Q3A(R2)-新原料药中的杂质(中英文)

INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

ICH H ARMONISED T RIPARTITE G UIDELINE

I MPURITIES I N N EW D RUG S UBSTANCES

Q3A(R2)

Current Step 4 version

dated 25 October 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 European Union, Japan and USA.

Q3A(R2) Document History

Current Step 4 version

I MPURITIES I N N EW D RUG S UBSTANCES

ICH Harmonised Tripartite Guideline

Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 7 February 2002, this guideline is recommended for

adoption to the three regulatory parties to ICH.

Attachment 2 has been 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)

3.1Organic Impurities (6)

3.2Inorganic Impurities (7)

3.3Solvents (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 MPURITIES I N N EW D RUG S UBSTANCES

新原料药中的杂质

1. PREAMBLE 序言

This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. It is not intended to apply to new drug substances used during the clinical research stage of development. The following types of drug substances are not covered in this guideline: biological/biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived therefrom, herbal products, and crude products of animal or plant origin.

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 substances are addressed from two perspectives:

新原料药中的杂质分两个方面阐述：

Chemistry Aspects include 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 Aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical 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 the following categories: 杂质可分为下列类型:

?Organic 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 solvents 残留溶剂

Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. 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：

?Starting materials 起始物

?By-products 副产物

?Intermediates中间体

?Degradation products降解产物

?Reagents, ligands and catalysts试剂、配位体、催化剂

Inorganic impurities can result from the manufacturing process. They are normally 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：

?Reagents, ligands 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 suspensions in the synthesis of a new drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished (see ICH Guideline Q3C on Residual Solvents).

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 document are: (1) extraneous contaminants that should not occur in new drug substances and are more appropriately addressed as Good Manufacturing 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 Organic Impurities 有机杂质

The applicant should summarise the actual and potential impurities most likely to arise during the synthesis, purification, and storage of the new drug substance. This summary should be based on sound scientific appraisal of the chemical reactions involved in the synthesis, impurities associated with raw materials that could contribute to the impurity profile of the new drug substance, and possible degradation products. This discussion can be limited to those impurities that might reasonably be expected based on knowledge of the chemical reactions and conditions involved.

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 addition, the applicant should summarise the laboratory studies conducted to detect impurities in the new drug substance. This summary should include test results of batches manufactured during the development 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 arising during storage. The impurity profile of the drug substance batches intended for marketing should be compared with those used in development, and any differences 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 conducted to characterise the structure of actual impurities present in the new drug substance at a level greater than (>) the identification threshold given in Attachment 1 (e.g., calculated using the response factor of the drug substance) should be described. Note that any impurity at a level greater than (>) the identification threshold in any 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 feasible, a summary of the laboratory studies demonstrating the unsuccessful effort should be included 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 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（≤）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 apparent level of not more than (≤) the identification threshold is generally not considered necessary. However, analytical 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 threshold. All impurities should be qualified as described later in this guideline.

通常没有必要对含量在阈值以下（≤）的杂质进行鉴定。然而，对那些含量不大于（≤）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 other appropriate procedures. Carry-over of catalysts to the new drug substance should be evaluated during development. The need for inclusion or exclusion of inorganic impurities in the new drug substance specification should be discussed. Acceptance criteria should be based on pharmacopoeial standards 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 Solvents溶剂

The control of residues of the solvents used in the manufacturing process for the new drug substance should be discussed and presented according to the ICH Q3C Guideline for Residual Solvents.

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 registration application should include documented evidence that the analytical procedures are validated and suitable for the detection and quantification of impurities (see ICH Q2A and Q2B Guidelines for Analytical Validation). Technical factors (e.g., manufacturing capability and control methodology) can be considered as part of the justification for selection of alternative thresholds based on manufacturing experience with 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 acceptable where justified and appropriately validated. Differences in the analytical procedures used during development and those proposed for the commercial product should be discussed in the registration application.

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 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（≤）报告阈值。

Organic impurity leve ls can be measured by a variety of techniques, including those that compare an analytical response for an impurity to that of an appropriate reference standard or to the response of the new drug substance itself. Reference standards used in the analytical procedures for control of impurities should be evaluated 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 response factors of the drug substance and the relevant impurity are not close, this practice can still be appropriate, provided a correction factor is applied or the impurities are, in fact, being overestimated. Acceptance criteria and analytical procedures used to estimate identified or unidentified impurities can be based on analytical assumptions (e.g., equivalent detector response). These assumptions should be discussed in 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 the proposed commercial process. Quantitative results should be presented numerically, and not in general terms such as “complies”, “meets limit” etc. Any impurity at a level greater than (>) the reporting 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 results 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 recommended. Impurities should be designated by code number 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 than (>) the reporting 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”。

When analytical procedures change during development, reported results should be linked to the procedure used, with appropriate validation information provided. Representative chromatograms should be provided. Chromatograms of representative batches from analytical validation studies showing separation and detectability of impurities (e.g., on spiked samples), along with any other impurity tests routinely performed, can serve as the representative impurity profiles. The applicant should ensure that complete impurity profiles (e.g., chromatograms) of individual 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的杂质概况（例如；色谱图）。

A tabulation should be provided that links the specific new drug substance batch to each safety study and each clinical study in which the new drug substance has been 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 substance, the report should include:

对每批新原料药、报告内容应包括：

?Batch identity and size 批号与批量

?Date of manufacture生产日期

?Site of manufacture 生产地点

?Manufacturing process 生产工艺

?Impurity content, individual and total单个杂质含量和总杂质含量

?Use of batches批次的用途

?Reference to analytical procedure used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 studies, chemical development studies, and routine batch analyses can be used to predict those impurities likely to occur in the commercial product. The selection of impurities in the new drug substance specification should be based on the impurities found in batches manufactured by the proposed commercial process. Those individual impurities with specific acceptance criteria included 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 rationale for the inclusion or exclusion of impurities in the specification should be presented. This rationale should include a discussion of the impurity profiles 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 level greater than (>) the identification threshold given in Attachment 1. For impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled. For unidentified impurities,

the procedure used and assumptions made in establishing the level of the impurity should be clearly stated. Specified, unidentified impurities should be referred to by an appropriate qualitative analytical descriptive label (e.g., “unidentified A", “unidentified with relative retention of 0.9”). A general acceptance criterion of not more than (≤) the identification 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（≤）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 consistent with the level achievable by the manufacturing process and the analytical capability. Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the new drug substance manufactured 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 can indicate that the manufacturing process of the new drug substance is not adequately controlled and validated (see ICH Q6A Guideline on Specifications, Decision 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 Attachment 1) does not necessarily indicate the precision of the acceptance 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 identified impurity每种特定的已鉴定杂质

?Each specified unidentified impurity每种特定的未鉴定的杂质

?Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold任何不大于（≤）鉴定阈值认可标准的非特定杂质。

?Total impurities杂质总量

Residual Solvents残留溶剂

Inorganic Impurities无机杂质。

7. QUALIFICATION OF IMPURITIES 杂质的界定

Qualification is 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. 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 adequately tested in safety and/or clinical studies would be considered qualified. Impurities that are also significant metabolites present in animal and/or human studies are generally considered qualified. A level of a qualified impurity higher than that present in a new drug substance can also be justified based on an analysis of the actual amount of impurity administered in previous relevant safety studies.

杂质的界定是获得和评估数值的过程，这些数值用于建立安全的阈值（水平），单个的或某些已明确的杂质含量在这个阈值水平下是可以确保生物安全性的。申报者应对所选定的杂质限度提供包括安全性研究在内的理由。对于一个通过充分的安全性研究和临床研究的新原料药，其中任何一个杂质的水平即被认为是已经通过界定了的。对于是动物和/或人体中的重要代谢物的那些杂质，也认为已通过界定。杂质的界定限量（水平）如果高于药物实际所含的杂质量，则同样可以根据对已完成的安全性研究中使用药物中的实际杂质量来判断其合理性。

If data are unavailable to qualify the proposed acceptance criterion of an impurity, studies to obtain such data can be appropriate when the usual qualification thresholds given in Attachment 1 are exceeded.

如果可获得的数据不能界定某一杂质拟定的认可标准，而且当该认可标准超过了附录1所列的界定阈值时，则必须进行进一步的研究，去获得必要的数据。

Higher or lower thresholds for qualification of impurities can be appropriate for some individual drugs based on scientific rationale and level of concern, including drug class effects and clinical experience. For example, qualification can be especially important when there is evidence that such impurities in certain drugs or therapeutic classes have previously been associated with adverse reactions in patients. In these instances, a lower qualification threshold can be appropriate. Conversely, a higher qualification threshold can be appropriate for individual drugs when the level of concern for safety is less than usual based on similar considerations (e.g., patient population, drug class effects, clinical considerations). Proposals for alternative thresholds would be considered on a case-by-case basis.

对于某些药物，可以根据科学原理并考虑药物的类别和临床经验，对其杂质界定阈值进行适当调整。例如，某些杂质在一些药物中或治疗类别中已证明与病人的不良反应有关，则该杂质的界定是非常重要的。在这种情况下，应制订更低的界定阈值。反之，如果考虑相似情况（病例数、药物类别、临床情况）后，对安全性的顾虑比通常情况小，那么这些药物的界定阈值可以高一些。对限度的改变应具体情况具体对待。

The "Decision Tree for Identification and Qualification" (Attachment 3) describes considerations for the qualification of impurities when thresholds are exceeded. In some cases, decreasing the level of impurity to not more than the threshold can be simpler than providing safety data. Alternatively, adequate data could be available in the scientific literature to qualify an impurity. If neither is the case, additional safety testing should be considered. The studies considered appropriate to qualify an impurity will depend on a number of factors, including the patient population, daily dose, and route and duration of drug administration. Such studies can be conducted on the new drug substance containing the impurities to be controlled, although studies using isolated impurities can sometimes be appropriate.

鉴定和界定判断图（附件3）描述了当杂质含量超过了界定阈值时所应考虑到的事项。在一些情况下降低杂质含量使其低于阈值要比提供安全性数据来的简单。或者可以选择文献资料提供的充分数据来界定某一杂质。如果两者均不可行，则应考虑进行附加的安全性试验。合理的界定一个杂质的研究将取决于许多因素，包括病例数，每日剂量、给药途径与疗程。这类试验虽然可用分离出来的杂质进行研究，但通常是用含有被控制的杂质的新原料药来进行研究。

Although this guideline is not intended to apply during the clinical research stage of development, in the later stages of development the thresholds in this guideline can be useful in evaluating new impurities observed in drug substance batches prepared by the proposed commercial process. Any new impurity observed in later stages of development should be identified if its level is greater than (>) the identification threshold given in Attachment 1 (see the “Decision Tree for Identification and Qualification” in Attachment 3). Similarly, the qualification of the impurity should be considered if its level is greater than (>) the qualification threshold given in Attachment 1. Safety assessment studies to qualify an impurity should compare the new drug substance containing a representative amount of the new impurity with previously qualified material. Safety assessment studies using a sample of the isolated impurity can also be considered.

虽然本指导原则在研发的临床研究阶段并不适用，但在研究后期，本指南的阈值对于评价拟上市新原料药生产过程中的各批次中出现的新杂质是有用的。在研究后期，任何含量大于（＞）附件1中鉴定阈值（见附件3鉴定和界定流程图）的新的杂质均许鉴定。同样，如果杂质量大于（＞）附录1中的界定阈值，应考虑杂质的界定。界定某杂质的安全性评价研究应将含有一定代表量新杂质的新原料药与以前界定过的原料进行比较。也可考虑用已分离出来的杂质样本进行安全性研究。

8. GLOSSARY 术语

Chemical Development Studies: Studies conducted to scale-up, optimise, and validate the manufacturing process for a new drug substance.

化学方面的开发研究:对新原料药合成工艺进行放大、优化以及确证的研究。Enantiomeric Impurity: A compound with the same molecular formula as the drug substance that differs in the spatial arrangement of atoms within the molecule and is a non-superimposable mirror image. 对映体:与药物具有相同的分子式，但其分子中原子的空间排列不同并且为非镜像叠加的化合物。

Extraneous Contaminant: An impurity arising from any source extraneous to the manufacturing process.

外源物质:来源于生产工艺以外的杂质。

Herbal Products: Medicinal products containing, exclusively, plant material and/or vegetable drug preparations as active ingredients. In some traditions, materials of inorganic or animal origin can also be present.

草药:以植物和/或植物药制品为活性组分制成的药物制剂。在一些传统药中，可能也含有无机物或动物组织。

Identified Impurity: An impurity for which a structural characterisation has been achieved.

已确定的杂质：已确证了其结构特征的杂质。

Identification Threshold: A limit above (>) which an impurity should be identified.

鉴定阈值：杂质应被鉴定的限度值。

Impurity: Any component of the new drug substance that is not the chemical entity defined as the new drug substance.

杂质：存在于新原料药中，但其化学结构与新原料药不一样的任何一种成分。

Impurity Profile: A description of the identified and unidentified impurities present in a new drug substance.

杂质概况：对存在于某一新原料药中的已知或未知杂质情况的描述。

Intermediate: A material produced during steps of the synthesis of a new drug substance that undergoes further chemical transformation before it becomes a new drug substance.

中间体：化学合成新原料药的过程中所产生的某一成分，必须进一步进行结构改变才能成为新原料药。

Ligand: An agent with a strong affinity to a metal ion.

配位体：对金属离子具有很强亲和力的试剂。

New Drug Substance: The designated therapeutic moiety that has not been previously registered in a region or member state (also referred to as a new molecular entity or new chemical entity). It can be a complex, simple ester, or salt of a previously approved drug substance.

新原料药：先前尚无在某一地区或成员国注册的具有治疗作用的活性部分（或为新分子体或新化学体）。它可以是某种已获批准的药物的一种复合物、简单的酯或盐。

Polymorphic Forms: Different crystalline forms of the same drug substance. These can include solvation or hydration products (also known as pseudo-polymorphs) and amorphous forms.

多晶型：某一药物的不同结晶形态。包括溶剂化或水合物（伪晶体及无定型）。

Potential Impurity: An impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the new drug substance.

潜在杂质：按照理论推测在生产过程中可能引入或产生的杂质。其在新原料药中可能存在，也可能是不存在的。

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.

界定：是获得和评价一些数据的过程，这些数据用于建立安全的阈值（水平），单个的或一些已确定的杂质的含量在这个阈值下可以确保生物安全性。

Qualification Threshold: A limit above (>) which an impurity should be qualified.

界定阈值：杂质应被界定的限度值。

Reagent: A substance other than a starting material, intermediate, or solvent that is used in the manufacture of a new drug substance.

试剂：一种与起始物、中间体或溶剂不同的物质，在新原料药的生产中使用

Reporting Threshold: A limit above (>) which an impurity should be reported. Reporting threshold is the same as reporting level in Q2B.

报告阈值：杂质应报告的限度，即Q2B中的“报告水平”。

Solvent:An inorganic or an organic liquid used as a vehicle for the preparation of solutions or suspensions in the synthesis of a new drug substance.

溶剂：在新原料药合成中用于制备溶液或混悬液的无机或有机液体。

Specified Impurity: An impurity that is individually listed and limited with a specific acceptance criterion in the new drug substance specification. A specified impurity can be either identified or unidentified.

特定杂质：在新原料药规范（标准）中规定要检测并有特定的认可标准的杂质。它可以是已鉴定或未鉴定的杂质。

Starting Material: A material used in the synthesis of a new drug substance that is incorporated as an element into the structure of an intermediate and/or of the new drug substance. Starting materials are normally commercially available and of defined chemical and physical properties and structure.

起始物：在新药的合成中，作为一种成分结合到中间体或新药中的物质。起始物通常市场上有供应，并具有确定的化学和物理性质及结构。

Unidentified Impurity: An impurity for which a structural characterisation has not been achieved and that is defined solely by qualitative analytical properties (e.g., chromatographic retention time).

未鉴定杂质：仅通过定性手段（例如：液相色谱相对保留时间）来定义的杂质。其结构尚未弄清。

Unspecified impurity: An impurity that is limited by a general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification.

非特定杂质：在新原料药规范（标准）中，其限度在总认可标准中控制而不单独控制的杂质。

1 The amount of drug substance administered per day

日常使用的药物剂量

2 Higher reporting thresholds should be scientifically justified

应当对较高的报告阈值进行科学论证

3 Lower thresholds can be appropriate if the impurity is unusually toxic 如果杂质具有特殊毒性，可以采用较低的阈值

ATTACHMENT 2 Illustration of Reporting Impurity Results for Identification and Qualification in an Application

附件2 申请表中鉴定或界定的报告杂质结果表

The attachment is only illustrative and is not intended to serve as template how results on impurities should be presented in an application file. Normally raw data are not presented.

本附件只是作为说明，并不是如何出具申请表中杂质结果模板。正常情况下，不出具原始数据。

Example 1: 0.5 g Maximum Daily Dose

Reporting threshold = 0.05%

Identification threshold = 0.10%

Qualification threshold = 0.15%

例1：0.5g 最大日剂量

报告阈值＝0.05%

鉴定阈值＝0.10%

界定阈值＝0.15%

Example 2: 0.8 g Maximum Daily Dose

Reporting threshold = 0.05% Identification threshold = 0.10%

Qualification threshold = 1.0 mg TDI

例2： 0.8g 最大日剂量

报告阈值＝0.05% 鉴定阈值＝0.10%

界定阈值＝1.0mg每天总摄入量

1) After identification, if the response factor is determined to differ significantly from the original assumptions, it may be appropriate to re-measure the actual amount of the impurity present and re-evaluate against the qualification threshold (see Attachment 1).

鉴定后，如果确定响应因子明显不同于原始假设值，则重新测量实际的杂质量及用界定阈值（附件1）重新评估。

2) To verify if a threshold is exceeded, a reported result has to be evaluated against the thresholds as follows: when the threshold is described in %, the reported result rounded to the same decimal place as the threshold should be compared directly to the threshold. When the threshold is described in TDI, the reported result should be converted to TDI, rounded to the same decimal place as the threshold and compared to the threshold. For example the amount of impurity at 0.12% level corresponds to a TDI of 0.96 mg (absolute amount) which is then rounded up to 1.0 mg; so the qualification threshold expressed in TDI (1.0 mg) is not exceeded.

确定如果超出一个阈值，则必须用以下阈值对报告结果进行评估：因为阈值是直接与阈值比较的，当阈值用%描述时，报告结果四舍五入到同样的小数位。当阈值用每天总摄入量（TDI）描述时，报告结果应当转换为每天总摄入量（TDI），四舍五入与阈值相同的小数位并用阈值进行比较。如杂质量0.12%对应的每天总摄入量（TDI）为0.96 mg（绝对值），然后约为1.0mg；因此并未超出用每天总摄入量（0.1mg）表示的界定阈值。

ATTACHMENT 3 Decision Tree for Identification and Qualification