Safe Handling of Alpha Emitting
Radiopharmaceuticals
Radium-223 Dichloride, Xofigo
IPET 2015, Vienna
Jürgen Gay
Bayer AG
BHC-GCPD Radiopharm
IPET 2015 – Vienna – Jürgen Gay, Bayer BHC - GCPD Radiopharm
Marie Curie (1867-1934)
1903 Nobel prize (physics) together with
P. Curie and H. Becquerel
"in recognition of the extraordinary services
they have rendered by their joint research
on the radiation phenomena discovered
by Henri Becquerel"
1911 Nobel prize (chemistry)
"in recognition of her services to the
advancement of chemistry by the
discovery of the elements radium and
polonium, by the isolation of radium and
the study of the nature and compounds of
this remarkable element"
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Quotations of Marie Curie
Nothing in life is to be feared, it is only to be understood.
Now is the time to understand more, so that we may fear less.
Marie Curie
We must not forget that when radium was discovered no one knew that it
would prove useful in hospitals. The work was one of pure science.
And this is proof that scientific work must not be considered from the point of
view of its direct usefulness . It must be done for itself, for the beauty of
science, and then there is always the chance that a scientific discovery may
become like radium a benefit for humanity.
Marie Curie, Lecture at Vassar College, May 14, 1921
One never notices what has been done;
one can only see what remains to be done.
Marie Curie, letter to her brother, 1894
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Radium-223 dichloride (Xofigo)
IPET 2015 – Vienna – Jürgen Gay, Bayer BHC - GCPD Radiopharm
Radium-223 Dichloride (Xofigo) is an Alpha-particle
Emitting Radiotherapeutic for Cancer
Patients with Prostate Bone Metastases
 Radium belongs to
the same group of
elements as Calcium
 Radium is a calciummimetic element
 Radium (Ra-223) is
quickly taken up in
newly forming bone
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Ca
88
Ra
5
Impact of Radiation Is Driven by Various Factors
Range
in air
Range
in tissue
Linear Energy
Transfer (LET)
Emission
energy
VERY LOW
< 5 cm
< 100 µm
5 -10 cell
diameters
High
ionization
5 – 8 MeV
LOW
Up to a
few meters
Few
centimeters
Medium
ionization
up to several
100 keV
Gamma
radiation
HIGH
Long-range
emission
Low attenuation
Low
ionization
up to several
100 keV
Neutrons
VERY HIGH
Long-range
emission
Low attenuation
No
ionization
up to
20 MeV
Alpha
particles
Beta
particles
+0
0+
Penetrating
ability
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Potent Anti-tumor Effect
 Radium-223 selectively targets bone,
specifically bone metastases
 It emits high-energy ionizing alpha particles which
cause lethal, double-strand DNA breaks in adjacent
cells
 This results in a highly localized anti-tumor effect
in bone metastases
Beta particle emission
Non-reparable
double-strand
DNA breaks
Single-strand
DNA breaks are
not lethal
Alpha particle emission
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Absorbed Doses Are Highest in Targeted Organs
Calculated Organ Doses to a 73 kg Patient given 50 kBq/kg
(OLINDA, contribution of alpha, beta and gamma radiation considered)
Organ
Gy per MBq
Rad per mCi
Gy
rad
Lower large intestine
0.04645
171.88
0.1669
16.69
Small intestine wall
0.00762
26.87
0.0265
2.65
Upper large intestine
0.03232
119.85
0.118
11.80
Red marrow
0.13879
513.51
0.5066
50.66
Osteogenic cells
1.15206
4262.62
4.2050
420.50
Urinary bladder wall
0.00403
14.90
0.0147
1.47
Kidneys
0.00320
11.86
0.0117
1.17
Liver
0.00298
11.01
0.0109
1.09
• No specific uptake in other organs, <0.01 Gy/MBq
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Radium-223 Dichloride Has Low Radioactive
Dose Compared With Commonly Used
Radiopharmaceuticals
4
Patient dose (GBq)
3
2
1
0
0.004
Ra-223
Bone
Metastases
Treatment
F-18
Tc-99m
Y-90
Sm-153
I-131
Diagnostic
PET
Bone Scan
Liver
Cancer
Treatment
Bone
Metastases
Palliation
Thyroid
Cancer
Treatment
All doses based on relevant PI, PET = positron emission tomography.
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Radium-223 Dichloride
Solution for Injection
• Standardized, stable,
vial-based product
• Ready to use,
direct injection via syringe
• 10 mL vial; 6 mL solution
• Ra-223 content at reference date
 6 MBq (162 µCi)
 1000 kBq/mL
• Shelf-life 28 days
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Manufacturing of Xofigo Has Been Contracted to
IFE (Institute for Energy Technology)
Manufacturing includes
 production of drug substance / drug product
 packaging
 quality control
 release
Institute for Energy
Technology (IFE)
Isotope laboratories
Instituttveien 18
NO-2007, Kjeller,
Norway
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Package Is Qualified in Accordance
with IAEA Requirements (IATA / ADR)
(A) Standardized, vial-based product
Syringe shielding
container
Type A box
• READY TO USE, DIRECT INJECTION VIA SYRINGE
• 10 ML VIAL; 6 ML SOLUTION, 6 MBQ (162 µCI)
(B) Prefilled syringe (U.S.)
• READY TO USE, DIRECT INJECTION
• PATIENT-READY-DOSAGE
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TYPE A box
Primary container
in lead pot
Primary container
encased
Primary container
No particular storage temperature required for
Radium-223 dichloride solution
12
Decay of Radium-223 Dichloride
• Radium-223 dichloride emits
mainly α-particles
• t½ = 11.43 days
• Of the total decay energy
 95.3% emitted as -particles
 3.6% emitted as -particles
 1.1% emitted as γ- or X-rays
Radium-223 decay chain*
223Ra
11.43 d

5.7 MeV
Any specific risks
on handling ?
219Rn
3.96 s

6.8 MeV
215Po
211Bi
1.78 ms
The gamma radiation allows
radioactivity measurement
(dose verification)
and detection of contaminations with
standard instruments

7.4 MeV
211Pb
36.1 min


211Po
516 ms
176 keV
2.14 min 0.57 MeV max

471 keV
1.4 MeV max
(0.27%)
6.6 MeV
(99.73%)
207Tl


7.4 MeV
207Pb
stable
493 keV
4.77 min 1.4 MeV max
No instruments dedicated to -emission needed
* National Nuclear Data Center, Brookhaven National Laboratory, Upton, NY, USA.
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Ra-223 and its Progeny Provide Suitable g-Emissions
to Allow Usage of Standard Monitoring Systems
Prominent photon emissions from the decay chain of Ra-223*
(Emissions with an intensity of 3 % or more)
Nuclide
Energy
(keV)
Abundance
% per decay
223Ra
11.7
23.9
45.8
55.8
81.1
83.8
94.9
136.2
144.2
154.2
171.1
269.5
271.2
323.9
351.1
401.8
404.9
832.0
22.90
7.47
12.70
18.50
15.20
25.10
11.50
3.36
3.27
5.70
9.29
13.90
10.80
3.99
13.00
6.59
3.78
3.52
223Ra
223Ra
223Ra
223Ra
223Ra
223Ra
223Ra
223Ra
223Ra
223Ra
223Ra
219Rn
223Ra
211Bi
219Rn
211Pb
211Pb
*National Nuclear Data Center, Brookhaven National Laboratory, Upton, NY, USA; www.nndc.bnl.gov
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Overview on Instruments Typically Found
in Medical Facilities
Instruments
Purpose
Measuring range
Dose calibrator
a)
kBq to GBq
b)
Patient dose
verification
Activity measurement
Contamination
monitor/
detector /
probe
Contamination
monitoring
Bq to kBq
Dose rate meter
Evaluation of
radiation exposure
µSv/h to mSv/h
Survey meter
a)
b)
µSv/h
Gamma counter
Activity measurement
(e.g. biological samples)
Dose rate meter
Contamination
monitoring
Bq to kBq
Commonly used instruments can be used for activity measurements
and monitoring of spills / contaminations
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Radiation Safety
IPET 2015 – Vienna – Jürgen Gay, Bayer BHC - GCPD Radiopharm
There Are Two Ways of Exposure to Be Considered
While Working with Unsealed Radioactive Sources
 Powerful beta/gamma sources require suitable shielding from
external radiation
 Shielding of alpha particles is not a big deal !
BUT:
Alpha-particles deposit their
energy over a very short range,
=> causing greater local damage
Radioprotection measures
shall focus on avoiding
internalization
(accidental intake)
IPET 2015 – Vienna – Jürgen Gay, Bayer BHC - GCPD Radiopharm
External
exposure
Internal
exposure
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Evaluation on Potential Exposure to Medical Staff
Dose rates derived from exposure rate
constants*
Measured dose rates (vial)
Distance from
point source*
Tc-99m
Ra-223 +
progeny
Distance from
vial
Radium-223
Dichloride
solution
One meter
0.02
0.047
One meter
<0.1
Ten
centimeters
2
~2
4.7
Ten
centimeters
<5
One
centimeter
200
~ 200
470
Ra-223
~ 0.02
All values in µSv/h per MBq
• Exposure rate constants of Ra-223 is comparable Tc-99m
• Measured values matches expectation, i.e. calculated values
• Direct contact with syringe is to be avoided,
suitable shielding measures are required#
* Smith DS, Stabin MG, Health Physics Society, 2012
IPET 2015 – Vienna – Jürgen Gay, Bayer BHC - GCPD Radiopharm
#
Statement of the Federal Office for Radiation Protection [BfS]
in Germany
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Exposure from Patients to Others
(Family Members, Caregivers)
Calculation of dose rates from patients for typical treatment activities
(unshielded source)*
Nuclide
Tc-99m
Ra-223
Activity
1110 MBq
3.5 MBq
Dose rate at
1 m distance
22.20 µSv/h
0.17 µSv/h
1000 hours constant exposure => only 170 µSv (<<1000 µSv/yr limit)
Xofigo patient is immediately releasable as per applicable guidelines on
patient dose rates
Justifications and statements shall be based on reliable sources
* Smith DS, Stabin MG, Health Physics Society, 2012
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Dose Rate Measurements from Patients Matches
Expectations*
Normalized dose rates [µSv/h per MBq] at various time points and distances from patients
Derived from
exposure rate
constant*
Time post Distance
admin [h] [m]
Memorial Sloan Kettering Cancer center## Yokohama City University Hospital#
50, 100 and 200 kBq/kg Ra-223 dichloride
100 kBq/kg Ra-223 dichloride
Ion chamber (Victoreen Model 451B-RYR)
NaI scintillation TCS-161 (ALOKA)
1.0 m
0m
0.3 m
1.0 m
0m
0.3 m
1.0 m
0
0.046
0.53
0.22
0.08
0.76
0.20
0.06
24
N/A
0.93
0.16
0.06
0.69
0.11
0.02
48
N/A
1.08
0.19
0.05
0.15
0.06
0.03
144
N/A
0.07
0.03
0.01
0.04
0.01
0.00
• The measured dose rates are low
• Maximum dose rates obtained within 48 hours time period
• Values differ due to:
 measuring devices, geometry
 patient’s specific PK profile (distribution and excretion)
 pattern of metastases
*Smith DS, Stabin MG. Health Physics Society, 2012
IPET 2015 – Vienna – Jürgen Gay, Bayer BHC - GCPD Radiopharm
## published in Health Physics 2014
# not published data
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Standard Clean-up Procedures for Spillage
Should Be Followed
General measures:
• Limit the spread of contamination
• Limit access to the area
•
•
•
•
Notify Radiation Safety Officer
Use protective clothing and disposable gloves
Quickly soak up any liquid with an absorbent pad
Wipe up the spill
Radium is not strongly absorbed by work surfaces or floors; a complexing agent such as
0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution will allow complete removal of radium-223
•
•
•
•
Check the success by wipe test or direct measurements
Continue cleaning and checking if necessary
Use a plastic bag to hold contaminated items
In case of contact with skin or eyes, the affected area should immediately
be thoroughly rinsed with water
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Administration of Radium-223 Dichloride
Is Similar to That of Other Radiopharmaceuticals
Practice Safety
• Protect area beneath administration site with plastic-backed absorbent
bench liner
• Administer drug as a slow IV injection directly to a 2- or 3-way adapter
• Verify IV access by flushing with
saline before and after drug injection
• Treat equipment as short-lived
radioactive waste;
store and dispose in accordance
with local regulations
ALARA radiation safety principles are to be followed
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Many Sites Choose to Use Certain Standard
Procedures for Radiopharmaceuticals
• Before getting started: choose appropriate syringe, cannulas and sterile filter
Step 1 • Keep the vial in the lead container while drawing the dose
Step 2
Step 3
• Insert vent needle with sterile filter connected to allow for pressure compensation
• Insert cannula of syringe
http://www.safety.duke.edu/safetymanuals/university/V-HazardousDrugs.pdf
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Dose drawing
Syringe and vent
system
Vent needle + sterile
filter
Equipment to be used
• Draw up the patient specific injection volume
Step 4 • If complete draining is required the vial should be inclined slightly
Internal exposure risk for Ra-223:
ALIs = Annual Limit of Intake
ALI is the limit for the amount of radioactive material taken into the
body of an adult worker by inhalation (Inh) or ingestion (Ing) in a year.
Intake of ALI values of a given radionuclide by the “reference man” would result in:
• a committed effective dose equivalent (CEDE) of 50 mSv per year
• a committed dose equivalent (CDE) of 500 mSv to any individual organ or tissue per year
Ra-223 (W)
Sr-89 (Y)
Sm-153 (W)
If 1/1E+06 of
Typical activity Typical activity
administered
ALI ing
ALI inh
administered administered
activity is
(µCi)
(µCi)
(70kg patient) (70kg patient)
ingested /inhaled
MBq
µCi
(µCi)
5,00E+00 7,00E-01
3,5
94,5
0,0000945
5,00E+02 1,00E+02
150
4050
0,00405
2,00E+03 3,00E+03
2960
80000
0,08
No. of ALIs
Ingestion
No. of ALIs
Inhalation
1,89E-05
8,10E-06
4,00E-05
1,35E-04
4,05E-05
2,67E-05
Internal exposure risks are similar to those of
commonly used radiopharmaceuticals
ALI data from NRC 10 CRF: Appendix B to Part 20; http://www.nrc.gov/reading-rm/doc-collections/cfr/part020/appb/
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Study from Denmark Suggests Spills Do Not Lead to
Significant Fractions of Airborne Activity*
Study design
• To measure airborne activity from simulated
spills, expected to occur during normal
handling of Xofigo solution
• Off-line measuring of released activity
1.
Contamination phase
•
•
paper (A1 = 596 kBq)
metal surface (A2 = 785 kBq)
2.
Dry-out phase
3.
Stress phase
•
•
•
Picture of glove box
Paper filter crumbled and bagged
Dragging of lead container across the metal surface
Wiping of metal surface
• Results are presented in fractions of
activity release during and after dry-out
Measuring equipment
*Airborne Release Fraction Ra-223 dichloride, Mikael Jensen, Report DTU-Hevesy Rad-150518; 2015
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Study from Denmark Suggests Spills Do Not Lead to
Significant Fractions of Airborne Activity*
Results
• For two items (F4/F6) activity
could be measured accurately
• Counting efficiency of
Liquid Scintillation Counting
(LSC) was higher in
comparison to gamma
spectroscopy
• No significant values on
airborne Ra-223 activity
observed during normal
handling, including dried spills
A1
0.0063%
A2
0.0058%
*Airborne Release Fraction Ra-223 dichloride, Mikael Jensen, Report DTU-Hevesy Rad-150518; 2015
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Exposure to Others Due to Accidental Intake of
Eliminated Activity Is Expected to Be Negligible
• Radium-223 dichloride goes immediately to the target after
IV administration or is excreted into the feces
• ~ 60% of activity injected is distributed into bone by 4 hours
• Excretion is predominantly through the feces
• ~ 76% excreted within 1 week
• < 5% excreted through urine
=> Contamination and intake of activity highly unlikely*
Minimal restrictions for the patients on interactions with others
(e.g. family members and caregivers), mainly standard hygiene measures
*RAPSODIE study, Germany; C Wanke et al. poster, EANM 2014, Gothenburg
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Appropriate Instructions for Outpatient Setting
Risk of accidental intake is very low. Patients and caregivers
should take basic hygienic measures, e.g.,
• Clean up bodily fluids with disposable items that can be flushed down the
toilet (such as toilet paper, tissue or paper towel)
• Wash your hands thoroughly with soap and water after each trip to the
bathroom. Caregivers should wash hands after each contact with any of
the patient’s body fluids.
• Wash clothes stained with bodily fluids separately
Patient should receive a “patient card”
• Since the remaining activity in the patient’s body may trigger
the highly sensitive security radiation monitors installed at
airports and other security checkpoints
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RAPSODIE*
Objectives
Measurement of RAdiation ExPoSure of Relatives and Caregivers
During Outpatient Therapy with Ra-223 DIchloridE (RAPSODIE)
Involved: 30-35 patients, 6 sites GER
Aim of the study
To confirm that neither the accidental intake of activity nor the exposure from the
patient over the course of Xofigo treatment will lead to an exposure < 1 mSv
Wipe samples at
patient‘s home
Patient‘s breath
*C Wanke et al. poster, EANM 2014, Gothenburg
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Gamma
spectroscopy
Gamma
spectroscopy
Liquid
scintillation
counting
Alpha
spectroscopy
Exposure
from patients
Dose rate
meter
Dose rate
measurements
Saliva samples
Radioactivity
measurements
Sweat samples
29
RAPSODIE‘s Program*
Exposure from Patients / Bodily Fluids
Dose rate
measurements
Exposure from
patients
Saliva
sampling
 1 and 2 meter
 1 hour after injection &
5-8 days after injection
Sweat
sampling
*C Wanke et al. poster, EANM 2014, Gothenburg
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RAPSODIE‘s Program
Radiation Exposure from Contaminations
Conduct of wipe-tests

collected on two consecutive days (2-4 after inj.)

toilet seat, door handle, kitchen table
Wipe samples at
patient‘s home
B
A
*C Wanke et al. poster, EANM 2014, Gothenburg
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RAPSODIE‘s Program*
Exhaled Activity
Measurement of activity in patient’s breath
Patient‘s breath
 30-60 min after application
 Radon-222 monitor, Alphaguard (GENITRON Instruments)
*C Wanke et al. poster, EANM 2014, Gothenburg
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RAPSODIE*
Outcome
Measurement of RAdiation ExPoSure of Relatives and Caregivers
During Outpatient Therapy with Ra-223 DIchloridE (RAPSODIE)
Effective dose have been calculated using ICRP coefficients#
Maximum value
Assessment on
radiation dose
Saliva
sampling
Sweat
sampling
Wipe tests at
patient’s home
Dose rates
measurements
124 Bq/g
0.60 Bq/cm²
(= 11 kBq total)
0.31 Bq
(toilet seat)
0.21 µSv/h
(1 m distance)
Ingestion of 0.1 g
=> 1.3 µSv
Ingestion of 145 Bq
(two palms)
=> 14.5 µSv
Ingestion of 0.31 Bq
=> 0.1 µSv
1000 hrs of exposure
=> 0.2 mSv
Accidental intake of radioactivity is not likely to lead
to radiation doses greater than 1 mSv
The same holds true for exposure from the patient (external radiation)
*C Wanke et al. poster, EANM 2014, Gothenburg
#ICRP dose coefficient for Ra-223 ingestion: 1.0E-7 Sv/Bq
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Potential Exposure to Others from Radon-219
Exhaled by Patients Has Been Estimated*
Observation


Radon-219 can escape from
the body
proved by measurements with
AlphaGuard instrument
Status of investigation


Good agreement with the data from
radioactivity measurements
The dose (< 0.1 mSv) to others is
below the limit for the public
=> Evaluation of radon measurements is ongoing
=> Calibration of measuring instrument toward Rn-219 is required
*Report on dose estimation, T. Schönmuth (22 March 2014)
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Key Messages
• Ready-to-use = straightforward preparation & administration
• Little external exposure risk
• Standard radiation safety practices are adequate to ensure safe
usage without contamination incidents
• Gamma emission allows for monitoring with standard equipment;
no alpha-radiation specific equipment needed
• Deliverable in an out-patient setting; no restrictions on normal
interactions with others
• No impact on the environment due to activity in
patients excretions
• Up to now ~13500 patients have been treated
without any radiation safety incident
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Thank you
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