指南1：阿昔洛韋（乳膏）指南草案（2016年）

指南2：ANDA申請中遞交的外用藥物產(chǎn)品的體外滲透（IVPT）研究（2022年10月）

指南3：ANDA申請中遞交的外用藥物產(chǎn)品的體外釋放（IVRT）研究（2022年10月）

指南4：ANDA 申請中遞交的外用藥物產(chǎn)品的物理化學(xué)和結(jié)構(gòu)（Q3）特性（2022年10月）

法規(guī)5：USP<3>外用和透皮制劑：產(chǎn)品質(zhì)量測試（現(xiàn)行版）

法規(guī)6：USP<1724> 半固體藥物制劑：性能測試（2022年05月討論稿）

文獻(xiàn)7：非腸道緩釋制劑體外加速釋放測試方法

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

Executive summary 概要

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

   其他指南未涵蓋的外用制劑的質(zhì)量。

2. On equivalence testing of topical products in lieu of therapeutic equivalence clinical trials.
   以局部外用藥品的等效性試驗(yàn)代替臨床治療等效性試驗(yàn)。
   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.

   現(xiàn)有指南指岀，對于外用藥物制劑，配方、劑型、給藥方法或生產(chǎn)工藝的變化均可能會顯著影響有效性和（或）安全性。臨床治療等效性研究在原則上是必要的，但也可以使用或開發(fā)其他模型。

   Guidance is provided on other models and studies that may be used to independently determine equivalence with respect to (i) quality, (ii) efficacy, and (iii) safety that taken together support a claim of therapeutic equivalence, when the method of administration is the same and risks of inequivalence to the patient are minimal.
   當(dāng)治療方法相同且對患者的不等效性風(fēng)險最小時，這一指南也可在其他模型和研究中提供指導(dǎo)。這些模型和研究可獨(dú)立用于確定與(i)質(zhì)量、(ii)功效和(iii)安全性相關(guān)的等效性以及上述三方面總結(jié)而成的治療等效性。
   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.
   這一指南應(yīng)被用于臨床治療等效性試驗(yàn)希望被實(shí)施的情況下。
   描述了這種方法的范圍、局限性和接收標(biāo)準(zhǔn)。

   這一指南應(yīng)被用于開發(fā)和解釋局部外用藥品專用的等效性草案。

• in vitro release 體外釋放
• in vitro human skinpermeation 體外人體皮膚滲透
• in vivo stratum corneum sampling (tapestripping) 體內(nèi)角質(zhì)層取樣（膠帶剝離）

• in vivo vasoconstriction assay forcorticosteroids 皮質(zhì)類固醇的體內(nèi)血管收縮試驗(yàn)

等效性指南適用于特定案例中新的局部外用藥品與現(xiàn)有的局部外用藥品之間等效性論證的情況。

1、Introduction and Background 緒論和背景

由于皮膚的復(fù)雜性、待治療的病癥范圍、以及患者與其需求的多樣性，局部外用藥品具有非常廣泛的多樣性。該指南并不是提出一個單一的程序來解決這種多樣性，而是提供一般性建議。這些建議可以適用于逐案分析基礎(chǔ)上的任何給定藥品。該指南闡述了現(xiàn)有的監(jiān)管指南，并通過現(xiàn)有的科學(xué)知識進(jìn)行告知。

1.1 Quality of Topical Products 外用制劑質(zhì)量

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

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.

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.

產(chǎn)品目標(biāo)質(zhì)量概況應(yīng)考慮患者的可接受性、是否易于從容器中轉(zhuǎn)移并給藥，以及整體美觀性，如外觀、鋪展性、觸感、微觀結(jié)構(gòu)/物理性質(zhì)、揮發(fā)性輔料的蒸發(fā)和適當(dāng)?shù)恼趽醯?，如適用。這些因素需要被表征，并且在必要時被作為關(guān)鍵質(zhì)量屬性進(jìn)行控制。

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.

需要一個穩(wěn)健的生產(chǎn)工藝，以確保藥品在整個上市貨架期內(nèi)質(zhì)量恒定。上市產(chǎn)品應(yīng)與已證明有令人滿意的有效性和安全性或等效性證據(jù)的批次具有相同的質(zhì)量。

應(yīng)通過穩(wěn)定性研究證明，各批次產(chǎn)品在貨架期開始和結(jié)束時具有相同的物理、化學(xué)和微生物質(zhì)量特性，且在特定情況情況下，具有相同的體外性能特征。

1.2 Equivalence of Topical Products 外用制劑等效性

在一個新的局部外用藥品的上市許可申請依賴于一個已上市藥品的檔案的情況下，或者在藥物的開發(fā)或批準(zhǔn)后發(fā)生的可能對藥品的安全性、質(zhì)量或有效性產(chǎn)生重大影響的情況下，需要對這一新的局部外用藥品的等效性進(jìn)行論證。

此外，在依賴于文獻(xiàn)來證明藥物產(chǎn)品的安全性和有效性的應(yīng)用的情況下，文獻(xiàn)的相關(guān)性應(yīng)該通過藥物產(chǎn)品與文獻(xiàn)中描述的藥品之間的等價性橋接數(shù)據(jù)來支持。這是因?yàn)樵谂浞健⑸a(chǎn)和給藥方法中質(zhì)量差異的影響是不可預(yù)則的。

現(xiàn)有指南指岀，對于外用藥物制劑，配方、劑型、給藥方法或生產(chǎn)工藝的變化可能會顯著影響有效性和（或）安全性。臨床治療等效性研究在原則上是必要的，但也可以使用或開發(fā)其他模型。本指南提供了關(guān)于體外和體內(nèi)模型如何替代臨床數(shù)據(jù)以建立治療等效性的進(jìn)一步細(xì)節(jié)。

對質(zhì)量的等效性的論證通常不足以預(yù)測治療等效性。但對于液體制劑（如皮膚用溶液）來說，當(dāng)給藥方法相同時，僅基于質(zhì)量等效性數(shù)據(jù)是可以通過治療等效性豁免的。

如適用，質(zhì)量的等效性可以通過與參照藥物產(chǎn)品（即已上市藥物制劑）的對比數(shù)據(jù)建立，包括：藥物劑型、定性和定量組成、顯微結(jié)構(gòu)/物理性質(zhì)、產(chǎn)品性能、給藥方式。在本指南中，這被稱為“擴(kuò)展的藥物等效性”。

關(guān)于藥效的等效性需要參比其滲透動力學(xué)，并在可能的情況下，進(jìn)行與參照藥物產(chǎn)品的藥效學(xué)對比研究。合適的滲透動力學(xué)方法是體外人體皮膚滲透和對人類志愿者活體角質(zhì)層（S.C.）采樣（膠帶剝離）以及體內(nèi)藥代動力學(xué)生物等效性實(shí)驗(yàn)。合適的藥效學(xué)研究包括對人類志愿者進(jìn)行的體內(nèi)皮質(zhì)類固醇血管收縮試驗(yàn)和針對防腐劑或殺菌劑的體內(nèi)微生物脫色實(shí)驗(yàn)。如果滲透動力學(xué)和藥效學(xué)研究不適用或被認(rèn)為不足以預(yù)測臨床反應(yīng)，則通常需要臨床療效數(shù)據(jù)。

關(guān)于安全性和局部耐受性的等效性可以從活性物質(zhì)的知識和已完善的輔料的選擇中推斷岀來。針對簡單配方，從滲透動力學(xué)或藥效等效性研究中可獲得生物等效豁免，即對質(zhì)量等效性進(jìn)行充分論證就足夠。一般性指導(dǎo)可以被應(yīng)用于開發(fā)藥物產(chǎn)品的特定技術(shù)要求以證明其等價性，必要時可尋求其他科學(xué)建議。

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.

本指南適用于應(yīng)用于局部皮膚并發(fā)揮局部作用藥物，也適用于其他藥物，例如眼用藥物與耳用藥物。

指南適用于局部外用藥品的質(zhì)量，包括其他—般性質(zhì)量準(zhǔn)則中未涉及的化學(xué)原料藥，和用于支持局部外用藥品與參照藥品的治療等效性試驗(yàn)，以替代臨床治療等效性試驗(yàn)。

• 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).

等效性指南不適用于：

• 生物醫(yī)藥產(chǎn)品，參見生物類似藥產(chǎn)品指南

• 中草藥產(chǎn)品

• 當(dāng)通過臨床治療等效性試驗(yàn)來證明療效的等效性時

• 當(dāng)試驗(yàn)中藥物劑型或定性和定量組成與參照藥品不相同或不等同時（見5.2.1節(jié)）。

3、Legal basis 法律依據(jù)

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

Quality Guidelines 質(zhì)量指南

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

  歐洲藥典，劑型通則：皮膚用液體制劑、 皮膚用粉末制劑、 皮膚用半固體制劑、耳用制劑、眼用制劑、加壓藥物制劑。

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

  藥物開發(fā)，ICH Q8(R2)，EMEA/CHMP/167068/2004；

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

  制劑成品生產(chǎn)，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;

  藥物制劑工藝驗(yàn)證的指南；監(jiān)督意見書EMA/ CHMP/ CVMP/ QWP/ BWP/ 70278/ 2012-Rev1中提供的信息與數(shù)據(jù)；

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

  醫(yī)藥產(chǎn)品上市許可申報資料中的輔料，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質(zhì)量標(biāo)準(zhǔn)：新原料藥和新藥制劑的檢測方法和認(rèn)可限度：化學(xué)物質(zhì)，CPMP/ICH/367/96-ICH；

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

  Q2(R1)分析方法驗(yàn)證：正文和方法學(xué)，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);

  新原料藥和制劑的穩(wěn)定性試驗(yàn)(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.;

  現(xiàn)有活性成分及相關(guān)藥物制劑的穩(wěn)定性試驗(yàn)，CPMP/QWP/122/02 Rev. 1 corr.；

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

  含已知成分的局部給藥、局部起效制劑的臨床要求指南的注解，CPMP/EWP/239/95 Final

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

  生物等效性研究指南，CPMP/EWP/QWP/1401/98 Rev. 1/ Corr
• Guideline on bioanalytical method validation EMEA/ CHMP/ EWP/ 192217/ 2009 Rev. 1 Corr. 2
  生物分析方法驗(yàn)證指南，EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2
• General Considerations for Clinical Trials (ICH topic E8, CPMP/ICH/291/95)
  臨床試驗(yàn)的一般考慮（ICH topic E8，CPMP/ICH/291/95）
• Guideline for Good Clinical Practice (ICH E6 (R1), CPMP/ICH/135/95)
  藥物臨床試驗(yàn)管理規(guī)范 (ICH E6 (R1), CPMP/ICH/135/95)
• Statistical Principles for Clinical Trials (ICH E9, CPMP/ICH/363/96)
  臨床試驗(yàn)的統(tǒng)計(jì)學(xué)原則 (ICH E9, CPMP/ICH/363/96)
• Reflection Paper on advice to Applicants/Sponsors/CROs of Bioequivalence Studies 222 EMEA/INS/GCP/468975/2007
  關(guān)于生物等效性研究中申請者/贊助商/合作研究機(jī)構(gòu)的建議的反饋文件， EMEA/INS/GCP/468975/2007
• Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development Draft (EMA/CHMP/138502/2017). Although a draft document, this paper provides current regulatory considerations regarding statistical aspects for the comparative assessment of quality attributes.

  關(guān)于藥物開發(fā)中質(zhì)量屬性的對比評估的統(tǒng)計(jì)方法的反饋文件Draft (EMA/CHMP/138502/2017)。盡管只是草案，不過該文提供了有關(guān)質(zhì)量屬性比較評估的統(tǒng)計(jì)方面的當(dāng)前監(jiān)管考慮。

體外皮膚滲透動力學(xué)等效性試驗(yàn)是產(chǎn)品認(rèn)證的關(guān)鍵，需經(jīng)國家主管部門檢查，并應(yīng)按照指令2001/20/EC進(jìn)行。

公司可以針對現(xiàn)行指南中未涉及特定事項(xiàng)向 CHMP 和 NCA 進(jìn)行科學(xué)咨詢。

4.1 Description and composition of the drug product 藥品描述與組成

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.

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.

根據(jù)藥物產(chǎn)品的設(shè)計(jì)和目的，對于具有多種功能的輔料，應(yīng)明確說明，例如：丙二醇可同時作為保濕劑、滲透促進(jìn)劑和増溶劑。

應(yīng)基于 SmPC（Summary of Product Characteristics 產(chǎn)品特性概要）中的使用說明和最大日用量，對單位面積上使用的活性物質(zhì)的量進(jìn)行說明。

4.2 Pharmaceuticaldevelopment 藥物開發(fā)

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.

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.

在患者方面，應(yīng)考慮的內(nèi)容包括：皮膚的適應(yīng)癥和病情；年齡適宜性、患者可接受性、給藥方式和可行性、給藥部位；功效（產(chǎn)品規(guī)格和劑量學(xué)、原料藥的溶質(zhì)狀態(tài)、生物利用度和/或滲透增強(qiáng)）；潤膚劑；安全性（組分的毒性、雜質(zhì)、微生物）；質(zhì)量（物理和化學(xué)穩(wěn)定性、關(guān)鍵質(zhì)量屬性、藥典和法規(guī)要求的符合性）。

應(yīng)說明活性物質(zhì)到達(dá)作用部位的方式和滲透動力學(xué)。如適用，通過這些內(nèi)容清楚的說明給藥方式、活性物質(zhì)的溶解狀態(tài)、藥物的溶解/釋放和通過人體皮膚的擴(kuò)散情況。

如適用，應(yīng)在申報資料中，遞交非臨床和臨床研究的交叉比對信息。

4.2.2 Active substance (P.2.1.1)  原料藥

原料藥的物理化學(xué)性質(zhì)對藥物的生物利用度、配方、性能和穩(wěn)定性具有重要作用，應(yīng)進(jìn)行識別和討論。如果原料藥以固態(tài)形式存在于藥品中，這些特性可能包括：分子量、分配系數(shù)、熔點(diǎn)（沸點(diǎn)，如適用）、pKa、對光、空氣或水分的敏感性、降解途徑、溶解度和pH依賴性，以及粒徑和多晶型性。在原料藥質(zhì)量標(biāo)準(zhǔn)中應(yīng)識別和控制這些關(guān)鍵質(zhì)量屬性。

4.2.3 Excipients (P.2.1.2)  輔料

在開發(fā)過程中，應(yīng)考慮并闡述輔料的批間差異和來源差異。如適用，應(yīng)根據(jù)輔料的功能，包括潤膚作用，對每個輔料的選擇、用量和相關(guān)的關(guān)鍵質(zhì)量屬性（CQAs）進(jìn)行討論，說明其合理性。

應(yīng)提供可能對活性物質(zhì)的滲透性和生物利用度有影響的輔料的詳細(xì)信息，例如增溶劑/滲透促進(jìn)劑，包括它們提供預(yù)期功能的能力和在整個藥品貨架期期間發(fā)揮作用的能力。

應(yīng)明確和描述加工助劑信息。

一些傳統(tǒng)上用于局部外用藥物的輔料可能引起刺激或過敏反應(yīng)，如可能的話，在新藥的開發(fā)中應(yīng)避免或盡可能的減少使用。作為參考，請參閱“人用藥品說明書和包裝標(biāo)簽中輔料”指南。

4.2.4 Formulation development 配方開發(fā)

應(yīng)從以下幾個方面，對藥品的開發(fā)過程進(jìn)行描述：已定義的目標(biāo)產(chǎn)品質(zhì)量概況（QTPP）；采用合適的測試來表征和控制關(guān)鍵質(zhì)量屬性（CQAs）；影響易使用性和持續(xù)時間的因素；和產(chǎn)品性能，例如溶解度、體外藥物釋放，如適用，體外皮膚滲透實(shí)驗(yàn)。應(yīng)提供用于評估產(chǎn)品的測試方法和接受標(biāo)準(zhǔn)的適用性的證據(jù)（另見附錄 I 和 II）。

在穩(wěn)定性研究中應(yīng)進(jìn)行適當(dāng)?shù)臏y試，以評估由溫度和儲存條件變化引起的晶體沉降、顆粒生長、結(jié)晶習(xí)性變化，或其他可能影響生物利用度的原料藥特性的變化風(fēng)險。

應(yīng)討論活性成分向皮膚作用部位的遞送情況。溶劑和透皮吸收促進(jìn)劑可用于幫助活性物質(zhì)運(yùn)送至不同的皮膚層次。軟膏可以封閉皮膚，從而起到促進(jìn)藥物透皮滲透和吸收的作用。使用的藥物制劑產(chǎn)品和皮膚作用部位之間的濃度梯度是經(jīng)皮吸收遞送的驅(qū)動力，因此實(shí)現(xiàn)藥物產(chǎn)品中活性物質(zhì)的飽和狀態(tài)是重要的關(guān)鍵性因素。

對于半固體制劑，其微觀結(jié)構(gòu)/物理性質(zhì)可能比較復(fù)雜，應(yīng)充分了解其微觀結(jié)構(gòu)/物理性質(zhì)及其形成機(jī)制，例如輔料的相互作用、批間差異和批量放大，從而促進(jìn)生產(chǎn)工藝的優(yōu)化，獲得質(zhì)量一致的產(chǎn)品。

應(yīng)詳細(xì)描述臨床試驗(yàn)配方和在對比研究中使用的批次。關(guān)鍵臨床試驗(yàn)批次和待上市藥品在配方和生產(chǎn)過程中的任何差異都應(yīng)該進(jìn)行合理性說明。應(yīng)提供體外或體內(nèi)的任何擴(kuò)展和延伸的制劑學(xué)等效性研究的結(jié)果。

當(dāng)確定配方組成，在即將開展的放大生產(chǎn)中，應(yīng)確定需控制的關(guān)鍵工藝參數(shù)。在這一階段，為達(dá)成和全面優(yōu)化生產(chǎn)工藝，進(jìn)行必要的調(diào)整是合理的。這些調(diào)整可能包括組成、生產(chǎn)工藝、設(shè)備或生產(chǎn)場所的變化。在某些情況下，應(yīng)評估這些調(diào)整對藥物產(chǎn)品功能的潛在影響，例如對藥物的生物利用度和可用性的影響。

當(dāng)藥品載體含有易燃揮發(fā)性溶劑時，如異丙醇和乙醇，應(yīng)根據(jù)相關(guān)ISO標(biāo)準(zhǔn)和產(chǎn)品信息中包含的相關(guān)警告確定其閃點(diǎn)或燃點(diǎn)（參見4.2.6節(jié)）。

使用石蠟作為基質(zhì)的產(chǎn)品本身并不具有易燃性，但是當(dāng)衣物、床上用品和敷料被其浸漬時會起到燈芯的作用，并且石蠟在著火時可以起到助燃的作用。應(yīng)評估其對患者帶來的風(fēng)險，并在產(chǎn)品信息中添加適當(dāng)?shù)木妫▍⒁?.2.6節(jié)）。

4.2.5 Product characterisation  產(chǎn)品特性表征

應(yīng)制定詳細(xì)的產(chǎn)品特性表征方法，以便于藥品生命周期管理，條件允許的情況下，可用于支持與原研或參照制劑產(chǎn)品的等效性論證。特性表征數(shù)據(jù)應(yīng)來自具有代表性的批次，考慮到分散系統(tǒng)相比于簡單溶液具有更大的可變性，選擇的批次數(shù)目不應(yīng)少于三個批次。為了進(jìn)行統(tǒng)計(jì)評估，樣品的數(shù)量應(yīng)足夠多以具備代表性，每個實(shí)驗(yàn)中每批至少要有12個樣本。也應(yīng)考慮到由于批量大小、生產(chǎn)日期和儲存期限等因素導(dǎo)致的批間差異。

Pharmaceutical Form 藥物劑型

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.

外用制劑的劑型包括皮膚用溶液、泡沫劑和噴霧劑、洗發(fā)劑、軟膏（油膏、吸收型基質(zhì)、水可洗去基質(zhì)和水溶性基質(zhì)）、乳膏（水包油型或油包水型）、凝膠、糊劑、膏劑、硬膏劑和皮膚貼劑。

For example：

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

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

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

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

例如：

溶液中的活性物質(zhì)，單相體系，如：皮膚用溶液劑、單相的凝膠劑或軟膏劑。

混懸劑中的活性物質(zhì)，單相體系，如：皮膚用混懸劑。

溶液中的活性物質(zhì)，兩相體系，如水包油型（o/w）乳膏，活性藥物在油相中或在水相中。

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.

對于混懸劑，需提供活性物質(zhì)粒徑分布和多晶型的研究結(jié)果，包括顯微照片。

對于互不混溶的配方制劑，需額外提供液滴的尺寸分布和外觀方面的表征，包括顯微照片。

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

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.

應(yīng)提供證據(jù)來表征藥物的微觀結(jié)構(gòu)/物理性質(zhì)，包括影響藥物的生物利用度、易用性，或指示生產(chǎn)工藝的變異和產(chǎn)品不穩(wěn)定的物理CQAs（關(guān)鍵質(zhì)量屬性）。

例如，對于溶液和懸浮液 — pH值、緩沖容量、粘度、密度、表面張力、滲透壓。

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

• 剪切應(yīng)力（或粘度）與剪切速率的完整流動曲線，包括在剪切速率的增加和減小范圍內(nèi)的多個數(shù)據(jù)點(diǎn)，以便清楚地識別出曲線上升或曲線下降的任何線性部分。所得曲線應(yīng)通過擬合（修正的）冪定律方程來表征，以便可以生成數(shù)值數(shù)據(jù)；
• 屈服應(yīng)力和蠕變試驗(yàn)；

• 線性粘彈性響應(yīng)（存儲損耗模量與頻率）。

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

應(yīng)提供根據(jù)剪切和時間效應(yīng)分類的流變圖和藥品行為，例如假塑性、膨脹性、觸變性，并使用適當(dāng)?shù)亩攘勘碚?。例如：流變圖中指定剪切速率下的粘度（例如 η100）；塑性流動屈服應(yīng)力值；觸變相對面積（SR）；粘彈性儲存和損耗模量（G' 和 G”）、表觀粘度、損耗角正切（tan δ）。

Product Performance 產(chǎn)品性能

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

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

應(yīng)擬定合適的檢測項(xiàng)目用于表征產(chǎn)品性能，如混懸液的溶解和體外藥物釋放（附件I），并證明樣品在儲存期間是穩(wěn)定的。

4.2.6 Administration 藥品使用

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和產(chǎn)品信息應(yīng)包含使用說明書和對藥品安全使用的必要警告。

相關(guān)時，應(yīng)描述藥品在給藥過程中的形變。

• 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;
• 用藥部位；
• 避免受損或未受損皮膚的必要性；
• 皮膚預(yù)處理的要求；
• 暴露于熱、冷、陽光照射的極端環(huán)境影響；

• 日常行為如洗滌、淋浴、使用防曬霜和保濕霜的影響；

• Any necessary restrictions e.g. avoidance of occlusion;
• The practical suitability of any special storage conditions;
• Avoiding inadvertent use by children;
• For drug products containing flammable volatile solvents, appropriate flammability safety warnings.
• 任何必要的限制，例如避免封閉；
• 任何特殊儲存條件的實(shí)際可行性；
• 避免兒童無意使用；

• 對于含有易燃揮發(fā)性溶劑的藥品，應(yīng)有適當(dāng)?shù)囊兹夹园踩妗?/span>

  For example:
  Danger: Flammable.
  Keep away from heat, hot surfaces, sparks, open flames and other ignition sources.
  No smoking. Protect from sunlight.
  Do not expose to temperatures exceeding 50°C.
  Do not spray on flames or other sources of ignition.
  例如：
  危險：易燃。
  遠(yuǎn)離熱源、熱表面、火花、明火和其他火源。
  禁止吸煙。避免陽光照射。
  不要暴露于超過50℃的溫度。

  不要噴在火焰或他火源上。

• 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.
• 當(dāng)患者使用以石蠟為基質(zhì)藥品且用藥量超過100g時，建議定期更換衣服、床上用品和敷料，并遠(yuǎn)離明火。
  For example: 例如
  When this paraffin-based product is covered by a dressing or clothing, there is a danger that smoking, or using a naked flame could cause your dressing or clothing to catch fire.
  Do not smoke, use naked flames (or be near people who are smoking or using naked flames) or go near to anything else which may cause a fire whilst these products are in contact with your clothes, dressing or bandages.
  當(dāng)這種以石蠟為基質(zhì)的產(chǎn)品被衣物覆蓋時，吸煙或使用明火可能導(dǎo)致衣物著火。

  不要吸煙、不要使用明火（或靠近吸煙者和使用明火者）、不要靠近任何可引發(fā)火災(zāi)的物品或令這些物品與你的衣物、敷料或繃帶接觸。

  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.
  確保定期（最好每天）更換衣服和床上用品，因?yàn)槭灂B入織物中，并可能引發(fā)火災(zāi)。還應(yīng)該小心，確保石蠟不會滲入椅子、座椅或其他家具中。
  把這些注意事項(xiàng)告訴你的親屬或護(hù)理者，并給他們看下這個手冊。

  如果你經(jīng)常吸煙，請告知你的醫(yī)生、護(hù)士或藥師。他們能給你提供戒煙的幫助和建議。

4.2.7 Manufacturing process development and Manufacture (P.2.3 and P.3) 生產(chǎn)工藝開發(fā)和生產(chǎn)

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.

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.

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.

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.

4.2.8 Container closure system(P.2.4)  容器密閉系統(tǒng)

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.

應(yīng)對容器密閉系統(tǒng)的適用性（在3.2.P.7中描述）進(jìn)行討論并證明其合理性，包括：材料的選擇；如適用，對潮濕、氧氣和光照的防護(hù)作用；相容性；劑量；可用性和安全性。

具有無菌要求的藥品應(yīng)包裝在一次性容器中。

4.2.9 Microbiological Attributes (P.2.5)  微生物屬性（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.

微生物學(xué)方面，與其它給藥途徑一致，應(yīng)加以考慮，因?yàn)槠つw產(chǎn)品有時會涂在受損的皮膚上。需符合EP 5.1.4 非無菌藥物制劑的微生物質(zhì)量。

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.

4.3 Control strategy 控制策略

如果可能的話，在藥物開發(fā)過程中，應(yīng)建立藥品性能質(zhì)量屬性和臨床療效之間的聯(lián)系

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.

藥品質(zhì)量標(biāo)準(zhǔn)相關(guān)指南可參考ICH Q6A、Q3B、Q3C和Q3D，此外，需符合歐洲藥典列出的劑型通則。

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.

晶型轉(zhuǎn)變可能會對功效產(chǎn)生不利影響，使產(chǎn)品質(zhì)量出現(xiàn)缺陷；脫水收縮，即從半固體中排出液體，是另一種缺陷。應(yīng)考慮容器中制劑的均勻性，以確認(rèn)是否有沉淀現(xiàn)象。

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.

如果質(zhì)量標(biāo)準(zhǔn)中包含性能測試（即：溶出，采用合成膜進(jìn)行的藥物釋放測試；皮膚滲透測試，如適用），應(yīng)根據(jù)已證明具有良好療效和安全性的臨床批次數(shù)據(jù)，說明擬定限度的合理性。除非提供合理的臨床數(shù)據(jù)支撐，放行標(biāo)準(zhǔn)和貨架期標(biāo)準(zhǔn)的限度應(yīng)保持一致。

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.

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.

穩(wěn)定性研究中應(yīng)進(jìn)行影響因素試驗(yàn)，以評估苛刻條件對藥品的影響，如溫度循環(huán)（低－高溫）對乳膏劑和乳劑的穩(wěn)定性影響。在穩(wěn)定性研究中，應(yīng)包括監(jiān)控容器密封系統(tǒng)適用性的檢測試驗(yàn)。如在貯藏過程中有特殊要求，應(yīng)明確指出，如不能冷藏。

5.1 Scope 范圍

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.

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:

對于比較復(fù)雜的制劑，或含有的輔料可能直接影響活性物質(zhì)生物利用度或產(chǎn)品性能的制劑，通常需要進(jìn)行額外的滲透動力學(xué)和藥效學(xué)等效性試驗(yàn)（如可能）。

• With a narrow therapeutic index.

• With dose related, systemic toxicity, except in those cases where equivalent systemic exposure is shown by conventional pharmacokinetic bioequivalence studies.
• Where the means e.g. dissolution, release, diffusion, and permeation kinetics by which the active substance reaches the local site of action is not established or understood.
• Where the method of administration is not the same.
• 治療指數(shù)窄的藥物
• 與劑量相關(guān)的全身毒性藥物，但在常規(guī)藥代動力學(xué)生物等效性研究中顯示具有等效全身系統(tǒng)暴露的情況除外
• 尚未建立或明確以下情況的，如藥物的溶解、釋放、擴(kuò)散以及滲透動力學(xué)研究中藥物到達(dá)的具體皮膚層

• 不同的給藥途徑

• That cannot be fully characterised with respect to quality attributes e.g. due to complex formulation, methodological limitations.
• Where it is not possible to measure a quantifiable permeation kinetic or pharmacodynamic event e.g. due to limited diffusion or insensitive tests.
• Where in vitro and in vivo permeation kinetic and pharmacodynamic studies are not applicable or considered insufficiently predictive of clinical response e.g. products indicated for the treatment of open wounds and ulcers.
• 不能用質(zhì)量屬性完全表征的藥物，如復(fù)雜的配方制劑、方法學(xué)的局限性
• 皮膚滲透動力學(xué)或藥效學(xué)無法量化時，例如有限的擴(kuò)散或?qū)y試不敏感。

• 當(dāng)體外和體內(nèi)滲透動力學(xué)和藥效學(xué)研究不適用或被認(rèn)為不能充分預(yù)測臨床反應(yīng)時，例如用于治療開放性傷口和潰瘍的產(chǎn)品。

5.2 Equivalence with respect to quality (extended pharmaceutical equivalence) 關(guān)于質(zhì)量的等效性（拓展藥物等效性研究）

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.

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.

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.

此外，還應(yīng)提供數(shù)據(jù)證明，在指定的貨架期內(nèi)，藥品的性質(zhì)保持不變且等效。

受試制劑和參照制劑之間的擴(kuò)展藥物等效性接受標(biāo)準(zhǔn)是：

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

• 藥品應(yīng)為相同的藥物劑型，在相同的不混溶相中具有相同的活性物質(zhì)溶液狀態(tài)。

Qualitative and Quantitative Composition 藥物組分的定性與定量

• 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.

• 活性藥物的含量和鹽型應(yīng)相同。

• 通常情況下，輔料的種類（如必須，包括輔料級別）和用量應(yīng)保持一致，盡管允許例外的情況存在。但是，對于某些功能性輔料，其可能影響藥物溶解度、熱力學(xué)性質(zhì)或生物利用度和產(chǎn)品性能，應(yīng)具有相同的質(zhì)量。

  輔料的標(biāo)稱用量應(yīng)相同或相差不超過±5％。例如，對于在參照藥品中含量為2%(w/w)的輔料，受試藥品中的允許范圍為1.9-2.1%(w/w)。

• A permitted exception for a qualitatively different excipient may be acceptable for: 允許定性組分存在差異的例外情況包括：

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

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

  主要功能與藥品性能或給藥無關(guān)的輔料（即抗氧化劑、抗菌防腐劑、色素），并且不具有影響活性物質(zhì)溶解度、熱力學(xué)活性或生物利用度和產(chǎn)品性能的任何其它功能或作用。

  應(yīng)使用常規(guī)劑量的已經(jīng)過良好表征的輔料，并應(yīng)考量和討論可能影響藥物生物利用度和/或溶解度特性的相互作用。

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

  具備載體或潤膚功能的石蠟同系物，其不影響活性物質(zhì)的溶解度、熱力學(xué)活性或生物利用度和產(chǎn)品性能，是可以接受的。

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

  即使采用不同的輔料對局部耐受性或安全性沒有影響。同時提供證明說明，輔料不影響活性物質(zhì)溶解度、熱力學(xué)活性或生物利用度和產(chǎn)品性能的任何其它功能或作用。也不能豁免生物等效性研究（見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.

• 允許的定量差異不大于±10％的例外情況，如下：

  √   輔料的作用僅與載體特性或潤膚性有關(guān)

  √   輔料的作用與產(chǎn)品性能或給藥無關(guān)，即抗氧化劑、抗菌防腐劑、色素

  應(yīng)說明，輔料不影響活性物質(zhì)的溶解度、熱力學(xué)活性或生物利用度和產(chǎn)品性能的任何其它功能或作用。

Acceptance Criteria 接受標(biāo)準(zhǔn)

• 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.

• 對于定量質(zhì)量特征，假設(shè)數(shù)據(jù)呈正態(tài)分布，則受試藥品和參照藥品的均值差異的90%置信區(qū)間應(yīng)包含在參照藥品平均值的+/-10％的接受標(biāo)準(zhǔn)之內(nèi)。

• 定性質(zhì)量特征應(yīng)基本相同。

Administration 藥品使用

• 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.

• 給藥方法和給藥裝置應(yīng)相似，并在給藥時達(dá)到相同的劑量。

• 如果適用，當(dāng)給藥后藥物發(fā)生形變，則受試藥品和參照藥品的殘留在質(zhì)量方面應(yīng)等效，即在擴(kuò)展藥物等效性方面一致。

5.3 Equivalence with respect to efficacy 藥效等效性

5.3.1 Methods  方法

Permeation Kinetics Studies 滲透動力學(xué)研究

• In vitro skin permeation 體外皮膚滲透
• Stratum Corneum Sampling (Tape Stripping)  角質(zhì)層取樣（膠帶剝離）
• Pharmacokinetic bioequivalence 藥代動力學(xué)生物等效性

其他技術(shù)（例如微透析和共聚焦拉曼光譜法）還不夠完善，無法提供關(guān)鍵的等效數(shù)據(jù)，但可能是有幫助的。

Pharmacodynamic Studies 藥效學(xué)研究

• Vasoconstriction Assay for corticosteroids. 皮質(zhì)類固醇的血管收縮測定

• 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.

5.3.2 General Considerations 概論

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.

測試條件應(yīng)標(biāo)準(zhǔn)化，以最大限度地降低除被測產(chǎn)品外的所有相關(guān)因素的可變性。建議進(jìn)行試點(diǎn)研究以開發(fā)和優(yōu)化程序。

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.

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.

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.

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.

Sample sizes 樣品量

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.

在體外皮膚滲透性研究中，供體的數(shù)量在合適的情況下可以小于12。

在體外皮膚滲透和角質(zhì)層取樣（膠帶剝離）研究中，需要進(jìn)行重復(fù)設(shè)計(jì)。每一個受試產(chǎn)品、參照產(chǎn)品和對照產(chǎn)品的實(shí)驗(yàn)數(shù)最低不能少于24。

對于每個受試者或供體而言，取樣時間點(diǎn)的數(shù)量和頻率應(yīng)足夠表征活性物質(zhì)的動力學(xué)模型和確定等效性參數(shù)。

Acceptance Criteria 接受標(biāo)準(zhǔn)

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.

等效性參數(shù)的接受標(biāo)準(zhǔn)是，除非有充分的理由，受試產(chǎn)品均值和參照產(chǎn)品均值比率的90%置信區(qū)間應(yīng)包含在 80.00-125.00% 的接受區(qū)間內(nèi)。

Accreditation 評審

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.

確保執(zhí)行實(shí)驗(yàn)室有資格進(jìn)行實(shí)驗(yàn)以及擁有有效地質(zhì)量管理體系是很有必要的，這應(yīng)該包括：        

• 符合適當(dāng)質(zhì)量體系的聲明。

• 應(yīng)定期對執(zhí)行實(shí)驗(yàn)室的技術(shù)能力和所用方法的有效性進(jìn)行內(nèi)部評估，并提供最近的結(jié)果；

• 由國家主管部門進(jìn)行的外部審計(jì)

5.3.3 Permeation Kinetic Studies 滲透動力學(xué)研究

• 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)

以下是三種方法的具體指南：

• 體外皮膚滲透 （本指南附件II）

• 角質(zhì)層取樣（膠帶剝離）（本指南附件III）

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

研究應(yīng)符合附件 IV 中描述的方法

對于在有創(chuàng)手術(shù)前使用的皮膚防腐劑，應(yīng)符合ATSM E1173–15用于手術(shù)前、導(dǎo)管術(shù)前或注射前皮膚處理評估的標(biāo)準(zhǔn)測試法 的要求。

在體外皮膚感染和 decolonisation equivalence 研究中，如果能獲得滿意的驗(yàn)證結(jié)果，可以與其他等效性研究一起提供有效性的保證。

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.

一般來說，可根據(jù)對活性物質(zhì)的認(rèn)知以及輔料的選擇，保證外用制劑的安全性和局部耐受性。

當(dāng)顯示質(zhì)量等效時，可為外用制劑的安全性和局部耐受性提供保障。

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.

對于局部作用、全身起效的外用制劑，應(yīng)進(jìn)行生物等效性研究，說明藥物的安全性和有效性。

5.5 Topical Product Specific Equivalence Protocols 外用制劑特定的等效規(guī)定

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

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:

• 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).

• 不開展臨床治療等效性研究的理由；該藥品在且不超出本指南的范圍（5.1節(jié)）

• 不進(jìn)行安全研究的理由（5.4節(jié)）

• 拓展藥物等效性研究和給藥方法的等效性（第5.2節(jié)）

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

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

• 如果藥物的療效與藥物通過皮膚的擴(kuò)散情況相關(guān)（5.3.3節(jié)），可進(jìn)行相應(yīng)的滲透動力學(xué)等效性研究，說明藥物的經(jīng)皮擴(kuò)散情況。如適用，也可說明無需進(jìn)行該研究的依據(jù)

• 如果可能和相關(guān)，還應(yīng)進(jìn)行藥效學(xué)研究。鼓勵采用新技術(shù)，進(jìn)行開發(fā)、驗(yàn)證等研究（5.3.4 節(jié)）

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

原則上，無需提供滲透動力學(xué)或藥效學(xué)等效數(shù)據(jù)的情況，包括：

• 活性物質(zhì)在單相溶液或懸浮液中的簡單配方制劑，如外用溶液劑、單相凝膠劑和軟膏劑、外用混懸劑

• 如果藥物產(chǎn)品的宗旨和目標(biāo)只是將活性藥物給予到皮膚表面（見4.2.1節(jié)），通常進(jìn)行拓展藥物等效性（包括凝膠劑、軟膏劑和混懸劑的體外藥物釋放）和給藥等效性研究即可。

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.

需要進(jìn)行功效等效性研究（第 5.3 節(jié)）的配方，包括：

• 包含影響活性物質(zhì)生物利用度、產(chǎn)品性能或增強(qiáng)藥物滲透性的輔料

• 包含不同供應(yīng)商來源或級別可能體內(nèi)性能或活性物質(zhì)穩(wěn)定性的復(fù)雜輔料

• 與參照產(chǎn)品比較，具有不同成分的輔料（見5.2.1節(jié)，定性和定量組成）

5.5.2 Strength Biowaiver 不同規(guī)格生物等效性豁免

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

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

如果產(chǎn)品有多個不同的規(guī)格，通常情況下，采用其中一個規(guī)格進(jìn)行等效性研究即可，但要求該規(guī)格在評估各配方制劑的潛在差異時最敏感。

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

   不同規(guī)格產(chǎn)品的生產(chǎn)工藝相同
   

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

   不同規(guī)格產(chǎn)品的組分相同
   

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

   受試產(chǎn)品與參照產(chǎn)品相比，相同規(guī)格的產(chǎn)品具有相似的定性和定量組分
   

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

   采用所有規(guī)格的受試產(chǎn)品與參照產(chǎn)品進(jìn)行擴(kuò)展藥物等效性（第 5.2 節(jié)）論證

6 Post-authorisation changes 批準(zhǔn)后變更

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:

對于提議的任何變更，都應(yīng)進(jìn)行風(fēng)險評估，以確定其對產(chǎn)品的質(zhì)量、安全或有效性的影響。

還應(yīng)考慮原藥物產(chǎn)品的變更引入的風(fēng)險。

• 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.

• 原料藥的物理化學(xué)狀態(tài)和/或熱力學(xué)活性的變化

• 影響藥物產(chǎn)品溶出、體外釋放、體外滲透動力學(xué)特性的變化

• 生產(chǎn)工藝的變化，例如關(guān)鍵工藝參數(shù)的變化

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).

用于等效性研究的參比藥物產(chǎn)品，通常具有特定的配方、生產(chǎn)工藝、包裝等，且經(jīng)過管理當(dāng)局批準(zhǔn)。

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

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

如果擬議的變更不符合拓展制劑等效性研究（5.2.1節(jié)）接受標(biāo)準(zhǔn)，包括藥物劑型、或藥物的定性與定量組成，則應(yīng)進(jìn)行適當(dāng)?shù)呐R床研究證明產(chǎn)品等效。

Annex I  In vitro release test (IVRT)  附件一 體外釋放試驗(yàn)（IVRT）

1. Scope of IVRT  IVRT適用范圍

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).

2. Rationale for IVRT  IVRT基本原理

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

• 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)

• 藥物釋放率（R）：以活性物質(zhì)的累計(jì)釋放量對時間平方根作圖，釋放曲線的線性部分斜率即為藥物釋放率。如果不能獲得線性部分，則IVRT無效

• 在線性部分的最后采樣時間點(diǎn)獲得的活性物質(zhì)的累計(jì)釋放量（A），通常以“質(zhì)量/面積”表述

• 延遲時間（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.

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.

3. Study design 研究設(shè)計(jì)

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:

1. Choice of membrane: 膜的選擇

   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.  膜應(yīng)有確保產(chǎn)品和接收介質(zhì)保持分離的能力，以確保在整個測試過程中配方制劑保持不變。且不應(yīng)限制活性物質(zhì)的釋放。

   ii.  膜應(yīng)與配方制劑相容，且不與活性物質(zhì)結(jié)合。

2. Choice of receptor medium: 接收介質(zhì)選擇
   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.  應(yīng)確認(rèn)漏槽條件?？山邮艿穆┎蹢l件是，在整個試驗(yàn)期間，接收介質(zhì)中活性物質(zhì)的最大濃度不應(yīng)超過在該接收介質(zhì)中活性物質(zhì)最大溶解度的30%。通常情況下，介質(zhì)的體積至少是飽和體積的3-10倍。

   ii.  應(yīng)盡量減少接收介質(zhì)的反向擴(kuò)散，以避免藥物產(chǎn)品的轉(zhuǎn)化。在整個釋放測試期間，應(yīng)使受體介質(zhì)的 pH 值保持恒定。

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

   應(yīng)明確采樣時間（每小時至少一次）和試驗(yàn)條件（如儀器、溫度、攪拌速率）。IVRT 的持續(xù)時間應(yīng)足以表征釋放曲線，理想情況下，釋放量至少為活性物質(zhì)的70%。在藥物釋放曲線的線性部分至少選取6個時間點(diǎn)，包括藥物擴(kuò)散達(dá)到穩(wěn)態(tài)后的第一個取樣時間點(diǎn)。

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

   應(yīng)描述配制制劑的上樣量和上樣方法，在偽無限上樣條件下，確保上樣量的一致性（在±5%范圍內(nèi)），且樣品可均勻的涂抹在膜上。在上樣過程中，應(yīng)盡量減少由于樣品的蒸發(fā)造成的影響。

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

   分析方法應(yīng)有足夠的靈敏度，并經(jīng)過驗(yàn)證，確保其可以準(zhǔn)確的測定各采樣點(diǎn)接收液中藥物的含量。

4. Method validation 方法驗(yàn)證

上市許可申請中應(yīng)提供證明性文件，說明IVRT方法已經(jīng)過驗(yàn)證，其適用于藥物產(chǎn)品的質(zhì)量控制。應(yīng)遞交IVRT方法開發(fā)總結(jié)，以便于選擇具有最佳區(qū)分力的測試條件。

1. Satisfactory evidence of discrimination should be provided, with respect to both of the following quality modifications: 如下所示，可通過改變產(chǎn)品的兩個質(zhì)量特性，說明方法具有令人滿意的區(qū)分力：

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

   考察配方制劑中不同藥物濃度（至少三個規(guī)格）的釋放速率。當(dāng)釋放的藥物可以完全溶解于接收介質(zhì)時，需確定制劑濃度與藥物的釋放速率（R）呈線性關(guān)系（r2>0.90）。對于混懸劑，也應(yīng)了解和討論藥物濃度與藥物釋放速率（R）之間的關(guān)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.

   通過改變配方制劑的關(guān)鍵質(zhì)量屬性（如活性物質(zhì)的粒度分布或制劑的流變學(xué)特性）、關(guān)鍵生產(chǎn)工藝或輔料的定量組成，論證擬定的方法的區(qū)分力；但是，不能完全去除配方制劑中一個或多種特定的輔料。

2. Method intermediate precision for the same batch should be studied with different operators on different days (CV<10%).
   采用相同批次產(chǎn)品、在不同日期、由不同實(shí)驗(yàn)員進(jìn)行方法的中間精密度考察（CV＜10%）。
3. Method robustness with respect to variations in mixing rate, amount of formulation applied, receptor mediums and temperature should be studied.

   通過改變攪拌速率、配方制劑的上樣量、接收介質(zhì)和溫度，評估方法的耐用性。

5.Presentation of data 遞交數(shù)據(jù)

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

For extended pharmaceutical equivalence testing:

在首次進(jìn)行方法驗(yàn)證或等效性評估時，每個批次的樣品最少需要12個重復(fù)。對于日常放行檢測，每個批次至少需要6個重復(fù)。在體外藥物釋放研究中，應(yīng)以表格和圖形格式遞交相關(guān)數(shù)據(jù)；以 “質(zhì)量/面積” 為單位，報告特定時間的活性物質(zhì)釋放量。

• 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.

• 活性物質(zhì)的累計(jì)釋放量與時間的平方根呈線性關(guān)系；

• 釋放速率（R）明顯大于0；

• 受試產(chǎn)品與參照產(chǎn)品釋放速率（R）均值比率的90%置信區(qū)間應(yīng)包含在90－111%的可接受范圍；

• 延遲時間一致（在±10%范圍內(nèi)），如有。

1. Scope and rationale for IVPT  IVPT 適用范圍和基本原理

在等效性研究中，可通過將受試產(chǎn)品與參照產(chǎn)品和陰性對照產(chǎn)品（如擬定配方制劑的50%規(guī)格）的測定結(jié)果進(jìn)行對比論證。

2. Study design 研究設(shè)計(jì)

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:

為了最大限度地降低誤差風(fēng)險，應(yīng)根據(jù) ICH E8，在研究方案中明確規(guī)定盲法和隨機(jī)化方法。建議采用受試產(chǎn)品與參照產(chǎn)品進(jìn)行IVPT探索性研究，以確認(rèn)活性物質(zhì)可滲透通過皮膚，同時對試驗(yàn)條件進(jìn)行確認(rèn)（如儀器、上樣量、采樣時間和攪拌速率等），并可能有助于評估IVPT正式研究中所需的樣本量。

1. Choice of skin membrane: 皮膚膜的選擇
   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.

   建議使用體外成人皮膚。研究方案中應(yīng)明確皮膚切片的納入/排除標(biāo)準(zhǔn)、解剖區(qū)域、保存條件和時間。應(yīng)排除有紋身、任何皮膚異常跡象或明顯濃密的末端毛發(fā)皮膚。

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

   可以使用不同的皮膚處理技術(shù)。應(yīng)提供證據(jù)證明皮膚處理技術(shù)和儲存不會引入人工制品，也不會改變皮膚屏障功能。使用全層皮膚可能會人為地延遲藥物滲透，除非有合理說明，否則應(yīng)避免使用。應(yīng)描述皮膚厚度和分離技術(shù)。

   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.

   應(yīng)在每次實(shí)驗(yàn)的前后分別檢查皮膚完整性。應(yīng)說明皮膚完整性的測試方法及其接受標(biāo)準(zhǔn)。雖然實(shí)驗(yàn)前后可以采用不同的接受標(biāo)準(zhǔn)，但在所有平行實(shí)驗(yàn)中接受標(biāo)準(zhǔn)應(yīng)該是合理的和一致的。

   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.

   應(yīng)采用多個不同的供體皮膚進(jìn)行評估。受試、參照和陰性對照產(chǎn)品每次重復(fù)測定，應(yīng)采用相同的供體皮膚，最好是相鄰部位的皮膚。

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

   皮膚供體的數(shù)量不應(yīng)少于 12 個，每個供體至少 2 個重復(fù)。

   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.

   儀器應(yīng)確保在整個實(shí)驗(yàn)過程中溫度恒定。皮膚表面溫度穩(wěn)定在32±1℃。

2. Choice of receptor medium: 接收介質(zhì)的選擇
   i.  Sink conditions should be confirmed as described with IVRT (Annex 1).
   應(yīng)按照 IVRT（附件 1）的要求確認(rèn)漏槽條件。
   ii.  The receptor medium should be aqueous buffer, unless otherwise justified. Evidence should be provided that the chosen receptor medium does not compromise the skin barrier integrity throughout the test.
   除非提供合理性依據(jù)，應(yīng)采用水性緩沖液作為接收介質(zhì)。應(yīng)提供證據(jù)說明所選接收介質(zhì)在整個測試過程中不會損害皮膚屏障的完整性。
   iii.  The inclusion of an anti-microbial agent in the receptor medium, to mitigate potential bacterial decomposition of the skin membrane, is acceptable, but it should not interfere with the properties of the skin or the assay.

   可以在接收介質(zhì)中添加抗菌劑，以減輕皮膚膜的潛在細(xì)菌分解，但添加的抗菌劑不應(yīng)干擾皮膚的特性或測定。

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

   應(yīng)有足夠的采樣時間點(diǎn)，以獲得有意義的釋放模型，即：捕獲吸收的最大速率和之后吸收速率的下降情況，并在吸收速率最大的時間段進(jìn)行更頻繁的采樣。測定持續(xù)的時間通常為24h。如果時間大于24h，應(yīng)證明試驗(yàn)前后皮膚具有可接受的屏障完整性。

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

   根據(jù)產(chǎn)品特性概要（SmPC）中的使用劑量要求，建議上樣量為2-15mg/cm2，除非另有規(guī)定。應(yīng)對上樣方式進(jìn)行確認(rèn)，確?？蓪⑴浞街苿┚鶆蛞恢碌耐磕ǖ狡つw膜上，且可重復(fù)（±5%）。除非SmPC中另有規(guī)定，供給室應(yīng)采用非閉環(huán)（un-occluded）上樣。

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

   為了識別潛在的污染和/或干擾，建議在上樣前，從每個擴(kuò)散池中收集接收液，同時進(jìn)行未上樣空白對照試驗(yàn)。

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

   應(yīng)在研究方案和最終報告中提供對盲法程序的詳細(xì)描述。受試、參照和陰性對照產(chǎn)品的包裝外觀應(yīng)相似，以保持足夠的致盲。應(yīng)在方案中描述隨機(jī)化方法，并同時提供隨機(jī)化時間表。

7. For low strength drug product, the analytical methods should be sensitive enough to quantify the amount of drug in the receptor solution at various time points and be appropriately validated.
   對于小規(guī)格制劑，分析方法應(yīng)有足夠的靈敏度并經(jīng)過合適的驗(yàn)證，確認(rèn)其可以準(zhǔn)確測定接收液中各采樣時間點(diǎn)的藥物含量。
8. The stability of the active substance in the receptor solution over the duration of IVPT study, and sample storage prior to analysis, should be confirmed.

   應(yīng)確認(rèn)在IVPT研究期間和測定前存放條件下，接收液中活性物質(zhì)的穩(wěn)定性。

3. Method validation 方法驗(yàn)證

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.

上市許可申請中，應(yīng)遞交IVPT驗(yàn)證資料，證明其適用于藥物的對比研究。

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.

4. Presentation of data 遞交數(shù)據(jù)

應(yīng)以表格和圖形格式遞交IVPT數(shù)據(jù)，列出所有的數(shù)據(jù)和參數(shù)，以及計(jì)算公式和匯總統(tǒng)計(jì)信息。為了表征釋放行為，應(yīng)將“單位面積的累計(jì)滲透量（質(zhì)量/平方厘米）與時間”作圖，同時將 “吸收速率（質(zhì)量/平方厘米/小時）與時間” 作圖，并遞交相關(guān)結(jié)果。

應(yīng)將相關(guān)的滲透參數(shù)或數(shù)據(jù)進(jìn)行比較，如最大吸收速率(J_max)和試驗(yàn)結(jié)束時的總滲透量(A_total)。在重復(fù)設(shè)計(jì)的情況下，應(yīng)在進(jìn)一步分析之前對來自同一供體的重復(fù)位點(diǎn)的結(jié)果進(jìn)行平均（幾何平均值）。

• 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.

  受試產(chǎn)品與參照產(chǎn)品均值比率的90% 置信區(qū)間應(yīng)包含在80.00－125.00%的可接受范圍，除非有正當(dāng)理由。

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

  對于小規(guī)格和擴(kuò)散量有限的藥物產(chǎn)品，如果觀察到具有高變異性，可通過臨床研究，放寬90%置信區(qū)間，采用更寬松的接受標(biāo)準(zhǔn)69.84-143.19。應(yīng)遵循生物等效性研究指南“第4.1.10節(jié)高度變異性藥物或藥物產(chǎn)品”的相關(guān)規(guī)定。

In addition, for the test to be valid: 此外，為了確認(rèn)測試結(jié)果可信：

The acceptance criteria for equivalence parameters (Jmax) and (Atotal) 等效性參數(shù)(Jmax)和(Atotal)的接受標(biāo)準(zhǔn)為：

• 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%.

  受試產(chǎn)品與陰性控制產(chǎn)品均值比率的 90% 置信區(qū)間應(yīng)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%.

  參照產(chǎn)品與陰性控制產(chǎn)品均值比率的 90% 置信區(qū)間應(yīng)全部在 80.00－125.00% 之外。

還應(yīng)報告其他滲透參數(shù)，例如最大吸收率(tmax)的時間和延遲時間。如存在延遲時間，受試產(chǎn)品和參照產(chǎn)品應(yīng)保持一致（即在±10%范圍內(nèi)）。應(yīng)對等效性研究中發(fā)現(xiàn)的滲透參數(shù)的任何不同之處進(jìn)行討論。

可以分別測定不同皮膚層（如角質(zhì)層和表皮層）中保留的活性物質(zhì)的量，以了解活性物質(zhì)在人體皮膚中的分布。

Annex III Stratum Corneum (S.C.) Sampling (Tape Stripping)  附件III 角質(zhì)層（S.C.）取樣（膠帶剝離 ）

1. Introduction 引言

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

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.

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.

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.

2. Method development and optimization 方法開發(fā)和優(yōu)化

在探索性研究中，應(yīng)對以下試驗(yàn)條件進(jìn)行確認(rèn)：

• 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.

  膠帶剝離研究應(yīng)在健康、正常、皮膚屏障功能良好的前臂（掌）皮膚區(qū)域進(jìn)行。應(yīng)明確皮膚的納入/排除標(biāo)準(zhǔn)。將有紋身、任何皮膚異常跡象或明顯濃密的末端毛發(fā)皮膚排除在外。在試驗(yàn)前，確定皮膚的處理和清潔方法，確保這些處理措施不會破壞皮膚的完整性。

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

  應(yīng)在實(shí)驗(yàn)前后確定皮膚完整性。通常采用經(jīng)皮水分散失法（TEWL）進(jìn)行測定，如適用，也可以采用其它技術(shù)。應(yīng)對接受標(biāo)準(zhǔn)進(jìn)行討論，說明其合理性。

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

  由于受試者之間的變異性，在產(chǎn)品的對比研究中應(yīng)采用同一受試者。此外，需考察與參照產(chǎn)品不等效的陰性控制產(chǎn)品，用于論證方法的區(qū)分力。建議負(fù)責(zé)配方應(yīng)用和膠帶剝離的研究者進(jìn)行盲檢，以最大限度降低偏倚風(fēng)險。

• 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.

  應(yīng)根據(jù)SmPC確定上樣量。在探索性研究期間，需確認(rèn)上樣量、上樣區(qū)域/面積，以滿足角質(zhì)層中活性物質(zhì)定量測定的需求。同時，確定上樣方式、盲法和隨機(jī)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.

  應(yīng)采用單劑量方法，即在單次上樣受試產(chǎn)品或參照產(chǎn)品后，進(jìn)行皮膚剝脫。

• 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.

  對于每個受試者，需要對兩個時間點(diǎn)（吸收、清除）的產(chǎn)品測定結(jié)果進(jìn)行對比。最佳的吸收和清除時間取決于藥物和產(chǎn)品的特性，應(yīng)在探索性研究期間進(jìn)行確定。理想情況下，吸收時間應(yīng)足夠長，以使藥物達(dá)到擴(kuò)散平衡狀態(tài)。這可以通過測定給藥后多個時間點(diǎn)，角質(zhì)層中藥物回收的量進(jìn)行確定。清除時間應(yīng)足夠長，以便于準(zhǔn)確測定從角質(zhì)層轉(zhuǎn)移至活體皮膚（和皮下）的情況，但不應(yīng)超過 48 小時，以避免任何皮膚脫屑效應(yīng)。與吸收階段相比，能使從角質(zhì)層中回收的藥物量至少降低25%的清除時間是最佳的。無論什么情況，都要仔細(xì)考慮采樣時間并證明其合理性。

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

  在特定的吸收時間后，應(yīng)將藥物從皮膚表面移除。需建立移除方法，確保在膠帶剝離前，殘留的配方制劑可有效的從給藥部位移除。

• 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).

  所用膠帶應(yīng)滿足以下要求：a）與皮膚表面粘附后，不損失重量；b）存儲過程中，重量減少和增加較小；c）藥物易從粘附在膠帶上的角質(zhì)層中提?。籨）膠帶的粘合劑或其他成分不干擾藥物的定量測定；e）膠帶應(yīng)有足夠的粘合力，即使采用較少的膠帶數(shù)量也可以除去大部分的角質(zhì)層（例如，不超過 30 條）。

• 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.

  對于每個皮膚位點(diǎn)，所用的膠帶剝離程序必須確保大部分角質(zhì)層（≥75%）被采樣。可以根據(jù)TEWL接受標(biāo)準(zhǔn)（或其它相關(guān)技術(shù)）確定所需膠帶的最少和最大數(shù)量，例如，基線值、安全停止值的八倍增量。

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

  最常見的是，先從膠帶中提取藥物，然后對提取溶劑進(jìn)行測定。如果有正當(dāng)理由，可以使用其他提取/定量方法。同時需證明，所采用的提取方法可獲得令人滿意的結(jié)果。

• Subjects – TS studies should be performed in healthy volunteers. The subjects should be screened for suitability in line with the principles of bioequivalence studies.
  受試者：在膠帶剝離研究中，需采用健康受試者，并根據(jù)生物等效性研究的原則對受試者進(jìn)行篩選。
• 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;

  給藥部位：可在每個前臂掌側(cè)健康皮膚區(qū)域的六個部位給藥。應(yīng)進(jìn)行皮膚完整性確認(rèn)，如采用TEWL進(jìn)行測定，同時，應(yīng)確保每個前臂的給藥部位相同、數(shù)量相同；

• Number of subjects – the choice of the number of subjects should be justified based on the variability estimated from the pilot studies and demonstrated to be statistically relevant. A minimum of 12 subjects should be used to demonstrate equivalence;
  受試者數(shù)量：受試者數(shù)量的選擇應(yīng)基于探索性研究中可變性評估進(jìn)行說明，以證明其滿足統(tǒng)計(jì)學(xué)相關(guān)要求。在等效性論證過程中，至少需要12名受試者；
• Number of replicates – at least two application sites per product (test, comparator and a negative control) per forearm. One forearm should be used for uptake samples and the other for clearance;

• 重復(fù)次數(shù)：每個樣品（受試、參照和陰性控制）在各前臂至少應(yīng)有兩個給藥位點(diǎn)。一個前臂用于藥物吸收，另外一個用于清除；

• The products should be applied at pre-determined doses (±5%) and spread evenly over the entire demarcated application sites. Blank samples should be collected from the adjacent areas to verify the absence of background levels of drug or other compounds that may interfere with the quantification of drug in the treated SC;
  產(chǎn)品應(yīng)按預(yù)定的劑量（±5%），均勻的涂抹到指定區(qū)域/位點(diǎn)，并從上樣區(qū)域的相鄰部位收集空白樣品，以確認(rèn)在角質(zhì)層中不存在可能干擾藥物定量的背景水平或其他化合物；
• The application sites should be randomised to avoid bias. The application time should be staggered to allow time for S.C. sampling;

  給藥位點(diǎn)應(yīng)隨機(jī)化，以避免偏倚；并錯開給藥時間，以便有充足的時間對角質(zhì)層進(jìn)行采樣；

• Un-occluded conditions, unless occlusion is recommended in the product information, or otherwise justified e.g. to prevent inadvertent removal of formulation.
  采用“非閉環(huán)（un-occluded）”條件，除非產(chǎn)品信息中推薦采用“閉環(huán)（occluded）”條件，或證明其合理性，如：防止無意中去除配方制劑。
• The formulation should be removed from all treatment sites (uptake and clearance) at the end  of the uptake phase. The total cleaning time should be minimised to avoid any artefacts due to further drug diffusion. Skin integrity of the treated area should be checked before stripping;

• 在吸收結(jié)束后，應(yīng)將給藥位點(diǎn)（吸收和清除）的樣品去除；并盡量減少總清潔時間，以避免由于藥物進(jìn)一步擴(kuò)散造成偏差。在膠帶剝離前，對上樣區(qū)域的皮膚完整性進(jìn)行測定；

• The 'uptake’ sites should be tape-stripped immediately after formulation removal. The 'clearance’ sites should be tape-stripped at the pre-defined clearance times;
  對于“吸收”位點(diǎn)，應(yīng)在去除配方制劑后立即用膠帶剝離。而“清除”位點(diǎn)是在預(yù)定的清除時間用膠帶剝離；
• 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;

  應(yīng)根據(jù)膠帶剝離區(qū)域的TEWL測定結(jié)果和探索性研究中建立的停止標(biāo)準(zhǔn)，確定所需膠帶的確切數(shù)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;

  應(yīng)確定每條膠帶去除的角質(zhì)層的重量，可通過稱量膠帶剝離前后的重量，以減重法進(jìn)行測定。如合理，也可采用其它可替代方法；

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

  收集用于每個治療位點(diǎn)剝離的所有膠帶，進(jìn)行測定。將剝離的前兩個膠帶單獨(dú)進(jìn)行測定，評估它們對藥物回收總量的貢獻(xiàn)。為增強(qiáng)方法的檢出能力，可將剩余的膠帶分組（如，每組應(yīng)包含所需最少量的角質(zhì)層）提取后進(jìn)行測定。角質(zhì)層中藥物的總量為從所有剝離膠帶中提取的樣品量之和。應(yīng)對每個治療位點(diǎn)的質(zhì)量平衡（包括從角質(zhì)層表面移除的藥物）進(jìn)行評估。藥物總回收率的可接受范圍是90%~110%；如超出該范圍，應(yīng)提供合理性說明。

4. Method validation 方法驗(yàn)證

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.

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.

應(yīng)采用不同質(zhì)量屬性的樣品（包括陰性控制樣品）對膠帶剝離（TS）方法的區(qū)分力進(jìn)行論證，如采用±50%標(biāo)稱規(guī)格的樣品，其結(jié)果與受試制劑和參照制劑相比，具有統(tǒng)計(jì)學(xué)差異且不等效。應(yīng)按照《生物分析方法驗(yàn)證指南》，對膠帶剝離角質(zhì)層中活性物質(zhì)含量的測定方法進(jìn)行驗(yàn)證。

5. Data analysis and metrics 數(shù)據(jù)分析與度量

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.

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.

對于每種產(chǎn)品，應(yīng)報告去除的角質(zhì)層（SC）厚度、剝離用的膠帶數(shù)量，和吸收與清除階段TEWL的測定結(jié)果。應(yīng)討論受試制劑與參照制劑之間這些參數(shù)的差異對等效性的影響。

在兩個產(chǎn)品的比較中，應(yīng)根據(jù)生物等效性研究指南（CPMP/EWP/QWP/1401/98 Rev. 1/ Corr），對等效性參數(shù)進(jìn)行統(tǒng)計(jì)分析。等效參數(shù)（M_uptake）和（M_clearance）的接受標(biāo)準(zhǔn)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.

  受試產(chǎn)品與參照產(chǎn)品均值比率的90% 置信區(qū)間應(yīng)包含在80.00－125.00%的可接受范圍，除非有正當(dāng)理由。
• Wider 90% confidence interval limits, to a maximum of 69.84 – 143.19, may be accepted in the case of high variability observed with low strength and limited diffusion drug products, and if clinically justified. The procedure in the Guideline on Investigation of Bioequivalence, “Section 4.1.10 Highly variable drugs or drug products” should be followed.

  對于小規(guī)格和擴(kuò)散量有限的藥物產(chǎn)品，如果觀察到具有高變異性，可通過臨床研究，放寬90%置信區(qū)間，采用更寬松的接受標(biāo)準(zhǔn)69.84-143.19。應(yīng)遵循生物等效性研究指南“第4.1.10節(jié)高度變異性藥物或藥物產(chǎn)品”的相關(guān)規(guī)定。

• 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%.

  受試產(chǎn)品與陰性控制產(chǎn)品均值比率的90% 置信區(qū)間應(yīng)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%.

  參照產(chǎn)品與陰性控制產(chǎn)品均值比率的90% 置信區(qū)間應(yīng)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.

對外用皮質(zhì)類固醇有適當(dāng)血管收縮的健康受試者必須包括在內(nèi)。

在正式研究中，至少應(yīng)包括12名受試者。

研究的時長應(yīng)足以使響應(yīng)恢復(fù)到基線水平，并確?？捎^察到最大的藥效學(xué)反應(yīng)。此外，必須對試驗(yàn)方法進(jìn)行優(yōu)化，使產(chǎn)品可以根據(jù) blanching curve 的線性部分進(jìn)行比較。在預(yù)試驗(yàn)中，應(yīng)對幾個不同的上樣時間進(jìn)行測定，以確定靈敏度下限。

血管收縮反應(yīng)的測量應(yīng)使用色度計(jì)或其他比目測更敏感的方法，并由獨(dú)立觀察者進(jìn)行二次臨床評估。

References: 參考文獻(xiàn)

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

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