Textual Amendments
For the purposes of this chapter, applications based upon Articles 6 (2) and 9 shall provide a full dossier in which the following specific details shall be included:
In the context of a radio-pharmaceutical kit, which is to be radio-labelled after supply by the manufacturer, the active substance is considered to be that part of the formulation which is intended to carry or bind the radio-nuclide. The description of the manufacturing method of radio-pharmaceutical kits shall include details of the manufacture of the kit and details of its recommended final processing to produce the radioactive medicinal product. The necessary specifications of the radio-nuclide shall be described in accordance, where relevant, with the general monograph or specific monographs of the European Pharmacopoeia . In addition, any compounds essential for the radio-labelling shall be described. The structure of the radio-labelled compound shall also be described.
For radio-nuclides, the nuclear reactions involved shall be discussed.
In a generator, both mother and daughter radio-nuclides shall be considered as active substances.
Details of the nature of the radio-nuclide, the identity of the isotope, likely impurities, the carrier, the use and the specific activity shall be provided.
Starting materials include irradiation target materials.
Considerations on chemical/radiochemical purity and its relationship to bio-distribution shall be provided.
Radio-nuclide purity, radiochemical purity and specific activity shall be described.
For generators, details on the testing for mother and daughter radio-nuclides are required. For generator-eluates, tests for mother radio-nuclides and for other constituents of the generator system shall be provided.
The requirement to express the content of active substances in terms of the mass of active entities shall onlyapply to radio-pharmaceutical kits. For radio-nuclides, radioactivity shall be expressed in Becquerels at a given date and, if necessary, time with reference to time zone. The type of radiation shall be indicated.
For kits, the specifications of the finished product shall include tests on performance of products after radio-labelling. Appropriate controls on radiochemical and radio-nuclidic purity of the radio-labelled compound shall be included. Any material essential for radio-labelling shall be identified and assayed.
Information on stability shall be given for radio-nuclide generators, radio-nuclide kits and radio-labelled products. The stability during use of radio-pharmaceuticals in multi-dose vials shall be documented.
It is appreciated that toxicity may be associated with a radiation dose. In diagnosis, this is a consequence of the use of radio-pharmaceuticals; in therapy, it is the property desired. The evaluation of safety and efficacy of radio-pharmaceuticals shall, therefore, address requirements for medicinal products and radiation dosimetry aspects. Organ/tissue exposure to radiation shall be documented. Absorbed radiation dose estimates shall be calculated according to a specified, internationally recognised system by a particular route of administration.
The results of clinical trials shall be provided where applicable otherwise justified in the clinical overviews.
In the specific case of a radio-pharmaceutical precursor intended solely for radio-labelling purposes, the primary objective shall be to present information which would address the possible consequences of poor radio-labeling efficiency or in vivo dissociation of the radio-labeled conjugate, i.e. questions related to the effects produced in the patient by free radio-nuclide. In addition, it is also necessary to present relevant information relating to occupational hazards, i.e. radiation exposure to hospital staff and to the environment.
In particular, the following information where applicable shall be provided:
The provisions of Module 3 shall apply to the registration of radio-pharmaceutical precursors as define above (indents a) to i)), where applicable.
Concerning single dose and repeat dose toxicity, the results of studies carried out in conformity with the provisions related to good laboratory practice laid down in Council Directives 87/18/EEC and 88/320/EEC shall be provided, unless otherwise justified.
Mutagenicity studies on the radio-nuclide are not considered to be useful in this particular case.
Information relating to the chemical toxicity and disposition of the relevant ‘ cold ’ nuclide shall be presented.
Clinical information generated from clinical studies using on the precursor itself is not considered to be relevant in the specific case of a radio-pharmaceutical precursor intended solely for radio-labelling purposes.
However, information demonstrating the clinical utility of the radio-pharmaceutical precursor when attached to relevant carrier molecules shall be presented.]