Q3A(R2)-新原料药中的杂质(中英文)

1、Impurities In New Drug Substa nces新原料药中的杂质 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH Harmonised Tripartite Guideline I MPURITIES I N NEW DRUG SUBSTANCES Q3A(R2) Current Step 4 version dated 25 October 2006 This Guideline

2、 has been developed by the appropriate ICH Expert Working Group and has bee n subject to con sultati on by the regulatory parties, in accorda nee with the ICH Process. At Step 4 of the Process the final draft is recommended for adopti on to the regulatory bodies of the Europea n Union, Japa n and US

3、A. Page 12 of 22 Q3A(R2) Docume nt History First Codificati on History Date New Codificati on November 2005 Q3 Approval by the Steering Committee underStep 2 and release for public con sultati on. 15 March 1994 Q3A Q3A Approval by the Steering Committee underStep 4 and recomme ndati onfor adopti on

4、to the three ICH regulatory bodies. Q3 was ren amed Q3A. 30 March 1995 Q3A Q3A(R) Approvalby the Steeri ngCommitteeof the first Revisi onun der Step 2 and release for public con sultati on. 7 October 1999 Q3A(R1) Q3A(R) Approval by the Steeri ng Committeeof the first Revisio n un der Step 4 and reco

5、mme ndati onfor adopti on to the three ICH regulatory bodies. 6 February 2002 Q3A(R1) Curre nt Step 4 vers ion Approval by the Steering Committee of the revision of 25 Q3A(R2) the Attachme nt 2 directly un der Step 4 without further October Q3A(R2) public con sultati on. 2006 Impurities In New Drug

6、Substances ICH Harmoni sed Tripartite Guideli ne Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting 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 CONTE

7、NTS 1. PREAMBLE 4 2. CLASSIFICATION OF IMPURITIES 4 3. rationale for the reporting and control OF IMPURITIES 6 3.1 Organic Impurities6 3.2 Inorganic Impurities 7 3.3 Solvents7 4. ANALYTICAL PROCEDURES 8 5. REPORTING IMPURITY content OF BATCHES 9 6. LISTING OF IMPURITIES in SPECIFICATIONS10 7. qualif

8、ication OF IMPURITIES12 8. GLOSSARY 14 ATTACHMENT 1 17 ATTACHMENT 2 18 ATTACHMENT 3 20 Impurities In New Drug Substances 新原料药中的杂质 1. PREAMBLE 序言 This docume nt is inten ded to provide guida nee for registrati on applicati ons on the content and qualification of impurities in new drug substancesprodu

9、ced by chemical syntheses and not previously registered in a region or member state. It is not intended to apply to new drug substa nces used duri ng the cli ni cal research stage of developme nt. The follow ing types of drug substa nces are not covered in this guideli ne: biological/biotech no logi

10、cal, peptide, olig onu cleotide, radiopharmaceutical, ferme ntatio n product and semi-s yn thetic products derived 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。

11、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: 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 procedu

12、res; 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 Aspects include specific guidance for qualifying those impurities that were not prese nt, or were prese nt at substa ntially lower levels, in batches of a new drug substa nce used in safety and cli ni cal studies. 安全性方面：对用于安全性研究和临床研究的新原料

13、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 the following categories:杂质可分为下列类型 : ?Orga nic impurities （process- and drug-related）有机杂质（与工艺和药物有关的） ?Inorganic impurities 无机杂质 ?Residual solve nts 残留溶剂 Organic impurities can arise during the manufactu

14、ring process and/or storage of the new drug substanee. They can be identified or unidentified, 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： ?Starti ng materials 起始物 ?By-products 副产物 ?In termediates 中间体 ?Degradation products 降解产物 ?Reage nts

15、, liga nds and catalyst试剂、配位体、催化剂 Inorganic impurities can result from the manu facturi ng process. They are no rmally known and identified and include: 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 catalysts试剂、配位体、催化剂 ? Heavy metals or other residual metals 重金属或其他残留金属 ? Inorganic salts 无机

16、盐 ? Other materials （e.g., filter aids, charcoal）其他物质（例如：过滤介质、活性炭等） Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspe nsions in the syn thesis of a new drug substa nee. Si nce these are gen erally of known toxicity, the selecti on of appropriate con

17、 trols is easily accomplished （see ICH Guideli ne Q3C on Residual Solve nts）. 溶剂是在新原料药合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 nt are: （1） extra neous con tam inants that should not occur in new drug substa nces and are more appropriately address

18、ed as Good Manu facturi ng Practice （GMP） issues, （2） polymorphic forms, and （3） enantiomeric 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 Orga nic Impurities有机杂质 The applicant should summarise t

19、he actual and potential impurities most likely to arise during the synthesis, purification, and storage of the new drug substanee. This summary should be based on sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could con t

20、ribute to the impurity profile of the new drug substanee, and possible degradation products. This discussion can be limited to those impurities that might reas on ably be expected based on kno wledge of the chemical reacti ons 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

21、。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 additi on, the applica nt should summarise the laboratory studies con ducted to detect impurities in the new drug substance.This summary should include test results of batches manufactured duri ng the developme

22、 nt process and batches from the proposed commercial process, as well as the results of stress testing (see ICH Guideline Q1A on Stability) used to identify potential impurities aris ing duri ng storage. The impurity profile of the drug substa nce batches in ten ded for market ing should be compared

23、 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 characterise the structure of actu

24、al impurities prese nt in the new drug substanceat a level greater than () the identification threshold given in Attachment 1 (e.g., calculated using the resp onse factor of the drug substa nce) should be described. Note that any impurity at a level greater than () the identification threshold in an

25、y batch manufactured by the proposed commercial process should be identified. In addition, any degradation product observed in stability studies at recommended storage conditions at a level greater than () the identification threshold should be identified. When identification of an impurity is not f

26、easible, a summary of the laboratory studies dem on strati ng the un successful effort should be in cluded in the application. Where attempts have been made to identify impurities present at levels of not more than ( ) the identification thresholds, it is useful also to report the results of these s

27、tudies. 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。 Identification of impurities present at an apparentlevel of not

28、 more than ( ) the identification threshold is gen erally not con sidered n ecessary. However, an alytical procedures should be developed for those potential impurities that are expected to be unusually potent, producing toxic or pharmacological effects at a level not more than () the identification

29、 threshold. All impurities should be qualified as 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。然而，对那些含量不大于( 勻 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 Inorganic impurities are normally detected and quantified using pharmacopoeial or

30、other appropriate procedures. Carry-over of catalysts to the new drug substa nee should be evaluated duri ng developme nt. The n eed for in clusi on or exclusi on of inorganic impurities in the new drug substanee specification should be discussed. Acceptanee criteria should be based on pharmacopoeia

31、l 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。其认可限度应根据药典标准或已知的安全性数据来制定。 3.3 Solve nts 溶剂 The control of residues of the solvents used in the manufacturing process for the new drug substa nee should be discussed and prese nted acco

32、rd ing 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. ANALYTICAL PROCEDURES分析方法 The registrati on applicati on should in clude docume nted evide nee that the an alytical procedures are validated and suitable for the detect ion and qua nti

33、ficati on of impurities (see ICH Q2A and Q2B Guideli nes for An alytical Validatio n). Tech ni cal factors (e.g., manu facturi ng capability and con trol methodology) can be con sidered as part of the justificati on for select ion of alter native thresholds based on manu facturi ng experie nee with

34、the proposed commercial process. The use of two decimal places for thresholds (See Attachment 1) does not necessarily reflect the precision of the analytical procedure used for routine quality control purposes. Thus, the use of lower precision techniques (e.g., thin-layer chromatography) can be acce

35、ptable where justified and appropriately validated. Differe nces in the an alytical procedures used duri ng developme nt and those proposed for the commercial product should be discussed in the registrati on applicati on. 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

36、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 quantitation limit for the analytical procedure should be not more than ( ) the reporting threshold. 分析方法的定量限度应不大于(菊报告阈值。 Organic impurity leve ls can be meas

37、ured by a variety of techniques, including those that compare an an alytical resp onse for an impurity to that of an appropriate refere nee sta ndard or to the response of the new drug substance itself. Reference standards used in the analytical procedures for control of impurities should be evaluat

38、ed and characterised according to their intended uses. The drug substance can be used as a standard to estimate the levels of impurities. In cases where the resp onse factors of the drug substa nce and the releva nt impurity are not close, this practice can still be appropriate, provided a correct i

39、on factor is applied or the impurities are, in fact, being overestimated. Acceptance criteria and analytical procedures used to estimate iden tified or uniden tified impurities can be based on an alytical assumptio ns (e.g., equivale nt detector resp on se). These assumpti ons should be discussed in

40、 the registrati on applicati on. 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 BA

41、TCHES 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 substa nee used for clinical, safety, and stability testing, as well as for batches representative of the proposed commercial process. Quantitative results should be presentednumerically, an

42、d not in general terms such as “ complies ” ,“ meets limit ” etc. Any impurity at a level greater than （） the rep（ threshold （see Attachment 1） and total impurities observed in these batches of the new drug substance should be reported with the analytical procedures indicated. Below 1.0%, the result

43、s should be 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 rounded using conventional rules （see Attachment 2）. A tabulation （e.g., spreadsheet） of the data is recomme nded. Impurities should

44、 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 at a level greater tha n （） the report ing threshold should be summed and reported as total impurities. 注册申请应提供用于临床、安全性研究、稳

45、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”。 W

46、he n an alytical procedures cha nge duri ng developme nt, reported results should be lin ked to the procedure used, with appropriate validati onin formatio n provided. Represe ntative chromatograms should be provided. Chromatograms of representative batchesfrom analytical validation studies showing

47、separation and detectability of impurities （e.g., on spiked samples）, along with any other impurity tests rout in ely performed, can serve as the represe ntative impurity profiles. The applicant should ensure that complete impurity profiles （e.g., chromatograms） of in dividual batches are available,

48、 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 batch to each safety study and e

49、ach cli nical 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 in clude: 对每批新原料药、报告内容应包括： ? Batch ide ntity and size 批号与批量 ?Date of manu facture生 产日期 ? Site of manu facture 生产地点 ? Manu fa

50、cturi ng process 生产工艺 ?Impurity conten t, i ndividual a nd total单个杂质含量和总杂质含量 ? Use of batches批 次的用途 ? Refere nee to an alytical procedure use所 采用分析方法的阐释 6. LISTING OF IMPURITIES 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 st

51、udies, 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 impurities in the new drug substa nce specificati on should be based on the impurities found in batches manu factured by the proposed c

52、ommercial process. Those in dividual impurities with specific accepta nce criteria in cluded in the specification for the new drug substance are referred to as specified impurities in this guideline. Specified impurities can be identified or unidentified. 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

53、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 ale for the in clusi on or exclusi on of impurities in the specificati on should be prese nted. This rati on ale should in clude a discussi on of the impurity profile

54、s observed in the safety and clinical development batches, together with a consideration of the impurity profile of batches manufactured by the proposed commercial process. Specified identified impurities should be included along with specified unidentified impurities estimated to be present at a le

55、vel greater than () the identification threshold given in Attachment 1. For impurities known to be unusually pote nt or to produce toxic or un expected pharmacological effects, the qua ntitati on/detecti on limit of the analytical procedures should be commensuratewith the level at which the impuriti

56、es should be con trolled. For uniden tified impurities, the procedure used and assumpti ons made in establishing the level of the impurity should be clearly stated. Specified, unidentified impurities should be referred to by an appropriate qualitative an alytical descriptive label （e.g.,“ A,“ uniden

57、tified with relative retention of 0.9” ）. A general acceptanee criterion of not m （）the identification threshold （Attachment 1） for any unspecified impurity and an acceptanee 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

58、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：朱鉴定杂质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 lev

59、el that can be justified by safety data, and should be con siste nt with the level achievable by the manu facturi ng process and the an alytical capability. Where there is no safety concernmpurity accepta nce criteria should be based on data gen erated on batches of the new drug substa nce manu fact

60、ured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substance. Although normal manufacturing variations are expected, significant variation in batch-to-batch impurity levels