**8. Quality control: pharmaceutical needs and radioactive specialties**

Quality defects of pharmaceutical can lead to serious consequences when they are applied. Consequently, the regulatory framework for production and quality control is very strict. In general, one main requirement in the production of pharmaceuticals is a comprehensive, integrated system of quality assurance. Its purpose is the monitoring and documentation of all processes as well as their functionality with respect to the rules of GMP.

Because radiopharmaceuticals are pharmaceutical preparations containing minimum one radionuclide for diagnostic or therapeutic purpose, in principle the same rules apply. Their quality control is intended to ensure that the quality meets the predefined specifications for the radiopharmaceutical. These specifications take into account the radionuclide, the precursor, the preparation process, the formulation and the intended administration route. Due to the nature of the contained radionuclides, not all necessary quality control tests can be performed before release for administration and require retrospective examination. In the available monographs, it is indicated if a test need not to be completed before release of the batch.

In the case of gallium-68, the short half-live and the limited available activities lead to further challenges. Here are sophisticated logistics for preparation and quality control essential.

In general, quality control of 68Ga-radiopharmaceuticals should include the following tests and information [59–61]:


**33**

sterility

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

used for quality control of 68Ga-radiopharmaceuticals.

normally ascertained with TLC and/or HPLC.

6.*Radiochemical purity*. Should discover all chemical forms containing the radionuclide and determine their percentage of the total radioactivity of the product. These radiochemical impurities arise from the synthesis method, radiolysis or the radionuclide production and can lower the quality of the final diagnostic examination. Principally be determined by any suitable analytical method but with respect to the short half-life and radiation TLC and HPLC are normally

7.*Chemical purity*. The chemical purity refers to the amount of the specified chemical form of a preparation if radioactivity is present or not [61]. Purity assessment is of special importance when diagnostic or therapeutic properties are directly linked to chemistry [63]. Therefore, particular attention is necessary for pharmacologically active impurities as they can affect the diagnostic value of the examination. The chemical purity of 68Ga-radiopharmaceuticals is

8.*Residual solvents*. Ph. Eur. as well as US pharmacopeia defines residual solvents as organic volatile chemicals used in the manufacture of drug substances/active substances, excipients or in the preparation of medicinal products (Eur. Ph. 5.4.; USP 467). As they represent a risk of health, they should be determined. Determination can be performed using gas chromatography (GC)

It has to be noted that the texts about residual solvents not cover solvents added

9.*Microbiological contamination*. Parenteral administered radiopharmaceuticals need to be compliant in terms of bacterial endotoxins or pyrogens as well as

Bacterial endotoxins are known to cause a wide spectrum of nonspecific pathophysiological reactions (fever, changes in white blood cell counts, hypotension, disseminated intravascular coagulation, shock and death) leading to death when injected in most mammals [64]. Thanks to the development of more and more efficient systems today tests (LAL-test) for bacterial endotoxins (BET) can be completed before release of the batch of the 68Ga-radiopharmaceuticals.

In contrary, the test for sterility of 68Ga-radiopharmaceuticals via direct inocula-

10.*Radioactivity content/concentration*. Defines the activity, measured with a dose

11.*Specific radioactivity*. The specific radioactivity (activity of the radionuclide per unit mass either of the element or the desired chemical form) is calculated using the concentrations of radioactivity and the chemical form. Referring to the consensus nomenclature rules for radiopharmaceutical chemistry [65], the specific activity is expressed as measured activity per gram of compound (e.g. MBq/μg), while it is called molar activity when expressing the measured

tion is necessarily retrospective nevertheless indispensable. Additionally, to the direct inoculation test the integrity of the sterile filter used for sterile filtration of the final product is performed. Due to the need for sterilization to obtain a sterile parenteral solution and the not applicability of autoclaving for short-living radiopharmaceuticals membrane filtration is normally the method of choice. The tests for the filter integrity (e.g. bubble point, diffusion rate, pressure hold) have the

advantage that they can be completed before batch release.

calibrator, within the volume of the final preparation.

by purpose or solvates. For those other limits and regulations may apply.

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

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


It has to be noted that the texts about residual solvents not cover solvents added by purpose or solvates. For those other limits and regulations may apply.

9.*Microbiological contamination*. Parenteral administered radiopharmaceuticals need to be compliant in terms of bacterial endotoxins or pyrogens as well as sterility

Bacterial endotoxins are known to cause a wide spectrum of nonspecific pathophysiological reactions (fever, changes in white blood cell counts, hypotension, disseminated intravascular coagulation, shock and death) leading to death when injected in most mammals [64]. Thanks to the development of more and more efficient systems today tests (LAL-test) for bacterial endotoxins (BET) can be completed before release of the batch of the 68Ga-radiopharmaceuticals.

In contrary, the test for sterility of 68Ga-radiopharmaceuticals via direct inoculation is necessarily retrospective nevertheless indispensable. Additionally, to the direct inoculation test the integrity of the sterile filter used for sterile filtration of the final product is performed. Due to the need for sterilization to obtain a sterile parenteral solution and the not applicability of autoclaving for short-living radiopharmaceuticals membrane filtration is normally the method of choice. The tests for the filter integrity (e.g. bubble point, diffusion rate, pressure hold) have the advantage that they can be completed before batch release.


*Medical Isotopes*

with respect to the rules of GMP.

ity control essential.

following tests and information [59–61]:

formed by visual inspection.

radiochemical species.

of the batch.

**8. Quality control: pharmaceutical needs and radioactive specialties**

Quality defects of pharmaceutical can lead to serious consequences when they are applied. Consequently, the regulatory framework for production and quality control is very strict. In general, one main requirement in the production of pharmaceuticals is a comprehensive, integrated system of quality assurance. Its purpose is the monitoring and documentation of all processes as well as their functionality

Because radiopharmaceuticals are pharmaceutical preparations containing minimum one radionuclide for diagnostic or therapeutic purpose, in principle the same rules apply. Their quality control is intended to ensure that the quality meets the predefined specifications for the radiopharmaceutical. These specifications take into account the radionuclide, the precursor, the preparation process, the formulation and the intended administration route. Due to the nature of the contained radionuclides, not all necessary quality control tests can be performed before release for administration and require retrospective examination. In the available monographs, it is indicated if a test need not to be completed before release of the batch. In the case of gallium-68, the short half-live and the limited available activities lead to further challenges. Here are sophisticated logistics for preparation and qual-

In general, quality control of 68Ga-radiopharmaceuticals should include the

2.*pH determination*. Should ensure that the pH of the final product is in the necessary range for its purpose. For the final injectable formulation of a radiopharmaceutical, the pH should be closed to the physiologic value of 7.4. With regard to the relatively low volume of radiopharmaceuticals and depending on the injected volume and rate, a wider range (3.5–8.5) is applicable. Contrary to this, the pH of the radionuclide precursor gallium-68 should not exceed 2 to

3.*Radionuclidic identification*. Identification of a radionuclide is generally conducted by determination of its half-life and/the nature and energy of its radiation emitted. For positron emitters like gallium-68 instead of energy and nature of the radiation, the identification is based on a γ-spectrum additional

4.*Radiochemical identification.* Identification of the desired radiochemical species via HPLC and/or TLC exploiting different chemical behavior of the different

5.*Radionuclidic purity*. Due to the contribution or formation of other radionuclides during the production of gallium-68, their amount present in the final radiopharmaceutical must be determined. Depending on the production route of gallium-68, different limits for radionuclidic impurities may apply. The test for those long-living radionuclides need to be performed after complete decay of the sample using γ-spectrometry, representing a test performed after release

prevent the formation of unwanted 68Ga-colloids.

to their half-life determination (e.g. with dose calibrator).

1.*Characters/appearance*. Should discover any visible container defects. The quality of the final product in terms of absence of particular matter [62] and/or turbidity should be ensured as well as its correct appearance. Typically per-

**32**

activity per mole of compound (MBq/nmol) [65]. As gallium-68 requires a complex ligand which is normally not fully removed during the final product purification, the measured specific or molar activity is lower than actual. Then the correct terms are apparent specific or molar activity [65].

The specific or molar activity is always given with reference date and time.

## **8.1 Generator obtained gallium-68**

For gallium-68 obtained from a 68Ge/68Ga-generator, the Ph. Eur. contains a distinct monograph (#2464). This monograph specifies the quality characteristics of 68Ga chloride solutions for radiolabeling independently if obtained directly from a generator or after post-processing the generator eluate. If a further purification of the generator eluate is performed, this has to be stated on the label.

Use of generator-produced gallium-68 in the USA is regulated under 10 CFR 35. 1000 and 10 CFR 30.33 [66] (**Table 3**).

For incoming starting materials, the GMP guidelines prescribe certain handling procedures to ensure their quality and suitability. For material acceptance of an incoming new 68Ge/68Ga-generator, minimum controls are needed. This include the conformation of the radionuclide identity, 68Ge-breakthrough and of activity stated in the Certificate of Analysis (CoA) all verified by activity measurement if possible [60]. Establishment of additional acceptance criteria may be required.

Nevertheless, the 68Ga-eluate used for radiolabeling should meet those specifications (**Table 4**), their verification is in clinical routine not possible for every production. This results from the different production routes of 68Ga-radiopharmaceuticals, which do not intend or allow an intervention for sampling of the eluate. Thus, the quality control of the starting material gallium-68 or of the final radiopharmaceuticals is allowed. This should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.

#### **8.2 Cyclotron produced gallium-68**

When produced via accelerator, the presence of the radioisotopes gallium-66 and gallium-67 is difficult to avoid due to zinc-66 and zinc-67 contaminating the


#### **Table 3.**

*Quality control specifications for diluted hydrochloric solutions of generator produced gallium-68 as defined by the Ph. Eur. (monograph #2464) [59].*

**35**

**Table 5.**

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

Eckert & Ziegler (Germany) GalliaPharm® 2.4 GBq

Obninsk Cyclotron Ltd. (Russia) 3.7 GBq IRE Elit (Belgium) Galio Eo® 1.85 GBq

ITG (Germany) 2 GBq iThemba Labs (South Africa) 1.85 GBq Pars Isotopes (Iran) Pars-GalluGEN 2.59 GBq

**Manufacturer Type Maximum nominal activity**

IGG100 2.4 GBq

Galli Ad® 1.85 GBq

target material. In return, germanium-68 is absent. Therefore, quality control and specifications for radionuclidic impurities are different to generator-produced

For gallium-68 obtained from a cyclotron, a new monograph (#3109) is already submitted for adoption to the Ph. Eur. [67]. This monograph specifies the quality characteristics of 68Ga-chloride solutions for radiolabeling obtained by irradiation of enriched zinc-68 in an accelerator with subsequent isolation of gallium-68 in

Similar to generator-produced gallium-68, quality control can be performed of the starting material obtained via cyclotron or on the final radiopharmaceutical. If quality control of the final radiopharmaceuticals performed, it should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and

As an example for the specifications and limitations for a 68Ga-

**WHAT? HOW? LIMITS** Appearance Visual inspection Clear, colorless solution

pH pH indicator strips <2 Radionuclide identity Half-life determination 62–74 min

radiopharmaceutical quality control as requested by the monograph #2464 of the

Radionuclidic purity γ-spectrometry <0.1% long living impurities

Radiochemical purity TLC >95% 68Ga(III) Chemical purity ICP-AES/ICP-MS <10 μg/GBq Fe

Bacterial Endotoxins LAL test ≤175 EU/total volume

*by a draft of a monograph for the Ph. Eur. Submitted for adoption (#3109) [67].*

*Quality control specifications for diluted hydrochloric solutions of accelerator-produced gallium-68 as defined* 

γ-spectrometry 511, (1022), 1077, (18,839 keV

<2% gallium-66 & gallium-67

<10 μg/GBq Zn

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

*In all conscience a list of 68Ge/68Ga-generators available.*

gallium-68.

**Table 4.**

acidic solution (**Table 5**).

**8.3 68Ga-Radiopharmaceuticals**

chemical purity.

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


**Table 4.**

*Medical Isotopes*

**8.1 Generator obtained gallium-68**

1000 and 10 CFR 30.33 [66] (**Table 3**).

**8.2 Cyclotron produced gallium-68**

activity per mole of compound (MBq/nmol) [65]. As gallium-68 requires a complex ligand which is normally not fully removed during the final product purification, the measured specific or molar activity is lower than actual. Then

The specific or molar activity is always given with reference date and time.

For gallium-68 obtained from a 68Ge/68Ga-generator, the Ph. Eur. contains a distinct monograph (#2464). This monograph specifies the quality characteristics of 68Ga chloride solutions for radiolabeling independently if obtained directly from a generator or after post-processing the generator eluate. If a further purification of

Use of generator-produced gallium-68 in the USA is regulated under 10 CFR 35.

For incoming starting materials, the GMP guidelines prescribe certain handling procedures to ensure their quality and suitability. For material acceptance of an incoming new 68Ge/68Ga-generator, minimum controls are needed. This include the conformation of the radionuclide identity, 68Ge-breakthrough and of activity stated in the Certificate of Analysis (CoA) all verified by activity measurement if possible

When produced via accelerator, the presence of the radioisotopes gallium-66 and gallium-67 is difficult to avoid due to zinc-66 and zinc-67 contaminating the

Radionuclidic purity γ-spectrometry <0.1% long living impurities

Radiochemical purity TLC >95% 68Ga(III) Chemical purity ICP-AES/ICP-MS <10 μg/GBq Fe

Bacterial Endotoxins LAL test ≤175 EU/total volume

*Quality control specifications for diluted hydrochloric solutions of generator produced gallium-68 as defined by* 

γ-spectrometry 511, (1022), 1077, (18,839 keV

<0.001% germanium-68

<10 μg/GBq Zn

**WHAT? HOW? LIMITS** Appearance Visual inspection Clear, colorless solution

pH pH indicator strips <2 Radionuclide identity Half-life determination 62–74 min

the correct terms are apparent specific or molar activity [65].

the generator eluate is performed, this has to be stated on the label.

[60]. Establishment of additional acceptance criteria may be required. Nevertheless, the 68Ga-eluate used for radiolabeling should meet those specifications (**Table 4**), their verification is in clinical routine not possible for every production. This results from the different production routes of 68Ga-radiopharmaceuticals, which do not intend or allow an intervention for sampling of the eluate. Thus, the quality control of the starting material gallium-68 or of the final radiopharmaceuticals is allowed. This should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.

**34**

**Table 3.**

*the Ph. Eur. (monograph #2464) [59].*

*In all conscience a list of 68Ge/68Ga-generators available.*

target material. In return, germanium-68 is absent. Therefore, quality control and specifications for radionuclidic impurities are different to generator-produced gallium-68.

For gallium-68 obtained from a cyclotron, a new monograph (#3109) is already submitted for adoption to the Ph. Eur. [67]. This monograph specifies the quality characteristics of 68Ga-chloride solutions for radiolabeling obtained by irradiation of enriched zinc-68 in an accelerator with subsequent isolation of gallium-68 in acidic solution (**Table 5**).

Similar to generator-produced gallium-68, quality control can be performed of the starting material obtained via cyclotron or on the final radiopharmaceutical. If quality control of the final radiopharmaceuticals performed, it should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.
