抗生素中相关杂质质量标准制定的指导原则【中英】

1、EUROPEAN MEDICINES AGENCYSCIENCE M E D C 1 N E S HEALTH30 June 2012EMA/CHMP/CVMP/QWP/199250/2009 corrCommittee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP)Guideline on setting specifications for related impurities in antibiotics抗生素中相关杂质质量标准制

2、定的指导原则Final定稿Draft Agreed by Quality Working Party2010年5月质量工作中批准草案May 2010Adoption by CHMP for release for consultation2010年6月24日被人用药委员会采纳，公布征求意见稿24 June 2010Adoption by CVMP for release for consultation2010年7月15日被兽用药委员会采纳，公布征求意见稿15 July 2010End of consultation (deadline for comments) 2011年1月31日结束征求

3、意见31 Jan 2011Agreed by Quality Working Party2012年5月质量工作组批准May 2012Adoption by CHMP2012年5月14日被人用药委员会采纳14 May 2012Adoption by CVMP2012年6月14日被兽用药委员会采纳14 June 2012Date for coming into effect2013年6月30日生效30 June 2013学习之名（译注）Table of contents目录Executive summary1. Introduction (background)2. Scope3. Legal b

4、asis4. General requirements5. Impurity profiling and reporting, identification and qualification thresholds6. New applications and variations7. Specifications for medicinal products8. Analytical proceduresDefinitionsAnnex 1: Explanatory note regarding thresholds.Annex 2: ThresholdsAnnex 3: Example o

5、f “ fingerprint chromatogram ” approach to control very complex impurity profiles概要1、背景介绍2、范围3、法规依据4、一般要求5、杂质分布以及报告、鉴别和界定阈值6、新申请和变更7、制剂产品质量标准8、分析方法定义附件 1：关于阈值的注释附件 2：阈值附件 3：利用基于 “指纹图谱”的方法对非 常复杂的杂质分布进行控制举例Executive summary概要Antibiotics active substances currently on the market are produced by ferment

6、ation, by fermentation followed by one or more synthetic steps (semi-synthetic substances) or by chemical synthesis. Fermentation processes are, in comparison to synthetic processes, more variable and less controllable, so the impurity profile of an active substance whose manufacturing process invol

7、ves fermentation may be more complex and less predictable than that of a purely synthetic product. For this reason fermentation products and semi-synthetic substances are not included in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines, which set thresholds for the identification, reporting

8、 and qualification of related impurities in active substances manufactured by chemical synthesis. 目前上市的抗生素类活性物质是由发酵、发酵加一步或几步合成步骤(半合成)、化学合成制得。与合成工艺相比，发 酵工艺更具多变性，不易控制，因此与单纯使用化学合成生产的产品相比，生产工艺含有发酵步骤的活性物质的杂质分 布一般比较复杂和难以预测。基于此原因，发酵产品和半合成产品并不适用于 ICH Q3 和 VICH GL10/GL11 指南。因 为这两个指南适用于由化学合成生产的活性物质。This guide

9、line has been developed in order to provide guidance on how specifications for related impurities in antibiotics that are fermentation products or semi-synthetic substances derived from fermentation products, and are therefore not included in the scope of the (V)ICH guidelines mentioned above, shoul

10、d be set.本指南旨在为不适用于 ICH Q3 指南的发酵产品或源于发酵产品的半合成物质中杂质质量标准的设定提供指导。Thresholds are given in the guideline for reporting, identification and qualification of related impurities for antibiotics medicinal products whose active substance is produced by fermentation or semisynthesis. In cases where the active

11、substance consists of a mixture of closely related compounds, where it may be difficult to apply general thresholds, general guidance is given on how to set specific thresholds and specifications and on how to qualify impurity profiles. The relationships between the requirements in the guideline and

12、 the applicable Ph.Eur. chapters and monographs are also addressed. 对于活性成分为发酵或半合成来源的抗生素制剂产品的相关杂质，本指南给出了报告、鉴定和界定阈值。在活性物质由 多个密切相关的化合物混合组成情况下，对其应用一般的阈值存在困难。针对此，本指南就如何设定阈值和如何论证杂 质分布给出了指导。对于本指南与欧洲药典要求的关系，本指南也做了阐述。 注：界定限(界定阈值)：指超过该限度的杂质需进行论 证，包括安全性、设定的限度合理性等。1. Introduction (background) 背景介绍Most of the an

13、tibiotics currently on the market are produced by fermentation or chemical synthesis. In certain cases the chemical structure of the antibiotics obtained by fermentation is further modified by some synthetic steps, before the substance is used as an active substance in the manufacture of medicinal p

14、roducts (semi-synthetic substances). 目前市售的大多数抗生素是由发酵或化学合成生产的。一些情况下，由发酵生产的抗生素在可用作生产制剂的活性成分 前，其结构会经过一些合成步骤进行修改(半合成物质)Fermentation processes involve biological systems which are less predictable, less controllable and more complex than straightforward chemical reactions. Because of this, the variabilit

15、y in products derived by fermentation is often greater than in products derived by chemical synthesis. Thus, the impurity profile of a fermentation product may be more complex and less predictable than that of a synthetic product. 与直接化学方应相比，发酵工艺包含不易预测、控制和复杂的生物系统，发酵产品比化学合成产品更具多变性。因 此，发酵产品的杂质分布会比化学合成产

16、品的更复杂和不易预测。For this reason, fermentation products and semi-synthetic substances derived from them are notincluded in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines that set thresholds for the identification, reporting and qualification of related impurities in active substances manufactur

17、ed by chemical synthesis. These thresholds are defined in the guidelines as limits above which an impurity has to be either identified, reported or qualified, and the same limits are applied in the Ph.Eur. general monograph Substances for Pharmaceutical Use'F.ermentation products and their semi

18、syntheticderivatives are also excluded from the scope of this general monograph. 基于此，发酵产品和源于发酵产品的半合成物质并不适用于 ICH Q3 和 VICH GL10/GL11 。这两个指南旨在为化学合 成物质的鉴别、报告和界定阈值提供指导。依据这两个指南设定的阈值也适用于欧洲药典总论“药用物质”。发酵产品 和基于发酵产品的半合成物质并不适用于总论。In the absence of other guidance, related impurities in these products have been

19、assessed on a case- by-case basis, which has resulted in the acceptance of different impurity thresholds for the same antibiotic and for different compounds within the same class (e.g. cephalosporins). There is also a need to ensure that the authorisation of new antibiotics is enabled by consistent

20、approaches in setting limits for their impurities. 在以前没有其他指南的条件下，这些产品中的杂质是基于个案进行评估的，这就导致同一抗生素或同类下不能化合物有 不同的杂质阈值。在批准新抗生素时也需要采用一致的方法来设定杂质限度。It is therefore necessary to provide guidance, based on current practice and experience, to formulate general recommendations for impurity thresholds in antibioti

21、cs produced by fermentation or semisynthesis. These are presented in this guideline. 因此，有必要基于目前的实践和经验，为发酵或源于发酵的半合成产品中杂质阈值设定提供指南。Even so, it is acknowledged that in some cases higher thresholds may be acceptable if necessary and justified taking account of use and exposure of the drug substance/produ

22、ct. This would also include analytical problems (see Annex 1: Explanatory note regarding thresholds). 尽管如此，若考虑到药品的使用和用量，如果需要，采用较高的阈值也是可以接受的。见附件 1 ：关于阈值的注释2. Scope 范围This document provides guidance for marketing authorisation applications on setting specifications for related impurities in antibiotic

23、s (i.e. antibacterial substances) that are fermentation products or semisynthetic substances derived from fermentation products. It is foreseen to widen the scope to other antibiotics (e.g. antifungal substances) at a later stage. 本指南为源于发酵产品或源于发酵产品的半合成抗生素(例如抗菌物质)申请销售许可时，提供相关杂质质量标准的 设定指导。可以预见，后续本指南适用

24、范围会进一步扩展(例如抗真菌物质)。It provides guidance for the content and qualification of related impurities in both active substances and medicinal products. The guideline is not intended to apply to new active substances used in investigational medicinal products used in clinical trials. 可为活性物质和制剂中相关杂质的含量和界定提供指

25、导。本指南不适用于处在临床试验阶段的研究用活性物质。In this guideline thresholds are given for reporting, identification and qualification of related impurities. For antibiotics where the active substance consists of a mixture of closely related compounds where it may be difficult to apply these general thresholds, general g

26、uidance is given on how to set thresholds and specifications and how to qualify impurity profiles. The thresholds given in this guideline would represent a general set of requirements, and this could be subject, for specific substances or products, to adaptation to the specific situation. Further re

27、quirements might be introduced when considered necessary, e.g. for safety reasons. 本指南中给出了相关杂质的报告、鉴定和界定阈值。对于活性物质为相近的化合物混合组成的抗生素，由于采用一般的 阈值存在困难，指南给出了如何设定阈值和质量标准以及如何确定杂质分布的通用指导。本指南中给出的阈值代表一般的设定要求，对于特定的物质，需要根据特定情况进行调整。若需要，可将其他要求考虑在内，如安全因素This guideline does not cover residues from the fermentation proc

28、ess, i.e. residues from the producer micro-organism, culture media, substrates and precursors; this is covered by the Ph.Eur. general monograph Products of fermentation'(.This monograph applies to substances manufactured byfermentation only, and not to substances manufactured by semi-synthesis).

29、 本指南不包括发酵过程的残留，如生产菌株、培养基、基质和前体。这些残留依据欧洲药典总论“发酵产品”进行控 制。此总论仅适用于发酵生产的产品，不包括半合成生产的产品。This guideline applies to new active substances and for new sources of existing active substances. It is the Applicant 'sresponsibility to demonstrate that the active substance has already been marketed in the EU w

30、hen relevant. 本指南适用于新活性物质或新来源的已存在活性物质。需要时，申请者需说明该物质是否已在欧洲上市。The guideline should not be applied retrospectively, but it is intended that this guideline will act as a stimulus to establish best practice and to initiate the revision of relevant Ph.Eur. monographs (i.e. for registered products revised

31、requirements according to the monograph will apply when the monograph is introduced/revised). For new sources of existing active substances this guideline should be read in conjunction with any existing Ph.Eur. monograph for the active substance. It should be noted that comparison with impurity leve

32、ls/profiles of active substance sources or products approved in the EU is one of the options for qualifying impurities.本指南不可回顾性使用 注：不适用于已完成注册上市销售的产品 ，但可作为建立最佳实践或推动欧洲药典专论修订的刺激因素 (例如，对已注册的产品，当增加了某专论或修订了某专论，需依据情况进行修订)。对于新来源的已存在的活性物 质，本指南阅读时需要结合相应的药典准了。需要指出的是，与已在欧洲批准上市的活性物质或制剂进行杂质分布对 比，是一个确定杂质分布的方法。It i

33、s foreseen to re-evaluate the Scope when more experience has been obtained.3. Legal basis 法规依据This guideline has to be read in conjunction with the introduction and general principles (4) and part 1 of the Annex Is to Directives 2001/82/EC and 2001/83/EC as amended.4. General requirements 一般要求The im

34、purity profile depends very much on the manufacturing process; even for the same strain of a micro-organism, impurity profiles may be different. In general, purification steps including column chromatography and ultra-filtration steps may be crucial to achieve a sufficiently pure active substance. 杂

35、质分布与生产工艺密切相关；甚至同一微生物生产产品的杂质分布也有不同。一般来说，纯化步骤包括柱层析和超 滤，对获得一个纯品至关重要。Semi-synthetic substances are not within the scope of the Ph.Eur. general monographProducts offermentation 'H.owever, the specification of the fermented starting material should be justified with reference to current guidance, incl

36、uding general concepts described in this general monograph, if necessary. (The thresholds in this guideline are not intended to apply for fermented starting materials). 半合成物质不在欧洲药典总论“发酵产品”要求范围内。然而，如果需要，半合成产品的源于发酵的起始物料质量 标准应当满足总论“发酵产品”要求。(本指南中的阈值不适用于源于发酵的起始物质 注：指半合成产品的起始物料 )The shorter the synthetic

37、route after the fermentation and the more complex the fermented starting material, the more relevance the general monograph has. Therefore, a detailed description of the fermentation steps as well as other aspects addressed in the general monograph, in particular purification steps, should be presen

38、ted for semi-synthetic antibiotics, unless justified by the noncomplexity of the fermented starting material and the number and/or nature of the synthetic steps following fermentation. 发酵后合成工艺越短、源于发酵的起始物料越复杂，越适用于药典总论“发酵产品”要求。因此，对于半合成抗生素， 应详细描述发酵工艺和总论中要求的其他方面，尤其是纯化步骤，除非有源于发酵的起始物料不复杂和发酵后的合成 工艺的证明。Thes

39、e synthetic steps should contribute to a relevant depletion and inactivation of fermentation byproducts in the final active substance, so for example, esterification, etherification and salification of fermentation products (e.g., erythromycin derivatives like erythromycin ethylsuccinate or erythrom

40、ycin lactobionate) are not considered as significant synthetic steps which would justify an omission of a detailed description of the fermentation process, in particular of the purification. 合成步骤应当可以在一定程度上消耗或使发酵副产物失活。例如，发酵产品的酯化、醚化和成盐步骤，这类操作不认为 是重要的合成步骤，此情况下不可省略发酵工艺的详细描述，尤其是纯化步骤。In cases where the fe

41、rmented starting material is not complex and taking into consideration the number and nature of the synthetic steps after fermentation, it may be sufficient to have a suitable specification for the fermented starting material including assay, component distribution (if relevant) and related impuriti

42、es (specified, unspecified, and total). This should be in any case justified. For active substances manufactured by semi-synthesis, the impurity profile of the fermented starting material should be critically evaluated for its contribution to the impurity profile of the final active substance. 在源于发酵

43、的起始物料不复杂的情况下，将发酵后合成工艺的步数和原理考虑在内，为源于发酵的起始物料建立包括含 量、成分组成和相关杂质(特定杂质、非特定杂质、总杂)在内的质量标准足够了，这在任何情况下都是合理的。对于 半合成生产的活性物质，应当对源于发酵的起始物料引入的杂质进行充分地评估。Related impurities observed after fermentation include by-products, intermediates and degradation products. For semi-synthesis the impurities also include the ferm

44、ented starting material and related substances in this starting material, synthesis by-products (including those derived from impurities in the starting material), synthesis intermediates and degradation products. 发酵后的相关杂质包括副产物、中间体和降解产物。对于半合成后的杂质，也包括起始物料、起始物料中的相关杂质、 合成副产物(包括来自起始物料的副产物)、合成中间体和降解产物。Sp

45、ecifications should be given for any critical intermediates (this also includes intermediates between different purification steps). These specifications should include limits for specified and single unspecified impurities. Impurities that contribute to the impurity profile of the active substance

46、should be specified. The applicant should provide a discussion on potential impurities, how they are removed and which impurities appear in the active substance. 应当为关键中间体建立质量标准(包括不同纯化步骤间的中间体)。标准应当包括特定杂质和非特定单一杂质的限度。 进入最终活性物质的杂质应当详细说明。申请人应当提供针对潜在杂质的讨论，论述它们是如何除去和哪些杂质会在成 品中出现。Even if manufactured by fer

47、mentation or semi-synthesis, an antibiotic may be structurally well defined as a mono component substance, and thus it may be efficiently purified. For each class of antibiotic, it is considered preferable to optimise purification steps as far as possible, in order to decrease the level of impurity

48、to below the qualification threshold, than to provide (additional) safety data. 虽然一个抗生素是由发酵或半合成生产的，但它仍然可以是一个结构明确的单一组分物质，因它可经过有效地纯化。对 于每类抗生素，充分利用纯化步骤尽可能地使杂质含量低于界定阈值比提供(额外的)安全数据更可取。For antibiotics manufactured by fermentation, the active substance may consist of a mixture of closely related compounds

49、that show the relevant biological activity. In such cases it may be difficult to decide whether a compound is part of the active substance or should be regarded as an impurity when setting specifications (e.g. gentamicin). The definition of which substances are components of the active substance sho

50、uld be based on pre-clinical and clinical studies unless the active substance is described in a Ph. Eur. monograph where the active substance components are defined. Related compounds that are not defined to be components of the active substance are regarded as related impurities.对于由发酵生产的抗生素，活性物质可能由

51、一组密切相关的化合物混合而成，从而表现出相应的生物活性。这种情况下， 在设定质量标准时很难确定某个化合物是有效成分还是作为杂质(例如庆大霉素)。有效成分的界定应当基于预临床和 临床研究数据，除非药典专论中有相应说明。The thresholds given in the ICH Q3 and VICH GL10/GL11 guidelines and in the guideline Chemistry ofNew Active Substances '(CPMP/QWP/130/96 Rev 1, EMEA/CVMP/541/03) do not apply to fermentat

52、ionproducts and semi-synthetic substances derived from fermentation products. For other aspects, where specific guidance is not given in the present guideline, reference is made to the principles described in these guidelines.ICH Q3 和 VICH GL10/GL11 指南以及新活性成分化学指南中的阈值不适用于发酵产品和源于发酵的半合成物质。对 于本指南未提及的方面，

53、可以参考这些指南。In qualifying an impurity or a given impurity profile at the level specified, several possibilities exist: appropriate battery of non-clinical tests, literature based data; comparison with impurity levels/profiles of active substance sources/products approved in the EU; or proving that the

54、relevant impurity is a significant metabolite of the active substance. 在界定指定的杂质或杂质分布时，存在几种方案：一套合适的非临床试验、文献数据、与已被批准的活性物质 / 制剂的 杂质水平进行对比、或证明相应杂质是活性物质的重要代谢物。5. Impurity profiling and reporting, identification and qualification thresholds 杂质分布以及杂质的报告、鉴定、界定阈值For antibiotic drug substances, the impurity p

55、rofile should be characterised according to the guidance described in ICH Q3A (VICH GL10).对于抗生素原料药，其杂质分布应当依据 ICH Q3A 进行描述。In accordance with that guidance, with respect to related substances, limits should be set for: 应当为以下相关物质设定限度：?Each specified identified impurity;每个特定的已鉴别杂质?Each specified uniden

56、tified impurity;每个特定的未鉴别杂质?Any unspecified impurity, with an acceptance criterion of not more than the identificationthreshold; 任意非特定杂质，标准为不高于鉴定阈值? Total impurities. 总杂Exceptionally, if it is shown that it is not practically possible to identify an individual impurity, sufficient evidence of its str

57、ucture should be provided (e.g. by HPLC/mass spectrometry to show that it may be satisfactorily classified as a related substance of the parent compound. In this case, it should be specified using an appropriate analytical marker e.g. HPLC Relative Retention Time (RRT), as a specified unidentified i

58、mpurity. As a general principle, for impurities which are not structurally closely related (see section 5.3 below) to the parent compound, thresholds as given by ICH Q3A (VICH GL10)HPLC/ 质谱）证明其可以分类为母体化合物HPLC 相对保留时间，作为一个特定的未鉴别杂5.3 部分），应依据 ICH Q3A 对其设定阈值，should be applied unless stated differently in

59、the following sections. 尤其，如果难以鉴定某个单一杂质，应提供其充足的结构证据（例如，通过 的有关杂质。此情况下，应当采用适当的分析标记对其进行说明，例如质。参照一般原则，对于在结构上与母体化合物非密切相关的杂质（见 除非后续部分有特殊阐述。For the reasons discussed in section 4 above, and taking into account that the duration of treatment with antibiotics is in most cases limited, for antibiotic related substances the thresholds to be