radiopharmaceuticals: general monograph revision … · working document qas/13.542 page 3 54...

Working document QAS/13.542

June 2013

RESTRICTED

1

THE INTERNATIONAL PHARMACOPOEIA 2

RADIOPHARMACEUTICALS: GENERAL MONOGRAPH 3

REVISION 4

(June 2013) 5

6

DRAFT FOR COMMENT 7

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9 10

DRAFT FOR COMMENTS 11

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13

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© World Health Organization 2013 17

All rights reserved. 18

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 19

draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in 20

whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned 21

staff and member organizations) without the permission of the World Health Organization. The draft should not be 22

displayed on any web site. 23

24

Please send any request for permission to: 25

26

Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, Department of 27

Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 28

791 4730; e-mail: [email protected]. 29

30

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 31

whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or 32

area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent 33

approximate border lines for which there may not yet be full agreement. 34

35

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 36

recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 37

Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 38

39

All reasonable precautions have been taken by the World Health Organization to verify the information contained in 40

this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. 41

The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 42

Organization be liable for damages arising from its use. 43

44

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 45

46

Should you have any comments on this draft, please send these to Dr Sabine Kopp, Medicines

Quality Assurance Programme, Quality Assurance and Safety: Medicines, World Health

Organization, 1211 Geneva 27, Switzerland; fax: (+41 22) 791 4730 or e-mail: [email protected]

(with copies to [email protected] and [email protected]) by 15 August 2013.


page 2

SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.542 47

PROPOSED TEXT FOR THE INTERNATIONAL PHARMACOPOEIA 48


REVISION 50

51

52

53

Date

First meeting at IAEA

3-7 December 2012

Second meeting at IAEA

6-10 May 2013

Preparation of revision of text by IAEA

May 2013

Discussion at informal consultation on new

medicines, quality control and laboratory

standards

12-14 June 2013

Revision of draft proposal

June 2013

Mailing of draft proposal for comments

June 2013

Collation of comments

August-September 2013

Presentation to WHO Expert Committee on

Specifications for Pharmaceutical

Preparations for discussion

October 2013

Further follow-up action as required


page 3

PROPOSED TEXT FOR THE INTERNATIONAL PHARMACOPOEIA 54


REVISION 56

57

Introduction 58

This general monograph is intended to be read in conjunction with the individual 59

monographs on radiopharmaceutical preparations. A radiopharmaceutical preparation that 60

is subject of an individual monograph in The International Pharmacopoeia complies with 61

the general requirements stated below and with the general monograph for the relevant 62

dosage form (most commonly that for Parenteral preparations) as modified by any of the 63

requirements given below and by any specific instruction included in the individual 64

monograph. 65

Requirements 66

Definition 67

Radiopharmaceutical preparation or radiopharmaceutical. A radiopharmaceutical 68

preparation or radiopharmaceutical is a medicinal product in a ready-to-use form suitable 69

for human use that contains a radionuclide. The radionuclide is integral to the medicinal 70

application of the preparation, making it appropriate for one or more diagnostic or 71

therapeutic applications. 72

For the purpose of this general monograph radiopharmaceuticals also cover: 73

Radionuclide generator. A system in which a daughter radionuclide (short half-life) is 74

separated by elution or by other means from a parent radionuclide (long half-life) and 75

later used for production of a radiopharmaceutical preparation. 76

Radionuclide precursor. A “radionuclide precursor” means any radionuclide not being a 77

radiopharmaceutical or generator or radionuclide kit which is produced for the 78

radiolabelling of another substance for administration. 79

Kit for radiopharmaceutical preparation. In general a vial containing the non-80

radionuclide components of a radiopharmaceutical preparation , usually in the form of a 81

sterilized, validated product to which the appropriate radionuclide is added or in which 82

the appropriate radionuclide is diluted before medical use. In most cases the kit is a 83


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multidose vial and production of the radiopharmaceutical preparation may require 84

additional steps such as boiling, heating, filtration and buffering. 85

Chemical precursor. Non-radioactive substances in combination with radionuclide. 86

Manufacture 87

The manufacturing process for radiopharmaceutical preparations should meet the 88

requirements of good manufacturing practice (GMP). 89

The manufacturer is responsible for ensuring the quality of his products and especially for 90

examining preparations of short-lived radionuclides for long-lived impurities after a 91

suitable period of decay. In this way, the manufacturer ensures that the manufacturing 92

processes employed are producing materials of appropriate quality. In particular, the 93

radionuclide composition of certain preparations is determined by the chemical and 94

isotopic composition of the target material (see ”Target materials” ) and pilot 95

preparations are advisable when new batches of target material are employed. 96

When the size of a batch of a radiopharmaceutical preparation is limited to one or few 97

units (for example, certain therapeutic preparations or very short-lived preparations) 98

release of the product must rely on the process control rather than product quality control 99

tests. Therefore validation and revalidation of manufacture process must be fully 100

implemented as well as the product quality control tests. 101

Radiation Protection. The relevant premises and equipment must be designed, built and 102

maintained so that they do not bear any negative impact on or represent any hazard to the 103

product, personnel or immediate surroundings. The corresponding supporting materials 104

are provided by various IAEA publications.1 105

Radionuclide production. In general ways of manufacturing radionuclides for use in 106

radiopharmaceutical preparations are: 107

Nuclear fission. Nuclides with high atomic number are fissionable and a 108

common reaction is the fission of uranium-235 by neutrons in a nuclear reactor. 109

For example, iodine-131, molybdenum-99 and xenon-133 can be produced in this 110

1See Supplementary information chapter: Radiopharmaceuticals and Radiation Protection and Safety of

Radiation Sources International Basic Safety Standards. Interim Edition. General Safety Requirements

(IAEA, Vienna, 2011); and Radiological Protection for Medical Exposure to Ionizing Radiation Safety

Guide (IAEA, Vienna, 2002) Safety Standard Series No. RS-G-1.5, Safety Standard Series No. RS-G-

1.5.Consult the IAEA website for the current Safety Standards and publications (http://www-

ns.iaea.org/standards/). For more supporting material refer to the list of IAEA publications in

Monographs: Radiopharmaceuticals: Supplementary information: Safety considerations.


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way. Radionuclides from such a process must be carefully controlled in order to 111

minimize the radionuclidic impurities. 112

Charged particle bombardment. Radionuclides may be produced by 113

bombarding target materials with charged particles in particle accelerators such as 114

cyclotrons. The isotopic composition and purity of the target material will 115

influence the radionuclidic purity of irradiated target 116

Neutron bombardment. Radionuclides may be produced by bombarding target 117

materials with neutrons in nuclear reactors. The rate of the nuclear reaction 118

depends on the energy of the incident particle, neutron flux and nuclear cross-119

section. The isotopic composition and purity of the target material will influence 120

the radionuclidic purity of irradiated target. 121

Radionuclide generator systems. Radionuclides of short half-life may be 122

produced by means of a radionuclide generator system involving separation of the 123

daughter radionuclide from a long-lived parent by chemical or physical separation. 124

Care must be taken to avoid contamination of daughter radionuclide with parent 125

radionuclide and decay products. 126

Starting materials (including chemical precursors and excipients). In the manufacture 127

of radiopharmaceutical preparations, measures shall be taken to ensure that all ingredients 128

are of appropriate quality, including those starting materials, such as chemical precursors 129

for synthesis, that are produced on a small scale and supplied by specialized producers or 130

laboratories for use in the radiopharmaceutical industry. The actual quantity of 131

radioactive material compared with quantities of excipients is normally very small 132

therefore excipients can greatly influence the quality of the radiopharmaceutical 133

preparation. 134

Target materials. The composition and purity of the target material and the nature and 135

energy of the incident particle will determine the relative percentages of the principal 136

radionuclide and other potential radionuclides (radionuclidic impurities) and thus 137

ultimately the radionuclidic purity. Strict control of irradiation parameters such as beam 138

energy, intensity and duration is also essential. For very short lived radionuclides 139

including the ones present in most positron emission tomography (PET) tracers the 140

determination of radiochemical and radionuclidic purity of radiopharmaceutical 141

preparation before patient use is difficult. Therefore before clinical use of these 142

radionuclides, strict operational conditions and extensive validations are essential. Any 143

subsequent change in operational conditions should be revalidated. 144

Where applicable (e.g. cyclotron irradiation of solid targets)each new batch of target 145

material must be tested and validated in special production runs before its use in routine 146

radionuclide production and manufacture of radiopharmaceutical preparation. This will 147

ensure that under specified conditions, the target yields a radionuclide in the desired 148

quantity and quality. 149


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Carriers. A carrier, in the form of inactive material, either isotopic with the radionuclide, 150

or non-isotopic, but chemically similar to the radionuclide, may be added during 151

radionuclide production and radiopharmaceutical preparation. In some situations it may 152

be added to enhance chemical, physical or biological properties of the 153

radiopharmaceutical preparation. The amount of carrier added must be controlled and 154

sufficiently small for it not to cause undesirable physiological effects. 155

Carrier-free preparation. It is a preparation free from stable isotope of the same 156

element as the radionuclide concerned present in the preparation in the stated chemical 157

form or at the position of the radionuclide in the molecule concerned. When appropriate, 158

specific radioactivity must be measured in the radiopharmaceutical preparation. 159

No-carrier added preparation. It is a preparation to which no stable isotopes of the 160

same element as the radionuclide concerned are intentionally added in the stated chemical 161

form or at the position of the radionuclide in the molecule concerned. When appropriate 162

specific radioactivity must be measured in the radiopharmaceutical preparation. 163

Production of radiopharmaceutical preparation. Radiopharmaceutical preparations 164

may contain the types of excipients permitted by the general monograph for the relevant 165

dosage form. 166

Sterilization. Radiopharmaceutical preparations intended for parenteral administration 167

are sterilized by a suitable method (see 5.8 Methods of sterilization). Whenever possible, 168

steam sterilization is recommended. 169

170

All sterilization processes must be validated. 171

Addition of antimicrobial preservatives. Radiopharmaceutical injections are commonly 172

supplied in multidose containers. The nature of the antimicrobial preservative, if present, 173

is stated on the label or, where applicable, that no antimicrobial preservative is present. 174

Radiopharmaceutical injections for which the shelf-life is greater than one day and that 175

do not contain an antimicrobial preservative should preferably be supplied in single-dose 176

containers. If, however, such a preparation is supplied in a multidose container 177

requirements of the general monograph for Parenteral Preparations should apply. 178

Radiopharmaceutical injections for which the shelf-life is greater than one day and that 179

do contain an antimicrobial preservative may be supplied in multidose containers. After 180

aseptic withdrawal of the first dose, the container should be stored at a temperature 181

between 2° and 8° C and the contents used within 7 days unless otherwise specified. 182


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Radiation protection 183

See Supplementary information chapter on Radiopharmaceuticals and Radiation Protection and 184

Safety of Radiation Sources International Basic Safety Standards. Interim Edition. General Safety 185

Requirements (IAEA, Vienna, 2011) and Radiological Protection for Medical Exposure to 186

Ionizing Radiation Safety Guide (IAEA, Vienna, 2002) Safety Standard Series No. RS-G-1.5. 187

Identity tests 188

Tests for identity of the radionuclide are included in the individual monographs for 189

radiopharmaceutical preparations. The radionuclide is generally identified by its half-life 190

or by the nature and energy of its radiation or by both as stated in the monograph. 191

Other tests 192

Half-life measurement. The half-life is a characteristic of the radionuclide that may be 193

used for its identification. The half-life is calculated by measuring the variation of 194

radioactivity of a sample to be tested as a function of time. Perform the measurements in 195

the linearity range of a calibrated instrument. Measurements should comply with the R 196

1.1 Detection and measurement of radioactivity. Approximate half-life can be determined 197

over a relatively short period of time to allow release for use of radiopharmaceutical 198

preparations. The calculated approximate half-life is within the range of the values stated 199

in the individual monograph. 200

Radionuclidic purity 201

Radionuclidic impurities may arise during the production and decay of a radionuclide. 202

Potential radionuclidic impurities may be mentioned in the monographs and their 203

characteristics are described in the general monograph: Annexes: Table of physical 204

characteristics. In most cases, to establish the radionuclidic purity of a 205

radiopharmaceutical preparation, the identity of every radionuclide present and its 206

radioactivity must be known. 207

Technical details of radionuclide identification and radionuclidic purity determination 208

are described in R1.2 Radiation spectrometry and R1.3 Determination of radionuclidic 209

purity. Because the level of radionuclidic impurities, expressed as a percentage of each 210

impurity, may increase or decrease with time, the measured radioactivity of each impurity 211

must be recalculated to the activity during the period of validity of the preparation. 212

The individual monographs prescribe the radionuclidic purity required and may set limits 213

for specific radionuclidic impurities (for example, molybdenum-99 in technetium-99m

). 214

While these requirements are necessary, they are not in themselves sufficient to ensure 215

that the radionuclidic purity of a preparation is sufficient for its clinical use. The 216

manufacturer must examine the product in detail and especially must examine 217

preparations of radionuclides with a short half-life for impurities with a long half-life 218


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after a suitable period of decay. In this way , information on the suitability of the 219

manufacturing processes and the adequacy of the testing procedures is obtained. In cases 220

where two or more positron-emitting radionuclides need to be identified and/or 221

differentiated, for example the presence of 18F-impurities in 13N-preparations, half-life 222

determinations need to be carried out in addition to gamma-ray spectrometry. 223

Radiochemical purity 224

A radioactive preparation may contain the radionuclide in different chemical forms other 225

than the intended one. Therefore it is necessary to separate the different substances 226

containing the radionuclide and determine the percentage of radioactivity due to the 227

radionuclide concerned associated with the stated chemical form and the contribution to 228

the total radioactivity due to the radionuclide concerned coming from other substances. 229

For this purpose instruments for the detection and measurement of radioactivity are used 230

in combination with a physic-chemical separation technique. 231

Radiochemical purity is assessed by a variety of analytical techniques such as 1.14.4 232

High-performance liquid chromatography, 1.14.2 Paper Chromatography, 1.14.1 Thin-233

layer Chromatography and 1.15 Electrophoresis combined with suitable radioactivity 234

measurement described in R1.1 Detection and measurement of radioactivity. 235

In all cases the radioactivity of each analyte is measured after the separation has been 236

achieved using the stated method. 237

The radiochemical purity section of an individual monograph may include limits for 238

specified radiochemical impurities, including isomers. 239

In some cases, it is necessary to determine the physiological distribution of the 240

radiopharmaceutical in a suitable test animal. 241

Specific radioactivity. Specific radioactivity is defined as radioactivity of a radionuclide 242

per unit mass of the element or of the chemical form concerned. Specific radioactivity is 243

usually calculated taking into account the radioactivity concentration and the 244

concentration of the chemical substance being studied. Specific radioactivity changes 245

with time. The statement of the specific radioactivity therefore includes reference to a 246

date and, if necessary, time. 247

Specific radioactivity must be measured in carrier added preparations. For some non-248

carrier added radiopharmaceutical preparations (for example, receptor ligands) it is 249

important to state specific radioactivity. Individual monographs might state the range of 250

specific radioactivity. 251

252


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Chemical purity 253

Chemical purity refers to the proportion of the preparation that is in the specified 254

chemical form regardless of the presence of radioactivity; it may be determined by 255

accepted methods of analysis. 256

In general, limits should be set for chemical impurities in preparations of 257

radiopharmaceuticals if they are toxic or if they modify the labelling process or alter 258

physiological uptakes that are under study or if they result in undesirable interactions (e.g. 259

aluminium can induce flocculation of Tc-99m sulphur colloid). Special attention is 260

necessary for impurities with a pharmacologically active or pharmacodynamic effect 261

even for very low amounts (for example, receptor ligands). Where appropriate, the stereo-262

isomeric purity has to be verified. In general, the type of limits for inorganic impurities 263

such as arsenic and heavy metals that are specified in monographs for pharmaceutical 264

substances are also valid for radiopharmaceuticals. 265

Characterize impurities as much as possible. Generic limits can be set for unidentified 266

impurities. The limits has to be chosen carefully considering amounts and toxicity based 267

upon toxicities of starting materials, precursors, possible degradation products and the 268

final product. 269

pH 270

When required, measure the pH of non-radioactive solutions as described under 1.13 271

Determination of pH. For radioactive solutions the pH may be measured using a pH 272

indicator strip R. 273

[Note from Secretariat: 274

Add pH indicator strip R to the section on Reagents using the following : 275

pH indicator strip. R. 276

Plastic or paper strip containing multiple segments of different dye-impregnated papers 277

allowing visual determination of pH in the prescribed range by comparison with a master 278

chart. ] 279

Sterility 280

A number of monographs for radiopharmaceuticals contain the requirement that the 281

preparation is sterile. Such preparations comply with 3.2 Test for sterility. The special 282

difficulty arise with the radiopharmaceuticals because of the short half-life of the 283


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radionuclide, the small size of batches and the radiation hazards. In the case that the 284

monograph states that the preparation can be released for use before completion of the 285

test for sterility, the sterility test must be started as soon as practically possible in relation 286

to the radiation. If not started immediately, samples are stored under conditions that are 287

shown to be appropriate in order to prevent false negative result. 288

When the size of the batch of a radiopharmaceutical is limited to one or few samples (e.g. 289

therapeutic or very short-lived radiopharmaceutical preparations), sampling the batch 290

may not be possible. In this case reliance is on process control rather than the final 291

product control. 292

Bacterial endotoxins/pyrogens 293

Where appropriate, an individual monograph for a radiopharmaceutical preparation 294

requires compliance with 3.4 Test for bacterial endotoxins. Validation of the test is 295

necessary to exclude any interference or artefact due to the nature of the 296

radiopharmaceutical. The pH of some radiopharmaceutical preparations will require to be 297

adjusted to pH 6.5–7.5 to achieve optimal results. 298

Where it is not possible to eliminate interference with the test for bacterial endotoxins 299

due to the nature of the radiopharmaceutical, compliance with 3.5 Test for pyrogens may 300

be specified. 301

Labelling 302

Every radiopharmaceutical preparation must comply with the labelling requirements 303

established under GMP. 304

[Note from Secretariat: Check that the text is consistent with current GMP text needs to 305

be undertaken in final version.] 306

The label on the primary container should include: 307

• a statement that the product is radioactive or the international symbol for 308

radioactivity; 309

• the name of the radiopharmaceutical preparation; 310

• where appropriate, that the preparation is for diagnostic or for therapeutic use; 311

• the route of administration; 312

• the total radioactivity present at a stated date and, where necessary, time; for 313

solutions, a statement of the radioactivity in a suitable volume (for example, in 314

MBq per ml of the solution) may be given instead; 315

• the expiry date and, where necessary, time; 316


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• the batch (lot) number assigned by the manufacturer; 317

• for solutions, the total volume. 318

The label on the outer package should include: 319

• a statement that the product is radioactive or the international symbol for 320

radioactivity; 321

• the name of the radiopharmaceutical preparation; 322

• where appropriate, that the preparation is for diagnostic or for therapeutic use; 323

• the route of administration; 324

• the total radioactivity present at a stated date and, where necessary, time; for 325

solutions, a statement of the radioactivity in a suitable volume (for example, in 326

MBq per ml of the solution) may be given instead; 327

• the expiry date and, where necessary, time; 328

• the batch (lot) number assigned by the manufacturer; 329

• for solutions, the total volume; 330

• any special storage requirements with respect to temperature and light; 331

• where applicable, the name and concentration of any added microbial 332

preservatives or, where necessary, that no antimicrobial preservative has been 333

added. 334

Note: The shipment of radioactive substances is subject to special national and 335

international2 regulations as regards to their packaging and outer labelling. 336

Storage 337

Radiopharmaceuticals should be kept in well-closed containers and stored in an area 338

assigned for the purpose. The storage conditions should be such that the maximum 339

radiation dose rate to which persons may be exposed is reduced to an acceptable level. 340

Care should be taken to comply with national regulations for protection against ionizing 341

radiation. 342

Radiopharmaceutical preparations that are intended for parenteral use should be kept in a 343

glass vial, ampoule or syringe that is sufficiently transparent to permit the visual 344

inspection of the contents. Glass containers may darken under the effect of radiation. 345

346

347

2 See Regulations for the Safe Transport of Radioactive Materials . Safety Requirements. No TS-R-1

(IAEA, Vienna, 2009).for further details. Consult the IAEA web site (http://www-ns.iaea.org/standards/)

for the current guidance.


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ANNEXES: TERMINOLOGY 348

Biological half-life 349

The biological half-life (T½b) of a radiopharmaceutical is the time taken for the 350

concentration of the pharmaceutical to be reduced 50% of its maximum concentration in 351

a given tissue, organ or whole body, not considering radioactive decay. 352

Critical organ 353

The critical organ is the organ or tissue which is the most vulnerable to radiation damage 354

This may not be the target tissue or the tissue that receives the highest dose and therefore 355

the dose to the critical organ will determine the maximum safe dose which can be 356

administered. 357

Effective half-life 358

The effective half-life (T½e) is the actual half-life of a radiopharmaceutical in a given 359

tissue, organ or whole body and is determined by a relationship including both the 360

physical half-life and biological half-lives. The effective half-life is important in 361

calculation of the optimal dose of radiopharmaceutical to be administered and in 362

monitoring the amount of radiation exposure. It can be calculated from the formula: 363

364

Where T1/2p and T1/2b are the physical and biological half-lives respectively. 365

Half-life 366

The time in which the radioactivity decreases to one-half its original value. 367

EXPLANATORY NOTE. The rate of radioactive decay is constant and characteristic for 368

each individual radionuclide. The exponential decay curve is described mathematically 369

by the equation: 370

371

where N is the number of atoms at elapsed time t, No is the number of atoms when t = 0, 372

and λ is the disintegration constant characteristic of each individual radionuclide. The 373

half-life period is related to the disintegration constant by the equation: 374


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375

Radioactive decay corrections are calculated from the exponential equation, or from 376

decay tables, or are obtained from a decay curve plotted for the particular radionuclide 377

involved (see Figure 1). 378

FIGURE 1. MASTER DECAY CHART 379

380

381


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Isotopes 382

Atoms of the same element with different atomic mass numbers are called isotopes. 383

Nuclide 384

Nuclide is defined as species of atom as characterized by the number of protons, the 385

number of neutrons, and the energy state of the nucleus. 386

Radioactive concentration 387

The radioactive concentration of a solution refers to the amount radioactivity per unit 388

volume of the solution. As with all statements involving radioactivity, it is necessary to 389

include a reference date and time of standardization. For radionuclides with a half-life of 390

less than one day, a more precise statement of the reference time is required. 391

Units for radioactive concentration are megaBecquerels per millilitre (MBq/ml). 392

Since the radioactive concentration will change with time due to decrease in the nuclide 393

radioactivity it is always necessary to provide a reference time. For short-lived 394

radionuclides the reference time will be more precise including time of day in addition to 395

date. 396

Radioactive decay 397

The property of unstable nuclides during which they undergo a spontaneous 398

transformation within the nucleus. This change results in the emission of energetic 399

particles or electromagnetic energy from the atoms and the production of an altered 400

nucleus. 401

EXPLANATORY NOTE. The term “disintegration” is widely used as an alternative to 402

the term “transformation”. Transformation is preferred as it includes, without semantic 403

difficulties, those processes in which no particles are emitted from the nucleus. 404

Radioactivity 405

Generally the term “radioactivity” is used both to describe the phenomenon of radioactive 406

decay and to express the physical quantity of this phenomenon. The radioactivity of a 407

preparation is the number of nuclear disintegrations or transformations per unit time. In 408

the International System (SI), the term “activity” is used, which corresponds to 409

radioactivity in the context of this general monograph. 410


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It is expressed in becquerel (Bq), which is 1 nuclear transformation per 411

second.EXPLANATORY NOTE. The term “disintegration” is widely used as an 412

alternative to the term “transformation”. Transformation is preferred as it includes, 413

without semantic difficulties, those processes in which no particles are emitted from the 414

nucleus. 415

Radiochemical purity 416

The ratio expressed as a percentage of radioactivity of radionuclide concerned which is 417

present in the radiopharmaceutical preparation in the stated chemical form, to the total 418

radioactivity of that radionuclide present in the radiopharmaceutical preparation. 419

Relevant potential radiochemical impurities are listed with their limits in the individual 420

monographs. (Note: Source of information: European Pharmacopoeia.) 421

As radiochemical purity may change with time, mainly because of radiolysis or chemical 422

decomposition, the result of the radiochemical purity test should be started at given date 423

and if necessary hour indicating when the test was carried out. The radiochemical purity 424

limit should be valid during the whole shelf-life. 425

Radionuclidic purity 426

The radionuclidic purity is the ratio expressed as a percentage of radioactivity of the 427

radionuclide concerned to the total radioactivity of the radiopharmaceutical preparation. 428

The relevant potential radionuclidic impurities are listed with their limits in their 429

individual monographs. 430

Specific radioactivity 431

The specific radioactivity of a radionuclide corresponds to the SI term “specific activity” 432

in the context of this monograph and is defined as radioactivity of radionuclide per unit 433

mass of the element or of the chemical form concerned, e.g. Bq/g or Bq/mole. 434

The term employed in radiochemical work is “specific activity”. As the word “activity” 435

has other connotations in a pharmacopoeia, the term should, where necessary, be 436

modified to “specific radioactivity” to avoid ambiguity. 437

Units of radioactivity 438

The activity of a quantity of radioactive material is expressed in terms of the number of 439

spontaneous nuclear transformations taking place in unit time. The SI unit of activity is 440

the becquerel (Bq), a special name for the reciprocal second (s-1

). The expression of 441


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activity in terms of the becquerel therefore indicates the number of transformations per 442

second. 443

The historical unit of activity is the curie. The curie (Ci) is equivalent to 3.7 x 1010

Bq. 444

The conversion factors between becquerel and curie and its submultiples are given in 445

Table 1. 446

Table 1. Units of radioactivity commonly encountered with radiopharmaceuticals 447

and the conversions between SI units and historical units 448

Number of atoms

transforming per second SI unit: becquerel (Bq) historical unit: curie (Ci)

1 1 Bq 27 picocurie (pCi)

1000 1 kilobecquerel (kBq) 27 nanocurie (nCi)

1 x 106 1 megabecquerel (MBq) 27 microcurie (µCi)

1 x 109 1 gigabecquerel (GBq) 27 millicurie (mCi)

37 37 Bq 1 (nCi)

37,000 37 kBq 1 (µCi)

3.7 x 107 37 MBq 1 (mCi)

3.7 x 1010

37 GBq 1 Ci

449

450


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ANNEXES: TABLE OF PHYSICAL CHARACTERISTICS 451

452

Physical characteristics of clinically relevant radionuclides 453

Information on the physical characteristics of key radionuclide used in nuclear medicine 454

is provided in the following Table 2. 455

Note from Secretariat: This table will be updated by IAEA. 456

*** 457

radiopharmaceuticals: general monograph revision … · working document qas/13.542 page 3 54...

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