PRINCE SATTAM BIN ABDUL AZIZ UNIVERSITY
COLLEGE OF PHARMACY
Nuclear Pharmacy
(PHT 433 )
Quality Control of
Radiopharmaceuticals
Dr. Shahid Jamil
7/31/2017
L15-16
1
Quality Control of
Radiopharmaceuticals
• Radiopharmaceuticals they undergo strict quality
control measures
• Involves several specific tests and
measurements that ensure
– Purity
– Potency
– Product identity
– Biologic safety
– Efficacy
Physicochemical Tests
• Tests that are essential for the
determination of the purity and
integrity of a
radiopharmaceutical.
• Some of these tests are unique
for radiopharmaceuticals
because they contain
radionuclides.
Physical Characteristics
• One should be familiar with the color and state
of a radiopharmaceutical
• A true solution should not contain any particulate
matter
• Any deviation from the original color and clarity
should be viewed with concern because it may
reflect changes in the radiopharmaceutical that
would alter its biologic behavior
• Colloidal or
aggregate
preparations
should have a
proper size range
of particles for a
given purpose
pH and Ionic Strength
• All radiopharmaceuticals should have
an appropriate hydrogen ion
concentration or pH for their stability
and integrity
• Ideal pH of a radiopharmaceutical
should be 7.4
• pH can vary between 2 and 9
because of the high buffer capacity of
the blood
pH and Ionic Strength
• Measured by a pH meter
• Radiopharmaceuticals must also have proper
– Ionic strength
– Isotonicity
– Osmolality
in order to be suitable for human administration
• How to achieve Correct ionic strength?
• By adding a proper
– Acid
– Alkali
– Electrolyte
Radionuclidic Purity
• Defined as
– The fraction of the total radioactivity in the
form of the desired radionuclide present in a
radiopharmaceutical
• Impurities arise from
– Extraneous nuclear reactions due to isotopic
impurities in the target material
– Fission of heavy elements in the reactor
Radionuclidic Purity
• The undesirable radionuclides may belong to the
same element as the desired radionuclide or to
a different element
• Impurities can be removed by appropriate
chemical methods
• Radionuclidic purity is determined by measuring
the half-lives and characteristic radiations
emitted by individual radionuclides
Radiochemical Purity
• Defined as
• The fraction of the total radioactivity in the
desired chemical form in the
radiopharmaceutical
• Radiochemical impurities arise from
• Decomposition due to the action of solvent
• Change in temperature or pH, light
• Presence of oxidizing or reducing agents
Radiochemical Purity
• The presence of radiochemical
impurities in a
radiopharmaceutical results in
poor-quality images due to the
high background from the
surrounding tissues and the blood,
and gives unnecessary radiation
dose to the patient
Radiochemical Purity
• Decomposition of labeled compounds by
radiolysis depends on
– The specific activity of the radioactive material
– The type and energy of the emitted radiation
– The half-life of the radionuclide
Radiochemical Purity
• Absorption of radiations by labeled molecules
results in the formation of free radicals with
unpaired electrons
• Which in turn leads to further decomposition of
other molecules.
• A secondary process due to radiolysis produces
H2O2 or HO2 : from decomposition of water
(solvent)
• Which reacts with and ultimately decomposes
labeled molecules.
Radiochemical Purity
• The stability of a compound is time-dependent
on exposure to light, change in temperature, and
radiolysis
• The longer a compound is exposed to these
conditions, the more it will tend to break down
• How to lessen the degradation of the
material?
• Substances such as sodium ascorbate, ascorbic
acid, and sodium sulfite are often added to
maintain the stability of radiopharmaceuticals
• Some radiopharmaceuticals are stored in the
dark under refrigeration
Radiochemical Purity
• Analytical methods used to detect and determine the
radiochemical impurities in a given
radiopharmaceutical:
– Precipitation
– Paper and Instant Thin-Layer Chromatography
– Gel Chromatography
– Paper or Polyacrylamide Gel Electrophoresis
– Ion Exchange
– Solvent Extraction
– High-Performance Liquid Chromatography
– Distillation
Chemical Purity
• The fraction of the material in the desired
chemical form whether or not all of it is in the
labeled form
• Aluminum is a chemical impurity in the 99mTceluate
• The presence of a slight amount of globulins in
the preparation of albumin is indicative of
impurities
Chemical Purity
• The presence of chemical impurities before
radiolabeling may result in undesirable labeled
molecules that may or may not interfere with the
diagnostic test
• Undue chemical impurities may also cause a
toxic effect
Chemical Purity
• Purification of radiopharmaceuticals from
Chemical impurities is often carried out by
methods of chemical separation such as
– Precipitation
– Solvent extraction
– Ion exchange
– Distillation
Radioassay
• The amount of radioactivity of a
radiopharmaceutical before dispensing as well
as that of each individual dosage before
administration to patients must be determined
• These activity determinations are carried out by
means of an isotope dose calibrator
Radioassay
Dose Calibrator Quality Control
• According to the NRC regulations the following
quality control tests must be performed at the
frequencies indicated:
1. constancy (daily)
2. accuracy (at installation, annually, and after
repairs)
3. linearity (at installation, quarterly, and after
repairs)
4. geometry (at installation and after repairs)
Radioassay
Dose Calibrator Quality Control
1. constancy (daily)
– The constancy test indicates the reproducibility of
measurements by a dose calibrator
2. accuracy (at installation, annually, and after repairs)
• The accuracy of a dose calibrator is determined by
measuring the activities of at least two long-lived
reference sources and comparing the measured activity
with the stated activity
• The measured activity must agree with the stated activity
within G10%.
Radioassay
Dose Calibrator Quality Control
3. linearity (at installation, quarterly, and after repairs)
• The linearity test indicates the dose calibrator’s ability to
measure the activity accurately over a wide range of values
4. geometry (at installation and after repairs)
• Variations in sample volumes or geometric configurations of
the container
Measurement of Radioactivity
• Radioactivity of a radiopharmaceutical is
measured by placing the sample inside the dose
calibrator with the appropriate isotope selector
setting
• The reading is displayed in appropriate units
(curie or becqurel) on the dial
Biological Tests
• Carried out essentially to
examine
– The sterility
– Apyrogenicity
– Toxicity
of radiopharmaceuticals before
human administration
Biological Tests
Sterility
• Sterility indicates the absence of any viable bacteria or
microorganisms in a radiopharmaceutical preparation
• Methods of Sterilization
– Autoclaving
– Membrane Filtration
Apyrogenicity
• All radiopharmaceuticals for human administration
are required to be pyrogen free
• Pyrogens are either polysaccharides or proteins
produced by the metabolism of microorganisms
• They are 0.05 to 1 mm in size, soluble and heat
stable
• Following administration pyrogens produce
symptoms of
– fever, chills, malaise, leukopenia, pain in joints,
flushing, sweating, headache, and dilation of the
pupils
• Pyrogenicity Testing
• USP Rabbit Test
• LAL (limulus amebocyte lysate)Test
– The principle of the test is based on the
formation of an opaque gel by pyrogens upon
incubating the sample with the LAL at 37C
– An assay mixture usually consists of 0.1 ml
LAL and a test sample at pH 6 to 8
– The reaction takes place within 15 to 60 min
after mixing and depends on the
concentration of pyrogens
Record Keeping
• Record keeping is mandatory for legal reasons
as well as for tracing any faulty preparation