Quality data collection for clinical translation

Deli e able D4.2
Quali y da a collec ion o clinical
ansla ion
This p ojec has ecei ed unding om he Eu opean Union’s Ho izon 2020 esea ch and
inno a ion p og amme unde g an ag eemen No 101008571 (PRISMAP). This
documen e lec s only he iew o he au ho (s). The Agency is no esponsible o any
use ha may be made o he in o ma ion i con ains.
Deli e able D4.2
ii
da a collec ion o clinical ansla ion
P ojec Ac onym
PRISMAP
P ojec Ti le
The Eu opean medical iso ope p og amme: P oduc ion o high pu i y
iso opes by mass sepa a ion
G an Ag eemen No.
101008571
Topic
INFRAIA-02-2020: In eg a ing Ac i i ies o S a ing Communi ies
P ojec s a da e
01 May 2021
Na u e
Repo
Dissemina ion le el
Public
Due da e
M51
Da e o deli e y
M51
Lead pa ne
MUI
Con ibu ing pa ne s
ARRONAX, CHUV, DTU, CERN, ILL, IST-ID, JRC, KULeu en, NCBJ, PSI, SCK CEN,
TUM
Au ho s
Clemens Dec is o o o, Hessam Rous aei Fi ouzabad (MUI); Rena a
Mikolajczak, Malgo za a Zol owska (NCBJ); Talip Zeynep, Susanne Geis lich,
Nick an de Meulen (PSI); Caloge o D'Alessand ia (TUM); Thie y S o a
(CERN); Cécile Bou deau, Fe id Haddad (ARRONAX); Da id Vie l (CHUV);
Clai e De ille, Cli e Naidoo, K is ina Søbo g Pede sen, Mikael Jensen (DTU);
Ulli Kös e (ILL); Lu des Gano (IST-ID); F ank B uche sei e (JRC); Maa en
Ooms, Michiel Van de Voo de (SCK CEN)
Re iewe
F ede ic Clee en (KULeu en)
An ónio Paulo (IST-ID)
Poin o Con ac
Clemens Dec is o o o
Ins i u ion
MUI
E-mail
Clemens.Dec is o o [email protected]
Phone
+4351250480951
© PRISMAP 2021. This wo k is licensed unde a C ea i e Commons
A ibu ion-NonComme cial-NoDe i a i es 4.0 In e na ional License.
Deli e able D4.2
iii
Re ision His o y
Ve sion
Da e
Au ho
Commen
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16.01.2025
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Final e sion, app o ed by he Gene al Assembly
Deli e able D4.2
i
Con en s
Abb e ia ions, Pa icipan sho names i
Abb e ia ions i
Pa icipan sho names ii
Lis o Figu es iii
Lis o Tables iii
Summa y 1
1. In oduc ion 2
1.1 S anda disa ion and ha monisa ion o Quali y Da a wi hin PRISMAP 2
1.2 Scope o deli e able 4.2 2
1.3 De ia ions om he o iginal plan 2
2. Gene al ac i i ies ela ed o quali y o no el adionuclides 3
2.1 Changes in he pha maceu ical egula o y amewo k in he EU 3
2.2 The e ision o he pha maceu ical Di ec i e and he egula o y de ini ion o no el adionuclides 3
2.3 The EMA guideline on Radiopha maceu icals and no el adionuclides 4
2.4 An EMA Inno a ion Task Fo ce mee ing on he quali y o no el adionuclides and
adiopha maceu icals he e om 4
2.4.1 EMA- egula o y expe ’s opinions on he de ini ion o a no el adionuclide in a clinical ial and
he equi emen o Ma ke ing au ho isa ion 5
2.4.2 EMA- egula o y expe ’s opinions on he GMP equi emen o a no el adionuclide in a clinical
ial 6
2.4.3 EMA- egula o y expe ’s opinions on he Radionuclidic and Radiochemical Impu i y le els o
no el adionuclides 6
2.4.4 EMA- egula o y expe ’s opinions on he c i e ia o a eliable and accu a e de e mina ion o
he amoun o adioac i i y in a adiopha maceu ical? 6
2.5 GMP- Annex 3 ques ions and answe s om he EMA GMP/GDP IWG on he GMP equi emen s o
no el adionuclides 6
2.6 Ac i i ies o PRISMAP wi h he IAEA 8
3. Quali y Da a om speci ic adionuclides om PRISMAP`s po olio 8
3.1 Te bium – 161 8
3.1.1 GMP conside a ions in he p oduc ion o adiopha maceu icals using Te bium-161 8
3.1.2 Quali y equi emen s o Te bium-161 – expe iences om he p oduc ion in he PRISMAP
p ojec 9
3.2 Coppe -64 13
3.2.1 Quali y conside a ions in he p oduc ion o adiopha maceu icals using Coppe -64 13
3.2.2 Quali y equi emen s o Cu-64 – expe iences om he p oduc ion in he PRISMAP p ojec 15
3.3 Ac inium-225 16
3.3.1 Quali y conside a ions in he p oduc ion o adiopha maceu icals using Ac inium-225 16
Deli e able D4.2
3.3.2 How o de ine quali y speci ica ions o Ac inium-225 18
4. Conclusions 20
5. Re e ences 21
6. Annexes 23
Annex 1: Response o he Eu opean Commission`s P oposal on he e ision o he EU gene al
pha maceu icals legisla ion 23
Annex 2: Le e o Membe s o he Eu opean Pa liamen ega ding he e ision o he EU gene al
pha maceu icals legisla ion 25
Annex 3: PRISMAP`s commen s o he Concep pape on he e ision o he 'Guideline on
Radiopha maceu icals-Re ision 1` (Ex ac ) 26
Annex 4: S a emen PRISMAP Radionuclides and GMP-Annex 3 and EMA esponse 29
Annex 5: Posi ion Pape on GMP equi emen s o no el adionuclides 34
Annex 6: Repo om he In e labo a o y Compa ison s udy (ILC) o 64Cu 40

Deli e able D4.2
i
Abb e ia ions, Pa icipan sho names
Abb e ia ions
AMA
Appa en Mola (Radio)Ac i i y
API
Ac i e Pha maceu ical Ing edien
CA
Conso ium Ag eemen
CoA
Ce i ica e o Analysis
DoA
Desc ip ion o Ac ion
EANM
Eu opean Associa ion o Nuclea Medicine
EDQM
Eu opean Di ec o a e o he Quali y o Medicines
EMA
Eu opean Medicines Agency
ESA
E ec i e Speci ic (Radio)Ac i i y
EU
Eu opean Union
GA
G an Ag eemen
GMP
Good Manu ac u ing P ac ices
HPG
High Pu i y Ge manium (de ec o )
IAEA
In e na ional A omic Ene gy Agency
ICP-MS
Induc i ely coupled plasma mass spec ome y
ICP-OES
Induc i ely coupled plasma op ical emission spec oscopy
ILC
In e labo a o y Compa ison (Ak onnym o a s udy conduc ed wi hin WP4)
IMPD
In es iga ional Medicinal P oduc Dossie
ITF
Inno a ion Task Fo ce
ITLC
Ins an Thin laye Ch oma og aphy
IWP
Inspec o s Wo king G oup
MA
Mola (Radio)Ac i i y
MAu h
Ma ke ing Au ho isa ion
Pha m Eu
Eu opean Pha macopoeia
QC
Quali y Con ol
QWP
Quali y Wo king Pa y
RCP
Radiochemical Pu i y
RNP
Radionuclidic Pu i y
SOP
S anda d Ope a ing P ocedu e
TLC
Thin laye Ch oma og aphy
Deli e able D4.2
ii
Pa icipan sho names
CERN
Eu opean o ganisa ion o nuclea esea ch
NPL
Na ional Physical Labo a o y
PSI
Paul Sche e Ins i u
CEA
Commissa ia à l’éne gie a omique e aux éne gies al e na i es
IST-ID
Associação do Ins i u o Supe io Técnico pa a a IST-ID In es igação e
Desen ol imen o
DTU
Danma ks Tekniske Uni e si e
CHUV
Cen e hospi alie uni e si ai e audois
GANIL
G and Accélé a eu Na ional d’Ions Lou ds
SCK CEN
S udiecen um oo Ke nene gie / Cen e d'é ude de l'éne gie nucléai e
ARRONAX
G oupemen d’in é ê public ARRONAX
ESS
Eu opean spalla ion sou ce ERIC
TUM
Klinikum ech s de Isa de echnischen Uni e si ä München
KULeu en
Ka holieke Uni e si ei Leu en
MedAus on
En wicklungs- und Be iebsgesellscha MedAus on GmbH
SCIPROM
SCIPROM Sà l
MUI
Medizinische Uni e si ä Innsb uck
ILL
Ins i u Max on Laue - Paul Lange in
JRC
JRC -Join Resea ch Cen e- Eu opean Commission
NCBJ
Na odowe Cen um Badań Jąd owych
GSI
GSI Helmhol zzen um  Schwe ionen o schung GmbH
LU
La ijas Uni e si ā e
INFN
Is i u o Nazionale di Fisica Nuclea e
UiO
Uni e si e e i Oslo
Deli e able D4.2
iii
Lis o Figu es
Figu e 1. Ti le page o he EMA Inno a ion Task Fo ce B ie ing mee ing epo om Ma ch 31s , 2023 5
Figu e 2. Exce p om he le e as esponse o PRISMAPs p oblem s a emen on GMP o he
p oduc ion and use o no el adionuclides 7
Figu e 3. Manu ac u ing s a egy o clinical 161Tb- adiopha maceu icals de eloped and app o ed by he
Swiss na ional heal h-au ho i y o i s clinical ials in-human 9
Figu e 4. Manu ac u ing s a egy o 64Cu- adiopha maceu icals used o compassiona e use and
clinical ials de eloped and app o ed by he Danish Heal h Au ho i y 14
Figu e 5. Manu ac u ing s a egy o Ac-225 om Th-232 mass sepa a ion p ocess ( om MEDICIS) 17
Lis o Tables
Table 1. Quali y Con ol esul s o Tb-161 adiolabelling solu ion p oduced a PSI o PRISMAP use s 10
Table 2. TLC esul s o adiochemical pu i y es ing o Tb-161 Te bium(III) p oduced a NCBJ o
PRISMAP use s 11
Table 3. Me als in Tb-161 solu ions de e mined by ICP OES o ba ches p oduced o PRISMAP use s a
NCBJ. 11
Table 4. Summa y quali y da a o ele an pa ame e s o adiolabelling pe o mance – ou come o Cu-
64 ILC s udy 16
Summa y
Radiopha maceu icals a e conside ed Medicinal P oduc s, he eby hey mus be p epa ed and applied wi hin
he egula ed a ea o pha maceu icals. This includes adionuclides, which ha e seen ex ao dina y
ad ancemen s in esea ch and de elopmen o e he las decade ega ding he anos ics. O e he pas ou
yea s WP4 o he PRISMAP p ojec on Ha monisa ion and S anda disa ion has analysed he egula o y
landscape in ela ion o chemical and pha maceu ical quali y aspec s o he use o no el adionuclides in
adiopha maceu icals, moni o ed he egula o y de elopmen s in his ield and ied o communica e he
challenges o clinical ansla ion. Wi hin hese ac i i ies he e ision o he pha maceu ical di ec i e was
e iewed and commen s om PRISMAP p o ided. Con ac wi h EMA esul ed in dedica ed e en s p o iding
he adionuclides communi y poin o iew on GMP and o he pha maceu ical egula ions o no el
adionuclides and inpu in IAEA ac i i ies we e gi en. This is desc ibed in his deli e able. In he second pa
o his deli e able speci ic quali y da a and conside a ion o h ee majo adionuclides om he PRISMAP
po olio, Tb-161, Cu-64 and Ac-225 a e desc ibed. In pa icula , GMP equi emen s in he p oduc ion and
use o hese adionuclides a e add essed, and also speci ic quali y issues and ac i i ies a e desc ibed. This
includes an ou come om an in e labo a o y compa ison s udy on Cu-64, compa ison o quali y da a o Tb-
161 p o ided wi hin PRISMAP and speci ic de elopmen s on he quali y o Ac-225. O e all, his deli e able
p o ides a summa y and insigh in o many aspec s ela ed o ha monisa ion and s anda disa ion o he
quali y o no el adionuclides.
Deli e able D4.2
8
Wi h espec o he applicabili y o GMP Annex 3 o IMPs and no el adionuclides, exemp ions we e
con i med, howe e , indica ing ha “Membe S a es shall make he p ocesses se ou in pa ag aph 5 subjec
o app op ia e and p opo iona e equi emen s o ensu e subjec sa e y and eliabili y and obus ness o he
da a gene a ed in he clinical ial. They shall subjec he p ocesses o egula inspec ions” as ou lined in he
Clinical T ial Regula ion leading o he si ua ion ha indi idual membe s a es may s ill equi e compliance
wi h GMP, he e o e applicabili y o Annex 3 o IMP should emain.
Rega ding no el p oduc ion me hods, a gene al exemp ion om GMP is also no suppo ed bu can be
conside ed on a case-by-case basis.
O e all, he egula o y expe s ag eed ha an upda e o GMP Annex 3 is needed in ligh o he scien i ic
p ocess and hey will seek and welcome he iews o s akeholde s du ing his e ision phase.
The opic o egula o y GMP equi emen s in he p oduc ion o no el adionuclides and he ac i i ies o he
PRISMAP conso ium we e ecen ly summa ised in a posi ion pape published in July 2025 (7), ha is ound
in Annex 5.
2.6 Ac i i ies o PRISMAP wi h he IAEA
WP4 also pa icipa ed in a echnical mee ing on “Heal h and Pha maceu ical Regula ions o
Radiopha maceu icals”, a he In e na ional A omic Ene gy Agency in Vienna, Aus ia, 6 o 10 Ma ch 2023,
whe e PRISMAP’s ac i i ies we e p esen ed. The o e all p oblems o pha maceu ical egula ions wi h
adiopha maceu icals (including no el adionuclides) we e discussed and a common amewo k was
elabo a ed. This wo k esul ed in a join pape published in EJNMMI Radiopha macy & Chemis y in Janua y
2024 (8) wi h he suppo o PRISMAP. This is a aluable e e ence o use s o PRISMAPs adionuclides in
e ms o egula o y issues.
3. Quali y Da a om speci ic adionuclides om PRISMAP`s po olio
3.1 Te bium – 161
3.1.1 GMP conside a ions in he p oduc ion o adiopha maceu icals using Te bium-161
3.1.1.1 In oduc ion
Cu en p oduc ion o Tb-161 (9–11) is based on he i adia ion o Gd-160 oxide a ge s in high neu on lux
eac o s based on he (n,γ) eac ion o Gd-161 which, subsequen ly, decays o Tb-161. A e sepa a ion om
gadolinium ia a ca ion exchange and/o ex ac ion ch oma og aphy he n.c.a. Tb-161 is ob ained in a dilu e
hyd ochlo ic acid solu ion sui able o adiolabelling. The speci ic ac i i y and adiochemical p ope ies o Tb-
161 a e simila o he cu en ly widely used Lu-177. E en hough Tb-161 p oduced wi hin PRISMAP has no
been di ec ly used in clinical ials, examples om Tb-161 p oduced o na ionally app o ed clinical ials
p o ide guidance on how chemical g ade Tb-161 may be in oduced in o GMP complian
adiopha maceu ical p oduc ion.

Deli e able D4.2
9
3.1.1.2 Example o a p ocess o Te bium-161 adiopha maceu icals
Figu e 3. Manu ac u ing s a egy o clinical 161Tb- adiopha maceu icals de eloped and app o ed by he Swiss
na ional heal h-au ho i y o i s clinical ials in-human
A p ocess o he p oduc ion o Tb-161 and subsequen manu ac u ing o a Tb-161 adiopha maceu ical o
i s in human clinical ials is shown in Figu e 3. The a ge ma e ials o i adia ion a e subjec o app op ia e
quali y con ol, all ma e ials unde go a cleaning p ocess and he a ge is p epa ed in a clean oom (i was
ag eed wi h he compe en au ho i y o use an exis ing clean oom o o he adiopha maceu ical p oduc ion
p ocesses in hese ea ly-phase clinical ials) unde GMP condi ions and s o ed unde qua an ine. The a ge
is conside ed a s a ing ma e ial and unde goes a quali y con ol elease p ocedu e be o e being sen ou o
i adia ion. The i adia ion is pe o med ou side a GMP-quali y amewo k unde p ede ined condi ions. The
i adia ed a ge is handled unde non-GMP con olled condi ions in a manual p ede ined p ocess un il he
inal chemical pu i ica ion s ep. The solu ion con aining he desi ed sepa a ed adionuclide is de ined as an
API s a ing ma e ial and he inal pu i ica ion is pe o med in a ho cell in a clean oom unde GMP con ol
and hen in oduced in o he inal adiopha maceu ical manu ac u ing p ocess owa ds inal asep ic
dispensing o he inal IMP o use in he clinical ial. Quali y con ol o he inal p oduc and elease is
pe o med acco ding o GMP equi emen s.
This p ocess has been app o ed by he compe en au ho i y o clinical ials which s a ed in 2023. The
speci ic conside a ions o ce ain p ocesses being ou side he GMP amewo k canno be gene alised o
adiopha maceu ical p oduc ion. Howe e , i is essen ial o conside less s ingen equi emen s in he ea ly
phases o he de elopmen , which, in his case, has been accep ed by he pha maceu ical au ho i y.
3.1.2 Quali y equi emen s o Te bium-161 – expe iences om he p oduc ion in he
PRISMAP p ojec
The quali y speci ica ion and es ing me hods o Tb-161 canno be ully ha monised wi hin PRISMAP a he
cu en s age o de elopmen . Howe e , Tb-161 p oduced by di e en PRISMAP pa ne s has eached a s age
o de elopmen , whe e main quali y pa ame e s can be de ined and me hods o de e mina ion be
ecommended. These a e desc ibed u he on wi h some “ eal wo ld da a” om ba ches o Tb-161 p oduced
and shipped o selec ed p ojec s wi hin PRISMAP. O e all quali y conside a ions can be ela ed o he
Deli e able D4.2
10
s anda ds p o ided by he Eu opean Pha macopoeia o Lu e ium-177 in he monog aph Lu e ium (177Lu)
solu ion o adiolabelling No 2798 (12), wi h e y simila cha ac e is ics and quali y conside a ions as
compa ed o Tb-161. Speci ic conside a ions on he quali y o Tb-161 o adiolabelling and Tb-161
adiopha maceu icals can be ound in (9–11,13). Quali y conside a ions ega ding ac i i y measu emen and
calib a ion ac o s a e summa ised in Table 1.
Table 1. Quali y Con ol esul s o Tb-161 adiolabelling solu ion p oduced a PSI o PRISMAP use s
Da e o Chemical Sepa a ion
Pa ame e
Requi emen
10.11.2023
09.04.2024
28.05.2024
RCP (HPLC)*
≥99%
99%
100%
100%
Iden i y (у-
spec ome y)
74.6 ± 1 keV
87.9 ± 1 keV
103.1 ± 1 keV
106.1 ± 1 keV
Complies
Complies
Complies
RNP a Expi y Da e (у-
spec ome y)
Tb-160 ≤ 0.1%
Tb-161 ≥ 99.9%
< 0.1%
> 99.9%
< 0.1%
> 99.9%
< 0.1%
> 99.9%
* AMA es : adiolabelling o DOTATOC a 100 MBq/nmol
3.1.2.1 Iden i y es s
The iden i y o Tb-161 can be ensu ed by gamma spec ome y as he cha ac e is ic gamma emissions can
be de ec ed. The mos p ominen gamma pho ons o Tb-161 ha e an ene gy o 25.7keV (23%), 48.9 keV
(17.0%), 74.6 keV (10.2%), 87.9 keV (0.18%), 103.1 keV (0.1%) and 106.1 keV (0.07%). Gamma pho ons wi h
an ene gy o 292.4 keV (0.06%) and 550.3 keV (0.04%) a e also p esen . High esolu ion gamma spec ome y
can ensu e p esence o all peaks desc ibed o he p oduc ion and elease o he p oduc , Table 1 shows
compliance o ba ches o Tb-161 p oduced wi hin PRISMAP wi h hese speci ica ions.
Howe e , he low abundance and close ene gies o se e al emissions makes i imp ac ical o use s in
hospi als o iden i y all lines e.g., wi h an a ailable NaI-gamma spec ome e . The e o e, use s may conside
o use he main gamma peaks a 48.9 keV and 74.6 keV as a main iden i ica ion ac o , based on isk
assessmen and conside a ions o o he adionuclides used in he espec i e acili y. A de ailed desc ip ion
o he p ope ies and in e e ing gamma emissions om o he adionuclides can be ound in he
supplemen a y in o ma ion o (13).
3.1.2.2 Radionuclidic pu i y
The main adionuclidic impu i y o be conside ed is Tb-160 wi h a hal -li e o 72.3 days, which is co-p oduced
in he i adia ion o he 160Gd2O3 a ge ma e ial ia a ious ou es (13).
Table 1 shows he Tb-160 con en a he ime o expi y (4 weeks a e end o bomba dmen ) o se e al
ba ches o Tb-161 p oduced o PRISMAP use s by PSI. These da a indica e ha a limi o 0.1% o Tb-160 can
be eached e en wi h a shel li e o se e al weeks, such an impu i y le el will lead o an addi ional adia ion
dose o 0.35% o he pa ien (13). Howe e , i is impo an o he use o be awa e o his impu i y and he
speci ica ions o ce ain p oduc ion, as i will ha e a conside able e ec on he was e managemen , especially
when used clinically in hospi als. Also, la e measu emen s e.g., in gamma coun e s, ha e o ake his in o
accoun .
Deli e able D4.2
11
3.1.2.3 Radiochemical pu i y
The adiochemical pu i y can be de e mined in analogy o Lu-177 as desc ibed in he espec i e monog aph
(12). A simple ITLC es using an acidi ied NaCl-solu ion allows he sepa a ion o he Lu-177 Lu e ium(III) ion
om bound o hyd olysed Lu-177. Table 2 shows complian esul s o ba ches p oduced o PRISMAP use s
a NCBJ.
Table 2. TLC esul s o adiochemical pu i y es ing o Tb-161 Te bium(III) p oduced a NCBJ o PRISMAP use s
NCBJ Ba ch
Radiochemical pu i y [%]
01/24
99.9
02/24
99.6
03/24
99.3
04/24
99.5
01/25
99.2
3.1.2.4 Me al de e mina ion
The de e mina ion o selec ed me als in adionuclide solu ions as a elease-c i e ia has been a ma e o
deba e. Dedica ed equipmen such as ICP-MS o ICP-OES allowing he de e mina ion o me als in highly
adioac i e solu ions is a challenge o many labo a o ies (Table 39. Addi ionally, he ques ion a ises which
me als a e ele an o he use o a adionuclide o adiolabelling. Toxici y o hea y me als is no conce n due
o he e y low amoun s o o al me als p esen . The main quali y conce n is he adiolabelling pe o mance
o he adionuclide, which depends on he speci ic chela o employed, he mola adioac i i ies and he o al
amoun s o adioac i i y equi ed o a pa icula applica ion. In he case o Lu-177, he Pha m Eu
monog aph desc ibes he de e mina ion o Lu, Cu, Fe, Pb and Zn and speci ies espec i e limi s. Howe e , in
a ecen d a o he monog aph on 68Ga o adiolabelling i is p oposed o eplace he es o me als by
he Appa en Mola Ac i i y (AMA) es (see 3.1.2.5. below). This could also be applied o Tb-161 and o he
adiome als. In ea ly phase clinical ials, he es ablishmen o he me allic impu i ies in he alida ion and
elease based on AMA- es s can be conside ed accep able. Table 3 shows esul s om me al de e mina ion
o me als by ICP-OES in Tb-161 ba ches p oduced a NCBJ o PRISMAP use s.
Table 3. Me als in Tb-161 solu ions de e mined by ICP OES o ba ches p oduced o PRISMAP use s a NCBJ.
NCBJ
Elemen s
01/24
02/24
03/24
04/24
01/25
[ppm]
Cu
0.111
< 0.892
1.92
< 0.586
< 3.58
Co
0.185
< 0.529
< 1.68
< 0.647
< 0.376
Fe
0.167
< 0.068
< 0.117
< 0.405
< 0.372
Ni
< 0.116
< 0.839
< 2.00
< 0.376
< 0.720
Pb
< 0.439
< 0.574
< 2.71
< 1.90
< 1.13
Zn
0.431
0.823
4.25
1.58
1.52
Gd
5.41
6.41
12.5
4.25
< 3.10
Tb
3.76
< 2.10
1.99
< 1.77
< 4.51
Dy
0.224
< 0.343
0.637
0.425
< 3.12
Deli e able D4.2
12
3.1.2.5 Appa en mola ac i i y (AMA) de e mina ion
A adiolabelling es wi h he adionuclide using a sui able chela o allows o in es iga e he p esence o
me als in e e ing in he adiolabelling p ocess o he adiopha maceu ical p epa a ion and can he e o e be
a subs i u e o he de e mina ion o indi idual me als as a quali y es . The es can be use ul o he
p oduce o he adionuclide, bu mo e impo an ly o he use . This es includes a adiolabelling s ep,
ollowed by he de e mina ion o he adiolabelling yield, ypically by a simple TLC- es . I can be designed as
a i a ion o dec easing amoun s o ligand o he adionuclide o see a which mola concen a ion he
adiolabelling ails o mee a p ede ined limi (e.g., 95%). This equi es a qui e labo ious es egime.
The e o e, once he espec i e concen a ion has been de ined in a alida ion, he es can be simpli ied o
wo k as a limi es using a single concen a ion o he ligand. The use will use he same ype o ligand as is
used o he adiopha maceu ical in ques ion. The p oduce o he adionuclide will use a s anda d chela o ,
in mos cases DOTA o a DOTA de i a i e.
Below is an example o a po en ial p o ocol o an AMA es o Tb-161 (modi ied om a p o ocol applied a
NCBJ, no alida ed):
 Tes solu ion. P epa e a solu ion con aining 2 nmol DOTATATE in 52 µL Asco bic acid bu e . Add a
solu ion o 200 MBq o Tb-161 in dilu e hyd ochlo ic acid and make up o a inal olume o 500µl wi h
asco bic acid bu e . Hea o 95°C and eac o 20 minu es.
 Pla e: TLC silica gel pla e R; use a glass- ib e pla e
1
.
 Mobile phase: 1M ammonium ace a e and me hanol in a olume a io o 1:1
 Applica ion: abou 3 µL
 De elopmen : immedia ely, o e a pa h o a leas 7 cm.
 D ying: in o en, 80°C
 De ec ion: sui able de ec o o de e mine he dis ibu ion o adioac i i y.
 Re a da ion ac o : [Tb-161]Tb-DOTA-TATE ≥0.9, [Tb-161]Te bium(III) ion ≤0.2
 Measu e he ela i e amoun o ac i i y o each pla e.
 Calcula e he pe cen age o he adioac i i y due o [Tb-161]Tb-DOTA-X o he p epa a ion
 Limi : ≥ 95% o he o al adioac i i y due o [Tb-161]Tb-DOTA-TATE
3.1.2.6 pH
The pH can be de e mined using an indica o s ip and should ensu e he acidic cha ac e o he Tb-161
solu ion o adiolabelling, in which he Tb3+ ion is p esen . Highe pH holds he isk o gene a ing hyd olysis
p oduc s. A pH be ween 1 and 2, as desc ibed in he monog aph Lu e ium (Lu-177) solu ion o adiolabelling
No 2798 (12), can be conside ed a sui able speci ica ion in iew o he ypical acid concen a ions used in he
inal o mula ion o Tb-161 o adiolabelling.
3.1.2.7 S e ili y and endo oxins
The e is no o mal necessi y om a quali y aspec o ha e a s e ile solu ion o he adionuclide o
adiolabelling as long as he p epa a ion p ocess o he inal adiopha maceu ical ensu es ha he inal
p oduc is s e ile. This has o be con i med in a documen ed isk assessmen by he use o he adionuclide.
Radionuclide p oduce s may conside p o iding a s e ile p oduc o wide clinical applica ions. In case he
p oduc is no s e ile, he biobu den o he adionuclide should be es ablished in he p ocess alida ion o
he adiopha maceu ical p epa a ion. This can include de e mina ion o endo oxins. The limi s o endo oxins
in he Tb-161 adiolabelling solu ion will depend on se e al ac o s: he o al olume o adiolabelling solu ion
used, he maximum olume used o one pa ien dose and whe he he p oduc ion p ocess o he
adiopha maceu icals includes s eps wi h he po en ial o educing he endo oxin le els. Also, he
con ibu ion o he endo oxin bu den in he inal p oduc by o he ma e ials used in he syn hesis p ocess
has o be aken in o accoun . The e o e, i is no possible o gi e a gene al ecommenda ion o Endo oxin
1
iTLC-SG (Agilen Technologies, SGI0001) is sui able
Deli e able D4.2
13
alues o a Tb-161 solu ion o adiolabelling, bu again, he Lu-177 can se e as a e e ence which s a es
“less han 175 IU/V, V being he maximum olume o be used o he p epa a ion o a single pa ien dose, i
in ended o use in he manu ac u e o pa en e al p epa a ions wi hou a u he app op ia e p ocedu e o
he emo al o bac e ial endo oxins.”(12)
Fo ea ly s ages o de elopmen and ea ly phase clinical ials he equi emen s o es s on endo oxins,
biobu den and s e ili y o he Tb-161 solu ions o adiolabelling as elease c i e ia should be iewed wi hin
a isk assessmen aking alida ion da a, adia ion sa e y aspec s and he inal p oduc ion p ocess o he
adiopha maceu ical in o accoun .
3.1.2.8 Labelling
The ial-label o a Tb-161 solu ion o adiolabelling should indica e:
 ha he solu ion is no o di ec adminis a ion o humans;
 he maximum olume ha can be used o he p epa a ion o a single pa ien dose;
 he concen a ion o hyd ochlo ic acid;
 ha he solu ion is in ended o use in he p epa a ion o Te bium-161-labelled adiopha maceu icals;
3.2 Coppe -64
3.2.1 Quali y conside a ions in he p oduc ion o adiopha maceu icals using Coppe -64
3.2.1.1 In oduc ion
In con as o Tb-161, Cu-64 was p o ided wi hin PRISMAP by di e en me hods. Cu-64 om DTU and PSI
o igina ed om p o on i adia ion o en iched Ni-64 a ge s, whe eas ARRONAX used deu e on i adia ions
o en iched Ni-64 a ge s. Addi ionally, eac o -p oduced Cu-64 wi h low speci ic ac i i y was a ailable om
NCBJ. The di e en p oduc ion pa hways o Cu-64, as well as quali y conside a ions ha e been summa ised
as an ou come o a Coo dina ed Resea ch P ojec by he IAEA in 2022 (14).
PRISMAP`s Cu-64 has no been di ec ly used in clinical ials, bu he expe ience wi hin PRISMAP will
con ibu e o s anda dizing he quali y o Cu-64 o adiopha maceu ical p epa a ions wi hin he Pha m Eu ,
whe e a monog aph on Cu-64 is cu en ly being d a ed.

Deli e able D4.2
14
3.2.1.2 Example o a p ocess o Cu-64 adiopha maceu icals
Figu e 4. Manu ac u ing s a egy o 64Cu- adiopha maceu icals used o compassiona e use and clinical ials
de eloped and app o ed by he Danish Heal h Au ho i y
Figu e 4 desc ibes he o e all manu ac u ing scheme o in-house p oduc ion o a Cu-64 adiopha maceu ical
o human use equi ing compliance wi h GMP. The inal adiopha maceu ical is manu ac u ed in clean
ooms acco ding o a GMP-complian (GMP Pa I) asep ic manu ac u ing p ocess wi h inal s e ile il a ion
and eleased by a quali ied pe son based on alida ed QC me hods.
Cu-64 o his p ocess is conside ed an API s a ing ma e ial, i s p oduc ion is, in many pa s, unde GMP
con ol, he whole p ocess is desc ibed in SOPs and de ailed manu ac u ing eco ds a e kep . The a ge
ma e ial is om quali ied supplie s wi h de ined speci ica ions and i is eleased based on de ined iden i y
and pu i y es s. O he eagen s equi ed a e also es ed agains p ede ined speci ica ions, he a ge is
p epa ed in a adiochemical labo a o y in a con olled a ea based on p ede ined alida ed p ocedu es, and
he Ni-64 pla ed a ge becomes a s a ing ma e ial in he p oduc ion p ocess.
I adia ion in he cyclo on is ou side he GMP amewo k, bu well con olled wi h de ined i adia ion
condi ions and imes, and ha ing wo cyclo ons quali ied o he p ocess. The cyclo on`s main enance and
epai s a e well-documen ed and aceable.
A e i adia ion, he a ge is ans e ed o a con olled a ea and handled unde s ic ly de ined and
alida ed p ocedu es om dissolu ion, and ion exchange pu i ica ion ollowed by ba ch ac iona ion in
pha maceu ical g ade glass ials, in which he solu ion is e apo a ed o d yness. These ials a e he API
s a ing ma e ial o he manu ac u ing o he adiopha maceu ical. QC samples o he Cu-64 solu ions a e
aken om he ba ch ac iona ion solu ion and es ed agains p ede ined speci ica ions using alida ed
me hods. The inal Cu-64 ials a e measu ed o ac i i y and kep in qua an ine un il ac i i y concen a ion,
iden i y and p ede ined me al limi s a e ensu ed. The p ocess up o elease o Cu-64 as an API s a ing
ma e ial ollows GMP Pa II (“Basic Requi emen s o Ac i e Subs ances used as S a ing Ma e ials”), he
ollowing adiopha maceu ical p epa a ion is acco ding o GMP Pa I (“Basic Requi emen s o Medicinal
P oduc s”).
Deli e able D4.2
15
O e all, his se up p o ides a GMP-complian p ocess ha allows he use o Cu-64 o adiopha maceu ical
p epa a ions bo h o ou ine clinical use as well as o in es iga ional Medicinal p oduc s. P oduc ion
pa hways wi h a educed co e age by GMP-complian p ocesses will be accep able, especially i Cu-64 is used
o he p oduc ion o in es iga ional adiopha maceu icals.
3.2.2 Quali y equi emen s o Cu-64 – expe iences om he p oduc ion in he PRISMAP
p ojec
3.2.2.1 Iden i y es s:
The iden i y o Cu-64 can be assu ed by he cha ac e is ic gamma emissions wi h he mos p ominen gamma
pho ons ep esen ing he 511 keV peak om he posi on annihila ion, addi ionally a 1345.8 keV gamma line
(6%) ensu ing unequi ocal iden i ica ion. The addi ional de e mina ion o he hal -li e, as i is equi ed o
pu e posi on emi e s like F-18 may no be equi ed by use s o he adionuclide due o hese cha ac e is ics.
3.2.2.2 Radionuclidic pu i y
The main adionuclidic impu i ies o he p oduc ion pa hways used wi hin PRISMAP a e cobal
adioiso opes, in pa icula Co-56, Co-57 and Co-58. These we e speci ied o Cu-64 om PRISMAP
p oduc ion o be below 0.01% a he ime o p oduc ion. Exac speci ica ions depend on applica ion and he
de ined shel li e o he Cu-64 o a speci ic p oduc ion and needs o be es ablished based on a isk
assessmen .
3.2.2.3 Radiochemical pu i y
In o de o e alua e he p esence o he ionic o ms o he adiome al iso opes and he absence o colloidal
species, adio hin laye ch oma og aphy (TLC) analysis o he pu i ied CuCl2-64 is s ongly ecommended.
This can be done using ITLC-SG as s a iona y phase and 0.1M Ci a e bu e pH 4-4.5, whe eby he e a da ion
ac o o Cu-64 in colloidal o m is <0.2 and o [Cu-64]Coppe (II) ion 1.0 (14).
3.2.2.4 Me al de e mina ion & Appa en Mola Ac i i y (AMA) de e mina ion (ILC s udy)
Simila o Tb-161, ace me als a e an impo an ac o in ela ion o he adiolabelling p ope ies o a Cu-
64 p oduc ion. Impo an me als include, Fe, Ni, Zn and Cu. The exac speci ica ions o hese me als again
will depend on he indi idual applica ion. A adiolabelling es o de e mine he appa en mola ac i i ies o
he concen a ion in which a ypical chela o s ill p o ides high adiolabelling yields he e o e is also
ecommended.
To compa e he quali y o Cu-64 p o ided by di e en PRISMAP use s an In e labo a o y Compa ison (ILC)
S udy was ini ia ed. One cen al labo a o y (ARRONAX) ecei ed samples o Cu-64 p oduced by o he
membe s o he PRISMAP conso ium (DTU, PSI, NCBJ). A s anda dised p o ocol was used o de e mine he
ac i i y, Appa en Mola Ac i i y (AMA) and Mola Ac i i y (MA). Addi ionally, me al de e mina ion o majo
me als (Co, Cu, Fe, Ni, Zn) by ICP-OES was a ailable o some es ba ches. The AMA es was designed as a
i a ion assay using dec easing concen a ions o DOTA as a chela o o Cu-64.
Be ween Feb ua y 2022 and Feb ua y 2024 i e di e en ba ches we e analysed a ARRONAX ( om each
p oduce , 2 ba ches om ARRONAX i sel ).
The main esul s o he s udy a e summa ised in Table 4. The low mola ac i i ies ound o Cu-64 om NCBJ
ma ch he eac o p oduc ion pa hway, all alues we e below 0.1 MBq/nmol. P oduc ion om o he
p oduce s esul ed in high mola ac i i ies o Cu-64 wi h alues >40 MBq/nmol. Fo mos p oduc ions he
AMA was conside ably lowe han he MA, e lec ing he in luence o o he me als han Coppe . The lowe
AMA and MA o p oduc ion o ARRONAX and PSI e lec he lowe ac i i ies p oduced in he espec i e
ba ches dec easing he limi o quan i ica ion. O e all, hese esul s indica e he expec ed high mola
ac i i ies eached o Cu-64 sui able o adiopha maceu ical p epa a ions.
Deli e able D4.2
16
Expe imen al de ails o he s udy can be ound in Annex 6.
Table 4. Summa y quali y da a o ele an pa ame e s o adiolabelling pe o mance – ou come o Cu-64 ILC s udy
Ins i u e
P oduc ion
Da e
AMA [MBq/nmol]
DOTA i a ion
MA
[MBq/nmol]
ICP
ESA
[MBq/nmol]
ICP
DTU
64Ni(p,n)64Cu
14/02/2022
1060
3225*
118**
PSI
64Ni(p,n)64Cu
10/10/2023
53
197
45
ARRONAX
64Ni(d,2n)64Cu
07/02/2024
78
72 (69)
48
NCBJ
63Cu(n,γ)64Cu
31/01/2024
0.012
Nd***
0.014
* de e mined om DTU ICP da a, Calcula ed om Cu 0.31nmol/GBq
** de e mined om DTU ICP da a, Calcula ed om Ni+Zn+Fe+Cu 8.47nmol/GBq
*** assumed ha only Cu-is p esen
n.d.: no de e mined
3.2.2.5 pH, S e ili y and endo oxins
Simila conside a ions as desc ibed o Tb-161 ha e o be aken in o conside a ion
3.2.2.6 Labelling
The label o a Cu-64 solu ion o adiolabelling should indica e:
 ha he solu ion is no o di ec adminis a ion o humans;
 he maximum olume ha can be used o he p epa a ion o a single pa ien dose;
 he concen a ion o hyd ochlo ic acid; in case i shipped in d y o m his has o be indica ed (including
addi ional in o ma ion on how o dissol e he p epa a ion)
 ha he solu ion is in ended o use in he p epa a ion o Cu-64-labelled adiopha maceu icals;
3.3 Ac inium-225
3.3.1 Quali y conside a ions in he p oduc ion o adiopha maceu icals using Ac inium-225
3.3.1.1 In oduc ion
Ac inium-225 has shown g ea p omise in a numbe o clinical applica ions (15), howe e no s anda disa ion
o ha monisa ion o p oduc ion and quali y pa ame e s has been achie ed so a . One eason is he a ie y
o p oposed p oduc ion ou es o Ac-225 (16). In 2018 he IAEA ini ia ed a Coo dina ed Resea ch P ojec on
Ac-225 o suppo hei membe s a es in he de elopmen o Ac-225 adionuclide and adiopha maceu ical
p oduc ion. A ecen Technical Documen om IAEA (17) p o ides echnical suppo on p oduc ion and
quali y con ol o Ac-225 adiopha maceu icals.
Wi hin PRISMAP, Ac-225 was p o ided by 2 p oduc ion ou es. The main ou e is Ac-225 om gene a o
p oduc ion ia Tho ium-229 decay. Al e na i ely, Ac-225 was p oduced by mass sepa a ion a e spalla ion
eac ion o Tho ium-232 using high-ene gy p o ons.
Deli e able D4.2
17
3.3.1.2 Example o a p ocess o Ac inium-225 adiopha maceu icals
Figu e 5. Manu ac u ing s a egy o Ac-225 om Th-232 mass sepa a ion p ocess ( om MEDICIS)
Figu e 5 desc ibes he p epa a ion o Ac-225 om Mass sepa a ion as pe o med by CERN a MEDICIS o
PRISMAP supply, a desc ip ion is ou lined below, mo e de ails can be ound in (18)
Ta ge p epa a ion: The a ge ma e ial sui able o iso ope mass sepa a ion mus adop speci ic chemical
and physical o ms, di e en om hose de eloped a cyclo on o nuclea eac o se ings. Fo adionuclides
whe e he a ge s mus be i adia ed a a eac o o cyclo on p io o (o line) mass sepa a ion, a p ocessing
s ep (e.g., chemical sepa a ion) is equi ed o in oduce he ma e ial in an iso ope mass sepa a ion
p oduc ion uni . This equi es eaching app op ia e physical s uc u es. In he case o ho ium-based a ge
ma e ials i adia ed a CERN applied o he p oduc ion o mass-sepa a ed 225Ac adionuclide samples, po ous
ma e ials and composi es mus be designed o be able o sus ain ex eme empe a u es o mo e han 2000
°C. This can ake he o m o po ous pelle s o ThC2+C2, ThO2 powde s, el s o ThO2 mic ome ic ib es.
I adia ion a CERN: The exploi a ion o high-ene gy pa icle beams o i adia e a ge s equi es
in as uc u es ha a e a ailable a la ge accele a o s and esea ch acili ies. The a ge i adia ion s ep
equi es sui able emo e anspo and handling sys ems, diagnos ics ools, exploi ing hick na u al a ge
ma e ials o se e al g ams in dedica ed i adia ion s a ions. The CERN PS Boos e , p o iding 1.4 GeV p o ons,
p oduces a la ge ange o eac ion channels in a ge s (made o a ious ma e ials depending on he nuclide
desi ed). As a esul , a as numbe o adionuclides a e p oduced in he hick a ge s ha , subsequen ly,
need o unde go a physical mass pu i ica ion s ep. Examples include i adia ing a ge s o 25-µm- hick oil
olls (300 g) used o e bium adioiso opes and Ba-128. When he mass sepa a ion s ep is pe o med du ing
he a ge i adia ion, he pu i ica ion s ep is called ISOL (Iso ope mass Sepa a ion OnLine), while i he
pu i ica ion occu s a e i adia ion di ec ly on he a ge , o a e a adiochemical pu i ica ion s ep, he
pu i ica ion is called o line mass sepa a ion o ba ch(-mode) iso ope mass sepa a ion.
T ans e o he a ge in he iso ope mass sepa a ion uni : The ans e o he a ge con aining he as
numbe o adionuclides p oceeds wi h ope a ion pe o med in sui able shielded nuclea labo a o ies, wi h
he exploi a ion o emo e handling sys ems and equipped wi h en ila ion and gas handling
decay/moni o ing sys ems, in labo a o ies se ing he mul iple esea ch communi ies. The a ge and ion
Deli e able D4.2
24

Deli e able D4.2
25
Annex 2: Le e o Membe s o he Eu opean Pa liamen ega ding he e ision o
he EU gene al pha maceu icals legisla ion
Dea MEP
The Eu opean Commission ecen ly pu o wa d a 'pha maceu ical package' o e ise he EU pha maceu ical
legisla ion; o os e inno a ion and o secu e pa ien access o medicines.
The PRISMAP-Eu opean Ne wo k o Medical Radionuclides conso ium would like o highligh i s impac on he u u e
de elopmen and clinical access o adiopha maceu icals based on inno a i e p oduc ion o no el adionuclides.
PRISMAP is a HORIZON 2020 unded p ojec whe e he main goal is o p o ide a sus ainable sou ce o new high pu i y
g ade medical adionuclides o nuclea medicine. In ol ing om he onse upcoming majo Eu opean in as uc u es,
PRISMAP p o ides a single-en y poin o access o eliable p oduc ion o medical adionuclides o esea che s g an ed
on an excellence selec ion basis. Cu en ly he main sou ce o adionuclides a e esea ch eac o s, wi h se e al o he
echnologies ha use cyclo ons, linea accele a o s and mass sepa a o s in use o unde de elopmen . The di e en
adionuclides and p oduc ion echnologies ely on highly specialised complex supply chains. In his p ocess he cu en
pha maceu ical egula o y amewo k o he scien i ic ansla ional p ocess om basic esea ch o clinical applica ion
mus o be conside ed. The e o e, PRISMAP suppo s he use communi y by allying a call o EU pha maceu ical
s anda disa ion and ha monisa ion in he use o no el adionuclides o adiopha maceu ical de elopmen
E e y yea , mo e han 9 million pa ien s in Eu ope bene i om he use o adiopha maceu icals in nuclea medicine;
o unique diagnos ic imaging p ocedu es (SPECT, PET, PET/MR) and speci ic ea men a ge ing he apies (wi h a
speci ic ocus on cance - mo e han 80% o all nuclea medicine he apies a e ela ed o cance ea men ), known as
adio he anos ics, o a “see i , ea i ” pa ien pe sonalised app oach, holding he p omise o ep esen a new pilla
o cance ca e. The adiopha maceu ical landscape has ad anced signi ican ly in he las 20 yea s wi h a di e se
numbe o adiopha maceu icals a ailable on he Eu opean ma ke and unde esea ch and de elopmen . In
pa icula , he de elopmen s in inno a i e adionuclide p oduc ion and a ailabili y o no el adionuclides, ini ia ed and
coo dina ed by he PRISMAP p ojec , which p o ides he basis o access o new diagnosis and ea men op ions o
pa ien s in need. These ad ances now need o be adequa ely suppo ed by a ailo ed egula o y amewo k in o de o
ensu e Eu ope’s leade ship posi ion in his ield.
PRISMAP he e o e, welcomes he Eu opean Commission's p oposal o a e ision, as well as he e o s and
commi men o he Eu opean Pa liamen , o ensu e ha he egula o y amewo k o medicinal p oduc s, including
adiopha maceu icals based on no el adionuclides, is no only adap ed o suppo he cu en p ac ice, bu also
os e s inno a ion and secu es pa ien access o he u u e.
To suppo his aim, PRISMAP p oposes o adap EC`s p oposal o a new di ec i e 2023/0132 (COD) and o amelio a e
i wi h he ollowing aspec s:
1. De ini ions (a icle 4) should e lec oday’s nuclea medicine and adiopha macy p ac ices. Upda ed
de ini ions (subs ance, adiopha maceu icals, ki , gene a o …) will lay he ounda ion o an upda ed egula o y
amewo k wi h adjus men s o unique aspec s o no el Radionuclides.
2. Cla i ica ion o ma ke ing au ho isa ion equi emen s o he use o no el adionuclides
3. Cla i ica ion o he ela ion o BSSD and Pha ma Di ec i e.
One may ind ha some poin s ha e al eady been add essed in he Eu opean pa liamen ENVI d a epo om
Oc obe 3 d 2023 (h ps://www.eu opa l.eu opa.eu/doceo/documen /ENVI-PR-753470_EN.pd ), o mo e de ails o
PRISMAP`s p oposed changes please e e o he a ached able.
The p oposed amelio a ed adap a ions will no only help o inc ease he le el o compliance among EU Membe S a es
bu will also suppo ha monisa ion ac oss Eu ope, while also ensu ing pa ien sa e y and pa ien access, by suppo ing
obus adionuclide and adiopha maceu ical supply o ad ancemen s in inno a ion and esea ch.
Deli e able D4.2
26
Annex 3: PRISMAP`s commen s o he Concep pape on he e ision o he
'Guideline on Radiopha maceu icals-Re ision 1` (Ex ac )
1. Gene al commen s on he Concep pape on he e ision o he Guideline on Radiopha maceu icals
S akeholde name
( o be epea ed in all ows)
Gene al commen
PRISMAP
PRISMAP e y much app ecia es he ini ia i e o e ise he cu en guideline on
adiopha maceu icals, especially aking in o accoun he emendous de elopmen s
in he ield o adiopha maceu icals and especially wi h he anos ics and he g ea
a ie y o no el adionuclides on he ho izon o hese applica ions.
PRISMAP
E en hough PRISMAP is mainly conce ned wi h inno a ion in ol ing no el medical
adionuclides, which a his s age will mainly be used in clinical ials, PRISMAP s ill
would like o add ess his guideline o he ollowing easons:
1.) I is expec ed ha many o he adionuclides now being add essed wi hin
he PRISMAP p ojec will ind hei way in o clinical de elopmen and some
in o ma ke ing au ho isa ion
2.) A lo o in es men in Eu ope bo h by he public (na ionally and EU) and he
indus y aims owa ds making no el p oduc ion ou es i o medical use,
e.g. in ol ing mass sepa a ion o high ene gy pa icle accele a o s
3.) E en hough in es iga ional use is no in i s scope, he “Guideline o
adiopha maceu ical” has been he only o icial EMA e e ence when i
comes o quali y o adiopha maceu icals, and he e o e ound widesp ead
conside a ion also in applica ions o in es iga ional use, esp. by egula o y
au ho i ies. In he e ision, ei he he scope o he guideline has o be mo e
p ecise o speci ically exclude in es iga ional applica ion o has o ake in o
accoun ha o in es iga ional use o he ules may apply (e.g. in ela ion
o he equi ed quali y amewo k, alida ion e c.)
PRISMAP
In iew o a ecen ITF b ie ing mee ing wi h EMA ep esen a i es PRISMAP has
engaged in discussions on he ollowing opics:
1.) Ma ke ing au ho isa ion equi emen s o no el adionuclides
2.) GMP equi emen s o p oduc ion o no el adionuclides: No el
de elopmen s
3.) Radionuclidic and Radiochemical impu i ies: In pa icula he ad en o
adionuclides wi h complex decay chains (e.g. Ac-225) o whe e he decay
p oduc is he “ac i e adionuclide (e.g. Pb-212 o Ba-
4.) A eliable and accu a e de e mina ion o he amoun o ( adioac i i y in a
adiopha maceu ical o a aceable na ional o in e na ional me ology
ins i u e.
PRISMAP
Di ec i e 2001/83, which o ms he basis o he “Guideline on
adiopha maceu icals” is cu en ly being e ised, a new p oposal has ecen ly been
published by he Commission. In eply o his new p oposal, main s akeholde s on
adiopha maceu icals including PRISMAP has p oposed e ision o de ini ions and
o he opics ela ed o adiopha maceu icals. In pa icula i has been sugges ed o
e ise he cu en de ini ions and especially he cu en legal meaning o
“ adionuclide p ecu so ”, meaning ha i will no be ea ed as a medicinal p oduc
as such. PRSMAP would like o s ess ha especially in he con ex o no el
adionuclides, hese should be seen as s a ing ma e ials. The de ini ion o
adionuclide p ecu so wi h i s equi emen o ma ke ing au ho isa ion is a ac o
slowing down inno a ion in he ield. This should also be e lec ed in he guideline
Deli e able D4.2
27
Ques ion 2. Speci ic commen s on ex
2.1. In oduc ion
Line numbe (s) o he ele an
ex (e.g. 20-23)
S akeholde name
( o be epea ed in all
ows)
Commen and a ionale
P oposed guidance ex
15-17
PRISMAP
We ag ee wi h he need o
e ision especially wi h espec
o no el de elopmen s o
adionuclide p oduc ion and
adiopha maceu ical
de elopmen
2.2 P oblem s a emen
Line numbe (s) o he
ele an ex (e.g. 20-
23)
S akeholde name
( o be epea ed in
all ows)
Commen and a ionale
P oposed guidance ex
33
PRISMAP
E en hough he concep o adionuclide
p ecu so s being handled in he same way
as medicinal p oduc s wi hin Di ec i e
2001/83, we belie e ha his concep
should be modi ied and ha adionuclides
should be seen as s a ing ma e ials in he
p ocess o adiopha maceu ical
p epa a ion, wi h app op ia e
conside a ions in e ms o he equi ed
quali y amewo k
Dele e “ adionuclide
p ecu so ”
46-47
PRISMAP
Po en ial e isions in he new di ec i e
should be conside ed
2.3 Discussion (on he p oblem s a emen )
Line
numbe (s)
o he
ele an
ex (e.g.
20-23)
S akeholde
name
( o be
epea ed in
all ows)
Commen and a ionale
P oposed guidance ex
59
PRISMAP
As ou lined abo e
adionuclides should be seen
as s a ing ma e ials
Radionuclide p ecu so s should be conside ed in module
3.2.S only
66
PRISMAP
Alignmen wi h de ini ions
and nomencla u e accep ed in
he scien i ic communi y
should be sough (e.g., mola
ac i i y, appa en mola
ac i i y, …)
Gi e e e ence o e.g.:
S a us o he ‘consensus nomencla u e ules in
adiopha maceu ical sciences’ ini ia i e - PMC (nih.go )
h ps://www.ncbi.nlm.nih.go /pmc/a icles/PMC10078979/
69
PRISMAP
No el p oduc ion ou es
should be conside ed o
adionuclides (e.g. inclusion o
mass sepa a ion echniques)
Deli e able D4.2
28
76
PRISMAP
Clea indica ions o
adionuclides as s a ing
ma e ials
79
PRISMAP
Conside no el adionuclides
wi h complex decay chains
and hei impac on
desc ip ion o adioanaly ical
p ocedu es
87
PRISMAP
E en hough gene al
h esholds a e no possible
due o he he e ogeneous
na u e o adionuclides and
adiopha maceu icals, usual
accep ed and o en applied
limi s should be men ioned
(e.g., 95% o adiochemical
pu i y and 99.9% o
adionuclidic pu i y)
92
PRISMAP
We e y much welcome hese
conside a ions, esp. in iew o
no el adionuclides being
de eloped and hei
challenges in app op ia e
me ology
2.4 Recommenda ion
Line numbe (s) o he ele an
ex (e.g., 20-23)
S akeholde name
( o be epea ed in all
ows)
Commen and
a ionale
P oposed guidance ex
102-104
PRISMAP
Conside no el
de elopmen s o
adionuclide
p oduc ion and
adionuclides wi h
complex decay
chains
Deli e able D4.2
29
Annex 4: S a emen PRISMAP Radionuclides and GMP-Annex 3 and EMA esponse
PRISMAP Conso ium – WP4 (Ha monisa ion & S anda disa ion)
PRISMAP - Backg ound, In oduc ion:
PRISMAP - The Eu opean medical adionuclide p og amme aims a p o iding eme ging and non-con en ional
adionuclides o scien is s ac oss di e en disciplines in biomedical esea ch.
The p og amme’s main goal is o p o ide a sus ainable sou ce o high-pu i y no el adionuclides owa ds po en ial
medical applica ion, in ol ing o hcoming majo Eu opean in as uc u es om he onse , as a single-en y poin o
all esea che s ac i e in his ield.
Figu e 1: PRISMAP b ings oge he a se o key la ge Eu opean, na ional and egional p oduc ion in as uc u es, chosen
speci ically o hei expe ise in he p oduc ion and dispa ch o non-con en ional adionuclides.
His o ically, he de elopmen has been limi ed by he di icul access o adionuclides no ye comme cially a ailable.
In pa icula , na ional bo de s o en hinde he ee exchange o goods. Wi h PRISMAP, we ede a e a Eu opean
conso ium o he key in ense neu on sou ces, iso ope mass sepa a ion acili ies and high-powe accele a o s and
cyclo ons, wi h leading biomedical and heal hca e esea ch ins i u es in he ac i e ansla ion o eme ging
adionuclides owa ds medical diagnosis and ea men ia p eclinical s udies (Fig 1).
PRISMAP o e s a single-en y poin o esea che s who a e seeking inno a i e adionuclides o high pu i y o medical
applica ions (Fig.2). Ou aim is o enable and accele a e ea ly-phase esea ch on adiopha maceu icals, a ge ed d ugs
o cance , he anos ics and pe sonalised medicine, hus, p o iding no el me hodologies o esea ch and
de elopmen o new e icien he apeu ic d ugs based on adionuclides ha a e no indus ially a ailable.

Deli e able D4.2
30
Figu e 2: PRISMAP Radionuclide po olio and example o speci ica ion
P oblem S a emen :
Exis ing egula ion (Di ec i e 2001/83/EC, De ini ions, A icle 1) includes he de ini ion o a adionuclide p ecu so as
«Any o he adionuclide p oduced o he adiolabelling o ano he subs ance p io o adminis a ion». This e y wide
de ini ion po en ially includes any adionuclide used in he p ocess o adiopha maceu ical p oduc ion/manu ac u e.
F om a p ac ical pe spec i e, his de ini ion seems o be based on he assump ion ha such a adionuclide p ecu so
(wi h a ma ke ing au ho isa ion) is combined wi h a (“cold”) ki (wi h ma ke ing au ho isa ion) in a simple p ocess o
yield he inal adiopha maceu ical, wi hou u he pu i ica ion and ull es ing o he inal p oduc by he p oduc ion
acili y (usually a Nuclea Medicine acili y). In such a case, he adionuclide p ecu so has o be handled by an
ex e nal p oduce equi alen o a D ug P oduc and, he e o e, GMP Pa I becomes applicable. Fo he p oduc ion o
adionuclides, GMP Annex 3 de ines ha “Reac o /Cyclo on P oduc ion” can be ou side GMP, GMP s a s wi h he
chemical syn hesis o he “ adioac i e p ecu so ” and “Pu i ica ion s eps (see Fig.3). Howe e , his igu e does no
ollow he API/d ug p oduc a ionale ha is ollowed in all GMP guidelines. Fu he mo e, i does no guide o
p ocesses ha a e di ided o e se e al si es.
Figu e 3. Ex ac om GMP Annex 3, desc ibing whe e GMP is applicable in a p ocess
In p inciple, howe e , i he adionuclide is in oduced in o a manu ac u ing p ocess in a acili y ha ul ils he
equi ed quali y amewo k (GMP), usually wi hin a manu ac u ing au ho isa ion o his acili y, he
adiopha maceu ical can be conside ed as an API s a ing ma e ial and GMP pa II should be applicable. This, in
p inciple, allows one o use a adionuclide ha is no p epa ed acco ding o GMP (unless i is decla ed o be s e ile).
This conside a ion o he adionuclide as a s a ing ma e ial seems o be in place in many indus ially manu ac u ed
adiopha maceu icals bu seems no o be ully unde s ood in he case o small-scale p epa a ion in hospi als and
heal h ca e es ablishmen s, also wi hin ea ly phase de elopmen s and clinical ials. This pa ly seems o come om
he cu en wo ding in Annex 3, which s a es:
Deli e able D4.2
31
 This annex is also applicable o adiopha maceu icals used in clinical ials.
 ha i is applicable o “Radioac i e P ecu so s o adiopha maceu ical p oduc ion” (in con as o he di ec i e,
which only de ines “Radionuclide P ecu so s”)
In a ecen mee ing wi h EMA and ep esen a i es om egula o y agencies, i became clea ha GMP equi emen s
a e, in p inciple, no applicable o In es iga ional Medicinal P oduc s (IMPs) p epa ed wi h such adionuclides, and
ha no GMP equi emen o he adionuclide in ques ion can be de i ed om he cu en guideline o he
p epa a ion o any adiopha maceu ical o a clinical ial. Ne e heless, e en hough GMP compliance o he
adionuclide as s a ing ma e ial may no be demanded om he applican o a clinical ial, i has become e y
di icul o p oduce s o such adionuclides o p o ide hem as s a ing ma e ials wi hou ul illing GMP equi emen s.
I appea s ha some s akeholde s (including some compe en au ho i ies) do no unde s and ha such a adionuclide
can be conside ed as a s a ing ma e ial and no as a adionuclide ( adioac i e?) p ecu so .
Fo PRISMAP, his poses pa icula p oblems. Wi h he in oduc ion o no el p oduc ion me hods (see example below)
i becomes mo e di icul o di e en ia e be ween p ocesses ha can be de ined as “Cyclo on/Reac o P oduc ion”
and “Chemical syn hesis” o “pu i ica ion”. In pa icula , he in oduc ion o mass-sepa a ion echniques equi es
physical p ocesses, chemical p ocesses, pu i ica ions e c. wi hin acili ies ha canno comply wi h he equi emen s o
GMP. I GMP is equi ed o such a p oduce o p o ide a use in hospi als o PET cen es wi h a no el adionuclide o
he p epa a ion o a adiopha maceu ical (usually wi hin a clinical ial), his will make ce ain inno a i e diagnos ic
and he apeu ic app oaches impossible.
P ac ical example:
The no el p oduc ion me hods unde lying he supply chain o PRISMAP, as in oduced in he i s pa o he
documen , equi es a numbe o sequen ial s eps ha ake place in mul idisciplina y esea ch cen es. We p o ide
he e a conc e e example wi h a b ie in oduc ion o he ela ed sequen ial s eps (Fig.4).
Figu e 4: Scheme o sequen ial s eps o a adionuclide p oduced ia mass sepa a ion
Ta ge p epa a ion
The a ge ma e ial sui able o iso ope mass sepa a ion mus adop speci ic chemical and physical o ms, di e en
om hose de eloped a cyclo on o nuclea eac o se ings. Fo adionuclides whe e he a ge s mus be i adia ed
a a eac o o cyclo on p io o (o line) mass sepa a ion, a p ocessing s ep (e.g. chemical sepa a ion) is equi ed o
in oduce he ma e ial in an iso ope mass sepa a ion p oduc ion uni . This equi es eaching app op ia e physical
s uc u es. In he case o ho ium-based a ge ma e ials i adia ed a CERN applied o he p oduc ion o mass-
sepa a ed 225Ac adionuclide samples, po ous ma e ials and composi es mus be designed o be able o sus ain
ex eme empe a u es o mo e han 2000 °C.
I adia ion a CERN
The exploi a ion o high-ene gy pa icle beams o i adia e a ge s equi es in as uc u es ha a e a ailable a la ge
accele a o and esea ch acili ies. The a ge i adia ion s ep equi es sui able emo e anspo and handling
sys ems, diagnos ics ools, exploi ing hick na u al a ge ma e ials o se e al g ams in dedica ed i adia ion s a ions.
The CERN PS Boos e , p o iding 1.4 GeV p o ons, p oduces a la ge ange o eac ion channels in a ge s (made o
a ious ma e ials depending on he nuclide desi ed). As a esul , a as numbe o adionuclides a e p oduced in he
hick a ge s ha , subsequen ly, need o unde go a physical mass pu i ica ion s ep. Examples include i adia ing
a ge s o 25-µm- hick oil olls (300 g) used o e bium adioiso opes and Ba-128.
T ans e o he a ge in he iso ope mass sepa a ion uni
The ans e o he a ge con aining he as numbe o adionuclides p oceeds wi h ope a ion pe o med in sui able
shielded nuclea labo a o ies, wi h he exploi a ion o emo e handling sys ems, in labo a o ies se ing he mul iple
esea ch communi ies. The a ge and ion sou ce uni used o iso ope mass sepa a ion can be ans e ed o he
dedica ed iso ope sepa a ion acili y, and is pe o med ully emo ely a MEDICIS.
Deli e able D4.2
32
Iso ope Mass Sepa a ion
Iso ope mass sepa a ion is a physical adionuclide pu i ica ion p ocess. I p oceeds on specialised accele a o acili ies
combining a ge uni handling, iso ope elease con ol, mos o en by high- empe a u e e apo a ion, iso ope
ionisa ion in a compac ion sou ce, and mass sepa a ion in a beam line o implan a ion in a collec o sys em. I
sepa a es a ac ion o he adionuclides om he a ge ha we e p oduced du ing he i adia ion. The online iso ope
mass sepa a ion p oceeds while he a ge is i adia ed. This can be pe o med a a ew acili ies such as ISOLDE a
CERN, while o line iso ope mass sepa a ion akes place a e he i adia ion and ans e o he a ge o he iso ope
mass sepa a o .
Collec ion
The adionuclides a e collec ed du ing he iso ope mass sepa a ion p ocess as ion beams by implan a ion in o small
oils a a beam ene gy o 1 o 100 keV. The oil ma e ial can be hin me al o sal backing on gold, sal c ys als,
polyme oils and ozen bu e solu ions. MEDICIS collec ions ypically p oceed wi h gold oil backed wi h zinc o
aluminum laye s, and al e na i ely wi h aluminum oils wi h NaCl sal backing. This s pe o med in a dedica ed
collec ion chambe unde acuum wi h ion implan a ion moni o ing sys ems.
Radiochemis y
T ans e o he oil o a adiochemical labo a o y o adionuclide dissolu ion and u he chemical pu i ica ion, o
p epa e he adionuclide in an app op ia e chemical o m is necessa y.
P oposal o Annex 3 amendmen s:
 Cla i ica ion o he e m adioac i e p ecu so s. adionuclide p ecu so : I should be clea ly s a ed ha Annex
3 only ully applies o adionuclides when hey ul il he c i e ia o he de ini ion in Di ec i e 2001/83 o a
adionuclide p ecu so , i.e., when applied o a d ug p oduc ha is p epa ed wi hin a ma ke ing au ho isa ion. I
should be pa icula ly cla i ied ha adionuclides (bu also po en ially gene a o s) ha a e p o ided as s a ing
ma e ial should be iewed wi hin GMP Pa II (o he ela ed documen o Clinical T ial use).
 Upda ing Annex 3 wi h guidance o cla i y applicabili y o GMP pa I, II o GMP o IMPs (“De ailed Commission
guidelines on good manu ac u ing p ac ice o in es iga ional medicinal p oduc s o human use, pu suan o he
second subpa ag aph o A icle 63(1) o Regula ion (EU) No 536/2014”) o cla i y con lic ing s a emen s. In
pa icula he s a emen “ his annex is also applicable o adiopha maceu icals used in clinical ials” should be
emo ed as i is misleading and indica es ha he same ules apply o adiopha maceu icals used as IMPs as o
hose wi h MA, which is in con adic ion o he Clinical T ials Regula ion and ela ed egula o y ex s.
 The able ha di e en ia es non-GMP only o “ eac o /cyclo on p oduc ion” should be modi ied in ha also
chemical and physical p ocesses o isola e adionuclides (e.g., o mass sepa a ion) should be exemp om
GMP.
Response om he GMDP IWG on he PRISMAP P oposal o Annex 3 amendmen
Deli e able D4.2
33
Deli e able D4.2
40
Annex 6: Repo om he In e labo a o y Compa ison s udy (ILC) o 64Cu
1. DTU Ba ch
 CoA supplied by DTU
P oduc ion labo a o y: He esy Labo a o y (Danma k) Solu ion: ≈ 1 mL in HCl (0.1 M)
Ac i i y/calib a ion ime: 6,77 GBq (14 FEB 2022 16:00)
 E ec i e speci ic ac i i y de e mina ion by DOTA i a ion
Ope a o : MB
Si e: ARRONAX
Raw ma e ials:
Ammonium ace a e – 99.999% T ace me al basis (Sigma – Re : 372331 – Ba ch : MKBW2885V) Chelex 100
sodium o m 50-100 mesh (Sigma – Re C7901 – Ba ch: 031M0175V)
DOTA, 6H2O (Mac ocyclics – Re :M-140 – Ba ch :M14010003-100127)
Solu ion p epa a ion (15 FEB 2022)
Ammonium ace a e 0.1M
Ammonium ace a e : 387.3 mg (ARRONAX balance e e ence # 162) Ammonium ace a e molecula weigh =
77.08 g/mol
Wa e ( om Millipo e sys em): 50 mL Ammonium ace a e concen a ion = 0.1 M
(addi ion o a spa ula ip o chelex esin in he inal solu ion)
DOTA 50 𝝁M
DOTA: 19.7 mg (ARRONAX balance e e ence # 162) DOTA molecula weigh = 512.5 g/mol
Ammonium ace a e 0.1 M: 3.845 mL (ARRONAX mic opipe e e ence # T1763 ZCE2)
DOTA concen a ion = 1.10-2 M
1/50 h Dilu ion o DOTA solu ion:
DOTA (0.01M): 100 𝜇L
Ammonium ace a e 0.1 M: 4.9 mL DOTA concen a ion = 2.10-4 M
1/200 h Dilu ion o DOTA solu ion:
DOTA (2.10-4M): 1 mL
Ammonium ace a e 0.1 M: 3 mL DOTA concen a ion = 50 𝜇M
TLC mobile phase (H20/MeOH 1:1 + NH4CH3COO 5%)
Wa e ( om Millipo e sys em): 23.75 mL
Me hanol: 23.75 mL

Deli e able D4.2
41
Ammonium ace a e 0.1 M: 2.5 mL
DOTA Radiolabelling (15 FEB 2022 – 16h37)
Vial
numbe
NH4CH3COO 0.1M
(𝜇L)
DOTA 50 𝜇𝑀 in
NH4CH3COO 0.1M (𝜇L)
Amoun o
DOTA (nmol)
[64Cu]-CuCl2
(𝜇L)
TLC
e
1
200
0
0
20
L4
2
198
2
0.1
20
L3
3
180
20
1
20
L2
4
100
100
5
20
L1
Radiolabelling condi ion: 90°C – 10 min.
Resul s
Vial numbe
Amoun o DOTA
(nmol)
TLC e
% ee 64Cu
% DOTA-64Cu
1
0
L4
100
0
2
0.1
L3
21.8
78.2
3
1
L2
0.1
99.9
4
5
L1
0
100
Conclusion
nmol o DOTA allows 78.2 % complexa ion yield o 64Cu.
In his condi ion, we could es ima e he amoun o compe i i e me al (mainly coppe and zinc and pa ially
i on) o 0.128 nmol in 20 𝜇L o 64Cu sample (i.e. 6.39 nmol/mL).
Consequen ly, he calcula e e ec i e speci ic ac i i y (ESA) is: 1.06 GBq/nmol.
Fo compa ison wi h ICP da a p o ided by He esy Labo a o y (VA = 6.77 GBq/mL @ TC): Ni: 0.41 𝜇g/GBq =
6.99 nmol/GBq = 47.29 nmol/mL
 Zn: 0.03 𝜇g/GBq = 0.46 nmol/GBq = 3.11 nmol/mL
 Fe: 0.04 𝜇g/GBq = 0.71 nmol/GBq = 4.85 nmol/mL
 Cu: 0.02 𝜇g/GBq = 0.31 nmol/GBq = 2.13 nmol/mL Cu + Zn = 5.24 nmol/mL
2. PSI Ba ch
 CoA supplied by PSI
Chemical o m: [64Cu]CuCl2
P oduc ion labo a o y: PSI
Solu ion: ≈ 0.720 mL in HCl (0.001 M)
Ac i i y/calib a ion ime: 1,96 GBq (10 OCT 2023
13h46)
 E ec i e speci ic ac i i y de e mina ion by DOTA i a ion
Ope a o : MB Si e: ARRONAX
Raw ma e ials:
Ammonium ace a e – 99.999% T ace me al basis (Sigma – Re : A7330-5006 – Ba ch : STBB9337V) Chelex 100
sodium o m 50-100 mesh (Sigma – Re C7901 – Ba ch: 031M0175V)
DOTA (Ald ich – Re :86734-50MG – Ba ch: BCCD5753)
Solu ion p epa a ion (06 OCT 2023)
Deli e able D4.2
42
Ammonium ace a e 0.1M
Ammonium ace a e: 387.3 mg (ARRONAX balance e e ence #
162) Ammonium ace a e molecula weigh = 77.08 g/mol
Wa e ( om Millipo e sys em): 50 mL
Ammonium ace a e concen a ion =
0.1 M
(addi ion o a spa ula ip o chelex esin in he inal solu ion)
DOTA 50 𝝁M
DOTA: 19.7 mg (ARRONAX balance e e ence # 162)
DOTA molecula weigh = 512.5 g/mol
Ammonium ace a e 0.1 M: 3.845 mL (ARRONAX mic opipe e e ence # T1763 ZCE2)
DOTA concen a ion = 1.10-2 M
1/50 h Dilu ion o DOTA solu ion:
DOTA (0.01M): 100 𝜇L
Ammonium ace a e 0.1 M:
4.9 mL DOTA concen a ion =
2.10-4 M
1/200 h Dilu ion o DOTA solu ion:
DOTA (2.10-4M): 1 mL
Ammonium ace a e 0.1 M: 3
mL DOTA concen a ion = 50
𝜇M
TLC mobile phase (H20/MeOH 1:1 + NH4CH3COO 5%) / TLC Pla e: Silica
Wa e ( om Millipo e sys em): 23.75
mL Me hanol: 23.75 mL
Ammonium ace a e 0.1 M: 2.5 mL
DOTA Radiolabelling
Vial
numbe
NH4CH3COO 0.1M
(𝜇L)
DOTA 50 𝜇𝑀 in
NH4CH3COO 0.1M (𝜇L)
Amoun o
DOTA (nmol)
[64Cu]-CuCl2
(𝜇L)
TLC
e
1
200
0
0
20
L4
2
198
2
0.1
20
L3
3
180
20
1
20
L2
4
100
100
5
20
L1
Radiolabelling condi ions: 90°C – 10 min.
Resul s
Vial numbe
Amoun o DOTA
(nmol)
TLC e
% ee 64Cu
% DOTA-64Cu
1
0
L4
100
0
2
0.1
L3
100
0
3
1
L2
1,8
98,2
4
5
L1
0,4
99,6
Conclusion
1.0 nmol o DOTA allows 98.2 % complexa ion yield o 64Cu
Deli e able D4.2
43
In his condi ion, we could es ima e he amoun o compe i i e me al (mainly coppe and zinc
and pa ially i on) o:
1.02 nmol in 20𝜇L o 64Cu sample (i.e. 50.92 nmol/mL).
Consequen ly, he calcula e concen a ion o coppe compe i i e me al is 50.92
nmol/mL. The ac i i y concen a ion @TC is 2.72 GBq/mL
Consequen ly, he calcula e e ec i e speci ic ac i i y (ESA) is comp ised be ween: 0.053
GBq/nmol @TC.
 Speci ic ac i i y de e mina ion by ICP-OES Analysis
Si e: ARRONAX
Raw ma e ials
Ul a-pu e ni ic acid 67-70% (SCP
Science) Milli Q wa e (18.2MΩ.cm)
Resul s
The olume ac i i y was de e mined using ou HPGe de ec o . An aliquo o he sample was
dilu ed o ob ain a dead ime lowe as 10% in ou geome y coun ing condi ions. The calib a ion
ime is de ined as 10 OCT 2023 01:46 PM o be in acco dance wi h he deli e ed ac i i y.
A ol = 2680 ± 180 MBq/mL
The Cu-64 ba ch was dilu ed by 50 o pe o m ICP-OES analysis. The esul s a e p esen ed in he able
below:
Elemen
Concen a ion (ppm)
Co
<0.06
Cu
0.87±0.01
Fe
0.040±0.001
Ni
<0.03
Zn
2.98±0.04
Conside ing hese concen a ions and he olume ac i i y o he Cu-64 ba ch, we calcula ed he speci ic
ac i i y o 64Cu (197±14 MBq/nmol) and he e ec i e speci ic ac i i y (45±3 MBq/nmol).
Conclusion
The esul s ob ained wi h ICP-OES analysis a e in good ag eemen wi h he esul s ob ained om DOTA
i a ion (53 MBq/nmol). We can hus be con iden conce ning he esul s.
3. Pola om Ba ch
 CoA supplied by Pola om
Chemical o m: [64Cu]-CuCl2 om na Cu(n,γ)64Cu p oduc ion ou e
P oduc ion labo a o y: Pola om
Solu ion: ≈ 4,998 mL in HCl
Ac i i y/calib a ion ime: 2 GBq ± 10% (31 JAN 2024 12h00)
Radioac i e concen a ion : 400.190 MBq/mL
Speci ic ac i i y: 234.40 MBq/mg Cu a
CT? Radionuclidic pu i y: >99.5%
Deli e able D4.2
44
 E ec i e speci ic ac i i y de e mina ion by DOTA i a ion
Si e: ARRONAX
Raw ma e ials
Ammonium ace a e – 99.999% T ace me al basis (Sigma – Re : A7330-5006 – Ba ch :
STBB9337V) Chelex 100 sodium o m 50-100 mesh (Sigma – Re C7901 – Ba ch: 031M0175V)
DOTA (Ald ich – Re :86734-50MG – Ba ch :BCCD5753)
Solu ion p epa a ion
sodium ace a e 0.1M
Sodium ace a e: 683.6 mg (ARRONAX balance e e ence #
162) sodium ace a e molecula weigh = 136.08 g/mol
Wa e ( om Millipo e sys em): 50 mL
Ammonium ace a e concen a ion = 0.1
M
(addi ion o a spa ula ip o chelex esin in he inal solu ion)
DOTA 8900 𝝁M
DOTA: 13.68 mg (ARRONAX balance e e ence #
162) DOTA molecula weigh = 512.5 g/mol
Sodium ace a e 0.1 M : 3 mL
DOTA concen a ion = 8.9
mM
TLC mobile phase (H20/MeOH 1:1 + NH4CH3COO 5%) / TLC Pla e: Silica
Wa e ( om Millipo e sys em): 20 mL
Me hanol: 20 mL
Ammonium ace a e: 2.0244 g
DOTA Radiolabelling
Essai
Sodium ace a e
0.1M (µL)
V DOTA (µL)
DOTA (nmol)
Cu-64 (µL)
n me al (nmol)
% Cu-DOTA
1
100
0
0.00
20
537.30
0.4
2
100
10
8.90
20
537.30
1.6
3
100
20
17.80
20
537.30
3.3
4
100
30
26.69
20
537.30
4.3
5
100
45
40.04
20
537.30
5.9
6
100
60
53.39
20
537.30
8.2
7
100
90
80.08
20
537.30
12.8
8
100
120
106.77
20
537.30
15
Deli e able D4.2
45
Figu e 1: adiolabelling o 64Cu wi h DOTA
Conclusion
F om igu e 1, we can de e mine he quan i y o me als in he inal solu ion. And we can deduce he appa en
speci ic ac i i y o he Cu-64 ba ch.
A spe appa en = 0.012±0.002 MBq/nmol
Conside ing ha only coppe is signi ican ly p esen in he inal solu ion we deduce :
A spe = 185±30 MBq/mg
 Speci ic ac i i y de e mina ion by ICP-OES Analysis
Si e: ARRONAX
Raw ma e ials:
Ul a-pu e ni ic acid 67-70% (SCP
Science) Miili Q wa e (18.2MΩ.cm)
Resul s
The olume ac i i y was de e mined using ou HPGe de ec o . An aliquo o he sample was
coun ed in ou geome y coun ing condi ions. The calib a ion ime is de ined as 31 JAN 2024 a
12:00 AM o be in acco dance wi h he deli e ed ac i i y.
A ol = 392 ± 25 MBq/mL
No adionuclide impu i ies we e de e mined. The Co-57/Cu-64 and Co-58/Cu-64 a ios a e
espec i ely unde 1.9E-08 and 4.3E-09.
The Cu-64 ba ch was dilu ed by 20000 o pe o m ICP-OES analysis. The esul s a e p esen ed in
he able below:

Deli e able D4.2
46
Elemen s
Concen a ion (ppm)
Co
<10
Cu
1740±92
Fe
<10
Ni
<10
Zn
60±10
Conside ing hese concen a ions and he olume ac i i y o he Cu-64 ba ch, we calcula ed he
speci ic ac i i y o Cu-64 : 225±19 MBq/mg o 0.014±0.001 MBq/nmol
Conclusion
The esul s ob ained wi h ICP-OES analysis a e in good ag eemen wi h he esul s supplied by Pola om
(234.4 mBq/mg). We can hus be con iden conce ning he esul s.
4. ARRONAX Ba ch (Cu64_240207)
 CoA supplied by ARRONAX
Chemical o m: [64Cu]CuCl2 om 64Ni(d,2n)64Cu p oduc ion ou e P oduc ion labo a o y: GIP ARRONAX
Radioac i e concen a ion : 2550±120 MBq/mL a CT (07 FEV 2024 08:00)
Speci ic ac i i y: 72±6 MBq/nmol Cu a CT
Appa en speci ic ac i i y: 48.4±3.1 MBq/nmol a CT
Radionuclidic pu i y: >99.97%
 Speci ic ac i i y de e mina ion by ICP-OES Analysis
Si e: ARRONAX
Raw ma e ials:
Ul a pu e ni ic acid 67-70% (SCP
Science) Miili Q wa e (18.2MΩ.cm)
Resul s
The olume ac i i y was de e mined using ou HPGe de ec o . An aliquo o he sample was
coun ed in ou geome y coun ing condi ions. The calib a ion ime is de ined as 07 FEV 2024 a
08:00 AM. The dilu ion ac o used o pe o m analysis is equal o 500.
A ol = 2550 ± 120 MBq/mL
No adionuclide impu i ies we e de e mined. The Co-57/Cu-64 and Co-58/Cu-64 a ios a e
espec i ely unde 2.3E-04 and 4.4E-05.
The Cu-64 ba ch was dilu ed by 500 o pe o m ICP-OES analysis. The esul s a e p esen ed in he
able below:
Elemen s
Concen a ion (ppm)
Co
<0.39
Cu
2.25±0.14
Fe
<0.18
Ni
<0.30
Zn
1.127±0.038
Deli e able D4.2
47
Conside ing hese concen a ions and he olume ac i i y o he Cu-64 ba ch, we calcula ed he speci ic
ac i i y o Cu-64: 1133± 78 GBq/mg o 72±5 MBq/nmol
The appa en speci ic ac i i y is equal o 755±52 GBq/mg o 48±3 MBq/nmol
 E ec i e speci ic ac i i y de e mina ion by DOTA i a ion
Si e: ARRONAX
Raw ma e ial
Ammonium ace a e – 99.999% T ace me al basis (Sigma – Re : A7330-5006 – Ba ch : STBB9337V)
Chelex 100 sodium o m 50-100 mesh (Sigma – Re C7901 – Ba ch: 031M0175V)
DOTA (Ald ich – Re :86734-50MG – Ba ch :BCCD5753)
Solu ion p epa a ion
sodium ace a e 0.1M
Sodium ace a e: 683.6 mg (ARRONAX balance e e ence # 162)
sodium ace a e molecula weigh = 136.08 g/mol
Wa e ( om Millipo e sys em): 50 mL
Ammonium ace a e concen a ion =
0.1 M
(addi ion o a spa ula ip o chelex esin in he inal solu ion)
DOTA 8900 𝝁M
DOTA: 13.68 mg (ARRONAX balance e e ence # 162) DOTA molecula weigh = 512.5 g/mol
Sodium ace a e 0.1 M : 3 mL
DOTA concen a ion = 8.9
mM
DOTA 25.06 𝝁M
0.025 mL o DOTA 8900 µM solu ion + 8.85mL o sodium ace a e solu ion
TLC mobile phase (H20/MeOH 1:1 + NH4CH3COO 5%) / TLC Pla e: Silica
Wa e ( om Millipo e sys em): 20 mL
Me hanol: 20mL
Ammonium ace a e: 2.0188 g
DOTA Radiolabeling
Essai
Sodium ace a e 0.1M
(µL)
V DOTA (µL)
DOTA (nmol)
Cu-64 (µL)
n me al (nmol)
% Cu-DOTA
1
100
0
0.00
20
0.31
0.4
2
100
10
0.25
20
0.31
38.6
3
100
20
0.50
20
0.31
76.7
4
100
30
0.75
20
0.31
98.2
5
100
45
1.13
20
0.31
99
6
100
60
1.50
20
0.31
98.6
7
100
90
2.26
20
0.31
98.2
8
100
120
3.01
20
0.31
98
Deli e able D4.2
48
Figu e 2: adiolabelling o 64Cu wi h DOTA (ARRONAX ba ch)
Conclusion
F om igu e 2, we can de e mine he quan i y o me als in he inal solu ion. And we can deduce he appa en
speci ic ac i i y o he 64Cu ba ch.
A spe appa en = 78±4 MBq/nmol
Conside ing ha only coppe is signi ican ly p esen in he inal solu ion we deduce :
A spe = 1230±58 GBq/mg
As ega d o DOTA i a ion esul s which seems o conclude ha only coppe is p esen in he inal solu ion,
a new ICP-OES analysis was pe o med wi h weake dilu ion o minimize he unce ain ies. The esul s a e
p esen ed below:
Elemen s
Concen a ion (ppm)
Co
<0.39
Cu
2.36±0.14
Fe
<0.12
Ni
<0.09
Zn
<0.09
These esul s con i m he DOTA i a ion esul s. No signi ican me al impu i ies a e p esen in he inal
solu ion. The speci ic ac i i ies om hese new esul s can be calcula ed:
A spe = 69±5 MBq/nmol
Conside ing ha only coppe is signi ican ly p esen in he inal solu ion we deduce:
A spe = 1082±74 GBq/mg
Conclusion
The impo an dilu ion ac o used o ICP-analysis (wi h ega d o adiosa e y conside a ions) can be
a sou ce o unce ain ies o some me als de e mina ion (Zn o example).