来源：http://zhuyujiao1972.blog.163.com/blog/static/98694727201521691536650/
Quality of medicines questions and answers: Part 1
药品质量问答：第一部分
These questions and answers address a number of questions that have been brought to the attention of the Joint Committee for Medicinal Products for Human Use / Committee for Medicinal Products for Veterinary Use Quality Working Party (QWP) by marketing-authorisation holders (MAHs) or European Economic Area (EEA) competent authorities, on matters related to the quality of medicines. They have been developed and are maintained by the QWP.
这些问答说明了大量由上市许可持有人（MAH）或欧盟经济区（EEA）药监当局提出，并引导起QWP（人药联合委员会/兽药委员会）注意的问题，这些问题都是关于药品质量的。这些问答由QWP建立和维护。
They provide the EEA's harmonised position on issues that can be subject to different interpretation or require clarification, typically arising from discussions or correspondence during assessment procedures.
这些问答阐明了EEA一致同意的观点。此前对这些问题的解读中可能会有不同的诠释，或需要澄清，或在评审程序中会引起典型的讨论或沟通。
If a question is not addressed, marketing-authorisation holders are encouraged to contact the European Medicines Agency for further information at qwp@ema.europa.eu.
如果还有这里未说明的问题，我们鼓励上市许可持有人通过上述邮箱联系EMA获得更多信息。
These questions have been produced to provide clarification or additional information, and should be read in conjunction with the European Pharmacopoeia , quality guidelines and other guidance documents.
以下这些回答用来提供澄清或额外的信息，应与欧洲药典、质量指南和其它指南文件联合解读。
Key:关键词
- H: applicable to medicinal products for human use适用于人用药品
- V: applicable to veterinary medicinal products适用于兽用药品
Table of contents内容
Active Substance - Active-substance-master-file procedure
活性物质---ASMF程序
1. Can a mixture of an active substance with an excipient be submitted through an active-substance-master-file (ASMF) procedure? H+V August 2007
活性物质与辅料的混合物是否可以通过ASMF程序来提交？H+V 2007年8月
No. A mixture of an active substance with an excipient cannot be submitted through an ASMF procedure.
不可以。活性物质与辅料的混合物不能通过ASMF程序来提交。
The blending of an active substance and an excipient is considered as the first step in the manufacture of the medicinal product, and therefore does not fall under the definition of an active substance.
活性物质与辅料的混合被认为是药品生产的第一步，因此不属于活性物质的定义范畴内。
The only exceptions can be made where the active substance cannot exist on its own, for example, due to insufficient stability without a stabilising agent, or in the case of herbal dry extracts if it is not possible to produce a solid extract without excipients.
以下情形是仅有的例外，就是活性物质不能单独存在，例如，没有稳定剂时其稳定性不够，或没有辅料时不能提取获得某种草药提取干物。
Active substance - Declaration by the qualified person on the good-manufacturing-practice status of the active substance manufacturer
原料药—受权人关于活性物质生产商的GMP状态声明
1. The notice to applicants requires the submission of a declaration signed by the qualified person that the active substance used is manufactured in accordance with good manufacturing practice. The active substance in my product is widely used, but not normally as a pharmaceutical active substance, and I am having some difficulty in confirming compliance. What should I do to furnish the required declaration? H+V September 2008
申报人需知要求提交一份由授权人签字的声明，说明所用的活性物质是在GMP条件下生产的。活性物质在我的药品里广泛伤脑筋，但通常并不作为活性药用物质，我要符合GMP有一定的困难。我应该要怎么做来完成所需要的声明？H+V 2008年9月
Full compliance with good manufacturing practice (GMP) for finished products and active substances is a legal obligation for manufacturing-authorisation holders. It is recognised that for a small number of medicinal products the primary use of the active substance is not in a medicinal product and the producer may therefore not be aiming to meet the specific requirements of pharmaceutical customers that represent an insignificant volume of business. Alternative sources should normally be sought but in exceptional circumstances the manufacturing-authorisation holder should assess and document to which extent GMP is complied with and provide a risk-based justification for the acceptance of any derogation. The declaration provided by the qualified person should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP. The European Medicines Agency will collect experience with this approach which can be used as a basis for discussion on related amendments to guidelines in the future.
保证原料药和制剂的GMP符合性是上市许可持有人的法定义务。对于少量的药品，活性物质的主要用途并非药用，因此生产商可能并不会为了只有相当少业务量的药业客户去符合特定的要求。一般会去寻找替代的货源，但有时候可能确实存在例外情况，此时上市许可持有人应评估和记录GMP符合程度如何，提供一份基于风险的论述。QP提交的声明应详细说明所适用的标准可以提供与GMP等同水平的保证。EMA将收集这方面的更多经验，用于将来讨论对指南进行相关的修订。
Active Substance - Good-manufacturing-practice compliance for sterilisation of an active substance
原料药---原料药无菌性的GMP符合性
1. What kind of good-manufacturing-practice documentation is needed for an active substance manufacturer who performs sterilisation of an active substance? H+V July 2010
生产无菌原料药的原料药生产商需要什么样的GMP文件记录？H+V 2010年7月
The good-manufacturing-practice (GMP) basic requirements for active substances used as starting materials (European Union (EU) GMP guide part II) only applies to the manufacture of sterile active substances up to the point immediately prior to the active substance being rendered sterile. The sterilisation and aseptic processing of sterile active substances are not covered by this guideline and shall be performed in accordance with GMP for medicinal products (Commission Directive 2003/94/EC ; as interpreted in the basic requirements for medicinal products including annex 1 of the EU GMP Guide part I). This implies that for any active-substance manufacturer who performs sterilisation and subsequent aseptic handling of the active substance, a valid manufacturing authorisation or GMP certificate from an EEA authority or from an authority of countries where mutual recognition or other Community arrangements apply has to be submitted.
作为起始物料的原料药的GMP基本要求（EU GMP指南第二部分）仅适用于无菌原料药至无菌前的步骤。无菌原料药的灭菌和无菌工艺不在该指南范围内，应符合药品的GMP指南（欧盟指令2003/94/EC），符合EU GMP指南第一部分附录1中的药品基本要求。这就是说所有从事原料药灭菌处理及之后的无菌操作的原料药生产商，应持有有效的生产许可或EEA药监机构或互认国药监机构颁发的GMP证书，或需要提交的其它适用证明。
Also, the active-substance manufacturer has to submit data on the sterilisation process of the active substance (including validation data) to the marketing-authorisation applicant or holder for inclusion in the dossier submitted for the finished product and approval by the licensing authority or authorities.
另外，原料药生产商必须向上市许可申请人或持有人提交原料药灭菌工艺的数据（包括验证数据），使其包括在制剂的申报文件中，由发证机构或药监机构进行批准。
Active Substance - Starting materials of herbal origin
原料药---草药来源的起始物料
1. How should the quality of a starting material of herbal origin be controlled when it is used to manufacture a semi-synthetic active substance? H+V February 2012
用于生产半合成活性物质的草药来源的起始物料要如何控制？H+V 2012年2月
There are several types of starting materials of herbal origin used to manufacture semi-synthetic active substances:
用于生产半合成活性物质的草药来源的起始物料有几种类型
· herbal drugs;
· 草药
· herbal preparations (typically extracts);
· 草药制剂（一般指提取物）
· isolated plant constituents (no additional synthetic steps).
· 分离出的植物成分（没有另外的合成步骤）
Starting materials of herbal origin should be characterised to ascertain their suitability and a contaminant profile should be established and submitted, taking into consideration the number of chemical steps between the starting material and the semi-synthetic active substance.
草药来源的起始物料应进行鉴定，以确定其稳定性，应建立其污染物概况并提交，同时要考虑起始物料药半合成活性物质之间的化学步骤的步数。
In all cases, the scientific name (genus, species, variety and author) of the plant and plant part used should be specified. If the starting material is an extract or an isolated constituent, the extraction solvent and strength (e.g. ethanol 50% v/v) used for the first extraction from the herbal drug should be specified as well.
在所有情形下，应说明所用植物和植物成分的科学名称（种属类纲）。如果起始物料是一种提取物或分离出的成分，还要说明从草药中进行第一次萃取所用的萃取溶剂和剂量（例如，乙醇50%V/V）。
The quality of the starting material of herbal origin should follow the principles set out in theEuropean Pharmacopoeia monographs on herbal drugs, herbal drug preparations, extracts and essential oils, as applicable: the potential presence of foreign matter, pesticides, microbiological contamination, total ash, heavy metals, aflatoxins, ochratoxin A, radioactive contamination, residual solvents, and other relevant impurities should be discussed.
草药来源的起始物料质量应遵守欧洲药典草药、草药制剂、提取物和精油各论中给出的原则，适用时，还应讨论潜在的外来物、杀虫剂、微生物污染、总灰分、重金属、黄曲霉素、赭曲霉素A、放射性污染物、残留溶剂和其它相关的杂质。
Potential contaminants that may be carried through the extraction and purification processes should be fully addressed taking into account the production of the herbal drug, and the subsequent extraction and purification processes.
可能通过提取和纯化工艺带入的潜在污染物应综合草药的生产、后续提取和精制工艺进行全面说明。
The specification for the starting material of herbal origin should be fully justified by the applicant and should include suitable tests for identity, assay, impurities and potential contaminants.
草药来源的起始物料质量标准应由申报人进行全面论述，应包括适当的鉴别、含量、杂质和潜在污染物测试。
Compliance with the guideline on good agricultural and collection practice (GACP) is not mandatory in the steps prior to the starting material of a semi-synthetic active substance, since it applies to herbal medicinal products and traditional herbal medicinal products. However, information on the geographical origin, collection or cultivation, harvesting, and post-harvest treatments (possible pesticides and fumigants used and possible radioactive contamination) could justify limited testing for (possible) contaminants.
在半合成原料药之前的步骤不是必须符合“优良种植和收割规范指南”（GACP）要求，因为它只是适用于草药产品和传统草药制品。但是，关于地理来源、采集或培育、收割和收割后处理（可能使用的杀虫剂和灭菌剂，以及可能的放射活性污染物）的资料可以对（可能的）污染物有限的测试进行论证。
Change in the appearance of tablets during storage
存贮期间片剂的外观变化
1. (When) is a change in the appearance of an oral medicinal product during its shelf life considered acceptable? H July 2013
如果一种口服药品在其货架期外观发生变化是否可以接受？H 2013年7月
A change in the appearance of an oral medicinal product during its shelf-life is considered acceptable when all of the following conditions are met:
符合以下所有条件时，口服药品在其货架期外观发生变化认为是可以接受的：
· The root cause of the change is known and the change has no influence on other product characteristics (e.g. flavour);
· 知晓变化的根本原因，变化对药品的属性没有影响（例如，口味）
· The change in appearance does not pose a potential serious risk to public health;
· 外观变化对公众健康不会形成潜在严重风险
· The change in appearance does not occur due to uncontrolled or inadequately chosen packaging and/or storage conditions e.g. inaccurate handling by the manufacturer during packaging, an insufficiently protective packaging or too wide storage conditions;
· 外观变化不是因为所选择的包装和/或存贮条件不受控或不充分引起的，例如，生产商在包装过程中处理不准确，包装保护性不充分，或存贮条件太宽泛
· The change in the appearance of the oral medicinal product during storage (e.g. color, speckling) is clearly stated in the shelf-life specification;
· 口服药品在存贮期间的外观变化（例如，颜色、长斑）在货架期质量标准中有明确描述
· The appearance of the oral medicinal product and the change in appearance during storage are clearly and unambiguously stated and explained in the PIL and SPC.
· 口服药品的外观和存贮期间外观变化在PIL和SPC中有清楚说明和解释
In all other situations, a change in appearance should be assessed on a case-by-case basis.
在所有情形下，外观变化均应各案进行评估。
Data submission 数据提交
1. Is the submission of data regarding manufacturing process validation, analytical validation, and stability studies, produced only by the developer of the product sufficient? Does it make any difference if the developer of the product is presented as one of the product manufacturers or not? H+V July 2008
关于生产工艺验证、分析方法验证和稳定性研究数据，如果只提交产品开发者的数据是否足够呢？产品开发者是否是产品生产商是否有区别呢？H+V 2008年7月
These questions and answers only concern products that are oral solid dosage forms manufactured by standard manufacturing methods. The new product has the same formula and manufacturing method of the developed product.
这个问答仅是关于采用标准生产方法生产的固体口服制剂的。新药品要具备与已研发药品相同配方和生产方法。
Provided that the formula, manufacturing process, analytical methods and packaging materials are the same, data originating from the developer of the product is normally sufficient. As regards manufacturing process validation, the marketing authorisation holder, according to theguideline on process validation, must submit with the new application the process validation scheme and the commitment to carry out process validation and initiate stability studies along with the batch analysis for production scale batches for the new manufacturing site. This is irrespective of whether the product developer is one of the manufacturing sites of the new product or not.
如果配方、生产工艺、分析方法和包装材料相同，则产品开发方产生的数据一般就足够了。关于和平工艺验证，上市许可持有人，根据工艺验证指南，必须在提交新申报同时提交工艺验证计划，以及实施工艺验证的承诺，和初始的稳定性研究及新的生产场所生产规模批次的批分析数据。这与产品开发者是否是一个新产品的生产场所不相关。
2. Who is responsible to verify the production scale validation data when this is available? H+V July 2008
当获得数据时，谁负责核实生产规模的验证数据？H+V 2008年7月
These questions and answers only concern products that are oral solid dosage forms manufactured by standard manufacturing methods. The new product has the same formula and manufacturing method of the developed product.
该问答仅是关于采用标准生产方法生产的固体口服制剂的。新药品要具备与已研发药品相同配方和生产方法。
According to the guideline on process validation, "the results can be subsequently verified by supervising authority according to national procedure.” Depending on the product and the concerns that may arise, in some countries this may be dealt with as a post-authorisation commitment or it may be brought to the attention of good-manufacturing-practice inspectors to be checked during their next inspection.
根据工艺验证指南，“结果可以在之后由监管机构根据国家程序进行核实”。根据产品不同，这些问题可能会存在。在有些国家，可能会作为批准后承诺来对待，也可能会由GMP检查员在其下次检查时关注。
The marketing-authorisation holder is usually not expected to present these data with the new application, unless it is requested by the licensing authorities.
一般不要求上市许可持有人将这些数据与新申报资料一起提交，除非颁证当局有要求。
3. Can the test product of a bioequivalence study be produced by the developer, irrespective of whether that developer is one of the manufacturing sites of the new product? H+V July 2008
生物等效性研究测试用产品可否用开发者生产，而不管开发者是否是新产品的生产场所之一？H_V 2008年7月
These questions and answers only concern products that are oral solid dosage forms manufactured by standard manufacturing methods. The new product has the same formula and manufacturing method of the developed product.
该问答仅是关于采用标准生产方法生产的固体口服制剂的。新药品要具备与已研发药品相同配方和生产方法。
The product used in the bioequivalence study must be representative of the industrial scale product to be marketed.
用于生物等效性研究的药品必须代表将用于上市的工业化规模的产品。
A bioequivalence study conducted using a test product produced by the developer is acceptable if the developer is also one of the manufacturers of the new product.
如果开发者也是新药品的生产商之一，则使用开发者生产的测试产品进行生物等效性研究是可以接受的。
If the developer is not one of the manufacturers of the new product, it has to be demonstrated that the bioequivalence batch is representative of the industrial scale product to be marketed.
如果开发者不是新药品的生产商之一，则必须证明生物等性研究所用批次能代表将要上市的工业化规模的产品。
For this the following applies: 则适用以下条款
· The developer product and the new product must have identical formula, specifications, manufacturing process and equipment;
· 开发者的药品和新药品必须具有相同的配方、质量标准、生产工艺和设备
· The active substance supplier is the same or it is ensured that characteristics of the active substance that may have an impact on the bioavailability are identical;
· 原料药供应商相同，或保证原料药中可能会对生物等效性产生影响的属性是相同的
· The excipients characteristics which may have an impact on the bioavailability of the active substance are identical;
· 可能会对原料药生物等效性产生影响的辅料的属性相同
· The dissolution profiles of batches produced by the developer (including the biobatch) and the product from the new manufacturer (at least pilot batches) must be similar;
· 开发者所生产的批次的（包括生物批）溶出度概况和新的生产商生产的产品（至少是中试批次）必须相似
Comparative pilot batch analysis between the developer product (including the biobatch) and the new manufacturer product must be presented.
必须提交中试批次（包括生物批）和新生产商生产批次的分析结果比较。
4. Is there any requirement for the marketing-authorisation holder to submit any kind of proof (e.g. statement or contract) that it has obtained the dossier from the developer legally? H+V July 2008
上市许可持有人是否需要提交任何形式的证明（例如，合同声明）来证实其文档是从开发者那里合法获得？H+V 2008年7月
These questions and answers only concern products that are oral solid dosage forms manufactured by standard manufacturing methods. The new product has the same formula and manufacturing method of the developed product.
该问答仅是关于采用标准生产方法生产的固体口服制剂的。新药品要具备与已研发药品相同配方和生产方法。
No such proof is necessary to be presented in the application dossier.
在申报资料中不需要提交此类证明。
European Pharmacopeia (Ph. Eur.) - Harmonised Ph. Eur. Chapters 2.6.12, 2.6.13 and 5.1.4
欧盟药典---一致性欧洲药典章节2.6.12，2.6.13和5.1.4
1. How should any update to the microbial quality control of a finished product, specifically linked to the update to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) harmonised Ph. Eur. methods (2.6.12 and 2.6.13) and limits (5.1.4) be achieved? H+V February 2012
如何才能符合对制剂的微生物质量的控制的更新要求，特别是与ICH更新相关EP方法（2.6.12和2.6.13）和限度（5.1.4）？H+V 2012年2月
Any changes to implement the harmonised methods (2.6.12 and 2.6.13) should be submitted under change code B.II.d.2.a (type IA).
对一致性方法(2.6.12 和2.6.13)实施的变更应根据变更代码B.II.d.2.a（第IA类）提交。
Any changes to implement the harmonised limits (5.1.4) should be submitted as follows:
对一致性限度（5.1.4）实施的变更应如下提交：
Changes to the limits – B.II.d.1.a (type IA), but only in the following situations:
限度变更---B.II.d.1.a（第IA类），但仅用于以下情形：
· The currently registered microbial control limits (present situation) are totally in line with the pre-January 2008 (non-harmonised) situation and did not include any additional specified controls over and above the Pharmacopoeia requirements for that particular dosage form. In addition, the proposed controls are totally in line with the harmonised monograph.
· 目前已注册的微生物控制限度（目前情形）与2008年1月前完全一致，和不包括任何药典要求以外的特定剂型的特定控制。另外，所提议的控制与一致性的各论完全相同。
If for any reason these criteria are not met, a type IB variation (B.II.d.1.z) should be submitted.
如有任何原因不能符合这些标准，则应提交IB类变更（B.II.d.1.z）。
In accordance with current requirements, any changes should be clearly identified (present / proposed) in the variation submission and the affected parts of the marketing-authorisation dossier should be appropriately updated, including a description of how the method is applied to the specific product.
根据现行要求，在变更申报资料中应对所有变更进行清楚界定（现行的/提议的），上市许可档案中受影响的部分应进行适当更新，包括描述方法是如何适用于特定产品。
Please note that this advice supersedes the questions and answers dated August 2007, which are now out of date.
请注意，本建议取代2007年8月的问答，该问题目前已不适用。
European Pharmacopeia - Monograph on tablets
欧洲药典---片剂各论
1. How should industry apply the revised test subdivision of tablets in the European Pharmacopeia monograph on tablets? H+V October 2006
制药企业要如何实施修订后的EP各论中片剂的检测部分？H+V 2006年10月
The requirements of the European Pharmacopoeia (Ph. Eur.) general monograph on tablets for tablets with one or more breaklines have been revised as of 1 July 2006. The previous version of the monograph, which has been in force since April 2002, requested compliance with either test A (uniformity of content of single-dose preparations) or the test for uniformity of mass of single-dose preparations. It did not, however, give any information on how to select the parts to be tested. Supplement 5.5 now provides background information on the use of breakmarks and describes the sampling procedure and the number of tablet parts to be tested in detail. As a test procedure, it prescribes determining uniformity of mass, while setting the somewhat wider acceptance criteria of the test of content uniformity, namely 85 - 115% (in this case of the average mass).
欧洲药典关于有一条或更多刻痕片剂通论的要求已于2006年7月修订。之前的各论版本是2002年4月起实施的，它要求符合测试A（单剂量含量均一性）或单剂量重量均一性测试。但是，它并没有给出信息如何来选择要测定的部分。增补5.5现在提供了使用刻痕的背景信息，详细描述了取样程序和应测试的片剂部分的数量。作为一个检验方法，它描述了重量均一性的测试方法，设定了一个相对宽的含量均一性测试可接受标准，即85-115%（这时指平均重量）。
According to [url=http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2001L0083:20070126:en
DF]Directives 2001/83/EC [/url]and [url=http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2001L0082:20090807:ENDF]2001/82/EC [/url], the monographs of the Ph. Eur. are the official standards of appropriate quality in the marketing authorisation procedures. In the pharmacopoeia it is also stated that a preparation must comply with the monograph throughout its period of validity.
根据指令2001/83/EC和2001/82/EC，欧洲药典的各论是上市许可程序中适当质量的官方标准。在药典中，还声明了制 剂必须在其整个有效期内均符合各论要求。
As the revised text defines lesser requirements with wider acceptance criteria than the previous version (see above), a decision has been taken by the regulatory authorities of the European Union (EU) that the revised test on subdivision of tablets is to be applied to all new applications for marketing authorisations as well as all existing products. It is acknowledged, however, that the new test will not have been applied to products which are in the final stages of their development. In order not to delay any immediate applications and in line with the period of time defined in the [url=http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ
:2008:334:0007:0024:enDF]variations regulation [/url], a transitional period of 6 months following the coming into force of Ph. Eur. 5.5 has been defined, in which the EU regulatory authorities will accept submission of results which have been generated using the previous version of the monograph.
由于修订后的文本相比前版本给定的要求更少，可接受标准范围更宽（见上），欧盟法规当局已做出决定，修订后的片剂测试部分将适用于所有新的上市许可申报，以及所有现有药品。但是，我们知道，新的测试将不适用于已处于其研发最终阶段的药品。为了不延误任何现有申报，并与变更法规定义的时间计划表一致，在欧洲药典5.5生效后6个月内为过渡期，期间将接受采用之前各论版本的结果所提交的申报资料。
As the requirements on subdivision of tablets are listed in the production section of the general monograph on tablets, it will normally be sufficient to perform the test only in the framework of pharmaceutical development. There is no need to include the test in the release specification. However, in situations where there is a significant change in tablet hardness during storage, it may be necessary to repeat the test at the end of shelf-life in order to ensure that the scorability has not changed as a function of hardness.
由于片剂的部分要求是列在片剂的一般各论的生产部分，所以只要在药品研发阶段实施测试应足够了。不需要将该测试包括在放行质量标准中。但是，如果片剂的硬度在存贮期间有显著变化，则有必要在货架期结束时重复该测试，以保证评分可操作性不会作为硬度的函数发生变化。
European Pharmacopeia (Ph. Eur.) - Harmonised chapter uniformity of dosage units
欧洲药典---单剂量均一度的一致性章节
Background. H+V June 2012
背景 H+V 2012年6月
Between 2004 and 2008, various questions and answers have been published on this website to clarify how the harmonised European Pharmacopoeia (Ph. Eur.) chapter on uniformity of dosage units (2.9.40) and the general chapters on uniformity of mass of single-dose preparations (2.9.5) and uniformity of content of single-dose preparations (2.9.6) should be applied in the European Union (EU), also in view of the compliance objection made by the United States Food and Drug Administration to the USP on the 2% relative-standard-deviation clause in general chapter 2.9.40. This matter has been recently reviewed by EU regulators and the resulting agreed position is presented in the following questions and answers, which replace the previous questions and answers 1 and 4 published on the same subject in 2004 and 2006, which have now been deleted from the website.
在2004年到2008年期间，在本网站公布了不同的问题和回答，来澄清在欧盟范围内应如何将欧洲药典剂型均一性（2.9.40），单一制剂型重量均一性（2.9.5）和单一剂量含量均一性（2.9.6）进行统一，同时从USFDA反对USP在2.9.40通论中关于2%RSD条款的角度来讨论。该问题近期由EU法规人员进行了审核，结果是大家同意以下问题的答案，该问答取代了2004年和2006年公布的关于同一主题的问答1和4，原问答1和4现在已从网页上删除了。
1. How should industry demonstrate compliance with the European Pharmacopoeia with regard to uniformity of dosage units? H+V June 2012
制药企业如何证明符合欧洲药典单剂量均匀度要求？H+V 2012年6月
Medicinal products marketed in the European Union need to be in compliance with the relevant requirements in the European Pharmacopoeia (Ph. Eur.).
在欧盟上市的药品需要符合欧洲药典中相关的要求。
From a pharmaceutical quality point of view, the approach taken in the harmonised general chapter on uniformity of dosage units (2.9.40) is considered equivalent to what was previously required in the Ph. Eur. through the general chapters on uniformity of mass of single-dose preparations (2.9.5) and uniformity of content of single-dose preparations (2.9.6). These general chapters, 2.9.5 and 2.9.6, are still included in the current version of the Ph. Eur.
从药品质量的角度来说，药典一致性通论关于单剂量均匀度所采用的方法被认为是等同于之前在欧洲药典里由单剂量重量均一性通论（2.9.5）和单剂量含量均一性（2.9.6）的要求。这些通论2.9.5和2.9.6仍包括在欧洲蒳的现行版本里。
Taking this into account, the decision on what approach to take is left to the applicant. Application of either the Ph. Eur. harmonised general chapter on uniformity of dosage units (2.9.40) or the Ph. Eur. general chapters on uniformity of mass of single-dose preparations (2.9.5) and uniformity of content of single-dose preparations (2.9.6) are both considered acceptable options to demonstrate compliance with the Ph. Eur. with regard to uniformity of dosage units.
考虑到此，留给申报者来决定采用何种方式。关于单剂型均一性，采用欧洲药典单剂量（2.9.40）一致性通论，或欧洲药典单剂量重量均一度通论（2.9.5）和单剂量含量均一度（2.9.6）均可以接受来证明符合欧洲药典的要求。
Please note that this advice supersedes the previous questions and answers 1 and 4 published on the same subject in 2004 and 2006. The remaining previously published questions and answers on the use of the general chapter 2.9.40 (former questions and answers 2, 3, 5 and 6) are still valid and remain published as questions and answers 2 to 5.
请注意，本建议取代之前2004年和2006年公布的同一主题的问答1和4。之前公布的问答中2.9.40通论（之前的2，3，5，6问答）的使用仍有效，还保留在公布的问答2和5中。
2. How should the new text be interpreted, in particular in relation to testing frequency (routine test / skip test / test on validation batches only)? H+V March 2006
新的文本要如何解释？特别是关于检测频次（日常检测/定期检测/仅对验证批次检测）？H_V 2006年3月
Where a dosage form monograph in the European Pharmacopoeia refers to this general chapter, the product should comply. This is normally verified by routine testing unless otherwise justified and authorised.
如果欧洲药典中剂型各论引用了该通论，则药品应符合该要求。除另有论述和批准外，一般是需要在日常检测中确认的。
3. How can the text be interpreted in light of the compliance objection made by the Food and Drug Administration to the United States Pharmacopeia on the 2% relative standard deviation clause? H+V March 2006
FDA反对USP关于2%的RSD条款要如何解释？H+V 2006年3月
The harmonised text is included in the European Pharmacopoeia and the 2% clause will thus be valid in the European Union. This will not be dependent on the final outcome of the discussion between the Food and Drug Administration and the United States Pharmacopeia .
欧洲药典里的一致性文件本和2%条款将在欧盟内有效。这不取决于FDA和USP之间最终的讨论结果。
4. When can the requirements in the harmonised European Pharmacopoiea general chapter on uniformity of dosage units (2.9.40) for mass variation, rather than content uniformity, be applied with reference to a relative standard deviation (RSD) of not more than 2%? Is it sufficient to determine the RSD on for example 3 validation batches? H+V July 2008
欧洲药典通论中单剂量均一性（2.9.40）对于质量差异，而不是含量均一性的一致性要求，何时适用NMT2%的RSD要求？如果只对3个验证批次检测RSD是否足够？H+V 2008年7月
It is the opinion of the Quality Working Party that the requirement in the harmonised chapter 2.9.40 regarding the 2% relative-standard-deviation clause represents minimum requirements. The use of this clause should be based on sufficient experience. Normally, results from 3 validation batches are not sufficient. It is rather to be used post-approval when more extensive production experience is gained.
QWP的观点，一致性章节2.9.40中关于2%RSD的条款代表了最低的要求。使用该条款应基于足够的经验。一般来说，3个验证批次的结果是不足够的。但当获得更多的生产经验时，可以用于批准后。
5. What is meant by single component and multiple component in the harmonised chapter 2.9.40? H+V July 2008
在一致性章节2.9.40中，单个组分和多个组分是什么意思？H+V 2008年7月
'Single component' means one active substance with no excipient. 'Multiple component' could mean 'at least 2 active substances' or 'at least 1 active substance and at least one excipient'; both cases are valid.
“单个组分”是指一种活性物质，没有辅料。“多个组成”可以是“至少2种活性物质”或“至少一种活性物质和至少一种辅料”，两种情况都算。
Impurities - Calculation of thresholds for impurities
杂质—杂质阈值计算
1. What is the basis for the calculation of thresholds to set limits for impurities in the finished product specification? H July 2009
计算制剂质量标准中杂质设定限度阈值的依据是什么？H 2009年 7月
Impurities - Harmonisation of policies on setting specifications for potentially genotoxic impurities, heavy-metal-catalyst residues and class-1 solvent residues
杂质—潜在基因毒性杂质、重金属催化剂残留和1类溶剂残留标准设定原则的协调一致
1. What is a reasonable policy for setting specifications for potentially genotoxic impurities which are theoretical or actual impurities in a drug substance manufacturing process? H June 2012
在设定理论上存在，或实际上存在于原料药生产工艺中的潜在基因毒性杂质时，设定质量标准的合理原则是什么？H 2012年6月
Different possible scenarios can be identified and the applicable policies to be applied for each of them are described below:
不同可能的情节所适用的原则描述如下：
Example 1 – A potential genotoxic impurity
例1---潜在基因毒性杂质
The definition for a potential genotoxic impurity is derived from the definition for 'potential impurity': an impurity that theoretically can arise during manufacture or storage. It may or may not actually appear in the (new) drug substance (ICH Q3A, glossary).
潜在基因毒性杂质的定义是从“潜在杂质”定义中衍生出来的：可能在生产和存贮过程中产生的一种理论上的杂质。它可能会也可能不会出现的（新）药品中。（ICH Q3A，术语）。
If a potential genotoxic impurity is just a theoretical impurity i.e. based on theoretical considerations but not found in practice at any key stage in the manufacturing process as demonstrated by studies during development of the manufacture, the impurity does not need to be included in the drug substance specification or a specification of an intermediate.
如果潜在基因毒性杂质只是一个理论上的杂质，即根据理论上的考量，但实际在生产研发研究中证明的生产工艺的各关键阶段均未发现该杂质并不需要包括在药品的质量标准中或中间体的质量标准中。
Example 2 – A (potentially) genotoxic impurity actually formed or introduced prior to the final step of the synthesis
例2---一种（潜在的）在合成最后步骤前生成或引入的基因毒性杂质
If a (potentially) genotoxic impurity is formed or introduced in a step before the final synthesis step, it is considered possible to not include this impurity in the drug substance specification if it is controlled by a suitable limit in a synthesis intermediate and if it is unambiguously demonstrated by analysis results (use of spiking experiments are encouraged) that presence of this impurity does not exceed 30 % of the limit, derived either from threshold of toxicological concern (TTC) or otherwise defined acceptable limit etc., in the drug substance.
如果一种（潜在的）基因毒性杂质在合成最后步骤前生成或引入，如果其通过合成中间体的一个适当限度来控制，或通过分析结果清楚证明（鼓励使用加样试验）该杂质存在的数量不超过限度的30%，则认为其可以不需要作为杂质包括在药品质量标准中。该限度应根据TTC来计算，或根据药品中既定的可接受限度。
It is considered possible to apply skip testing if the level of the impurity in a synthesis intermediate does not exceed 30% of the limit, derived from either TTC or otherwise defined acceptable limit etc, in the intermediate. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the intermediate is needed. If the impurity exceeds 30% of the limit, derived either from TTC or otherwise defined acceptable limit etc., in the drug substance the impurity has to be included in the drug substance specification and the test has to be carried out on a routine basis.
如果合成中间体中杂质水平不超过根据TTC计算的或其它定义的中间体中可接受限度的30%，则可以考虑应用周期检测的方式。所提交的数据应包括至少6批连续中试批次或3批生产规模批次。如果不满足该条件，则应对中间体进行逐批检测。如果杂质在原料药中超过TTC计算限度或其它定义的可接受限度30%的水平，则该杂质的质量标准必须包括在原料药质量标准中，并逐批检测。
Should a genotoxic impurity not be controlled at the intermediate stage, then the scenario of example 3 applies.
如果一种基因毒性杂质在中间体阶段不控制，则适用例3的情形。
Example 3 - A (potentially) genotoxic impurity is formed or introduced in the last synthesis step
例3---在合成的最后步骤形成或引入的（潜在）基因毒性杂质
If a (potentially) genotoxic impurity is formed or introduced in the final synthesis step, it should be included in the specifications. However, it is considered possible to apply skip testing if the level of the impurity does not exceed 30% of the limit, derived from either TTC or otherwise defined acceptable limit etc., in the drug substance. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the drug substance specification is needed.
如果一种（潜在的）基因毒性杂质在最终合成步骤中形成或引入，则应包括在质量标准中。但是，如果杂质的水平不超过30%限度（限度采用TTC计算或药品中既定的其它可接受限度）水平的话，可以进行周期检测。要提交至少6批连续中试批次或3批连续生产批次的数据。如果不满足该条件，则需要对根据药品的质量标准进行日常检测。
Definitions: 定义
For the purpose of these questions and answers, the following definitions apply:
以下定义适用于这些问题：
· Genotoxic impurity: an impurity that has been demonstrated to be genotoxic in an appropriate genotoxicity test model, e.g. bacterial gene mutation (Ames) test.
· 基因毒性杂质：被证明在适当的基因毒性测试模式，例如，细菌基因突变（AMES）测试为基因毒性的杂质
· Potentially genotoxic impurity: an impurity that shows (a) structural alert(s) for genotoxicity but that has not been tested in an experimental test model. Here potentially relates to genotoxicity, not to the presence or absence of this impurity.
· 潜在基因毒性杂质：其结构显示出基因毒性警示性，但并未通过实验测试模式得到证明的杂质。这里“潜在”一词是指可能有基因毒性，而不是指该杂质是否可能存在。
2. In order to harmonise the policies to be applied for setting specifications for genotoxic impurities and heavy-metal-catalyst residues, what are reasonable policies to be applied when setting specifications for heavy-metal-catalyst residues? H June 2012
为了与适用于基因毒性和重金属催化剂残留的质量标准设定原则相协调一致，在设定重金属催化剂残留时，要应用什么样的合理原则呢？H 2012年6月
In order to harmonise the policy for setting specifications for metal residues with that for setting specifications for genotoxic impurities, some clarifications of the interpretation of sections 4.5 and 4.6 of the heavy-metal-catalyst guideline (EMEA/CHMP/SWP/4446/2000) are given below.
为了保持金属残留设定标准的原则与设定基因毒性杂质的原则一致，以下给出了“重金属催化剂指南(EMEA/CHMP/SWP/4446/2000)”第4.5和4.6部分的一些解释澄清：
Since it is the class-1 metals that are the most toxic metals with permitted daily exposures (PDEs) that approach the level of the threshold of toxicological concern (TTC) applied for genotoxic impurities, it seems reasonable that class-1 metals are the prime focus for harmonisation with the policy for genotoxic impurities while class-2 and 3 metals could be treated similarly but somewhat less strictly.
由于1类金属是最具毒性的金属，其PDE值接近基因毒性杂质所采用的TTC阈值，因此将1类杂质作为与基因毒性杂质原则协调一致的首要关注对象看起来是比较合理的，而2类和3类金属可以类似处理，但相对可以不需要那么严格。
Example 1 – A class-1 metal is not used or suspected to be present in a synthesis process
例1---在合成工艺中未使用或怀疑会出现的1类金属
Metals are not expected to be formed in synthesis processes. Only if deliberately introduced or suspected to be present for other reasons, residues of metals can be expected. If not used or suspected to be present, the metal does not need to be included in the drug substance specification or a specification of an intermediate.
在合成工艺中是不应该会形成金属的，只有在有意引入或因其它原因怀疑会出现时才预期会出现的金属杂质。如果未使用或怀疑会出现，则不需要包括在药用物质或中间体的质量标准中。
Example 2 – A class-1 metal is formed or introduced prior to the final step of the synthesis
例2---在合成最终步骤前形成或引入的一种1类金属
If a class-1 metal is introduced in a step before the final synthesis step, it is considered possible to not include this metal in the drug substance specification if it is controlled by a suitable limit in a synthesis intermediate and if it is unambiguously demonstrated by analysis results that the presence of this metal does not exceed 30% of the guideline limit in the drug substance.
如果在最终合成步骤之前的步骤引入1类金属，在一个合成中间体中通过适当的限度进行控制，且检验结果已清楚证明该金属存在的水平不超过药用物质中指南限度的30%，则可以考虑在药用物质的质量标准中不包括该金属。
It is considered possible to apply skip testing if the level of the class-1 metal in a synthesis intermediate does not exceed 30% of the guideline limit in the intermediate. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the intermediate is needed. If the class-1 metal exceeds 30% of the guideline limit in the drug substance the impurity has to be included in the drug substance specification and the test has to be carried out on a routine basis.
如果合成中间体中的1类金属残留水平不超过中间体中指南限度的30%，则可以考虑实施定期检测。需要提交至少6批连续中试规模或3批连续生产规模批次的数据。如果不满足该条件，则需要对中间体进行日常检测。如果药用物质中的1类金属残留超过指南限度的30%，则该杂质必须包括在药用物质的质量标准中，且必须进行常规检查。
Should a class-1 metal not be controlled at the intermediate stage, then the scenario of example 3 applies.
如果1类金属在中间体阶段未控制，则适用例3情形。
Example 3 – A class-1 metal is introduced in the last synthesis step
例3—在最终合成步骤引入的一种1类金属
If a class-1 metal is introduced in the final synthesis step, it should be included in the specifications. However, it is considered possible to apply skip testing if the level of the metal does not exceed 30% of the guideline limit in the drug substance. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the drug substance specification is needed.
如果在最终合成步骤引入一种1类金属，则需要将其包括在质量标准。但是，如果金属残留水平不超过药用物质里的指南限度的30%，则可以考虑实施定期检测。应提交至少6批连续中试批次或3批连续生产批次的数据。如果不满足该条件，则应在药用物质的质量标准中作为日常检测。
3. In order to harmonise the policies to be applied for setting specifications for genotoxic impurities and class-1 solvent residues, what are reasonable policies to be applied when setting specifications for class-1 solvent residues? H June 2012
为了与基因毒性和1类溶剂残留质量标准设定所应用的原则相协调一致，在为1类溶剂残留设定质量标准时应适用何种合理的原则？+ 2012年6月
In order to harmonise the policy for setting specifications for class-1 solvents with that for setting specifications for genotoxic impurities, some clarifications of the interpretation of annex I to the residual solvents guideline (CPMP/ICH/283/96 / CVMP/VICH/502/99): Specifications for class 1 and class 2 residual solvents in active substances (CPMP/QWP/450/03 / EMEA/CVMP/511/03)are given below.
为了将1类溶剂质量标准设定方针与基因毒性杂质的质量标准设定协调一致，以下给出了一些关于“残留溶剂指南 (CPMP/ICH/283/96 / CVMP/VICH/502/99)附录1：原料药中1类和2类残留溶剂质量标准(CPMP/QWP/450/03 / EMEA/CVMP/511/03)”解释的澄清。
Since it is the class-1 solvents that are most toxic solvents and have permitted daily exposures (PDEs) that approach the level of the threshold of toxicological concern (TTC) applied for genotoxic impurities, it seems reasonable that class- 1 solvents are the focus for harmonisation with the policy for genotoxic impurities.
由于1类溶剂是毒性最强的溶剂，具有PDE值，接近基因毒性杂质所用的TTC，貌似使用基因毒性杂质原则来应用于1类溶剂很是合理。
Example 1 – A class-1 solvent is not used or suspected to be present in a synthesis process
例1---在合成路线中未使用或怀疑会出现的一类溶剂
If a class-1 solvent is just a potential impurity, not used directly or found in practice as demonstrated by studies during development of the manufacture, the class-1 solvent does not need to be included in the drug substance specification or a specification of an intermediate.
如果某个1类溶剂仅一个潜在的杂质，并没有直接使用，或通过生产研发阶段的研究在实践中发现，则该一类溶剂不需要包括在原料药或中间体的质量标准中。
Example 2 – A class-1 solvent is formed or introduced prior to the final step of the synthesis
例2---在合成的最后步骤之前形成或引入一个1类溶剂
If a class-1 solvent is formed or introduced in a step before the final synthesis step, it is considered possible to not include this solvent in the drug substance specification if it is controlled by a suitable limit in a starting material or synthesis intermediate and if it is unambiguously demonstrated by analysis results that the presence of this solvent does not exceed 30% of the guideline limit in the drug substance.
如果在最终合成步骤之前的一步形成或引入一个1类溶剂，且在起始物料或合成中间体中控制在适当的限度，则可以考虑不将该溶剂包括在原料药的质量标准中。此时要证明该溶剂分析结果不超过原料药中指南限度的30%。
It is considered possible to apply skip testing if the level of the solvent in a synthesis intermediate does not exceed 30% of the guideline limit in the intermediate. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches. If this condition is not fulfilled, a routine test in the intermediate is needed. If the solvent exceeds 30% of the guideline limit in the drug substance the solvent has to be included in the drug substance specification and the test has to be carried out on a routine basis.
如果合成中间体中该溶剂的水平不超过指南限度的30%，则可以考虑使用周期检测。提交的数据应包括至少6批连续的中试规模或3批连续的生产规模。如果不能满足该条件，则需要对中间体进行逐批检测。如果溶剂超过原料药中指南限度的30%，则该溶剂必须包括在原料药质量标准中，并需要逐批检测。
Should a class-1 solvent not be controlled at the starting material or intermediate stage, then the scenario of example 3 applies.
如果1类溶剂没有在起始物料中或中间体阶段控制，则适用例3情形。
Example 3 – A class-1 solvent is formed or introduced in the last synthesis step
例3---在最后一步合成步骤中形成或引入的一个1类溶剂
If a class-1 solvent is formed or introduced in the final synthesis step, it should be included in the specifications. However, it is considered possible to apply skip testing if the level of the solvent does not exceed 30% of the guideline limit in the drug substance. Data should be presented for at least 6 consecutive pilot scale or 3 consecutive production scale batches.
如果在最后一个合成步骤中形成中引入了一个一类溶剂，则应将其包括在质量标准中。但是，如果原料药中溶剂的水平不超过指南的30%限度，则可以考虑进行周期检测。要提供至少6批连续的中试批数据或3批连续的生产规模数据。
Impurities - Residual solvents
杂质---残留溶剂
1. Is there a need to take the actual batch results into consideration when specifying class-2 residual solvents for active substances or medicinal products? H+V August 2007
在界定原料药或制剂中的二类溶剂时，是否需要考虑实际的批检验结果？H+V 2007年8月
For class-2 residual solvents in active substances or medicinal products, it is sufficient to restrict the specification to the concentration limit (parts per million) as defined in the notes for guidance on impurities: residual solvents (CPMP/ICH/283/95 & EMEA/CVMP/511/03) and related maintenance guidelines or to calculate it based on the respective permitted daily exposure (mg/day) outlined in the guidelines.
对于原料药或制剂中的2类溶剂，只要限制其标准在“”和相关的后续指南中定义的浓度限（ppm），或根据指南中列出的对应允许日暴露剂量（mg/天）进行计算就足够了。
It has been agreed by the QWP that there is no need for further tightening of the specification in line with batch results, as the limits in the guideline are based on safety assessment.
QWP已认可不需要根据批结果将该限度进一步加严，因为指南中的限度是基于安全评估的。
Manufacture of the medicinal products - Process control
制剂生产---工艺控制
1. When validating a manufacturing process, if a common bulk is used to manufacture a series of products, how should the pilot batch size be decided upon? H+V September 2007
在验证一个生产工艺时，如果一个通用的散装物料用于生产一系列的制剂，中试批次的批量该依据什么来定义？H+V 2007年9月
It is the applicant’s responsibility to select and justify the pilot batch size.
The joint Committee for Medicinal Products for Human Use and Committee for Medicinal Products for Veterinary Use guideline on process validation (CPMP/QWP/848/96, CVMP/598/99) states that, “pilot-batch size should correspond to at least 10% of the future industrial scale batch i.e. such that the multiplication factor for scale-up does not exceed 10. For oral solid dosage forms this size should be at least 10% or 100,000 units whichever is greater* unless otherwise justified”.
申报人有责任来选择并论证中试批次的批量。
“人用药品联合委员会和兽药委员会关于工艺验证的指南（CPMP/QWP/848/96, CVMP/598/99）”中说明，“中试的批量应对应工业化规模生产批量的至少10%，即放大生产系统不应超过10倍。对于口服固体制剂，该批量应为至少10%或十万个单位，取大者，另有论证者除外”。
The guideline does not dictate that the 10% figure should always be linked to the scale of manufacture of individual product presentations. In addition, it allows for departures from the guidance where this is justified. Furthermore, the guideline does not preclude the use of bracketing.
指南没有说明这个10%的数字应总是与单个产品所代表的生产规模相链接。此外，在经过论证时，它允许偏出指南。另外，指南未说明分组法的使用。
Certain bulk products are used to produce a series of presentations, for example a bulk powder blend may be used to produce 50-mg, 100-mg and 200-mg direct compression tablets with the same percentage composition. In such instances, as long as the applicant can demonstrate a satisfactory link between the pilot batch size used for validation and the routine production batch size, it will usually be acceptable to define the pilot batch size as 10% of the planned production scale for the bulk product. During the process validation study, the complete pilot scale bulk batch should be used to manufacture the individual presentations. The division of the bulk batch between the different presentations should also be justified.
特定的散装药品用于生产一系列药品时，例如，一种散装的粉末混合物可能用于生产50Mg,100mg和200mg的直接压片，其配料百分比是一样的。在这种情况下，只要申报者可以证明用于验证的批量和常规生产批量之间的关系令人满意，则通常可以接受将中试生产批量定为计划生产的散装药品批量的10%。在工艺验证期间，完整的中试规模散装药品批次应用于生产单个代表的制剂。散装批量拆分用于不同药品的代表规格也应进行论证。
*In the case of veterinary medicinal products, the minimum pilot size may be smaller than 100,000 units where justified.
*对于兽药产品，如果经过论证，则最小中试批量可以小于10万单位。
Variation变更
What is understood by “manufactured by complex manufacturing processes” in change code B.II.b.4 (change in batch size of the finished product)? H+V October 2010
变更代码B.II.b.4（制剂的批量变更）中“复杂生产工艺生产的”表示什么意思？H+V 2010年10月
Complex manufacturing processes is intended to cover situations where the actual manufacture of the finished product involves a process which includes one or more processing steps that may give rise to scale-up difficulties. These will be considered on a case by case basis.
复杂生产工艺是为了覆盖涉及工艺包括一个或多个工艺步骤，可能会对放大批量造成困难的实际生产情形。这种情况下要各案讨论。
Where relevant, if a change is submitted as a type IB variation, it is up to the applicant to provide adequate justification for not considering a manufacturing process as a 'complex' one, in terms of scale-up. However, under the safeguard clause, it should be noted that if the supplied justification is not accepted, it is possible for the competent authority to upgrade the submission to a type II variation during the validation phase.
相关情况下，如果一个变更作为一个IB类变更提前，则申报人要提交足够的论述，说明为什么不将一个生产工艺作为“复杂工艺”来考虑。但是，为安全起见，应注意如果提交的论证未被接受，则在核查阶段，药监机构可能会将变更申报升级为II类变更。
If unsure, applicants should consult the relevant competent authority before submitting the variation.
如果不确定的话，申报人可以在提交变更前向相关的药监机构咨询。
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