Eckert & Ziegler

Ga < 1 µg/mCi

Eckert & Ziegler IGG100 and IGG101

GMP (Gallia Pharm)23

TiO2

0.1 M HCl < 0.001%

5 ml

Fe < 10 µg/mCi IGG100 = 10 kg

Zn < 10 µg/mCi IGG101 = 14 kg

Cyclotron Co. Ltd. TiO2 0.1 M HCl < 0.005% 5 ml Ni < 1 µg/mCi 11.7 kg (Obninsk)23

iThemba LABS, SnO

0.6 M HCl < 0.002% 5 ml 1–20 ppm for Sn,

Pars Isotope (PARS- GalluGEN®), Tehran,

Iran23

SnO

2

0.6 M HCl < 0.00002%

>1 ppm for Fe,

Sn and Zn

South Africa23 2

Fe, Cu, Mn, and Al

< 10 µg/GBq of

Fleurus, Belgium

metal-ion impurities in the 68Ga eluates were analyzed by inductively coupled plasma-mass spectrometry (ICP‐ MS).

Evaluation of 68Ga elution

A 21-months-old 68Ge/68Ga generator (Isotope Technologies München (ITM) Medical Isotopes GmbH, Germany) loaded at the manufacturer site with 68Ge 50 mCi was used for the study evaluation. Before starting the experiments, the generator was eluted with 30 ml of

0.05 M HCl to wash away 68Ge breakthrough and other impurities accumulated in the pyrogallol-formaldehyde resin column as recommended by the manufacturer

68Ge breakthrough measurement

68Ge breakthrough was measured after the separated 68Ga eluates were allowed to decay for at least 48 h to a level where the 68Ge activity could be indirectly detected as a decay product. All the eluates were measured under the following conditions: constant geometry using 1.5 ml, placed at a distance of 10 cm from the detector, and then all the decayed samples were counted to determine 68Ge breakthrough with a measuring time of 1,000 sec per fraction and with a dead time of less than 10%. Due to the half-life of 68Ge being much longer than that of 68Ga, the activity of 68Ga was theoretically calculated by using the secular equilibrium equation26 (Equation 1):

because the system had not been used for several months.

At = A0 = (1-e(ln 2/t1/2)t) (Equation 1)

The ITM 68Ge/68Ga generator was manually eluted with

4.0 ml of 0.05 M HCl. Subsequently, the elution profile

Ga Ge

where At and A0

are 68Ga activity at time points

Ga Ge

was studied by collecting the eluates in fractions of 1 ml for 4 fractions. The elution yield of 68Ga activity in each fraction was immediately determined in a dose calibrator.

t after elution and 68Ge activity when co-eluted (i.e., at breakthrough), and λ = ln 2/t1/2

The percentage of 68Ge-breakthrough in all the samples should be lower than 0.005%. (According to the generator specification and 68GaCl3 monograph.)

Metal impurities measurement

The potential metal-ion impurities in the 68Ga eluates were analyzed by inductively coupled plasma- mass spectrometry (ICP‐MS) after the fractionated 68Ga eluates had been allowed to decay for at least 48 h. The trace metals of interest were 57Fe, 60Ni, 63Cu, 66Zn, and 208Pb measured as contaminants per elution and per fraction. The operating conditions for the ICP‐MS during the measurements were as follows: plasma power, 1550 W; cool flow, 14 L/min; auxiliary flow, 0.8 L/min; nebulizer flow, 1.043 L/min; helium flow, 0 ml/min; sampling depth, 5 mm; spray chamber temp, 2.7 °C; and pump speed, 40 rpm.

To determine the contents of these metals, calibration standards containing these elements in the following concentration were prepared to obtain a concentration series for the calibration curve: 1, 10, 50, and 100 ppb. The generator eluent was diluted by a factor of 5 with

0.05 M HCl. The 0.05 M HCl was further measured as the blank sample.

Results and Discussion

Generator elution and elution yield

68Ga activity in each eluate (mCi)

At 21 months after its last calibration date, the GMP- certified ITM 68Ge/68Ga generator contained 10.643 mCi of 68Ga. The elution yield of 68Ga was 35.2 ± 8.1%; n = 5 (decay corrected), ranging from 28.6% to 44.3%. The elution yield decreased with a linear trend in a similar pattern to in a previous report (R2 = 0.957)27 over the course of the study. The majority of the 68Ga activity was found in fractions 2 to 4. The elution profiles of

each eluate are shown in Fig 1. Slightly different elution profiles were observed with the activity eluted in fractions 2–3 compared to in fractions 2–4 at the beginning time of the generator operation.

68Ge breakthrough measurement

68Ge breakthrough is expressed as a percentage of 68Ge activity on the elution day relative to 68Ga activity at calibration time. In this study, 68Ge breakthrough from the ITM 68Ge/68Ga generator could not be detected as the minimal sensitivity of the HPGe probe was 10- 5%. However, a previous report by Chakravarty et al mentioned that the 68Ge breakthrough of a SiO2-based

68Ge/68Ga generator was always <10-3% over the period

of 1 year.27

68Ge was strongly absorbed on the pyrogallol- formaldehyde resin column. The breakthrough of 68Ge in all the samples was below the detectable level over the extended periods of generator usage (lower than 0.005% according to the generator specification and 68GaCl3

monograph). According to the recommendation of a

monograph of the European Pharmacopeia, the limitation for 68Ge breakthrough could be high as >100 times the safety level for patients.28 The decreased percentage 68Ge breakthrough (down to 0.0012%) showed the beneficial characteristics of the ITM generator, which could be extrapolated to an overall decrease in radiolysis.29 Therefore, the level of 68Ge breakthrough from the ITM 68Ge/68Ga generator after its recommended shelf-life was considered acceptable for both basic research as well as animal imaging research.

3

68Ga elution profiles

2.5

2

1.5

1

0.5

0

Fraction 1 Fraction 2 Fraction 3 Fraction 4

Elution fraction (ml)

Fig 1. 68Ga elution profiles of a 21-month-old ITM 68Ge/68Ga generator after its recommended shelf-life.

Metal impurities

The common chemical impurities of concern in 68Ga elution are the metallic ions Fe, Zn, Pb, Ni, and Cu. These metal impurities are generally expressed in mg/l (ppm). The average amounts of the metallic ions Fe, Zn, Pb, Ni, and Cu found in this study were 18.60, 9.86, 2.42, 0.52, and 0.47 µg/GBq, respectively. The analysis results for the metal impurities are shown in Table 2. Although the excess amount of Fe3+ (approximately 8 µg/GBq) in the eluent from the over-lifespan ITM 68Ge/68Ga generator could potentially compete with 68Ga during complex formation30,31 to reduce the radiochemical yield (RCY), the calculated radioactivity of the final product here was more than 0.3 mCi (1.1 MBq), which was still enough

for use in animal experiments and studies.32 Moreover, the Fe3+ residue can be removed in a purification step by reversed-phase Sep-Pak (C-18). Therefore, the radiochemical purity (RCP) of the final product can be obtained in the same quality as required for use in clinical practice.

Other metallic ions, such as Pb, Cu, and Ni, were found in amounts of less than 10 µg/GBq according to the eluate specification. Since the ITM generator employed a modified dodecyl-3,4,5-trihydroxybenzoate hydrophobically bound to an octadecyl-modified silica resin, which allows its authorized marketing in Europe as a pharmaceutical-grade generator29, the other metallic contents of the eluate were found to be extremely low.

TABLE 2. Analysis of the metal impurities in the 68Ga eluate using inductively coupled plasma-mass spectrometry (ICP-MS)

CONCLUSION

The manufacturer’s recommended lifespan for the pyrogallol-formaldehyde resin-based 68Ge/68Ga generator produced by ITM GmbH Germany is 12 months or 250 elutions; however, it still provides an adequate amount of 68Ga eluent that could be effectively used to prepare 68Ga-radiopharmaceuticals for basic research after 21 months, long past its recommended shelf-life. The ITM 68Ge/68Ga generator demonstrated consistent and reliable 68Ga elution profiles with the absence of 68Ge breakthrough in the eluant samples as verified by the manufacturer. Even though free Fe ions were found in an excess amount of 18 µg/GBq, which can affect the RCY, the radioactivity in the final product was still enough for animal experiments and studies. The other metallic ions Zn, Pb, Ni, and Cu, except Fe, were all less than 10 µg/GBq as indicated in the manufacturer’s specification. Therefore, the ITM 68Ge/68Ga generator has enhanced use beyond its recommended shelf-life to prepare 68Ga radiopharmaceuticals that are considered safe and suitable for further animal experiments and studies.

ACKNOWLEDGEMENTS

The dissertation was financially supported under Grant no. DO2875 of Liam Tuntawiroon, Siriraj Foundation.

Conflict of interest: All authors declare that they have no conflicts of interest.

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