Tech Radiopharmacy

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The Radiopharmacy

A Technologists Guide

European Association of Nuclear Medici

ne

Produced with the kind Support o


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Contributors

James R Ballinger, PhD

Chie Radiopharmaceutical Scientist

Guys and St Thomas NHS Foundation Trust

London, United Kingdom

Clemens Decristooro, PhD (*)

Chair o the EANM Radiopharmacy Committee

Clinical Department o Nuclear Medicine

Medical University Innsbruck

Innsbruck, Austria

Brit Farstad

Member o the EANM Radiopharamcy Committee

M.Pharm/Radiopharmacist

Department Head, Isotope Laboratories

Institute or Energy Technology

Kjeller, Norway

Brendan McCoubrey

Radiation Saety Ocer

Dept. o Diagnostic Imaging

St. Jamess Hospital

Dublin, Ireland

Geraldine OReilly, PhD

Radiation Protection Advisor

Dept. o Medical Physics and BioEngineeringSt. Jamess Hospital

Dublin, Ireland

Helen Ryder

Clinical Specialist Radiographer


St. Jamess Hospital

Dublin, Ireland

Tanja Gmeiner Stopar, PhD

Member o the Education Board,

EANM Radiopharmacy Committee

Radiopharmacy, Head

University Medical Centre Ljubljana

Department or Nuclear Medicine

Ljubljana, Slovenia

Wim van den Broek

Chair o the EANM Technologist Committee

Chie Technologist

Dept o Nuclear Medicine

University Medicine Centre

Nijmegen, The Netherlands

Editors

Suzanne Dennan

Vice-Chair o the EANM Technologist Committee

Acting Radiographic Services Manager


St. Jamess HospitalDublin, Ireland

Clemens Decristooro, PhD *

This booklet was sponsored by an educational grant from Lantheus Medical Imaging . The views expressed are those

of the authors and not necessarily of Lantheus Medical Imaging.


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Contents

Foreword

Wim van den Broek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Introduction

Clemens Decristooro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Chapter 1 - Radiopharmacy Technology

Brit Farstad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Chapter 2 - Radiopharmacy Design

James Ballinger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

Chapter 3 - Radiopharmacy: Preparing & Dispensing Radiopharmaceuticals

Geraldine OReilly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Chapter 4 - Radiopharmacy: Kits & Techniques

Helen Ryder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22

Chapter 5 Radiopharmacy: Blood Labelling

Tanja Gmeiner Stopar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33

Chapter 6 - Radiopharmacy: Record Keeping & Administration

Brendan McCoubrey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41

Reerences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49

Imprint. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51


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ForewordWim van den Broek

should be provided or all sta working in ra-

diopharmacy departments in the aspects o

quality assurance in which they are involved.

This includes: preparation, release, quality con-

trol and analytical techniques, cleaning, trans-

portation, calibration o equipment (especially

or the measurement o radioactivity), working

practices in the radiopharmacy, preparation o

the individual doses, documentation, hygiene,pharmaceutical microbiology, and microbio-

logical monitoring. Oten a Nuclear Medicine

Technologist is the person who is involved

in the preparation and quality control o the

radiopharmaceuticals.

I am grateul or the eort and hard work o all

the contributors, who are the key to the con-

tents and educational value o this booklet.The most essential and relevant aspects o ra-

diopharmacy in daily practice are emphasised

here. This booklet is prepared in cooperation

with the Radiopharmacy Committee o the

EANM. This Committee is very active and criti-

cal in the eld o regulations and guidelines or

the production o radiopharmaceuticals and

constantly proposes practical solutions. Many

thanks to Suzanne Dennan who coordinated

this project.

With this new booklet, the EANM Technolo-

gist Committee oers to the NMT community

again a useul and comprehensive tool that

may contribute to the advancement o their

daily work.

Since it was ormed, the EANM Technologist

Committee has been devoted to the improve-

ment o nuclear medicine technologists

(NMTs) proessional skills. Publications that will

assist in the setting o high standards or NMTs

work have been developed and since 2004

a series o brochures, Technologists Guides,

have been published yearly. This booklet

about radiopharmacy is already the th vol-ume. The new and stricter regulations in the

eld o preparation o radiopharmaceuticals

changed the daily practice in the radiophar-

macy in the last 5 years.

Nuclear medicine is a multidisciplinary special-

ty in which medicine, physics and pharmacy

are involved. The Radiopharmacy is an integral

part o a nuclear medicine department and itsprime responsibility is the preparation o high

quality radiopharmaceuticals, the base or a

high quality nuclear medicine examination.

The majority o these radiopharmaceuticals

is mainly used or diagnostic imaging, which

is the main activity o nuclear medicine. Ra-

diopharmaceuticals are medical products

dened in the European directive 2004/27/

EC amending the directive 2001/83/EC. As in

other disciplines the complex changes driven

by European legislation had their impact on

everyday practice in the preparation o radio-

pharmaceuticals.

Only trained people should be responsible or

and participate in the preparation and qual-

ity control o radiopharmaceuticals. Training


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I want to congratulate the Technologists Com-

mittee o the EANM or this excellent Tech-

nologists Guide on the Radiopharmacy. Issues

o quality assurance especially in the eld o

pharmaceutical preparations are becoming

increasingly important. The Radiopharmacy

Committee o the EANM thereore recently

has issued general guidelines or Current

Good Radiopharmacy Practice describingthe quality standards in the preparation o

conventional and PET radiopharmaceuticals

(http://www.eanm.org/scientic_ino/guide-

lines/gl_radioph_cgrpp.php) . These serve as

a general reerence standard or radiophar-

maceutical preparation as radiopharmacy

practice still shows a great variability all over

Europe.

Technologists in many countries are the

backbone or radiopharmacy services within

nuclear medicine departments. This is espe-

cially true or the preparation and handling

o conventional radiopharmaceuticals includ-

ing eluting radionuclide generators, prepara-

tion o99mTc-radiopharmaceuticals rom kits,

dispensing and cell labelling. Thereore the

current issue o the Technologists Guides is

dedicated to radiopharmacy practice.

The Technologists Committee o the EANM

has been very active in promoting proes-

sional skills o technologists and to support

high quality standards in daily practice. The

series o Technologists Guide booklets by the

Eductional Sub-Committee has been a valu-

able part o these initiatives. The current issue

o this series intends to provide guidance or

a good radiopharmacy practice, to describequality standards and to bring radiopharmacy

practice to equal standards throughout Eu-

rope.

This booklet contains chapters o all relevant

topics o daily radiopharmacy practice o tech-

nologists such as radiopharmacy design, prep-

aration and dispensing as well as documenta-

tion written by European experts in the eld,both radiopharmacists and technologists.

I am very condent that this booklet will not

only provide valuable inormation and quick

reerence or problems arising in daily prac-

tice, but also will help to continuously improve

quality standards o radiopharmacy practices

in nuclear medicine.

IntroductionClemens Decristooro, PhD


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Chapter 1 Radiopharmacy TechnologyBrit Farstad

A radiopharmaceutical can be as simple as a

radioactive element such as 133Xe, a simple salt

such as 131I-NaI, or a labelled compound such

as 131I-iodinated proteins and 99mTc-labeled

compounds.

Usually, radiopharmaceuticals contain at least

two major components:

A radionuclide that provides the desired

radiation characteristics.

A chemical compound with structural or

chemical properties that determine the in

vivo distribution and physiological behav-

iour o the radiopharmaceutical.

Radiopharmaceuticals should have severalspecic characteristics that are a combination

o the properties o the radionuclide used as

the label and o the nal radiopharmaceutical

molecule itsel.

Decay o radionuclides

Radionuclides are unstable nuclei that are sta-

bilised upon radioactive decay. Approximately

3000 nuclides have been discovered so ar;

most o these are unstable, but only about 30

o these are routinely used in nuclear medicine.

Most o these are articial radionuclides, which

may be produced by irradiation in nuclear re-

actors, cyclotrons, or large linear accelerators.

A radionuclide may decay by emitting dier-

ent types o ionising radiation: alpha (), beta(-), positron (+) and gamma () radiation.

Radiopharmacy

Radiopharmacy encompasses studies related

to the pharmaceutical, chemical, physical,

biochemical, and biological aspects o ra-

diopharmaceuticals. Radiopharmacy com-

prises a rational understanding o the design,

preparation and quality control o radiophar-

maceuticals, the relationship between the

physiochemical and biological properties oradiopharmaceuticals and their clinical appli-

cation, as well as radiopharmaceuticals chem-

istry and issues related to the management,

selection, storage, dispensing, and proper use

o radiopharmaceuticals.

Characteristics o radiopharmaceuticals

A radiopharmaceutical is a pharmaceutical

that, when ready or use, incorporates oneor more radionuclides (radioactive isotopes).

Radiopharmaceuticals are used or diagnosis

or therapeutic treatment o human diseases;

hence nearly 95% o radiopharmaceuticals are

used or diagnostic purposes, while the rest is

used or therapy.

Radiopharmaceuticals usually have no phar-

macologic eects, as they are used in tracer

quantities. There is no dose-response relation-

ship in this case, which thus diers signicantly

rom conventional drugs.

Radiation is an inherent characteristic o all

radiopharmaceuticals, and patients always re-

ceive an unavoidable radiation dose. In the case

o therapeutic radiopharmaceuticals, radiationis what produces the therapeutic eect.


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Chapter 1 Radiopharmacy Technology

Depending on the radiation characteristics

o the radionuclide, the radiopharmaceutical

is used either or diagnosis or or therapy. Di-

agnostic radiopharmaceuticals should decay

by gamma emission or positron emission, and

never emit alpha particles or even beta par-

ticles. On the other hand, therapeutic radio-

pharmaceuticals should decay by particulate

decay (alpha or beta) since the intended eectis in act radiation damage to specic cells.

Gamma radiation is characterised as electro-

magnetic radiation. When used in diagnostic

radiopharmaceuticals, the nally produced

gamma rays should be powerul enough to

be detected outside the body o the patient.

The ideal energy or conventional (SPECT)

nuclear medicine equipment is around 150keV. Normally, these radiopharmaceuticals are

in such small quantities that the radiation dose

received by the patient can be compared to

that o a simple radiology investigation.

Alpha decay is characterised by the emission o

an alpha particle rom the nucleus. This particle

is a helium ion containing two protons and two

neutrons. In beta decay a negatively charged

particle with the same charge and mass as an

electron is emitted. Alpha emitters, which are

monoenergetic and have a very short range

in matter due to their mass, thus leaving much

o its energy on a very small area (only a ew

cell diameters), are used only or therapeutic

purposes. Their clinical use is very limited, and

they are mainly used or research purposes, orstill are in early phase clinical trials.

Neutron rich radionuclides disintegrate by

beta (-) decay. Beta emitters represent di-

erent energy levels, and have dierent range

in matter (40 100m) depending on their

energy. Beta emitting radionuclides are also

used in radiopharmaceuticals mainly or thera-

peutic purposes.

Positron (+

) decay occurs in proton rich nuclei.The range o a positron is very short in matter.

At the end o the path o +-particles, positrons

combine with electrons and are thus annihilat-

ed, giving rise to two photons o 511 keV that

are emitted in opposite directions. Positron

emitters are used to label radiopharmaceuti-

cals or diagnostic purposes by imaging.

Radioactivity unitsRadioactivity is expressed in Becquerels (Bq)

as the SI-unit. One Becquerel is dened as one

disintegration per second (dps). Normally, ac-

tivities used in radiopharmacy are in the range

o megabecquerels (MBq) or gigabecquerels

(GBq). There is a non-SI-unit or radioactivity

called Curie (Ci), which is used in some occa-

sions. One Ci represents the disintegration o

one g o radium. The equivalence between

the Bq and the Ci is as ollows:

1 Bq = 2,7 x 10-11 Ci

1 Ci = 37 GBq

Every radionuclide is characterised by a hal-lie,

which is dened as the time required to reduce

its initial activity to one hal. It is usually denotedby t

, and is unique or a given radionuclide.


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Principles o radiation protection

Production, transportation and use o radio-

pharmaceuticals, as radioactive products, are

governed by regulatory agencies dealing with

radiation protection and nuclear saety. Only

licensed personnel in an authorised acility

are authorised to handle and use radiophar-

maceuticals.

The general principles oradiation protec-

tion are:

Justication: All procedures involving ra-

dioactive material must be justied.

Optimisation: The radiation exposure to

any individual should be as low as reason-

ably achievable. This principle is the widelyknown ALARA concept (as low as reason-

able achievable).

Limitation: The radiation dose received

by the personnel handling radioactive

material will never exceed the legally es-

tablished dose limits.

When planning acilities and procedures or

handling o radioactive materials according

to the ALARA principle, it is important to keep

in mind the basic principles or reduction o

radiation doses:

Time: The shorter the time o exposure to

radiation, the lower the dose to the op-

erator.

Distance: The radiation dose decreases

with a actor equal to the square root o

the distance rom the radiation source. The

operators distance rom the source can

be increased by using orceps, tongs, ormanipulators in handling the radioactive

material.

Shielding: The radiation dose can be re-

duced by placing shielding material be-

tween the source and the operator. For

protection against gamma radiation, walls

made o heavy concrete or lead bricks are

used. For transport containers, materialsuch as tungsten may be used or higher

energy gamma irradiation radionuclides,

giving a higher shielding per weight unit

when compared to lead.

Formulation and production o

radiopharmaceuticals

When designing a radiopharmaceutical, one

should have in mind the potential hazard the

product may have to the patient. The goal

must be to have a maximum amount o pho-

tons with a minimum radiation exposure o

the patient.


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The unction o the carrier molecule in a ra-

diopharmaceutical is to carry the radioactiv-

ity to the target organ, and to make sure the

radioactivity stays there. The uptake o radio-

activity should be as specic as possible, in

order to minimise irradiation o other organs

and parts o the body. This is particularly im-

portant when using radiopharmaceuticals or

therapy. But also or use in diagnostics, it isdesirable that the radiopharmaceutical is lo-

calised preerentially in the organ under study

since the activity rom non-target areas can

obscure the structural details o the pictures

o the target organ. It is thereore important

to know the specic uptake in an organ or a

potential chemical carrier, and also the rate o

leaking out o the organ/organ system. Thus,

the target-to-background activity ratio shouldbe large.

In a radiolabelled compound, atoms or groups

o atoms o a molecule are substituted by simi-

lar or dierent radioactive atoms or groups

o atoms. When a labelled compound is to

be prepared, the rst criterion to consider is

whether the label can be incorporated into the

molecule to be labelled. This may be assessed

rom knowledge o the chemical properties o

the two partners. Furthermore, one needs to

know the amount o each component to be

added. This is particularly important in tracer

level chemistry and in 99mTc-chemistry.

As the radiolabelled substances emerge rom

the laboratory to the clinics, there will be a

need or scaling up the batch size o the prod-

uct. This can be done either by increasing the

total volume o the produced batches or by

increasing the specic activity o the product,

or both. When doing this, one has to consider

two important aspects:

The infuence on the stability o the prod-

uct itsel due to possible radiolysis.

The need or additional operator protec-

tion due to handling o increased amounts

o radioactivity.

Manuacturing o radiopharmaceuticals is

potentially hazardous. Both small- and large-scale production must take place on prem-

ises designed, constructed, and maintained

to suit the operations to be carried out. Ra-

diation protection regulations stipulate that

radionuclides must only be used in specially

designed and approved radioisotope labora-

tories. National regulations with regard to the

design and classication o radioisotope labo-

ratories must be ullled. Such laboratories are

normally classied according to the amount

o the various radionuclides to be handled at

any time, and the radiotoxicity grading given

to each radionuclide.


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Premises must be designed with two impor-

tant aspects in mind:

The product should not be contaminated

by the operator.

The operator and the environment should

be protected rom contamination by the

radioactive product.

This is the basic principle o GRP Good Radio-

pharmaceutical Practice.

Quality considerations

The key elements o GRP comprise a previ-

ously dened manuacturing process known

to lead to a radiopharmaceutical o the de-

ned quality administered to the patient inthe prescribed dosage and orm. GRP is carried

out and recorded by trained and qualied sta

provided with the necessary acilities, includ-

ing adequate premises, suitable equipment,

correct materials and established procedures

in written orm. Quality must also be main-

tained during transportation and storage.

Training and qualications should cover gen-

eral principles o GMP (Good Manuacturing

Practice) and radiation protection. All training

must be recorded. Premises and equipment

must have a layout and design that minimise

the risks o errors by avoiding cross-contam-

ination and build up o dust and dirt, as well

as permit eective cleaning and maintenance.

They must also be designed to give proper

radiation protection to personnel and the

environment. Documentation is an essential

part o a quality system. Its purpose is to dene

the control system, to reduce the risk o error

that is inherent in oral communication and

to ensure that detailed instructions are avail-

able to personnel. The documentation system

should allow tracking o use and disposal o

any batch.

Radiopharmaceuticals are a special orm o

drugs that require much more handling im-

mediately beore administration to the pa-

tient, when compared to other drugs. Due

to the short hal lie o the radionuclide, it is

necessary or the nal preparation o many

radiopharmaceuticals to take place shortly

beore use. Only a minor proportion o all ra-diopharmaceuticals is delivered to hospitals in

a ready-or-use-orm. Handling o radiophar-

maceuticals in hospitals is thus an integral part

o the system by which the quality o these

pharmaceuticals is established.

Quality control o radiopharmaceuticals

All quality control procedures that are ap-

plied to non-radioactive pharmaceuticals are

in principle applicable to radiopharmaceu-

ticals. In addition, tests or radionuclidic and

radiochemical purity must be carried out.

Furthermore, since radiopharmaceuticals are

short-lived products, methods used or qual-

ity control should be ast and eective. Still,

some radiopharmaceuticals with very short

hal-lives may have to be distributed and


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used ater assessment o batch documenta-

tion even though all quality control tests have

not been completed.

Hospital departments dealing with radiop-

harmaceuticals should have a programme

or quality control o products beore admin-

istration to the patient. The complexity o

the quality control depends on whether theproduct is a ready-or-use-orm, or the product

is labelled in the department prior to admin-

istration (labelling kits).The specications and

quality control testing procedures or most o

the currently used radiopharmaceuticals are

given in the European Pharmacopeia, or other

Pharmacopeia (BP, USP etc.). For labelling kits,

a simple quality control procedure should be

stated in the package insert or the particularproduct. The quality control system should

include a procedure which describes mea-

sures to be taken i unsatisactory test results

are obtained.


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Chapter 2 Radiopharmacy DesignJames R. Ballinger, PhD

The radiopharmacy should be conveniently

located or deliveries and shipments (i supply-

ing external units). There should be arrange-

ments or receipt o out o hours deliveries,

such as a locked cupboard adjacent to the

unit but not requiring direct access to the

radiopharmacy by unauthorised personnel

such as couriers.

Layout

Restricted access is important, rom both a

radiation security and pharmaceutical manu-

acturing point o view. Only persons with

business in the radiopharmacy should be

allowed access. Within the radiopharmacy,

there will be urther restriction o access to

the clean areas. The principle is moving rom

dirty to clean areas with appropriate changeo apparel and sanitation o materials at each

interace. The dirty areas include delivery and

dispatch, an oce or preparation o paper-

work, a supplies store, a waste store, and a

QC laboratory. It is particularly important to

unpack supplies in the dirty area where there

is bulk storage; only minimal supplies are kept

in the clean area. Some radiopharmacies may

have a separate area or handling o131I. The

clean areas include a 99mTc dispensing room,

a support room, and a separate blood cell la-

belling acility. The layout should enable an

orderly fow o work, both within and between

rooms.

Facilities

Although many o the principles o radiophar-

macy design are universal, there may be di-

erences between countries in how rigorously

these principles are regulated. The radiation

aspects are covered in the EC Euratom Direc-

tive [1] while pharmaceutical manuacturing

is controlled under EudraLex [2]. The EANM

Radiopharmacy Committee has issued guid-ance on Good Radiopharmacy Practices [3]

which addresses both aspects. With respect

to both acilities and operations, there can be

conficting requirements between radiation

saety and aseptic processing. Another impor-

tant consideration is complete segregation

between radiopharmaceutical preparation

(aseptic processing) and blood cell labelling,

to minimise the risk o cross contamination.

In general, the radiopharmacy should be at

one end o a nuclear medicine/radiology de-

partment rather than in the middle. Indeed,

it is best i it is on an outside wall as there

is less concern about shinethrough o radia-

tion. Although high levels o radioactivity are

handled, in most cases local shielding is used

(e.g. around generators and individual vials)

rather than extensive shielding in walls.


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Chapter 2 Radiopharmacy Design

Figure 1 presents a sample layout o a large

radiopharmacy with ideal separation o di-

erent working areas required or handling

and radiolabelling o99mTc and other SPECT

radiopharmaceuticals.

Figure 1: Sample layout o a radiopharmacy

Equipment and ttings

Standard equipment includes one or more

dose calibrators (ionisation chambers), labora-

tory equipment (e.g. balance, centriuge), and

appropriate radioanalytical equipment (radio-

chromatogram scanner, gamma counter; more

advanced laboratories may have a multichannel

analyser and radio-HPLC system). This equip-

ment should be dedicated to use in the radiop-

harmacy and not shared with outside users.

Radiation survey meter(s) must be available to

check or contamination within the unit and at

the boundary o the radiation controlled area. I

radioactive material is shipped, there must be

a dose rate monitor (i.e. calibrated in Sv/h) to

allow determination o the Transport Index.

Rerigerators and other areas where sensitive

supplies are stored should have temperature

monitoring. This can be as simple as manual

recording on a daily basis o minimum and

maximum temperatures on a calibrated ther-

mometer or an electronic output to a chart

recorder or monitoring sotware.

Volatile materials such as131

I products and or-ganic solvents should be handled in a ume

cupboard with a minimum infow o 0.5 m/s.

The exhausted air is vented to the atmosphere

and care must be taken in the location o the

stack. Filters are not generally used as they

could become radiation hazards themselves.

The clean areas should be lined (foor, walls, and

ceiling) with a smooth, continuous, impervious,non absorbent, cleanable material such as weld-

ed sheet vinyl. Corners should be coved (curved)

to minimise dirt collection. Light xtures should

be recessed and fush with the surace. Benches

must be made o impervious material (solid is

preerred over laminate) and may require ad-

ditional support or lead shielding.

There should be transer hatches with inter-

locking doors so supplies can be sanitised and

passed into the next room without allowing

direct contact. Entry/change rooms should

have interlocking doors and a physical barrier,

or at least a line on the foor, to demarcate the

two sides. Changing on entry will involve, at a

minimum: clean low-lint lab coat, shoe covers,

hair cover, and gloves.


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Aseptic manipulations should be perormed

either in a pharmaceutical isolator or a laminar

airfow hood.

The bulk o the work or the oreseeable uture

will continue to be reconstitution o kits with99mTc pertechnetate. Thus, a single workstation

is adequate even i there is occasional handling

o other radionuclides (e.g. preparation o111

Inpentetreotide or 90Y ibritumomab tiuxetan).

However, i the usage o other radionuclides is

more extensive, a separate workstation should

be provided. In addition to minimising the po-

tential o cross contamination o99mTc prod-

ucts with longer lived and/or particle emitting

radionuclides, it also reduces the risk that a

major spill o one o these radionuclides could

impede 99mTc dispensing or a number o days.In the uture, some products such as 90Y or177Lu labelled peptides might be prepared by

automated synthesis units located in a sepa-

rate workstation.

In general, radiation saety is maintained by

local shielding (e.g. vial shields, syringe shields,

bench top shields) rather than shielding in the

walls. The waste store may require shielding, as

may an area where high levels o radioactivity

are handled i there is a signicant radiation

eld in the adjacent room. The 99Mo/99mTc

generator usually requires additional exter-

nal shielding.

It is simplest to dispose o all sharps into rigid

biohazard containers behind a lead shield.

Once the radioactivity has decayed to back-

ground levels, the containers are disposed as

biohazard waste. Radionuclides should be

segregated by hal lie to minimise the build

up o waste.

The blood labelling suite will require a vari-able speed centriuge capable o accepting a

range o tube sizes. Ideally the centriuge will

be located within the workstation, to minimise

the number o transers out o the Grade A

environment.

Area designation

A radiation controlled area is one in which a

ull time worker might receive an exposure o6 mSv/yr whole body or 150 mSv/yr extrem-

ity. For a radiation supervised or monitored

area, the exposure limits are 1 mSv/yr whole

body or 50 mSv/yr extremity. Because o the

presence o generators and the amount o

radioactivity handled, the hot lab will be des-

ignated a controlled area. Other areas may be

classied as supervised.

Radiation designated areas must be physically

demarcated and have signs indicating the

type o hazard. There should be washing and

changing acilities available at the perimeter;

and radiation monitoring or contamination

must be perormed. Eating and drinking is

prohibited in designated areas.


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15

Chapter 2 Radiopharmacy Design

Conicts between radiation and aseptic

regulations

As noted above, there can be conficts be-

tween the requirements o dierent regula-

tory systems. However, there are also areas o

agreement. For example, segregation o ac-

tivities, with change o apparel and dedicated

equipment, minimises cross contamination

with both radioactivity and microbes, as doesa separate air handling system and the use

o containment hoods/glove boxes. Special-

ist trained sta are required and meticulous

record keeping is important.

However, even within these areas, there are

conficts. For radioprotection, the production

area should be at negative pressure relative

to the outside world (containment o gaseousor aerosol discharge), while pharmaceutical

aseptic units are at positive pressure to mini-

mise ingress o microbes. The compromise is

a negative pressure isolator within a positive

pressure room. From a pharmaceutical point

o view, there should be a minimum number

o trained sta, whereas or radioprotection

there should be a rotation o sta to share

the radiation dose. Radioprotection requires

handwashing acilities at the perimeter o

the controlled area, while the medicines in-

spectors dont want a sink anywhere near a

cleanroom. Radiopharmacy managers must

nd a delicate balance to satisy both sets o

inspectors.


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16

Chapter 3 RadiopharmacyPreparing & Dispensing Radiopharmaceuticals

Geraldine OReilly, PhD

Most radiopharmaceuticals are administered

by IV injection; so good pharmaceutical prac-

tice is an important consideration in their

preparation. All manipulation o radioactive

materials should be carried out, using asep-

tic techniques, within the shielded contained

workstation or laminar fow cabinet (LAFC)

(Figure 1). No ood or drink, cosmetic or smok-

ing materials, crockery or cutlery should bebrought into an area where unsealed radioac-

tive substances are used.

Figure 1: Laminar fow unit or preparation o

99mTc radiopharmaceuticals

Personnel monitoring

All sta classied as radiation workers must

wear a personal dosimeter (TLD, lm badge,

electronic dosimeter). In addition to their regu-

lar whole body dosimeter, sta preparing and

handling radioactive materials should wear a

nger TLD to monitor extremity dose. Prior to

each use, the TLD should be wiped, using an

alcohol wipe, and worn inside the glove. Upon

leaving the preparation area, the nger TLDshould be removed and appropriately stored.

Introduction

The radiopharmacy would normally be desig-

nated as a controlled area; and access will be

restricted. Only properly trained sta should

be permitted to work in the radiopharmacy;

and strict adherence to work procedures is

essential. There are three undamental pa-

rameters that aect sta doses in the radio-

pharmacy:

1. the distance between the sta member

and the source,

2. the time spent manipulating the source

and

3. the amount o shielding used to reduce

the dose rate rom the source.

Sometimes there is a trade o between theseparameters as using more shielding might in-

crease handling time. With this in mind, care-

ul design o procedures should optimise the

workfow. Skill and expertise o the sta carry-

ing out the procedures are also important ac-

tors. Thus, it is crucial that sta are adequately

trained.

Work practices in the radiopharmacy should

be standardised and incorporated in standard

operating procedures (SOPs). These proce-

dures should be documented and made

readily available to those working in the ra-

diopharmacy. This will ensure harmonisation

o practice and maintenance o standards. Ac-

curate and comprehensive record keeping is

an essential part o good work practice in aradiopharmacy.


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17

Chapter 3 Radiopharmacy: Preparing & Dispensing Radiopharmaceuticals

Protective clothing

Prior to commencing work in the radio-

pharmacy, sta should ensure that they wash

their hands thoroughly. Beore a person en-

ters an area where radioactive substances are

handled, any cut or break in the skin should

be covered. Dressings should incorporate a

waterproo adhesive strapping. Protective

coats or gowns should be worn or prepara-tion and dispensing o radiopharmaceuticals.

Disposable gowns oer benets in terms o

maintaining sterility. Gloves worn in the LAFC

or contained workstation must be powder ree

in order to prevent clogging o the air lters

within the cabinet. Alcohol rub should be

rubbed onto gloves and allowed to evapo-

rate beore entering the LAFC. Ater handling

radioactive materials, gloves must alwaysbe removed and disposed o as radioactive

waste beore handling/touching any other

materials/suraces within the radiopharmacy.

Hands should be washed again ater removal

o gloves. Upon leaving the radiopharmacy,

disposable gowns should be removed. Prior to

disposal, they should be stored as radioactive

waste until monitoring conrms that they are

at background radiation levels.

Protective equipment

The use o protective equipment, when han-

dling radioactive materials, can have a signi-

cant impact on reducing sta dose. Laborato-

ries and other work areas or manipulation o

unsealed radioactive substances should be pro-

vided with equipment kept specically or thispurpose, and should include the ollowing:

1. tools or maximising the distance rom the

source, or example tongs and orceps,

2. syringe shields,

3. vial shields,

4. drip trays or minimising the spread o con-

tamination in the case o spillage,

5. shielded syringe carriers and

6. decontamination kit

Unshielded syringes or vials should never be

used during manipulation o radiopharma-

ceuticals. Equipment should be stored outside

the laminar fow cabinet when not in use and

should be cleaned regularly in accordance

with local recommendations.

Work procedures

GeneralBeore starting the preparation and dispensing

o radiopharmaceuticals, all o the materials

required should be assembled and placed in

or close to the contained workstation/LAFC

(Figure 2). All vials containing radioactive

materials must be shielded while handling;

and vials should only be removed rom their

shields or assay, inspection or disposal. All sy-

ringes containing radioactive liquids must be

shielded while handling, except during an as-

say. Unshielded vials or syringes should not be

handled directly. Long handled tongs should

be used to place and remove unshielded ma-

terials in the dose calibrator.


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18

Work procedures should be designed so as

to minimise exposure rom external radiation

and contamination. Care must be taken to pre-

vent spillage rom occurring. All manipulation

or dispensing radioactive materials should

be carried out over a drip tray, in order to

minimise the spread o contamination due

to breakages or spills. Should a spill occur then

it should be cleaned up beore proceedingany urther. All items that might be contami-

nated should be removed rom the aected

area and stored saely. Care should be taken

doing this, in order to minimise the spread

o contamination. As with all spills, it is more

convenient to allow natural decay to take care

o the contamination, i the items are not re-

quired immediately. For those items that are

needed, they should be cleaned with alcoholswabs taking care not to spread the contami-

nation. Using multiple swabs which are then

disposed is the most eective way to remove

contamination.

Figure 2: Preparation o work area

(courtesy o VirRAD)

Reconstitution o pharmaceuticals

The manuacturers recommendations should

be ollowed closely as many pharmaceutical

kits have specic reconstitution instructions in

terms o the activity and volume to be added

to the kit. Recommended incubation times

also vary and must be adhered to. Some ra-

diopharmaceuticals must be rerigerated ater

preparation. Thereore consideration should begiven to the provision o suitably shielded re-

rigeration acilities. Most radiopharmaceuticals

are reconstituted with 99mTc; and this assump-

tion applies to the ollowing paragraphs.

Protective caps should be removed rom the

pharmaceutical vials; and the vials should be

placed in the appropriate labelled vial shields.

The rubber septum o each pharmaceutical vialshould be swabbed with alcohol; and the alco-

hol should be allowed to evaporate (Figure 3).

Shielded 10ml or 5ml syringes capped with

21G needles are generally used to recon-

stitute the pharmaceuticals.

The appropriate activity o 99mTc solution

should be added to each shielded phar-

maceutical vial; and the pharmaceutical

should be allowed to incubate or the

specied length o time.

Having introduced 99mTc solution to a pharma-

ceutical vial, the needle should not be placed

back into the shielded elution vial. In the event

that additional

99m

Tc solution is required, a newsyringe and needle must be used.


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19


When introducing 99mTc solution or saline

to a vial, it may be necessary to equalise

pressure by withdrawing an equivalent

volume o air at the same time. This can

be done gradually as the solution is added.

In general, breather needles are not recom-

mended and should not be used unless

specically recommended by the manu-

acturer o the pharmaceutical.

The activity and volume o 99mTc solution

added to each pharmaceutical should be

recorded in the laboratory log book.

Figure 3: Disinection o a kit beore use

(courtesy o VirRAD)

Preparation o patient injections

Ater the recommended incubation time

has elapsed, patient activities are with-

drawn using shielded 2ml syringes capped

with 21G.

Each patient activity must be measured

and recorded in the radiopharmacy log.

The activity withdrawn or each patientmust be within 10% o the required activ-

ity at the specied injection time.

Patient injections are usually prepared in

a volume o 1ml. There are exceptions to

this: the manuacturers instructions on the

volume should be ollowed. Saline may be

used to increase the volume i the volume

in which the required activity is obtainedis below 1ml.

Once the patient injection is prepared,

the green needle must be replaced with a

needle o the appropriate gauge, and the

air in the syringe must be expelled. When

expelling the air, ensure that the needle

is capped.

When changing needles, withdraw the

plunger suciently so as to pull liquid rom

the syringe tip.

I, at any time, there is a droplet o liquid vis-

ible in the needle cap, replace the needle

and cap.


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20

Each patient injection must be labelled

with an appropriate label detailing the

patient name, scan type, activity to be ad-

ministered, date and time o injection.

Waste management procedures

Non-radioactive waste should be separated

rom radioactive waste to minimise storage

requirements; and it should be disposed oas normal hospital waste. Shielded waste bins

should be lined with plastic liners that can be

easily removed when ull.

Technetium 99m is the main isotope in use

in the radiopharmacy: the duration o stor-

age will be determined by its hal lie o 6.02

hours. Longer lived waste should be stored

separately. Radioactive waste generated dailywithin the radiopharmacy includes syringes,

elution vials, pharmaceutical vials, needles and

swabs. Waste arising rom the preparation and

dispensing o radiopharmaceuticals should

be primarily disposed in the waste bin built

into the contained workstation/LAFC. Some

bulky items such as paper waste and gloves

may be disposed in a shielded waste bin in the

pharmacy, as long as there is no risk o con-

taminating the room by removing them rom

the cabinet. Radioactive waste contaminated

by blood (e.g. syringes ollowing cell labelling

procedures) should not be let in the worksta-

tion but removed to a shielded bin.

The waste container in the workstation should

not be allowed to overfow and should be

emptied regularly. The bin is best emptied

beore starting work in the cabinet, when the

waste in the bin has decayed over night.

Segregation o waste according to hal-lie

is good practice and can reduce the length

o time that waste arising rom shorter livedisotopes has to be stored.

Paper waste

Any gloves used in the cabinet or used to

handle blood or isotopes will be considered

to be contaminated. Paper tray liners in the

cabinet or paper used to clean suraces in

the cabinet are also considered to be con-

taminated. Contaminated gloves and papershould be disposed in a shielded bin in the

pharmacy, as long as there is no biological

contamination (blood or plasma). Otherwise

this waste should be placed in a sharps bin, us-

ing tongs. For long term storage o waste, the

waste should be removed rom the shielded

bin, labelled with details o the contents and

stored as radioactive waste in a designated

store.

Sharps bins

Syringes, needles, butterfies etc. should be

disposed o ater use to shielded sharps bins.

Bins should not be allowed to overll. Full

sharps bins should be closed, marked radio-

active, dated and removed to the radioactive

waste store.


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21


Disposal o waste

All radioactive waste - sharps bins, paper

waste, ventilation kits - should be securely

stored and monitored regularly. Waste should

be checked by using a suitable meter in a low

background environment and should be dis-

posed o, once it has decayed to background

level. Any items above background should

be retained or a urther period o decay instorage. All radioactive warning labels should

be removed rom waste, prior to disposal in

hospital waste. The hospital waste disposal

policy should be adhered to.

Dose calibrator quality assurance

The accuracy and constancy o the dose

calibrator should be checked regularly with

a reerence source. Isotopes such as Co-57,Ra-226 or Cs-137 with a relatively long hal lie

are suitable. The use o more than one source

will allow checking o the calibrator over a

range o energies. A daily check o system

operation, accuracy and constancy should

be carried out. Linearity tests may be carried

out less requently.

Beore starting the QA, remove all radioactive

sources rom the vicinity o the calibrator and

record the background reading. The isotope

selected on the dose calibrator should be that

o the reerence source. The accuracy test en-

sures that the activity is within 10 percent o

a given calibrated reerence source o known

activity (within 5%). At least two sealed sourc-

es with dierent principal photon energies,

one o which has a principal energy between

100 keV and 500 keV, should be used to deter-

mine accuracy upon installation, and at least

annually thereater. For the routine accuracy

check, place the reerence source in the dose

calibrator and record the activity measured.

The value recorded should be within the al-

lowable tolerance (typically 10%).

The constancy test looks at reproducibility in

measuring the activity o a known source over a

long period o time. The dose calibrator should

be checked daily or constancy at the setting o

the most requently used isotope. To carry out

this test, the reerence source is let in place; but

the setting is changed to Tc-99m and the value

indicated is recorded. This can also be done

or other isotopes that are selectable on thedose calibrator. The ratio o the values indicated

to that o the activity o the reerence source

should be constant over time.

The linearity test ensures that the dose calibrator

can indicate the correct activity over the range

o use o administered or measured activities.

The dose calibrator should be tested or linearity

upon installation and at least quarterly therea-

ter. Technetium-99m is most requently used or

the linearity test because o its availability and

short hal-lie. The variation between indicated

and known activity should not exceed 10%.

The results o the routine QA should be docu-

mented and stored as part o the radiophar-

macy records.


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22

Chapter 4 RadiopharmacyKits & Techniques

Helen Ryder

patient movement; or too short a time per

image resulting in poor count statistics. I

the hal-lie is too long, then there may be

excessive radiation exposure to the patient

over its period o decay.

3. High target - background ratio

The radionuclide is only o use i it accu-

mulates within the target organ, and this

is oten enhanced by binding the radionu-clide onto a tracer that will take it to the

organ under study. The binding should be

sucient that little radionuclide is let ree

in the body tissues, thus enhancing the

target-to-background ratio.

4. Low dose rate to both patient and per-

sonnel

To avoid excessive received radiation dose,

it is necessary to avoid those radionuclideswhich have signicant particulate emis-

sions i.e. alpha and beta particles. The short

range o emission means that these are

absorbed within the patient, adding to the

radiation dose with no increase in image

quality. Because o the reality o radiation

decay, that is the attempt to balance the

particles in the nucleus, beta rays are oten

ound as a product o decay. The rate o

emission o these rays can be signicantly

lower in two particular decay processes:

isomeric transition and electron capture.

5. Non-toxicity of radiopharmaceuticals

Most radiopharmaceuticals must be inject-

ed, with a small amount being ingested or

inhaled. Thus they must be non-toxic in

nature, sterile and pyrogen-ree.

Radiopharmaceuticals have been dened as

radioactive drugs that, when used or the

purpose o diagnosis or therapy, typically elicit

no physiological response rom the patient.

In the main this is true, and though some

radiopharmaceuticals have been known to

cause minor side eects (such as urticaria,

or changes in blood pressure), these are notcommonly seen in practice.

Ideal radionuclide

Properties o the ideal diagnostic radionuclide

include:

1. Pure gamma emitter, with a gamma en-

ergy within the range of 100 - 250 keV, to

match the optimum scanning range of agamma camera.

The radiation emitted by a radionuclide

should be sucient to be detected outside

the patient or imaging purposes, thus lim-

iting the choices to X-rays or gamma rays.

However, too high an energy will result in

the gamma ray penetrating the detector o

the imaging device without being stopped

and hence recorded.

2. A half-life which is suitable for diagnostic

use i.e. 1.5 X test duration

The hal-lie o a radionuclide determines

the rate o radioactive decay. I the hal-lie

is very short, then the activity may have

decayed to a very low level beore imag-

ing can be started. This can result in either

a long scanning time, where there may be


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23

Chapter 4 Radiopharmacy: Kits & Techniques

6. Chemical stability during use

Not all radioisotopes are suitable or binding

to tracers. Technetium 99m has the ability to

readily bind to a wide variety o compounds

under physiological conditions [1] without

causing physiological changes in the patient.

7. Inexpensive and readily available

Many suitable radionuclides are obtainable

rom a generator, which may be deliveredto a nuclear medicine acility and eluted as

required. This results in economical use o

the radionuclide.

Other radionuclides are produced in cyclo-

trons as specialised units and are shipped

ready or use. These are decaying rom the

moment they are manuactured and thus

must be ordered or use on a particular

day, either as the resultant product or orpreparation with other tracers. This can be

expensive and uneconomical or everyday

requirements.

8. Ease of preparation and appropriate

quality control

Preparation requirements o more than three

steps do not usually meet the denition o

ease o preparation. Nor should a complex

variety o equipment be required. Quality

control procedures should be available to

check each batch o the radiopharmaceuti-

cal reconstituted in the working laboratory.

This ensures that the preparation received by

the patient will result in high-quality images

without detrimental eect on the patient.

Radionuclide generator

A radionuclide generator is a source o radio-

nuclides or the preparation o radiopharma-

ceuticals. It is based on the separation o a

short lived radionuclide (daughter) rom a

long lived radionuclide (parent). Examples o

radionuclide generators are provided in Table

1. The most commonly used generator in Nu-

clear Medicine is the99

Mo/99m

Tc generator.

Table 1: Radionuclide generators

Molybdenum/Technetium (99Mo/99mTc)

generator

The molybdenum/technetium generator con-

sists o an alumina-lled column onto which is

absorbed 99Mo. The 99Mo is present as 99MoO4

2-,

which decays to its daughter radionuclide 99mTc

as pertechnetate 99mTcO4

- (Figure 1). 99mTc is re-

moved rom the columns as 99mTcO4

- by draw-

ing over a solution o sodium chloride (NaCl)

0.9% w/v across the column (Figure 2). This

process is known as eluting the generator and

the resultant eluate is used to compound the

radiopharmaceuticals (Figure 3).


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24

Figure 1: Decay scheme or 99Mo and 99mTc

(courtesy o VirRAD)

Figure 2: Molybdenum/Technetium generator

Figure 3: Eluting the generator (courtesy o VirRAD)

The time o maximum yield o99mTechnetium is

23 hours, ater which the 99mTc appears to decay

with the hal-lie o99Mo (66hrs). This time o

almost one day is thereore eminently suitable

or the requirements o the Nuclear Medicine

department (Figure 4).

Attach Saline Vial Insert Elution vial

in lead shielding

Attach Elution vial and wait

until elution is completed

Remove elution vial and attach

protecting vial/Cap


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25


Figure 4: Plot o logarithm o99Mo and 99mTc

activities against time showing transient

equilibrium. The generator is eluted daily and

the 99mTc activity grows again until transient

equilibrium is reached (courtesy o VirRAD).

Preparation o99mTc-

radiopharmaceuticals rom kits

Categories o radiopharmaceuticals:Ready-to-use radiopharmaceuticals

Instant kits or preparation o 99mTc products

Kits requiring heating

Products requiring signicant manipulation

Reconstitution o proprietary kits:

The basic steps involved in the reconstitution

o99mTc radiopharmaceuticals rom generators

and kits are outlined in Figure 5. Appendix 1

urther details the procedure or reconstitu-

tion o proprietary kits. An example o how

to calculate the required activity is provided

in Appendix 2.

Figure 5: Reconstitution o99mTc

radiopharmaceuticals rom generators and kits

Appendix 1: Reconstitution o proprietary

kits with 99mTc

Record the ollowing inormation in the

injection log:

The batch number and expiry date o

the elution vial, pharmaceutical vials

and saline bottles.

The activity and volume o the eluate.

The activity and volume o 99mTc solu-

tion introduced to each pharmaceutical

vial during labelling.

The generator is eluted

every morning and used

or reconstitution o the

kits. Some departments

may have a high genera-

tor and a low generator.

The low generator is

useul or lung perusion

scanning, Meckels diver-

ticulum and thyroid scintigraphy.


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26

Remove the fip/

oil cap rom the

pharmaceutical

vial and place

the vial in a la-

belled shielded

container. Swab

the rubber septum with alcohol, and al-

low the alcohol to evaporate.

When reconstituting the pharmaceu-

tical use a shielded 5ml syringe

capped with a green needle.

10ml and 2ml syringes may also

be used, depending on the re-

quired volume.

The required activity o 99mTc solution mayneed to be topped up to the required vol-

ume with saline.

Patient injections are typically made

up to a volume o 1ml. The re-

quired activity o radio-labelled

pharmaceutical may need to

be topped up to 1ml with

saline.

All patient injections are to be labelled with

an appropriate label, detailing the patient

name, date and time o procedure, proce-

dure type and activity to be administered.

99mTc-Cardiolite

Act ............MBq Date ...............Pt. Name

Appendix 2: Calculation o activity

Example calculation o activity to add to vial

Example: What is the minimum activity o99m

Tc eluate needed to be added to a vial o99mTc-

Cardiolite at 8a.m., to obtain ve injections o

740Mbq each 2 injections at 8a.m., 3 injec-

tions at 11a.m.?

The equation to calculate radioactive decay is:

At= A

oe-t

1. Calculating

is the decay constant which or any ra-

dionuclide is dened as

2. Where Ao = 740MBq, t= -3

(When calculating an activity *prior* to the

time o known activity, the value o t is nega-

tive. To calculate the decay o a radionuclide

*rom* a known activity to a later time then t

has a positive value.)

At= A

oe-(0.115)(t)

At= A

oe-(0.115)(-3)

At= 740 x e0.346

At = 740 x 1.413 = 1045.6MBq


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27


Thereore the required activity to be drawn up

per injection at 8a.m. is 1045.6MBq.

The total activity o99mTc to be added to the

vial o Cardiolite is:

a. 2 x 740MBq or two injections at 8a.m.

=1480MBq

b. 3 x 81045.6MBq or three injections at11a.m. = 3136.9MBq

c. Add (a) to (b) to get total o 4616.9MBq to

add to vial o HDP

Quality control in the radiopharmacy

Rationale or perorming quality control

I a radiopharmaceutical is improperly pre-

pared it can result in a non-diagnostic study.

The procedure must then be repeated result-

ing in increased radiation dose and patient

discomort. Many dierent classications o

impurities aecting the imaging process canbe distinguished, as outlined in Table 2. Meth-

odologies or detecting these impurities are

briefy outlined in Table 3.

Table 2: Classication o impurities

Type o Impurity Example Efect

Radionuclidic 99Mo Increased radiation dose; poor image quality

Radiochemical Free 99mTc-pertechnetate Poor image quality; increased radiation

Chemical Al3+ Poor image quality due to labelling problems

Table 3: Detection o impurities

Method Type o Impurity

Dose calibrator/multichannel analyzer Radionuclidic

Thin layer chromatography Radiochemical

Colorimetric Chemical

QC test procedures or Mo/Tc generator

1. Mo-99 breakthrough:

Mo-99 is assayed directly in the special lead pig supplied by the manuacturer o the dose calibra-

tor. 99mTc is then assayed directly in the plastic sleeve in the dose calibrator. The activity o99Mo

must not exceed 0.1% o the total 99mTc-activity. Dose calibrators have dierent methods how

to determine whether this amount is exceeded dependent on manuacturer and age.


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28

The timetable o required testing is shown in Table 4, and or optional testing in Table 5.

Table 4: Required QC testing o a 99Mo/99mTc generator

Test Frequency Specications

Mo breakthrough Every elution


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29


Radiochemical purity, paper and thin layer

chromatography

The radiochemical purity (RCP) o a radio-

pharmaceutical is the ratio o the radionuclide

present in a bound orm (i.e. as a bound radio-

pharmaceutical) to the radionuclide present in

its unbound orm (i.e. reeradionuclide).

It can happen that, during the binding o radio-nuclide to pharmaceutical, the complete re-

duction o pertechnetate does not occur and

some ree or unbound technetium is present

in the resulting solution. This can also happen

i the reduced radionuclide becomes oxidised

again. A result can be poor imaging o the

radiopharmaceutical and increased radiation

dose or the patient. To ensure radiochemical

purity, it is important to perorm regular qual-ity control on the radiopharmaceuticals.

General principles o planar chromatography

or radiochemical purity testing

The test strip or chromoplate may be obtained

as a commercial product, and dierent types

are produced or dierent pharmaceuticals.

Generally a ew microlitres o the product to

be tested is applied near the bottom (origin)

o the chromoplate. The chromoplate is then

placed in a solvent, ensuring that the bottom

(origin) point is not immersed. The solvent is

then allowed to rise or migrate up along the

plate. The dierent chemical species separate;

the most soluble product moving the urthest

distance along the chromoplate. (Figure 7)

Figure 7: A chromatography strip with the

position o the origin and solvent ront

shown. The sample is placed at the point

marked on the origin.

When the solvent has moved the required

distance along the chromoplate (the solvent

ront), then it is removed rom the solvent and

allowed to dry. As a next step, this is read by

scanning the radiochromatogram, either by

passing it under a scintillation detector or on

the surace o a gamma camera. The distance

travelled along the chromoplate by each o

the radiochemical species is expressed as a

raction o the distance travelled by the sol-

vent ront (Rvalue). From these R

values can

be determined the quantity o activity in each

portion and thus the respective binding qual-

ity o the radiopharmaceutical.


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Radiochemical impurities in 99mTc

radiopharmaceuticals

Common impurities in 99mTc-kits are 99mTc-

pertechnetate and 99mTc-colloid. However a

number o 99mTc-preparations may contain

dierent impurities that have to be covered

by respective validated tests (e.g. 99mTc-Tartrate

in 99mTc-MAG3). A number o recommended

chromatography methods are shown belowin Table 6 and Table 7.

Separation o radiopharmaceutical and

impurity

Radiochemical purity testing can be based

on thin layer or paper chromatography (TLC),

solid phase extraction methods based on

cartridges (SPE), ltration methods, HPLC or

electrophoresis. Methods may derive romthe European Pharmacopeia, the SPC o the

labelling kit or validated literature methods. In

many cases a variety o methods are available

or one particular radiopharmaceutical. TLC

methods and SPE are most commonly used

and recommendations in this guidance are

based on these methods.

Equipment and location:

The determination o the radiochemical purity

in the hospital with TLC can be perormed with

little expenditure o material and equipment.

It should be perormed in a dedicated area

with radiation protection and proper ventila-

tion (organic solvents).

Quantication:A variety o methods may be used to quantiy

impurities including cut and count in the dose

calibrator, using dedicated scanner, gamma

cameras and others. The dierences are in

sensitivity, resolution, linear range, speed,

availability and practicability and should

be chosen dependent on available space,

throughput and general organisation o the

radiopharmacy. Equipment used or qual-ity control should be regularly calibrated.

Generally, the quantication o the radio-

chemical purity is based on the equation

below.

In case the radiochemical purity limit is not

reached, the preparation has to be discarded

and clearly labelled that it may not be used

or patient application.


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Table 6: Recommended methods or quality control based on TLC

Solid Phase / Mobile PhaseR Radio-

pharmaceuticalR Impurity

Pertechnetat ITLC-SG/0.9% NaCl Front Start

99mTc-DMSA ITLC-SG/ 2- Butanone Start Front

99mTc-Diphosphonates

MDP, DPD, HEDP

A) ITLC-SG/ 1M NaAcetate

B) ITLC-SG/ 2-Butanone

Front

Start

Start

Front

99mTc-DTPAA) ITLC-SG / NaCl

B) ITLC-SG / 2-Butanone

Front

Start

Start

Front

99mTc-ECD Ethylacetate / Baker Silica gel Front Start

99mTc-HMPAOA) ITLC-SG/ 2-Butanone

B) ITLC-SG/ 0.9% NaCl

Front

Start

Start

Front

99mTc-IDA-Derivates

A) saturated saline solution /

ITLC-SG

B) 50% Acetonitril / ITLC-SG

Start

Front

Front

Start

99mTc-Colloids ITLC-SG / 2-Butanone Start Front

99mTc-MAA ITLC-SG / 2-Butanone Start Front

99mTc-ECA) ITLC-SG/2-Butanone

B) ITLC-SG/ 0.3M Acetic acid

Start

Front

Front

Start

99mTc-MIBI Ethanol /Baker Aluminiumoxide Front Start

99mTc-Depreotide

A) ITLC-SG / saturated NaClB) / ITLC-SG

Methanol/1Ammonacetate

(50/50)

Start

Front

Front

Start

99mTc-TetroosminITLC-SG / Aceton :

Dichloromethane =35:65 /Middle Start/Front

99mTc-monoclonal Anti-

bodies; HIG, ZevalinITLC-SG/ 0.9% NaCl Start Front

111

In Octreotide 0.1M Na-Citrat pH5 / ITLC-SG Start Front


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Table 7: Recommended methods or quality control based on SPE

Cartridge / SolventRadiopharma-

ceutocalImpurity

99mTc-MAG3SEPPAK C18 light1.) 0.001N HCl,2.) Ethanol/0,9% NaCl (50% 50%)

Eluate 2 column/ eluate 1


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Several blood cellular elements can be ra-

diolabelled with dierent radionuclides and

radiolabelling approaches or varies clinical

applications (Table 1). Regardless o the na-

ture o the blood cells, o the radionuclide

used or o the clinical application, it is neces-

sary to maintain both cell viability and steril-

ity and to avoid the operators exposure to

biological and radiation hazard during cellmanipulation and radiolabelling. Manipula-

tions and radiolabelling procedures o cells

require strict aseptic conditions and should

ollow the EANM guidelines on current Good

Radiopharmacy Practice (cGRPP) in the Prepa-

ration o Radiopharmaceuticals [1]. The use o

an open or closed vial system on a laboratory

workbench is not an alternative to a controlled

sterile environment. Cross contamination ormix-up o blood should be prevented at all

times. Preparation o radiolabelled cells must

be perormed successively or by dierent peo-

ple in dierent locations. All suraces should

be properly cleaned, decontaminated and dis-

inected prior to use, ater all procedures are

completed, and whenever suraces are overtly

contaminated.

Chapter 5 RadiopharmacyBlood Labelling

Tanja Gmeiner Stopar, PhD

During radiolabelling, approved written proce-

dures should be ollowed at all times. All mate-

rials used should be identied and certied or

human use. Whenever possible radiochemical

purity should be checked and radiolabelling

eciency (percentage o radiolabelling o

cells) calculated. Beore release, radiolabelled

blood should be checked or aggregation o

clumping o cells and or presence o particu-late contamination. At regular intervals, the

integrity o the cells should be ascertained

by use o suitable procedures i.e. using trypan

blue. Prior to administration, control o patient

identity should be perormed [1-3].

Red blood cells

Red blood cells (RBCs) are the most common

type o blood cell. Their main unction is de-livering oxygen rom lungs to body tissues.

Erythrocytes are continuously being produced

in the red bone marrow o large bones. They

develop rom committed stem cells through

reticulocytes to mature erythrocytes and

live a total o about 120 days. The aging o

erythrocyte undergoes changes in its plasma

membrane making it susceptible to recogni-

tion by phagocytes and subsequently they

are destroyed in the spleen, liver and bone

marrow [4].


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Table 1: Clinical applications o radiolabelled cells and radiolabelling approach

Clinical application Blood cellular elementRadionuclide

/radiolabel

Radiolabelling

approach

Cardiac and vascular

imagingRed cells 99mTc-pertechnetate

In vivo

In vivo/in vitro

Gastrointestinal

bleedingRed cells 99mTc-pertechnetate

In vivo

In vivo/in vitro

Spleen imaging Denaturated red cells 99mTc-pertechnetateIn vitro

In vivo/in vitro

Blood volume and red

cell volumeRed cells

99mTc-pertechnetate51Cr-chromate

In vitro

Red cell survival Red cells 51Cr-chromate In vitro

Site o red blood cell

destruction Red cells51Cr-chromate In vitro

Inection and

infammationWhite blood cells

111In-oxine111In-tropolone99mTc-HMPAO

In vitro

Abnormal platelet

depositionPlatelets

111In-oxine111In-tropolone99m

Tc-HMPAO

In vitro


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Radiolabelling with 99mTc

Radiolabelling approaches may by in vivo, in

vitro and combined in vivo/in vitro. The basic

mechanism o the radiolabelling o RBCs with99mTc is in all approaches the same. The RBCs

are pre-tinned by stannous ions or 10-30

min beore 99mTc-pertechnetate is added to

the cells. The stannous ions diuse into the

cell and are rmly bound to cellular compo-nents. The pertechnetate diuses reely across

the cell membrane and becomes reduced in

the presence o stannous ions in the cell and

subsequently binds to the beta chain o hae-

moglobin. At physiological pH, stannous ions

are likely to hydrolyse and precipitate and are

rapidly removed rom the blood by the reticu-

loendothelial system. To prevent hydrolysis

and precipitation, stannous ions are thus usu-ally in a complex o a weak chelator, such as

pyrophosphate or medronate. The amount o

stannous ions required or optimal radiolabel-

ling is in the range o 10-20g per kilogram o

body weight.

In vitro radiolabelling

In vitro radiolabelling o RBCs gives by ar the

highest labelling eciency and the most sta-

ble labelling over time. It may be used or the

determination o red cell and blood volume.

It may also be employed in patients who are

taking drugs which may interere or inhibit

stannous ion transport through the cell mem-

brane such as heparin or hydralazine, resulting

in lower labelling eciency.

A small volume o anticoagulated blood (hep-

arin or ACD) is incubated with an aliquot o a

reconstituted stannous agent. Any excess o

Sn2+ is oxidised by addition o 0.1% sodium

hypochlorite and may be removed by cen-

triugation. The cells are separated and incu-

bated with 99mTc-pertechnetate or 5-20 min-

utes with occasional mixing. Ater incubation,

unbound activity is washed away by additiono a ew mls o saline and centriugation. The

cells are separated and re-suspended in saline

beore re-injection.

In vivo radiolabelling

This is the simplest and least time consum-

ing radiolabelling technique. An injection o

a reconstituted solution o stannous agent is

ollowed by injection o 99mTc-pertechnetate20-30 min later. The major disadvantage o

this radiolabelling approach is a generally

lower and more variable labelling eciency.

This may be due to insucient Sn2+ incorpora-

tion into the cells which results in reduction o99mTc-pertechnetate outside the RBC. Reduced99mTc is then not able to diuse across the red

cell membrane, resulting in a high background

activity. Low labelling yields may also be a con-

sequence o low haemoglobin concentration

and/or low haematocrit.

In vivo/in vitro radiolabelling

More variations o the in vivo/in vitro radiola-

belling approach are in use. In all approaches,

the intravenous administration o a stannous

agent is ollowed by withdrawal o an aliquot


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o pre-tinned blood 15-30 min ater applica-

tion. The excess o Sn2+ not incorporated into

cells may be removed by centriugation beore99mTc-pertechnetate is added to the cells. Al-

ternatively blood may be taken into a shielded

syringe containing an anticoagulant and the

required amount o99mTc-pertechnetate.The

blood is then mixed with the 99mTc-pertech-

netate and allowed to incubate or 5-20 min atroom temperature with occasional mixing. The

unbound activity is washed away by centriu-

gation beore reinjection. Radiolabelled blood

may alternatively also be re-injected without

removal o unbound activity. With the later ap-

proach in which no washing step is involved

one can expect lower radiolabelling eciency

and higher background activity, depending

on the complexity (number o washing stepsavoided) o the procedure.

Heat-damaged RBCs

When radiolabelled RBCs are damaged by

heat, they will be recognised by phagocytes

and subsequently destroyed in the spleen,

liver and bone marrow. This mechanism en-

ables the use o heat-damaged 99mTc-RBCs or

spleen imaging studies. Radiolabelled RBCs

are damaged by incubation in water bath at

49.5 C or 15 min beore reinjection. To su-

ciently denature RBCs but prevent bursting

them, the temperature and incubation time

are critical. Localisation in liver indicates pres-

ence o cell destruction ormatting bursting

ragments.

Radiolabelling o RBCs can be aected by pa-

tient medication. Drugs may interere directly

by reaction with Sn2+ by preventing accumula-

tion o Sn2+ in the cells or indirectly by aect-

ing the RBC membrane or reducing the hae-

matocrit and/or haemoglobin concentration.

For more detailed inormation see [2,5-7].

The usual administered activity o99m

Tc-RBCsor adult patients is within the range o 500

1050 MBq. For children the activity may be

adjusted according to body weight, with a

minimum activity o 80 MBq in order to ob-

tain images o sucient quality [8]. Only when

in vivo radiolabelling approach is employed,

breast eeding should be interrupted and the

expressed eeds discarded due to the pres-

ence o ree 99mTc-pertechnetate which con-centrates in the mammary gland. The total

ractional activity ingested by the baby rom in

vivo radiolabelled RBCs is estimated to be 3 5

times higher than the activity in milk rom in

vitro radiolabelling.Ater in vitro radiolabelling

breast eeding can be continued [9].

General recommendations or application o

radioactive drugs are applicable or adminis-

tration o radiolabelled RBCs. Use o a tefon

catheter or cannula should be avoided or ad-

ministration o Sn2+ compounds because Sn2+

can react with the catheter [10]. To prevent

reaction o 99mTc-pertechnetate with traces

o Sn2+ the stannous agent in the cannula

and 99mTc-pertechnetate should not be given

through the same system.


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Radiolabelling with 51Cr

Radiolabelling o RBCs with 51Cr is carried out

in vitro: 51Cr in the orm o sodium chromate

is incubated with whole blood containing

ACD or approximately 10 -15 min. Chromate

ion reely diuses into the RBCs, where it is

reduced to chromic ion (Cr3+). Cr3+ bound

to beta globin chain o the haemoglobin

molecule is retained in the cell. The labellingprocess is stopped by adding ascorbic acid

which reduces the chromate outside the cells

to chromic ion. Alternatively, ree chromate is

washed away by centriugation.

Non imaging studies

The basic principle in all non-imaging studies

using radiolabelled RBCs is the same: a known

quantity o radiolabelled RBCs is added to anunknown volume o blood in the body. Radio-

labelled blood is allowed to mix, and a known

quantity o the mixture is then removed and

quantitated (counted in a gamma counter).

The ratio o the quantity measured ater mix-

ing (number o counts per mass) to the quan-

tity added is the base or calculation o the

unknown volume [2,11,12].

RBC mass and volume determination

For RBC mass and volume determination, one

part o the radiolabelled blood is injected to

the patient and the other part is used as a stan-

dard or urther calculations. When complete

mixing o re-injected radiolabelled blood has

taken place (ater 30 min or longer i the pa-

tient has splenomegaly), blood samples are

taken or counting in a gamma counter. The

red cell mass and plasma volume are calcu-

lated by using the dilution equations. The true

blood volume is then obtained by summing

up the red cell mass and the plasma volume.

The total body haematocrit can be calculated

by dividing the red cell mass by the true blood

volume.

RBC survival

For RBC survival and sequestration studies,51Cr-RBCs are reinjected to the patient and

blood samples are obtained 3 times a week

or 2 to 4 weeks ater injection. To eliminate

the need or decay correction, the samples are

counted at the end o the study. For the 51Cr

survival curve, activity o the blood samplesover time can be plotted on a semilog pa-

per to linearise the curve. The patients RBC

eective hal-lie is calculated rom the curve,

the normal being 25 to 35 days. In case o a

signicant splenic sequestration o RBCs, a sig-

nicant and progressive increase in splenic

uptake relative to the other expected site o

RBCs, like blood pool or liver, may be present.51Cr-RBC uptake is monitored using thyroid

uptake probe positioning over spleen, liver

and heart.

The usual administered activity o51Cr-RBC or

RBC mass and volume determination is 0.8

1.5 MBq and 2.0 - 4.0 MBq or survival and

sequestration studies.


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Leucocytes and platelets

White blood cells (WBCs) or leukocytes are

cells o the immune system deending the

body against both inectious disease and or-

eign materials. Several dierent and diverse

types o WBC exist. They are all produced and

derived rom a multipotent hematopoietic

stem cell in the bone marrow. WBCs are ound

throughout the body, including the blood andlymphatic systems.One primary technique

to classiy WBCs is to look or the presence

o granules, which allows the dierentiation

o cells into two categories: granulocytes

(neutrophils, basophils and eosinophils) and

agranulocytes (lymphocytes, monocytes and

macrophages) [4].

Platelets or thrombocytes are blood cells involvedin the cellular mechanisms o primary haemosta-

sis leading to the ormation o blood clots [4].

Radiolabelling o WBCs and platelets

Non-selective lipophilic 111In and 99mTc complex-

es, which label all cells indiscriminately are used

or radiolabelling o WBCs and platelets. Gen-

erally radiolabelling eciency is higher when111In complexes are used (80-90%) compared

to 99mTc-HMPAO, where radiolabelling eciency

is normally 50-80%. Availability, low radiation

exposure and better imaging characteristics are

major advantages when 99mTc-HMPAO is used

or radiolabelling. The clinical results using 111In

or 99mTc-HMPAO WBC are similar. However when99mTc is used or radiolabelling, scans can be

completed sooner, because imaging takes placeat 1 hour and at between 4-6 hours [2,12].

Neutral lipophilic complexes rapidly diuse

across cell membranes. Once inside the cell,

the complex either dissociates and allows 111In

to bind to intracellular proteins (111In-oxine) or

breaks down to a more hydrophilic complex

which is unable to cross the cell membrane

and is thus trapped in the cell (99mTc-HMPAO).

In the case o radiolabelling with 111In-oxine,111

In also binds to transerrin present in theplasma. Thereore the cells have to be washed

thoroughly to remove plasma beore radiola-

belling. In the case o radiolabelling with either111In-tropolone or 99mTc-HMPAO, radiolabel-

ling can take place in the presence o small

amounts o plasma.

Because o the non-selective approach, the

cells need to be separated prior to radiolabel-ling. The separation o WBCs and platelets rom

RBC in the blood can be achieved by sedimen-

tation o anticoagulated blood. 30-50 ml o

blood is taken into a 60 ml syringe containing

an anti-coagulant. The anti-coagulant o choice

is acid-citrate-dextrose (ACD) in concentration

1.5 parts o ACD to 8.5 parts o whole blood.

Erythrocyte sedimentation may be accelerated

by the use o sedimentation agents such as

6% hydroxyethyl starch (Hespan). Alternatively

6% dextran or methylcellulose may be used.

Normally 3 ml o Hespan per 30 ml o whole

blood is used. Hespan may be added to ACD

in a syringe beore blood is taken. Sedimenta-

tion time is generally 45-60 min and may be

aected by dierent actors such as number

o cells and certain disease states. Sedimenta-tion may be carried out in the syringe placed


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upward in a suitable holder or in a universal

tube. Ater sedimentation, the upper layer con-

taining WBCs and platelets is transerred into a

sterile universal tube. To separate WBCs rom

platelets, the plasma is spinned at low speed

e.g. 150 g. Platelet rich plasma is removed be-

ore the radiolabelling agent is added to the

pellet containing WBCs and small amounts o

RBCs. The mixture is incubated at room tem-perature. Incub

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