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Radiation protection and radiation safety in production and delivery of PET radiopharmaceuticals
Mikael Jensen,
Professor of Applied Nuclear Physics,
The Hevesy Laboratory DTU-Nutech (“RISØ”)
Roskilde
Denmark
DTU Nutech, Technical University of Denmark
Reason to listen: I made my first radiopharmaceutical in 1977 (F-18 NaF !)
I have been QP for 15 years..
DTU Nutech, Technical University of Denmark
5.5 MeV protons 1938
I did 100 mCi F-18 F- for bone scans on this machine 40 years ago
…But I am trained as a nuclear physicist….
DTU Nutech, Technical University of Denmark
Used many cyclotronsfor PET !
DTU Nutech, Technical University of Denmark
I am still making PET radiopharmaceuticals…. and developing new cyclotrons
5 29 September
2017
DTU Nutech, Technical University of Denmark 6
PET has evolved from a research
tool
” push from national labs…”
DTU Nutech, Technical University of Denmark
… into a widespread clinical modality…
Through modern whole-body
PET-CT
.. This example F-18 FDG
DTU Nutech, Technical University of Denmark
PET is an now important tool for oncology
Remission
Before Chemotherapy
After Chemotherapy
Molecular imaging of tumor metabolism and apoptosis U Haberkorn, A Markert, W Mier, V Askoxylakis and A Altmann Oncogene (2011) 30, 4141–4151
[18F]FDG
DTU Nutech, Technical University of Denmark
O-15 water +CTRb-82
CARDIOLOGY: The problem of the myocardium perfusion tracer
O-15 ?N-13 ?F-18 ?Rb-82 ?Cu-62 ?…
DTU Nutech, Technical University of Denmark
C-11 CDSAB
But why not PET and Psychiatry………I mean clinical !
A worthy goal !
Somebody has to make the gunpowder for all this firework
…. and it is not a ”zero dose operation”..
DTU Nutech, Technical University of Denmark
THE RADIATION SAFETY ASPECTS
What you can expect from this talk :• Not many legislative details.
• Not much on rules, regulations, work practices, … all already said, also in this meeting!
• We can all play safe , … and by the book.
But I will try to take the ´Devils Role,
and try to break
the “box-thinking”
12 29 September
2017
DTU Nutech, Technical University of Denmark
What I will probably talk about
• Cyclotron performance and cyclotron shielding
• Hotcells and clean rooms
• Synthesis boxes and dispensers
• Shielding and lead pots
• Gaseous waste,stacks and stack monitors
• Radioactive waste water
• Dose distribution and patient injections
• Beta dose, fingers, skin, eye
• ALARA
• Optimisation
• Instruments
• Economics and the global scale
• Philosophy and sustainability
13 29 September
2017
DTU Nutech, Technical University of Denmark
Examples of hig-end PET cyclotrons –tools of the trade
14
IBA Kiube
GE PETtrace
Both available as self-shielded
DTU Nutech, Technical University of Denmark
From target to patient- turnkey and plug and play- what are we missing here ?
DTU Nutech, Technical University of Denmark
Turnkey ?
16 29 September
2017
DTU Nutech, Technical University of Denmark
Inherently safe ?
17 29 September
2017
DTU Nutech, Technical University of Denmark
Nothing is simple, and nothing is safe without the staff
18 29 September
2017
DTU Nutech, Technical University of Denmark
How we trained and developed…
19 29 September
2017
DTU Nutech, Technical University of Denmark
”Automated” Cu-64 production
Do we still have a problem?
DTU Nutech, Technical University of Denmark
PETtracer production is not a zero dose operation ! And not a zero risk operation.
• it has many unusual pitfalls and dangers
• Cyclotron and targets can deliver hundreds of GBq in most unexpected places
• Gamma dose at 50 cm distance from 100 GBq is over 1 mSv/min.
• Glass vials or tubing may break, and suddenly the activity is outside the shield
• Systems may stop working in the middle of activity handling
• Our production tools for most tracers are not mature
21 29 September
2017
DTU Nutech, Technical University of Denmark
Are we protected by our dosimeters ?
22 29 September
2017
DTU Nutech, Technical University of Denmark
Listen !
23 29 September
2017
DTU Nutech, Technical University of Denmark
We can measure the gammas, and the neutrons
24 29 September
2017
But what about theBeta radiation ?
Probably best to calculate..But how ?
VARSKIN ( US ! )
Depends on isotope !
DTU Nutech, Technical University of Denmark
Conflicting regulations..
25 29 September
2017
DTU Nutech, Technical University of Denmark
What kind of surface contamination is important ?
F-18 ≠ I-124
Theranostic ”pairs”leads us towardstherapeutic isotopes
26 29 September
2017
DTU Nutech, Technical University of Denmark
Dispensing – ”Open” or ”Closed” ?
27 29 September
2017
Automatic ? By robot ?
DTU Nutech, Technical University of Denmark
Isolator technologynot alwaysmade forhumans
28 29 September
2017
29
Despite being mature and commercial technology , PET ”tracer” production is changing
• Tabletop
• Dose on demand
• N-13, O-15, Ga-68 ”generators”
• Tc-99m cyclotrons
• Radiometal cyclotrons
• Scale of operation
• Staffing
• Regulation
• Money
DTU Nutech, Technical University of Denmark
Ga-68 DOTA TOC (2)
F-18 FDG
Patient with small cellLung carcinoma
(Maecke et al JNM 46 (2005)
DTU Nutech, Technical University of Denmark
64Cu-DOTATATE
Pfiefer et al. J Nucl Med. 2012 Aug;53(8):1207-15
64Cu
• Clear delineation of the metastatic disease
• Very specific targeting• Notice the brain
Ga-68 version also good, but our clinicians prefer Cu-64. Why ?
DTU Nutech, Technical University of Denmark
Can we make enough Ga-68 ?
Can we do 7 million procedures per year ?( > 20.000 generators full time service)
DTU Nutech, Technical University of Denmark
The “Moly” situation:
33
1957
1957
1961
1961 1964
All Mo-99 made inResearchReactors
Build and operated by public money
DTU Nutech, Technical University of Denmark
Not many reactors are needed
…. but there will be a reactor deficit unless policies and economics changes…
34
Bye, bye cheap neutrons and plentiful fission products
DTU Nutech, Technical University of Denmark
We know how to make new reactors,and we know how to make Mo-99 from LEU!
35
But who’s going to pay for the next generation of reactors and separation facilities ?
What’s the price and construction time for a new set of research reactors ?
What’s the price of waste management and facility decommissioning ?
…it is not economically sustainable….
DTU Nutech, Technical University of Denmark
The development in SPECT-CT and PET-CT
36
The hardware in a BGO based low end PET system is not necessarily more expensive than a SPECT-CT system
Tc-99m, I-123, In-111… F-18, Ga-68, Rb-82, C-11…
DTU Nutech, Technical University of Denmark
RADIOMETALS
Radiometals offer:
• Longer-lived PET isotopes
• Facile labeling chemistry
• Therapeutic analogs
Cu-64, Zr-89, Sc-44….
They ARE made with standard medical cyclotrons.
But specific activity, availability and cost will benefit from:
• Cyclotrons with 12- 13 MeV protons, no degrader !
• Uniform beam spot matched to targets
• Reliable operation in 8+ hour runs
• Solid targets with ”metal free” transport systems
DTU Nutech, Technical University of Denmark
General Radiometal Labeling Chemistry
• Metal ions have unique chemistry, but in general, can be matched to organic macromolecules by polydentate chelation.
• Appropriate chelators work with many many metals.
DTPA DOTA Desferrioxamine
Almost everything
Lanthanides, Cu, Ga, Co, MnHard oxophyllic metals (Zr, Nb etc)
DTU Nutech, Technical University of Denmark
Radiometals fit well to chelation, “late state labelling”
and kit chemistry
39
Any good biovector
Ga-68 for the simple “physological markers”- lung and kidney
But our cyclotrons can also do
Ti-45 = good positron T½=3 hour workhorse
Simple target, but needs new chelators !
DTU Nutech, Technical University of Denmark 40
What would it take to make Ga-68 labelled aggregated human albumin ?
Would you see more in the picture ?Would you need more examples ?
?
You will never get it approved
!
DTU Nutech, Technical University of Denmark
Radiometals come with the price of longer lived isotopes and waste
41 29 September
2017
DTU Nutech, Technical University of Denmark42 29 September
2017
Autoinjectors ?
How to handle multiple tracers ?
How to inject Ga-68 ? High beta energy !Many ”small” tracers
9/29/2017
The new ”eye dose ” constraint
EURATOM, on its way to national legislation
We need to measure, and we must do risk assessment
DTU Danchip, Technical University of Denmark
ALARA, OPTIMISATION AND JUSTIFICATION
44 29 September
2017
BUT:We can not use the ”MEDICAL” Justification !
DTU Nutech, Technical University of Denmark
Can we scale our PET operations to global dissemination ?
45 29 September
2017
DTU Nutech, Technical University of Denmark
Can we scale our PET operations to global dissemination ?
46 29 September
2017
Excellent guidelines AND textbooksFreely available for download
DTU Nutech, Technical University of Denmark
One of many solutions”Point of demand production”
47 29 September
2017
DTU Nutech, Technical University of Denmark
Now,- if we dream “point of demand” ..
48
Why not , at last, do “Clinical C-11” ?
C-11 acetateC-11 methionineC-11 choline…..
Will need better and deeper automation.
Will need automatic QC
Will ned new regulatory approach
DTU Nutech, Technical University of Denmark
Before you start dreaming:
49 29 September
2017
Dose to the public
ANY member of the public !
The ”T” problem
< 100 uSv/year
VERY DIFFICULT TO CALCULATE
DTU Nutech, Technical University of Denmark50 29 September
2017
There is a cyclotron and hot lab somewhere below here
DTU Nutech, Technical University of Denmark
Our success is forcing us to difficult service situations
51 29 September
2017
DTU Nutech, Technical University of Denmark
The beauty of sustainable, small scale operation ?
52 29 September
2017
We may produce 180 GBq FDG and 120 GBq on a given day
…. But only 20 patients are injected
… only 7 GBq used
DTU Nutech, Technical University of Denmark
Monolitic pharmaceutical regulationis forcing non optimal radiation practice
”GMP” overhead and ”propiatory” marketing authorisations is working towards centralised production
Slow or impossible introduction of new products or leaner production procedures
53 29 September
2017
DTU Nutech, Technical University of Denmark54 29 September
2017
We need the
”Radiation protection Officer”
The Medical Physicist
The PET production world is changingA revolution in both quantity and scope of workWe need to integrate, again, the physicist !This is not generally accepted, .. Who will pay ?
DTU Nutech, Technical University of Denmark 13-aug-2008Præsentationens
55
Thank you for your attention,….. Questions ?