A radiopharmaceutical is a radioactive medicinal product for diagnostic, therapeutic or palliative use. Parenteral radiopharmaceuticals usually consist of a radionuclide coupled to another pharmaceutical compound, also called a ligand. Some radionuclides are administered as such. Alternative dosage forms are capsules for oral use or a radioactive gas for inhalation. All dosage forms are shielded, in lead or tungsten for gamma and positron emitters and in plastics for beta and alpha emitters.

The physical and biopharmaceutical properties of a radiopharmaceutical determine its potential use [1, 2].

The design of radiopharmaceuticals is based upon the physiological function of the target organ. The mechanism of targeting a particular organ can be different, for example physical trapping of particles, binding to structures in tissues or organs or an antigen-antibody reaction. In general, a high target-to-background ratio is pursued.

A radiopharmaceutical emitting alpha or beta radiation can be used for therapeutic or palliative purposes. These types of radiopharmaceuticals deposit their energy on very short distances. For alpha emitters this distance is much shorter than for beta emitters. This high-dose locally accumulated radioactivity is used in radionuclide therapy (pain palliation of bone metastases, therapy for some specific types of cancer).

Some radionuclides are emitting a combined spectrum of radiation. One type of the radiation spectrum (alpha or beta) is used for its therapeutic properties; the other type of the radiation spectrum (gamma) might be used for localisation of the tracer and the targeted tissue or for dosimetry. These radiopharmaceuticals are called theranostics.

Sometimes other medicines are used in combination with the radiopharmaceutical, as co-medication in the diagnostic process, e.g. intravenous diuretics to promote renal clearance, adenosine to induce pharmacological stress and thyroid stimulating hormone in thyroid studies. These pharmacological interventions increase the sensitivity or specificity of a procedure used in nuclear medicine.

Most radiopharmaceuticals are administered intravenously. After injection, the radioactive substance is distributed fast to the target site thereby avoiding unnecessary radiation dose to the stomach and gut after oral dosing. Scanning may start immediately or after a certain period.

The selective biodistribution and pharmacokinetics of the radiopharmaceutical within the body are determined by the properties of the pharmaceutical agent, the stability of the labelling, the physical and radiochemical properties of the radiopharmaceutical, the purity of the radiopharmaceutical preparation, the pathophysiologic status of the patient and the possible influence of interfering medicines.

By choosing the radionuclide the diagnostic use of the radiopharmaceutical can be determined: gamma emitters or positron emitters can be used for diagnostic procedures by providing static or dynamic images following the distribution of the radiopharmaceutical within the body. For the detection of gamma radiation a classical gamma camera is used, for positron-emitters a PET-camera has to be used. See also next sections.

Adverse effects of radiopharmaceuticals for diagnosis are extremely rare [3]. Radiopharmaceuticals for therapy may have adverse effects, for example bone marrow depression if used for treatment of bone metastases. Radiopharmaceuticals can interact with other (non-radioactive) medicines given to the same patient [4]. Food and glucose in food can disturb the quality of certain types of imaging (interaction of glucose (dextrose) with ¹⁸F-FDG in PET imaging).

Parenteral radiopharmaceuticals are available as a simple radionuclide in solution, for instance ¹³¹I-sodium iodide solution for injection, or are prepared by labelling a non-radioactive pharmaceutical moiety (ligand) with a radionuclide. Many kits or ligands for the preparation of radiopharmaceuticals are available in the form of sterile, freeze-dried powders in an injection vial. These kits are non-radioactive.

Radiopharmaceuticals for parenteral use must comply with the Ph. Eur. monograph for parenteral preparations, so they have to be sterile and with a very low or absent endotoxin concentration. For parenteral administration a sterile injection in a disposable injection syringe is often filled from a multiple dose solution in a glass vial.

Oral radiopharmaceuticals are administered as gelatin capsules. Absorption after oral use is relatively slow so it will take time before the content is distributed in the body and delivered to target organs or tissues (the bone, the heart, the thyroid, brain etc.).

¹²³I and ¹³¹I Sodium iodide are examples of radiopharmaceuticals that can be administered in capsules for oral administration.

Some radiopharmaceuticals are administered by inhalation in the form of a radioactive gas. ^81mKrypton is an example of a gaseous inhalation radiopharmaceutical that is used in inhalation or ventilation/perfusion studies.

Since radiopharmaceuticals are medicines, the purchasing, preparation, quality control and handling are subject to the same legislation and guidelines as other medicines (see Sect. 35.​5). However, radiopharmaceuticals are regulated as radioactive substances as well. Therefore, two sources of legislation: medicine legislation and nuclear safety regulations (e.g. nuclear energy legislation) are applicable. Sometimes this can lead to conflicting situations, see Sect. 15.6.3 for the discussion about pressure hierarchy in pharmaceutical clean rooms, where GMP rules demand relative overpressure and radiation safety rules ask for relative underpressure. The most important regulations for the (small scale) preparation and dispensing of radiopharmaceuticals are summarised below.

Like other medicinal products, licensed radiopharmaceuticals are covered by EU Directive 2001/83/EC [5]. The most important requirements are a marketing authorisation and a manufacturing license.

A marketing authorisation is mandatory for the production of radionuclide generators, radionuclide kits and radionuclide precursors.

For all investigational medicinal products (IMPs) used in a clinical trial EU Directive 2001/20/EC (“Clinical Trial Directive”) and GMP Annex 13 are applicable [6, 7], see Sect. 35.​5.​10. The clinical trial directive has recently been replaced by the new and less stringent EU regulation 536/2014 [8, 9]. In this regulation, GMP and a manufacturing license will no longer be required for the preparation of diagnostic radiopharmaceuticals used in clinical trials when they are prepared in a hospital radiopharmacy from licensed sources and used within the Member State.

Annex 3 (Manufacture of Radiopharmaceuticals) is the only part of the GMP framework entirely dedicated to radiopharmaceuticals [10]. Preparation of radiopharmaceuticals using authorised generators and kits is excluded from this Annex. The production of radionuclides in reactors and cyclotrons is a physical process and is regarded as a non-GMP activity. Annex 3 describes general GMP principles (quality assurance, personnel, premises and equipment, documentation, production, quality control, reference and retention samples, distribution) in relation to radiopharmaceuticals. As with other medicinal products, other GMP annexes may be applicable, for instance Annex 1 Manufacture of Sterile Medicinal Products [11].

The General Monograph 0125 Radiopharmaceutical preparations provides general information about the preparation and quality control of radiopharmaceuticals [12]. More than 65 radiopharmaceutical monographs are available in the Ph. Eur., in which specific requirements are elaborated.

Recently a new General Chapter has been drafted on extemporaneous preparation of radiopharmaceutical preparations [13]. This new chapter will provide minimal requirements for kit-based preparations, PET radiopharmaceuticals and radiolabelled blood cells. As with all General Chapters it will not be obligatory, unless mentioned in a product monograph.

Legislation for extemporaneous preparation of radiopharmaceuticals is in principle not different from extemporaneous preparation in general (Sect. 35.​5). There is a great variation in interpretation and approach in Europe [14]. In some countries radiopharmaceuticals are prepared based on the pharmacy status of the radiopharmacy unit. In other countries radiopharmaceuticals are prepared in laboratories, in university institutions or research laboratories without pharmacy status, with authorisation based on radiation protection legislation only.

Anyway, several guidance documents are available, which can be used as standards. The European Association of Nuclear Medicine (EANM) issued guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals [15, 16]. In these guidelines GMP and radiation safety requirements are interpreted for radiopharmaceuticals not intended for commercial purposes.

Annex 3 of the PIC/S guide to good practices for preparation of medicinal products in healthcare establishments interprets GMP issues for the small-scale preparation of radiopharmaceuticals [17] (see also Sect. 35.​5.​5).

Directive 96/29/EURATOM (Basic safety standards) provides safety standards for the protection of health workers and the general public against the dangers of ionising radiation [18]. Directive 97/43/EURATOM (Medical exposure directive) gives rules concerning radiation in relation to medical exposure and provides dose limits [19].

The International Commission on Radiological Protection (ICRP) has issued many recommendations and guidance documents on radiation protection. In addition to European legislation, national and local provisions can be applicable.

Radiation safety is based on general occupational safety and health risk mitigation principles (see also Sect. 26.​7): justification (of the use of ionising radiation), ALARA (as low as reasonably achievable; this means aim for the lowest possible exposure) and exposure limits (dose limits for ionising radiation).

It is not easy to interpret all above mentioned legislation and to give uniform guidance for each country and each situation. The determination of adequate quality assurance measures, for example the GMP-classification of the clean room, should be the result of a risk assessment [20]. Table 15.2 gives a practical overview of the applicable guidance and the appropriate quality assurance level when preparing radiopharmaceuticals.