Radiopharmaceuticals preparation process

Quality assurance of radiopharmaceutical preparation and use is obviously a very important topic because of its direct impact on patient diagnosis, treatment and health (see, e.g. Abreu 1996). Reference materials play only a small - but nevertheless important -role in this process, mainly in the area of calibration of radioactivity-measuring instruments. The materials of interest are all pure chemical containing calibrated activities of selected radionuclides used commonly in nuclear medicine (e.g. Co, Ga, I,... 

Breaking points are the availability of the raw materials and primary containers of reliable suppliers, the feasibility of analysis of the drug substance and the preparation and the availability of equipment. As an example, preparation processes such as tableting, freeze-drying or aseptic production are accessible in a few pharmacies. The preparation of oral solids with controlled release is not possible in pharmacies mainly to lacking equipment (fluidised-bed techniques and instrumental analysis, etc). Working with radiopharmaceuticals also requires very specific facilities, as is the case with preparation of solid dosage forms with hazardous substances. 

The Ph. Eur. gives limits for radiopharmaceuticals in general but for some individual radiopharmaceutical preparations as well. In most radiopharmacy departments the endotoxin content of radiopharmaceutical preparations is not tested before injection. In some situations, e.g. development of a new preparation process or when using generators for longer periods of time (weeks to some months) endotoxin testing may be useful (see further Sect. 19.3.4). 

The required apparatus and utensils, the preparation processes they are used for and the required provisions such as air conditioning, clean water, electricity, compressed air and gasses. For extremely hazardous preparations (antineoplastics, radiopharmaceuticals, see Sect 26.3.5) and for sterile preparations separate premises may be required to protect products and operators adequately, as is also laid down in GMP. Scaling up of the processes may lead to partitioning of the rooms into areas for dedicated functions. 

The O-donor complexes of Tc(V) exhibit moderate and differential stability in aqueous solution. In the presence of reducing agents, such as stannous chloride, they are reduced to mainly undefined products of Tc in a lower oxidation state. However, at the low technetium concentration of "mTc that is used in nuclear medicine, the rate of the reduction process is very low. This makes it possible to prepare Tc(V) radiopharmaceuticals with O-donor ligands by the usual procedure, in which an excess of reducing agent over technetium is unavoidably used. The Tc(V) complexes also tend either to be easily oxidized or to disproportionate [23],... 

In order to be able to trace a specific biological process in the body, or investigate the functioning of a body organ, it is necessary to make a careful choice of both the radionuclide and the chemical form in which it is administered to the patient. Such radionuclide preparations are called radiopharmaceuticals. Today, some 100-300 radiopharmaceuticals are in routine use for diagnosis, most of which are commercially available. The majority of these compounds are organic in nature (see Table 4.6 for details). 

The bis-Cp titanium molecules shown in Scheme 765 have been synthesized and used as potential antiestrogenic vectors to the estradiol receptor and a recognized cytotoxic molecule. They also proved to be particularly easy to exchange with Re in order to prepare organometallic radiopharmaceutical compounds with antiestrogenic properties.2020 These processes have been used as a source for Re(CO)3 through thermal ligand-transfer reaction between Cp titanium complexes and Re2(CO)i0. 

To get a radiopharmaceutical of satisfactory quality each time, it is important that the manufacturing process as well as the process of preparation comply with current GMP. This is of utmost significance for radiopharmaceuticals that, due to their often-short shelf-lives (physical and chemical), have to be released before all QC measures are performed and evaluated. That is to say, radiopharmaceuticals in most cases are administrated to the patient before the results from all tests are available. 

QC on Ready-for-Use Products from a Manufacturer. These radiopharmaceuticals are to be administrated to the patient without further preparation. As the manufacturing is inspected by competent authorities in order to ensure a high quality of the production process, the QC in the hospital in most cases can be reduced to control of transport documents, labels, and radioactivity. Tests on radionuclidic or radiochemical purity are normally not required. 

The preparation of a radiopharmaceutical in routine application is usually done in a one-or two-step procedure. O Figure 43.1 gives in the context of coordination chemistry later an overview of the different processes for the production of a radiopharmaceutical in relation to the required fundamental coordination chemistry. Perfusion agents such as pure complexes can be prepared in most cases in one single step upon kit reconstitution. The kit is a vial that contains all the ingredients necessary for performing the chemical reaction to form the... 

---