Levels of radiopharmacy

The procedures performed in the field of hospital radiopharmacy can vary considerably in different parts of the world. However, hospital radiopharmacy facilities can generally be classified into operational levels 1, 2 and 3 [8].

Each category can be further subdivided to provide essential advice on staff qualifications, training, facilities, equipment, and types of procedures, record keeping, and quality assurance and quality control essential at that level.

The radiopharmacy needs to be equipped with at least one radionuclide activity meter (dosimeter) to measure all radioactivities accurately. A reference source (e.g. ¹³⁷Cs) will also be necessary to ensure stability of response of the radionuclide activity meter [34]. Since radiopharmacies will be handling unsealed sources of radioactivity, contamination monitors will be required to routinely

monitor different areas of the radiopharmacy and to check for any radioactivity that may have been spilt.

Storage areas will be necessary for radioactive materials as well as for non-radioactive components used in radiopharmaceutical preparation. These areas will need suitable shielding and, depending on the type of product being prepared, a refrigerator and freezer may also be required. A store for flammable products, such as sanitization fluids, solvents used in quality control procedures is also being required.

7.8.1. Operational level 1a

Operational level 1a is the dispensing of radiopharmaceuticals purchased or supplied in their final form from recognized or authorized manufacturers or centralized radiopharmacies. This includes unit doses or multiple doses of prepared radiopharmaceuticals for which no further manipulation or pharmaceutical compounding is required. Increasingly, dispensing from multidose vials is conducted in a separate room with the necessary radiation shielding for the radionuclides handled and procedures performed. The facility may also have a class A (or ISO 5) dispensing laminar flow cabinet [35, 36] or isolator for preparing final patient radiopharmaceutical injections.

Handling of volatile radiopharmaceuticals solutions, particularly those based on ¹³¹I, which are intended for oral administration, should be performed within a fume cupboard with suitable filters (active carbon filter) that exhausts air away from the operator. The inflow over the working aperture should not be less than 0.5 m/s. The fume cupboard should be annually tested to provide good operator protection [37]. The exhausted air is ducted to the atmosphere, and great care has to be taken when positioning the exhaust duct to ensure it effectively disperses the discharged air. There should be adequate shielding to provide protection from ¹³¹I high energy gamma irradiation and there should be a secure system for delivery and storage of ¹³¹I therapy activities.

A secure waste storage area with shielded containers is necessary. There should be a sufficient number of lead lined sharps bins (at least two — one for short life radionuclides and the other for longer half-life radionuclides) with sufficiently thick walls to store radioactive waste.

7.8.2. Operational level 2a

Many of the nuclear medicine facilities prepare radiopharmaceuticals using a ^99mTc generator and approved reagent kits using ‘closed aseptic procedure’.

Closed aseptic procedure is one in which the prepared product is contained in a sealed vial with a rubber septum and therefore transferred material is not exposed

to external environment. The type of generator most commonly used consists of ⁹⁹Mo, as sodium molybdate, adsorbed onto an alumina (Al₂O₃) column.

Technetium-99m is eluted from the generator by drawing sterile normal saline (0.9% w/v sodium chloride) injection through the column. This is achieved by the use of a sterile evacuated vial supplied with the generator so that the operator does not need to be in close proximity to the generator during the process.

Preparation of radiopharmaceuticals involves sodium pertechnetate (eluted from the generator) mixed to a sterile kit vial that contains all the ingredients necessary to produce the required radiopharmaceutical. The final medicine prepared is free from other contaminants from the environment and free from microbial contamination. This has to be demonstrated by regular microbiological test of the environment, operator practice and the final product (referred to as an end product test).

In order to achieve these conditions the procedures described in operational level 2a should be performed in a vertical LAF cabinet [36] placed in a room divided into ‘dirty’ and ‘clean’ zones, with a stepover benchmarking the boundary between the two zones. Traditional horizontal pharmacy LAF are not suitable for use in the radiopharmacy. Consideration needs to be given to the siting of workstations to provide suitable working conditions for aseptic transfer. This means high level of hygiene, on a grade depending on national or international regulation, defining standards for the number of particles permissible [8, 35]. All material placed in the LAF should be sanitized using a ‘spray and wipe’ technique with sterile biocide or 70% IMS solution. At least a two staged sanitization is required of all materials before use in an LAF. Caution is required in the use of biocides in radiopharmacies, as they are strong oxidizing agents which can alter and effect chemistry of the radiopharmaceuticals. Strict aseptic practices are essential during the dispensing process. The operators should also be well trained and demonstrate competencies is aseptic techniques. The integrity of the LAF cabinet filter should be checked at regular intervals and according to the manufacturer’s guidelines.

Air filtration to the room is required and access need to be controlled.

Personnel should wear protective clothing (mop cap, clean gown, beard covers, overshoes), which in addition to protecting them from radioactive contamination will also help to reduce the number of particles being shed into the environment from their skin, hair and clothing. A separate changing room or a buffer zone which has a stepover bench or other means of demarcation, is a useful way to control access to the room, and also helps to keep the air in the radiopharmaceutical preparation room less contaminated. As little material (especially paper based) as possible should be stored in the laboratory to reduce the accumulation of dirt and radioactive contamination. Materials required for the

preparation of radiopharmaceuticals can be passed into the laboratory through a transfer hatch when required.

Although it is essential to provide facilities for washing hands and the disposal of liquid radioactive waste, care must be taken in the siting of sinks, since they provide a site for accumulation of microbial contamination. The current practice is not to locate sinks in radiopharmaceutical manufacturing rooms, although ready access to sinks in the adjacent rooms is necessary. Personal should have access to comprehensive decontamination facilities. In situations where chemicals are handled, it may be desirable to have dedicated eye wash facilities available.

In the general design of a nuclear medicine facility, the entry, flow and exit of patients and staff should be separated from the entry, flow and exit of radioactive materials. A dedicated area for delivery and receipt of radiopharmaceuticals, storage room, and changing room or area, office area for records keeping and waste storage area. For radiolabelling of blood cells, a separate dedicated room with the same air quality as for dispensing is required (see Fig. 16).

7.8.3. Operational level 2b

Operational level 2b includes the radiolabelling of red bloods cells, platelets and white cells commonly used for infection or inflammation imaging.

FIG. 16. Layout of an operational level 2 radiopharmacy.

It is desirable to have a separate LAF or isolator for this function, which can be readily cleaned and disinfected after each labelling procedure, thus minimizing the possibility of cross contamination of blood between patients and other environmental contaminants. Patient blood may contain viruses and other infective elements and these should not contaminate the environment, operator or other products handled with the radiopharmacy. It is equally important to ensure that blood samples are never crossed over between patients. A three point labelling of each blood sample (e.g. full name, hospital number, date of birth) is necessary. In addition, strict one product blood radiolabelling policy is required i.e. two patients’ blood should never be radiolabelled at the same time (see Ref. [38] for further details). Totally enclosed workstations incorporating centrifuges are available, enabling the entire labelling process to be performed in a more dedicated and protected environment.

7.8.4. Operational level 3a

Operational level 3a includes the compounding of radiopharmaceuticals from ingredients and radionuclides for diagnostic application (including open procedure), modification to existing commercial kits (dimercaptosuccinic acid), and individualized and tailored patient diagnostics. Ideally, disposable equipment and laboratory glassware should be used for compounding any radiopharmaceutical reagent kits and radiopharmaceuticals (therefore no need to wash and prevent cross contamination).

In addition to the details stated in operational level 2a, the procedures described for operational level 3a should be performed in a class II LAF cabinet/isolator placed in aseptic environment and better air quality depending on national regulations. The quality systems also require significant advancement and regular quality audit [4].

7.8.5. Operational level 3b

The scope of operational level 3b relates specifically patient prescribed compounding of radiopharmaceuticals from basic ingredients or unlicensed intermediates and radionuclides for therapeutic application (open procedure), related research and development, and individualized and tailored patient therapies (see Refs [38, 39] for information on radiolabelled monoclonal antibodies and peptides). The compounding of these have serious complications including biological safety practices, quality assurance systems, actual methods for therapy formulation, including formulation of alpha emitting therapeutics.

Again the quality systems also require significant advancement and regular quality audit [4].

7.8.6. Operational level 3c

Operational level 3c is the synthesis of PET radiopharmaceuticals, including those produced from long lived generators (e.g. ⁶⁸Ga).

7.9. HOSPITAL POSITRON EMISSION TOMOGRAPHY FACILITY