原料中杂质的控制

1、原料药中杂质的控制原料药中杂质的控制The Control of ImpuritiesThe Control of Impuritiesin Drug Substancesin Drug Substances杨仲元杨仲元（广州市药品检验所）（广州市药品检验所）Yang Zhong-YuanYang Zhong-Yuan（Guangzhou Municipal Institute for Drug Control)Guangzhou Municipal Institute for Drug Control)The First Joint USP-ChP Conference The First

2、Joint USP-ChP Conference 15 August 2004 Shanghai15 August 2004 Shanghai原料药中杂质的控制The Control of Impurities in Drug Substances 本部分将讨论中国药典对药品杂质分析的新的指导原则，包括ICH 和其他药典的有关要求。 This part of the program will focus on the new guideline of the 2005 Chinese Pharmacopoeia for the analysis of drug impurities,inclu

3、ding relevant requirements of ICH and other pharmacopoeias原料药中杂质的控制The Control of Impurities in Drug Substances 本讨论包括： ICH新原料药中对杂质的指导原则 ICH关于杂质指导原则在国外药典中的引用 中国药典(2005)药品杂质分析指导原则原料药中杂质的控制The Control of Impurities in Drug Substances 虽然ICH指导原则是对申报新化学药和新生物制品的技术要求，但经ICH三方成员国制药工业部门和药品管理部门的协调，其原则切实可行，在保证药品

4、安全有效，药品的生产按GMP的要求，起一定作用，逐步为各国采用。不仅作为申报新药的要求，有的还作为修订药典正文的要求。ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances 文件Q3A（R）为未曾在ICH 三方注册过的化学合成新原料药申报时关于杂质的指导原则 This document is intended to provide guidance for registration application on content and qualification of impurities in new drug su

5、bstances produced by chemical syntheses and not previously registered in a region or member state.ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Q3A（R）杂质分类 Classification of Impurities 有机杂质 Organic Impurities 无机杂质 Inorganic Impurities 残留溶剂 Residual solventsICH新原料药中的杂质指导原则ICH Guide

6、line on Impurities in New Drug Substances 其中有机杂质包括起始原料、副产物、中间体、降解产物、试剂、配位体、催化剂。可以是经鉴定或未鉴定的 The organic impurities include starting materials,by-products,intermediates, Degradation products, reagents, ligands and catalysts( identified or unidentified)ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New

7、Drug Substances Q3A (R) 关于有机杂质的报告和控制中几点说明 Rational for the reporting and control of organic impuritiesICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances 为便于理解，先介绍ICH杂质指导原则中的几个术语： Reporting Threshold: A limit above () which an impurity should be reported. 报告限：系指一个限度，大于该限度的杂质，应该（在申报资料中）

8、报告ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Identification Threshold: A limit above () which an impurity should be identified. 鉴定限：系指一个限度，大于该限度的杂质，应作鉴定ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Qualification Threshold: A limit above () which an impurity

9、 should be qualified. 论证限：系指一个限度，大于该限度的杂质应进行论证ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. 论证：系指对单个

10、杂质，或含规定量已知或未知杂质的新原料药获得生物安全性数据并进行评价的过程ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances The applicant should provide a rationale for establishing impurity acceptance criteria that includes safety considerations. The level of any impurity present in a new drug substance that has been a

11、dequately tested in safety and/or clinical studies would be considered qualified. 申报者应提供设定杂质限度的理由，包括安全性的理由。新原料药中含有的一定量的任何杂质，经安全性试验或临床研究，即认为是论证了的。ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances ICH规定的杂质报告限鉴定限论证限 ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances 1. 说明

12、在合成、纯化和贮存中该新原料药实际和可能存在的杂质 The applicant should summaries the actual and potential impurities most likely to arise during synthesis, purification and storage 应依据合成的化学反应，可能带来杂质的原料，以及降解产物ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances 2. 申报者应叙述检测新原料药中杂质的实验研究 The applicant should summa

13、rize the laboratory studies conducted to detect impurities in the new drug substance 应报告研究开发规模和商品规模批生产结果，稳定性强制试验的结果ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances 3. 叙述按Q3A（R）附表1 对新原料药中大于鉴定限的实际存在杂质进行的结构确证研究 The studies conducted to characterize the structure of actual impurities pr

14、esent in the new drug substance at a level greater than the identification threshold given in attachment 1 should be describedICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances 按拟订工艺的商业化生产任一批大于鉴定限的任何杂质均应做鉴定 Any impurity at a level greater than the identification threshold in any batch

15、 manufactured by proposed commercial process should be identifiedICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances 在建议贮存条件下进行的稳定性试验中发现的任何大于鉴定限的降解产物均应做鉴定(鉴定不成功的，应附相关资料） Any degradation product observed in stability studies at recommended storage conditions at a level greater than the

16、identification threshold should be identifiedICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances 对不大于鉴定限的潜在的具显著毒性或药理作用的杂质，应研究分析方法 Analytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effect

17、s at a level not more than the identification thresholdICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Q3A （R） 对分析的要求 在注册申报中应有成文的依据，说明分析方法经过验证，并适合于杂质的检出和定量 The registration application should include documented evidence that the analytical procedures are validated and suitable for

18、the detection and quantification of impuritiesICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Q3A (R) 对定量限的要求 分析方法的定量限不能大于报告限 The quantitation limit for the analytical procedure should be not more than the reporting thresholdICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Su

19、bstances Q3A （R）对杂质对照品的要求 分析方法中检验杂质用的对照品，按其用途，应经评价并确定（结构） Reference standards used in the analytical procedure for control of impurities should be evaluated and characterized according to their intended usesICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Q3A (R) 对批杂质含量报告要求 用于临床、安全、

20、稳定性研究的全部批，以及拟订商业化生产代表性批的分析结果均应提供在申报资料中，用数字结果，不用“符合”字样 Analytical results should be provided in the application for all batches of the new drug substance used for clinical, safety and stability testing, as well as for batches representative of proposed commercial processICH新原料药中的杂质指导原则ICH Guideline o

21、n Impurities in New Drug Substances 大于报告限的杂质和杂质总量，应连同分析方法进行报告 1.0%以下的结果,报告到小数点后2位, 1.0%及以上的, 报告到小数点后1位, 结果应按规定进行修约 杂质应用代码或描述符号表示 提高报告限应经说明, 全部大于报告限的杂质应求和报告总量ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Q3A （R）附表1 限度表ATTACHMENT 1ThresholdsICH新原料药中的杂质指导原则ICH Guideline on Impuritie

22、s in New Drug Substances 新原料药的报告应包括：批标识和量、生产日期、生产场地、生产工艺、杂质含量、批的利用、参照的分析方法 The report should include: Batch identity and size, Date of manufacture, Site of manufacture, Manufacturing process, Impurity content( individual and total), Use of batches, Reference to analytical procedure usedICH新原料药中的杂质指导

23、原则ICH Guideline on Impurities in New Drug Substances 关于质量标准中列出的杂质 新原料药的质量标准中应列出杂质。稳定性研究、化学研究开发、批的常规分析，可预测商业生产产品中的杂质。质量标准中列出的杂质应为拟订商业生产工艺批中出现的杂质 The selection of impurities in the new drug substance specification should be based on the impurity found in batches manufactured by the proposed commercial

24、 processICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Q3A（R）质量标准中的指定杂质 新原料药质量标准中收载的具有规定限度的单个杂质，在本指导原则中称为指定杂质，已知或未知 Those individual impurities with specific acceptance criteria included in the specification for the new drug substance are referred to as “specified impurity” in thi

25、s guideline. Specified impurities can be identified or unidentified.ICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Q3A（R）对非指定杂质限度要求 非指定杂质的限度一般应不大于鉴定限, 并应有总杂质限度 A general acceptance criterion of not more than the identification threshold for any unspecified impurity and an acceptan

26、ce criterion for total impurities should be includedICH新原料药中的杂质指导原则ICH Guideline on Impurities in New Drug Substances Q3A（R）关于质量标准中列出杂质检查项的要求，有机杂质：每个指定已知杂质，每个指定未知杂质，非指定杂质的限度不得大于鉴定限，总杂质 For organic impurities the following items should be listed in the specification: each specified identified impurit

27、y, each specified unidentified impurity, any unspecified impurity with an acceptance criterion of not more than the identification threshold, total impuritiesICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias ICH指导原则为新化合物申报用，通过药典协调，也被国际主要药典引用 The ICH gu

28、idelines are applicable to the new chemical entities for registration application. After harmonization the requirements of the guidelines are adopted by internationally recognized pharmacopoeias, such as USP,EP,BP,etcICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign

29、pharmacopoeias 如：美国药典关于法定品种中的杂质 USP 27 Impurities in official articles 正文原料药纯度检查通常用下列方法（1）色谱纯度检查，加上非专属含量测定，（2）用能反映纯度的色谱法做含量测定，（3）对已知杂质规定专属检查和限度，对已知杂质的检查通常用杂质对照标准品Monographs on bulk pharmaceutical chemicals usually cite one of three type of purity tests (1) a chromatographic purity test coupled with

30、a nonspecific assay;(2) a chromatographic purity-indicating method that serves as the assay; or (3) a specific test and limit for a known impurity , an approach that usually requires a reference standard for that impurityICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by fore

31、ign pharmacopoeias USP制剂正文杂质检查收载原则 一般，USP原料正文中检查的杂质，该杂质不再增加的，在其制剂中不再重复检查 In general, this pharmacopoeia does not repeat impurity tests in subsequent preparations where these appear in the monograph of bulk pharmaceutical chemicals and where these impurities are not expected to increaseICH关于杂质指导原则在国外

32、药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 相关术语：外来物质（foreign substances)，毒性杂质（toxic impurities)，共存物质（concomitant components)，信号杂质（signal impurities)，普通杂质（ordinary impurities)ICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign ph

33、armacopoeias 除另有规定外，正文中用相对方法检查普通杂质，或非专属检查 Unless otherwise specified in an individual monograph, estimation of the amount and number of ordinary impurities is made by relative methods rather than by strict comparison to individual reference standards. Nonspecific detection of ordinary impurities is

34、also consistent with this classificationICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias USP27 普通杂质的限度，一般为2.0% The value of 2.0%was selected as the general limit on ordinary impurities in monograph where documentation did not support adoption of other

35、 valuesICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 如正文设置共存物、信号杂质和毒性杂质限度，除另有规定外，这些不作为普通杂质 Where a monograph sets limits on concomitant compounds, signal impurities, and/or toxic impurities, these species are not to be included in the estimation of

36、 ordinary impurities unless so stated in the individual monographICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 有关物质-与原料药结构有关，有关物质可能是已知或未知的降解产物，或从生产工艺及贮存中产生 Related substances are structurally related to a drug substance. These substances may be ide

37、ntified or unidentified degradation products or impurities arising from a manufacturing process or during storage of a materialICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 工艺污染物-工艺污染物为已知或未知物质（有关物质和水分除外），包括试剂、无机物、原料和溶剂，可能从生产及处置过程中引入 Process contami

38、nants are identified or unidentified substances (excluding related substances and water), including reagents, inorganics, raw materials, and solvents. These substances may be introduced during manufacturing or handling proceduresICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline

39、 by foreign pharmacopoeias USP27 凡例（General Notices)对其他杂质的规定 法定原料药中出现（正文）未标明的杂质，其量为0.1%或以上时，且是由于变更工艺或其他可说明原因产生的，检测方法应报USP，申请收载入正文，否则应在分析证其他杂质项下标明，并注明量。其他杂质加上正文检出的杂质总量不得过2.0%ICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias The presence of any unlabeled

40、 impurity in an official substance is a variance from the standard if the content is 0.1% or greater. Tests suitable for detection and quantitating unlabeled impurities ,when present as the result of process change or other identifiable, consistent occurrence , shall be submitted to the USP for incl

41、usion in the individual monograph. Otherwise, the impurity shall be identified, preferably by name, and the amount listed under the heading Other Impurities in the labeling (COA) of the official substance. The sum of all other impurities combined with the monograph-detected impurities does not excee

42、d 2.0%, unless otherwise stated in the monographICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias USP关于修订USP-NF申报要求指导原则（征求意见稿）中，非复杂有效成分中杂质检查新要求 New requirement for testing of impurities in the non-complex actives See USP Guideline for Submitting Reques

43、ts for Revision to the USP-NF ICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 对于新的原料药正文（New monograph for a drug substance), 杂质检查应对全部指定杂质规定限度，所有非指定杂质的限度均为0.10% The impurity test of a drug substance monograph is intended to limit all specified impurit

44、ies, with a further limit of 0.10% for all unspecified impuritiesICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias USP 新的正文（new monographs) 的杂质将按表中的命名法 For new monographs, USP will follow nomenclature and approaches shown in the tableICH关于杂质指导原则在国外药典中的

45、引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeiasICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias USP原料药正文仅收载检查实际存在的，而不是理论存在杂质的方法 USP drug substance monographs will include only procedures that control actual, not theoret

46、ical , impuritiesICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 由于合成路线不同，产生不同的杂质，需用不同方法检查，此情况下，在有关文件上（如COA）应说明附加的可行方法 Where different routes of synthesis yield different impurity profiles, different impurity procedure may be needed. In this case, th

47、e additional applicable procedure should be included in the labelingICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 如果申报资料中有FDA未评价过的已知毒性的杂质，则在申报资料中应包括毒性数据 If the request for revision describes an impurity of known toxicity that has not previously bee

48、n evaluated by the FDA, toxicity data should be included in the Request for RevisionICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 对有机杂质（for organic impurities) 色谱识别和定量用外标法 To identify and quantify impurities, an external rather than an internal sta

49、ndard is preferred. The use of external standards is preferable, as internal standards may obscure other impuritiesICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 有机杂质用原料药对照标准品或外标杂质对照品比对定量。尽可能用需要限量的指定杂质的USP对照标准品对已知杂质进行定量 The quantification of organic

50、 impurities should be done by comparison to either the drug substance reference standard or to an external impurity reference standard. Where possible, official USP Reference Standards of specified impurities to be limited are the best option when quantifying identified impuritiesICH关于杂质指导原则在国外药典中的引

51、用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 杂质的限度应符合ICHQ3A的要求，并对每个指定杂质规定限度，并在必要时规定非指定杂质的限度，总杂质限度，报告限度，杂质的限度应适应于货架效期 Acceptance criteria should comply with ICH Q3A and should be provided for each specified impurity, any unspecified impurity as appropriate, total imp

52、urities, and report thresholds. These acceptance criteria are applicable throughout shelf-lifeICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 英国药典2003版补充附录“杂质检查”，其中的有关物质 The supplementary chapters of BP 2003, A. Control of Impurities related substanc

53、esICH关于杂质指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 起草正文时，要求企业提供杂质的性质、杂质存在的理由、按GMP生产条件下杂质的量，贮存期变化情况，与原料药本身有关的杂质毒性说明When preparation of a monograph is initiated the manufacturer is asked to provide information concerning the nature of such impurities, t

54、he reason for their presence, the amounts that may be encountered in material prepared under conditions of GMP and the manner in which proportions may vary on storage, together with an indication of the toxicity of any impurities in relation to that of the substance itselfICH关于杂质指导原则在国外药典中的引用关于杂质指导原

55、则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 生产工艺或降解产生的特殊杂质，根据毒性等理由，需规定限度的，用专属检查 A specific test is included where a particular impurity arising from the manufacturing process or from degradation needs to be limited on ground of toxicity or for another special reasonICH关于杂质

56、指导原则在国外药典中的引用关于杂质指导原则在国外药典中的引用Citation of ICH impurity guideline by foreign pharmacopoeias 该补充附录说明了，与生产企业有关的指导原则，见ICH Q3A 和 Q3B Other guidance related to manufacturers is provided in, for example, ICH guidelines on impurities in new drug substances(Q3A) and new drug preparations(Q3B)中国药典(2005)药品杂质分析

57、指导原则 Ch P( 2005) Guideline on Analysis of Drug Impurities 本指导原则为参考人用药品注册申报技术要求国际协调会，根据中国的具体情况起草的2005年版中国药典新增附录 This is a new guideline to be included in the Chinese Pharmacopoeia 2005 ,drafted on the basis of ICH relevant requirements and recent progress in pharmaceutical research and drug standard

58、development in China中国药典(2005)药品杂质分析指导原则 Ch P( 2005) Guideline on Analysis of Drug Impurities 本附录为药品质量标准中化学合成或半合成的有机原料药及其制剂杂质分析的指导原则,供药品研究、生产、质量标准起草和修订参考 This is the guideline on the analysis of impurities in synthesized or semi-synthesized organic drug substances and their preparations for drug res

59、earch, pharmaceutical manufacturing, and revision of drug standards中国药典(2005)药品杂质分析指导原则 Ch P( 2005) Guideline on Analysis of Drug Impurities 任何影响药品纯度的物质均称为杂质 Any substance that affects the purity of a drug is considered as an impurity中国药典(2005)药品杂质分析指导原则 Ch P( 2005) Guideline on Analysis of Drug Imp

60、urities 药品质量标准中的杂质系指，在按照经国家有关药品监督管理部门依法审查批准的规定工艺和规定原辅料生产的药品中，由其生产工艺或原辅料带入的杂质，或经稳定性试验确证的在贮存过程中产生的降解产物 Impurities listed in a drug standard may be introduced from production process, starting materials or excipients of the drug produced with specified process and materials officially approved by the c