2015年5月FDA口服速释制剂根据BCS分类系统的生物利用度与生物等效性研究及生物等效性豁免

bcs四类药物研发流程BCS四类药物是指根据生物利用度和溶解度将药物分为四类的一种分类方法。

BCS四类药物研发流程是指将药物从研发到上市的整个过程，包括药物发现、药物设计、药物开发、临床试验、上市审批等环节。

本文将从BCS四类药物的定义、研发流程、临床试验等方面进行详细阐述。

一、BCS四类药物的定义BCS四类药物是指根据生物利用度和溶解度将药物分为四类的一种分类方法。

BCS分类方法是美国食品药品监督管理局（FDA）于1995年提出的，旨在为药物研发提供指导。

BCS四类药物的分类标准如下：1. BCSⅠ类药物：生物利用度高，溶解度高，如阿司匹林、维生素C等。

2. BCSⅡ类药物：生物利用度低，溶解度低，如硝酸甘油、地高辛等。

3. BCSⅢ类药物：生物利用度低，溶解度高，如氢氯噻嗪、氨苯蝶啶等。

4. BCSⅣ类药物：生物利用度低，溶解度低，如格列本脲、卡马西平等。

二、BCS四类药物研发流程1. 药物发现药物发现是药物研发的第一步，主要包括药物筛选、药物设计等环节。

药物筛选是指从大量的化合物中筛选出具有潜在药效的化合物，常用的筛选方法包括高通量筛选、虚拟筛选等。

药物设计是指根据药物靶点的结构和功能设计出具有药效的化合物，常用的设计方法包括分子对接、分子模拟等。

2. 药物开发药物开发是指将药物从实验室转化为可供临床使用的药物，主要包括药物制剂开发、药物安全性评价等环节。

药物制剂开发是指将药物与适宜的载体结合，制成适合人体使用的药物制剂，常用的制剂包括片剂、胶囊、注射剂等。

药物安全性评价是指对药物进行毒理学、药代动力学等方面的评价，以确定药物的安全性和剂量范围。

3. 临床试验临床试验是指将药物在人体内进行测试，以确定药物的疗效和安全性。

临床试验分为三个阶段，分别是I期、II期和III期临床试验。

I期临床试验是指对健康志愿者进行的药物安全性评价，主要评价药物的毒副作用和药代动力学等方面。

II 期临床试验是指对患者进行的药物疗效评价，主要评价药物的疗效和剂量范围。

F D A《食物影响的生物利用度及饮食条件下的生物等效性研究》指导原则介绍20070716发布日期化药药物评价>>临床安全性和有效性评价栏目FDA《食物影响的生物利用度及饮食条件下的生物等效性研究》指导原则介绍标题赵亚男赵明作者部门正文内容审评三部赵亚男、赵明美国卫生与人类服务部食品药品监督管理局药品评审和研究中心（CDER）2002年4月BPI 前言本指南为新药临床试验（INDs）、新药上市申请（NDAs）、仿制药申请和补充申请（ANDAs）的申办和/或申请者提供了食物对生物利用度和饮食条件下生物等效性研究的建议。

本指南适用于速释制剂和缓控释制剂。

本指南指出当用于口服制剂时，如何和21CFR320，314.50(d)(3)和314.94(a)(7)对BA、BE要求一致。

本指南对试验设计、数据分析、药物标签、试验如何实施方面提出了建议和参考。

II 背景食物影响生物利用度的研究通常在IND阶段的新药和药物上进行，目的是比较饮食和禁食情况下，食物对新药的吸收速度和程度的影响。

另一方面，针对ANDAs，饮食条件下生物等效性研究是比较在饮食情况下与对照品（RLD）的生物等效性。

A：食物影响生物利用度可能的机制食物可能改变药物的生物利用度，可能影响参比制剂和试验制剂的生物等效性。

食物对生物等效性的影响可能带来临床上严重后果。

食物可能通过如下方式改变生物利用度：－延迟胃排空；－刺激胆汁流量；－改变胃肠道（GI）pH值；－增加内脏的血流量；－改变药物的代谢；－与制剂或药物发生物理和化学反应刚刚摄取食物后服药，食物对药物生物利用度影响往往是最大的。

食物的营养成分、热量、食物的体积和食物的温度能改变胃肠道的生理环境，由此影响药物在胃肠道内的滞留时间、溶解度、渗透性和机体可利用度。

通常情况下，高脂、高热量食物更容易影响胃肠道的生理功能，结果导致药物或制剂的生物利用度发生较大的改变。

我们建议在食物影响生物利用度及饮食条件下生物等效性研究中采用高热量和高脂肪食物。

BCS在药物制剂设计和研究中的应用与意义1142111 管泓湦生物药剂学分类系统（BCS）是药物制剂在口服吸收药分类方面的一个重要概念。

围绕体外溶解性和体内渗透性这两个核心特征，将口服类药物分成四个类别加以区分。

即Ⅰ类：高溶解性，高渗透性；Ⅱ类：低溶解性，高渗透性；Ⅲ类：高溶解性，低渗透性；Ⅳ类：低溶解性，低渗透性。

本文将以BCS对药剂设计和研究中的四个制剂策略以及两个重要意义展开论述。

一、BCS对口服药剂的设计思路及剂型改良的应用从BCS对口服药物的基本分类上，我们可以看出，针对不同的溶解和渗透性药物，我们应选择不同的改进方案，使其能自原有药物基础上，尽可能提高生物利用度和病人对药物的顺应性。

（一）Ⅰ类药物的制剂设计：高溶高渗的特点注定了此类药物的基础生物利用度，对于此类药物，我们在辅料的选择上应该尽可能的减少对药物溶解和渗透的影响。

其限速步骤通常存在于胃的排空速率以及药物自身在胃酸环境下的稳定性。

对于易于在胃酸环境中分解的药物，选择进一步包衣和定位控释的技术，可以有效提高药物在体内发挥作用的程度。

（二）Ⅱ类药物的制剂设计：对于这一类低溶高渗的药物，BCS可以给我们提供一个基本的制剂策略，我们应进一步注意此类药物在肠内的溶出速率，将改良的重点放在改善制剂的崩解与溶出。

当我们提高了药物在肠道环境中的溶解问题，生物利用度将得到较大提升。

常用的改进策略：1.制成可溶性盐类：我们可以通过将难溶弱酸性药物制成碱金属盐、弱碱性药物制成强酸盐的方法，提高溶解度和吸收率。

2.筛选晶型和溶媒化物：不同晶型的晶胞内分子空间构型、构想和排列不同，使药物的溶解性存在较大差异，导致制剂在体内有不同的溶出速率，直接影响药物的生物利用度，造成临床药效的显著差异。

而对于药物来说，这种多晶型现象非常普遍，例如38种巴比妥类药物中有63%存在多晶型，48种甾体化合物中67%有多晶型。

对于这种晶型的差异，我们在制剂的选择中，通常选择溶出度大，溶出速度快的晶型。

BCS和BDDCS的简介和比较摘要：生物药剂学分类系统(BCS)的概念自从1995年被提出后，人们对其有效性和适用性进行了广泛而深人的研究。

经过十多年的发展，BCS现已成为世界药品管理中一个越来越重要的工具。

基于药物体内处置的生物药剂学分类系统（BDDCS)则在BCS的基础上作以改进,使用药物体内代谢程度作为渗透性的替代指标,对药物进行分类。

BDDCS 系统不但可以补充现有仿制药物生物等效性豁免的评审标准，还可以对药物在体内的各种特征进行预测。

本文将对BCS和BDDCS作以简要的介绍，并对二者进行比较。

关键词：生物药剂学；BCS；BDDCS前言：人体生物等效性研究（Bioequivalence，BE）是评价同一种药物的相同或者不同剂型的制剂是否可以达到相同疗效的通用标准，也用作非专利药品的审批。

生物等效性试验要求试验药品与对照药物间具有相同的血药浓度－时间曲线，即统计学意义上相同的峰浓度（Cmax）和药时曲线下面积（AUC）。

1995 年，Amidon 等人提出了生物药剂学分类系统（Bio-pharmaceutics Classification System，BCS），将药物按照溶解度和渗透性进行分类，并以此来预测药物在体内的吸收。

该系统在 2000 年被 FDA 采用，作为《基于生物药剂学分类系统对口服速释固体制剂免除生物利用度和生物等效性的工业指导原则》的理论基础。

根据 BCS 理论，非专利药品若能在体外试验中证实具有高溶解度和高渗透性（BCS 第Ⅰ类），其速释制剂可以申请免除体内生物等效性研究。

在 BCS 中，高渗透性定义为≥90％口服给药可被吸收。

在 2005 年，Benet 教授又提出了基于药物体内分布的生物药剂学分类系统（Bio-pharmaceutics Drug Disposition Classification System），提出以药物的代谢作为渗透性新的替代指标。

本文将对 BCS 和 BDDCS 系统做以介绍，并对其在实际应用中的价值作以探讨。

人体生物等效性试验豁免指导原则集团文件版本号：（M928-T898-M248-WU2669-I2896-DQ586-M1988）附件人体生物等效性试验豁免指导原则本指导原则适用于仿制药质量和疗效一致性评价中口服固体常释制剂申请生物等效性（Bioequivalence）豁免。

该指导原则是基于国际公认的生物药剂学分类系统（Biopharmaceutics Classification System，以下简称BCS）起草。

一、药物BCS分类BCS系统是按照药物的水溶性和肠道渗透性对其进行分类的一个科学架构。

当涉及到口服固体常释制剂中活性药物成分（Active Pharmaceutical Ingredient，以下简称API）在体内吸收速度和程度时，BCS系统主要考虑以下三个关键因素，即：药物溶解性（Solubility）、肠道渗透性（Intestinal permeability）和制剂溶出度（Dissolution）。

（一）溶解性溶解性分类根据申请生物等效豁免制剂的最高剂量而界定。

当单次给药的最高剂量对应的API在体积为250ml（或更少）、pH值在1.0—6.8范围内的水溶性介质中完全溶解，则可认为该药物为高溶解性。

250ml的量来源于标准的生物等效性研究中受试者用于服药的一杯水的量。

（二）渗透性渗透性分类与API在人体内的吸收程度间接相关（指吸收剂量的分数，而不是全身的生物利用度），与API在人体肠道膜间质量转移速率直接相关，或者也可以考虑其他可以用来预测药物在体内吸收程度的非人体系统（如使用原位动物、体外上皮细胞培养等方法）对渗透性进行分类。

当一个口服药物采用质量平衡测定的结果或是相对于静脉注射的参照剂量，显示在体内的吸收程度≥85%以上（并且有证据证明药物在胃肠道稳定性良好），则可说明该药物具有高渗透性。

（三）溶出度口服固体常释制剂具有快速溶出的定义是：采用中国药典2015版附录通则（0931）方法1 （篮法），转速为每分钟100转,或是方法2（桨法），转速为每分钟50或75转，溶出介质体积为500ml（或更少），在溶出介质：（1）0.1mol/L HCl或是不含酶的模拟胃液；（2）pH4.5缓冲介质；（3）pH6.8缓冲介质或是不含酶的模拟肠液中，30分钟内API的溶出均能达到标示量的85%以上。

Waiver of In VivoBioavailability andBioequivalence Studies for Immediate-Release Solid OralDosage Forms Based on a Biopharmaceutics ClassificationSystemGuidance for IndustryDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to . Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified withthe docket number listed in the notice of availability that publishes in the Federal Register.For questions regarding this draft document contact (CDER) Mehul Mehta 301-796-1573.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)May 2015BiopharmaceuticsRevision 1Waiver of In VivoBioavailability and Bioequivalence Studies for Immediate-Release Solid OralDosage Forms Based on a Biopharmaceutics ClassificationSystemGuidance for IndustryAdditional copies are available from:Office of Communications,Division of Drug InformationCenter for Drug Evaluation and ResearchFood and Drug Administration10001 New Hampshire Ave., Hillandale Bldg., 4th FloorSilver Spring, MD 20993-0002Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353Email: druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)May 2015BiopharmaceuticsRevision 1TABLE OF CONTENTSI.INTRODUCTION (1)II.THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM (2)A. Solubility (3)B. Permeability (3)C. Dissolution (3)III. RECOMMENDED METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING THE DISSOLUTIONCHARACTERISTICS OF A DRUGPRODUCT (3)A. Determining Drug Substance Solubility Class (3)B. Determining Drug Substance Permeability Class (4)1.Pharmacokinetic Studies in Humans (4)2.Intestinal Permeability Methods (5)3.Instability in the Gastrointestinal Tract (7)C. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity .. 7 IV.BIOWAIVERS BASED ON BCS (8)V. ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER (9)A. Excipients (9)B. Prodrugs (9)C. Fixed Dose Combinations (10)D. Exceptions (10)1.Narrow Therapeutic Range Drugs (10)2.Products Designed to be Absorbed in the Oral Cavity (10)VI. REGULATORY APPLICATIONS OF THE BCS (11)A. INDs/NDASs (11)B. ANDAs (11)C. Supplemental NDAs/ANDAs (Postapproval Changes) (11)VII. DATA TO SUPPORT A REQUEST FOR BIOWAIVERS (12)A. Data Supporting High Solubility (12)B. Data Supporting High Permeability (12)C. Data Supporting Rapid, Very Rapid, and Similar Dissolution (13)D. Additional Information (13)ATTACHMENT A (14)Waiver of In Vivo Bioavailability and Bioequivalence Studies for 1Immediate-Release Solid Oral Dosage Forms Based on a2Biopharmaceutics Classification System3Guidance for Industry14567This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 8thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 9bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 10the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 11staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 12the appropriate number listed on the title page of this guidance.1314151617I. INTRODUCTION1819This guidance provides recommendations for sponsors of investigational new drug applications20(INDs), and applicants that submit new drug applications (NDAs), abbreviated new drug applications 21(ANDAs), and supplements to these applications for immediate-release (IR) solid oral dosage forms, 22and who wish to request a waiver of in vivo bioavailability (BA) and/or bioequivalence (BE) studies.23These waivers are intended to apply to: (1) subsequent in vivo BA or BE studies of formulations24after the initial establishment of the in vivo BA of IR dosage forms during the IND period, and (2) in 25vivo BE studies of IR dosage forms in ANDAs.2627Regulations at 21 CFR part 320 address the requirements for BA and BE data for approval of drug 28applications and supplemental applications. Provision for waivers of in vivo BA/BE studies29(biowaivers) under certain conditions is provided at 21 CFR 320.22.2 This guidance updates the30guidance for industry on Waiver of In Vivo Bioavailability and Bioequivalence Studies for31Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System,3 32published in August 2000, and explains when biowaivers can be requested for IR solid oral dosage 33forms based on an approach termed the Biopharmaceutics Classification System (BCS). This1 This guidance has been prepared by the Office of Pharmaceutical Quality and the Office of Translational Sciencesin the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.2 In addition to waiver of an in vivo BE requirement under 21 CFR 320.22, there are certain circumstances in whichBE can be evaluated using in vitro approaches under 21 CFR 320.24(b)(6). The scientific principles described in this guidance regarding waiver of an in vivo requirement also apply to consideration of in vitro data under thatregulation. 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, and reproducible 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 decision to waive an in vivo BErequirement under 21 CFR 320.22 or the decision to accept in vitro BE data in accordance with 21 CFR 320.24(a) as a “biowaiver.”3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDADrugs guidance Web page at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.34guidance includes biowaiver extension to BCS class 3 drug products, and additional modifications, 35such as criteria for high permeability and high solubility.36In general, FDA’s guidance documents do not establish legally enforceable responsibilities.3738Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 39as recommendations, unless specific regulatory or statutory requirements are cited. The use of 40the word should in Agency guidances means that something is suggested or recommended, but 41not required.424344II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM4546The BCS is a scientific framework for classifying drug substances based on their aqueous solubility 47and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes 48into account three major factors that govern the rate and extent of drug absorption from IR solid oral 49dosage forms: (1) dissolution, (2) solubility, and (3) intestinal permeability.4 According to the BCS, 50drug substances are classified as follows:5152Class 1: High Solubility – High Permeability53Class 2: Low Solubility – High Permeability54Class 3: High Solubility – Low Permeability55Class 4: Low Solubility – Low Permeability5657In addition, some IR solid oral dosage forms are categorized as having rapid or very rapid558dissolution. Within this framework, when certain criteria are met, the BCS can be used as a drug59development tool to help sponsors/applicants justify requests for biowaivers.6061Observed in vivo differences in the rate and extent of absorption of a drug from two62pharmaceutically equivalent solid oral products may be due to differences in drug dissolution in63vivo.6 However, when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid 64in relation to gastric emptying and the drug has high solubility, the rate and extent of drug absorption 65is unlikely to be dependent on drug dissolution and/or gastrointestinal (GI) transit time. Under such 66circumstances, demonstration of in vivo BA or BE may not be necessary for drug products67containing class 1 and class 3 drug substances, as long as the inactive ingredients used in the dosage 68form do not significantly affect absorption of the active ingredients.6970The BCS approach outlined in this guidance can be used to justify biowaivers for highly soluble and 71highly permeable drug substances (i.e., class 1) as well as highly soluble and low permeable drug 72substances (i.e., class 3) in IR solid oral dosage forms that exhibit rapid or very rapid in vitro73dissolution using the recommended test methods. The recommended methods for determining74solubility, permeability, and in vitro dissolution are discussed below.754 Amidon GL, Lennernäs H, Shah VP, and Crison JR, 1995, A Theoretical Basis For a Biopharmaceutics DrugClassification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res, 12: 413-420.5 Yu LX, Amidon GL, Polli JE, Zhao H, Mehta MU, Conner DP, et al, 2002, Biopharmaceutics classificationsystem: The scientific basis for biowaiver extensions, Pharm Res, 19(7):921-5.6 See footnote 4.A. Solubility767778The solubility class boundary is based on the highest strength of an IR product that is the subject of a 79biowaiver request. A drug substance is considered highly soluble when the highest strength is80soluble in 250 mL or less of aqueous media over the pH range of 1-6.8. The volume estimate of 250 81mL is derived from typical BE study protocols that prescribe administration of a drug product to82fasting human volunteers with a glass (about 8 ounces) of water.8384B. Permeability8586The permeability class boundary is based indirectly on the extent of absorption (fraction of dose87absorbed, not systemic BA) of a drug substance in humans, and directly on measurements of the rate 88of mass transfer across human intestinal membrane. Alternatively, other systems capable of89predicting the extent of drug absorption in humans can be used (e.g., in situ animal, in vitro epithelial 90cell culture methods). A drug substance is considered to be highly permeable when the extent of91absorption in humans is determined to be 85 percent or more of an administered dose based on a92mass balance determination (along with evidence showing stability of the drug in the GI tract) or in 93comparison to an intravenous reference dose.9495C. Dissolution9697An IR drug product is considered rapidly dissolving when 85 percent or more of the labeled amount 98of the drug substance dissolves within 30 minutes, using United States Pharmacopeia (USP)99Apparatus I at 100 rpm (or Apparatus II at 50 rpm or at 75 rpm when appropriately justified (see 100section III.C.)) in a volume of 500 mL or less in each of the following media: (1) 0.1 N HCl or101Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or102Simulated Intestinal Fluid USP without enzymes.103104An IR product is considered very rapidly dissolving when 85 percent or more of the labeled amount 105of the drug substance dissolves within 15 minutes using the above mentioned conditions.106107108III. RECOMMENDED METHODOLOGY FOR CLASSIFYING A DRUG109SUBSTANCE AND FOR DETERMINING THE DISSOLUTIONCHARACTERISTICS OF A DRUG PRODUCT110111112The following approaches are recommended for classifying a drug substance and determining the 113dissolution characteristics of an IR drug product according to the BCS.114115A. Determining Drug Substance Solubility Class116117An objective of the BCS approach is to determine the equilibrium solubility of a drug substance 118under physiological pH conditions. The pH-solubility profile of the test drug substance should be 119determined at 37 ± 1o C in aqueous media with a pH in the range of 1-6.8. A sufficient number of pH 120conditions should be evaluated to accurately define the pH-solubility profile within the pH range of 1211-6.8. The number of pH conditions for a solubility determination can be based on the ionization 122characteristics of the test drug substance to include pH = pKa, pH = pKa +1, pH = pKa-1, and at pH 123= 1 and 6.8. A minimum of three replicate determinations of solubility in each pH condition is124recommended. Depending on study variability, additional replication may be necessary to provide a 125reliable estimate of solubility. Standard buffer solutions described in the USP are considered126appropriate for use in solubility studies. If these buffers are not suitable for physical or chemical 127reasons, other buffer solutions can be used. Solution pH should be verified after addition of the drug 128substance to a buffer. Methods other than the traditional shake-flask method, such as acid or base 129titration methods, can also be used with justification to support the ability of such methods to predict 130equilibrium solubility of the test drug substance. Concentration of the drug substance in selected 131buffers (or pH conditions) should be determined using a validated stability-indicating assay that can 132distinguish the drug substance from its degradation products.7 If degradation of the drug substance 133is observed as a function of buffer composition and/or pH, it should be reported. The solubility class 134should be determined by calculating the volume of an aqueous medium sufficient to dissolve the 135highest strength in the pH range of 1-6.8. A drug substance should be classified as highly soluble 136when the highest strength is soluble in < 250 mL of aqueous media over the pH range of 1-6.8. In 137other words, the maximum dose divided by 250 should be greater than or equal to the lowest138solubility observed over the entire pH range of 1-6.8.139140B. Determining Drug Substance Permeability Class141142The permeability class of a drug substance can be determined in human subjects using mass balance, 143or absolute BA, which are the preferred methods, or intestinal perfusion approaches. Recommended 144methods not involving human subjects include in vivo or in situ intestinal perfusion in a suitable 145animal model (e.g., rats), or in vitro permeability methods using excised intestinal tissues, or146monolayers of suitable epithelial cells. In many cases, a single method may be sufficient: (i) when 147the absolute BA is 85 percent or more, or (ii) when 85 percent or more of the administered drug is 148excreted unchanged in urine, or (iii) when 85 percent or more of the administered drug is recovered 149in urine as parent and metabolites with evidence indicating stability in the GI tract. When a single 150method fails to conclusively demonstrate a permeability classification, two different methods may be 151advisable. In case of conflicting information from different types of studies, it is important to note 152that human data supersede in vitro or animal data.1531541.Pharmacokinetic Studies in Humans155156•Mass Balance Studies157158Pharmacokinetic (PK) mass balance studies using unlabeled, stable isotopes or a159radiolabeled drug substance can be used to document the extent of absorption of a 160drug. A sufficient number of subjects should be enrolled to provide a reliable161estimate of extent of absorption.162163When mass balance studies are used to demonstrate high permeability, additional data 164to document the drug’s stability in the GI tract is required, unless 85 percent or more 165of the drug is excreted unchanged in urine. Please see method details in section166III.B.3.1677 Refer to the FDA guidance for industry on Submitting Documentation for the Stability of Human Drugs andBiologics (February 1987), posted at /downloads/Drugs/Guidances/UCM070632.pdf.•Absolute Bioavailability Studies168169170Oral BA determination using intravenous administration as a reference can be used. 171Depending on the variability of the studies, a sufficient number of subjects should be 172enrolled in a study to provide a reliable estimate of the extent of absorption. When 173the absolute BA of a drug is shown to be 85 percent or more, additional data to174document drug stability in the GI fluid is not necessary.1751762.Intestinal Permeability Methods177178The following methods can be used to determine the permeability of a drug substance from 179the GI tract: (1) in vivo intestinal perfusion studies in humans; (2) in vivo or in situ intestinal 180perfusion studies using suitable animal models; (3) in vitro permeation studies using excised 181human or animal intestinal tissues; or (4) in vitro permeation studies across a monolayer of 182cultured epithelial cells.183184In vivo or in situ animal models and in vitro methods, such as those using cultured185monolayers of animal or human epithelial cells, are considered appropriate for passively186transported drugs. The observed low permeability of some drug substances in humans could 187be caused by efflux of drugs via membrane efflux transporters such as P-glycoprotein (P-gp). 188When the efflux transporters are absent in these models, or their degree of expression is low 189compared to that in humans, there may be a greater likelihood of misclassification of190permeability class for a drug subject to efflux compared to a drug transported passively. 191Expression of known transporters in selected study systems should be characterized.192Functional expression of efflux systems (e.g., P-gp) can be demonstrated with techniques 193such as bidirectional transport studies, demonstrating a higher rate of transport in the194basolateral-to-apical direction as compared to apical-to-basolateral direction (efflux ratio 195>2)8,9, using selected model drugs or chemicals at concentrations that do not saturate the 196efflux system (e.g., digoxin, vinblastine, rhodamine 123). We recommend limiting the use of 197animal or in vitro permeability test methods for drug substances that are transported by198passive mechanisms (efflux ratio of the test drug should be <2). PK studies on dose linearity 199or proportionality may provide useful information for evaluating the relevance of observed in 200vitro efflux of a drug. For example, there may be fewer concerns associated with the use of 201in vitro methods for a drug that has a higher rate of transport in the basolateral-to-apical202direction at low drug concentrations but exhibits linear PK in humans.203204For BCS-based permeability determination, an apparent passive transport mechanism can be 205assumed when one of the following conditions is satisfied:206207• A linear (pharmacokinetic) relationship between the dose (e.g., relevant clinical 208dose range) and measures of BA (area under the concentration-time curve) of a 209drug is demonstrated in humans.2108 KM Giacomini, SM Huang, DJ Tweedie, LZ Benet, KLR Brouwer, X Chu, A Dahlin, R Evers, V Fischer, et al.March 2010, The International Transporter Consortium, Membrane transporters in drug development, NatureReviews Drug Discovery, 9:215-236.9 See the FDA draft guidance for industry on Drug Interaction Studies--Study Design, Data Analysis, Implicationsfor Dosing, and Labeling Recommendations, (Feb 2012).211•Lack of dependence of the measured in vivo or in situ permeability is212demonstrated in an animal model on initial drug concentration (e.g., 0.01, 0.1, 213and 1 times the highest strength dissolved in 250 mL) in the perfusion fluid.214215•Lack of dependence of the measured in vitro permeability on initial drug216concentration (e.g., 0.01, 0.1, and 1 times the highest strength dissolved in 250 217ml) is demonstrated, or on transport direction (e.g., no statistically significant 218difference in the rate of transport between the apical-to-basolateral and219basolateral-to-apical direction for the drug concentrations selected) using a220suitable in vitro cell culture method that has been shown to express known efflux 221transporters (e.g., P-gp).222223METHOD SUITABILITY: One of the critical steps in using in vitro permeability 224methods for permeability classification is to demonstrate the suitability of the225method. To demonstrate suitability of a permeability method intended for BCS-226based permeability determination, a rank-order relationship between experimental 227permeability values and the extent of drug absorption data in human subjects should 228be established using a sufficient number of model drugs. For in vivo intestinal229perfusion studies in humans, six model drugs are recommended. For in vivo or in 230situ intestinal perfusion studies in animals, and for in vitro cell culture methods,231twenty model drugs are recommended. Depending on study variability, a sufficient 232number of subjects, animals, excised tissue samples, or cell monolayers should be 233used in a study to provide a reliable estimate of drug permeability. This relationship 234should allow precise differentiation between drug substances of low and high235intestinal permeability attributes.236237To demonstrate the suitability of a method, model drugs should represent a range of 238zero, low (e.g., < 50 percent), moderate (e.g., 50 – 84 percent), and high (≥ 85239percent) absorption. Sponsors/applicants may select compounds from the list of240drugs and/or chemicals provided in Attachment A, or they may select other drugs for 241which there is information available on mechanism of absorption and reliable242estimates of the extent of drug absorption in humans.243244After demonstrating suitability of a method and maintaining the same study protocol, 245it is not necessary to retest all selected model drugs for subsequent studies intended to 246classify a drug substance. Instead, a low and a high permeability model drug should 247be used as internal standards (i.e., included in the perfusion fluid or donor fluid along 248with the test drug substance). These two internal standards are in addition to the fluid 249volume marker (or a zero permeability compound such as PEG 4000) that is included 250in certain types of perfusion techniques (e.g., closed loop techniques). The choice of 251internal standards should be based on compatibility with the test drug substance (i.e., 252they should not exhibit any significant physical, chemical, or permeation253interactions). When it is not feasible to follow this protocol, the permeability of254internal standards should be determined in the same subjects, animals, tissues, or 255monolayers, following evaluation of the test drug substance. The permeability values 256of the two internal standards should not differ significantly between different tests, 257including those conducted to demonstrate suitability of the method. For example, the 258laboratory may set acceptance criteria for the permeability values of its high, low, and259zero permeability standard compounds. At the end of an in situ or in vitro test, the 260amount of drug in the membrane should be determined to assist in calculation of261mass balance.262263For a given test method with set conditions, selection of a high permeability internal 264standard with permeability in close proximity to the low/high permeability class265boundary may be used to facilitate classification of a test drug substance. For266instance, a test drug substance may be determined to be highly permeable when its 267permeability value is equal to or greater than that of the selected internal standard 268with high permeability.269270When intestinal permeability methods are used to demonstrate high permeability, 271additional data to document the drug’s stability in the GI tract is required. Please see 272method details in section III.B.3.2732743. Instability in the Gastrointestinal Tract275276Determining the extent of absorption in humans based on mass balance studies using total 277radioactivity in urine does not take into consideration the extent of degradation of a drug in 278the GI fluid prior to intestinal membrane permeation. In addition, some methods for279determining permeability could be based on loss or clearance of a drug from fluids perfused 280into the human and/or animal GI tract either in vivo or in situ. Documenting the fact that 281drug loss from the GI tract arises from intestinal membrane permeation, rather than a282degradation process, will help establish permeability. Stability in the GI tract may be283documented using simulated gastric and intestinal fluids. Obtaining GI fluids from human 284subjects requires intubation and may be difficult. Therefore, use of simulated fluids such as 285Gastric and Intestinal Fluids USP may be reasonable.286287Drug solutions in these fluids should be incubated at 37o C for a period that is representative 288of in vivo drug contact with these fluids; for example, 1 hour in gastric fluid and 3 hours in 289intestinal fluid. Drug concentrations should then be determined using a validated stability-290indicating assay method. Significant degradation (>5 percent) of a drug in this study could 291suggest potential instability.292C. Determining Drug Product Dissolution Characteristics and Dissolution Profile 293294Similarity10295296Dissolution testing should be carried out in USP Apparatus I at 100 rpm or Apparatus II at 50 297rpm (or at 75 rpm when appropriately justified) using 500 mL of the following dissolution 298media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; 299and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes. For capsules and 300tablets with gelatin coating, Simulated Gastric and Intestinal Fluids USP (with enzymes) can 301be used.30210 See the FDA guidance for industry on Dissolution Testing of Immediate Release Solid Oral Dosage Forms(August 1997).The dissolution testing apparatus used in this evaluation should conform to the requirements 303in USP (<711> Dissolution). Selection of the dissolution testing apparatus (USP Apparatus I 304or II) during drug development should be based on a comparison of in vitro dissolution and in 305vivo PK data available for the product. The USP Apparatus I (basket method ) is generally 306preferred for capsules and products that tend to float, and USP Apparatus II (paddle method ) 307is generally preferred for tablets. For some tablet dosage forms, in vitro (but not in vivo) 308dissolution may be slow due to the manner in which the disintegrated product settles at the 309bottom of a dissolution vessel. In such situations, USP Apparatus I may be preferred over 310Apparatus II. If the testing conditions need to be modified to better reflect rapid in vivo 311dissolution (e.g., use of a different rotating speed), such modifications can be justified by 312comparing in vitro dissolution with in vivo absorption data (e.g., a relative BA study using a 313simple aqueous solution as the reference product). 314315A minimum of 12 dosage units of a drug product should be evaluated to support a biowaiver 316request. Samples should be collected at a sufficient number of intervals to characterize the 317dissolution profile of the drug product (e.g., 5, 10, 15, 20, and 30 minutes). 318319When comparing the test and reference products, dissolution profiles should be compared 320using a similarity factor (f 2). 321322f 2 = 50 • log {[1 + (1/n)Σt=1n (R t - T t )2]-0.5 • 100} 323324The similarity factor is a logarithmic reciprocal square root transformation of the sum of 325squared error and is a measurement of the similarity in the percent (%) of dissolution 326between the two curves; where n is the number of time points, Rt is the dissolution value of 327the reference batch at time t, and Tt is the dissolution value of the test batch at time t. 328329Two dissolution profiles are considered similar when the f 2 value is ≥50. To allow the use of 330mean data, the coefficient of variation should not be more than 20 percent at the earlier time 331points (e.g., 10 minutes), and should not be more than 10 percent at other time points. Note 332that when both test and reference products dissolve 85 percent or more of the label amount of 333the drug in 15 minutes using all three dissolution media recommended above, the profile 334comparison with an f 2 test is unnecessary. 335 336337IV. BIOWAIVERS BASED ON BCS 338339This guidance is applicable for BA/BE waivers (biowaivers) based on BCS, for BCS class 1 and 340class 3 immediate-release solid oral dosage forms. 341342For BCS class 1 drug products, the following should be demonstrated: 343344• the drug substance is highly soluble 345• the drug substance is highly permeable 346• the drug product (test and reference) is rapidly dissolving, and347。

工业指南基于生物药剂学分类系统的口服固体速释制剂体内生物利用度和生物等效性研究的豁免美国卫生和人类服务部食品和药物管理局药品评价与研究中心（CDER）2000年8月BP工业指南基于生物药剂学分类系统的口服固体速释制剂体内生物利用度和生物等效性研究的豁免有关其它资料可从下列机构获得：培训与通信事业部通信管理药品信息科办公室HFD-2105600 渔民巷罗克维尔，MD 20857 电话：301-827-4573网址：/cder/guidance/index.htm美国卫生和人类服务部食品和药物管理局药品评价与研究中心（CDER）2000年8月BP目录I. 简介 (1)II. 生物药剂学分类系统 (1)A. 溶解度............................................................................. 错误！未定义书签。

B. 渗透性............................................................................. 错误！未定义书签。

C. 溶出度............................................................................. 错误！未定义书签。

III. 原料药分类和确定成品药溶解特性的方法.. (2)A. 确定药物成分的溶解性分类 (2)B. 确定药物成分的渗透性分类 (3)1. 人体药代动力学研究 (3)2. 肠道渗透性方法....................................................... 错误！未定义书签。

3. 肠胃道内的不稳定性 (5)C. 确定成品药的溶解特性和溶解外观相似性 (5)IV. 请求生物豁免的额外注意事项 (6)A. 辅料 (7)B. 前药 (7)C. 例外处理 (7)1.治疗范围狭窄的药物 (7)2.专门适用于口腔的药品 (7)V.BCS的管理应用 (8)A. 新药研发（INDs）/新药批准（NDAs） (8)B. 仿制药批准（ANDAs） (8)C. 批准后的变更 (8)VI. 支持生物豁免请求的数据 (8)A.高溶解性的数据支持 (9)B.高渗透性的数据支持 (9)C.快速和相似溶出的数据支持 (9)D.附加说明 (10)附件一 (11)工业指南1基于生物药剂学分类系统的口服固体速释制剂体内生物利用度和生物等效性研究的豁免I. 简介本指南为主办方提供新药临床研究申请、新药申请、仿制药申请的建议和口服固体速释制剂（IR）体内生物利用度(BA)和/或生物等效性(BE)研究豁免申请的补充意见。