Radiopharmaceuticals quality assurance

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,... 

Frier, M., Hesslewood, S. Quality assurance of radiopharmaceuticals — a guide to hospital practice. Nucl. Med. Commun. Special Issue 1980. 

The quality control of the final product must be carried out before release of the batch (except for the sterility and the endotoxin tests for extremely short-lived radionuclides). Consequently, all procedures must not only be very fast but also very accurate, and in all cases it is very important to have a properly established quality assurance system that might permit parametric release of the produced batches. The quality control assays that must be carried out in the radiopharmaceutical includ the following ... 

Independent of which regulation applies at a national level to extemporaneous or magistral preparation of radiopharmaceuticals, the patients should be entitled to expect that these products are prepared accurately, are suitable for use, and will meet the expected standards for quality assurance. Pharmacists involved in this kind of production must ensure that they and any other staff involved are competent to undertake the tasks to be performed and that the requisite facilities and equipment are available [11], As for other radiopharmaceutical production, systems must be in place to ensure the operator safety due to handling of radioactive materials. All involved staff must have sufficient training in radiation safety issues, in addition to training in GMP. 

Whereas readers are referred to these specific documents for details available on the Web site http //www.fda.gov/cder/fdama, some of the specifics are briefly mentioned here. The essence of this guidance emphasizes the importance of the overall quality assurance in manufacturing a PET radiopharmaceutical. All equipment and measurements used in the manufacture must be validated. The areas and hoods in which PET radiopharmaceuticals are manufactured must be run in a sterile condition. The personnel responsible for the manufacture must be well trained in the methodology, and an appropriate number of personnel are required in a production laboratory. Each step of the production must be verified and records must be maintained. The sterility and pyrogen testing of the finished product must be performed by appropriate methods. If a PET radiopharmaceutical is to be commercially distributed, appropriate containers and techniques must be adopted for safe shipments. 

In contrast, ACR emphasizes the quality control, calibration of the equipment, and technology used in the procedures, and accordingly has developed three modules - module 1 for oncology, module 2 for brain, and module 3 for heart. A PET center must apply for all modules that are performed at the facility. For accreditation, the facility is required to submit information on the quality control and quality assurance program, data collection, reporting, radiopharmaceuticals procedures, and laboratory safety, along with chnical and approved phantom images. So, all equipment in a PET center is required to be calibrated and tested for accurate functionahty for accreditation by ACR. 

Bish RE, Silverstein D, Bede JI (1980) Radiopharmaceutical-radiochromatography quality assurance with a radioisotope calibrator. J Radioanal Chem 57 565-573 Carpenter AP (1986) Radioanalytical techniques ITLC, TLC, mini columns and electrophoresis. In Wieland DM, Tobes MC, Mangner TJ (eds) Analytical and chromatographic techniques in radiopharmaceutical chemistry. Springer, Berlin Heidelberg New York Council of Europe (1982) Sodium pertechnetate [ " Tc] injection (fission). Monograph (124). European pharmacopeia. Strasbourg... 

Blau M, Wicks R, Thomas SR, Lathrop KA (1982) MIRD dose estimate report no. 10. Radiation absorbed dose from albumin microspheres labelled with technetium-99m. J Nucl Med 23 915-917 Bolles TF, Kubiatowicz DO, Evans RL, Grotenhuis IM, Nora JC (1973) Tc-99m-labelled albumin (human) microspheres (15-30 micron). Their preparation, properties and uses. In Radiopharmaceuticals and labelled compounds, vol. 1. International Atomic Energy Agency, Vienna, p 151-167 Council of Europe (1992) Guide for the preparation, use and quality assurance of blood components. Strasbourg... 

Millar AM (1989) Quality assurance of radiopharmaceuticals In Theobald AE (ed) Radiopharmaceuticals using radioactive compounds in pharmaceutics and medicine. Horwood, Chichester, pp 83-102... 

The manufacturing and handling of radiopharmaceuticals is potentially hazardous. The types of radiation emitted and the half-lives of the radioactive isotopes are parameters contributing to the level of risk. Particular attention must be paid to the prevention of cross-contamination, to the retention of radionuclide contaminants, and to waste disposal. Special consideration may be necessary with reference to the small batch sizes made frequently for many radiopharmaceuticals. Due to their short half-life some radiopharmaceuticals are released before completion of certain Quality Control tests. In this case, the continuous assessment of the effectiveness of the Quality Assurance system becomes very important. 

Kabalka, G.W. and Goodman, M.M. (1991). Synthesis of radiopharmaceuticals via organohoranes. In (ed. A.M. Emram), New Trends in Radiopharmaceutical Synthesis, Quality Assurance and Regulatory Control. Plenum Press, New York, NY. 

Meyer, G., Coenen, H.H., Waters, S. et al. (1993). Quality assurance and quality control of short-lived radiopharmaceuticals for PET. In (eds G. Stocklin and V. Pike), Radiopharmaceuticals for Positron Emission Tomography. Kluwer Academic Publishers, Boston, MA, pp. 91-130. 

Annex 3 (Manufacture of Radiopharmaceuticals) is the only part of the GMP framework entirely dedicated to radiopharmaceuticals [10]. Preparation of radiopharmaceuticals using authorised generators and kits is excluded from this Annex. The production of radionuclides in reactors and cyclotrons is a physical process and is regarded as a non-GMP activity. Annex 3 describes general GMP principles (quality assurance, personnel, premises and equipment, documentation, production, quality control, reference and retention samples, distribution) in relation to radiopharmaceuticals. As with other medicinal products, other GMP annexes may be applicable, for instance Annex 1 Manufacture of Sterile Medicinal Products [11]. 

It is not easy to interpret aU above mentimied legislatimi and to give uniform guidance for each country and each situatimi. The determination of adequate quality assurance measures, for example the GMP-classificati(Mi of the clean room, should be the result of a risk assessment [20]. Table 15.2 gives a practical overview of the applicable guidance and the appropriate quality assurance level when preparing radiopharmaceuticals. 

Table 15.2 Overview of the guidance and main quality assurance issues of the different steps in the extemporaneous preparation of radiopharmaceuticals ...

The quality assurance and quality control of commercially available radionuclides, non-radioactive labelling kits and ready-to-use radiopharmaceuticals as well as their release are the responsibility of the manufacturer. 

The quality assurance, quality control and release of radiopharmaceuticals prepared in the radiopharmacy and their radionuclide precursors are the responsibility of the radiopharmacist. 

As for manufacturing of other pharmaceuticals, a system should be established to verify the quality of the starting materials used in manufacturing radiopharmaceuticals. This system must assure that no material is used for production until it has been released by a competent person [qualified person (QP) or others given this responsibility]. 

Short-lived radiopharmaceuticals have to be manufactured, quality-tested, and dispensed within a short time, adding constraint on safety procedures. In order to comply with the strict requirements of GMP, special methods for synthesis and in process quality control have been developed, assuring high quality of radiopharmaceuticals, without actually testing sterility and apyrogenicity before dispensing the labeled product. 

The quality of radiopharmaceuticals must be assured and a system designed, documented, implemented, and controlled, to give a product appropriate for the intended use. 

Several European centers were engaged in implementing GMP standards for the preparation of " Tc radiopharmaceuticals in nuclear medicine, and thus have contributed to establish a protocol for analytical procedures, which can validate the performance of generator systems from different manufacturers and assure the quality of short-lived generator eluates. The protocol is presented in Appendix A1 of this chapter. 

The scientific goal of Working Group 1(a) has been the development and updating of quality control methods to assure safety of Tc radiopharmaceuticals for parenteral application in nuclear medicine. Scientific institutions in 12 European countries have contributed their experience and results for comparison of the available analytical methods. Some results are presented in the monographs. 

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