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-个人翻译
仿制药质量一致性评价的体内体外相关性
结果表明，一个仿制制剂（N-BE）的Cmax与原研不等效！
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SC Useche et al., Mol. Pharm., 8;12(9):3167-74.(2015)
• 对大多药品来说，循环系统的药物暴露差别在20%以内，将不会对临床 治疗效果产生显著影响；
75rpm，在500ml介质中，30分钟溶出限度不少于85%。
药物活性成分为BCS 1或3类药物：
• BCS 1类要求：药品不含有任何影响药物吸收速率或吸收程 度的辅料；
• BCS 3类要求：试验制剂与参比制剂的辅料性质相同、含量 相似。（由于渗透性是限制步骤，因此要求与参比制剂的 辅料性质相同、含量相似）
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• 比如我国恒瑞药业生产的多西他赛注射液（艾素）价格仅 是原研药（泰素帝）的1/4。
• 质量过硬、价格易于接受的仿制药成为众多患者的首选。
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原研药与仿制药的开发历程
原研药的开发经历了发现、临床前、申报临床（IND）、临床123期、新 药申请报生产（NDA）到上市的过程；仿制药是待原研药上市进行的简 略新药申请（ANDA）
绝大多数药物口服给药后 经血液循环转运到达起效部位 相似的血药浓度，可以保证相似的疗效 国际监管部门均将BE试验作为仿制药物上市批准的依据
由于伦理、经费、时间等因素的限制，无法对 每批药品进行BE试验
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由于伦理、经费、时间等因素的限制, 美国FDA和欧盟 EMA在2000年陆续以BCS作为BE豁免的依据，2015年 FDA对BE豁免指南做了进一步修订
两个仿制制剂与原研制剂的溶出曲线比较
原研及2个仿制制剂在50rpm桨法pH1.2、4.5、6.0、6.5 、6.8介质中，15min均大于85%，达到BE豁免条件
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》指导原则介绍教程文件
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。
一致性评价_FDA,WHO和EMA关于基于BCS的生物等效性豁免异同
一致性评价| FDA，WHO 和EMA 关于基于BCS的生物等效性豁免异同2016-04-22 度衡之道体生物等效性研究是证明制剂之间治疗等效性的一种手段。
随着BCS 概念的提出和不断得到论证，越来越多的监管机构开始考虑并接受基于BCS 的生物等效性豁免，特别是中国国家局刚刚发布的，更是激起了中国药企的学习的热情。
我们了解一下最具权威性的FDA、WHO 和EMA 的指导原则。
指导原则发布的历史监管机构将BCS 应用于生物等效性豁免最早可追溯到1995 年。
美国FDA 最早对原料药进行BCS 分类，目的是允许工艺放大和上市后变更的产品豁免生物等效性研究。
当时，仅仅是上市后制剂的变更才考虑应用BCS 分类豁免生物等效性研究。
随着对BCS 了解的不断加深，基于BCS 的生物等效性豁免的应用围也得以拓宽。
2000 年8 月，FDA 发布了将BCS 应用于速释固体口服制剂的生物等效性豁免的指导原则。
随后，其他监管机构开始接受这一理念并发布了相应的指导原则，例如WHO 于2006 年发布的Technical Report SeriesNo．937，其中Annex 7 和Annex 8 引入了基于BCS 的生物等效性豁免，EMA 于2010 年发布的生物等效性研究指南也引入了类似容。
BCS 和基于BCS 的生物等效性豁免1. 什么是BCSBCS 全称为biopharmaceutics classification system，国一般译作生物药剂学分类系统，是根据药物在水中的溶解度和肠壁渗透能力对药物进行科学分类的标准。
对于口服固体速释制剂而言，原料药的溶解性、渗透性和制剂的溶出度这 3 个方面基本决定了药物在体的吸收速度和程度。
根据FDA指导原则的定义，原料药按照BCS 可分为以下几类: BCS Ⅰ: 高溶解性-高渗透性; BCS Ⅱ: 低溶解性-高渗透性; BCS Ⅲ: 高溶解性-低渗透性; BCS Ⅳ: 低溶解性-高渗透性。
BE豁免指导原则
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。
生物药剂学分类系统和基于药物体内分布的生物药剂学分类系统
BCD与BDDCS简介通过查阅相关文献和资料，了解到生物药剂学分类系统和基于药物体内分布的生物药剂学分类系统是近二十年新兴的药物分类系统，它们还未被相关学科的科学家和相关机构完全认可。
不过，目前FDA、EMA已经WHO已经根据这两种分类系统的内容颁发了一些指导原则，还有许多科学家在积极推进这两种分类系统的发展和应用。
由于文献研读的时间较有限，下面就从四个方面简单描述一下自己的研读收获。
一、生物药剂学分类系统简介生物药剂学分类系统（Biopharmaceutics Classification System，BCS）是一个根据药物在水中的溶解度和肠壁渗透能力对药物进行科学分类的标准。
1995年，BCS的概念首次被提出。
BCS概念的提出最初是基于对药品上市后的变更以及放大给予免除生物等效性研究的考虑，即在考证变更前后产品以及放大前后的产品是否保持生物等效时，不再采用耗时耗资源的体内研究来进行验证，而是采用体外溶出度的测定方法。
2000年，美国FDA 颁布《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》，标志着基于BCS分类体系免除生物等效研究的应用正式扩展至口服仿制药的申请，不过主要是局限在口服速释固体制剂。
BCS将药物分为四类，分类如下：第一类，高溶解度—高渗透性药物，如维拉帕米(verapamil)、美托洛尔(metoprolol)；第二类，低溶解度—高渗透性药物，如环孢素(ciclosporin)、苯妥英(phenytoin)；第三类，高溶解度—低渗透性药物，如阿昔洛韦(acyclovir)，西咪替丁(cimetidine)；第四类，低溶解度—低渗透性药物，如呋塞米(furosemide)、氯噻嗪(chlorothiazide)。
BCS界定高溶解度的标准是：在37℃，pH 1.0 ~ 7.5范围内，药物的最高使用剂量可以完全溶解于250 mL或更少的水溶性介质中，即为高溶解度；界定高渗透性的标准是：明确药物在胃肠道内保持稳定的情况下，有90%以上的药物可以被吸收，即为高渗透性。
人体生物等效性试验豁免指导原则
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。
仿制药一致性评价概况与药品质量研究-2019年华医网继续教育答案
2019年华医网继续教育答案-599-仿制药一致性评价
概况与药品质量研究
备注:红色选项或后方标记“[正确答案]”为正确选项
(一)仿制药一致性评价的研究背景
1、我国生物等效性评价Cmax90%可信限是（）
A、50%-150%
B、90%-110%
C、80-125%
D、75%-133%[正确答案]
E、60%-120%
2、生物等效性评价指标中，表示药物吸收快慢的参数是（）
A、清除率
B、表观分布容积
C、达峰浓度
D、达峰时间[正确答案]
E、血药浓度-时间曲线下面积
3、药学等效药品不要求（）
A、相同的剂型
B、相同的给药途径
C、相同的形状[正确答案]
D、相同的规格
E、相同的活性成分
4、关于仿制药的质量要求说法最确切的是（）
A、与原研药药学等效
B、与原研药生物等效
C、与原研药含量等效
D、与原研药药学等效且生物等效[正确答案]
E、与原研药药物经济学相当。
FDA：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
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。
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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（草案）Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a BiopharmaceuticsClassification System Guidance for Industry2015年5月一、介绍本指南为IND、NDA、ANDA、口服固体速释制剂的补充申请以及申请体内生物利用度或生物等效性研究的申请人提供建议。
这些生物等效豁免包括：（1）subsequent in vivo BA or BE studies of formulations after the initial establishment of the in vivo BA of IR dosage forms during the IND period；（2）in vivo BE studies of IR dosage forms in ANDAs.美国食品及药物管理局颁发的“联邦法规21章”（21CFR）第320部分描述了药品申请和补充申请对生物利用度和生物等效性数据的要求。
同时在21CFR 320.22部分有关于体内生物利用度或生物等效性豁免的有关条款。
本指南是在2000年8月份颁布的“Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classific ation System”基础上的更新，指南中说明的关于口服固体制剂生物等效的豁免是基于BCS分类系统的方法。
本指南关于还将生物等效豁免拓宽至BCS 3类的药物，还包括一些其他的修改，比如对高溶解性和高渗透性的定义。
二、BCS分类系统BCS是针对API的水溶性和肠道渗透性对药物进行分类的一个科学的框架性系统。
当涉及到制剂的溶出时，BCS系统需要考虑影响API从制剂中溶出的速率和药物的吸收程度的三个关键因素：1、溶出（dissolution）；2、溶解性（solubility）；3、胃肠道的渗透性（intestinal permeability）BCS分类：此外，有一些口服固体速释制剂被分类为有一个快速的或是非常快速的溶出度。
（In addition, some IR solid oral dosage forms are categorized as having rapid or very rapid dissolution.）在此框架下，当满足某些特定条件，BCS分类系统可以被用来作为药品申请人证明生物等效性豁免请求的工具。
如果观察到两个不同来源的同一口服固体制剂在体内的吸收速率和吸收程度（rate and extent of absorption）有差别，则可能是因为二者在体外溶出的区别（differences in drug dissolution in vivo）。
然而当口服固体速释制剂在体外溶出相对于胃排空时间快或是非常快并且药物的水溶性很高，那么药物的吸收速率和吸收程度就不可能依赖于药物的溶出时间或胃肠道通过时间。
（However, when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid in relation to gastric emptying and the drug has high solubility, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or gastrointestinal (GI) transit time）因此在这种情况下，对于BCS分类1类和3类的药物，只要处方中的非活性成份不显著影响API的吸收，那么证明体内生物利用度或生物等效可能就不是必须的。
（Under such circumstances, demonstration of in vivo BA or BE may not be necessary for drug products containing class 1 and class 3 drug substances, as long as the inactive ingredients used in the dosage form do not significantly affect absorption of the active ingredients.）本指南中关于BCS分类方法的概述可以被用来证明对于那些使用推荐的测定方法并在体外表现出快速或是非常快速的高溶解-高渗透性药物（比如BCS1类）和高溶解性-低渗透性的药物（比如BCS 3类）豁免生物等效是合理的（2000版只有BCS1类）。
推荐的测定溶解性、渗透性以及体外溶出的方法将在下面进行讨论。
（The BCS approach outlined in this guidance can be used to justify biowaivers for highly soluble and highly permeable drug substances (i.e., class 1) as well as highly soluble and low permeable drug substances (i.e., class 3) in IR solid oral dosage forms that exhibit rapid or very rapid in vitro dissolution using the recommended test methods. The recommended methods for determining solubility, permeability, and in vitro dissolution are discussed below）1、溶解性关于溶解性的分类是根据申请生物等效豁免制剂的最大规格进行界定。
当制剂的最大规格对应的API在250ml（或是更少）pH1~6.8的水溶性介质中自由溶解则可认为该API是高溶解性药物（2000版是pH1~7.5）。
250ml的体积估算值是参照针对空腹的志愿者处方口服药物需要的一杯水的体积的典型BE研究方案。
2、渗透性渗透性的分类是间接依据API在体内的吸收程度（剂量吸收分数，而不是全身的生物利用度）和直接测量药物的跨膜质量转移速率进行界定。
（The permeability class boundary is based indirectly on the extent of absorption (fraction of dose absorbed, not systemic BA) of a drug substance in humans, and directly on measurements of the rate of mass transfer across human intestinal membrane）另外，其他可以用来预测药物在体内吸收程度的方法也可以使用。
（比如使用原位动物，体外上皮细胞培养的方法等）。
当一个口服药物采用质量平衡测定的结果或是相较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。
（2000版的限度时90%）（A drug substance is considered to be highly permeablewhen the extent of absorption in humans is determined to be percent or more of an administered dose based on a mass balance determination (along with evidence showing stability of the drug in the GI tract) or in comparison to an intravenous reference dose.）3、溶出度口服速释制剂具有快速溶出（rapidly dissolving）的定义是：采用美国药典的方法，方法1—在100rpm（或是方法2在50rpm或75rpm的合理转速条件，见第三部分）、500ml （或是更少）的以下每个溶出介质中在30min内API的溶出均能达到标示量的85%以上。
（2000版是900ml的介质）介质包括：（1）0.1mol/L HCL或是USP中不含酶的模拟胃液；（2）pH4.5缓冲介质；（3）pH6.8缓冲介质或是USP中不含酶的的模拟肠液。
（！注意介质中不含有水！）（An IR drug product is considered rapidly dissolving when 85 percent or more of the labeled amount of the drug substance dissolves within 30 minutes, using United States Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm or at 75 rpm when appropriately justified (see section III.C.)) in a volume of 500 mL or less in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.）口服速释制剂具有极快速溶出（very rapidly dissolving）的定义是：在上述条件下15min 溶出在85%以上。