Q3A(R2)-新原料药中的杂质(中英文).doc

Impurities In New Drug Substances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

Impurities In New Drug Substances
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

First Codification
History
Date
New Codification
November 2005
Q3
Approval by the Steering Committee under Step 2 and release for public consultation.
15
March 1994
Q3A
Q3A
Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies.
Q3 was renamed 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(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)

Current Step 4 version
Q3A(R2)
Approval by the Steering Committee of the revision of the Attachment 2 directly under Step 4 without further public consultation.
25 October 2006
Q3A(R2)

Impurities In New Drug Substances
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 1
2. CLASSIFICATION OF IMPURITIES 1
3. RATIONALE FOR THE REPORTING AND CONTROL
OF IMPURITIES 2
3.1 Organic Impurities 2
3.2 Inorganic Impurities 4
3.3 Solvents 4
4. ANALYTICAL PROCEDURES 4
5. REPORTING IMPURITY CONTENT OF BATCHES 5
6. LISTING OF IMPURITIES IN SPECIFICATIONS 6
7. QUALIFICATION OF IMPURITIES 8
8. GLOSSARY 9
ATTACHMENT 1 13
ATTACHMENT 2 14
ATTACHMENT 3 15

Impurities In New Drug Substances
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