radiation protection and radiation safety in production and ......radiation protection and radiation...

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..


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….


Used many cyclotronsfor PET !


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…”


… into a widespread clinical modality…

Through modern whole-body

PET-CT

.. This example F-18 FDG


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


O-15 water +CTRb-82

CARDIOLOGY: The problem of the myocardium perfusion tracer

O-15 ?N-13 ?F-18 ?Rb-82 ?Cu-62 ?…


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”..


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


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


Examples of hig-end PET cyclotrons –tools of the trade

14

IBA Kiube

GE PETtrace

Both available as self-shielded


From target to patient- turnkey and plug and play- what are we missing here ?


Turnkey ?

16 29 September

2017


Inherently safe ?

17 29 September

2017


Nothing is simple, and nothing is safe without the staff

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2017


How we trained and developed…

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2017


”Automated” Cu-64 production

Do we still have a problem?


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

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2017


Are we protected by our dosimeters ?

22 29 September

2017


Listen !

23 29 September

2017


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 !


Conflicting regulations..

25 29 September

2017


What kind of surface contamination is important ?

F-18 ≠ I-124

Theranostic ”pairs”leads us towardstherapeutic isotopes

26 29 September

2017


Dispensing – ”Open” or ”Closed” ?

27 29 September

2017

Automatic ? By robot ?


Isolator technologynot alwaysmade forhumans

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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


Ga-68 DOTA TOC (2)

F-18 FDG

Patient with small cellLung carcinoma

(Maecke et al JNM 46 (2005)


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 ?


Can we make enough Ga-68 ?

Can we do 7 million procedures per year ?( > 20.000 generators full time service)


The “Moly” situation:

33

1957

1957

1961

1961 1964

All Mo-99 made inResearchReactors

Build and operated by public money


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


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….


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…


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


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)


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

!


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 !


Can we scale our PET operations to global dissemination ?

45 29 September

2017


Can we scale our PET operations to global dissemination ?

46 29 September

2017

Excellent guidelines AND textbooksFreely available for download


One of many solutions”Point of demand production”

47 29 September

2017


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


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


2017

There is a cyclotron and hot lab somewhere below here


Our success is forcing us to difficult service situations

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2017


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


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


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

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Thank you for your attention,….. Questions ?

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