**2.2.1 Radiometrologic parameters and their determination**

**(i) Activity, Bq, and derived quantity Radioactive Concentration (Massic Activity), expressed in Bq g-1 of solution, or Bq mL-1**. These are basic parameters of a radiopharmaceutical product, as the precise determination of the activity administrated to the patient, in full compliance with the prescriptions of the medical doctor, determines his/her committed effective dose, mSv, in radionuclide diagnosis and absorbed dose in the organ/tissue, mGy, in radionuclide therapy, and assures the safety and effectiveness of the medical procedure. Due to this reason, the special requirements regarding the reporting of total activity of a radiopharmaceutical product, on a reference time, are specified by the *Basic Safety Standards* 

\*\*) When a natural Rhenium target is irradiated, a mixture 186Re+188Re is obtained. It can be used in this composition, for the short time irradiation of the external part of large dimension tumors by 188Re and for the long time irradiation of their cores by 186Re. Otherwise, after a week period 188Re decays and almost pure 186Re is obtained. 186Re and 188Re are very important for the obtaining of therapy pharmaceuticals, due to their similar chemical behavior (VII b group) with 99mTc, very extensively

One radiopharmaceutical product is characterized by several types of parameters, whose determination requires a very good knowledge of the physico-nuclear parameters of the radionuclide and the use of adequate methods and equipment for measurements. Their accepted limit values and methods of determination are described in international and national technical regulatory documents, such as the European Pharmacopoeia (2002). It is considered that the radiopharmaceuticals are products with a high pharmaceutical risk. The parameters are determined first of all in the radiopharmacy, which must dispose of control laboratories in full compliance with the requirements for Good Laboratory Practice (GLP) and accredited according to the international standard *"General Requirements for the Competence of Testing and Calibration Laboratories"*, ISO/IEC 17025:2005. Their determined values are confirmed by the national control laboratories, or are internationally recognized by conventions. Some parameters are controlled only in radiopharmacy, while others are compulsory for the nuclear medicine units, mainly when supplementary operations are carried. A detailed description of the requirements and of their accomplishment mode, regarding quality assurance in radiopharmaceutical measurement is presented in the document *Technical Report Series 454 (TRS 454)*, elaborated by the International Atomic

Three types of radiopharmaceuticals' parameters are generally defined and controlled:

**(i) Activity, Bq, and derived quantity Radioactive Concentration (Massic Activity), expressed in Bq g-1 of solution, or Bq mL-1**. These are basic parameters of a radiopharmaceutical product, as the precise determination of the activity administrated to the patient, in full compliance with the prescriptions of the medical doctor, determines his/her committed effective dose, mSv, in radionuclide diagnosis and absorbed dose in the organ/tissue, mGy, in radionuclide therapy, and assures the safety and effectiveness of the medical procedure. Due to this reason, the special requirements regarding the reporting of total activity of a radiopharmaceutical product, on a reference time, are specified by the *Basic Safety Standards* 

radiometrologic, physico-chemical and biological-microbiological parameters.

**2.2.1 Radiometrologic parameters and their determination** 

radiations

16.98 h β Max

Energy, keV; Intensity

1962-2118. mean 706-784;100% Tissue range Max./Mean

11 mm/ 3.5 mm

Obtaining Half life Type of

Type Radio

studied.

nuclide

Energy Agency (IAEA) (2006).

188Re\*\* NR:

187Re(n, γ)188Re

186W(n, γ)187 W (n, γ)188W (69.4 d) Generator

Table 2. Radionuclides used for therapy radiopharmaceuticals.

**2.2 Technical parameters of radiopharmaceuticals and control methods** 

or

(*1996), para.II.19,* such as follows: *"the calibration of sources used for medical exposure shall be traceable to a Standard dosimetry laboratory*" and *"unsealed sources for nuclear medicine procedures shall be calibrated in terms of activity of the radiopharmaceutical to be administrated, the activity being determined and recorded at the time of administration"*. The conclusion of these assertions is that the activity must be precisely measured and the metrological traceability up to the primary level must be assured.

In radiopharmacy and nuclear medicine units, the activity is usually determined using Radionuclide Activity Calibrators, or Dose Calibrators. They contain a reentrant (well type) ionization chamber under pressure, connected to an electrometric system. The manufacturers perform the calibration of the equipment in terms of calibration factors, introduced in dial settings, established for a list of the most used medical radionuclides. The calibrations are performed using sets of standard solutions, provided by the radionuclide metrology laboratories or by commercial producers, having metrological traceability to a primary activity standard declared. Usually, these factors are determined for various types of recipients used in hospitals, such as: P6 or Schott 10-R vials, syringes, gelatin iodide capsules, etc.

The pharmacopoeias impose the uncertainty limits in the measurement of activity, as: <5% for therapy and <10% for dignosis. The activity is measured in radiopharmacy, but it must be measured also in the hospital, as several operations, such as portioning, administration with a syringe, are carried by the involved staff**.** Due to the crucial importance of these measuremens, the radionuclide calibrator precision in the calibration and maintenance of its corresponding technical condition, together with the correct method of activity measurement in the nuclear medicine units are matters of concern at international level. The IAEA initiated a program aimed to improve and harmonize the quality of activity measurements. In November 2002 a group of consultants had a meeting in the IAEA Vienna headquarters, giving advice on the Methodology of Radioactivity Standardization. The Coordinated Research Project (CRP) codified as: E2.10.05, entitled: *"Harmonization of quality practices for nuclear medicine radioactivity measurements*" was started in 2004. Following the recommendations of the first meeting, a second consultants meeting was held and recommended to develop a set of procedures in the form of a draft Code of Practice in radioactivity measurement. Among other results of the CRP deployment, the elaboration of the above named document TRS454: *Quality Assurance for Radioactivity Measurement in Nuclear Medicine* was very important. The document presents in detail (Table 4, page 69) the types of tests and acceptance criteria for radionuclide activity calibrators to be performed upon the initial acceptance in the unit or after repair, daily checks in the hospital, monthly and annually. As for accuracy of measurement, an upper limit of 5% is imposed. In this respect, a radionuclide metrology laboratory is the entity providing assurance of metrological traceability chain directly, by providing standards, by performing calibrations and by organizing proficiency tests among the personnel doing measurements in radiopharmacy, in the control authorities, at the calibrators' producers and the nuclear medicine staff.The requirement of accuracy in the metrology laboratory is 2%. It can be primary activity standard, or a secondary one, metrologically traceable to a primary activity standard, disposing of a calibrated reentrant ionisation chamber, such as described by (Schrader, 1997).

**(ii) Specific activity, expressed in units, Bq g-1 of solid mass**. It defines the activity of the mass unit of the chemical element or solid compound and determines the capacity of

Role of the Radionuclide Metrology in Nuclear Medicine 145

used. Some relevant examples:

used (Wyngaardt. 2006).

must be certified with uncertainties <5%.

2000).

allowing the determination of full absorption peak areas and for performing corrections for: geometry, matrix and sample volume, coincidence summation for multigamma emitting radionuclides. The determination of purity consists from the following steps: identification of the main radionuclide and of the impurities in the sample, according to the energy calibration; measurement of the areas of all full absorption peaks; calculation of individual activities, using the efficiency calibration curve and the gamma-ray emission intensity from the radionuclide decay scheme; calculation of the ratios between the activity of the main radionuclide and the sum (main radionuclide plus radio impurities). Generally, the impurity level is controlled only in the radiopharmacy, but in the case of molybdenum breakthrough, it must be controlled also in the hospital, due to the possible deterioration of molybdenum retention in the alumina column along its use. On this purpose, the radionuclide calibrators are usually provided with a lead shield, which absorbs the 99m Tc, 140.5 keV gamma-rays. The detection of sole 99Mo gamma-rays and use of 99Mo calibration factor, corrected for the absorption of its gamma-radiations in the shield, allows the determination of the impurity level, expressed as the ratio between 99Mo and 99mTc activities. The problem is more complex when pure beta or alpha-ray emitters are

a. Determination of 90Sr content in 90Y when a 90(Sr+Y) generator is used. In this case, only liquid scintillation spectrometry (Grau Malonda et al. 1994) or counting is

b. Determination of alpha and beta impurities in 99mTc, due to fission 99Mo used for generator production. In this case, the restrictive limits for alpha impurities are of the order of 10-9 and for beta emitters of the order of 10-6. This level of impurities is possible to be measured only after the complete decay of the 99m Tc elute by using the liquid scintillation counting, alpha/beta discrimination (Terlikowska et al.

**(ii) Radiochemical purity or ratio between the activity of the main compound and sum of all chemical compounds.** The determination is compulsory in the radiopharmacy, but it is advisable also in the hospital, when operations like the preparation of labeled kits is performed. For example, the determination of radiochemical purity of Labeled 99mTcMDP, expressed as the ratio: 99mTcMDP/( 99mTcMDP+Na99mTO4). This purity determination is important, as the tropism of the compound to the target organ/tissue is affected, resulting in the dangerous irradiation of other organs. The imposed limits are generally of 97-98%. The radiochemical purity is determined by using the radiochromatographic methods: either thin layer chromatography (TLC) or more sophisticated - high purity liquid chromatography (high pressure liquid chromatography)-HPLC. The determination consists of the measuring the activities of the two fractions and calculating the ratio between the activity of the main fraction and the sum of main and impurity fractions. The precision of measurement depends mainly on the linearity of the measurement instrument, which must be verified by using two standard sources with activity ratio of about 100, similar with the ratio of measured activities. The counting rates ratio must be equal with the ratio of sources activities, which

**(iii) Chemical purity, defined by the existence of some nonradioactive elements.** The

from a generator. Their presence can produce the toxicity of the radiopharmaceutical, or can

in 99mTc elutes

chemical impurities can be: alumina, cooper, ions types (NH4)+ or (NO3)-

labeling, mainly for biomolecules, and also the radiopharmaceutical's toxicity for human body. Two situations must be taken into consideration:


#### **2.2.2 Physico-chemical parameters**

**(i) Radionuclidic purity, expressed as the ratio between the activity of the base radionuclide and total activity.** This parameter is important from two points of view:


labeling, mainly for biomolecules, and also the radiopharmaceutical's toxicity for human



**(i) Radionuclidic purity, expressed as the ratio between the activity of the base radionuclide and total activity.** This parameter is important from two points of view:

ii. their contribution in the committed effective dose of the patient, mainly when the impurities have values of the *E/A* higher than the main radionuclide. One relevant example is the (99Mo- 99mTc) generator, where (*E/A*)Mo-99 =1.2 *mSv/MBq*, 55 times higher than for 99mTc; a 2% 99Mo impurity will duplicate the committed effective dose. For this reason the 99Mo impurity in 99mTc elute, known as "molybdenum breakthrough", is restricted at 0.1%. The precise determination of impurity level depends on the knowledge of the decay parameters, such as presented in the Monographie BIPM-5 (2004): half life, type and intensity of emitted radiations for all impurities and also on the precision of the method used in determination. In the simple case, when the involved radionuclides are gamma-ray emitters, the well-known gamma-ray spectrometry method, based on spectrometers provided with high resolution HPGe or Ge(Li) detectors, multichannel analyzers (MCA) and sets of software for processing of data, is used (Debertin & Helmer.1988). The energetic resolution is expressed in terms of full width at half maximum (FWHM) and reflects the ability of the system to distinguish two close energy full absorption peaks. Their calibration contains two



body. Two situations must be taken into consideration:

under the use of stanous chloride as catalist.

**2.2.2 Physico-chemical parameters** 

components:

contained in a sample;

irradiation of 130Te, the obtained radionuclide is carrier free.

i. influence of impurities on accuracy of activity measurements and

allowing the determination of full absorption peak areas and for performing corrections for: geometry, matrix and sample volume, coincidence summation for multigamma emitting radionuclides. The determination of purity consists from the following steps: identification of the main radionuclide and of the impurities in the sample, according to the energy calibration; measurement of the areas of all full absorption peaks; calculation of individual activities, using the efficiency calibration curve and the gamma-ray emission intensity from the radionuclide decay scheme; calculation of the ratios between the activity of the main radionuclide and the sum (main radionuclide plus radio impurities). Generally, the impurity level is controlled only in the radiopharmacy, but in the case of molybdenum breakthrough, it must be controlled also in the hospital, due to the possible deterioration of molybdenum retention in the alumina column along its use. On this purpose, the radionuclide calibrators are usually provided with a lead shield, which absorbs the 99m Tc, 140.5 keV gamma-rays. The detection of sole 99Mo gamma-rays and use of 99Mo calibration factor, corrected for the absorption of its gamma-radiations in the shield, allows the determination of the impurity level, expressed as the ratio between 99Mo and 99mTc activities. The problem is more complex when pure beta or alpha-ray emitters are used. Some relevant examples:


**(ii) Radiochemical purity or ratio between the activity of the main compound and sum of all chemical compounds.** The determination is compulsory in the radiopharmacy, but it is advisable also in the hospital, when operations like the preparation of labeled kits is performed. For example, the determination of radiochemical purity of Labeled 99mTcMDP, expressed as the ratio: 99mTcMDP/( 99mTcMDP+Na99mTO4). This purity determination is important, as the tropism of the compound to the target organ/tissue is affected, resulting in the dangerous irradiation of other organs. The imposed limits are generally of 97-98%. The radiochemical purity is determined by using the radiochromatographic methods: either thin layer chromatography (TLC) or more sophisticated - high purity liquid chromatography (high pressure liquid chromatography)-HPLC. The determination consists of the measuring the activities of the two fractions and calculating the ratio between the activity of the main fraction and the sum of main and impurity fractions. The precision of measurement depends mainly on the linearity of the measurement instrument, which must be verified by using two standard sources with activity ratio of about 100, similar with the ratio of measured activities. The counting rates ratio must be equal with the ratio of sources activities, which must be certified with uncertainties <5%.

**(iii) Chemical purity, defined by the existence of some nonradioactive elements.** The chemical impurities can be: alumina, cooper, ions types (NH4)+ or (NO3) in 99mTc elutes from a generator. Their presence can produce the toxicity of the radiopharmaceutical, or can

Role of the Radionuclide Metrology in Nuclear Medicine 147

level, by demonstrating the equivalence of its standards to the International System (SI), can

Figure 1 presents the equivalence and traceability chain to be established in activity measurement, from the International System (SI), assured by the International Bureau of Weights and Measures (Bureau International des Poids et Mesures-BIPM) through primary standard laboratories which disseminate the standards to the SSLs and end users, in our case the nuclear medicine units. In order to accomplish its duties, one primary laboratory has to solve the following tasks: it must set up the installations for absolute standardization of radionuclides, demonstrate its international equivalence and assure traceability to the

Fig. 1. Dissemination pathways for SI values of activity (From Woods & Sahagia. 2008).

The distinction between the radionuclide metrology and other metrology branches consists of the necessity to elaborate specific standardization methods almost for each radionuclide, due to the variability of decay schemes, and in the impossibility to construct an immuable

In radionuclide metrology, an absolute standardization is done by the following procedure: one detects the radiations emitted by a radioactive source and the method for establishing an adequate relation between the counting rate and the activity of the source is elaborated.

<sup>0</sup> =

*Nrad* is the counting rate, s-1 (impulses per second) for the detected radiation; *ε* is the detection efficiency of the system; *s*, denoted also as *(I, p)* is the intensity of detected

*N sA sN rad* (1)

ε = ε

**3.1.1 Methods and installations for primary (absolute) standardization** 

standard, due to the radioactive dizintegration.

A general relation is expressed as:

solve entirely this task.

lower levels.

deteriorate the labeling yield of the kits. They are usually determined in the radiopharmacy, but in some cases, the medicine units can dispose of the necessary equipment for control. The methods are specific to the analytical non radiation chemistry, such as spectrophotometry or colorimetry.
