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ORIGINAL ARTICLE
Year : 2021  |  Volume : 36  |  Issue : 3  |  Page : 282-287  

Installation and optimization of 68Ga synthesis module for clinical use: An institutional experience


1 Department of Nuclear Medicine, Kailash Cancer Hospital and Research Centre, Muni Seva Ashram, Vadodara, Gujarat, India
2 Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital; Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission22-Jan-2021
Date of Decision09-May-2021
Date of Acceptance29-May-2021
Date of Web Publication23-Sep-2021

Correspondence Address:
Mr. Sachin Tayal
Department of Nuclear Medicine, Kailash Cancer Hospital and Research Centre, Muni Seva Ashram, Goraj, Vadodara, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijnm.ijnm_7_21

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   Abstract 


Introduction: With advent of gallium-labeling somatostatin analogs and its evaluation under positron emission tomography–computed tomography, there has been a tremendous surge in its application. Gallium 68 can be made available either from onsite cyclotron production or in the form of ready-to-use 68Ge/68Ga generators. Wherein setting up and running of cyclotron amounts to huge investment and dedicated team, the 68Ge/68Ga generator has proved to be a better option and viable project. Moreover, due to long half-life of 68Ge, i.e. 271 days, it enables the usage of generator for several months. The preparation of gallium-labeled peptides is much simpler in comparison to 18F radiochemistry, but the radiation exposure has always been an area of concern owing to high-energy annihilation photon of 511 keV. Materials and Methods: In this study, we share our experience of self-installation of 68Ge/68Ga generator during lockdown and the various steps involved in installation of fully automated peptide-labeling system in customized mini hot cell module, synthesis steps, and quality control steps of gallium-based radiopharmaceutical. Results: The installation was successfully completed with online assistance during the pandemic situation. The average elution yield met company specification (>80%), and 68Ga-labeled peptides were prepared with high radiochemical purity (>95%). The overall exposure in single batch of production and quality control never exceeded 3 μSv as shielding was well-taken care of with customized mini hot cell. Conclusion: With the described experience and validation process, one can easily think of making an installation at his/her center and cater to the needs of society with a new radiopharmaceutical.

Keywords: 68Ga prostate-specific membrane antigen-11, mini hot cell, positron emission tomography–computed tomography, quality control


How to cite this article:
Tayal S, Ali A, Kumar V, Jha AK, Gandhi A. Installation and optimization of 68Ga synthesis module for clinical use: An institutional experience. Indian J Nucl Med 2021;36:282-7

How to cite this URL:
Tayal S, Ali A, Kumar V, Jha AK, Gandhi A. Installation and optimization of 68Ga synthesis module for clinical use: An institutional experience. Indian J Nucl Med [serial online] 2021 [cited 2021 Dec 8];36:282-7. Available from: https://www.ijnm.in/text.asp?2021/36/3/282/326554




   Introduction Top


Gallium-68-based radiopharmaceuticals have been established for cancer imaging worldwide. Gallium is available in the form of 68Ge/68Ga generator and due to long half-life of 68Ge, i.e. 271 days; it enables the usage of the generator for several months. Long shelf-life of generator makes it easily available in any part of the world.[1] The availability of 68Ga elute at any time and ease of 68Ga-based radiopharmaceutical synthesis gives 68Ga radiopharmaceuticals significant edge over the 18F-based radiopharmaceuticals, which is only available from cyclotron.[2] The few most important aspects of development of 68Ga radiopharmaceuticals are the versatility of 68Ga chemistry, short half-life of 67.7 min, and development of small tumor-affine peptides.[3] Notably, the development of targeted somatostatin receptor peptides, i.e., DOTA-TOC, NOC, and TATE, is one of the major breakthroughs in the development of 68Ga radiopharmaceuticals.[4] The advent of small peptides and short half-life of 68Ga enables the rapid pharmacokinetics resulting in low radiation burden to the patient.[5] Among the various peptides available, DOTA peptides and prostate-specific membrane antigen (PSMA)-11 had gained wide popularity. On the one hand, 68Ga DOTA octreotide derivatives were the breakthrough vector molecules and were fundamental for development of present-day 68Ga radiopharmacy and the 68Ge/68Ga generator;[6],[7] on the other hand, 68Ga-labeled PSMA-11 proved to have a significant impact in management of prostate cancer patients.[8],[9],[10] Although the preparation of gallium-labeled peptides is much simpler in comparison to 18F radiochemistry, the radiation exposure has always been an area of concern owing to high-energy positron of 1.92 MeV with a mean energy of 0.89 MeV and annihilation photon of 511 keV. Hence, mini hot cell becomes important to reduce radiation burden to professionals. Our hospital is a dedicated cancer hospital and situated in a rural area of western state of India, i.e. Gujarat. We have dedicated nuclear medicine department with one positron emission tomography/computed tomography (PET/CT), one single-photon emission computerized tomography/CT, and high-dose therapy ward. Being a cancer hospital, we were also encouraged by our administration to have 68Ga chemistry laboratory in our department. We placed an order for mini hot cell, 68Ge/68Ga generator, 68Ga synthesis module, and consumables, which was delivered in the 2nd week of March 2020 amid the pandemic situation of COVID-19. The whole world had almost come to a halt, and the health-care services for oncological patients were also affected, with no exception to nuclear medicine department. Because of shutdown of all transport services, there was a halt to production and supply of the most commonly used 18F-labeled radiopharmaceutical and 99Mo-99mTc generators. On top of this, we were facing a challenge to installation of 68Ge/68Ga generator with automated synthesis module which had reached just few days before announcement of lockdown. With the passage of each day, the uncertainty of its functioning was piling on, and the buildup of 68Ge along with impurities such as Zn (II) from decay of 68Ga was bound to increase.[11] The company person who had to come for installation was stuck up due to transportation lockdown, and we were left with no way out. We thought of taking the tasks of installation by ourselves with online assistance from supplier, keeping the instruction manual by our side to come out of this phase of lockdown. We also decided to establish the synthesis and quality control procedure to start operation in our department. In the present study, we have shown the various steps involved in installation of a fully automated peptide-labeling system in a mini hot cell module, synthesis steps, and the quality control step of the gallium-based radiopharmaceutical.


   Materials and Methods Top


Installation of equipment

Installation process was executed locally by us under the online supervision of the installation engineer. We sequentially installed all the components of synthesis module required for routine synthesis of 68Ga radiopharmaceutical for clinical operations.

Installation of mini hot cell

The mini hot cell was specially customized to meet our requirements of shielding. The cell is comprised of three compartments [Figure 1]. The middle compartment shown in [Figure 1] was the one which is designed to install the synthesis module with generator, and this compartment has shielding of 45 mm of lead all around. It has power supply required to run the automated synthesis module. We got this hot cell installed with the help of our local support staff and electrical engineering department.
Figure 1: Hot cell to house 68Ga iQS-TS Synthesis module, ITG, Germany

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Installation of Automated synthesis module and 68Ge/68Ga generator

iQS-TS Synthesis module, ITG, Germany

It is an automated cassette-based synthesis module approved by European agency as Good Manufacturing practice (GMP) certified module. It has capability to synthesis 68Ga-based radiopharmaceuticals by automated process of elution, formulation, and purification of radiopharmaceuticals such as 68Ga-DOTATOC, 68Ga-PSMA-11, 68Ga-exendin, and 68Ga-RGD. The specialized cassette with consumable is required for the synthesis of specific 68Ga-based radiopharmaceuticals.

itG 68Ge/68Ga Generator, ITG, Germany

This generator has nonmetallic column (silica gel-modified dodecyl gallate) which does not require prepurification steps unlike metallic column 68Ge/68Ga generator. The column can be eluted by 0.05 M HCl solution. This is a self-shielded generator with lead shielding of 36–50 mm thick.

Installation

We installed itG 68Ge/68Ga Generator, fully automated iQS-TS Synthesis module, and mini hot cell in our laboratory maintaining hygienic condition and keeping radiation safety in mind. We dressed up with personal protective equipment kit and first examined the parcel containing the 68Ge/68Ga generator with fully automated synthesis module for any physical damage or sign of leakage visible externally and then disinfected by spraying sanitizer on its outer surface and proceeded for unpacking taking a snapshot of the received material for documenting the quantity and condition of the material on receipt. Two major components, a synthesis module with a laptop and the 68Ge/68Ga generator, were unpacked. Synthesis module and generator were installed in the hot cell first. After installation of both in hot cells, synthesis cassette was installed in the synthesis module and the outlet and inlet tube of generator was connected with the respective port of cassette of the synthesis module. All the electric connection of synthesis module and laptop was established and power was switched on.

Testing of equipment postinstallation

After the laptop and synthesis module were switched on, we opened the synthesis module software Isotope Technologies Garching (ITG) Theranostics Synthesizer (iQS-TS) software version 2.30 on the laptop. Software established connection with hardware of synthesis module successfully, and mechanical test was performed automatically and completed successfully. Following the successful installation, we performed rinsing of the generator as described in [Figure 2].
Figure 2: Elution of 68Ge/68Ga generator

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Postsuccessful rinsing, we together with online installation engineer accepted this synthesis module for routine operations.

Synthesis of radiopharmaceuticals

Preparation of reagents

The stock peptide, 500 μg of PSMA-11, was dissolved in 3 mL of ultrapure water, and 30 aliquots of 100 μL each were dispensed in 1 mL Eppendorf tube aseptically, closed and stored at −20°C. Similarly, the stock peptide, 1000 μg of DOTATOC, was dissolved in 3 mL of ultrapure water, and 30 aliquots of 100 μL each were dispensed in 1 mL Eppendorf tube aseptically and stored at −20°C. On the day of synthesis, one Eppendorf containing peptide (PSMA-11/DOTATOC) was taken out and allowed to attain room temperature before use.

Radiopharmaceutical synthesis process in iQS-TS Synthesis module is an automated process which involves several steps. The entire synthesis process can be divided into four sections, mechanical testing, presynthesis steps, radiopharmaceutical synthesis, and filter integrity test. Entire process is summarized in [Figure 3].
Figure 3: 68Ga radiopharmaceutical synthesis sequence in iQS-TS Synthesis module, ITG, Germany

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Synthesis module and laptop connected to it were switched on, and iQS-TS software is switched on. Software automatically establishes connection with the synthesis module and starts mechanical test.

Mechanical test

The mechanical test involves test for syringe actuator, rotary valves, inbuilt radioactive detectors, and heater functionality. After the successful completion of mechanical test, software prompts to place the sterile cassette on iQS-TS automated Synthesis module.

Presynthesis steps

Cassette is removed from its package, and all the connections are assured for mechanical integrity and attached to the dedicated slots available for attachment. After installation of cassette, all the consumables such as HCl, saline, and ethanol bottles are attached to the respective port on the cassette. The product and waste vials are also attached to the respective places to the cassette. Finally, generator's output port is attached with the cassette, and peptide PSMA-11/DOTATOC is inserted in the reaction vial from peptide port (red connector). Here end the presynthesis steps.

Radiopharmaceutical synthesis

After the presynthesis steps, synthesis has to be initiated on the software and entire process of synthesis takes around 17 min. The synthesis process involves multiple steps described in [Figure 3]. Process starts with automated elution of 4.15 ml of 0.05 M HCl into the reactor vial containing reconstituted peptide (PSMA-11/DOTATOC) in 1 ml Na-acetate buffer. Meanwhile, the inbuilt heater used for heating the reaction vial mixture achieves the ambient temperature for labeling (95°C), and C18-cartridge conditioning is prompted automatically. The C-18 cartridge is conditioned with 50% ethanol and purged with saline to get activated. The mixture in the reaction vial is heated for 5 min for successful labeling peptide (PSMA-11/DOTATOC) with 68Ga. After the labeling, the content of the reactor vial is passed over reversed-phase C18 cartridge, wherein the labeled peptide is trapped in the C18 ion exchange cartridge and the remaining unbound content in reaction solution is transferred to the waste vial. Subsequently, the reactor is rinsed again for any remaining activity and passed over C18 ion exchange cartridge. Final elution and formulation of the product with 50% ethanol and saline, respectively, are done via a 0.22 μm Millipore filter. A schematic flowchart of the above-mentioned steps can be seen, as mentioned in [Figure 3]. The synthesis module with cassette installed is shown in [Figure 4].
Figure 4: Fully automated PC controlled synthesis module (cassette installed)

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Filter integrity and rinsing

The filter integrity of 0.22 μm filter requires one-time operator intervention in removal of product tubing having 0.22 μm filter and attached needle from the product vial and putting it into the waste vial for performing the test. It is performed by subjecting the filter to 2.37 bar (237 kPa) pressure. Pass/fail of integrity test is displayed as a popup screen. If integrity test passes, the product is free of microbes; second, if integrity test fails, it is re-performed; and if it fails twice, we need to filter the product again using Millipore filter.

Analysis and quality control of the radiopharmaceutical was evaluated as follows:

  • pH: pH test of product was performed using pH paper after every synthesis
  • Half-life of the radionuclide: The half-life of the radionuclide was calculated by decay method using calibrated dose calibrator CRC®-25PET Dose Calibrator, Capintec Inc., NY, USA. Eluted activity was measured eight times from 0 min to 70 min at 10-min interval and plotted on semi-log paper, and half-life was calculated
  • Gamma-ray spectra: It was acquired under a calibrated multichannel analyzer (CAPRAC-t, Capintec, Inc.) using a point source of the product. The sample was also evaluated at 24 and 48 h after production to determine the 68Ge breakthrough
  • Radiochemical purity: Radiochemical purity was performed using Sillica Gel – Instant Thin Layer Chromatography (SG-ITLC) strip of 8 cm × 1 cm and 0.5 M sodium citrate buffer as solid and mobile phases, respectively. A drop of final product was spotted on the SG-ITLS strip at point of spotting (PS), and chromatogram was developed up to solvent front (SF). 68Ga-labeled radiopharmaceuticals remain at PS, and unlabeled fraction of 68Ga moves to SF. Counting was performed in well counter (gamma-ray spectrometer), and Radiochemical Purity (RCP) was calculated as shown in Equation 1 below.




Where

%RCP = Percentage radiochemical purity

Cnt (PS) = Count at PS

Cnt (SF) = Count at SF

Synthesis yield

Synthesis yield was calculated to know the efficiency of the synthesis. Synthesis yield was calculated by using Equation 2.



Where

%Yield = Percentage synthesis yield

Acti (GaRP) = Measured activity of 68Ga radiopharmaceutical just after synthesis

Acti (Ge) = Theoretically calculated activity of 68Ge

Sterility test

The small amount of prepared radiopharmaceutical from every batch was stored in the airtight sterile vial, and after 5 syntheses, it was sent for sterility test in microbiology laboratory.

Radiation monitoring

Radiation survey was performed using Radiation Alert Ranger-05805 of SE International during the synthesis. Radiation exposure to the radiochemist was measured using pocket dosimeter, Polimaster PM-1610.


   Results Top


We were able to perform installation of the synthesis module and were successfully done and certified by installation engineer after successful run of rinsing sequence. We carried out 20 times radiopharmaceutical synthesis (7 times 68Ga-DOTATOC and 13 times 68Ga-PSMA-11) using this synthesis module till now. All the synthesis was completed successfully including filter integrity test. In all the synthesis, final product (68Ga-DOTATOC/68Ga-PSMA-11) was clear colorless solution free from particulate matter, and pH was in the range of 4–6. The average half-life calculated from the graph plotted was 68 min, and there were a prominent peak at 511 keV and a small peak at 1022 keV (summation peak) under gamma-ray spectrometer at all the occasions, as shown in [Figure 5]. The 68Ge breakthrough was <0.0001%. The average % synthesis yield and average % radiochemical purity obtained over all the synthesis were 62.6 (±2.3) and 99.1 (±0.2) %, respectively [Table 1]. We performed sterility test three times, and all the three times, it was free from microbes.
Table 1: Percentage synthesis yield, pH, and percentage radiochemical purity over all the synthesis

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Figure 5: Spectrum of 68Ga elute in multichannel analyzer

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Radiation monitoring

Radiation exposure outside the hot cell was found to be at background level. The average whole-body radiation exposure during the synthesis and quality control per batch was in range from 1 μSv to 3 μSv. Major portion of radiation exposure was received during dose calibration and quality control.


   Discussion Top


The average yield of 68Ga from our generator was 84.76% which was quite good in comparison to the value indicated by the manufacturer, claiming it to be not <80%. In the 10 productions of gallium-labeled peptides, we recorded the radiochemical yield to be always greater than the reported value with improved reproducibility, as has been observed by Milos Petrik et al.[12] In a study reported by Aslani et al.,[13] it clearly highlighted the reduction in 68Ge breakthrough, which was in consensus to the germanium-68 breakthrough observed at our Institute. It was always below the recommended level of 0.001% of the total radioactivity. Second, the exposure dose range to the radiochemist during the entire production and quality control was between 1 μSv to 3 μSv, wherein an average of 1 μSv was registered during the automated synthesis under the customized mini hot cell and the extra radiation was generally recorded/received while carrying out the quality control parameters. The same has also been observed by Nanabala et al. wherein the radiation dose measured with pocket dosimeter never exceeded 3 μSv in a production batch.

Finally, there are multiple inbuilt sensors such as thermocouples, pressure detector, flow meters and activity detectors, which help in better analysis of the situation/process undergoing during the various steps of synthesis along with a real-time report being generated from the fully automated system which helps us in documentation of the radiopharmaceutical preparation. Moreover, with the single use of sterile cassettes, there is no wastage of time for intense cleaning and sanitation process; second, by simply changing the cassette, multiple syntheses can be easily carried out for various tracers and with a different radionuclide. The major one-time cost is the cost of generator, otherwise the routine consumables used for radiosynthesis of various peptides are low enough to make it viable after installation. Indeed, the experience of radiolabeling peptides under a fully automated system is advantageous.


   Conclusion Top


iQS-TS Synthesis module is easy to install, and a qualified radiochemist can install it under the supervision of installation engineer. Our study shows that the synthesis yield and radiochemical purity of the product were at par with published literature with very little radiation exposure to the radiochemist and maintaining sterility of the product.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Boschi S, Malizia C, Lodi F. Overview and perspectives on automation strategies in (68)Ga radiopharmaceutical preparations. Recent Results Cancer Res. 2013;194:17-31. doi: 10.1007/978-3-642-27994-2_2. PMID: 22918752.  Back to cited text no. 7
    
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Eiber M, Maurer T, Souvatzoglou M, Beer AJ, Ruffani A, Haller B, et al. Evaluation of hybrid 68Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med 2015;56:668-74.  Back to cited text no. 8
    
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Afshar-Oromieh A, Avtzi E, Giesel FL, Holland-Letz T, Linhart HG, Eder M, et al. The diagnostic value of PET/CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2015;42:197-209.  Back to cited text no. 9
    
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Zhernosekov KP, Filosofov DV, Baum RP, Aschoff P, Bihl H, Razbash AA, et al. Processing of generator-produced 68Ga for medical application. J Nucl Med 2007;48:1741-8.  Back to cited text no. 11
    
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Petrik M, Knetsch PA, Knopp R, Imperato G, Ocak M, von Guggenberg E, et al. Radiolabelling of peptides for PET, SPECT and therapeutic applications using a fully automated disposable cassette system. Nucl Med Commun 2011;32:887-95.  Back to cited text no. 12
    
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Aslani A, Snowdon GM, Bailey DL, Schembri GP, Bailey EA, Roach PJ. Gallium-68 DOTATATE production with automated PET radiopharmaceutical synthesis system: A three year experience. Asia Ocean J Nucl Med Biol 2014;2:75-86.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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