Professional Documents
Culture Documents
The Radiopharmacy A Technologist
The Radiopharmacy A Technologist
opea ne
n Association of Nuclear Medi ci
The Radiopharmacy
A Technologist’s Guide
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.
2
EANM
Contents
Foreword
Wim van den Broek. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Introduction
Clemens Decristoforo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Chapter 1 - Radiopharmacy Technology
Brit Farstad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Chapter 2 - Radiopharmacy Design
James Ballinger. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Chapter 3 - Radiopharmacy: Preparing & Dispensing Radiopharmaceuticals
Geraldine O’Reilly. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Imprint. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3
Foreword
Wim van den Broek
Since it was formed, the EANM Technologist should be provided for all staff working in ra-
Committee has been devoted to the improve- diopharmacy departments in the aspects of
ment of nuclear medicine technologists’ quality assurance in which they are involved.
(NMTs’) professional skills. Publications that will This includes: preparation, release, quality con-
assist in the setting of high standards for NMT’s trol and analytical techniques, cleaning, trans-
work have been developed and since 2004 portation, calibration of equipment (especially
a series of brochures, “Technologists Guides”, for the measurement of radioactivity), working
have been published yearly. This booklet practices in the radiopharmacy, preparation of
about radiopharmacy is already the fifth vol- the individual doses, documentation, hygiene,
ume. The new and stricter regulations in the pharmaceutical microbiology, and microbio-
field of preparation of radiopharmaceuticals logical monitoring. Often a Nuclear Medicine
changed the daily practice in the radiophar- Technologist is the person who is involved
macy in the last 5 years. in the preparation and quality control of the
radiopharmaceuticals.
Nuclear medicine is a multidisciplinary special-
ty in which medicine, physics and pharmacy I am grateful for the effort and hard work of all
are involved. The Radiopharmacy is an integral the contributors, who are the key to the con-
part of a nuclear medicine department and its tents and educational value of this booklet.
prime responsibility is the preparation of high The most essential and relevant aspects of ra-
quality radiopharmaceuticals, the base for a diopharmacy in daily practice are emphasised
high quality nuclear medicine examination. here. This booklet is prepared in cooperation
The majority of these radiopharmaceuticals with the Radiopharmacy Committee of the
is mainly used for diagnostic imaging, which EANM. This Committee is very active and criti-
is the main activity of nuclear medicine. Ra- cal in the field of regulations and guidelines for
diopharmaceuticals are medical products the production of radiopharmaceuticals and
defined in the European directive 2004/27/ constantly proposes practical solutions. Many
EC amending the directive 2001/83/EC. As in thanks to Suzanne Dennan who coordinated
other disciplines the complex changes driven this project.
by European legislation had their impact on
everyday practice in the preparation of radio- With this new booklet, the EANM Technolo-
pharmaceuticals. gist Committee offers to the NMT community
again a useful and comprehensive tool that
Only trained people should be responsible for may contribute to the advancement of their
and participate in the preparation and qual- daily work.
ity control of radiopharmaceuticals. Training
4
Introduction
Clemens Decristoforo, PhD
EANM
I want to congratulate the Technologists Com- The Technologists Committee of the EANM
mittee of the EANM for this excellent Tech- has been very active in promoting profes-
nologists Guide on the Radiopharmacy. Issues sional skills of technologists and to support
of quality assurance especially in the field of high quality standards in daily practice. The
pharmaceutical preparations are becoming series of “Technologists Guide” booklets by the
increasingly important. The Radiopharmacy Eductional Sub-Committee has been a valu-
Committee of the EANM therefore recently able part of these initiatives. The current issue
has issued general guidelines for “Current of this series intends to provide guidance for
Good Radiopharmacy Practice” describing a “good radiopharmacy practice,” to describe
the quality standards in the preparation of quality standards and to bring radiopharmacy
conventional and PET radiopharmaceuticals practice to equal standards throughout Eu-
(http://www.eanm.org/scientific_info/guide- rope.
lines/gl_radioph_cgrpp.php). These serve as
a general reference standard for radiophar- This booklet contains chapters of all relevant
maceutical preparation as radiopharmacy topics of daily radiopharmacy practice of tech-
practice still shows a great variability all over nologists such as radiopharmacy design, prep-
Europe. aration and dispensing as well as documenta-
tion written by European experts in the field,
Technologists in many countries are the both radiopharmacists and technologists.
backbone for radiopharmacy services within
nuclear medicine departments. This is espe- I am very confident that this booklet will not
cially true for the preparation and handling only provide valuable information and quick
of conventional radiopharmaceuticals includ- reference for problems arising in daily prac-
ing eluting radionuclide generators, prepara- tice, but also will help to continuously improve
tion of 99mTc-radiopharmaceuticals from kits, quality standards of radiopharmacy practices
dispensing and cell labelling. Therefore the in nuclear medicine.
current issue of the Technologists Guides is
dedicated to radiopharmacy practice.
5
Chapter 1 – Radiopharmacy Technology
Brit Farstad
6
Chapter 1 – Radiopharmacy Technology
EANM
Depending on the radiation characteristics Neutron rich radionuclides disintegrate by
of the radionuclide, the radiopharmaceutical beta (β-) decay. Beta emitters represent dif-
is used either for diagnosis or for therapy. Di- ferent energy levels, and have different range
agnostic radiopharmaceuticals should decay in matter (40 – 100μm) depending on their
by gamma emission or positron emission, and energy. Beta emitting radionuclides are also
never emit alpha particles or even beta par- used in radiopharmaceuticals mainly for thera-
ticles. On the other hand, therapeutic radio- peutic purposes.
pharmaceuticals should decay by particulate
decay (alpha or beta) since the intended effect Positron (β+) decay occurs in proton rich nuclei.
is in fact radiation damage to specific cells. The range of a positron is very short in matter.
At the end of the path of β+ - particles, positrons
Gamma radiation is characterised as electro- combine with electrons and are thus annihilat-
magnetic radiation. When used in diagnostic ed, giving rise to two photons of 511 keV that
radiopharmaceuticals, the finally produced are emitted in opposite directions. Positron
gamma rays should be powerful enough to emitters are used to label radiopharmaceuti-
be detected outside the body of the patient. cals for diagnostic purposes by imaging.
The ideal energy for conventional (SPECT)
nuclear medicine equipment is around 150 Radioactivity units
keV. Normally, these radiopharmaceuticals are Radioactivity is expressed in Becquerels (Bq)
in such small quantities that the radiation dose as the SI-unit. One Becquerel is defined as one
received by the patient can be compared to disintegration per second (dps). Normally, ac-
that of a simple radiology investigation. tivities used in radiopharmacy are in the range
of megabecquerels (MBq) or gigabecquerels
Alpha decay is characterised by the emission of (GBq). There is a non-SI-unit for radioactivity
an alpha particle from the nucleus. This particle called Curie (Ci), which is used in some occa-
is a helium ion containing two protons and two sions. One Ci represents the disintegration of
neutrons. In beta decay a negatively charged one g of radium. The equivalence between
particle with the same charge and mass as an the Bq and the Ci is as follows:
electron is emitted. Alpha emitters, which are
monoenergetic and have a very short range 1 Bq = 2,7 x 10-11 Ci
in matter due to their mass, thus leaving much 1 Ci = 37 GBq
of its energy on a very small area (only a few
cell diameters), are used only for therapeutic Every radionuclide is characterised by a half-life,
purposes. Their clinical use is very limited, and which is defined as the time required to reduce
they are mainly used for research purposes, or its initial activity to one half. It is usually denoted
still are in early phase clinical trials. by t½, and is unique for a given radionuclide.
7
Principles of radiation protection • Time: The shorter the time of exposure to
Production, transportation and use of radio- radiation, the lower the dose to the op-
pharmaceuticals, as radioactive products, are erator.
governed by regulatory agencies dealing with
radiation protection and nuclear safety. Only • Distance: The radiation dose decreases
licensed personnel in an authorised facility with a factor equal to the square root of
are authorised to handle and use radiophar- the distance from the radiation source. The
maceuticals. operator’s distance from the source can
be increased by using forceps, tongs, or
The general principles of radiation protec- manipulators in handling the radioactive
tion are: material.
• Justification: All procedures involving ra- • Shielding: The radiation dose can be re-
dioactive material must be justified. duced by placing shielding material be-
tween the source and the operator. For
• Optimisation: The radiation exposure to protection against gamma radiation, walls
any individual should be as low as reason- made of heavy concrete or lead bricks are
ably achievable. This principle is the widely used. For transport containers, material
known ALARA concept (as low as reason- such as tungsten may be used for higher
able achievable). energy gamma irradiation radionuclides,
giving a higher shielding per weight unit
• Limitation: The radiation dose received when compared to lead.
by the personnel handling radioactive
material will never exceed the legally es- Formulation and production of
tablished dose limits. radiopharmaceuticals
When designing a radiopharmaceutical, one
When planning facilities and procedures for should have in mind the potential hazard the
handling of radioactive materials according product may have to the patient. The goal
to the ALARA principle, it is important to keep must be to have a maximum amount of pho-
in mind the basic principles for reduction of tons with a minimum radiation exposure of
radiation doses: the patient.
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Chapter 1 – Radiopharmacy Technology
EANM
The function of the carrier molecule in a ra- As the radiolabelled substances emerge from
diopharmaceutical is to carry the radioactiv- the laboratory to the clinics, there will be a
ity to the target organ, and to make sure the need for scaling up the batch size of the prod-
radioactivity stays there. The uptake of radio- uct. This can be done either by increasing the
activity should be as specific as possible, in total volume of the produced batches or by
order to minimise irradiation of other organs increasing the specific activity of the product,
and parts of the body. This is particularly im- or both. When doing this, one has to consider
portant when using radiopharmaceuticals for two important aspects:
therapy. But also for use in diagnostics, it is
desirable that the radiopharmaceutical is lo- • The influence on the stability of the prod-
calised preferentially in the organ under study uct itself due to possible radiolysis.
since the activity from non-target areas can
obscure the structural details of the pictures • The need for additional operator protec-
of the target organ. It is therefore important tion due to handling of increased amounts
to know the specific uptake in an organ for a of radioactivity.
potential chemical carrier, and also the rate of
leaking out of the organ/organ system. Thus, Manufacturing of radiopharmaceuticals is
the target-to-background activity ratio should potentially hazardous. Both small- and large-
be large. scale production must take place on prem-
ises designed, constructed, and maintained
In a radiolabelled compound, atoms or groups to suit the operations to be carried out. Ra-
of atoms of a molecule are substituted by simi- diation protection regulations stipulate that
lar or different radioactive atoms or groups radionuclides must only be used in specially
of atoms. When a labelled compound is to designed and approved “radioisotope labora-
be prepared, the first criterion to consider is tories”. National regulations with regard to the
whether the label can be incorporated into the design and classification of radioisotope labo-
molecule to be labelled. This may be assessed ratories must be fulfilled. Such laboratories are
from knowledge of the chemical properties of normally classified according to the amount
the two partners. Furthermore, one needs to of the various radionuclides to be handled at
know the amount of each component to be any time, and the radiotoxicity grading given
added. This is particularly important in tracer to each radionuclide.
level chemistry and in 99mTc-chemistry.
9
Premises must be designed with two impor- radiation protection to personnel and the
tant aspects in mind: environment. Documentation is an essential
part of a quality system. Its purpose is to define
• The product should not be contaminated the control system, to reduce the risk of error
by the operator. that is inherent in oral communication and
to ensure that detailed instructions are avail-
• The operator and the environment should able to personnel. The documentation system
be protected from contamination by the should allow tracking of use and disposal of
radioactive product. any batch.
This is the basic principle of GRP – Good Radio Radiopharmaceuticals are a special form of
pharmaceutical Practice. drugs that require much more handling im-
mediately before administration to the pa-
Quality considerations tient, when compared to other drugs. Due
The key elements of GRP comprise a previ- to the short half life of the radionuclide, it is
ously defined manufacturing process known necessary for the final preparation of many
to lead to a radiopharmaceutical of the de- radiopharmaceuticals to take place shortly
fined quality administered to the patient in before use. Only a minor proportion of all ra-
the prescribed dosage and form. GRP is carried diopharmaceuticals is delivered to hospitals in
out and recorded by trained and qualified staff a ready-for-use-form. Handling of radiophar-
provided with the necessary facilities, includ- maceuticals in hospitals is thus an integral part
ing adequate premises, suitable equipment, of the system by which the quality of these
correct materials and established procedures pharmaceuticals is established.
in written form. Quality must also be main-
tained during transportation and storage. Quality control of radiopharmaceuticals
All quality control procedures that are ap-
Training and qualifications should cover gen- plied to non-radioactive pharmaceuticals are
eral principles of GMP (Good Manufacturing in principle applicable to radiopharmaceu-
Practice) and radiation protection. All training ticals. In addition, tests for radionuclidic and
must be recorded. Premises and equipment radiochemical purity must be carried out.
must have a layout and design that minimise Furthermore, since radiopharmaceuticals are
the risks of errors by avoiding cross-contam- short-lived products, methods used for qual-
ination and build up of dust and dirt, as well ity control should be fast and effective. Still,
as permit effective cleaning and maintenance. some radiopharmaceuticals with very short
They must also be designed to give proper half-lives may have to be distributed and
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Chapter 1 – Radiopharmacy Technology
EANM
used after assessment of batch documenta-
tion even though all quality control tests have
not been completed.
11
Chapter 2 – Radiopharmacy Design
James R. Ballinger, PhD
12
Chapter 2 – Radiopharmacy Design
EANM
Figure 1 presents a sample layout of a large Refrigerators and other areas where sensitive
radiopharmacy with ideal separation of dif- supplies are stored should have temperature
ferent working areas required for handling monitoring. This can be as simple as manual
and radiolabelling of 99mTc and other SPECT recording on a daily basis of minimum and
radiopharmaceuticals. maximum temperatures on a calibrated ther-
mometer or an electronic output to a chart
Figure 1: Sample layout of a radiopharmacy recorder or monitoring software.
13
Aseptic manipulations should be performed It is simplest to dispose of all sharps into rigid
either in a pharmaceutical isolator or a laminar biohazard containers behind a lead shield.
airflow hood. Once the radioactivity has decayed to back-
ground levels, the containers are disposed as
The bulk of the work for the foreseeable future biohazard waste. Radionuclides should be
will continue to be reconstitution of kits with segregated by half life to minimise the build
99m
Tc pertechnetate. Thus, a single workstation up of waste.
is adequate even if there is occasional handling
of other radionuclides (e.g. preparation of 111In The blood labelling suite will require a vari-
pentetreotide or 90Y ibritumomab tiuxetan). able speed centrifuge capable of accepting a
However, if the usage of other radionuclides is range of tube sizes. Ideally the centrifuge will
more extensive, a separate workstation should be located within the workstation, to minimise
be provided. In addition to minimising the po- the number of transfers out of the Grade A
tential of cross contamination of 99mTc prod- environment.
ucts with longer lived and/or particle emitting
radionuclides, it also reduces the risk that a Area designation
major spill of one of these radionuclides could A radiation controlled area is one in which a
impede 99mTc dispensing for a number of days. full time worker might receive an exposure of
In the future, some products such as 90Y or 6 mSv/yr whole body or 150 mSv/yr extrem-
177
Lu labelled peptides might be prepared by ity. For a radiation supervised or monitored
automated synthesis units located in a sepa- area, the exposure limits are 1 mSv/yr whole
rate workstation. body or 50 mSv/yr extremity. Because of the
presence of generators and the amount of
In general, radiation safety is maintained by radioactivity handled, the hot lab will be des-
local shielding (e.g. vial shields, syringe shields, ignated a controlled area. Other areas may be
bench top shields) rather than shielding in the classified as supervised.
walls. The waste store may require shielding, as
may an area where high levels of radioactivity Radiation designated areas must be physically
are handled if there is a significant radiation demarcated and have signs indicating the
field in the adjacent room. The 99Mo/99mTc type of hazard. There should be washing and
generator usually requires additional exter- changing facilities available at the perimeter;
nal shielding. and radiation monitoring for contamination
must be performed. Eating and drinking is
prohibited in designated areas.
14
Chapter 2 – Radiopharmacy Design
EANM
Conflicts between radiation and aseptic
regulations
As noted above, there can be conflicts be-
tween the requirements of different regula-
tory systems. However, there are also areas of
agreement. For example, segregation of ac-
tivities, with change of apparel and dedicated
equipment, minimises cross contamination
with both radioactivity and microbes, as does
a separate air handling system and the use
of containment hoods/glove boxes. Special-
ist trained staff are required and meticulous
record keeping is important.
15
Chapter 3 – Radiopharmacy
Preparing & Dispensing Radiopharmaceuticals
Geraldine O’Reilly, PhD
16
Chapter 3 – Radiopharmacy: Preparing & Dispensing Radiopharmaceuticals
EANM
Protective clothing 1. tools for maximising the distance from the
Prior to commencing work in the radio source, for example tongs and forceps,
pharmacy, staff should ensure that they wash 2. syringe shields,
their hands thoroughly. Before a person en- 3. vial shields,
ters an area where radioactive substances are 4. drip trays for minimising the spread of con-
handled, any cut or break in the skin should tamination in the case of spillage,
be covered. Dressings should incorporate a 5. shielded syringe carriers and
waterproof adhesive strapping. Protective 6. decontamination kit
coats or gowns should be worn for prepara-
tion and dispensing of radiopharmaceuticals. Unshielded syringes or vials should never be
Disposable gowns offer benefits in terms of used during manipulation of radiopharma-
maintaining sterility. Gloves worn in the LAFC ceuticals. Equipment should be stored outside
or contained workstation must be powder free the laminar flow cabinet when not in use and
in order to prevent clogging of the air filters should be cleaned regularly in accordance
within the cabinet. Alcohol rub should be with local recommendations.
rubbed onto gloves and allowed to evapo-
rate before entering the LAFC. After handling Work procedures
radioactive materials, gloves must always General
be removed and disposed of as radioactive Before starting the preparation and dispensing
waste before handling/touching any other of radiopharmaceuticals, all of the materials
materials/surfaces within the radiopharmacy. required should be assembled and placed in
Hands should be washed again after removal or close to the contained workstation/LAFC
of gloves. Upon leaving the radiopharmacy, (Figure 2). All vials containing radioactive
disposable gowns should be removed. Prior to materials must be shielded while handling;
disposal, they should be stored as radioactive and vials should only be removed from their
waste until monitoring confirms that they are shields for assay, inspection or disposal. All sy-
at background radiation levels. ringes containing radioactive liquids must be
shielded while handling, except during an as-
Protective equipment say. Unshielded vials or syringes should not be
The use of protective equipment, when han- handled directly. Long handled tongs should
dling radioactive materials, can have a signifi- be used to place and remove unshielded ma-
cant impact on reducing staff dose. Laborato- terials in the dose calibrator.
ries and other work areas for manipulation of
unsealed radioactive substances should be pro-
vided with equipment kept specifically for this
purpose, and should include the following:
17
Work procedures should be designed so as Reconstitution of pharmaceuticals
to minimise exposure from external radiation The manufacturer’s recommendations should
and contamination. Care must be taken to pre- be followed closely as many pharmaceutical
vent spillage from occurring. All manipulation kits have specific reconstitution instructions in
for dispensing radioactive materials should terms of the activity and volume to be added
be carried out over a drip tray, in order to to the kit. Recommended incubation times
minimise the spread of contamination due also vary and must be adhered to. Some ra-
to breakages or spills. Should a spill occur then diopharmaceuticals must be refrigerated after
it should be cleaned up before proceeding preparation. Therefore consideration should be
any further. All items that might be contami- given to the provision of suitably shielded re-
nated should be removed from the affected frigeration facilities. Most radiopharmaceuticals
area and stored safely. Care should be taken are reconstituted with 99mTc; and this assump-
doing this, in order to minimise the spread tion applies to the following paragraphs.
of contamination. As with all spills, it is more
convenient to allow natural decay to take care Protective caps should be removed from the
of the contamination, if the items are not re- pharmaceutical vials; and the vials should be
quired immediately. For those items that are placed in the appropriate labelled vial shields.
needed, they should be cleaned with alcohol The rubber septum of each pharmaceutical vial
swabs taking care not to spread the contami- should be swabbed with alcohol; and the alco-
nation. Using multiple swabs which are then hol should be allowed to evaporate (Figure 3).
disposed is the most effective way to remove
contamination. • Shielded 10ml or 5ml syringes capped with
21G needles are generally used to recon-
Figure 2: Preparation of work area stitute the pharmaceuticals.
(courtesy of VirRAD)
• The appropriate activity of 99mTc solution
should be added to each shielded phar-
maceutical vial; and the pharmaceutical
should be allowed to incubate for the
specified length of time.
18
Chapter 3 – Radiopharmacy: Preparing & Dispensing Radiopharmaceuticals
EANM
• When introducing 99mTc solution or saline Preparation of patient injections
to a vial, it may be necessary to equalise • After the recommended incubation time
pressure by withdrawing an equivalent has elapsed, patient activities are with-
volume of air at the same time. This can drawn using shielded 2ml syringes capped
be done gradually as the solution is added. with 21G.
In general, breather needles are not recom-
mended and should not be used unless • Each patient activity must be measured
specifically recommended by the manu- and recorded in the radiopharmacy log.
facturer of the pharmaceutical. The activity withdrawn for each patient
must be within 10% of the required activ-
• The activity and volume of 99mTc solution ity at the specified injection time.
added to each pharmaceutical should be
recorded in the laboratory log book. • Patient injections are usually prepared in
a volume of 1ml. There are exceptions to
Figure 3: Disinfection of a kit before use this: the manufacturer’s instructions on the
(courtesy of VirRAD) volume should be followed. Saline may be
used to increase the volume if the volume
in which the required activity is obtained
is below 1ml.
19
• Each patient injection must be labelled The waste container in the workstation should
with an appropriate label detailing the not be allowed to overflow and should be
patient name, scan type, activity to be ad- emptied regularly. The bin is best emptied
ministered, date and time of injection. before starting work in the cabinet, when the
waste in the bin has decayed over night.
Waste management procedures
Non-radioactive waste should be separated Segregation of waste according to half-life
from radioactive waste to minimise storage is good practice and can reduce the length
requirements; and it should be disposed of of time that waste arising from shorter lived
as normal hospital waste. Shielded waste bins isotopes has to be stored.
should be lined with plastic liners that can be
easily removed when full. Paper waste
Any gloves used in the cabinet or used to
Technetium 99m is the main isotope in use handle blood or isotopes will be considered
in the radiopharmacy: the duration of stor- to be contaminated. Paper tray liners in the
age will be determined by its half life of 6.02 cabinet or paper used to clean surfaces in
hours. Longer lived waste should be stored the cabinet are also considered to be con-
separately. Radioactive waste generated daily taminated. Contaminated gloves and paper
within the radiopharmacy includes syringes, should be disposed in a shielded bin in the
elution vials, pharmaceutical vials, needles and pharmacy, as long as there is no biological
swabs. Waste arising from the preparation and contamination (blood or plasma). Otherwise
dispensing of radiopharmaceuticals should this waste should be placed in a sharps bin, us-
be primarily disposed in the waste bin built ing tongs. For long term storage of waste, the
into the contained workstation/LAFC. Some waste should be removed from the shielded
bulky items such as paper waste and gloves bin, labelled with details of the contents and
may be disposed in a shielded waste bin in the stored as radioactive waste in a designated
pharmacy, as long as there is no risk of con- store.
taminating the room by removing them from
the cabinet. Radioactive waste contaminated Sharps bins
by blood (e.g. syringes following cell labelling Syringes, needles, butterflies etc. should be
procedures) should not be left in the worksta- disposed of after use to shielded sharps bins.
tion but removed to a shielded bin. Bins should not be allowed to overfill. Full
sharps bins should be closed, marked ‘radio-
active’, dated and removed to the radioactive
waste store.
20
Chapter 3 – Radiopharmacy: Preparing & Dispensing Radiopharmaceuticals
EANM
Disposal of waste one of which has a principal energy between
All radioactive waste - sharps bins, paper 100 keV and 500 keV, should be used to deter-
waste, ventilation kits - should be securely mine accuracy upon installation, and at least
stored and monitored regularly. Waste should annually thereafter. For the routine accuracy
be checked by using a suitable meter in a low check, place the reference source in the dose
background environment and should be dis- calibrator and record the activity measured.
posed of, once it has decayed to background The value recorded should be within the al-
level. Any items above background should lowable tolerance (typically 10%).
be retained for a further period of decay in
storage. All radioactive warning labels should The constancy test looks at reproducibility in
be removed from waste, prior to disposal in measuring the activity of a known source over a
hospital waste. The hospital waste disposal long period of time. The dose calibrator should
policy should be adhered to. be checked daily for constancy at the setting of
the most frequently used isotope. To carry out
Dose calibrator quality assurance this test, the reference source is left in place; but
The accuracy and constancy of the dose the setting is changed to Tc-99m and the value
calibrator should be checked regularly with indicated is recorded. This can also be done
a reference source. Isotopes such as Co-57, for other isotopes that are selectable on the
Ra-226 or Cs-137 with a relatively long half life dose calibrator. The ratio of the values indicated
are suitable. The use of more than one source to that of the activity of the reference source
will allow checking of the calibrator over a should be constant over time.
range of energies. A daily check of system
operation, accuracy and constancy should The linearity test ensures that the dose calibrator
be carried out. Linearity tests may be carried can indicate the correct activity over the range
out less frequently. of use of administered or measured activities.
The dose calibrator should be tested for linearity
Before starting the QA, remove all radioactive upon installation and at least quarterly thereaf-
sources from the vicinity of the calibrator and ter. Technetium-99m is most frequently used for
record the background reading. The isotope the linearity test because of its availability and
selected on the dose calibrator should be that short half-life. The variation between indicated
of the reference source. The accuracy test en- and known activity should not exceed 10%.
sures that the activity is within 10 percent of
a given calibrated reference source of known The results of the routine QA should be docu-
activity (within 5%). At least two sealed sourc- mented and stored as part of the radiophar-
es with different principal photon energies, macy records.
21
Chapter 4 – Radiopharmacy
Kits & Techniques
Helen Ryder
Radiopharmaceuticals have been defined as patient movement; or too short a time per
‘radioactive drugs that, when used for the image resulting in poor count statistics. If
purpose of diagnosis or therapy, typically elicit the half-life is too long, then there may be
no physiological response from the patient.’ excessive radiation exposure to the patient
over its period of decay.
In the main this is true, and though some 3. High target - background ratio
radiopharmaceuticals have been known to The radionuclide is only of use if it accu-
cause minor side effects (such as urticaria, mulates within the target organ, and this
or changes in blood pressure), these are not is often enhanced by binding the radionu-
commonly seen in practice. clide onto a tracer that will take it to the
organ under study. The binding should be
Ideal radionuclide sufficient that little radionuclide is left free
Properties of the ideal diagnostic radionuclide in the body tissues, thus enhancing the
include: target-to-background ratio.
4. Low dose rate to both patient and per-
1. Pure gamma emitter, with a gamma en- sonnel
ergy within the range of 100 - 250 keV, to To avoid excessive received radiation dose,
match the optimum scanning range of a it is necessary to avoid those radionuclides
gamma camera. which have significant particulate emis-
The radiation emitted by a radionuclide sions i.e. alpha and beta particles. The short
should be sufficient to be detected outside range of emission means that these are
the patient for imaging purposes, thus lim- absorbed within the patient, adding to the
iting the choices to X-rays or gamma rays. radiation dose with no increase in image
However, too high an energy will result in quality. Because of the reality of radiation
the gamma ray penetrating the detector of decay, that is the attempt to balance the
the imaging device without being stopped particles in the nucleus, beta rays are often
and hence recorded. found as a product of decay. The rate of
2. A half-life which is suitable for diagnostic emission of these rays can be significantly
use i.e. 1.5 X test duration lower in two particular decay processes:
The half-life of a radionuclide determines isomeric transition and electron capture.
the rate of radioactive decay. If the half-life 5. Non-toxicity of radiopharmaceuticals
is very short, then the activity may have Most radiopharmaceuticals must be inject-
decayed to a very low level before imag- ed, with a small amount being ingested or
ing can be started. This can result in either inhaled. Thus they must be non-toxic in
a long scanning time, where there may be nature, sterile and pyrogen-free.
22
Chapter 4 – Radiopharmacy: Kits & Techniques
EANM
6. Chemical stability during use Radionuclide generator
Not all radioisotopes are suitable for binding A radionuclide generator is a source of radio-
to tracers. Technetium 99m has ‘the ability to nuclides for the preparation of radiopharma-
readily bind to a wide variety of compounds ceuticals. It is based on the separation of a
under physiological conditions [1] without short lived radionuclide (daughter) from a
causing physiological changes in the patient. long lived radionuclide (parent). Examples of
7. Inexpensive and readily available radionuclide generators are provided in Table
Many suitable radionuclides are obtainable 1. The most commonly used generator in Nu-
from a generator, which may be delivered clear Medicine is the 99Mo/99mTc generator.
to a nuclear medicine facility and eluted as
required. This results in economical use of Table 1: Radionuclide generators
the radionuclide.
Other radionuclides are produced in cyclo-
trons as specialised units and are shipped
ready for use. These are decaying from the
moment they are manufactured and thus
must be ordered for use on a particular
day, either as the resultant product or for
preparation with other tracers. This can be
expensive and uneconomical for everyday
requirements. Molybdenum/Technetium (99Mo/99mTc)
8. Ease of preparation and appropriate generator
quality control The molybdenum/technetium generator con-
Preparation requirements of more than three sists of an alumina-filled column onto which is
steps do not usually meet the definition of absorbed 99Mo. The 99Mo is present as 99MoO42-,
‘ease of preparation’. Nor should a complex which decays to its daughter radionuclide 99mTc
variety of equipment be required. Quality as pertechnetate 99mTcO4- (Figure 1). 99mTc is re-
control procedures should be available to moved from the columns as 99mTcO4- by draw-
check each batch of the radiopharmaceuti- ing over a solution of sodium chloride (NaCl)
cal reconstituted in the working laboratory. 0.9% w/v across the column (Figure 2). This
This ensures that the preparation received by process is known as ‘eluting the generator’ and
the patient will result in high-quality images the resultant eluate is used to compound the
without detrimental effect on the patient. radiopharmaceuticals (Figure 3).
23
Figure 1: Decay scheme for 99Mo and 99mTc Figure 2: Molybdenum/Technetium generator
(courtesy of VirRAD)
Attach Saline Vial Insert Elution vial Attach Elution vial and wait Remove elution vial and attach
in lead shielding until elution is completed protecting vial/Cap
24
Chapter 4 – Radiopharmacy: Kits & Techniques
EANM
Figure 4: Plot of logarithm of 99Mo and 99mTc Figure 5: Reconstitution of 99mTc
activities against time showing transient radiopharmaceuticals from generators and kits
equilibrium. The generator is eluted daily and
the 99mTc activity grows again until transient
equilibrium is reached (courtesy of VirRAD).
25
• Remove the flip/ Appendix 2: Calculation of activity
foil cap from the
pharmaceutical Example calculation of activity to add to vial
vial and place Example: What is the minimum activity of 99m
the vial in a la- Tc eluate needed to be added to a vial of 99mTc-
belled shielded Cardiolite at 8a.m., to obtain five injections of
container. Swab 740Mbq each – 2 injections at 8a.m., 3 injec-
the rubber septum with alcohol, and al- tions at 11a.m.?
low the alcohol to evaporate.
The equation to calculate radioactive decay is:
• When reconstituting the pharmaceu-
tical use a shielded 5ml syringe At = Aoe-λt
capped with a green needle.
10ml and 2ml syringes may also 1. Calculating λ
be used, depending on the re- λ is the decay constant which for any ra-
quired volume. dionuclide is defined as
26
Chapter 4 – Radiopharmacy: Kits & Techniques
EANM
Therefore the required activity to be drawn up Quality control in the radiopharmacy
per injection at 8a.m. is 1045.6MBq.
Rationale for performing quality control
The total activity of 99mTc to be added to the If a radiopharmaceutical is improperly pre-
vial of Cardiolite is: pared it can result in a non-diagnostic study.
The procedure must then be repeated result-
a. 2 x 740MBq for two injections at 8a.m. ing in increased radiation dose and patient
=1480MBq discomfort. Many different classifications of
b. 3 x 81045.6MBq for three injections at impurities affecting the imaging process can
11a.m. = 3136.9MBq be distinguished, as outlined in Table 2. Meth-
c. Add (a) to (b) to get total of 4616.9MBq to odologies for detecting these impurities are
add to vial of HDP briefly outlined in Table 3.
1. Mo-99 breakthrough:
Mo-99 is assayed directly in the special lead pig supplied by the manufacturer of the dose calibra-
tor. 99mTc is then assayed directly in the plastic sleeve in the dose calibrator. The activity of 99Mo
must not exceed 0.1% of the total 99mTc-activity. Dose calibrators have different methods how
to determine whether this amount is exceeded dependent on manufacturer and age.
27
The timetable of required testing is shown in Table 4, and for optional testing in Table 5.
28
Chapter 4 – Radiopharmacy: Kits & Techniques
EANM
Radiochemical purity, paper and thin layer Figure 7: A chromatography strip with the
chromatography position of the origin and solvent front
The radiochemical purity (RCP) of a radio shown. The sample is placed at the point
pharmaceutical is the ratio of the radionuclide marked on the origin.
present in a bound form (i.e. as a bound radio-
pharmaceutical) to the radionuclide present in
its unbound form (i.e. ‘free’radionuclide).
General principles of planar chromatography When the solvent has moved the required
for radiochemical purity testing distance along the chromoplate (the solvent
The test strip or chromoplate may be obtained front), then it is removed from the solvent and
as a commercial product, and different types allowed to dry. As a next step, this is read by
are produced for different pharmaceuticals. scanning the radiochromatogram, either by
Generally a few microlitres of the product to passing it under a scintillation detector or on
be tested is applied near the bottom (origin) the surface of a gamma camera. The distance
of the chromoplate. The chromoplate is then travelled along the chromoplate by each of
placed in a solvent, ensuring that the bottom the radiochemical species is expressed as a
(origin) point is not immersed. The solvent is fraction of the distance travelled by the sol-
then allowed to rise or migrate up along the vent front (Rf value). From these Rf values can
plate. The different chemical species separate; be determined the quantity of activity in each
the most soluble product moving the furthest portion and thus the respective binding qual-
distance along the chromoplate. (Figure 7) ity of the radiopharmaceutical.
29
Radiochemical impurities in 99mTc Equipment and location:
radiopharmaceuticals The determination of the radiochemical purity
Common impurities in 99mTc-kits are 99mTc- in the hospital with TLC can be performed with
pertechnetate and 99mTc-colloid. However a little expenditure of material and equipment.
number of 99mTc-preparations may contain It should be performed in a dedicated area
different impurities that have to be covered with radiation protection and proper ventila-
by respective validated tests (e.g. 99mTc-Tartrate tion (organic solvents).
in 99mTc-MAG3). A number of recommended
chromatography methods are shown below Quantification:
in Table 6 and Table 7. A variety of methods may be used to quantify
impurities including cut and count in the dose
Separation of radiopharmaceutical and calibrator, using dedicated scanner, gamma
impurity cameras and others. The differences are in
Radiochemical purity testing can be based sensitivity, resolution, linear range, speed,
on thin layer or paper chromatography (TLC), availability and practicability and should
solid phase extraction methods based on be chosen dependent on available space,
cartridges (SPE), filtration methods, HPLC or throughput and general organisation of the
electrophoresis. Methods may derive from radiopharmacy. Equipment used for qual-
the European Pharmacopeia, the SPC of the ity control should be regularly calibrated.
labelling kit or validated literature methods. In Generally, the quantification of the radio
many cases a variety of methods are available chemical purity is based on the equation
for one particular radiopharmaceutical. TLC below.
methods and SPE are most commonly used In case the radiochemical purity limit is not
and recommendations in this guidance are reached, the preparation has to be discarded
based on these methods. and clearly labelled that it may not be used
for patient application.
30
Chapter 4 – Radiopharmacy: Kits & Techniques
EANM
Table 6: Recommended methods for quality control based on TLC
Rf Radio
Solid Phase / Mobile Phase Rf Impurity
pharmaceutical
Pertechnetat ITLC-SG/0.9% NaCl Front Start
99m
Tc-DMSA ITLC-SG/ 2- Butanone Start Front
Tc-Diphosphonates
99m
A) ITLC-SG/ 1M NaAcetate Front Start
MDP, DPD, HEDP B) ITLC-SG/ 2-Butanone Start Front
99m
Tc-Colloids ITLC-SG / 2-Butanone Start Front
99m
Tc-MAA ITLC-SG / 2-Butanone Start Front
ITLC-SG / Aceton :
99m
Tc-Tetrofosmin Middle Start/Front
Dichloromethane =35:65 /
Tc-monoclonal Anti-
99m
ITLC-SG/ 0.9% NaCl Start Front
bodies; HIG, Zevalin
In Octreotide
111
0.1M Na-Citrat pH5 / ITLC-SG Start Front
31
Table 7: Recommended methods for quality control based on SPE
Radiopharma-
Cartridge / Solvent Impurity
ceutocal
SEPPAK C18 light
Tc-MAG3
99m
1.) 0.001N HCl, Eluate 2 column/ eluate 1
2.) Ethanol/0,9% NaCl (50% – 50%)
32
Chapter 5 – Radiopharmacy
Blood Labelling
Tanja Gmeiner Stopar, PhD
EANM
Several blood cellular elements can be ra- During radiolabelling, approved written proce-
diolabelled with different radionuclides and dures should be followed at all times. All mate-
radiolabelling approaches for varies clinical rials used should be identified and certified for
applications (Table 1). Regardless of the na- human use. Whenever possible radiochemical
ture of the blood cells, of the radionuclide purity should be checked and radiolabelling
used or of the clinical application, it is neces- efficiency (percentage of radiolabelling of
sary to maintain both cell viability and steril- cells) calculated. Before release, radiolabelled
ity and to avoid the operator’s exposure to blood should be checked for aggregation of
biological and radiation hazard during cell clumping of cells and for presence of particu-
manipulation and radiolabelling. Manipula- late contamination. At regular intervals, the
tions and radiolabelling procedures of cells integrity of the cells should be ascertained
require strict aseptic conditions and should by use of suitable procedures i.e. using trypan
follow the EANM guidelines on current Good blue. Prior to administration, control of patient
Radiopharmacy Practice (cGRPP) in the Prepa- identity should be performed [1-3].
ration of Radiopharmaceuticals [1]. The use of
an open or closed vial system on a laboratory Red blood cells
workbench is not an alternative to a controlled Red blood cells (RBCs) are the most common
sterile environment. Cross contamination or type of blood cell. Their main function is de-
mix-up of blood should be prevented at all livering oxygen from lungs to body tissues.
times. Preparation of radiolabelled cells must Erythrocytes are continuously being produced
be performed successively or by different peo- in the red bone marrow of large bones. They
ple in different locations. All surfaces should develop from committed stem cells through
be properly cleaned, decontaminated and dis- reticulocytes to mature erythrocytes and
infected prior to use, after all procedures are live a total of about 120 days. The aging of
completed, and whenever surfaces are overtly erythrocyte undergoes changes in its plasma
contaminated. membrane making it susceptible to recogni-
tion by phagocytes and subsequently they
are destroyed in the spleen, liver and bone
marrow [4].
33
Table 1: Clinical applications of radiolabelled cells and radiolabelling approach
Radionuclide Radiolabelling
Clinical application Blood cellular element
/radiolabel approach
Gastrointestinal In vivo
Red cells 99m
Tc-pertechnetate
bleeding In vivo/in vitro
In vitro
Spleen imaging Denaturated red cells 99m
Tc-pertechnetate
In vivo/in vitro
111
In-oxine
Infection and
White blood cells 111
In-tropolone In vitro
inflammation 99m
Tc-HMPAO
111
In-oxine
Abnormal platelet
Platelets 111
In-tropolone In vitro
deposition 99m
Tc-HMPAO
34
Chapter 5 – Radiopharmacy: Blood Labelling
EANM
Radiolabelling with 99mTc A small volume of anticoagulated blood (hep-
Radiolabelling approaches may by in vivo, in arin or ACD) is incubated with an aliquot of a
vitro and combined in vivo/in vitro. The basic reconstituted stannous agent. Any excess of
mechanism of the radiolabelling of RBCs with Sn2+ is oxidised by addition of 0.1% sodium
99m
Tc is in all approaches the same. The RBCs hypochlorite and may be removed by cen-
are “pre-tinned” by stannous ions for 10-30 trifugation. The cells are separated and incu-
min before 99mTc-pertechnetate is added to bated with 99mTc-pertechnetate for 5-20 min-
the cells. The stannous ions diffuse into the utes with occasional mixing. After incubation,
cell and are firmly bound to cellular compo- unbound activity is washed away by addition
nents. The pertechnetate diffuses freely across of a few mls of saline and centrifugation. The
the cell membrane and becomes reduced in cells are separated and re-suspended in saline
the presence of stannous ions in the cell and before re-injection.
subsequently binds to the beta chain of hae-
moglobin. At physiological pH, stannous ions In vivo radiolabelling
are likely to hydrolyse and precipitate and are This is the simplest and least time consum-
rapidly removed from the blood by the reticu- ing radiolabelling technique. An injection of
loendothelial system. To prevent hydrolysis a reconstituted solution of stannous agent is
and precipitation, stannous ions are thus usu- followed by injection of 99mTc-pertechnetate
ally in a complex of a weak chelator, such as 20-30 min later. The major disadvantage of
pyrophosphate or medronate. The amount of this radiolabelling approach is a generally
stannous ions required for optimal radiolabel- lower and more variable labelling efficiency.
ling is in the range of 10-20μg per kilogram of This may be due to insufficient Sn2+ incorpora-
body weight. tion into the cells which results in reduction of
99m
Tc-pertechnetate outside the RBC. Reduced
In vitro radiolabelling 99m
Tc is then not able to diffuse across the red
In vitro radiolabelling of RBCs gives by far the cell membrane, resulting in a high background
highest labelling efficiency and the most sta- activity. Low labelling yields may also be a con-
ble labelling over time. It may be used for the sequence of low haemoglobin concentration
determination of red cell and blood volume. and/or low haematocrit.
It may also be employed in patients who are
taking drugs which may interfere or inhibit In vivo/in vitro radiolabelling
stannous ion transport through the cell mem- More variations of the in vivo/in vitro radiola-
brane such as heparin or hydralazine, resulting belling approach are in use. In all approaches,
in lower labelling efficiency. the intravenous administration of a stannous
agent is followed by withdrawal of an aliquot
35
of pre-tinned blood 15-30 min after applica- Radiolabelling of RBCs can be affected by pa-
tion. The excess of Sn2+ not incorporated into tient medication. Drugs may interfere directly
cells may be removed by centrifugation before by reaction with Sn2+ by preventing accumula-
99m
Tc-pertechnetate is added to the cells. Al- tion of Sn2+ in the cells or indirectly by affect-
ternatively blood may be taken into a shielded ing the RBC membrane or reducing the hae-
syringe containing an anticoagulant and the matocrit and/or haemoglobin concentration.
required amount of 99mTc-pertechnetate.The For more detailed information see [2,5-7].
blood is then mixed with the 99mTc-pertech-
netate and allowed to incubate for 5-20 min at The usual administered activity of 99mTc-RBCs
room temperature with occasional mixing. The for adult patients is within the range of 500
unbound activity is washed away by centrifu- – 1050 MBq. For children the activity may be
gation before reinjection. Radiolabelled blood adjusted according to body weight, with a
may alternatively also be re-injected without minimum activity of 80 MBq in order to ob-
removal of unbound activity. With the later ap- tain images of sufficient quality [8]. Only when
proach in which no washing step is involved in vivo radiolabelling approach is employed,
one can expect lower radiolabelling efficiency breast feeding should be interrupted and the
and higher background activity, depending expressed feeds discarded due to the pres-
on the complexity (number of washing steps ence of free 99mTc-pertechnetate which con-
avoided) of the procedure. centrates in the mammary gland. The total
fractional activity ingested by the baby from in
Heat-damaged RBCs vivo radiolabelled RBCs is estimated to be 3 – 5
When radiolabelled RBCs are damaged by times higher than the activity in milk from in
heat, they will be recognised by phagocytes vitro radiolabelling. After in vitro radiolabelling
and subsequently destroyed in the spleen, breast feeding can be continued [9].
liver and bone marrow. This mechanism en-
ables the use of heat-damaged 99mTc-RBCs for General recommendations for application of
spleen imaging studies. Radiolabelled RBCs radioactive drugs are applicable for adminis-
are damaged by incubation in water bath at tration of radiolabelled RBCs. Use of a teflon
49.5 °C for 15 min before reinjection. To suf- catheter or cannula should be avoided for ad-
ficiently denature RBCs but prevent bursting ministration of Sn2+ compounds because Sn2+
them, the temperature and incubation time can react with the catheter [10]. To prevent
are critical. Localisation in liver indicates pres- reaction of 99mTc-pertechnetate with traces
ence of cell destruction formatting bursting of Sn2+ the stannous agent in the cannula
fragments. and 99mTc-pertechnetate should not be given
through the same system.
36
Chapter 5 – Radiopharmacy: Blood Labelling
EANM
Radiolabelling with 51Cr tient has splenomegaly), blood samples are
Radiolabelling of RBCs with 51Cr is carried out taken for counting in a gamma counter. The
in vitro: 51Cr in the form of sodium chromate red cell mass and plasma volume are calcu-
is incubated with whole blood containing lated by using the dilution equations. The true
ACD for approximately 10 -15 min. Chromate blood volume is then obtained by summing
ion freely diffuses into the RBCs, where it is up the red cell mass and the plasma volume.
reduced to chromic ion (Cr3+). Cr3+ bound The total body haematocrit can be calculated
to beta globin chain of the haemoglobin by dividing the red cell mass by the true blood
molecule is retained in the cell. The labelling volume.
process is stopped by adding ascorbic acid
which reduces the chromate outside the cells RBC survival
to chromic ion. Alternatively, free chromate is For RBC survival and sequestration studies,
washed away by centrifugation. 51
Cr-RBCs are reinjected to the patient and
blood samples are obtained 3 times a week
Non imaging studies for 2 to 4 weeks after injection. To eliminate
The basic principle in all non-imaging studies the need for decay correction, the samples are
using radiolabelled RBCs is the same: a known counted at the end of the study. For the 51Cr
quantity of radiolabelled RBCs is added to an survival curve, activity of the blood samples
unknown volume of blood in the body. Radio- over time can be plotted on a semilog pa-
labelled blood is allowed to mix, and a known per to linearise the curve. The patient’s RBC
quantity of the mixture is then removed and effective half-life is calculated from the curve,
quantitated (counted in a gamma counter). the normal being 25 to 35 days. In case of a
The ratio of the quantity measured after mix- significant splenic sequestration of RBCs, a sig-
ing (number of counts per mass) to the quan- nificant and progressive increase in splenic
tity added is the base for calculation of the uptake relative to the other expected site of
unknown volume [2,11,12]. RBCs, like blood pool or liver, may be present.
51
Cr-RBC uptake is monitored using thyroid
RBC mass and volume determination uptake probe positioning over spleen, liver
For RBC mass and volume determination, one and heart.
part of the radiolabelled blood is injected to
the patient and the other part is used as a stan- The usual administered activity of 51Cr-RBC for
dard for further calculations. When complete RBC mass and volume determination is 0.8
mixing of re-injected radiolabelled blood has – 1.5 MBq and 2.0 - 4.0 MBq for survival and
taken place (after 30 min or longer if the pa- sequestration studies.
37
Leucocytes and platelets Neutral lipophilic complexes rapidly diffuse
White blood cells (WBCs) or leukocytes are across cell membranes. Once inside the cell,
cells of the immune system defending the the complex either dissociates and allows 111In
body against both infectious disease and for- to bind to intracellular proteins (111In-oxine) or
eign materials. Several different and diverse breaks down to a more hydrophilic complex
types of WBC exist. They are all produced and which is unable to cross the cell membrane
derived from a multipotent hematopoietic and is thus trapped in the cell (99mTc-HMPAO).
stem cell in the bone marrow. WBCs are found In the case of radiolabelling with 111In-oxine,
throughout the body, including the blood and 111
In also binds to transferrin present in the
lymphatic systems. One primary technique plasma. Therefore the cells have to be washed
to classify WBCs is to look for the presence thoroughly to remove plasma before radiola-
of granules, which allows the differentiation belling. In the case of radiolabelling with either
of cells into two categories: granulocytes 111
In-tropolone or 99mTc-HMPAO, radiolabel-
(neutrophils, basophils and eosinophils) and ling can take place in the presence of small
agranulocytes (lymphocytes, monocytes and amounts of plasma.
macrophages) [4].
Because of the non-selective approach, the
Platelets or thrombocytes are blood cells involved cells need to be separated prior to radiolabel-
in the cellular mechanisms of primary haemosta- ling. The separation of WBCs and platelets from
sis leading to the formation of blood clots [4]. RBC in the blood can be achieved by sedimen-
tation of anticoagulated blood. 30-50 ml of
Radiolabelling of WBCs and platelets blood is taken into a 60 ml syringe containing
Non-selective lipophilic 111In and 99mTc complex- an anti-coagulant. The anti-coagulant of choice
es, which label all cells indiscriminately are used is acid-citrate-dextrose (ACD) in concentration
for radiolabelling of WBCs and platelets. Gen- 1.5 parts of ACD to 8.5 parts of whole blood.
erally radiolabelling efficiency is higher when Erythrocyte sedimentation may be accelerated
111
In complexes are used (80-90%) compared by the use of sedimentation agents such as
to 99mTc-HMPAO, where radiolabelling efficiency 6% hydroxyethyl starch (Hespan). Alternatively
is normally 50-80%. Availability, low radiation 6% dextran or methylcellulose may be used.
exposure and better imaging characteristics are Normally 3 ml of Hespan per 30 ml of whole
major advantages when 99mTc-HMPAO is used blood is used. Hespan may be added to ACD
for radiolabelling. The clinical results using 111In in a syringe before blood is taken. Sedimenta-
or 99mTc-HMPAO WBC are similar. However when tion time is generally 45-60 min and may be
99m
Tc is used for radiolabelling, scans can be affected by different factors such as number
completed sooner, because imaging takes place of cells and certain disease states. Sedimenta-
at 1 hour and at between 4-6 hours [2,12]. tion may be carried out in the syringe placed
38
Chapter 5 – Radiopharmacy: Blood Labelling
EANM
upward in a suitable holder or in a universal tion step at higher speed where the platelets
tube. After sedimentation, the upper layer con- are spinned in the pellet and plasma can be
taining WBCs and platelets is transferred into a removed. The radiolabelling procedure of the
sterile universal tube. To separate WBCs from platelets is the same as for leucocytes.
platelets, the plasma is spinned at low speed
e.g. 150 g. Platelet rich plasma is removed be- The recommended dose for 111In-WBCs is 18.5
fore the radiolabelling agent is added to the MBq; and for 99mTc-HMPAO-WBCs, it is 400 MBq
pellet containing WBCs and small amounts of (range of 185-450 MBq). For children the activ-
RBCs. The mixture is incubated at room tem- ity may be adjusted according to body weight,
perature. Incubation time varies depending with a minimum activity of 40 MBq of 99mTc-
on the radiolabelling agent used. Generally HMPAO-WBCs in order to obtain images of
it is longer when 99mTc-HMPAO is used. After sufficient quality [8]. Breast feeding should be
radiolabelling, the cells are re-suspended in interrupted and the expressed feeds discarded
saline; and free fraction of radiolabel is washed when 99mTc-HMPAO-WBCs is used for imag-
away by centrifugation. Radiolabelled cells are ing [9]. Cell radiolabelling could be affected
re-suspended before re-injection with saline or by a patient drug therapy. For more detailed
diluted plasma. Plasma is prepared from plated information see [2,5].
rich plasma by centrifugation at higher speed
e.g. 500-700 g. Radiolabelling efficiency
The percentage of radioactivity incorporated
To ensure optimal viability of radiolabelled into the cells is usually described as radiola-
cells, the labelling should be completed as belling efficiency. It should be determined as
quickly as practical; and the cells should be the last step before radiolabelled cells are re-
injected within 3 hours of removal. suspended and re-injected: the radiolabelled
cells are separated from the labelling medium
Platelet rich plasma removed from the WBCs by centrifugation. The activity of the labelled
may also be used for separation of platelets. cells is measured before and after separation.
This is achieved by an additional centrifuga- Labelling efficiency is then calculated:
39
Nevertheless a high radiolabelling efficiency is
not necessarily indicative of a good labelling
procedure or viable cells. Regardless of the ra-
diolabelling efficiency, it is important to obtain
a viable population of cells for reinjection.
Cell viability
It is essential that radiolabelled cells remain
viable when they are re-injected to the body.
They may be damaged from the harvesting
and/or radiolabelling procedures. Cell viability
is most frequently assessed by Trypan blue
exclusion assay. Trypan blue is a stain which is
incorporated into dead cells, whereas live cells
are not coloured. Equal volumes (0.1 – 0.2 ml)
of radiolabelled cell suspension and 0.4% Try-
pan blue are gently mixed in an appropriate
tube and incubated at room temperature for 5
minutes. The mixture is applied on a haemocy-
tometer slide and cells counted under a light
microscope. The percentage of viable cells
is the number of viable cells divided by the
number of dead and viable cells. Usually it
should be >95%.
40
Chapter 6 – Radiopharmacy
Record Keeping and Administration
Brendan McCoubrey
EANM
Historical legislative framework Legislative rationale
Council Directive 65/65/EEC (1965) dealt with The principal concerns of existing legislation
the use of radionuclide generators, their stor- and guidelines with regard to radiopharmacy
age and elution and the production of radio- record keeping and documentation are:
pharmaceuticals thereof for the purpose of
administration to patients. Quality Assurance: The implementation of
standards and frequencies of quality control
Council Directive 75/319/EEC (1975) dealt with testing and of equipment monitoring within
the placing on the market of radiopharma- the radiopharmacy to ensure continued com-
ceuticals and the conditions for authorising pliance with the relevant legislation regarding
the manufacturing and marketing of these radiopharmaceutical standards.
radiopharmaceuticals.
Training of personnel: The professional com-
Council Directive 87/21/EEC and Council Direc- petence of the staff in the implementation of
tive 83/570/EEC amended the two above Direc- the working practices and the documented
tives respectively with regard to additional pro- procedures in the facility. This has a large part
visions laid down for radiopharmaceuticals. to play in ongoing radiation protection within
the radiopharmacy. The training should be ap-
Council Directive 89/343/EEC issued in 1989, propriate to the tasks performed by the indi-
extended the scope of both Council Directive vidual. Ability and competence of staff should
87/21/EEC and Council Directive 83/570/EEC be assessed initially and reviewed regularly by
particularly with regard to the incorporation the person managing the facility. A detailed
of the provisions of 84/466/Euratom (patients) description of the training process and a re-
and 84/467/Euratom (staff and public). cord of completion should be maintained.
42
Chapter 6 – Radiopharmacy: Record Keeping and Administration
EANM
Healthcare quality management Quality Assurance documentation should
documentation originate with the purchase of materials for
The holder of a manufacturing authorisation use as radiopharmaceuticals; and the audit
must manufacture medicinal products so as to trail should extend to the administration of
ensure that they are fit for their intended use, that individual patient doses. The receipt of all ma-
they comply with the requirements of the mar- terials by the facility should be documented
keting authorisation, and that they do not place and checked for correctness. These records
patients at risk due to inadequate safety, quality should be capable of tracing all materials from
or efficacy. To achieve this, a comprehensively source and up to final delivery. A system of
designed and correctly implemented system of documentation must be in operation such
Quality Assurance, incorporating Good Manufac- that the history of each preparation can be
turing Practice (GMP) and Quality Control (QC), adequately traced.
must be in place. It should be fully documented
and its effectiveness monitored. All aspects of EANM reporting scheme
the Quality Assurance (QA) system should be ad- The European Association of Nuclear Medicine
equately resourced with competent personnel, has established two central European Data-
suitable and sufficient premises, equipment and bases for the reporting of possible defective
facilities. Accurate and complete record keeping products and for the reporting of adverse re-
is essential so that it will be possible to trace the actions to administered radiopharmaceuticals.
source, composition and activity of all radiophar- Adverse incidents involving the preparation
maceuticals administered to patients. or administration of radiopharmaceuticals
should be notified to the relevant local au-
Quality assurance documentation thority in the first instance; and details should
Due to short half-lives it is not possible to rig- also be forwarded to the EANM. A link to the
orously test before administration. QA is retro- EANM website is provided below.
spectively achieved through strict adherence
to written procedures. Accurate records must EANM Adverse Reactions Report 2002
be maintained and kept up to date. The work- http://www.eanm.org/committees/radiop-
ing environment must be suitably monitored harmacy/adverse_reactions.pdf
to ensure that microbiological, particulate and
radioactive contamination levels comply with Inventory of radiopharmacy records and
established standards. All equipment must be documentation
subject to regular performance checks and To ensure a complete systematic recording
calibrated against suitable standards where and documentation process, it is necessary
appropriate. Operator techniques must also to first separate the operation of the radio
be regularly monitored. pharmacy facility into its component elements.
43
A detailed Standard Operating Policy (SOP) Radiopharmaceutical reconstitution records
concerning record keeping and documenta- • Name of the preparation
tion should be drawn up for each of the fol- • Route of administration
lowing areas, specifically listing the required • Activity in Becquerel’s
data fields to be completed for each separate • Volume
operation within the radiopharmacy. • Time / Date measured
• Batch no.
General radiopharmacy operative records • Radiation warning trefoil
• Standard Operation Protocols (SOPs) • Applicable special storage conditions
• Records of workstation performance • Expiry date
• Records of microbial and particulate levels • Applicable special preparatory
in the lab and workstation instructions
• Data on starting materials and • Address of radiopharmacy
ingredients • Transport index of the packaged product
• Data on the production process • Personnel at all stages
• Data on distribution of the final product to
allow recall or halting Gamma Camera/s Records
• Disposal of radioactive waste • Date
• Emergency procedures • Personnel
• Risk assessment forms • Camera peaking
• Minor / major spill incident forms • Peaked
• Window
Radiopharmacy generator/s records • Dead time
• Date • Co57 flood source
• Generator lot no. • % UFOV result
• Generator expiry • % CFOV result
• Elution activity • Ionisation chamber
• Elution time • Constancy test Cs137
• Elution volume • Calibration test Tc99m
• Mo breakthrough test • Ionisation chamber self test
• Radiopharmaceutical lot no.
• Radiopharmaceutical expiry Patient Records
• Reconstitution time • Patient name
• Reconstitution volume • Medical record no.
• Reconstitution activity • Patient source
• Personnel at all stages • Consent
44
Chapter 6 – Radiopharmacy: Record Keeping and Administration
EANM
• Examination type • Generator ordering and delivery
• Examination no. • Accessories
• Date of exam • Software upgrades
• Radiographer
• Radiopharmaceutical kit Internal hospital supply records
• Radiopharmaceutical expiry • Pharmacy
• Activity • Stores
• Time of injection • CSSD
• Administrator • Technical services
• Administrator route
• Patient incident forms Release or failure of preparations
In accordance with GMP, procedures must be
Workload statistics put in place whereby a final product is subject
• Exam type to release/failure assessment. For the holder of
• GA a manufacturing authorisation, there should
• Sedation be a written procedure detailing all produc-
• Demographics tion and quality control data, which should
be reviewed before the batch is dispatched.
Personnel dosimetry records The procedure should also describe the mea-
• Personnel readings sures to be taken by the facility if unsatisfac-
• Extremity readings tory test results are obtained after dispatch.
• Contamination levels Recall operations should be shown to be oper-
• Background readings able within a short space of time. Conditions
for the release/failure of preparations should
National authority records include:
• Correspondence
• Certificates of compliance: a) A formal recorded decision of approval
• Camera taken by an authorised person prior to
• Dose calibrator release of preparations.
• Contamination monitor b) A written release procedure, effected only if:
• Dose rate meter i) The product has been prepared in
accordance with GMP;
External Suppliers’ Records ii) The product complies with the release
• Manuals specifications.
• Repairs and logbooks c) A written procedure which should take ef-
• Kit ordering fect where a failure to meet the required
45
standard is recorded. The event should be External Transport of Radioactive
documented and investigated. Materials
d) A written procedure should exist for the Packages for external transport from the
recall of defective radiopharmaceuticals. radiopharmacy must be labelled with the
correct international transport labels show-
Transport of Radioactive Materials ing the radionuclide, activity and transport
All of the regulations and codes of practice index. Criteria for these labels are strictly pre-
covering the transport of radioactive material scribed by the IAEA. Figure 1 gives an example
are based on the safety standard publications of the criteria pertaining to the dimensions
of the IAEA. Responsibility for transport must and ratios of radiation warning labels. Figure
be clearly allocated; and adequate records 2 demonstrates the criteria for the classifica-
of dispatch and receipt should be kept. All tion of packages. Figure 3 gives an example
containers should be suitably labelled; and of a Category II package warning label. Trans-
these labels should be removed from empty port documents must also be completed as
containers. Procedures for transport should required by national legislation.
be laid down in the Local Rules. These should
take account of any hazardous situations that
may arise during transport and of detailed pro-
cedures for dealing with those. Links to the
International Atomic Energy Agency (IAEA)
Transport Regulations 2005 may be found on
the following websites:
46
Chapter 6 – Radiopharmacy: Record Keeping and Administration
EANM
Figure 1: Basic trefoil symbol with Figure 3: Category II Yellow Label. The
proportions based on a central circle of background colour of the upper half of
radius X. The minimum allowable size of X the label shall be yellow and the lower
shall be 4 mm (1). half white, the colour of the trefoil and the
printing shall be black, and the colour of the
category bars shall be red (1).
47
tional Data Protection legislation. Alternative
arrangements should be in place in the event
of a breakdown; and these temporary records
should be incorporated into the permanent
log as soon as possible after the re-establish-
ment of normal service.
Control of documents
A Master Document should be created and
the number and location of approved copies
recorded. Every document should contain a
version number and a review date. A system
should be in place to prevent the inadvertent
use of superseded documents.
48
References
EANM
Chapter 1 Chapter 5
Chapter 4
Chapter 6
1. Sharp P F, Gemmel H G, Smith F W. Practical Nuclear
IAEA. Regulations for the Safe Transport of Radioactive
Medicine. 3rd Ed. Oxford, UK: University Press; 2005.
Material. Safety Standards for Protecting People and the
Environment. Available at: http://www-pub.iaea.org/MTCD/
publications/PDF/Pub1225_web.pdf
(as of August 1, 2008). 2005.
49
Imprint
Publisher:
European Association of Nuclear Medicine
Technologist Committee and Technologist Education Subcommittee
Hollandstrasse 14, 1020 Vienna, Austria
Tel: +43-(0)1-212 80 30, Fax: +43-(0)1-212 80 309
E-mail: info@eanm.org
URL: www.eanm.org
Content:
No responsibility is taken for the correctness of this information.
Information as per date of preparation: August 2008
Printing:
Colordruck Helminger & Co. Ges.m.b.H.
Vogelweiderstraße 116, 5020 Salzburg, Austria
Tel: +43-(0)662-882393-0, Fax: +43-(0)662-882393-22
E-mail: office@colordruck.at
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EANM
Eur
opea ne
n Association of Nuclear Medi ci