February 2013
Production of 177Lu n.c.a. in
high-flux reactors
R. Henkelmann, S. Marx, K. Zhernosekov, M. Harfensteller
www.itg-garching.de Page 2
Targeted Radionuclide Therapy
Therapeutic Radionuclides
c.a. vs n.c.a. Lutetium
Production of n.c.a. Lu-177
Security of supply
Market overview
Conclusion
Preview to practical part
Outline
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Targeted RadionuclideTherapy
Principle of Targeted Radionuclide Therapy:
Targeting biomolecule
Labeling Therapy
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Targeted RadionuclideTherapy
Courtesy Prof. Roger Schibli ETH Zürich
… delivery of therapeutic doses of
ionizing radiation to the malignant cells
Principle of Targeted Radionuclide Therapy:
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Targeted RadionuclideTherapy
Target:
ReceptorBiomolecule:
Peptide
Radionuclide
Linker
Peptide Receptor Radionuclide Therapy (PRRT):
177Lu, 90Y, 213Bi etc.
e.g. GPCR receptors like
Somatostatin receptors e.g. Peptide hormon analoga
conjugates like DOTA-TATE
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Targeted RadionuclideTherapy
Somatostatin receptors are
overexpressed in:
Neuroendocrine Tumors
(Tumors of the nervoussystem)
(Renal cell carcinoma)
(Malignant lymphoma)
(Breast cancer)
N
N
O
OHO
HO
OH
O
(D)Phe - Cys - Tyr - (D)Trp
Thr(ol) - Cys - Thr - Lys
N
N
177Lu
PRRT with Somatostatin analoga:
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Therapeutic Radionuclides
More crossfire
Less damage of
healthy tissue
Radionuclides for Targeted Radionuclide Therapy:
Radionuclide Halflife E mean (keV) E (y) keV Range in tissue
Y-90 64 h 934 β - 12 mm
Re-188 17 h 763 β 155 11 mm
I-131 8 d 182 β 364 3 mm
Lu-177 7 d 134 β 208 2 mm
Tb-161 7 d 154 β 75 2 mm
Bi-213 46 m 5870 α 440 45 µm
Ac-225 10 d 5830 α 100 45 µm
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Therapeutic Radionuclides
1 mm
Particle emitting radionuclides
High-energy beta emitter 90Y
mean particle energy 0.933 MeV
Low-energy beta emitter 177Lu
mean particle energy 0.134 MeV
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Therapeutic Radionuclides
177Lu: rising demand
Number of scientific publications vs time:
Therapeutic applications of 90Y and 177Lu
1990 1995 2000 2005 2010
0
10
20
30
40
50
90
Y
177
Lu
Pub Med
Therapeutic Studies
Year
GMP 90Y
GMP 177Lu
90Y high-energy beta emitter
- In GMP quality available since 2003
- Zevalin®, SIRT, PRRT …
90Y
177Lu
177Lu low-energy beta emitter
- In GMP quality available since 2011
- Abs, PRRT …
Less side effects; imageable photons
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Therapeutic Radionuclides
Imageable Photons: Observation during treatment (SPECT):
Roelf Valkema, EANM-2008
www.itg-garching.de Page 11
Lutetium c.a. vs n.c.a
Possible production routes for Lu-177
Lu 176
2.59
σ 3 + 2070
Lu 175
97.41
σ 8
Yb 176
12.7
σ 3
Lu 177
6.647d
-
Yb 177
1.9 h
160.1 d
-
Yb 175
4.2 d
Yb 174
31.8
σ 68
Hf 177
18.60
Hf 176
5.206
176Lu(n,)177Lu
“Carrier added” c.a. 177Lu “No carrier added” n.c.a. 177Lu
Lu 176
2.59
σ 3 + 2070
Lu 175
97.41
σ 8
Yb 176
12.7
σ 3
Lu 177
6.647d
-
Yb 177
1.9 h
160.1 d
-
Yb 175
4.2 d
Yb 174
31.8
σ 68
Hf 177
18.60
Hf 176
5.206
176Yb(n,)177Yb → 177Lu
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Lutetium c.a. vs n.c.a
Impact of the cross capture section:
176Lu: 2100 barn 176Yb: 2,4 barn
177Lu: 865 barn
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Lutetium c.a. vs n.c.a
“Carrier added” c.a. 177Lu
Specific activity only 20 – 30 Ci/mg
(vs. theoretical 110 Ci/mg)
only 25 % of hot 177Lu atoms
75% of cold 175/176Lu atoms
Long-lived radioactive impurities:
up to 0.05 % of long-lived 177mLu!
Poor quality of c.a. 177Lu results in:
limited radiolabeling performance
long-lived waste management problem; environment exposure
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Lutetium c.a. vs n.c.a
“No carrier added” n.c.a. 177Lu
No long-lived radioactive impurities:
less than 10-5 % of 177mLu!
(below detection limit)
Highest quality of n.c.a. 177Lu offers:
best radiolabeling performance
no waste problem!
longer shelf-life up to 2 weeks
Highest specific activity > 80 Ci/mg
(vs. theoretical 110 Ci/mg)
and highest radionuclide purity
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Lutetium c.a. vs n.c.a
Physics:Radiochemistry (EOB):
Reactor physics:
Radiochemistry (EOP):
Nuclear medicine:?
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Lutetium c.a. vs n.c.a
Impact of the specific activity on the tumor uptake:
300 MBq of 177Lu c.a.
Dose to tumor - 35 Gy
300 MBq of 177Lu n.c.a.
Dose to tumor - 70 Gy
Marion de Jong et al.; 2012 ICTR-PHE
www.itg-garching.de Page 17
Lutetium c.a. vs n.c.a
0 2 4 6 8 10 12 14
0
25
50
75
100
0
25
50
75
100
Sth = 110 Ci/mg
S1/2
= 92 Ci/mg
S1/2
= 16 Ci/mg
Sp
ecif
ic A
cti
vit
y [
Ci/m
g]
Days
shelf-life/ c.a. vs n.c.a. 177Lu
Improved logistics with n.c.a. 177Lu !
www.itg-garching.de Page 18
Market overview
Producer 1 Producer 2
ITG Isotope
Technologies
Garching GmbH
c.a c.a n.c.a
Specific Activity > 740 GBq/mg
at calibration date
~ 740 GBq/mg
at calibration time
> 3,000 GBq/mg
at expiry date
177mLu content< 0.05 %
at calibration date
< 0.1 %
at expiry date
< 10-5 %
at expiry date
Calibration time/
Delivery12:00 at production day,
delivery after calibration time
12:00 on Monday,
Thuesday, Wednesday, Friday
upon request,
24 h on 365 d/a
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Market overview
ITG:
Exceptionally high specific activity,
more than 3000 GBq/mg at expiry
No Long-lived 177Lu
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Production of n.c.a.177Lu
Yb
Yb
Yb + 177Lu
177Lu
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Production of n.c.a.177Lu
Ytterbium oxide Ampoule preparation Ampoule closing Irradiation Ampoule opening
Packing and shipping Dispensing Lu / Yb -SeparationTargeted RadionuclideTherapy
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Production of n.c.a.177Lu
First GMP- certified production process!
- Industrialized production process
- pharmaceutical grade (sterile and
endotoxin-tested)
- GMP- certified since 12/2011
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Security of supply
Security of supply: global reactor network
N
N
O
OHO
HO
OH
O
N
N
1,6∙1014 cm-2 s-1
3,5∙1014 cm-2 s-1
1,3∙1014 cm-2 s-1
1,4∙1015 cm-2 s-1
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Security of supply
Standardization of irradiation processes
Implementation of fast and realiable logistics
Intelligent scheduling
August 31 32 33 34 35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
1
2
3
4
5
6
7
8
9
Lu-177 Incoming
Ampoules shipment
Security of supply: planning!
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Security of supply
177Lu
Security of supply: global collaborations
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Conclusion
177Lu c.a. 177Lu n.c.a.
future177Lu n.c.a.
Process Complexity
Redundant
Reactors
Redundant
Production Sites
Long-lived Waste
Problem
o
o
--++
++
Criteria
--
3: 7: ++ 8: ++
o3: 1: 3: ++o
-- ++ ++
Specific Activity
Security of Supply o ++ ++
Problems are
Headache of…Customer Manufacturer Manufacturer
++
+
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Conclusion
Quality is:
The Right…
Product Amount TimePurity PricePlace
But:
• Hardest Customer Complaint: we changed the labels on the vial
Not even one single of promised shipment missed since April 2009
Shortest order lead time
Highest specific activity: labelling even after 3 weeks possible
Highest activity concentrations
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Thank you for your attention!