Hospital positron emission tomography facility

radiopharmaceutical production) within a large hospital has the advantage of delivering health care at a single location that is convenient for patients and all patients that meet prescribed criteria can thereby rapidly access PET–CT investigations. There are also PET facilities that are established as a stand alone centre (i.e. outside a hospital). These facilities are set up as outpatient clinics as the vast majority of patients can undergo PET–CT on an outpatient basis.

Depending on the clinical services and decision to purchase or prepare PET radiopharmaceuticals is critical to overall cost. The purchase and use of PET radiopharmaceuticals would then be considered as IAEA radiopharmacy operational level 1. Caution is advice on purchased PET radiopharmaceuticals as the users need to ensure receipt of quality certificate (radiopharmaceutical certificate of conformity) from the supplier before injecting the first patient dose (see Ref. [40] for details of ¹⁸F-FDG production and tests).

7.9.1. Cyclotron

The cyclotron produces radionuclides by bombarding stable isotopes with charged particles, mainly protons. There are many cyclotrons suitable for PET radionuclides with energies in the range of 7–30 MeV. The smallest cyclotrons with a proton energy of around 7 MeV and beam currents up to 70 µA; the next level of cyclotrons have an energy around 10 MeV and beam currents up to 100 µA. With this energy, all the four ‘classical’ PET radionuclides can be manufactured in multipatient amounts (see Table 3). These accelerators are either self-shielded or needs to be placed in a radiation shielded ‘bunker’. These accelerators are good for PET centres with up to three PET–CT cameras. The highest level of PET cyclotrons are those with a proton energy of 30 MeV and beam currents above 100 µA. All the four classical PET radionuclides can be produced in multipatient doses and ¹⁸F can be manufactured in such large amounts to cover a certain number of PET–CT cameras. Other long lived PET radionuclides can be produced, such as ⁶⁴Cu, ¹²⁴I, ⁸⁶Y and ⁸⁹Zr, and the SPECT radionuclides ¹²³I and ^99mTc.

Several major pieces of equipment, highly qualified and trained staff and highly developed QMS are essential in the establishment of a PET centre.

Methodology of decision making and the choice of a cyclotron will depend entirely on the programme in place at a new facility. In order to choose a cyclotron, a methodology should be followed which takes into consideration the requirements of the facility and the environment in which the accelerator will be placed. A procedure that has proven to be very useful is as follows:

(a) Interview all the stakeholders and users to define the proposed programme.

(b) Generate a list of radioisotopes which will be needed from these users.

Clinical need for very short half-life PET tracers (e.g. ¹¹C) will necessitate the need to have cyclotron facility on the site.

(c) Develop priorities for the programme, either clinical or research.

(d) Evaluate the space allotted to this project. Hospital space is always competitive challenge.

(e) Evaluate the potential cyclotrons with respect to this programme and space.

(f) Examine construction obstacles, staffing and chemistry requirements.

(g) Evaluate all alternatives, such as public–private partnership, ‘to make or purchase’ services and radiopharmaceuticals.

The most important considerations in the choice of a cyclotron are the particle beam energy and the beam current. The beam current of the cyclotron determines how much radioisotope can be produced at a given energy. The choice of the synthesis module, the radionuclide activity meter and the hot cells also needs consideration (see Ref. [41] for detailed information on the equipment needed to produce and qualify radiopharmaceuticals).

TABLE 3. HALF-LIVES OF

CLASSICAL PET RADIONUCLIDES

Radionuclide Half-life

(min)

15O 2

13N 10

11C 20

18F 110

7.9.2. Hot cells

One of the key pieces of equipment in the radiopharmacy are hot cells. The hot cell provides a shielded enclosure for handling highly radioactive materials and serves as an isolator providing clean environment for the preparation of radiopharmaceuticals. Hot cells are commercially available from several manufacturers. The thickness of lead shielding is determined by the quantity of FDG being processed (75 mm of lead or equivalent is typical). For radiation safety reasons, the air pressure inside the hot cells should be maintained well below the pressure of the room where the hot cell is situated. Furthermore, the hot cells should be equipped with an appropriate air handling system (inlet and outlet air filters as a minimum). Lead glass windows or TV monitors should be provided with the hot cells. Consideration for hot cells include such as weight bearing capacity, temperature stability, and adequate power supply, as well as issues concerning radiation safety (e.g. shielding).

The choice of hot cell will depend on whether one wants two independent modules or two modules in the same hot cell. This will depend on the type of facility and the production schedule. Having the ability to carry out a second synthesis is very advantageous in a clinical programme when patients are waiting for the radiopharmaceutical. The key issue is radiation protection in case of synthesis failure. If the synthesis modules are in two separate shielded enclosures, there will be a lower radiation dose than if the hot cell must be opened in order to load the second module or to clean and prepare the same module for a second synthesis. To optimize on-site cyclotron and enable seamless production the use of several enclosures are required including a final sterile dispensing module providing grade A, ISO 5 conditions.

7.9.3. Automated radiopharmaceutical module

Synthesis of PET radiopharmaceuticals are performed in automated modules that are usually placed in lead shielded hot cells for radiation protection purposes and high level of cleanliness (hot cells are generally grade C, ISO 7).

The modules use radiochemical synthesis for which the reaction parameters have been determined in detail. The final product is transferred for terminal sterilization before supply radiopharmaceutical for patient administration.

7.9.4. Final aseptic product

Terminal sterilization processes are rarely carried out on the final radiopharmaceutical prepared because of time constraints. In addition, some radiopharmaceuticals cannot withstand high temperatures, rendering them

unsuitable for autoclaving, and filtration is not applicable for particulate radiopharmaceuticals. This means that the procedure has to be carried out aseptically in order to prevent microbial contamination. The final product must be sterilized in hot cell able to achieve grade A, ISO 5 conditions. The filter must also be tested for integrity following a strict protocol to ensure the radiopharmaceutical is sterile and acceptable for human administration.

7.9.5. Quality control equipment

As safety of drugs has become a particularly important issue in the last years, it is of great importance that the appropriate QMSs for validation and the appropriate radioanalytical equipment for radioanalytical testing are duly considered [18]. The modules applied for performing the syntheses also include high performance liquid chromatography (HPLC) systems for isolating the product out of the reaction solution. At any rate, careful analysis of each batch is necessary for ensuring radionuclide purity, the chemical (including solvents) and radiochemical purity and identity of the product. Routinely thin layer chromatography (TLC) is generally used and for developmental tracer HPLC is employed. Most pharmacopeia permit the use of TLC methods.

The purity of the radionuclides produced at a cyclotron is controlled by gamma spectroscopy. As some of the important radionuclides can only be differentiated by their half-life, a programme for automated determination of the half-lives is particularly useful. The impurity of ¹³N in ¹⁸F can only be determined in this way.

Other key equipment includes gas chromatography for determination of residual solvents in the final radiopharmaceuticals. An endotoxin test (limulus amebocyte lysate) is also essential at the time of radiopharmaceutical product release. As in any chemical laboratory, equipment includes a pH meter, osmometer, melting point apparatus, balances, microevaporator with vacuum pump, distillation unit and glassware, and for simple organic chemical work, a small infrared spectrometer and an ultrasound bath.