Quality Control ofRadiopharmaceuticals

Lab # 5

Quality Control ofRadiopharmaceuticals

• 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 99mTc-eluate

• The presence of a slight amount of globulins in the preparation of albumin is indicative of impurities

• 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

Chemical Purity

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

• 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)

RadioassayDose 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%.

RadioassayDose 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

RadioassayDose Calibrator Quality Control

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 TestsSterility

• 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