Gallium-68 a candidate for use in clinical

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Gallium-68 – a candidate for use in clinical routine M. Harfensteller, R. Henkelmann, J. Gallium-68 – a candidate for use in clinical routine M. Harfensteller, R. Henkelmann, J. Moreno, O. Leib, T. August, O. Buck, T. Nikula Isotope Technologies Garching A. Türler, K. Zhernosekov Uni Bern, Bern; Paul Scherrer Institut, Villigen February 3, 2010, CERN

Outline 1. 68 Ga and it‘s applications 2. The generator system and it‘s application Outline 1. 68 Ga and it‘s applications 2. The generator system and it‘s application 3. The way from a scientific proof-of-concept to a pharmaceutical product February 2010 www. itg-garching. de Page 2

68 Ga • properties Physical properties • Halflife T 1/2 = 68 min • 68 Ga • properties Physical properties • Halflife T 1/2 = 68 min • Positron branching 89% (PET nuclide) • Available via a 68 Ge/68 Ga generator • Mother 68 Ge cyclotron produced (T 1/2 = 271 d) • Chemical properties of Ga • Trivalent metal • Chelation chemistry • Applicability • Short half-life useful for molecules with fast biokinetics (Peptides, Ab-fragments, small complexes, …) February 2010 www. itg-garching. de Page 3

Use of 68 Ga as PET nuclide Somatostatin analogues Bisphonates (68 Ga compared to Use of 68 Ga as PET nuclide Somatostatin analogues Bisphonates (68 Ga compared to 18 F) 68 Ga 18 F Galligas™ (Fellner et al. ; Eur J Nucl Med Mol Imaging 2010) Bombesin (Kotzerke et al. ; Eur J Nucl Med Mol Imaging 2010) February 2010 www. itg-garching. de Ga-microspheres Page 4

Use of 68 Ga as PET nuclide February 2010 www. itg-garching. de Page 5 Use of 68 Ga as PET nuclide February 2010 www. itg-garching. de Page 5

Outline 1. 68 Ga and it‘s applications 2. The generator system and it‘s application Outline 1. 68 Ga and it‘s applications 2. The generator system and it‘s application 3. The way from a scientific proof-of-concept to a pharmaceutical product February 2010 www. itg-garching. de Page 6

68 Ga application – Production of 68 Ga-DOTATOC 1. Production of chelator (DOTA) and 68 Ga application – Production of 68 Ga-DOTATOC 1. Production of chelator (DOTA) and peptide (TOC) 2. Elution of 68 Ga + 68 Ga 3+ 3. Chelation reaction of 68 Ga with DOTATOC 4. Administration to the patient (receptor binding to cell receptor) and PET scan February 2010 Metallic impurities Time critical process Ga + + Ga www. itg-garching. de Page 7

68 Ga application Labelling of biomolecules • Decentralized distribution and compound manufacturing • Automated 68 Ga application Labelling of biomolecules • Decentralized distribution and compound manufacturing • Automated elution and labelling systems in the hospitals • Generator elution 15 -40 min synthesis time Transfer in injectable form Zhernosekov et al. J Nucl Med 2007 February 2010 EZAG, Scintomics; Comecer www. itg-garching. de Page 8

68 Ga generator cycle Todays generators are not recycled and remain as long-lived waste 68 Ga generator cycle Todays generators are not recycled and remain as long-lived waste in the hospitals (generating additional cost). • Some hospitals couple generators to extend lifetime (not compliant to pharmaceutical requirements). Compared to Mo/Tc generators the shelf life of Ge/Ga generators is increased by at least one order of magnitude (3 -10 months compared to 1 -2 weeks). This increases the requirements of the generator performance. • Manufacturing of the generator • • 68 Ge production Poor logistics. Use in hospital Waste Disposal February 2010 www. itg-garching. de Page 9

68 Ga generator logistics (nowadays) MBq Month • Generators have usually yield of up 68 Ga generator logistics (nowadays) MBq Month • Generators have usually yield of up to 80% but drop to 50% over 1 T 1/2(Ge) • Generators are coupled to extend shelf life („expert mode“) • >50% of the 68 Ge activity is unused, in the beginning also of the 68 Ga (unnecessary dose for personnel) • Today logistics is driven by economics not by pharmaceutical reasons! February 2010 www. itg-garching. de Page 10

68 Ga generator logistics in a pharmaceutical environment MBq Month • Sterility and Endotoxin 68 Ga generator logistics in a pharmaceutical environment MBq Month • Sterility and Endotoxin level • Defined shelf-life depending on specifications • Optimized activity for customer needs and radiation protection Shelf life of the generators will decrease for pharmaceutical demands February 2010 www. itg-garching. de Page 11

68 Ga generator cycle 68 Ge production • • Manufacturing of the generator and 68 Ga generator cycle 68 Ge production • • Manufacturing of the generator and Conversion to pharmaceutical grade system Use in hospital February 2010 Due to an expected shorter shelf-life the generators have to be recycled Customers want to have a guaranteed activity and quality Recycling of the used generator www. itg-garching. de Page 12

Overview of today’s available generators All generators on the market „not for human use“ Overview of today’s available generators All generators on the market „not for human use“ Cyclotron Co Ltd. Eckert&Ziegler IPL I. D. B. Holland B. V. Isotope Technologies Garching Origin Russia USA South Africa Germany Resin Titanium-dioxide Tin-dioxide Organic Material Eluent 0, 1 M HCl 0, 6 M HCl 0, 05 M HCl Elution Yield 60 -75% 70 -75% 80% (>80%) *) Breakthrough **) <0, 01% <0, 001% **) <0, 007% (<0, 001%) *) Elution yield over lifetime **) Breakthrough of 68 Ge in % of eluted 68 Ga at calibration ***) Breakthrough of 68 Ge in % of loaded 68 Ge on the column February 2010 www. itg-garching. de Page 13

Outline 1. 68 Ga and it‘s applications 2. The generator system and it‘s application Outline 1. 68 Ga and it‘s applications 2. The generator system and it‘s application 3. The way from a scientific proof-of-concept to a pharmaceutical product February 2010 www. itg-garching. de Page 14

The way to a radiopharmaceutical product Timeline 4 -5 68 Gagenerator systems available First The way to a radiopharmaceutical product Timeline 4 -5 68 Gagenerator systems available First paper on Start of clinical use of 68 Ga-generator 1960 1980 2000 Marketing Authorization GMP generators 2010 2020 Commercial PET-CT Commercial PET Commercial To. F-PET HD-PET (dose reduction down to 50%) Industry Research February 2010 www. itg-garching. de Page 15

The way to a radiopharmaceutical product Principle • Research on isotopes /isotope systems with The way to a radiopharmaceutical product Principle • Research on isotopes /isotope systems with potential in diagnostic use • Development of the technical system (production, feasibility, logistics, …) • Establishment of stable production and product parameters (breakthrough, yield, …) Depending on application Pharmaceutical Product • Manufacturing Authorization Medicinal Product • CE certification • Marketing Authorization February 2010 www. itg-garching. de Page 16

The way to a radiopharmaceutical product GMP production = quality in production • Qualification The way to a radiopharmaceutical product GMP production = quality in production • Qualification and validation of ALL product, production, production system and quality control related parameters • Definition of specifications • Radionuclidic purity • Chemical purity • Radiochemical purity • Biological properties (sterility, endotoxin load) • Excellence of production (production processes stable) • Quality control and release procedures • Timeline: 1 -2 years depending on existing GMP facilities and processes Establishment of production environment according to pharmaceutical requirements • Production in clean room environments Manufacturing authorization February 2010 www. itg-garching. de Page 17

The way to a radiopharmaceutical product Registration for a marketing authorization • Decision to The way to a radiopharmaceutical product Registration for a marketing authorization • Decision to register pharmaceutical or API (active pharmaceutical ingredient; part of pharmaceutical == radioisotope) • Decision on central or decentral application for the marketing authorization • Decentral (example: germany) • Application form consists of 5 modules thereof one includes the whole manufacturing description • Justification of specifications Timeline: Several years • Pharmacology (Toxicology, …) • Clinical trials (Dose, Indication, …) • Marketing authorization for the given country Marketing authorization for 1 country February 2010 www. itg-garching. de Page 18

The way to a radiopharmaceutical product Registration for a marketing authorization (cont. ) • The way to a radiopharmaceutical product Registration for a marketing authorization (cont. ) • Start of mutual recognition process (enlarge the marketing authorization to other countries) Timeline: • Other authorities ask for changes in production worst case: 10 changes in production methods for 10 countries Several years Marketing authorization for other countries February 2010 www. itg-garching. de Page 19

Conclusion ü 68 Ga is a promising PET isotope ü Independant from cyclotron ü Conclusion ü 68 Ga is a promising PET isotope ü Independant from cyclotron ü Generators are available ü Use is established in big PET centers But: • Not yet registered as radiopharmaceutical • Logistics must be improved • Waste problem must be solved February 2010 www. itg-garching. de Page 20

Thank You February 2010 www. itg-garching. de Page 21 Thank You February 2010 www. itg-garching. de Page 21




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