Filères d Approvisionnement Des Radiopharmaceutiques AIPES_JP_Cabocel Janvier 2009

7/25/2019 Filres d Approvisionnement Des Radiopharmaceutiques AIPES_JP_Cabocel Janvier 2009

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Jean-Pierre CABOCEL


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AGENDA I. Who is AIPESII. Evolution of Healthcare

III. Nuclear MedicineIV. Supply of raw materialV. Next steps


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ASSOCIATION OF IMAGING PRODUCERS &EQUIPMENTS SUPPLIERS

AVENUE LOUISE 65 B1050 BRUXELLESwww.aipes-eeig.org
http://www.aipes-eeig.org/http://www.aipes-eeig.org/


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CYCLOPHARMALABORATOIRES
http://www.iason.eu/http://www.iason.eu/http://www.iason.eu/


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Executive CommitteeMarc Gheeraert, President & Secretary GeneralVittorio Puppo, Vice PresidentGuy Turquet de Beauregard, Vice President

Director GeneralJean Pierre Cabocel

Working Groups

Regulatory Affairs

Gerhard Vollberg

Covidien

New Technologies

Thomas Beyer

Reactor & Isotopes

Bernard David

IRE

Transport

Charlie Carrington

GE Healthcare

Admini st rat ionJocelyne Baldasso

Law FirmJean Luc Laffineur

Team RA Team New Tech Team R&I Team TR


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MISSION

Imaging & Therapy with Molecular and Radioactive Tracers

Promote Nuclear Medicine & Molecular HealthcareLobby for Appropriate Regulations & Funding Push for Cost Effectiveness and InnovationacceptanceSupport & Facilitate Logistics and Operations


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Patients safetyFull compliance: adoption of all relevant requirements, both onradioactivity and pharmaceuticalsCompliance covers the entire process: from R&D, to manufacturing, todistribution, to any after sale events

InnovationTradition of innovation and commitment to novel, future tracersDevelopment of new drugs will require a more tailored regulatoryapproach

Healthcare for everyoneEnsuring products and technology availability for all requiredprocedures all over Europe


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Diseaseprogression

Geneticpredis-position

First cellmutations

asympto-maticdisease

Diseased cells releasebiological markers

First symptoms/manifestation

diseaseproliferation

Environmental trigger

Current approach

Symptoms

Imaging


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Mortality &treatment costs

Diseaseprogression


First cellmutations






Current approach

Symptoms


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Diseaseprogression


First cellmutations






Molecular Medicine approach

Molecular Diagnostics

Current approach


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Diseaseprogression


First cellmutations






Molecular Medicine approach

Current approach

Earlierin Care Cycle

Symptoms

Molecular Diagnostics

Source: Philips Medical Systems


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Major Health ConcernsBrain and Degenerative Diseases

OncologyCardiology

Major InvestmentsResearch & Development

Diagnostic Equipment & InfrastructureTherapyHomecare


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THE RIGHT BALANCEINFLUENCED BYIndustry Type

Consumer Ethics

Environment

Breakthrough

Economic Viability Market Volume

Public Opinion

Regulatory&

Compliance


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In Vivo Imaging Modalities for Research & Diagnostic

after: Meikle et al., Phys. Med. Biol. 50 (2005) R45-R61

LimitingResolution

Depth of Penetration

MRS

smart MRI

Bioluminescense

Fluorescense

smart U/S

SPECT

PET


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In Vivo Imaging Modalities for Research & Diagnostic

after: Meikle et al., Phys. Med. Biol. 50 (2005) R45-R61

LimitingResolution

Depth of Penetration

MRS

smart MRI

Bioluminescense

Fluorescense

smart U/S

SPECT

PET

-ATP

-ATP-ATP

PCr

GPC

GPE

PiPC

PE

31 P Liver spectrum

(Courtesy Vanderbilt University, USA)


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The Imaging Application for Metabolism

Small lesion detectionTherapy efficacyNew drug development

Gateway to Molecular Healthcare


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New product introductionLegislation not specific for Radio-pharmaceuticalsGMP

Availability of raw material& Opportunities

Installed base of thousands of cameras Same technology, high resolution and available in hybrid 9-15 year life cycle, lower purchase cost.

Innovation through Molecular Healthcare Imaging

Therapy


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10001FDA

App roved Agen t

DRUG DEVELOPMENT


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35 million procedures (2nd Imaging Technique afterCT, before MR)

20 USA9 Europe3 Japan

3 ROW

28 million of Tc99m

2 million of FDG


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Cardiac Imaging 12 millionProcedures

Tc 99mTl 201

Bone 10Tc 99m

Lung 5Tc 99m

Thyroid 5I 131 / 123Tc 99m


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Imaging:conventional, single

photon emissiontomography SPECT,

SPECT/CT

Imaging: positronemission

tomography(PET, PET/CT,

PET/MRI)

Therapy, pain palliation,radioimmunotherapeutics

67 Ga (a) 18 F(a) 67 Cu (a) 131 I(r)

99m Tc/ 99 Mo(r)(g) 61 Cu(a) 89 Sr(r) 153 Sm(r)

111 In(a) 64 Cu(a) 89 Zr(a) 169 Er(r)

123 I(a) 68 Ga/ 68 Ge(a)(g) 90 Y/90 Sr(r)(g) 177 Lu(r)

131 I(r) 82m Rb/ 82 Sr(a)(g) 90 Y(r) 186 Re(r)

133 Xe(r) 89 Zr(a) 117m Sn(r) 188 Re/ 188 W(r)(g)

201 TI(a) 124 I(a) 123 I(a) Alpha emitters,e.g. 213 Bi/

225 Ac (g) (a)Production route: (r)=reactor, (g)=generator, (a)= accelerator


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SPECT Agent Phase Application99 Tc-metronidazole A RadioRx efficacy99 Tc-Humanaspect A GI cancer 99 Tc-CEAscan A GI/Breast Cancer 99 Tc-NeoTect A Lung cancer 111 In-Prostascint A Prostate cancer 111 In-Zevalin A NHL111 In Octreoscan A Neuro tumors123 I Ioflupane A Parkinson90 Y-Zevalin A NHL90 Y-Octreother A Neuro tumors99 Tc-sestamibi III/A Drug Resistance99 Tc- annexin V II Chemo efficacy99 Tc-deoxyglucose I Tumors188 Re-deoxyglucose I Tumors188 Re-annexin V I Tumors188 Re-metronidazole I Tumors188 Re-sestamibi I Tumors90 Y-Prostascint I Prostate cancer

PET Agent Phase ApplicationFDG A Tumor MetabolismRb A PerfusionF-Dopa III Dopamin-receptor FLT I ProliferationFMISO I Hypoxia

MRI Agent Phase ApplicationGd-DTPA A Perfusion

SPIO A Liver-Tumor MS325-Albumin A Blood-PoolGd-Fibrin I Thrombus

US Agent Phase Application

Microbubble A PerfusionMicrobubble I Breast Tumor

Optical Agent Phase Application ALA-IX A Tumor Metabolism

Molecular Imaging and Therapy Agents


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Industry follows two types of regulations formanufacturing radiopharmaceuticals:

Pharmaceuticals

RadioactiveHigh level of investment

Radiopharmaceuticals are considered aspharmaceutical drugs since 1989

(Directive 89/343/CEE)


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ProductionPharmaceutical LaboratorycGMP(current Good Manufacturing Practice)

Marketing approval

Nuclear Safety & RadioprotectionFacilitiesTransportation


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Objective = to obtain a pure pharmaceutical-graderadionuclide

3 methods :By irradiation of non-radioactive element with protons incyclotrons (cyclotron activation method)

By irradiation of non-radioactive element with neutron inreactor (reactor activation method)

By irradiation of uranium 235 target in reactor to createfission by-products (fission by-product method)


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Cyclotron phase :Proton irradiation in cyclotrons of the target to

generate radioactive isotopesRadiochemical phase in labs :

Transfer of the irradiated target from cyclotron to aradiochemistry laboratoryChemical purification of radioisotope (as Thallium201 or Fluor 18) from the target

Radiopharmaceutical phase in labs :Manufacturing of radiopharmaceutical (e.g.Thallium or FDG vials) in pharmaceutical conditions


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Reactor phase :Neutron irradiation in approved reactor of the stableisotope target to generate radioactive isotopes

Radiochemical phase in labs :Transfer of the irradiated target from reactor to aradiochemistry laboratoryChemical purification of radioisotope (as Samarium 153)from the target

Radiopharmaceutical phase in labs :Manufacturing of radiopharmaceutical in

pharmaceutical conditions


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REACTOR


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Reactor phase :Neutron irradiation in approved reactor of the highlyenriched uranium 235 (HEU) target to generate fissions

Radiochemical phase in specialized producerlabs:

Transfer of the irradiated target from reactor to aradiochemistry laboratoryChemical extraction and purification of fission by-

product (e.g. Molybdenum99

) from the targetRadiopharmaceutical phase in labs:

Manufacturing of radiopharmaceutical (e.g.Technetium generator) in pharmaceutical conditions


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Reactor European Licensed Supplier

NRG Petten (NL) X

CEA Osiris (Fr) X

MOL BR2 (Bel) X

AECL NRU (Can) X

Safari NTP (AFS) X


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Specialized producer European Licensed Supplier Covidien (NL) X

IRE (Bel) X

Nordion (Can) X

NTP (AFS) X


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Specialized producer European Licensed Supplier

Covidien (NL) X

IBA - CisBio (F) X

Nordion (Can) X (not commercialised)

GE (UK) X

MAP (Fin) X

Monrol (Turk) X


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What Happened

In the Summer of 08 ?


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Petten Mol Saclay RSA CanadaPhaseI. Irradiation

Covidien IBA GE MAP Monrol etc MDSPhase III. Generators

Covidien IRE MDSPhaseII. Extraction


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Demand & Supply study


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Major currentradionuclide

production reactors

by country/location

Name

Design

thermal

powerMW

Thermalflux

cm -2s -1

Fuel Criticalitymonth

Status Operating days

per year

(nominal)

Australia, LucasHeights

OPAL 20 1.0X10 14 20%LEU

AUG 06 Oper (age2)

?

Belgium, Mol BR2 100 3.5x10 14 93%HEU

JUN 61 Oper (age47)

120Canada, ChalkRiver

NRU 135 1.5x10 14 20%LEU

Nov 57 Oper (age51)

270France, Saclay OSIRIS 70 1.0x10 14 20%LE

USEP 66 Oper (age

42)180

The Netherlands,Petten

HFR 45 1.5x10 14 20%LEU

NOV 61 Oper (age47)

270

South Africa,Pelindaba

SAFARI-1

20 0.75x10 14

20%LEU

MAR 65 Oper (age43)

310


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Major potentialfuture

radionuclideproduction

reactors

Country/location

Name

Design

thermal

powerMW

Thermal flux

cm -2s -1Fuel Criticalit

y monthStatus

Operating days

peryear

(nominal)France,

CadaracheRJH 100 1.3X10 1

5

20%LEU

_ Underconstruction (operating

2015)

250?

The Netherlands,Petten

PALLAS

45 2.0x10 14 LEU _ Planneddate notdecided

280

South Africa SAFARI-2

? ? LEU _ Planned ?


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Other current

radionuclideproduction

reactors

Country/location

Name

Design

thermal

powerMW

Therma

l flux

cm -2s -1Fuel Criticalit

y monthStatus

Operating

days peryear

(nominal)

Czech Rep., REZ LVR-15 10 1.5X101

4 36%HEU SEP 57 Oper (age51) 200Germany, Munich FRM II 20 8X10 14 93%HEU

MAR 04 Oper (age 4) 250

Korea, Taejon HANARO

30 4,5X10 14

? FEB 95 Oper (age13)

150?

Poland, Otwock-

Swierk

MARIA 30 4,5x10 1

4

36-80%

HEU

DEC 74 Oper (age

34)

280

Argentina, Ezeira RA-3 5-10 1x10 14 20%LEU

AUG 68 Oper (age40)

230

USA, Columbia,

Missouri

MURR 10 6x10 14 ? Oct 66 Oper (age

42) currentlyno 99 Moproduction

280?


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Reactor Schedule 2009


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January 2009Th F Sa Su M Tu W Th F Sa Su M Tu W Th F Sa Su M Tu W Th F Sa Su M Tu W Th F Sa

01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

HFR PettenOSI SaclayBR2 Mol

Safari PelindabaNRU Chalk Riv.

February 2009

Su M Tu W Th F Sa Su M Tu W Th F S a Su M Tu W Th F Sa Su M Tu W Th F Sa01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

HFR PettenOSI SaclayBR2 Mol

Safari PelindabaNRU Chalk Riv.

week 5

week 6 week 7 week 8 week 9

Week 1 week 2 week 3 week 4


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Short TermRefurbish existing dedicated reactorsIncrease medical application in existing dedicatedreactorsUpgrade existing research reactors for medicalapplication.

Long TermUse Horowitz reactor for MolybdenumBuild a dedicated medical reactor with backupNew technology


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Documents

Filères d Approvisionnement Des Radiopharmaceutiques AIPES_JP_Cabocel Janvier 2009