Присутствие возможных примесей в радиофармацевтических лекарственных препаратах и методы их определения

Основными показателями качества любого радиофармацевтического лекарственного препарата, которые обеспечивают его эффективность и безопасность, и при этом отсутствуют в спецификациях других лекарственных средств, являются подлинность по радионуклиду, активность, радионуклидная чистота и радиохимическая чистота. Цель работы – анализ возможности образования различных видов примесей в радиофармацевтических лекарственных препаратах и методов определения этих примесей. Рассмотрены препараты на основе радионуклидов различных групп: технеция-99м и рения-188; изотопов йода и фтора-18; галлия-68 и некоторых других радионуклидов-металлов, применяемых в тераностических схемах «радионуклидная диагностика/радионуклидная терапия». Проанализированы источники образования радионуклидных, радиохимических и химических примесей, их влияние на качество визуализации и дозиметрические характеристики радиофармпрепаратов, различные подходы к методам обнаружения и количественного определения примесей,  фармакопейные требования к качеству радиофармпрепаратов и результаты исследований, опубликованные в научной литературе. Показана необходимость разработки и аттестации отечественных стандартных образцов для определения показателей качества радиофармацевтических лекарственных препаратов в рамках гармонизации отечественной фармакопеи с Фармакопеей Евразийского экономического союза и Европейской фармакопеей.

1. Bornholdt MG, Woelfel KM, Fang P, Jacobson MS, Hung JC. Rapid ITLC system for determining the radiochemical purity of 68Ga-DOTATATE. J Nucl Med Technol. 2018;46(3):285–7. https://doi.org/10.2967/jnmt.117.200873

2. Zolle I., ed. Technetium-99m pharmaceuticals: Preparation and quality control in nuclear medicine. Berlin, Heidelberg, New York: Springer; 2007. https://doi.org/10.1007/978-3-540-33990-8

3. Papagiannopoulou D. Technetium-99m radiochemistry for pharmaceutical applications. J Labelled Comp Radiopharm. 2017;60(11):502–20. https://doi.org/10.1002/jlcr.3531

4. Hou X. Determination of radionuclidic impurities in 99mTc eluate from 99Mo/99mTc generator for quality control. J Radioanal Nucl Chem. 2017;314:659–68. https://doi.org/10.1007/s10967-017-5369-9

5. Hasan S, Prelas MA. Molybdenum 99 production pathways and the sorbents for 99Mo/99mTc generator systems using (n, γ) 99Mo: a review. SN Applied Sciences. 2020;2:1782. https://doi.org/10.1007/s42452-020-03524-1

6. Tsivadze AYu, Filyanin AT, Filyanin OA, Avetisyan AA, Zykov MP, Kodina GE, et al. Radiochemical technology for production of preparations of technetium - 99m on extraction centrifugal semi-countercurrent generator. J Nucl Med Radiol Radiat Ther. 2017;2:007. https://doi.org/10.24966/NMRR-7419/100007

7. Vallabhajosula S, Killeen RP, Osborne JR. Altered biodistribution of radiopharmaceuticals: role of radiochemical/pharmaceutical purity, physiological, and pharmacologic factors. Semin Nucl Med. 2010;40(4):220–41. https://doi.org/10.1053/j.semnuclmed.2010.02.004

8. Opportunities and approaches for supplying molybdenum-99 and associated medical isotopes to global markets. Proceedings of a symposium. National Academies of Sciences, Engineering, and Medicine. Washington (DC): The National Academies Press; 2018. https://doi.org/10.17226/24909

9. Selivanova SV, Lavallée É, Senta H, Caouette L, Sader JA, van Lier EJ, et al. Radioisotopic purity of sodium pertechnetate 99mTc produced with a medium-energy cyclotron: implications for internal radiation dose, image quality, and release specifications. J Nucl Med. 2015;56(10):1600–8. https://doi.org/10.2967/jnumed.115.156398

10. Selivanova SV, Lavallée É, Senta H, Caouette L, McEwan AJB, Guérin B, et al. Clinical trial with sodium 99mTc-pertechnetate produced by a medium-energy cyclotron: biodistribution and safety assessment in patients with abnormal thyroid function. J Nucl Med. 2017;58(5):791–98. https://doi.org/10.2967/jnumed.116.178509

11. Tymiński Z, Saganowski P, Kołakowska E, Listkowska A, Ziemek T, Cacko D, et al. Impurities in Tc-99m radiopharmaceutical solution obtained from Mo-100 in cyclotron. Appl Radiat Isot. 2018;134:85–8. https://doi.org/10.1016/j.apradiso.2017.10.021

12. Andersson JD, Thomas B, Selivanova SV, Berthelette E, Wilson JS, McEwan AJB, et al. Robust high-yield ~1 TBq production of cyclotron based sodium [99mTc]pertechnetate. Nucl Med Biol. 2018;60:63–70. https://doi.org/10.1016/j.nucmedbio.2018.02.003

13. Meléndez-Alafort L, Ferro-Flores G, De Nardo L, Bello M, Paiusco M, Negri A, et al. Internal radiation dose assessment of radiopharmaceuticals prepared with cyclotron-produced 99mTc. Med Phys. 2019;46(3):1437–46. https://doi.org/10.1002/mp.13393

14. Lepareur N, Lacœuille F, Bouvry C, Hindré F, Garcion E, Chérel M, et al. Rhenium-188 labeled radiopharmaceuticals: current clinical applications in oncology and promising perspectives. Front Med (Lausanne). 2019;6:132. https://doi.org/10.3389/fmed.2019.00132

15. Цивадзе АЮ, Филянин АТ, Романовский ВН, Зыков МП, Кодина ГЕ, Малышева АО и др. Экстракционный центробежный генератор 188Re и радиофармпрепараты на его основе для радионуклидной терапии. Радиохимия. 2016;58(5):443–9. https://doi.org/10.1134/S1066362216050118

16. Зверев АВ, Клементьева ОЕ, Жукова МВ, Красноперова АС. Доклиническая оценка терапевтического потенциала радиофармацевтического лекарственного препарата на основе микросфер альбумина 5–10 мкм с рением-188. РМЖ. 2018;4(1):31–5.

17. Кодина ГЕ, Малышева АО, Клементьева ОЕ, Таратоненкова НА, Лямцева ЕА, Жукова МВ и др. «Синорен,188Re» – потенциальный радиофармацевтический лекарственный препарат для радиосиновэктомии. Радиация и риск. 2018;27(4):76–86. https://doi.org/10.21870/0131-3878-2018-27-4-76-86

18. Hammermaier A, Reich E, Biigl W. Chemical, radiochemical, and radionuclide purity of eluates from different commercial fission 99Mo/99mTc generators. Eur J Nucl Med. 1986;12(1):41–6. https://doi.org/10.1007/bf00638794

19. Brandau W, Hotze L-A, Meyer G-J. Radiochemie. In: Bаll U, Schicha H, Biersack H-J, Knapp WH, Reiners Chr, Schober O, eds. Nuklearmedizin. Stuttgart: Georg Thieme; 1996. P. 79–113.

20. Ullah H, Ahmad I, Khattak MR, Shah S, Ahmad S, Khan K, et al. Evaluation of radiochemical purities of routinely used radiopharmaceuticals: Three years’ experience of a single institute. Iran J Nucl Med. 2019;27(1):19–25.

21. Maioli C, Luciniani G, Strinchini A, Tagliabue L, Del Sole A. Quality control on radiochemical purity in Technetium-99m radiopharmaceuticals labelling: three years of experience on 2280 procedures. Acta Biomed. 2017;88(1):49–56.

22. Mang’era K, Wong D, Douglas D, Franz K, Biru T. Evaluation of alternative rapid thin layer chromatography systems for quality control of technetium-99m radiopharmaceuticals. Appl Radiat Isot. 2014;86:57–62. https://doi.org/10.1016/j.apradiso.2013.12.016

23. Ponto JA, Swanson DP, Freitas JE. Clinical manifestations of radiopharmaceutical formulation problems. In: Hladik WB III, Saha GB, Study KT, eds. Essentials of nuclear medicine science. Baltimore: Williams & Wilkins; 1987. P. 270–4.

24. McCready VR. Radioiodine – the success story of nuclear medicine. Eur J Nucl Med Mol Imaging. 2017;44(2):179–82. https://doi.org/10.1007/s00259-016-3548-5

25. Mishra A, Singh T. Estimation and verification of 131I yield from fission and irradiation of tellurium. Appl Radiat Isot. 2021;168:109535. https://doi.org/10.1016/j.apradiso.2020.109535

26. Smart BE. Fluorine substituent effects (on bioactivity). J of Fluorine Chem. 2001;109(1):3–11. https://doi.org/10.1016/S0022-1139(01)00375-X

27. Chiappiniello A, Iacco M, Rongoni A, Susta F, Sabatini P, Beneventi S, Tarducci R. Assessment of radionuclide impurities in [18F]fluoromethylcholine ([18F]FMCH). Phys Med. 2020;78:150–5. https://doi.org/10.1016/j.ejmp.2020.09.025

28. Bowden L, Vintro LL, Mitchell PI, O’Donnell RG, Seymour AM, Duffy GJ. Radionuclide impurities in proton-irradiated [18O]H2O for the production of 18F: Activities and distribution in the [18F]FDG synthesis process. Appl Radiat Isot. 2009;67(2):248–55. https://doi.org/10.1016/j.apradiso.2008.10.015

29. Siikanen J, Ohlsson T, Medema J, Van-Essen J, Sandell A. A niobium water target for routine production of [18F]Fluoride with a MC 17 cyclotron. Appl Radiat Isot. 2013;72:133–6. https://doi.org/10.1016/j.apradiso.2012.10.011

30. Metzger RL, Lasche GP, Eckerman KF, Leggett RW. Long-lived contaminants in cyclotron-produced radiopharmaceuticals: measurement and dosimetry. J Radioanal Nucl Chem. 2018;318(4):7–10. https://doi.org/10.1007/s10967-018-5970-6

31. Dziel T, Tymiński Z, Sobczyk K, Walęcka-Mazur А, Kozanecki P. Radionuclidic purity tests in 18F radiopharmaceuticals production process. Appl Radiat Isot. 2016;109:242–6. https://doi.org/10.1016/j.apradiso.2015.11.008

32. Savisto N, Bergman J, Aromaa, J, Forsback S, Eskola O, Viljanen T. et al. Influence of transport line material on the molar activity of cyclotron produced [18F]fluoride. Nucl Med Biol. 2018;64–65:8–15. https://doi.org/10.1016/j.nucmedbio.2018.06.004

33. Koziorowski J. A simple method for the quality control of [18F]FDG. Appl Radiat Isot. 2010;68(9):1740–2. https://doi.org/10.1016/j.apradiso.2010.03.006

34. Kuntzsch M, Lamparter D, Brüggener N, Müller M, Kienzle GJ, Reischl G. Development and successful validation of simple and fast TLC spot tests for determination of Kryptofix 2.2.2 and tetrabutylammonium in 18F-labeled radiopharmaceuticals. Pharmaceuticals (Basel). 2014;7(5):621–33. https://doi.org/10.3390/ph7050621

35. Antuganov D, Antuganova Y, Zykova T, Krasikova R. Use of capillary electrophoresis for the determination of impurities in preparations of fluorine-18 labelled PET radiopharmaceuticals. J Pharm Biomed Anal. 2019;173:68–74. https://doi.org/10.1016/j.jpba.2019.05.016

36. Rösch F. and Riss P.J. The reneaissance of the 68Ge/68Ga radionuclide generator initiates new development in 68Ga radiofarmaceutical chemistry. Curr Top Med Chem. 2010;10(16):1633–68. https://doi.org/10.2174/156802610793176738

37. Ambrosini V, Kunikowska J, Baudin E, Bodei L, Bouvier C, Capdevila J, et al. Consensus on molecular imaging and theranostics in neuroendocrine neoplasms. Eur J Cancer. 2021;146:56–73. https://doi.org/10.1016/j.ejca.2021.01.008

38. Lepareur N. Cold kit labeling: the future of 68Ga radiopharmaceuticals? Front Med (Lausanne). 2022;9:812050. https://doi.org/10.3389/fmed.2022.812050

39. Velikyan I. 68Ga-based radiopharmaceuticals: Production and application relationship. Molecules. 2015;20(7):12913–43. https://doi.org/10.3390/molecules200712913

40. Velikyan I. Prospective of 68Ga-radiopharmaceutical development. Theranostics. 2014;4(1):47–80. https://doi.org/10.7150/thno.7447

41. Satpati D. Recent breakthrough in 68Ga-radiopharmaceuticals cold kits for convenient PET radiopharmacy. Bioconjug Chem. 2021;32(3):430–47. https://doi.org/10.1021/ACS.BIOCONJCHEM.1C00010

42. Kumar K. The current status of the production and supply of gallium-68. Cancer Biother Radiopharm. 2020;35(3):163–6. https://doi.org/10.1089/cbr.2019.3301

43. Tsionou MI, Knapp CE, Foley CA, Munteanu CR, Cakebread A, Imberti C, et al. Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling. RSC Adv. 2017;7(78):49586–99. https://doi.org/10.1039/C7RA09076E

44. Spang P, Herrmann C, Roesch F. Bifunctional gallium-68 chelators: past, present, and future. Semin Nucl Med. 2016;46(5):373–94. https://doi.org/10.1053/J.SEMNUCLMED.2016.04.003

45. Burke BP, Clemente GS, Archibald SJ. Recent advances in chelator design and labelling methodology for 68Ga radiopharmaceuticals. J Label Compd Radiopharm. 2014;57(4):239–43. https://doi.org/10.1002/JLCR.3146

46. Kubíček V, Havlíčková J, Kotek J, Tircsó G, Hermann P, Tóth E, et al. Gallium(III) complexes of DOTA and DOTA-Monoamide: Kinetic and thermodynamic studies. Inorg Chem. 2010;49(23):10960–9. https://doi.org/10.1021/ic101378s

47. Wood SA, Samson IM. The aqueous geochemistry of gallium, germanium, indium and scandium. Ore Geol Rev. 2006;28(1):57–102. https://doi.org/10.1016/j.oregeorev.2003.06.002

48. Bois F, Noirot C, Dietemann S, Mainta IC, Zilli T, Garibotto V, et al. [68Ga]Ga-PSMA-11 in prostate cancer: a comprehensive review. Am J Nucl Med Mol Imaging. 2020;10(6):349–74. PMID: 33329937

49. Hennrich U, Eder M. [68Ga]Ga-PSMA-11: the first FDA-approved 68Ga-radiopharmaceutical for PET imaging of prostate cancer. Pharmaceuticals (Basel). 2021;14(8):713. https://doi.org/10.3390/PH14080713

50. Eder M, Wängler B, Knackmuss S, LeGall F, Little M, Haberkorn U, et al. Tetrafluorophenolate of HBED-CC: a versatile conjugation agent for 68Ga-labeled small recombinant antibodies. Eur J Nucl Med Mol Imaging. 2008;35(10):1878–86. https://doi.org/10.1007/S00259-008-0816-Z

51. Schuhmacher J, Klivényi G, Hull WE, Matys R, Hauser H, Kalthoff H, et al. A bifunctional HBED-derivative for labeling of antibodies with 67Ga, 111In and 59Fe. Comparative biodistribution with 111In-DPTA and 131I-labeled antibodies in mice bearing antibody internalizing and non-internalizing tumors. Int J Radiat Appl Instrumentation Part B Nucl Med Biol. 1992;19(8):809–24. https://doi.org/10.1016/0883-2897(92)90167-W

52. Schuhmacher J, Klivényi G, Matys R, Stadler M, Regiert T, Hauser H. et al. Multistep tumor targeting in nude mice using bispecific antibodies and a gallium chelate suitable for immunoscintigraphy with positron emission tomography. Cancer Res. 1995;55(1):115–23. PMID: 7805020

53. Eder M, Neels O, Müller M, Eder M, Neels O, Müller M. et al. Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC: a new PET tracer for imaging of prostate cancer. Pharmaceuticals (Basel). 2014;7(7):779–96. https://doi.org/10.3390/ph7070779

54. Zhernosekov KP, Filosofov DV, Baum RP, Aschoff P, Bihl H, Razbash AA, et al. Processing of generator-produced 68Ga for medical application. J Nucl Med. 2007;48(10):1741–8. https://doi.org/10.2967/JNUMED.107.040378

55. Mueller D, Klette I, Baum RP, Gottschaldt M, Schultz MK, Breeman WAP. Simplified NaCl based 68Ga concentration and labeling procedure for rapid synthesis of 68Ga radiopharmaceuticals in high radiochemical purity. Bioconjug Chem. 2012;23(8):1712–7. https://doi.org/10.1021/bc300103t

56. Meisenheimer M, Kürpig S, Essler M, Eppard E. Ethanol effects on 68Ga-radiolabelling efficacy and radiolysis in automated synthesis utilizing NaCl post-processing. EJNMMI Radiopharm Chem. 2019;4(1):1–10. https://doi.org/10.1186/S41181-019-0076-1

57. Mu L, Hesselmann R, Oezdemir U, Bertschi L, Blanc A, Dragic M, et al. Identification, characterization and suppression of side-products formed during the synthesis of high dose 68Ga-DOTA-TATE. Appl Radiat Isot. 2013;76:63–9. https://doi.org/10.1016/j.apradiso.2012.07.022

58. Martins AF, Prata MIM, Rodrigues SPJ, Geraldes CF, Riss PJ, et al. Spectroscopic, radiochemical, and theoretical studies of the Ga3+-N-2-hydroxyethyl piperazine-N′-2-ethanesulfonic acid (HEPES buffer) system: Evidence for the formation of Ga3+- HEPES complexes in 68Ga labeling reactions. Contrast Media Mol Imaging. 2013;8(3):265–73. https://doi.org/10.1002/cmmi.1517

59. Breeman WA, De Jong M, Visser TJ, Erion JL, Krenning EP. Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities. Eur J Nucl Med Mol Imaging. 2003;30(6):917–20. https://doi.org/10.1007/s00259-003-1142-0

60. Jussing E, Milton S, Samén E, Moein MM, Bylund L, Axelsson R, et al. Clinically applicable cyclotron-produced Gallium-68 gives high-yield radiolabeling of DOTA-based tracers. Biomolecules. 2021;11(8):1118. https://doi.org/10.3390/biom11081118