生物等效性豁免指南中英对照
GUIDANCE FOR INDUSTRY1
Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Relea Solid Oral Dosage Forms Bad on a
Biopharmaceutics Classification System
基于生物制剂分类系统的速释固体口服制剂
国务院机构改革和职能转变方案体内生物利用度和生物等效性研究
豁免指南
I. INTRODUCTION 引言 (3)
II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM 生物制剂分类系统 (3)
A. Solubility 溶解 (4)
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B. Permeability 渗透 (4)
C. Dissolution 分解 (5)
III. METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT 药物分类和制剂溶解特性测定方法 (5)
A. Determining Drug Substance Solubility Class 判定原料药的溶解度分类 (5)
B. Determining Drug Substance Permeability Class 判定原料药渗透性分类 (6)
1. Pharmacokinetic Studies in Humans 人体内药代动力学研究 (7)opus magnum
2. Intestinal Permeability Methods 肠道通透性检测方法 (7)
3. Instability in the Gastrointestinal Tract 胃肠道稳定性研究 (10)
dentistC. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity 测定药
物的溶解特性和溶解相似性 (11)
IV. ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER 生物豁免请求其他注意事项 (12)
A. Excipients 辅料 (12)
B. Prodrugs 药物前体 (13)
C. Exceptions 不适用情况 (13)
1. Narrow Therapeutic Range Drugs 治疗范围狭窄的药品 (13)上海美发学校
2. Products Designed to be Absorbed in the Oral Cavity 口腔吸收制剂 (13)
V. REGULATORY APPLICATIONS OF THE BCS BCS的申请 (13)
A. INDs/NDAs (13)
B. ANDAs (14)
C. Postapproval Changes 批准后变更 (14)
VI. DATA TO SUPPORT A REQUEST FOR BIOWAIVERS 生物豁免请求支持数据 (15)
A. Data Supporting High Solubility 支持高溶解度的数据 (15)
B. Data Supporting High Permeability 高渗透性支持数据 (15)periodical
C. Data Supporting Rapid and Similar Dissolution 快速及相似溶出支持数据 (16)
D. Additional Information 其他信息 (17)
ATTACHMENT A 附录A (18)
I. INTRODUCTION 引言
This guidance provides recommendations for sponsors of investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements to the applications who wish to request a waiver of in vivo
bioavailability (BA) and/or bioequivalence (BE) studies for immediate relea (IR) solid oral dosage forms. The waivers are intended to apply to (1) subquent 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, and (2) in vivo BE studies of IR dosage forms in ANDAs. Regulations at 21 CFR part 320 address the requirements for bioavailability (BA) and BE data for approval of drug applications and supplemental applications. Provision for waivers of in vivo BA/BE studies (biowaivers) under certain conditions is provided at 21 CFR 320.22. This guidance explains when biowaivers can be requested for IR solid oral dosage forms bad on an approach termed the Biopharmaceutics Classification System (BCS).
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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. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM 生物药剂分类系统
The BCS is a scientific framework for classifying drug substances bad on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: dissolution, solubility, and intestinal permeability.2 According to the BCS, 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: High Solubility – High Permeability 第一类：高溶解性高渗透性
Class 2: Low Solubility – High Permeability 第二类：低溶解性高渗透性
Class 3: High Solubility – Low Permeability 第三类：高溶解性低渗透性
Class 4: Low Solubility – Low Permeability 第四类：低溶解性低渗透性
In addition, IR solid oral dosage forms are categorized as having rapid or slow dissolution. Within this framework, when certain criteria are met, the BCS can be ud as a drug development tool to help sponsors justify requests for biowaivers.
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。
Obrved in vivo differences in the rate and extent of absorption of a drug from two pharmaceutically equivalent solid oral products may be due to differences in drug dissolution in vivo.2 However, when the in vivo dissolution of an IR solid oral dosage form is rapid in relation to gastric emptying and the drug has high permeability, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or gastroint
estinal transit time. Under such circumstances, demonstration of in vivo BA or BE may not be necessary for drug products containing Class 1 drug substances, as long as the inactive ingredients ud in the dosage form do not significantly affect absorption of the active ingredients. The BCS approach outlined in this guidance can be ud to justify biowaivers for highly soluble and highly permeable drug substances (i.e., Class 1) in IR solid oral dosage forms that exhibit rapid in vitro dissolution using the recommended test methods (21 CFR 320.22(e)). The recommended methods for determining solubility, permeability, and in vitro dissolution are discusd 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
数学公式大全况下，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
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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
madoff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
The solubility class boundary is bad on the highest do strength of an IR product that is the subject of a biowaiver request. A drug substance is considered highly soluble when the highest do strength is soluble in 250 ml or less of aqueous media over the pH range of 1-
7.5. The volume estimate of 250 ml is derived from typical BE study protocols that
prescribe administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water.
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。
