**5. The Radionuclide Metrology Laboratory support to the nuclear medicine**

A primary/secondary standard laboratory is the entity which can assure the continuity of the metrological traceability in the measurement and characterization of radiopharmaceuticals in radiopharmacy units, national control authorities and hospitals from the top level, SI, up to the end user, the patient, by the following standards delivery and calibration operations (Zimmerman et al. 2007):


These activities need to be accomplished under the regime of national accreditation, as a Calibration and Testing Laboratory, according to the provisions of the standard EN ISO/IEC 17025:2005 *"General requirements for the competence of testing and calibration laboratories".* For example IFIN-HH, RML obtained the accreditation for both types of activities, from the Romanian accreditation body, RENAR, member of the European Accreditation (EA), for the products and services for clients, after implementing a Quality Management System (QMS). The QMS consists of the documentation and practical realization of the documents' provisions. The main documents, covering the Chapters 4 and 5 of the EN ISO/IEC 17025:2005 standard, are: RML Manual-containing the basic statement of the QMS, an Organizational procedure and two sets of procedures: System (Management) procedures (MP) and Work procedures (WP) and instructions (WI). The accreditation was obtained in 2009, for a 4-year period; annual survey audits of RENAR representatives are done. In contrast with other calibration or testing laboratories, where the accreditation refers to some well-defined activities, in our quality of primary standard laboratory, we have first of all the responsibility for the quality of primary, absolute standardizations, on the top of traceability chain, not in direct connection with customers' requirements. The first consequences are: (i) The traceability chain must be well defined and demonstrated in the laboratory. (ii) An internationally recognized expert must conduct the technical evaluation

Another use of the IFIN-HH, RML's spectrometric system is the precise determination of the emission intensity of gamma-rays for radionuclides of medical use. These parameters are of maximum importance for activity standardization by primary methods, as in most of measurements they are basic parameters in activity calculation. On the other hand, the efficiency and safety of the medical procedure depends directly on their precise knowledge. The precise value of half life is directly used in nuclear medicine units for the calculation of activity at the moment of administration. The calculation of patients' doses is based on the values of: activity, half life, radiations - types, energies and emission intensities. On the international scale, projects of the type*: "EURAMET.RI(II)-S5.Radionuclide"* are organized, for the experimental determination of emission intensities and evaluation projects coordinated by the Decay Data Evaluation Program (DDEP) are deployed. IFIN-HH, RML participates in both types of programs. For example, recently the laboratory participated at the exercise, organized for the new PET radionuclide 64Cu, EURAMET project 1085 (Bé et al. 2011). RML standardized absolutely solutions from 64Cu and 68Ga by the coincidence method (Sahagia et al. 2011). Point solid sources from standard solution were prepared gravimetrically, and were used for the determination of their decay parameters: gammarays emission intensities with the calibrated HPGe spectrometric system and half life by the

use of the CENTRONIC IG12/20A ionization chamber (Luca et al.2011).

and calibration operations (Zimmerman et al. 2007):



**5. The Radionuclide Metrology Laboratory support to the nuclear medicine**  A primary/secondary standard laboratory is the entity which can assure the continuity of the metrological traceability in the measurement and characterization of radiopharmaceuticals in radiopharmacy units, national control authorities and hospitals from the top level, SI, up to the end user, the patient, by the following standards delivery

These activities need to be accomplished under the regime of national accreditation, as a Calibration and Testing Laboratory, according to the provisions of the standard EN ISO/IEC 17025:2005 *"General requirements for the competence of testing and calibration laboratories".* For example IFIN-HH, RML obtained the accreditation for both types of activities, from the Romanian accreditation body, RENAR, member of the European Accreditation (EA), for the products and services for clients, after implementing a Quality Management System (QMS). The QMS consists of the documentation and practical realization of the documents' provisions. The main documents, covering the Chapters 4 and 5 of the EN ISO/IEC 17025:2005 standard, are: RML Manual-containing the basic statement of the QMS, an Organizational procedure and two sets of procedures: System (Management) procedures (MP) and Work procedures (WP) and instructions (WI). The accreditation was obtained in 2009, for a 4-year period; annual survey audits of RENAR representatives are done. In contrast with other calibration or testing laboratories, where the accreditation refers to some well-defined activities, in our quality of primary standard laboratory, we have first of all the responsibility for the quality of primary, absolute standardizations, on the top of traceability chain, not in direct connection with customers' requirements. The first consequences are: (i) The traceability chain must be well defined and demonstrated in the laboratory. (ii) An internationally recognized expert must conduct the technical evaluation of the laboratory. On the other hand, as a national provider of radioactive standards, the RML must meet quality requirements in their production.

(i) *Definition of Activities and Establishment of Traceability Chain.* Clear distinction of the two types of activities in relation with the RENAR accreditation was defined: Calibration activities and Testing activities. (a) The calibration branch required a sharp definition of the traceability chain and activities deployed in regime of quality management. The declared activities under accreditation are: (I) Attestation of the installations for the absolute (direct) standardization, mainly used for international comparisons, in order to prove the international equivalence of the Romanian standards, and for the preparation of standard sources and solutions used for the calibration of the secondary equipment. (II) Calibration and metrological check of the secondary installations for the relative (indirect) standardization. (III) Standardization of the radioactive standard sources and solutions. (IV) Preparation and relative or absolute standardization of radioactive sources and solutions, under the quality management system. The traceability chain continues outside the laboratory, in connection with the users, and implies: (V) The delivery of radioactive sources, with Calibration Certificates, under the quality management system. (VI) The calibration and metrological check of activity measurement installations. (VII) The organization of inter laboratory comparisons (ILCs) and proficiency tests (PTs) for the testing and calibration laboratories. (b) The testing branch of accredited activities refers at the Analysis of very low activity samples by the gamma-ray spectrometry. Another special aspect in the application of the requirements of the 17025:2005 Standard in our case is the responsibility of the National Nuclear Authority (CNCAN) regarding the radioprotection of the workers, public and patients. In this respect IFIN-HH, RML was CNCAN designed also as a notified calibration and testing laboratory for the nuclear field.

#### **5.1 Radioactive standards for nuclear medicine**

The calibration and metrological check of the equipment for measurement of the radioactivity imposed the development of technics for the preparation of a large variety of standard sources and solutions, to be used in-house, or delivered to the external customers which are performing radioactivity measurement. A general WP, coded AC-PL-LMR-10, describes the common operations and detailed WIs present the specific operations.

*Radioactive Solutions*. A large variety of radioactive solutions, physico-chemically stable, adequate as radioactivity standards, are prepared (Grigorescu et al.1975). Some of them, even for external users' delivery, are standardized absolutely, or alternatively, by the use of the calibrated ionization chamber. They are certified in terms of radioactive concentration, *Bq g*-1, and in total activity, *Bq,* per recipient, flame or mechanically sealed in glass ampoules or P6 vials.

*Point and Large Area Alpha and Beta Sources.* These sources are of immediate interest, both for calibration of contamination monitors (contaminometers), as well as for the effective measurement of the so called "Gross Alpha" and "Gross Beta" radioactive content of environmental, industrial and food chain samples. Their preparation and measurement of the particle emission rate in a 2πsr geometry are described in (Sahagia et al. 1996a).

#### **5.2 Calibration and metrological check of measurement equipment**

The main requirements regarding the characteristics of the equipment for the measurement of activity and of the physico-chemical parameters were described in section 2. In order to satisfy them, a radionuclide metrology laboratory is asked to perform calibrations or other

Role of the Radionuclide Metrology in Nuclear Medicine 159

for a scientific output, in order to understand which explanations for noncorresponding results are. The comparisons regarded the measurement of 131I (Sahagia et al.1996b) and the set 99mTc and 57Co, (Sahagia & Woods. 2008c). Within the frame of the above cited *IAEA, CRP E2.10.05*, a series of international actions were deployed, in order to harmonize the measurements in the participant countries, all over the world. The actions were organized in two steps. The first step was the participation of the national reference laboratories (primary or secondary) in two comparisons organized by the IAEA, recognized also as supplementary CCRI(II) –S6 comparisons, on 131I and 57Co (used a as mock solution for 99mTc), intended to verify their calibration capability. The results were presented by the comparisons organizers in the papers (Zimmerman et al. 2008; Zimmerman & Palm. 2010). After the evaluation of the results, each national laboratory organized then two national comparisons, for the radionuclides 131I and 99mTc. IFIN-HH, RML organized the comparisons according to the prescriptions of the WP code AC-PL-LMR-07, written in accordance with the international documents: ISO Guide 43 *"Proficiency testing by interlaboratory comparisons"* Part 1: "*Development and operation of proficiency testing schemes*" and Part 2: "*Selection and use of proficiency testing schemes by laboratory accreditation bodies"* and following also the recommendations from the *Protocols on the organization of national comparisons of radiopharmaceuticals*, established within the frame of the *IAEA CRP. E2.10.05*.The analysis of the results was reported in the papers (Sahagia et al. 2009; Sahagia et al. 2010b). As conclusions from these tests are the proportions of hospitals measuring satisfactory the activities of the two radionuclides. In the case of 131I, from a total number of 15 reported values, a number of 11 results are within the difference limit from reference value <5%, and 12 results within the limit <10%, a proportion of 80% from participating units, being in compliance with the Pharmacopoeia; for 99mTc, from 7 reported values, a number of 5 results are within < 5 % difference from the reference value, and 7 results within the limit < 10 %, a proportion of 100% from participating units. Regarding 131I comparisons, after finalizing the *IAEA CRP. E2.10.05*, an interesting paper, summarizing all 8 national laboratories comparisons' organization and results was published recently (Olsovcova et al. 2010); a

similar paper is in preparation, for presentation of the 99mTc national comparisons.

radiopharmaceuticals for diagnosis and therapy procedures.

metrological, physico-chemical, biological.

of the radiopharmaceuticals' parameters.






**6. Conclusions** 

therapy.

to be declared.

metrology checks over it. The radionuclide calibrators are the most used devices for the measurement of activity in radiopharmacy, control units and hospitals (Razdolescu et al.2002b). In some cases the National Metrology legislation imposes their metrological control, according to legal metrology norms, and in others it is required their calibration at defined time intervals, by a metrology laboratory, accredited for calibration. In our case, the legal metrological control was mandatory until 2009. Starting with 2010, the calibrationrecalibration was preferred. In this respect, IFIN-HH, RML obtained the RENAR accreditation for these operations within its QMS. The WP codified as AC-PL-LMR-11 is applied. As a general remark from our calibration experience is that the Romanian hospitals staff increased in time its awareness regarding the quality of activity measurement and more and more nuclear medicine units benefit from our laboratory's services of calibration, at present time regarding the radionuclides: 99mTc and 131I. The deviations of the calibration factors from the reference values are generally within ±5%. The IFIN-HH radiopharmacy is under the permanent metrological survey of the RML. As this unit has under study new radiopharmaceuticals, the laboratory was asked to assess calibration factors to the radionuclide calibrators for the new radiouclides: 186Re, 188Re, 153Sm, 177Lu.

The second important action is the calibration of the HPGe spectrometric system used in the radiopharmacy for the control of radionuclidic impurities. It is calibrated and regularly recalibrated in energy and efficiency by the representatives of RML, using standard solutions prepared in RML, under accreditation regime, and the calibration procedure WP code AC-PL-LMR-0100 is applied.

Other equipment, belonging the radiopharmacy unit, are the radiochromatographs used in the control of the radiochemical purity; for their calibration and linearity check, a set of solid point standard gamma-ray emitting sources are used; for the case of 131I control, two 133Ba standard sources are measured. The action is also under accreditation regime and the WP code AC-PL-LMR-12 is applied.

Each nuclear medicine unit, operating with open radioactive sources, is provided with contaminometers for the control of radioactive contamination of surfaces, devices, clothes, operator hands, etc., which can occur during the medical procedures. This equipment can be under the legal metrological control of the state as it is in Romania, or only is recalibrated at defined intervals. The Romanian secondary standard laboratories performing these checks use large area standard sources emitting beta radiations, in most cases 90(Sr+Y) sources. IFIN-HH, RML is the provider of these standard sources and also performs their calibration (Sahagia et al. 1996b).

#### **5.3 Organization of national comparisons and proficiency tests**

The most significant test, recognized as relevant in the evaluation of the capability of a laboratory performing measurements, is the participation in proficiency tests. For example, even when the calibration factors of the radionuclide calibrators are correct, the measurement in a hospital implies also the skill of the operating staff. Non experienced people are possible to choose wrong calibration factors' values, to do wrong readings and activity calculation on the administration time. From our practical experience, one may conclude that the proportion of laboratories with unsatisfactory results in proficiency tests is higher than that of wrong calibrated equipment. This is the reason for which in some countries the participation in proficiency tests is mandatory, but in others like Romania, it is only voluntary. IFIN-HH, RML organized in the past several national comparisons mainly

metrology checks over it. The radionuclide calibrators are the most used devices for the measurement of activity in radiopharmacy, control units and hospitals (Razdolescu et al.2002b). In some cases the National Metrology legislation imposes their metrological control, according to legal metrology norms, and in others it is required their calibration at defined time intervals, by a metrology laboratory, accredited for calibration. In our case, the legal metrological control was mandatory until 2009. Starting with 2010, the calibrationrecalibration was preferred. In this respect, IFIN-HH, RML obtained the RENAR accreditation for these operations within its QMS. The WP codified as AC-PL-LMR-11 is applied. As a general remark from our calibration experience is that the Romanian hospitals staff increased in time its awareness regarding the quality of activity measurement and more and more nuclear medicine units benefit from our laboratory's services of calibration, at present time regarding the radionuclides: 99mTc and 131I. The deviations of the calibration factors from the reference values are generally within ±5%. The IFIN-HH radiopharmacy is under the permanent metrological survey of the RML. As this unit has under study new radiopharmaceuticals, the laboratory was asked to assess calibration factors to the

The second important action is the calibration of the HPGe spectrometric system used in the radiopharmacy for the control of radionuclidic impurities. It is calibrated and regularly recalibrated in energy and efficiency by the representatives of RML, using standard solutions prepared in RML, under accreditation regime, and the calibration procedure WP

Other equipment, belonging the radiopharmacy unit, are the radiochromatographs used in the control of the radiochemical purity; for their calibration and linearity check, a set of solid point standard gamma-ray emitting sources are used; for the case of 131I control, two 133Ba standard sources are measured. The action is also under accreditation regime and the WP

Each nuclear medicine unit, operating with open radioactive sources, is provided with contaminometers for the control of radioactive contamination of surfaces, devices, clothes, operator hands, etc., which can occur during the medical procedures. This equipment can be under the legal metrological control of the state as it is in Romania, or only is recalibrated at defined intervals. The Romanian secondary standard laboratories performing these checks use large area standard sources emitting beta radiations, in most cases 90(Sr+Y) sources. IFIN-HH, RML is the provider of these standard sources and also performs their calibration

The most significant test, recognized as relevant in the evaluation of the capability of a laboratory performing measurements, is the participation in proficiency tests. For example, even when the calibration factors of the radionuclide calibrators are correct, the measurement in a hospital implies also the skill of the operating staff. Non experienced people are possible to choose wrong calibration factors' values, to do wrong readings and activity calculation on the administration time. From our practical experience, one may conclude that the proportion of laboratories with unsatisfactory results in proficiency tests is higher than that of wrong calibrated equipment. This is the reason for which in some countries the participation in proficiency tests is mandatory, but in others like Romania, it is only voluntary. IFIN-HH, RML organized in the past several national comparisons mainly

radionuclide calibrators for the new radiouclides: 186Re, 188Re, 153Sm, 177Lu.

**5.3 Organization of national comparisons and proficiency tests** 

code AC-PL-LMR-0100 is applied.

code AC-PL-LMR-12 is applied.

(Sahagia et al. 1996b).

for a scientific output, in order to understand which explanations for noncorresponding results are. The comparisons regarded the measurement of 131I (Sahagia et al.1996b) and the set 99mTc and 57Co, (Sahagia & Woods. 2008c). Within the frame of the above cited *IAEA, CRP E2.10.05*, a series of international actions were deployed, in order to harmonize the measurements in the participant countries, all over the world. The actions were organized in two steps. The first step was the participation of the national reference laboratories (primary or secondary) in two comparisons organized by the IAEA, recognized also as supplementary CCRI(II) –S6 comparisons, on 131I and 57Co (used a as mock solution for 99mTc), intended to verify their calibration capability. The results were presented by the comparisons organizers in the papers (Zimmerman et al. 2008; Zimmerman & Palm. 2010). After the evaluation of the results, each national laboratory organized then two national comparisons, for the radionuclides 131I and 99mTc. IFIN-HH, RML organized the comparisons according to the prescriptions of the WP code AC-PL-LMR-07, written in accordance with the international documents: ISO Guide 43 *"Proficiency testing by interlaboratory comparisons"* Part 1: "*Development and operation of proficiency testing schemes*" and Part 2: "*Selection and use of proficiency testing schemes by laboratory accreditation bodies"* and following also the recommendations from the *Protocols on the organization of national comparisons of radiopharmaceuticals*, established within the frame of the *IAEA CRP. E2.10.05*.The analysis of the results was reported in the papers (Sahagia et al. 2009; Sahagia et al. 2010b). As conclusions from these tests are the proportions of hospitals measuring satisfactory the activities of the two radionuclides. In the case of 131I, from a total number of 15 reported values, a number of 11 results are within the difference limit from reference value <5%, and 12 results within the limit <10%, a proportion of 80% from participating units, being in compliance with the Pharmacopoeia; for 99mTc, from 7 reported values, a number of 5 results are within < 5 % difference from the reference value, and 7 results within the limit < 10 %, a proportion of 100% from participating units. Regarding 131I comparisons, after finalizing the *IAEA CRP. E2.10.05*, an interesting paper, summarizing all 8 national laboratories comparisons' organization and results was published recently (Olsovcova et al. 2010); a similar paper is in preparation, for presentation of the 99mTc national comparisons.
