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EMEA/CHMP/QWP/396951/2006 药物上市许可申报文件中辅料指南
非常感谢：Julia
London, 19 June 2007 Doc. Ref. EMEA/CHMP/QWP/396951/2006 COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) |
GUIDELINE ON EXCIPIENTS IN THE DOSSIER FOR APPLICATION FOR MARKETING AUTHORISATION OF A MEDICINAL PRODUCT 药物上市许可申报文件中辅料指南 |
Draft agreed by quality working party | | | | Adoption by CHMP for release for consultation | | | | End of consultation (deadline for comments) | | | | New draft agreed by quality working party | | | | Adoption by CHMP for release for consultation | | | | End of consultation (deadline for comments) | | | | New draft agreed by quality working party | | | | | | | | Date for coming into effect | | | |
For human medicinal products, this Guideline replaces the Guideline on Excipients in the Dossier for Application for Marketing Authorisation of a Medicinal Products (Eudralex 3AQ9a) and the Note for Guidance on Inclusion of Antioxidants and Antimicrobial Preservatives in Medicinal Products (CPMP/CVMP/QWP/115/95). 对于人用药，本指南替代“药品上市许可申报资料中的辅料指南”(Eudralex 3AQ9a)和“药品中加入防氧剂和微生物防腐剂指南解释”(CPMP/CVMP/QWP/115/95)。 The latter Guideline remains a CVMP guideline and remains applicable to Veterinary products. 后一指南仍保留作为CVMP指南，仍适用于兽药产品。 Keywords | Excipients, human, novel excipient, antioxidant, preservative | | |
GUIDELINE ON EXCIPIENTS IN THE DOSSIER FOR APPLICATION FOR MARKETING AUTHORISATION OF A MEDICINAL PRODUCT 药物上市许可申报文件中辅料指南 |
TABLE OF CONTENTS 目录 EXECUTIVE SUMMARY | | 1. INTRODUCTION (BACKGROUND) | | | | | | | | 4.1 DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT (3.2.P.1) | | 4.2 PHARMACEUTICAL DEVELOPMENT (3.2.P.2) | | 4.3 SPECIFICATIONS (3.2.P.4.1) | | a) Excipients described in the European Pharmacopoeia or in the pharmacopoeia of an EU Member State | | b) Excipients described in a third country pharmacopoeia | | c) Excipients not described in any pharmacopoeia | | 4.4 JUSTIFICATION OF SPECIFICATIONS(3.2.P.4.4) | | 4.5 EXCIPIENTS OF HUMAN OR ANIMALORIGIN (3.2.P.4.5) | | 4.6 NOVEL EXCIPIENTS (3.2.P.4.6) | | 4.7 CONTROL OF DRUG PRODUCT (3.2.P.5) | | | | | | | | | | | | | | | |
EXECUTIVE SUMMARY 实施摘要 This guideline describes the information that needs to be submitted in relation to excipients including antioxidants and antimicrobial preservatives, in the context of applications for marketing authorisations or variations relating to an excipient in authorised medicinal products. 本指南描述了在上市许可申报时，或已批准的药品辅料相关的变更时，需要提交的与辅料相关的资料，包括抗氧剂和防腐剂。 1. INTRODUCTION (BACKGROUND) 介绍（背景） Excipients are the constituents of a pharmaceutical form apart from the active substance. 辅料是制剂中除活性物质以外的成分。 Excipients include e.g. fillers, disintegrants, lubricants, colouring matters, antioxidants, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, solubilisers, permeation enhancers, flavouring and aromatic substances etc., as well as the constituents of the outer covering of the medicinal products, e.g. gelatine capsules. 辅料包括，例如充填剂、崩解剂、润滑剂、着色物质、抗氧剂、防腐剂、佐剂、稳定剂、增稠剂、乳化剂、增溶剂、促渗剂、香料和芳香物质等，以及药品外覆成分，例如明胶胶囊。 Examples of different types of excipients are given in annex 1. Information on the excipients used in a medicinal product should be provided in part 3.2.P.1, 3.2.P.2, 3.2.P.4 and 3.2.A.3 of the dossier. 附录1中给出了不同类型辅料的例子。用于制剂中的辅料的信息应包括在申报文件的3.2.P.1, 3.2.P.2, 3.2.P.4 和3.2.A.3部分。 Excipients to be used in formulations for the paediatric population should be selected with special care. Possible sensitivities of the different age groups should be taken into consideration. For example, colouring agents with documented safety risks, e.g. azo dyes and other synthetic colouring agents, should not be used in medicinal products for paediatric use when only intended for aesthetic purposes. 选择用于小儿药物中的辅料应特别注意，要考虑不同年龄组可能的敏感度。例如，有安全风险记录的着色剂，如，偶氮染料和其它合成着色剂，不应该仅为了美观而用于小儿药物中。 Antioxidants are excipients which are used to improve stability of medicines by delaying the oxidation of active substances and other excipients. Antimicrobial preservatives are normally added to prevent microbial proliferation arising under in use conditions. These properties are due to certain chemical groups which are usually harmful to living cells and might therefore be associated with certain risks when used in humans. Thus inclusion of antimicrobial preservatives or antioxidants in a medicinal product needs special justification. Wherever possible the use of these substances should be avoided, particularly in case of paediatric formulations. The concentration used should be at the lowest feasible level. Further information is given in annex 2. 抗氧剂是通过延迟活性物质和其它辅料的氧化反应，从而提高药品的稳定性的辅料。防腐剂一般添加用以防止微生物在使用条件下滋长。这些特性都是源于通常会对活细胞有害的特定的化学基团，因此在用于人类时可能会伴随产生特定的风险。所以，将防腐剂或抗氧剂加入至药品中需要特殊的论证。应尽可能避免使用这些物质，特别是对于小儿用药。所用的浓度应保持在可能的最低水平。更多信息在附录2中给出。 Parenteral infusions should not contain added antimicrobial preservatives. Antimicrobial preservatives must not be added to medicinal products intended for use by any route of administration that will give access to the cerebrospinal fluid or in products that will be injected retro-ocularly. 静脉注射剂不应含有添加的防腐剂。经由任何给药途径向脑脊液给药的药品，或会通过眼后注射给药的药品均不得添加防腐剂。 Permeation enhancers are excipients which have the ability to modify the penetration of active substances through the skin and therefore could influence significantly the in-vivo performance of a transdermal formulation. Information and control of these substances is essential for all transdermal formulations, where a constant and persistent release of active substances over several hours, or even days, is necessary for therapeutic efficacy. Further information is given in annex 3. 促渗剂是改善活性物质的透皮渗入的辅料，因此可能会显著影响透皮制剂的体内行为。如果为达到治疗效果，活性物质需要在几小时，或甚至几天内持续稳定释放，则这些物质的资料和控制方法对透皮制剂来说是很重要的。 2. SCOPE 范围 This guideline is applicable to all excipients in medicinal products for human use, in the context of applications for marketing authorisations or variations relating to an excipient in authorised medicinal products. 本指南适用于人用药物所有辅料，在药品上市许可申报中，或已批准的药品中所用辅料变更有关事项。 The guideline does not apply to excipients used in products in the clinical research stages of drug development. However, the principles in this guideline are important to consider during those stages as well. 本指南不适用于药物研发阶段的临床研究药物中使用的辅料。但是，本指南中的原则在那些阶段考虑中也是很重要的。 The data should be presented according to the standard format described in the Common Technical Document (CTD) Module 3 sections P.1, P.2, P.4, P.5, P.8 and A.3. 数据应按CTD格式要求放入模块3第P.1, P.2, P.4, P.5, P.8 和A.3部分。 3. LEGAL BASIS 法规依据 Directive 2001/83/EC, as amended 指令2001/83/EC及修订内容。 4. MAIN GUIDELINE TEXT 主要指南正文 4.1 Description and Composition of the Drug Product (3.2.P.1) 制剂外观和组成 Excipients should be listed specifying their common name, the quantity present, their function and a reference to a relevant standard. When the common name is not sufficient to indicate functional properties, the brand name with commercial grade should be specified. In the case of excipients presented as a mixture of compounds, details of the composition should be provided in qualitative and quantitative terms. However, for flavouring agents it is allowed to state the qualitative composition only. 辅料清单应指明其通用名、所用数量、功能和对相关标准的引用。如果通用名不足以说明其功能特性，则需要指明其商标名称和商业级别。如果辅料是以混合物形式使用，则要提供各成分的质量和数量。但是，对于香精可以允许只声明其成分名称。 4.2 Pharmaceutical Development (3.2.P.2) 药品研发 According to the Notes for Guidance on Pharmaceutical Development (CHMP/ICH/167068/04 and CHMP/QWP/055/96), this section should include an explanation of the choice of the excipient(s) (and grade where necessary). Compatibility of the excipients with active substances and, where relevant, with other excipients, should be established. The excipients chosen, their concentration, and the characteristics that can influence the drug product performance (e.g., stability, bioavailability) or manufacturability should be discussed in relation to the respective function of each excipient. Tests in addition to the pharmacopoeial ones, identified through development, should be described in section 3.2.P.4.2 and 3.2.P.4.3. 根据“药物研发指南解释” (CHMP/ICH/167068/04 和CHMP/QWP/055/96)，本部分应包括对辅料（及所需级别）选择的解释。辅料与活性物料的相容性，以及必要时，与其它辅料的相容性均应确定。所选用的辅料、其浓度、会对制剂性能（例如，稳定性、生物利用度）或生产能力产生影响的特性均应联系各辅料相应作用进行讨论。在研发过程中所确认的除药典项目外加检的测试项目均应在3.2.P.4.2 和3.2.P.4.3描述。 4.3 Specifications (3.2.P.4.1) 质量标准 Colouring matters shall, in all cases, satisfy the requirements of Directives 78/25/EEC, as amended and/or 94/36/EC (colours for use in foodstuffs). In addition, colouring matters in medicinal products have to comply with the specifications of the Annex of Directive 95/45/EC, laying down specific purity criteria concerning colours for use in foodstuffs. 着色物质在所有情况下均应满足法令78/25/EEC及修订内容和/或法令94/36/EC（用于食物的色素）的要求。另外，药品中的着色物质还必须符合法令95/45/EC附录“食品中使用的色素的特定纯度标准”的质量标准。 The references in Directive 78/25/EEC, as amended are interpreted in a way, which permits the use in medicinal products of all colourants mentioned in Annex I of Directive 94/36/EC. 指令78/25/EEC及修订内容可解释为其允许在药品中使用法令94/36/EC附录1中提到的所有色素。 The bioburden and, where relevant, the endotoxin limits for excipients used in the manufacture of sterile medicinal products shall be stated. However, if bioburden/endotoxin content of the bulk solution prior to sterilisation is checked using appropriate in process controls, the testing of the individual excipient may be omitted. 用于无菌药品生产的辅料中的生物负载以及，相关时，内毒素限度应进行声明。但是，如果在灭菌前散装溶液中的生物负载/内毒素含量采用了适当的中控方式进行检查，则可以省略对单个辅料的测试。 Data concerning residual solvents in excipients should be submitted in accordance with the Note for Guidance on Impurities: Residual Solvents (CPMP/ICH/283/95). 辅料中的残留溶剂数据应根据“杂质指南解释：残留溶剂” (CPMP/ICH/283/95)进行提交。 a) Excipients described in the European Pharmacopoeia or in the pharmacopoeia of an EU Member State欧洲药典或欧盟成员国药典中收载的辅料 Reference to the current edition of the pharmacopoeia should be included in the dossier for marketing authorisation. When the monograph covers a group of related materials (i.e. polymers), the particular specification chosen for the excipient, should be submitted, together with the rationale for its selection. If tests other than those mentioned in the pharmacopoeia are used, proof should be supplied that the test methods are at least equivalent to those described in the pharmacopoeia (see European Pharmacopoeia, 1.1. General Statements). It may be necessary to add tests and acceptance criteria to the pharmacopoeial specification, depending on the intended use of the excipient (functionality-related characteristics). 在上市申报资料中要包括对现行版本药典的引用。如果各论覆盖了一组有关的物质（例如聚合物），则应提交作为辅料的特定的质量标准，以及选择的合理性原因。如果采用了药典以外的测试方法，则要提供证据证明所用的测试方法至少与药典方法相等同（参见欧洲药典1.1凡例）。根据辅料的用途（功能性相关特性），可能需要增加药典质量标准以外的测试和可接受标准。 b) Excipients described in a third country pharmacopoeia第三国药典中收载的辅料 Where an excipient is neither described in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmacopoeia (e.g. United States Pharmacopoeia/National Formulary and Japanese Pharmacopoeia) can be accepted. 如果辅料未收载在欧洲药典，也没有收载在成员国药典中，符合第三国药典（例如美国药典和日本药典）各论时也可以接受。 The applicant should justify the reference to such pharmacopoeia and submit justified specifications in accordance with the general monograph of the European Pharmacopoeia: Substances for Pharmaceutical use. 申请人应论述对药典的引用，并提交符合欧洲药典通用各论“药用物质”的质量标准。 c) Excipients not described in any pharmacopoeia未在任何药典中收载的辅料 An appropriate specification for the excipient should be established, based on the following types of tests: 辅料应建立适当的质量标准，标准应基于以下类型的测试 l Physical characteristics l 物理特性 l Identification tests l 鉴别试验 l Purity tests, including limits for total and individual impurities, which should be named, e.g. by reference to a chromatographic relative retention time. Purity tests may be physical, chemical, biological and, if appropriate, immunological. l 纯度测试，包括总杂和单杂限度，单杂应进行命名，例如根据色谱的相对保留时间。纯度测试可以是物理、化学、生物，或适当时，免疫方法 l Assay or limit tests if necessary and corresponding validation parameters. l 必要时，含量或限度测试，相应的验证参数 l Other relevant tests e.g. tests on parameters (quantitative), which have been determined to influence the performance of the dosage form. l 其它相关的测试，例如，认为会影响剂型性能的参数测试（定量）， 4.4 Justification of Specifications (3.2.P.4.4) 质量标准论述 Justification of a specification takes into account the choice and particular use of the excipient (see Note for Guidance on Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (CPMP/ICH/367/96)). 论述时要考虑辅料的选择和特殊使用（参见质量标准指南解释：新原料药和制剂的检测方法和可接受标准(CPMP/ICH/367/96)）。 For excipients described in the European Pharmacopoeia, or in the pharmacopoeia of an EU Member State, justification of specifications will normally not be required. However, any particular acceptance criteria concerning the characteristics, as defined in Section 3.2.P.2.1.2, should be justified (e.g. particle size testing of a micronised substance). In addition, justification of a specification is not systematically required for well-known excipients. For example, it is not required for excipients which have been used in similar medicinal products for a long period of time and when their characteristics and properties have not changed significantly. 如果辅料收载在欧洲药典或欧盟成员国药典中，则一般不需要对其质量标准进行论证。但是，如果其特性有不一样的可接受标准，则应该在3.2.P.2.1.2中界定，并进行论述（例如微粉化物质的粒径测试）。另外，如果对辅料性质已有很好的认识，则不需要对质量标准进行全面论证。例如，如果一种辅料已在一种类似的制剂中使用了很长时间，且其特征和性质并未有重大改变，则不需进行全面论证。 Where critical, the justification of specifications should provide information on excipient characteristics relevant to the medicinal product performance. For example, for solid and semi-solid dosage forms, special tests may be necessary to demonstrate the capability of the excipient to emulsify and disperse, or to provide appropriate viscosity (Functionality related characteristics). 对于关键辅料，则要论证其与制剂相关的特性的质量标准。例如，对于固体和半固体剂型，需要证明辅料的乳化和分散能力，或具有适当的粘度（与功能相关的特性）。 4.5 Excipients of Human or Animal Origin (3.2.P.4.5) 人或动物来源的辅料 Viral Safety and TSE Risk should be documented in accordance with the relevant directives and guidelines (see European Pharmacopoeia General Chapter 5.1.7 Viral Safety and 5.2.8. Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products). 病毒安全和TSE风险应根据相关指令和指南进行记录。（参见欧洲药典通论5.1.7病毒安全和5.2.8降低TSE通过人兽用制剂传播的风险） 4.6 Novel Excipients (3.2.P.4.6) 创新辅料 Full details of manufacture, characterisation and controls with cross references to supporting safety data should be provided for novel excipients, according to the drug substance format. 对于创新辅料，应根据药品配方，提供该辅料的生产详细信息、特性和控制方法，并交叉引用其支持性安全数据。 a) A detailed description of the excipient, its function and its conditions of use should be provided. If the excipient is complex or consists of a mixture of compounds, the composition should be specified in qualitative and quantitative terms.
辅料的详细说明，其作用，使用条件均应提供。如果该辅料较为复杂，或是数种化合物的混合物则其成分应进行定性和定量说明 b) For novel excipients and for excipients presented as a mixture of compounds the following should be taken into consideration:
对于创新辅料，以及以混合物方式出现的辅料，应考虑以下内容 l Any bibliographical data on the chemistry and on the toxicology and the field in which the product is already used. l 所有化学和毒理的文献数据，以及该产品已应用的领域 l The Community provisions concerning additives in foodstuffs: any criteria which are based on the toxicological data, with cross-references to these data. l 欧盟关于食品添加剂的条款：所有基于毒理学数据所获得的标准，交叉引用这些数据 l The quality specifications which have been laid down in the directives are satisfactory as long as the routine control tests used are validated. l 只要所用的常规控制测试已经过验证，则可以采用在欧盟指令中已设定的质量标准 l The international specifications (FAO/WHO/JECFA), and other publications, such as the Food Chemical Codex. l 国际质量标准(FAO/WHO/JECFA)，和其它出版物，例如“食品化学法典” l For medicinal products for cutaneous use, data on the ingredient used in cosmetic products (see Directive 76/768/EEC, as amended). l 对于皮肤用药，参考化妆品中使用的辅料的数据（参见指令76/768/EEC及修订内容） l Data concerning the toxicology of the novel excipient according to the dosage form and the route of administration of the medicinal product (if applicable) in Module 4, the safety section of the dossier. l 根据药品剂型和摄入途径（适用时）所进行的创新辅料毒理学数据放入模块4申报文件的安全部分 c) Documentation on chemistry of excipients is required for all novel excipients, taking as its basis the CPMP Guideline on the Chemistry of New Active Substances (CPMP/QWP/130/96) and should include:
所有创新辅料均需提交辅料的化学文件，以“CPMP新活性物质的化学指南”(CPMP/QWP/130/96)为基础，同时考虑以下内容 l The origin of the excipient, including the name and address of manufacturer. l 辅料来源，包括生产商名称和地址 l A general outline of the manufacturing and purification procedures. l 生产和纯化程序的大概流程 l Structure. l 结构 l Physical, chemical properties, identification and purity tests. l 物理，化学性质、鉴别和纯度测试 l Validated methods of analysis with a presentation of batch results. l 分析方法验证及批检测结果 l Miscellaneous information (microbiological tests, etc). l 其它资料（微生物测试等） l Contamination, presence of foreign substances, residual solvents, etc. l 污染，异物检查，残留溶剂等 l In the case of an excipient obtained from a mixture of several components, the quality of each component and the physico-chemical tests for the mixture should be described. l 如果一种辅料由几种成分混合而成，每种成分的质量，混合物的理化测试应进行描述 l Stability data should be provided as required for the active substances in the Note for Guidance on Stability Testing of New Drug Substances and Products (CPMP/ICH/2736/99). l 应根据“新原料药和制剂的稳定性试验指南”(CPMP/ICH/2736/99)对活性物质的要求提供稳定性数据 The routine test procedures and limits should be established on the basis of the documentation given in the dossier. 常规测试程序和限度应基于申报文件基础建立。 4.7 Control of Drug Product (3.2.P.5) 制剂的控制 Apart from those situations envisaged in the Note for Guidance on Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, it is not necessary to carry out identity testing and an assay of the excipients in the medicinal product at release. The control of antioxidants and antimicrobial preservatives, however, should comply with the requirements outlined in the guideline mentioned above. 除了在“质量标准指南解释：新原料药和新制剂检测方法和可接受标准：化学物质” (CPMP/ICH/367/96)中设定的情形之外，不需要在放行时对制剂中的辅料进行鉴别和含量测试。但是，对抗氧剂和防腐剂的控制要符合上述指南中的要求。 The medicinal product release specifications should include an identification test and a content determination test with acceptance criteria and limits for each antioxidant and antimicrobial preservative present in the formulation. The medicinal product shelf-life specification should also include limits for antimicrobial preservatives when present. 制剂产品放行标准应包括所含的每种抗氧剂和防腐剂的测试鉴别测试和含量测试，并符合可接受标准和限度。制剂的货架期质量标准中也应包括防腐剂的限度。 Where antioxidants are used during the manufacture of the medicinal product, the release limits should be justified by batch data or a sound justification has to be provided, if the proposed specifications do not include an identification test and a content determination test for the antioxidant. If needed, the adequacy of the specified limits should be justified on the basis of controlled conditions and (in-use) stability testing, to ensure that sufficient antioxidant remains, to protect the medicinal product throughout its entire shelf-life and during the proposed in-use period. 如果在制剂生产中使用了抗氧剂，而所拟质量标准并不包括对抗氧剂的检测和含量测试，则放行限度应根据批数据进行论证，或提供一个合理的论证。必要时，应根据受控条件下和（在用）稳定性试验情况来论证指定限度的充分性，以保证有足够的抗氧剂保留在制剂中，能在整个货架期和所拟的使用期间一直对制剂起到保护作用。 4.8 Stability (3.2.P.8) 稳定性 The maintenance of the physico-chemical properties of the medicinal product is partly dependent upon the properties and the stability of the excipients. 制剂的理化性质的维持部分依赖于辅料的特性和稳定性。 For the medicinal product the application should follow current CHMP/ICH stability guidelines and should ensure that antimicrobial preservative and, if appropriate, antioxidant levels are quantified periodically throughout the shelf-life. The antimicrobial preservative content should be monitored throughout the shelf-life to ensure that antimicrobial preservative levels remain above the level challenged for preservative efficacy and within the specifications. 制剂的申报应遵守现行CHMP/ICH稳定性指南，应保证防腐剂和，适当时，抗氧剂水平在其货架期内均被定量测定。防腐剂含量应在其货架期内进行监测，以保证其水平保持在防腐效果挑战水平之上，并在质量标准限度以内。 In the case of non-solid medicinal products presented in multidose containers that contain preservatives, the efficacy of the antimicrobial preservative under simulated in-use conditions should be established. The tests should be performed under conditions simulating the dosage recommendations, as stated in the SPC. 如果单包装多次使用非固体制剂含有防腐剂，则应研究模拟在用条件下防腐剂的效果。测试应按SPC中对相应剂型的推荐模拟条件下进行。 4.9 Labelling 标识 For all excipients included in a medicinal product, the relevant guidance documents: Excipients in the Label and Package leaflet of Medicinal Products for Human Use (Eudralex 3BC7A) and CPMP Position Paper on Thiomersal, Implementation of the Warning Statement Relating to Sensitisation (CPMP/2612/99) have to be taken into account. 所有用于制剂的所有辅料，在标识时均应考虑相关指南文件：“人用药标签和包装说明书中辅料内容”(Eudralex 3BC7A)“CPMP关于硫柳汞的立场，关于变态反应的警告声明的实施”(CPMP/2612/99)。 DEFINITIONS 定义 Novel excipient: A novel excipient is an excipient which is being used for the first time in a drug product, or by a new route of administration (ICH). It may be a new chemical entity or a well established one which has not yet been used for human administration and /or for a particular human administration pathway in the EU and/or outside the EU. 创新辅料：指在药品是首次使用，或首次用于某种新的摄入途径（ICH）。它可能是一种新的化学实体，或已经成熟的产品但在欧盟和/或欧盟以外地区从未用于人体摄入，和/或常规人体摄入途径。 REFERENCES 参考文献 This guideline should be read in conjunction with: 本指南应与以下指南一起解读 l Note for Guidance on Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (CPMP/ICH/367/96) l 质量标准指南解释：新原料药和新制剂检测方法和可接受标准：化学物质 l Note for Guidance on Impurities: Residual Solvents (CPMP/ICH/283/95) l 杂质指南解释：残留溶剂 l Note for Guidance on Stability Testing of New Drug Substances and Products (CPMP/ICH/2736/99) l 新原料药和制剂稳定性试验指南解释 l Guideline on the Chemistry of New Active Substances (CPMP/QWP/130/96) l 新活性物质的化学指南 l European Pharmacopoeia General Monograph, Substances for Pharmaceutical Use (2034) l 欧洲药典通用各论：药用物质 l European Pharmacopoeia General Chapter 5.1.3 Efficacy on Antimicrobial Preservation l 欧洲药典通论5.1.3抗微生物防腐剂效果 l European Pharmacopoeia General Chapter 5.1.7 Viral Safety l 欧洲药典通论5.1.7病毒安全 l European Pharmacopoeia General Chapter 5.2.8 Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products l 欧洲药典通论5.2.8降低TSE通过人用或兽用药品传播风险 l Individual monographs of the European Pharmacopoeia l 欧洲药典各论 l Note for Guidance on Development Pharmaceutics (CPMP/QWP/155/96) l 药物研发指南解释 l Note for Guidance on Pharmaceutical Development (CHMP/ICH/167068/2004) l 药物研发指南解释 l Rules governing Medicinal Products in the European Community, Notice to Applicants, Volume 3B – “Excipients in the Label and Package leaflet of Medicinal Products for Human Use” (Eudralex 3BC7A) l 欧共体药品管理规定，申请人通知，第3B卷---“人用药标签和包装说明书中的辅料内容” l Note for Guidance on Maximum Shelf-life for Sterile Products for Human Use After First Opening or Following Reconstitution (CPMP/QWP/159/96 corr) l 人用无菌药在首次开启后或之后的重组后的最长货架期指南解释 l Note for Guidance on In-use Stability Testing of Human Medicinal Products (CPMP/QWP/2934/99). l 人用药品持续稳定性试验指南 ANNEX 1 附录1 DIFFERENT TYPES OF EXCIPIENTS AND THEIR REQUIREMENTS 不同辅料类型及其要求 1. Excipients that are a single chemical entity include, for example, organic and inorganic acids and their salts, sugars and alcohols.
辅料成份为单一的化学实体，包括如，有机酸、无机酸及其盐、糖、乙醇 They may have undergone physical treatments, which gave them special technological characteristics (e.g. micronisation).
它们可能经过物理处理，从而具有特殊的技术特性（例如微粉化） 2. Chemically transformed excipients include excipients which have undergone a special chemical treatment in order to confer certain technological characteristics (e.g. modified starch).
经过化学转换的辅料，包括经过特殊的化学处理以使其具有特定的技术特性（例如改性淀粉） The name and quality of such excipients should be defined in such a way as to avoid confusion with an unmodified excipient.
这种辅料的名称和质量应适当命名，以避免与未经改性的辅料相混淆。 3. Mixtures of chemically related components include, for example, polyol esters (mixture of mono, di and tri esters), hydrogenated glucose syrup, maltitol syrup.
化学相关成分的混合物，包括如多元醇酯（单酯、二元酯和三元酯的混合物）、氢化葡萄糖浆、麦芽糖醇糖浆。 For these products the dossier should specify the following characteristics of the excipient:
对于这类产品，申报文件应说明辅料的以下特性 l the nature and content of each component with a statement of its acceptable limits; l 每种成分的属性和含量，声明其可接受限度 l technological criteria (appropriate criteria to the performance of dosage form); l 技术标准（保证剂型性能的适当的标准） l any additive which may be present and their quality if appropriate. l 可能会出现的添加剂及其质量，适当时 4. Mixed excipients are ready-for-use preparations, to be used for example for direct compression or film coating.
经制备可直接使用的混合辅料，例如可直接压片或薄膜包衣 l The qualitative and quantitative composition of the mixed excipient should be submitted, the specifications of the mixture as a whole and of each component should be stated. l 要提交混合辅料的定性和定量组成，说明混合辅料作为一个整体的质量标准，以及各成分的质量标准 5. Excipients of natural origin, so called "natural" products have often undergone some kind of chemical treatment.
所谓“天然”的产品的天然来源辅料通常会经过某些化学处理。 In general and if relevant for the quality control of the product, data should give an outline of the operations carried out to obtain and to purify the product, and any special characteristics: decomposition products, specific impurities, chemical substances used during the treatment with residual limits, methods of sterilisation or decontamination, with a description of the effect of these processes on the excipient (e.g. modification of the physical structure).
一般来说为控制产品质量，所提供的数据要能说明为获得和纯化该产品所进行的操作，及所有特殊特性：降解产物、特定杂质、在处理过程中所用的化学物质及残留限度、灭菌方法或除污染方法，以及这些处理对辅料产生的影响描述（例如，物理结构的改性） 6. Flavouring agents (flavours and aromatic substances) are either natural products and/or products obtained by chemical synthesis. Because of the complexity of their composition, it is only necessary to describe the general qualitative composition mentioning the main constituents with an appropriate process of identification to ensure the consistency of the composition (in particular, identification of the main constituents and if necessary carriers). Most constituents of artificial flavours have internationally accepted purity criteria in food use (FAO/WHO). Reference to these standards is acceptable for medicinal products.
香味添加剂（香料和芳香物质）可以是天然产品和/或由化学合成的产品。由于其成份复杂，只需要描述其一般定性成分，指出其主要成分及适当的鉴定过程，以保证其成分的一致性即可（尤其是主要成分，和必要时其载体）。大部分人工香精成分是有国际可接受食品用纯度标准的(FAO/WHO)，药品只要引用这些标准即可接受。 7. An adjuvant is a substance that helps and enhances the pharmacological effect of a drug or increases the ability of an antigen to stimulate the immune system.
非特异性免疫增生剂（佐剂）是指一种帮助或增强药品免疫效果或增加刺激免疫系统免疫力的物质。 ANNEX 2 附录2 ANTIOXIDANTS & ANTIMICROBIAL PRESERVATIVES 抗氧剂和抗微生物防腐剂 For each antioxidant and antimicrobial preservative the application should contain: 对每一种抗氧剂和抗微生物防腐剂，申报文件应包括 l reason for inclusion and justification of level of inclusion l 加入的理由和加入数量论述 l proof of safety and efficacy l 安全性和有效性的证明 l the method of control in medicinal product (not applicable for synergists e.g. sodium edetate) l 药品的控制方法（不适用于增效剂，例如EDTA钠盐） l levels on storage of broached and unbroached containers l 打开和未打开的容器的存贮水平 l details on the labelling of the medicinal product l 药品标识详细内容 The safety of the antioxidant or antimicrobial preservatives should be supported by bibliographic and/or experimental data unless the antioxidant or antimicrobial preservative is well known and generally used at same concentrations and by the same route of administration. 抗氧剂或防腐剂的安全性应由文献和/或实验数据来支持，除非该抗氧剂或防腐剂已知是众所周知的，且使用一个相同的浓度，经由相同的摄入途径。 ANTIOXIDANTS 抗氧剂 Antioxidants are used to reduce the oxidation of active substances and excipients in the medicinal product. Antioxidants should not be used to disguise poorly formulated products or inadequate packaging. The need to include an antioxidant should be explained and fully justified. Oxidative degradation can be accelerated by light and by the presence of mineral or metallic impurities, due to the formation of free radicals. 抗氧剂用于降低药品中活性物质和辅料的氧化。抗氧剂不应用于掩盖配方瑕疵或包装不足。加入抗氧剂的原因需要进行解释并全面论述。氧化降解可能在光照下，及因为形成游离基团，导致矿物或金属杂质出现而加速。 The effect obtained from an antioxidant depends on its nature, the stage at which it is incorporated into the medicinal product, the nature of the container and the formulation. 抗氧剂所能产生的效果取决于其属性，在什么阶段加入到药品中，以及包装和配方的情况。 Types of antioxidants. 抗氧剂类型 Type 类型 | | | | These are thought to block chain reactions by reacting with free radicals | Butylated hydroxytoluene (BHT) | | | | | These have a lower redox potential than the drug or excipient they are protecting | | | | | | These enhance the effects of antioxidants | | | | |
ANTIMICROBIAL PRESERVATIVES 防腐剂 Antimicrobial preservatives are used to prevent or inhibit the growth of micro-organisms which could present a risk of infection to or degradation of the medicinal product. These micro-organisms may proliferate during normal conditions of use of the product by the patient, particularly in multidose preparations. 防腐剂用来防止或抑制微生物的生长，这些微生物的生长可能会带来感染风险，或使药品降解。这些微生物可能会在患者正常使用这些药品时增殖，尤其是在多剂量制剂中。 On no account should antimicrobial preservatives be used as an alternative to Good Manufacturing Practice (GMP). 不管在任何情况下，防腐剂均不可以用来代替GMP要求。 Preparations at greatest risk of contamination are those which contain water such as solutions, suspensions and emulsions to be taken orally, solutions for external use, creams and sterile preparations used repeatedly (e.g. injectable multidose preparations and eye-drops). 最具有被污染风险的是那些含水的制剂，如口服溶液、混悬液和乳剂，外用溶液，重复使用的膏剂和无菌制剂（例如注射用多剂量制剂和滴眼液）。 The level of efficacy will vary according to the chemical structure of the antimicrobial preservative, its concentration, the physical and chemical characteristics of the medicinal product (especially pH) and the type and level of initial microbial contamination. The design of the pack and the temperature at which the product is stored will also affect the activity of any antimicrobial preservatives present. 防腐效果会因为防腐剂化学结构、浓度，制剂的化学和物理特性（尤其是pH值）和初始的微生物污染水平不同而不同。包装设计和产品存贮温度也会影响防腐剂活性。 The antimicrobial efficacy of the antimicrobial preservative in the medicinal product should be assessed during product development, and at the end of the proposed shelf-life, using the method described in the respective Ph. Eur. General Chapter 5.1.3. 药品中防腐剂的抗微生物效果应在产品研发期间，以及拟定的货架期结束时，采用欧洲药典通论5.1.3所述方法进行评估。 If non-solid medicinal products do not contain an antimicrobial preservative and do not have self-preserving properties or the container closure system is not able to prevent microbial ingress into the formulation they should not be packaged in multidose presentations without a sound justification. 如果非固体制剂不包括任何防腐剂，也没有自我防腐特性，容器密闭系统也不能防止微生物侵入制剂，如果没有合理论述，则这种制剂不能采用多次使用的包装形式。 ANNEX 3 附录3 SOLUBILISERS AND PERMEATION ENHANCERS 增溶剂和促渗剂 Solubilisers and permeation enhancers incorporated in transdermal formulations (e.g. transdermal gel or patches) modify the delivery of an active substance into the systemic circulation via the transdermal application route. Strategies to chemically enhance or modify the in-vivo flux comprise disrupture of the stratum corneum structure (effect on diffusion), alter the solubility of the active substance in the stratum corneum (effect on partition) or influencing the thermodynamic activity of an active substance -the driving force for the passive diffusion process- within the formulation (vehicle). Chemical permeation enhancers can alter the barrier function and the effect can be either reversible or irreversible. 加入到透皮制剂（例如透皮胶或透皮贴剂）中的增溶剂和促渗剂改良了活性物质通过透皮应用途径向系统循环的传送。化学增加策略，或改良体内体内流的策略使用角质层结构（影响扩散）的扰乱变差，转换了活性物质在角质层里的溶解度（影响其分配），或制剂（传送媒介）中影响活性物质的热力学活性----被动扩散过程的动力。化学促渗剂可以转换屏障功能，其效果可能是可逆的，也可能是不可逆的。 Different types of substances are known for their ability to enhance the permeation through the skin and are commonly used in transdermal formulations. Although representing partly different mechanisms by which they alter the stratum corneum (e.g. extracting lipids from lipid bilayer, partition into bilayers and disrupting its order or fluidisation of the lipid structure), those substances have one property in common: they increase the active substance permeability through the skin. 各种不同的物质因其可以促进皮肤渗透的能力而为人所知，它们通常被用于透皮制剂。尽管它们以不同机理改变角质层（例如，从双分子脂膜中抽提脂质层，部分进入双分子层，破坏其顺序，或脂质层结构流动化性质），这些物质具有一个共同的特性：它们增加了活性物质渗透皮肤的能力。 Excipients able to modulate the in vivo performance of a transdermal formulation are often not identified and declared as substances with a distinctive influence on the permeation (e.g,: terpene containing oils, declared as fragrances; propylenglycol, declared as solubiliser although permeation enhancing effects can be observed). 可以改善透皮制剂的体内行为的辅料通常并没有经过识别，声明该物质可以对渗透有显著影响（例如，萜类包括油，声称作为芳香剂，丙二醇，声称作为增溶剂，尽管可以观察到它们的促渗效果）。 Groups of chemical substances known for their ability to act as permeation enhancers or solubilisers in transdermal formulations are for example (list is not exhaustive) surfactants, fatty acids and their salts, fatty esters, alkyl amines, alcohols, azone like molecules, pyrrolidones, sulfoxides and terpenes. 已知具有在透皮制剂中作为促渗剂或增溶剂能力的化学物质包括（列表并非排他性），如表面活性剂、脂肪酸及其盐、脂肪酯、烷基胺、乙醇、N一正十二烷基己内酰胺、吡咯酮、亚砜类和萜类。 If one of the above mentioned chemical substances is incorporated into a transdermal formulation, a permeation enhancing or influencing effect on the barrier function of the stratum corneum can be expected, unless otherwise shown by experimental data. The need to include a permeation enhancer or solubiliser and the amount necessary to guarantee adequate flux rates should be explained in detail and justified by skin permeation studies during pharmaceutical development. The degree of enhancement by a permeation enhancer is depending on its concentration, other excipients in the formulation and the physico-chemical properties of the respective active substance. It is necessary to evaluate those effects on a case by case basis; no generalization for a certain group of excipients is possible. 如果透皮制剂中放入了上述某一个化学物质，除非有实验数据证明其它情况，否则则应该是对渗透角质层屏障有促进或影响效果。在药品研发中，应由皮肤角质层研究来论述，或对充分解释为什么必须加入促渗剂或增溶剂，以及要加入多少数量来保证具有足够的流通率。促渗剂能促进渗透的程度依赖于其浓度、制剂中其它辅料，以及相应活性物质的理化性质。有必要各案研究这些影响并进行评估，对于一组特定的辅料没有通用的理论。 A release and shelf life specification based on the results of clinical or at least permeation studies needs to be established in order to ensure a reproducible in-vivo performance of the respective formulation. 要根据临床，或至少是渗透研究的结果建立放行和货架期质量标准，以保证相应配方的具有可重现的体内行为。
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发表于 2014-5-11 09:09:46
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