FDA发布速释口服生物豁免修订草案（征求意见7月截止）

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201505 FDA发布速释口服生物豁免修订草案（征求意见7月截止）  

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2015-05-22

2015年5月，FDA发布速释口服固体制剂的生物豁免修订草案，公开征求意见。

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其中，整体内容与前版本 （2000年）并无太大变化，修订主要反映在以下几方面：

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1. 溶解度测试PH值则1-7.5改为1-6.8

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2. 渗透性高渗标准由90%改为85%

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3. 溶出度测试介质体积由900ml改为500ml，增加75rpm转速

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4.方法适用性吸收模型中高吸收率标准由89%/90%改为84%/85%。

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5. 增加一个章节“基于BCS的生物豁免”

6.其它事项中，辅料将BCS一类和三类分开讨论

7.其它事项中，增加“固定剂量复方制剂”的讨论

8.附录A中表格按渗透性等特性分类重新编制

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以下黄色为新增内容，划删除线者为本次删除内容。征求意见稿PDF文稿可以FDA官网下载。

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Waiver of In Vivo Bioavailability andBioequivalence Studies for

Immediate-Release Solid Oral DosageForms Based on a Biopharmaceutics Classification System

Guidance for Industry

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DRAFT GUIDANCE

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This guidance document is beingdistributed for comment purposes only.

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Comments and suggestions regarding thisdraft document should be submitted within 60 days of publication in theFederalRegister of the notice announcing theavailability of the draft guidance. Submit electronic comments tohttp://www.regulations.gov. Submit writtencomments to the Division of Dockets Management (HFA-305), Food and DrugAdministration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All commentsshould be identified with the docket number listed in the notice ofavailability that publishes in the Federal Register.

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For questions regarding this draftdocument contact (CDER) Mehul Mehta 301-796-1573.

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Additional copies are available from:

Office of Communications, Division ofDrug Information

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Center for Drug Evaluation and Research

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Food and Drug Administration

10001 New Hampshire Ave., HillandaleBldg., 4th Floor

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Silver Spring, MD 20993-0002

Phone: 855-543-3784 or 301-796-3400;Fax: 301-431-6353

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Email: druginfo@fda.hhs.gov

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and HumanServices

Food and Drug Administration

Center for Drug Evaluation and Research(CDER)

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May 2015

Biopharmaceutics

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Revision 1

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GUIDANCE FOR INDUSTRY 1

Waiver of In Vivo Bioavailability andBioequivalence Studies for

Immediate-Release Solid Oral DosageForms Based on a Biopharmaceutics Classification System

基于生物制剂分类系统的速释固体口服制剂

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体内生物利用度和生物等效性研究

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豁免指南

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This draft guidance, when finalized, will represent the Food and Drug  Administration’s (FDA’s) current 7 thinking on this topic. It does not create or confer any rights for or  on any person and does not operate to 8 bind FDA or the public. You can use an alternative approach if the  approach satisfies the requirements of 9 the applicable statutes and regulations. If you want to discuss an  alternative approach, contact the FDA 10 staff responsible for implementing this guidance. If you cannot identify  the appropriate FDA staff, call 11 the appropriate number listed on the title page of this guidance.

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GUIDANCE FOR INDUSTRY[1]

Waiver of In Vivo Bioavailability andBioequivalence Studies for

Immediate-Release Solid Oral DosageForms Based on a Biopharmaceutics Classification System

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基于生物制剂分类系统的速释固体口服制剂

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体内生物利用度和生物等效性研究

豁免指南

I.INTRODUCTION   引言

This guidanceprovides recommendations for sponsors of investigational new drug applications(INDs), new drug applications (NDAs), abbreviated new drug applications(ANDAs), and supplements to these applications for immediate-release(IR) solid oral dosage forms, who wish torequest a waiver of in vivo bioavailability (BA) and/or bioequivalence (BE)studies for immediaterelease (IR) solid oral dosage forms. These waiversare intended to apply to (1) subsequent in vivo BA or BE studies offormulations after the initial establishment of the in vivo BA of IR dosageforms during the IND period, and (2) in vivo BE studies of IR dosage forms inANDAs.

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Regulations at 21 CFR part 320 addressthe requirements for bioavailability (BA) and BE data for approval of drugapplications and supplemental applications. Provision for waivers of in vivoBA/BE studies (biowaivers) under certain conditions is provided at 21 CFR320.22[2]. Thisguidance explains when biowaivers can be requested for IR solid oral dosageforms based on an approach termed the Biopharmaceutics Classification System(BCS).  This guidance updates the  guidance for industry on Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on aBiopharmaceutics Classification System[3],  published in August 2000, and explains when biowaivers can berequested for IR solid oral dosage forms based on an approach termed theBiopharmaceutics Classification System (BCS). This guidance includes biowaiverextension to BCS class 3 drug products, and additional modifications, such ascriteria for high permeability and high solubility.

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In general, FDA’sguidance documents do not establish legally enforceable responsibilities.Instead, guidances describe the Agency’s current thinking on a topic and shouldbe viewed only as recommendations, unless specific regulatory or statutoryrequirements are cited. The use of the word should in Agency guidancesmeans that something is suggested or recommended, but not required.

本指南给INDs、MDAs、ANDAs和增补申请主办方为速释固体口服制剂请求获得生物利用度和/或生物等效性研究豁免提供建议。该豁免适用于：1：IND研究期间，起始建立的IR剂型体内生物利用度研究的后续配方体内生物利用度或生物等效性研究；2： ANDAs的IR剂型体内生物等效性研究。21 CFR 302部分的规定声明了通过药物申请和增补申请的BA、BE数据的要求。特定情况下的体内BA/BE研究规定在 21 CFR 320.22部分提供。本指南解释了何时IR口服剂型能够按照术语是生物药剂分类系统这种途径来请求豁免的情况。

II. THEBIOPHARMACEUTICS CLASSIFICATION SYSTEM   生物药剂分类系统

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The BCS is ascientific framework for classifying drug substances based on their aqueoussolubility and intestinal permeability. When combined with the dissolution ofthe drug product, the BCS takes into account three major factors that governthe rate and extent of drug absorption from IR solid oral dosage  forms1)dissolution, (2)solubility, and (3)intestinal permeability[4].  According to theBCS, drug substances are classified as follows:

BCS是按照制剂的水溶性和肠道通透性来将药品分类的一个科学结构。结合药品的溶出，BCS考虑了三个决定速释固体口服制剂的药物吸收率和吸收程度的主要因素，他们是：溶出度，溶解性和肠道通透性。根据BCS，药品被分为以下几类：

Class 1: HighSolubility – High Permeability 第一类：高溶解性高渗透性

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Class 2: LowSolubility – High Permeability 第二类：低溶解性高渗透性

Class 3: HighSolubility – Low Permeability 第三类：高溶解性低渗透性

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Class 4: LowSolubility – Low Permeability 第四类：低溶解性低渗透性

In addition, IRsolid oral dosage forms are categorized as having rapid or very rapid[5] slow dissolution.Within this framework, when certain criteria are met, the BCS can be used as adrug development tool to help sponsors justify requests for biowaivers.

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此外，IR固体口服制剂也按照溶出速度快慢分类。在这个框架之内，若满足特定条件，BCS能够被当做一个药物发展工具，来帮助主办方判定争取生物豁免的要求。

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Observed in vivodifferences in the rate and extent of absorption of a drug from twopharmaceutically equivalent solid oral products may be due to differences indrug dissolution in vivo[6].However, when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid in relation togastric emptying and the drug has high solubility permeability, the rate andextent of drug absorption is unlikely to be dependent on drug dissolutionand/or gastrointestinal transit time. Under such circumstances, demonstrationof in vivo BA or BE may not be necessary for drug products containing Class 1 and class 3drug substances,as long as the inactive ingredients used in the dosage form do notsignificantly affect absorption of the active ingredients.

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The BCS approachoutlined in this guidance can be used to justify biowaivers for highly solubleand highly permeable drug substances (i.e., Class 1) as well as highlysoluble and low permeable drug substances (i.e., class 3) in IR solid oraldosage forms that exhibit rapid or very rapid in vitrodissolution using the recommended test methods (21 CFR320.22(e)). The recommended methods for determining solubility,permeability, and in vitro dissolution are discussed below.

在两个药剂学等价的固体口服制剂上观察到的体内吸收率和吸收度的区别，可能是由于它们在体内溶出方面的差别。然而，当某一速释固体口服制剂的体内溶解在胃排空时十分迅速，且具有高肠道渗透性，则该药品的吸收率和吸收程度就不太可能依靠它的溶出和/或胃肠通过时间了。在这种情况下，说明包含第一类的原料药制剂的体内BA或者BE，只要制剂中使用的非活性物质不会显著影响活性物质的吸收，就不一定要求。本指南阐述的BCS途径，可以用来阐述证明速释固体口服制剂原料药的生物豁免，这种原料药应具有高溶解性和高渗透性（即第一类药物），且在使用推荐的检测方法时便显出迅速的体外溶出特性。判定药物溶解度，渗透性和体外溶解性的推荐检测方法在下文讨论。

A.Solubility   溶解

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The solubilityclass boundary is based on the highest dose strength of an IR product that isthe subject of a biowaiver request. A drug substance is considered highlysoluble when the highest dose strength is soluble in 250 ml or less of aqueousmedia over the pH range of 1-6.87.5.The volume estimate of 250 ml is derived from typical BE study protocols thatprescribe administration of a drug product to fasting human volunteers with aglass (about 8 ounces) of water.

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溶解性的分组界限基于速释制剂的最高剂量强度，这也是生物豁免要求的受试项。若药物最高剂量时，在250ml或者更少的水介质中、pH值1-7.5范围内能正好完全溶解，则该药物被认为是高溶解性的。250ml的量的来源是经典BE试验规程，其规定，空腹时用一玻璃杯水（约8盎司）为志愿者给药。

B.Permeability   渗透性

The permeabilityclass boundary is based indirectly on the extent of absorption (fraction of doseabsorbed, not systemic BA) of a drug substance in humans and directly on  measurements ofthe rate of mass transfer across human intestinal membrane. Alternatively, other nonhuman systems capableof predicting the extent of drug absorption in humans can be used (e.g., in situ animal, in vitroepithelial cell culture methods). In the absence of evidence suggesting instability inthegastrointestinal tract, a drug substanceis considered to be highly permeable when the extent of absorption in humans isdetermined to be 85 percent 90% or more of anadministered dose based on a mass balance determination (along with evidenceshowing stability of the drug in the GI tract) or in comparisonto an intravenous reference dose.

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渗透性分级标准上下限与原料药在人体内的吸收程度间接相关（指单一剂量吸收的部分，而不是全身的生物利用度），与原料药在人体肠道膜间质量转移测量率直接相关。或者，能够预测药物在人体内的吸收程度的非人体系统也可以参考（例如离体上皮细胞培养技术）。若缺乏胃肠道稳定性的证明，单次给药质量平衡测定时，相比于静脉注射参考剂量来说，体内吸收程度达到或超过90%，该药物就被认为是高渗透性的。

C.Dissolution   溶出性

In thisguidance, an IR drugproduct is considered rapidly dissolving when no less than 85% or more of the labeledamount of the drug substance dissolves within 30minutes, using U.S.Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm or at 75 rpm whenappropriately justified (see section III.C.) ) in a volume of 500 mL 900 ml or less in eachof the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP withoutenzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated IntestinalFluid USP without enzymes.

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An IR product is considered very rapidly dissolving when 85 percent or more of the labeled amount of the drug substancedissolves within 15 minutes using the above mentioned conditions.

在本指南中，若按以下方式，速释口服制剂能在30分钟内溶出标示量的85%或更多，则该制剂被认为是速溶的：按照USP标准，使用设备I，转速100rpm或设备II，转速50rpm，使用900ML或更少下列溶媒：（1）0.1N HCl或者药典标准无酶人工胃液；(2)pH 4.5 缓冲液；或(3)pH 6.8缓冲液或者药典标准无酶人工肠液。

III. METHODOLOGYFOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING THEDISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT   药物分类和制剂溶出特性测定方法

The followingapproaches are recommended for classifying a drug substance and determining thedissolution characteristics of an IR drug product according to the BCS:

下面的方法是根据生物制剂分类系统制定的药物推荐分类方法和速释制剂溶出特性测定方法:

A. DeterminingDrug Substance Solubility Class   判定原料药的溶解度分类

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An objective ofthe BCS approach is to determine the equilibrium solubility of a drug substanceunder physiological pH conditions. The pH-solubility profile of the test drugsubstance should be  determined at 37± 1?C in aqueousmedia with a pH in the range of 1-6.87.5.A sufficient number of pH conditions should be evaluated to accurately definethe pH-solubility profile within the pH range of 1-6.8. The number of pH conditions for asolubility determination can be based on the ionization characteristics of thetest drug substance to include pH = pKa, pH = pKa +1, pH = pKa-1, and at pH = 1 and 6.8. For example,when the pKa of a drug is in the range of 3-5, solubility should be determinedat pH = pKa, pH = pKa +1, pH = pKa-1, and at pH = 1 and 7.5. A minimum ofthree replicate determinations of solubility in each pH condition isrecommended.

该BCS方法的一个目标是，测定原料药在生理pH条件下的溶解平衡。被测原料药的不同pH溶解度测定应在37℃±1℃、使用pH值在1-7.5的水介质测定。应测定足够的pH条件下的数据，以便精确的计算确定pH溶解度。溶解度测定的pH条件个数可以基于被测原料药的离子化特性来确定。例如，当被测原料药的pKa值在3-5范围内，则其溶解度可以在pH=pKa, pH=pKa+1, pH=pKa-1, 以及pH=1和7.5这几个条件下测量。测定溶解度时每个pH条件至少要有3个平行测定实验。

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Depending onstudy variability, additional replication may be necessary to provide areliable estimate of solubility. Standard buffer solutions described in the USPare considered appropriate for use in solubility studies. If these buffers arenot suitable for physical or chemical reasons, other buffer solutions can beused. Solution pH should be verified after addition of the drug substance to abuffer. Methods other than the traditional shake-flask method, such as acid orbase titration methods, can also be used with justification to support theability of such methods to predict equilibrium solubility of the test drugsubstance.

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基于变异性研究，补充的重复试验也可能是提供一个可靠地溶解度估计所必须的。USP中的标准缓冲溶液在溶解度测定中是适用的。若这些缓冲溶液在物理或者化学角度不适用，则也可以采用其他的缓冲液。在缓冲液中加入原料药后，也要测量溶液的pH值。和传统的震荡瓶法不同的方法，例如酸碱滴定法，也能在充分理由支撑下用来检测被测原料药的平衡溶解度。

Concentration ofthe drug substance in selected buffers (or pH conditions) should be determinedusing a validated stability-indicating assay that can distinguish the drugsubstance from its degradation products.3 If degradation of the drug substanceis observed as a function of buffer composition and/or pH, it should bereported along with otherstability data recommended in section III.B.3.

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原料药在选定缓冲溶液（或pH条件）中的浓度应该用通过验证的稳定性检测方法检测，该方法应能区分原料药及原料药的降解产物。若原料药的降解被观察出是缓冲液成分或者pH造成的，则也应该和III.B.3.部分其他的建议稳定性数据一起报告。

The solubilityclass should be determined by calculating the volume of an aqueous mediumsufficient to dissolve the highest dose strength in the pH range of 1-6.87.5. A drug substance should beclassified as highly soluble when the highest dose strength is soluble in <250 ml of aqueous media over the pH range of 1-6.87.5.  In other words, themaximum dose divided by 250 should be greater than or equal to the lowestsolubility observed over the entire pH range of 1-6.8.

溶解度类别可以根据测量pH值在1-7.5范围内足够溶解最高剂量的水介质的量来确定。当一个原料药最大剂量时能在pH值1-7.5范围内、完全溶解在小于250ml的水介质时，被认为是高溶解性的。

B. DeterminingDrug Substance Permeability Class   判定原料药渗透性分类

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The permeabilityclass of a drug substance can be determined in human subjects using massbalance, or absolute BA, which are thepreferred methods, or intestinalperfusion approaches. Recommended methods not involving human subjects includein vivo or in situ intestinal perfusion in a suitable animal model (e.g.,rats), and/or in vitro permeability methods using excised intestinal tissues,or monolayers of suitable epithelial cells. In many cases, a single method maybe sufficient (e.g., when theabsolute BA is 90% or more, or when 90% or more of the administered drug isrecovered in urine).  (i) when the absolute BA is 85 percent or more, or (ii) when 85 percent ormore of the administered drug is excreted unchanged in urine, or (iii) when 85percent or more of the administered drug is recovered in urine as parent andmetabolites with evidence indicating stability in the GI tract.

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原料药的渗透性可以在人体内使用质量平衡，绝对生物利用度，或者肠道灌注来测定。不包括受试者的建议检测方法包括，合适的动物模型的体内或原位肠道灌注，离体肠道组织的渗透性检测，或者合适的单层上皮细胞的渗透性检测。很多情况下（例如，让绝对生物利用度达到或超过90%。或90%或更多的药物在尿液中检出时），单一的检测方法可能不够充分。

When a singlemethod fails to conclusively demonstrate a permeability classification, two differentmethods may be advisable. Chemicalstructure and/or certain physicochemical attributes of a drug substance (e.g.,partition coefficient in suitable systems) can provide useful information aboutits permeability characteristics. Sponsors may wish to consider use of suchinformation to further support a classification. In case of conflictinginformation from different types of studies, it is important to note that humandata supersede in vitro or animal data.

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当一个单一的渗透性检测不足以充分说明药物的渗透性类别，建议采用两个不同的分析方法。原料药的化学结构或者某一物化特性（例如在适当的系统中的分配系数）能够为其渗透性特性提供有用信息。主办方应考虑使用这些信息以进一步确定分类。

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1.Pharmacokinetic Studies in Humans  人体内药代动力学研究

a. Mass BalanceStudies   质量平衡研究

Pharmacokinetic (PK) mass balancestudies using unlabeled, stable isotopes or a radiolabeled drug substance canbe used to document the extent of absorption of a drug. Depending on thevariability of the studies, a sufficient number of subjects should be enrolled toprovide a reliable estimate of extent of absorption. Because thismethod can provide highly variable estimates of drug absorption for many drugs,other methods described below may be preferable.

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药代动力学质量平衡研究用无标记药物、稳定同位素或者放射性标记的原料药都能证明药物的吸收程度。根据研究的可变性，应考察足够的受试项数据来提供可靠地吸收程度估计。因为这种方式可能给很多药物的药物吸收带来高度相异的估计，下述其他方法也可能适用。

When mass balance studies are used to demonstrate high permeability,additional data to document the drug’s stability in the GI tract is required,unless 85 percent or more of the drug is excreted unchanged in urine. Pleasesee method details in section III.B.3.

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如果使用了质量守衡研究来证明高渗性，则需要另外的数据来记录药物的在GI通道的稳定性，除非有大于或等于85%的药物以原形从尿液排出。参见第III.B.3部分。

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b. AbsoluteBioavailability Studies   绝对生物利用度研究

Oral BAdetermination using intravenous administration as a reference can be used.Depending on the variability of the studies, a sufficient number of subjectsshould be enrolled in a study to provide a reliable estimate of the extent ofabsorption. When the absolute BA of a drug is shown to be 85 percent 90% or more,additional data to document drug stability in the GIgastrointestinal fluid is notnecessary.

口服的生物利用度测试可以用静脉给药作为参考。根据研究的可变性，一个研究中要考虑多个受试项以提供有效的吸收度估计。当一个药物的绝对生物利用度显示达到或超过90%，则不需要再补充做药物在消化液中的稳定性测定。

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2. IntestinalPermeability Methods   肠道通透性检测方法

The followingmethods can be used to determine the permeability of a drug substance from thegastrointestinal tract: (1) in vivo intestinal perfusion studies in humans; (2)in vivo or in situ intestinal perfusion studies using suitable animal models;(3) in vitro permeation studies using excised human or animal intestinaltissues; or (4) in vitro permeation studies across a monolayer of culturedepithelial cells.

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以下方法可以用来测定胃肠道中药物的渗透性：(1)人体体内肠道灌注研究；(2)使用合适的动物模型，体内或原位肠道灌注研究；(3)离体人或动物肠道组织的体外渗透性研究；(4)单层人工培养上皮细胞的离体渗透性研究。

In vivo or insitu animal models and in vitro methods, such as those using culturedmonolayers of animal or human epithelial cells, are considered appropriate forpassively transported drugs. The observed low permeability of some drugsubstances in humans could be caused by efflux of drugs via membranetransporters such as P-glycoprotein (P-gp). When the efflux transporters areabsent in these models, or their degree of expression is low compared to thatin humans, there may be a greater likelihood of misclassification ofpermeability class for a drug subject to efflux compared to a drug transportedpassively.

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体内或原位动物模型、以及体外方法，例如使用动物或人类单层培养上皮细胞，都适用于被动传输的药物。有些原料药在人体内观测到的低渗透性可能是由于药物在膜转运蛋白（如p-糖蛋白）上的流失造成。当这些模型中和药物流失相关的转运蛋白缺失，或者其表达程度和人体相比较低，则当药物和转运流失相关的时候，渗透性分级失误的几率比被动运输药物几率大。

Expression ofknown transporters in selected study systems should be characterized.  Functionalexpression of efflux systems (e.g., P-gp) can be demonstrated with techniquessuch as bidirectional transport studies, demonstrating a higher rate oftransport in the basolateral-to-apical direction as compared toapical-to-basolateral direction (efflux ratio >2)[7][8], using selected model drugs or chemicals atconcentrations that do not saturate the efflux system (e.g., cyclosporin A,vinblastine, rhodamine 123). An acceptancecriterion for intestinal efflux that should be  present in atest system cannot be set at this time. Instead, this guidance recommends We recommend limiting the useof animal or in vitro nonhuman permeabilitytest methods for drug substances that are transported by passivemechanisms.

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选定的研究方案中要表征出已知转运蛋白的表达。流失机制的函数表达式可以用双向传输研究技术来说明，即在使用未将外排系统饱和的特定药物或化学物质时，相较细胞膜顶部-基底侧端方向的传输率，检测到更高的细胞膜基底测端-顶部方向的传输率。此时，监测体系中必须的肠道外排置信区间无法确定。相反，本指南中建议，对于被动运输的药物来说，要限制非人体的渗透性检测方法。

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Pharmacokinetic PK studies on doselinearity or proportionality may provide useful information for evaluating therelevance of observed in vitro efflux of a drug. For example, there may befewer concerns associated with the use of in vitro methods for a drug that hasa higher rate of transport in the basolateral-to-apical direction at low drugconcentrations but exhibits linear pharmacokinetics in humans.

线性或成比例的剂量的药代动力学研究可以给评估药物的体外外排提供有用的信息。例如，当一个药物在低浓度时在细胞膜基底侧端-顶端方向表现出很高的传输率，但是在人体内表现出线性的药代动力学特性时，其使用体外试验方法就没有什么关系了。

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For BCS-based permeabilitydetermination application ofthe BCS, an apparent passive transport mechanism can be assumed when one of thefollowing conditions is satisfied:   

申请BCS时，当满足下列条件时，可以很明确的推断出药物是被动传输机制：

l  A linear(pharmacokinetic) relationship between the dose (e.g., relevant clinical doserange) and measures of BA (area under the concentration-time curve) of a drugis demonstrated in humans

l  人体内，剂量（例如相关的临床剂量范围）和BA测量值（浓度-时间曲线下面积）表现出线性（药代动力学）关系。

l  Lack ofdependence of the measured in vivo or in situ permeability is demonstrated inan animal model on initial drug concentration (e.g., 0.01, 0.1, and 1 times thehighest dose strength dissolved in 250 ml) in the perfusion fluid

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l  测量的体内或原位渗透性与采用动物模型时灌注液的初始药物浓度（例如，250ml液体中分别溶解0.01、0.1和1倍最高剂量）无关。

l  Lack ofdependence of the measured in vitro permeability on initial drug concentration(e.g., 0.01, 0.1, and 1 times the highest dose strength dissolved in 250 ml) isdemonstrated in donor fluidand or on transportdirection (e.g., no statistically significant difference in the rate oftransport between the apical-to-basolateral and basolateral-to-apical directionfor the drug concentrations selected) using a suitable in vitro cell culturemethod that has been shown to express known efflux transporters (e.g.,P-gp)

l  使用适当的、已被证明能表达已知转运蛋白的细胞培养方法时，其供体液和转运方向（例如，在给定的药物浓度中，细胞膜基底侧端-顶端方向和细胞膜顶端-基地侧端方向的传输率并无显著统计学上的差异）证明测得的体外渗透性与药物的起始浓度（例如，在250ml液体中溶解0.01,0.1和1倍最高剂量）无关。

METHOD SUITABILITY: One of the critical steps in using in vitropermeability methods for permeability classification is to demonstrate thesuitability of the method. To demonstratesuitability of a permeability method intended for application of the BCS, arank-order relationship between test permeability values and the extent of drugabsorption data in human subjects should be established using a sufficientnumber of model drugs. For in vivo intestinal perfusion studies in humans, sixmodel drugs are recommended. For in vivo or in situ intestinal perfusionstudies in animals and for in vitro cell culture methods, twenty model drugsare recommended. Depending on study variability, a sufficient number ofsubjects, animals, excised tissue samples, or cell monolayers should be used ina study to provide a reliable estimate of drug permeability. This relationshipshould allow precise differentiation between drug substances of low and highintestinal permeability attributes.

为了申请BCS而解释一个渗透性检测方法的实用性，应当用足够的模型药物来说明受试者体内的渗透性检测值和药物吸收程度数据的顺序关系。人体内肠道灌注研究，推荐使用6种模型药物。动物的体内或原位关注研究、或者体外培养细胞研究，推荐20种模型药物。根据研究的可变性，研究中应使用足够数量的被试者，动物，离体组织样品或者单层细胞，以提供可靠的药物渗透性估计。这个顺序关系应考虑到高、低肠道通透性的原料药的精确区别。

Fordemonstration of To demonstrate the suitability of amethod, model drugs should represent a range of low (e.g., < 50%), moderate(e.g., 50 - 8489%), and high (≥ 8590%) absorption. Sponsors may select compounds from the list of drugs and/orchemicals provided in Attachment A or they may choose to select other drugs forwhich there is information available on mechanism of absorption and reliableestimates of the extent of drug absorption in humans.

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为了说明一个分析方法的适用性，模型药物应该叙述以下吸收范围：低吸收率(如, < 50%)、中等吸收率(如, 50 - 89%)和高吸收率(≥ 90%)。主办方可以在附录A里面提供的药物和/或化学物质列表里面选择化合物，若其他药物有已知的吸收机制和体内药物吸收度的可靠估计，也可以选择这些药物。

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Afterdemonstrating suitability of a method and maintaining the same study protocol,it is not necessary to retest all selected model drugs for subsequent studiesintended to classify a drug substance. Instead, a low and a high permeabilitymodel drug should be used as internal standards (i.e., included in theperfusion fluid or donor fluid along with the test drug  substance).These two internal standards are in addition to the fluid volume marker (or azero permeability compound such as PEG 4000) that is included in certain typesof perfusion  techniques(e.g., closed loop techniques). The choice of internal standards should bebased on compatibility with the test drug substance (i.e., they should notexhibit any significant physical, chemical, or permeation interactions).

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在阐述了一个分析方法的适用性，且修改维护了同一个研究规程后，就不用为了给一个原料药分类而在后续研究中重新测试所有的模型药物。相反，一个低渗透率和一个高渗透率的模型药物应拿来作为内标（例如，包括灌注液或供体液在内的被测原料药）。在阐述了一个分析方法的适用性，且修改维护了同一个研究规程后，就不用为了给一个原料药分类而在后续研究中重新测试所有的模型药物。相反，一个低渗透率和一个高渗透率的模型药物应拿来作为内标（例如，包括灌注液或供体液在内的被测原料药）。这两个内标是在流体体积标记之外的（或是像PEG4000一样，零渗透率的化合物），这个流量体积标记包括在特定类型的灌输技术中（如闭环技术）。内标物质的选择应该基于和被测原料药的兼容性上（例如，他们应该不具备任何显著的物理，化学，或者渗透性相互作用）。

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When it is notfeasible to follow this protocol, the permeability of internal standards shouldbe determined in the same subjects, animals, tissues, or monolayers, followingevaluation of the test drug substance. The permeability values of the twointernal standards should not differ significantly between different tests,including those conducted to demonstrate suitability of the method. For example, thelaboratory may set acceptance criteria for the permeability values of its high,low, and zero permeability standard compounds. At the end of anin situ or in vitro test, the amount of drug in the membrane should bedetermined. to assist in calculation of mass balance.

当无法遵循该规程时，内标物质的渗透性测定应该和被测原料药一样，使用同样的受试者，动物，组织或表皮细胞。内标物质的渗透性测试值在不同试验中不应相差巨大，包括用来证明稳定性的试验。在体外或原位试验的末尾，应该测定膜中药物的含量。

For a given testmethod with set conditions, selection of a high permeability internal standardwith permeability in close proximity to the low/high permeability classboundary may facilitate classification of a test drug substance. For instance,a test drug substance may be determined to be highly permeable when itspermeability value is equal to or greater than that of the selected internalstandard with high permeability.

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对于给定的特定条件下的分析方法，挑选一个和高/低渗漏率分级上下限接近的内标物质对被测药物的分级有有利作用。例如，当一个被测药物的渗透性检测值和选定的高渗透率内标药物的渗透性一样或更高，则该药物被认为是具有高渗透性的。

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When intestinal permeability methods are used to demonstrate highpermeability, additional data to document the drug’s stability in the GI tractis required. Please see method details in section III.B.3.  

3. Instabilityin the Gastrointestinal Tract   胃肠道稳定性研究

Determining theextent of absorption in humans based on mass balance studies using totalradioactivity in urine does not take into consideration the extent ofdegradation of a drug in the gastrointestinal fluid prior to intestinalmembrane permeation. In addition, some methods for determining permeabilitycould be based on loss or clearance of a drug from fluids perfused into thehuman and/or animal gastrointestinal tract either in vivo or in situ.Documenting the fact that drug loss from the gastrointestinal tract arises fromintestinal membrane permeation, rather than a degradation process, will helpestablish permeability.

在测定吸收度时，以尿液的总放射性作为研究对象的质量平衡研究，并没有考虑到药物在肠道膜渗透之前在胃肠液中发生降解的程度。此外，有些测定渗透性的分析方法可能是基于体内或原位灌注到人类和/或动物的胃肠道中的药物的减少或清除。证明药物在胃肠道的流失是发生在肠道薄膜渗透，而不是降解反应，将帮助确定药物的渗透性。

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Stability in thegastrointestinal tract may be documented using simulated gastric andintestinal fluids. Obtaining GI fluidsfrom human subjects requires intubation and may be difficult. Therefore, use ofsimulated fluids such as Gastric and Intestinal Fluids USP may be reasonable. gastric andintestinal fluids obtained from human subjects. Drug solutionsin these fluids should be incubated at 37o C for a period that isrepresentative of in vivo drug contact with these fluids; for example, 1 hourin gastric fluid and 3 hours in intestinal fluid. Drug concentrations shouldthen be determined using a validated stability-indicating assay method.Significant degradation (>5%) of a drug in this study protocol could suggestpotential instability.Obtaining gastrointestinal fluids from human subjectsrequires intubation and may be difficult in some cases. Use of gastrointestinalfluids from suitable animal models and/or simulated fluids such as Gastric andIntestinal Fluids USP can be substituted when properly justified.  

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药物在胃肠道中的稳定性可以利用在人体内取出的胃液和肠液来证明。药物溶液应在这些液体中以37摄氏度孵化一段时间，以模拟药物在人体内和该液体的接触过程；例如，胃液中1小时，肠液中3小时。之后应该用已验证的稳定性检测分析方法来测定药物浓度。这个规程中药物显著地分解(>5%)可能代表着潜在的不稳定性。获得人胃肠液一般采用插管法，某些情况下会比较困难。在经过适当的调整后，某些合适的动物模型的胃肠液或者模拟液体，例如药典标准的胃液和肠液，也可以作为替代品使用。

C. DeterminingDrug Product Dissolution Characteristics and Dissolution ProfileSimilarity   测定药物的溶解特性和溶解相似性

Dissolutiontesting should be carried out in USP Apparatus I at 100 rpm or Apparatus II at50 rpm using (or at 75 rpm when appropriately justified) 900 500 ml of thefollowing dissolution media: (1) 0.1 N HCl or Simulated Gastric Fluid USPwithout enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or SimulatedIntestinal Fluid USP without enzymes. For capsules and tablets with gelatincoating, Simulated Gastric and Intestinal Fluids USP (with enzymes) can beused.

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溶出试验应用USP规定的设备实施：设备I，转速1000rpm，或设备II，转速50rpm，都使用900ml下述溶媒：（1）0.1 N HCl 或者USP无酶人工胃液；（2）pH 4.5缓冲液；（3）pH 6.8缓冲液或者USP无酶人工肠液。有明胶包衣的胶囊和片剂，则可以采用有酶的USP人工肠液和胃液。

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Dissolutiontesting apparatus used in this evaluation should conform to the requirements inUSP (<711> Dissolution). Selection of the dissolution testing apparatus(USP Apparatus I or II) during drug development should be based on a comparisonof in vitro dissolution and in vivo  pharmacokineticdata available for the product. The USP Apparatus I (basket method) isgenerally preferred for capsules and products that tend to float, and USPApparatus II (paddle method) is generally preferred for tablets.

该实验中所用的溶出试验装置应符合USP(<711> 溶出)要求。药物开发过程中溶出试验装置的选择 (USP装置I或II)应该建立在该制剂体外溶出和体内药代动力学数据之上。USP装置I（篮法）一般偏向适用于胶囊和上浮性制剂，USP装置II（浆法）则偏向适用于片剂。

For some tabletdosage forms, in vitro (but not in vivo) dissolution may be slow due to themanner in which the disintegrated product settles at the bottom of adissolution vessel. In such situations, USP Apparatus I may be preferred overApparatus II. If the testing conditions need to be modified to better reflectrapid in vivo dissolution (e.g., use of a different rotating speed), suchmodifications can be justified by comparing in vitro dissolution with in vivoabsorption data (e.g., a relative BA study using a simple aqueous solution asthe reference product).

对于有些片剂来说，体外（但不是体内）溶出可能比较慢，因为这些被测溶出物沉淀在溶出容器的底部。在这类情况下，USP装置I就比装置II更加好用。如果试验条件需要修改以达到更好的反应体内溶出速度（例如，使用不同的转速），这些修改可以通过比较体外溶出速率和体内吸收数据来证明（例如，有关的生物利用度研究采用单一的水溶液做参比制剂）。

A minimum of 12dosage units of a drug product should be evaluated to support a biowaiver request.Samples should be collected at a sufficient number of intervals to characterizethe dissolution profile of the drug product (e.g., 10, 15, 20, and 30minutes).

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至少应评估12个制剂计量单位来支持生物豁免请求。收集样品时应提供足够的时间间隔（例如10,15,20,30分钟）以更好地确定制剂的溶出特性。

When comparingthe test and reference products, dissolution profiles should be compared usinga similarity factor (f2 ). The similarityfactor is a logarithmic reciprocal square root transformation of  the sum ofsquared error and is a measurement of the similarity in the percent (%) ofdissolution between the two curves.

当比较被测试剂和参比制剂时，应使用相似系数(f2)来比较溶出特性。相似系数是误差平方和的对数平方根的倒数变换，是两个曲线之间溶出百分率的相似性的表征。

The similarity factor is a logarithmic reciprocal square roottransformation of the sum of squared error and is a measurement of thesimilarity in the percent (%) of dissolution between the two curves; where n isthe number of time points, Rt is the dissolution value of the reference batchat time t, and Tt is the dissolution value of the test batch at time t.

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Two dissolutionprofiles are considered similar when the f2 value is ≥50. To allow the use ofmean  data, thecoefficient of variation should not be more than 20% at the earlier time points(e.g., 10 minutes), and should not be more than 10% at other time points. Notethat when both test and reference products dissolve 85% or more of the labelamount of the drug in ≤15 minutes usingall three dissolution media recommended above, the profile comparison with anf2  test isunnecessary.

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当f2值≥50时认为两个物质有相似的溶出特性。为了可以使用平均值，则变异系数在最早时间点时不应超过20%，在其他时间点不应超过10%。请注意，当使用上述种溶媒时，若被测制剂和参比制剂都能在15分钟内溶出标示量的85%，则不必要利用f2检测比较相似性。

IV. BIOWAIVERS BASED ON BCS 基于BCS的生物豁免

This guidance is applicable for BA/BE waivers (biowaivers) based on BCS,for BCS class 1 and class 3 immediate-release solid oral dosage forms.

本指南适用于一类和三类速释固体口服制剂基于BCS的BA/BE豁免（生物豁免）。

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For BCS class 1 drug products, the following should be demonstrated:

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对于BCS一类药物，要证明以下内容

l  the drug substance is highly soluble

l  药用物质非常易溶解

l  the drug substance is highly permeable

l  药用物质具有高渗性

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l  the drug product (test and reference) is rapidly dissolving, and

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l  药物（测试药物和参比药物）溶解很快，且

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l  the product does not contain any excipients that will affect the rate orextent of absorption of the drug (see section V.A.)

l  药物不含有任何影响药物吸收速度和程度的辅料（参见第V.A部分）

ForBCS class 3 drug products, the following should be demonstrated:

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对于BCS三类药物，需要证明以下内容

l  thedrug substance is highly soluble

l  药用物质为高溶解度

l  thedrug product (test and reference) is very rapidly dissolving (see sectionII.C.), and

l  药物（测试药物和参照药物）溶解非常快速（参见第II.C部分），且

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l  thetest product formulation is qualitatively the same and quantitatively verysimilar, e.g., falls within scale-up and post-approval changes (SUPAC) IR level1 and 2 changes, in composition to the reference (see section V.A.)

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l  测试药物配方成分与对照药物相同，比例类似，例如属于放大和批准后变更（SUPAC）IR一级和二级变更（参见第V.A部分）

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IV. V. ADDITIONALCONSIDERATIONS FOR REQUESTING A BIOWAIVER  生物豁免请求其他注意事项

When requestinga BCS-based waiver for in vivo BA/BE studies for IR solid oral dosage forms,applicants should note that the following factors can affect their request orthe documentation of their request:

当为一个速释固体口服制剂请求基于BCS的生物豁免时，申请人应注意，以下因素可能影响申请或影响起草申请。

A.Excipients   辅料

(i) BCS class 1 drug products: Excipients cansometimes affect the rate and extent of drug absorption. In general, usingexcipients that are currently in FDA-approved IR solid oral dosage forms willnot affect the rate or extent of absorption of a highly soluble and highlypermeable drug substance that is formulated in a rapidly dissolving IR product.To support a biowaiver request, the quantity of excipients in the IR drugproduct should be consistent with the intended function (e.g.,lubricant).

(i)BCS一类药物：辅料在某些情况下能影响制剂的吸收率和吸收程度。一般来说，若使用FDA已批准的速释口服制剂所使用的辅料，是不会影响按快速溶出速释配方生产的制剂的高溶解度、高渗透性原料药的吸收率或吸收程度的。速释制剂中的辅料量应该与预期功能（例如润滑剂）一致以支持生物豁免请求。

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When newexcipients or atypically large amounts of commonly used excipients are includedin an IR solid dosage form, additional information documenting the absence ofan impact on BA of the drug may be requested by the Agency. Such informationcan be provided with a relative BA study using a simple aqueous solution as thereference product. Large quantities of certain excipients, such as surfactants(e.g., polysorbate 80) and sweeteners (e.g., mannitol or sorbitol) may beproblematic, and sponsors are encouraged to contact the review division whenthis is a factor.

如果在速释口服固体制剂中使用了新的辅料，或者非常规使用了大量的常规辅料时，药监部门可能要求申请人另外提交证明上述情况对制剂的生物利用度没有影响的文件。该信息可以利用以单一水溶液做参比制剂的生物利用度研究来提供。大量使用特定的辅料，例如表面活性剂（例如聚山梨醇酯80）和甜味剂（例如甘露醇或山梨醇），可能会有问题，这种情况下，鼓励申请人联系审核部门。

(ii) BCS class 3 drug products: Unlike for BCS class 1 products, for abiowaiver to be scientifically justified, BCS class 3 test drug product mustcontain the same excipients as the reference product. This is due to theconcern that excipients can have a greater impact on absorption of lowpermeability drugs. The composition of the test product must be qualitativelythe same and should be quantitatively very similar to the reference product.

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（ii）BCS三类药物：与BCS一类药物不同，BCS三类测试药物必须含有与参照药物相同的辅料，其生物豁免必须进行科学论证。这是因为担心辅料可能会对低渗性药物的吸收产生更大影响。测试药物的组份必须与参照药物相同，且数量比例非常类似。

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B.Prodrugs   药物前体

Permeability ofprodrugs will generally depend on themechanism and (anatomical) site of conversion to the drug substance. When theprodrug-to-drug conversion is shown to occur predominantly after intestinalmembrane permeation, the permeability of the prodrug should be measured. Whenthis conversion occurs prior to intestinal permeation, the permeability of thedrug should be determined. Dissolution and pH-solubility data on both prodrugand drug can be relevant. Sponsors may wish to consult with appropriate reviewstaff before applying the BCS approach to IR products containingprodrugs.

制剂的渗透性取决于原料药的转换机制和（解剖学上的）转换位置。若药物前体-药物的转换主要表现在肠道膜渗透之后，则应测试该药物前体的渗透性。若转换表现在肠道膜渗透之前，则应测定该药物的渗透性。药物前体和药物的溶出、pH溶解度数据也可能与之相关。在对含有药物前体的速释药品应用BCS方法之前，申请人最好咨询合适的审评人员。

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C. Fixed Dose Combinations 固定剂量复方制剂

a. If all active components belong to BCS class 1: BCS-based biowaiversare applicable for IR fixed dose combination products if all the drugs in thecombination belong to BCS class 1; provided there is no PK interaction betweenthe components, and the excipients fulfill the considerations outlined insection V.A. (i). If there is a PK interaction, the excipients should fulfillthe considerations outlined in section V.A. (ii). Otherwise, in vivobioequivalence testing is required.  

如果所有的活性成分均属于BCS一类：如果复方中的所有药物均属于BCS一类，在复方成分之间没有PK相互作用，辅料满足第V.A（i）部分列出的考量内容，则基于BCS的生物豁免适用于固定剂量的复方制剂。如果有PK相互作用，辅料应满足第V.A(ii)部分列出的考量要求。否则，需要实施体内BE测试。

b. If all components of the combination belong to BCS class 3 or acombination of class 1 and 3: BCS-based biowaivers are applicable for IR fixeddose combination products in this situation provided the excipients fulfill theconsiderations outlined in section V.A. (ii). Otherwise, in vivo bioequivalencetesting is required.

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如果复方制剂中的所有成分均属于BCS二类，或者是一类和三类的组合：如果辅料满足第V.A(ii)部分列出的考量要求，则基于BCS的生物豁免适用于速释固定剂量复方制剂。否则，需要实施体内BE测试。

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C. D. Exceptions   不适用情况

BCS-basedbiowaivers are not applicable for the following: 基于BCS的生物豁免对下列情况不适用：

1. NarrowTherapeutic Range Drugs[9]   治疗范围狭窄的药品

This guidancedefines narrow therapeutic range drug products as those containing certain drugsubstances that are subject to therapeutic drug concentration orpharmacodynamics (PD) monitoring,and/or where product labeling indicates a narrow therapeutic range designation.Examples include digoxin, lithium, phenytoin, theophylline, and warfarin.Because not all drugs subject to therapeutic drug concentration orpharmacodynamic monitoring are narrow therapeutic range drugs, sponsors shouldcontact the appropriate review division to determine whether a drug should beconsidered to have a narrow therapeutic range.

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本指南定义，受治疗药物浓度或药效监控支配，和/或产品说明书上表明该制剂按狭窄的治疗范围设计的药品，称为狭窄治疗范围的药品。例子包括地高辛，锂，苯妥英，茶碱和法华令阻凝剂。因为并不是所有受制于治疗药物浓度或药效监控的药物都是狭窄治疗范围的药物，建议主办方咨询合适的审核部门来确定是否该药品应被定义为狭窄治疗范围的药品。

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2. ProductsDesigned to be Absorbed in the Oral Cavity   口腔吸收制剂

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A request for awaiver of in vivo BA/BE studies based on the BCS is not appropriate for dosageforms intended for absorption in the oral cavity (e.g., sublingual or buccaltablets). Similarly, a biowaiver for an orally disintegrating tablet can beconsidered, based on BCS, only if the absorption from the oral cavity is ruledout.

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对口腔吸收制剂基于BCS的体内BA/BE研究生物豁免申请不适用。同样，基于BCS，口服崩解片也可以考虑生物豁免，但口腔腔洞吸收者除外。

VI. REGULATORY APPLICATIONS OF THE BCS   BCS的申请管理

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A.INDs/NDAs

Evidencedemonstrating in vivo BA or information to permit FDA to waive this evidencemust be included in NDAs (21 CFR 320.21(a)). A specific objective is toestablish in vivo performance of the dosage form used in the clinical studiesthat provided primary evidence of efficacy and safety. The sponsor may wish todetermine the relative BA of an IR solid oral dosage form by comparison with anoral solution, suspension, or intravenous injection (21 CFR 320.25 (d)(2) and320.25 (d)(3)). The BA of the clinical trial dosage form should be optimizedduring the IND period.

NDAs中必须包括说明体内BA的证明，或允许FDA豁免该证明的信息。具体目标就是，确定临床研究中能提供该制剂的药效和安全性原始证据的剂型的体内表现。主办方可以通过和口服液，口服混悬剂或注射剂比较来确定速释口服制剂剂型的相关BA (21 CFR320.25 (d)(2)和 320.25 (d)(3))。IND期间应优化临床试验剂型的BA。

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Once the in vivoBA of a formulation is established during the IND period, waivers of subsequentin vivo BE studies, following major changes in components, composition, and/ormethod of  manufacture(e.g., similar to SUPAC-IR Level 3 changes[10] ) may bepossible using the BCS. BCS-based biowaivers are applicable to theto-be-marketed formulation when changes in components, composition, and/ormethod of manufacture occur to the clinical trial formulation, as long as thedosage forms have rapid, very rapid and similar invitro dissolution profiles (see sections II and III).

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一旦IND期间确定了一个配方的体内BA，随后的体内BE豁免、随后的组分、成分及制造方法上的重大变更(例如,类似SUPAC-IR 级别3 变更6的情况)可能利用BCS来完成。对于即将上市的剂型，其与临床试验剂型上有组成、组分及制造方式上的变化，只要其剂型具有快速和相似的体外溶出特性（见第II和III部分），基于BCS的生物豁免就适用。

This approach isuseful only when the drug substance is belongs to BCS class 1 or 3 highly solubleand highly permeable (BCS Class 1), and the formulations pre- and postchangeare pharmaceutical equivalents (under the  definition at 21CFR 320.1 (c)). BCS-based biowaivers are intended only for BE studies. They donot apply to food effect BA studies or otherpharmacokineticPK studies. BCS-based biowaivers may be applicable for pharmaceutical alternatives, ifappropriately justified. The sponsor should contact the appropriate reviewdivision in such situations.

只要原料药是高溶解度高渗透性（BCS的I级原料药），且配方变更前后的制剂是等值制剂(如 21 CFR 320.1 (c)所定义)，则该方法适用。基于BCS的生物豁免只针对BE研究。其并不适用于食物影响BA或其他药代动力学的研究。 如果有适当的论证，基于BCS的生物豁免也可适用于药物替代性。这种情况下，申报人请与适当的审核中心联系。

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B. ANDAs

BCS-basedbiowaivers are appropriate for IR test products that meet the criteria for BCS class1 or 3 as discussed abovecan be requested for rapidly dissolving IRtest products containing highly soluble and highly permeable drug substances, provided thatthe reference listed drug product also meets those criteria is also rapidlydissolving and the testproduct exhibits similar dissolution profiles to the reference listed drugproduct (see sections II and III). This approach is useful when the test andreference dosage forms are pharmaceutical equivalents. The choice ofdissolution apparatus (USP Apparatus I or II) should be the same as thatestablished for the reference listed drug product.

含有高溶解性高渗透性的快速溶出的IR测试制剂可以请求基于BCS的生物豁免，只要原研药物也是快速溶出的，且测试制剂与原研药表现出相似的溶出特性。当测试制剂和参考剂型是等值制剂时，该方法适用。此时溶出试验装置(USP装置I或II)应和原研制剂确定的溶出试验装置一致。

C. SupplementalNDAs/ANDAs (PostapprovalChanges)   NDA/ANDA增补（批准后变更 ）

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BCS-basedbiowaivers can be requested for significant postapproval changes (e.g., Level 3changes in components and composition) to IR test product thatmeets the criteria for BCS class 1 or 3 as discussed above a rapidlydissolving IR product containing a highly soluble, highly permeable drugsubstance, provided that dissolution remains rapid for the postchange product and both pre-and postchange products exhibit similar dissolution profiles (see sections IIand III). This approach is useful only when the drug products pre- andpostchange are pharmaceutical equivalents.

含有高溶解性高渗透性原料药的速溶速释制剂的重大批准后变更可以请求基于BCS的生物豁免，只要变更后的制剂依然快速溶出，且表现出相似的溶出特性(见II和III部分)。只有当变更前后的制剂等价时，这个方法才适用。

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VII.  DATA TO SUPPORT A REQUEST FOR BIOWAIVERS   支持生物豁免申请的数据

The drugsubstance for which a waiver is being requested should include a drugsubstance that is highly soluble (BCS class 1 and BCS class 3) and highlypermeable (BCS class 1), and the drug product should be rapidly dissolving (BCSclass 1) or very rapidly dissolving (BCS class 3). be highlysoluble and highly permeable. Sponsors requesting biowaivers based on the BCS should submit thefollowing information to the Agency for review by the Office ofClinical Pharmacologyand Biopharmaceutics (for NDAs) or Office of GenericDrugs, Division of Bioequivalence (for ANDAs):

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申请豁免的原料药必须具有高溶解性高渗透性。基于BCS的生物豁免的主办方必须提交如下文件，以便临床药理学和生物药剂学办公室(NDAs)或者仿制药办公室生物等效性部门(ANDAs)审核：

A. DataSupporting High Solubility   高溶解度支持数据

Data supportinghigh solubility of the test drug substance should be developed (see sectionIII.A). The following information should be included in the application:

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应提供支持被测原料药的高溶解度的数据（见III.A部分）。申请中应该包含以下信息：

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l  A description oftest methods, including information on analytical method and composition of thebuffer solutions

l  试验方法的描述，包括分析方法和缓冲溶液的组成信息。

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l  Information onchemical structure, molecular weight, nature of the drug substance (acid, base,amphoteric, or neutral), and dissociation constants (pKa(s))

l  原料药的化学结构，分子量，性质（酸，碱，两性或中性）和解离常数（pKa(s)）

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l  Test results(mean, standard deviation, and coefficient of variation) summarized in a tableunder solution pH, drug solubility (e.g., mg/ml), and volume of media requiredto dissolve the highest dose strength

l  按溶剂pH值，药物溶解度（例如mg/ml）和溶解最高剂量制剂所需溶媒量列表，总结试验结果（平均值，标准偏差和变异系数）。

l  A graphicrepresentation of mean pH-solubility profile

l  表示平均pH-溶解度特性的图示。

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B. DataSupporting High Permeability   高渗透性支持数据

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Data supportinghigh permeability of the test drug substance should be developed (see sectionIII.B). The following information should be included in the application:

应提供支持被测原料药的高渗透性的数据（见III.B部分）。申请中应该包含以下信息：

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l  A description of test methods, including information on analyticalmethod(s) and composition of the buffer solutions.

l  检验方法描述，包括分析方法和缓冲液组份信息

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l  For human pharmacokineticPK studies,information on study design and methods used along with the pharmacokineticPKdata

l  对于人体药代动力学研究，研究方案设计和使用方法信息应和药代动力学数据同时提交。

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l  For directpermeability methods, information supporting the suitability of a selectedmethod that encompasses a description of the study method, criteria forselection of human subjects, animals, or epithelial cell line, drugconcentrations in the donor fluid, description of the analytical method, methodused to calculate extent of absorption or permeability, and where appropriate,information on efflux potential (e.g., bidirectional transport data)

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l  对于直接渗透性研究方法，需要以下说明所采取的方法的适用性的信息，包括研究方案的描述，受试人、动物和上皮细胞系的选择标准，供体液里的药物浓度，分析方法的描述，计算吸收程度或渗透性的方法，以及，若可以，流失潜能的信息。

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l  A list ofselected model drugs along with data on extent of absorption in humans (mean,standard deviation, coefficient of variation) used to establish suitability ofa method,  permeabilityvalues for each model drug (mean, standard deviation, coefficient ofvariation), permeability class of each model drug, and a plot of the extent ofabsorption as a function of permeability (mean ± standard deviation or 95%confidence interval) with identification of the low/high permeability classboundary and selected internal standard. Information to support highpermeability of a test drug substance (mean, standard deviation, coefficient of variation) should includepermeability data on the test drug substance, the internal standards (mean, standarddeviation, coefficient of variation), GI stabilityinformation, data supporting passive transport mechanism where appropriate, andmethods used to establish high permeability of the test drug substance.

l  选择的模型药物的清单，且包含以下数据：说明研究方法的适用性的人体内的吸收度数据（平均值，标准偏差，变异系数），每个模型药物的渗透率值（平均值，标准偏差，变异系数），每个模型药物的渗透性分类，并根据渗透性数据（平均值±标准偏差或95%置信区间）给吸收程度按照渗透性分类上下限和所选内标作出标示。支持一个被测原料药高渗透性的信息包括，被测原料药的渗透性数据，内标（平均值，标准偏差，变异系数），稳定性信息，适当的时候包括支持主动运输机制的数据，以及确定被测原料药的高渗透性的研究方法。

C. DataSupporting Rapid, Very Rapid, and SimilarDissolution   支持快速及相似溶出的数据

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For submissionof a biowaiver request, an IR product should be rapidly dissolving (BCS class 1) or veryrapidly dissolving (BCS class 3). Data supporting rapid dissolutionattributes of the test and reference products should be developed (see sectionIII.C). The following information should be included in the application:

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若要提交生物豁免请求，速释制剂必须是快速溶出的。要提供被测制剂和参比制剂的快速溶出属性的支持数据(见III.C部分)。申请中应包含以下信息：

l  A description of test methods, including information on analyticalmethod(s) and composition of the buffer solutions.

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l  检验方法的描述，包括分析方法和缓冲液组成的信息

l  A briefdescription of the IR products used for dissolution testing, includinginformation on batch or lot number, expiry date, dimensions, strength, andweight

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l  应包含溶出试验使用的速释制剂的简要描述，包括批号，有效期，规格，剂量和质量。

l  Dissolution dataobtained with 12 individual units of the test and reference products usingrecommended test methods in section III.C. The percentage of labeled claimdissolved at each specified testing interval should be reported for eachindividual dosage unit. The mean percent dissolved, range (highest and lowest)of dissolution, and coefficient of variation (relative standard deviation)should be tabulated. A graphic representation of the mean dissolution profilesfor the test and reference products in the three media should also beincluded.

l  按III.C描述的推荐试验方法，使用12个被测试剂和参比试剂的独立单元所得到的的溶出数据。应报告每个独立被测单元在每个特定的试验区间里的标示溶出百分数。应将平均溶出百分数，溶出范围（高低）和变异系数（相对标准偏差）制表。在三种溶媒中的被测制剂和参比制剂的平均溶出特性也应图示出来。

l  Data supportingsimilarity in dissolution profiles between the test and reference products ineach of the three media, (see section IIIC) using the f2metric

l  应提供支持被测制剂和参比制剂在这三种溶媒中的溶出特性相似性的数据，使用f2度量标准。

D. AdditionalInformation   其他信息

Themanufacturing process used to make the test product should be described brieflyto provide information on the method of manufacture (e.g., wet granulation vs.direct compression). A list of excipients used, the amount used, and theirintended functions should be provided. Excipients used in the test productshould have been used previously in FDA-approved IR solid oral dosage forms. In addition, it isimportant to provide quantitative comparison of excipients between the test andreference product, for BCS class 3 drug products.

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制造方法（例如湿法制粒或直接压片）中应该包括被测制剂制造过程的简单描述。应提供包含使用的辅料，使用量和其预期功能的列表。被测制剂中的辅料应在FDA批准的速释固体口服制剂中使用过。

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ATTACHMENT A 附录A

This attachmentincludes model drugs suggested for use in establishing suitability of apermeability method as described in section III. Zero permeabilitymarkers and efflux substrates are also identified. The permeabilityof these compounds was determined based on data available to the FDA.Potential internal standards (IS) and efflux pump substrates (ES) are alsoidentified.

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本附录提供III部分描述的、说明渗透性试验适用性的推荐试剂。这些实际的渗透性都已按照FDA提供的数据划分。其可能的内标(IS)和外流泵载体(ES)也已标明。零渗内标物和流出基质也进行了识别。

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Drug	Permeability  Class 渗透性类别
Antipyrine	High  (Potential IS candidate潜在内标)
Caffeine	High
Carbamazepine	High
Fluvastatin	High
Ketoprofen	High
Metoprolol	High  (Potential IS candidate潜在内标)
Naproxen	High
Propranolol	High
Theophylline	High
Verapamil	High  (Potential ES candidate潜在外流泵载体)
Amoxicilline	Low
Aatenolol	Low
Furosemide	Low
Hydrochlorthiazide	Low
Mannitol	Low  (Potential IS candidate潜在内标)
Α-Methyldopa	Low
Polyethylene  glycol (400)	Low
Polyethylene  glycol (1000)	Low
Polyethylene  glycol (4000)	Low  (Zero permeability marker零渗透性内标)
Ranitidine	Low

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Group	Drug
High Permeability (fa≥85percent)	Antipyrine Caffeine Ketoprofen Naproxen Theophylline Metoprolol Propranolol Carbamazepine Phenytoin Disopyramide Minoxidil
Moderate Permeability (fa = 50-84 percent)	Chlorpheniramine Creatinine Terbutaline Hydrochlorothiazide Enalapril Furosemide Metformin Amiloride Atenolol Ranitidine
Low Permeability (fa<50 percent)	Famotidine Nadolol Sulpiride Lisinopril Acyclovir Foscarnet Mannitol Chlorothiazide Polyethylene glycol 400 Enalaprilat
Zero Permeability	FITC-Dextran Polyethylene glycol 4000 Lucifer yellow Inuline Lactulose
Efflux Substrates	Digoxin Paclitaxel Quinidine Vinblastine

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[1] This guidance has been prepared by theOffice of Pharmaceutical Quality and the Office of Translational Sciences inthe Center for Drug Evaluation and Research (CDER) at the Food and DrugAdministration.  

[2] In addition to waiver of an in vivo BErequirement under 21 CFR 320.22, there are certain circumstances in which BEcan be evaluated using in vitro approaches under 21 CFR 320.24(b)(6). Thescientific principles described in this guidance regarding waiver of an in vivorequirement also apply to consideration of in vitro data under that regulation.In such circumstances, an in vivo data requirement is not waived, but rather,FDA has determined that in vitro data is the most accurate, sensitive, andreproducible for a product, as required under 21 CFR 320.24(a). Nonetheless,for ease of the reader, in this guidance we will refer to either the decisionto waive an in vivo BE requirement under 21 CFR 320.22 or the decision toaccept in vitro BE data in accordance with 21 CFR 320.24(a) as a “biowaiver.”  

[3] We update guidances periodically. Tomake sure you have the most recent version of a guidance, check the FDA Drugsguidance Web page at http://www.fda.gov/Drugs/Guidanc ... dances/default.htm.  

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[4] Amidon GL, Lennern?s H, Shah VP, andCrison JR, 1995, A Theoretical Basis For a Biopharmaceutics DrugClassification: The Correlation of In Vitro Drug Product Dissolution and InVivo Bioavailability, Pharm Res, 12: 413-420.  

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[5] Yu LX, Amidon GL, Polli JE, Zhao H,Mehta MU, Conner DP, et al, 2002, Biopharmaceutics classification system: Thescientific basis for biowaiver extensions, Pharm Res, 19(7):921-5.

[6] See footnote 4.  

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[7] KM Giacomini, SM Huang, DJ Tweedie, LZBenet, KLR Brouwer, X Chu, A Dahlin, R Evers, V Fischer, et al. March 2010, TheInternational Transporter Consortium, Membrane transporters in drugdevelopment, Nature Reviews Drug Discovery, 9:215-236.  

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[8] See the FDA draft guidance for industryon Drug Interaction Studies--Study Design, Data Analysis,Implications for Dosing, and Labeling Recommendations, (Feb 2012).

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[9] This guidance uses the term narrowtherapeutic range instead of narrowtherapeutic index, although the latter is more commonly used.

[10] See the FDA guidance for industry on ImmediateRelease Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes(November 1995).

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