EMEA 注册要求
European Medicines AgencyInspectionsLondon, 27 April 2005EMEA/CVMP/134/02 Rev 2 ConsultationCPMP/QWP/227/02 Rev 2 Consultation COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) COMMITTEE FOR MEDICINAL PRODUCTS FOR VETERINARY USE (CVMP)GUIDELINE ON ACTIVE SUBSTANCE MASTER FILE PROCEDUREDISCUSSION AT THE HMPC November 2005 – January 2006 ADOPTION BY THE HMPC 22 January 2006 DRAFT AGREED BY QUALITY WORKING PARTY February 200623 March 2006 ADOPTION BY CHMP FOR RELEASE FORCONSULTATION20 April 2006 ADOPTION BY CVMP FOR RELEASE FORCONSULTATION30 August 2006 END OF CONSULTATION (DEADLINE FORCOMMENTS)Note:From 1st November 2005, Directive 2004/24/EC1 relating to traditional herbal medicinal products came into force in all Member States in the European Union allowing the establishment of a simplified procedure for the registration of traditional herbal medicinal products for human use.In order to facilitate the use of the ASMF procedure in the area of herbal medicinal products, the Committee for Herbal Medicinal Products proposes an Annex on herbal substances/preparations (see Annex 1, table 3) to the Guideline on the Active Substance Master File procedure.It should be noted that the principles which are outlined in this guideline in relation to traditional herbal medicinal products are equally applicable to other herbal medicinal products, both for Human and Veterinary use, which do not follow the simplified registration procedure. The new table (Annex 1, table 3) takes into account the particularities of herbal substances/preparations whilst also highlighting that this procedure is/can be applied to active substances/preparations of herbal origin, whether they be for human or veterinary use.1 Directive2004/24/EC of the European Parliament and of the Council of 31 March 2004, amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use.Since this revision introduces clarification rather than changing principles, the publication of a concept paper was not considered necessary.The final Guideline has been adapted to the new template for Guidelines.Comments should be provided using this template to***********.int, with a copy to ************.intGUIDELINE ON ACTIVE SUBSTANCE MASTER FILE PROCEDURETABLE OF CONTENTSEXECUTIVE SUMMARY (4)1 INTRODUCTION (4)2 SCOPE (4)BASIS (4)3 LEGAL4 MAIN GUIDELINE TEXT (4)4.1 Content of the Active Substance Master File (4)4.2 Use of the Active Substance Master File Procedure (5)4.3 Content of the Ma Dossier when the Active Substance Master File Procedure is used6 4.4 Changes and updates to the Active Substance Master File (6)ANNEX 1 (8)ANNEX 2 (13)ANNEX 3 (14)ANNEX 4 (15)ANNEX 5 (16)EXECUTIVE SUMMARY1 INTRODUCTIONThe main objective of the Active Substance Master File (ASMF) procedure, commonly known as the European Drug Master File (EDMF) procedure, is to allow valuable confidential intellectual property or 'know-how' of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or marketing authorisation (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. Competent Authorities/EMEA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product.2 SCOPEThis Guideline is intended to assist Applicants/MA holders in the compilation of the active substance section of their dossiers for a marketing authorisation application (MAA) or a marketing authorisation variation (MAV) of a medicinal product. It is also intended to help EDMF holders in the compilation of their EDMFs. This Guideline is not intended to give instructions to the Competent Authorities/EMEA in the administrative and scientific handling of EDMFs and related MAAs and MAVs.ASMF Procedure and herbal substances/preparationsIn accordance with Directive 2004/24/EC, the quality of traditional herbal medicinal products for human use has to be documented in accordance with existing European legislative requirements. These criteria are laid down in the following guidelines (which are applicable for all Human and Veterinary Herbal Medicinal products): ‘Guideline on quality of herbal medicinal products/traditional herbal medicinal products’ (CPMP/QWP/2819/00, EMEA/CVMP/814/00, in their latest revisions) and the ‘Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/ traditional herbal medicinal products’ (CPMP/QWP/2820//00, EMEA/CVMP/815/00, in their latest revisions).It should be noted that the principles which are outlined in table 3 of Annex 1 in relation to traditional herbal medicinal products are equally applicable to other herbal medicinal products, both for Human and Veterinary use, which do not follow the simplified registration procedure.References:1. ‘Guideline on quality of herbal medicinal products/traditional herbal medicinal products’(CPMP/QWP/2819/00, EMEA/CVMP/814/00, in their latest revisions.)2. ‘Guideline on specifications: test procedures and acceptance criteria for herbal substances,herbal preparations and herbal medicinal products/ traditional herbal medicinal products’(CPMP/QWP/2820/00, EMEA/CVMP/815/00, in their latest revisions.)3. ‘Guideline on summary of requirements for active substances in the quality part of the dossier’(CHMP/QWP/297/97, EMEA/CVMP/1069/02, in their latest revisions.)BASIS3 LEGALAnnex I to Directive 2001/83/EC Part I, 3.2 Basic principles and requirements, (8) Active Substance Master FileTEXT4 MAINGUIDELINE4.1 Content of the Active Substance Master FileThe overall content of the EDMF should contain detailed scientific information as indicated under the various headings of the relevant Notice to Applicants for Marketing Authorisations for Medicinal Products in the Member States of the European Union (NtA). EDMFs linked to human medicinal products should be presented in the format of the Common Technical Document (CTD), see Annex 1 table 1. EDMFs linked to veterinary medicinal products should be presented in accordance withAnnex 1 table 2. EDMFs for veterinary medicinal products may also be presented in CTD format after consultation with the Competent Authorities/EMEA.The scientific information in the EDMF should be physically divided into two separate parts, namely the Applicants Part (AP) and the Restricted Part (RP). The AP contains the information that the EDMF holder regards as non-confidential to the Applicant/MA holder, whereas the RP contains the information that the EDMF holder regards as confidential, see Annex 1. It is emphasized that the AP is still a confidential document that cannot be submitted by anyone to third parties without the written consent of the EDMF holder. In all cases the AP should contain sufficient information to enable the Applicant/MA holder to take full responsibility for an evaluation of the suitability of the specifications for the active substance to control the quality of this active substance for use in the manufacture of a specified medicinal product.The RP may contain the remaining information, such as detailed information on the individual steps of the manufacturing method (reaction conditions, temperature, validation and evaluation data of critical steps) and the quality control during the manufacture method of the active substance. The Competent Authorities/EMEA may not accept that particular information has not been disclosed to the Applicant/MA holder. In such cases, the Competent Authorities/EMEA may ask for an amendment to the AP.In addition to the AP and RP, the EDMF should contain a table of contents, and a separate summary for the AP and the RP. In cases where the EDMF is provided in the CTD format, both summaries should be presented as a Quality Overall Summary (QOS). In cases where the old human or current veterinary NtA format is used, each summary should be made in the form of a written and tabulated expert report (ER). The AP and RP should each have a version number. The structure of the version numbers should be unique and follow a logical order. Preferably the following structure is used.Name EDMF holder / Name active substance / AP or RP/ version number / date in yyyy-mm-dd. 4.2 Use of the Active Substance Master File ProcedureAn EDMF can only be submitted in support of an MAA or MAV. The relationship between the quality of the active substance and its use in the medicinal product needs to be justified in this MAA or MAV. Although the EDMF procedure is developed to keep intellectual property of the ASM confidential, it is also permissible to use the procedure when there is no confidentiality issue between the Applicant/MA holder and the ASM (e.g. when the Applicant/MA holder synthesises the active substance himself). It is expected that the ASM is also the holder of the EDMF.The EDMF procedure can be used for the following active substances, including herbal active substances/preparations (except biological active substances, see the CHMP procedural announcement at the last page of this Guideline), i.e.:activesubstancesA. NewB. Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or thepharmacopoeia of an EU Member StateC. Pharmacopoeial active substances included in the Ph. Eur. or in the pharmacopoeia of an EUMember StateThe EDMF holder may have an EDMF as well as a CEP for a single active substance. Generally, it is however not acceptable that the Applicant/MA holder refers to an EDMF as well as to a CEP for a single active substance of a particular MAA. In cases where the CEP contains too little information (e.g. stability) the Competent Authorities/EMEA may decide that additional information should be provided in the dossier. In such case it may be acceptable to refer both to an EDMF and a CEP.The EDMF holder should give permission to the Competent Authorities/EMEA to assess the data in the EDMF in relation to a specific MAA/MAV, in the form of a ‘Letter of Access’, see Annex 2.The EDMF holder should submit to the Applicant/MA holder:- a copy of the latest version of the AP.- a copy of the QOS/ ER on the latest version of the AP- the letter of access where this letter has not been submitted earlier for the product concerned.In addition, the EDMF holder should submit to the Competent Authorities/EMEA:- the EDMF accompanied by a covering letter, see Annex 3.- the Letter of Access where this letter has not been submitted earlier for the product concerned. The EDMF holder should submit the EDMF to the Competent Authority/EMEA either for each MAA and each MAV or only once according to national requirements. The submission of the relevant documentation by the EDMF holder to the Competent Authority/EMEA must be synchronised to arrive at approximately the same time as the MAA or the MAV.Where the EDMF procedure is used, the Applicant/MA holder should submit the MAA or MAV to the Competent Authorities/EMEA together with the Letter of Access where this Letter has not been submitted earlier by the MA holder/Applicant himself or by the EDMF holder for the product concerned.Where the same active substance is used in a number of applications for different products in one or more Member States, the EDMF holder should submit identical documentation to every Competent Authority/EMEA. Consequently, the Competent Authorities/EMEA may require that any EDMF updates made in relation to one MA should apply to all. It is the EDMF holder’s responsibility to notify the MA holders and Competent Authorities/EMEA concerned about any changes to the AP and/or RP, so that the MA holders can update all affected MAs accordingly.4.3 Content of the Ma Dossier when the Active Substance Master File Procedure is usedThe Applicant/MA holder is responsible for ensuring that he has access to all relevant information concerning the current manufacture of the active substance.The specifications used by the Applicant/MA holder to control the correct quality of the active substance should be laid down unambiguously in the MA dossier (NtA CTD format section 3.2.S.4.1 and 3.2.S.4.2 or old human/veterinary NtA format part IIC1). The Applicant/MA holder should include a copy of the AP in the MA dossier (NtA CTD format section 3.2.S or NtA old human/veterinary format part IIC1). The version of the AP in the MA dossier should be the most recent and it should be identical to the AP as supplied by the EDMF holder to the Competent Authority/EMEA as part of the EDMF. The Applicant/MA holder should include all relevant details from the AP in the QOS/ER of the MA dossier. Issues of the EDMF that are specifically relevant to the product under consideration should be highlighted in the QOS/ER of the MA dossier.In the case of a single supplier and where the EDMF procedure or CEP procedure is used, the specifications of the Applicant/MA holder in the MA dossier should in principle be identical to those of the EDMF holder or the CEP holder. The Applicant/MA holder does however not need to accept redundant specifications, unnecessarily tight specification limits or outdated analytical methods. In cases where the Applicant/MA holder uses a different analytical method than that described in the EDMF, both methods should be validated. Technical specifications relevant for the medicinal product, which are normally not part of the specifications in the EDMF (e.g. particle size), should be part of the specifications of the Applicant/MA holder.In cases where there is more than one supplier, there should be one single compiled specification that is identical for each supplier. It is acceptable to lay down in the specification more than one acceptance criterion and/or analytical method for a single parameter with the statement ‘if tested’ (e.g. in case of residual solvents).4.4 Changes and updates to the Active Substance Master FileAs for medicinal products, EDMF holders should keep the content of their EDMFs updated with respect to the actual synthesis/manufacturing process. The quality control methods should be kept inline with the current regulatory and scientific requirements. EDMF holders shall not modify the contents of their EDMF (e.g. manufacturing process or specifications) without informing each Applicant/MA holder and each Competent Authority/EMEA. Before implementation, any change to the EDMF should be reported by every MA holder to the relevant Competent Authority/EMEA by means of an appropriate variation procedure. A covering letter should be provided. In cases where the contents of the EDMF cannot be changed for a certain period of time because of other procedural provisions (i.e. mainly because of ongoing MRP procedures), the EDMF holder should still provide the aforementioned data to the MA holder and Competent Authorities/EMEA making reference to this reason and requesting a later date of implementation.The EDMF holders’ covering letter to the Competent Authorities/EMEA should contain the following information (if available):- A tabular list summarising the changes carried out since the first compilation of the EDMF.- An overview comparing the old and new content of the EDMF.- Information as to whether the change has already been accepted, rejected or withdrawn by another Member State.- The names of the relevant Applicants, MA holders and MAs.- The new AP and/or RP with each the new version number.- An updated QOS/ER if relevant.At the occasion of the 5-yearly renewal of a medicinal product, MA holders are required to declare that the quality of the product, in respect of the methods of preparation and control, has been regularly updated by variation procedure to take account of technical and scientific progress, and that the product conforms with current CPMP/CVMP quality guidelines. They will also declare that no changes have been made to the product particulars other than those approved by the Competent Authority/EMEA.MA holders should therefore verify with their EDMF holders whether the above declaration can be met in respect to the active substance particulars. In case changes have not been notified to the MA holder and Competent Authority/EMEA, the necessary variation procedure should be initiated without delay.ANNEX 1 OVERVIEW EDMF CONTENTSTable 1 NtA CTD format ApplicantsPart Restricted Part3.2.S.1 Generalinformation x3.2.S.1.1 Nomenclature x3.2.S.1.2 Structure x3.2.S.1.3 Generalproperties x3.2.S.2 Manufacture x X3.2.S.2.1 Manufacturer(s) x3.2.S.2.2 Description of Manufacturing Process and Processcontrols1) 2) 3.2.S.2.3 Control of Materials X3.2.S.2.4 Control of critical steps and intermediates 3) 4)3.2.S.2.5 Process validation and/or Evaluation X3.2.S.2.6 Manufacturing Process Development X3.2.S.3 Characterisation x3.2.S.3.1 Elucidation of Structure and other Characteristics x3.2.S.3.2 Impurities x 5)3.2.S.4 Control of Drug Substance x3.2.S.4.1 Specification x3.2.S.4.2 Analyticalprocedures x3.2.S.4.3 Validation of analytical procedures x3.2.S.4.4 Batchanalysis x3.2.S.4.5 Justification of specification x 6)3.2.S.5 Reference standards or materials x3.2.S.6 Container Closure System x3.2.S.7 Stability x3.2.S.7.1 Stability summary and conclusion x3.2.S.7.2 Post-approval Stability Protocol and StabilityCommitmentx 3.2.S.7.3 Stabilitydata xTable 2 NtA veterinary format / old human format ApplicantsPart Restricted PartIIC.1 Name(s) and site(s) of ASM x XIIC.1.1 Specifications and routine tests xIIC.1.2.1 Nomenclature xIIC.1.2.2 Description xIIC.1.2.3 Brief outline of the manufacturing route (flow chart) xIIC.1.2.3 Detailed description manufacturing method XIIC.1.2.4 QC during manufacture 3) 4) Process validation and evaluation of data XIIC.1.2.5 DevelopmentChemistry xEvidence of structure xPotentialIsomerism xPhysiochemicalcharacterisation xAnalyticalvalidation xIIC.1.2.6 Impurities x 5) IIC.1.2.7 Batchanalysis xIIF1 Stability xFlow chart and short description is regarded as sufficient, if detailed information is presented in the Restricted Part. However, full validation data on the sterilisation process may be requested in the Applicants Part (in cases where there is no further sterilisation of the final product).detailed information.In so far as the information is also relevant for the Applicant/MA holder.In so far as the information is related to the detailed description of the manufacturing process and in so far as this information is not relevant for the Applicant/MA holder.In so far as the information is related to the detailed description of the manufacturing process and in so far as the EDMF holder sufficiently justifies that there is no need to control these impurities in the final active substance.In so far as the information is related to the detailed description of the manufacturing process, control of materials and process validation.Table 3 NtA CTD format 2Herbal Active Substances/ PreparationsApplicants Part Restricted Part 3.2.S.1 Generalinformation X3.2.S.1.1 Nomenclature XFor herbal substance:Binomial scientific name of plant (genus, species, varietyand author), and chemotype (where applicable)Parts of the plantsDefinition of the herbal substanceOther names (synonyms mentioned in otherPharmacopoeias)Laboratory codeFor herbal preparationsBinomial scientific name of plant (genus, species, varietyand author), and chemotype (where applicable)Parts of the plantsDefinition of the herbal preparationRatio of the herbal substance to the herbal preparationExtraction solvent(s)Other names (synonyms mentioned in otherPharmacopoeias)Laboratory code3.2.S.1.2 Structure X- Physicalform- Description of the constituents withknown therapeutic activity or markers (molecularformula, relative molecular mass, structural formula,including relative and absolute stereochemistry, themolecular formula, and the relative molecular mass).- Otherconstituent(s)3.2.S.1.3 General properties X3.2.S.2 Manufacturer(s)For herbal substancesThe name, address, and responsibility of each supplier,including contractorseach proposed site or facility involved inproduction/collection and testing of the herbal substanceshould be provided, where appropriate.For herbal preparationsThe 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 XX2 EDMFs for Veterinary herbal medicinal products should be presented in the Veterinary NtA format (see table 2) unless prior authorisation has been received from the Competent Authorities/EMEA. (A ‘Correlation Table’ for the CTD and NtA formats is available at /F2/eudralex/vol-2/B/ctd_06-2004.pdf)should be provided, where appropriate.3.2.S.2.2 Description of critical steps and intermediates Flow chart Detailedinformation For herbal substancesInformation should be provided to adequately describethe plant productionand plant collection, including:Geographical source of medicinal plantCultivation, harvesting, drying and storage conditionsFor herbal preparationsInformation should be provided to adequately describethe manufacturingprocess of the herbal preparation, including:Description of processingSolvents, reagentsPurification stagesStandardisation3.2.S.2.3 Control of materials X3.2.S.2.4 Control of critical steps and intermediates If also relevant forXthe MAholder/applicant3.2.S.2.5 Process validation and/or evaluation X X3.2.S.2.6 Manufacturing Process Development XA brief summary describing the development of theherbal substance(s) and herbal preparation(s) whereapplicable should be provided, taking into considerationthe proposed route of administration and usage. Resultscomparing the phytochemical composition of the herbalsubstance(s) and herbal preparation(s) where applicableused in supporting bibliographic data and the herbalsubstance(s) and herbal preparation(s) where applicabledescribed in S1 should be discussed, where appropriate.3.2.S.3 Characterisation X3.2.S.3.1 Elucidation of structure and other characteristics XFor herbal substancesInformation on the botanical, macroscopical,microscopical, phytochemical characterisation, andbiological activity if necessary, should be provided:For herbal preparationsInformation on the phyto- and physicochemicalcharacterisation, and biological activity if necessary,should be provided:3.2.S.3.2 Impurities X3.2.S.4 Control of drug substance X3.2.S.4.1 Specification X3.2.S.4.2 Analytical procedure X3.2.S.4.3 Validation of analytical procedure X3.2.S.4.4 Batch analysis X3.2.S.4.5 Justification of specification X X 3.2.S.5 Reference standards of materials X3.2.S.6 Container closure system X3.2.S.7 Stability X3.2.S.7.1 Stability summary and conclusion X3.2.S.7.2 Post-approval stability protocol and stability commitment X3.2.S.7.3 Stability data XTEMPLATE LETTER OF ACCESS[Address of Competent Authority/EMEA][Date and place]LETTER OF ACCESSNumber of Active Substance Master File: [if known, or to be given by the Competent Authority/EMEA or procedure reference number/community reference number in Centralised Procedure ]Manufacturing site: [name and address]Active Substance Master File holder: [name and address]The aforementioned Active Substance Master File holder hereby authorises the [name of Competent Authority/EMEA including all CPMP or CVMP Members and their experts] to refer to and review the above mentioned Active Substance Master File in support of the following Marketing Authorisation Application(s) or Marketing Authorisation Variation(s)3 submitted by [name /Marketing Authorisation holder/Applicant] on [planned date of submission]:[Name of product and Marketing Authorisation number, if known][Name of Applicant or Marketing Authorisation holder]The aforementioned Active Substance Master File holder commits to ensure batch to batch consistency and to inform [name of Marketing Authorisation holder/Applicant] and Competent Authority/EMEA of any change in the Active Substance Master File.Signature for the Active Substance Master File holder[Name and address][Signature]3 i.e. to introduce a new EDMF from a new AS manufacturer.PART OF COVERING LETTERThis Active Substance Master File is submitted in relation to the Marketing Authorisation Application/Marketing Authorisation Variation:[Number of national, centralised or mutual recognition procedure][Name of product in national, centralised or mutual recognition procedure][Name of Applicant/Marketing Authorisation holder for the application concerned][Concerned Member States in mutual recognition]And describes <changes to> the manufacturing process and specifications of the (or one of the) active substance(s) of this Marketing Authorisation Application or Marketing Authorisation Variation. [Name active substance]The version number of this Active Substance Master File isApplicants part: version [version number]Restricted part: version [version number]This Active Substance Master File has previously been submitted for assessment in combination with a Marketing Authorisation Application/ Marketing Authorisation Variation for a medicinal product within the European Union:NoYes, within the following National, Centralised or Mutual recognition procedure:[Number of National, Centralised or Mutual Recognition Procedure][Name of product in National, Centralised or Mutual Recognition Procedure] [Authorisation number and date of approval of the products concerned][Rapporteur or Reference Member State][Concerned Member States in Mutual Recognition][Version number Applicants Part][Version number Restricted Part]Note:Information in italic font can be left blank if not known.Information in normal font is always required.LIST OF ABBREVIATIONSAbbreviation Full text AP Applicants Part (of EDMF) ASM Active Substance Manufacturer ASMF Active Substance Master File CEP European procedure for a certificate of suitability of monographs of theEuropean pharmacopoeia (here on chemical purity)CTD Common Technical Document EDMF European Drug Master File EDQM European Directorate for the Quality of Medicines EMEA European Medicines Evaluation Agency ER Written and tabulated expert report (refers to MA dossiers in old human or existingNtA veterinary format)ICH International Conference on HarmonisationMA Marketing Authorisation MAA Marketing Authorisation Application (including line extensions) MAV Marketing Authorisation Variation NtA Notice to Applicants Ph. Eur. European Pharmacopoeia RP Restricted Part (of EDMF) QOS Quality Overall Summary (refers to MA dossiers in NtA CTD format)GLOSSARYItem DefinitionActive Substance Manufacturer A party involved in the manufacturing chain of the activesubstance, including agents, brokers, traders, distributors,repackers or relabellers.Active Substance Master File holder This is the company that has the ultimate responsibility forthe Active Substance Master File.Applicant This is the company requesting a Marketing Authorisationfor a medicinal product.European Drug Master File The old name of the Active Substance Master File Marketing Authorisation holder This is the company that is responsible for the medicinalproduct on the marketManufacturing chain A clear flow chart or written text explaining themanufacturing and distribution route of the active substancefrom the first starting materials to the final active substanceas delivered to the Applicant/Marketing Authorisationholder.New active substance According to ICH Q6A new drug substance that isThe designated therapeutic moiety, which has not previouslybeen registered in a region or Member State (also referred toas a new molecular entity or new chemical entity). It may bea complex, simple ester, or salt of a previously approved drugsubstance.Quality According to ICH Q6A that isThe suitability of either a drug substance or drug product forits intended use. This term includes such attributes as theidentity, strength and purity.Specification According to ICH Q6A that isA list of test, references to analytical procedures, andappropriate acceptance criteria which are numerical limits,ranges or other criteria to which a drug substance or drugproduct should conform to be considered acceptable for itsintended use. Conformance to specifications means that thedrug substance and/or drug product, when tested according tothe listed analytical procedures will meet the listedacceptance criteria. Specifications are critical qualitystandards that are proposed and justified by the manufacturerand approved by regulatory authorities.。
欧盟药品评价管理局(EMEA)直接接触塑料包装材料指导原则
2003年10月欧盟药品评价管理局(EMEA）起草了直接接触塑料包装材料指导原则（GUIDELINE ON PLASTICIMMEDIATE PACKAGING MATERIALS)，并与2005年12月1日发布.该指导原则根据风险级别，对于直接接触原料药或制剂的塑料包材应进行哪些研究，如何在申报资料中呈现，提供了指导意见。
这一指导原则对于我国直接接触药品的塑料包材研究具有很高的借鉴意义。
因此笔者进行了翻译，特此供业界参考研究。
以下为指导原则正文。
目录1 介绍1。
1 目标1。
2 概述1.3 一般原则2 在申请上市文件中的位置3 应提交的数据3。
1 总体信息3.2 质量标准4 提取研究5 相互作用研究5。
1 迁移（浸出)研究5。
2 吸附研究6 毒理学资料/文献7 术语解释附件1 申报资料决策树附件2 塑料包装材料申报资料决策树附件3 提交信息对照表1 介绍1.1 目标制定本指导原则旨在替代《医药产品管理办法》3AQ10a的“直接接触塑料包装材料指导原则”，同时进一步强调在原料药和制剂申请上市时，应针对其直接接触药品的塑料包装材料提供相关信息。
本指导原则涉及人用药品和兽药所用的直接接触药品的塑料包装材料的申请.对于人用药品，本指导原则涉及欧盟法规2003/63/EC（法规2001/83/EC的修正版)附录I第一部分第3单元的章节3.2。
1.6、3。
2。
2.2和3.2。
2.7;对于兽药，则涉及欧盟法规2001/82/EC的附录I第二部分的章节A、C和G。
1.2 概述本指导原则囊括了对直接接触药品塑料包装材料的具体要求。
对于其他包装材料或容器密封系统的特性，如包材性能，本指导原则不会考虑为它们制定一个合适的总体要求。
本指导原则范围仅限于直接接触药品塑料包装材料，也就是与原料药或制剂发生直接接触的包装材料，它们可能只是容器密封系统中的容器、封盖或其他部件的某一部分。
弹性体、天然和人工橡胶不在本指导原则范围之内.本指导原则不适用于对采用已批准包材的上市药品进行回顾性研究。
欧洲药品评价局EMEA和欧洲药品质量管理局(EDQM)介绍
欧洲药品评价局EMEA和欧洲药品质量管理局（EDQM）介绍一九九四年经欧共体与欧洲议会协商后，以设在法国的欧洲药典委员会秘书处为基础成立了欧洲药品质量管理局(EDQM)。
相对于设在英国伦敦主要负责对新药和新生物制品审评的欧洲药品审评委员会(EMEA)，EDQM主要功能之一是对上市后的仿制药品的监督管理，其主要监管手段是对产品的Certification of Suitability和对通过欧洲各国家官方药品检验所（OMCL）之间的欧洲网络系统来对药品的市场监督。
EMEA （European Medicines uation Agency）翻译为欧洲药品评价局，其机构正在改革变化中，首先，EMEA将从现有的“欧洲药品评价局(European Medicines uation Agency，EMEA) 更名为“欧洲药品局(European Medicines Agency，EMA)“。
欧洲药品质量理事会EDQM （European Directorate for the Quality of Medicines）作为另一重要欧洲官方药管机构，欧洲药品质量管理局是由欧洲药典委员会技术秘书处演化而来，它有很多职能，具体职能如下：1、欧洲药典委员会的技术秘书处提供技术支持2、负责欧洲药典及相关产品的出版与发行3、负责化学药物标准品和生物制品标准品的制备与销售4、负责对欧洲药典各论的适用性认证5、负责构建欧洲官方药品检验实验室网络，承担生物制品批签发与上市药品的监督任务。
EMEA和EDQM之间的关系？欧洲药品评价局EMEA(European Agency for the uation of Medicinal Products)是欧洲官方药管机构之一，它有很多职能，其中很重要的一点就是负责药品（制剂）上市核准程序；而欧洲药品质量理事会EDQM（European Directorate for the Quality of Medicines）作为另一重要欧洲官方药事管理机构，它有很多职能，如：建立药品的质量标准以供欧洲药典委员会使用，制备标准品CRS，执行COS程序最终颁发COS证书等等。
各类药物临床试验入组和排除标准
各类药物临床试验入组和排除标准一、过敏临床试验入选标准(1)年龄为18—65岁，男女不限。
(2)变应原皮脓试验至少有1种十十或十十以上(红晕直径比对照大5mm以 . 上)，过敏性鼻炎诊断明确。
(3)至少有两个鼻部症状在中度以上(评分2分或2分以上)。
(4)病程大于1年。
(5)受试者阅读并充分理解患者须知，签署知情同意书。
3.2排除标准(1)从事需注意力高度集中职业者，如高空作业者、驾驶员。
(2)器质性心脏病或心律失常者。
(3)肝肾功能不正常者。
(4)妊娠试验阳性或哺乳期妇女，计划近期内生育的男女。
(5)对地洛他定片主药成分或其辅料过敏者。
(6)对多种药物有过敏史者。
(7)正在使用皮质激素治疗者。
(8)正在使用抗组胺类药物治疗者。
(9)两周内应用过大环内酯类抗生素及眯唑类药物的患者。
(10)育光眼患者。
(11) 有如下药物使用史，且停药时间少于下表要求者。
表1停药时间要求药物名称或类别停药时间要求长效皮质激素90天口服皮质激素30天阿司米唑30天除阿司米唑外的抗组胺类药物(12) 在最近的3个月内参加其他药物临床试验者。
(13) 有渐进性严重疾病者(如癌症)。
(14) 酗酒或吸毒者。
(15) 因严重精神障碍或语言障碍不能按临床试验方案(16) 不能按期随访者或不能与研究者配合者下列药物在筛选时需停药，并且在试验中不能使用(1) I类和III类抗心律失常药。
(2) 吸入皮质类固醇，剂量超过2000微克每日。
(3) 口服色苷酸钠。
(4) 阿司匹林和非甾体类抗炎药。
(5) 抗胆碱能药。
(6) 镇静药，抗抑郁药，鸦片制剂，催眠药。
(7) H2受体拮抗剂。
(8) 有抗组胺活性的药物。
(9) 大环内脂类抗生素和抗真菌药物(酮康唑等)。
二、老年痴呆临床试验入选标准 .A 符合《中国精神障碍分类与诊断标准第3版(CCMD—3)》器质性精神障碍症状诊断标准中的脑器质性精神障碍B 受试者年龄18—76周岁，性别不限C 意识障碍患者格拉斯哥昏迷评分表评分7—13分，若格拉斯哥昏迷评分表评分＞13—15分患者及无意识障碍患者须符合D项D 简易精神状态检查量表(MMSE)评分11—23分(轻、中度认知障碍)。
关于国内治疗疼痛药物注册临床试验的考虑要点
发布日期20071121栏目化药药物评价>>综合评价标题关于国内治疗疼痛药物注册临床试验的考虑要点作者黄钦王水强马玉楠部门正文内容审评四部八室黄钦王水强马玉楠一、前言根据国际疼痛学会（IASP）的定义，疼痛可被描述为一种与急性或潜在组织损伤相关的不适感觉和情感体验。
疼痛的分类很复杂繁多，按病程长短可分为急性和慢性，按发病机制可分为伤害性疼痛、神经病理性疼痛、癌痛等，按疼痛的强度又可分为轻、中、重度。
而由于人类对疼痛的认识尚不是完全清楚，由此诊断、治疗的临床实践也存在某些混乱和不明确性。
如何考虑用于疼痛治疗适应症的药物注册临床试验应遵循的基本原则，使其与当前的临床实践和科学认识相统一，则是一个较为棘手的问题，EMEA今年拟定了若干疼痛治疗药物的临床研究考虑要点，而FDA也曾经制定过多个指导原则，但多数已过时，废弃不用，而新的也正在拟定之中。
从这些先进国家当前的进展中，我们可以捕捉到其共同的动向和趋势：疼痛指导原则的更新较快，随着对其认识水平的不断深入，也必然及时对其重新考虑。
疼痛的分类趋向以发病机制为原则。
疼痛的适应症越来越具体化，含糊笼统的泛泛意义的适应症已多不使用。
在学习和消化先进国家思路的基础上，我们结合国内的具体情况提出以下考虑要点。
由于偏头痛等头痛疾病的机制和治疗较为特殊，将另文阐述，本文不涉及该类药物。
二、考虑要点(一) 适应症疼痛的适应症的获准应根据所针对的具体疼痛模型的临床试验验证结果最终确定。
对于同一个疼痛模型的疗效和安全性须经过重复的研究验证。
一般地，希望有数个研究能够支持所报的适应症，举例如下：● 为获准上市，申报用于手术急性疼痛的药物应当显示对于躯体性（如大的整形手术）和内脏性疼痛（腹部、妇产科和胸科手术）的安全性和有效性。
对于内脏性和躯体性之间的相互外推是不允许的。
● 对于特定模型的局限研究，其适应症仅限于定位为具体的疼痛，如大的整形手术后的疼痛。
● 对于适应症为除外原发性痛经的轻中度急性疼痛，可以用2个以上的不同疼痛模型（如一个研究针对拔牙，一个研究针对扭伤）的研究来支持。
欧盟药品评价管理局(EMEA)直接接触塑料包装材料指导原则(1)教程文件
2003年10月欧盟药品评价管理局（EMEA）起草了直接接触塑料包装材料指导原则（GUIDELINE ON PLASTICIMMEDIATE PACKAGIN GMATERIALS），并与2005年12月1日发布。
该指导原则根据风险级别，对于直接接触原料药或制剂的塑料包材应进行哪些研究，如何在申报资料中呈现，提供了指导意见。
这一指导原则对于我国直接接触药品的塑料包材研究具有很高的借鉴意义。
因此笔者进行了翻译，特此供业界参考研究。
以下为指导原则正文。
目录1 介绍1.1 目标1.2 概述1.3 一般原则2 在申请上市文件中的位置3 应提交的数据3.1 总体信息3.2 质量标准4 提取研究5 相互作用研究5.1 迁移（浸出）研究5.2 吸附研究6 毒理学资料/文献7 术语解释附件1 申报资料决策树附件2 塑料包装材料申报资料决策树附件3 提交信息对照表1 介绍1.1 目标制定本指导原则旨在替代《医药产品管理办法》3AQ10a的“直接接触塑料包装材料指导原则”，同时进一步强调在原料药和制剂申请上市时，应针对其直接接触药品的塑料包装材料提供相关信息。
本指导原则涉及人用药品和兽药所用的直接接触药品的塑料包装材料的申请。
对于人用药品，本指导原则涉及欧盟法规2003/63/EC（法规2001/83/EC的修正版）附录I第一部分第3单元的章节3.2.1.6、3.2.2.2和3.2.2.7；对于兽药，则涉及欧盟法规2001/82/EC的附录I 第二部分的章节A、C和G。
1.2 概述本指导原则囊括了对直接接触药品塑料包装材料的具体要求。
对于其他包装材料或容器密封系统的特性，如包材性能，本指导原则不会考虑为它们制定一个合适的总体要求。
本指导原则范围仅限于直接接触药品塑料包装材料，也就是与原料药或制剂发生直接接触的包装材料，它们可能只是容器密封系统中的容器、封盖或其他部件的某一部分。
弹性体、天然和人工橡胶不在本指导原则范围之内。
原料药国际注册
Issue Date Issue Date 24/10/2012 21/02/2006 17/03/2015 23/01/2008
Status Status VALID WITHDRAWN BY HOLDER VALID WITHDate
Type Type Chemistry
基于保密原则，无任何信息公布 年度数量统计 /Drugs/DevelopmentApprovalProcess/H owDrugsareDevelopedandApproved/DrugandBiologicAppro valReports/INDActivityReports/default.htm
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ORA：Office of Regulatory Affairs
483报告：仅部分可见 /AboutFDA/CentersOffice s/OfficeofGlobalRegulatoryOperationsandPol icy/ORA/ORAElectronicReadingRoom/default .htm
US 药品注册——New Drug Application (NDA)
Approval Letter NDA涉及场地的现场审查
GMP/cGMP
NAI No Action Indicated VAI Voluntary Action Indicated OAI Official Action Indicated /scripts/inspsearch/ 483： /AboutFDA /CentersOffices/OfficeofGlobal RegulatoryOperationsandPolicy /ORA/ORAElectronicReadingRo om/default.htm
欧洲药品评价局emea和欧洲药品质量管理局（edqm）介绍
欧洲药品评价局EMEA和欧洲药品质量管理局（EDQM）介绍一九九四年经欧共体与欧洲议会协商后，以设在法国的欧洲药典委员会秘书处为基础成立了欧洲药品质量管理局(E DQM)。
相对于设在英国伦敦主要负责对新药和新生物制品审评的欧洲药品审评委员会(EMEA)，EDQM主要功能之一是对上市后的仿制药品的监督管理，其主要监管手段是对产品的Certification of Suitability和对通过欧洲各国家官方药品检验所（OMCL）之间的欧洲网络系统来对药品的市场监督。
E MEA （European Medici nes uation Agency）翻译为欧洲药品评价局，其机构正在改革变化中，首先，EMEA将从现有的“欧洲药品评价局(European Medicinesuation Agency，EMEA)更名为“欧洲药品局(European M edicines Agency，EMA)“。
欧洲药品质量理事会EDQ M（European Directora te for the Quality o f Medicines）作为另一重要欧洲官方药管机构，欧洲药品质量管理局是由欧洲药典委员会技术秘书处演化而来，它有很多职能，具体职能如下：1、欧洲药典委员会的技术秘书处提供技术支持2、负责欧洲药典及相关产品的出版与发行3、负责化学药物标准品和生物制品标准品的制备与销售4、负责对欧洲药典各论的适用性认证5、负责构建欧洲官方药品检验实验室网络，承担生物制品批签发与上市药品的监督任务。
EMEA和EDQM之间的关系？欧洲药品评价局EMEA(Europ ean Agency for the u ation of Medicinal P roducts)是欧洲官方药管机构之一，它有很多职能，其中很重要的一点就是负责药品（制剂）上市核准程序；而欧洲药品质量理事会EDQM（European Dire ctorate for the Qual ity of Medicines）作为另一重要欧洲官方药事管理机构，它有很多职能，如：建立药品的质量标准以供欧洲药典委员会使用，制备标准品CRS，执行COS程序最终颁发COS证书等等。
EMA药品注册技术
EMA药品注册技术1、1欧盟概况欧洲联盟(简称欧盟,EU)就是由欧洲共同体(EEC)发展而来得,就是一个集政治实体与经济实体于一身、在世界上具有重要影响得区域一体化组织。
截至2014年10月,欧盟共有28个成员国,人口超过5亿,就是世界上最大经济实体。
2014年1～9月我国与欧盟贸易额达到4、58千亿美元, 累计同比增长10、2%。
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欧洲理事会(EuropeanCouncil),即首脑会议,就是欧盟得最高权利机构,由成员国国家元首或政府首脑及欧盟委员会主席组成,欧洲理事会主席由成员国选举产生,任期为两年半。
欧盟理事会(Council of the European Union),即部长理事会,主席由各成员国得代表轮流担任,任期半年。
它就是欧盟最高决策机构,分为由各成员国外长组成得总务理事会与由农业、财经、科研、工业等部长组成得专门委员会。
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欧洲议会(EuropeanParliament),就是欧洲联盟得执行监督与咨询机构,在某些领域有立法职能,并有部分预算决定权,并可以三分之二多数弹劾欧盟委员会,迫其集体辞职。
全体会议在斯特拉斯堡与布鲁塞尔举行,委员会会议也设在布鲁塞尔举行,会议秘书处设在卢森堡;自1979年起,欧洲议会议员由成员国直接普选产生,任期5年。
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欧盟委员会(Europeanmission),就是欧洲联盟得常设机构与执行机构。
负责实施欧洲联盟条约与欧盟理事会做出得决定,向理事会与欧洲议会提出报告与立法动议,处理联盟得日常事务,代表欧盟对外联系与进行贸易等方面得谈判等。
在欧盟实施共同体外交与安全政策范围内,只有建议权与参与权。
根据《马斯特里赫特条约》,自1995年起,欧盟委员会任期为5年,设主席1人,副主席2人。
该委员会由来自不同成员国28名代表组成。
欧盟委员会主席人选由欧盟各成员国政府征询欧洲议会意见后共同提名,欧盟委员会其她委员人选由各成员国政府共同协商提议。
EMEA “治疗抑郁药物临床研究指南说明”中有关抗抑郁药物临床研究特殊问题的几点考虑
发布日期20060124栏目化药药物评价>>临床安全性和有效性评价EMEA “治疗抑郁药物临床研究指南说明”中有关抗抑郁药物临床研究特殊问题的标题几点考虑作者王水强赵建中部门正文内容审评四部王水强赵建中摘要：本文介绍了抗抑郁药物临床研究中的一些特殊问题，包括安慰剂应用、复发与再燃、增加适应症、难治性患者、老年患者和儿童患者等内容。
关键词：抑郁症药物治疗临床试验特殊问题在开发治疗抑郁的药品时，可能会遇到一些特殊问题，需特别关注。
1、安慰剂的使用：临床研究应该证明药物的抗抑郁活性，有效剂量或剂量范围的确切（unambiguous）证据。
在抗抑郁治疗的过程中，由于安慰剂效明显而且不稳定，试验药品与参比制剂间的疗效差异没有统计学意义并不能确切提示治疗等效，所以试验药品与参比制剂间的抗抑郁疗效比较（depression comparisons）是难以解释的。
实际上，在临床研究中，大约有1/3到2/3的试验采用阳性药物对照作为第三组，活性对照药物的作用可能并不明显优于安慰剂。
在特定的试验中，由于有效率是如此不确定，因而不能确定非劣效的阈值。
作为证明疗效的研究手段，非劣效试验并非唯一选择。
从科学的角度出发，与活性药物比较显示优效性可能是一种可取的方法，但需要与安慰剂进行随机、双盲比较研究，以便对疗效进行适当评估。
此外，为鉴别疾病表现与药物的不良反应，与安慰剂比较也是有价值的。
在伦理学上对应用安慰剂尚有争议，特别是在急性发作期和/或门诊病人中进行研究时。
但是，批准未确证活性的一种药品用于治疗抑郁症有害于公众健康，在伦理学上不能接受。
在研究中应注意采取措施，以尽量减小给患者带来的损害：如通过限制研究疗程（6周的治疗应该是充分的，若延长治疗周期，应采用安全防备措施）；病情恶化时允许撤出试验；在开放情况下给予标准治疗等。
因而，本指南推荐采用包括安慰剂和活性对照的三臂试验。
2、复发与再燃（Relapse and Recurrence）复发是本次发作症状再次出现，再燃（recurrence）是出现新的发作症状，而反跳和撤药反应见于撤药时。
欧盟药品GMP[指南]
欧盟药品GMP简介欧盟（EU）是欧洲联盟（European Union）的简称，总部设在比利时首都布鲁塞尔，是由欧洲共同体（European Communities）发展而来的。
至2009年1月，欧盟共有包括英、法、德等共27个成员国。
欧盟的制药业相当发达，是欧洲重要的支柱性产业之一，在国际药品市场起着十分重要的作用。
欧盟的药品管理非常系统、完善，深得国际制药业的认可。
不少发展中国家效仿欧盟药品的管理模式，取得了可喜的成果。
欧盟通过ICH（人用药品注册技术标准国际协会）、PIC/S（药品检查合格计划）组织等方式，扩大了国际间的合作交流，尤其是发展中国家的合作与交流。
1、欧盟药品管理机构欧洲药品管理局（EMEA European Agency for the Evaluation of Medicinal Products）是欧洲药品注册审评及检查的主管机构。
欧盟药品的审评及检查是由欧洲药品管理局和欧盟成员国共同承担的。
欧洲药品管理局于1995年1月1日正式开始运作，其理事会由各成员国各派出2个代表（其中1个为候补代表）、1名欧洲议会代表、2名欧洲委员会代表以及病人组织代表、医生组织代表、兽医组织代表各1名组成。
无论是按集中审评程序还是按互认审评程序申报，欧洲药品管理局的使命就是协调所申报药品的安全性、有效性和质量的技术评价。
，并处理二个申报程序中的各种科学问题。
集中审评程序的实际工作由欧洲药品管理局承担，但在互认程序中，只有成员国的专家在审评过程中出现严重分歧时，才由欧洲药品管理局进行仲裁。
欧洲药品管理局下设人用药品委员会、兽药委员会、罕用药委员会及草药委员会等4个专家委员会。
人用药品委员会（CHMP）是欧洲药品管理局在人用药品领域的专家班子，它按（EC）No726/2004法规要求，处理人用药品注册审评中的各种科学及技术等方面的问题。
兽药委员会（CVMP）是欧洲药品管理局在兽药领域的专家班子，它按（EC）No726/2004法规要求，处理兽药注册审评中的各种科学及技术等方面的问题。