safe handling of alpha emitting radiopharmaceuticals ... · safe handling of alpha emitting...

IPET 2015 – Vienna – Jürgen Gay, Bayer BHC - GCPD Radiopharm

Safe Handling of Alpha Emitting

Radiopharmaceuticals

Radium-223 Dichloride, Xofigo

IPET 2015, Vienna

Jürgen Gay

Bayer AG

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"

2


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

3


Radium-223 dichloride (Xofigo)


Radium-223 Dichloride (Xofigo) is an Alpha-particle

Emitting Radiotherapeutic for Cancer

Patients with Prostate Bone Metastases

Ra 88

20

Ca

Radium belongs to

the same group of

elements as Calcium

Radium is a calcium-

mimetic element

Radium (Ra-223) is

quickly taken up in

newly forming bone

5


Impact of Radiation Is Driven by Various Factors

6

Range

in tissue

Range

in air

< 100 µm

5 -10 cell

diameters

< 5 cm Alpha

particles

Beta

particles

Gamma

radiation

Penetrating

ability

VERY LOW

LOW

HIGH

Linear Energy

Transfer (LET)

High

ionization

Medium

ionization

Low

ionization

Emission

energy

5 – 8 MeV

up to several

100 keV

up to several

100 keV

Up to a

few meters

Long-range

emission

Few

centimeters

Low attenuation

Neutrons VERY HIGH No

ionization

up to

20 MeV

Long-range

emission Low attenuation

+ 0 + 0


Beta particle emission

Alpha particle emission

Non-reparable

double-strand

DNA breaks

Single-strand

DNA breaks are

not lethal

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

7


Absorbed Doses Are Highest in Targeted Organs

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

Calculated Organ Doses to a 73 kg Patient given 50 kBq/kg

(OLINDA, contribution of alpha, beta and gamma radiation considered)

8


Radium-223 Dichloride Has Low Radioactive

Dose Compared With Commonly Used

Radiopharmaceuticals

0.004

Bone Scan Diagnostic

PET

Liver

Cancer

Treatment

Bone

Metastases

Palliation

Thyroid

Cancer

Treatment

0

1

2

3

4

Ra-223 F-18 Tc-99m Y-90 Sm-153 I-131

Patient dose (GBq)

All doses based on relevant PI, PET = positron emission tomography.

9

Bone

Metastases

Treatment


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

10


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

11


(A) Standardized, vial-based product

• 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

Package Is Qualified in Accordance

with IAEA Requirements (IATA / ADR)

Pri

mary

conta

iner

Pri

mary

conta

iner

encase

d

Pri

mary

conta

iner

in lead p

ot

TYPE A b

ox

No particular storage temperature required for

Radium-223 dichloride solution

12

Syringe shielding

container Type A box


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*

13

The gamma radiation allows

radioactivity measurement

(dose verification)

and detection of contaminations with

standard instruments

No instruments dedicated to -emission needed

471 keV

1.4 MeV max

211Po 516 ms

223Ra 11.43 d

219Rn 3.96 s

215Po 1.78 ms

211Pb 36.1 min

207Tl 4.77 min

211Bi 2.14 min

207Pb stable

5.7 MeV

6.8 MeV

7.4 MeV

7.4 MeV

176 keV

0.57 MeV max (0.27%)

493 keV

1.4 MeV max

6.6 MeV (99.73%)

Any specific risks

on handling ?

* National Nuclear Data Center, Brookhaven National Laboratory, Upton, NY, USA.


Ra-223 and its Progeny Provide Suitable g-Emissions

to Allow Usage of Standard Monitoring Systems

14

Nuclide

Energy

(keV)

Abundance

% per decay 223Ra 11.7 22.90

223Ra 23.9 7.47

223Ra 45.8 12.70

223Ra 55.8 18.50

223Ra 81.1 15.20

223Ra 83.8 25.10

223Ra 94.9 11.50

223Ra 136.2 3.36

223Ra 144.2 3.27

223Ra 154.2 5.70

223Ra 171.1 9.29

223Ra 269.5 13.90

219Rn 271.2 10.80

223Ra 323.9 3.99

211Bi 351.1 13.00

219Rn 401.8 6.59

211Pb 404.9 3.78

211Pb 832.0 3.52

Prominent photon emissions from the decay chain of Ra-223*

(Emissions with an intensity of 3 % or more)

*National Nuclear Data Center, Brookhaven National Laboratory, Upton, NY, USA; www.nndc.bnl.gov


Instruments Purpose Measuring range

Dose calibrator a) Patient dose

verification

b) Activity measurement

kBq to GBq

Contamination

monitor/

detector /

probe

Contamination

monitoring

Bq to kBq

Dose rate meter

Evaluation of

radiation exposure

µSv/h to mSv/h

Survey meter a) Dose rate meter

b) Contamination

monitoring

µSv/h

Gamma counter

Activity measurement

(e.g. biological samples)

Bq to kBq

Overview on Instruments Typically Found

in Medical Facilities

15

Commonly used instruments can be used for activity measurements and monitoring of spills / contaminations

http://carbondalecomputerrepair.com/ecotox/wp-content/uploads/2009/09/Ebbs-gamma-counter.JPG


Radiation Safety


BUT: Alpha-particles deposit their energy over a very short range, => causing greater local damage

Radioprotection measures shall focus on avoiding internalization (accidental intake)

There Are Two Ways of Exposure to Be Considered

While Working with Unsealed Radioactive Sources

17

External exposure

Internal exposure

Powerful beta/gamma sources require suitable shielding from external radiation

Shielding of alpha particles is not a big deal !


Evaluation on Potential Exposure to Medical Staff

• 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#

Dose rates derived from exposure rate

constants*

Measured dose rates (vial)

Distance from

point source*

Tc-99m

Ra-223

Ra-223 +

progeny

Distance from

vial

Radium-223

Dichloride

solution

One meter 0.02 ~ 0.02 0.047 One meter <0.1

Ten

centimeters

2 ~ 2 4.7 Ten

centimeters

<5

One

centimeter

200 ~ 200 470

18

All values in µSv/h per MBq

* Smith DS, Stabin MG, Health Physics Society, 2012

# Statement of the Federal Office for Radiation Protection [BfS]

in Germany


Exposure from Patients to Others

(Family Members, Caregivers)

1000 hours constant exposure => only 170 µSv (<<1000 µSv/yr limit)

19

Xofigo patient is immediately releasable as per applicable guidelines on patient dose rates

* Smith DS, Stabin MG, Health Physics Society, 2012

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

Justifications and statements shall be based on reliable sources


Normalized dose rates [µSv/h per MBq] at various time points and distances from patients

Derived from

exposure rate

constant*

Memorial Sloan Kettering Cancer center##

50, 100 and 200 kBq/kg Ra-223 dichloride

Ion chamber (Victoreen Model 451B-RYR)

Yokohama City University Hospital#

100 kBq/kg Ra-223 dichloride

NaI scintillation TCS-161 (ALOKA) Time post

admin [h]

Distance

[m]

1.0 m 0 m 0.3 m 1.0 m 0 m 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

Dose Rate Measurements from Patients Matches

Expectations*

*Smith DS, Stabin MG. Health Physics Society, 2012 ## published in Health Physics 2014 # not published data

20

• 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


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

21


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

22

ALARA radiation safety principles are to be followed


Many Sites Choose to Use Certain Standard

Procedures for Radiopharmaceuticals

Equip

ment

to b

e u

sed

Vent

needle

+ s

teri

le

filt

er

Syri

nge a

nd v

ent

syst

em

Dose

dra

win

g

Step 1

•Before getting started: choose appropriate syringe, cannulas and sterile filter

•Keep the vial in the lead container while drawing the dose

Step 2 • Insert vent needle with sterile filter connected to allow for pressure compensation

Step 3 • Insert cannula of syringe

Step 4

•Draw up the patient specific injection volume

• If complete draining is required the vial should be inclined slightly

http://www.safety.duke.edu/safetymanuals/university/V-HazardousDrugs.pdf





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

ALI ing (µCi)

ALI inh (µCi)

Typical activity administered (70kg patient)

MBq

Typical activity administered (70kg patient)

µCi

If 1/1E+06 of administered

activity is ingested /inhaled

(µCi)

No. of ALIs Ingestion

No. of ALIs Inhalation

Ra-223 (W) 5,00E+00 7,00E-01 3,5 94,5 0,0000945 1,89E-05 1,35E-04

Sr-89 (Y) 5,00E+02 1,00E+02 150 4050 0,00405 8,10E-06 4,05E-05

Sm-153 (W) 2,00E+03 3,00E+03 2960 80000 0,08 4,00E-05 2,67E-05

24

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/

http://www.nrc.gov/reading-rm/doc-collections/cfr/part020/appb/








Study from Denmark Suggests Spills Do Not Lead to

Significant Fractions of Airborne Activity*

25

*Airborne Release Fraction Ra-223 dichloride, Mikael Jensen, Report DTU-Hevesy Rad-150518; 2015

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 • 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

Picture of glove box

Measuring equipment


Study from Denmark Suggests Spills Do Not Lead to

Significant Fractions of Airborne Activity*

26

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

A2 0.0058%

0.0063%

*Airborne Release Fraction Ra-223 dichloride, Mikael Jensen, Report DTU-Hevesy Rad-150518; 2015


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*

27

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


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

28


Dose

rate

measu

rem

ents

Radio

acti

vit

y

measu

rem

ents

RAPSODIE*

Objectives

29

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

Measurement of RAdiation ExPoSure of Relatives and Caregivers

During Outpatient Therapy with Ra-223 DIchloridE (RAPSODIE)

Involved: 30-35 patients, 6 sites GER

*C Wanke et al. poster, EANM 2014, Gothenburg

Sweat samples

Saliva samples

Wipe samples at

patient‘s home

Patient‘s breath

Gamma

spectroscopy

Gamma

spectroscopy

Liquid

scintillation

counting

Alpha

spectroscopy

Exposure

from patients

Dose rate

meter


RAPSODIE‘s Program*

Exposure from Patients / Bodily Fluids

Dose rate

measurements

1 and 2 meter

1 hour after injection &

5-8 days after injection

30

Saliva

sampling

Sweat

sampling


Exposure from

patients


Conduct of wipe-tests

collected on two consecutive days (2-4 after inj.)

toilet seat, door handle, kitchen table

RAPSODIE‘s Program

Radiation Exposure from Contaminations

A B

31


Wipe samples at

patient‘s home


30-60 min after application

Radon-222 monitor, Alphaguard (GENITRON Instruments)

RAPSODIE‘s Program*

Exhaled Activity

32

Measurement of activity in patient’s breath


Patient‘s breath


RAPSODIE*

Outcome

33

Measurement of RAdiation ExPoSure of Relatives and Caregivers

During Outpatient Therapy with Ra-223 DIchloridE (RAPSODIE)

Saliva

sampling

Sweat

sampling

Wipe tests at

patient’s home

Dose rates

measurements

Maximum value 124 Bq/g 0.60 Bq/cm²

(= 11 kBq total)

0.31 Bq

(toilet seat)

0.21 µSv/h

(1 m distance)

Assessment on

radiation dose

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

Effective dose have been calculated using ICRP coefficients#


Potential Exposure to Others from Radon-219

Exhaled by Patients Has Been Estimated*

34

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

*Report on dose estimation, T. Schönmuth (22 March 2014)

=> Evaluation of radon measurements is ongoing

=> Calibration of measuring instrument toward Rn-219 is required


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

35

Clinical treatments:

ALSYMPCA 1000

EAP USA 200

EAP RoW 700

Current program

(4/15) 600

Commercial (Launch-04.2015)

EU&Can 3400

US 2500?

Germany 1500


Thank you

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