Impurities In New Drug Substances新原料药中的杂质
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
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Impurities In New Drug Substances新原料药中的杂质
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）。
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Impurities In New Drug Substances新原料药中的杂质
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 ? ? ? ? ? ? 6.
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
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 \impurities\
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拟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
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Impurities In New Drug Substances新原料药中的杂质
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\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含量估计大于（＞）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质的认可标准）。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:
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