Traceability for radionuclides

Deliverable D11.2 Traceability for radionuclides This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101008571 (PRISMAP). This document reflects only the view of the author(s). The Agency is not responsible for any use that may be made of the information it contains. Deliverable D11.2 ii Project Acronym PRISMAP Project Title The European medical isotope programme: Production of high purity isotopes by mass separation Grant Agreement No. 101008571 Topic INFRAIA-02-2020: Integrating Activities for Starting Communities Project start date 01 May 2021 Nature Report Dissemination level Public Due date M36 Date of delivery M36 Lead partner NPL Contributing partners - Author Seán Collins (NPL) Reviewer Maija Radziņa (LU) Point of Contact Seán Collins Institution National Physical Laboratory E-mail sean.m.co[email protected]o.uk Phone +442089438508 © PRISMAP 2021. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Deliverable D11.2 iii Revision History Version Date Author Comment 0.1 21.04.2024 Seán Collins First draft 0.2 23.04.2024 Ulli Köster Review 0.3 24.04.2024 Seán Collins Amended after consideration of reviewer comments. 0.4 24.04.2024 Maija Radzina Review 0.5 25.04.2024 Seán Collins Updates after consideration of reviewer comments 0.9 Kirsten Leufgen Review and minor revisions. Version for review by the PRISMAP General Assembly 1.0 30.04.2024 Kirsten Leufgen Final version, approved by the General Assembly Deliverable D11.2 iv Contents Abbreviations, Participant short names v ... v Abbreviations v … v Participant short names vi List of Figures vii ...... vii // Keep this line in place. It is need to fix a W ord-bug in the TOC. vii ... vii - vii Summary 1 ... 1 // Keep this line in place. It is need to fix a W ord-bug in the TOC. 1 1. Introduction 2 2. Traceability 2 3. SI unit of the Becquerel 4 4. The role of NMIs 4 5. The International Reference System and International Equivalence 5 6. Submissions to the SIR of PRISMAP radionuclides 6 6.1 Submissions of PRISMAP radionuclides prior to PRISMAP 6 6.2 Tb-161 6 7. Conclusion 7 References 8 Deliverable D11.2 v Abbreviations, Participant short names ... Abbreviations … BIPM Bureau International Des Poids et Mesures CA Consortium Agreement CCRI Consultative Committe for Ionising Radiation CIPM International Committee for Weights and Measures CMCs Calibration and Measurement Capability DoA Description of Action DoE Degree of Equivalence FDA Food and Drug Administration GA Grant Agreement IAEA International Atomic Energy Agency ICRU International Commission on Radiation Units and Measurements KCDB Key Comparison Database KCRV Key Comparison Reference Value LS Liquid Scintillation MRA Mutual Recognition Arrangement NIST National Institute of Standards and Technology NMI National Metrology Institute PET Positron Emission Tomography PS Plastic Scintillation SIR International Reference System SIRTI SIR Transfer Instrument SPECT Single Photon Emission Computer Tomography Deliverable D11.2 vi Participant short names CERN European organization for nuclear research NPL National Physical Laboratory PSI Paul Scherrer Institut CEA Commissariat à l’énergie atomique et aux énergies alternatives IST-ID Associação do Instituto Superior Técnico para a IST-ID Investigação e Desenvolvimento DTU Danmarks Tekniske Universitet CHUV Centre hospitalier universitaire vaudois GANIL Grand Accélérateur National d’Ions Lourds SCK CEN Studiecentrum voor Kernenergie / Centre d'étude de l'énergie nucléaire ARRONAX Groupement d’intérêt public ARRONAX ESS European spallation source ERIC TUM Klinikum rechts der Isar der technischen Universität München KULeuven Katholieke Universiteit Leuven MedAustron Entwicklungsund Betriebsgesellschaft MedAustron GmbH SCIPROM SCIPROM Sàrl MUI Medizinische Universität Innsbruck ILL Institut Max von Laue - Paul Langevin JRC JRC -Joint Research CentreEuropean Commission NCBJ Narodowe Centrum Badań Jądrowych GSI GSI Helmholtzzentrum fr Schwerionenforschung GmbH LU Latvijas Universitāte INFN Istituto Nazionale di Fisica Nucleare UiO Universitetet i Oslo Deliverable D11.2 vii List of Figures ...... // Keep this line in place. It is need to fix a W ord-bug in the TOC. ... - Figure 1. The metrological hierarchy to SI units for traceability for activity measurements in nuclear medicine. 3 Figure 2. Degrees of equivalence for equivalent activity of Tb-161(Michotte et al., 2024). 7 Summary ... // Keep this line in place. It is need to fix a W ord-bug in the TOC. Radionuclides play an important role in the diagnosis of a range of key diseases or for the delivery of targeted cancer therapies. This unique capability has been utilised for decades and drives the development of new radiopharmaceuticals using well known radionuclides and the search for novel radionuclides that can expand the pool of treatments available and lead to improvements in patient outcomes. The development and manufacture of these radiopharmaceuticals and use in a patient requires the accurate measurement of the activity of the radionuclide to provide the efficient and safe use of the drug. To achieve this, regulators look to radiopharmaceutical manufacturers and radiopharmacies to be capable of accurately measuring the activity of the radionuclide present in a manner traceable to national or international standards of activity. Traceability provides the best route to ensure that the measurement devices being used, and their calibrations are providing accurate results, through a documented unbroken chain of calibrations. As new radionuclides are identified and developed for use in nuclear medicine National Metrology Institutes (NMIs) play a crucial role in developing these national and international standards through the realisation of primary standards of activity of the radionuclide. The NMIs are responsible for providing a method for disseminating these standards to the radiopharmaceutical manufacturers, radiopharmacies and clinics to provide the link to the SI unit of the becquerel and give confidence in the activity measurements. Through the well-established comparison systems of the International Reference System (SIR) at the Bureau International Des Poids et Mesures (BIPM) the NMIs can compare their national standards against those of other nations and show their equivalence and provide confidence in the standards being provided. Over the years many primary standards for radionuclides with applications in medicine have been developed and compared, with some of PRISMAP radionuclides already having been compared by NMIs. With many new radionuclides being proposed for nuclear medicine applications, there is still a substantial amount of work for the NMIs and the BIPM to perform to provide traceability. Deliverable D11.2 2 1. Introduction In Nuclear Medicine, the use of radionuclides provides a unique capability to detect and diagnose cancer of a range of diseases or deliver targeted personalised cancer therapies. This capability continues to drive the development of new radiopharmaceuticals based on well-established radionuclides (e.g., F-18, Tc-99m) and novel radionuclides (e.g., Tb-161, Ac-225) to expand the range of applications and improve treatment outcomes. Unlike with external beam therapy, the dose delivered to a tumour or organ is intrinsically linked to the activity of the radionuclide administered to the patient. Accurate knowledge of the activity delivered to the tumour or critical organs is difficult due to the individuality of patients due to their unique metabolism. The main method for estimating the activity, and thus dose, to the tumour and organ is based on the total activity of the radionuclide administered to the patient, which is typically determined using a radionuclide calibrator based at the clinic, and a measured or assumed biodistribution of the radiopharmaceutical, and an appropriate dose model [1]. Recently, the use of quantitative imaging enables researchers and clinicians to quantify the activity of a diagnostic radionuclide delivered to the tumour region and organs and thus provide information on the potential effective dose of a therapeutic partner radionuclide [2,3]. At a pre-clinical or clinical level these activity measurements of the total administered activity are typically performed using a radionuclide “dose” calibrator with calibration factors or dial settings provided by the manufacturer. However, these factors may not always be accurate or traceable to national or international standards, especially for novel radionuclides (see section 2 for the definition of traceability). Errors may also be introduced due to the use of different vessel geometries, which may have significant effects for low energy gamma-ray emitting radionuclides (e.g., Tb-161)[4] or due to the matrix of the radiopharmaceutical, for example, where the radionuclide has been absorbed onto a resin particle [5]. The introduction of quantitative imaging brings with it many new challenges to ensure the accuracy of the activity measurements and the calibration of SPECT and PET cameras [2,6]. Due to the importance of the activity being administered to the patient, to ensure the safe use and effectiveness of the radiopharmaceutical, the accurate measurement of the activity content is required. This is reflected in authorities imposing a regulatory framework requiring a specific accuracy to be achieved, for example, a maximum allowed deviation of 10 % between the prescribed and administered activity as recommended by the ICRU [7], which is consistent with the pharmaceutical requirements in the European Pharmacopoeia for the declared activity. The best way to achieve accurate activity measurements are being made is for the measurement devices and their respective calibrations to be traceable to national and international standards [8]. Whilst PRISMAP has been in operation since 2021, NMIs have been realising primary standards for radionuclides since their inception for use as medical radionuclides, with primary standards for medical radionuclides at NMIs, like NPL, going back to the 1950s. For example, the first primary standardisation of 131I was performed at NPL in 1956 followed by 90Y in 1958 and has continued to the present day as novel medical radionuclides are identified and developed. 2. Traceability Metrological traceability is defined as the “property of a measurement result whereby the result can be related to a reference through a documented unbroken chain of calibration, each contributing to the measurement uncertainty” [9]. Through this unbroken chain, measurement results can be traced back to the International System of Units (SI) [10]. Traceability for nuclear medicine has previously been extensively described in Zimmerman and Judge [8] the following highlights some key points from that review. In figure 1 the typical metrological hierarchy to SI units is shown for traceability for activity measurements in nuclear medicine. At the top of this hierarchy is the SI units, which are maintained by the BIPM and proceed at a national level through a country’s NMI who realise primary measurement standards to the derived SI Deliverable D11.2 9 24. Ratel, G., et al., Activity measurements of the radionuclide 153Sm for the ANSTO, Australia in the ongoing comparison BIPM.RI(II)-K1.Sm-153. Metrologia, 2005. 42(1A): p. 06008. 25. Ratel, G. and Michotte, C., BIPM comparison BIPM.RI(II)-K1.Pb-203 of the activity measurements of the radionuclide 203Pb. Metrologia, 2003. 40(1A): p. 06032. 26. Coulon, R., et al., Update of the BIPM comparison BIPM.RI(II)-K1.Ra-223 of activity measurements of the radionuclide 223Ra to include the 2021 result of the POLATOM (Poland). Metrologia, 2023. 60(1A): p. 06002. 27. Coulon, R., et al., Update of the BIPM comparison BIPM.RI(II)-K1.Ac-225 of activity measurements of the radionuclide 225Ac to include the 2021 result of the POLATOM (Poland). Metrologia, 2023. 60(1A): p. 06001. 28. BIPM The key comparison database (available at: www.bipm.org/kcdb/) 29. Michotte, C., et al., Update of the BIPM comparison BIPM.RI(II)-K1.Tb-161 of activity measurements of the radionuclide 161Tb to include the 2022 result of the NPL (United Kingdom). Metrologia, 2024. 61(1A): p. 06005.