Quality Control of Radiopharmaceuticals: Essential Tests and Measures
Radiopharmaceuticals undergo strict quality control involving specific tests ensuring purity, potency, identity, safety, and efficacy. Physicochemical tests are vital for determining purity and integrity, including physical characteristics, pH, ionic strength, and radionuclidic purity.
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Presentation Transcript
QUALITY CONTROL OF RADIOPHARMACEUTICALS Lab # 5
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
A- 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.
1- 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
2- 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
2- 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
3- Radionuclidic Purity Defined as The fraction of the total radioactivity in the form of the desired radionuclide present in a radiopharmaceutical A compound has absolute radionuclidic purity if it contains no radionuclide other than the one of interest. The radionuclidic purity is an essential parameter in the quality control of radiopharmaceuticals Impurities arise from Extraneous nuclear reactions due to isotopic impurities in the target material Fission of heavy elements in the reactor 1. 2.
3- 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
4- Radiochemical Purity Defined as The fraction of the total radioactivity in the desired chemical form in the radiopharmaceutical Radiochemical purity is important in radiopharmacy since it is the radiochemical form which determines the biodistribution of the radiopharmaceutical. Radiochemical impurities will have different patterns of biodistribution which may obscure the diagnostic image obtained and render the investgation meaningless.
4- 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
4- Radiochemical Purity Radiochemical impurities arise from 1. Decomposition due to the action of solvent 2. Change in temperature or pH, light 3. Presence of oxidizing or reducing agents
4- 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 1. 2. 3.
4- 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.
4- 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? 1. Substances such as sodium ascorbate, ascorbic acid, and sodium sulfite are often added to maintain the stability of radiopharmaceuticals 2. Some radiopharmaceuticals are stored in the dark under refrigeration
4- 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 1. 2. 3. 4. 5. 6. 7. 8.
5- 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
5- Chemical Purity The presence of chemical impurities before radiolabeling may result in 1. Undesirable labeled molecules that may or may not interfere with the diagnostic test 2. Undue chemical impurities may also cause a toxic effect
5- Chemical Purity Purification of radiopharmaceuticals from Chemical impurities is often carried out by methods of chemical separation such as 1. Precipitation 2. Solvent extraction 3. Ion exchange 4. Distillation
CRC-25R Dose Calibrator 6- 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 using a dose calibrator The performance of the dose calibrator must be checked by carrying out several quality control tests.
6- 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) CRC-25R Dose Calibrator
CRC-25R Dose Calibrator 6- Radioassay Dose Calibrator Quality Control constancy (daily) The constancy test indicates the reproducibility of measurements by a dose calibrator 1. 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 10%.
6- 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 Correction factors must be established for changes in volume or container configuration
B- Biological Tests Carried out essentially to examine 1. The sterility 2. Apyrogenicity 3. Toxicity of radiopharmaceuticals before human administration
Biological Tests 1- Sterility Sterility indicates the absence of any viable bacteria or microorganisms in a radiopharmaceutical preparation Methods of Sterilization 1. Autoclaving 2. Membrane Filtration
Biological Tests 2- 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 1. USP Rabbit Test 2. 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 The reaction takes place within 15 to 60 min after mixing and depends on the concentration of pyrogens
C- Record Keeping Record keeping is mandatory for legal reasons as well as for tracing any faulty preparation
