Differences between 99m Tc and PET radiopharmacy

differently and have very different properties, both physical and nuclidic;

leading to different handling and monitoring requirements. Table 3 summarizes the major differences between ^99mTc labelled radiopharmaceuticals and PET radiopharmaceuticals.

TABLE 3. IMPORTANT DIFFERENCES BETWEEN Tc-99m AND PET RADIOPHARMACY

Tc-99m radiopharmacy PET radiopharmacy

T1/2 = 6 h T1/2 = 110 min for F-18, 20 min for C-11, 10 min for N-13 and 2 min for O-15 Sterile ^99mTcO4 produced on-site from

a generator

Isotope produced on-site from a cyclotron

Tc-99m radiopharmaceuticals are complexes of Tc-99m and a chelating agent attached to biologically active molecules with the desired properties, and easy to prepare, with no chemical synthesis.

PET radiopharmaceuticals are biologically active molecules that are synthesized with the PET isotope attached covalently at a specific site within the molecule.

‘Cold’ sterile reagent and Tc-99m available in separate sterile vials — preparation requires addition of sterile ^99mTcO4– with a ‘cold kit’ and good mixing (no further processing or minimal without opening the vial)

Rapid chemical synthesis of the PET radiopharmaceutical is necessary using special precursors (to reduce synthesis time) for F-18 and C-11 labelled radiopharmaceuticals.

Only simple molecules possible with N-13 and O-15

Quality control (QC) of

radiopharmaceutical is minimal since the cold kit used for making the Tc-99m radiopharmaceutical is certified to be sterile and free of endotoxins.

Quality control is more elaborate, since the PET radiopharmaceutical is synthesized every day.

‘Parametric release’ permitted if quality assurance (QA) is validated

‘Parametric release’ permitted if QA is validated

The time available for the labelling of PET molecules (including purification and quality control (QC)) is limited, which raises new challenges and a need for more efficient systems to be implemented before clinical use. The busy and demanding nature of clinical settings compounds these complexities. Estab-lishing criteria for ensuring better acceptance practices for PET systems and parametric acceptance of PET tracers for clinical applications is therefore essential.

This class of radiopharmaceuticals includes isotopes with relatively short half-lives (2–110 min), and therefore makes it difficult to follow rules prescribed for therapeutic radiopharmaceuticals or even those prescribed for diagnostic radiopharmaceuticals with longer half-lives.

PET radiopharmaceuticals, as with all human parenteral drugs, must be produced in a work environment designed for production of sterile injectable products. In addition, these radiopharmaceuticals should pass the local governing pharmacopoeial tests or equivalent specifications on various properties including: (a) chemical purity, (b) pH, (c) isotonicity, (d) sterility, (e) apyrogenicity and (f) toxicity, as well as on (g) radionuclidic purity and (h) radiochemical purity, prior to administration to humans.

The radiopharmaceutical prepared can be used throughout the day — for at least eight hours.

Because of the short physical half-life of its isotope, ¹⁸F-RP has to be used within a few hours, perhaps requiring multiple syntheses on the same day.

In the case with ¹¹C radiopharmaceutical, each synthesis could cover one or two patients.

g = 140 keV, 20 mm lead shielding is adequate.

b⁺ emitters, g = 2 ¥ 511 keV; 70 mm lead shielding required

Multipatient dose in a single vial possible. Up to 12.95 GBq (350 mCi) of Tc-99m

Preferred as maximum of two to three doses in a vial. Doses preferred in syringes, ready to inject to minimize handling

Should be sterile Should be sterile

Endotoxin levels below 175/V^a (IU)^b Endotoxin levels below 175/V (IU)

a V: Maximum recommended dose.

b IU: International units.

TABLE 3. IMPORTANT DIFFERENCES BETWEEN Tc-99m AND PET RADIOPHARMACY (cont.)

Tc-99m radiopharmacy PET radiopharmacy

The complexities involved in establishing a radiopharmaceutical preparation facility arise from the cooperation required from multiple regulatory and governing agencies to ensure safety. Unlike typical pharmaceu-tical production facilities, the risk from radiopharmaceupharmaceu-ticals results mainly from their inherent radiations. Therefore, in addition to microbial contami-nation risks, radiopharmaceutical facilities should be compliant with local radiation safety guidelines.

In addition to pharmacopoeial regulations, PET radiopharmaceuticals, owing to their radioactive nature, also have to comply with local radiation safety regulations. There are separate implementation authorities for these two sets of regulations and, hence, a PET radiopharmaceutical production facility requires clearances from both regulators. Fulfilling both regulations is a prerequisite for a PET radiopharmaceutical production facility, and has been the topic of much debate. A prominent concern is adequate shielding of the cyclotron, because there are very high ambient gamma and neutron radiations during irradiation of the target. Adequate shielding is required for the transport of the radioactivity produced from the cyclotron to the radio-chemistry hot cells where the synthesis of the PET radiopharmaceutical takes place, as well as a shielded area for doing the QC tests, packaging and dispatch of the PET radiopharmaceutical. Adequate monitoring for radioactive spillage/

contamination and the need for radiation safety personnel to make regular checks are also necessary. Minimum specifications for radiation safety while handling radioactive isotopes is mandatory by law, and permission to handle radioactivity can only be granted after the prescribed specifications have been met.

All radiopharmaceuticals have a limited shelf life, although this can vary from minutes to a few weeks. For PET radiopharmaceuticals, the maximum shelf life is a few hours for ¹⁸F products and minutes for ¹³N and ¹¹C products.

Hence, they have typically been prepared in-house or ‘compounded’ by the nuclear medicine department of a hospital, and QC and use were supervised by the radiopharmacist in charge of compounding. However, different radio-pharmacists have adopted different procedures and protocols to compound the same PET radiopharmaceutical. For example, ¹⁸F-FDG can be compounded using either nucleophilic or electrophilic substitution reactions, using different precursors and different synthesis routes. As a result, yields and specific activities of the final product vary considerably. The ¹⁸F-FDG produced via any of the synthesis routes would fulfil radiochemical and pharmaceutical purity requirements; however, there were various impurities (unreacted precursors, unhydrolysed ¹⁸F precursors, residual phase transfer catalysts, solvents, etc.), which were present to varying extents. Production of PET radiopharma-ceuticals cannot be controlled in the same way as ^99mTc radiopharmaceuticals,

which are mainly produced by simply mixing the sterile ^99mTcO₄^– solution with the sterile complexing agent supplied in a vial. There has been no consensus amongst PET radiochemists and radiopharmacists regarding what should constitute a common acceptable good radiopharmacy practice for ¹⁸F-FDG, let alone PET radiopharmaceuticals in general.

There is limited time available immediately after production and prior to their administration for tests to be performed. Criteria for ‘parametric release’

have therefore been established in the form of a carefully devised standard operating procedure (SOP), whereby many production runs of the radio-pharmaceutical are devoted exclusively to the QC tests listed above. The SOP is said to be validated, to a high degree of confidence, when a specified number of production runs comply with all the QC tests, without any failures (at least three clear runs). This ‘high degree of confidence’ protocol allows the PET