Textual Amendments
However, where a material in the European Pharmacopoeia or in the pharmacopoeia of a Member State has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described. In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the marketing authorisation holder. The competent authorities shall inform the authorities responsible for the pharmacopoeia in question. The marketing authorisation holder shall provide the authorities of that pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.
In the case of analytical procedures included in the European Pharmacopoeia, this description shall be replaced in each relevant section by the appropriate detailed reference to the monograph(s) and general chapter(s).
detailed description of the manufacturing process,
quality control during manufacture, and
process validation
to be supplied in a separate document directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File.
In this case, the manufacturer shall, however, provide the applicant with all of the data, which may be necessary for the latter to take responsibility for the medicinal product. The manufacturer shall confirm in writing to the applicant that he shall ensure batch to batch consistency and not modify the manufacturing process or specifications without informing the applicant. Documents and particulars supporting the application for such a change shall be supplied to the competent authorities; these documents and particulars will be also supplied to the applicant when they concern the open part of the active substance master file.
Special attention shall be paid to the following selected elements.
Information on the nomenclature of the active substance shall be provided, including recommended International Non-proprietary Name (INN), European Pharmacopoeia name if relevant, chemical name(s).
The structural formula, including relative and absolute stereo-chemistry, the molecular formula, and the relative molecular mass shall be provided. For biotechnological medicinal products if appropriate, the schematic amino acid sequence and relative molecular mass shall be provided.
A list shall be provided of physicochemical and other relevant properties of the active substance, including biological activity for biological medicinal products.
For the purposes of this Annex, starting materials shall mean all the materials from which the active substance is manufactured or extracted.
For biological medicinal products, starting materials shall mean any substance of biological origin such as micro-organisms, organs and tissues of either plant or animal origin, cells or fluids (including blood or plasma) of human or animal origin, and biotechnological cell constructs (cell substrates, whether they are recombinant or not, including primary cells).
A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing, together with the production process and its control. The following shall be considered as biological medicinal products: immunological medicinal products and medicinal products derived from human blood and human plasma as defined, respectively in paragraphs (4) and (10) of Article 1; medicinal products falling within the scope of Part A of the Annex to Regulation (EEC) No 2309/93; advanced therapy medicinal products as defined in Part IV of this Annex.
Any other substances used for manufacturing or extracting the active substance(s) but from which this active substance is not directly derived, such as reagents, culture media, foetal calf serum, additives, and buffers involved in chromatography, etc. are known as raw materials.
The description of the active substance manufacturing process represents the applicant's commitment for the manufacture of the active substance. To adequately describe the manufacturing process and process controls, appropriate information as laid down in guidelines published by the Agency shall be provided.
All materials needed in order to manufacture the active substance(s) shall be listed, identifying where each material is used in the process. Information on the quality and control of these materials shall be provided. Information demonstrating that materials meet standards appropriate for their intended use shall be provided.
Raw materials shall be listed and their quality and controls shall also be documented.
The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing shall be provided.
For biological medicinal products, the following additional requirements shall apply.
The origin and history of starting materials shall be described and documented.
Regarding the specific measures for the prevention of the Transmission of animal Spongiform Encephalopathies, the applicant must demonstrate that the active substance complies with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the Commission in the Official Journal of the European Union.
When cell banks are used, the cell characteristics shall be shown to have remained unchanged at the passage level used for the production and beyond.
Seed materials, cell banks, pools of serum or plasma and other materials of biological origin and, whenever possible, the materials from which they are derived shall be tested for adventitious agents.
If the presence of potentially pathogenic adventitious agents is inevitable, the corresponding material shall be used only when further processing ensures their elimination and/or inactivation, and this shall be validated.
Whenever possible, vaccine production shall be based on a seed lot system and on established cell banks. For bacterial and viral vaccines, the characteristics of the infectious agent shall be demonstrated on the seed. In addition, for live vaccines, the stability of the attenuation characteristics shall be demonstrated on the seed; if this proof is not sufficient, the attenuation characteristics shall also be demonstrated at the production stage.
For medicinal products derived from human blood or plasma, the origin and the criteria and procedures for collection, transportation and storage of the starting material shall be described and documented in accordance with provisions laid down in Part III of this Annex.
The manufacturing facilities and equipment shall be described.
Tests and acceptance criteria carried out at every critical step, information on the quality and control of intermediates and process validation and/or evaluation studies shall be provided as appropriate.
If the presence of potentially pathogenic adventitious agents is inevitable, the correspondent material shall be used only when further processing ensures their elimination and/or inactivation and this shall be validated in the section dealing with viral safety evaluation.
A description and discussion of the significant changes made to the manufacturing process during development and/or manufacturing site of the active substance shall be provided.
Data highlighting the structure and other characteristics of the active substance(s) shall be provided.
Confirmation of the structure of the active substance(s) based on any physico-chemical and/or immuno-chemical and/or biological methods, as well as information on impurities shall be provided.
Detailed information on the specifications used for routine control of active substance(s), justification for the choice of these specifications, methods of analysis and their validation shall be provided.
The results of control carried out on individual batches manufactured during development shall be presented.
Reference preparations and standards shall be identified and described in detail. Where relevant, chemical and biological reference material of the European Pharmacopoeia shall be used.
A description of the container and the closure system(s) and their specifications shall be provided.
The types of studies conducted, protocols used, and the results of the studies shall be summarised
Detailed results of the stability studies, including information on the analytical procedures used to generate the data and validation of these procedures shall be presented in an appropriate format
The post authorisation stability protocol and stability commitment shall be provided
A description of the finished medicinal product and its composition shall be provided. The information shall include the description of the pharmaceutical form and composition with all the constituents of the finished medicinal product, their amount on a per-unit basis, the function of the constituents of:
the active substance(s),
the constituent(s) of the excipients, whatever their nature or the quantity used, including colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances, etc.,
the constituents, intended to be ingested or otherwise administered to the patient, of the outer covering of the medicinal products (hard capsules, soft capsules, rectal capsules, coated tablets, films-coated tablets, etc.),
these particulars shall be supplemented by any relevant data concerning the type of container and, where appropriate, its manner of closure, together with details of devices with which the medicinal product will be used or administered and which will be delivered with the medicinal product.
The ‘ usual terminology ’ , to be used in describing the constituents of medicinal products, shall mean, notwithstanding the application of the other provisions in Article 8 (3) (c):
in respect of substances which appear in the European Pharmacopoeia or, failing this, in the national pharmacopoeia of one of the Member States, the main title at the head of the monograph in question, with reference to the pharmacopoeia concerned,
in respect of other substances, the international non-proprietary name (INN) recommended by the World Health Organisation, or, failing this, the exact scientific designation; substances not having an international non-proprietary name or an exact scientific designation shall be described by a statement of how and from what they were prepared, supplemented, where appropriate, by any other relevant details,
in respect of colouring matter, designation by the ‘E’ code assigned to them in Council Directive 78/25/EEC of 12 December 1977 on the approximation of the rules of the Member States concerning the colouring matters authorised for use in medicinal products (1) and/or European Parliament and Council Directive 94/36/EC of 30 June 1994 on colours for use in foodstuffs (2) .
In order to give the ‘ quantitative composition ’ of the active substance(s) of the finished medicinal products, it is necessary, depending on the pharmaceutical form concerned, to specify the mass, or the number of units of biological activity, either per dosage-unit or per unit of mass or volume, of each active substance.
Active substances present in the form of compounds or derivatives shall be designated quantitatively by their total mass, and if necessary or relevant, by the mass of active entity or entities of the molecule.
For medicinal products containing an active substance, which is the subject of an application for marketing authorisation in any Member State for the first time, the quantitative statement of an active substance, which is a salt or hydrate shall be systematically expressed in terms of the mass of the active entity or entities in the molecule. All subsequently authorised medicinal products in the Member States shall have their quantitative composition stated in the same way for the same active substance.
Units of biological activity shall be used for substances, which cannot be defined molecularly. Where an International Unit of biological activity has been defined by the World Health Organisation, this shall be used. Where no International Unit has been defined, the units of biological activity shall be expressed in such a way as to provide unambiguous information on the activity of the substances by using where applicable the European Pharmacopoeia Units.
This chapter shall be devoted to information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the intended use specified in the marketing authorisation application dossier.
The studies described in this chapter are distinct from routine control tests conducted according to specifications. Critical parameters of the formulation and process attributes that can influence batch reproducibility, medicinal product performance and medicinal product quality shall be identified and described. Additional supportive data, where appropriate, shall be referenced to the relevant chapters of Module 4 (Non Clinical Study Reports) and Module 5 (Clinical Study Reports) of the marketing authorisation application dossier.
The compatibility of the active substance with excipients as well as key physicochemical characteristics of the active substance that can influence the performance of the finished product or the compatibility of different active substances with each other in the case of combination products, shall be documented.
The choice of excipients, in particular relative to their respective functions and concentration shall be documented.
A description of the development of the finished product shall be provided, taking into consideration the proposed route of administration and usage.
Any overages in the formulation(s) shall be warranted.
As far as the physiochemical and biological properties are concerned, any parameter relevant to the performance of finished product shall be addressed and documented.
The selection and optimisation of the manufacturing process as well as differences between the manufacturing process(es) used to produce pivotal clinical batches and the process used for manufacturing the proposed finished medicinal product shall be provided.
The suitability of the container and closure system used for the storage, shipping and use of the finished product shall be documented. A possible interaction between medicinal product and container may need to be considered.
The microbiological attributes of the dosage form in relation with non-sterile and sterile products shall be in accordance with and documented as prescribed in the European Pharmacopoeia.
In order to provide appropriate and supportive information for the labelling the compatibility of the finished product with reconstitution diluent(s) or dosage devices shall be documented.
The description of the manufacturing method accompanying the application for Marketing Authorisation pursuant to Article 8 (3) (d), shall be drafted in such a way as to give an adequate synopsis of the nature of the operations employed.
For this purpose it shall include at least:
mention of the various stages of manufacture including process controls and corresponding acceptance criteria, so that an assessment can be made of whether the processes employed in producing the pharmaceutical form might have produced an adverse change in the constituents,
in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity of the finished product,
experimental studies validating the manufacturing process, where a non-standard method of manufacture is used or where it is critical for the product,
for sterile medicinal products, details of the sterilisation processes and/or aseptic procedures used,
a detailed batch formula.
The name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing shall be provided.
Particulars relating to the product control tests that may be carried out at an intermediate stage of the manufacturing process, with a view to ensuring the consistency of the production process shall be included.
These tests are essential for checking the conformity of the medicinal product with the formula when, exceptionally, an applicant proposes an analytical method for testing the finished product which does not include the assay of all the active substances (or of all the excipient constituents subject to the same requirements as the active substances).
The same applies where the quality control of the finished product depends on in-process control tests, particularly if the medicinal product is essentially defined by its method of preparation.
Description, documentation, and results of the validation studies for critical steps or critical assays used in the manufacturing process shall be provided.
All the materials needed in order to manufacture the excipient(s) shall be listed identifying where each material is used in the process. Information on the quality and control of these materials shall be provided. Information demonstrating that materials meet standards appropriate for their intended use shall be provided.
Colouring matter shall, in all cases, satisfy the requirements of Directives 78/25/EEC and/or 94/36/EC. In addition, colouring matter shall meet purity criteria as laid down in Directive 95/45/EC, as amended.
For each excipient, the specifications and their justifications shall be detailed. The analytical procedures shall be described and duly validated.
Specific attention shall be paid to excipients of human or animal origin.
Regarding the specific measures for the prevention of the Transmission of animal Spongiform Encephalopathies, the applicant must demonstrate also for excipients that the medicinal product is manufactured in accordance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the Commission in the Official Journal of the European Union.
Demonstration of compliance with the aforementioned Note for Guidance can be done by submitting either preferably a certificate of suitability to the relevant monograph on Transmissible Spongiform Encephalopathies of the European Pharmacopoeia, or by the supply of scientific data to substantiate this compliance.
Novel excipients:
For excipient(s) used for the first time in a medicinal product or by a new route of administration, full details of manufacture, characterisation, and controls, with cross references to supporting safety data, both non-clinical and clinical, shall be provided according to the active substance format previously described.
A document containing the detailed chemical, pharmaceutical and biological information shall be presented. This information shall be formatted in the same order as the chapter devoted to Active Substance(s) of Module 3.
Information on novel excipient(s) may be presented as a stand-alone document following the format described in the former paragraphs. Where the applicant differs from the novel excipient manufacturer the said stand-alone document shall be made available to the applicant for submission to the competent authority.
Additional information on toxicity studies with the novel excipient shall be provided in Module 4 of the dossier.
Clinical studies shall be provided in Module 5.
For the control of the finished medicinal product, a batch of a medicinal product is an entity which comprises all the units of a pharmaceutical form which are made from the same initial quantity of material and have undergone the same series of manufacturing and/or sterilisation operations or, in the case of a continuous production process, all the units manufactured in a given period of time.
Unless there is appropriate justification, the maximum acceptable deviation in the active substance content of the finished product shall not exceed ± 5 % at the time of manufacture.
Detailed information on the specifications, (release and shelf life) justification for their choice, methods of analysis and their validation shall be provided.
Reference preparations and standards used for testing of the finished medicinal product shall be identified and described in detail, if not previously provided in the section related to the active substance.
A description of the container and the closure system(s) including the identity of each immediate packaging material and their specifications shall be provided. The specifications shall include description and identification. Non-pharmacopoeial methods (with validation) shall be included where appropriate.
For non-functional outer packaging materials only a brief description shall be provided. For functional outer packaging materials additional information shall be provided.
The types of studies conducted, protocols used, and the results of the studies shall be summarised;
Detailed results of the stability studies, including information on the analytical procedures used to generate the data and validation of these procedures shall be presented in an appropriate format; in case of vaccines, information on cumulative stability shall be provided where appropriate;
The post authorisation stability protocol and stability commitment shall be provided.]