EDQM的COS申请文件内容要求指南（英文）

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Manufacture (3.2.S.2) Manufacturer(s) (3.2.S.2.1): If different sites/facilities are involved for a single defined process for manufacture and/or testing this should be explained and it should be made clear which production step is conducted on which site and the names and addresses of each of them should be given. Description of manufacturing process and Process Controls (3.2.S.2.2): Applicants are reminded that the requirements of the general monographs Products of Fermentation (1468) and Products with risk of transmitting agents of animal spongiform encephalopathies (1483) should be respected when applicable. The following information should be supplied:

— An outline (flow chart, including the structural formula for the starting materials and all intermediates), — The description of the manufacturing method should include all the steps of the process,

proceeding from the starting materials(s) to any isolated intermediates, and ultimately to the active substance. — Detailed description of each stage of the manufacture, including information on solvents and

reagents, catalysts, conditions of reactions, information on intermediates, which are isolated and purified, quantities of all materials used in the process to produce a batch of the typical commercial size and yields for isolated intermediates should be indicated for each process step. Special emphasis should be given to the final steps including purification procedures. — The maximum batch size for which the manufacturer has acquired experience with the

defined method, and which should correspond to batches referred to in the dossier, should be stated. Where the substance has yet to be produced in commercial quantities (only pilot scale batches manufactured) the certificate can be granted provided scale-up is immediately reported to the EDQM. For a sterile product, an application for a variable and/or alternative batch size should be justified. — In case of semi-synthetically manufactured substances the fermented starting material should be well characterised, and the possibility of carrying impurities from the fermentation process to the final substance should be discussed. Each supplier should give a declaration on the use/non-use of material of animal origin during manufacture of the starting material. Note that products obtained only by purification or salification of a fermented starting material cannot be considered as semi-synthetic products and should therefore be subject to the same requirements as true products of fermentation. — Different manufacturing sites and different manufacturing methods or alternatives could be

described in a single dossier provided that proof is given that for each case the specifications

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and the impurities profiles are exactly the same. If more than one manufacturer/facility is involved in manufacture, the responsibilities of each party should be clearly indicated. — Whatever type of manufacturing process is used, alternatives are not allowed unless they are

clearly defined and detailed as part of 2nd, 3rd etc. processes. Batch analysis results corresponding to the substance manufactured according to the different alternatives must be provided to demonstrate that there are no significant differences in impurity profiles, which may affect the specifications. If this provision is not met, the application will need revision to delete one or more of the options, which results in a product that does not conform to the 'standard' profile. ‘Deleted’ options may be included in further applications for additional certificates. If re-processing (i.e. re-application of a step already described in the process) is a possibility it should be mentioned and should be treated as a procedural option.

Normally re-working (application of steps different from those of the process) is not acceptable since this implies the use of different solvents, which leads to a change in the specifications, and /or impurity profile of the substance. A separate certificate application would therefore be necessary to cover material produced using such a procedure.

Recovery (e.g. from mother liquors or filtrates) of reactants, intermediates or the final substance is considered acceptable provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use. The specifications should be described. However, recovery of the substance without any further purification of the obtained substance according to the usual process should be considered as a re-working and is not acceptable.

Blending of production batches of the final substance to obtain a larger size is acceptable provided each batch incorporated into the blend is individually tested and found to meet specifications set for the final substance prior to blending. Control of materials (3.2.S.2.3): Appropriate specifications for raw materials and solvents should be supplied. If materials are recycled then justified specifications for the recycled materials should be supplied and it should be made clear in which manufacturing step they are used. When a class 1 solvent could be present in a solvent used during manufacture e.g. benzene in toluene a suitable limit and analytical method for its control should be introduced.

Applicants should propose and justify which substance(s) should be considered as the starting material(s). They should be fully characterised and complete specifications should be provided including an impurities profile. The possibility that impurities present in the starting material may be carried through the process unchanged or as derivatives should be discussed and if relevant be controlled in starting material by appropriate acceptance criteria. A description of analytical controls applied to ensure the quality of the starting materials should be given. Relevant viral safety and/or TSE data should be provided if any animal derived material is used during the manufacturing process. Starting materials from vegetable origin should be fully characterised to ascertain suitability, and a contaminant profile should be established and submitted.

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In the case of a route of synthesis consisting of one or only a few steps, full details of the manufacture of the starting material(s) should be given and/or at least detailed specifications especially regarding the impurity profile including residual solvents and catalysts. Alternatively, for starting materials described in the European Pharmacopoeia certificates of suitability can be provided, if available.

The supplier(s) of the starting materials(s) should be declared and where more than one supplier is used batch analysis results from the substance manufactured from the different suppliers should be given.

Controls of critical steps and intermediates (3.2.S.2.4); Any critical steps should be identified. Tests and acceptance criteria performed at the critical steps should be provided. In-process controls should be described. Information on the quality and control of intermediates isolated during manufacture should be provided. Process validation and/or evaluation (3.2.S.2.5); Process validation and/or evaluation studies shall be provided as appropriate. In particular, sterilisation processes including filtration and aseptic processing should be validated. Therefore, when a request to mention sterile in the sub-title of the certificate is made validation data should be presented in the dossier. European Pharmacopoeia General text 5.1 should be taken into consideration. In addition, a full description of the sterilisation process is required, including for sterilisation by filtration, the maximum acceptable bio-burden prior to the sterilisation, the type of microbial retentive filter used and its pore size (pore sizes of 0.22 μm or less are acceptable without further justification), any in-process controls (i.e. filter integrity) as well as the method(s) of sterilisation of the primary packaging material. CEP holders and MA holders should be aware that when the active substance is used after sterilisation as a medicinal finished product e.g. sterile powder distributed in sterile packaging, the sterilisation of the active substance will be considered as an intrinsic part of the manufacturing process of the medicinal product. Consequently, full data must be provided in the application file for a medicinal product or by the licensing authority requesting the assessment report from the EDQM.

When the monograph indicates specific additional requirements for the manufacturing process (i.e. in the production section of the monograph) compliance to this aspect should be demonstrated when reference to a specific test(s) is given. For biological substances (such as heparin sodium), and even if a specific microbial grade is not requested to be mentioned on the certificate (sterile, endotoxin free, ..), the dossier should include information demonstrating suitable inactivation and/or removal of any infectious agent. Elucidation of Structure and other Characteristics ((3.2.S.3.1) Impurities (3.2.S.3.2) Related substances: The requirements of the related substances section of the general monograph Substances for Pharmaceutical Use (2034) and the guideline Control of impurities of pharmacopoeial

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substances (CPMP/QWP/1529/04) should be met. It should be demonstrated that all applied methods are suitable to control impurities at the applicable levels set by the general monograph. Furthermore the provisions of the general chapter Control of impurities in substances for pharmaceutical use (5.10) are to be taken into consideration.

Possible impurities originating from the route of synthesis or from degradation should be listed and discussed with an indication of their origin (starting material, reagent, solvent, catalyst, intermediate, degradation product). The impurities that are controlled should be presented together with details of the analytical methods used, and a list of the related substances found in the substance. The related substances found in batches of the active substance should be compared with the related substances listed in the transparency statement of the monograph (where one exists) together with their typical levels and the proposed limits.

The suitability of the method(s) of the monograph to control the quality of the substance must be discussed and demonstrated. In particular, where additional impurities (i.e. those not listed in the transparency statement of the monograph) are found above the relevant reporting threshold and disregard limit of the monograph it must be demonstrated whether the monograph controls them and where applicable retention times or Rf values and limits of detection and/or quantification should be provided. If the monograph does not control the additional impurities, suitably validated sadditional test(s), should be proposed. Evidence should be given of the absence of impurities not routinely tested for in the product or its intermediates.

Chromatograms for production batches of the substance suitably zoomed and annotated and with peak area results should be supplied.

Where additional related substances are present (those not already mentioned in the monograph) they should be considered according to the related substances section in the general monograph Substances for Pharmaceutical Use (2034) (which corresponds to the requirements of the ICH note for guidance Impurities in New Drug Substances CPMP/ICH/2737/99). Suitable limits should be set which should be justified. In particular, where present above the relevant identification threshold they are identified and when present above the relevant qualification threshold they should be qualified. Alternatively, and where appropriate, it may be demonstrated by other means that the impurity profile (number, nature, amount) of the substance is comparable to that of products already on the market. For active substances excluded from the requirements on related substances of the general monograph Substances for Pharmaceutical Use (2034), and which contain additional impurities, qualified limits should be proposed and where necessary toxicological data should be supplied.

In the case of particularly toxic impurities, the determination of acceptable levels is a critical issue to be documented. The EMEA CHMP Guideline on the Limits of Genotoxic Impurities (EMEA/CHMP/QWP/251344/2006), effective as of 01 January 2007, is applicable to new applications for existing active substances in conditions described in the scope of the guideline. A specific discussion as part of the overall discussion on impurities should be provided with regard to impurities with potential genotoxicity. If a genotoxic impurity is liable to be present in the substance then conformity to the requirements of the guideline should be demonstrated in the CEP application file.

In discussing possible degradation products, reference to data from real time stability studies or from stress testing or reference to the literature may be helpful. However, results from formal stability studies are not a requirement when there is no request to mention a retest period on the certificate.