Chapter 6 Preparation of Technetium 99mTc Pharmaceuticals 6

J. Mallol and I. Zolle

6.1 Introduction

Technetium-99m (99mTc) is widely used in radiopharmaceutical preparations due to its excellent physical and chemical properties. In fact, more than 80% of all radiopharma- ceuticals used in diagnostic nuclear medicine are based on this short-lived radionu- clide, which is obtained by elution of a 99Mo/99mTc generator system that is available in any radiopharmacy and nuclear medicine facility.

6.1.1 Physical Characteristics

99mTc decays with a half-life of 6 h by isomeric transition and emission of 140.5-keV gamma radiation. Large amounts of radioactivity may be used with the single-photon emission computed tomography (SPECT) technology, producing high-contrast images with the gamma camera. In fact, the energy window of the gamma camera is optimized to 140.5 keV (110±220 keV).

6.1.2 Chemical Characteristics

99mTc is eluted from the generator as a pertechnetate anion. It has been demonstrated that heptavalent technetium must be reduced to a lower valency state in order to be chemically reactive for labeling. Most 99mTc pharmaceuticals comprise complexes of 99mTc at various oxidation states (I±V). The preparation of 99mTc pharmaceuticals is greatly facilitated by the availability of commercial cold kits containing the chemical ingredients as a lyophilized formulation ready for labeling with 99mTc-pertechnetate.

6.2 Kit Preparations

The preparation of any 99mTc pharmaceutical is performed by using a commercial cold kit and adding the required 99mTc activity in a certain volume of 99mTc eluate (pertech- netate). Kits offer convenience and ease of preparation for ad hoc labeling. Cold kits are considered as semimanufactured products, which need marketing authorization as medicinal products (European Economic Community 1998). Cold kits are commonly produced at the industrial level. The preparation of a 99mTc pharmaceu- tical by a nuclear medicine facility or a nuclear pharmacy by adding 99mTc eluate to an 96 6.2 Kit Preparations

approved cold kit according to the instructions given by the producer does not need a specific authorization (Nordic Council on Medicines 1998). The labeling procedure is termed as ªreconstitution of the kitº, which may be interpreted as preparation of an of- ficial formula as described in the European regulations (Cox 1993). Similarly, 99mTc pharmaceuticals described in the European Pharmacopeia in specific monographs (Council of Europe 2005), as well as the preparation of any medicinal product accord- ing to pharmacopeia specifications, is conceptually an official formula.

6.2.1 General Considerations

The concept reconstitution of a kit is erroneous, because radiolabeling is an active pro- cess by which a new chemical compound (a 99mTc pharmaceutical) is formed involving chemical reactions, in any case the reduction of pertechnetate, and in most cases com- plex formation, which might need heating in a boiling water bath. Moreover, a kit may be perfectly reconstituted (dissolved) but labeling might be inadequate. Preparation of 99mTc radiopharmaceuticals by using aseptic techniques has to com- ply with the regulations issued in the Good Manufacturing Practice Guidelines ([GMP] European Economic Community 1997; European Free Trade Agreement 1992). Labeling by a closed procedure is defined as a procedure whereby a sterile radiopharmaceutical is prepared by the addition of sterile ingredients to a presterilized closed container via a system closed to the atmosphere (Lazarus 1994). 99mTc eluate is added to the sterile vial (kit) with a syringe through the rubber stop- per. An excess of pressure in the vial is avoided by withdrawing an equal volume of gas with the same syringe. A breather needle should not be used because oxygen may affect the stability of the radiopharmaceutical, and may cause microbial contamination. The instructions given by the manufacturer of the kit should be strictly followed, particularly with respect to the maximum activity and volume of 99mTc eluate that is transferred to the kit for labeling. The labeled product is a sterile, pyrogen-free solu- tion suitable for intravenous injection. Any abnormality observed by visual inspection of the injection solution is a cause to reject the preparation. 99mTc radiopharmaceuti- cals have a short shelf-life (generally 6 h); they are used right after preparation.

6.2.2 Cold Kits

Cold kits are prepacked sets of sterile ingredients designed for the preparation of a specific radiopharmaceutical. Kits are fully tested to verify the specific characteristics, which are guaranteed by the producer. A kit contains the active ingredient, a reducing agent, and may contain authorized ex- cipients and additives, such as antimicrobial agents, antioxidants, buffer, a nitrogen atmo- sphere, etc. The active ingredient is the compound to be labeled with the radionuclide. The reducing agent is responsible for the reduction of pertechnetate to a lower valency state; it is considered an essential material. Without reduction, there is no labeling reaction. In fact, the stability of kits had been of considerable concern until freeze-drying was applied to kit production. Exact filling of the sterilized vials is performed automatically by a sterile dispensing/stoppering device, whereby a certain volume (1 ml) of the kit formulation is delivered and subjected to lyophilization. When closing the vial, nitro- Chapter 6 Preparation of Technetium 99mTc Pharmaceuticals 97 gen gas is introduced through a sterile filter. By this computer-assisted automatic filling device with subsequent lyophilization, kit contents are stable for long periods; addition- ally, oxidative processes no longer affect the labeling yield. The shelf-life of kits is usually in excess of 1 year. It is important that kits are stored according to the specific conditions (temperature, humidity) indicated on the package, since radiolabeling de- pends on the integrity of the reducing agent. Cold kits may also be prepared in a radiopharmacy similar to other medicinal prod- ucts prepared in a pharmacy. The radiopharmacist then functions as the qualified per- son responsible for preparation of an official formula (formulation, pharmaceutical re- quirements, stability, etc.)

6.2.3 99mTc-Pertechnetate

The 99mTc eluate used for radiolabeling must comply with the specifications stated in the pharmacopeia. Additionally, the specific activity (activity/Tc carrier) and the activ- ity concentration (activity/ml) should be known. Since the specific activity of the 99mTc eluate is related to the time elapsed between elutions, daily elution of the generator at an interval of 24 h will produce eluates with the best quality. Kits are compatible with eluates from different commercial generators; however, high specific activity is mandatory with some kits, especially when labeling biomolecules. The total 99mTc activity and the volume injected into the vial (kit) should comply with the recommendations by the manufacturer. Dilutions should be performed with isotonic saline.

6.2.4Incubation

After dissolving the lyophilisate in the added volume, incubation is an essential step to obtain the radiolabeled medicinal product. In this phase, the chemical reactions take place, resulting in 99mTc labeling. If incubation is inadequate, the labeling reaction may not be completed, and the radiopharmaceutical may not be suitable for administration. Each kit requires specific incubation conditions, but in general, this process is car- ried out at room temperature in a clean area. In certain cases, the incubation must be performed in a boiling water bath; in such cases it is necessary to operate carefully. Incubation is normally performed with occasional agitation of the shielded reaction vial.

6.2.5 Quality Control

Quality is directly related to the labeling yield, which is measured by the amount of unbound 99mTc activity. Limits of radiochemical impurities are stated in the official monographs (Council of Europe 2005). The determination of the radiochemical purity lies in the responsibility of the user (Theobald 1994). To assure safety and efficacy of a 99mTc radiopharmaceutical, the product should be tested regularly, in certain cases before application to the patient. 98 References

Radiochemical purity is analyzed by thin-layer chromatography, described in this book. Poor quality of a radiopharmaceutical would affect the clinical information and cause unnecessary radiation exposure of a patient.

6.2.6 Dispensing

Dispensing is the compliance of a prescribed medicinal product with the required qual- ity standards (Lazarus 1994). For dispensing a prescribed amount of radioactivity, it is necessary to determine the total radioactivity and the radioactivity concentration of the radiopharmaceutical. A single dose may be withdrawn aseptically from the multidose vial by using a suit- able syringe; each syringe must be measured in the dose calibrator to verify the pre- scribed amount of radioactivity for a patient. Syringes with individual doses of the radiopharmaceutical may be prepared in ad- vance. In this case, the correct identification of each syringe is mandatory, stating on the label: · Identification of patient (name and/or number) · Name of the radiopharmaceutical · Amount of radioactivity and time of preparation · Relevant comments (storage, cautions, etc.) · Name of dispenser, if necessary

References

Cox PH (1993) EEC Directives and guidelines applicable to radiopharmaceuticals. Eur J Nucl Med 20:712±715 Council of Europe (2005) European pharmacopeia, 5th edn. Maisonneuve, Paris European Economic Community (1997) Pharmaceutical legislation for medicinal products for hu- man and veterinary use in the European Union. Good manufacturing practices. (Directive 91/ 356/EEC). Eudralex, vol. IV. European Economic Community, Luxembourg European Economic Community (1998) Notice to applicants for marketing authorization for med- icinal products for human use in the European Union, Volume IIA (III/3567/92) European Free Trade Agreement (1992) Guide to good manufacturing practice for pharmaceutical products, the convention for the mutual recognition of inspections in respect of the manufac- ture of pharmaceutical products, Document 5/92 (PIC guidelines on GMP). Lazarus CR (1994) Techniques for dispensing of radiopharmaceuticals. In: Sampson CB (ed) Text- book of radiopharmacy, theory and practice, 2nd enlarged edn. Gordon and Breach, Philadel- phia, pp 59±68 Nordic Council on Medicines (1989) Radiopharmacy: preparation and control of radiopharmaceu- ticals in hospitals. National Library of Norway (NLN) publication No. 26, Uppsala Theobald AE (1994) Quality control of radiopharmaceuticals. In: Sampson CB (ed) Textbook of radiopharmacy: theory and practice, 2nd enlarged edn. Gordon and Breach, Philadelphia, pp 103±125