Radiopharmacy

Pharmacy is the science of manufacturing and dispensing drugs. A compound of biological interest labelled with a radionuclide is referred to as radiopharmaceuticals. Depending on the decay mode of the radionuclide, these radiopharmaceuticals are used mainly for diagnostic or therapeutic purposes. In most cases radiopharmaceuticals are administered intravenously, however, other application modes exist as well. Typical examples for oral administration of radiopharmaceuticals are Iodine-131 capsules or solutions. Another type of administration is applied for example for lung ventilation studies using Technetium-99m, here the radiopharmaceutical (^99mTc-labelled carbon microparticles) is nebulized and inhaled by the patient. Inhalation is as well used if the radiopharmaceutical by its nature is a gas, such as ¹⁵O or ¹³³Xe

For diagnostic radiopharmaceuticals the amount of radioactivity that is given to the patient depends mainly on the sensitivity of the camera system, since the radiation exposure caused by a diagnostic radiopharmaceutical should be kept as low as possible. In contrast, the amount of radioactivity given for therapeutic purposes is determined by the energy dose that should be delivered the target organ. The ideal way to determine the required amount of activity would be by doing an individual dosimetry assessment that takes into account such parameters as organs uptake, biological half-life, and excretion pathways. However, commercially available therapeutic radiopharmaceuticals are often prescribed according to body weight only.

Manufacturing of radiopharmaceuticals must comply with certain quality standards also referred to as Good Manufacturing Practice (GMP). Within the territorial validity of the European Union, these quality standards are defined in the EU GMP guideline, which is part of the European legislation governing medicinal products in the European Union. The guideline is structured into three parts and addresses several aspects of manufacturing of pharmaceuticals such as quality management systems, personnel, premises, equipment, and quality control. The guideline is supplemented by (currently 18) annexes with annex 1 (manufacture of sterile medicinal products), annex 3 (manufacture of radiopharmaceuticals), annex 13 (manufacture of investigational medicinal products) and annex 15 (qualification and validation) being the most important concerning the production of radiopharmaceuticals. EANM has issued specific guidelines for the small scale preparation of radiopharmaceuticals, and these take into account specific requirements for hospitals or PET centres.

Radiopharmaceuticals that are administered intravenously must comply with the requirements for sterile medicinal products. A terminal sterilization of the product solution is in most cases not applicable either due to the short half-lives of the radionuclide or thermal instability of the drug product. In these cases, sterilization of the product can be achieved by sterile filtration in combination with aseptic manufacturing. In order to minimize the potential introduction of microbiological contaminants or particles, the starting materials must be controlled and manufacturing must take place using dedicated equipment in a controlled environment, i.e., cleanrooms. Critical steps such as manipulation of sterile equipment (primary container, tubing, filters, etc.), sterile filtration, and filling must be conducted in higher cleanroom classes, whereas manufacturing steps conducted in closed systems require a less demanding environment. The suitability and classification of the cleanrooms must be controlled by suitable means such as particle counting and hygienic monitoring (DIN EN ISO 14644-1:2015) on a regular basis.

A particular case of radiopharmaceuticals is radiolabelled autologous cells such as leukocytes, erythrocytes, platelets and granulocytes. While granulocytes are labelled in vivo by injection of labelled antibodies, leukocytes and platelets are isolated from patients’ blood, labelled in vitro and finally reinjected. For erythrocytes, both in vivo and in vitro labelling is possible.

The manufacturing process for radiopharmaceuticals often uses automated systems (synthesis modules), since the high amount of starting activity usually required circumvents manual manipulations during the synthetic process (see Chapter 5). The radionuclides needed for radiolabelling may come from radionuclide generators, from in-house cyclotrons, or from external suppliers (Chapter 5).

After completion of the manufacturing process, samples are taken from the batch for both quality control purposes as well as a retainment sample in case additional testing is required later. Quality control usually covers the determination of radiochemical purity and identity, chemical purity, radionuclidic purity and identity, pH-value, endotoxin content, and sterility.

Because of the short half-life of the radionuclide, it is not possible to perform all required tests before release of the batch, therefore sterility testing and radionuclide purity are often determined after batch release. The individual tests and test limits for the most commonly used radiopharmaceuticals are described in the European Pharmacopeia (Ph. Eur.), which is published by the European Directorate for the Quality of Medicines & Healthcare (https://www.edqm.eu/).

The requirements for personnel at a production site manufacturing radiopharmaceuticals do not differ from those in an ordinary pharmaceutical company (personnel). Head of Production and Head of Quality Control must be independent persons, while one of them can also serve as the Qualified Person responsible for batch release.