重庆高校在线开放课程平台 温馨教导：用电脑不雅看，后果愈加        译者：刘新；校对：潘宪伟对于复杂制剂，本公众号已推出以下指南或律例 中英文版 供行家参考，络续如下：指南1：阿昔洛韦（乳膏）指南草案（2016年）指南2：ANDA肯求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肯求中递交的外用药物产品的体外开释（IVRT）研究（2022年10月）指南4：ANDA 肯求中递交的外用药物产品的物理化学和结构（Q3）特质（2022年10月）律例5：USP<3>外用和透皮制剂：产品质地测试（现行版）律例6：USP<1724> 半固体药物制剂：性能测试（2022年05月计议稿）文献7：非肠说念缓释制剂体外加快开释测试方法厚爱阅读了解上述 “指南1、2、3” 和 “律例6”，校服行家对 IVRT 和 IVPT 的研究会有比较深的体会，包括：IVRT 和 IVPT 研究的办法和区别、方法开发考据、覆按想象以及数据统计分析等。对于外用制剂关键质地属性的适度，本号已推出  指南4 和 USP<3>；本文推出 EMA 对于 “外用制剂质地和等效性”指南，其中波及的内容包括：外用制剂质地（描摹与构成、产品开发、适度战略、清爽性）、等效性、批准后变更、IVRT、IVPT、角质层取样（胶带剥离）等 。闲扯少说，下文谨慎先容 EMA 指南：Draft guideline on quality and equivalence of topical products外用制剂质地和等效性指南草案18 October 2018 2018年10月18日CHMP/QWP/708282/2018  东说念主用药品委员会/质地职责组/708282/2018Committee for Medicinal Products for Human Use (CHMP)  东说念主用药品委员会（CHMP）Draft Agreed by QWP  草案经质地职责组（QWP）喜悦7 June2018Adoption by CHMP for release forconsultation CHMP选择并发布接头倡导18 October2018Start of publicconsultation 运行征求公众倡导14 December2018End of consultation (deadline forcomments)  收尾征求倡导（计议截止日历）30 June2019Agreed by QWP  QWP 喜悦Adopted by CHMP CHMP选择Date for coming intoeffect 顺利日历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《透皮贴剂质地指南》(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 QWP@ema.europa.eu应使用此模板提供计议。完好的计议或建议可发送至 QWP@ema.europa.euKeywords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、局部给药阐述局部作用药物、皮肤渗透、体外开释、角质层取样、胶带剥离Executive summary 选录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阐述局部作用药物，也适用于其他药物，举例眼用药物与耳用药物。具体内容包括：On the quality of topical products not covered by otherguidelines.其他指南未涵盖的外用制剂的质地。On equivalence testing of topical products in lieu of therapeutic equivalence clinical trials.以局部外用药品的等效性覆按代替临床调治等效性覆按。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.现存指南指岀，对于外用药物制剂，配方、剂型、给药方法或坐褥工艺的变化均可能会权臣影响灵验性和（或）安全性。临床调治等效性研究在原则上是必要的，但也不错使用或开发其他模子。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.当调治方法疏导且对患者的不等效性风险最小时，这一指南也可在其他模子和研究中提供率领。这些模子和研究可孤苦用于细目与(i)质地、(ii)功效和(iii)安全性相关的等效性以及上述三方面回归而成的调治等效性。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调治等效性覆按但愿被实施的情况下。描摹了这种方法的范围、局限性和采纳圭臬。这一指南应被用于开发息争释局部外用药品专用的等效性草案。In addition， equivalence test protocols are providedfor: 此外，还提供了以劣等效性性覆按决策：in vitro release 体外开释in vitro human skinpermeation 体外东说念主体皮肤渗透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覆按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.质地指南适用于新的上市许可肯求和批准后变更。等效性指南适用于特定案例中新的局部外用药品与现存的局部外用药品之间等效性论证的情况。1、Introduction and Background 绪言和配景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、待调治的病症范围、以及患者与其需求的各种性，局部外用药品具有相称平庸的各种性。该指南并不是建议一个单一的轨范来处罚这各种种性，而是提供一般性建议。这些建议不错适用于逐案分析基础上的任何给定药品。该指南论说了现存的监管指南，并通过现存的科学学问进行见告。1.1 Quality of Topical Products 外用制剂质地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地指南中未波及的对于局部外用药品的指南。需要先了解药物的安妥症、方向东说念主群和作用部位，从而不错在药物剂型、构成和给药方法上作念出最贤慧的弃取。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邀功能。这不错通过疏忽地将活性物资施加到皮肤名义。在许厚情况下，不错通过在药物中加入约略蜕变活性物资的热力学性质的辅料加多药物的生物利费用，举例通过増溶和过饱和来蜕变活性物资的扩散，或通过促渗剂阻扰生理樊篱。皮肤的闭塞或药物载体自身，如保湿剂和润滑剂，可能影响待调治的景色。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.产品方向质地概况应试虑患者的可经受性、是否易于寂静器中鼎新并给药，以及全体好意思不雅性，如外不雅、铺展性、触感、微不雅结构/物感性质、蒸发性辅料的蒸发和适当的装束等，如适用。这些因素需要被表征，况兼在必要时被看成关键质地属性进行适度。应聘用讲究的先验学问，已拓荒的科学表面依据和凭证来开发药品配方。所产生的质地特质应从可代表上市产品的多个批次中细目。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.需要一个稳健的坐褥工艺，以确保药品在通盘这个词上市货架期内质地恒定。上市产品应与已证明有令东说念主闲散的灵验性和安全性或等效性凭证的批次具有疏导的质地。应通过清爽性研究证明，各批次产品在货架期运行和收尾时具有疏导的物理、化学和微生物资量特质，且在特定情况情况下，具有疏导的体外性能特征。适度战略应确保产品合适其预期办法，并合适相关药典圭臬。不行通过参考临床覆按来证明产品的开发或质地不及。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肯求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、质地或灵验性产生首要影响的情况下，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灵验性的应用的情况下，文献的相关性应该通过药物产品与文献中描摹的药品之间的等价性桥接数据来支握。这是因为在配方、坐褥和给药方法中质地相反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.现存指南指岀，对于外用药物制剂，配方、剂型、给药方法或坐褥工艺的变化可能会权臣影响灵验性和（或）安全性。临床调治等效性研究在原则上是必要的，但也不错使用或开发其他模子。本指南提供了对于体外和体内模子怎么替代临床数据以拓荒调治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.对证地的等效性的论证泛泛不及以预计调治等效性。但对于液体制剂（如皮肤用溶液）来说，当给药方法疏导期，仅基于质地等效性数据是不错通过调治等效性豁免的。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，质地的等效性不错通过与参照药物产品（即已上市药物制剂）的对比数据拓荒，包括：药物剂型、定性和定量构成、显微结构/物感性质、产品质能、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.对于药效的等效性需要参比其渗透能源学，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。合适的渗透能源学方法是体外东说念主体皮肤渗透和对东说念主类志愿者活体角质层（S.C.）采样（胶带剥离）以及体内药代能源学生物等效性实验。合适的药效学研究包括对东说念主类志愿者进行的体内皮质类固醇血管收缩覆按和针对防腐剂或杀菌剂的体内微生物肃清实验。若是渗透能源学和药效学研究不适用或被觉得不及以预计临床反应，则泛泛需要临床疗效数据。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.对于安全性和局部耐受性的等效性不错从活性物资的学问和已完善的辅料的弃取中推断岀来。针对疏忽配方，从渗透能源学或药效等效性研究中可取得生物等效豁免，即对证地等效性进行充分论证就饱和。一般性率领不错被应用于开发药物产品的特定期间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阐述局部作用药物，也适用于其他药物，举例眼用药物与耳用药物。指南适用于局部外用药品的质地，包括其他—般性质地准则中未波及的化学原料药，和用于支握局部外用药品与参照药品的调治等效性覆按，以替代临床调治等效性覆按。质地指南适用于新的上市许可肯求和批准后变更。等效性指南适用于特定案例中新的局部外用药品与现存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，参见生物访佛药产品指南中草药产品当通过临床调治等效性覆按来证明疗效的等效性时当覆按中药物剂型或定性和定量构成与参照药品不疏导或不等同期（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.本指南应都集指示2001/83/EC及相关药典通则和指南阅读。Quality Guidelines 质地指南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;制剂成品坐褥，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;药物制剂工艺考据的指南；监督倡导书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诉府上中的辅料，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质地圭臬：新原料药和新药制剂的检测方法和认同限定：化学物资，CPMP/ICH/367/96-ICH；Q2(R1) Validation of Analytical Procedures: Text and Methodology， CPMP/ICH/381/95 - ICH Q2 208 (R1);Q2(R1)分析方法考据：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);新原料药和制剂的清爽性覆按(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.;现存活性要素及相关药物制剂的清爽性覆按，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含已知要素的局部给药、局部起效制剂的临床要求指南的注解，CPMP/EWP/239/95 FinalGuideline 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/ CorrGuideline on bioanalytical method validation EMEA/ CHMP/ EWP/ 192217/ 2009 Rev. 1 Corr. 2生物分析方法考据指南，EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2General Considerations for Clinical Trials (ICH topic E8， CPMP/ICH/291/95)临床覆按的一般辩论（ICH topic E8，CPMP/ICH/291/95）Guideline for Good Clinical Practice (ICH E6 (R1)， CPMP/ICH/135/95)药物临床覆按管制轨范 (ICH E6 (R1)， CPMP/ICH/135/95)Statistical Principles for Clinical Trials (ICH E9， CPMP/ICH/363/96)临床覆按的统计学原则 (ICH E9， CPMP/ICH/363/96)Reflection Paper on advice to Applicants/Sponsors/CROs of Bioequivalence Studies 222 EMEA/INS/GCP/468975/2007对于生物等效性研究中肯求者/扶植商/联结研究机构的建议的反馈文献， EMEA/INS/GCP/468975/2007Reflection 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.对于药物开发中质地属性的对比评估的统计方法的反馈文献Draft (EMA/CHMP/138502/2017)。尽管只是草案，不外该文提供了相关质地属性比较评估的统计方面确刻下监管辩论。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中使用东说念主类志愿者进行的等效性覆按应按照指示2001/20/EC进行。体外表肤渗透能源学等效性覆按是产品认证的关键，需经国度期骗部门搜检，并应按照指示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.在欧盟除外进行的覆按并准备将其用于 EU/EEA 的上市许可肯求中的，应当按照指示 2001/83/EC 共同守则的附录一中制定的圭臬进行。公司不错针对现行指南中未波及特定事项向 CHMP 和 NCA 进行科学接头。4 Quality of Topical Products 外用制剂质地4.1 Description and composition of the drug product 药品描摹与构成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.应注意描摹药物的构成要素和辅料的功能。辅料的称号应该是具体且唯独的。保举使用国外非专利称号(INN或INN modifie(INNM))( 若是与盐相关应加上盐称号)，或欧洲药典称号，或其常用的通用名，或化学称号，若非上述称号则应证明拟命称号合感性。为了确保达到一致的工业坐褥武艺和产品质地，应包括级别或品牌（交易）称号。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.根据药物产品的想象和办法，对于具有多种功能的辅料，应明确说明，举例：丙二醇可同期看成保湿剂、渗透促进剂和増溶剂。应基于 SmPC（Summary of Product Characteristics 产品特质选录）中的使用说明和最大日用量，对单元面积上使用的活性物资的量进行说明。应当对低级包装，必要时包括二级包装，或其他影响药品清爽性或给药的材料或要素进行说明。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.应在申诉府上的药物开发部分，注意的描摹外用产品工艺开发的科学合感性，以及通盘相关的数据。4.2.1 Therapeutic objectives and topical productdesign 调治方向和外用制剂想象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.根据方向产品质地概况（QTPP），细目产品的预期调治方向和办法，并解释怎么通过产品想象竣事这些方向的。在患者方面，应试虑的内容包括：皮肤的安妥症和病情；年岁安妥性、患者可经受性、给药方式和可行性、给药部位；功效（产品规格和剂量学、原料药的溶质景色、生物利费用和/或渗透增强）；润肤剂；安全性（组分的毒性、杂质、微生物）；质地（物理和化学清爽性、关键质地属性、药典和律例要求的合适性）。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：皮肤名义；皮肤里面（角质层、表皮或真皮层）；或皮下和皮下摆布组织（区域）。应说明活性物资到达作用部位的方式和渗透能源学。如适用，通过这些内容走漏的说明给药方式、活性物资的熔解景色、药物的熔解/开释和通过东说念主体皮肤的扩散情况。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，举例皮肤杀菌或抑菌溶液，不错仅辩论给药方式。但其他情况，举例非甾体抗炎药乳膏，就必须覆按以上通盘的因素。对可进步生物利费用和润肤性的辅料的加入应作出解释并证明其合感性。对配方的弃取，举例为何弃取凝胶、乳膏和软膏，应作出解释并证明其合感性。如条目允许，叮咛不同规格的配比和用量进行计议。如适用，应在申诉府上中，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费用、配方、性能和清爽性具有要紧作用，应进行识别和计议。若是原料药以固态样子存在于药品中，这些特质可能包括：分子量、分拨所有、熔点（沸点，如适用）、pKa、对光、空气或水分的明锐性、降解蹊径、熔解度和pH依赖性，以及粒径和多晶型性。在原料药质地圭臬中应识别和适度这些关键质地属性。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时常进展岀批间相反和着手相反，举例烃链同系物构成、不饱和度、分子量、多态性。这反过来可能导致产品流变特质、微不雅结构/物感性质、原料药或其他要素的晶型、清爽性或生物利费用的不可料念念的变化。在开发经由中，应试虑并论说辅料的批间相反和着手相反。如适用，应根据辅料的功能，包括润肤作用，对每个辅料的弃取、用量和相关的关键质地属性（CQAs）进行计议，说明其合感性。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蜕变活性物资的生物利费用、产品可制造性或质地时，应明确该辅料的级别或型号。质地圭臬中应适度辅料的关键质地属性（CQAs），并拟定合理的适度限定。应提供可能对活性物资的渗透性和生物利费用有影响的辅料的注意信息，举例增溶剂/渗透促进剂，包括它们提供预期功能的武艺和在通盘这个词药品货架期期间阐述作用的武艺。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.若是辅料是数种化合物的夹杂物，应提供其组分的定性和定量信息，如适用，包括流变学信息。对于新式辅料，应提供制造、表征和质控的完好细节信息，并交叉援用支握的安全数据。对于同期也在化妆品中使用的辅料，不错提供合适化妆品律例1223/2009的数据。应明确和描摹加工助剂信息。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，在新药的开发中应幸免或尽可能的减少使用。看成参考，请参阅“东说念主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，对药品的开发经由进行描摹：已界说的方向产品质地概况（QTPP）；聘用合适的测试来表征和适度关键质地属性（CQAs）；影响易使用性和握续期间的因素；和产品质能，举例熔解度、体外药物开释，如适用，体外表肤渗透实验。应提供用于评估产品的测试方法和经受圭臬的适用性的凭证（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.药品华夏料药的存在方式（举例熔解如故混悬）和饱和进度是其关键质地属性（CQAs），应通过对产品的灵验性和安全性的影响，对这些属性进行论证，并提供在坐褥经由中怎么达到其方向景色和在储存期间怎么保握原始方向景色的凭证来佐证。在清爽性研究中应进行适当的测试，以评估由温度和储存条目变化引起的晶体千里降、颗粒孕育、结晶习性变化，或其他可能影响生物利费用的原料药特质的变化风险。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.应计议活性要素向皮肤作用部位的寄递情况。溶剂和透皮招揽促进剂可用于匡助活性物资运输至不同的皮肤脉络。软膏不错顽固皮肤，从而起到促进药物透皮渗透和招揽的作用。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招揽寄递的驱能源，因此竣事药物产品中活性物资的饱和景色是要紧的关键性因素。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.应试虑患者的可经受性以及药物产品的易使用性，举例是否浅易给药、是否易于涂布，这对于每单元名义积的剂量和肤感（干燥或浓重）都曲直常要紧的。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，招揽型基质）、乳膏、亲水软膏。对于半固体制剂，其微不雅结构/物感性质可能比较复杂，应充分了解其微不雅结构/物感性质过甚形成机制，举例辅料的相互作用、批间相反和批量放大，从而促进坐褥工艺的优化，取得质地一致的产品。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.应计议局部外用制剂的给药方式带来的药物拯救的问题，非常是蒸发性溶剂或辅料的蒸发，或其他气象，可能影响药物是否能灵验地寄递到作用部位。应注意描摹临床覆按配方和在对比研究中使用的批次。关键临床覆按批次和待上市药品在配方和坐褥经由中的任何相反都应该进行合感性说明。应提供体外或体内的任何扩展和延长的制剂学等效性研究的终结。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.当细目配方构成，在行将开展的放大坐褥中，应细目需适度的关键工艺参数。在这一阶段，为达成和全面优化坐褥工艺，进行必要的调整是合理的。这些调整可能包括构成、坐褥工艺、设备或坐褥气象的变化。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，举例对药物的生物利费用和可用性的影响。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).应提供凭证，说明外用制剂合适欧洲药典（Ph. Eur.）的要求。应充分计议方向产品质地概况（QTPP）、关键质地属性与药品质地圭臬之间的关系。当药品载体含有易燃蒸发性溶剂时，如异丙醇和酒精，应根据相关ISO圭臬和产品信息中包含的相关告诫细目其闪点或燃点（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).使用石蜡看成基质的产品自身并不具有易燃性，可是当衣物、床上用品和敷料被其浸渍时会起到灯炷的作用，况兼石蜡在着火时不错起到助燃的作用。应评估其对患者带来的风险，并在产品信息中添加适当的告诫（参见4.2.6节）。4.2.5 Product characterisation  产品特质表征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.应制定注意的产品特质表征方法，以便于药品质命周期管制，条目允许的情况下，可用于支握与原研或参照制剂产品的等效性论证。特质表征数据应来自具有代表性的批次，辩论到分散系统比拟于疏忽溶液具有更大的可变性，弃取的批次数量不应少于三个批次。为了进行统计评估，样品的数量应饱和多以具备代表性，每个实验中每批至少要有12个样本。也应试虑到由于批量大小、坐褥日历和储存期限等因素导致的批间相反。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、招揽型基质、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资的熔解景色、分散和不混溶相和制剂类型等药物剂型的凭证。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.举例：溶液中的活性物资，单相体系，如：皮肤用溶液剂、单相的凝胶剂或软膏剂。混悬剂中的活性物资，单相体系，如：皮肤用混悬剂。溶液中的活性物资，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。混悬剂中的活性物资，两相体系，如水包油型（o/w）乳膏，活性物资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，需提供活性物资粒径溜达和多晶型的研究终结，包括显微相片。对于互不混溶的配方制剂，需额外提供液滴的尺寸溜达和外不雅方面的表征，包括显微相片。若是可能的话，不错聘用激光衍射、拉曼化学成像和显微镜等不同方法进行粒度分析。Appearance 外不雅This should be characterised visually and with microphotography - particularly for dispersed systems.应通过视觉和显微摄影来表征 - 非常是对于分散系统。Microstructure / Physical Properties 微不雅结构/物感性质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.应提供凭证来表征药物的微不雅结构/物感性质，包括影响药物的生物利费用、易用性，或辅导坐褥工艺的变异和产品不清爽的物理CQAs（关键质地属性）。举例，对于溶液和悬浮液 — pH值、缓冲容量、粘度、密度、名义张力、渗透压。举例，对于半固体制剂 — pH、密度、流变行动。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 testingThe linear viscoelastic response (storage and loss modulus vs. frequency)非牛顿流变行动应使用合适的齐全流变仪进行表征，包括：剪切应力（或粘度）与剪切速度的完好流动弧线，包括在剪切速度的加多和减小范围内的多个数据点，以便走漏地识别出弧线上涨或弧线着落的任何线性部分。所得弧线应通过拟合（修正的）幂定律方程来表征，以便不错生成数值数据；屈服应力和蠕变覆按；线性粘弹性反馈（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.应提供根据剪切和期间效应分类的流变图和药品行动，举例假塑性、扩张性、触变性，并使用适当的度量表征。举例：流变图中指定剪切速度下的粘度（举例 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”）、表不雅粘度、损耗角正切（tan δ）。流变特质的适当表征可使在成品圭臬中使用的疏忽覆按的识别或想象成为可能。Product Performance 产品质能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.应拟定合适的检测神色用于表征产品质能，如混悬液的熔解和体外药物开释（附件I），并证明样品在储存期间是清爽的。也不错聘用体外表肤渗透（附件II）实验表征产品质能。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告诫。相关时，应描摹药品在给药经由中的形变。应试虑以下事项：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；幸免受损或未受损皮肤的必要性；皮肤预处理的要求；走漏于热、冷、阳光映照的极点环境影响；日常行动如洗涤、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.任何须要的截止，举例幸免顽固；任何特殊储存条目的本体可行性；幸免儿童巧合使用；对于含有易燃蒸发性溶剂的药品，应有适当的易燃性安全告诫。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.举例：危急：易燃。隔离热源、热名义、火花、明火和其他火源。谢绝抽烟。幸免阳光映照。不要走漏于跨越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跨越100g时，建议依期更换一稔、床上用品和敷料，并隔离明火。For example: 举例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掩饰时，抽烟或使用明火可能导致衣物着火。不要抽烟、不要使用明火（或围聚抽烟者和使用明火者）、不要围聚任何可激生气灾的物品或令这些物品与你的衣物、敷料或绷带构兵。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.确保依期（最好每天）更换一稔和床上用品，因为石蜡会浸透织物中，并可能激生气灾。还应该小心，确保石蜡不会浸透椅子、座椅或其他产品中。把这些注重事项告诉你的支属或看护者，并给他们看下这个手册。若是你频繁抽烟，请见告你的大夫、照顾或药师。他们能给你提供戒烟的匡助和建议。4.2.7 Manufacturing process development and Manufacture (P.2.3 and P.3) 坐褥工艺开发和坐褥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，举例两相乳液，配方或坐褥工艺的变化可能影响产品的灵验性和/或安全性，因此对其进行评估和适度是很要紧的。配方制剂中不同组分的添加法令，以及温度和均质化条目（举例速度和握续期间）等工艺参数曲直常要紧的。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.对于一般的坐褥工艺而言，关键设施泛泛是单相体系形成两相或多相体系的经由，以及活性物资添加的设施。由于药物产品的药物开释速度、微不雅结构/物理特质和流变特质易受放大效应的影响，因此在交易化规模放大时叮咛这些特质进行阐明。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.应在申诉府上的模块3.2.P.3.3和3.2.P.3.4中提供饱和注意的信息，包括关键和非关键工艺参数，并提供所进行的坐褥工艺开发数据证明其合感性。应提供适当的清爽性研究和其他相关数据，论证不同溶液和中间体的保存期间和储存条目。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.许多散装外用制剂在坐褥后的几天会出现剪切致稠的气象。此时，可能需要优化产品坐褥和灌装的期间拆开。此外，还应计议包装对中间体、散装产品储存、运载（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.叮咛容器密闭系统的适用性（在3.2.P.7中描摹）进行计议并证明其合感性，包括：材料的弃取；如适用，对湿气、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。若是需将相关设备一说念包装以便于，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；若是是测量设备，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，与其它给药蹊径一致，应加以辩论，因为皮肤产品有时会涂在受损的皮肤上。需合适EP 5.1.4 非无菌药物制剂的微生物资量。若是要在大的怒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（举例术前皮肤杀菌剂），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，需辩论防腐剂在不同相中的熔解度。4.3 Control strategy 适度战略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.对于药物产品适度战略的拓荒和论证信息可参考其他相关指南，包括 ICH Q8、Q9 和 Q10。关联词，应注重适度与药物开释相关的 CQA，即体外药物开释/熔解、体外表肤渗透（如适用）。若是可能的话，在药物开发经由中，应拓荒药品质能质地属性和临床疗效之间的筹备4.3.1 Drug product specification (P.5)  药品质地圭臬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.药品质地圭臬相关指南可参考ICH Q6A、Q3B、Q3C和Q3D，此外，需合适欧洲药典列出的剂型通则。药品质地圭臬应包含物理、化学和微生物资量测试，以及4.2.5中描摹的产品质能测试。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.晶型拯救可能会对功效产生不利影响，使产品质地出现漏洞；脱水收缩，即从半固体中排出液体，是另一种漏洞。应试虑容器中制剂的均匀性，以阐明是否有千里淀气象。对于外用制剂，因调治的握续期间和所需的量泛泛具有较大的可变性，用最大日剂量细目降解产物限值并不像固体口服制剂或打针剂那么疏忽。泛泛觉得与系统性走漏比拟，皮肤用制剂的走漏珠平要低得多。可从安全角度说明，与圭臬预计打算存在一定偏差的合感性。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，在预计打算杂质的经受限定时，应明确相关的注重事项。若是质地圭臬中包含性能测试（即：溶出，聘用合成膜进行的药物开释测试；皮肤渗透测试，如适用），应根据已证明具有讲究疗效和安全性的临床批次数据，说明拟定限定的合感性。除非提供合理的临床数据支撑，放行圭臬和货架期圭臬的限定应保握一致。4.4 Stability program (P.8) 清爽性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.为了确保通盘这个词储存经由中产品具有清爽的质地和一致的特质，应基于产品的物理、化学和微生物学清爽性，以及体外开释或其他性能测试数据，拟定合理的货架期。叮咛可能影响产品清爽的风险因素进行评估，举例千里淀/析出、颗粒孕育、结晶习性变化、或其他可能影响热力学性质的活性物资特质，以及乳液特质变化。除了质地圭臬中包含的搜检项，在药品清爽性研究中，也叮咛其它合适的质地属性进行覆按。剪切致稠和产品微不雅结构的变化亦然要辩论的风险因素。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.清爽性研究中应进行影响因素覆按，以评估薄情条目对药品的影响，如温度轮回（低－高温）对乳膏剂和乳剂的清爽性影响。在清爽性研究中，应包括监控容器密封系统适用性的检测覆按。如在贮藏经由中有特殊要求，应明确指出，如不行冷藏。应开展产品使用中清爽性覆按。根据药品的包装规格和用量信息，拟定合理的覆按握续期间，这点非常要紧。不应形成无须要的耗损，或拟定一个较短的产品使用中清爽性期限。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.本部分先容了外用制剂的等效性测试，用于支握与参照药物比拟的调治等效性，以代替等效性临床覆按。并对与质地、功效和安全性相关的方面进行计议。对于疏忽的配方制剂（举例单相的溶液剂、凝胶剂和软膏剂），证明质地等效性（即扩展的药学等效性），可能就饱和了。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，或含有的辅料可能平直影响活性物资生物利费用或产品质能的制剂，泛泛需要进行额外的渗透能源学和药效学等效性覆按（如可能）。在可量化渗透能源学和药效学等效性覆按中聘用的分析方法，应具有饱和精通度、永别力、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。以下类型的药物不行仅聘用以上方法，原则上需要进行临床调治等效性研究：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.调治指数窄的药物与剂量相关的全身毒性药物，但在惯例药代能源学生物等效性研究中炫耀具有等效全身系统走漏的情况除外尚未拓荒或明确以下情况的，如药物的熔解、开释、扩散以及渗透能源学研究中药物到达的具体皮肤层不同的给药蹊径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.不行用质地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能源学或药效学无法量化时，举例有限的扩散或对测试不解锐。当体外和体内渗透能源学和药效学研究不适用或被觉得不行充分预计临床反适时，举例用于调治怒放性伤口和溃疡的产品。5.2 Equivalence with respect to quality (extended pharmaceutical equivalence) 对于质地的等效性（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，可将取得的产品表征数据（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、定性和定量构成、微不雅结构/物感性质、产品质能（如溶出、体外开释覆按）和给药方法。对于基于蒸发性溶剂的外用制剂，还应比较产品在给药时的回荡。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.在药品质地等效性研究中，应聘用可代表拟上市销售和坐褥工艺的批次进行，即达到或接近坐褥规模的批次。此外，若是坐褥工艺和设备莫得变化，且有凭证标明放大不会影响产品质地，则不错使用终点于坐褥批量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.无人不晓，在提交申诉时可能只好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，药品的性质保握不变且等效。5.2.1 Extended pharmaceutical equivalence acceptance criteria 拓展药物等效性的经受圭臬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经受圭臬是：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.药品应为疏导的药物剂型，在疏导的不混溶相中具有疏导的活性物资溶液景色。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疏导。泛泛情况下，辅料的种类（如必须，包括辅料级别）和用量应保握一致，尽管允许例外的情况存在。可是，对于某些功能性辅料，其可能影响药物熔解度、热力学性质或生物利费用和产品质能，应具有疏导的质地。辅料的标称用量应疏导或收支不跨越±5％。举例，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: 允许定性组分存在相反的例外情况包括：√   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.主邀功能与药品质能或给药无关的辅料（即抗氧化剂、抗菌防腐剂、色素），况兼不具有影响活性物资熔解度、热力学活性或生物利费用和产品质能的任何其它功能或作用。应使用惯例剂量的也曾过讲究表征的辅料，并应试量和计议可能影响药物生物利费用和/或熔解度特质的相互作用。√  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，其不影响活性物资的熔解度、热力学活性或生物利费用和产品质能，是不错经受的。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.即使聘用不同的辅料对局部耐受性或安全性莫得影响。同期提供证明说明，辅料不影响活性物资熔解度、热力学活性或生物利费用和产品质能的任何其它功能或作用。也不行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.允许的定量相反不大于±10％的例外情况，如下：√   辅料的作用仅与载体特质或润肤性相关√   辅料的作用与产品质能或给药无关，即抗氧化剂、抗菌防腐剂、色素应说明，辅料不影响活性物资的熔解度、热力学活性或生物利费用和产品质能的任何其它功能或作用。Acceptance Criteria 经受圭臬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.对于定量质地特征，假定数据呈正态溜达，则受试药品和参照药品的均值相反的90%置信区间应包含在参照药品平均值的+/-10％的经受圭臬之内。定性质地特征应基本疏导。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.给药方法和给药安设应雷同，并在给药时达到疏导的剂量。若是适用，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场所面应等效，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: 下列方法被觉得适用于等效性测试，可代替临床调治研究：Permeation Kinetics Studies 渗透能源学研究In vitro skin permeation 体外表肤渗透Stratum Corneum Sampling (Tape Stripping)  角质层取样（胶带剥离）Pharmacokinetic bioequivalence 药代能源学生物等效性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不错测量应用于完好皮肤的药品中活性物资渗透能源学方法。当活性物资具有可量化的全身生物利费用时，则恰当进行东说念主体生物等效性研究。当活性物资通过皮肤扩散参加采纳室，可通过测定采纳液对其进行定量时，则恰当进行体外表肤渗透研究。若是在角质层上有饱和的可量化药物扩散，则恰当进行角质层取样（胶带剥离）。其他期间（举例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，但可能是有匡助的。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不错测量应用于完好皮肤的药物中活性物资药遵循源学等效的方法。其他药物的药效学研究尚不充分，不行提供关键的等效性数据，但可看成支握性凭证。该模子应进行适当的考据，况兼必须证明其与调治情况的关系。5.3.2 General Considerations 概论Managing Variability 适度变量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.测试条目应圭臬化，以最大限定地镌汰除被测产品外的通盘相关因素的可变性。建议进行试点研究以开发和优化轨范。因为研究是单次上样，是以产品应用是一个要紧的变异着手。应根据参照产品的SmPC，按照本体情况，注意描摹剂量的应用轨范（和角质层取样的剥离轨范（胶带剥离）），并进行严格适度，举例，由单一或数量有限的经过培训的东说念主员使用管制模板或辅助器具。叮咛该轨范进行考据，确保其测定的终结与本体应用的剂量一致。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.研究握续期间应足以对扩散进行定量不雅察，且需最猛进度地减少在覆按中可能天然发生的，引起能源学溜达偏倚的变化，举例脱屑、皮肤完好性吃亏、反向扩散、巧合吃亏或所应用剂量的鼎新。该方法波及多个复杂设施，应由说明丰富且鸿篇巨制的职责主说念主员严格按照规程操作，以确保终结的可靠性。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.在体外表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。可通过交叉研究想象使不同受试者或供体之间皮肤变异性最小化。在体外表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聘用并吞志愿者或捐赠者的疏导皮肤。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资浓度可能是变异的一个要紧着手。应使用精通的分析测试方法，如耦合色谱－质谱系统。分析方法应合适《生物分析方法考据指南》。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质选录（SmPC）中使用说明，细目样品的具体剂量，包括：（a）活性物资的质地，（b）应用区域和（c）药物产品的质地或体积。应用区域至少应足以竣事可量化的终结。如有必要，在莫得安全费神的情况下，应用区域可大于本体应用区域。对于体内研究，要说明皮肤弃取位置的合感性。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.东说念主类志愿者样本数量应该基于合适的样品数量的预计打算，且不应少于12。在体外表肤渗透性研究中，供体的数量在合适的情况下不错小于12。在体外表肤渗透和角质层取样（胶带剥离）研究中，需要进行相通想象。每一个受试产品、参照产品和对照产品的实验数最低不行少于24。对于每个受试者或供体而言，取样期间点的数量和频率应饱和表征活性物资的能源学模子和细目等效性参数。Acceptance Criteria 经受圭臬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.等效性参数的经受圭臬是，除非有充分的事理，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% 的经受区间内。对于90%置信区间的更平庸经受圭臬（最大为69.84-143.19），若是临床证明是合理的，适用于在小规格和扩散量有限的药物产品上不雅察到的受试者或供体内的高变异的情况。同期应解任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” 中的相关章程。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.确保践诺实验室有履历进行实验以及领有灵验地质地管制体系是很有必要的，这应该包括：合适适当质地体系的声明。应依期对践诺实验室的期间武艺和所用方法的灵验性进行里面评估，并提供最近的终结；由国度期骗部门进行的外部审计5.3.3 Permeation Kinetic Studies 渗透能源学研究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：体外表肤渗透 （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覆按被经受用于等效性测试。研究应合适附件 IV 中描摹的方法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.皮肤防腐剂应合适欧洲药典（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。若是给药方法界说不解确或聘用新的给药方法，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归附（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，应合适ATSM E1173–15用于手术前、导管术前或打针前皮肤处理评估的圭臬测试法 的要求。Antimicrobial drug products for treatment of skin infections 用于调治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.在体外表肤感染和 decolonisation equivalence 研究中，若是能取得闲散的考据终结，不错与其他等效性研究一说念提供灵验性的保证。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，可根据对活性物资的领悟以及辅料的弃取，保证外用制剂的安全性和局部耐受性。当炫耀质地等效时，可为外用制剂的安全性和局部耐受性提供保险。此外，应通过渗透能源学等效性研究说明，与参照产品比拟，受试产品中活性物资达到疏导作用部位和/或全身轮回的量疏导。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灵验性。如5.1章节所述，与剂量相关的全身毒性不在本指南的计议范围内，需要进行局部耐受性和临床安全性研究。关联词，若是全身走漏是可测量的，通过生物等效性研究标明，受试产品与参照产品比拟具有雷同的全身药代能源学特征，则不错说明受试产品的全身走漏量不高于参照产品。5.5 Topical Product Specific Equivalence Protocols 外用制剂特定的等效章程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决策的制定和等效性覆按的弃取，应试虑以下关键因素：药物剂型；产品配方；药物溶出和开释；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:在运行等效性研究之前，应拟定谨慎的外用制剂特定等效决策，包括测试方法过甚经受圭臬，并说明其合感性。无论终结是非，需递交研究经由中取得的所少见据。若是终结合适预定的经受圭臬，不错得出等效性论断。一般而言，产品的等效性决接应包括：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).不开展临床调治等效性研究的事理；该药品在且不超出本指南的范围（5.1节）不进行安全研究的事理（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).若是药物的疗效与药物通过皮肤的扩散情况相关（5.3.3节），可进行相应的渗透能源学等效性研究，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若是可能和相关，还应进行药效学研究。饱读舞聘用新期间，进行开发、考据等研究（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，无需提供渗透能源学或药效学等效数据的情况，包括：活性物资在单相溶液或悬浮液中的疏忽配方制剂，如外用溶液剂、单相凝胶剂和软膏剂、外用混悬剂若是药物产品的宗旨和方向只是将活性药物赐与到皮肤名义（见4.2.1节），泛泛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开释）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：包含影响活性物资生物利费用、产品质能或增强药物渗透性的辅料包含不同供应商着手或级别可能体内性能或活性物资清爽性的复杂辅料与参照产品比较，具有不同要素的辅料（见5.2.1节，定性和定量构成）若是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费用，在这种情况下，泛泛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:若是产品有多个不同的规格，泛泛情况下，聘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相反时最明锐。如要求其它规格豁免生物等效性研究，必须满足以下条目：the different strengths of the test products are manufactured by the same manufacturing process.不同规格产品的坐褥工艺疏导the different strengths of the test products have the same qualitative composition.不同规格产品的组分疏导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比拟，疏导规格的产品具有雷同的定性和定量组分extended pharmaceutical equivalence (section 5.2) is demonstrated between the test and comparator medicinal product for all strengths.聘用通盘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，以细目其对产品的质地、安全或灵验性的影响。还应试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、质地或灵验性有潜在的首要影响：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.原料药的物理化学景色和/或热力学活性的变化影响药物产品溶出、体外开释、体外渗透能源学特质的变化坐褥工艺的变化，举例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，泛泛具有特定的配方、坐褥工艺、包装等，且经过管制当局批准。若是拟议的变更合适拓展制剂等效性研究（5.2.1节）经受圭臬，包括药物剂型、药物的定性与定量构成；根据本指南，参考产品特定等效性研究决策，拟定合适的测试方法和经受圭臬（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.若是拟议的变更不合适拓展制剂等效性研究（5.2.1节）经受圭臬，包括药物剂型、或药物的定性与定量构成，则应进行适当的临床研究证明产品等效。无论是那种情况，都应聘用合适的和有代表性的批次对其关键质地属性进行覆按，将变更前后批次的数据进行对比分析，以支握变更的合感性。Annex I  In vitro release test (IVRT)  附件一 体外开释覆按（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).本附件论说半固体药物制剂（如乳膏剂、凝胶剂或软膏剂）和液体混悬剂的体外开释覆按（IVRT）信息。但以下类型的外用制剂，如疏忽的溶液、外用粉末和其他非圭臬外用配方制剂（如泡沫剂）等，不适于进行IVRT研究，可能需要聘用其它体外覆按进行评估。2. Rationale for IVRT  IVRT基本旨趣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是聘用扩散池以伪无穷上样的方式，评估拟定配方制剂中活性物资的开释速度和进度。在IVRT研究中，应细目以下参数：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)药物开释率（R）：以活性物资的累计开释量对期间平方根作图，开释弧线的线性部分斜率即为药物开释率。若是不行取得线性部分，则IVRT无效在线性部分的临了采样期间点取得的活性物资的累计开释量（A），泛泛以“质地/面积”表述延迟期间（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.尽管该测定不行模拟体内性能情况，但开释速度（R）仍是一项关键质地属性（CQA），应订入产品放行和货架期质地圭臬，除非有合理的依据进行说明。应根据具有闲散的疗效或等效性的临床批次的体外开释测定终结或数据，论证体外开释速度限定制定的合感性。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.泛泛情况下，放行圭臬和货架期圭臬中开释速度的限定应保握一致；若是存在相反，应通过对临床批次的研究，说明这种相反不影响产品的质地和疗效；严控放行限定，以确保产品在货架期内合适质地圭臬。叮咛体外开释测试（IVRT）方法进行考据，以支握拓展药物等效性。3. Study design 研究想象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:建议聘用受试产品与参照产品进行IVRT探索性研究，以阐明所选膜和覆按条目的适用性。可通过以下几个方面，说明覆按条目的合感性：Choice of membrane: 膜的弃取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.  膜应有确保产品和采纳介质保握分离的武艺，以确保在通盘这个词测试经由中配方制剂保握不变。且不应截止活性物资的开释。ii.  膜应与配方制剂相容，且不与活性物资都集。Choice of receptor medium: 采纳介质弃取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.  应阐明漏槽条目。可经受的漏槽条目是，在通盘这个词覆按期间，采纳介质中活性物资的最大浓度不应跨越在该采纳介质中活性物资最大熔解度的30%。泛泛情况下，介质的体积至少是饱和体积的3-10倍。ii.  应尽量减少采纳介质的反向扩散，以幸免药物产品的回荡。在通盘这个词开释测试期间，应使受体介质的 pH 值保握恒定。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.应明确采样期间（每小时至少一次）和覆按条目（如仪器、温度、搅动速度）。IVRT 的握续期间应足以表征开释弧线，理念念情况下，开释量至少为活性物资的70%。在药物开释弧线的线性部分至少选取6个期间点，包括药物扩散达到稳态后的第一个取样期间点。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.应描摹配制制剂的上样量和上样方法，在伪无穷上样条目下，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。在上样经由中，应尽量减少由于样品的蒸发形成的影响。The analytical methods should be sensitive enough to quantify the amount of drug in the receptor solution at various time points and validated.分析方法应有饱和的精通度，并经过考据，确保其不错准确的测定各采样点采纳液中药物的含量。4. Method validation 方法考据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.上市许可肯求中应提供证明性文献，说明IVRT方法也曾过考据，其适用于药物产品的质地适度。应递交IVRT方法开发回归，以便于弃取具有最好永别力的测试条目。Satisfactory evidence of discrimination should be provided， with respect to both of the following quality modifications: 如下所示，可通过蜕变产品的两个质地特质，说明方法具有令东说念主闲散的永别力：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.覆按配方制剂中不同药物浓度（至少三个规格）的开释速度。当开释的药物不错完全熔解于采纳介质时，需细目制剂浓度与药物的开释速度（R）呈线性关系（r2>0.90）。对于混悬剂，也应了解和计议药物浓度与药物开释速度（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.通过蜕变配方制剂的关键质地属性（如活性物资的粒度溜达或制剂的流变学特质）、关键坐褥工艺或辅料的定量构成，论证拟定的方法的永别力；可是，不行完全去除配方制剂中一个或多种特定的辅料。Method intermediate precision for the same batch should be studied with different operators on different days (CV<10%).聘用疏导批次产品、在不同日历、由不同实验员进行方法的中间精密度覆按（CV＜10%）。Method robustness with respect to variations in mixing rate， amount of formulation applied， receptor mediums and temperature should be studied.通过蜕变搅动速度、配方制剂的上样量、采纳介质和温度，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:在初次进行方法考据或等效性评估时，每个批次的样品最少需要12个相通。对于日常放行检测，每个批次至少需要6个相通。在体外药物开释研究中，应以表格和图形款式递交相关数据；以 “质地/面积” 为单元，回报特定期间的活性物资开释量。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.活性物资的累计开释量与期间的平方根呈线性关系；开释速度（R）赫然大于0；受试产品与参照产品开释速度（R）均值比率的90%置信区间应包含在90－111%的可经受范围；延迟期间一致（在±10%范围内），如有。Annex II  In vitro skin permeation studies (IVPT)  附件 II  体外表肤渗透研究（IVPT）1. Scope and rationale for IVPT  IVPT 适用范围和基本旨趣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.聘用有永别力的体外渗透测试（IVPT）拓荒药物的特征渗透弧线，对药物通盘这个词生命周期管制中的变更适度和聘用可经受的渗透能源学覆按证明药物的等效性具有要紧价值。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）的测定终结进行对比论证。2. Study design 研究想象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:为了最大限定地镌汰纰谬风险，应根据 ICH E8，在研究决策中明确章程盲法和立时化方法。建议聘用受试产品与参照产品进行IVPT探索性研究，以阐明活性物资可渗透通过皮肤，同期对覆按条目进行阐明（如仪器、上样量、采样期间和搅动速度等），并可能有助于评估IVPT谨慎研究中所需的样本量。可通过以下几个方面，说明覆按条目的合感性：Choice of skin membrane: 皮肤膜的弃取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.建议使用体外成东说念主皮肤。研究决策中应明确皮肤切片的纳入/扬弃圭臬、剖解区域、保存条目和期间。应扬弃有纹身、任何皮肤极度迹象或赫然浓密的终端毛发皮肤。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.不错使用不同的皮肤处理期间。应提供凭证证明皮肤处理期间和储存不会引入东说念主工成品，也不会蜕变皮肤樊篱功能。使用全层皮肤可能会东说念主为地延迟药物渗透，除非有合理说明，不然应幸免使用。应描摹皮肤厚度和分离期间。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搜检皮肤完好性。应说明皮肤完好性的测试方法过甚经受圭臬。天然实验前后不错聘用不同的经受圭臬，但在通盘平行实验中经受圭臬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.应聘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相通测定，应聘用疏导的供体皮肤，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 个相通。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.仪器应确保在通盘这个词实验经由中温度恒定。皮肤名义温度清爽在32±1℃。Choice of receptor medium: 采纳介质的弃取i.  Sink conditions should be confirmed as described with IVRT (Annex 1).应按照 IVRT（附件 1）的要求阐明漏槽条目。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.除非提供合感性依据，应聘用水性缓冲液看成采纳介质。应提供凭证说明所选采纳介质在通盘这个词测试经由中不会挫伤皮肤樊篱的完好性。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.不错在采纳介质中添加抗菌剂，以松开皮肤膜的潜在细菌理解，但添加的抗菌剂不应搅扰皮肤的特质或测定。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.应有饱和的采样期间点，以取得有赞佩的开释模子，即：拿获招揽的最大速度和之后招揽速度的着落情况，并在招揽速度最大的期间段进行更频繁的采样。测定握续的期间泛泛为24h。若是期间大于24h，应证明覆按前后皮肤具有可经受的樊篱完好性。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.根据产品特质选录（SmPC）中的使用剂量要求，建议上样量为2-15mg/cm2，除非另有章程。叮咛上样方式进行阐明，确保可将配方制剂均匀一致的涂抹到皮肤膜上，且可相通（±5%）。除非SmPC中另有章程，供给室应聘用非闭环（un-occluded）上样。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.为了识别潜在的期侮和/或搅扰，建议在上样前，从每个扩散池中网罗采纳液，同期进行未上样空缺对照覆按。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.应在研究决策和最终回报中提供对盲律例范的注意描摹。受试、参照和阴性对照产品的包装外不雅应雷同，以保握饱和的致盲。应在决策中描摹立时化方法，并同期提供立时化期间表。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，分析方法应有饱和的精通度并经过合适的考据，阐明其不错准确测定采纳液中各采样期间点的药物含量。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.应阐明在IVPT研究期间和测定前存放条目下，采纳液中活性物资的清爽性。3. Method validation 方法考据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.上市许可肯求中，应递交IVPT考据府上，证明其适用于药物的对比研究。不错聘用不同质地属性（包括阴性对照）的配方制剂，论证测定条目的适用性，如聘用拟申诉制剂的50%规格，与参照产品进行比较，应有统计上的相反和不等效。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.为竣事这一丝，应坐褥与拟申诉终产品具有权臣变更的批次，如定量配方、关键质地属性和/或工艺参数的变更。在弃取要蜕变的质地属性时，必须辩论从活性物资和制剂中取得的特质确刻下学问。但不行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 (Jmax) and total amount permeated at the end of experiment (Atotal) 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.应以表格和图形款式递交IVPT数据，列出通盘的数据和参数，以及预计打算公式和汇总统计信息。为了表征开释行动，应将“单元面积的累计渗透量（质地/平方厘米）与期间”作图，同期将 “招揽速度（质地/平方厘米/小时）与期间” 作图，并递交相关终结。应将相关的渗透参数或数据进行比较，如最大招揽速度(Jmax)和覆按收尾时的总渗透量(Atotal)。在相通想象的情况下，应在进一步分析之前对来自并吞供体的相通位点的终结进行平均（几何平均值）。The acceptance criteria for equivalence parameters (Jmax) and (Atotal) are:等效性参数(Jmax)和(Atotal)的经受圭臬如下：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%的可经受范围，除非有正直事理。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，若是不雅察到具有高变异性，可通过临床研究，放宽90%置信区间，聘用更宽松的经受圭臬69.84-143.19。应解任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”的相关章程。In addition， for the test to be valid: 此外，为了阐明测试终结真正：The acceptance criteria for equivalence parameters (Jmax) and (Atotal) 等效性参数(Jmax)和(Atotal)的经受圭臬为：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%.受试产品与阴性适度产品均值比率的 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%.参照产品与阴性适度产品均值比率的 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.还应回报其他渗透参数，举例最大招揽率(tmax)的期间和延迟期间。如存在延迟期间，受试产品和参照产品应保握一致（即在±10%范围内）。叮咛等效性研究中发现的渗透参数的任何不同之处进行计议。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.研究经由中应合适质地均衡的要求。递交以下三个部分的数据：活性物资渗透参加采纳液的总量(Atotal)、皮肤组织中活性物资的总量(Stotal)和残留在皮肤或覆按设备上的总量(Ttotal)。上述三个部分检测量之和应在90－110%范围内，如跨越该范围需提供合感性依据。不错分别测定不同皮肤层（如角质层和表皮层）中保留的活性物资的量，以了解活性物资在东说念主体皮肤中的溜达。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 序文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.本附件是对于半固体制剂体内角质层取样（或胶带剥离 (TS)）的研究信息，该研究是一种炫耀等效性的渗透能源学方法，可用于替代调治等效性研究。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期间，该期间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：药物从配方制剂中浸透角质层的量、药物通过角质层扩散和参加活体组织的量。胶带剥离的一个主要优点是，该实验是在体内皮肤微轮回功能完好的条目下进行的，药物易于从皮肤上捣毁。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.胶带剥离数据提供相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费用的平直测量和信息，举例抗真菌产品。在方向作用部位不是角质层的情况下，胶带剥离数据不错提供合适的替代办法来表征药物招揽到基层组织的速度和进度。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参加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（举例怒放性伤口、烧伤）或早产腾达儿皮肤的药物产品。此外，也不适用于含有蒸发性药物的制剂或主要作用部位为皮肤附庸组织的药物制剂（举例毛囊、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经由，需仔细辩论实验想象，这点至关要紧。谨慎研究的实验条目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阐明。还应提供胶带剥离方法开发和优化的回归。在探索性研究中，叮咛以下覆按条目进行阐明：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、皮肤樊篱功能讲究的前臂（掌）皮肤区域进行。应明确皮肤的纳入/扬弃圭臬。将有纹身、任何皮肤极度迹象或赫然浓密的终端毛发皮肤扬弃在外。在覆按前，细目皮肤的处理和清洁方法，确保这些处理法子不会阻扰皮肤的完好性。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.应在实验前后细目皮肤完好性。泛泛聘用经皮水分消失法（TEWL）进行测定，如适用，也不错聘用其它期间。叮咛经受圭臬进行计议，说明其合感性。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聘用并吞受试者。此外，需覆按与参照产品不等效的阴性适度产品，用于论证方法的永别力。建议负责配方应用和胶带剥离的研究者进行盲检，以最大限定镌汰偏倚风险。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细目上样量。在探索性研究期间，需阐明上样量、上样区域/面积，以满足角质层中活性物资定量测定的需求。同期，细目上样方式、盲法和立时化方法。A single dose approach should be followed， i.e. skin stripping is performed after a single application of the test and comparator products.应聘用单剂量方法，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，需要对两个期间点（招揽、捣毁）的产品测定终结进行对比。最好的招揽和捣毁期间取决于药物和产品的特质，应在探索性研究期间进行细目。理念念情况下，招揽期间应饱和长，以使药物达到扩散均衡景色。这不错通过测定给药后多个期间点，角质层中药物回收的量进行细目。捣毁期间应饱和长，以便于准确测定从角质层鼎新至活体皮肤（和皮下）的情况，但不应跨越 48 小时，以幸免任何皮肤脱屑效应。与招揽阶段比拟，能使从角质层中回收的药物量至少镌汰25%的捣毁期间是最好的。无论什么情况，都要仔细辩论采样期间并证明其合感性。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.在特定的招揽期间后，应将药物从皮肤名义移除。需拓荒移除方法，确保在胶带剥离前，残留的配方制剂可灵验的从给药部位移除。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）与皮肤名义粘附后，不吃亏分量；b）存储经由中，分量减少和加多较小；c）药物易从粘附在胶带上的角质层中索取；d）胶带的粘合剂或其他要素不搅扰药物的定量测定；e）胶带应有饱和的粘协力，即使聘用较少的胶带数量也不错除掉大部分的角质层（举例，不跨越 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，所用的胶带剥离轨范必须确保大部分角质层（≥75%）被采样。不错根据TEWL经受圭臬（或其它相关期间）细目所需胶带的最少和最大数量，举例，基线值、安全罢手值的八倍增量。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，先从胶带中索取药物，然后对索取溶剂进行测定。若是有正直事理，不错使用其他索取/定量方法。同期需证明，所聘用的索取方法可取得令东说念主闲散的终结。3. Study design 研究想象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，应注意描摹圭臬操作规程，以精准适度上样、捣毁/清洁、剥离、索取、定量和其他研究变量或实验偏差的潜在着手；并在决策中明确章程纳入/扬弃圭臬。保举按照底下的研究想象进行胶带剥离研究，并说明最终细目研究想象决策的合感性。

图片少妇空姐

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，需聘用健康受试者，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。应进行皮肤完好性阐明，如聘用TEWL进行测定，同期，应确保每个前臂的给药部位疏导、数量疏导；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：受试者数量的弃取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。在等效性论证经由中，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;相通次数：每个样品（受试、参照和阴性适度）在各前臂至少应有两个给药位点。一个前臂用于药物招揽，另外一个用于捣毁；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网罗空缺样品，以阐明在角质层中不存在可精通扰药物定量的配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;给药位点应立时化，以幸免偏倚；并错开给药期间，以便有充足的期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.聘用“非闭环（un-occluded）”条目，除非产品信息中保举聘用“闭环（occluded）”条目，或证明其合感性，如：贯注巧合中去除配方制剂。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;在招揽收尾后，应将给药位点（招揽和捣毁）的样品去除；并尽量减少总清洁期间，以幸免由于药物进一步扩散形成偏差。在胶带剥离前，对上样区域的皮肤完好性进行测定；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“招揽”位点，应在去除配方制剂后立即用胶带剥离。而“捣毁”位点是在预定的捣毁期间用胶带剥离；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测定终结和探索性研究中拓荒的罢手圭臬，细目所需胶带的真是数量；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;应细目每条胶带去除的角质层的分量，可通过称量胶带剥离前后的分量，以减重法进行测定。如合理，也可聘用其它可替代方法；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.网罗用于每个调治位点剥离的通盘胶带，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孝顺。为增强方法的检出武艺，可将剩余的胶带分组（如，每组应包含所需最少许的角质层）索取后进行测定。角质层中药物的总量为从通盘剥离胶带中索取的样品量之和。叮咛每个调治位点的质地均衡（包括从角质层名义移除的药物）进行评估。药物总回收率的可经受范围是90%~110%；如超出该范围，应提供合感性说明。4. Method validation 方法考据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，对赐与药物一定期间后的皮肤名义进行清洁很要紧，且必须确保不错移除过量的配方制剂（即未被招揽的药物），使药物不会不受控的参加皮肤樊篱。常用的清洁方法是，聘用干/湿纸巾或绵纸、棉签和/或崭新的酒精湿巾快速关爱地擦抹皮肤。所用的清洁器具应不影响药物扩散参加和通过角质层。在谨慎研究前，叮咛清洁方法进行小心的评估和阐明，确保其可灵验的清洁皮肤名义；举例，在上样后立即对皮肤进行清洁，终结标明，从皮肤名义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%，则是比较令东说念主闲散的终结。如合理，也可聘用其它的方式进行考据。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.在胶带剥离覆按中，叮咛用于药物定量的生物分析方法进行考据。在谨慎研究前，叮咛索取方法（包括对分组的剥离用胶带的索取）的灵验性进行阐明，确保其不错灵验的索取，并可产生一致的终结。应聘用不同质地属性的样品（包括阴性适度样品）对胶带剥离（TS）方法的永别力进行论证，如聘用±50%标称规格的样品，其终结与受试制剂和参照制剂比拟，具有统计学相反且不等效。应按照《生物分析方法考据指南》，对胶带剥离角质层中活性物资含量的测定方法进行考据。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.应回报通盘受试者的数据，并对终结的灵验性和可变性进行计议。在统计分析中，应纳入通盘受试者和给药部位。数据的扬弃必须基于决策中事先章程的圭臬。只是基于统计分析或能源学原因，是不不错经受的。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，应回报去除的角质层（SC）厚度、剥离用的胶带数量，和招揽与捣毁阶段TEWL的测定终结。应计议受试制剂与参照制剂之间这些参数的相反平等效性的影响。对于每个给药部位，应细目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，叮咛每个受试者、每个产品的相通测定终结取平均值（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 (Muptake) and (Mclearance)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），平等效性参数进行统计分析。等效参数（Muptake）和（Mclearance）的经受圭臬是：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%的可经受范围，除非有正直事理。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，若是不雅察到具有高变异性，可通过临床研究，放宽90%置信区间，聘用更宽松的经受圭臬69.84-143.19。应解任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”的相关章程。In addition， for the test to be valid: 此外，为了阐明测试终结真正：The acceptance criteria for equivalence parameters (Muptake) and (Mclearance) 等效性参数(Muptake)和(Mclearance)的经受圭臬为：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%.受试产品与阴性适度产品均值比率的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%.参照产品与阴性适度产品均值比率的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论断，并通过合理的科学计议和胶带剥离（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覆按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.应提供对覆按方法的描摹。应解任以下测试原则：应进行剂量督察期间—反馈的体内探索性研究，以细目在谨慎等效性研究中等效参数的研究要求。在探索性研究和谨慎研究中，应说明相关的东说念主类志愿者的纳入和扬弃圭臬。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立时刻拨到前臂内侧的应用部位。该研究应适当聘用盲律例范。在谨慎研究中，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期间点（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反馈归附到基线水平，并确保可不雅察到最大的药效学反应。此外，必须对覆按方法进行优化，使产品不错根据 blanching curve 的线性部分进行比较。在预覆按中，叮咛几个不同的上样期间进行测定，以细目精通度下限。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.应在几个不同的期间点对血管收缩反应进行测定，以取得弧线底下积（AUC）数据。单期间点预计血管收缩反应是不可经受的。血管收缩反应的测量应使用色度计或其他比目测更明锐的方法，并由孤苦不雅察者进行二次临床评估。References: 参考文献FDA Guidance for Industry: Topical Dermatologic Corticosteroids: in vivo bioequivalence 2 June 1995.“Quantification of corticosteroid-induced skin vasoconstriction”， Dermatology， (2002)， 205， 3-10.“The skin-blanching assay”， Journal of the European Academy of Dermatology and Venerology (2012)， 26， 1197-1202. 本站仅提供存储干事，通盘内容均由用户发布，如发现存害或侵权内容，请点击举报。