Isotope Technologies Garching GmbH · Page 11 Lutetium c.a. vs n.c.a Possible production routes for Lu-177 Lu 176 2.59 σ3 + 2070 Lu 175 97.41 σ8 Yb 176 12.7 σ3 Lu 177 6.647d

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


Targeted RadionuclideTherapy

Principle of Targeted Radionuclide Therapy:

Targeting biomolecule

Labeling Therapy



Courtesy Prof. Roger Schibli ETH Zürich

… delivery of therapeutic doses of

ionizing radiation to the malignant cells

Principle of Targeted Radionuclide Therapy:



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



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:



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



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



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



Imageable Photons: Observation during treatment (SPECT):

Roelf Valkema, EANM-2008


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



Impact of the cross capture section:

176Lu: 2100 barn 176Yb: 2,4 barn

177Lu: 865 barn



“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



“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



Physics:Radiochemistry (EOB):

Reactor physics:

Radiochemistry (EOP):

Nuclear medicine:?



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



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 !


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


Market overview

ITG:

Exceptionally high specific activity,

more than 3000 GBq/mg at expiry

No Long-lived 177Lu


Production of n.c.a.177Lu

Yb

Yb

Yb + 177Lu

177Lu



Ytterbium oxide Ampoule preparation Ampoule closing Irradiation Ampoule opening

Packing and shipping Dispensing Lu / Yb -SeparationTargeted RadionuclideTherapy



First GMP- certified production process!

- Industrialized production process

- pharmaceutical grade (sterile and

endotoxin-tested)

- GMP- certified since 12/2011


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


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!


Security of supply

177Lu

Security of supply: global collaborations


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

++

+


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


Thank you for your attention!

Documents

Isotope Technologies Garching GmbH · Page 11 Lutetium c.a. vs n.c.a Possible production routes for Lu-177 Lu 176 2.59 σ3 + 2070 Lu 175 97.41 σ8 Yb 176 12.7 σ3 Lu 177 6.647d