Radiopharmacy

Pharmacy is the science of manufacturing and dispensing drugs. A compound of biological interest labelled with a radionuclide is referred to as radiopharmaceutical. Depending on the decay mode of the radionuclide, these radiopharmaceuticals are used mainly either 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 Reasonably Achievable (ALARA). Moreover, there is Diagnostic Reference Level (DRL) defined. A Diagnostic Reference Level (DRL) is a tool used in medical imaging, including nuclear medicine, to help optimize radiation protection for patients. In nuclear medicine, it refers specifically to the recommended activity of a radiopharmaceutical administered to a patient for a standard clinical diagnostic procedure and represents typical activity levels for standard-sized patients undergoing routine clinical procedures. In contrast, the amount of radioactivity given for therapeutic purposes is determined by the energy dose that should be delivered to 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 under fixed dose/cycle regimen.

Manufacturing of radiopharmaceuticals for clinical human use must comply with certain quality standards also referred to as Good Manufacturing Practice (GMP). In contrast, Good Laboratory Practice (GLP) is a set of quality principles intended to ensure the integrity, reliability, and reproducibility of non-clinical laboratory studies, especially those related to the safety testing of pharmaceuticals, including radiopharmaceuticals. GLP in radiopharmacy ensures the scientific credibility of laboratory research data, particularly during the development phase of new radiopharmaceuticals whereas GMP governs the production and quality assurance of radiopharmaceuticals that are administered to patients, ensuring that they meet regulatory safety and quality standards. Both GLP and GMP play essential but distinct roles in the lifecycle of a radiopharmaceutical, with GLP supporting the early-phase development and testing, and GMP ensuring safe clinical use.

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 19) 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 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.) http://online.pheur.org/EN/entry.htm, 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.