EMA制剂质量问答第一部分

Removal of heavy metals tests from a specification - Substances with a Ph. Eur. monograph in existing marketed products

从质量标准中删除重金属——有EP各论的已上市药品中物质2问

1. Is it necessary to submit a variation when removing a general test for heavy metals (Ph. Eur.) from the specification of a substance with a Ph. Eur. monograph in a medicinal product for human use? (H+V) March 2017

从有EP各论的人药物质质量标准中删除重金属检查项（EP）时是否需要提交变更？ （H+V） 2017年3月

No. Reference to the general Heavy metals test (2.4.8) has been deleted in the Ph. Eur. 9.0 from all individual monographs for substances for pharmaceutical use (except those for veterinary use only). Instead the Ph. Eur. General Monograph Substances for Pharmaceutical Use will require that elemental impurities are c**idered in a risk assessment and the Ph. Eur. General Monograph Pharmaceutical Preparati** will make ICH Q3D mandatory for all medicines within the scope of the guideline. Compliance with the revised monographs is an expectation and therefore the deletion of the general Heavy metals test from the specification would not require a variation.

不需要。在EP9.0中，已删除了所有药用物质单品（仅供兽药使用者除外）各论中对重金属（2.4.8）检查的引用。作为替代，EP通论“药用物质”将要求在风险评估中考虑元素杂质，EP通论“制剂”中将强制要求所有指南范围内的药品执行ICH Q3D。符合修订后的各论是法规要求，因此从质量标准中删除常规重金属检查不需要提交变更。

2. Is it necessary to submit a variation when removing a general test for heavy metals (Ph. Eur.) from the specification of a substance with a Ph. Eur. monograph in a medicinal product for veterinary use, when the test is removed from the monograph? (V) March 2017

从有EP各论的兽药物质质量标准中删除重金属检查项（EP）时是否需要提交变更？（V）2017年3月

No. Reference to the Heavy metals test (2.4.8) has been deleted in Ph. Eur. 9.0 from all individual monographs for substances for pharmaceutical use (except those for veterinary use only). Instead the Ph. Eur. General Monograph Substances for Pharmaceutical Use will require that elemental impurities are c**idered in a risk assessment and the Ph. Eur. General Monograph Pharmaceutical Preparati** will require elemental impurities to be controlled based on a risk assessment for products outside the scope of Ph. Eur. Chapter 5.20. Compliance with the revised monographs is an expectation and therefore the deletion of the Heavy metals test from the specification would not require a variation.

不需要。在EP9.0中，已删除了所有药用物质单品（仅供兽药使用者除外）各论中对重金属（2.4.8）检查的引用。作为替代，EP通论“药用物质”将要求基于风险评估中对不在EP5.20范围内的药品中的元素杂质进行控制。符合修订后的各论是法规要求，因此从质量标准中删除常规重金属检查不需要提交变更。

Removal of heavy metals tests from a specification - Substances without a Ph. Eur. monograph in existing marketed products

从质量标准中删除重金属——无EP各论的已上市药品中物质1问

1. Is it necessary to submit a variation when removing a general test for heavy metals from the specification of a substance without a Ph. Eur. monograph in a medicinal product? (H) March 2017

从没有EP各论的药品物质质量标准中删除重金属通用检查时是否需要提交变更？（H）2017年3月

Yes. The deletion of a general Heavy metals test from the specification of an ingredient is accepted as a Variation Type 1A. The change does not have to be justified.

需要。从一个成分的质量标准中删除通用重金属检查项可作为IA类变更接受。该变更不需要论证。

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 c**idered 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 excepti** 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。

2. Quality Working ** questi** and answers on API mix H+V April 216

质量工作组关于原料药混合的问答 （H+V）2016年4月（译者注：该问答当时官方曾以单行文发布，发布文编号EMA/CHMP/CVMP/QWP/152772/2016）

These Q&A have been developed to provide information on how to deal with mixtures of API and excipients (called API mix), and to identify situati** where it will be acceptable to use the ASMF/CEP procedure and perform manufacture under EU GMP Part II for the API mix.

这些问答是为了提供关于如何处理原料药与辅料混合物（称为原料药预混剂）的信息，识别出什么情形采用ASMF/CEP程序是可以接受的，以及根据EU GMP第二部分来生产原料药预混剂。

1. What is the definition of an API mix? 原料药预混剂的定义是什么？

An `API mix’ is defined as a mixture of an API (active pharmaceutical ingredient) with one or more excipients. Typical examples are the addition of an antioxidant to an API, or the introduction of an API into a matrix.

“原料药预混剂”定义为一种原料药（活性药用成分）与一种或多种辅料的混合物。典型的例子是将抗氧剂加入到一种原料药中，或者引入一种原料药到一种基底物质中。

The manufacture of an API mix is c**idered to be the first step of the manufacture of a finished product.

原料药预混物的生产被认为是制剂生产的第一步。

a) Under which circumstances can an API Mix be submitted as part of 3.2.S (or 2.C.1) or via an ASMF resp. a CEP? 在什么情形下，原料药预混物可以作为3.2.S（或者2.C.1）的一部分提交，或者通过ASMF以及CEP来提交？

In certain circumstances, i.e. stability or safety reas**, the applicant can submit data on such a mixture under part 3.2.S (or part 2.C.1 for products for veterinary use) or in the form of an ASMF or via a CEP. The API mix should comply with the same requirements as for an API with regard to GMP Part II, unless the mixture is sterile (in which case GMP Part I is mandatory for the sterilisation activities and steps after sterilisation). A re-test period for the API mix can in such cases be accepted, if justified.

在特定情形下，即稳定性或安全性原因，申报者可以在第3.2.S部分（或2.C.1部分兽用药品）提交此类预混剂的数据，或者以ASMF或通过CEP形式提交。原料药预混剂应符合对原料药的相同要求，即GMP第二部分要求，除非预混剂是无菌的（在这种情形下，则灭菌活动和灭菌之后的操作均必须符合GMP第一部分要求）。在这种情形下，原料药预混物的复验期如果经过论证是可以接受的。

In case of an API mix prepared due to workability purposes or reas** other than safety and stability, the manufacturing steps from the addition of the excipient to the API should be described in (the appropriate part of CTD 3.2P....). In addition the steps following addition of the excipient must be conducted in accordance with GMP Part I and an appropriate manufacturing authorisation.

如果原料药预混剂是为了可加工性的目的或原因，而不是安全性和稳定性的原因，则从加入辅料至原料药的生产步骤开始即需要在（CTD3.2P的适当部分）进行描述。此外，在加入辅料之后 的所有步骤均必须根据GMP第一部分和适当的生产许可要求实施。

b) Is an API mix acceptable when it is stated in a pharmacopoeial monograph “A suitable antioxidant may be added” (under ’Definition’)? 如果原料药预混剂在药典各论中被作为“可以添加的适当的抗氧化剂”（在“定义”项下），是否会被接受？

A statement in a pharmacopoeial monograph, such as “A suitable antioxidant may be added” is c**idered sufficient and acceptable per se as a justification for the use of an API mix.

在药典各论声明中，像“可以添加的适当的抗氧化剂”被认为是充分的，可以用来支持论述原料药预混剂。

However, additional justification on the choice and level of antioxidant needs to be provided, and a control test is required for the antioxidant in the API mix.

但是，要提交关于抗氧剂的选择及抗氧剂添加水平的论述，以及在原料药预混剂中抗氧剂所需的控制测试。

Particular care should be given regarding API mix acceptability in cases where different sources of API are used in the same medicinal product to avoid a medicinal product with alternative compositi**

如果在相同药品中使用了不同来源的原料药，要特别注意关于原料药预混剂是否能被接受，以避免药品具有不同的成分。

c) Are APIs in soluti** (e.g. Benzalkonium chloride solution) c**idered as an API mix, and are ASMFs or CEP applicati** for soluti** of APIs acceptable? 溶液形式的原料药（例如苯扎氯铵）是否能被当作是原料药预混剂，原料药溶液ASMF或CEP申报是否可接受？

APIs in soluti** are c**idered as API mixes. ASMFs for soluti** are acceptable in certain circumstances as explained under question 1.b.

溶液形式的原料药可以作为原料药预混剂。溶液的ASMF在特定情形下，如问题1.b中解释，是可以接受的。

d) Is there a difference if there is a Ph. Eur. monograph that permits an API mix or not? EP各论是否允许原料药混合有什么区别吗？

For an existing Ph. Eur. monograph for an API mix, an ASMF can be accepted or CEP can be granted, with the assumption that new monographs for mixtures would normally not be introduced into the Ph. Eur. if not justified by the safety or stability of the API.

对于一个已有原料药预混剂的EP各论，可以接受ASMF，也可以颁发CEP**。如果不是经过原料药安全性或稳定性论证，新的混合物各论一般不会再引入EP。

If there is no Ph. Eur. monograph for an API mix then an ASMF can be accepted only for safety or stability reas** on a case by case basis.

如果一种原料药预混物没有EP各论，则ASMF不会被接受，除非各案判定具有安全性或稳定性原因存在。

2. An API mix is acceptable when there are safety or stability issues: What data should be submitted to justify the acceptability of an API mix for which there is no Ph. Eur. monograph? 当因为安全性或稳定性原因时可以接受原料药预混，那么当原料药预混剂没有EP各论时，要提交什么数据来论证一种原料药预混剂的可接受性呢？

In all cases the choice and level of excipient should be justified.

所有情形下都需要论证辅料种类和数据的选择。

In case the originator uses no stabiliser, it is expected that the same approach as the originator is taken by any subsequent new product.

如果原研药公司没有使用稳定剂，则期望后续的新产品采用与原研药相同的方法。

Acceptable stability reas** include both chemical and physical stability.

可接受的稳定性理由包括化学和物理两种。

Documentation to be provided: A comparison of the stability data of both the stabilised and non-stabilised API under (V)ICH long term conditi** for up to 6 months (in a refrigerator/freezer/inert atmosphere where relevant). Results with a stabiliser should dem**trate a relevant stability improvement.

要提交的文件：在（V）ICH长期稳定性试验条件下长达6个月（必要时在冰箱、冷冻、惰性氛下）的加了稳定剂与未加稳定剂的稳定性数据对比。加了稳定剂的结果应能证明对稳定性的相应改善。

For APIs of an explosive nature the use of an API mix may be justified, and an appropriate explanation is c**idered sufficient.

对于具有爆炸性的原料药，使用原料药预混剂是可以论证的，提交适当的解释会被认为是足够的。

A justification based only on workability reas**, e.g. to ease handling when processed into final dosage form, is not acceptable.

仅仅是基于可加工性质的原因的论证，例如，为了易于处理加工成为最终的剂型，是不会被接受的。

Toxicological c**iderati** (e.g. very potent drugs) fall under workability reas** and are not accepted as justificati**.

毒性考虑（例如，效价很高的药品）也属于可加工性质的理由，基于该原因的论证不会被接受。

3. If an ASMF/CEP for an API mix is accepted: 如果原料药预混剂ASMF/CEP可以接受：

a) What data are required and how should the data be organised in the dossier/ASMF? 在文档/ASMF中，需要什么数据，数据要如何组织？

If an ASMF for an API mix is accepted, the open part of the ASMF/dossier should contain all relevant information on the mixing process, qualitative and quantitative composition of the mixture and control strategy. Data supporting the choice and the amount of the excipient should also be provided.

如果原料药预混剂的ASMF是可以接受的，则ASMF/CEP文档的公开部分应包括混合工艺的所有相关信息、混合物定量和定性成分、控制策略。还要提供支持辅料种类和数量选择的数据。

Information requested for the excipient(s) – Ref. Annex I (section 3.2.2.4) of Directive 2001/83/EC for products for human use and Annex I (section 2.C.1.2) of Directive 2001/82/EC for products for veterinary use.

辅料所需信息---人药参见指令2001/83/EC附录I（第3.2.2.4）部分，兽药参见指令2001/82/EC附录I第2.C.1.2部分。

b) Where should the excipient be stated? 要在哪里说明辅料信息？

Excipients should be stated in the composition of the drug product (Module 3.2.P.1 for products for human use or Part 2.A for products for veterinary use); in the SmPC – 6.1, 2 (in the case of antioxidants and/or preservatives or if required according to the CxMP excipients guidelines); in the PL – 6 and in the labelling (if required according to the CxMP excipients guidelines). For the PL for products for veterinary use: section 3 (i.e. composition, only antioxidants and/or preservatives). See also QRD templates.

辅料信息应在药品成分里说明（人药在模块3.2.P.1中，兽药在2.A部分中）、在SMPC---6.1.2（如果是抗氧剂和/或防腐剂或者必要时根据CxMP辅料指南）、在PL—6以及在标签（必要时根据CxMP辅料指南）中说明。对于兽药PL，应在第3部分说明（即，成份，仅抗氧剂和/或防腐剂）。也请参见QRD模板。

c) What should be required as additional information in the case of a CEP? 如果CEP可以接受，需要提交哪些附加信息？

The same principles apply as for ASMFs. The following information should be required as additional information in the case of a CEP:

同样的原则也适用于ASMF。如果提交CEP，则需要提交以下附加信息：

?   The description of the manufacturing process for preparation of the mixture should be provided by the API manufacturer to the applicant - in addition to the CEP. This information should be part of section 3.2.S.2.2 in the MA application dossier for human products or section 2.C.1.1 for veterinary products;

?   原料药生产商要向申报人提交混合物制备生产工艺的描述—除了CEP里提交以外。此信息应该成为人药上市许可申报资料中3.2.S.2.2部分的一部分，或者兽药申报资料第2.C.1.1部分。

?   Stability data of the mixture if not mentioned on the CEP;

?   如果CEP里没有提及的话，要提交混合物的稳定性数据。

?   Information on the packaging material if not mentioned on the CEP.

?   如果CEP里没有提到的话，要提交关于包装材料的信息。

If a new CEP is presented as a variation then these above mentioned elements should also be included as part of that submission.

如果针对一份新的CEP提交变更，则上述要素也要被包括作为申报的一部分。

In addition, as far as the variation submission category is concerned and whether or not a Type IA or even a variation will be possible at all, particular c**ideration should be given to the potential impact of the change on the currently registered specificati** of both the API and the finished product (conditi** 1 and 2 under variation change code B.III.1). In this instance, as far as condition 2 is concerned, it is important to note that product specific requirements also include the qualitative, and where relevant, quantitative composition of the API mix, as indicated in the CEP, which may impact the currently registered composition of the finished product (see question 1b).

另外，只要是关于变更申报类型的问题，不管是否IA类型，甚至都不是一个变更，尤其要注意变更对现在注册的原料药和制剂（变更代码B.III.1下条件1和2）质量标准的影响。在此情形下，只要是关于条件2的，很重要的需要注意产品特定要求也应包括定性要求，相关时还要包括原料药的定量成分要求，如CEP里显示的一样，这可能会对目前注册的制剂成分产生影响（参见问题1b）。

3. The Active Substance Master File (ASMF) procedure guidance requires only one version of the ASMF (“most recent”) to be in use at any one time. What happens if product specific attributes are necessary in the active substance by only one applicant/MAH? H+V July 216

ASMF程序指南要求同时只能使用一个ASMF版本（最新版本）。如果有某个特定的原料药属性只有一个申报者/MAH需要会怎么样？ （H+V）2016年7月

The Active Substance Master File (ASMF) procedure guidance already allows for technical tests in the specification of the active substance that are relevant for the medicinal product, and which are not normally part of the specification in the ASMF (e.g. particle size), but which should be part of the active substance specification of a particular Applicant/MA holder. It is also common practice where a CEP is used that additional information can be provided in the marketing authorisation application dossier (e.g. concerning particle size, microbial quality or bacterial endotoxins).

ASMF程序指南已允许在原料药质量标准中进行与制剂有关的技术测试，通常它并不是ASMF质量标准的一部分（例如，粒径），但应该是特定的申报人/MA持有人的原料药质量标准的一部分。通常如果使用了一份CEP，则可以在上市许可申报资料中提交额外信息（例如，相关的粒径、微生物质量或细菌内毒素）。

Therefore, in situati** where an Applicant/MAH requires product-specific attributes to the active substance then these may be included in the relevant section of the MA dossier/Module 3 (or Part 2 for veterinary medicinal products) rather than the ASMF dossier to maintain the “one version” philosophy for the ASMF.

因此，如果一个申报人/MAH对原料药有与专用于其制剂的属性要求，则可以将此类要求包括在MA文档模块3（或兽药第2部分）的相关部分中，而不是放在ASMF文档中，以维护ASMF的“一个版本”原则。

Active substance - Declaration by the qualified person on the good-manufacturing-practice status of the active substance manufacturer

活性物质—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使用，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。对于少数药品，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---原料药灭菌的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 the European Pharmacopoeiamonographs 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 questi** 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 the guideline 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 resp**ible 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 questi** 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 questi** 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 dem**trated 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: 此时适用以下条款

?  The developer product and the new product must have identical formula, specificati**, 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 questi** 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---已协调欧洲药典章节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).

对已协调方法(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:

对已协调限度（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 situati**:

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，所提议的控制与已协调的各论完全相同。

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 questi** 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 preparati**) or the test for uniformity of mass of single-dose preparati**. 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=C**LEG:2001L0083:20070126:enDF]Directives 2001/83/EC [/url]and [url=http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=C**LEG: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 applicati** for marketing authorisati** 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 applicati** 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]variati** 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 situati** 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。

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 March 2015

制剂质量标准中杂质限度设定的阈值计算基础是什么？ H  2015年3月

Mono-component products 单组份药品

For medicinal products containing only one active substance, the calculated thresholds should be based on the highest maximum daily dose of the respective active substance in authorised medicinal products and the limits in the specification set accordingly. The threshold for impurities should be the same for all strengths. The applicant is resp**ible to c**ider the maximum daily dose (MDD) that is approved for a given active substance in those Member States where the medicinal product is to be licensed.

对于只含有一种活性物质的药品，计算阈值应基于批准的制剂中对应活性物质的日最高剂量和相应质量标准系列中的限度。所有剂量中杂质阈值应相同。申报人有义务考虑在批准药品的成员国内所批准的指定活性物质日最大剂量（MDD）。

Fixed Dose Combination products (FDC) 固定剂量复方药品（FDC）

For medicinal products containing more than one active substance, the calculated threshold should be based on the maximum daily dose (MDD) described in the SPC of the FDC(s) under evaluation. The FDC(s) are indeed developed in a specific ratio of active substances composing the medicinal product and therefore c**idering the MDD of an active substance in mono-component medicinal products would not be appropriate.

对于含有不止一种活性成分的制剂，计算阈值应基于在评FDC的SPC中所述的日最大剂量（MDD）。FDC实际上在组成制剂的活性物质的特定比例下制订的，因此考虑单成分药品中活性物质的MDD是不恰当的。

If an unidentified impurity cannot be assigned to one of the active substances in the FDC it has to be compared to the signals of all active substances in order to verify whether the respective ICH identification threshold is exceeded or not. If exceeded, the impurity should be identified and assigned to the signal of the respective active substance. If not exceeded, the specification limit should be set with reference to the active substance that would ensure the lowest amount/exposure to the patient.

如果有某种未鉴定的杂质不能归因于FDC中的任一活性物质，则必须将其与所有活性物质的信号进行比较，以核对是否超出ICH对应的鉴别阈值。如果超出，则应对杂质进行鉴别并将其归因于对应的活性物质信号。如果未超出，则其质量标准限度应参考活性物质设定，从而确保患者摄入/暴露最低。

2. Is it required to c**ider the content of elemental impurities in a veterinary medicinal product? V October 2017

在兽药中是否需要考虑元素杂质的含量？ V 2017年10月

Yes. In accordance with Annex I of Directive 2001/82/EC, all relevant European Pharmacopoeia (Ph. Eur.) monographs, including general monographs and general chapters, are applicable with respect to the quality (pharmaceutical) part of dossiers for non-immunological veterinary medicinal products.

需要。依指令2001/82/EC附录1，所有相关的药典（EP）各论，包括通用各论和通则，均适用于非免疫兽药文件的质量部分（药学部分）。

The Ph. Eur. General Monograph Substances for Pharmaceutical Use* requires that elemental impurities are c**idered in a risk assessment and the Ph. Eur. General Monograph Pharmaceutical Preparati*** requires elemental impurities to be controlled based on a risk assessment for products outside the scope of Ph. Eur. Chapter 5.20 on Elemental Impurities*.

EP通用各论“药用物质”要求在风险评估中考虑元素杂质，EP通用各论“制剂”要求基于风险评估控制不在EP 5.20“元素杂质”范围内药品的元素杂质。

Whilst specific guidance for veterinary medicinal products is currently not available with respect to application of these principles to elemental impurities, the principles elaborated in the ICH guideline Q3D can be adapted and applied to veterinary medicinal products, or other justified approaches used.

虽然兽药特定指南目前尚无关于此元素杂质原则的应用，但ICH Q3D指南中所含原则可用于兽药，否则应采用其它经论证的方法。

* Note: Published in revised form in Ph. Eur. 9.3 in July 2017

注：2017年7月在EP9.3的修订表格中发布。

Impurities - Residual solvents

杂质---残留溶剂

1. Is there a need to take the actual batch results into c**ideration 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“杂质：残留溶剂(CPMP/ICH/283/95 & EMEA/CVMP/511/03)指南注释”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 resp**ibility to select and justify the pilot batch size.

申报人有责任来选择并论证中试批次的批量。

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”.

“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 presentati**. 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，指南未排除分组法的使用。

Certain bulk products are used to produce a series of presentati**, 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 dem**trate 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 presentati**. The division of the bulk batch between the different presentati** 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包装形式的制剂。散装批拆分用于不同包装形式也应进行论证。

*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。

Vancomycin drug products

万古霉素药品1问

1. For vancomycin drug products, how should the potency (IU) be declared in the quantitative and qualitative details in the product information? H October 2017

对于万古霉素药品，其效价（IU）应如何在药品信息中进行详细的定量和定性声明？H 2017年10月

By convention, the strength of vancomycin products is stated on labels and prescribed in terms of mass (that is in milligram [mg]) e.g. 500 mg and 1000 mg for IV administration; 125 mg and 250 mg for oral capsules. The product information also includes the quantitative amount of active substance, expressed in international units (IU), i.e. the potency, as determined by microbiological assay.

按惯例，万古霉素药品的剂量应标签和处方中按质量（即毫克【mg】标示，例如静脉给药500mg和1000mg，口服胶囊125mg和250mg。药品信息也包括原料药的定量数量，按微生物含量测定结果表述为国际单位（IU），即效价。

Historically, the manufacturing formulae and expressi** of declared strength have been based on a nominal potency of 1,000 IU/mg. For example, when a dose of 500 mg vancomycin for IV administration was prescribed, then not less than 500,000 IU of vancomycin would be administered.

历史上，生产配方和所声明剂量表述曾有依名义效价1,000IU/mg的。例如，如果开具处方为一剂500mg万古霉素静脉注射，则需给药不低于500,000IU万古霉素。

The potency specified by the European Pharmacopoeia (Ph. Eur.) monograph for vancomycin hydrochloride has changed since the first publication and currently specifies a minimum potency of 1,050 IU/mg. This change has led to discrepancies in the manufacturing formulae and expression of potency in the product information.

欧洲药典（EP）各论所指定的万古霉素盐酸盐效价自首次发布以来已经进行了修改，目前指定的最低效价为1,050IU/mg。此修订已导致生产配方和药品信息中效价表述的分歧。

To avoid confusion in clinical practice it is essential that the convention of labelling vancomycin products by mass, i.e. mg, is retained. However, to ensure that the established therapeutic dose in terms of IU, e.g. 500,000 IU or 1,000,000 IU, is maintained, the amount (mg) of active substance in the drug product should be adjusted to achieve the declared product strength in terms of IU.

为避免临床使用中的混淆，有必要保持按质量标示万古霉素药品，即mg标示。当然，为确保以IU为单位的既定治疗剂量得到保证，即500,000IU或1,000,000IU，制剂中活性物质的数量（mg）应进行调整以达到所声称的IU剂量。

The manufacturing process and batch formulae should be revised where necessary, to achieve the declared content e.g. 500,000 IU or 1,000,000 IU.

生产工艺和批配方在必要时应进行修订，以达到所声称的含量，如500,000IU或1,000,000IU。

To take account of the convention used for vancomycin products, the product information should be expressed as follows:

考虑到万古霉素药品惯例用法，产品信息应表述如下：

Vancomycin 500mg powder for concentrate for solution for infusion:

万古霉素500mg粉末：

Each vial contains 500mg vancomycin hydrochloride equivalent to 500,000 IU vancomycin.

每个小瓶含有等同于500,000IU万古霉素的500mg万古霉素盐酸盐。

Vancomycin 1000mg powder for concentrate for solution for infusion:

万古霉素1000mg粉末用作注射剂溶液浓缩物：

Each vial contains 1000mg vancomycin hydrochloride equivalent to 1,000,000 IU vancomycin.

每个小瓶含有等同于1,000,000IU万古霉素的1000mg万古霉素盐酸盐。

Vancomycin 125mg capsule:

万古霉素125mg胶囊：

Each capsule contains 125mg vancomycin hydrochloride equivalent to 125,000IU vancomycin.

每粒胶囊含有等同于120,000IU万古霉素的125mg万古霉素盐酸盐。

Vancomycin 250mg capsule:

万古霉素250mg胶囊：

Each capsule contains 250mg vancomycin hydrochloride equivalent to 250,000IU vancomycin.

每粒胶囊含有等同于250,000IU万古霉素的250mg万古霉素盐酸盐。

The product name should remain c**istent with prescribing convention as follows:

药品名称应保持与处方惯例一致，如下：

Vancomycin 500mg powder for concentrate for solution for infusion.

万古霉素500mg粉末用作注射剂溶液浓缩物

Vancomycin 1000mg powder for concentrate for solution for infusion.

万古霉素1000mg粉末用作注射剂溶液浓缩物

Vancomycin 125mg capsule.

万古霉素125mg胶囊

Vancomycin 250mg capsule.

万古霉素250mg胶囊

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) or in change code B.II.b.1 (replacement or addition of a manufacturing site)? H+V October 2015

如何理解变更代码B.II.b.4 （制剂批量变更）或变更代码B.II.b.1（增加或更换一个生产现场）中所指的“复杂生产工艺所生产的”？ H+V 2015年10月

In change code B.II.b.4 在变更代码B.II.b.4中

Complex manufacturing processes is intended to cover situati** 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.

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。

In change code B.II.b.1在变更代码B.II.b.1中

Complex manufacturing processes is, amongst others, intended to cover situati** where the link between quality characteristics and in-vivo performance is not fully understood (e.g. nanomedicines).

复杂生产工艺意在覆盖尚未完全了解质量属性与体内表现之间关联的情形（例如纳米药品）。

In both cases these will be c**idered on a case by case basis.

在此两种情形下，需各案讨论。

Where relevant, if a change is submitted as a type IB variation, it is up to the applicant to provide adequate justification for not c**idering a manufacturing process as a 'complex' one. 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. If unsure, applicants should c**ult the relevant competent authority before submitting the variation.

相关情况下，如果一个变更作为一个IB类变更提交，则由申报人来确定是否提交足够的论证来支持其不认为一个生产工艺是“复杂”的生产工艺。但是，依安全起见条款，应注意如果所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。如果不确定，申报人可以在提交变更之前向相关的药监机构咨询。