Q3A(R2)-新原料药中的杂质(中英文)

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1、Impurities In New Drug Substa nces 新原料药中的杂质 INTERNATIONAL REQUIREMENTS HUMAN USE CONFERENCE ON HARMONISATION OF TECHNICAL FOR REGISTRATION OF PHARMACEUTICALS FOR ICH H ARMONISED T RIPARTITE GUIDELINE I MPURITIES I n N ew D rug Substances Q3A(R2) Current Step 4 version dated 25 October

2、2006 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the Europea n Union

3、, Japa n and USA. Page 1 of 22 Impurities In New Drug Substa nces 新原料药中的杂质 Q3A(R2) Docume nt History First Codificati on History Date New Codificati on November 2005 Q3 Approval by the Steering Committee under Step 2 and release for public con sultati on. 15 March 1994 Q3A Q3A

4、Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies. Q3 was ren amed Q3A. 30 March 1995 Q3A Q3A(R) Approval by the Steering Committee of the first Revision under Step 2 and release for public consultation. 7 October 1999 Q3A(

5、R1) Q3A(R) Approval by the Steering Committee of the first Revision under Step 4 and recommendation for adoption to the three ICH regulatory bodies. 6 February 2002 Q3A(R1) Curre nt Step 4 vers ion Q3A(R2) Approval by the Steering Committee of the revision of the Attachment 2 directly unde

6、r Step 4 without further public con sultati on. 25 October 2006 Q3A(R2) Page 2 of 22 Impurities In New Drug Substa nces 新原料药中的杂质 I MPURITIES I N N EW D RUG SUBSTANCES ICH Harmoni sed Tripartite Guideli ne Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting

7、on 7 February 2002, this guideli ne is recomme nded for adopti on to the three regulatory parties to ICH. Attachme nt 2 has bee n revised on 25 October 2006. TABLE OF CONTENTS 1. PREAMBLE 4 2. CLASSIFICATION OF IMPURITIES 4 3. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES 6 3.1 Orga

8、 nic Impurities 6 3.2 In orga nic Impurities 7 3.3 Solvents 7 4. ANALYTICAL PROCEDURES 8 5. REPORTING IMPURITY CONTENT OF BATCHES 9 6. LISTING OF IMPURITIES IN SPECIFICATIONS 10 7. QUALIFICATION OF IMPURITIES 12 8. GLOSSARY 14 ATTACHMENT 1 17 ATTACHMENT 2 18 ATTACHMENT 3 20 I MPURITIE

9、S I N N EW D RUG SUBSTANCES 新原料药中的杂质 1. PREAMBLE 序言 This document is intended to provide guidanee for registration applicationson the content and qualificati on of impurities in new drugjbsta nces）roduced by chemicals yn thesesa nd not previously registered in a regi on or member state. It is not

10、 inten ded to apply to new drug substa nces used duri ng the cli nical research stage of developme nt. The followi ng typedrog substa ncesare not covered in this guideli ne:biological/biotech no logicapeptide, olig onu cleotide,radiopharmaceuticaferme ntatio n product and semi-s yn thetic products d

11、erived therefrom, herbal products, and crude products of ani mal or pla nt orig in. 本文件旨在为化学合成的新原料药（这些新原料药尚未在任何地区或成员国注册）在注册 申请时，对其杂质的含量和界定的申报提供指导。本报导原则不适用于临床研究期间所用 的新原料药。本文件不涵盖生物/生物制品、肽、寡聚核苷酸。放射性药物、发酵和半合 成产品、草药以及来源于动、植物的粗制品。 Impurities in new drug substa nces are addressed from two perspectives:

12、新原料药中的杂质分两个方面阐述： Chemistry Aspectsinclude classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures; and 化学方面：包括对杂质的分类和鉴定、杂质生成、规范中杂质的检查项目以及对分 析方法的简要讨论。 Safety Aspectsi nclude specific guida nee for q

13、ualify ing those impurities that were not prese nt, or were prese nt at substa ntially lower levels, in batches of a new drug substa nee used in safety and cli nical studies. 安全性方面：对用于安全性研究和临床研究的新原料药批次中不存在或含量很低的 那些杂质的界定的指南。 2. CLASSIFICATION OF IMPURITIES 杂质的分类 Impurities can be classified into t

14、he following categolfe质可分为下列类型 ： • Orga nic impurities （process- and drug-related 机杂质（与工艺和药物有关的） • Inorganic impurities无 机杂质 • Residual solve nts 残留溶剂 Orga nic impurities can arise duri ng the manu facturi ng process an d/or storage of the new drug substa nee. They can be identified or unidentif

15、ied, volatile or non-volatile, and include: 有机杂质可能会在新原料药的生产过程和（或）储存期间有所增加。这些杂质可能是已确定的 或者是未确定的、挥发性的或者非挥发性的。它包括： * Start ing materials起 始物 * By-products 副产物 * In termediate中间体 * Degradatio n product降 解产物 * Reage nts, liga nds and catalyi试剂、配位体、催化剂 Inorganic impurities can result from the manu f

16、acturi ng process. They are no rmally known and ide ntified and in clude: 无机杂质可能来源于生产过程，它们一般是已知的和确定的。包括： * Reage nts, liga nds and catalyi剂、配位体、催化剂 * Heavy metals or other residual meta重金属或其他残留金属 * Inorganic salts无 机盐 * Other materials （e.g., filter aids, charco其 他物质（例如：过滤介质、活性炭等） Solvents are

17、 inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the syn thesis of a new drug substa nee. Since these are gen etfakiyow n toxicity, the selectionof appropriate con trols is easily accomplished （see ICH Guideli ne Q3C on Residual Solve nts）. 溶剂是在新原料药合

18、成过程中用于制备溶液或混悬液的有机或无机液体，由于它们一般具 有已知毒性，故容易选择控制方法（见ICH指导原则Q3C残留溶剂项下）。 Excluded from this docume ntare: （1） extra neousc on tam inan tshat should not occur in new drug substa nces and are more appropriately addressed as Good Manu facturi ng Practice （GMP） i（2）jes, polymorphic forms, and （3） enan tiomer

19、ic impurities. 不包括在本文件中的杂质为：（ 1）外源性污染物（不应该存在于新原料药中，可以用 GMP来控制）；（2）多晶型；（3）对映体杂质。 3. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES 杂质报告和控制的说明 3.1 Organic Impurities 有机杂质 The applicant should summarisethe actual and potential impurities most likely to arise during the synthesis, purificat

20、ion, and storage of the new drug substanee. This summary should be based on sound scientificappraisalof the chemicalreactionsinvolved in the synthesisjmpuritiesassociatedwith raw materialsthat could con tribute to the impurity profile of the new drug substa nce,a nd possible degradatio nproducts. Th

21、is discussionca n be limited to those impuritiesthat might reas on ablybe expected based on kno wledge of the chemical react ions and con diti ons invo lved. 申报者应对新原料药在合成、精制和储存过程中最可能产生的那些实际存在的和潜在的杂 质进行概述。该描述应建立在对合成所涉及的化学反应、由原材料引入的杂质及可能的降 解产物进行合理地、科学地评估的基础上。可以局限于根据化学反应以及相关条件下可能 会产生的杂质进行讨论。 In addit

22、i on, the applica nt should summarise the laboratory studies con ducted to detect impurities in the new drug substance.This summaryshould include test results of batchesmanufacturecduring the developme ntprocess and batchesfrom the proposed commercialprocess,as well as the resultsof stress testing (

23、see ICH Guideline Q1An Stability) usedto identifypotentialimpuritiesarisingduring storage. The impurity profile of the drug substa nce batches in ten ded for market ing should be compared with those used in developme nt, and any differe nces discussed. 此外，申报者还应对新原料药中杂质检测的实验室研究工作进行概述，其内容包括对研制 期间和模拟上

24、市的所有批次产品的试验结果、以及为鉴定在储存期间可能产生的潜在杂质 而进行强力破坏试验的结果(见ICH指导原则Q1A稳定性项下)。同时应对那些模拟上 市的原料批次中的杂质概况和用于研制开发过程的原料批次中的杂质概况进行比较，任何 不同之处均应加以讨论。 The studies con ducted to characterisethe structure of actual impurities prese nti n the new drug substance at a level greater than (>) the identification threshold give

25、n in Attachn(e^.1 calculated using the resp onse factor of the drug substa nce) should be described. Note that any impurity at a level greater than (>) the ide ntificati on threshold in any batch manu facturedby the proposed commercial process should be ide ntified. In additi on, any degradati on

26、 product observed in stability studiesat recomme ndedstorage con diti ons at a level greater tha n (>) the ide ntificationthresholdshould be identified. When identificationof an impurity is not feasible,a summaryof the laboratory studies dem on strati ng the un successful effort should be in clud

27、ed in the applicati on. Where attemptsehave made to identify impurities present at levels of not more th^the identification thresholds, it is useful also to report the results of these studies. 申报资料中还应对那些在新原料药中实际存在的、含量大于（＞）附录 1中鉴定阈值的杂 质（例如：以原料药的响应因子计算）的结构特征进行描述。应该注意，在模拟上市生产 的批次中，所有出现的大于（＞）鉴定阈值的杂质应

28、予鉴定；也应同样鉴定在推荐的放置 条件下的稳定性研究中发现大于（＞）鉴定阈值的降解产物；当某个杂质无法鉴定时。申 报资料中应包括对该杂质所进行的不成功的试验研究的概述。如果已尝试过鉴定含量不大 于（弓鉴定阈值的杂质。那么把这些研究结果也报告进去是很有用的。 Iden tificati on of impurities prese nt at an appare nt level of not more dhthe（ide ntificati on threshold is gen erally not con sidered necessary.However, an alyticalpro

29、ceduresshould be developedfor those pote ntial impurities that are expected to be unu sually pote nt, produci ng toxic or pharmacological effects at a level not more than J） the identification threshold. All impurities should（b@alifiedas described later in this guideli ne. 通常没有必要对含量在阈值以下（ 弓 的杂质进行鉴定

30、。然而，对那些含量不大于（ 弓 阈值但可能产生不寻常功效或毒性药理作用的潜在杂质，则应力求鉴定他们。所有杂质均 应按照本指导原则后续章节中的要求来鉴定。 3.2 Inorganic Impurities无机杂质 Inorganicimpuritiesare normallydetectedand quantifiedusingpharmacopoeiabr other appropriate procedures. Carry-over of catalysts to the new drug substa nee should be evaluated duri ng developme

31、 nt. The need for inclusion or exclusion of inorganic impurities in the new drug substance specification should be discussed. Accepta nce criteria should be based on pharmacopoeial sta ndards or known safety data. 无机杂质通常按药典或其他适当的方法来检测和定量。在新药的研制过程中应对遗留在新 原料药中的催化剂进行评估。在新原料药规范中是否收载无机杂质检查项目，应进行讨 论。其认可限

32、度应根据药典标准或已知的安全性数据来制定。 3.3 Solvents溶剂 The con trol of residues of the solve nts usedtire manu facturi ngprocessfor the new drug substa nce should be discussed and prese nted accordi ng to the ICH Q3C Guideli ne for Residual Solve nts. 应按ICH Q3C“残留溶剂”指导原则的要求，对新原料药生产过程中所用的溶剂的残留量的 控制进行讨论和申报。 4. ANALY

33、TICAL PROCEDURES 分析方法 The registratio napplicati on should in elude docume ntedevide ncethat the an alyticalproceduresare validated and suitable for the detectionand quantificationof impurities(see ICH Q2A and Q2B Guidelinesfor Analytical Validation). Technicalfactors (e.g., manufacturingcapability

34、 and control methodology) can be con sidered as part of the justificati on for selecti on of alter native thresholds based on manu facturi ng experie nee with the proposed commercial process. The use of two decimal places for thresholds (See Attachment 1) does not necessarily reflect the precision o

35、f the analytical procedure used for routine quality control purposes. Thus, the use of lower precision techniques(e.g., thin-layer chromatography)ca n be acceptablewhere justified and appropriatelyvalidated. Differe nces in the an alytical procedures used duri ng developme nt and those proposed for

36、the commercial product should be discussed in the registrati on applicatio n. 注册申请中应提供书面文件，证明分析方法是经过论证并适用于杂质的检测和定量(见 ICH Q2A及Q2B分析方法论证指导原则项下)，技术因素(如生产能力与质控方法)可 用于说明为什么在准备上市产品中采用其他的阈值。阈值采用两位小数(见附录 1)并不 代表常规质量控制中分析方法的精度。因此，只需经过验证和论证，可以使用较低精度的 技术(如薄层色谱法)。如果研发中所采用的分析方法和准备上市产品的分析方法不同， 在申报资料中应予以讨论。 The

37、qua ntitati on limit for the an alytical procedure should be not more-thttne(report ing threshold. 分析方法的定量限度应不大于(菊报告阈值。 Orga nic impurity leve ls can be measured by a varieftech niq uesj ncludi ngthose that compare an an alytical resp onse for an impurity to that of an appropriate refere nee sta nd

38、ard or to the resp onse of the new drug substance itself. Reference standards used in the analytical procedures for control of impurities should be evaluated and characterised accord ing to their inten ded uses. The drug substa nce can be used as a standardto estimatethe levels of impurities」n cases

39、where the responsefactors of the drug substa nceand the releva ntimpurity are not close, this practice can still be appropriate, provided a correct ion factor is applied or the impurities are, i n fact, being overestimaAdepta ncecriteria and analyticalproceduresused to estimateidentifiedor unidentif

40、iedimpuritiescan be based on analytical assumpti on s(e.g., equivale ntdetector resp on se). These assumptio nsshould be discussedi n the registration application. 可用各种技术测定有机杂质的含量，这些技术包括把杂质的响应值与适当的参比标准品的 响应值比较或与药物本身的响应值比较。应根据使用目的，对分析过程中用于控制杂质的 参比标准品进行定性和定量。可用原料药作为标准物质来估计杂质的量，如果原料要和杂 质的响应因子不接近，只要应用了

41、校正因子或测得的杂质量膏腴实际的杂质量，该方法仍 是可行的。用于评估已鉴定或未鉴定杂质的认可标准和分析方法可基于分析的假设(例 如：相同的检测响应等)。为此，这些假设也应在注册申请中加以讨论。 5. REPORTING IMPURITY CONTENT OF BATCHES 各批次产品杂质含量的报告 An alytical results should be provided in the applicati on for all batches of the new drug subsUsede for clinical, safety, and stability testing, a

42、s well as for batches representative of the proposed commercial process. Quantitative results should be presented numerically,and not in generalterms such as “ complies ”eetimit etc. Any impurity at a level greater than （＞） the reporting threshold（see Attachme nt1） and total impuritiesobserved in t

43、hese batchesof the new drug substa nceshouldbe reported with the an alytical procedures in dicated. Below 1.0%, the resdlteuldbe reported to two decimal places （e.g., 0.06%, 0.13%）; at and above 1.0%, the results should be reported to one decimal place （e.g., 1.3%）. Results should be roun ded using

44、conven ti onal rules （see Attachme nt 2）. A tabulati on （e.g., spreadsheet） of the data is recomme nded. Impurities should be desig nated by code nu mber or by an appropriate descriptor, e.g., retention time. If a higher reporting threshold is proposed, it should be fully justified. All impurities a

45、a level greatertha n （＞） the report ing thresholdshouldbe summeda nd reported as total impurities. 注册申请应提供用于临床、安全性研究、稳定性试验的所有新原料药批次产品的分析结果 以及用于准备上市产品的分析结果。定量测定结果应数字化，不应用 符合规定”，符合 限度”等一般性术语。在新原料药的所有批次中，应报告检测到的大于（＞）报告阈值 （见附录1）的任何杂质和总杂质，并附所用的分析方法。若低于 1.0%，结果应报告至 小数点后两位（如0.06%，0.13%），若大于或等于1.0%，结果报告

46、至小数点后1位（如 1.3%）。结果应按传统规则修约（见附录 2）。建议使用数据表格（如电子数据表），各 杂质均应以编号或合适的描述表示（如保留时间）。如果采用较高的报告阈值，应进行充 分论证。所有大于（＞）报告阈值的杂质应进行累加，报告为 总杂质”。 Whe n an alyticalprocedurescha ngeduri ng developme nt,reported results should be lin ked to the procedure used, with appropriate validatio n in formatio n provided. Repre

47、se ntativechromatograms should be provided. Chromatogramsof representativeoatches from analytical validation studies showing separationand detectability of impurities （e.g., on spiked samples）,along with any other impurity tests rout in ely performed, can serve as the represe ntativeimpurity profile

48、s. The applica nt should en sure that complete impurity profiles （e.g., chromatograms） of in dividual batches are available, if requested. 若在研制期间，分析方法发生了变化，报告测试结果时，应附上所用的分析方法。并提供 相应的方法学论证资料。应提供有代表性的色谱图。方法学论证中，显示杂质分离度和检 测灵敏度的、具有代表性批次（例如：加样试验）的色谱图和常规杂质检测得到的色谱 图，可以反映出有代表性的杂质概况。申报者应保证：如需要，可提供各个批次产品的完 整

49、的杂质概况（例如；色谱图）。 A tabulatio n should be provided that li nks the specific new drug substa nee batchach safety study and each cli ni cal study in which the new drug substa nee has bee n used. 另外，申报者还应提供应用在每个安全性研究和临床研究中的新原料药的每个批次一一对 应的名单。 For each batch of the new drug substa nee, the report should

50、in clude: 对每批新原料药、报告内容应包括： * Batch ide ntity and size比号与批量 * Date of manu factur生 产日期 * Site of manu facture生 产地点 * Manu facturi ng process^ 产工艺 * Impurity con te nt, i ndividual a nd to单个杂质含量和总杂质含量 * Use of batche批次的用途 * Refere nee to an alytical procedure u所采用分析方法的阐释 6. LISTING OF IMPURIT

51、IES IN SPECIFICATIONS 规范中所列的杂质检查项目 The specification for a new drug substance should include a list of impurities. Stability studies, chemical development studies, and routine batch analyses can be used to predict those impurities likely to occur in the commercial product. The select ion of impurit

52、ies in the new drug substa nce specificati on should be based on the impuritiesfo und in batchesma nu facturedby the proposed commercialprocess.Those in dividual impuritieswith specific accepta ncecriteria in cludedi n the specificati onfor the new drug substance are referred to as "specified i

53、mpurities" in this guideline. Specified impurities can be identified or uniden tified. 在新原料药的规范中应包括杂质检查项目。稳定性研究、化学方面的开发研究以及日常批 次分析检验的结果有助于预测在市售产品中可能出现的杂质。在新原料药规范中收载的杂 质应根据在准备上市生产的批次中所发现的杂质来选择。在本指导原则中。列入新原料药 规范中、具有特定的认可标准的各个杂质称为特定杂质。特定杂质可以是已鉴定的，也可 以是未鉴定的。 A rati on alefor the in clusi onor exc

54、lusionof impuritiesi n the specificationshould be prese nted.This rati on ale should in clude a discussi onof the impurity profiles observed in the safety and cli ni cal developme nt batches, together with a con siderati on of the impurity profile of batches manu faloyured the proposed commercial pr

55、ocess. Specified identified impurities should be included along with specifiedunidentifiedimpuritiesestimatedto be present at a level greater than (>) the identification threshold given in Attachment 1. Fcbmpuritiesknown to be unusuallypotent or to produce toxic or un expected pharmacological eff

56、ects, the qua ntitati on /detect ion limit of the an apyticaduresshould be comme nsurate with the level at which the impurities should be con trolled. For uniden tified impurities, Page 10 of 22 Impurities In New Drug Substa nces 新原料药中的杂质 the procedure used and assumptio nsmade in establishi

57、nghe level of the impurity shouldbe clearly stated. Specifiedunidentifiedimpuritiesshouldbe referredto by an appropriatequalitativeanalytical descriptive label （e.g., “ unidentifieA", “ unidentifieWith relative retention of 0.9 ” A general acceptance criterion of not more thaf） （he identificati

58、on threshold （Attachment 1） for any unspecified impurity and an acceptance criterion for total impurities should be included. 应对用于安全性和临床研究中的批次中所发现杂质情况，以及对拟上市生产的原料中杂质 概况综合进行考虑后，再对规范中列入或不列入哪些杂质的理由进行说明。特定的已鉴定 杂质应与特定的其喊两估计大于（＞）鉴定阈值（附录 1）的未鉴定杂质一起考虑。对于 那些具有特殊功效或产生毒性或为预料到的药理作用的杂质，其分析方法的定量限或检测 限度必须与该杂质应被控制

59、的量相当。对于未鉴定的杂质，所使用的检测方法和确定杂质 量时所采用的假设应予明确说明。特定的未鉴定的杂质应采用适当的方法描述标记（例 如：未鉴定杂质A”相对保留时间为0.9的杂质”）。对于任何一个非特定杂质应有一个 不大于（弓鉴定阈值（附录1）的认可标准，对总杂质也应建立一个认可标准。 Acceptance criteria should be set no higher than the level that can be justified by safety data, and should be con siste nt with the level achievable by th

60、e manu facturi ng process and the an alytical capability. Where there is no safety concern」mpurity accepta nce criteria should be based on data gen erated on batches of the new drug substancemanufacturedby the proposed commercialprocess, allowing sufficient latitude to deal with normal manufacturing

61、 and analytical variation and the stability characteristics of the new drug substa nceAlthough no rmal manu facturi ng/ariati on sare expected, sig nifica ntvariati on in batch-to-batch impurity levels can in dicate that the manu facturi ng process of the new drug substa nce is not adequately con tr

62、olled and validated （see ICH Q6A Guideli ne on Specificati ons, Decisio n Tree #1, for establishing an acceptance criterion for a specified impurity in a new drug substance）. The use of two decimal places for thresholds（See Attachme nt1） does not n ecessarilyi ndicatethe precisi onof the acceptance

63、criteria for specified impurities and total impurities. 建立认可标准不能高于经安全资料界定合理的水平，并且必须与生产工艺和分析能力所能 达到的水平一致。如果没有安全性方面的问题，杂质认可标准应根据拟上市生产的新原料 药批次测定的数据来建立，并应为常规生产和分析上的正常变异及药物的稳定性特性留有 足够的余地。尽管常规生产中的变化是可以预料的，然而批与批之间杂质水平的显著变化 可能预示着新原料药的生产工艺尚未得到充分的控制和论证（见 ICH Q6A规范”指南判 断流程图1,建立新原料药中的特殊杂志的认可标准）。阈值的两位小数（见附录 1）并

64、 不代表特定杂质和总杂质认可标准的精度。 In summary, the new drug substance specification should include, where applicable, the following list of impurities: 总之，新原料药规范中应包括以下杂质检查项： Organic Impurities 有机杂质： • Each specified ide ntified impuri每种特定的已鉴定杂质 Page 11 of 22 Impurities In New Drug Substa nces 新原料药中的杂质

65、« Each specified uniden tified impu每ty中特定的未鉴定的杂质 « Any unspecifiedimpurity with an acceptancecriterion of not more than （_） the identification threshold任何不大于（马鉴定阈值认可标准的非特定杂质。 * Total impuritie杂质总量 Residual Solve n残留溶剂 Inorganic Impuritie无 机杂质。 7. QUALIFICATION OF IMPURITIES 杂质的界定 Qua

66、lificati on is the process of acquiri ng and evaluati ng data that estabtfeteedDlogicalsafety of an in dividual impurity or a give n impurityrofile at the level（s） specified. The applica ntshould provide a rati on ale for establishi ng impurity accepta nee criteria that in cludes safety con siderati ons. The level of any impurity prese nt in a new drug substa nee that has bee n adequately tested in safety an d/or cli ni cal studies would be con sidered qualified. Impurities that are asig nifica ntmetabolitesprese ntin ani mala nd/o