RADIOPHARMACEUTICALS - Europa

1 175_____3AQ20a nRADIOPHARMACEUTICALSG uideline TitleRadiopharmaceuticalsLegislative basisDirectives 65/65/EEC, 75/318/EEC as amended, Directive89/343/EECDate of first adoptionDecember 1990 Date of entry intoforceJune 1991 StatusLast revised December 1990 Previous titles/otherreferencesNone/III/3936/89 Additional NotesThis note for guidance concerns the application toradiopharmaceuticals of Directive 65/65/EEC and of parts2, 3 and 4 of the Annex to Directive 75/318/EEC asamended, with a view to the granting of a marketingauthorisation for a , BIOLOGICAL OR MICROBIOLOGICAL TESTS OFMEDICINAL AND PHARMACOLOGICAL AND PACKAGING177_____3AQ20a for marketing authorisation in respect of RADIOPHARMACEUTICALS should beaccompanied, as in the case of all medicinal products, by the particulars and documentsreferred to in Directives 65/65/EEC and 75/319/EEC, as amended, and in the Annex ofDirective 75/318/EEC as amended.

2 The provisions of Directive 89/343/EEC also apply. Therelevant provisions of the European Pharmacopoeia should be observed. Due account must betaken of the other relevant CPMP RADIOPHARMACEUTICALS are used for the purpose of medical diagnosis. They are usuallygiven only once, or sometimes on a few occasions, and contain only small amounts of theactive substances with a radionuclide attached to them to allow scintigraphic imaging ormeasurement of biodistribution. Such RADIOPHARMACEUTICALS do not often show a n ymeasurable pharmacodynamic effect. Radiation is a general property of a l lradiopharmaceuticals, which when administered give the patient an inevitable radiationdose. In the case of therapeutic RADIOPHARMACEUTICALS , the radiation effect is the wantedproperty. Evaluation of the safety and efficacy of RADIOPHARMACEUTICALS should includeradiopharmaceutical and radiation hygiene aspects and radiation dosimetry in addition togeneral have changing composition with time, associated with the radioactivedecay.

3 The physical half-life of the radionuclide is often so short that, in these cases, thefinal preparation has to be done immediately before administration to the patient; this leadsto the use of semi-manufactured products such as radionuclide generators, precursors andkits. Evaluation of the safety and efficacy of RADIOPHARMACEUTICALS is also concerned withthe specifications of generators, kits and other semi-manufactured products. Specificationsmay also require special attention in cases where samples from the patient are labelled witha radioactive substance before readministration (precursor RADIOPHARMACEUTICALS ). Whenradiopharmaceuticals go directly from the generator to the patient ( ultra short-livedradioactive gases), the consistency of the production process has a particularly note for guidance covers the following products: ready-for-use RADIOPHARMACEUTICALS ; non-radioactive components (kits) for combination with a radioactive component(usually the eluate from a radionuclide generator); radionuclide generators; precursors used for radiolabelling other substances prior to administration( samples from patients).

4 178n , BIOLOGICAL OR MICROBIOLOGICALTESTS OF MEDICINAL Qualitative and quantitative particulars of the constituents anddevelopment pharmaceuticsFor the radionuclides, details must be given of their source, whether fission or targetmaterial is should be expressed in Bequerels at a given date, and hour in appropriate cases(other units may be added). If a calibration time is stated, the time zone used should be stated( GMT/CET).Where practicable, the proportion (specific activity, carrier free or carrier added) of inactiveisotopes in the carrier should be radiopharmaceutical kits, any added compound ( stannous salt for reduction ofpertechnetate ions in the eluate from a technetium 99mTc generator) and manipulationessential for radiolabelling should be applicable, evidence to confirm the efficacy and specificity of the radiolabelling of thelabelling medium ( 99mTc) should be supplied.

5 A discussion of the necessaryspecification ( purity, pH) of radiolabelling medium should be stated for radiolabelling, the compatibility of the product with the containers and closures shouldbe considered and validated where Description of method of preparationBecause of the complexity of the production of RADIOPHARMACEUTICALS , it is important thatmethods for obtaining and maintaining sterility during manufacture ( preparation andassembly) are adequately described. Information should be given on validation of )Radiopharmaceutical kits: the instructions for final preparation should include: minimum and maximum for both volume and amount of radioactivity to beadded; any special quality requirement for the radiolabelling medium; the standing time and any other manipulation necessary during finalpreparation (detailed and justified); details supporting recommendations on quality control procedures such aschecking radiochemical purity of the prepared radiopharmaceutical prior toadministration.

6 As relevant, data on stability of particles ( of colloidal size) afterreconstitution and justification for the quantity of added aspects should be discussed and documented adequately in the DevelopmentPharmaceutics part of the )GeneratorsThe recommendations for use of the generators should be discussed and nc )PrecursorsThe recommendations for use of the precursors should be discussed and Control of starting materialsFor the purposes of this section starting materials shall mean all the constituents of themedicinal product, if necessary, all the constituents of its containers and closures and whereapplicable, all constituents of the radionuclide source and any other materials used in thefinal process prior to administration. A full description is required of the separation ofradionuclides and the control of radionuclide purity, as well as specific activity (with respectto impurities and degradation products).

7 Specifications of components of the container(including the name of the approved producers) should be given. Specifications of anyradiation shielding of the finished products should also be some RADIOPHARMACEUTICALS , it is difficult to distinguish between control of startingmaterials and control of the finished product. For such products, all the information shouldpreferably be placed in the section Control tests on the finished product . Control tests on the finished productFor products intended for intrathecal injection, regardless of volume, an appropriateendotoxin test is required unless its omission can be fully and adequately terminally-sterilised products, process parameter release* (sometimes called parametricrelease) could well be justified. In the case of an aseptically-assembled product a sterility testis some RADIOPHARMACEUTICALS it may not be possible to obtain the results of certain tests, sterility test, pyrogenicity tests, before the product is released.

8 However, these tests shouldbe done as a monitor for the manufacturing and actual impurities should be considered not only for any direct effect on thepatient but also for their possible influence on the radiochemical purity or biodistribution ofthe Stability testsFor all RADIOPHARMACEUTICALS , the shelf life of the product as supplied by the manufacturershould be specified and justified, as should a shelf life after reconstitution where applicable,taking into account radiochemical and radionuclide degradation radiopharmaceutical kits, the shelf life of the prepared product should be defined; in thiscase, data should be submitted which detail the minimum and maximum levels ofradioactivity (and maximum and minimum volumes) and other relevant factors that arerecommended for use in the preparation of the product to be administered to the RADIOPHARMACEUTICALS prepared in multiple-dose vials, the stability following removal ofsuccessive doses should be discussed.

9 * For the purpose of this guideline, process parameter release is defined as the decision to release a batch ofproduct for sale or supply based on an assessment of measured and recorded information relating to thevalidation , maintenance, operation and control of a process. 180n and Pharmacological TestsIt is appreciated that toxicity may be associated with a radiation dose. This toxicity is aconsequence of the use of RADIOPHARMACEUTICALS in diagnosis and the wanted property ofradiopharmaceuticals used in therapy. The evaluation of safety and efficacy ofradiopharmaceuticals should, therefore, address both general parameters of the medicinalproduct and radiation dosimetry studies should be designed to examine the chemical rather than the radiationaspects of of the toxicology of the ligand per se is of value.

10 However, if the radiolabel i slikely to produce chemical changes in the ligand, it would be preferable to carry out thetoxicity studies on material in which radioactive decay has proceeded for long enough as toexpose the test animals to breakdown products as well as to the parent other RADIOPHARMACEUTICALS , consideration should be given to ascertaining the toxicity ofthe parent molecule, either by reacting the ligand with a non-radioactive isotope of theelement in question, or, if appropriate, by allowing decay of the product to occur so that thereis no significant residual the strategy and method chosen, it should be and elimination studies should be performed with the labelled no-carrier-added radioactive elements and simple salts thereof, if the toxicity of theelement or simple salt is known and can be submitted in the application, no additionaltoxicity studies would normally be contents in many final preparations ( kit preparations) may be so small that is m a ybe justified to use a bulk preparation for toxicity testing but the stability of the bulk materialover the period of testing should be validated.