Radiopharmaceuticals quality control

Typical validation for radiochemical and radiopharmaceutical purity. Quality control is very important to ensure the safety and efficacy of radiopharmaceuticals. One important quality parameter is the radiochemical purity of the radiolabeled product. This is defined as the fraction of the total radioactivity in the desired chemical form in the radiopharmaceutical [56]. Radiochemical impurities come from incomplete labeling, shift of equilibrium, radiolysis ((3 decay), temperature or pH change, exposure to light,... 

Theobald, A. E. Quality control of radiopharmaceuticals. In Textbook of Radiopharmacology Theory and Practice. New York Gordon Breach, 1990, pp 115-148. 

E. J. Knust, H.J. Machulla, C. Astfalk, Radiopharmaceuticals V F-Labeling with water target produced fluorine-18—Synthesis and quality control of 6- F-nicotinic acid diethylamide, Radiochem. Radioanal. Lett. 55 (1983) 249-255. 

Radiopharmacy comprises a rational understanding of the design, preparation, and quality control of radiopharmaceuticals, the relationship between the physicochemical and biological properties of radiopharmaceuticals and their clinical applications, as well as radiopharmaceutical chemistry and issues related to the management, selection, storage, dispensing, and proper use of radiopharmaceuticals. 

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 ... 

A PET radiopharmaceutical laboratory must include the cyclotron bunker (where positron-emitting radionuclides are produced), the production laboratory, the quality control laboratory, and several different ancillary areas. 

All quality control procedures that are applied to nonradioactive pharmaceuticals are in principle applicable to radiopharmaceuticals. In addition, tests for radio-nuclidic and radiochemical purity must be carried out. Furthermore, since radiopharmaceuticals are short-lived products, methods used for quality control should... 

Visual Inspection of Finished Product As part of the quality control, all parenter-als will be subject to an inspection for the possible content of particles. Visual inspection of radiopharmaceuticals is more complicated than for other pharmaceuticals, as radiation protection guidelines strongly discourage any direct eye contact with radioactive sources. Normally, the visual inspection of a radiopharmaceutical is performed by placing the vial on a rotating station connected to a camera. The station is properly shielded, and the operators can study the solution on a distant screen. 

Develop methods for labelling, purification and quality control of therapeutic radiopharmaceuticals for an appropriate disease model, based on suitable carrier molecules and radionuclides ... 

DOTATATE) with and lutetium ( Lu). The quality control and purification procedures are also described. Biodistribution studies were performed in normal Swiss mice and in nude mice bearing AR42J tumours. In vitro studies were used to evaluate the affinity of the radiopharmaceuticals for somatostatin receptors in rat brain cortex and tumour cells. Saturation binding and the internalization of the labelled peptides were determined. The frequency of micronuclei in peripheral blood lymphocytes exposed to different radioactive concentrations of [ IJDOTATATE and [ Lu]DOTATATE was evaluated by micronucleus assay. 

In the present study, the methodology used for labelling DOTATATE with and Lu is described, along with the purification and quality control procedures. In vitro methods and in vivo procedures were also applied to elucidate the biodistribution of radiopharmaceuticals and their affinity for somatostatin receptors. 

ISHFAQ, M.M., HUSSAIN, N., HAIDER, I., JEHANGIR, M., i Lu potential therapeutic agent Preparation and quality control of Lii-EDTMP and Lu-DOTA-Tyr -Octreotate complexes , paper presented at 12th Eur. Symp. Radiopharmacy and Radiopharmaceuticals, Gdansk, 2004. 

The quality control tests have been categorized for PET radiopharmaceuticals into two groups those with nuclides with ty2 > 20 min and those with nuclides with ty2 < 20 min. In the case of the former, each production on a given day is considered a batch while in the latter group, a batch is defined as... 

In the above section, requirements for compounding of PET radiopharmaceuticals have been presented. In this section, the methods of quality control tests for these products are briefly described below. Since PET radiopharmaceuticals are short-lived, some lengthy tests cannot be performed prior to release for human use and so they are performed within a short time after the release. 

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. 

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. 

Determination of Sn(ll) (Quality Control). Determination of the Sn(ll) content in radiopharmaceutical kits is an important aspect of quality control for commercial producers and registration authorities (Rakias and Zolle 1997). Classical methods for the determination of Sn(II) involve titrimetric, electrochemical, spectrophotometric, and chromatographic methods (Lejeune et al. 1996). 

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

Good manufacturing practice (GMP) is that part of QA that is aimed at ensuring that radiopharmaceuticals are consistently manufactured or prepared and handled in hospitals to a quality appropriate to their intended use (Kristensen 1979 Nordic Council on Medicines 1989). It is concerned -with both manufacture or preparation in hospitals, and quality control (QC). The principles and guidelines of GMP for medicinal products have been laid do-wn in Council Directive 91/356/EEC, presented in volume IV of the European Regulations (European Economic Community 1997). 

Nordic Council on Medicines (1989) Radiopharmacy preparation and control of radiopharmaceuticals 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... 

The determination of the radiochemical purity of radiopharmaceuticals by ITLC requires an experienced operator to produce accurate results. Quality control should be performed daily and not on demand, when abnormal distribution or poor image quality is reported. 

Electrophoresis has been used for quality control of certain radiopharmaceuticals (Belkas and Archimandritis 1979 Pauwels and Feitsma 1979). Paper electrophoresis has been applied successfully for the determination of the relative charge on some Tc complexes. 

Belkas EP, Archimandritis S (1979) Quality control of colloid and particulate " Tc-labelled radiopharmaceuticals. Eur J Nucl Med 4 375... 

Radiopharmaceutical kits for labeling with Tc eluate contain tin(II)-ion for reduction of sodium pertechnetate to lower valency states, which are chemically reactive. Tin(II) salts are easily oxidized, even by the oxygen in air. Certain chemicals are also assumed to enhance the oxidation of tin(II) to tin(IV). Therefore, determination of tin(II) in radiopharmaceutical kits is an important aspect of quality control. 

Kristensen K (1979) Preparation and control of radiopharmaceuticals in hospitals. Technical Reports Series No. 194. International Atomic Energy Agency, Vienna Kristensen K, Muller T, Rhodes BA (1977) Good radiopharmacy practice, quality control in nuclear medicine. Mosby, St. Louis, Mo., pp 268-275... 

Zimmer AM, Pavel DG (1977) Rapid miniaturized chromatographic quality control procedures for Tc-99m radiopharmaceuticals. J Nucl Med 18 1230... 

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. 

---