LUTETIUM 177 BROAD PRODUCTION CAPABILITIES ARE EXPECTED TO STIMULATE CLINICAL APPLICATIONS OF THIS IMPORTANT THERAPEUTIC RADIOISOTOPE

Transcription

1 LUTETIUM 177 BROAD PRODUCTION CAPABILITIES ARE EXPECTED TO STIMULATE CLINICAL APPLICATIONS OF THIS IMPORTANT THERAPEUTIC RADIOISOTOPE F. F. (Russ) Knapp, Jr. Nuclear Medicine Program Nuclear Science and Technology Division Oak Ridge National Laboratory (ORNL) Oak Ridge, Tennessee TECHNICAL MEETING ON THERAPEUTIC RADIOPHARMACEUTICALS INTERNATIONAL ATOMIC ENERGY AGENCY (IAEA) VIENNA, AUSTRIA, NOVEMBER 16 20, 2009

2 Goals of Presentation Describe technical Issues for Lutetium 177 Direct and Indirect Production Strategies Discuss the relative advantages and disadvantages of these methods Provide a brief summary of expected relative costs for either production method and the expected Lu 177 product lines

3 Why So Much Interest in Lutetium 177? Radionuclide therapy (RNT) with unsealed sources continues to emerge as an important future for nuclear medicine Established efficacy for both targeted therapy and palliation with Lu 177 have been demonstrated Widespread availability of reactor produced Lu 177 Lutetium 177 is a rare example which can be reactor produced with very high specific activity good half life for distribution good chemistry Production capacity far exceeds current needs ORNL a/rra

4 Range of Betas in Soft Tissue Average Range (mm) Re 186 Lu-177 Sm 153 P 32 Y 90 Re 188 Sm 117m (CE) Augers Intracellular Alphas Several Cell Diameters Electron Energy (MeV) ORNL b/rra

5 Some Major Advantages for Widespread Use of Lutetium 177 for Therapy Beta Energy β max = MeV (50%) Low soft tissue penetration advantages for targeting small tumor/micrometastatic disease Imaging 112 (6.4%) & 208 kev γ s (11 %) for imaging Half life 6.7 days major advantage permits broad distribution Chemistry + 3 metal forms strong chelates DOTA/phosphonates, etc. Processing Simple for direct production from Lu 176 Production Lu 177 can be produced with adequate specific activity in a large variety of research reactors ORNL a/rra

6 Key Therapeutic Applications of Lutetium 177 Broad Applications in Nuclear Medicine And Oncology 11 Papers at this Meeting Cancer Therapy Primary/Metastatic NE Tumors Prof. Baum > 1,000 patient cycles Bone Pain Palliation Metastatic disease IAEA Multicenter trial Lu EDTMP Radionuclide Synovectomy ORNL a/rra

7 INTEREST IN LUTETIUM 177 IS REFLECTED IN PUBLICATIONS 40 Number of Lu 177 Publications Prior to Year Through October

8 Radioisotope Production Facilities Accelerators Can be dedicated for radioisotope production About 350 worldwide, often installed in hospitals or research institutions No established route for accelerator production of lutetium 177 with sufficient specific activity Research Reactors Very unusual for dedication for radioisotope production nearly always at government owned facilities production normally secondary role 238 worldwide = Broad international capabilities for reactor production of high specific activity lutetium naweb.iaea.org/napc/physics/research_reactors/database/database.html

9 Reactor Production of Lu 177 Direct Route Lu 176 (>74%) (n, γ) 2090 barn High Production Yield > 70 Ci/mg Simple Processing Lu days + Lu 177m Impurity 160 days Radioactive Decay Indirect Route No Carrier Added Low Production Yield < 300 mci/mg Route Requires Lu/Yb Separation Yb 176 (>97%) (n, γ) 285 barn Yb 177 (Beta Decay 1.9 hours

10 Direct Production of Lutetium 177 from Lutetium 176 Target Activity (Ci/mg) 176 Lu Target High thermal neutron cross section σ = 2090 barn Use of High Flux Approaches Theoretical Specific Activity x n cm 2 s 1 (thermal) 1 x n cm 2 s 1 (epithermal) ORNL HFIR SM3 1 x n cm 2 s 1 (thermal) 1 x n cm 2 s 1 (epithermal) 177 Lu Theoretical Specific Activity = 109 Ci/mg 30% of Theoretical HANARO MURR 4 5 x n cm 2 s 1 (thermal) 1 x n cm 2 s 1 (epithermal) Irradiation Time (Days) ORNL /jcn

11 Lutetium 177 Gamma Spectrum 4 Days After Reactor Discharge

12 LIMITED REACTORS USED FOR FISSION PRODUCTION OF Mo 99 HEU AND LEU. nru? NEW? NEW 238 Research Reactors Worldwide NEW naweb.iaea.org/napc/physics/research_reactors/database/database.html

13 TUNGSTEN 188 PRODUCTION RESEARCH REACTORS WITH SUFFICIENT THERMAL FLUX > 1 X NEUTRONS/CM 2 /SEC.?

14 LUTETIUM 177 PRODUCTION MANY RESEARCH REACTORS HAVE SUFFICIENT THERMAL FLUX LUTETIUM 177 PRODUCTION MANY RESEARCH REACTORS HAVE SUFFICIENT THERMAL FLUX. > 1 X NEUTRONS/CM 2 /SEC = IAEA CRP Production Sites

15 LUTETIUM 177 PRODUCTION EVEN WITHOUT EUROPE & NORTH AMERICA SUFFICIENT REACTORS ARE AVAILABLE. > 1 X NEUTRONS/CM 2 /SEC = IAEA CRP Production Sites

16 Lutetium 177 Indirect Production Provides Highest SA and Avoids Lu 177m Impurity Lu 176 Direct Route n, γ Lu days σ = 2090 barrn Beta Decay Route Provides No Carrier Added Lu Lu 177m 160 days Indirect Route Beta Decay Improved/optimized separation required Yb 176 n, γ σ = 2.85 barn Yb hours

17 Indirect" Production of Lutetium 177 from Ytterbium 176 Activity (mci/mg 176 Yb Target) Thermal Cross Section σ = 2.85 barn 2 x n cm 2 s 1 (thermal) 1 x n cm 2 s 1 (epithermal) 4 x n cm 2 s 1 (thermal) 9 x n cm 2 s 1 (epithermal) SM3/ORNL HFIR > 300 Ci/gram HANARO MURR > 50 Ci/gram 1 x n cm 2 s 1 (thermal) 1 x n cm 2 s 1 (epithermal) Irradiation Time (d)

18 SEPARATION OF LUTETIUM 177 FROM YTTERBIUM Challenge is Effective Separation of the NCA Lu 177 from the Yb 176 Target Material LANTHANIDES ARE NOTORIOUSLY DIFFICULT TO SEPARATE Cementation Process Initial Yb precipitation followed by Lu 177 cation column purification Extraction Column Chromatography Use of Eichrome LN HDEHP resin with acid elution High Performance Liquid Chromatography ORNL a/rra

19 Typical Ytterbium/Lutetium Separation ORNL ORNL b/rra

20 Challenges for Indirect Lu 177 Production from Decay of Reactor Produced Yb 177 Low Production Yields Only mci Lu 177 per mg Yb 176 target even at very high thermal flux Higher Target Volume Large targets would be required at modest flux for multi Curie production High Costs of LN Resin Large amounts of resin can be required for Lu 177 separation from large mass of Yb Decay Loss from Column Separation Column separation can require long periods plus concentration Recovery of Enriched Yb 176 Time/Expense Generation of high volumes of radioactive waste Large volumes of radioactive acid wastes can be generated ORNL a/rra

21 EXAMPLES OF REACTORS FOR INDIRECT PRODUCTION OF LUTETIUM 177 > 1 X NEUTRONS/CM 2 /SEC.

22 Lutetium 177 How to Produce and Where to Process? Some Key Issues to Consider Localized or centralized processing facility? Which radiopharmaceutical product? Low, modest or high Lu 177 specific activity? Are low levels of metastable lutetium 177m impurity acceptable from Rad Waste perspective?

23 COMPARISON OF ISSUES FOR DIRECT AND INDIRECT Lu 177 PRODUCTION Target Material mgs/cost per Ci Batch (High Flux) Target Preparation Direct From En. Lu 176 Indirect From En. Yb mg/$ 300 > 200 mg/ $ 4K Same Irradiation Time similar Modest Flux High Flux? Target Transportation Open Target Dissolution Same Same Same Lu 177 Processing 4 8 hours > 1 day Analytical Dispensing Shipment (Type A Max Ci) Same Same Same

24 COMPARISON OF DIRECT AND INDIRECT PRODUCTION OF LUTETIUM 177 Targets Issues Lu 177 Spec. Act. Processing Target Impurities Product Impurities Costs Potential Advantages Direct Production From Lu 176 Very small targets even at modest flux acceptable expense Even at modest flux up to Ci/mg Lu Simple dissolution and dispensing High purity from Enriched targets Low levels of Lu 177m Cost Effective High yields/batch Cost Effective & Many Reactors Worldwide Can be Used

25 COMPARISON OF DIRECT AND INDIRECT PRODUCTION OF LUTETIUM 177 Issues Targets Direct Production From Lu 176 Very small targets even at modest flux Indirect Production From Yb 176 Large targets yields < 300 mci Lu 177/mg Yb 176 Recover Spec. Act. Up to > 70 Ci/mg Lu Theoretically, no carrier added Processing Simple dissolution Time consuming Sep. Lu/Yb Target Impurities Product Impurities High purity from Enriched targets Lu 177m, T1/2 160 days Waste storage issue High purity from Enriched targets No Lu 177m co produced No waste storage issue Costs High yields/batch Much more expensive/batch Potential Advantage Less Expensive & Many Reactors Can be Used No Carrier Added but far less reactors available no Lu 177m

26 COMPARISON OF COSTS FOR DIRECT Lu 177 PRODUCTION AT MODEST AND HIGH FLUX High Flux = ~ 70 Ci/mg Lu Modest Flux = ~ 20 Ci/mg Lu The Costs for effort (manpower) would be the same Ci at Activity + 3 D mg Lu 176/Batch Lu 176 Target Costs Shipment Decay/# Patients Modest High Modest Flux High Flux Ci x $ 138 $ Ci x $ 690 $ Ci x $ 1,380 $ 415 Use of High Flux would decrease costs by a factor of ~ 3

27 Cost Comparison for Indirect Lu 177 Production from Enriched Yb 176 at Modest 5 x Thermal Flux Assume > 60 mci/mg Yb 176 Yield 3 Days Effort to process and recover ~ 80 % Yb 176 target Ci at Shipment Activity + 3 D Decay/# Patients Yb 176 For Batch Ci x mg $ 2,400 Yb 176 Target Costs versus Loss ($ 480) Ci x mg $ 12,000 ($ 2,400) Ci x 240 1,200 mg $ 24,000 ($ 4,800)

28 Indirect Lu 177 Production from Enriched Yb 176 at Very High 2.5 x Thermal Neutron Flux Assume > 300 mci/mg Yb 176 Yield 3 Days Effort to process and recover ~ 80 % Yb 176 target Ci at Shipment Activity + 3 D Decay/# Patients Yb 176 For Batch Ci x mg $ 480 Yb 176 Target Costs versus Loss ($ 96) Ci x mg $ 2,400 ($ 480) Ci x mg $ 4,800 ($ 960)

29 COMPARISON OF INDIRECT Lu 177 PRODUCTION AT MODEST AND HIGH FLUX The Costs for effort (manpower) would be the same Ci at Activity + 3 D Yb 176 Costs Shipment Decay/# Patients Modest Flux High Flux Ci x 20 $ 2,400 ($ 480) $ 480 ($ 96) Ci x 120 $ 12,000 ($ 2,400) $ 2,400 ($ 480) Ci x 240 $ 24,000 ($ 960) $ 4,800 ($ 960) Use of High Flux would decrease costs by a factor of ~ 5

30 Lutetium 177 How to Produce and Where to Process? Local or centralized processing Facilities? Which radiopharmaceutical product? Low to modest specific activity Indirect production Route Are low levels of lutetium 177m impurity acceptable?

31 Lutetium 177 How to Produce and Where to Process? Local or centralized processing Facilities? For localized/small markets, production/processing and dispensing at same site works well Multiple cgmp quality programs at many sites would be challenge country/region dependent Localized ould be expected scenario in some regions and has been demonstrated through the IAEA For large countries/markets the use of centralized site using by shipment of unprocessed targets from reactor network has many advantages API would be provided from qualified reactor sites

32 Lutetium 177 How to Produce and Where to Process? Which radiopharmaceutical product? Significant number of recent studies/publications for bone pain palliation (IAEA RCM), peptides (DOTA TATE/TOC), antibodies, etc. In many cases low to modest SA is acceptable Even for some peptides targeted to receptors, Ci/mg Lu is sufficient

33 Lutetium 177 How to Produce and Where to Process? Low to modest specific activity Large inventories of enriched Lu 176 available only small amounts required for multici production Processing and dispensing straight forward Production/processing costs are very reasonable Low metastable Lu 177m not an issue for patient dose may be for waste disposal? Which countries will waste be an issue? Real advantage, many low to modest thermal flux reactors can be used as demonstrated by IAEA RCM

34 Lutetium 177 How to Produce and Where to Process? Indirect Production Route Are low levels of lutetium 177m impurity acceptable? Inventory of enriched Yb 176 $ 20/mg Need large targets compared to Lu 176 costs Probably need thermal flux > 1 x Probably need to recover Yb 176 Costs much higher then for Direct Lu 177m waste issue function of country/region

35 SUMMARY FOR DIRECT VERSUS INDIRECT Lu 177 PRODUCTION AS FUNCTION OF FLUX Modest Thermal Flux Reactor Many more reactors can be used if high SA not required bone pain, synovectomy, targeted therapy? But more expensive to produce NCA from Yb 176 High Thermal Flux Reactor Limited availability of High Flux Research Reactors Much higher SA can be produced from Lu 176 Much higher activity levels produced from Yb 176

36 WHAT WE MAY EXPECT AS THERAPEUTIC USE OF LUTETIUM 177 INCREASES For High Demand Western Countries Targeted Therapy Europe and North America Many advantages for central GMP processing facility using targets of high SA Lu 177 either directly or indirectly produced from a research reactor network Any one Facility would not be expected to pursue more then one product line For Regions Especially Where lower SA is Adequate Bone pain palliation, synovectomy, etc., local production and processing has been shown by IAEA Project to work effectively

37 POSSIBLE LUTETIUM 177 PRODUCT LINES Possible Lu 177 Product Lines Very High Specific Activity 40 > 100 Ci/mg Lu Low Specific Activity < 5 10 Ci/mg Absence of Lu 177m impurity How and Where Can These Products be Produced High Flux for High SA direct Medium to High Flux for High SA Indirect Low to Medium Flux for low SP direct

38 PRODUCTION STRATEGY WILL DEPEND UPON DESIRED Lu 177 PRODUCT SPECIFICATIONS Direct from Lu 176 Number of Reactors IAEA Data Base 238 Total Indirect from Yb > Thermal Flux = Very High High Medium Issues: Lu 177 total yield/target/sa? Can Lu 177m be tolerated?

39 Summary The Take Home Message Lutetium 177 is a unique example of a therapeutic radioisotope which can be widely produced throughout the world in research reactors High specific activity is a Hallmark Relatively high specific activity Lu 177 can be readily produced in modest flux reactors by the direct route Our clinical and commercial colleagues should be encouraged to further develop and use Lu 177 labeled radiopharmaceuticals

40 ACKNOWLEDGEMENTS Colleagues at ORNL U.S. Department of Energy The IAEA and Local Organizers for opportunity to participate in this Symposium Drs. Ambi Pillai and Clemens Decristoforo and colleagues

41 Commercial Interests in Availability of Lutetium 177 Oak Ridge Experience Scenario A Unprocessed irradiated Yb 176 target shipped to central processing cgmp facility Scenario B Unprocessed irradiated Lu 176 target shipped to central processing cgmp facility Scenario C cgmp locally processed Lu 177 from Lu 176 Scenario D cgmp locally processed Lu 177 from Yb 176 For Commercial facility using reactor network, shipment of unprocessed targets to central cgmp processing facility may be optimal However IATA Type A Package Limit = 18.9 Curies

42 SUMMARY LUTETIUM 177 FOR THERAPY A SUCCESS STORY IN PROGRESS Relevant Serious Continued and Sustained interest in a portfolio of Lu 177 labeled therapeutic agents Chemistry DOTA An excellent Lu +3 chelator Radiopharmacy Kit radiolabeling is usually simple and easy Production Essentially unlimited international production capacity which far exceeds current needs Clinical Products