欧盟复方草药质量指南-译.doc

欧洲药品管理局GUIDELINE ON QUALITY OF COMBINATION HERBAL（复方草药质量指南）内容解析COMMITTEE ON HERBAL MEDICINAL PRODUCTS(HMPC)草药产品委员会This guideline applies to herbal medicinal products containing combinations of herbal substances本指导适用于含有草药和草药提取物的草药制品本指南引用的其它指南附件(1), “Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products” “草药材、草药制剂和草药产品/传统草药产品的分析程序和验收标准的指导原则”(2), Annex 7 “Manufacture of herbal medicinal products” of Good Manufacturing Practices (GMP) for medicinal products, Volume 4, Rules governing medicinal products in the European Union附件7：草药产品良好生产规范(GMP),第4卷,欧盟医药产品管理规定MAIN GUIDELINE TEXTHerbal medicinal products contain herbal substances/preparations each consisting of a large number of chemical constituents of which only a few may be characterized.草药产品中含有的草药材/草药提取物包含大量的化学组成，但是其中只有少数可明确其成分及结构。Furthermore, herbal substances are natural in origin and consequently their chemical composition varies. In addition, in most cases the constituents responsible for the therapeutic activity are unknown or only partly explained and often markers are used to characterize these products.另外，由于草药材来源于自然，其化学成分多变，在多数情况下，这些起到治疗作用的活性成分往往是未知的或者仅仅部分可知，其标记物经常被用来指示产品质量。In herbal medicinal products containing combinations of herbal substances and/or herbal preparations, quality control may be more problematic because, in addition to the above-mentioned difficulties, other herbal substances and/or preparations may interfere with the analysis, e.g. extraction or detection of a marker may be affected by other herbal substances present (co-elution) in the finished product. 在含有混合草药材和/或草药提取物的草药产品中，质量控制可能会变得很复杂，因为除了上述提及的检测困难外，其他草药材和/或提取物也可能会干扰分析结果，举例来说，在产品中某一个标记物的提取或分析可能会受到产品中其他草药材的影响。The quality of a combination herbal medicinal product should in general be guaranteed and demonstrated in accordance with the existing guidance. All relevant parameters should be tested in the finished product， and identification and assay of each herbal substance/herbal preparation included in the product are required. 复方草药产品的质量标准一般来说应保证和与现有指南相一致。在进行所有的终产品检测项时，产品中每一味药材/提取物的鉴定和含量分析也是必需的。The stability of the finished product must be guaranteed. For some combination herbal medicinal products, identification and quantification of individual herbal substances/herbal preparations in the product are difficult to perform and sometimes impossible. Clarification on how the requirements on identification and assay should be interpreted is provided below. It should be stressed that notwithstanding the guidance given, all usual analytical methods for identification and assay should be investigated first, e.g. the methods described in the Ph. Eur. General Chapter 2 “Methods of analysis”. Furthermore, each approach taken should be justified by the applicant, and should take into account the combination herbal medicinal product that is subject of the application.草药产品的稳定性必须得到保证。对于某些复方草药产品来说，终产品中每一味药材/提取物的鉴别和含量分析很难进行，有时甚至不可能做到。复方草药分析和鉴别的具体要求将在以下章节详细说明，需要强调的是，虽然已经给出了相关的指南文件，但所有通用的鉴定和分析方法，如欧洲药典通则二中所描述的“分析方法”，在正式采用前都应先作调查。此外，每一个方法的合理性均需申请者自行判断，并考虑是否符合复方草药申请标准。If individual active substance testing for identity, assay or to demonstrate stability cannot be performed in the finished product, alternative strategies may be considered. The simple omission of (a) test(s) is not acceptable as the quality of combination herbal medicinal products should be fully comparable to the quality of other (herbal) medicinal products. 如果针对产品中单一物质的鉴别、含量分析或申明其稳定性的分析检测不可能完成，可以考虑替代策略。由于复方草药的质量标准参照其它医药品的质量，因此，忽略其中一个（或多个）检测项是不能接受的。In this regard, reducing the number of active substances in the herbal medicinal product could increase the possibilities to perform all tests (e.g. identification, assay etc.) in the finished product.就这一点而言，减少复方草药产品的药味数，助于完成产品中所有的相关检测项目（如鉴别和含量分析等）。As required for all medicinal products, GMP, process validation and batch records documenting each step in the manufacturing process of the finished product and including results of IPC testing should ensure that, in combination with suitable testing criteria, a product of good and consisting quality is obtained. The manufacturing process should, as required for all medicinal products, be designed in such a way that the manufacture and composition of the finished product is well-controlled and conforms with the declared composition. 对所有药品的要求而言，产品GMP、过程验证、记载生产过程每一步骤的批记录以及包括中间品检测都应该得到保证（与适当的测试标准一起），以达到产品质量的良好一致性。生产过程应该进行良好设计，以保证使产品组成均有良好控制并与已声明的质量组成一致。The manufacturing process design should be supported by strict and well-documented process validation. 制造过程设计应由严格且良好记录的过程验证结果来支持。An appropriate IPC testing programme (e.g. testing at various points during the stepwise addition of the herbal substances/preparations) and an identification test of the herbal substance/herbal preparation immediately before the introduction in the manufacturing process of the finished product are measures to ensure the consistent quality and declared composition of the finished product. 应进行适当的IPC分析（如在草药材/提取物生产步骤中进行的多点取样检测）和制剂生产工序前引入的药材/提取物鉴定分析，以保证产品与所声明质量和组成的一致性。Each step of the manufacturing process should be regarded as critical and appropriate procedures to ensure correct addition of ingredients should be in place as routine control. Documentation on GMP should be available to the Competent Authorities upon inspection, and manufacturing and process validation data should be submitted in the marketing authorisation/registration dossier.生产过程中的每一步都应被认定为关键和适当步骤，以保证正确的常规控制方法得到使用。同时，GMP文件应该留用以备药政当局现场审查，生产和过程验证的数据应该在申请产品许可时递交。Where a joint assay is performed, the active substance specification should include a (additional, if different from the pharmacopoeial marker) limit for the common marker.当进行综合分析时，药材质量标准应该包括通用标记物的限量分析。Where applicable, the same principles apply to control tests carried out at an intermediate stage of the manufacturing process of the finished product. 如适用，同样的原则适用于产品生产过程的中间品控制。The following requirements apply for identification and quantitative determination of each active substance in the combination herbal medicinal product:以下要求适用于复方草药中每一味药材的鉴别和定量分析：IDENTIFICATION TEST OF EACH ACTIVE SUBSTANCE每一味药材的鉴别 (read in conjunction with Decision tree # 1: Identification test of each active substance in combination herbal medicinal products) （阅读决策树#1：复方草药中每一味药材的鉴别分析）l Where constituents with known therapeutic activity or active markers of the herbal substance/preparation are known, the identification of the active constituents should be performed in the finished product in accordance with the Guideline on specifications (2). l 针对在药材/提取物中起治疗作用的成分或活性标记物已知的情况，产品中活性成分都应按照质量标准指南的要求（2）进行鉴别。l Where constituents with known therapeutic activity or active markers of the herbal substance/preparation are not known: 针对在药材/提取物中治疗作用成分或活性标记物未知的情况：- Each herbal substance/preparation that can be identified should be identified in the finished product in accordance with the Guideline on specifications (2). - 每一个能鉴别的药材/提取物，都应该根据质量标准指南（2）的要求进行鉴别。- Where the herbal substance/preparation cannot be identified in the finished product, appropriate justification and documentation that all usual analytical methods, e.g. the methods described in the Ph. Eur. General Chapter 2 “Methods of analysis”, have been investigated should be provided. Furthermore: - 对于产品中未知部分的草药材/提取物应有适当的证明表示所有常用的分析方法，例如欧洲药典第2章中所述的“分析方法”，均使用过，此外：n The identification test of the herbal substance/preparation should be performed as an in process control at the latest point in the manufacturing process of the finished product where analysis is still possible. The approach taken should be fully justified by the applicant. The identification test should be supported by documented evidence on the manufacture of the finished product batch and process validation.n 草药材/提取物的鉴别分析应作为工序控制的一部分，如有可能，应在制剂生产的最后检测点进行。所采用方法的合理性应由申请者自行判断。鉴别分析方法的有效性应由良好记录的制剂生产和过程验证数据来支持。 In addition, the release specifications of the finished product should include suitable identification methods for the combination, e.g. characteristic fingerprints, in line with the Guideline on specifications (2). The sum of the identification methods should allow appropriate characterisation of the combination. 此外，产品放行标准应该包括复方制剂适当的鉴别方法。如结构图谱，以与质量标准指南原则（2）是的要求一致，多种鉴别方法应该允许复方草药得到适当的结构确证。 If IPC testing of the herbal substance/preparation is not possible, it is required that the herbal substance/preparation is identified according to the active substance specifications immediately before the introduction of the active substance in the manufacture of the finished product. The approach taken should be fully justified by the applicant. The identification test should be supported by documented evidence on the manufacture of the finished product batch and process validation. 如果药材/草药提取物的IPC分析不可行，则复方产品中药材/提取物的鉴别应在引入制剂生产以前，根据药材的质量标准来进行。所采用方法的合理性应被申请人自行判断，鉴别分析方法的有效性应由良好记录的制剂生产和过程验证数据来支持。In addition, the release specifications of the finished product should also include suitable identification methods, e.g. characteristic fingerprints in line with the Guideline on specifications (2). The sum of the identification methods should allow appropriate characterisation of the combination 此外，终产品的放行标准应包括适当的鉴别方法，如特征指纹图谱信息，以与质量标准指南保持一致。多种鉴别方法应该允许复方草药得到适当的结构确证。ASSAY OF EACH ACTIVE SUBSTANCE 每一味药材的含量分析(read in conjunction with Decision tree # 2: Assay of each active substance in combination herbal medicinal products) （阅读决策树#2：复方草药产品中每一味药材的含量分析）l Where constituents with known therapeutic activity or active markers of the herbal substance/preparation are knownl 针对药材/提取物中治疗作用的有效成分已知的情况- an individual assay of the active substance should be performed in the finished product in accordance with the Guideline on specifications (2).- 应根据质量标准指南的要求，可进行制剂中药材单一组分的含量分析- If an individual assay of the herbal substance/preparation is not possible, the quantitative determination can be carried out jointly for two or more herbal substances/preparations (e.g. joint determination of group of anthraquinone-derivatives) in accordance with the Guideline on specifications (2). - 如果针对药材/提取物单一成分的含量分析不可行，可针对两种或多种药材/提取物进行综合定量分析（如蒽醌衍生物成分群的综合定量分析），其方法可参照质量标准指导原则进行。l where constituents with known therapeutic activity or active markers of the herbal substance/preparation are not known: l 针对药材/提取物中治疗作用的有效成分未知的情况l Each herbal substance/preparation that can be assayed, should be quantified in the herbal medicinal product in accordance with the Guideline on specifications (2). l 每一种可以进行含量分析的药材/提取物，应该根据质量标准指南的要求，在终产品中进行含量分析。l If an individual assay of the herbal substance/preparation is not possible, the quantitative determination can be carried out jointly for two or more herbal substances/preparations in accordance with the Guideline on specifications (2). l 如果针对药材/提取物进行的单一成分含量分析不可行，其定量分析可以针对两种或多种药材/提取物进行，分析方法可参照质量标准指导原则进行。An assay of a common marker gives limited information on the relative composition of the concerned herbal substances/preparations in the herbal medicinal product. As such, markers for joint analysis should be carefully selected and justified. If a joint analysis is considered acceptable, the specifications of the concerned herbal substances/preparations should include a (additional, if different from the pharmacopoeial marker) limit for the common marker. The approach taken should be fully justified by the applicant. Each approach should be supported by careful process validation and documentary evidence should be available. 如果对某一通用标记物的含量测定结果得出制剂中相关药材/提取物相关组成很有限的信息，在这一种情况下，应谨慎选择和判断是否对标记物成分进行综合分析。如果综合分析的结果可被接受，制剂中相关草药材/提取物的质量标准应包括（另外，如果不同于药典标记物）通用标记物的限量。所采用的方法应该由严谨的过程验证结果以及有记录的数据来支持。n Where the herbal substance/preparation cannot be quantified in the finished product, appropriate justification and documentation that all usual analytical methods, e.g. the methods described in the Ph. Eur. General Chapter 2 “Methods of analysis”, have been investigated should be provided. 如果产品中的药材/提取物不能被定量，应提供针对所有通用分析方法的适当判断和文献信息，如欧盟药典中所述分析方法的确认。Furthermore, an appropriate manufacturing process design, supported by strict and well-documented process validation, should ensure that the manufacture and quality of the finished product is well-controlled and that the composition of the finished product conforms with the declared composition. 此外，由严格和良好记录的过程验证数据支持的适当生产工艺设计应确保产品生产工艺和质量标准已经得到了良好控制，而且产品的组成与声明的质量相一致。The manufacturing process development studies (e.g. analytical profiles during the stepwise addition of the herbal substances/preparations, degradation studies during the manufacture of the finished product) and other studies e.g. stability studies of the active substance(s) are pivotal in this regard and should underpin the proposed approach to ensure the quality and composition of the finished product e.g. assay of the active substance as IPC. 工艺过程开发研究（药材/提取物生产过程中的全面分析，终产品生产过程中的降解研究）以及其他研究【如药材的稳定性研究】作为关键过程，应该强化这一途径以保证产品质量和组成（如IPC过程中药材的含量分析）。The approach taken should be fully justified by the applicant. Tests should be supported by documented evidence on the manufacture of the finished product batch. 方法合理性由申请人自行判断，检测分析应有终产品生产批次记录的数据来支持。In addition, the release and shelf life specification of the combination should include suitable assay methods for the combination in line with the Guideline on specifications (2), including e.g. semi-quantitative fingerprints, allowing a characteristic quantitative determination of the combination. 另外，复方草药的放行及货架期标准应该包括合适的含量分析方法，这一方法基于质量标准指南（2）进行，包括诸如半定量指纹图谱分析，允许复方草药中特征性的定量测定。The requirements above apply to the identification and quantification of each herbal substance/preparation in a combination herbal medicinal product. The overall release and shelf life specifications of a combination herbal product will therefore in general be a mixture of tests that individually identify and quantify the herbal substance(s)/preparation(s) in the finished product and/or tests that jointly quantify herbal substances/preparations in the finished product, and all other suitable identification tests and assays that allow an appropriate characterisation and a characteristic quantitative determination of the combination. 上文所述要求适用于复方草药产品中的每一味草药材/提取物的鉴别定量分析。复方草药的整体的放行及货架期标准因此是混合型分析检测，第一种混合的情况是针对复方草药种的每一味药材/提取物的鉴别和定量分析的混合，第二种混合的情况是复方草药制剂中所有药材提取物的联合分析，第三种情况是所有其他适当的鉴别和定量分析的混合，这种方式允许复方草药中采用一种适当的结构确认和特征性定量测定。Stability of the finished product 终产品的稳定性The stability of the c