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Textual Amendments
This Part lays down specific requirements related to the nature of identified medicinal products.
For medicinal products derived from human blood or plasma and by derogation from the provisions of Module 3, the dossier requirements mentioned in ‘ Information related to the starting and raw materials ’ , for starting materials made of human blood/plasma may be replaced by a Plasma Master File certified in accordance with this Part.
For the purposes of this Annex:
Plasma Master File shall mean a stand-alone documentation, which is separate from the dossier for marketing authorisation which provides all relevant detailed information on the characteristics of the entire human plasma used as a starting material and/or a raw material for the manufacture of sub/intermediate fractions, constituents of the excipient and active substance(s), which are part of medicinal products or medical devices referred to in Directive 2000/70/EC of the European Parliament and of the Council of 16 November 2000 amending Council Directive 93/42/EC as regards medical devices incorporating stable derivatives of human blood or human plasma (1) .
Every centre or establishment for fractionation/processing of human plasma shall prepare and keep updated the set of detailed relevant information referred to in the Plasma Master File.
The Plasma Master File shall be submitted to the Agency or to the competent authority by the applicant for a marketing authorisation or the holder of the marketing authorisation. Where the applicant for a marketing authorisation or the marketing authorisation holder differs from the holder of the Plasma Master File, the Plasma Master File shall be made available to the applicant or marketing authorisation holder for submission to the competent authority. In any case, the applicant or marketing authorisation holder shall take responsibility for the medicinal product.
The competent authority that is evaluating the marketing authorisation shall await for the Agency to issue the certificate before deciding on the application.
Any marketing authorisation dossier containing a human plasma-derived constituent shall refer to the Plasma Master File corresponding to the plasma used as a starting/raw material.
In accordance with the provisions of Article 109, as amended by Directive 2002/98/EC, which refers to the requirements for donors and the testing of donations, the Plasma Master File shall include information on the plasma used as starting/raw material, in particular:
Plasma origin
information on centres or establishments in which blood/plasma collection is carried out, including inspection and approval, and epidemiological data on blood transmissible infections.
information on centres or establishments in which testing of donations and plasma pools is carried out, including inspection and approval status.
selection/exclusion criteria for blood/plasma donors.
system in place which enables the path taken by each donation to be traced from the blood/plasma collection establishment through to finished products and vice versa.
Plasma quality and safety
compliance with European Pharmacopoeia Monographs.
testing of blood/plasma donations and pools for infectious agents, including information on test methods and, in the case of plasma pools, validation data on the tests used.
technical characteristics of bags for blood and plasma collection, including information on anticoagulants solutions used.
conditions of storage and transport of plasma.
procedures for any inventory hold and/or quarantine period.
characterisation of the plasma pool.
System in place between the plasma-derived medicinal product manufacturer and/or plasma fractionator/processor on the one hand, and blood/plasma collection and testing centres or establishments on the other hand, which defines the conditions of their interaction and their agreed specifications.
In addition, the Plasma Master File shall provide a list of the medicinal products for which the Plasma Master File is valid, whether the medicinal products have been granted a marketing authorisation or are in the process of being granted such an authorisation, including medicinal products referred to in Article 2 of Directive 2001/20/EC of the European Parliament and of the Council relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.
For medicinal products not yet authorised, the marketing authorisation applicant shall submit a full dossier to a competent authority, which shall be accompanied by a separate Plasma Master File where one does not already exist.
The Plasma Master File is subject to a scientific and technical evaluation carried out by the Agency. A positive evaluation shall result in a certificate of compliance with Community legislation for the Plasma Master File, which shall be accompanied by the evaluation report. The certificate issued shall apply throughout the Community.
The Plasma Master File shall be updated and re-certified on an annual basis.
Changes subsequently introduced to the terms of a Plasma Master File must follow evaluation procedure laid down by Commission Regulation (EC) No 542/95 (2) concerning the examination of variations to the terms of a marketing authorisation falling within the scope of Council regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products (3) . Conditions for the assessment of these changes are laid down by Regulation (EC) No 1085/2003.
As a second step to the provisions in the first, second, third and fourth indents, the competent authority that will grant or has granted the marketing authorisation shall take into account the certification, re-certification or variation of the Plasma Master File on the concerned medicinal product(s).
By derogation from the provisions of the second indent of the present point (evaluation and certification), where a Plasma Master File corresponds only to blood/plasma-derived medicinal products the marketing authorisation of which is restricted to a single Member State, the scientific and technical evaluation of the said Plasma Master File shall be carried out by the national competent authority of that Member State.
For vaccines for human use and by derogation from the provisions of Module 3 on ‘ Active substance(s) ’ , the following requirements when based on the use of a Vaccine Antigen Master File system shall apply.
The marketing authorisation application dossier of a vaccine other than human influenza vaccine, shall be required to include a Vaccine Antigen Master File for every vaccine antigen that is an active substance of this vaccine.
For the purposes of this Annex:
Vaccine Antigen Master File shall mean a stand-alone part of the marketing authorisation application dossier for a vaccine, which contains all relevant information of biological, pharmaceutical and chemical nature concerning each of the active substances, which are part of this medicinal product. The stand-alone part may be common to one or more monovalent and/or combined vaccines presented by the same applicant or marketing authorisation holder.
A vaccine may contain one or several distinct vaccine antigens. There are as many active substance(s) as vaccine antigen(s) present in a vaccine.
A combined vaccine contains at least two distinct vaccine antigens aimed at preventing a single or several infectious diseases.
A monovalent vaccine is a vaccine, which contains one vaccine antigen aimed at preventing a single infectious disease.
The Vaccine Antigen Master File shall contain the following information extracted from the relevant part (Active substance) of Module 3 on ‘ Quality Data ’ as delineated in Part I of this Annex:
Active Substance
General Information, including compliance with the relevant monograph(s) of the European Pharmacopoeia.
Information on the manufacture of the active substance: this heading must cover the manufacturing process, information on the starting and raw materials, specific measures on TSEs and adventitious agents safety evaluation and facilities and equipment.
Characterisation of the active substance
Quality control of the active substance
Reference standard and materials
Container and closure system of the active substance
Stability of the active substance.
For novel vaccines, which contain a novel vaccine antigen, the applicant shall submit to a competent authority a full marketing-authorisation application dossier including all the Vaccine Antigen Master Files corresponding to each single vaccine antigen that is part of the novel vaccine where no master file already exists for the single vaccine antigen. A scientific and technical evaluation of each Vaccine Antigen Master File shall be carried out by the Agency. A positive evaluation shall result in a certificate of compliance to the European legislation for each Vaccine Antigen Master File, which shall be accompanied by the evaluation report. The certificate shall apply throughout the Community.
The provisions of the first indent shall also apply to every vaccine, which consists of a novel combination of vaccine antigens, irrespective of whether or not one or more of these vaccine antigens are part of vaccines already authorised in the Community.
Changes to the content of a Vaccine Antigen Master File for a vaccine authorised in the Community shall be subject to a scientific and technical evaluation carried out by the Agency in accordance with the procedure laid down in Commission Regulation (EC) No 1085/2003. In the case of a positive evaluation the Agency shall issue a certificate of compliance with Community legislation for the Vaccine Antigen Master File. The certificate issued shall apply throughout the Community.
By derogation from the provisions of the first, second and third indents of the present point (evaluation and certification), where a Vaccine Antigen Master File corresponds only to a vaccine which is the subject of a marketing authorisation which has not been/will not be granted according to a Community procedure, and, provided the authorised vaccine includes vaccine antigens which have not been evaluated through a Community procedure, the scientific and technical evaluation of the said Vaccine Antigen Master File and its subsequent changes, shall be carried out by the national competent authority that has granted the marketing authorisation.
As a second step to the provisions in the first, second, third and fourth indents, the competent authority that will grant or has granted the marketing authorisation shall take into account the certification, re-certification or variation of the Vaccine Antigen Master File on the concerned medicinal product(s).
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.
This section sets out specific provisions on the application of Modules 3 and 4 to homeopathic medicinal products as defined in Article 1(5).
The 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.
Terminology
The 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.
Control of starting materials
The 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.
The 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.
In case dilutions are involved, these dilution steps should be done in accordance with the homeopathicmanufacturing methods laid down in the relevant monograph of the European Pharmacopoeia or, in absence thereof, by an official pharmacopoeia of a Member State.
Control tests on the finished medicinal product
The general quality requirements shall apply to the homeopathic finished medicinal products, any exception needs to be duly justified by the applicant.
Identification 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.
Stability tests
The 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.
The provisions of Module 4 shall apply to the simplified registration of homeopathic medicinal products referred to in Article 14(1) with the following specifications.
Any 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.
Applications for herbal medicinal products shall provide a full dossier in which the following specific details shall be included.
The 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.
The following aspects specific to herbal medicinal products shall be considered:
For 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.
With respect to the nomencRlature 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.
With 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.
To 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.
To 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.
To 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.
With 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.
With 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.
With 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.
With respect to the elucidation of the structure and other characteristics of the herbal substance, information on the botanical, macroscopical, microscopical, phyto-chemical characterisation, and biological activity if necessary, shall be provided.
With respect to the elucidation of the structure and other characteristics of the herbal preparation, information on the phyto- and physicochemical characterisation, and biological activity if necessary, shall be provided.
The specifications for the herbal substance(s) and herbal preparation(s) where applicable shall be provided.
The analytical procedures used for testing the herbal substance(s) and herbal preparation(s) where applicable shall be provided.
With respect to the validation of analytical procedures, analytical validation information, including experimental data for the analytical procedures used for testing the herbal substance(s) and herbal preparation(s) where applicable shall be provided.
With respect to batch analyses, description of batches and results of batch analyses for the herbal substance(s) and herbal preparation(s) where applicable shall be provided, including those for pharmacopoeial substances.
Justification for the specifications of the herbal substance(s) and herbal preparation(s) where applicable shall be provided.
Information on the reference standards or reference materials used for testing of the herbal substance(s) and herbal preparation(s) where applicable shall be provided.
Where the herbal substance or the herbal preparation is the subject of a monograph, the applicant can apply for a certificate of suitability that was granted by the European Directorate for the Quality of Medicines.
With respect to the formulation development, a brief summary describing the development of the herbal medicinal product should be provided, taking into consideration the proposed route of administration and usage. Results comparing the phyto-chemical composition of the products used in supporting bibliographic data and the herbal medicinal product applied for shall be discussed, where appropriate.
In the case of an orphan medicinal product in the meaning of Regulation (EC) No 141/2000, general provisions of Part II-6 (exceptional circumstances) can be applied. The applicant shall then justify in the non-clinical and clinical summaries the reasons for which it is not possible to provide the complete information and shall provide a justification of the benefit/risk balance for the orphan medicinal product concerned.
When an applicant for an marketing authorisation for an orphan medicinal product invokes the provisions of Article 10 (1)(a)(ii) and Part II-1 of this Annex (well-established medicinal use), the systematic and documented use of the concerned substance can refer — as way of derogation — to the use of that substance in accordance with the provisions of Article 5 of this Directive.]