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应用及生物等效性豁免.doc

口服速释制剂依照BCS分类系统生物运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 Biopharmaceutics Classification System Guidance for Industry
5月

一、 简介
本指南为IND、NDA、ANDA、口服固体速释制剂补充申请以及申请体内生物运用度或生物等效性研究申请人提供建议。
这些生物等效豁免涉及：（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“联邦法规21章”（21CFR）第320某些描述了药物申请和补充申请对生物运用度和生物等效性数据规定。同步在21CFR 320.22某些关于于体内生物运用度或生物等效性豁免关于条款。本指南是在8月份颁布“Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System”基本上更新，指南中阐明关于口服固体制剂生物等效豁免是基于BCS分类系统办法。
本指南关于还将生物等效豁免拓宽至BCS 3类药物，还涉及某些其她修改，例如对高溶解性和高渗入性定义。

二、 BCS分类系统
BCS是针对API水溶性和肠道渗入性对药物进行分类一种科学框架性系统。
当涉及到制剂溶出时，BCS系统需要考虑影响API从制剂中溶出速率和药物吸取限度三个核心因素：1、溶出（dissolution）；2、溶解性（solubility）；3、胃肠道渗入性（intestinal permeability）
BCS分类：
BCS分类
Solubility
Permeability
Class1
High
High
Class 2
Low
High
Class 3
High
Low
Class4
Low
Low

此外，有某些口服固体速释制剂被分类为有一种迅速或是非常迅速溶出度。（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物申请人证明生物等效性豁免祈求工具。
如果观测到两个药剂学等效固体制剂体内吸取速率和吸取限度（rate and extent of absorption）有差别，也许是由于两者在体内溶出区别（differences in drug dissolution in vivo）。然而当口服固体速释制剂在体内溶出相对于胃排空时间快或是非常快并且药物水溶性很高，那么药物吸取速率和吸取限度就不也许依赖于药物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）因而在这种状况下，对于BCS分类1类和3类药物，只要处方中非活性成分不明显影响API吸取，那么证明体内生物运用度或生物等效也许就不是必要。（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分类办法概述可以被用来证明对于那些使用推荐测定办法并在体外体现出迅速或是非常迅速高溶解-高渗入性药物（例如BCS1类）和高溶解性-低渗入性药物（例如BCS 3类）豁免生物等效是合理（只有BCS1类）。推荐测定溶解性、渗入性以及体外溶出办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
关于溶解性分类是依照申请生物等效豁免制剂最大规格进行界定。当制剂最大规格相应API在250ml（或是更少）pH1~6.8水溶性介质中自由溶解则可以为该API是高溶解性药物（是pH1~7.5）。250ml体积估算值是参照针对空腹志愿者处方口服药物需要一杯水体积典型BE研究方案。
2、 渗入性
渗入性分类是间接根据API在体内吸取限度（剂量吸取分数，而不是全身生物运用度）和直接测量药物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）此外其她可以用来预测药物在体内吸取限度办法也可以使用。（例如使用原位动物，体外上皮细胞培养办法等）。当一种口服药物采用质量平衡测定成果或是相较于静脉注射参照剂量，显示在体内吸取限度≥85%以上（并且有证据证明药物在胃肠道稳定性良好）则可阐明该药物具备高渗入性。（限度时90%）（A drug substance is considered to be highly permeable when 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
口服速释制剂具备迅速溶度度（rapidly dissolving）定义是：采用美国药典办法，办法1—在100rpm（或是办法2在50rpm或75rpm合理转速条件，见第三某些）、500ml（或是更少）如下每个溶出介质中在30min内API溶出均能达到标示量85%以上。（是900ml介质）介质涉及：（1）0.1mol/L HCL或是USP中不含酶模仿胃液；（2）pH4.5缓冲介质；（3）pH6.8缓冲介质或是USP中不含酶模仿肠液。（！注意介质中不具有水！）（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.）
口服速释制剂具备非常迅速溶度度（very rapidly dissolving）定义是：在上述条件下15min溶出在85%以上。（没有该定义）

三、 推荐原料药分类办法和测定制剂溶出特性办法（RECOMMENDED METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT）
如下是根据BCS分类系统推荐API分类和口服速释制剂溶出度特性测定办法。
1、拟定API溶解性分类
BCS办法目之一是测定API在生理pH条件下平衡溶解度。原料药pH-溶解性曲线测定应当在37℃±1℃，pH1~6.8水溶性介质中测定。pH-溶解度曲线上pH选取应当有充分点，并且是在pH1~6.8范畴内。（A sufficient number of pH conditions should be evaluated to accurately define the pH-solubility profile within the pH range of 1-6.8.）溶解度测定pH点选取可以参照药物解离常数，涉及pH = pKa，pH = pKa +1，pH = pKa-1,以及pH1.0和pH6.8点。推荐办法是每个pH点溶解度至少重复测定三次！由于研究变异性，为了保证溶出度数据可靠性也许还需要更多次重复测定。USP中规定原则缓冲溶液用来测定溶解度被以为是恰当。如果上述规定缓冲介质对药物理化性质有影响，其她缓冲介质也可以使用。当原料药加入到介质中，介质pH需要进行验证。除了老式摇瓶法，酸碱滴定法也可以被用来阐明预测药物平衡溶解度办法是合理。（Methods other than the traditional shake-flask method，such as acid or base 128 titration methods，can also be used with justification to support the ability of such methods to predict 129 equilibrium solubility of the test drug substance）在选定介质中API浓度下，应当使用经验证含量测定办法以区别API和其降解产物。如果API降解产物影响缓冲介质构成，如pH，需要报告。If degradation of the drug substance is observed as a function of buffer composition and/or pH，it should be reported. The solubility class should be determined by calculating the volume of an aqueous medium sufficient to dissolve the highest strength in the pH range of 1-6.8. A drug substance should be classified as highly soluble when the highest strength is soluble in < 250 mL of aqueous media over the pH range of 1-6.8. In other words，the maximum dose divided by 250 should be greater than or equal to the lowest solubility observed over the entire pH range of 1-6.8.
2、拟定药物渗入性分类
API渗入性分类可以通过受试者体内实验拟定，例如质量平衡（Mass Balance Studies）或是全身体内生物运用度（Absolute Bioavailability Studies），这普通被以为是比较好办法，也可以通过肠灌注办法。推荐不涉及人体受试者办法涉及在动物模型上体内或原位肠灌注或是使用切下肠组织体外渗入办法。
在诸多状况下单一办法也许是足够，如果单一办法无法确认渗入性分类，建议使用两种办法。如果采用不同办法获得了互相矛盾信息，更应当关注人体数据。
（1） 人体药代动力学研究：涉及Mass Balance Studies和Absolute Bioavailability Studies，详细略。
（2） 胃肠道渗入性办法：略。
（3） 胃肠道不稳定（Instability in the Gastrointestinal Tract）：略

3、测定制剂溶出特性和溶出曲线相似性
Dissolution testing should be carried out in USP Apparatus I at 100 rpm or Apparatus II at 50 rpm (or at 75 rpm when appropriately justified) using 500 mL of the following dissolution 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. 对于胶囊剂或是有明胶包衣片剂，也可以使用USP中规定模仿胃液或是模仿肠液。For capsules and tablets with gelatin coating，Simulated Gastric and Intestinal Fluids USP (with enzymes) can be used.
溶出测定装置需要满足USP规定。在药物开发过程中溶出装置选取（USP 1法和2法）应当根据产品体外溶出和体内药代动力学数据对比。USP Apparatus I （篮法）普通合用于胶囊剂和易于漂浮产品，USP Apparatus II（桨法）普通合用于片剂。对于某些片剂，在体外（不是在体内）溶出也许由于片剂崩解后沉在溶出杯底部而导致溶出很慢。在这种状况下USP1法也许要优于2法。For some tablet dosage forms，in vitro (but not in vivo) dissolution may be slow due to the manner in which the disintegrated product settles at the bottom of a dissolution vessel. In such situations，USP Apparatus I may be preferred over Apparatus II.如果溶出测定条件为了更好地反映产品在体内迅速溶出而需要调节（例如使用不同搅拌转速），这样调节需要使用体外溶出和体内吸取数据进行对比，证明其合理性。（例如使用单一水溶液作为对照品相对生物运用度研究）If the testing conditions need to be modified to better reflect rapid in vivo dissolution (e.g.，use of a different rotating speed)，such modifications can be justified by comparing in vitro dissolution with in vivo absorption data (e.g.，a relative BA study using a simple aqueous solution as the reference product).
生物等效豁免实验需要至少12个单剂量产品进行支持评估。溶出曲线测定过程需要取足够多时间点进行溶出曲线绘制。（例如：5min、10min、15min、20min和30min）
当进行供试品和参比制剂溶出曲线对比时应使用相似因子办法（f2）。

当f2 value is ≥50可判断两条溶出曲线相似。为了保证可以使用平均数据，在初始取样点（如10min）溶出数据变异系数不能超过20%，其她取样点变异系数不能超过10%。需要注意是当供试品和参比制剂在推荐三种溶出介质中15min内溶出均达到标示量85%以上，就不需要进行f2因子对比。

4、 基于BCS生物等效豁免
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.
对于BCS 1类药物需要证明如下几点：
（1） the drug substance is highly soluble
（2） the drug substance is highly permeable
（3） the drug product (test and reference) is rapidly dissolving，and the product does not contain any excipients that will affect the rate or extent of absorption of the drug (see section V.A.)
对于BCS 3类药物需要证明如下几点：
（1） the drug substance is highly soluble
（2） the drug product (test and reference) is very rapidly dissolving；
（3） and the test product formulation is qualitatively the same and quantitatively very similar e.g.，falls within scale-up and post-approval changes (SUPAC- SUPAC-IR指引原则：速释口服固体制剂：放大生产和批准后变更) IR level 1 and 2 changes，in composition to the reference (see section V.A.)

5、 生物等效豁免申请其她考虑
When requesting a BCS-based biowaiver for in vivo BA/BE studies for IR solid oral dosage forms，sponsors/applicants should note that the following factors can affect their request or the documentation of their request。
（1） 辅料
BCS1类药物：辅料有时候也许会影响药物吸取速率和吸取限度。普通来说使用FDA已经批准速释制剂中使用辅料，对于BCS1类速释制剂药物吸取速率和吸取限度不会有影响。为了支持生物等效豁免申请，速释制剂中辅料用量应当和辅料在处方中相应功能保持一致（例如说润滑剂）。但是处方中使用新辅料或是辅料用量超过常规用量范畴，申请人必要提供文献证明该行为对生物运用度没有影响。Such information can be provided with a relative BA study using a simple aqueous solution as the reference product.某些辅料如果用量很大也许是个问题，例如说表面活性剂（吐温80）和甜味剂（如甘露醇和山梨醇），当遇到这种状况勉励申请人与监管部门沟通。
BCS3类药物：BCS3类药物和BCS1类药物不同，如果想要申请生物等效豁免，BCS3类药物必要与参比制剂具有相似辅料构成。这重要是考虑辅料也许对低渗入性药物吸取影响更明显。因而，供试样品与参比制剂必要有相似辅料构成，辅料用料也应当与参比制剂相似。（Unlike for BCS class 1 products，for a biowaiver to be scientifically justified，BCS class 3 test drug product must contain the same excipients as the reference product. This is due to the concern that excipients can have a greater impact on absorption of low permeability drugs. The composition of the test product must be qualitatively the same and should be quantitatively very similar to the reference product.）
（2） 前药（Prodrugs）
前体药物渗入性普通取决于前提药物转化为活性成分机制和转化部位。当前药转化为活性成分（prodrug-to-drug）重要是发生在胃肠道膜转运之后，那么应当测定前药渗入性。（When the prodrug-to-drug conversion is shown to occur predominantly after intestinal membrane permeation，the permeability of the prodrug should be measured.）相反，如果转化发生在药物跨膜转运之前，则应当测定活性成分渗入性。溶出度和pH-溶解性数据对于前药和活性成分可以是有关联。（Dissolution and pH-solubility data on both prodrug and drug can be relevant）。申请者如果申请该类药物可以征询相应审评人员。
（3） 复方药物（Fixed Dose Combinations）
如果所有活性成分均为BCS1类：BCS-based biowaivers are applicable for IR fixed dose combination products if all the drugs in the combination belong to BCS class 1；provided there is no PK interaction between the components， and the excipients fulfill the considerations outlined in section 5.（1）. (i). If there is a PK interaction，the excipients should fulfill the considerations outlined in section 5.（1）. (ii). Otherwise，in vivo bioequivalence testing is required
如果所有活性成分均属于BCS3类或是一种是BCS1类此外一种是3类：BCS-based biowaivers are applicable for IR fixed dose combination products in this situation provided the excipients fulfill the considerations outlined in section V.A. (ii). Otherwise，in vivo bioequivalence testing is required

6、 其她状况
BCS-based biowaivers are not applicable for the following：
（1） 窄治疗窗药物：
This guidance defines narrow therapeutic range drug products as those containing certain drug substances that are subject to therapeutic drug concentration or pharmacodynamic (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 or PD monitoring are narrow therapeutic range drugs，sponsors should contact the appropriate review division to determine whether a drug should be considered to have a narrow therapeutic range.
（2） 口腔吸取药物：
A request for a waiver of in vivo BA/BE studies based on the BCS is not appropriate for dosage forms intended for absorption in the oral cavity (e.g.，sublingual（舌下） or buccal（颊）tablets). Similarly，a biowaiver for an orally disintegrating tablet can be considered，based on BCS，only if the absorption from the oral cavity is ruled out

7、 BCS监管应用
A. INDs/NDAs
B. ANDAs
C. Supplemental NDAs/ANDAs (Postapproval Changes)

8、 支持生物等效豁免需要提供数据
（1） 高溶解性数据支持
Data supporting high solubility of the test drug substance should be developed (see section III.A). The following information should be included in the application:
Ø 测定办法描述，涉及分析办法和缓冲溶液构成
Ø 化学构造式、分子量、药物属性（酸性、碱性、两性、中性）和解离常数（pKa（s））
Ø 测试成果（平均值、原则偏差、变异系数）以表格形式汇总，不同pH溶液、药物溶解度（如mg/ml）以及溶解最大规格需要介质体积
Ø pH-溶解度曲线图

（2） 高渗入性数据支持
Data supporting high permeability of the test drug substance should be developed (see section III.B). The following information should be included in the application:
Ø 测定办法描述，涉及分析办法和缓冲溶液构成
Ø 人体药物代谢动力学研究（PK），涉及设计方案和PK数据相应办法
Ø 对于直接渗入性测定：
Ø …………

（3） 对于迅速溶出、非常迅速溶出和相似溶出数据规定
For submission of a biowaiver request，an IR product should be rapidly dissolving (BCS class 1) or very rapidly dissolving (BCS class 3). Data supporting rapid dissolution attributes of the test and reference products should be developed (see section III.C). The following information should be included in the application:
Ø 测定办法描述，涉及分析办法和缓冲溶液构成
Ø 详细描述溶出测定使用样品信息，涉及批号、有效期、规格、重量、直径
Ø 溶出数据必要是使用12个单位计量样品测定成果，且必要按照上述推荐测试办法。每个单位计量在不同取样点溶出数据均需要提供。对于平均溶出度、溶出范畴（上下限）以及变异系数应当汇总成表格。三种介质中供试品和对照品溶出曲线均需要提供
Ø 还需要提供供试品和参比制剂在三种介质中溶出曲线具备相似性数据

（4） 其他信息
自制样品制备工艺也需要详细描述（如湿法制粒or直接压片）
涉及辅料列表、用量、功能；辅料种类必要是FDA已批准口服速释固体制剂中使用过辅料。对于BCS3类药物还需要提供自制样品和参比制剂辅料用量对比。

附件：This attachment includes model drugs suggested for use in establishing suitability of a permeability method as described in section III. Zero permeability markers and efflux substrates are also identified
Group
Drug
High Permeability
(fa ≥ 85 percent)
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
Inulin
Lactulose
Efflux Substrates
Digoxin
Paclitaxel
Quinidine
Vinblastine