Changes from plenary report to adopted text

Addeda) 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.

AddedFor radio-nuclides, the nuclear reactions involved shall be discussed.

AddedIn a generator, both mother and daughter radio-nuclides shall be considered as active substances.

Addedb) 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.

Addedc) Starting materials include irradiation target materials.

Addedd) Considerations on chemical/radiochemical purity and its relationship to bio-distribution shall be provided.

Addede) Radio-nuclide purity, radiochemical purity and specific activity shall be described.

Addedf) 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.

Addedg) The requirement to express the content of active substances in terms of the mass of active entities shall only apply 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.

Addedh) 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.

Addedi) 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.

AddedModule 4

AddedIt 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.

AddedModule 5

AddedThe results of clinical trials shall be provided where applicable otherwise justified in the clinical overviews.

Added2.2. Radio-pharmaceutical precursors for radio-labelling purposes

AddedIn 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.

AddedIn particular, the following information where applicable shall be provided:

AddedModule 3

AddedThe provisions of Module 3 shall apply to the registration of radio-pharmaceutical precursors as define above (indents a) to i)), where applicable.

AddedModule 4

AddedConcerning 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.

AddedMutagenicity studies on the radio-nuclide are not considered to be useful in this particular case.

AddedInformation relating to the chemical toxicity and disposition of the relevant ‘cold’ nuclide shall be presented.

AddedModule 5

AddedClinical 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.

AddedHowever, information demonstrating the clinical utility of the radio-pharmaceutical precursor when attached to relevant carrier molecules shall be presented.

Added3. HOMEOPATHIC MEDICINAL PRODUCTS

AddedThis section sets out specific provisions on the application of Modules 3 and 4 to homeopathic medicinal products as defined in Article 1(5).

AddedModule 3

AddedThe provisions of Module 3 shall apply to the documents submitted in accordance with Article 15 in the simplified registration of homeopathic medicinal products referred to in Article 14(1) as well as to the documents for authorisation of other homeopathic medicinal products referred to in Article 16(1) with the following modifications.

Addeda) Terminology

AddedThe Latin name of the homeopathic stock described in the marketing authorisation application dossier must be in accordance with the Latin title of the European Pharmacopoeia or, in absence thereof, by an official pharmacopoeia of a Member State. Where relevant the traditional name(s) used in each Member State shall be provided.

Addedb) Control of starting materials

AddedThe particulars and documents on the starting materials, i.e. all of the materials used including raw materials and intermediates up to the final dilution to be incorporated into the finished medicinal product, accompanying the application shall be supplemented by additional data on the homeopathic stock.

AddedThe general quality requirements shall apply to all of the starting and raw materials as well as intermediate steps of the manufacturing process up to the final dilution to be incorporated into the finished medicinal product. If possible, an assay is required if toxic components are present and if the quality cannot be controlled on final dilution to be incorporated because of the high dilution degree. Every step of the manufacturing process from the starting materials up to the final dilution to be incorporated into the finished medicinal product must be fully described.

AddedIn case dilutions are involved, these dilution steps should be done in accordance with the homeopathic manufacturing methods laid down in the relevant monograph of the European Pharmacopoeia or, in absence thereof, by an official pharmacopoeia of a Member State.

Addedc) Control tests on the finished medicinal product

AddedThe general quality requirements shall apply to the homeopathic finished medicinal products, any exception needs to be duly justified by the applicant.

AddedIdentification and assay of all the toxicologically relevant constituents shall be carried out. If it can be justified that an identification and/or an assay on all the toxicologically relevant constituents is not possible e.g. due to their dilution in the finished medicinal product the quality shall be demonstrated by complete validation of the manufacturing and dilution process.

Addedd) Stability tests

AddedThe stability of the finished medicinal product must be demonstrated. Stability data from the homeopathic stocks are generally transferable to dilutions/triturations obtained thereof. If no identification or assay of the active substance is possible due to the degree of dilution, stability data of the pharmaceutical form may be considered.

AddedModule 4

AddedThe provisions of Module 4 shall apply to the simplified registration of homeopathic medicinal products referred to in Article 14(1) with the following specifications.

AddedAny missing information must be justified, e.g., justification must be given why demonstration of an acceptable level of safety can be supported although some studies are lacking.

Added4. HERBAL MEDICINAL PRODUCTS

AddedApplications for herbal medicinal products shall provide a full dossier in which the following specific details shall be included.

AddedModule 3

AddedThe provisions of Module 3, including compliance with monograph(s) of the European Pharmacopoeia, shall apply to the authorisation of herbal medicinal products. The state of scientific knowledge at the time when the application is lodged shall be taken into account.

AddedThe following aspects specific to herbal medicinal products shall be considered:

Added(1) H e r b a l s u b s t a n c e s a n d h e r b a l p r e p a r a t i o n s

AddedFor the purposes of this Annex the terms ‘herbal substances and preparations’ shall be considered equivalent to the terms ‘herbal drugs and herbal drug preparations’, as defined in the European Pharmacopoeia.

AddedWith respect to the nomenclature of the herbal substance, the binomial scientific name of plant (genus, species, variety and author), and chemotype (where applicable), the parts of the plants, the definition of the herbal substance, the other names (synonyms mentioned in other Pharmacopoeias) and the laboratory code shall be provided.

AddedWith respect to the nomenclature of the herbal preparation, the binomial scientific name of plant (genus, species, variety and author), and chemotype (where applicable), the parts of the plants, the definition of the herbal preparation, the ratio of the herbal substance to the herbal preparation, the extraction solvent(s), the other names (synonyms mentioned in other Pharmacopoeias) and the laboratory code shall be provided.

AddedTo document the section of the structure for herbal substance(s) and herbal preparation(s) where applicable, the physical form, the description of the constituents with known therapeutic activity or markers (molecular formula, relative molecular mass, structural formula, including relative and absolute stereo-chemistry, the molecular formula, and the relative molecular mass) as well as other constituent(s) shall be provided.

AddedTo document the section on the manufacturer of the herbal substance, the name, address, and responsibility of each supplier, including contractors, and each proposed site or facility involved in production/collection and testing of the herbal substance shall be provided, where appropriate.

AddedTo document the section on the manufacturer of the herbal preparation, the name, address, and responsibility of each manufacturer, including contractors, and each proposed manufacturing site or facility involved in manufacturing and testing of the herbal preparation shall be provided, where appropriate.

AddedWith respect to the description of manufacturing process and process controls for the herbal substance, information shall be provided to adequately describe the plant production and plant collection, including the geographical source of the medicinal plant and cultivation, harvesting, drying and storage conditions.

AddedWith respect to the description of manufacturing process and process controls for the herbal preparation, information shall be provided to adequately describe the manufacturing process of the herbal preparation, including description of the processing, solvents and reagents, purification stages and standardisation.

AddedWith respect to the manufacturing process development, a brief summary describing the development of the herbal substance(s) and herbal preparation(s) where applicable shall be provided, taking into consideration the proposed route of administration and usage. Results comparing the phyto-chemical composition of the herbal substance(s) and herbal preparation(s) where applicable used in supporting bibliographic data and the herbal substance(s) and herbal preparation(s), where applicable, contained as active substance(s) in the herbal medicinal product applied for shall be discussed, where appropriate.