The handling and testing of radiopharmaceuticals (radioactive pharmaceuticals) require specialized techniques in order that correct results may be obtained and hazards to personnel minimized. All operations should be carried out or supervised by personnel who have received expert training in handling radioactive materials.
Definitions
Nuclide
A species of atom characterized by its mass number, atomic number, and nuclear energy state, provided that the mean life in that state is long enough to be observable.
Radioactivity
The property of certain nuclides of emitting radiation by the spontaneous transformation of their nuclei into those of other nuclides.
EXPLANATORY NOTE. The term "disintegration" is widely used as an alternative to the term "transformation". Transformation is preferred as it includes, without semantic difficulties, those processes in which no particles are emitted from the nucleus.
Radionuclide
A nuclide that is radioactive.
Units of radioactivity
The activity of a quantity of radioactive material is expressed in terms of the number of nuclear transformations taking place in unit time. The SI unit of activity is the becquerel (Bq), a special name for the reciprocal second (s-1). The expression of activity in terms of the becquerel therefore indicates the number of disintegrations per second. One curie (Ci) equals 3.7 × 1010 Bq.
The conversion factors between becquerel and curie and its submultiples are given in "Units of measurement".
Half-life period
The time in which the radioactivity decreases to one-half its original value.
EXPLANATORY NOTE. The rate of radioactive decay is constant and characteristic for each individual radionuclide. The exponential decay curve is described mathematically by the equation
where N is the number of atoms at elapsed time t, No is the number of atoms when t = 0, and λ is the disintegration constant characteristic of each individual radionuclide. The half-life period is related to the disintegration constant by the equation
Radioactive decay corrections are calculated from the exponential equation, or from decay tables, or are obtained from a decay curve plotted for the particular radionuclide involved (see Fig. 1).
FIG. 1. MASTER DECAY CHART
Radioactive concentration
The radioactive concentration of a solution refers to the radioactivity in a unit volume of the solution. As with all statements involving radioactivity, it is necessary to include a reference date of standardization. For radionuclides with a half-life period of less than 30 days, the time of standardization should be expressed to the nearest hour. For radionuclides with a half-life period of less than one day, a more precise statement of the reference time is required.
Specific radioactivity (or specific activity)
The specific activity of a preparation of a radioactive material is the radioactivity per unit mass of the element or of the compound concerned.
EXPLANATORY NOTE. It is usual to specify the radionuclide concerned and also it is necessary to express the time thus: "1 mCi of iodine-131 per mg of o-iodohippuric acid at 12.00 hours UT on 1 January 1979", or "40 MBq of selenium-75 per mg of selenomethionine on 1 January 1979".
Specific radioactivity is often not determined directly but is calculated from a knowledge of the radioactive concentration of the solution and of the chemical concentration of the radioactive compound. Thus, if a solution contains x mCi of 131I per ml, and if the 131I is entirely in the chemical form of sodium o-iodohippurate of which the concentration is y mg per ml, then at that time the specific activity is:
x/y mCi of iodine-131 per mg of o-iodohippuric acid.
Where necessary, the radiochemical purity of the preparation (see below) must be taken into account.
The term employed in radiochemical work is "specific activity". As the word "activity" has other connotations in a pharmacopoeia, the term should, where necessary, be modified to "specific radioactivity" to avoid ambiguity.
Radionuclidic purity
The radionuclidic purity of a preparation is that percentage of the total radioactivity that is present in the form of the stated radionuclide.
EXPLANATORY NOTE. Some radionuclides decay into nuclides that are themselves radioactive: these are referred to as mother (or parent) and daughter radionuclides, respectively. Such daughter radionuclides are often excluded when calculating the radionuclidic purity; for example, iodine-131 will always contain its daughter xenon-131m, but this would not be considered an impurity because its presence is unavoidable.
In employing the definition, the radioactivity must be measured in appropriate units: that is, in the number of nuclear transformations that occur in unit time (in terms of curies or becquerels). If, for example, a preparation stated to be iodine-125 is known to contain 99 mCi of iodine-125 and 1 mCi of iodine-126, and no other radionuclide, then the preparation is said to be of 99% radionuclidic purity. It will be noted that the relative amounts of iodine-125 and iodine-126, and hence the radionuclidic purity, will change with time. An expression of radionuclidic purity must therefore contain a statement of the time, such as: "Not more than 1% of the total radioactivity is due to iodine-126 at the reference date stated on the label". In the case of radionuclides with a half-life period of less than 30 days the reference hour should also be included.
It is clear that, in order to give a statement of the radionuclidic purity of a preparation, the activities (and hence the identities) of every radionuclide present must be known. There are no simple and certain means of identifying and measuring all the radionuclidic impurities that might be present in a preparation. An expression of radionuclidic purity must either depend upon the judgement of the person concerned, or it must be qualified by reference to the method employed, for example: "No radionuclidic impurities were detected by gamma scintillation spectrometry using a sodium iodide detector."
Radiochemical purity
The radiochemical purity of a preparation is that percentage of the stated radionuclide that is present in the stated chemical form. As radiochemical purity may change with time, mainly because of radiation decomposition, the time at which the radiochemical purity limit is applicable must be specified.
EXPLANATORY NOTE. If, for example, a preparation of cyanocobalamin (57Co) is stated to be 99% radiochemically pure, then 99% of the cobalt-57 is present in the form of cyanocobalamin. Radiochemical impurities might include such substances as cobaltous (57Co) ion or hydroxycobalamin (57Co).
The possible presence of radionuclidic impurities is not taken into account in the definition. If the radionuclidic impurity is not isotopic with the stated radionuclide, then it cannot possibly be in the identical chemical form. If the radionuclidic impurity is isotopic with the stated radionuclide, it could be, and indeed is likely to be, in the same chemical form.
Radiochemical impurities may arise during the preparation of the material or during storage, because of ordinary chemical decomposition or, what is often more important, because of radiation decomposition (that is, because of the physical and chemical effects of the radiation).
Production and Handling of Radiopharmaceuticals
The following paragraphs concern special considerations applying to the monographs on radiopharmaceuticals. The facilities for the production, use, and storage of radiopharmaceuticals are generally subject to licensing by national authorities. They often have to comply with 2 sets of regulations, those concerned with pharmaceutical preparations and those concerned with radioactive materials. Each producer or user must be thoroughly cognizant of the national requirements pertaining to the articles concerned.
Carriers
The mass of radioactive material usually encountered in radioactive pharmaceuticals is often too small to be measured by ordinary chemical or physical methods. Since such small amounts may not be subject to the usual methods of separation and purification, a carrier, in the form of inactive material, either isotopic with the radionuclide, or non-isotopic, but chemically similar to the radionuclide, may be added during processing and dispensing to permit ready handling. Thus sodium phosphate carrier is present in "Natrii Phosphatis (32P) Injectio" and rhenium is used as a carrier in certain colloidal preparations of technetium-99m. The amount of carrier added must be sufficiently small for it not to cause undesirable physiological effects. The mass of an element formed in a nuclear reaction may be exceeded by that of the inactive isotope present in the target material or in the reagents used in the separation procedures.
Radioactive preparations in which no carrier is intentionally added during the manufacture or processing are often loosely referred to as carrier-free.
Detection and Measurement
Radioactive transformations may involve the emission of charged particles, the process of electron capture, or the process of isomeric transition. The charged particles emitted from the nucleus may be alpha particles (helium nuclei of mass number 4) or beta particles (electrons of negative or positive charge, β- or β+ respectively, the latter known as positrons). The emission of charged particles from the nucleus may be accompanied by gamma rays, which are of the same physical nature as X-rays. Gamma rays are also emitted in the process of isomeric transition (i.t.). X-rays, which may be accompanied by gamma rays, are emitted in the process of electron capture (e.c.). Positrons are annihilated on contact with matter. Each positron annihilated is accompanied by the emission of 2 gamma rays, each with an energy of 0.511 MeV.
The physical characteristics of radionuclides are summarized in Table 1.
The methods employed for the detection and measurement of radioactivity are dependent upon the nature and energy of the radiation emitted. Radioactivity may be detected and/or measured by a number of different instruments based upon the action of radiation in causing the ionization of gases and solids, or the fluorescence of certain solids and liquids, or by the effect of radiation on a photographic emulsion.
In general, a counting assembly consists of a sensing unit and an electronic scaling device. The sensing unit may be a Geiger-M1/4ller tube, a proportional counter, a scintillation detector in which a photomultiplier tube is employed in conjunction with a scintillator, or a solid-state semiconductor.
Geiger-M1/4ller counters and proportional counters are generally used for the measurement of the beta emitters. Scintillation counters employing liquid or solid phosphors may be used for the measurement of alpha, beta, and gamma emitters. Solid-state devices may also be used for alpha, beta, and gamma measurements. The electronic circuitry associated with a detector system usually consists of a high-voltage supply, an amplifier, a pulse-height selector, and a sealer, a ratemeter, or other readout device. When the electronic scaling device or the sealer in a counting assembly is replaced by an electronic integrating device, the resultant assembly is a ratemeter. Ratemeters are used for the purpose of monitoring and surveying radioactivity and are somewhat less precise as measuring instruments than the counters. Ionization chambers are often used for measuring gamma-ray activities and, provided they are thin-walled, for measuring X-rays.
TABLE 1. PHYSICAL CHARACTERISTICS OF RADIONUCLIDES
Nuclide | Half-life | Type of | Particle energies and transition probabilities | Electromagnetic transitions | |||
energy | transition | photon energy | photons emitted | transitions | |||
Cesium-137 | 30.1 a | β- | 0.512 | 94.6% | |||
1.174 | 5.4% | ||||||
..................................................................................... | |||||||
via 2.6 min 137mBa | |||||||
0.662 | 85.1% | 9.5% | |||||
0.032-0.038 | 8% (Ba K X-rays) | ||||||
Chromium-51 | 27.7 d | e.c. | 100% | 0.320 | 9.83% | ||
0.005-0.006 | ~22% (V K X-rays) | ||||||
Cobalt-57 | 270 d | e.c. | 100% | 0.014 | 9.4% | 78.0% | |
0.122 | 85.2% | 2.0% | |||||
0.136 | 11.1% | 1.5% | |||||
0.570 | 0.02% | ||||||
0.692 | 0.16% | ||||||
others | low intensity | ||||||
0.006-0.007 | ~55% (Fe K X-rays) | ||||||
Cobalt-58 | 70.8 d | β+ | 0.475 | 15.0% | 0.511 | from β+ | |
e.c. | 85.0% | 0.811 | 99.4% | ||||
0.864 | 0.7% | ||||||
1.675 | 0.5% | ||||||
0.006-0.007 | ~26% (Fe K X-rays) | ||||||
Cobalt-60 | 5.27 a | β- | 0.318 | 99.9% | 1.173 | 99.86% | 0.02% |
1.491 | 0.1% | 1.333 | 99.98% | 0.01% | |||
others | <0.01% | ||||||
Gallium-67 | 78.3 h | e.c. | 100% | 0.091 | 3.6% | 0.3% | |
0.185 | 23.5% | 0.4% | |||||
0.209 | 2.6% | 0.02% | |||||
0.300 | 16.7% | 0.06% | |||||
0.394 | 4.4% | 0.01% | |||||
0.494 | 0.1% | ||||||
0.704 | 0.02% | ||||||
0.795 | 0.06% | ||||||
0.888 | 0.17% | ||||||
0.008-0.010 | 43% (Zn K X-rays) | ||||||
..................................................................................... | |||||||
via 9.2 μs 67mZn | |||||||
0.093 | 37.6% | 32.4% | |||||
0.008-0.010 | 13% (Zn K X-rays) | ||||||
Gold-198 | 2.70 d | β- | 0.285 | 1.32% | 0.412 | 95.45% | 4.3% |
0.961 | 98.66% | 0.676 | 1.06% | 0.03% | |||
1.373 | 0.02% | 1.088 | 0.23% | ||||
Gold-199 | 3.13 d | β- | 0.25 | 21% | 0.050 | 0.3% | 3.5% |
0.29 | 72% | 0.158 | 39.6% | 36.4% | |||
0.45 | 7% | 0.208 | 8.8% | 8.3% | |||
0.069-0.083 | ~18% (Hg K X-rays) | ||||||
Indium-111 | 2.81 d | e.c. | 100% | 0.172 | 89.6% | 10.4% | |
0.247 | 94.0% | 6.0% | |||||
Indium-113m | 99.5 min | i.t. | 100% | 0.392 | 64.9% | 35.1% | |
0.024-0.028 | 24% (In K X-rays) | ||||||
Iodine-123 | 13.2 h | e.c. | 100% | 0.159 | 83.0% | 16.3% | |
0.347 | 0.10% | ||||||
0.440 | 0.35% | ||||||
0.506 | 0.26% | ||||||
0.529 | 1.05% | ||||||
0.539 | 0.27% | ||||||
0.027-0.032 | ~86% (Te K X-rays) | ||||||
Iodine-125 | 60.0 d | e.c. | 100% | 0.035 | 7% | 93% | |
0.027-0.032 | 138% (Te K X-rays) | ||||||
Iodine-126 | 13 d | β- | 0.38 | 3% | 0.389 | 32% | 0.5% |
0.88 | 30% | 0.491 | 2% | ||||
1.27 | 15% | 0.511 | from β+ | ||||
β+ | 0.46 | ~0.1% | 0.666 | 30% | 0.1% | ||
1.1 | ~0.4% | 0.754 | 4% | ||||
e.c. | 51.5% | 0.880 | 0.8% | ||||
1.420 | 0.3% | ||||||
others | <0.1%> | ||||||
0.027-0.032 | ~38% (Te K X-rays) | ||||||
Iodine-131 | 8.06 d | β- | 0.247 | 1.8% | 0.080 | 2.4% | 3.8% |
0.304 | 0.6% | 0.284 | 5.9% | 0.3% | |||
0.334 | 7.2% | 0.364 | 81.8% | 1.7% | |||
0.606 | 89.7% | 0.637 | 7.2% | ||||
0.806 | 0.7% | 0.723 | 1.8% | ||||
....................................................................................................................................................... | |||||||
1.3% of 131I decays via 12 d 131mXe | |||||||
(Xenon-131m) | i.t. | 100% | 0.164 | 2% | 98% | ||
(percentages relate to disintegrations of 131m Xe) | |||||||
Iodine-132 | 2.29 h | β- | 0.84 | 16.0% | 0.506 | 5.0% | |
1.01 | 3.5% | 0.523 | 16.1% | 0.2% | |||
1.07 | 6.5% | 0.621 | 2.0% | ||||
1.09 | 3.0% | 0.630 | 13.7% | 0.1% | |||
1.10 | 2.6% | 0.651 | 2.7% | ||||
1.26 | 2.9% | 0.668 | 98.7% | 0.4% | |||
1.29 | 18.4% | 0.670 | 4.9% | ||||
1.57 | 10.8% | 0.672 | 5.2% | ||||
1.72 | 12.7% | 0.727 | 6.5% | ||||
2.24 | 20.2% | 0.773 | 76.2% | 0.3% | |||
others | 3.4% | 0.810 | 2.9% | ||||
0.812 | 5.6% | ||||||
0.955 | 18.1% | ||||||
1.136 | 3.0% | ||||||
1.295 | 2.0% | ||||||
1.372 | 2.5% | ||||||
1.399 | 7.1% | ||||||
1.433 | 1.4% | ||||||
1.921 | 1.2% | ||||||
2.002 | 1.1% | ||||||
others | <1.5% | ||||||
Iron-55 | 2.69 a | e.c. | 0.006 | ~28% (Mn K X-rays) | |||
Iron-59 | 44.6 d | β- | 0.084 | 0.1% | 0.143 | 0.8% |
|
0.132 | 1.1% | 0.192 | 2.8% |
| |||
0.274 | 45.8% | 0.335 | 0.3% |
| |||
0.467 | 52.7% | 0.383 | 0.02% |
| |||
1.566 | 0.3% | 1.099 | 55.8% |
| |||
1.292 | 43.8% |
| |||||
1.482 | 0.06% |
| |||||
Mercury-197 | 64.4 h | e.c. | 100% | 0.077 | 19.2% | 80.7% | |
0.192 | ~1.1% | 0.9% | |||||
0.268 | ~0.1% | ||||||
0.067-0.080 | ~73% (Au K X-rays) | ||||||
Mercury-197m | 24 h | e.c. | 6.5% | 0.134 | 31.8% | 61.7% | |
i.t. | 93.5% | 0.165 | 0.3% | 93.2% | |||
0.067-0.083 | 36% (Au/Hg K X-rays) | ||||||
..................................................................................... | |||||||
via 7.8 s 197mAu | |||||||
0.130 | 0.5% | 6% | |||||
0.279 | 5.0% | 1.5% | |||||
0.409 | <0.005% | ||||||
0.067-0.080 | ~2% (Au K X-rays) | ||||||
....................................................................................................................................................... | |||||||
Daughter 197Hg | |||||||
Mercury-203 | 46.6 d | β- | 0.212 | 100% | 0.279 | 81.5% | 18.5% |
0.071-0.085 | 12.8% (Tl K X-rays) | ||||||
Molybdenum-99 | 66.2 h | β- | 0.454 | 18.3% | 0.041 | 1.2% | 4.8% |
0.866 | 1.4% | 0.141 | 5.4% | 0.7% | |||
1.232 | 80% | 0.181 | 6.6% | 1.0% | |||
others | 0.3% | 0.366 | 1.4% | ||||
0.412 | 0.02% | ||||||
0.529 | 0.05% | ||||||
0.621 | 0.02% | ||||||
0.740 | 13.6% | ||||||
0.778 | 4.7% | ||||||
0.823 | 0.13% | ||||||
0.961 | 0.1% | ||||||
..................................................................................... | |||||||
via 6.02 h 99mTc in equilibrium | |||||||
0.002 | ~0% | 93.9% | |||||
0.141 | 83.9% | 10.0% | |||||
0.143 | 0.03% | 0.8% | |||||
Phosphorus-32 | 14.3 d | β- | 1.709 | 100% | |||
Selenium-75 | 118.5 d | e.c. | 100% | 0.066 | 1.1% | 0.3% | |
0.097 | 2.9% | 3.0% | |||||
0.121 | 15.7% | 0.7% | |||||
0.136 | 54.0% | 1.6% | |||||
0.199 | 1.5% | ||||||
0.265 | 56.9% | 0.4% | |||||
0.280 | 18.5% | 0.2% | |||||
0.401 | 11.7% | ||||||
others | <0.05%> | ||||||
0.010-0.012 | ~50% (As K X-rays) | ||||||
..................................................................................... | |||||||
via 16.4 ms 75mAs | |||||||
0.024 | 0.03% | 5.5% | |||||
0.280 | 5.4% | ||||||
0.304 | 1.2% | 0.1% | |||||
0.010-0.012 | ~2.6% (As K X-rays) | ||||||
Technetium-99m | 6.02 h | i.t. | 100% | 0.002 | ~0% | 99.1% | |
0.141 | 88.5% | 10.6% | |||||
0.143 | 0.03% | 0.87% | |||||
....................................................................................................................................................... | |||||||
Daughter 99Tc | |||||||
Thallium-201 | 73.5 h | e.c. | 100% | 0.031 | 0.29% | 10.1% | |
0.032 | 0.25% | 9.6% | |||||
0.135 | 2.9% | 8.9% | |||||
0.166 | 0.13% | 0.2% | |||||
0.167 | 8.81% | 16.0% | |||||
Tin-113 | 115 d | e.c. | 100% | 0.255 | 21% | 0.1% | |
0.024-0.028 | 73% (In K X-rays) | ||||||
....................................................................................................................................................... | |||||||
Daughter 131mIn | |||||||
Tritium (3H) | 12.35 a | β- | 0.0186 | 100% | |||
Xenon-131m | 11.9 d | i.t. | 100% | 0.164 | 2% | 98% | |
0.029-0.035 | ~52% (Xe K X-rays) | ||||||
Xenon-133 | 5.25 d | β- | 0.266 | 0.9% | 0.080 | 0.4% | 0.5% |
0.346 | 99.1% | 0.081 | 36.6% | 63.3% | |||
0.160 | 0.05% | ||||||
0.030-0.036 | ~46% (Cs K X-rays) | ||||||
Xenon-133m | 2.26 d | i.t. | 100% | 0.233 | 8% | 92% | |
0.029-0.035 | ~59% (Xe K X-rays) | ||||||
....................................................................................................................................................... | |||||||
Daughter 133Xe | |||||||
Ytterbium-169 | 32.0 d | e.c. | 100% | 0.021 | 0.21% | 12.3% | |
0.063 | 45.16% | 50.4% | |||||
0.094 | 0.78% | 12.3% | |||||
0.110 | 3.82% | 56.2% | |||||
0.117 | 0.04% | ||||||
0.118 | 1.90% | 3.2% | |||||
0.131 | 11.42% | 13.5% | |||||
0.177 | 17.31% | 17.7% | |||||
0.198 | 26.16% | 25.7% | |||||
0.240 | 0.12% | ||||||
0.261 | 1.74% | ||||||
0.308 | 11.04% | 0.7% | |||||
a μs = microsecond; ms = millisecond; s = second; min = minute; h = hour; d = day; a = year.
b e.c. = electron capture; i.t. = isomeric transition.
Radiation from a radioactive source is emitted in all directions. Procedures for the standardization and measurement of such sources by means of a count of the emissions in all directions are known as 4π-counting; those based on a count of the emissions in a solid angle of 2π steradians are known as 2π-counting; and those based on a fraction of the emissions defined by the solid angle subtended from the detector to the source are known as counting in a fixed geometry. It is customary to assay the radioactivity of a preparation by comparison with a standardized preparation using identical geometry conditions. The validity of such an assay is critically dependent upon the reproducibility of the spatial relationships of the source to the detector and its surroundings and upon the accuracy of the standardized preparation. In the primary standardization of radionuclides coincidence techniques are employed in preference to simple 4π-counting whenever the decay scheme of the radionuclide permits. One of the most commonly employed coincidence techniques is 4π-beta/gamma coincidence counting, which is used for nuclides in which some or all of the disintegrations are followed by prompt photon emission. An additional adjacent detector, sensitive only to photons, is used to measure the efficiency in the 4π-counter of those disintegrations with which the photons are coincident. 4π-Gamma/gamma coincidence counting techniques are often employed for the standardization of pure gamma emitters.
The construction and performance of instruments and accessory apparatus vary. The preparation of samples must be modified to obtain satisfactory results with a particular instrument. The operator must follow carefully the manufacturer's instructions for optimum instrument performance and substantiate results by careful examination of known samples. Proper instrument functioning and reliability must be monitored on a day-to-day basis through the use of secondary reference preparations.
Radioactivity due to materials of construction, to cosmic rays, and to spontaneous discharges in the atmosphere contributes what is known as the background activity. All sample radioactivity measurements must be corrected by subtracting background activity.
In the counting of samples at high activity levels, corrections must be made also for loss of counts due to inability of the equipment to resolve pulses arriving in close succession. Such coincidence-loss corrections must be made prior to the subtraction of background correction.
The corrected count rate, R, is given by the formula
where r is the observed count rate, and τ is the resolving time.
A radioactivity count is a statistical value, i.e. it is a measure of nuclear decay probabilities, and is not exactly constant over any given time interval. The magnitude of the standard deviation is approximately equal to the square root of the number of counts. In general, at least 10 000 counts are necessary to obtain a standard deviation of 1%
Absorption
Ionizing radiation is absorbed in the material surrounding the source of the radiation. Such absorption occurs in air, in the sample itself (self-absorption), in sample coverings, in the window of the detection device, and in any special absorbers placed between the sample and the detector. Since alpha particles have a short range of penetration in matter, beta particles have a somewhat greater range, and gamma rays are deeply penetrating, identification of the type and energy of radiation emitted from a particular radionuclide may be determined by the use of absorbers of varying thickness. In practice, this method is little used, and then only in connection with beta emitters. However, variations in counting rate due to variations in thickness and density of sample containers can be a major problem with beta emitters and with X-ray emitters, such as iodine-125. Plastic tubes, in which variations of density and thickness are minimal, are, therefore, often employed.
The absorption coefficient (μ), which is the reciprocal of the "thickness" expressed in mg/cm2, or the half-thickness (the thickness of absorber required to reduce the radioactivity by a factor of two), is commonly determined to characterize the beta radiation emitted by a radionuclide.
Method
The following procedure is used for the identification test in "Natrii Phosphatis (32P) Injectio" for the measurement of beta activity and for calculation of the absorption coefficient of half-thickness:
Place the radioactive substance, suitably mounted for counting, under a suitable counter. Make count rate determinations individually and successively, using at least 6 different thicknesses of aluminium foil chosen from a range of 10 to 200 mg/cm2 and a single absorber with a thickness of at least 800 mg/cm2. The sample and absorbers should be as close as possible to the detector in order to minimize scattering effects. Obtain the net beta count rate at the various absorbers used by subtracting the count rate found with the thickest absorber (800 mg/cm2 or more). Plot the logarithm of the net beta count rate as a function of the total absorber thickness. The total absorber thickness is the thickness of the aluminium plus the thickness of the counter window (as stated by the manufacturer), plus the air-equivalent thickness (the distance, expressed in cm, of the sample from the counter window multiplied by 1.205), all expressed in mg/cm2. An approximately straight line results.
Choose two of the absorber thicknesses (t1 and t2) that are 20 mg/cm2 or more apart and that fall on the plot, and calculate the absorption coefficient (μ) from the equation
where t1 is the thinner absorber, t2 is the thicker absorber, and 
The choice of absorber thickness depends on the radionuclide. For radionuclides other than phosphorus-32, which have higher or lower beta energy, greater or lesser absorber thicknesses are necessary.
For characterization of the radionuclide, the absorption coefficient or the half-thickness should be within ± 5% of that found for a sample of the same radionuclide of known purity when determined in parallel.
The count rate at zero total absorber thickness may be determined by plotting a curve identical with the one described for determination of the absorption coefficient and extrapolating the straight line plot to zero absorber thickness, taking into consideration the thickness, expressed in mg/cm2, of sample coverings, the air, and the counter window.
Radiation spectrometry
Crystal scintillation spectrometry
When the energy of beta or gamma radiation is dissipated within materials known as scintillators, light is produced in an amount proportional to the energy dissipated. This quantity of light may be measured by suitable means, and is proportional to the energy absorbed in the scintillator. The light emitted under the impact of a gamma photon or a beta particle is converted into an electric output pulse by a photomultiplier. Scanning of the output pulses with a suitable pulse-height analyser results in an energy spectrum of the source.
The scintillators most commonly used for gamma spectrometry are single crystals of thallium-activated sodium iodide. Gamma-ray scintillation spectra show one or more sharp, characteristic photoelectric peaks, corresponding to the energies of the gamma radiation of the source. They are thus useful for identification purposes and also for the detection of gamma-emitting impurities in a preparation. These peaks are accompanied by other peaks due to secondary effects of radiation on the scintillator and its surroundings, such as backscatter, positron annihilation, coincidence summing, and fluorescent X-rays. In addition, broad bands known as the Compton continua arise from the scattering of the gamma photons in the scintillator and in surrounding materials. Calibration of the instrument is achieved with the use of known samples of radionuclides whose energy spectra have been characterized. The shape of the spectrum produced will vary with the instrument used, owing to such factors as differences in the shape and size of the crystal, in the shielding materials used, the distance between the source and the detector, and in the types of discriminator employed in the pulse-height analysers. When using the spectrum for identification of radionuclides it is, therefore, necessary to compare the spectrum with that of a known sample of the radionuclide obtained in the same instrument under identical conditions.
Certain radionuclides, for example, iodine-125, emit characteristic X-rays of well-defined energies that will produce photoelectric peaks in a suitable gamma spectrometer. Beta radiation also interacts with the scintillators, but the spectra are continuous and diffuse and generally of no use for identification of the radionuclide or for the detection of beta-emitting impurities in a preparation.
Semiconductor detector spectrometry
Gamma-ray and beta-particle spectra may be obtained using solid-state detectors. The peaks obtained do not suffer to the same extent the broadening shown in crystal scintillation spectrometry, and the resolution of gamma photons of similar energies is very much improved. However, the efficiencies of such detectors are much lower.
The energy required to create an electron-hole pair or to promote an electron from the valence band to the conduction band in a semiconductor is far less than the energy required to produce a photon in a scintillation crystal. In gamma-ray spectrometry a lithium-drifted germanium detector can provide an energy resolution of 0.33% for the 1.33 MeV photon of cobalt-60, as compared with 5.9% with a 7.6-cm × 7.6-cm thallium-activated sodium iodide crystal.
Liquid scintillation counting
For weak beta-emitters like 35S, 14C and 3H, where self-absorption of the low-energy beta particles is significant, the preferred counting method is by liquid scintillation, which can occasionally be employed also for emitters of X-rays, alpha particles, and gamma-rays. If the sample to be counted is dissolved in, or mixed with, a solution of an appropriate scintillator material, the decay energy from the sample is converted into light photons. These are sensed by a photomultiplier, which converts them into an electric pulse, whose intensity is proportional to the energy of the initial radiation. Thus, simultaneous counting of several radionuclides differing in the energy of emitted radiation can be effected with suitable discriminators (pulse-height analysers), providing the energy separation is sufficient. Detection efficiencies approaching 95% for 14C and 60% for 3H are reached because self-absorption is minimized.
The scintillator solute usually consists of a polycyclic aromatic compound, such as p-terphenyl or 2,5-diphenyloxazole (primary solute), together with a secondary solute, such as 1,4-di[2-(4-methyl-5-phenyloxazole)]benzene (Dimethyl-POPOP), that shifts the wavelength of the light emitted to match the highest sensitivity of the photomultiplier tube. Water-immiscible solvents, such as toluene, or water-miscible solvents, such as dioxan, can be used. To facilitate the counting of aqueous solutions, special solvents have been developed. Alternatively, samples may be counted as suspensions in scintillator gels. As a means of attaining compatibility and miscibility with aqueous specimens to be assayed, many additives, such as surfactants and solubilizing agents, are also incorporated into the scintillator. For accurate determination of sample radioactivity, care must be exercised to prepare a sample that is truly homogeneous. The presence of impurities and colour in the solution causes a decrease in the number and energy of photons reaching the photomultiplier tube; such a decrease is known as quenching. Accurate radioactivity measurement requires correcting for count-rate loss due to quenching. Solutions containing organic scintillators are prone to photo-excitation and samples may need to be prepared in subdued light and kept in darkness before counting.
Radiation shielding
Adequate shielding must be used to protect laboratory personnel from ionizing radiation, and measuring instruments must be suitably shielded from background radiation.
Alpha and beta radiations are readily shielded because of their limited range of penetration, although the production of Bremsstrahlung by the latter must be taken into account (see below). The range of alpha and beta particles varies inherently with their kinetic energy. The alpha particles are monoenergetic and have a range of a few centimetres in air. The absorption of beta particles, owing to their continuous energy spectrum and scattering, follows an approximately exponential function. The range of beta particles in air varies from centimetres to metres.
The secondary radiation produced by beta radiation upon absorption by shielding materials is known as Bremsstrahlung and resembles soft X-rays in its property of penetration. The higher the atomic number or density of the absorbing material, the greater the intensity of the Bremsstrahlung produced. Elements of low atomic number produce low-energy Bremsstrahlung, which is readily absorbed; therefore, materials of low atomic number or of low density, such as aluminium, glass, or transparent plastic, are used to shield sources of beta radiation.
Gamma-ray radiation is deeply penetrating. Attenuation of gamma-ray radiation in matter is exponential and is given in terms of half-value layers. The half-value layer is the thickness of shielding material necessary to decrease the intensity of radiation to half its initial value. A shield of 7 half-value layers is of a thickness that will reduce the intensity of radiation to less than 1% of its unshielded intensity of activity. Gamma-ray radiation is commonly shielded with lead.
Intensity of gamma-ray radiation is diminished according to the inverse square of the intervening distance between the source and the point of reference. Radioactive materials of multimillicurie strength can be handled safely in the laboratory by using proper shielding and/or by arranging for the maximum practicable distance between the source and the operator by means of remote-handling devices.
Determination of Radionuclidic Purity
For gamma emitters the most useful method of examination for radionuclidic purity is gamma spectrometry. It is not, however, a completely certain method, because:
(a) beta-emitting impurities are, in general, not detected;
(b) when sodium iodide detectors are employed, the photoelectric peaks due to impurities may be obscured by those due to the major radionuclide, or, in other words, the degree of resolution of the instrument is insufficient; this problem can be overcome through the use of high-resolution, solid-state, semiconductor detectors, such as a lithium-drifted germanium (Ge:Li) detector;
(c) unless the instrument has been calibrated with a standard source of known radionuclidic purity under identical conditions of geometry, it is difficult to determine whether additional peaks are due to impurities or whether they result from such secondary effects as backscatter, coincidence summation, or fluorescent X-rays.
The range of gamma spectrometry may be extended in two ways: first, by observing changes in the spectrum of a preparation with time (this is especially useful in detecting the presence of long-lived impurities in a preparation of a short-lived radionuclide); secondly, by the use of chemical separations, whereby the major radionuclide may be removed by chemical means and the residue examined for impurities, or whereby specific impurities may be separated chemically and then quantified. It is evident that chemical means will not separate an impurity that is isotopic with the major radionuclide.
Requirements for radionuclidic purity
Requirements for radionuclidic purity are specified in two ways:
1. By expression of a minimum level of radionuclidic purity. Unless otherwise stated in the individual monograph, the gamma-ray spectrum, as determined by simple gamma spectrometry employing a sodium iodide detector, should not be significantly different from that of a standardized solution of the radionuclide before the expiry date is reached. As discussed above, it is difficult to set more precise requirements for a minimum level of radionuclidic purity.
2. By expression of maximum levels of specific radionuclidic impurities in the individual monographs. In general, such impurities are those that are known to be likely to arise during the production of the material - for example, mercury-203 in a preparation of mercury-197.
It is evident that while the above requirements are necessary, they are not in themselves sufficient to ensure that the radionuclidic purity of a preparation is sufficient for human use. A duty must remain with the manufacturer to examine his products in detail, and especially to examine preparations of short-lived radionuclides for long-lived impurities after a suitable period of decay. In this way, the manufacturer may satisfy himself that the manufacturing processes employed are producing materials of appropriate purity. In particular, the radionuclidic composition of certain preparations is determined by the chemical and isotopic composition of the target material, which is irradiated with neutrons, and trial preparations are advisable when new batches of target material are employed.
Determination of Radiochemical Purity
Radiochemical purity can be studied by a variety of techniques, but 1.14.2 Paper chromatography and 1.14.1 Thin-layer chromatography are of particular importance. After completion of the separation, the distribution of radioactivity on the chromatogram is determined. The weight of substance applied to the chromatogram is often extremely small (because of the great sensitivity of detection of the radioactivity) and particular care has to be taken in interpretation with regard to the formation of artefacts. Instead of chromatography, electrophoresis may be used for separation (see 1.15 Electrophoresis). As mentioned above, the addition of carriers (i.e. the corresponding non-radioactive compounds) for both the radiopharmaceutical itself and the suspected impurities is sometimes helpful. There is, however, a danger that when an inactive carrier of the radiopharmaceutical is added it may interact with the radiochemical impurity, leading to underestimation of these impurities. Another useful technique involves monitoring the biological distribution of the injected radiopharmaceutical in suitable test animals.
Determination of Chemical Purity
Chemical purity refers to the proportion of the preparation that is in the specified chemical form regardless of the presence of radioactivity; it may be determined by normal methods of analysis.
The chemical purity of a preparation is often no guide to its radiochemical purity. Preparations, especially those resulting from exchange reactions (for example, a preparation of o-iodohippuric acid in which some of the iodine atoms are replaced by atoms of iodine-131), may be of high chemical purity but may contain impurities of high specific activity (that is, a tiny weight of an impurity may be associated with a relatively large amount of the radionuclide).
In general, chemical impurities in preparations of radiopharmaceuticals are objectionable only if they are toxic or if they modify the physiological processes that are under study.
Tests for Sterility and Pyrogens
A number of monographs for radiopharmaceuticals contain the requirement that the product be sterile and free of pyrogens. The half-life of radiopharmaceutical products is such that, as a rule only tests for pyrogens can be completed prior to release. Tests for sterility must, in general, be completed retrospectively.
Sterility tests
The manufacturer should begin the sterility test as soon as possible and read the results after release.
A particular responsibility falls upon the manufacturer of radiopharmaceuticals to validate the sterilization process by all suitable measures, which may include careful and frequent calibration of sterilizers and the use of biological and chemical indicators of the efficiency of the sterilization process.
Pyrogen tests
The manufacturer also bears a particular responsibility to ensure that all substances used in the preparation of radiopharmaceuticals are handled in a manner that ensures their freedom from pyrogens. Pyrogen tests are specified in certain monographs where there are special dangers.
Addition of Bacteriostatic Agents
Injections of radiopharmaceuticals are commonly supplied in containers that are sealed to permit the withdrawal of successive doses on different occasions. The International Pharmacopoeia normally requires that such injections should contain a suitable bacteriostatic agent in a suitable concentration.
Many common bacteriostatic agents (for example, benzyl alcohol) are gradually destroyed by the effect of radiation in aqueous solutions. The rate of destruction is dependent upon a number of factors, including the nature of the radionuclide and the radioactive concentration of the solution. It is, therefore, not always possible to prescribe an effective bacteriostatic agent for an injection of a radiopharmaceutical and for certain preparations the addition of an agent is undesirable; for this reason the inclusion of bacteriostatic agents is not mandatory. The nature of the bacteriostatic agent, if present, must be stated on the label; if no bacteriostatic agent is present, this must also be stated. Radiopharmaceuticals whose expiry periods are greater than one day and that do not contain a bacteriostatic agent should preferably be supplied in single-dose containers.
Other Requirements
Radiopharmaceuticals administered parenterally should comply with the relevant requirements for injections in the International Pharmacopoeia, except that they are not subject to the requirements concerning volume of injection in a single-dose container.
Expiry Date
The special nature of a radiopharmaceutical requires that it be assigned an expiry period (or an expiry date), beyond which its continued use is not recommended. The expiry period so designated begins with the date at which the radioactivity is expressed on the label, and may be stated in terms of days, weeks or months. For longer-lived radionuclides, the expiry period does not exceed 6 months. The expiry period depends on the radiochemical stability and the content of longer-lived radionuclidic impurity in the preparation under consideration. At the end of the expiry period, the radioactivity will have decreased to the extent where insufficient radioactivity remains to serve the intended purpose or where the dose of active ingredient must be increased so much that undesirable physiological responses occur. In addition, chemical or radiation decomposition may have reduced the radiochemical purity to an unacceptable extent. Also the radionuclidic impurity content may be such that an unacceptable radiation dose would be delivered to the patient. The use of products beyond their expiry periods is, therefore, inadvisable.
Labelling
In general, the label should include:
(1) the name of the preparation;
(2) a statement that the product is radioactive;
(3) the name and location of the manufacturer;
(4) the total radioactivity present at a stated date and hour (whenever the half-life period is more than 30 days only the date need be stated);
(5) the expiry date or the expiry period;
(6) a number or other indication by which the history of the product may be traced (for example, batch or lot number);
(7) in the case of solutions, the total volume of the solution;
(8) special storage requirements with respect to temperature and light.
NOTE: In the case of a solution, instead of a statement of the total radioactivity, a statement of the radioactive concentration (for example, in mCi or MBq per ml of the solution) may be given.
The shipment of radioactive substances is subject to special national and international regulations as regards their packaging and outer labelling.
Storage
Radiopharmaceuticals should be kept in well-closed containers and stored in an area assigned for the purpose. The storage conditions should be such that the maximum radiation dose rate to which persons may be exposed is reduced to an acceptable level. Care should be taken to comply with national regulations for protection against ionizing radiation. Glass containers may darken under the effect of radiation
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