QA issues in radioisotope production for nuclear medicine

LFMCong
82701
QA issues in radioisotope
production for nuclear medicine
Leonard F. Mausner, Ph.D.
Medical Department
Brookhaven Science Associates
U.S. Department of Energy

LFMCong
82701
Radioisotopes are crucial to
modern patient care
36,000 nuclear medicine
procedures per day in the US
Brookhaven Science Associates
U.S. Department of Energy

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82701
Technetium-99m
N
N
O
Tc
N
N
Ceretec ®
H 3 C
C CH 3
Cardiolite®
O
O O
HO
O
P
P
O Tc OH
P O P
O
O
O
Bone Imaging
O
®
Technescan-MDP
O
O
O O
H
Brain Imaging
H 3 CO
H 3 C
H 3 C
H 3 CO
C
C
OCH 3
OCH 3
CH 2
CH
H 3 C
3
OCH 3
C
CH 2 CH 2
N C N
CH 3
C C
Tc
C C
N C N
CH
CH 2 CH 3
2
N
C
CH 3
H 3 C
CH 2
H 3 C
C CH 3
Normal
Stroke
OCH 3
Heart Imaging
Normal
Normal
Epilepsy
Normal
Metastatic
Prostate Cancer
Brookhaven Science Associates
U.S. Department of Energy
Heart Attack

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82701
Definitions
Radioisotope: unstable form of an element that
spontaneously “decays” with the emission of
energy
Half life: the time required for an initial large
number of nuclei to be reduced to half that
number by decay
Radiopharmaceutical: a carrier molecule
containing a radioisotope, administered in trace
quantity, designed to target a specific organ or
physiological function
Brookhaven Science Associates
U.S. Department of Energy

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82701
Properties of Radioactive Emissions
alpha particles are helium nuclei; non
penetrating; very toxic to cells; potential use for
cancer therapy
beta particles are energetic electrons or
positrons; low penetration; toxic to cells; used in
cancer therapy
gamma rays are high energy electromagnetic
radiation; highly penetrating; less toxic to cells;
critical to diagnostic imaging
Auger electrons are low energy atomic electrons;
non penetrating; very toxic to cells; potential use
for cancer therapy
Brookhaven Science Associates
U.S. Department of Energy

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Sources of Radioisotopes
Naturally Occurring
– primordial (eg. Uranium-235, Potassium-40)
– cosmic ray produced continuously (eg.
Carbon-14, tritium)
Man made
– reactor produced with neutrons
– accelerator produced with protons or other
charged particles
Brookhaven Science Associates
U.S. Department of Energy

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Radioisotope Production Reactor
The experimental area of a
research reactor
Core of the reactor showing tubes for
insertion/retrieval of isotope targets
Brookhaven Science Associates
U.S. Department of Energy

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Accelerators
for Isotope
Production-Cyclotron
A commercial low energy
isotope production cyclotron, in
the U.S. approximately 24
operated by industry and 90 by
medical centers
Typical facility layout
Brookhaven Science Associates
U.S. Department of Energy

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82701
Accelerators for Isotope
Production-LINAC
The high energy proton LINAC at
Brookhaven National Laboratory
Beam lines direct protons to
production targets in the
Brookhaven Linac Isotope
Producer (BLIP)
Brookhaven Science Associates
U.S. Department of Energy

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The Radioisotope Generator
If a long lived “parent” radioisotope decays into a
short lived “daughter” radioisotope and
If the parent and daughter are chemically
separable
Then a “generator” or cow is a practical,
convenient method to transport and use (milk)
very short lived radioisotopes without having to
produce them at each site
This technique has been of utmost importance to
nuclear medicine
Brookhaven Science Associates
U.S. Department of Energy

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82701
Radioisotope Processing
and Purification
All isotope production
targets require some
chemical processing
Radiation shielding for
the chemist is often
required, so “hot cells”
are often used
Brookhaven Science Associates
U.S. Department of Energy

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Some Common Clinically Used Isotopes
Isotope Half life Facility Medical Applications
Molybdenum-99/ 2.75d/ reactor* numerous diagnostic scans
Technetium-99m 6.0h
Thallium-201 73h cyclotron** heart stress test
Iodine-131 8.0d reactor* thyroid function & Rx, cancer Rx
Iodine-125 60.1d reactor* prostate cancer Rx, research
Xenon-133 5.3d reactor* lung function
Indium-111 2.8d cyclotron** inflammation & tumor detection
Gallium-67 3.2d cyclotron** inflammation & tumor detection
Strontium-89 14.3d reactor* bone cancer Rx
Palladium-103 17.0d cyclotron** prostate cancer Rx
Fluorine-18 110m cyclotron † cancer detection & brain research
Yttrium-90 2.7d reactor waste cancer Rx
*foreign; **domestic industry; † domestic hospital & university
Brookhaven Science Associates
U.S. Department of Energy

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Brookhaven Science Associates
U.S. Department of Energy

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Brookhaven Science Associates
U.S. Department of Energy

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82701
Brookhaven Science Associates
U.S. Department of Energy

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Radionuclide and Radiopharmaceutical
Research (R&RR) Program at BNL
Isotope Production and Distribution at BLIP
– Process development: new isotopes as per DOE guidance,
improve quality, minimize waste and personnel exposure;
target design.
Radiopharmaceutical R&D
– High specific activity Tin-117m for bone cancer therapy &
cardiovascular applications
– Radiolabeled stem cells for non invasive imaging
Radiation damage studies of materials for future high
power accelerators
– Collaboration with BNL Physics & Energy Science &
Technology Departments
Training
– Support for ACS Nuclear Chemistry Summer School
Brookhaven Science Associates
U.S. Department of Energy

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Current BLIP Radioisotope Menu
Half
Isotope life Status Application
Beryllium-7 53.3d research gamma ray source
Iron-52 8.3h research PET/MRI tracer
Zinc-65 244.3d research zinc tracer
Copper-67 2.6d research cancer imaging and therapy
Germanium-68 270.8d routine PET scanner calibrations
Arsenic-73 80.3d research environmental tracer
Strontium-82 25.5d routine heart scans with PET
Yttrium-86 14.7h research cancer imaging with PET
Y-88 106.6d routine gamma ray source
Technetium-95m 61d research environmental tracer
Brookhaven Science Associates
U.S. Department of Energy

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82701
QA challenges with radioactivity
Radiation levels limit direct handling by staff
Most processing must be done remotely in a hot cell
Cleaning, contamination control, sterility difficult to maintain
since direct manned access to hot cell interiors very restricted
New glassware and reagents always used. [high radiation levels
and harsh chemistry from concentrated acids can limit bacterial
growth]
Production of very small number of units and very small volumes
(in my group 2-4 batches/month each ~10mL of 0.1N HCl)
QC in this situation means every batch must be analyzed rather
than selected units
For short lived radioisotopes (eg. O-15, half life=2min) it is not
possible to complete all assays (chemical purity,sterility,
pyrogenicity) prerelease or even before human use
Process validation data and post release assay is done in this
case
Brookhaven Science Associates
U.S. Department of Energy

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Measurement issues for radioactive
products
Measurements of product quality and quantity cannot
be done remotely because the equipment is too large
for hot cell use and the electronics cannot survive the
radiation fields for long
Samples for assay must be removed but only very
small aliquots can be used (20-25microliter typical) in
order to keep staff radiation exposure as low as
possible
Then large dilutions are necessary to bring volumes
up to amounts needed by the instrumentation
Brookhaven Science Associates
U.S. Department of Energy

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Measurement techniques of
radioactive products
Radioisotopic purity is determined by gamma or beta
spectroscopy [ we presently do not handle alpha emitters] using
NIST traceable radioactivity standards and ANSI methodology
guidelines for measurement and calibration
Chemical purity is determined by standard analytical
instrumentation (eg. optical emission or atomic absorption
spectroscopy for elemental measurements, HPLC for
pharmaceutical content) and standard methodology. Calibrations
with purchased analytical standards
Note that the isotope mass is negligible and that what is being
measured is trace metal content in the HCl final solution
Sterility and pyrogenicity tests must be done in house if direct
human use is involved
Brookhaven Science Associates
U.S. Department of Energy

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82701
Our QA status
Drug Master File #5531: Production of Sr-82
submitted and maintained active
CGMP guidelines followed for an active
pharmaceutical ingredient (API)
FDA registered under labeler code 66711
CGMP also used for Ge-68 preparation, other
products follow GLP guidelines
QA audits performed by the final product
manufacturer (GE HealthCare for Sr-82, Siemens
for Ge-68)
Brookhaven Science Associates
U.S. Department of Energy