EMA 外用制剂质量和等效性指南草案

温馨提示：用电脑观看，效果更加        译者：刘新；校对：潘宪伟

关于复杂制剂，本公众号已推出以下指南或法规 中英文版 供大家参考，链接如下：

指南1：阿昔洛韦（乳膏）指南草案（2016年）

指南2：ANDA申请中递交的外用药物产品的体外渗透（IVPT）研究（2022年10月）

指南3：ANDA申请中递交的外用药物产品的体外释放（IVRT）研究（2022年10月）

指南4：ANDA 申请中递交的外用药物产品的物理化学和结构（Q3）特性（2022年10月）

法规5：USP<3>外用和透皮制剂：产品质量测试（现行版）

法规6：USP<1724> 半固体药物制剂：性能测试（2022年05月讨论稿）

文献7：非肠道缓释制剂体外加速释放测试方法

认真阅读了解上述 “指南1、2、3” 和 “法规6”，相信大家对 IVRT 和 IVPT 的研究会有比较深的体会，包括：IVRT 和 IVPT 研究的目的和区别、方法开发验证、试验设计以及数据统计分析等。

关于外用制剂关键质量属性的控制，本号已推出  指南4 和 USP<3>；本文推出 EMA 关于 “外用制剂质量和等效性”指南，其中涉及的内容包括：外用制剂质量（描述与组成、产品开发、控制策略、稳定性）、等效性、批准后变更、IVRT、IVPT、角质层取样（胶带剥离）等 。

言归正传，下文正式介绍 EMA 指南：

Draft guideline on quality and equivalence of topical products

外用制剂质量和等效性指南草案

18 October 2018 2018年10月18日

CHMP/QWP/708282/2018  人用药品委员会/质量工作组/708282/2018

Committee for Medicinal Products for Human Use (CHMP)  人用药品委员会（CHMP）

Draft Agreed by QWP  草案经质量工作组（QWP）同意	7 June2018
Adoption by CHMP for release forconsultation CHMP采纳并发布咨询意见	18 October2018
Start of publicconsultation 开始征求公众意见	14 December2018
End of consultation (deadline forcomments)  结束征求意见（评论截止日期）	30 June2019
Agreed by QWP  QWP 同意
Adopted by CHMP CHMP采纳
Date for coming intoeffect 生效日期

Annexes I and II of this guideline replace Annex 1 of the Guideline on Quality of Transdermal Patches EMA/CHMP/QWP/608924/2014)

本指南的附件I和II替代了《透皮贴剂质量指南》(EMA/CHMP/QWP/608924/2014) 的附件1。

The guideline replaces Questions and Answer on Guideline: Clinical Investigation of Corticosteroids Intended for Use on The Skin CHMP/EWP/21441/2006.

该指南取代了以下指南中的“问答”：拟用于皮肤的皮质类固醇的临床研究 CHMP / EWP / 21441/2006。

Comments should be provided using this template. The completed  comments form should be sent to [e-mail] 应使用此模板提供评论。完整的评论或建议可发送至 [e-mail]

Keywords 关键词

Medicinal products for cutaneous use, topical products, locally applied locally acting medicinal products, skin permeation, in vitro release, stratum corneum sampling, tape stripping. 皮肤用药物、外用制剂、局部给药发挥局部作用药物、皮肤渗透、体外释放、角质层取样、胶带剥离

Executive summary 概要

The guideline relates to locally applied and locally acting medicinal products for cutaneous use andis also relevant for other medicines e.g. preparations for auricular or ocularuse. Specific guidance isprovided: 

本指南适用于应用于局部皮肤并发挥局部作用药物，也适用于其他药物，例如眼用药物与耳用药物。具体内容包括：

1. On the quality of topical products not covered by otherguidelines.

   其他指南未涵盖的外用制剂的质量。

2. On equivalence testing of topical products in lieu of therapeutic equivalence clinical trials.
   以局部外用药品的等效性试验代替临床治疗等效性试验。
   Existing guidelines state that, for topical products, changes in formulation, dosage form, method of administration or manufacturing process may significantly influence the efficacy and/or safety. Clinical therapeutic equivalence studies are in principle necessary, but other models may be used or developed.

   现有指南指岀，对于外用药物制剂，配方、剂型、给药方法或生产工艺的变化均可能会显著影响有效性和（或）安全性。临床治疗等效性研究在原则上是必要的，但也可以使用或开发其他模型。

   Guidance is provided on other models and studies that may be used to independently determine equivalence with respect to (i) quality, (ii) efficacy, and (iii) safety that taken together support a claim of therapeutic equivalence, when the method of administration is the same and risks of inequivalence to the patient are minimal.
   当治疗方法相同且对患者的不等效性风险最小时，这一指南也可在其他模型和研究中提供指导。这些模型和研究可独立用于确定与(i)质量、(ii)功效和(iii)安全性相关的等效性以及上述三方面总结而成的治疗等效性。
   Guidance is provided on situations where therapeutic equivalence clinical trials will be expected.
   Scope, limitations and acceptance criteria of this approach are described.
   The guidance should be used to develop and justify topical product-specific equivalence protocols.
   这一指南应被用于临床治疗等效性试验希望被实施的情况下。
   描述了这种方法的范围、局限性和接收标准。

   这一指南应被用于开发和解释局部外用药品专用的等效性草案。

In addition, equivalence test protocols are providedfor: 此外，还提供了以下等效性性试验方案：

• in vitro release 体外释放
• in vitro human skinpermeation 体外人体皮肤渗透
• in vivo stratum corneum sampling (tapestripping) 体内角质层取样（胶带剥离）

• in vivo vasoconstriction assay forcorticosteroids 皮质类固醇的体内血管收缩试验

The quality guidance applies to new marketing authorisation applications and post approval changes.

The equivalence guidance is applicable to certain cases of demonstration of equivalence of a new topical medicinal product with an existing medicinal product.

质量指南适用于新的上市许可申请和批准后变更。

等效性指南适用于特定案例中新的局部外用药品与现有的局部外用药品之间等效性论证的情况。

1、Introduction and Background 绪论和背景

The diversity of topical products is very wide given the complex nature of skin, the range ofconditions to be treated and the variety of patients and their needs. The guideline cannot present a single procedure to address such diversity, instead general recommendations are provided. These can be applied to any given product on a case-by-case basis. The guideline elaborates existing regulatory guidance and is informed by current scientific knowledge.

由于皮肤的复杂性、待治疗的病症范围、以及患者与其需求的多样性，局部外用药品具有非常广泛的多样性。该指南并不是提出一个单一的程序来解决这种多样性，而是提供一般性建议。这些建议可以适用于逐案分析基础上的任何给定药品。该指南阐述了现有的监管指南，并通过现有的科学知识进行告知。

1.1 Quality of Topical Products 外用制剂质量

Guidance on the quality of topical products, not covered by other general quality guidelines, is provided. The indication, target population and site of action need to be understood to enable informed choices with respect to pharmaceutical form, composition, and method of administration.

提供了其他一般性质量指南中未涉及的关于局部外用药品的指南。需要先了解药物的适应症、目标人群和作用部位，从而可以在药物剂型、组成和给药方法上做出最明智的选择。

The principal function(s) of the drug product need to be understood. This may simply be administration of the active substance to the surface of the skin. In many cases, bioavailability is increasedby including in the product formulation excipients that change the thermodynamic activity of the active substance, e.g. by solubilisation and supersaturation, that modify active substance diffusion, or disrupt the physiological barrier-penetration enhancers. Occlusion and the vehicle itself, e.g. moisturisers and emollients, may influence the condition to be treated.

需要了解药物产品的主要功能。这可以通过简单地将活性物质施加到皮肤表面。在许多情况下，可以通过在药物中加入能够改变活性物质的热力学性质的辅料增加药物的生物利用度，例如通过増溶和过饱和来改变活性物质的扩散，或通过促渗剂破坏生理屏障。皮肤的闭塞或药物载体本身，如保湿剂和润滑剂，可能影响待治疗的状态。

The quality target product profile should consider patient acceptability, ease of removal from the container and administration, bulk aesthetic properties such as appearance, spreadability, feel, the microstructure/physical properties, evaporation of volatile excipients, and occlusion if appropriate. These elements need to be characterised and, when necessary, controlled as critical quality attributes.

The product formulation should be developed using sound prior knowledge, established scientific rationale and evidence. The resultant quality characteristics should be determined from multiple batches representative of the product to be marketed.

产品目标质量概况应考虑患者的可接受性、是否易于从容器中转移并给药，以及整体美观性，如外观、铺展性、触感、微观结构/物理性质、挥发性辅料的蒸发和适当的遮挡等，如适用。这些因素需要被表征，并且在必要时被作为关键质量属性进行控制。

应采用良好的先验知识，已建立的科学理论依据和证据来开发药品配方。所产生的质量特性应从可代表上市产品的多个批次中确定。

A robust manufacturing process is required to assure consistent product quality through its marketing life-cycle. Marketed products should have the same quality as those batches for which satisfactory evidence of efficacy and safety or equivalence has been demonstrated.

Stability is shown when batches at release and at the end of their shelf life have equivalent physical, chemical and microbiological quality characteristics, and includes in vitro performance if appropriate.

The control strategy should ensure that the product is fit for its intended purpose and complies with relevant pharmacopoeial standards. Inadequate product development or quality cannot be justifiedby reference to clinical trials.

需要一个稳健的生产工艺，以确保药品在整个上市货架期内质量恒定。上市产品应与已证明有令人满意的有效性和安全性或等效性证据的批次具有相同的质量。

应通过稳定性研究证明，各批次产品在货架期开始和结束时具有相同的物理、化学和微生物质量特性，且在特定情况情况下，具有相同的体外性能特征。

控制策略应确保产品符合其预期目的，并符合相关药典标准。不能通过参考临床试验来证明产品的开发或质量不足。

1.2 Equivalence of Topical Products 外用制剂等效性

Demonstration of equivalence of a new topical medicinal product with an existing medicinal product may be required in the context of marketing authorisation applications relying on the dossier of an existing medicinal product, and in case of product changes during pharmaceutical development or post-approval, which could have a potentially significant impact on the safety, quality or efficacy ofthe medicinal product.

在一个新的局部外用药品的上市许可申请依赖于一个已上市药品的档案的情况下，或者在药物的开发或批准后发生的可能对药品的安全性、质量或有效性产生重大影响的情况下，需要对这一新的局部外用药品的等效性进行论证。

Furthermore in the case of applications which rely on literature to demonstrate the safety and efficacy of the medicinal product the relevance of the literature should be supported by equivalence bridging data between the test product and the product described in the literature. This is because the effect of quality differences in formulation, manufacture and method of administration is not predictable.

此外，在依赖于文献来证明药物产品的安全性和有效性的应用的情况下，文献的相关性应该通过药物产品与文献中描述的药品之间的等价性桥接数据来支持。这是因为在配方、生产和给药方法中质量差异的影响是不可预则的。

Existing guidelines state that, for topical products, changes in formulation, dosage form, method of administration or manufacturing process may significantly influence the efficacy and/or safety. Clinical therapeutic equivalence studies are in principle necessary, but other models may be used or developed. This guideline provides further detail on how in vitro and in vivo models may substitute for clinical data for the purpose of establishing therapeutic equivalence.

现有指南指岀，对于外用药物制剂，配方、剂型、给药方法或生产工艺的变化可能会显著影响有效性和（或）安全性。临床治疗等效性研究在原则上是必要的，但也可以使用或开发其他模型。本指南提供了关于体外和体内模型如何替代临床数据以建立治疗等效性的进一步细节。

Demonstration of equivalence with respect to quality is normally not sufficient to predict therapeutic equivalence. In the case of solutions, e.g. cutaneous solutions, a waiver of therapeutice quivalence data may be accepted based on quality equivalence alone, when the method of administration is the same.

对质量的等效性的论证通常不足以预测治疗等效性。但对于液体制剂（如皮肤用溶液）来说，当给药方法相同时，仅基于质量等效性数据是可以通过治疗等效性豁免的。

Equivalence with respect to quality can, where appropriate, be established using comparative data with the comparator medicinal product (i.e. existing medicinal product) comprising pharmaceutical form; qualitative and quantitative composition; microstructure/physical properties; product performance; administration. This is termed “extended pharmaceutical equivalence” for the purpose of this guideline.

如适用，质量的等效性可以通过与参照药物产品（即已上市药物制剂）的对比数据建立，包括：药物剂型、定性和定量组成、显微结构/物理性质、产品性能、给药方式。在本指南中，这被称为“扩展的药物等效性”。

Equivalence with respect to efficacy requires comparative permeation kinetic and, where possible, pharmacodynamic studies with the comparator medicinal product. Suitable permeation kinetic methods are in vitro human skin permeation and in vivo stratum corneum (S.C.) sampling (tape stripping) of  human volunteers and pharmacokinetic bioequivalence. Suitable pharmacodynamic studies includethe in vivo vasoconstriction assay for corticosteroids and in vivo microbial decolonisation studiesfor antiseptics, undertaken on human volunteers. If permeation kinetics and pharmacodynamic studiesare not applicable or are considered insufficiently predictive of clinical response, clinical efficacy data will normally be required.

关于药效的等效性需要参比其渗透动力学，并在可能的情况下，进行与参照药物产品的药效学对比研究。合适的渗透动力学方法是体外人体皮肤渗透和对人类志愿者活体角质层（S.C.）采样（胶带剥离）以及体内药代动力学生物等效性实验。合适的药效学研究包括对人类志愿者进行的体内皮质类固醇血管收缩试验和针对防腐剂或杀菌剂的体内微生物脱色实验。如果渗透动力学和药效学研究不适用或被认为不足以预测临床反应，则通常需要临床疗效数据。

Equivalence with respect to safety and local tolerance may be inferred from knowledge of the active substance and the choice of well-established excipients. Biowaivers from permeation kinetic or pharmacodynamic equivalence studies are described for simple formulations, i.e. in cases where demonstration of equivalence with respect to quality alone would be sufficient. The general guidance should be used to develop product-specific protocols to demonstrate equivalence, facilitated by obtaining scientific advice, as necessary.

关于安全性和局部耐受性的等效性可以从活性物质的知识和已完善的辅料的选择中推断岀来。针对简单配方，从渗透动力学或药效等效性研究中可获得生物等效豁免，即对质量等效性进行充分论证就足够。一般性指导可以被应用于开发药物产品的特定技术要求以证明其等价性，必要时可寻求其他科学建议。

2、Scope 范围

The guideline applies to locally applied and locally acting medicinal products for cutaneous use and may also be relevant for other medicines, e.g. preparations for auricular or ocular use.

Guidance is provided on the quality of topical products, containing chemical active substance(s), not covered by other general quality guidelines and on equivalence testing of topical products to supporta claim of therapeutic equivalence with comparator medicinal products, in lieu of therapeutic equivalence clinical trials.

The quality guidance applies to new marketing authorisation applications and post approval changes. The equivalence guidance is applicable to certain cases of demonstration of equivalence of a new topical medicinal product with an existing medicinal product.

本指南适用于应用于局部皮肤并发挥局部作用药物，也适用于其他药物，例如眼用药物与耳用药物。

指南适用于局部外用药品的质量，包括其他—般性质量准则中未涉及的化学原料药，和用于支持局部外用药品与参照药品的治疗等效性试验，以替代临床治疗等效性试验。

质量指南适用于新的上市许可申请和批准后变更。等效性指南适用于特定案例中新的局部外用药品与现有的局部外用药品之间等效性论证的情况。

The equivalence guidance does not apply:

• To biological medicinal products, see guidelines on similar biological medicinal products.

• To herbal medicinal products.

• When equivalence with respect to efficacy is demonstrated by therapeutic equivalence clinical trials.

• When the pharmaceutical form or qualitative and quantitative composition of the test and comparator products are not the same or equivalent (see section 5.2.1).

等效性指南不适用于：

• 生物医药产品，参见生物类似药产品指南

• 中草药产品

• 当通过临床治疗等效性试验来证明疗效的等效性时

• 当试验中药物剂型或定性和定量组成与参照药品不相同或不等同时（见5.2.1节）。

3、Legal basis 法律依据

This guideline should be read in conjunction with Directive 2001/83/EC and relevant Pharmacopoeial monographs and Guidelines.

本指南应结合指令2001/83/EC及相关药典通则和指南阅读。

Quality Guidelines 质量指南

• Ph. Eur. Dosage Form Monographs: Liquid Preparations for Cutaneous Application; Powders for Cutaneous Application; Semi-Solid Preparations for Cutaneous Application; Ear Preparations; Eye Preparations; Pressurised Pharmaceutical Preparations.

  欧洲药典，剂型通则：皮肤用液体制剂、 皮肤用粉末制剂、 皮肤用半固体制剂、耳用制剂、眼用制剂、加压药物制剂。

• Pharmaceutical Development, ICH Q8 (R2), EMEA/CHMP/167068/2004;

  药物开发，ICH Q8(R2)，EMEA/CHMP/167068/2004；

• Manufacture of the Finished Dosage Form, EMA/CHMP/QWP/245074/2015;

  制剂成品生产，EMA/CHMP/QWP/245074/2015；

• Guideline on Process Validation for finished products. Information and data to be provided in Regulatory Submissions EMA/ CHMP/ CVMP/ QWP/ BWP/ 70278/ 2012-Rev1;

  药物制剂工艺验证的指南；监督意见书EMA/ CHMP/ CVMP/ QWP/ BWP/ 70278/ 2012-Rev1中提供的信息与数据；

• Excipients in the Dossier for Application for Marketing Authorisation of a Medicinal Product CHMP/QWP/396951/06;

  医药产品上市许可申报资料中的辅料，CHMP/QWP/396951/06；

• Q6A Specifications: Test Procedures and Acceptance Criteria for New Active substances and New Drug Products: Chemical Substances CPMP/ICH/ 367/96-ICH Q6A;

  Q6A质量标准：新原料药和新药制剂的检测方法和认可限度：化学物质，CPMP/ICH/367/96-ICH；

• Q2(R1) Validation of Analytical Procedures: Text and Methodology, CPMP/ICH/381/95 - ICH Q2 208 (R1);

  Q2(R1)分析方法验证：正文和方法学，CPMP/ICH/381/95 - ICH Q2 (R1)；

• Stability Testing of New Active substances and Drug Products (ICH Q1A (R2)), CPMP/ICH/2736/99-ICH Q1A (R2);

  新原料药和制剂的稳定性试验(ICH Q1A (R2))，CPMP/ICH/2736/99-ICH Q1A (R2)；

• Stability Testing of Existing Active Ingredients and Related Finished Products, CPMP/QWP/122/02 Rev. 1 corr.;

  现有活性成分及相关药物制剂的稳定性试验，CPMP/QWP/122/02 Rev. 1 corr.；

Equivalence Guidelines 等效性指南

• Note for Guidance on the Clinical Requirements for Locally Applied, Locally Acting Products containing Known Constituents CPMP/EWP/239/95 Final

  含已知成分的局部给药、局部起效制剂的临床要求指南的注解，CPMP/EWP/239/95 Final

• Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/ Corr

  生物等效性研究指南，CPMP/EWP/QWP/1401/98 Rev. 1/ Corr
• Guideline on bioanalytical method validation EMEA/ CHMP/ EWP/ 192217/ 2009 Rev. 1 Corr. 2
  生物分析方法验证指南，EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2
• General Considerations for Clinical Trials (ICH topic E8, CPMP/ICH/291/95)
  临床试验的一般考虑（ICH topic E8，CPMP/ICH/291/95）
• Guideline for Good Clinical Practice (ICH E6 (R1), CPMP/ICH/135/95)
  药物临床试验管理规范 (ICH E6 (R1), CPMP/ICH/135/95)
• Statistical Principles for Clinical Trials (ICH E9, CPMP/ICH/363/96)
  临床试验的统计学原则 (ICH E9, CPMP/ICH/363/96)
• Reflection Paper on advice to Applicants/Sponsors/CROs of Bioequivalence Studies 222 EMEA/INS/GCP/468975/2007
  关于生物等效性研究中申请者/赞助商/合作研究机构的建议的反馈文件， EMEA/INS/GCP/468975/2007
• Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development Draft (EMA/CHMP/138502/2017). Although a draft document, this paper provides current regulatory considerations regarding statistical aspects for the comparative assessment of quality attributes.

  关于药物开发中质量属性的对比评估的统计方法的反馈文件Draft (EMA/CHMP/138502/2017)。尽管只是草案，不过该文提供了有关质量属性比较评估的统计方面的当前监管考虑。

Equivalence trials conducted using human volunteers in the EU/EEA should be carried out in accordance with Directive 2001/20/EC.

In vitro human skin permeation kinetic equivalence trials, which are pivotal to product approval, are subject to National Competent Authority inspection and should also be carried out in accordance with Directive 2001/20/EC.

在 EU/EEA中使用人类志愿者进行的等效性试验应按照指令2001/20/EC进行。

体外皮肤渗透动力学等效性试验是产品认证的关键，需经国家主管部门检查，并应按照指令2001/20/EC进行。

Trials conducted outside of the Union and intended for use in a Marketing Authorisation Applicationin the EU/EEA should be conducted to the standards set out in Annex I of the community code,Directive 2001/83/EC.

Companies may apply for CHMP and NCA Scientific Advice for specific queries not covered by existing guidelines.

在欧盟以外进行的试验并准备将其用于 EU/EEA 的上市许可申请中的，应当按照指令 2001/83/EC 共同守则的附录一中制定的标准进行。

公司可以针对现行指南中未涉及特定事项向 CHMP 和 NCA 进行科学咨询。

4 Quality of Topical Products 外用制剂质量

4.1 Description and composition of the drug product 药品描述与组成

The drug product composition and excipient functions should be described indetail. The names of excipients should be specific and distinct. The recommended international non-proprietary name (INN or INN modified (INNM)) accompanied by the salt if relevant, or the European Pharmacopoeia name, or their usual common name, or the chemical name, otherwise theproposed name should be justified. The name should include the grade or brand (commercial) name, if required for consistent manufacturability and product quality.

应详细描述药物的组成成分和辅料的功能。辅料的名称应该是具体且唯一的。推荐使用国际非专利名称(INN或INN modifie(INNM))( 如果与盐有关应加上盐名称)，或欧洲药典名称，或其常用的通用名，或化学名称，若非上述名称则应证明拟定名称合理性。为了确保达到一致的工业生产能力和产品质量，应包括级别或品牌（商业）名称。

It should be explicitly stated when an excipient contributes in a multifunctional way to the designand purpose of the drug product, e.g. propylene glycol acting as a humectant, penetration enhancer and solubiliser.

The applied dose, in terms of mass of active substance per unit area, based on the SmPC instructions for use, and maximum daily dose, should be stated.

The primary packaging and, if necessary, secondary packaging or other materials or components required for reasons of stability or administration, should be described.

根据药物产品的设计和目的，对于具有多种功能的辅料，应明确说明，例如：丙二醇可同时作为保湿剂、渗透促进剂和増溶剂。

应基于 SmPC（Summary of Product Characteristics 产品特性概要）中的使用说明和最大日用量，对单位面积上使用的活性物质的量进行说明。

应当对初级包装，必要时包括二级包装，或其他影响药品稳定性或给药的材料或成分进行说明。

4.2 Pharmaceuticaldevelopment 药物开发

The pharmaceutical development component of the dossier should form a sound scientific basis forthe topical product for its intended use, providing a clear narrative of product development, and include all relevant data.

应在申报资料的药物开发部分，详细的描述外用产品工艺开发的科学合理性，以及所有相关的数据。

4.2.1 Therapeutic objectives and topical productdesign 治疗目标和外用制剂设计

The Quality Target Product Profile (QTPP) should identify the intended therapeutic objectivesand purpose of the drug product and explain how these objectives are achieved by the product design.

A patient-focussed approach should consider: indication and disease state of skin; age appropriateness, patient acceptability, administration and usability, administration site; efficacyin terms of product strength and posology, solute status of the active substance, and bioavailability and/or penetration enhancement; emolliency; safety in terms of ingredient toxicity, impurities, microbial quality; and quality in terms of physical and chemical stability, critical quality attributesand compliance with pharmacopoeial and regulatory requirements.

根据目标产品质量概况（QTPP），确定产品的预期治疗目标和目的，并解释如何通过产品设计实现这些目标的。

在患者方面，应考虑的内容包括：皮肤的适应症和病情；年龄适宜性、患者可接受性、给药方式和可行性、给药部位；功效（产品规格和剂量学、原料药的溶质状态、生物利用度和/或渗透增强）；润肤剂；安全性（组分的毒性、杂质、微生物）；质量（物理和化学稳定性、关键质量属性、药典和法规要求的符合性）。

The local site of action should be identified: skin surface; skin interior (stratum corneum, epidermisor dermis); or subcutaneous, adjacent tissues below the skin (regional).

The means and permeation kinetics by which the active substance reaches the local site of action should be explained. As applicable, this should address administration, the solution state of the active substance, dissolution, release from the product and diffusion through human skin.

应明确作用部位：皮肤表面；皮肤内部（角质层、表皮或真皮层）；或皮下和皮下邻近组织（区域）。

应说明活性物质到达作用部位的方式和渗透动力学。如适用，通过这些内容清楚的说明给药方式、活性物质的溶解状态、药物的溶解/释放和通过人体皮肤的扩散情况。

In some cases, e.g. skin antiseptic cutaneous solutions, consideration of the method of administration only is appropriate. In others, e.g. NSAID creams, all elements should beconsidered.

The inclusion of excipients to enhance bioavailability and for emolliency should be explainedand justified. The choice of formulation, e.g. aqueous gel, cream, ointment, should be explainedand justified.

If applicable, the proportionality of different strengths should be discussed.

Cross references to relevant non-clinical and clinical sections of the dossier should be provided, as appropriate.

在某些情况下，例如皮肤杀菌或抑菌溶液，可以仅考虑给药方式。但其他情况，例如非甾体抗炎药乳膏，就必须考察以上所有的因素。

对可提高生物利用度和润肤性的辅料的加入应作出解释并证明其合理性。对配方的选择，例如为何选择凝胶、乳膏和软膏，应作出解释并证明其合理性。

如条件允许，应对不同规格的配比和用量进行讨论。

如适用，应在申报资料中，递交非临床和临床研究的交叉比对信息。

4.2.2 Active substance (P.2.1.1)  原料药

Active substance physicochemical properties that are important for bioavailability, the formulation, performance and stability of the drug product should be identified and discussed. Such properties may include molecular weight, partition coefficient, melting point (boiling point if applicable), pKa, sensitivity to light, air or moisture, degradation pathway, solubility and pH effects, as well as particle size and polymorphism, if the active substance is present in the solid state in the drug product. Critical quality attributes should be identified and controlled in the Drug Substance Specification.

原料药的物理化学性质对药物的生物利用度、配方、性能和稳定性具有重要作用，应进行识别和讨论。如果原料药以固态形式存在于药品中，这些特性可能包括：分子量、分配系数、熔点（沸点，如适用）、pKa、对光、空气或水分的敏感性、降解途径、溶解度和pH依赖性，以及粒径和多晶型性。在原料药质量标准中应识别和控制这些关键质量属性。

4.2.3 Excipients (P.2.1.2)  辅料

Excipients used in topical products often show batch and source variation e.g. homologue composition of hydrocarbon chains, the degree of unsaturation, molecular weight, polymorphism. This in turn may lead to unforeseen variability in the product rheological properties, microstructure/physicalproperties, crystallisation of the active substance or other ingredient, stability, or bioavailability.

Batch and source variation of excipients should be considered and addressed during development. The choice and quantity of each excipient, and relevant critical quality attributes (CQAs), should be discussed and justified in relation to its function(s), including an emollient function, if applicable.

在局部外用制剂中使用的辅料常常表现岀批间差异和来源差异，例如烃链同系物组成、不饱和度、分子量、多态性。这反过来可能导致产品流变特性、微观结构/物理性质、原料药或其他成分的晶型、稳定性或生物利用度的不可预见的变化。

在开发过程中，应考虑并阐述辅料的批间差异和来源差异。如适用，应根据辅料的功能，包括润肤作用，对每个辅料的选择、用量和相关的关键质量属性（CQAs）进行讨论，说明其合理性。

The grade of the excipient should be specified, when active substance bioavailability, product manufacturability and / or quality is altered if other grades are used.

CQAs of the excipients should be controlled in their specifications and their limits justified (P.4.).

Detailed information on those excipients which might have an influence on the active substance permeation and bioavailability, e.g. solubiliser, penetration enhancer, should be provided, including their ability to provide their intended function and to perform throughout the intended drug product shelf life.

当使用其它级别或型号的辅料会改变活性物质的生物利用度、产品可制造性或质量时，应明确该辅料的级别或型号。

质量标准中应控制辅料的关键质量属性（CQAs），并拟定合理的控制限度。

应提供可能对活性物质的渗透性和生物利用度有影响的辅料的详细信息，例如增溶剂/渗透促进剂，包括它们提供预期功能的能力和在整个药品货架期期间发挥作用的能力。

In the case of excipients presented as a mixture of compounds, details of the composition shouldbe provided in qualitative and quantitative terms and characterised, including rheological properties if appropriate. For novel excipients, full details of manufacture, characterisation and controls with cross referencesto supporting safety data should be provided. For excipients also used in cosmetics, data showing compliance with Regulation 1223/2009 on osmetic Products, would be supportive.

Processing aids should be identified and described.

如果辅料是数种化合物的混合物，应提供其组分的定性和定量信息，如适用，包括流变学信息。对于新型辅料，应提供制造、表征和质控的完整细节信息，并交叉引用支持的安全数据。对于同时也在化妆品中使用的辅料，可以提供符合化妆品法规1223/2009的数据。

应明确和描述加工助剂信息。

Some excipients traditionally used in topical products may cause irritation or sensitivity reactionsand should if possible be avoided, or minimised if unavoidable, in the development of a new product. For reference, see the guideline on “Excipients in the label and package leaflet of medicinal products for human use”.

一些传统上用于局部外用药物的辅料可能引起刺激或过敏反应，如可能的话，在新药的开发中应避免或尽可能的减少使用。作为参考，请参阅“人用药品说明书和包装标签中辅料”指南。

4.2.4 Formulation development 配方开发

The development of the drug product should be described with respect to the defined QTPP, employing suitable tests to characterise and control CQAs, factors affecting ease of administration and duration of use, and product performance e.g. dissolution, in vitro drug release and if appropriate in vitro skin permeation. Evidence of the suitability of the test methods and acceptance criteria used to assess the product should be provided (see also Annexes I and II).

应从以下几个方面，对药品的开发过程进行描述：已定义的目标产品质量概况（QTPP）；采用合适的测试来表征和控制关键质量属性（CQAs）；影响易使用性和持续时间的因素；和产品性能，例如溶解度、体外药物释放，如适用，体外皮肤渗透实验。应提供用于评估产品的测试方法和接受标准的适用性的证据（另见附录 I 和 II）。

The presentation of the active substance in the drug product e.g. as a solute or in a suspension, and the degree of saturation are CQAs, which should be justified in terms of product efficacy and safety, supported by evidence of how the target state is achieved during manufacture and maintained during storage.

The risks of precipitation / particle growth / change in crystal habit, or changes to other active substance characteristics likely to affect bioavailability, arising from changes in temperature and on storage should be assessed and appropriate tests included in the stability studies.

药品中原料药的存在方式（例如溶解还是混悬）和饱和程度是其关键质量属性（CQAs），应通过对产品的有效性和安全性的影响，对这些属性进行论证，并提供在生产过程中如何达到其目标状态和在储存期间如何保持原始目标状态的证据来佐证。

在稳定性研究中应进行适当的测试，以评估由温度和储存条件变化引起的晶体沉降、颗粒生长、结晶习性变化，或其他可能影响生物利用度的原料药特性的变化风险。

The delivery of the active substance to the site of action needs to be discussed. Solvents and enhancers can be used to aid transport through the different layers of the skin. Ointments may function to occlude the skin and thus facilitate permeation. The concentration gradient of the active substance between the drug product and the site of action is a driving force for delivery and achieving a saturated status of the active substance in the drug product can therefore be crucial.

应讨论活性成分向皮肤作用部位的递送情况。溶剂和透皮吸收促进剂可用于帮助活性物质运送至不同的皮肤层次。软膏可以封闭皮肤，从而起到促进药物透皮渗透和吸收的作用。使用的药物制剂产品和皮肤作用部位之间的浓度梯度是经皮吸收递送的驱动力，因此实现药物产品中活性物质的饱和状态是重要的关键性因素。

Patient acceptability and usability of the drug product should be considered e.g. ease of administration, spreadability, which can be of importance for dose per surface area, and feel (dry or greasy).

Where appropriate, the type of the pharmaceutical form should be identified e.g. hydrophobic ointment (hydrocarbon base, absorption base), water emulsifying ointment, hydrophilic ointment.

Product microstructure/physical properties, which may be complex for semisolid products, and mechanisms responsible for its formation during processing, should be understood e.g. in terms of excipient interactions, batch variation and scale-up, so that the manufacturing process can be optimised to give a consistent quality product.

应考虑患者的可接受性以及药物产品的易使用性，例如是否方便给药、是否易于涂布，这对于每单位表面积的剂量和肤感（干燥或油腻）都是非常重要的。

如适用，应该明确药物的具体剂型，如疏水性软膏（全油相基质，吸收型基质）、乳膏、亲水软膏。

对于半固体制剂，其微观结构/物理性质可能比较复杂，应充分了解其微观结构/物理性质及其形成机制，例如辅料的相互作用、批间差异和批量放大，从而促进生产工艺的优化，获得质量一致的产品。

Transformation of the topical product on administration should be discussed. Particularly in those cases where evaporation of volatile solvents and excipients, or other phenomena, are necessary for effective drug delivery to the site of action.

The clinical trial formulation and the batches used in the comparative studies should be described in detail. Any differences in formulation and manufacturing processes between pivotal clinical batches and the drug product to be marketed should be justified. Results from comparative extended pharmaceutical equivalence studies, in vitro studies or in vivo studies should be provided.

应讨论局部外用制剂的给药方式带来的药物转变的问题，特别是挥发性溶剂或辅料的蒸发，或其他现象，可能影响药物是否能有效地递送到作用部位。

应详细描述临床试验配方和在对比研究中使用的批次。关键临床试验批次和待上市药品在配方和生产过程中的任何差异都应该进行合理性说明。应提供体外或体内的任何扩展和延伸的制剂学等效性研究的结果。

When the formulation composition is decided, up-scaling of the manufacturing process will start and the critical process parameters should be identified and controlled. During this period, it is reasonable to expect that necessary adjustments will be made to reach and optimise full-scale production. These adjustments might be changes in composition, manufacturing processes, equipment or manufacturing site. In some cases, the potential impact of these adjustments on the functions of the drug product, e.g. with respect to bioavailability and usability, should be assessed.

当确定配方组成，在即将开展的放大生产中，应确定需控制的关键工艺参数。在这一阶段，为达成和全面优化生产工艺，进行必要的调整是合理的。这些调整可能包括组成、生产工艺、设备或生产场所的变化。在某些情况下，应评估这些调整对药物产品功能的潜在影响，例如对药物的生物利用度和可用性的影响。

Evidence of compliance with Ph. Eur. requirements for the topical dosage form should be provided. The relationship between the QTPP, critical quality attributes and the drug product specification should be fully discussed.

Where the drug product vehicle contains flammable volatile solvents, e.g. isopropyl alcohol and ethanol, the flash point should be determined in compliance with relevant ISO standards and appropriate warnings included in the product information (see also section 4.2.6).

应提供证据，说明外用制剂符合欧洲药典（Ph. Eur.）的要求。应充分讨论目标产品质量概况（QTPP）、关键质量属性与药品质量标准之间的关系。

当药品载体含有易燃挥发性溶剂时，如异丙醇和乙醇，应根据相关ISO标准和产品信息中包含的相关警告确定其闪点或燃点（参见4.2.6节）。

Drug products with a paraffin vehicle are not in themselves flammable, but when clothing, bedding and dressings become impregnated with these, the material acts as a wick and the paraffin acts as an accelerant when ignited. The patient risks should be assessed, and appropriate warnings included in the product information (see also section 4.2.6).

使用石蜡作为基质的产品本身并不具有易燃性，但是当衣物、床上用品和敷料被其浸渍时会起到灯芯的作用，并且石蜡在着火时可以起到助燃的作用。应评估其对患者带来的风险，并在产品信息中添加适当的警告（参见4.2.6节）。

4.2.5 Product characterisation  产品特性表征

A detailed product characterisation should be developed to facilitate life-cycle management and, where applicable, to support a claim of equivalence to original or comparator medicinal products. Characterisation data should be derived from a representative number of batches taking account of the likely variation seen with disperse systems compared with simple solutions, and should not be less than three batches. To enable statistical evaluation, the number of samples should be representative, with at least 12 units per batch for each experiment. Between batch variability e.g. due to batch size, date of manufacture and period of storage, should also be taken into account.

应制定详细的产品特性表征方法，以便于药品生命周期管理，条件允许的情况下，可用于支持与原研或参照制剂产品的等效性论证。特性表征数据应来自具有代表性的批次，考虑到分散系统相比于简单溶液具有更大的可变性，选择的批次数目不应少于三个批次。为了进行统计评估，样品的数量应足够多以具备代表性，每个实验中每批至少要有12个样本。也应考虑到由于批量大小、生产日期和储存期限等因素导致的批间差异。

Pharmaceutical Form 药物剂型

The diverse topical dosage forms include cutaneous solutions, foams and sprays, shampoos, ointments (hydrocarbon, absorption, water-removable and water-soluble bases), creams (oil in water or water in oil), gels, pastes, poultices, medicated plasters and cutaneous patches.

Evidence should be provided that characterises the pharmaceutical form in terms of the solution state of the active substance, disperse and immiscible phases and dosage form type.

外用制剂的剂型包括皮肤用溶液、泡沫剂和喷雾剂、洗发剂、软膏（油膏、吸收型基质、水可洗去基质和水溶性基质）、乳膏（水包油型或油包水型）、凝胶、糊剂、膏剂、硬膏剂和皮肤贴剂。

应提供可证明活性物质的溶解状态、分散和不混溶相和制剂类型等药物剂型的证据。

For example：

Active substance in solution, single phase vehicle: e.g. cutaneous solution, single phase gel or ointment.

Active substance in suspension, single phase: e.g. cutaneous suspension.

Active substance in solution, two phase vehicle: e.g. o/w cream, active substance in solution in oily phase.

Active substance in suspension, two phase vehicle: e.g. o/w cream, active substance insoluble in either phase in suspension.

例如：

溶液中的活性物质，单相体系，如：皮肤用溶液剂、单相的凝胶剂或软膏剂。

混悬剂中的活性物质，单相体系，如：皮肤用混悬剂。

溶液中的活性物质，两相体系，如水包油型（o/w）乳膏，活性药物在油相中或在水相中。

混悬剂中的活性物质，两相体系，如水包油型（o/w）乳膏，活性物质不溶于其中的任一相。

For suspensions, additional characterisation in terms of active substance particle size distribution and polymorphic form, including photomicrographs, is required.

For immiscible phase formulations, additional characterisation in terms of globule size distribution and appearance, including photomicrographs, is required.

Particle size analysis by diverse methodologies should be employed, if possible e.g. laser light diffraction, Raman chemical imaging, as well as microscopy.

对于混悬剂，需提供活性物质粒径分布和多晶型的研究结果，包括显微照片。

对于互不混溶的配方制剂，需额外提供液滴的尺寸分布和外观方面的表征，包括显微照片。

如果可能的话，可以采用激光衍射、拉曼化学成像和显微镜等不同方法进行粒度分析。

Appearance 外观

This should be characterised visually and with microphotography - particularly for dispersed systems.

应通过视觉和显微照相来表征 - 特别是对于分散系统。

Microstructure / Physical Properties 微观结构/物理性质

Evidence should be provided to characterise the microstructure/physical properties in terms of bulk physical CQAs that influence bioavailability, usability or indicate variability in the manufacturing process and product instability.

e.g. for solutions and suspensions – pH, buffering capacity, viscosity, density, surface tension, osmolality.

e.g. for semisolid formulations – pH, density, rheological behaviour.

应提供证据来表征药物的微观结构/物理性质，包括影响药物的生物利用度、易用性，或指示生产工艺的变异和产品不稳定的物理CQAs（关键质量属性）。

例如，对于溶液和悬浮液 — pH值、缓冲容量、粘度、密度、表面张力、渗透压。

例如，对于半固体制剂 — pH、密度、流变行为。

Non-Newtonian rheological behaviour should be characterised using an appropriate absolute rheometer and include:

• A complete flow curve of shear stress (or viscosity) versus shear rate, comprising multiple data points across the range of increasing and decreasing shear rates so that any linear portionsof the up-curves or down-curves are clearly identified. The resulting curves shouldbe characterised by fitting to (modified) power law equations so that numerical data canbe produced.
• Yield stress and creep testing
• The linear viscoelastic response (storage and loss modulus vs. frequency)

非牛顿流变行为应使用合适的绝对流变仪进行表征，包括：

• 剪切应力（或粘度）与剪切速率的完整流动曲线，包括在剪切速率的增加和减小范围内的多个数据点，以便清楚地识别出曲线上升或曲线下降的任何线性部分。所得曲线应通过拟合（修正的）幂定律方程来表征，以便可以生成数值数据；
• 屈服应力和蠕变试验；

• 线性粘弹性响应（存储损耗模量与频率）。

Rheograms should be provided and the product’s behaviour classified according to shear and time effects e.g. pseudoplastic, dilatant, thixotropic, and characterised using appropriate metrics. For example: viscosities at specified shear rates across the rheograms (e.g. η100); plastic flow yield stress values; thixotropic relative area (SR); viscoelastic storage and loss moduli (G’ and G”), apparent viscosity, loss tangent (tan δ).

Appropriate characterisation of rheological properties may enable the identification or design of a simpler test to be used in the Finished Product Specification.

应提供根据剪切和时间效应分类的流变图和药品行为，例如假塑性、膨胀性、触变性，并使用适当的度量表征。例如：流变图中指定剪切速率下的粘度（例如 η100）；塑性流动屈服应力值；触变相对面积（SR）；粘弹性储存和损耗模量（G' 和 G”）、表观粘度、损耗角正切（tan δ）。

流变特性的适当表征可使在成品标准中使用的简单试验的识别或设计成为可能。

Product Performance 产品性能

Appropriate tests to characterise product performance such as dissolution of suspensions and in vitro drug release (Annex I) should be developed and shown to be stable during storage.

In vitro skin permeation (Annex II) testing may also be of value.

应拟定合适的检测项目用于表征产品性能，如混悬液的溶解和体外药物释放（附件I），并证明样品在储存期间是稳定的。

也可以采用体外皮肤渗透（附件II）实验表征产品性能。

4.2.6 Administration 药品使用

The SmPC and product information should include instructions for use and any necessary warnings for the safe use of the drug product.

Where relevant, transformation of the drug product on administration should be described.

The following should be considered:

SmPC和产品信息应包含使用说明书和对药品安全使用的必要警告。

相关时，应描述药品在给药过程中的形变。

应考虑以下事项：

• Site of administration;

• The necessity to avoid damaged or undamaged skin;
• The requirements for skin pre-treatment;
• Effect of exposure to environmental extremes of heat, cold, sunlight;
• Effect of normal human behaviour such as washing, showers, use of sun screens and moisturisers;
• 用药部位；
• 避免受损或未受损皮肤的必要性；
• 皮肤预处理的要求；
• 暴露于热、冷、阳光照射的极端环境影响；

• 日常行为如洗涤、淋浴、使用防晒霜和保湿霜的影响；

• Any necessary restrictions e.g. avoidance of occlusion;
• The practical suitability of any special storage conditions;
• Avoiding inadvertent use by children;
• For drug products containing flammable volatile solvents, appropriate flammability safety warnings.
• 任何必要的限制，例如避免封闭；
• 任何特殊储存条件的实际可行性；
• 避免儿童无意使用；

• 对于含有易燃挥发性溶剂的药品，应有适当的易燃性安全警告。

  For example:
  Danger: Flammable.
  Keep away from heat, hot surfaces, sparks, open flames and other ignition sources.
  No smoking. Protect from sunlight.
  Do not expose to temperatures exceeding 50°C.
  Do not spray on flames or other sources of ignition.
  例如：
  危险：易燃。
  远离热源、热表面、火花、明火和其他火源。
  禁止吸烟。避免阳光照射。
  不要暴露于超过50℃的温度。

  不要喷在火焰或他火源上。

• Patients being dispensed or treated with large quantities (> 100g) of any paraffin-based product should be advised to regularly change clothing, bedding or dressings impregnated with the product and keep away from naked flames.
• 当患者使用以石蜡为基质药品且用药量超过100g时，建议定期更换衣服、床上用品和敷料，并远离明火。
  For example: 例如
  When this paraffin-based product is covered by a dressing or clothing, there is a danger that smoking, or using a naked flame could cause your dressing or clothing to catch fire.
  Do not smoke, use naked flames (or be near people who are smoking or using naked flames) or go near to anything else which may cause a fire whilst these products are in contact with your clothes, dressing or bandages.
  当这种以石蜡为基质的产品被衣物覆盖时，吸烟或使用明火可能导致衣物着火。

  不要吸烟、不要使用明火（或靠近吸烟者和使用明火者）、不要靠近任何可引发火灾的物品或令这些物品与你的衣物、敷料或绷带接触。

  Ensure that your clothes and bedding are changed regularly (preferably daily) as the paraffin soaks into the fabrics and can potentially be a fire hazard. You should also be careful to make sure that the paraffin does not soak into chairs, seating or other furniture.
  Tell your relatives or carers about your treatment and show them this leaflet.
  Tell your doctor, nurse or pharmacist if you normally smoke. They will be able to offer you help and advice to stop smoking.
  确保定期（最好每天）更换衣服和床上用品，因为石蜡会渗入织物中，并可能引发火灾。还应该小心，确保石蜡不会渗入椅子、座椅或其他家具中。
  把这些注意事项告诉你的亲属或护理者，并给他们看下这个手册。

  如果你经常吸烟，请告知你的医生、护士或药师。他们能给你提供戒烟的帮助和建议。

4.2.7 Manufacturing process development and Manufacture (P.2.3 and P.3) 生产工艺开发和生产

For dispersed drug products, e.g. two-phase emulsions, changes in formulation or manufacturing process may influence the efficacy and/or safety of the product and are therefore important to evaluate and control. The order of addition of different components to the formulation can be of importance as well as process parameters such as temperature and homogenisation conditions e.g. speed and duration.

对于分散的药物产品，例如两相乳液，配方或生产工艺的变化可能影响产品的有效性和/或安全性，因此对其进行评估和控制是很重要的。配方制剂中不同组分的添加顺序，以及温度和均质化条件（例如速率和持续时间）等工艺参数是非常重要的。

In a typical manufacturing process, the critical points are generally the formation of a two- or multi-phase system from one-phase systems and the point at which the active substance is added. As the drug release rate, microstructure/physical properties and rheological profiles of the drug product may be susceptible to scale-up effects, it is particularly important that these properties are verified at the commercial scale.

对于一般的生产工艺而言，关键步骤通常是单相体系形成两相或多相体系的过程，以及活性物质添加的步骤。由于药物产品的药物释放速率、微观结构/物理特性和流变特性易受放大效应的影响，因此在商业化规模放大时应对这些特性进行确认。

Module 3.2.P.3.3 and 3.2.P.3.4 should be sufficiently detailed and include both critical and non-critical process parameters and justified by reference to the manufacturing process development undertaken. Hold times and storage conditions of different solutions and intermediate materials should be stated and justified, supported by appropriate stability studies and other relevant data.

应在申报资料的模块3.2.P.3.3和3.2.P.3.4中提供足够详细的信息，包括关键和非关键工艺参数，并提供所进行的生产工艺开发数据证明其合理性。应提供适当的稳定性研究和其他相关数据，论证不同溶液和中间体的保存时间和储存条件。

Many bulk topical products exhibit shear thickening in the days following manufacture. The time between product manufacture and assembly may need to be optimised. The suitability of the packaging for intermediates, bulk storage, and transportation (shipping) should also be discussed.

很多散装外用制剂在生产后的几天会出现剪切致稠的现象。此时，可能需要优化产品生产和灌装的时间间隔。此外，还应讨论包装对中间体、散装产品储存、运输（航运）的适用性。

4.2.8 Container closure system(P.2.4)  容器密闭系统

The suitability of the container closure system (described in 3.2.P.7) should be discussed and justified. This should include the choice of materials, protection from moisture, oxygen and light where applicable, drug product compatibility, dosing, usability and safety.

Drug products having sterile requirements should be packaged in single-use containers.

If any device is co-packaged to facilitate e.g. the measuring or application of the product, the device should be CE-marked. Compatibility between the device and the medicinal product should be shown and if it is a measuring device, the dose accuracy should be demonstrated with the applied product.

应对容器密闭系统的适用性（在3.2.P.7中描述）进行讨论并证明其合理性，包括：材料的选择；如适用，对潮湿、氧气和光照的防护作用；相容性；剂量；可用性和安全性。

具有无菌要求的药品应包装在一次性容器中。

如果需将相关设备一起包装以便于，如产品的测量或应用等，设备应带有CE标记。应证明该设备与药品之间的相容性；如果是测量设备，则应论证所用产品的剂量准确性。

4.2.9 Microbiological Attributes (P.2.5)  微生物属性（P.2.5）

Microbiological aspects should be considered in the same manner as for other administration routes, bearing in mind that cutaneous products are sometimes applied to damaged skin. Reference should be made to European Pharmacopoeia 5.1.4., Microbiological quality of non-sterile pharmaceutical preparations.

Sterility of the drug product is required if it is to be used on large open or deep wounds or on severely injured skin, and products used prior to invasive procedures (e.g. preoperative skin antiseptic) and for preparations for irrigation.

微生物学方面，与其它给药途径一致，应加以考虑，因为皮肤产品有时会涂在受损的皮肤上。需符合EP 5.1.4 非无菌药物制剂的微生物质量。

如果要在大的开放性伤口或深部伤口或受伤严重的皮肤上使用，或是在侵入性手术之前使用（例如术前皮肤杀菌剂），或是用于冲洗的制剂，则需要满足无菌要求。

For non-sterile drug products in multiple-use containers the need to include an antimicrobial preservative should be addressed and justified. The concentration used should be at the lowest feasible level. Reference should be made to European Pharmacopoeia 5.1.3., Efficacy of antimicrobial preservation. For multi-phase formulations, the solubility of the preservative in the different phases needs to be considered.

对于多剂量包装的非无菌制剂，应论证并说明添加抗菌防腐剂的必要性。使用的浓度应处于最低可行水平。应参考EP 5.1.3抗菌防腐的功效。对于多相制剂，需考虑防腐剂在不同相中的溶解度。

4.3 Control strategy 控制策略

General regulatory guidance on the establishment and justification of a control strategy for the drug Product is given in other relevant guidelines, including ICH Q8, Q9, and Q10. Attention should however be paid to the control of CQAs required for the control of drug release, i.e. the in vitro drug release/dissolution and, if appropriate in vitro skin permeation.

If possible, pharmaceutical development should establish the link between product performance quality attributes and clinical efficacy.

关于药物产品控制策略的建立和论证信息可参考其他相关指南，包括 ICH Q8、Q9 和 Q10。然而，应注意控制与药物释放相关的 CQA，即体外药物释放/溶解、体外皮肤渗透（如适用）。

如果可能的话，在药物开发过程中，应建立药品性能质量属性和临床疗效之间的联系

4.3.1 Drug product specification (P.5)  药品质量标准

General guidance on the drug product specification is given in ICH Q6A, Q3B, Q3C and Q3D and the European Pharmacopoeia lists dosage form monographs.

The drug product specification should contain tests for the physical, chemical and microbiological quality, and product performance i.e. the established product characteristics (see 4.2.5) are controlled.

药品质量标准相关指南可参考ICH Q6A、Q3B、Q3C和Q3D，此外，需符合欧洲药典列出的剂型通则。

药品质量标准应包含物理、化学和微生物质量测试，以及4.2.5中描述的产品性能测试。

Crystal formation is a quality deficiency likely to adversely influence efficacy. Syneresis, the extraction or expulsion of a liquid from a semisolid, is another deficiency. Uniformity of the finished product in the container should be considered to detect sedimentation phenomena.

For topical products, the calculation of maximum daily dose for limits for degradation products is not as straightforward as for solid oral preparations or injections. The duration of treatment and amount required is usually more varied. The exposure levels from cutaneous products can usually be considered much less than from routes with systemic exposure. Deviations from standard calculations should be justified from a safety perspective.

晶型转变可能会对功效产生不利影响，使产品质量出现缺陷；脱水收缩，即从半固体中排出液体，是另一种缺陷。应考虑容器中制剂的均匀性，以确认是否有沉淀现象。

对于外用制剂，因治疗的持续时间和所需的量通常具有较大的可变性，用最大日剂量确定降解产物限值并不像固体口服制剂或注射剂那么简单。通常认为与系统性暴露相比，皮肤用制剂的暴露水平要低得多。可从安全角度说明，与标准计算存在一定偏差的合理性。

Specific precautions in calculating acceptance limits for impurities should be made for cutaneous products applied to damaged skin or products containing penetration enhancers.

Limits for performance tests, i.e. dissolution, drug release using a synthetic membrane and, if appropriate skin permeation testing, if included in the specification should be justified by reference to clinical batches for which satisfactory efficacy and safety has been demonstrated. The limits should be the same at release and shelf life, unless justified and qualified by clinical data.

对应用于受损皮肤的皮肤类产品或含有渗透促进剂的产品，在计算杂质的接受限度时，应明确相关的注意事项。

如果质量标准中包含性能测试（即：溶出，采用合成膜进行的药物释放测试；皮肤渗透测试，如适用），应根据已证明具有良好疗效和安全性的临床批次数据，说明拟定限度的合理性。除非提供合理的临床数据支撑，放行标准和货架期标准的限度应保持一致。

4.4 Stability program (P.8) 稳定性

To assure quality and stable product characteristics throughout storage, the designated shelf life needs to be based on physical, chemical and microbiological stability, and in vitro release or other performance tests. The risk factors to product stability should be assessed e.g. precipitation, particle growth, change in crystal habit, or other active substance characteristics likely to affect the thermodynamic activity, changes in emulsion characteristics. Appropriate tests, additional to those in the product specification, should be included in the drug product stability study quality specification. Shear thickening and changes in the product microstructure are also risk factors that should be considered.

为了确保整个储存过程中产品具有稳定的质量和一致的特性，应基于产品的物理、化学和微生物学稳定性，以及体外释放或其他性能测试数据，拟定合理的货架期。应对可能影响产品稳定的风险因素进行评估，例如沉淀/析出、颗粒生长、结晶习性变化、或其他可能影响热力学性质的活性物质特性，以及乳液特性变化。除了质量标准中包含的检查项，在药品稳定性研究中，也应对其它合适的质量属性进行考察。剪切致稠和产品微观结构的变化也是要考虑的风险因素。

The stability programme should include stress testing to assess the effect of severe conditions on the drug product e.g. temperature cycling for creams and emulsions. The stability study quality specification should include tests to monitor the suitability of the container closure system. Requirements for special storage conditions e.g. do not refrigerate, should be addressed.

An in-use stability programme should be undertaken. It is important that these tests have a reasonable length considering dosage regimen and package size. Unnecessary wastage or too short in-use shelf-lives should not be proposed.

稳定性研究中应进行影响因素试验，以评估苛刻条件对药品的影响，如温度循环（低－高温）对乳膏剂和乳剂的稳定性影响。在稳定性研究中，应包括监控容器密封系统适用性的检测试验。如在贮藏过程中有特殊要求，应明确指出，如不能冷藏。

应开展产品使用中稳定性试验。根据药品的包装规格和用量信息，拟定合理的考察持续时间，这点特别重要。不应造成不必要的浪费，或拟定一个较短的产品使用中稳定性期限。

5 Equivalence of Topical Products 外用制剂的等效性

5.1 Scope 范围

This section addresses equivalence testing of topical products to support a claim of therapeutic equivalence with comparator medicinal products, in lieu of therapeutic equivalence clinical trials. Aspects relating to quality, efficacy, and safety are discussed. For simple formulations (e.g. single-phase solutions, gels, ointments) demonstration of equivalence with respect to quality, i.e. extended pharmaceutical equivalence, may be sufficient.

本部分介绍了外用制剂的等效性测试，用于支持与参照药物相比的治疗等效性，以代替等效性临床试验。并对与质量、功效和安全性有关的方面进行讨论。对于简单的配方制剂（例如单相的溶液剂、凝胶剂和软膏剂），证明质量等效性（即扩展的药学等效性），可能就足够了。

For more complex formulations, or those containing excipients that might directly influence the active substance bioavailability or product performance, then additional permeation kinetic and, if possible, pharmacodynamic equivalence tests are normally required.

The formulation and strength of the drug product must also be such that the equivalence tests and associated analytical methods are sufficiently sensitive, discriminating, accurate and precise to measure a quantifiable permeation kinetic or pharmacodynamic event. This approach is not applicable and clinical therapeutic equivalence studies are in principle required for the following drug products:

对于比较复杂的制剂，或含有的辅料可能直接影响活性物质生物利用度或产品性能的制剂，通常需要进行额外的渗透动力学和药效学等效性试验（如可能）。

在可量化渗透动力学和药效学等效性试验中采用的分析方法，应具有足够灵敏度、区分力、准确度和精密度，以辨识规格不同配方和规格药品的等效性。以下类型的药物不能仅采用以上方法，原则上需要进行临床治疗等效性研究：

• With a narrow therapeutic index.

• With dose related, systemic toxicity, except in those cases where equivalent systemic exposure is shown by conventional pharmacokinetic bioequivalence studies.
• Where the means e.g. dissolution, release, diffusion, and permeation kinetics by which the active substance reaches the local site of action is not established or understood.
• Where the method of administration is not the same.
• 治疗指数窄的药物
• 与剂量相关的全身毒性药物，但在常规药代动力学生物等效性研究中显示具有等效全身系统暴露的情况除外
• 尚未建立或明确以下情况的，如药物的溶解、释放、扩散以及渗透动力学研究中药物到达的具体皮肤层

• 不同的给药途径

• That cannot be fully characterised with respect to quality attributes e.g. due to complex formulation, methodological limitations.
• Where it is not possible to measure a quantifiable permeation kinetic or pharmacodynamic event e.g. due to limited diffusion or insensitive tests.
• Where in vitro and in vivo permeation kinetic and pharmacodynamic studies are not applicable or considered insufficiently predictive of clinical response e.g. products indicated for the treatment of open wounds and ulcers.
• 不能用质量属性完全表征的药物，如复杂的配方制剂、方法学的局限性
• 皮肤渗透动力学或药效学无法量化时，例如有限的扩散或对测试不敏感。

• 当体外和体内渗透动力学和药效学研究不适用或被认为不能充分预测临床反应时，例如用于治疗开放性伤口和溃疡的产品。

5.2 Equivalence with respect to quality (extended pharmaceutical equivalence) 关于质量的等效性（拓展药物等效性研究）

Equivalence requires comparative quality data with the relevant comparator medicinal product. The products should be characterised (see sections 4.2.5 and 5.5). Pharmaceutical form, qualitative and quantitative composition, microstructure/physical properties, product performance e.g. dissolution, in vitro release test, and method of administration should be compared. For volatile solvent based topical products, product transformation on administration should also be compared.

在等效性研究中，可将获得的产品表征数据（见4.2.5和5.5节）与相关的参照制剂数据进行对比论证。对比研究的内容包括：药物剂型、定性和定量组成、微观结构/物理性质、产品性能（如溶出、体外释放试验）和给药方法。对于基于挥发性溶剂的外用制剂，还应比较产品在给药时的转化。

Product quality equivalence should be undertaken on batches representative of the product to be marketed and the manufacturing process – i.e. batches at or near production scale. Alternatively, pilot scale batches, at least 1/10 production scale may be used for characterisation and comparative purposes, if there are no changes in the manufacturing process and equipment, and evidence provided that scale-up does not affect product quality.

在药品质量等效性研究中，应采用可代表拟上市销售和生产工艺的批次进行，即达到或接近生产规模的批次。此外，如果生产工艺和设备没有变化，且有证据表明放大不会影响产品质量，则可以使用相当于生产批量1/10及以上的中试规模批次进行表征和比较。

It is acknowledged that there may be only a limited number of representative batches available at the time of submission, and at least three different batches of both the test and comparator products should be compared.

To enable statistical evaluation, the number of samples should be at least 12 units per batch for each experiment.

Data are also required to show that the product characteristics remain consistent and equivalent throughout the designated shelf-life.

众所周知，在提交申报时可能只有有限数量的批次具有代表性，但至少应提供3个批次的受试制剂和3个批次的参照制剂的对比研究数据。

为了进行统计评估，每个实验的样品数量应至少为每批12个样本。

此外，还应提供数据证明，在指定的货架期内，药品的性质保持不变且等效。

5.2.1 Extended pharmaceutical equivalence acceptance criteria 拓展药物等效性的接受标准

The extended pharmaceutical equivalence acceptance criteria between the test and comparator medicinal product are:

受试制剂和参照制剂之间的扩展药物等效性接受标准是：

Pharmaceuticalform 药物剂型

• The drug product should be the same pharmaceutical form, with the same solution state of the active substance in the same immiscible phases.

• 药品应为相同的药物剂型，在相同的不混溶相中具有相同的活性物质溶液状态。

Qualitative and Quantitative Composition 药物组分的定性与定量

• The active substance content, and its salt form should be the same.

• In general, the excipients qualitative composition, including grade, if necessary, and quantitative composition of excipients should be the same, although some exceptions are permitted. In particular, excipients whose function is to influence the active substance solubility, thermodynamic activity or bioavailability and product performance should be qualitatively the same.

  The nominal quantitative composition of the excipients should be the same or differences not greater than ±5%. For example, for an excipient present in the comparator medicinal product at 2%w/w, the permitted range in the test product is 1.9–2.1%w/w.

• 活性药物的含量和盐型应相同。

• 通常情况下，辅料的种类（如必须，包括辅料级别）和用量应保持一致，尽管允许例外的情况存在。但是，对于某些功能性辅料，其可能影响药物溶解度、热力学性质或生物利用度和产品性能，应具有相同的质量。

  辅料的标称用量应相同或相差不超过±5％。例如，对于在参照药品中含量为2%(w/w)的辅料，受试药品中的允许范围为1.9-2.1%(w/w)。

• A permitted exception for a qualitatively different excipient may be acceptable for: 允许定性组分存在差异的例外情况包括：

  √   Excipients whose primary function is not related to product performance or administration, i.e. antioxidants, antimicrobial preservatives, colours, and do not have any other functions or effect that influences the active substance solubility, thermodynamic activity or bioavailability and product performance.

  Well-established excipients in usual amounts should be employed and possible interactions affecting drug bioavailability and/or solubility characteristics should be considered and discussed.

  主要功能与药品性能或给药无关的辅料（即抗氧化剂、抗菌防腐剂、色素），并且不具有影响活性物质溶解度、热力学活性或生物利用度和产品性能的任何其它功能或作用。

  应使用常规剂量的已经过良好表征的辅料，并应考量和讨论可能影响药物生物利用度和/或溶解度特性的相互作用。

  √  Excipient paraffin homologues may be acceptable for excipients whose function relates to the vehicle or emolliency, and do not influence the active substance solubility, thermodynamic activity or bioavailability and product performance.

  具备载体或润肤功能的石蜡同系物，其不影响活性物质的溶解度、热力学活性或生物利用度和产品性能，是可以接受的。

  The different excipient should have no effect on local tolerance or safety. It should be shown that the excipients do not have any other functions or effect that influences the active substance solubility, thermodynamic activity or bioavailability and product performance. In these cases, a biowaiver (section 5.5.1) cannot be justified and is not permitted.

  即使采用不同的辅料对局部耐受性或安全性没有影响。同时提供证明说明，辅料不影响活性物质溶解度、热力学活性或生物利用度和产品性能的任何其它功能或作用。也不能豁免生物等效性研究（见5.5.1）

• A permitted exception for a quantitative difference of not greater than ±10% is acceptable:

  √   For excipients whose function only relates to the vehicle properties or emolliency.

  √   For excipients whose function is not related to product performance or administration, i.e. antioxidants, antimicrobial preservatives, colours.

  It should be shown that the excipients do not have any other functions or effect that influences the active substance solubility, thermodynamic activity or bioavailability and product performance.

• 允许的定量差异不大于±10％的例外情况，如下：

  √   辅料的作用仅与载体特性或润肤性有关

  √   辅料的作用与产品性能或给药无关，即抗氧化剂、抗菌防腐剂、色素

  应说明，辅料不影响活性物质的溶解度、热力学活性或生物利用度和产品性能的任何其它功能或作用。

Acceptance Criteria 接受标准

• For quantitative quality characteristics, the 90% confidence interval for the difference of means of the test and comparator products should be contained within the acceptance criteria of +/- 10% of the comparator product mean, assuming normal distribution of data.

• Qualitative quality characteristics should be essentially the same.

• 对于定量质量特征，假设数据呈正态分布，则受试药品和参照药品的均值差异的90%置信区间应包含在参照药品平均值的+/-10％的接受标准之内。

• 定性质量特征应基本相同。

Administration 药品使用

• The method of administration and administration devices should be similar and achieve the same dose on application.

• If applicable, when product transformation occurs following administration, the test and comparator medicinal product residues are equivalent with respect to quality i.e. in terms of extended pharmaceutical equivalence.

• 给药方法和给药装置应相似，并在给药时达到相同的剂量。

• 如果适用，当给药后药物发生形变，则受试药品和参照药品的残留在质量方面应等效，即在扩展药物等效性方面一致。

5.3 Equivalence with respect to efficacy 药效等效性

5.3.1 Methods  方法

The following methods are considered suitable for equivalence testing, in lieu of a clinical therapeutic study: 下列方法被认为适用于等效性测试，可代替临床治疗研究：

Permeation Kinetics Studies 渗透动力学研究

• In vitro skin permeation 体外皮肤渗透
• Stratum Corneum Sampling (Tape Stripping)  角质层取样（胶带剥离）
• Pharmacokinetic bioequivalence 药代动力学生物等效性

These tests provide a means of measuring equivalence in active substance permeation kinetics of drug products applied to intact skin. Human bioequivalence studies are appropriate when the active substance has quantifiable systemic bioavailability. In vitro skin permeation studies are suitable when the active substance diffuses through the skin to permit quantification in the receptor cell. Stratum Corneum Sampling (Tape Stripping) is suitable when there is sufficient quantifiable drug diffusion across the stratum corneum.

Other techniques, such as Microdialysis and Confocal Raman spectroscopy are not sufficiently established to provide pivotal equivalence data but may be supportive.

这些测试提供了一种可以测量应用于完整皮肤的药品中活性物质渗透动力学方法。当活性物质具有可量化的全身生物利用度时，则适合进行人体生物等效性研究。当活性物质通过皮肤扩散进入接收室，可通过测定接收液对其进行定量时，则适合进行体外皮肤渗透研究。如果在角质层上有足够的可量化药物扩散，则适合进行角质层取样（胶带剥离）。

其他技术（例如微透析和共聚焦拉曼光谱法）还不够完善，无法提供关键的等效数据，但可能是有帮助的。

Pharmacodynamic Studies 药效学研究

• Vasoconstriction Assay for corticosteroids. 皮质类固醇的血管收缩测定

• Antiseptic and anti-infective studies. 防腐和抗感染研究

These studies provide a means of measuring equivalence in active substance pharmacodynamic activity of drug products applied to intact skin. Pharmacodynamic studies for other drugs are not sufficiently established to provide pivotal equivalence data but may be supportive. The model should be suitably valid and its relationship with the therapeutic situation must be demonstrated.

这些研究提供了一种可以测量应用于完整皮肤的药物中活性物质药效动力学等效的方法。其他药物的药效学研究尚不充分，不能提供关键的等效性数据，但可作为支持性证据。该模型应进行适当的验证，并且必须证明其与治疗情况的关系。

5.3.2 General Considerations 概论

Managing Variability 控制变量

The test conditions should be standardised to minimise the variability of all factors involved except those of the products being tested. Pilot studies are recommended to develop and optimise procedures.

Because the studies are single-dose, product application is a significant source of variability. The dose application procedure (and removal procedure for stratum corneum sampling (tape stripping)) should be practical and carefully described, in accordance with the SmPC of the comparator product, and          strictly controlled, e.g. use of administration templates or aids by a single or limited number of trained personnel. The procedure should enable determination of the actual dose applied. The procedure should be validated.

测试条件应标准化，以最大限度地降低除被测产品外的所有相关因素的可变性。建议进行试点研究以开发和优化程序。

因为研究是单次上样，所以产品应用是一个重要的变异来源。应根据参照产品的SmPC，按照实际情况，详细描述剂量的应用程序（和角质层取样的剥离程序（胶带剥离）），并进行严格控制，例如，由单一或数量有限的经过培训的人员使用管理模板或辅助工具。应对该程序进行验证，确保其测定的结果与实际应用的剂量一致。

The study duration should be sufficient to permit quantitative observation of diffusion, but optimally limited to minimise changes in test conditions that may naturally occur, which introduce bias to kinetic profiles, e.g. desquamation, loss in skin integrity, back diffusion, accidental loss or transfer of applied dose. The methods involve multiple complex steps. The studies should be conducted following strict protocols by experienced trained staff, with quality assurance in place.

研究持续时间应足以对扩散进行定量观察，且需最大程度地减少在试验中可能自然发生的，引起动力学分布偏倚的变化，例如脱屑、皮肤完整性损失、反向扩散、意外损失或所应用剂量的转移。该方法涉及多个复杂步骤，应由经验丰富且训练有素的工作人员严格按照规程操作，以确保结果的可靠性。

In vitro skin permeation and stratum corneum sampling (tape stripping) studies should include negative controls that are not equivalent to the test and comparator products. Inter-subject or inter-donor skin variability should be minimised by a cross-over study design. For in vitro skin permeation and stratum corneum sampling (tape stripping) studies, the test, comparator and negative control formulations should each be tested on the same set of volunteers or donor skin.

在体外皮肤渗透和角质层取样（胶带剥离）研究中应包括不同于受试产品和参照产品的阴性对照。可通过交叉研究设计使不同受试者或供体之间皮肤变异性最小化。在体外皮肤渗透和角质层取样（胶带剥离）研究中，受试产品、参照产品和阴性对照产品的测定应采用同一志愿者或捐赠者的相同皮肤。

For low strength and limited diffusion drug products, the very low active substance concentrations expected in samples may be a significant source of variability. Sensitive analytical methods should be used, e.g. coupled chromatography – mass spectroscopy systems. The analytical methods should comply with the Guideline on bioanalytical method validation.

对于小规格和扩散量有限的药物产品，样品中预期的极低活性物质浓度可能是变异的一个重要来源。应使用灵敏的分析测试方法，如耦合色谱－质谱系统。分析方法应符合《生物分析方法验证指南》。

Dose 剂量

The dose, in terms of (a) mass of active substance, (b) application area, and (c) mass or volume of  drug product used, should be specified and based on the comparator product SmPC instructions for use. The application area should be at least sufficient to achieve quantifiable results. If necessary, the area may be greater than normally indicated, if without safety concerns. For in vivo studies, the skin site should be justified.

应根据参照制剂的产品特性概要（SmPC）中使用说明，确定样品的具体剂量，包括：（a）活性物质的质量，（b）应用区域和（c）药物产品的质量或体积。应用区域至少应足以实现可量化的结果。如有必要，在没有安全顾虑的情况下，应用区域可大于实际应用区域。对于体内研究，要说明皮肤选择位置的合理性。

Sample sizes 样品量

The number of human volunteer subjects should be based on an appropriate sample size calculation and not less than 12.

For in vitro skin permeation studies, the number of donors may be less than 12, if justified.

For in vitro skin permeation and stratum corneum sampling (tape stripping) studies, a replicate design is required. The minimum number of experiments for each of the test, comparator and control products should not be less than 24.

The number and frequency of sample time points, per subject or replicate, should be sufficient to characterise the active substance kinetic profile and determine equivalence parameters.

人类志愿者样本数目应该基于合适的样品数量的计算，且不应少于12。

在体外皮肤渗透性研究中，供体的数量在合适的情况下可以小于12。

在体外皮肤渗透和角质层取样（胶带剥离）研究中，需要进行重复设计。每一个受试产品、参照产品和对照产品的实验数最低不能少于24。

对于每个受试者或供体而言，取样时间点的数量和频率应足够表征活性物质的动力学模型和确定等效性参数。

Acceptance Criteria 接受标准

The acceptance criteria for equivalence parameters is that the 90% confidence interval for the ratioof means of the test and comparator products should be contained within the acceptance interval of 80.00-125.00%, unless justified.

Wider acceptance criteria for the 90% confidence interval, to a maximum of 69.84 – 143.19, may be accepted in the case of high within-subject or within-donor variability observed with low strength and limited diffusion drug products, and if clinically justified. The procedure in the Guideline on Investigation of Bioequivalence, “Section 4.1.10 Highly variable drugs or drug products” should be followed.

等效性参数的接受标准是，除非有充分的理由，受试产品均值和参照产品均值比率的90%置信区间应包含在 80.00-125.00% 的接受区间内。

对于90%置信区间的更广泛接受标准（最大为69.84-143.19），如果临床证明是合理的，适用于在小规格和扩散量有限的药物产品上观察到的受试者或供体内的高变异的情况。同时应遵循生物等效性研究指南 “第4.1.10节高度变异性药物或药物产品” 中的相关规定。

Accreditation 评审

It should be ensured that the performing laboratory is qualified to undertake the studies and that an effective quality system is in place. This should include:

• A declaration of compliance with a suitable quality system.

• The technical ability of the performing laboratory and the validity of the method used should be internally assessed at regular intervals and recent results provided;

• External audit by a National Competent Authority.

确保执行实验室有资格进行实验以及拥有有效地质量管理体系是很有必要的，这应该包括：        

• 符合适当质量体系的声明。

• 应定期对执行实验室的技术能力和所用方法的有效性进行内部评估，并提供最近的结果；

• 由国家主管部门进行的外部审计

5.3.3 Permeation Kinetic Studies 渗透动力学研究

Specific guidance for each of the three methods is available:

• In vitro skin permeation (Annex II of this guideline)
• Stratum Corneum Sampling (Tape Stripping) (Annex III of this guideline)
• Bioequivalence  Guideline on Investigation of Bioequivalence (CPMP/ EWP/ QWP/ 1401/98 Rev. 1)

以下是三种方法的具体指南：

• 体外皮肤渗透 （本指南附件II）

• 角质层取样（胶带剥离）（本指南附件III）

• 生物等效性研究指南（CPMP/EWP/QWP/1401/98 Rev.1）

5.3.4 Pharmacodynamic Studies 药效学研究

Corticosteroids 皮质类固醇

The vasoconstriction assay for corticosteroids is accepted for equivalence testing.

The study should comply with the methodology described in Annex IV.

皮质类固醇的血管收缩试验被接受用于等效性测试。

研究应符合附件 IV 中描述的方法

Skin Antiseptics 皮肤防腐剂

Skin antiseptics should comply with Ph.Eur 5.1.11. Determination of bactericidal, fungicidal or yeasticidal activity of antiseptic medicinal products. Where the method of administration is poorly defined or new then in vivo volunteer tests should be undertaken. In these studies, volunteer’s indigenous flora are recovered before and after skin antisepsis, with justified criteria for microbial recovery log reduction.

For skin antiseptics for use prior to invasive procedures, a study in compliance with ATSM E1173–15 Standard Test Method for Evaluation of Pre-operative, Pre-catheterization, or Pre-injection Skin Preparations would be acceptable.

皮肤防腐剂应符合欧洲药典（Ph.Eur） 5.1.11抗菌药物产品的细菌、真菌或酵母菌活性测定 的要求。如果给药方法定义不明确或采用新的给药方法，则应进行体内研究。在这些研究中，志愿者的固有菌群会在皮肤消毒前后恢复（在合理的微生物回收对数去除率范围内）。

对于在有创手术前使用的皮肤防腐剂，应符合ATSM E1173–15用于手术前、导管术前或注射前皮肤处理评估的标准测试法 的要求。

Antimicrobial drug products for treatment of skin infections 用于治疗皮肤感染的抗菌药物产品

In vitro skin infection and decolonisation equivalence studies, if satisfactorily validated, may be acceptable to provide an assurance of equivalence in efficacy, in conjunction with other equivalence studies.

在体外皮肤感染和 decolonisation equivalence 研究中，如果能获得满意的验证结果，可以与其他等效性研究一起提供有效性的保证。

5.4 Equivalence with respect to safety 安全方面的等效性

In general, safety and local tolerance may be guaranteed by knowledge of the active substance and the choice of well-established excipients.

Equivalence with respect to quality, when shown, provides an assurance of safety and local tolerance.

In addition, equivalence seen with permeation kinetic equivalence studies would show that the same amount of active substance is expected to reach the site of action and/or the systemic circulation as the comparator medicinal product.

一般来说，可根据对活性物质的认知以及辅料的选择，保证外用制剂的安全性和局部耐受性。

当显示质量等效时，可为外用制剂的安全性和局部耐受性提供保障。

此外，应通过渗透动力学等效性研究说明，与参照产品相比，受试产品中活性物质达到相同作用部位和/或全身循环的量相同。

For topical products, with a regional site of action, where the active substance has systemic bioavailability, bioequivalence studies provide evidence of both efficacy and safety.

As discussed in section 5.1, drugs with dose related, systemic toxicity are out of scope and require local tolerance and clinical safety studies. However, if systemic exposure is measurable, a bioequivalence study showing a similar systemic pharmacokinetic profile would be sufficient to conclude that systemic exposure is not higher for the test product than for the comparator product.

对于局部作用、全身起效的外用制剂，应进行生物等效性研究，说明药物的安全性和有效性。

如5.1章节所述，与剂量有关的全身毒性不在本指南的讨论范围内，需要进行局部耐受性和临床安全性研究。然而，如果全身暴露是可测量的，通过生物等效性研究表明，受试产品与参照产品相比具有相似的全身药代动力学特征，则可以说明受试产品的全身暴露量不高于参照产品。

5.5 Topical Product Specific Equivalence Protocols 外用制剂特定的等效规定

The development of topical product specific equivalence protocols and choice of equivalence tests should consider the following key factors: pharmaceutical form; product formulation; drug dissolution and release; drug diffusion in the skin and site of action.

局部外用产品特定等效性方案的制定和等效性试验的选择，应考虑以下关键因素：药物剂型；产品配方；药物溶出和释放；药物在皮肤和作用部位的扩散。

A formal topical product specific equivalence protocol, with test methods and their acceptance criteria, should be provided and justified. The protocol should be prepared before commencing the equivalence studies. All data available, positive and negative, should be provided. Equivalence may be concluded if results comply with the protocol criteria specified a priori.

In general, the product-specific equivalence protocol should comprise:

在开始等效性研究之前，应拟定正式的外用制剂特定等效方案，包括测试方法及其接受标准，并说明其合理性。无论结果好坏，需递交研究过程中获得的所有数据。如果结果符合预定的接受标准，可以得出等效性结论。一般而言，产品的等效性方案应包括：

• Justification for the absence of a clinical therapeutic equivalence study; that the drug product is within and not out of the scope of this guideline (Section 5.1).

• Justification for the absence of safety studies (section 5.4).

• Extended pharmaceutical equivalence studies and equivalence in the method of administration (Section 5.2).

• 不开展临床治疗等效性研究的理由；该药品在且不超出本指南的范围（5.1节）

• 不进行安全研究的理由（5.4节）

• 拓展药物等效性研究和给药方法的等效性（第5.2节）

• An appropriate permeation kinetic equivalence study, if diffusion through the skin is relevant to efficacy (Section 5.3.3) and justification of the choice of study or studies. Alternatively, if applicable, justification for the absence of kinetic equivalence studies.

• Pharmacodynamic studies should also be performed, if possible and relevant. The  development, validation and conduct of novel studies is encouraged (Section 5.3.4).

• 如果药物的疗效与药物通过皮肤的扩散情况相关（5.3.3节），可进行相应的渗透动力学等效性研究，说明药物的经皮扩散情况。如适用，也可说明无需进行该研究的依据

• 如果可能和相关，还应进行药效学研究。鼓励采用新技术，进行开发、验证等研究（5.3.4 节）

5.5.1 Biowaivers 生物等效性豁免

A waiver of the need to provide permeation kinetic or pharmacodynamic equivalence data can in principle be acceptable for:

• Simple formulations with a single-phase base in which the active substance is in solution or suspension e.g. cutaneous solutions, single phase gels and ointments; cutaneous suspensions.

• If the objectives and purpose of the drug product is only administration of the active substance to the surface of the skin (see section 4.2.1), then extended pharmaceutical equivalence, including in vitro drug release for gels, ointments and suspensions, and equivalence in administration should normally be sufficient

原则上，无需提供渗透动力学或药效学等效数据的情况，包括：

• 活性物质在单相溶液或悬浮液中的简单配方制剂，如外用溶液剂、单相凝胶剂和软膏剂、外用混悬剂

• 如果药物产品的宗旨和目标只是将活性药物给予到皮肤表面（见4.2.1节），通常进行拓展药物等效性（包括凝胶剂、软膏剂和混悬剂的体外药物释放）和给药等效性研究即可。

Equivalence studies with respect to efficacy (Section 5.3) are always required if the formulation:

• Includes excipients whose function is to influence the active substance bioavailability, product performance or enhance drug penetration;

• Includes complex excipients where different suppliers or grades may affect the in vivo performance or stability of the active substance;

• Has a qualitatively different excipient composition from the comparator product (see section 5.2.1, Qualitative and Quantitative Composition).

Bioequivalence studies should usually be provided if the products have a regional site of action, where the active substance has quantifiable systemic bioavailability.

需要进行功效等效性研究（第 5.3 节）的配方，包括：

• 包含影响活性物质生物利用度、产品性能或增强药物渗透性的辅料

• 包含不同供应商来源或级别可能体内性能或活性物质稳定性的复杂辅料

• 与参照产品比较，具有不同成分的辅料（见5.2.1节，定性和定量组成）

如果产品具有特定作用部位，且活性药物具有一定的全身生物利用度，在这种情况下，通常需进行生物等效性研究。

5.5.2 Strength Biowaiver 不同规格生物等效性豁免

If several strengths of a test product are applied for, it may be sufficient to establish equivalence at only one strength, which is most sensitive to detect potential differences between formulations.

The following requirements must all be met where a waiver for additional strength(s) is claimed:

如果产品有多个不同的规格，通常情况下，采用其中一个规格进行等效性研究即可，但要求该规格在评估各配方制剂的潜在差异时最敏感。

如要求其它规格豁免生物等效性研究，必须满足以下条件：

1. the different strengths of the test products are manufactured by the same manufacturing process.

   不同规格产品的生产工艺相同
   

2. the different strengths of the test products have the same qualitative composition.

   不同规格产品的组分相同
   

3. the qualitative and quantitative compositions of the different strengths of the test products are equivalent to the different strengths of the comparator medicinal products.

   受试产品与参照产品相比，相同规格的产品具有相似的定性和定量组分
   

4. extended pharmaceutical equivalence (section 5.2) is demonstrated between the test and comparator medicinal product for all strengths.

   采用所有规格的受试产品与参照产品进行扩展药物等效性（第 5.2 节）论证

6 Post-authorisation changes 批准后变更

For any proposed change, a risk assessment should be performed to determine its impact on quality, safety, or efficacy of the product.

Risks arising from cumulation of changes from the original drug product should also be considered.

The following changes are considered to have a potential significant impact on the safety, quality or efficacy of the drug product:

对于提议的任何变更，都应进行风险评估，以确定其对产品的质量、安全或有效性的影响。

还应考虑原药物产品的变更引入的风险。

药物产品的下列变化，对其安全性、质量或有效性有潜在的重大影响：

• A change in the physicochemical state and / or thermodynamic activity of the active substance;

• A change that affects dissolution, in vitro release, in vitro permeation kinetic characteristics of the drug product.

• A change in the manufacturing process e.g. a change in a critical process parameter.

• 原料药的物理化学状态和/或热力学活性的变化

• 影响药物产品溶出、体外释放、体外渗透动力学特性的变化

• 生产工艺的变化，例如关键工艺参数的变化

The comparative medicinal product for use in equivalence studies is usually that authorised under the currently registered formulation, manufacturing process, packaging etc.

If the proposed change meets the extended pharmaceutical equivalence acceptance criteria (section 5.2.1) for pharmaceutical form, and qualitative and quantitative composition, then equivalence should be demonstrated according to this guideline using a product specific equivalence protocol, with justified test methods and acceptance criteria (section 5.5).

用于等效性研究的参比药物产品，通常具有特定的配方、生产工艺、包装等，且经过管理当局批准。

如果拟议的变更符合拓展制剂等效性研究（5.2.1节）接受标准，包括药物剂型、药物的定性与定量组成；根据本指南，参考产品特定等效性研究方案，拟定合适的测试方法和接受标准（5.5节），论证产品的等效性。

If the proposed change does not meet the extended pharmaceutical equivalence acceptance criteria (section 5.2.1) for pharmaceutical form, or qualitative and quantitative composition, then equivalence should be demonstrated using an appropriate clinical study.

In all cases, the change should be supported by appropriate and representative batch data of the original and proposed change of all critical quality attributes.

如果拟议的变更不符合拓展制剂等效性研究（5.2.1节）接受标准，包括药物剂型、或药物的定性与定量组成，则应进行适当的临床研究证明产品等效。

无论是那种情况，都应采用合适的和有代表性的批次对其关键质量属性进行考察，将变更前后批次的数据进行对比分析，以支持变更的合理性。

Annex I  In vitro release test (IVRT)  附件一 体外释放试验（IVRT）

1. Scope of IVRT  IVRT适用范围

This annex provides information for in vitro release rest (IVRT) of semisolid drug products (e.g. creams, gels or ointments) and liquid suspensions. The following types of topical products are out scope for IVRT, but other in vitro tests may be applicable: simple liquid solutions, topical powders and other non-standard topical formulations (such as foams).

本附件阐述半固体药物制剂（如乳膏剂、凝胶剂或软膏剂）和液体混悬剂的体外释放试验（IVRT）信息。但以下类型的外用制剂，如简单的溶液、外用粉末和其他非标准外用配方制剂（如泡沫剂）等，不适于进行IVRT研究，可能需要采用其它体外试验进行评估。

2. Rationale for IVRT  IVRT基本原理

An IVRT with pseudo-infinite dosing using diffusion cells evaluates the rate and extent of release of an active substance in the proposed formulation. The following parameters should be determined:

IVRT是采用扩散池以伪无限上样的方式，评估拟定配方制剂中活性物质的释放速率和程度。在IVRT研究中，应确定以下参数：

• Drug release rate (R): The slope of the cumulative amount of active substance released versus the square root of time for the linear portion of the drug release profile. If a linear portion of the drug release profile cannot be obtained, the IVRT is not valid.

• The cumulative amount (A) of active substance released, usually expressed in mass units per surface area, at the last sampling time of the linear portion.

• Lag time (if present)

• 药物释放率（R）：以活性物质的累计释放量对时间平方根作图，释放曲线的线性部分斜率即为药物释放率。如果不能获得线性部分，则IVRT无效

• 在线性部分的最后采样时间点获得的活性物质的累计释放量（A），通常以“质量/面积”表述

• 延迟时间（如有）

Although the test does not model in vivo performance, the release rate (R) is a CQA to be specified in the finished product release and shelf life specification, unless otherwise justified. The in vitro release limits should be justified by reference to the in vitro release observed with clinical batches for which satisfactory efficacy or equivalence has been demonstrated.

尽管该测定不能模拟体内性能情况，但释放速率（R）仍是一项关键质量属性（CQA），应订入产品放行和货架期质量标准，除非有合理的依据进行说明。应根据具有满意的疗效或等效性的临床批次的体外释放测定结果或数据，论证体外释放速率限度制定的合理性。

Release and shelf life limits should normally be the same, unless the reasons for the differences are satisfactorily explained on quality grounds and justified by reference to clinical batches, and tighter limits at release are set, to ensure that the product will remain within the shelf life specification. A validated in vitro release test is required to support extended pharmaceutical equivalence.

通常情况下，放行标准和货架期标准中释放速率的限度应保持一致；如果存在差异，应通过对临床批次的研究，说明这种差异不影响产品的质量和疗效；严控放行限度，以确保产品在货架期内符合质量标准。应对体外释放测试（IVRT）方法进行验证，以支持拓展药物等效性。

3. Study design 研究设计

A pilot IVRT study comparing the test and comparator products is recommended to confirm the suitability of the chosen membrane and to validate the experimental conditions. The experimental conditions should be justified with respect to the following:

建议采用受试产品与参照产品进行IVRT探索性研究，以确认所选膜和试验条件的适用性。可通过以下几个方面，说明试验条件的合理性：

1. Choice of membrane: 膜的选择

   i.  The membrane should ensure that the product and the receptor medium remain separate to ensure the tested formulation remains unchanged throughout the testing period. The membrane should not be rate-limiting to active substance release.
   ii.  The membrane should be compatible with the drug product formulation and not bind to the active substance.
   i.  膜应有确保产品和接收介质保持分离的能力，以确保在整个测试过程中配方制剂保持不变。且不应限制活性物质的释放。

   ii.  膜应与配方制剂相容，且不与活性物质结合。

2. Choice of receptor medium: 接收介质选择
   i.  Sink conditions should be confirmed. An acceptable sink condition is one where the maximum concentration of the active substance in the receptor medium achieved during the experiment does not exceed 30% of its maximum solubility in the receptor medium. Sink conditions normally occur in a volume of medium that is at least 3-10 times the saturation volume.
   ii.  Back diffusion of the receptor medium should be minimised to avoid transformation of the applied drug product. The pH of the receptor medium should remain constant throughout the release test.
   i.  应确认漏槽条件。可接受的漏槽条件是，在整个试验期间，接收介质中活性物质的最大浓度不应超过在该接收介质中活性物质最大溶解度的30%。通常情况下，介质的体积至少是饱和体积的3-10倍。

   ii.  应尽量减少接收介质的反向扩散，以避免药物产品的转化。在整个释放测试期间，应使受体介质的 pH 值保持恒定。

3. The sampling time (at least hourly) and experimental conditions (such as apparatus, temperature, mixing speed) should be defined. The duration of IVRT should be sufficient to characterise the release profile, ideally at least 70% of the active substance applied is  released. At least 6 time points should be obtained in the linear portion of the drug release profile, including the first sample immediately after drug diffusion has reached a steady state.

   应明确采样时间（每小时至少一次）和试验条件（如仪器、温度、搅拌速率）。IVRT 的持续时间应足以表征释放曲线，理想情况下，释放量至少为活性物质的70%。在药物释放曲线的线性部分至少选取6个时间点，包括药物扩散达到稳态后的第一个取样时间点。

4. The amount and method of formulation application should be described, consistent (±5% between samples) and validated to ensure homogeneous spreading of the formulation over the membrane and pseudo-infinite dose conditions. The effects of formulation evaporation should be minimised.

   应描述配制制剂的上样量和上样方法，在伪无限上样条件下，确保上样量的一致性（在±5%范围内），且样品可均匀的涂抹在膜上。在上样过程中，应尽量减少由于样品的蒸发造成的影响。

5. The analytical methods should be sensitive enough to quantify the amount of drug in the receptor solution at various time points and validated.

   分析方法应有足够的灵敏度，并经过验证，确保其可以准确的测定各采样点接收液中药物的含量。

4. Method validation 方法验证

The marketing authorisation application should include documented evidence that the IVRT has been validated and is suitable for the quality control of the drug product. A summary of the development of IVRT should be provided. Testing conditions providing the most suitable discrimination should be chosen.

上市许可申请中应提供证明性文件，说明IVRT方法已经过验证，其适用于药物产品的质量控制。应递交IVRT方法开发总结，以便于选择具有最佳区分力的测试条件。

1. Satisfactory evidence of discrimination should be provided, with respect to both of the following quality modifications: 如下所示，可通过改变产品的两个质量特性，说明方法具有令人满意的区分力：

   i.  The release rate as a function of drug concentration (at least three strengths) in the formulation should be investigated. The linearity (r2>0.90) of the correlation of formulation concentration to rate of drug release (R) should be confirmed when the drug is fully dissolved. For suspensions, the relation between drug concentration and rate of drug release (R) should also be understood and discussed.

   考察配方制剂中不同药物浓度（至少三个规格）的释放速率。当释放的药物可以完全溶解于接收介质时，需确定制剂浓度与药物的释放速率（R）呈线性关系（r2>0.90）。对于混悬剂，也应了解和讨论药物浓度与药物释放速率（R）之间的关系。

   ii.  Discriminative power of the proposed method should be demonstrated with altered product formulations with changes in critical quality attributes (such as the active substance particle size distribution or drug product rheological profile), critical manufacturing variables or quantitative excipient composition; the complete omission of one or more specific excipients from the altered product formulation is not supported.

   通过改变配方制剂的关键质量属性（如活性物质的粒度分布或制剂的流变学特性）、关键生产工艺或辅料的定量组成，论证拟定的方法的区分力；但是，不能完全去除配方制剂中一个或多种特定的辅料。

2. Method intermediate precision for the same batch should be studied with different operators on different days (CV<10%).
   采用相同批次产品、在不同日期、由不同实验员进行方法的中间精密度考察（CV＜10%）。
3. Method robustness with respect to variations in mixing rate, amount of formulation applied, receptor mediums and temperature should be studied.

   通过改变搅拌速率、配方制剂的上样量、接收介质和温度，评估方法的耐用性。

5.Presentation of data 递交数据

A minimum of 12 samples per batch should be used for initial method validation or to demonstrate equivalence. For routine release, a minimum of 6 samples would be accepted. The in vitro drug release profile data should be provided in tabular and graphical formats. For the drug release profiles, the quantity of active substance released in mass units per unit area at a given time should be reported.

For extended pharmaceutical equivalence testing:

在首次进行方法验证或等效性评估时，每个批次的样品最少需要12个重复。对于日常放行检测，每个批次至少需要6个重复。在体外药物释放研究中，应以表格和图形格式递交相关数据；以 “质量/面积” 为单位，报告特定时间的活性物质释放量。

对于拓展药物等效性测试：

• The cumulative amount of active substance released versus the square root of time should be linear.

• The parameter R should be significantly different from zero.

• The 90% confidence interval for the ratio of means of the test and comparator products for the parameters (R), (A) should be contained within the acceptance interval of 90 – 111%.

• Lag times should be the same (i.e. within ±10%), if present.

• 活性物质的累计释放量与时间的平方根呈线性关系；

• 释放速率（R）明显大于0；

• 受试产品与参照产品释放速率（R）均值比率的90%置信区间应包含在90－111%的可接受范围；

• 延迟时间一致（在±10%范围内），如有。

Annex II  In vitro skin permeation studies (IVPT)  附件 II  体外皮肤渗透研究（IVPT）

1. Scope and rationale for IVPT  IVPT 适用范围和基本原理

Establishing the characteristic permeation profile of the drug product, using a discriminative in vitro permeation test (IVPT), is of value in change control during life-cycle management and an acceptable permeation kinetic test to demonstrate equivalence.

For equivalence studies, test and comparator products, together with a negative control such as a formulation with 50% of the proposed product strength, are compared.

采用有区分力的体外渗透测试（IVPT）建立药物的特征渗透曲线，对药物整个生命周期管理中的变更控制和采用可接受的渗透动力学试验证明药物的等效性具有重要价值。

在等效性研究中，可通过将受试产品与参照产品和阴性对照产品（如拟定配方制剂的50%规格）的测定结果进行对比论证。

2. Study design 研究设计

To minimise risk of bias, the study protocol should specify methods of blinding and randomisation in line with ICH E8. A pilot IVPT study comparing the test and comparator products is recommended to confirm that the active substance permeates through the skin, to validate the experimental conditions (such as apparatus, dosing amount, sampling times, stirring rate, etc.) and may be of value in estimating sample size required for the pivotal study.

The experimental conditions should be justified with respect to the following:

为了最大限度地降低误差风险，应根据 ICH E8，在研究方案中明确规定盲法和随机化方法。建议采用受试产品与参照产品进行IVPT探索性研究，以确认活性物质可渗透通过皮肤，同时对试验条件进行确认（如仪器、上样量、采样时间和搅拌速率等），并可能有助于评估IVPT正式研究中所需的样本量。

可通过以下几个方面，说明试验条件的合理性：

1. Choice of skin membrane: 皮肤膜的选择
   i.  It is recommended to use ex vivo adult human skin. The study protocol should specify the inclusion/exclusion criteria for skin sections, the anatomical region, condition and duration of skin storage. Skin with tattoos, any signs of dermatological abnormality or exhibiting a significant density of terminal hair should be excluded.

   建议使用体外成人皮肤。研究方案中应明确皮肤切片的纳入/排除标准、解剖区域、保存条件和时间。应排除有纹身、任何皮肤异常迹象或明显浓密的末端毛发皮肤。

   ii.  Different skin preparation techniques can be used. Evidence should be provided to demonstrate that the skin preparation technique and storage does not introduce artefacts, nor alter the skin barrier function. The use of full-thickness skin may artificially delay drug permeation and should be avoided unless otherwise justified. The skin thickness and separation technique should be described.

   可以使用不同的皮肤处理技术。应提供证据证明皮肤处理技术和储存不会引入人工制品，也不会改变皮肤屏障功能。使用全层皮肤可能会人为地延迟药物渗透，除非有合理说明，否则应避免使用。应描述皮肤厚度和分离技术。

   iii.  The skin integrity should be checked prior to and after each experiment. The choice of the skin integrity test and its acceptance criteria should be explained. Different acceptance criteria maybe proposed for before and after the experiment, these acceptance criteria should be justified and consistent across all parallel experiments.

   应在每次实验的前后分别检查皮肤完整性。应说明皮肤完整性的测试方法及其接受标准。虽然实验前后可以采用不同的接受标准，但在所有平行实验中接受标准应该是合理的和一致的。

   iv.  Skin from different donors should be chosen. Test, comparator and negative control formulations should be tested using the same donor skin, ideally from adjacent sites, per replicate.

   应采用多个不同的供体皮肤进行评估。受试、参照和阴性对照产品每次重复测定，应采用相同的供体皮肤，最好是相邻部位的皮肤。

   v.  The number of skin donors should not be less than 12, with at least 2 replicates per donor.

   皮肤供体的数量不应少于 12 个，每个供体至少 2 个重复。

   vi.  The apparatus should ensure consistent temperature control throughout the duration of the experiment. The skin surface temperature should be stable at 32±1°C.

   仪器应确保在整个实验过程中温度恒定。皮肤表面温度稳定在32±1℃。

2. Choice of receptor medium: 接收介质的选择
   i.  Sink conditions should be confirmed as described with IVRT (Annex 1).
   应按照 IVRT（附件 1）的要求确认漏槽条件。
   ii.  The receptor medium should be aqueous buffer, unless otherwise justified. Evidence should be provided that the chosen receptor medium does not compromise the skin barrier integrity throughout the test.
   除非提供合理性依据，应采用水性缓冲液作为接收介质。应提供证据说明所选接收介质在整个测试过程中不会损害皮肤屏障的完整性。
   iii.  The inclusion of an anti-microbial agent in the receptor medium, to mitigate potential bacterial decomposition of the skin membrane, is acceptable, but it should not interfere with the properties of the skin or the assay.

   可以在接收介质中添加抗菌剂，以减轻皮肤膜的潜在细菌分解，但添加的抗菌剂不应干扰皮肤的特性或测定。

3. The number of sampling time points should be sufficient to obtain meaningful profiles, i.e. capturing the maximal rate of absorption and a decline in the rate of absorption thereafter, with more frequent sampling during the period of greatest change. The duration for testing should be 24 hours. If the study duration is longer than 24 hours, it should be shown that skin barrier function and integrity is adequately maintained.

   应有足够的采样时间点，以获得有意义的释放模型，即：捕获吸收的最大速率和之后吸收速率的下降情况，并在吸收速率最大的时间段进行更频繁的采样。测定持续的时间通常为24h。如果时间大于24h，应证明试验前后皮肤具有可接受的屏障完整性。

4. The recommended dosing amount should be in the rage of 2-15mg/cm2, based on SmPC posology, unless otherwise justified. Dose application should be validated to ensure reproducibility (±5 %) and homogeneous spreading of the formulation over the skin membrane. The donor compartment should be un-occluded unless otherwise specified in the SmPC.

   根据产品特性概要（SmPC）中的使用剂量要求，建议上样量为2-15mg/cm2，除非另有规定。应对上样方式进行确认，确保可将配方制剂均匀一致的涂抹到皮肤膜上，且可重复（±5%）。除非SmPC中另有规定，供给室应采用非闭环（un-occluded）上样。

5. To identify potential contamination and/or interferences, pre-dose samples collected from each diffusion cell and a parallel non-dosed blank control skin experiment are recommended.

   为了识别潜在的污染和/或干扰，建议在上样前，从每个扩散池中收集接收液，同时进行未上样空白对照试验。

6. A detailed description of the blinding procedure should be provided in the study protocol and final report. The packaging of the test, comparator and negative control products should be similar in appearance to maintain adequate blinding. The method of randomization should be described in the protocol and the randomization schedule provided.

   应在研究方案和最终报告中提供对盲法程序的详细描述。受试、参照和阴性对照产品的包装外观应相似，以保持足够的致盲。应在方案中描述随机化方法，并同时提供随机化时间表。

7. For low strength drug product, the analytical methods should be sensitive enough to quantify the amount of drug in the receptor solution at various time points and be appropriately validated.
   对于小规格制剂，分析方法应有足够的灵敏度并经过合适的验证，确认其可以准确测定接收液中各采样时间点的药物含量。
8. The stability of the active substance in the receptor solution over the duration of IVPT study, and sample storage prior to analysis, should be confirmed.

   应确认在IVPT研究期间和测定前存放条件下，接收液中活性物质的稳定性。

3. Method validation 方法验证

The Marketing Authorisation Application should include documented evidence that the IVPT has been validated and are suitable for drug product comparison.

The suitability of the test conditions should be demonstrated using batches with different quality attributes (a negative control), such as a drug formulation with 50% of the proposed product strength, that is shown to be statistically different and non-equivalent to the comparator product.

上市许可申请中，应递交IVPT验证资料，证明其适用于药物的对比研究。

可以采用不同质量属性（包括阴性对照）的配方制剂，论证测定条件的适用性，如采用拟申报制剂的50%规格，与参照产品进行比较，应有统计上的差异和不等效。

To achieve this, batches with meaningful changes compared to the applied finished product should be manufactured. Such changes may relate to the quantitative formulation, critical quality attributes and/or using slightly modified process parameters. Current knowledge of the characteristics derived from the active substance and the finished product formulation must be considered when choosing the quality attributes to change. The complete omission of one or more specific excipients from the formulation (e.g., penetration enhancer, preservatives) is not supported.

为实现这一点，应生产与拟申报终产品具有显著变更的批次，如定量配方、关键质量属性和/或工艺参数的变更。在选择要改变的质量属性时，必须考虑从活性物质和制剂中获得的特性的当前知识。但不能完全去除配方制剂中一个或多种特定的辅料（如渗透促进剂、防腐剂）。

4. Presentation of data 递交数据

IVPT data should be provided in tabular and graphical formats. All individual data and parameters should be listed by formulation together with summary statistics. Both the plots of the cumulative amounts permeated per unit area (mass unit/cm²) as function of time and the plot of the rate of absorption (mass unit/cm²/hr) as a function of time should be provided to characterise the release profile.

Relevant permeation parameters, e.g., the maximal rate of absorption (J_max) and total amount permeated at the end of experiment (A_total) should be determined and compared. In the case of a replicate design, results obtained in the duplicate sites from the same donor should be averaged (geometric mean) prior to further analysis.

应以表格和图形格式递交IVPT数据，列出所有的数据和参数，以及计算公式和汇总统计信息。为了表征释放行为，应将“单位面积的累计渗透量（质量/平方厘米）与时间”作图，同时将 “吸收速率（质量/平方厘米/小时）与时间” 作图，并递交相关结果。

应将相关的渗透参数或数据进行比较，如最大吸收速率(J_max)和试验结束时的总渗透量(A_total)。在重复设计的情况下，应在进一步分析之前对来自同一供体的重复位点的结果进行平均（几何平均值）。

The acceptance criteria for equivalence parameters (Jmax) and (Atotal) are:

等效性参数(Jmax)和(Atotal)的接受标准如下：

• The 90% confidence interval for the ratio of means of the test and comparator products should be contained within the acceptance interval of 80.00- 125.00%, unless justified.

  受试产品与参照产品均值比率的90% 置信区间应包含在80.00－125.00%的可接受范围，除非有正当理由。

• Wider 90% confidence interval limits, to a maximum of 69.84 – 143.19, may be accepted in the case of high variability observed with low strength and limited diffusion drug products, and if clinically justified. The procedure in the Guideline on Investigation of Bioequivalence, “Section 4.1.10 Highly variable drugs or drug products” should be followed.

  对于小规格和扩散量有限的药物产品，如果观察到具有高变异性，可通过临床研究，放宽90%置信区间，采用更宽松的接受标准69.84-143.19。应遵循生物等效性研究指南“第4.1.10节高度变异性药物或药物产品”的相关规定。

In addition, for the test to be valid: 此外，为了确认测试结果可信：

The acceptance criteria for equivalence parameters (Jmax) and (Atotal) 等效性参数(Jmax)和(Atotal)的接受标准为：

• The 90% confidence interval for the ratio of means of the test and negative control products should be entirely outside the interval of 80.00- 125.00%.

  受试产品与阴性控制产品均值比率的 90% 置信区间应全部在 80.00－125.00% 之外。

• The 90% confidence interval for the ratio of means of the comparator and negative control products should be entirely outside the interval of 80.00- 125.00%.

  参照产品与阴性控制产品均值比率的 90% 置信区间应全部在 80.00－125.00% 之外。

Additional permeation parameters, such as the time of maximal rate of absorption (tmax) andlag-times, should also be reported. The lag-times between the test and comparator products should be thesame (i.e. within ± 10%) if present. Any differences in the permeation parameters should beappropriately discussed with respect toequivalence.

还应报告其他渗透参数，例如最大吸收率(tmax)的时间和延迟时间。如存在延迟时间，受试产品和参照产品应保持一致（即在±10%范围内）。应对等效性研究中发现的渗透参数的任何不同之处进行讨论。

The mass balance should be determined. The cumulative amount of the active substancepermeated into the receptor medium (Atotal), the total amount of active substance retained (Stotal) in theskin samples and amount of active substance retained on the cleaning or experimental equipment(Rtotal) should be presented. The overall recovery of the active substance of 90-110% would beacceptable without justification, larger variation should be fully justified andexplained.

The amount of active substance retained in different skin layers (such as the stratum corneumand epidermis) may be analysed separately to understand the active substance distribution in humanskin.

研究过程中应符合质量平衡的要求。递交以下三个部分的数据：活性物质渗透进入接收液的总量(Atotal)、皮肤组织中活性物质的总量(Stotal)和残留在皮肤或试验设备上的总量(Ttotal)。上述三个部分检测量之和应在90－110%范围内，如超过该范围需提供合理性依据。

可以分别测定不同皮肤层（如角质层和表皮层）中保留的活性物质的量，以了解活性物质在人体皮肤中的分布。

Annex III Stratum Corneum (S.C.) Sampling (Tape Stripping)  附件III 角质层（S.C.）取样（胶带剥离 ）

1. Introduction 引言

This annex provides information for an in vivo stratum corneum sampling (or tape stripping(TS)) study for semi-solid formulations as a permeation kinetic method to show equivalence, in lieu ofa therapeutic equivalencestudy.

本附件是关于半固体制剂体内角质层取样（或胶带剥离 (TS)）的研究信息，该研究是一种显示等效性的渗透动力学方法，可用于替代治疗等效性研究。

The S.C. sampling study is a minimally invasive technique that involves sequential removal of the outermost skin layer (i.e., the stratum corneum (S.C.)) using adhesive tapes after application of a drug-containing formulation. The amount of drug in the S.C. depends on three main processes: drug partitioning from the formulation into the SC, drug diffusion across the S.C., and drug partitioning out of the S.C. into the viable tissues. A major advantage of TS is that the experiment is conducted invivo with a fully functioning cutaneous microcirculation so that drug clearance from the skin isunimpeded.

角质层取样研究是一种微创技术，该技术是在皮肤应用配方制剂后，用胶带将最外层的皮肤（即角质层（S.C））逐次剥离。药物在角质层（S.C）的量，主要取决于三个方面：药物从配方制剂中渗入角质层的量、药物通过角质层扩散和进入活体组织的量。胶带剥离的一个主要优点是，该实验是在体内皮肤微循环功能完整的条件下进行的，药物易于从皮肤上清除。

TS data provide direct measurements and information on the local bioavailability of semi-soliddrug products that act on or in the S.C. e.g. antifungal products. In cases when the target sites of actionare beyond the S.C., TS data may provide a suitable surrogate to characterise the rate and extent of drug absorption to the underlying tissues.

胶带剥离数据提供有关作用于角质层上或角质层中的半固体药物产品的局部生物利用度的直接测量和信息，例如抗真菌产品。在目标作用部位不是角质层的情况下，胶带剥离数据可以提供合适的替代指标来表征药物吸收到下层组织的速率和程度。

In vivo TS studies are only applicablefor products where drug diffusion into and through the SC takes place. Thus, TS should not be used for testing of drug products to be applied on significantly damaged skin (e.g. open wounds, burns) or skin of premature new-born. In addition, any products that contain volatile drugs or target primarily the cutaneous appendages (e.g. hair follicles, sebaceous glands) are also not suitable.

体内胶带剥离研究仅适用于药物扩散进入和通过角质层的产品。因此，胶带剥离不适用于拟用于严重创伤皮肤（例如开放性伤口、烧伤）或早产新生儿皮肤的药物产品。此外，也不适用于含有挥发性药物的制剂或主要作用部位为皮肤附属组织的药物制剂（例如毛囊、皮脂腺）。

2. Method development and optimization 方法开发和优化

A TS study is not an automated process and careful consideration of the experimental design is vital. The experimental conditions of the pivotal study should be assessed individually for the concerned products and should be established by performing a pilot TS study. A summary of the development and optimisation of the TS method should be provided.

The following experimental conditions should be established and verified during the pilot study:

胶带剥离研究不是一个自动化的过程，需仔细考虑实验设计，这点至关重要。正式研究的实验条件应针对相关产品进行单独评估，并应通过探索性胶带剥离研究进行确认。还应提供胶带剥离方法开发和优化的总结。

在探索性研究中，应对以下试验条件进行确认：

• TS study should be conducted on healthy, normal forearm (volar) skin areas with adequate skin barrier function. The inclusion/exclusion criteria for skin conditions should be defined. Skin with tattoos, any signs of dermatological abnormality or exhibiting a significant density of terminal hair should be excluded. The preparation and cleaning procedures prior to the experiment should be established and further, that the treatment sites are not damaged by these processes.

  胶带剥离研究应在健康、正常、皮肤屏障功能良好的前臂（掌）皮肤区域进行。应明确皮肤的纳入/排除标准。将有纹身、任何皮肤异常迹象或明显浓密的末端毛发皮肤排除在外。在试验前，确定皮肤的处理和清洁方法，确保这些处理措施不会破坏皮肤的完整性。

• Skin integrity should be determined before and after the experiment. This is normally performed by the measurement of Transepidermal Water Loss (TEWL), although other techniques may be applicable if appropriate. The acceptance criteria should be fully discussed and justified.

  应在实验前后确定皮肤完整性。通常采用经皮水分散失法（TEWL）进行测定，如适用，也可以采用其它技术。应对接受标准进行讨论，说明其合理性。

• Due to inter-subject variability, the products to be compared should be applied on the same subject. Additionally, a negative control that is non-equivalent to the comparator product should also be included to demonstrate the discriminatory power of the method. It is recommended to blind the investigator responsible for formulation application and tape stripping to minimise risk of bias.

  由于受试者之间的变异性，在产品的对比研究中应采用同一受试者。此外，需考察与参照产品不等效的阴性控制产品，用于论证方法的区分力。建议负责配方应用和胶带剥离的研究者进行盲检，以最大限度降低偏倚风险。

• The dosing amount should be determined based on the SmPC. During the pilot study, the dosage and area of dose application should be verified to achieve a quantifiable mass of active substance in the SC. The dosing technique, blinding and randomisation procedures should also be established.

  应根据SmPC确定上样量。在探索性研究期间，需确认上样量、上样区域/面积，以满足角质层中活性物质定量测定的需求。同时，确定上样方式、盲法和随机化方法。

• A single dose approach should be followed, i.e. skin stripping is performed after a single application of the test and comparator products.

  应采用单剂量方法，即在单次上样受试产品或参照产品后，进行皮肤剥脱。

• It is necessary that the products are compared at two time points (one uptake, one clearance) for each subject. The optimal uptake and clearance times depend on the characteristics of the drugs and products and should be determined during the pilot study. Ideally and when  relevant, the uptake time should be sufficiently long for the drug to have attained the diffusional steady-state. This can be established by testing at multiple uptake times and from which time the mass of drug recovered from the SC remains constant. The clearance time should be long enough to allow measurable transfer of drug from the SC into the viable skin (and beyond) but should not exceed 48 hours to avoid any skin desquamation effect. The clearance time providing at least a 25% decrease in the mass of drug recovered from the SC with respect to that at the uptake phase is preferred. In all cases, the sampling times should be carefully considered and justified.

  对于每个受试者，需要对两个时间点（吸收、清除）的产品测定结果进行对比。最佳的吸收和清除时间取决于药物和产品的特性，应在探索性研究期间进行确定。理想情况下，吸收时间应足够长，以使药物达到扩散平衡状态。这可以通过测定给药后多个时间点，角质层中药物回收的量进行确定。清除时间应足够长，以便于准确测定从角质层转移至活体皮肤（和皮下）的情况，但不应超过 48 小时，以避免任何皮肤脱屑效应。与吸收阶段相比，能使从角质层中回收的药物量至少降低25%的清除时间是最佳的。无论什么情况，都要仔细考虑采样时间并证明其合理性。

• The drug product should be removed from the skin surface after the specified uptake time. The cleaning procedure should be established to ensure that the residual formulation is efficiently removed from the treatment sites before stripping.

  在特定的吸收时间后，应将药物从皮肤表面移除。需建立移除方法，确保在胶带剥离前，残留的配方制剂可有效的从给药部位移除。

• The adhesive tape chosen should meet the following requirements: a) does not lose mass when applied and rubbed against the skin surface; b) minimal weight loss and gain during storage; c) the drug is readily extracted from the SC adhered to the tape; d) the adhesive or other components of the tape do not interfere with the analytical quantification of the drug; and e) the adhesive power should be such that the majority of the SC is removed with a sufficiently low number of tapes (e.g. not more than 30 tapes).

  所用胶带应满足以下要求：a）与皮肤表面粘附后，不损失重量；b）存储过程中，重量减少和增加较小；c）药物易从粘附在胶带上的角质层中提取；d）胶带的粘合剂或其他成分不干扰药物的定量测定；e）胶带应有足够的粘合力，即使采用较少的胶带数量也可以除去大部分的角质层（例如，不超过 30 条）。

• The TS procedure followed must ensure that most of the SC (≥75%) is sampled for each skin site. The minimum and maximum number of tapes should be established based on the TEWL (or other relevant) criteria, e.g. eight-fold increment over baseline value, safety stop value.

  对于每个皮肤位点，所用的胶带剥离程序必须确保大部分角质层（≥75%）被采样。可以根据TEWL接受标准（或其它相关技术）确定所需胶带的最少和最大数量，例如，基线值、安全停止值的八倍增量。

• Most commonly, the drug is first extracted from the tapes then quantified in the extraction solvent(s). Alternative methods of extraction/quantification may be used if justified. Satisfactory efficiency should be demonstrated for the proposed extraction method.

  最常见的是，先从胶带中提取药物，然后对提取溶剂进行测定。如果有正当理由，可以使用其他提取/定量方法。同时需证明，所采用的提取方法可获得令人满意的结果。

3. Study design 研究设计

Detailed standard operating procedures should be prepared for the conduct of TS studies to ensure precise control of dosing, cleaning, stripping, extraction, quantification and other study variables or potential sources of experimental bias. The inclusion/exclusion criteria should be pre-defined and clearly stated in the protocol.

The following study design is recommended for TS studies. The final protocol developed for each specific case should be justified.

在胶带剥离研究中，应详细描述标准操作规程，以精确控制上样、清除/清洁、剥离、提取、定量和其他研究变量或实验偏差的潜在来源；并在方案中明确规定纳入/排除标准。

推荐按照下面的研究设计进行胶带剥离研究，并说明最终确定研究设计方案的合理性。

• Subjects – TS studies should be performed in healthy volunteers. The subjects should be screened for suitability in line with the principles of bioequivalence studies.
  受试者：在胶带剥离研究中，需采用健康受试者，并根据生物等效性研究的原则对受试者进行筛选。
• Treatment area –healthy skin of the volar forearm areas sufficient to accommodate at least six application sites per forearm. Skin integrity should be verified e.g. by TEWL measurement. The same number of application sites should be assigned to each forearm;

  给药部位：可在每个前臂掌侧健康皮肤区域的六个部位给药。应进行皮肤完整性确认，如采用TEWL进行测定，同时，应确保每个前臂的给药部位相同、数量相同；

• Number of subjects – the choice of the number of subjects should be justified based on the variability estimated from the pilot studies and demonstrated to be statistically relevant. A minimum of 12 subjects should be used to demonstrate equivalence;
  受试者数量：受试者数量的选择应基于探索性研究中可变性评估进行说明，以证明其满足统计学相关要求。在等效性论证过程中，至少需要12名受试者；
• Number of replicates – at least two application sites per product (test, comparator and a negative control) per forearm. One forearm should be used for uptake samples and the other for clearance;

• 重复次数：每个样品（受试、参照和阴性控制）在各前臂至少应有两个给药位点。一个前臂用于药物吸收，另外一个用于清除；

• The products should be applied at pre-determined doses (±5%) and spread evenly over the entire demarcated application sites. Blank samples should be collected from the adjacent areas to verify the absence of background levels of drug or other compounds that may interfere with the quantification of drug in the treated SC;
  产品应按预定的剂量（±5%），均匀的涂抹到指定区域/位点，并从上样区域的相邻部位收集空白样品，以确认在角质层中不存在可能干扰药物定量的背景水平或其他化合物；
• The application sites should be randomised to avoid bias. The application time should be staggered to allow time for S.C. sampling;

  给药位点应随机化，以避免偏倚；并错开给药时间，以便有充足的时间对角质层进行采样；

• Un-occluded conditions, unless occlusion is recommended in the product information, or otherwise justified e.g. to prevent inadvertent removal of formulation.
  采用“非闭环（un-occluded）”条件，除非产品信息中推荐采用“闭环（occluded）”条件，或证明其合理性，如：防止无意中去除配方制剂。
• The formulation should be removed from all treatment sites (uptake and clearance) at the end  of the uptake phase. The total cleaning time should be minimised to avoid any artefacts due to further drug diffusion. Skin integrity of the treated area should be checked before stripping;

• 在吸收结束后，应将给药位点（吸收和清除）的样品去除；并尽量减少总清洁时间，以避免由于药物进一步扩散造成偏差。在胶带剥离前，对上样区域的皮肤完整性进行测定；

• The 'uptake’ sites should be tape-stripped immediately after formulation removal. The 'clearance’ sites should be tape-stripped at the pre-defined clearance times;
  对于“吸收”位点，应在去除配方制剂后立即用胶带剥离。而“清除”位点是在预定的清除时间用胶带剥离；
• The exact number of tapes required should be determined based on TEWL measurements of the stripped area and the stopping criteria established from the pilot study;

  应根据胶带剥离区域的TEWL测定结果和探索性研究中建立的停止标准，确定所需胶带的确切数量；

• The mass of SC removed per tape should be determined using a gravimetric method by weighing the tapes strips before and after stripping. Alternative methods of quantification of the SC can be used if suitably described and justified;

  应确定每条胶带去除的角质层的重量，可通过称量胶带剥离前后的重量，以减重法进行测定。如合理，也可采用其它可替代方法；

• All stripped tapes collected from each treatment site should be analysed. The first two tapes should be analysed separately from the remaining tapes, so their contribution to the total amount of drug recovered can be evaluated. To enhance analytical detectability, the subsequent tapes can be combined in groups (e.g. each group containing the required minimum content of SC) for extraction. The total mass of drug in the SC should be calculated as the sum extracted from all tape strip samples. The mass balance, including the drug content removed from the surface by cleaning should be determined for each treatment site. The overall recovery of 90-110% would be acceptable without justification; larger variation should be fully explained.

  收集用于每个治疗位点剥离的所有胶带，进行测定。将剥离的前两个胶带单独进行测定，评估它们对药物回收总量的贡献。为增强方法的检出能力，可将剩余的胶带分组（如，每组应包含所需最少量的角质层）提取后进行测定。角质层中药物的总量为从所有剥离胶带中提取的样品量之和。应对每个治疗位点的质量平衡（包括从角质层表面移除的药物）进行评估。药物总回收率的可接受范围是90%~110%；如超出该范围，应提供合理性说明。

4. Method validation 方法验证

Cleaning the skin surface at the end of the application period prior to tape-stripping is important and must be capable of removing excess formulation (i.e. unabsorbed drug) efficiently without inadvertently 'driving’ the drug into the barrier. The cleaning procedure usually involves quickly and gently wiping the skin with dry/wet tissue, cotton swabs and/or fresh alcohol wipes. The cleaning components should be known not to influence drug diffusion into and through the SC. A careful evaluation and validation of an efficient skin cleaning procedure should be performed prior to the pivotal study, e.g. by demonstrating satisfactory recovery (>90%) of the drug formulation removed from the skin surface and the negligible drug content (<10%) recovered by stripping the cleaned skin immediately after application. Other ways of validation may be used if suitably justified.

在胶带剥离前，对给予药物一定时间后的皮肤表面进行清洁很重要，且必须确保可以移除过量的配方制剂（即未被吸收的药物），使药物不会不受控的进入皮肤屏障。常用的清洁方法是，采用干/湿纸巾或绵纸、棉签和/或新鲜的酒精湿巾快速轻柔地擦拭皮肤。所用的清洁工具应不影响药物扩散进入和通过角质层。在正式研究前，应对清洁方法进行小心的评估和确认，确保其可有效的清洁皮肤表面；例如，在上样后立即对皮肤进行清洁，结果表明，从皮肤表面移除的配方制剂回收率大于90%，胶带剥离得到回收率小于10%，则是比较令人满意的结果。如合理，也可采用其它的方式进行验证。

The bioanalytical method employed for drug quantification in the tape strips should be validated. The efficiency of the extraction procedures (including extraction of tape strips in groups) should be established and demonstrated as consistent prior to the pivotal study.

The discriminatory power of the TS method should be demonstrated for batches with different quality attributes (a negative control), such as a drug formulation with ±50% of the proposed product strength, that is shown to be statistically different and non-equivalent to the test and comparator products. The analytical methods for determining the content of active substance in the tape-stripped SC should be validated according to the Guideline on Bioanalytical Method Validation.

在胶带剥离试验中，应对用于药物定量的生物分析方法进行验证。在正式研究前，应对提取方法（包括对分组的剥离用胶带的提取）的有效性进行确认，确保其可以有效的提取，并可产生一致的结果。

应采用不同质量属性的样品（包括阴性控制样品）对胶带剥离（TS）方法的区分力进行论证，如采用±50%标称规格的样品，其结果与受试制剂和参照制剂相比，具有统计学差异且不等效。应按照《生物分析方法验证指南》，对胶带剥离角质层中活性物质含量的测定方法进行验证。

5. Data analysis and metrics 数据分析与度量

Data from all subjects should be reported and the validity and variability of the results shouldbe discussed. All treated subjects and application sites should be included in the statistical analysis.The permitted reasons for exclusion must be pre-specified in the protocol. Data exclusion basedon statistical analysis or for kinetic reasons alone is not acceptable.

应报告所有受试者的数据，并对结果的有效性和可变性进行讨论。在统计分析中，应纳入所有受试者和给药部位。数据的排除必须基于方案中预先规定的标准。仅仅基于统计分析或动力学原因，是不可以接受的。

For each product, the thickness of SC removed, the number of tapes used and final TEWL value measured at both uptake and clearance times should be reported.Any differences in the separameters between the test and comparator products should be discussed with respect toequivalence.

A plot of drug content profile in the SC should be presented for each application site, e.g. the drug content of each SC tape strip (single or grouped) versus SC depth. The duplicated measurements for each product in each subject should be averaged (population geometric mean) prior toanalysis.

对于每种产品，应报告去除的角质层（SC）厚度、剥离用的胶带数量，和吸收与清除阶段TEWL的测定结果。应讨论受试制剂与参照制剂之间这些参数的差异对等效性的影响。

对于每个给药部位，应确定药物在角质层中的概况，如每组胶带剥离的角质层中药物的含量与角质层深度的关系。在分析之前，应对每个受试者、每个产品的重复测定结果取平均值（总体几何平均）。

For the comparison of products, the equivalence parameters: mass of drug recovered from the uptake (Muptake) and clearance (Mclearance) sites, should be statistically compared, according to the Guidelineon the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr). The acceptance criteria for equivalence parameters (M_uptake) and (M_clearance)are:

在两个产品的比较中，应根据生物等效性研究指南（CPMP/EWP/QWP/1401/98 Rev. 1/ Corr），对等效性参数进行统计分析。等效参数（M_uptake）和（M_clearance）的接受标准是：

• The 90% confidence interval for the ratio of means of the test and comparator products should be contained within the acceptance interval of 80.00- 125.00%, unless justified.

  受试产品与参照产品均值比率的90% 置信区间应包含在80.00－125.00%的可接受范围，除非有正当理由。
• Wider 90% confidence interval limits, to a maximum of 69.84 – 143.19, may be accepted in the case of high variability observed with low strength and limited diffusion drug products, and if clinically justified. The procedure in the Guideline on Investigation of Bioequivalence, “Section 4.1.10 Highly variable drugs or drug products” should be followed.

  对于小规格和扩散量有限的药物产品，如果观察到具有高变异性，可通过临床研究，放宽90%置信区间，采用更宽松的接受标准69.84-143.19。应遵循生物等效性研究指南“第4.1.10节高度变异性药物或药物产品”的相关规定。

In addition, for the test to be valid: 此外，为了确认测试结果可信：

The acceptance criteria for equivalence parameters (Muptake) and (Mclearance) 等效性参数(Muptake)和(Mclearance)的接受标准为：

• The 90% confidence interval for the ratio of means of the test and negative control products should be entirely outside the interval of 80.00- 125.00%.

  受试产品与阴性控制产品均值比率的90% 置信区间应全部在80.00－125.00%之外。

• The 90% confidence interval for the ratio of means of the comparator and negative control products should be entirely outside the interval of 80.00- 125.00%.

  参照产品与阴性控制产品均值比率的90% 置信区间应全部在80.00－125.00%之外。

• The 90% confidence interval for the ratio of means of the test product clearance (Mclearance)and (Muptake)  comparator products should be entirely below1.0.

• The 90% confidence interval for the ratio of means of the comparator productclearance (Mclearance) and (Muptake)  comparator products should be entirely below 1.0.

The overall conclusions of the study should be provided. This should be supported by a sound scientific discussion and interpretation of the TS data.

应递交该研究的总体结论，并通过合理的科学讨论和胶带剥离（TS）数据的解释，进行说明。

Annex IV  Vasoconstriction assay for corticosteroids 附件 IV 皮质类固醇的血管收缩试验

A description of the protocol for the assay should be provided.

The following testing principles should be followed:

An in vivo pilot dose duration-response study should be undertaken to determine the study requirements for determining the equivalence parameters to be used in the pivotal equivalence study.

Relevant human volunteer inclusion and exclusion criteria should be stated and adhered to for both pilot and pivotal studies.

Healthy subject with an adequate vasoconstriction to topical corticosteroids must be included.

应提供对试验方法的描述。

应遵循以下测试原则：

应进行剂量维持时间—响应的体内探索性研究，以确定在正式等效性研究中等效参数的研究要求。

在探索性研究和正式研究中，应说明相关的人类志愿者的纳入和排除标准。

对外用皮质类固醇有适当血管收缩的健康受试者必须包括在内。

Test product, vehicle, comparator product, and untreated control should be randomly assigned to application sites on the ventral forearms.

The study should be appropriately blinded.

For the pivotal study, a minimum of 12 subjects should be included.

受试产品、载体、参照产品和未上样的对照应随机分配到前臂内侧的应用部位。

该研究应适当采用盲法程序。

在正式研究中，至少应包括12名受试者。

The vasoconstriction reaction should be determined at baseline (before drug application), time of drug product removal, and several times after drug product removal (e.g. 2, 4, 6, 19, 24 hours).

The time course of response should be followed until return to baseline to ensure that maximal pharmacodynamic response is observed. The assay must be optimised to ensure that the products are compared in the linear portion of the blanching curve. Several application times should be tested in pre-test. The lower limit of sensitivity should be determined.

应分别在基线（上药前）、移除药物产品时以及移除药物产品后的几个时间点（如2、4、6、19、24小时）对血管收缩反应进行测定。

研究的时长应足以使响应恢复到基线水平，并确保可观察到最大的药效学反应。此外，必须对试验方法进行优化，使产品可以根据 blanching curve 的线性部分进行比较。在预试验中，应对几个不同的上样时间进行测定，以确定灵敏度下限。

The vasoconstriction reaction should be determined at several time points and AUC data should be generated. A single time point for estimation of the vasoconstriction reaction is not acceptable.

The measurement of the vasoconstriction reaction should be performed by using a chromameter, or other methods more sensitive than visual estimation, and by a secondary clinical assessment by an independent observer.

应在几个不同的时间点对血管收缩反应进行测定，以获得曲线下面积（AUC）数据。单时间点估计血管收缩反应是不可接受的。

血管收缩反应的测量应使用色度计或其他比目测更敏感的方法，并由独立观察者进行二次临床评估。

References: 参考文献

1. FDA Guidance for Industry: Topical Dermatologic Corticosteroids: in vivo bioequivalence 2 June 1995.

2. “Quantification of corticosteroid-induced skin vasoconstriction”, Dermatology, (2002), 205, 3-10.
3. “The skin-blanching assay”, Journal of the European Academy of Dermatology and Venerology (2012), 26, 1197-1202.