EUROPEAN PHARMACOPOEIA 11.
1 Radiopharmaceutical preparations
04/2023:0125 It is related to the decay constant (λ) by the following equation :
RADIOPHARMACEUTICAL
PREPARATIONS
Radiopharmaceutica
DEFINITIONS
Radiopharmaceuticals, also called radiopharmaceutical
preparations, are medicinal products which, when ready for
use, contain one or more radionuclides (radioactive isotopes)
included for a medicinal purpose.
This general monograph also covers :
– radionuclide generators : any system incorporating a fixed
parent radionuclide from which is produced a daughter
radionuclide that is to be obtained by elution or by
any other method and used as a radiopharmaceutical
preparation or in a radiopharmaceutical preparation ;
– kits for radiopharmaceutical preparation : any preparation
to be reconstituted or combined with radionuclides in
the final radiopharmaceutical preparation, usually before
administration ;
– radionuclide precursors : any radionuclide produced for
radiolabelling of another substance before administration.
Radionuclide precursors may be supplied as solutions for
radiolabelling. If a radionuclide precursor is processed into a
final radiopharmaceutical in a continuous process in which it
is not isolated, full testing of the radionuclide precursor is not
possible. However, the production method must ensure the
identity and radionuclidic purity.
Radioactivity : generally the term ‘radioactivity’ is used
both to describe the phenomenon of radioactive decay and
to express the physical quantity of this phenomenon. The
physical quantity is also referred to as “activity”.
The radioactivity of a preparation is the number of nuclear
disintegrations or transformations per unit time.
In the International System of Units (SI), radioactivity is
expressed in becquerels (Bq). One becquerel is 1 nuclear
transformation per second. Absolute radioactivity
measurements require a specialised laboratory but
identification of radioactivity and quantitative measurement
of radioactivity can be carried out relatively by comparing the
measured samples with standardised preparations provided
by laboratories recognised by the competent authority or by
using a calibrated instrument.
Detection and measurement of radioactivity are carried
out according to general method 2.2.66. Detection and
measurement of radioactivity.
Radioactive decay : all radionuclides decay at an exponential
rate with their characteristic decay constant.
The curve of exponential decay (decay curve) is described by
the following expression :
At = A0 e-λt
At = the radioactivity at time t ;
A0 = the radioactivity at time t = 0 ;
λ = the decay constant, characteristic of each
radionuclide ;
e = the base of natural logarithms.
The half-life (T1/2) is the time in which a given radioactivity
(amount) of a radionuclide decays to half its initial value.
General Notices (1) apply to all monographs and other texts
ln 2
T1/2 =
λ
The equation of exponential decay can thus also be expressed
in the following way, useful for the fast estimation of the
radioactivity remaining after elapsed time t :
t
æ 1 öT1 /2
At = A0 çç ÷÷÷
çè 2 ø
The penetrating power of each radiation varies considerably
according to its nature and its energy. Alpha particles are
completely absorbed in a thickness of a few micrometres
to some tens of micrometres of matter. Beta particles are
completely absorbed in a thickness of several millimetres to
several centimetres of matter. Gamma rays are not completely
absorbed but only attenuated and a tenfold reduction may
require, for example, several centimetres of lead. The denser
the absorbent, the shorter the range of alpha and beta particles
and the greater the attenuation of gamma rays.
Each radionuclide is characterised by an invariable half-life,
expressed in units of time and by the nature and energy
of its radiation or radiations. The energy is expressed in
electronvolts (eV).
Isotopic carrier : a stable isotope of the element concerned
either present in or added to the radioactive preparation in
the same chemical form as that in which the radionuclide is
present.
Specific radioactivity : the radioactivity of the radionuclide
concerned in the stated chemical form per unit mass of the
element or of the chemical form concerned, expressed in Bq/g.
Molar radioactivity : the radioactivity of the radionuclide
concerned in the stated chemical form per mole of the
chemical form concerned, expressed in Bq/mol.
Radioactivity concentration : the radioactivity of the
radionuclide concerned per unit volume or unit mass of the
preparation. For radiopharmaceutical solutions, it is expressed
as radioactivity per unit volume of the preparation.
Total radioactivity : the radioactivity of the radionuclide
concerned, expressed per unit (vial, capsule, ampoule,
generator, etc).
Shelf life : the time during which specifications described in
the monograph must be fulfilled. Expiry date and, if necessary,
time must be clearly stated on the label.
Maximum recommended dose in millilitres (V) : the
authorised maximum volume of a dose in millilitres of a
radiopharmaceutical preparation. Maximum volume of
a dose in millilitres (V) must be specified to ensure that
specification limits that are provided on a concentration basis
are toxicologically qualified.
PRODUCTION
Radionuclides
A radiopharmaceutical preparation contains its radionuclide :
– as an element in atomic or molecular form, e.g. 133Xe,
[15O]O2 ;
– as an ion, e.g. [131I]iodide, [99mTc]pertechnetate ;
– included in, adsorbed on or attached to molecules by
chelation, e.g. [111In]indium oxine, or by covalent bonding,
e.g. 2-[18F]fluoro-2-deoxy-D-glucose.
Radionuclides are mostly produced in the following ways :
– by neutron irradiation (target irradiation in nuclear
reactors) ;
– by charged particle irradiation (target irradiation using
accelerators, in particular cyclotrons) ;
– by their separation from radionuclide generators.
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Radiopharmaceutical preparations
In addition to the desired nuclear reaction, simultaneous
transformations may occur, resulting in radionuclidic
impurities.
In the production of radionuclides, and particularly of
radionuclides with a short half-life, it may not be possible
to determine the chemical state and the chemical purity of
the radionuclides before further processing and production
of radiopharmaceutical preparations. Therefore the quality
of each batch of target material is assessed before its use in
routine radionuclide production and the manufacture of
radiopharmaceutical preparations.
To evaluate all effects on the efficiency of the production of the the specified range, potentiometric determination of the pH
radionuclide in terms of quality and quantity, the production
procedure must clearly describe and take into consideration :
the target material ; construction of the holder for the target
material ; method of irradiation and separation of the desired
radionuclide.
Chemical precursors and excipients
Chemical precursors and excipients used in the preparation
and formulation of radiopharmaceutical preparations
comply with the requirements of the respective monographs
and relevant general monographs Chemical precursors for
radiopharmaceutical preparations (2902) and Substances for
pharmaceutical use (2034), respectively.
CHARACTERS
The general chapter 5.7. Table of physical characteristics of
radionuclides mentioned in the European Pharmacopoeia
summarises the most commonly accepted physical
characteristics of radionuclides used in preparations that are
the subject of monographs in the European Pharmacopoeia.
In addition, the Table states the physical characteristics of the should be part of the specifications of the preparation.
main potential radionuclidic impurities of the radionuclides
mentioned in the monographs.
The term ‘transition probability’ means the probability of
the transformation of a nucleus in a given energy state, via
the transition concerned. Instead of ‘probability’ the term
‘abundance’ is also used.
The term ‘emission probability’ means the probability that
the decay of a radionuclide gives rise to the emission of the
particles or radiation concerned.
Irrespective of which meaning is intended, probability is
usually stated as a percentage.
IDENTIFICATION
Appropriate analytical procedures are used to provide
confirmation of the identity of the preparation.
A radionuclide is identified by its half-life or by the nature and procedures according to general method 2.4.20. Determination
energy of its radiation or radiations, or by both (2.2.66).
Approximate half-life. The half-life as determined over
a relatively short time period to allow confirmation of
the radionuclide identity and to allow release for use of
radiopharmaceutical preparations.
The calculated approximate half-life is within the range of the procedure.
values stated in the individual monograph which allows an
unambiguous identification of the radionuclide.
Determination of the nature and energy of the radiation.
The nature and energy of the radiation emitted are
determined using spectrometry. The nature and energy of
the radiation of positron emitters is usually not determined ;
their identification is performed by determination of the
approximate half-life and gamma-ray spectrum.
TESTS
It is sometimes difficult to carry out some of the following
tests before releasing the batch for use when the shelf life of
the preparation is short relative to the time for pre-release
testing. The individual monograph indicates the tests that do
not need to be completed before release for use. These tests then short half-life of some radionuclides, small batch sizes and
constitute a control of the quality of production.
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EUROPEAN PHARMACOPOEIA 11.1
pH. The pH of radiopharmaceutical preparations made by
different production methods may be different, for example
due to the use of different stabilisers. Consequently, the pH
range specified in a monograph may be wide. The pH for
a preparation of a particular composition would however
be expected to be in a much narrower range. Where a
specification requirement on pH is given to two significant
figures (for example, 4.5-7.0) and the prescribed analytical
procedure specifies use of a pH indicator strip R (2.2.4), a
narrow range pH indicator strip is recommended and the
outcome of the test should be reported to two significant
figures. In case no narrow range pH strip can be found in
(2.2.3) is considered to be a suitable alternative.
Particulate contamination : visible particles (2.9.20).
Radiopharmaceutical preparations for parenteral use,
examined under suitable conditions of visibility, are practically
free from visible particles.
CHEMICAL PURITY
In monographs on radiopharmaceutical preparations, chemical
purity is controlled by specifying non-radioactive chemical
impurities.
Non-radioactive analogues of the radioactive substance,
related substances and other non-radioactive substances.
Non-radioactive analogues of the radioactive substance,
related substances and other non-radioactive substances that
can be present are determined. Unless otherwise prescribed,
the limits must be defined and justified. The presence of
potential impurities must be investigated and subjected to a
risk assessment. Based on the outcome of the risk assessment,
limits and analytical procedures for the relevant impurities
Recommendations on testing for visible particles are given in
general chapter 5.17.2.
Elemental impurities
General chapter 5.20. Elemental impurities applies to
pharmaceutical preparations except radiopharmaceutical
preparations, unlicensed preparations and other products that
are excluded from the scope of this chapter.
Producers of pharmaceutical preparations outside the scope
of general chapter 5.20 remain responsible for controlling
the levels of elemental impurities using the principles of
risk management. A risk assessment identifies, for example,
metal ions with a potential to interfere with the radiolabelling
capabilities of the radiopharmaceutical or elemental impurities
that present a safety concern. If appropriate, limits are defined
and justified. Testing is performed using suitable analytical
of elemental impurities.
Residual solvents. Residual solvents are limited according
to general chapter 5.4. Residual solvents, using the analytical
procedures given in general chapter 2.4.24. Identification
and control of residual solvents or another suitable analytical
Physiological distribution
Tests involving animals should be avoided wherever possible.
Where the radiochemical species in a radiopharmaceutical
preparation are not sufficiently identified and controlled by
other tests, a physiological distribution test may be required. A
physiological test can also serve to confirm batch consistency.
Sterility
Radiopharmaceuticals for parenteral administration comply
with the test for sterility. They must be prepared using
precautions designed to exclude microbial contamination
and to ensure sterility. The test for sterility is carried out as
described in the general method (2.6.1). Special difficulties
arise with radiopharmaceutical preparations because of the
radiation hazards. In the case that the monograph states that
See the information section on general monographs (cover pages)
EUROPEAN PHARMACOPOEIA 11.1
the preparation can be released for use before completion of
the test for sterility, the sterility test must be started as soon
as practically possible. If not started immediately, samples
are stored under conditions that are shown to be appropriate
in order to prevent false negative and false positive results.
Parametric release (5.1.1) may be the best choice for terminally
sterilised preparations. When aseptic production is used, the
test for sterility must be performed as a control of the quality
of production.
Radionuclide precursors comply with the test for sterility if
intended for use in the production of a radiopharmaceutical
for parenteral administration without a further appropriate
procedure for the removal of microbial contamination.
When the size of a batch of the radiopharmaceutical
preparation is limited to one or a few samples, sampling the
batch for sterility testing according to the recommendations
of the general method (2.6.1) may not be applicable.
When the half-life of the radionuclide is less than 5 minutes,
the administration of the radiopharmaceutical preparation to
the patient is generally on-line with a validated production
process.
For the routine control of the filtration process for the aseptic
production of sterile radiopharmaceutical preparations
and where justified and authorised on the basis of a risk
assessment, the pre-filtration filter integrity test may be
omitted and only a post-filtration integrity test performed.
Radiopharmaceutical preparations for parenteral use should
be used within 24 h after opening/reconstitution. If the
preparation is intended to be used later than 24 h after
opening, it must include antimicrobial preservatives in the
formulation.
Bacterial endotoxins - pyrogens
Radiopharmaceuticals for parenteral administration comply
with the test for bacterial endotoxins (2.6.14) or with the test
for pyrogens (2.6.8).
Eluates of radionuclide generators, radionuclide precursors
(solutions for radiolabelling) and kits for radiopharmaceutical
preparations also comply with the test for bacterial endotoxins.
The limits on the bacterial endotoxins level must allow for a
contribution from other sources in the radiolabelling process,
if intended for the preparation of radiopharmaceuticals for
parenteral administration without further purification.
The test for bacterial endotoxins is carried out as described in
the general method (2.6.14). The limit for bacterial endotoxins
is indicated in the individual monograph or calculated
according to general chapter 5.1.10. Guidelines for using the
test for bacterial endotoxins.
In the case of radionuclides with a half-life shorter than
90 minutes and where justified and authorised on the basis
of a risk assessment, the preparation may be released for use
before completion of the test.
When the nature of the radiopharmaceutical preparation
results in interference in the test for bacterial endotoxins by
inhibition or activation and it is not possible to eliminate
the interfering factor(s), the test for pyrogens (2.6.8) may be
specifically prescribed.
RADIONUCLIDIC PURITY
The radionuclidic purity of a radiopharmaceutical preparation
is the ratio, expressed as a percentage, of the radioactivity of
the radionuclide concerned to the total radioactivity of the
radiopharmaceutical preparation. Radionuclidic impurities
may arise during the production and decay of a radionuclide.
The relevant potential radionuclidic impurities are listed
with their limits in the monograph and their characteristics
are described in general chapter 5.7. Table of physical
characteristics of radionuclides mentioned in the European
Pharmacopoeia. In the absence of a monograph, the level of
radionuclidic impurities must be justified and specified.
General Notices (1) apply to all monographs and other texts
Radiopharmaceutical preparations
In most cases, to establish the radionuclidic purity of a
radiopharmaceutical preparation, the identity of every
radionuclide present and its radioactivity must be known.
Generally, the most useful analytical procedure for
examination of the radionuclidic purity of gamma- and X-ray
emitting radionuclides is gamma-ray spectrometry. The use
of sodium iodide detectors may not be suitable due to poor
energy resolution and their use must be justified. High-purity
germanium detectors are preferred. Alpha- and beta-particle
emitting impurities that do not emit gamma- or X-rays cannot
be detected in this way. For alpha- and beta-emitters other
analytical procedures must be employed.
Individual monographs prescribe the radionuclidic
purity required and may set limits for specific radionuclidic
impurities (for example, molybdenum-99 in technetium-99m).
While these requirements are necessary, they are not in
themselves sufficient to ensure that the radionuclidic purity
of a preparation is sufficient for its clinical use. The producer
must examine the product in detail and especially must
examine preparations of radionuclides with a short half-life for
impurities with a long half-life after a suitable period of decay.
In this way, information on the suitability of the production
processes and the adequacy of the testing procedures is
obtained.
A preparation must comply with the radionuclidic purity
requirements throughout the shelf life. If a preparation is
made with a solution for radiolabelling that is the subject of a
monograph in the European Pharmacopoeia, the preparation
must comply throughout its shelf life with the radionuclidic
purity requirements prescribed in the monograph on the
radionuclide precursor.
In cases where two or more positron-emitting radionuclides
need to be identified and/or differentiated, for example the
presence of 13N-impurities in 18F-preparations, determination
of the approximate half-life may need to be carried out in
addition to gamma-ray spectrometry.
Due to differences in the half-lives of the different
radionuclides present in a radiopharmaceutical preparation,
the radionuclidic purity changes with time.
RADIOCHEMICAL PURITY
The radiochemical purity of a radiopharmaceutical
preparation is the ratio, expressed as a percentage, of the
radioactivity of the radionuclide concerned which is present
in the radiopharmaceutical preparation in the stated chemical
form, to the total radioactivity of that radionuclide present
in the radiopharmaceutical preparation. Radiochemical
impurities may originate from :
– radionuclide production ;
– subsequent chemical procedures ;
– incomplete preparative separation ;
– chemical changes during transportation and storage.
Unless otherwise prescribed or justified and authorised
relevant potential radiochemical impurities are listed with
their limits.
The determination of radiochemical purity requires
separation of the different chemical substances containing
the radionuclide and determination of the percentage of
radioactivity of the radionuclide concerned associated with
the stated chemical form. The radiochemical purity section
of an individual monograph may include limits for specified
radiochemical impurities, including isomers.
Certain precautions specific to radiopharmaceuticals must
also be considered, such as radiation protection, measurement
geometry, detector linearity, use of carriers and dilution of
the preparation.
Specific radioactivity
If prescribed in an individual monograph, specific radioactivity
is usually calculated taking into account the radioactivity
concentration and the concentration of the chemical substance
being studied, after verification that the radioactivity is
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Radiopharmaceutical preparations EUROPEAN PHARMACOPOEIA 11.1

attributable only to the radionuclide (radionuclidic purity) For preparations prepared at the site of use, the labelling can
and the chemical species (radiochemical purity) concerned. be modified.
Specific radioactivity changes with time. The radioactivity of a preparation is stated at a given date. If
the half-life is less than 70 days the time is also indicated, with
RADIOACTIVITY reference to a time zone. The radioactivity at other times may
The radioactivity of the main radionuclide (or, if applicable, be calculated from the decay equation or from tables.
the main radionuclides) of the radiopharmaceutical In addition to the above, the label on the container, the
preparation is determined. Unless otherwise prescribed, limits package, a leaflet accompanying the package or a certificate of
must be defined and justified. analysis accompanying the radiopharmaceutical preparation
states :
STORAGE
– the route of administration ;
Store preparations containing radioactive substances in an
airtight container that is sufficiently shielded to protect – where applicable, the maximum recommended dose in
personnel from irradiation by primary or secondary emissions millilitres ;
and that complies with national and international regulations – where applicable, the route of radionuclide production ;
concerning the storage of radioactive substances. During – where applicable, the concentration of ethanol and other
storage, containers may darken due to irradiation. Such additives ;
darkening does not necessarily involve deterioration of the – the name and concentration of any added antimicrobial
preparations. preservative ;
LABELLING – where applicable, any special storage conditions ;
The labelling of radiopharmaceutical preparations complies – the expiry time in clear terms (date/h/min) with reference
with the relevant national and European legislation. to a specific time zone.

4590 See the information section on general monographs (cover pages)