Cyclotron Production of Gallium-68 Radiopharmaceuticals Using the ⁶⁸Zn(p,n)⁶⁸Ga Reaction and Their Regulatory Aspects

Abstract

Designing and implementing various radionuclide production methods guarantees a sustainable supply, which is important for medical use. The use of medical cyclotrons for radiometal production can increase the availability of gallium-68 (⁶⁸Ga) radiopharmaceuticals. Although generators have greatly influenced the demand for ⁶⁸Ga radiopharmaceuticals, the use of medical cyclotrons is currently being explored. The resulting ⁶⁸Ga production is several times higher than obtained from a generator. Moreover, the use of solid targets yields end of purification and end of synthesis (EOS) of up to 194 GBq and 72 GBq, respectively. Furthermore, experiments employing liquid targets have provided promising results, with an EOS of 3 GBq for [⁶⁸Ga]Ga-PSMA-11. However, some processes can be further optimized, specifically purification, to achieve high ⁶⁸Ga recovery and apparent molar activity. In the future, ⁶⁸Ga will probably remain one of the most in-demand radionuclides; however, careful consideration is needed regarding how to reduce the production costs. Thus, this review aimed to discuss the production of ⁶⁸Ga radiopharmaceuticals using Advanced Cyclotron Systems, Inc. (ACSI, Richmond, BC, Canada) Richmond, Canada and GE Healthcare, Wisconsin, USA cyclotrons, its related factors, and regulatory concerns.

1. Introduction

Gallium-68 (half-life 67.6 min, 89% β⁺, 830 keV) has been increasingly well-known due to its role as a radioisotope for positron emission tomography (PET) in the 2000s. The advent of the Gallium-68 (⁶⁸Ga) generator widened the use of ⁶⁸Ga despite its short half-life for various examinations. More importantly, its radiochemistry and chelator development has been understood. A Scopus search shows that the number of publications on ⁶⁸Ga has exponentially increased from 2000 to 2021 (Figure 1A). Interest in ⁶⁸Ga radiopharmaceuticals further came into the limelight with the introduction of radiopharmaceuticals for neuroendocrine tumor imaging (NET), i.e., [⁶⁸Ga]Ga-DOTA-TOC, [⁶⁸Ga]Ga-DOTA-NOC, and [⁶⁸Ga]Ga-DOTA-TATE [1,2,3,4,5]. ⁶⁸Ga-DOTA-TATE was approved by the United States Food and Drug Administration (USFDA) in 2016 [6], followed by ⁶⁸Ga-DOTA-TOC in 2019 [7].

Developments in PET imaging for prostate cancer (PCa) with radiolabeled [⁶⁸Ga]Ga-PSMA-11 have also attracted the interest of nuclear medicine physicians [8,9,10]. The product was approved in 2020 [11], making it the third ⁶⁸Ga-based product approved by the USFDA in 5 years. The ⁶⁸Ga-based radiopharmaceuticals have been increasingly well-known due to the superior quality of PET imaging over single photon emission computed tomography [12,13], expanding the knowledge about gallium radiochemistry and, most importantly, ⁶⁸Germanium/⁶⁸Gallium (⁶⁸Ge/⁶⁸Ga) generator availability. Recent developments combining ⁶⁸Ga with therapeutic radionuclides such as lutetium-177 (¹⁷⁷Lu) for theranostic application in both NET and PCa [14,15,16] further increase the demand for ⁶⁸Ga-based radiopharmaceuticals.

The main source of ⁶⁸Ga in many nuclear medicine facilities is the ⁶⁸Ge/⁶⁸Ga generator (Figure 1B). The short-lived daughter isotope is eluted with hydrochloric acid, resulting in a high activity with a low ⁶⁸Ge breakthrough. Depending on the type and age of the generator, between 0.74 GBq and 3.7 GBq of ⁶⁸Ga activity is produced per elution, and the generator can be operated for 1 year, albeit with a limited yield [17]. In addition to the generator, the ⁶⁸Ga produced in the cyclotron has recently received more attention due to (1) the cost and uncertainty of a constant supply of ⁶⁸Ge/⁶⁸Ga generators and (2) the upsurge of medical cyclotrons worldwide [18,19]. Two promising production methods using medical cyclotrons are ⁶⁸Zn(p,n)⁶⁸Ga and ⁶⁵Cu(α,n)⁶⁸Ga reactions. The first method can be performed with a small medical cyclotron [20] and provide a highly specific activity suitable for routine production and radiopeptide labeling [21,22,23].

The production of ⁶⁸Ga-labeled peptides from a medical cyclotron (Figure 2) involves four main steps: (1) target preparation; (2) proton irradiation; (3) dissolution, purification, and separation of target material; and (4) radiolabeling of ⁶⁸Ga-labeled peptides.

The production of ⁶⁸Ga via the ⁶⁸Zn(p,n)⁶⁸Ga nuclear reaction results in the co-production of ⁶⁶Ga and ⁶⁷Ga [24]. Removing ⁶⁶Ga and ⁶⁷Ga impurities is difficult through separation techniques due to similar chemical properties and would be impractical as ⁶⁸Ga has a short half-life. However, these impurities can be limited during irradiation with the proton irradiation energy range Ep = 14 → 5 MeV, consequently preventing ⁶⁸Zn(p,2n)⁶⁷Ga and ⁶⁸Zn(p,3n)⁶⁶Ga nuclear reactions [24]. Co-production of ⁶⁶Ga and ⁶⁷Ga can also exist through ⁶⁶Zn(p,n)⁶⁶Ga and ⁶⁷Zn(p,n)⁶⁷Ga nuclear reactions. Thus, a highly enriched ⁶⁸Zn [25] and proton irradiation energy below 14 MeV can produce high ⁶⁸Ga radioactivity with below limit ⁶⁶Ga, and ⁶⁷Ga [26].

Depending on the method, ⁶⁸Ga production using cyclotrons can reach up to 37.5 GBq per production with a nominal proton energy of 12.5 MeV cyclotron [27]. The large ⁶⁸Ga production would allow large-scale labeling of peptides. The problem of the possible occurrence of radiolysis can be solved by adding radical scavengers, such as sodium ascorbate and ethanol [28,29]. Furthermore, the apparent molar activity (AMA) which accounts for the amount of radioactivity per unit mole of non-radiolabeled, radiolabeled impurities, and remaining precursor for cyclotron production, is on par with or improved from the ⁶⁸Ge/⁶⁸Ga generator production [30,31]. The progress in ⁶⁸Ga radionuclide production with cyclotrons encourages further studies that could lead to the establishment of a routine route for ⁶⁸Ga-labeled peptide preparation.

This review discusses the production of ⁶⁸Ga with cyclotron using solid and liquid targets and the prospects and issues associated with cyclotron production.

2. Cyclotron-Produced ⁶⁸Ga Using a Solid Target

⁶⁸Ga can be produced from solid targets using galvanized, pressed, foil, or molten targets. The irradiation parameters discussed were based on Advanced Cyclotron Systems, Inc. (ACSI) Richmond, Canada or GE Healthcare, Milwaukee, WI, USA cyclotrons. The introduction of pneumatic transfer systems, such as the QUANTM Irradiation System™ (Vancouver, Canada), Solid Target Transfer ACSI (Richmond, Canada), and ALCEO Solid Target Processing System, COMECER (Castel Bolognese, Italy) was a critical development for ⁶⁸Ga production using solid target [32]. After the target irradiation, the target material is transferred to hot cells for dissolution with either concentrated hydrochloric acid (HCl) or nitric acid (HNO₃). The separation of target material, purification, and formulation utilizing one-, two-, or three-column methods, making it possible to obtain high AMA in the shortest time at the end of purification (EOP) [22,32,33,34,35,36,37,38,39].

2.1. ⁶⁸Ga Production Using a Solid Target in a Medical Scale PETtrace Cyclotron (GE Healthcare, Milwaukee, WI, USA)

Previous experience with the GE PETtrace cyclotron has shown promising results [22,32,34,38,39], subsequently opening the possibility of distributing ⁶⁸Ga radiopharmaceuticals to multiple centers. The setup shows a saturation yield and EOP of above 1 GBq/μA and 3.7 GBq, respectively, as displayed in

Table 1. ⁶⁸Ga production with PETtrace Cyclotron with ⁶⁸Zn irradiation. Included yield activity at EOB and EOP.

Target Preparation	Nominal Proton Energy	Irradiation Parameters	EOB (GBq)	Specific Activity (GBq/μg)	Saturation Yield (GBq/μA)	EOP (GBq)	Ref.
Target material: Electroplated on a platinum disc Dimension: 7.0 mm 68Zn mass: 104.1 ± 2.7 mg	14.5 MeV	Current: 30 μA Time: 60 min	60.9 ± 1.8	NR	2.72 ± 0.08	NR	[22]
Target material: Electroplated on a platinum backing Dimension: 10.0 mm 68Zn mass: 35.3 ± 2.2 mg	14.5 MeV with 320 μm aluminium degrader foils	Current: 35 μA Time: 8.5 min	6.3 ± 0.4	2530	1.26 ± 0.08	3.7 ± 0.18	[38]
Target material: Electroplated water-cooled silver backing Dimension: 10.0 mm 68Zn mass: 300 mg	13.0 MeV on target. helium-cooled aluminium foil energy degrader	Current: 80 µA Time: 120 min	>370	NR	NR	194	[31]
Target material: Foil Dimension: 15.5 mm 68Zn mass: ~140 mg	12.6 MeV with 500 μm aluminium energy degrader	Current: 25 μA Time: 68 min	31 ± 1	1209 ± 18	2.48 ± 0.06	18 ± 2	[34]
Target material: Electroplated on a silver backing Dimension: ~10.0 mm 68Zn mass: 216 ± 10 mg	13.0 MeV with 500 μm aluminum foil degrader	Current: 80 μA Time: 102 min	370	NR	7.1	175.2	[39]

NR—Not reported.

.

The highest yield at the end of bombardment (EOB) was more than 370 GBq [32,39]. Both studies recorded the same target material, current and nominal proton energy. However, Thisgaard and co-workers [32] used 28% more mass of enriched ⁶⁸Zn and a longer irradiation time than Svedjehed and group [39]. This was subsequently reflected in an increase in end-of-purification (EOP) activity of 18.8 GBq (approximately 10% more yield). For smaller-scale production, Siikanen and co-authors [34] reported that their capacity to produce an EOB activity of 31 ± 1 GBq ⁶⁸Ga with a respectable saturation yield of 2.48 ± 0.06 GBq/μA using a foil target with a dimension of 15.5 mm or a target mass of 40 mg, respectively. This method is advantageous in centers that lack electroplating equipment and expertise.

Although influenced by other variables, the electroplated target produces a higher yield than the foil target. As recorded by Lin and his colleagues [22] with an electroplated target, the EOB was 60.9 ± 1.8 GBq, and the saturation yield was 2.72 ± 0.08 GBq/μA. Meanwhile, as mentioned in the study with a foil target, Siikanen and group [34] achieved an EOB of 31 ± 1 GBq with a saturation yield of 2.48 ± 0.06 GBq/μA, albeit with about 34% more ⁶⁸Zn target. It was suggested that using a platinum disc reduced metallic impurities, especially during dissolution, thereby improving the EOP yield. Tieu and others [38] found that an EOP of 3.7 ± 0.18 GBq [⁶⁸Ga]GaCl₃ could be achieved with a low target mass (35.3 ± 2.2 mg) and a shorter time (8.5 min). Furthermore, Lin and colleagues [22] reported that the co-production of ⁶⁷Ga impurities was less than 0.2% which can be reduced if the nominal proton energy is decreased to below 14 MeV. Specifically, for PETtrace cyclotron, this can be achieved by modifying the thickness of the energy degrader.

2.2. ⁶⁸Ga Production Using a Solid Target with ACSI Cyclotron

The ACSI cyclotron, namely TR-19 and TR-24, has the ability to provide a variable energy spectrum without entirely relying on an energy degrader. Alnahwi and group [33] and Nelson and group [27] studied the production of ⁶⁸Ga using a solid target and the TR-19/TR-24 cyclotrons ACSI utilizing a pressed target, as presented in

Table 2. ⁶⁸Ga production using solid target on an Advanced Cyclotron Systems, Inc. (ACSI) Cyclotrons.

Cyclotron	Pressed Target Preparation	68Zn Mass (mg)	Nominal Proton Energy (MeV)	Irradiation Parameter	Saturation Yield (GBq/μA)	EOB (GBq)	% Total 67Ga and 66Ga post 6 h	Ref.
TR-19	68Zn powder (ISOFLEX, San Francisco, CA, USA) Dimension: ~10.0 mm Thickness: 0.55 mm Density: 1.43 g/cm3	247	14	Current: 30 μA Time: 30 min Proton beam energy: 17.2 MeV	8.7	68.8 a	<2	[33]
TR-24	68Zn powder (ISOFLEX, CA, USA) Dimension: ~10.0 mm Thickness: 0.40 mm Density: 3.18 g/cm3	100	12.5	Current: 30 μA Time: 73 min b Proton beam energy: 17 MeV	2.4 ± 0.12	37.5 ± 1.9	0.51	[27]

^a Taken from entry number 5; ^b Taken from the second experiment where irradiation was 2200 μA·min.

. To prepare the target, Alnahwi and co-workers used a few steps in which the target was pressed with 250 mg of enriched ⁶⁸Zn at 17,600 psi for 5 min before being inserted into a magnetic target carrier [33]. On the other hand, Nelson and group [27] used 100 mg of hydraulically pressed, enriched ⁶⁸Zn at 35 kN to produce a 400 μm thick pellet, which was then sintered at 350 °C for 5 h before being placed on a silver support. The target was then pressed with 20 kN at 120 °C for 30 s to achieve a target density of 3.18 g/cm3 [27].

Alnahwi and co-workers [33] used a 400 μm aluminum integrated degrader to decrease the proton beam from 17.2 MeV to 13-14 MeV on the target material, while Nelson and group [27] used a 250 μm silver degrader to decrease the proton beam from 17 to 12.5 MeV. The saturation yield (8.7 GBq/μA) produced by Alnahwi and co-workers was higher than that of other studies presented in this review. Remarkably, the mass of the enriched ⁶⁸Zn in their experiment was only 3.39 mg to produce 1 GBq of ⁶⁸Ga. Thus, this method may be the most cost-effective, as it uses only pressed targets, and an irradiation time of 30 min is required to produce 68.8 GBq.

Pressed targets are usually less time-consuming to produce. However, Nelson and their group found traces of ¹⁰⁷Cd and long-lived ¹⁰⁹Cd related to the activation of silver backing. Metallic impurities other than Gallium isotopes can be removed during the separation of target material and purification. Nevertheless, the co-production of ⁶⁶Ga and ⁶⁷Ga was less than 0.1% of total radioactivity 4 h post-irradiation. Furthermore, they validated the silver disc pellet for 10 irradiations without significant degradation, limiting the time required to prepare the silver disc [27].

2.3. Solid Target Dissolution, Target Material (⁶⁸Zn) Separation and Purification, and ⁶⁸GaCl₃ Formulation

Following irradiation, the solid target is transferred using a pneumatic transfer system for dissolution. The dissolution of the target is another important aspect related to the final activity obtained, and in the case of the short half-life of ⁶⁸Ga, the time required for purification and its AMA are crucial. Thus, an automated procedure for target material (⁶⁸Zn) separation and purification, and [⁶⁸Ga]GaCl₃ formulation using one-, two-, and three-column strategies has been reported. The typical steps of preconditioning and loading, washing, and eluting with an appropriate solution are performed on each column. This is to achieve low-volume and low-molarity of [⁶⁸Ga]GaCl₃, which in turn results in either high AMA, similar or improved from post-processing of the ⁶⁸Ge/⁶⁸Ga generator eluate [40,41,42,43,44,45].

The dissolution of the solid target and purification of [⁶⁸Ga]GaCl₃ using TR-19 and TR-24 cyclotrons is presented in

Table 3. Dissolution of solid target for TR cyclotron and purification of [⁶⁸Ga]GaCl₃.

Target Dissolution	Separation of Target Material and Purification	Formulation	Time (min)	EOP (GBq)	[68Ga]GaCl3 Molarity (Volume)	EOS (GBq)	AMA (GBq/µmol)	Ref.
S: 7 M HNO3 V: 1–2 mL Additional: adjust pH using NH4HCO2 (2–2.5 mL, 2.5 M) to pH 2	R: Hydroxamate (200–330 mg) C: acetonitrile (10 mL), water (20 mL), 2 M HCl (2 mL), water (20 mL) W: 0.01N HCl (50 mL) E: 0.75 N HCl (2 mL)	R: CUBCX123 C: 0.5 mL 6 N HCl, 5 mL waterL: pre dilution using 0.01 M HCL (8 mL) W: 0.01 N HCl (30 mL) E: NaCl 5 M/HCl 5.5 N (12.5 μL)	<12	NR	5 M NaCl/5.5 M HCl (12.5 μL)	4.6 ± 0.1 a	28.3 ± 6.8	[33]
10 M HCl in 5 min	R: 5 g of AG® 50WX8 resin C: 20 mL of ethanol, 15 mL of 10 M HCl W: 20 mL of 10 M HCl E: 20 mL of 4 M HCl	R: 500 mg of UTEVA resin C:10 mL of ethanol, followed by 15 mL of 4 N HCl. W: 5 mL of 4 N HCl E: 2.5 mL of 0.05 M HCl	<30	37.5 ± 1.9	0.05 N HCl (2.5 mL)	NR	9.5 ± 1.3	[27]

S: Solution; V: Volume; T: Time; R: Resin; C: Conditioning; L: Load W: Wash; E: Elution; NR: Not reported. ^a 20 min irradiation at ~5 μA and Ep = 14 MeV.

. The typical dissolution solution would be using a concentrated HCl of 7 M or more to form [⁶⁸Ga]GaCl₃. This is imperative to ensure maximum dissolution and the right molarity for optimized retention. In contrast, Alnahwi and co-workers used a different approach using 7 M HNO₃ [33]. This proceeds by adjusting the pH using ammonium formate (NH₄HCO₂) to retain up to 97% of the EOB activity in the hydroxamate resin. The group also noted a dark red (ferric hydroxamate) on the top of the hydroxamate resin. They, therefore, recommended using 200–300 mg of hydroxamate resin and 2 mL of 0.75 M HCl as the eluent to limit the iron in the ⁶⁸Ga solution. The collected ⁶⁸Ga was then diluted with 8 mL of 0.01 M HCl, transferred into the cation exchange resin CUBCX123, and washed with 30 mL of 0.01 M HCl. The final [⁶⁸Ga]GaCl₃ was collected in 12.5 μL NaCl 5 M/HCl 5.5 N, with an AMA of 28.3 ± 6.8 GBq/μmol [33].

Nelson and colleagues [27] performed the dissolution method using 10 M HCl for 5 min. The column used for the separation of target material and formulation was different from Alnahwi and group [33], as depicted in Figure 3. The retention of ⁶⁸Ga performed by Nelson et al. [27] was 5 g AG^® 50WX8 resin. The ⁶⁸Ga was then transferred into a UTEVA column for formulation in 0.05 M HCl. Nonetheless, the method performed by Alnahwi et al. [33] resulted in higher AMA, mainly contributed by the low final volume of 12.5 μL of [⁶⁸Ga]GaCl₃.

The dissolution of a solid target from works using a GE PETtrace cyclotron is presented in

Table 4. Dissolution of solid target for GE PETtrace cyclotron and purification of [⁶⁸Ga]GaCl₃.

Target Dissolution	Separation of Target Material and Purification	Formulation	Time (min)	EOP (GBq)	[68Ga]GaCl3 Molarity (Volume)	EOS (GBq)	AMA (GBq/µmol)	Ref.
S: 7 M HCl V: 0.5 mL	R: TK400 resin C: 7M HCl (5 mL) W: 7 M HCl (28 mL), 0.05 M HCl (0.7 mL) E: 0.05 M HCl (3.5 mL)	NA	32 a	3.31	0.05 M HCl (3.5 mL)	1.56 b	7.1	[38]
S: 10 M HCl V: 10 mL T: <10 min	R: 5 g of 50W-X4 C: 10 M HCl (25 mL) W: 10 M HCl (30 mL) E: 4 M HCl (12 mL)	R: 100 mg UTEVA® C: 4 M HCl (10 mL) W: 4 M HCl (10 mL) E: 0.05 M HCl (2 mL)	10	NR	0.05 M HCl (2.0 mL)	NR	6.7 ± 0.8	[22]
S: 9.5 M HCl V: 2 mL T: 2 min	R: UTEVA L: Pre-dilution4 M HCl (11.5 mL) W: 10 mL of 4 M, HCl and 10 mL of 2.5 M HCl E: 2 mL water and re-distributed into 10 mL of 4 M HCl	R: UTEVA W: 20 mL of 2.5 M HCl E: 1 mL water	23	18 ± 2	Water (1 mL)		86 ± 22 c	[34]
S: 30% HCl (~90 °C) V: 2 mL	R: 250 mg ZR resin. W:15 mL of 30% HCl E: 8 mL of 1 M HCl and passed through a LN Resin	R: TK200 resin. W: Nitrogen purging E: 2.5 mL of 0.1 M HCl	35	194 d	0.1 M HCl (2.5 mL)	72.2	25 e	[32]

S: Solution; V: Volume; T: Time; R: Resin; C: Conditioning; L: Load W: Wash; E: Elution; NR: Not reported. ^a From dissolution until end of purification; ^{b 68}Zn target (23 mg) was irradiated at 14.5 MeV and 30 mA for 15 min to give 6.30 GBq; ^c DOTA; ^d Production run number 4; ^e DOTA.

. Thisgaard and co-workers heated concentrated HCl to 90 °C using the QIS Dissolution System to dissolve the target [32]. In contrast, Siikanen and group [34] dissolved the foil target in 9.5 M HCl for 2 min, the fastest of all methods in this review. Studies using single-column purification indicated respectable yields for peptide radiolabeling, which took less than 45 min [38,46]. The single-column strategy purifies ⁶⁸Ga, separates ⁶⁸Zn, and finally formulates to [⁶⁸Ga]GaCl₃ in 0.05 M HCl using octanol-based TK400 resin. Before elution, the column was washed with 0.7 mL of 0.05 M HCl to remove acid residues from 7 M HCl that could affect the [⁶⁸Ga]GaCl₃ eluate. The final volume and concentration of [⁶⁸Ga]GaCl₃ were 3.5 mL in 0.05 M HCl, corresponding to the generator eluate resulting in an AMA of 7.1 GBq/μmol. However, the group reported significant radiolysis in their study [38]. This may occur during radiolabeling or chelation reactions where radiosensitive precursors are degraded [47,48,49].

Other studies have used two-column methods with a strong cation-exchange column and UTEVA resin. Lin and co-workers utilized 4% cross-linking of 5 g AG 50W-X4 [22], while Nelson and his group used 8% cross-linking of 5 g AG 50W-X8 of a strong cation-exchange column [27]. The same solution was used in both studies, although Nelson and their group added ethanol when conditioning both columns. In contrast, Siikanen and his colleagues [34] eluted [⁶⁸Ga]GaCl₃ with 1 mL of water, producing the highest AMA of 86 ± 22 GBq/μmol. In this method, two UTEVA columns were used to purify and formulate [⁶⁸Ga]GaCl₃. [⁶⁸Ga]GaCl₃ was trapped with 4 M HCl, and both 4 M HCl and 2.5 M HCl were used for washing. The volume and residual acidity of the final [⁶⁸Ga]GaCl₃ may have contributed to the high AMA. The method contributed to an activity recovery of 76 ± 8% at EOP. The AMA in this work demonstrates the effect of highly concentrated [⁶⁸Ga]GaCl₃ at a presumably low acidic molarity [34]. Apart from Alnahwi and co-workers, the use of hydroxamate resin was also investigated by Thisgaard and group [32]. They used a three-column strategy with the addition of LN resin between hydroxamate (ZR resin) and TK200 resin. The specific role of LN resin in this setup was to trap excess iron impurities before ⁶⁸Ga was retained in TK200 resin. The setup produced [⁶⁸Ga]GaCl₃ in 2.5 mL of 0.1 M HCl with an AMA of 25 GBq/μmol [32].

3. Cyclotron-Produced ⁶⁸Ga Using a Liquid Target

Further developments in the production of ⁶⁸Ga using medical cyclotrons have been attempted, with the most recent success with liquid targets [35,36,50,51]. These results will encourage the routine production of ⁶⁸Ga, particularly in facilities unable to produce via solid targets. Currently, three notable works [35,36,37] use the PETtrace cyclotron described in

Table 5. Target preparation or modification.

Internal Volume	Degrader	Support	Ref.
2.5 mL	250 µm foil of niobium liquid niobium-body target	25 µm Havar® foils for helium cooling chamber and the helium cooling	[35]
2.0 mL	Dual foils of 200 µm aluminum	Havar (40 µm) separated by helium cooling.	[36]
2.2 mL	200 µm aluminum foil	25 μm Havar foil for support and 25 μm niobium foil for chemical inertness with the target media	[37]

. In contrast to the solid target, the ⁶⁸Zn target was prepared in nitric acid ([⁶⁸Zn]Zn(NO₃)₂) in the liquid form. Previous experience with irradiation of zinc salt, especially ZnCl₂, reported gas formation that subsequently increased the pressure inside the target [52]. This reaction is caused by the radiolysis of water after ionizing radiation and forming radicals [53]. The presence of chloride ions further enhances gas formation, whereas nitrates induce the opposite. Thus, nitric salts are used to reduce gas formation, whereas the addition of nitric acid prevents the formation of a solid precipitate [35].

Table 6. Published articles related to the production of cyclotron ⁶⁸Ga.

Process	Method	Result	Ref.
Target material preparation and irradiation using GE PETtrace 800 cyclotron	Target: 1.7 M [68Zn]Zn(NO3)2 in 0.2 M HNO3 Current: 46 µA Time: 32 min Nominal proton energy: 12 MeV	EOB = 4.3 ± 0.3 GBq	[35]
	Target: 1.42 M [68Zn]Zn(NO3)2 in 1.2 M HNO3 Current: 40 µA Time: 60 min Nominal proton energy: 14 MeV	EOB = 9.85 ± 1.6 GBq (266 mCi)	[36]
	Target: 1.0 M [68Zn]Zn(NO3)2 in 0.2–0.3 M HNO3 Volume: 2.2 mL Current: 30 μA Time: 60 min Nominal proton energy: 14.3 MeV	EOB = 3.7 GBq (100 mCi)	[37]

,

Table 7. Methods for separation of target material and purification and formulation of [⁶⁸Ga]GaCl₃.

Process	Method	Result	Ref.
Separation of target material and purification, and formulation	Platform: FastLab2 Developer, GE Healthcare, Wisconsin, USA Purification: Zr Resin washed with 0.1 M HNO3 (9 mL), elute with 2 M HCl (5 mL) Formulation: TK200, elute with 0.1 N HCl (5 mL)	EOS = 2.3 ± 0.2 GBq	[35]
	Platform: Trasis All-in-One, Belgium Purification: 100 mg, hydroxamate resin (50–100 μm); washed with of 0.005 M HNO3 (50 mL); elute with of 5.5 M HCl (7 mL). Formulation: 400 mg, AG-1X-8 anion exchange resin; elution with 2 mL of water.	NR	[36]
	Platform: FastLab2 Developer, GE Healthcare, Milwaukee, WI, USA Purification: Zr Resin; condition with 0.1 M HNO3 (7 mL); washed with 0.1 M HNO3 (15 mL), elution with 1.75 M HCl (5–6 mL). Formulation: TK200 resin; condition with water (7 mL) followed by 1.75 M HCl (4 mL) before use; washed with 2.0 M NaCl (3.5 mL) in 0.13 M HCl; elute with 1–2 mL H2O followed by dilute HCl to formulate	EOS= 2.0  ±  0.3 GBq 50 mCi	[37]

and

Table 8. Method for [⁶⁸Ga]Ga-PSMA-11 radiolabelling and the EOS radioactivity.

Process	Method	Result	Ref.
Radiolabeling	100 °C for 10 min at pH 4.0–4.5	[68Ga]Ga-PSMA-11 1.78–3.16 GBq (48.1–85.5 mCi, uncorrected)	[36]
	50 °C for 5 min	[68Ga]Ga-PSMA-11 were near quantitative (~1.67 GBq, 45 mCi)	[37]

represents an overview of studies on cyclotron-produced ⁶⁸Ga with a liquid target. Riga and co-workers [35] produced 4.3 GBq ± 0.3 ⁶⁸Ga activity using 1.7 M [⁶⁸Zn]Zn(NO₃)₂ in 0.2 M nitric acid after 32 min of irradiation at 46 µA. More than 75% of the initial activity was retained during post-processing. Pandey and group [36] reported a higher EOB of 9.85 ± 1.6 GBq using 1.42 M [⁶⁸Zn]Zn(NO₃)₂ in 1.2 M nitric acid as starting material when irradiated with 40 µA for 60 min as described in Table 6. The group further experimented with the effect of [⁶⁸Zn]Zn(NO₃)₂ concentration and irradiation time on yield activity [51,53]. They found that reducing the [⁶⁸Zn]Zn(NO₃)₂ concentration to 0.6 M would decrease the yield to 3.94 GBq ± 0.20. Moreover, shortening the irradiation time to 30 min and lowering the beam current to 30 µA reduces the activity, as 0.6 M [⁶⁸Zn]Zn(NO₃)₂ only produces 1.64 GBq ± 0.07 of ⁶⁸Ga, whereas 1.2 M [⁶⁸Zn]Zn(NO₃)₂ produces 3.37 GBq ± 0.17 of ⁶⁸Ga at EOB. In addition, the lower yield owing to the longer irradiation time could be avoided by increasing the nitric acid concentration. This effect was mainly due to the high nitric acid consumption at a long irradiation time (<30 min) and high beam current. Nonetheless, increasing the nitric acid concentration can potentially damage the materials connected to the target. Thus, it is important to properly evaluate the equipment and materials used to potentiate high concentrations of nitric acid in the preparation of the target material [51,53].

The irradiated [⁶⁸Zn]Zn(NO₃)₂ was then transferred to a synthesizer for separation of target material and purification to form [⁶⁸Ga]GaCl₃ as described in Table 7. The separation of target material and purification processes were performed using a two-column method: (1) ZR resin and (2) TK200 resin or AG-1X-8 anion exchange resin. The ZR resin was conditioned with 0.1 M HNO₃ before trapping. After ⁶⁸Ga trapping, the ZR resin was washed with 0.1 M HNO₃ and then eluted with 1.75 M–2 M HCl to TK200. This method produces 5 mL [⁶⁸Ga]GaCl₃ in 0.1 M HCl. Rodnick and co-workers [37] highlighted a clear difference in using TK200 resin. The group introduced the NaCl/HCl purge method to reduce the residual acid in the final [⁶⁸Ga]GaCl₃ formulation of 0.1 M HCl in 5 mL [37]. Pandey and co-workers had a different approach whereby the pH of target solution was adjusted to 5.5–6.0 using sodium bicarbonate to improve the retention of ⁶⁸Ga. In addition, an AG-1X-8 anion exchange resin was used for formulation and only 2 mL water was needed to elute the [⁶⁸Ga]GaCl₃ for radiolabeling [36]. Both methods were important to ensure a high AMA, especially when using a liquid target, thus reducing the impact of a lower EOB compared to a solid target.

The radiolabeling proceeds with elevated temperature and a typical pH of 4.0 to 4.5 as presented in Table 8. Pandey and co-workers were able to obtain [⁶⁸Ga]Ga-PSMA-11 EOS of 1.78–3.16 GBq, whereas Rodnick and group produced 1.67 GBq [36,37]. The differences in EOS published by both authors were largely contributed to the EOB activity as presented in Table 6.

Some areas can be added to improve the EOS of ⁶⁸Ga produced using liquid targets. Al-Nahwi and colleagues [33] found that the pH of ⁶⁸Ga in nitric acid influenced trapping in hydroxamate resin. More than 97% of the activity was retained at a pH above 2. However, at pH 3 and above, the activity that persisted in the dissolution vial was high. Although this study was performed using a solid target, it would be valuable if it was implemented for a liquid target. Moreover, the extension of the irradiation time to more than 60 min should be studied further. Pandey and co-workers noted the influence of nitric acid concentration in ensuring a high saturation yield [36]. However, this should depend on the material used because a high nitric acid concentration could damage targets and possibly cyclotrons, which would necessitate frequent target maintenance [32].

4. Matters in ⁶⁸Ga Cyclotron Production

The promising future for cyclotron production of ⁶⁸Ga will increase the availability of such radiopharmaceuticals, especially parallel to the number of medical cyclotrons reported by the International Atomic Energy Agency (IAEA). However, a few considerations should be considered to ensure consistent production and sustainable supply of cyclotron-produced ⁶⁸Ga radiopharmaceuticals [54,55,56].

4.1. Expansion of Solid Target ⁶⁸Ga Preparations

The production of radionuclides with solid targets requires technical skills and knowledge, such as target preparation, irradiation, target transport, and dissolution methods. Recent developments, such as the automated target transport and dissolution system allow minimal work, consequently reducing radiation exposure and improving product consistency.

For future expansion, a solid [⁶⁸Zn]ZnO target should be commercially available to complement the advances in automated target transport and dissolution systems. Experience suggests that the electroplated target offers a higher EOB yield with less [⁶⁸Zn]ZnO than the foil and pressed target, despite the long and tedious procedure. This would be advantageous for central nuclear pharmacies only if the cost of the commercially available electroplated [⁶⁸Zn]ZnO target was economical. In addition, cassette-based synthesis should be readily available for cost efficiency and reliable production, which minimizes the influence of human error and enables more consistent production [57].

4.2. Sustainable Practice in Cyclotron-Produced ⁶⁸Ga: [⁶⁸Zn]ZnO Target Reprocessing

The cost of upgrading the cyclotron to produce ⁶⁸Ga radiopharmaceuticals for liquid targets appears to be much lower than that for solid targets, allowing access to and continuity of service, especially in developing countries [58]. Priority should be given to reprocessing the recovered ⁶⁸Zn target to maximize resource use and increase cost-effectiveness. The investigation of the reprocessing of ⁶⁸Zn targets is presented in

Table 9. Method, yield, and ⁶⁸Zn quality of ⁶⁸Zn target reprocessing.

Method	Yield and 68Zn Quality	Ref.
Adjust the pH of the recovered 68Zn to ≤5 and use dilute nitric acid. Condition the cation exchange resin (AG-50WX8) with 60 mL water and 20 mL air. Load the recovered 68Zn onto the AG-50WX8 resin and wash with 20 mL of air, followed by 10 mL of water and 20 mL of air. Elute 68Zn with 15 mL of 8 M HNO3. Remove HNO3 under vacuum at 40 °C for 30 min and then at 60 °C. Freeze-dry overnight to remove residual water.	Yield: 82.6% ± 13.6 Purity: 99.5% Impurities: 0.5% Na as NaNO3	[36]
Heat the recovered 68Zn to dryness. Dissolve the remaining 68Zn with 6 M HNO3 and heat again until dry. Redissolve with 0.2 N HNO3.	Not available	[35]

. Pandey and group [36] and Riga and group [35] reprocessed the recovered ⁶⁸Zn with purities up to 99%, the former using a cation exchange resin (AG-50WX8) and the latter using a drying method. Only minor impurities were detected which shows that reprocessing the recovered ⁶⁸Zn target is possible with minimal labor. Further experiments should be performed to evaluate the quality of the irradiated reprocessed ⁶⁸Zn.

Metal impurities in the [⁶⁸Zn]ZnO target affect the EOB and the final product, especially if ⁶⁶Ga and ⁶⁷Ga are present. Several precautions should be taken to prevent metal contamination of reprocessed [⁶⁸Zn]ZnO during pre-processing, processing, and post-processing. In general, the use of metals should be avoided, including contact with metal equipment. As described in

Table 10. Precaution measures to be considered for [⁶⁸Zn]ZnO reprocessing.

Step	Precaution Measure
Pre-processing	Use ultra-trace metal grade water to prepare the [68Zn]ZnO target. Use trace metal grade HNO3 to prepare for [68Zn]ZnO target. Avoid any contact with metal during the preparation of the [68Zn]ZnO target. Ensure that the chemicals used to capture and purify 68Ga are trace metal grade. Collect the 68Zn recovery in a clean, sterile vial. Never use a metal needle to collect the 68Zn recovery. Clean the target with trace metal grade HNO3. Ensure that the proton irradiation energy does not co-produce 67Ga via the 68Zn(p,2n)67Ga route.
Processing	Use ultra-trace metal water. Use trace metal analysis grade of HNO3. Use clean equipment cleaned with ultrapure water. Minimize any contact with metallic equipment for drying or removing moisture.
Post-processing	Keep the reprocessed [68Zn]ZnO in an airtight container, preferably in a vial. Perform isotopic analysis, preferably using ICP-MS, to detect 66Zn and 67Zn. Perform cyclotron irradiation of the reprocessed [68Zn]ZnO and analyze it with a gamma spectrometer to detect any co-production of 68Ga. Perform three consecutive validation runs using the same production sequence

, pre-processing precautions include using trace metal-free water and HNO₃ specifically in the production of [⁶⁸Zn]ZnO and any chemicals that come into contact with [⁶⁸Zn]ZnO during production. To recover [⁶⁸Zn]ZnO, a clean, sterile vial with a coated or plastic needle is preferred.

The presence of ⁶⁷Zn may have arisen as a by-product of the ⁶⁸Zn(p,2n)⁶⁷Ga reaction. Although this is difficult to determine because ⁶⁷Zn may be present only in minimal amounts, any change in the production process or any low yield result should be considered for the possibility of ⁶⁷Zn presence.

During the processing of the recovered [⁶⁸Zn]ZnO, it is important to take preventive measures, such as using trace metal-grade water and chemicals for dilution and equipment cleaning. The equipment used should also be dedicated to preventing cross-contamination with materials that could affect the reprocessed [⁶⁸Zn]ZnO quality. The reprocessed [⁶⁸Zn]ZnO was stored in an airtight container. For validation purposes, both inductively coupled plasma mass spectrometry (ICP-MS) and gamma spectrometry analyses were performed for three consecutive runs. In the case of multiple [⁶⁸Zn]ZnO reprocessing, a risk assessment and appropriate study should be considered. This may have regulatory implications, such as the potential cause of cross-contamination with other metals.

4.3. Optimization of ⁶⁸Ga Radiopharmaceutical Production via a Liquid Target

The production of ⁶⁸Ga radiopharmaceuticals via a cyclotron is touted as “production on demand,” given that it can be produced with a consistent EOS activity at any time upon need throughout the year. This development may create more opportunities for cyclotron centers to upgrade for ⁶⁸Ga production. Installing a solid target may be costly; hence, the liquid target is the better option, especially for medical cyclotrons. Nonetheless, the liquid target production of ⁶⁸Ga radiopharmaceuticals has more room for optimization to ensure cost efficiency for each production. This can be deduced as improvements in EOS.

The ideal characteristics of a cyclotron-produced ⁶⁸Ga radiopharmaceutical include (1) a short production time, (2) minimal ⁶⁸Ga losses during purification, and (3) a high AMA. Due to the short half-life of ⁶⁸Ga, the purification and radiolabeling steps must be rapid to achieve a high yield at EOS. However, using two-column methods for purification and formulation became an obstacle to shorter preparation time. Further work can be considered for purification and formulation using liquid target production to reduce time and improve EOS.

5. Regulatory Aspects of Cyclotron-Produced ⁶⁸Ga Radiopharmaceuticals

Recently, the direct production of cyclotron-based ⁶⁸Ga, particularly the proton irradiation of enriched ⁶⁸Zn target route, has expanded and been practiced elsewhere. Currently, most medical cyclotron produces ⁶⁸Ga radiopharmaceuticals to cater for in-house use, which does not require marketing authorization (MA) from regulatory bodies. To produce medicinal products for human use, each country follows a set of national or international guidelines that are being enforced by local regulatory bodies, such as the US Food and Drug Administration (US FDA), World Health Organization (WHO), the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), or Pharmaceutical Inspection Co-Operation Scheme (PIC/S) [59].

Producing radiopharmaceuticals compound may be categorized under Good Manufacturing Practices (GMP) or Good Preparation Practices (GPP). The main differences between GMP and GPP are summarized in

Table 11. Main differences between Good Manufacturing Practices (GMP) and Good Preparation Practices (GPP).

Good Manufacturing Practice (GMP)	Good Preparation Practice (GPP)
Guidance for Industry on Manufacture of Medicinal Products	Guidance for Healthcare Establishments on the Preparation of Medicinal Products
Distribution of manufactured radiopharmaceuticals to local/international market	Direct supply to patient for in-house use
Manufacture in large-scale of radiopharmaceuticals	Preparation in a small scale of radiopharmaceuticals according to prescription
Starting from raw materials to finished products	Products are being prepared in dilution or reconstitution and/or mixing of products
High-Risk Preparation	Low-Risk Preparation
Distribution of radiopharmaceuticals needs to obtain Marketing Authorization (MA)	Distribution of radiopharmaceuticals does not need for Marketing Authorization (MA)
Full quality control test as per monograph	Partial quality control test based on manufacturer recommendation or in-house method

. The nature of cyclotron-produced ⁶⁸Ga radiopharmaceuticals falls under the grey area. Although the criteria mostly fit the elements listed under GMP, the radioisotope’s short half-life limits the labeled compound’s distribution to other centers or institutions.

As mentioned, most medical cyclotron facilities produce ⁶⁸Ga radiopharmaceuticals for in-house use only; thus, it is considered a small-scale preparation. EANM recently released a Guideline on the current Good Radiopharmacy Practice (cGRPP) for the small-scale preparation of radiopharmaceuticals to cater to in-house radiopharmaceutical preparations [60]. The cGRPP guidance was not much different from the PIC/S GPP guidance document practices elsewhere. EANM position for in-house radiopharmaceutical preparation also clearly stated that MA is not mandatory [61].

However, using a solid target to produce ⁶⁸Ga radiopharmaceuticals may yield a different opinion from manufacturers and regulators. The capacity to produce ⁶⁸Ga radiopharmaceutical through a solid target using a medical cyclotron can be considered a large-scale production with a range of minimum EOP and EOB between 3.7 to 18 GBq and 6.3 to 31 GBq, respectively [34,38]. With this range of [⁶⁸Ga]GaCl₃ produced, the ⁶⁸Ga radiopharmaceutical could be distributed to other centers. This scenario may require MA approval from local authorities, which requires a GMP license to produce the dedicated radiopharmaceuticals as well as registration of products.

There are a few options on how cyclotron-based ⁶⁸Ga radiopharmaceuticals can be supplied either as [⁶⁸Ga]GaCl₃ or as a labeled radiopharmaceutical such as [⁶⁸Ga]Ga-DOTA-TATE or [⁶⁸Ga]Ga-PSMA. The nature of the ⁶⁸Ga radiopharmaceutical also significantly determines the need for MA approval. Generally, medicinal products required to be registered and obtain MA are intended for human use to diagnose, cure, treat or prevent any ailment or disease. Thus, [⁶⁸Ga]GaCl₃ does not fit the definition of the medicinal product, unlike [^99mTc]TcO⁴⁻ in pertechnetate, from where it can be given directly for thyroid scintigraphy. The [⁶⁸Ga]GaCl₃ cannot be administered in free form unless it is radiolabeled with a precursor, such as DOTA-TATE and PSMA. In this case, [⁶⁸Ga]GaCl₃ needs to be supplied as an active pharmaceutical ingredient requiring full quality testing and documentation for approval by regulatory bodies.

Besides that, there are also arguments that the labeled [⁶⁸Ga]Ga-DOTA-TATE or [⁶⁸Ga]Ga-PSMA does not fit the manufacturing elements as the nature of the production process is more towards reconstitution instead of manufacturing. The radiolabeling process is the same as the one generator produced except that cyclotron-produced ⁶⁸Ga needs additional steps, such as processing of the solid target and purification steps before it is in the form of ready-to-label [⁶⁸Ga]GaCl₃. These additional steps are critical and will determine the fate of the final product; therefore, it is considered a high-risk preparation that fits the manufacturing element.

When considering GMP for cyclotron-based ⁶⁸Ga radiopharmaceuticals, a few parameters need to be considered starting from target transfer and processing, chemical preparations, synthesis module software, process validation, quality control testing, and metal testing. These parameters will be discussed briefly in the following subsection.

5.1. Target Transfer System and Processing

Under PIC/S GMP Guide Annex 3 (manufacture of radiopharmaceuticals) stated that the GMP requirement is not mandatory for the cyclotron. However, the cyclotron and its transfer system may consider the first steps of active substance manufacture, which require the process to be included under the GMP element [62]. The performance qualification (PQ) for the cyclotron liquid target is straightforward and easily implemented. Cyclotron target PQ shall include ⁶⁸Ga EOB activity, radionuclidic purity, percentage of activity lost, and volume test. For solid target production, additional steps are required where the solid target needs to be dissolved in an acidic solution, such as HCl or HNO₃; only then can it be further purified using single or multiple resins. There are a few options on how the dissolution process can be performed: (1) process within the cyclotron vault (in-situ); (2) process in a dedicated hot cell; and (3) process within the same hot cell where the synthesis module is located (integrated with synthesis module [39,63,64]. Option (1) and (3) are the most suitable for medical-grade cyclotron as such a system does not require a dedicated hot cell for the dissolution process while providing automation that reduces unnecessary radiation exposure for operators. From a GMP point of view, these processes need to be validated and included in the PQ for a solid target system. Additional testing parameters for the equipment qualification shall be considered for heating verification, consistency in the volume of acid for the dissolution process, and time verification for the whole solid target transfer and dissolution process.

5.2. Chemical Preparations

Generally, cyclotron-based ⁶⁸Ga production employs manual chemical preparations versus commercial cassettes, as the latter is costly and is not widely available. Preparing cyclotron-based ⁶⁸Ga radiopharmaceuticals using a commercial cassette may have advantages in terms of simplicity and GMP compliance. There is no need to perform validation for chemical components except for raw material sampling, which can be conducted initially for vendor qualification purposes. The procedure needs to be validated for manual chemical preparation, and the preparation must be completed aseptically under controlled environments. The laboratory apparatus and glassware must be calibrated. Furthermore, the glassware cleaning procedures shall also be validated to avoid cross-contamination, which will affect the integrity of chemical preparation. The most critical point to be considered is the random sampling of the manually prepared chemicals for sterility and endotoxin limits that need to be established for each lot.

5.3. Synthesis Module Supervision Software

The synthesis module relies on the software to control the equipment’s specific operation and capture production data. Under PIC/S GMP Annex 11, all applications and IT infrastructure related to production equipment or process must be qualified. However, the software for the synthesizer platform is categorized as configurable software where the Programmable Logic Controller (PLC) is built-in on the equipment. The software is limited to controlling specific operations and functions; thus, complete validation and qualification are not mandatory to be performed by the user. The manufacturer shall comply with Good Automated Manufacturing Practice 5 (GAMP 5) during the development of the synthesis module software. The software validation certificate shall be issued during Installation Qualification (IQ). The only concern is the synthesis sequence that can be manipulated depending on needs and situations. Unlike [¹⁸F]Fluorodeoxyglucose (FDG) manufacturing, the synthesis sequence and software are fully qualified by the manufacturer, where a Common Technical Document (CTD) is provided that describes the technical aspects of manufacturing and regulatory support information. Meanwhile, for ⁶⁸Ga manufacturing, the synthesis sequence is categorized as ‘open-sequence’ where the parameter can be adjusted/interrupted during the synthesis, which may or may not be a concern for regulators. Nonetheless, some software platforms can limit operator control by password, plus the software will capture any manual interruptions during synthesis, and the information is stated in the production report.

5.4. Quality Control of ⁶⁸Ga Radiopharmaceuticals

Since the monograph for Accelerator Produced [⁶⁸Ga]GaCl₃, [⁶⁸Ga]Ga-DOTA-TATE, and [⁶⁸Ga]Ga-PSMA are available, there should be no issue in performing the QC test accordingly. Strict validation should be performed, in particular for co-produced ⁶⁶Ga and ⁶⁷Ga impurities, since the testing is performed up to 24 h after the production. Though the production of radiopharmaceuticals is not alienated from performing tests after administration to patients, typically for sterility tests, it is vital to ensure that the output is within the specifications. Hence, these validation data should be compiled, and the routine production should not deviate from the standard procedure. These risks should also be considered in low EOB or EOS cases. In addition, an impurity detection test should be validated and performed considering the risk of cross-contamination, mainly if different ⁶⁸Ga radiopharmaceuticals are produced within the same day.

5.5. Metal Testing for [⁶⁸Ga]GaCl₃

The metal testing result is required for [⁶⁸Ga]GaCl₃ but not mandatory for a labeled compound. The metal that needs to be assessed is Zn and Fe, where the limits are 10 µg/GBq after EOP as stated in the EU monograph. Most medical cyclotron facilities do not equip with a metal testing device as such equipment is costly, and the test is limited to one test only, thus will result in low usage. Since the metal test for [⁶⁸Ga]GaCl₃ does not require the sample to be tested immediately, the sample can decay out in a proper container or vial and be sent to a third-party laboratory for metal testing. The test is required each time [⁶⁸Ga]GaCl₃ has been produced. Thus, stages of product release shall be employed and stated clearly in the procedure. Furthermore, a contractual agreement shall be in place with a third-party analytical lab that details the manufacturer’s and analytical lab’s scope and role. These elements shall be considered if the manufacturer intends to obtain a GMP license.

5.6. Process Validation

Process validation, including media fill validation that exposes microbial growth media to the product contact surface, equipment, or container closure system mimics the actual production, shall be performed periodically as a requirement of sterile product manufacturing. In the synthesizer platform, the media cannot replace the chemicals and reagents as it is impossible to perform synthesis runs using microbial growth media such as Tryptic Soy Broth (TSB) that cannot pass through the small tubing and cassette due to the media thickness. A proper media simulation validation protocol shall be designed accordingly not to compromise the main objectives of process validation. One can consider diluting the media with water for injection (WFI). Still, the dilution ratio needs to be validated to ensure that it can promote microbial growth with the diluted media.

5.7. Other Consideration

Since the cyclotron can produce ⁶⁸Ga radiopharmaceutical on a large scale, other options can be considered to utilize the labeled compounds fully. Typically, most nuclear medicine facilities are equipped with one PET; thus, producing a large-scale ⁶⁸Ga radiopharmaceutical is not worthwhile because the ⁶⁸Ga scans are limited to the number of FDG scans. To maximize the utilization of large-scale ⁶⁸Ga production, other patients from nearby non-cyclotron PET centers within the same district or area can perform injections on-site and the scans at their facility. The idea is to provide a new clinical service instead of supplying radiopharmaceuticals to other centers needing MA approval. The advantage of this innovative service is that the patient preparation for ⁶⁸Ga scans is not as tight as FDG scans; thus, the patient can be ready for injection once the synthesis is completed, and the QC results are within the specification. Nevertheless, some limitations must be considered, such as transporting ‘radioactive’ patients that may require approval from local authorities.

6. Conclusions

In addition to the significant clinical benefits, radioisotope supply sustainability is crucial for meeting current and future needs. The cost and availability of radioisotopes are critical factors in ensuring a future-proof supply. Though alternatives to ⁶⁸Ga, such as [¹⁸F]AlF radiopharmaceuticals, are being intensively discussed [65,66,67,68], the narrative for theranostic ⁶⁸Ga/¹⁷⁷Lu for PRRT remains critical through the work on the expansion of the production route, as reviewed in this article. With the increasing use of ⁶⁸Ga in nuclear medicine and the introduction of new ⁶⁸Ga radiopharmaceuticals, ⁶⁸Ga availability is becoming increasingly critical. Therefore, the innovative cyclotron method for producing ⁶⁸Ga is touted as a significant advancement in this field, particularly because it allows for a very high ⁶⁸Ga yield. The innovative approach described in this article to producing liquid targets will soon be feasible, subject to the approval of local authorities. The producers of enriched [⁶⁸Zn]ZnO from the local region and validated/automated for reprocessing [⁶⁸Zn]ZnO could later ensure the cost-effectiveness of ⁶⁸Ga produced from the cyclotron.