抗生素中相关杂质质量标准制定的指导原则 中英

人用药品注册技术要求国际协调会（ICH）文件目录ICH的论题主要分为四类，因此ICH根据论题的类别不同而进行相应的编码分类：1. “Q”类论题：Q代表QUALITY，指那些与化工和医药，质量保证方面的相关的论题。

Q1/Q2...Q10都属于这类。

2. “S”类论题：S代表SAFETY，指那些与实验室和动物实验，临床前研究方面的相关的论题。

3. “E”类论题：E代表EFFICACY，指那些与人类临床研究相关的课题。

4. “M”类论题：M代表MULTIDISCIPLINARY, 指那些不可单独划入以上三个分类的交叉涉及的论题。

同时M又细分为5个小类：M1: 常用医学名词（Med DRA）M2: 药政信息传递之电子标准M3: 与临床试验相关的临床前研究时间的安排M4: 常规技术文件(CTD)M5: 药物词典的数据要素和标准一、ICH. 质量部分（Quality）稳定性1.Quality质量2.Q1: Stability稳定性3.Q1A(R2): Stability Testing of New Drug Substances and Products 新原料药和制剂的稳定性试验4.Q1B: Photostability Testing of New Drug Substances and Products 新原料药和制剂的光稳定性试验5.Q1C: Stability Testing for New Dosage Forms 新剂型的稳定性试验6.Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products原料药和制剂稳定性试验的交叉和矩阵设计 Q1E: Evaluation of Stability Data 稳定性数据的评估7.Q1F: Stability Data Package for Registration Applications in Climatic Zones III andIV在气候带III和IV，药物注册申请所提供的稳定性数据8.Q2: Analytical Validation分析验证9.Q2(R1): Validation of Analytical Procedures: Text and Methodology分析程序的验证：正文及方法论10.Q3: Impurities 杂质11.Q3A(R2): Impurities in New Drug Substances 新原料药中的杂质12.Q3B(R2): Impurities in New Drug Products (Revised Guideline) 新制剂中的杂质13.Q3C(R3): Impurities: Guideline for Residual Solvents 杂质：残留溶剂指南Impurities: Guideline for Residual Solvents (Maintenance) 杂质：残留溶剂指南(保留)PDE for Tetrahydrofuran (in Q3C(R3)) 四氢呋喃的日允许接触剂量PDE for N-Methylpyrrolidone (in Q3C(R3)) N-甲基吡咯烷酮的日允许接触剂量14.Q4: Pharmacopoeias药典15.Q4A: Pharmacopoeial Harmonisation 药典的协调16.Q4B: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions药典内容的评估及推荐为用于ICH地区17.Q4B Annex1 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Residue on Ignition/Sulphated Ash General Chapter附录1 药典内容的评估及推荐为用于ICH地区关于灼烧残渣/灰分常规篇18.Q4B Annex2 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Test for Extractable Volume of Parenteral Preparations General Chapter附录2 药典内容的评估及推荐为用于ICH地区关于注射剂可提取容量测试常规篇19.Q4B Annex3 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regionson Test for Particulate Contamination: Sub-Visible Particles General Chapter附录3 药典内容的评估及推荐为用于ICH地区关于颗粒污染物测试:不溶性微粒常规篇20.Q5: Quality of Biotechnological Products 生物技术制品质量21.Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin来源于人或者动物细胞系的生物技术产品的病毒安全性评估22.Q5B: Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products生物技术产品的质量：源于重组DNA的蛋白质产品的生产中所用的细胞中的表达构建分析23.Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products生物技术产品的质量：生物技术/生物产品的稳定性试验24.Q5D: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products用于生产生物技术/生物产品的细胞底物的起源和特征描述25.Q5E: Comparability of Biotechnological/Biological Products Subject to Changes inTheir Manufacturing Process基于不同生产工艺的生物技术产品/生物产品的可比较性26.Q6: Specifications规格27.Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (including decision trees) 质量规格：新原料药和新制剂的检验程序和可接收标准：化学物质(包括决定过程)28.Q6B: Specifications: Test Procedures and Acceptance Criteria for29.Biotechnological/Biological Products质量规格：生物技术/生物产品的检验程序和可接收标准30.Q7: Good Manufacturing Practices （GMP）31.Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients活性药物成份的GMP指南32.Q8: Pharmaceutical Development药物研发33.Annex to Q8Q8附录34.Q9: Quality Risk Management质量风险管理35.Q10: Pharmaceutical Quality System药物质量体系二、ICH.安全性部分(Safety) 致癌试验1.S1A Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals 药物致癌试验的必要性2.S1B Testing for Carcinogenicity of Pharmaceuticals 药物致癌试验3.S1C(R2) Dose Selection for Carcinogenicity Studies of Pharmaceuticals药物致癌试验的剂量选择4.S1C’药物致癌试验的剂量选择的附件：补充剂量限度和有关注释遗传毒性5.S2(R1) Guidance on Genotoxicity Testing and Data Interpretation forPharmaceuticals Intended for Human Use 人用药物的遗传毒性试验和数据分析指导原则6.S2A药物审评遗传毒性试验的特殊性指导原则7.S2B遗传毒性：药物遗传毒性试验标准组合药代8.S3A Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposurein Toxicity Studies 毒代动力学指导原则：毒性研究中全身暴露的评价9.S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies药代动力学：重复给药的组织分布研究指导原则慢性毒性10.S4Duration of Chronic Toxicity Testing in Animals (Rodent and Non RodentToxicity Testing) 动物慢性毒性试验的周期（啮齿类和非啮齿类）生殖毒性11.S5(R2) Detection of Toxicity to Reproduction for Medicinal Products andToxicity to Male Fertility (the Addendum dated November 1995 has beenincorporated into the core guideline in November 2005 )12.S5A药品的生殖毒性检测13.S5B雄性生育力毒性其他14.S6Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals 生物技术药品的临床前安全性试验15.S7A Safety Pharmacology Studies for Human Pharmaceuticals 人用药物的安全性药理研究16.S7B The Non-clinical Evaluation of the Potential for Delayed VentricularRepolarization (QT Interval Prolongation) by Human Pharmaceuticals人用药延迟心室复极化（QT间期延长）潜在作用的非临床评价指导原则17.S8Immunotoxicity Studies for Human Pharmaceuticals人类药品的免疫毒性研究18.S9 Nonclinical Evaluation for Anticancer Pharmaceuticals抗癌药物的临床前评价19.S10 Photosafety Evaluation三、ICH.临床部分(Efficacy)1.E1The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions 评价临床长期给药方案的安全性2.E2A Definitions and Standards for Expedited Reporting 快速报告的定义和标准3.E2B(R3) Data Elements for Transmission of Individual Case Safety Reports个体病例安全性报告传递的数据要素4.E2C Periodic Benefit-Risk Evaluation Report 上市药品定期安全性更新报告5.E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting批准后安全性数据管理：快速报告的定义和标准6.E2E Pharmacovigilance Planning药物警戒计划7. E2F Development Safety Update Report8.E3Structure and Content of Clinical Study Reports 临床研究报告的结构与内容9.E4Dose-Response Information to Support Drug Registration 新药注册所需量-效关系的资料10.E5(R1)Ethnic Factors in the Acceptability of Foreign Clinical Data 对国外临床研究资料的种族因素的可接受性11.E6(R1) Good Clinical Practice: Consolidated Guideline 药品临床研究规范（GCP）一致性指导原则12.E7Studies in Support of Special Populations: Geriatrics 老年人群的临床研究13.E8General Considerations for Clinical Trials 临床试验的一般考虑14.E9Statistical Principles for Clinical Trials 临床试验统计原则15.E10Choice of Control Group and Related Issues in Clinical Trials 对照组的选择16.E11Clinical Investigation of Medicinal Products in the Pediatric Population 儿童人群的临床研究17.E12按治疗分类的各类药物临床评价E12 Principles for Clinical Evaluation of New Antihypertensive Drugs18.E14The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs 非抗心律失常药物致QT/QTc间期延长及潜在心律失常作用的临床评价19.E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories20.E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure and Format of Qualification Submissions四、ICH.综合部分 (Multidisciplinary)1.M1医学术语Med DRA2.M2Electronic Transmission of Individual Case Safety Reports MessageSpecification (ICH ICSR DTD Version 2.1) companion document to E2B(R3)注册资料传递所需的电子代码3.M3Guidance on Nonclinical Safety Studies for the Conduct of Human ClinicalTrials and Marketing Authorization for Pharmaceuticals与临床研究有关的临床前研究的时间安排4.M4 Organisation of the Common Technical Document for the Registration ofPharmaceuticals for Human Use (Edited with Numbering and Section Header Changes, September 2002). Including the Annex : the Granularity Document(Revised November 2003).CTD（common technical document）（包括CTD、CTD-Q、CTD-S、CTD-E和eCTD）药品词汇的数据要素和标准5.M4Q (R1) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Quality (Edited with Numbering and Section Header Changes, September 2002)6.M4S (R2) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Safety (Edited with Numbering and SectionHeader Changes, September 2002)7.M4E (R1) The Common Technical Document for the Registration ofPharmaceuticals for Human Use: Efficacy (Edited with Numbering and Section Header Changes, September 2002)8.M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities inPharmaceuticals to Limit Potential Carcinogenic Risk Reference:1. 《ICH 药品注册的国际要求》2. 3. /health/Health/yx/yao/2007-08-07/6326.html。

<232>ELEMENTALIMPURITIES—LIMITSINTRODUCTIONThis general chapter specifies limits for the amounts of elemental impurities in drug products. Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment and the container closure system). When elemental impurities are known to be present, have been added, or have the potential for introduction, assurance of compliance to the specified levels is required.A risk-based control strategy may be appropriate when analysts determine how to assure compliance with this standard. Due to the ubiquitous nature of arsenic, cadmium, lead,assessment. Regardless of the approach used, compliance with the limits specified is required for all drug products unless otherwise specified in an individual monograph or excluded in paragraph three of this introduction.The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or non-recombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this chapter, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides.This chapter does not apply to radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and<232>元素杂质-限度介绍本通则规定了制剂中元素杂质的限度。

抗生素类药品杂质限度标准《抗生素类药品杂质限度标准》随着现代医学的发展，抗生素类药品在临床应用中的重要性越来越被认识到。

然而，抗生素类药品在生产过程中可能会产生一些杂质，这些杂质可能对患者的健康造成影响，因此制定了抗生素类药品杂质限度标准，以确保药品的质量和安全性。

抗生素类药品的杂质主要分为有机杂质和无机杂质两类。

有机杂质包括有机溶剂残留物、杂质与活性成分相关的化合物、光谱杂质等。

有机溶剂残留物指生产过程中使用的溶剂残留下来的成分，这些溶剂可能对人体产生毒性作用。

杂质与活性成分相关的化合物是指与药物活性成分有一定化学关系的杂质，这些化合物可能影响药物的疗效或产生不良反应。

光谱杂质主要指药物在生产过程中产生的未知化合物，这些化合物难以被鉴定和定量，因此需要对其进行限制。

无机杂质主要包括重金属和无机盐类。

重金属是指铅、铬、汞等对人体有毒的金属元素。

这些重金属可能通过药物吸收进入人体，对肝脏、肾脏等器官造成损害。

无机盐类包括磷酸盐、硫酸盐等，虽然无机盐类一般不会对人体造成直接伤害，但过高的含量可能影响药物的稳定性和药效。

制定抗生素类药品杂质限度标准的目的是为了保证药品的质量和安全性。

这些标准根据药品的特性和临床应用的需要制定，严格限制了有机杂质和无机杂质的含量。

在药品生产过程中，需要进行严格的质控，确保药品的质量符合标准要求。

同时，在药品上市后，还需要进行药品的质量监测，确保药品的质量在正常范围内。

抗生素类药品杂质限度标准的制定与药品监管部门、药品生产企业以及科研机构密切相关。

这些组织通过不断的研究和实验，不断完善和更新抗生素类药品杂质限度标准，以确保患者在使用抗生素类药品时的安全性和有效性。

总之，抗生素类药品杂质限度标准的制定对于保障药品的质量和安全性至关重要。

通过限制有机杂质和无机杂质的含量，可以确保患者在使用抗生素类药品时不受到不良反应的影响，从而促进临床治疗的有效进行。

此外，药品监管部门、药品生产企业和科研机构也需要持续的努力，不断完善相关的标准和规范，以确保抗生素类药品的质量和安全性得到有效的保障。

药品质量标准制定原则及内容是怎样的呢除了⾷品安全，⼤家最关注的就是药品质量安全了，那么，⼤家知道药品质量标准是怎样的吗？制定这个标准的原则是什么呢？请⼤家阅读下⾯的⽂章了解！药品质量标准总原则(1)必须坚持质量第⼀，充分体现“安全有效，技术先进，经济合理”的原则，并要尽可能采⽤先进标淮，使标准能起到推动提⾼质量、保证择优发展和促进对外贸易的作⽤。

(2)要从⽣产、流通、使⽤的各个环⾏去考察影响药品质量的因素，有针对性地规定检测项⽬，切实加强对药品内在质量的控制。

(3)检验⽅法的选择，应根据“准确、灵敏、简便、快速”的原则，要强调⽅法的适⽤性，并注意吸收国内科研成果和国外先进经验;既要考虑当前国内实际条件，⼜要反应新技术的应⽤利发展，进⼀步完善和提⾼检测⽔平。

对于某些抗⽣素、⽣化药品和必须采⽤⽣物测定的品种，在不断改进⽣物测定法的同时，也可采⽤化学和仪器分析的⽅法控制其纯度。

(4)标准中的限度的规定，应密切结合实际要保证药品在⽣产、贮存、销售和使⽤过程中的质量，并可能全⾯符合规定：在制定药品质量标准过程中，对⼀些细节有⼀些具体的规定。

标准名称制定药品质量标准时，⾸先应给⼀个药品以法定的名称，根据卫⽣部颁布的《新药审批办法》规定：“新药的名称应明确、科学、简短，不得使⽤代号及容易混同或夸⼤疗效的名称”。

国际上，世界卫⽣组织制定公布了国际⾮专有药品名，审定出版了单⼀药物通-⽤名《国际⾮专利药名》供国际间统⼀使⽤。

WHO的专家委员会对药品命名提出了两个主要原则：(1)药品名称读⾳应清晰易辨，全词不宜过长，且应避免与⽬前已经使⽤的药名相似;(2)属于同⼀药效类别的药物，其名称应⼒求⽤适当的⽅法使之显⽰这⼀关系：凡是易令病⼈从解剖学、⽣理学、病理学和治疗学⾓度猜测药效的名称，⼀般不应采⽤。

我国药典委员会和《新药审批办法》对药品命名的原则规定是：(1)药品的名称包括中⽂名、汉语拼⾳名、英⽂名⼆种。

(2)药品的名称应明确、简短、科学，不⽤代号、政治性名词、容易混同或夸⼤疗效的名称。

GUIDELINE FOR ELEMENTAL IMPURITIES元素杂质指南Q3D1. INTRODUCTION 介绍药品中的元素杂质可能会有几个来源，它们可能是有意加入合成反应的催化剂的残留，也可能是作为杂质出现（例如，通过与工艺设备或容器/密闭系统相互反应，或出现在药品的组分中）。

由于元素杂质并不给患者提供任何治疗益处，其在药品中的水平应被控制在可接受限度以内。

本指南分为三个部分：潜在元素杂质毒性数据的评估、为每个毒性关注元素建立PDE值，以及应用基于风险的方法来控制药品中的元素杂质。

如果药品中的元素杂质没有超过PDE阈值的话，申报人不需要根据其工艺能力加严限度。

本指南中建立的PDE阈值足以保护所有患者人群的公共健康。

在有些情况下，如果毒性阈值以下的元素杂质水平表示出对药品的其它质量属性有影响（例如，对药品降解有催化作用的元素），则可能需要保证一个更低的元素杂质水平。

另外，对于具有较高PDE值的元素，可能需要从药品质量的角度，以及要参照的其它指南（例如ICH Q3A）来考虑其它限度。

本指南给出一个采用ICH Q9中所述风险管理原则来评估和控制药品中元素杂质的方法。

该方法提供了一个基于风险控制策略的平台来限制药品中的元素杂质。

2. SCOPE 范围本指南适用于新的制剂产品（如ICH Q6A和Q6B定义）和含有已有原料药的新药品。

含有纯化后的蛋白质和多肽（包括采用复合或非复合来源生产的蛋白质和多肽）的药品、其衍生物，以及其复方药品（例如，偶合物）在本指南适用范围内。

含有合成多肽、多核苷酸和低聚糖的药品也适用本指南。

本指南不适用于草药产品、放射性药品、疫苗、细胞代谢物、DNA产品、过敏提取物、细胞、全血、细胞血成分或血液制品，包括血浆和血浆制品、非系统循环用透析液，和用于治疗用途加入的元素。

本指南不适用于基于基因（基因治疗）、细胞（细胞治疗）和组织（组织工程）的药品。

在有些地区，这些产品是作为先进治疗药品的。

杂质：残留溶剂的指导原则1．介绍本指导原则旨在介绍药物中残留溶剂在保证人体安全条件下的可接受量，指导原则建议使用低毒的溶剂，提出了一些残留溶剂毒理学上的可接受水平。

药物中的残留溶剂在此定义为在原料药或赋形剂的生产中，以及在制剂制备过程中产生或使用的有机挥发性化合物，它们在工艺中不能完全除尽。

在合成原料药中选择适当的溶剂可提高产量或决定药物的性质，如结晶型。

纯度和溶解度。

因此．有时溶剂是合成中非常关键的因素。

本指导原则所指的溶剂不是谨慎地用作赋形剂的溶剂，也不是溶剂化物，然而在这些制剂中的溶剂含量也应进行测定，并作出合理的判断。

出于残留溶剂没有疗效，故所有残留溶剂均应尽可能．去，以符合产品规范、GMP或其他基本的质量要求。

制剂所含残留溶剂的水平不能高于安全值，已知一些溶剂可导致不接受的毒性（第一类，表1），除非被证明特别合理，在原药、赋形剂及制剂生产中应避免使用。

一些溶剂毒性不太大（第二类，表2）应限制使用，以防止病人潜在的不良反应。

使用低毒溶剂（第三类，表3）较为理想。

附录1中列出了指导原则中的全部溶剂。

表中所列溶剂并非详尽无遗，其他可能使用的溶剂有待日后补充列人。

第一、二类溶剂的建议限度或溶剂的分类会随着。

新的安全性资料的获得而调整。

含有新溶剂的新药制剂、其上市申请的安全性资料应符合本指导原则或原料药指导原则（Q3A新原料药中的杂质）或新药制剂（Q3B新药制剂中的杂质）中所述的杂质控制原则，或者符合上述三者。

2. 指导原则的范围指导原则范围包括原料药、赋形剂或制剂中所含残留溶剂．因此，当生产或纯化过程中会出现这些溶剂时。

应进行残留溶剂的检验。

也只有在上述情况下，才有必要作溶剂的检查。

虽然生产商可以选择性地测定制剂，但也可以从制剂中各成分的残留溶液水平来累积计算制剂中的残留溶剂。

如果计算结果等于或低于本原则的建议水平，该制剂可考虑不检查残留溶剂，但如果计算结果高于建议水平则应进行检测，以确定制剂制备过程中是否降低了有关溶剂的量以达到可接受水平。

30 June 2012EMA/CHMP/CVMP/QWP/199250/2009 corrCommittee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP)Guideline on setting specifications for related impurities in antibiotics抗生素中相关杂质质量标准制定的指导原则Final 定稿学习之名（译注）Table of contents 目录Executive summary1. Introduction (background)2. Scope3. Legal basis4. General requirements5. Impurity profiling and reporting, identification and qualification thresholds6. New applications and variations7. Specifications for medicinal products8. Analytical proceduresDefinitionsAnnex 1: Explanatory note regarding thresholds.Annex 2: ThresholdsAnnex 3: Example of “fingerprint chromatogram” approach to control very complex impurity profiles 概要1、背景介绍2、范围3、法规依据4、一般要求5、杂质分布以及报告、鉴别和界定阈值6、新申请和变更7、制剂产品质量标准8、分析方法定义附件1：关于阈值的注释附件2：阈值附件3：利用基于“指纹图谱”的方法对非常复杂的杂质分布进行控制举例Executive summary 概要Antibiotics active substances currently on the market are produced by fermentation, by fermentation followed by one or more synthetic steps (semi-synthetic substances) or by chemical synthesis. Fermentation processes are, in comparison to synthetic processes, more variable and less controllable, so the impurity profile of an active substance whose manufacturing process involves fermentation may be more complex and less predictable than that of a purely synthetic product. For this reason fermentation products and semi-synthetic substances are not included in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines, which set thresholds for the identification, reporting and qualification of related impurities in active substances manufactured by chemical synthesis.目前上市的抗生素类活性物质是由发酵、发酵加一步或几步合成步骤（半合成）、化学合成制得。

<467>溶剂残留简介：INTRODUCTIONThis general chapter applies to existing drug substances, excipients, and products. All substances and products are subject to relevant control of solvents likely to be present in a substance or product.本章节适用于现有的原料药，辅料和制剂。

应对原料药或制剂产品中可能存在溶剂的所有原料及制剂产品进行控制。

Where the limits to be applied comply with those given below, tests for residual solvents are not generally mentioned in specific monographs, because the solvents employed may vary from one manufacturer to another.当限值与下面提供的数值相符合，残留溶剂的测试方法一般不会在专论中特别，因为不同制造商所使用的溶剂不同。

The objective of this general chapter is to provide acceptable amounts of residual solvents in pharmaceuticals for the safety of the patient. The chapter recommends the use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.本指导原则旨在介绍药物中残留溶剂在保证人体安全条件下的可接受量，指导原则建议使用低毒的溶剂，提出了一些残留溶剂毒理学上的可接受水平。

《中华人民共和国药典（2015年版）》（二部）中抗生素类药品部分的增、修订情况介绍裘亚;刘浩;杨美成【摘要】The trend of the quality control of antibiotics is discussed through an introduction to the main changes related to standards of antibiotics in Pharmacopoeia of the People’s Republic of China (2015 version) volume II. This is of beneift not only to the implementation of new pharmacopoeia, but also to deifning an direction for the amendments of the quality standards of antibiotics in the future.%通过介绍《中华人民共和国药典（2015年版）》（二部）中抗生素类药品部分的增、修订情况，分析抗生素类药品质量标准的变化趋势。

这不仅有益于《中华人民共和国药典（2015年版）》的实施，而且也明确了今后抗生素类药品质量标准的增、修订方向。

【期刊名称】《上海医药》【年(卷),期】2016(037)007【总页数】4页(P5-8)【关键词】《中华人民共和国药典(2015年版)》;抗生素类药品;增;修订【作者】裘亚;刘浩;杨美成【作者单位】上海市食品药品检验所抗生素室/微生物室上海 201203;上海市食品药品检验所抗生素室/微生物室上海 201203;上海市食品药品检验所抗生素室/微生物室上海 201203【正文语种】中文【中图分类】R921.2《中华人民共和国药典（2015年版）》（以下简称为“2015年版《中国药典》”）已自2015年12月1日起正式实施。

Guideline on setting specifications for related impurities inantibioticsTable of contents 目录Executive summary概要 (3)1. Introduction (background)介绍（背景） (3)2. Scope 范围 (4)3. Legal basis 法规依据 (4)4. General requirements一般性要求 (5)5. Impurity profiling and reporting, identification and qualification thresholds 杂质概况和报告限，鉴定限和界定限 (6)5.1. Active substances manufactured by semi-synthesis 半合成法生产的活性物质 (6)5.2. Active substances manufactured by fermentation, single compound发酵法生产的活性物质，单一化合物 (7)5.3. Active substances manufactured by fermentation, family of compounds 发酵法生产的活性物质，同族化合物 (7)5.4. Peptides manufactured by fermentation/semi-synthesis发酵法和半合成法生产的多肽 (7)5.5. Active substances for veterinary use 兽用活性物质 (7)5.6. Special cases for very complex impurity profiles非常复杂的杂质概况特例 (7)6. New applications and variations 新申请和不同情况 (8)6.1. New active substances新的活性物质 (8)6.2. Existing active substances, not subject to a Ph. Eur. monograph 无EP专论的活性物质 (8)6.3. Active substances subject to a Ph. Eur. monograph 有EP专论的活性物质 (8)6.3.1. Existing active substances subject to a Ph. Eur. monograph with transparencystatement and availability of a CRS for peak identification or relative retention times for the related substances有EP专论，有透明度声明和峰鉴别对照品或有关物质相对保留时间的活性物质 (8)6.3.2. Existing active substances subject to Ph. Eur. monograph, with transparency statement, but no availability of a CRS for peak identification or relative retention times for the related substances有EP专论，有透明度声明但无峰鉴别对照品或有关物质相对保留时间的活性物质 (8)6.3.3. Existing active substances subject to Ph. Eur. monograph, without transparency statement 有EP专论，无透明度声明的活性物质 (9)6.3.4. Revision of Ph. Eur. monographs EP专论的修改 (9)7. Specifications for medicinal products药物产品的标准 (9)8. Analytical procedures分析方法 (10)Definitions定义 (10)References 参考文献 (11)Annex 1: Explanatory note regarding thresholds附录1：有关限度的注释 (12)Annex 2: Thresholds附录2：限度 (13)Annex 3: Example of “fingerprint chromatogram” approach to control very complex impurity profiles 附录3：“指纹图谱”方法来控制非常复杂的杂质概况的示例 (14)Executive summary 概要（略）1.Introduction (background) 介绍（背景）（略）2.Scope （范围）本指南提供上市批准申请中，设定抗生素（如抗菌物质）的有关杂质的指导意见，这些抗生素是发酵产品或由发酵产品衍生的半合成物质。

30 June 2012EMA/CHMP/CVMP/QWP/199250/2009 corrCommittee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP)Guideline on setting specifications for related impurities in antibiotics抗生素中相关杂质质量标准制定的指导原则Final 定稿学习之名（译注）Table of contents 目录Executive summary1. Introduction (background)2. Scope3. Legal basis4. General requirements5. Impurity profiling and reporting, identification and qualification thresholds6. New applications and variations7. Specifications for medicinal products8. Analytical proceduresDefinitionsAnnex 1: Explanatory note regarding thresholds.Annex 2: ThresholdsAnnex 3: Example of “fingerprint chromatogram” approach to control very complex impurity profiles 概要1、背景介绍2、范围3、法规依据4、一般要求5、杂质分布以及报告、鉴别和界定阈值6、新申请和变更7、制剂产品质量标准8、分析方法定义附件1：关于阈值的注释附件2：阈值附件3：利用基于“指纹图谱”的方法对非常复杂的杂质分布进行控制举例Executive summary 概要Antibiotics active substances currently on the market are produced by fermentation, by fermentation followed by one or more synthetic steps (semi-synthetic substances) or by chemical synthesis. Fermentation processes are, in comparison to synthetic processes, more variable and less controllable, so the impurity profile of an active substance whose manufacturing process involves fermentation may be more complex and less predictable than that of a purely synthetic product. For this reason fermentation products and semi-synthetic substances are not included in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines, which set thresholds for the identification, reporting and qualification of related impurities in active substances manufactured by chemical synthesis.目前上市的抗生素类活性物质是由发酵、发酵加一步或几步合成步骤（半合成）、化学合成制得。

9102药品杂质分析指导原则本附录为药品质量标准中化学合成或半合成的有机原料药及其制剂杂质分析的指导原则,供药品研究㊁生产㊁质量标准起草和修订参考㊂任何影响药品纯度的物质均称为杂质㊂药品质量标准中的杂质系指在按照经国家有关药品监督管理部门依法审查批准的规定工艺和规定原辅料生产的药品中,由其生产工艺或原辅料带入的杂质,或在贮存过程中产生的杂质㊂药品质量标准中的杂质不包括变更生产工艺或变更原辅料而产生的新的杂质,也不包括掺入或污染的外来物质㊂药品生产企业变更生产工艺或原辅料,并由此带进新的杂质对原质量标准的修订,均应依法向有关药品监督管理部门申报批准㊂药品中不得掺入或污染药品或其组分以外的外来物质㊂对于假劣药品,必要时应根据各具体情况,可采用非法定分析方法予以检测㊂1.杂质的分类及其在药品质量标准中的项目名称按化学类别和特性,杂质可分为:有机杂质㊁无机杂质㊁有机挥发性杂质㊂按其来源,杂质可分为:有关物质(包括化学反应的前体㊁中间体㊁副产物和降解产物等)㊁其他杂质和外来物质等㊂按结构关系,杂质又可分为:其他甾体㊁其他生物碱㊁几何异构体㊁光学异构体和聚合物等㊂按其毒性,杂质又可分为:普通杂质和毒性杂质等㊂普通杂质即为在存在量下无显著不良生物作用的杂质,而毒性杂质为具强烈不良生物作用的杂质㊂由于杂质的分类方法甚多,所以,药品质量标准中检查项下杂质的项目名称,应根据国家药典委员会编写的‘国家药品标准工作手册“的要求进行规范㊂如有机杂质的项目名称可参考下列原则选用㊂(1)检查对象明确为某一物质时,就以该杂质的化学名作为项目名称,如磷酸可待因中的 吗啡 ,氯贝丁酯中的 对氯酚 ,盐酸苯海索中的 哌啶苯丙酮 ,盐酸林可霉素中的 林可霉素B 以及胰蛋白酶中的 糜蛋白酶 等㊂如果该杂质的化学名太长,又无通用的简称,可参考螺内酯项下的 巯基化合物 ㊁肾上腺素中的 酮体 ㊁盐酸地芬尼多中的 烯化合物 等,选用相宜的项目名称㊂在质量标准起草说明中应写明已明确杂质的结构式㊂(2)检查对象不能明确为某一单一物质而又仅知为某一类物质时,则其项目名称可采用 其他甾体 ㊁ 其他生物碱 ㊁ 其他氨基酸 ㊁ 还原糖 ㊁ 脂肪酸 ㊁ 芳香第一胺 ㊁ 含氯化合物 ㊁ 残留溶剂 或 有关物质 等㊂(3)未知杂质,仅根据检测方法选用项目名称,如 杂质吸光度 ㊁ 易氧化物 ㊁ 易炭化物 ㊁ 不挥发物 ㊁ 挥发性杂质 等㊂2.质量标准中杂质检查项目的确定新原料药和新制剂中的杂质,应按国家有关新药申报要求进行研究,也可参考I C H的文本Q3A(新原料药中的杂质)和Q3B(新制剂中的杂质)进行研究,并对杂质和降解产物进行安全性评价㊂新药研制部门对在合成㊁纯化和贮存中实际存在的杂质和潜在的杂质,应采用有效的分离分析方法进行检测㊂对于表观含量在0.1%及其以上的杂质以及表观含量在0.1%以下的具强烈生物作用的杂质或毒性杂质,予以定性或确证其结构㊂对在稳定性试验中出现的降解产物,也应按上述要求进行研究㊂新药质量标准中的杂质检查项目应包括经研究和稳定性考察检出的,并在批量生产中出现的杂质和降解产物,并包括相应的限度,结构已知和未知的这类杂质属于特定杂质(s p e c i f i e d i m p u r i t i e s)㊂除降解产物和毒性杂质外,在原料中已控制的杂质,在制剂中一般不再控制㊂原料药和制剂中的无机杂质,应根据其生产工艺㊁起始原料情况确定检查项目,但对于毒性无机杂质,应在质量标准中规定其检查项㊂在仿制药品的研制和生产中,如发现其杂质模式与其原始开发药品不同或与已有法定质量标准规定不同,需增加新的杂质检查项目的,应按上述方法进行研究,申报新的质量标准或对原质量标准进行修订,并报有关药品监督管理部门审批㊂共存的异构体和抗生素多组分一般不作为杂质检查项目,作为共存物质,必要时,在质量标准中规定其比例,以保证生产用的原料药与申报注册时的一致性㊂但当共存物质为毒性杂质时,该物质就不再认为是共存物质㊂在单一对映体药物中,其可能共存的其他对映体应作为杂质检查,并设比旋度项目;㊁对消旋体药物,当已有其单一对映体药物的法定的质量标准时,应在该消旋体药物的质量标准中可以设旋光度检查项目㊂残留溶剂,应根据生产工艺中所用有机溶剂及其残留情况,确定检查项目㊂可参考本药典关于残留溶剂的要求,或参考I C H文本Q3C(残留溶剂指导原则)㊂对残留的毒性溶剂,应规定其检查项目㊂3.杂质检查分析方法和杂质的限度杂质检查分析方法应专属㊁灵敏㊂杂质检查应尽量采用现代分离分析手段,主成分与杂质和降解产物均能分开,其检测限应满足限度检查的要求,对于需作定量检查的杂质,方法的定量限应满足相应的要求㊂杂质检查分析方法的建立应按本药典的要求作方法验证㊂在研究时,应采用几种不同的分离分析方法或不同测试条件以便比对结果,选择较佳的方法作为质量标准的检查方法㊂杂质检查分析方法的建立,应考虑普遍适用性,所用的仪器和试材应容易获得㊂对于特殊试材,应在质量标准中写明㊂在杂质分析的研究阶段,可用可能存在的杂质㊁强制降解产物,分别或加入主成分中,配制供试溶液进行色谱分析,调整色谱条件,建立适用性要求,保证方法专属㊁灵敏㊂新药研究中的杂质和降解产物,或在非新药中发现的新杂质和新降解产物杂质研究中,应进行杂质的分离纯化制备㊃543㊃9102药品杂质分析指导原则9102药品杂质分析指导原则或合成制备,以供进行安全性和质量研究㊂对确实无法获得的杂质和降解产物,研制部门在药物质量研究资料和药物质量标准起草说明中应写明理由㊂在采用现代色谱技术对杂质进行分离分析的情况下,对特定杂质中的已知杂质和毒性杂质,应使用杂质对照品进行定位;如无法获得该对照品时,可用相对保留值进行定位;特定杂质中的未知杂质可用相对保留值进行定位㊂应使用多波长检测器研究杂质在不同波长下的检测情况,并求得在确定的一个波长下,已知杂质,特别是毒性杂质对主成分的相对响应因子㊂已知杂质或毒性杂质对主成分的相对响应因子在0.9~1.1范围内时,可以用主成分的自身对照法计算含量,超出0.9~1.1范围时,宜用对照品对照法计算含量㊂也可用经验证的相对响应因子进行校正后计算㊂特定杂质中未知杂质的定量可用主成分自身对照品法进行计算㊂非特定杂质(u n s p e c i f i e di m p u r i t i e s)的限度一般为不得超过0.10%㊂杂质定量计算方法应明确规定在质量标准中㊂一般,质量标准中还应有单个杂质限量和总杂质限量的规定㊂在用薄层色谱法分析杂质时,可采用杂质对照品或主成分的梯度浓度溶液比对,对杂质斑点进行半定量评估,质量标准中应规定杂质的个数及其限度㊂杂质含量应按照薄层色谱法(通则0502)和高效液相色谱法(通则0512)测定㊂对于立体异构体杂质的检测广泛采用手性色谱法和高效毛细管电泳法等㊂尤其是手性高效液相色谱法,包括手性固定相法和手性流动相添加剂法(直接法)㊁手性试剂衍生化法(间接法),其中手性固定相法由于其一般不需衍生化㊁定量分析准确性高㊁操作简便等特点,在手性药物的杂质检测中应用较多,缺点是每种固定相的适用对象有限制,需根据药物的结构特征选择合适的手性柱㊂对于立体异构体杂质检查方法的验证,立体专属性(选择性)和手性转化是实验考察的重点;通常立体异构体杂质的出峰顺序在前,而母体药物在后,有利于两者的分离和提高检测灵敏度㊂另外,由于手性色谱法不能直接反映手性药物的光学活性,需要与旋光度或比旋度测定相互补充,以有效控制手性药物的质量㊂由于色谱法杂质限度检查受色谱参数设置值的影响较大,有关操作注意事项应在起草说明中写明,必要时,可在质量标准中予以规定㊂杂质限度的制订应考虑如下因素:杂质及含一定限量杂质的药品的毒理学研究结果;给药途径;每日剂量;给药人群;杂质药理学可能的研究结果;原料药的来源;治疗周期;在保证安全有效的前提下,药品生产企业对生产高质量药品所需成本和消费者对药品价格的承受力㊂药品质量标准对毒性杂质和毒性残留有机溶剂应严格规定限度㊂残留有机溶剂的限度制订可参考本药典和I C H的有关文本㊂㊃643㊃。

抗生素的分级管理及使用原则英文回答：Antibiotics are classified into different categories based on their spectrum of activity and mechanism of action. The classification system helps healthcare professionals choose the most appropriate antibiotic for treatingspecific infections. The principles of antibiotic use are also important to ensure their effectiveness and minimize the development of antibiotic resistance.The classification of antibiotics is mainly based on their spectrum of activity, which refers to the range of bacteria that a particular antibiotic can target. Broad-spectrum antibiotics are effective against a wide range of bacteria, including both Gram-positive and Gram-negative bacteria. Examples of broad-spectrum antibiotics include fluoroquinolones, cephalosporins, and carbapenems. On the other hand, narrow-spectrum antibiotics are only effective against specific types of bacteria. Penicillin anderythromycin are examples of narrow-spectrum antibiotics.Another important factor in antibiotic classificationis their mechanism of action. Antibiotics can target bacteria by interfering with their cell wall synthesis, protein synthesis, DNA replication, or other essential processes. For example, penicillin inhibits cell wall synthesis, while tetracycline inhibits protein synthesis. Understanding the mechanism of action is crucial in selecting the appropriate antibiotic for a particular infection.The principles of antibiotic use include appropriate selection, proper dosing, and duration of treatment. The selection of antibiotics should be based on the susceptibility of the bacteria causing the infection. This can be determined through laboratory testing, such as culture and sensitivity tests. It is important to choose the narrowest spectrum antibiotic that is effective against the identified pathogen to minimize the risk of resistance.Proper dosing is also crucial to ensure that theantibiotic reaches therapeutic levels in the body. Underdosing may result in suboptimal treatment, while overdosing can lead to toxicity. The dose of antibiotics should be adjusted based on factors such as age, weight, renal function, and severity of the infection.The duration of antibiotic treatment should be appropriate to effectively eliminate the infection. In some cases, a short course of antibiotics is sufficient, while in others, a longer duration may be necessary. It is important to complete the full course of antibiotics as prescribed, even if symptoms improve, to prevent the development of antibiotic resistance.In conclusion, antibiotics are classified intodifferent categories based on their spectrum of activity and mechanism of action. The principles of antibiotic use include appropriate selection, proper dosing, and duration of treatment. Following these principles is essential to ensure the effectiveness of antibiotics and to minimize the development of antibiotic resistance.中文回答：抗生素根据其抗菌谱和作用机制进行分类。

物质）等方式制造的。

与合成工艺相比，发酵工艺中可变性更大，可控性更低，因此与纯合成产品相比，在生产中含有发酵工艺的活性物质的杂质谱可能更复杂及难以预测。

由于上述原因，发酵产品和半合成产品未包括在ICHQ3和VICH10/11指导原则之内，这些指导原则就化学合成活性物质中引入的杂质的鉴定、报告和控制限度制订了质量标准。

* 本指导原则旨在为未包括在上述（V）ICH指导原则中的内容提供如下指导，即如何规范发酵产品或源于发酵产品的半合成物质的抗生素中的有关物质。

指导原则中制订了抗生素药品中有关况，如活性物质由几种密切相关的化合物混合组成，可能难以适用通行的限度，提供了常规原则，就如何制定具体限度、标准以及如何确定杂质谱限度进行了规定。

对于指导原则中的要求与欧洲药典中对应章节及各论之间的关系也进行了解释。

1. 介绍（背景）性物质使用（半合成物质）。

和纯化学反应相比，发酵工艺涉及到生物系统，预测性差，可控性低，且更为复杂。

因此发酵产品的波动性比化学合成产品更大。

所以，发酵产品的杂质谱比合成产品更为复杂和难以预料。

为此，发酵产品以及由此得到的半合成物质并未包含在ICHQ3和VICH10/11指导原则中，这些指导原则制订了化学合成活性物质中有关物质的鉴定、报告和控制限度。

指导原则中对限度的定义是，如果超出了该限度，该杂质即应该被鉴定、报告或控制，该限度同样适用于欧洲药典总论“药用物质”。

发酵产品及其半合成衍生物不在该总论范围内。

没有其他指导原则的情况下，这些产品中的有关物质曾经根据一对一（case-by-case）的方式进行评估，这导致了相同抗生素或同类抗生素中的不同化合物（如头孢菌素）可能存在不同的杂质限度。

因此，在批在某些情况下更高的限度要求是合理和可行的。

2. 范围本文件的规范对象为申请上市许可，为发酵所得或发酵后半合成所得的抗生素（即，抗细菌物质）中的有关物质制定标准。

未来可能将把范围扩大到其他抗生素（如抗真菌物质）。

7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom30 June 2012 EMA/CHMP/CVMP/QWP/199250/2009 corr Committee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP) Guideline on setting specifications for related impurities in antibioticsFinal Draft Agreed by Quality Working PartyMay 2010 Adoption by CHMP for release for consultation24 June 2010 Adoption by CVMP for release for consultation15 July 2010 End of consultation (deadline for comments)31 Jan 2011 Agreed by Quality Working PartyMay 2012 Adoption by CHMP14 May 2012 Adoption by CVMP14 June 2012 Date for coming into effect30 June 2013KeywordsAntibiotics, specifications, related impuritiesGuideline on setting specifications for related impurities in antibioticsTable of contentsExecutive summary (3)1. Introduction (background) (3)2. Scope (4)3. Legal basis (4)4. General requirements (5)5. Impurity profiling and reporting, identification and qualification thresholds (6)5.1. Active substances manufactured by semi-synthesis (6)5.2. Active substances manufactured by fermentation, single compound (7)5.3. Active substances manufactured by fermentation, family of compounds (7)5.4. Peptides manufactured by fermentation/semi-synthesis (7)5.5. Active substances for veterinary use (7)5.6. Special cases for very complex impurity profiles (7)6. New applications and variations (8)6.1. New active substances (8)6.2. Existing active substances, not subject to a Ph. Eur. monograph (8)6.3. Active substances subject to a Ph. Eur. monograph (8)6.3.1. Existing active substances subject to a Ph. Eur. monograph with transparency statement and availability of a CRS for peak identification or relative retention times for the related substances (8)6.3.2. Existing active substances subject to Ph. Eur. monograph, with transparency statement, but no availability of a CRS for peak identification or relative retention times for the related substances (8)6.3.3. Existing active substances subject to Ph. Eur. monograph, without transparency statement (9)6.3.4. Revision of Ph. Eur. monographs (9)7. Specifications for medicinal products (9)8. Analytical procedures (10)Definitions (10)References (11)Annex 1: Explanatory note regarding thresholds (12)Annex 2: Thresholds (13)Annex 3: Example of “fingerprint chromatogram” approach to control very complex impurity profiles (14)Executive summaryAntibiotics active substances currently on the market are produced by fermentation, by fermentation followed by one or more synthetic steps (semi-synthetic substances) or by chemical synthesis. Fermentation processes are, in comparison to synthetic processes, more variable and less controllable, so the impurity profile of an active substance whose manufacturing process involves fermentation may be more complex and less predictable than that of a purely synthetic product. For this reason fermentation products and semi-synthetic substances are not included in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines, which set thresholds for the identification, reporting and qualification of related impurities in active substances manufactured by chemical synthesis.This guideline has been developed in order to provide guidance on how specifications for related impurities in antibiotics that are fermentation products or semi-synthetic substances derived from fermentation products, and are therefore not included in the scope of the (V)ICH guidelines mentioned above, should be set.Thresholds are given in the guideline for reporting, identification and qualification of related impurities for antibiotics medicinal products whose active substance is produced by fermentation or semi-synthesis. In cases where the active substance consists of a mixture of closely related compounds, where it may be difficult to apply general thresholds, general guidance is given on how to set specific thresholds and specifications and on how to qualify impurity profiles. The relationships between the requirements in the guideline and the applicable Ph.Eur. chapters and monographs are also addressed.1. Introduction (background)Most of the antibiotics currently on the market are produced by fermentation or chemical synthesis. In certain cases the chemical structure of the antibiotics obtained by fermentation is further modified by some synthetic steps, before the substance is used as an active substance in the manufacture of medicinal products (semi-synthetic substances).Fermentation processes involve biological systems which are less predictable, less controllable and more complex than straightforward chemical reactions. Because of this, the variability in products derived by fermentation is often greater than in products derived by chemical synthesis. Thus, the impurity profile of a fermentation product may be more complex and less predictable than that of a synthetic product.For this reason, fermentation products and semi-synthetic substances derived from them are not included in the scope of the ICH Q3 and the VICH GL10/GL11 guidelines that set thresholds for the identification, reporting and qualification of related impurities in active substances manufactured by chemical synthesis. These thresholds are defined in the guidelines as limits above which an impurity has to be either identified, reported or qualified, and the same limits are applied in the Ph.Eur. general monograph ‘Substances for Pharmaceutical Use’. Fermentation products and their semi synthetic derivatives are also excluded from the scope of this general monograph.In the absence of other guidance, related impurities in these products have been assessed on a case-by-case basis, which has resulted in the acceptance of different impurity thresholds for the same antibiotic and for different compounds within the same class (e.g. cephalosporins). There is also a need to ensure that the authorisation of new antibiotics is enabled by consistent approaches in setting limits for their impurities.It is therefore necessary to provide guidance, based on current practice and experience, to formulate general recommendations for impurity thresholds in antibiotics produced by fermentation or semi-synthesis. These are presented in this guideline.Even so, it is acknowledged that in some cases higher thresholds may be acceptable if necessary and justified taking account of use and exposure of the drug substance/product. This would also include analytical problems (see Annex 1: Explanatory note regarding thresholds).2. ScopeThis document provides guidance for marketing authorisation applications on setting specifications for related impurities in antibiotics (i.e. antibacterial substances) that are fermentation products or semi-synthetic substances derived from fermentation products. It is foreseen to widen the scope to other antibiotics (e.g. antifungal substances) at a later stage.It provides guidance for the content and qualification of related impurities in both active substances and medicinal products. The guideline is not intended to apply to new active substances used in investigational medicinal products used in clinical trials.In this guideline thresholds are given for reporting, identification and qualification of related impurities. For antibiotics where the active substance consists of a mixture of closely related compounds where it may be difficult to apply these general thresholds, general guidance is given on how to set thresholds and specifications and how to qualify impurity profiles. The thresholds given in this guideline would represent a general set of requirements, and this could be subject, for specific substances or products, to adaptation to the specific situation. Further requirements might be introduced when considered necessary, e.g. for safety reasons.This guideline does not cover residues from the fermentation process, i.e. residues from the producer micro-organism, culture media, substrates and precursors; this is covered by the Ph.Eur. general monograph ‘Products of fermentation’. (This monograph applies to substances manufactured by fermentation only, and not to substances manufactured by semi-synthesis).This guideline applies to new active substances and for new sources of existing active substances. It is the Applicant’s responsibility to demonstrate that the active substance has already been marketed in the EU when relevant.The guideline should not be applied retrospectively, but it is intended that this guideline will act as a stimulus to establish best practice and to initiate the revision of relevant Ph.Eur. monographs (i.e. for registered products revised requirements according to the monograph will apply when the monograph is introduced/revised). For new sources of existing active substances this guideline should be read in conjunction with any existing Ph.Eur. monograph for the active substance. It should be noted that comparison with impurity levels/profiles of active substance sources or products approved in the EU is one of the options for qualifying impurities.It is foreseen to re-evaluate the Scope when more experience has been obtained.3. Legal basisThis guideline has to be read in conjunction with the introduction and general principles (4) and part 1 of the Annex Is to Directives 2001/82/EC and 2001/83/EC as amended.4. General requirementsThe impurity profile depends very much on the manufacturing process; even for the same strain of a micro-organism, impurity profiles may be different. In general, purification steps including column chromatography and ultra-filtration steps may be crucial to achieve a sufficiently pure active substance.Semi-synthetic substances are not within the scope of the Ph.Eur. general monograph ‘Products of fermentation’. However, the specification of the fermented starting material should be justified with reference to current guidance, including general concepts described in this general monograph, if necessary. (The thresholds in this guideline are not intended to apply for fermented starting materials).The shorter the synthetic route after the fermentation and the more complex the fermented starting material, the more relevance the general monograph has. Therefore, a detailed description of the fermentation steps as well as other aspects addressed in the general monograph, in particular purification steps, should be presented for semi-synthetic antibiotics, unless justified by the non-complexity of the fermented starting material and the number and/or nature of the synthetic steps following fermentation.These synthetic steps should contribute to a relevant depletion and inactivation of fermentation by-products in the final active substance, so for example, esterification, etherification and salification of fermentation products (e.g., erythromycin derivatives like erythromycin ethylsuccinate or erythromycin lactobionate) are not considered as significant synthetic steps which would justify an omission of a detailed description of the fermentation process, in particular of the purification.In cases where the fermented starting material is not complex and taking into consideration the number and nature of the synthetic steps after fermentation, it may be sufficient to have a suitable specification for the fermented starting material including assay, component distribution (if relevant) and related impurities (specified, unspecified, and total). This should be in any case justified. For active substances manufactured by semi-synthesis, the impurity profile of the fermented starting material should be critically evaluated for its contribution to the impurity profile of the final active substance. Related impurities observed after fermentation include by-products, intermediates and degradation products. For semi-synthesis the impurities also include the fermented starting material and related substances in this starting material, synthesis by-products (including those derived from impurities in the starting material), synthesis intermediates and degradation products.Specifications should be given for any critical intermediates (this also includes intermediates between different purification steps). These specifications should include limits for specified and single unspecified impurities. Impurities that contribute to the impurity profile of the active substance should be specified. The applicant should provide a discussion on potential impurities, how they are removed and which impurities appear in the active substance.Even if manufactured by fermentation or semi-synthesis, an antibiotic may be structurally well defined as a mono component substance, and thus it may be efficiently purified. For each class of antibiotic, it is considered preferable to optimise purification steps as far as possible, in order to decrease the level of impurity to below the qualification threshold, than to provide (additional) safety data.For antibiotics manufactured by fermentation, the active substance may consist of a mixture of closely related compounds that show the relevant biological activity. In such cases it may be difficult to decide whether a compound is part of the active substance or should be regarded as an impurity when setting specifications (e.g. gentamicin). The definition of which substances are components of the activesubstance should be based on pre-clinical and clinical studies unless the active substance is described in a Ph. Eur. monograph where the active substance components are defined. Related compounds that are not defined to be components of the active substance are regarded as related impurities.The thresholds given in the ICH Q3 and VICH GL10/GL11 guidelines and in the guideline ‘Chemistry of New Active Substances’ (CPMP/QWP/130/96 Rev 1, EMEA/CVMP/541/03) do not apply to fermentation products and semi-synthetic substances derived from fermentation products. For other aspects, where specific guidance is not given in the present guideline, reference is made to the principles described in these guidelines.In qualifying an impurity or a given impurity profile at the level specified, several possibilities exist: appropriate battery of non-clinical tests, literature based data; comparison with impurity levels/profiles of active substance sources/products approved in the EU; or proving that the relevant impurity is a significant metabolite of the active substance.5. Impurity profiling and reporting, identification and qualification thresholdsFor antibiotic drug substances, the impurity profile should be characterised according to the guidance described in ICH Q3A (VICH GL10).In accordance with that guidance, with respect to related substances, limits should be set for:•Each specified identified impurity;•Each specified unidentified impurity;•Any unspecified impurity, with an acceptance criterion of not more than the identification threshold;•Total impurities.Exceptionally, if it is shown that it is not practically possible to identify an individual impurity, sufficient evidence of its structure should be provided (e.g. by HPLC/mass spectrometry to show that it may be satisfactorily classified as a related substance of the parent compound. In this case, it should be specified using an appropriate analytical marker e.g. HPLC Relative Retention Time (RRT), as a specified unidentified impurity. As a general principle, for impurities which are not structurally closely related (see section 5.3 below) to the parent compound, thresholds as given by ICH Q3A (VICH GL10) should be applied unless stated differently in the following sections.For the reasons discussed in section 4 above, and taking into account that the duration of treatment with antibiotics is in most cases limited, for antibiotic related substances the thresholds to be applied may be higher than those stated in ICH Q3A/VICH GL10, and also different for each of the different classes of antibiotic. These thresholds are given below.5.1. Active substances manufactured by semi-synthesisSemi-synthetic substances are obtained from a fermented starting material by a process involving at least cleavage and formation of covalent bonds and including extraction/purification steps. Acceptance criteria for related impurities should be set in accordance with the thresholds given below.The ICH Q3A thresholds for reporting, identification and qualification apply.Reporting threshold: 0.05%/0.03%Identification threshold: 0.10%/0.05%Qualification threshold: 0.15%/0.05%If the semi-synthetic active substance consists of a family of closely related compounds it may benecessary to apply requirements up to the thresholds described for substances manufactured byfermentation, family of compounds (see 5.3). A justification should be given.5.2. Active substances manufactured by fermentation, single compoundAcceptance criteria for related impurities should be set in accordance with the thresholds given below.Reporting threshold: 0.10%Identification and qualification thresholds: 0.15% 5.3. Active substances manufactured by fermentation, family ofcompoundsAcceptance criteria for related impurities should be set in accordance with the thresholds given below.Reporting threshold: 0.10%Identification threshold: 0.15%Qualification threshold: 0.50%/0.2%The qualification threshold of 0.50% for structurally closely related impurities (see definition) iscombined with a qualification threshold of 0.2% for other related impurities. Justification for claimingthat a related impurity (compound not defined to be included in the active substance) is structurallyclosely related to the parent compounds should at least be based on evidence such as HPLC/massspectrometry or the use of reference materials. The proposed 0.50%/0.2% limits are suggested toapply even for daily doses of ≥2 g, which may be relevant for some of these antibiotics.5.4. Peptides manufactured by fermentation/semi-synthesisFor antibiotics that are peptides (e.g. gramicidin, tyrothricin and bacitracin) the same thresholds as forsynthetic peptides as given in the Ph. Eur. General Monograph Substances for Pharmaceutical would be considered acceptable without any justification. Other thresholds should be justified. These thresholdsdo not apply to certain modified peptides containing other moieties than amino acids (e.g.glycopeptides).5.5. Active substances for veterinary useFor active substances used in veterinary medicine only the VICH GL 10 thresholds for reporting,identification and qualification (of 0.10%, 0.20% and 0.50%, respectively) apply. For activesubstances used in veterinary medicines only, manufactured by fermentation and consisting of a familyof compounds, the thresholds may be justified and assessed on a case-by-case basis.For active substances used in both veterinary and human medicine, the thresholds given for therespective human classes above apply.5.6. Special cases for very complex impurity profilesIn case of a very complex impurity profile or where two impurities are very similar, it may not betechnically feasible to obtain peak separation. In such cases it may be necessary to set a limit for acombination of unresolved peaks. In this case, where possible, thresholds should be applied for thecombination of peaks. For qualification, the composition of the batches used in the toxicological studies should be taken into account.Exceptionally, for controlling very complex impurity profiles where identification of individual peaks is impossible, the applicant should propose a combination of different tests that give a reasonable batch consistency with regard to impurities. Where an applicant has qualified a drug substance (from a given manufacturer) and needs to ensure consistency with future batches then as a minimum it could be possible to characterise the impurity profiles by a descriptive specification based on a sufficient number of manufactured batches.A descriptive specification could consist of the following parameters: (1) Limitation of the number of peaks (if applicable: as a range) and their corresponding contents (as a sum) occurring within a predefined, narrow RRT-window. (2) Relative specification limits in a predefined RRT-window (e.g. at least one peak between RRT x and y with content between A and B%). (3) Limitation of the number of peaks occurring above a threshold in a predefined RRT-window (e.g. any individual peak between RRT w and z not more than (NMT) C%, but NMT one peak above D% whereby C > D, e.g. C = 2.0%,D = 1.5% or similar dependent on drug substance and drug product profile). This approach should be restricted to active substances consisting of a mixture of components. An example is given in Annex 3 to this guideline.6. New applications and variations6.1. New active substancesThe impurity profile should be characterised and individual impurities should be identified and, if necessary, qualified by an appropriate battery of non-clinical and clinical tests.6.2. Existing active substances, not subject to a Ph. Eur. monographThe impurity profile should be characterised and individual impurities should be identified and, if necessary, qualified as described in the General requirements section.6.3. Active substances subject to a Ph. Eur. monograph6.3.1. Existing active substances subject to a Ph. Eur. monograph with transparency statement and availability of a CRS for peak identification or relative retention times for the related substancesThe impurity profile should be characterised and individual impurities identified.Specified impurities should be controlled according to the monograph requirements.New impurities should be identified, when necessary to comply with this guideline.New impurities should be qualified when necessary to comply with this guideline as described in the General requirements section.6.3.2. Existing active substances subject to Ph. Eur. monograph, with transparency statement, but no availability of a CRS for peak identification or relative retention times for the related substancesThe impurity profile should be characterised and individual impurities identified, when necessary to comply with this guideline, using as reference the transparency statement of the monograph.Specified impurities should be controlled according to the monograph requirements.Any new impurity should be identified and qualified, when necessary, to comply with this guideline asdescribed in the General requirements section.6.3.3. Existing active substances subject to Ph. Eur. monograph, without transparency statementThe impurity profile should be characterised and individual impurities identified, when necessary tocomply with this guideline.Impurities should be qualified, when necessary to comply with this guideline as described in theGeneral requirements section.6.3.4. Revision of Ph. Eur. monographsA revision of the Ph. Eur. monograph should be initiated when:•The means of identification of known impurities have been established•New impurities have been identified or qualifiedAccording to Directives 2001/82/EC and 2001/83/EC as amended, the Pharmacopoeia should beinformed by the relevant authority when a monograph is insufficient to control the quality of asubstance.7. Specifications for medicinal productsSpecifications should be set for related impurities that are degradation products. Impurities originatingfrom the manufacture of the drug substance should not be specified unless they are also degradationproducts.Information on the impurity profile may be obtained from the source of the active substance.Acceptance criteria for related impurities should be set within the thresholds given below. The same specifications should apply to the product after any opening/reconstitution/dilution (in-use shelf life) asfor the finished product, unless justified by suitable qualification data e.g. by comparison to levelsfound in an approved product. New degradants not included in the finished product specification shouldbe listed in a specification for the reconstituted product. Data for in-use shelf life afterreconstitution/dilution should be provided.Active substance manufactured by semi-synthesis:Reporting threshold: 0.1%Identification and qualification thresholds: 0.2%Active substance manufactured by fermentation, single compound: Reporting threshold: 0.15%Identification and qualification thresholds: 0.2% Active substance manufactured by fermentation, family of compounds:Reporting threshold: 0.15%Identification threshold: 0.2%Qualification threshold: 0.5%/0.2% (see explanation in section 5.3)For all three groups of active substances, higher acceptance criteria for identification and qualification may be set according to the doses/thresholds in ICH Q3B for low doses.For veterinary medicinal products the VICH GL11 thresholds for reporting, identification and qualification (0.3%, 1.0% and 1.0%, respectively) should be applied. For active substances used in veterinary medicines only, manufactured by fermentation and consisting of a family of compounds, thresholds may be justified and assessed on a case-by-case basis.8. Analytical proceduresWhen analysing the final active substance and the medicinal product, whenever possible, an external standard should be used calculating w/w to evaluate and exclude any possible mass imbalance. If using area normalisation the relevant components and related impurities should give similar responses in the detector (see Ph. Eur. 2.2.46). Otherwise correction factors should be used (the use of correction factors is always expected for impurities which do not give similar response to any standard used, except for unknown impurities).Area normalisation (2.2.46) may (instead of using an external standard) be acceptable for certain active substances consisting of a family of compounds. This may be used when analysing relevant intermediates. When using area normalisation, linearity for the intended range should be demonstrated and an unambiguously defined disregard criterion should be given.When performing qualification of an impurity profile versus an approved product, a sufficiently specific analytical procedure should be used. For complicated mixtures the separation technique (e.g. HPLC) should be combined with mass spectrometry (or other techniques). For routine testing, simpler procedures may be used, if justified.The quantitation limit for the analytical procedure should b e not more than (≤) the reporting threshold. For substances having weak chromophores, other detection methods than UV absorption should be used. If in some cases it is not possible to report or identify impurities at the thresholds given in this guideline, this will be taken into account in the assessment.DefinitionsProduct of fermentation: Indirect gene products (primary or secondary metabolites) of micro-organisms such as bacteria, yeast, fungi and micro-algae, irrespective of whether or not the micro-organism have been modified by traditional procedures or by recombinant DNA technology.Semi-synthesis: One or more synthesis steps following fermentation. A synthesis step involves cleavage and formation of covalent bonds.Single compound: The active substance consists of only one compound, as usual.Family of compounds: The active substance consists of a mixture of compounds. The composition regarding names and amounts of relevant components is defined in the active substance specification in accordance with composition used in pre-clinical and clinical studies. The composition will appear in any Ph. Eur. monograph available.Complex/not complex fermented starting material for semi-synthesis: The starting material is not complex if the molecular entity is simple, comprehensive characterisation is possible and the。