**7.2 Module**

With the growing interest for gallium-68 not only for research but also for clinical routine and patient care the need for pharmacopeia compliant preparation of 68Ga-radiopharmaceuticals. This led to promotion of the automation of the traditional manual synthesis from which numerous semi- and fully automated devices have emerged. Today, those systems are designed with respect to Good

#### **Figure 4.**

*Schematic description of the 68Ga-radiolabeling procedure (I) preparation of the reaction mixture by adding gallium-68 eluted from a generator or after post-processing to a mixture of a suitable buffer and precursor, (II) incubation of the reaction mixture for a certain time. If elevated temperatures are needed or not depends on the chelator, (III) purification step using solid phase extraction (SPE). For example, the 68Ga-radiopharmaceutical is trapped on a SPE C18-cartridge where it is washed with water to remove free gallium-68, germanium-68 and buffer, (IV) the purified product is finally eluted with diluted ethanol solution and formulated after sterile filtration in the product vial.*

**31**

licensed kits.

without great expense.

*Gallium-68: Radiolabeling of Radiopharmaceuticals for PET Imaging - A Lot to Consider*

**Chelator Radiolabeling conditions** DOTA 37–90°C, 10–30 min, pH 4.0–5.5 [52, 53] HBED 25°C, 10–20 min, pH 4.0–4.5 [54]

Manufacturing Practice (GMP) Guidelines provided, for example, by the FDA, EU/EMA, ICH, WHO or others [55]. They use software and methods designed to minimize user interventions and utilize single-use consumables produced under

terms of higher reliability and reduced variability [56–58].

final user responsibility to verify the reconstitution procedure.

of the final preparation is suitable for the intended, use [26].

While the module production requires a fully equipped laboratory and quality control, it reduces radiation exposure of the operator the production process in

Accordingly, the amount of contaminated waste materials is higher due to the procedure as well the complete quality control. Nevertheless, these systems are suitable for a variety of tracers and in most cases for more radionuclides not only for gallium-68 (e.g. Scintomics GRP series; Eckert & Ziegler Modular-Lab

Recently, cold kits for radiolabeling entered the scene enable production of 68Ga-radiopharmaceuticals as easy as that of 99mTc-radiopharmaceuticals. This method allows the reconstitution of the pre-formulated cold kit with no previous post-processing of the eluate or subsequent purification of the final product. They are available in GMP quality and leaves only minimum quality control tests to the

For example, the European Pharmacopeia (Ph. Eur.) states the marketing authorization (MA) holder of a licensed kit is responsible to ensure compliance of the kit with the requirements of its MA, while the final user carries the responsibility for the quality of the preparation and the handling. If the given instructions are not strictly followed or if one or more components used for the reconstitution do not have MA, it is the responsibility of the final user to demonstrate that the quality

Therefore, preparation as well as quality control requires at least the equipment according to the instructions provided by the manufacturer. In addition, minimum contaminated waste materials remain. It has to be noted, according to the Ph. Eur. that applies only for licensed kits in combination with the generator mentioned in the instructions from the manufacturer. In contrast, unlicensed kits or a licensed kit used with an unlicensed generator or cyclotron produced gallium-68 also require full quality control according to the monograph.

Additionally, local authorities may require more detailed quality control even for

Indeed, these cold kits contain relatively high amounts of precursor and additional filler materials. They still require manual handling and are only commercially available as single-dose kits for radiolabeling PSMA-11 (e.g. illumet™) and DOTA-TOC (e.g. NETSPOT®). In addition, the use of unpurified generator eluates requires very strict specifications for the generators in terms of 68Ge-breakthrough to ensure the quality of the final product. Nevertheless, there is a possibility for small sites to offer 68Ga-radiopharmaceuticals to their patients

*DOI: http://dx.doi.org/10.5772/intechopen.90615*

*Radiolabeling conditions for gallium-68 for DOTA and HBED.*

GMP standard.

**Table 2.**

**7.3 Kits**

PharmTracer; Trasis AllInOne).

*Gallium-68: Radiolabeling of Radiopharmaceuticals for PET Imaging - A Lot to Consider DOI: http://dx.doi.org/10.5772/intechopen.90615*


**Table 2.**

*Medical Isotopes*

**7.1 Manual**

ing kinetics.

impurities.

**7.2 Module**

long time, the only available method.

post-processed gallium-68 can be used.

in the product vial (**Table 2**).

formation of gallium with the used chelator.

*and formulated after sterile filtration in the product vial.*

**7. Radiolabeling: complexation chemistry in clinical settings**

The manual radiolabeling approach is a leftover from times, where gallium-68 was mainly used for research purpose, with lower 68Ga-activities and not in a clinical setting for patient care. It is widely used in research and development of new tracers [11–13, 29, 30, 45–51]. Its main advantage is full control over the complete process (pH, time and temperature) and the possibility to easily access radiolabel-

Due to its general setup, this method is not suitable and indented for clinical use. Nevertheless, before the introduction of module systems or the cold kits, it was a

In general (**Figure 4**), the first step is the preparation of the reaction mixture by mixing [68Ga]GaCl3 with a suitable buffer in the required pH range and the radiolabeling precursor. Here, the purified cyclotron-produced, generator eluate or

Then, the reaction vial is incubated to form the 68Ga-complex. Reaction period and reaction temperature are selected in accordance to the kinetics of the complex

After the reaction, the reaction mixture can be purified using, for example, solid phase extraction from, for example, free gallium-68 and residual germanium-68

In the final step, the 68Ga-radiopharmaceutical is sterile filtrated and formulated

With the growing interest for gallium-68 not only for research but also for clinical routine and patient care the need for pharmacopeia compliant preparation of 68Ga-radiopharmaceuticals. This led to promotion of the automation of the traditional manual synthesis from which numerous semi- and fully automated devices have emerged. Today, those systems are designed with respect to Good

*Schematic description of the 68Ga-radiolabeling procedure (I) preparation of the reaction mixture by adding gallium-68 eluted from a generator or after post-processing to a mixture of a suitable buffer and precursor, (II) incubation of the reaction mixture for a certain time. If elevated temperatures are needed or not depends on the chelator, (III) purification step using solid phase extraction (SPE). For example, the 68Ga-radiopharmaceutical is trapped on a SPE C18-cartridge where it is washed with water to remove free gallium-68, germanium-68 and buffer, (IV) the purified product is finally eluted with diluted ethanol solution* 

**30**

**Figure 4.**

*Radiolabeling conditions for gallium-68 for DOTA and HBED.*

Manufacturing Practice (GMP) Guidelines provided, for example, by the FDA, EU/EMA, ICH, WHO or others [55]. They use software and methods designed to minimize user interventions and utilize single-use consumables produced under GMP standard.

While the module production requires a fully equipped laboratory and quality control, it reduces radiation exposure of the operator the production process in terms of higher reliability and reduced variability [56–58].

Accordingly, the amount of contaminated waste materials is higher due to the procedure as well the complete quality control. Nevertheless, these systems are suitable for a variety of tracers and in most cases for more radionuclides not only for gallium-68 (e.g. Scintomics GRP series; Eckert & Ziegler Modular-Lab PharmTracer; Trasis AllInOne).

#### **7.3 Kits**

Recently, cold kits for radiolabeling entered the scene enable production of 68Ga-radiopharmaceuticals as easy as that of 99mTc-radiopharmaceuticals. This method allows the reconstitution of the pre-formulated cold kit with no previous post-processing of the eluate or subsequent purification of the final product. They are available in GMP quality and leaves only minimum quality control tests to the final user responsibility to verify the reconstitution procedure.

For example, the European Pharmacopeia (Ph. Eur.) states the marketing authorization (MA) holder of a licensed kit is responsible to ensure compliance of the kit with the requirements of its MA, while the final user carries the responsibility for the quality of the preparation and the handling. If the given instructions are not strictly followed or if one or more components used for the reconstitution do not have MA, it is the responsibility of the final user to demonstrate that the quality of the final preparation is suitable for the intended, use [26].

Therefore, preparation as well as quality control requires at least the equipment according to the instructions provided by the manufacturer. In addition, minimum contaminated waste materials remain. It has to be noted, according to the Ph. Eur. that applies only for licensed kits in combination with the generator mentioned in the instructions from the manufacturer. In contrast, unlicensed kits or a licensed kit used with an unlicensed generator or cyclotron produced gallium-68 also require full quality control according to the monograph. Additionally, local authorities may require more detailed quality control even for licensed kits.

Indeed, these cold kits contain relatively high amounts of precursor and additional filler materials. They still require manual handling and are only commercially available as single-dose kits for radiolabeling PSMA-11 (e.g. illumet™) and DOTA-TOC (e.g. NETSPOT®). In addition, the use of unpurified generator eluates requires very strict specifications for the generators in terms of 68Ge-breakthrough to ensure the quality of the final product. Nevertheless, there is a possibility for small sites to offer 68Ga-radiopharmaceuticals to their patients without great expense.
