Strontium-90-Yttrium-90 generator, Jakarta, Indonesia, 2010

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Therapeutic Radionuclide Generators:

90Sr/90Y Generator & Issues in Quality control of 90Y

M.R.A.Pillai Division of Physical and Chemical

SciencesInternational Atomic Energy Agency

Vienna, Austria

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Topics

• 90Y as a therapeutic radionuclide• 90Y radiopharmaceuticals• 90Sr/90Y generator options• Electrochemical 90Sr/90Y generator• 90Y issues in quality control of

90Y• Extraction paper chromatography (EPC)

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90Y• Advantages

• T1/2 64 h, 2.28 MeV b-max, No gammas

• 28 Y T1/2 of 90Sr enables generators with very long shelf life

• Can be locally produced using a generator

• High specific activity, suitable for targeted therapy

• Very good chemistry, +3 chemistry• Good ligands are available

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90Y Radiopharmaceuticals• Rheumatoid arthritis: 90Y-Silicate/citrate colloid

• Liver cancers: 90Y-microsphere (glass or resin)

• Non-Hodgkin’s lymphoma: 90Y-Ibritumomab (zevalin)

• Bone pain palliation: 90Y-EDTMP

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90Y radiopharmaceuticals

Disease• Lymphoma• Breast cancer• Colon cancer• Pancreatic cancer• Neroendocrine tumors• Liver cancers • Lung, prostate, breast cancers

Targeting molecule90Y-Epratuzomab90Y-Anti-CEA mAb90Y-pretargeted bispecific Ab

90Y-PAM4 Ab90Y-DoTA-TATE90Y-Anti-CEA mAb90Y-Bombesin/GRP analog

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Issues related to 90Y-based radiopharmaceuticals

• Availability of 90Y, T1/2 64 h• High cost (10-15 Euro/mCi)• Import is ruled out for most countries• Local production mandatory

• Availability of a 90Sr/90Y generator• Long term characteristics of the generator

• A QC procedure that can be adapted in a

hospital radiopharmacy to assure below permissible limits of 90Sr in 90Y

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Production of 90Y

• Reactor production• 89Y(n,g)90Y• Yttrium is mononuclidic • Pure target• Very small cross section 0.001 barns

• High flux reactor needed• Very low specific activity• Not suitable for targeted therapy

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90Sr/90Y Generator

• 90Sr: T1/2 28.68 Y• Ebmax 0.546 MeV• 90Y: T1/2 64 h• Ebmax: 2.28 MeV• 90Zr is stable

Decay scheme of 90Sr90Sr (T½ 28.78 y)

90Y (T½ 2.67 d)

90Zr (stable)

β- (Emax 0.546 MeV)

β- (Emax 2.28 MeV)

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Why do we need to develop a generator?

• Price of 90Y is ~ 10-15 Euros per mCi

• Landed cost of 90Y will depend on how far is the user from the supplier

• 64 hour half life is too short to take care of transportation logistics

• Limited suppliers, either in Europe or in the USA

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90Y makes business sense• 10 Euro per mCi, 500 mCi per patient, and 200,000 patients, 90Y is a Billion Euro business

• Over 25 million diagnostic investigations; 200,000 therapy is a modest estimate

World Intellectual Property Organization (WIPO) Patents in 2006

• Betenekov N.D., Sharygin L.M., Brown R.W., Sr-90/Y-90 radionuclide generator for production of high quality Y-90 solution. WO/2006/046966.

• Bray L.A., Method for separating and purifying Yttrium-90 from Strontium-90. WO 2006/025975.

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90Sr/90Y Generator

• 90Sr is fission product

• 90Sr decays to 90Y • 90Y can be separated periodically from a 90Sr solution

• A single stock of 90Sr can suffice for a long long time

0 5 10 15 20 25 300

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Gro

wth

of 90Y

in 100

0 mCi 90Sr

Tim e (days)

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90Sr/90Y Generator: Different Options

• Solvent extraction• Ion exchange• Extraction chromatography or a combination of all the above

• Supported liquid membrane• Electrochemical

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IAEA CRP on Generators (2004-2007)• The CRP focussed on the development of 188W/188Re and 90Sr/90Ygenerators

• Several technologies for 90Sr/90Y were developed

• Some of the technologies are in routine use

• Some are under scaling up

• The TRS summarises the technologies and can be adapted

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Generator Based on Ion Exchange Chromatography (Cuba)

90Sr-90Y

DOWEX 50 WX8

DOWEX 50 WX8

DOWEX 50 WX8

AG 50 WX12

90Sr 90Y 90Y-EDTA

EDTA

burning AG 1 X4

90Sr for QC

Evap. of

acids

90YCl3

Final 90Y

product

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Features

• Pure Y-90 obtained• Multiple processing and columns• EDTA elution• Need to remove EDTA • Waste generation• Methods have been modified by using Sr-Specific resins

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Single Stage SLM generator

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Supported Liquid Membrane

• Elegant technology

• Simple to operate• 8-10 hours operation needed

• Current technology upto 100 mCi

• Scaling up needed• QC proved tolerable limit for 90Sr

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0 50 100 150 200 250 300Time (min.)

Transport of beta activity (%

)feed compartmentProduct compartment

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Two Stage SLM generatorDHAMI, P.S., et al., Sep. Sci. Technol. 42 (2007) 1107-1121

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Two stage Supported Liquid Membrane

Generator • Modification to the Single stage SLM generator

• Purification• 8-10 hours operation needed

• Current technology up to 100 mCi

• Scaling up needed• QC proved tolerable limit for 90Sr• <2 Ci 90Sr in 100 mCi 90Y product 0

102030405060708090100

0 100 200 300 400 500 600 700Tim e (m in.)

Beta activity (%

)

FeedInterm ediateProduct

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Electrochemical generator

• Development of an electrochemical 90Sr-90Y generator for separation of 90Y suitable for targeted therapy, Nucl. Med. Biol. 35 (2008) 245-253.

• Two stage electrolysis to separate and purify 90Y for 90Sr

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Electrochemical generator• Step 1: Electrolysis of

90SrNO3 at pH 2.5-3.0 for 90 minute

• 90Y is deposited in the cathode, rinse it with acetone

• Step 2: Electrolysis using the above electrode in a fresh cell containing. Reverse the polarity, 90Y is leached and gets deposited in the new cathode

• Step3: The cathode, which contains pure 90Y is recovered by washing with dilute acid

• Ready for radiolabelling

Argon GasCylinder

D.C.Power

StirrerMagnetic

PlatinumPlate

SCE ReferenceElectrode

Parent-daughterElectrolyte

PlatinumPlate

V

Potentiostat

Inert GasBubbling

Vent

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Advantages• 90Sr feed solution is left intact for reuse. The pH of the solution can be adjusted; and reused

• Minimum use of chemicals, hence no possibility of metal contamination

• Minimum waste generation, the only waste is the HNO3 solution in the second cell containing traces of 90Sr

• Electrodes are reusable• Minimum steps

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One Ci 90Sr feed solution

• 500 mCi of 90Y can be removed twice a week.

• ~10 % 90Sr is lost in five years which can be supplemented

• Yield per year is 50 Ci.• At current cost it is a million USD per year

• Can be a permanent source of 90Y, with negligible operational cost

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Yttrium Kamadhenu• Radionuclide generators are called ‘cow’ and elution of the daughter is referred milking

• All generators like the cows have a life time

• 99mTc generator needs replacement every week

• 90Y generator need no replacement, 10% replenishment once in five years

• This sounds unbelievable, a cow which can give milk permanently

• Hence it is referred as ‘Kamadhenu’

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Yttrium Kamadhenu

•

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Automation: J. Comor

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How much will it cost?• Automated module ~ 40,000 Euros• Scaling up upto 10 Co of 90Sr is possible

• 10 Ci 90Sr as the stock solution ~ 70,000 Euros

• Hot cell and other facilities ~ 100,000 Euros

• Production capacity 1 Ci/day• Cost of 1 Ci of 90Y is 15,000 Euros• Developing 90Y radiopharmaceuticals to make use of the full capacity of the generator

• Radionuclide therapy can reach to countries which do not have radioisotope production

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Opens up new possibilities for therapeutic radiopharmaceuticals production• 90Y labelled antibodies• 90Y labelled peptides (DOTATATE)• Synovectomy agents• Hepatocarcinoma agents• Bone pain palliation agents?• ????

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Concerns on the use of 90Y• 90Y is separated from 90Sr and hence 90Sr is a potential contamination

• 90Sr is a bone seeking radionuclide with high radiotoxicity due to the long half life and high energy b- particles.

• Maximum permissible body burden is 74 KBq• Permissible limits of 90Sr in 90Y used for therapy is <10-4 % or in ppm level.

• Need to measure a few counts of 90Sr in a million counts of 90Y

• Overlapping b- spectrum with no gammas• QC methods available are unable to be adapted in a hospital radiopharmacy

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Estimation of 90Sr in 90Y: The challenge

0 10 20 30 40 50

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T1/2 = 64.654 ± 0.003 h

com parison w ith litterature value (T 1/2 = 64.14 h) 0.86 %

Cou

nts p

er se

cond

[s-1]

Tim e [d]

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Extraction Paper Chromatography (EPC)

• PANDEY, U et.al., Anal. Chem. 80 (2008) 801-807.

• A simple paper chromatographic technique

• EPC combines solvent extraction with paper chromatography

• Can be adapted in a hospital radiopharmacy

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Method• A chelate, KSM-17 is applied at the point of spotting of a PC strip and allowed to dry

• Test sample is applied to the chelate impregnated portion of the chromatography paper

• The paper is developed in saline• The paper is dried and cut into 3 pieces

• 90Sr which moves to the solvent front is estimated by LSC for 60 minutes.

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Efficiency of separation

0.0 0.2 0.4 0.6 0.80

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10090Y in P C (S aline) in presence of K S M -17

90Y

%Activity

Rf

0.0 0.2 0.4 0.6 0.8 1.00

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% Activity

Rf

85+89S r in P C saline (presence of K S M -17)

0.0 0.2 0.4 0.6 0.8 1.00

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5090Y

90Sr

% Activity

R f

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0.0 0.2 0.4 0.6 0.80

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10090Y in P C (S aline) in presence of K S M -17

90Y

%Ac

tivity

Rf

0.0 0.2 0.4 0.6 0.8 1.01

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1000000

90S r

90Y

coun

ts per m

inute

R f

Typical EPC patterns of 90Y sample eluted from a generator

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Conclusion• 90Y is an important radionuclide for therapy

• There are number of useful 90Y based therapeutic radiopharmaceuticals

• 90Sr/90Y generator is a viable option• There are several generator concepts available

• A cost effective generator technology can be set up in MS

• Commercial module (prototype) based on Electrochemical separation is available

• Estimation of 90Sr in 90Y is important• EPC can be used as a real time quality control technique for estimation 90Sr contamination in 90Y prior to administration to the patient

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