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

word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与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 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与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：1subsequent 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；2in vivo BE studies of IR dosage forms in ANDAs.美国食品与药物管理局颁发的“联邦法规21章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 Classification System根底上的更新，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展分类的一个科学的框架性系统。当涉与到制剂的溶出时，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 permeabilityBCS分类：BCS分类SolubilityPermeabilityClass1HighHighClass 2LowHighClass 3HighLowClass4LowLow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。如果观察到两个药剂学等效的固体制剂体内的吸收速率和吸收程度rate and extent of absorption有差异，可能是因为二者在体内溶出的区别differences in drug dissolution in vivo。然而当口服固体速释制剂在体内的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、渗透性以与体外溶出的方法将在下面进展讨论。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 remended test methods. The remended methods for determining solubility, permeability, and in vitro dissolution are discussed below1、 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展界定。当制剂的最大规格对应的API在250ml或是更少2000版是pH17.5。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展界定。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如此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 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 parison to an intravenous reference dose.3、 溶出度口服速释制剂具有快速溶度度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，见第三局部、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：10.1mol/L HCL或是USP中不含酶的模拟胃液；2pH4.5缓冲介质；3pH6.8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.口服速释制剂具有非常快速溶度度very rapidly dissolving的定义是：在上述条件下15min溶出在85%以上。2000版没有该定义三、 推荐的原料药分类方法和测定制剂溶出特性的方法REMENDED METHODOLOGY FOR CLASSIFYING A DRUGSUBSTANCE AND FOR DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT以下是依据BCS分类系统推荐的API的分类和口服速释制剂溶出度特性的测定方法。1、确定API的溶解性分类BCS方法的目的之一是测定API在生理pH条件下的平衡溶解度。原料药pH-溶解性曲线的测定应该在371，pH16.8的水溶性介质中测定。pH-溶解度曲线上的pH。A sufficient number of pH conditions should be evaluated to accurately define the pH-solubility profile within the pH range of 1-6.8.溶解度测定的pH点的选择可以参照药物的解离常数，包括pH = pKa, pH = pKa +1, pH = pKa-1,以与pH1.0和pH6.8的点。推荐的方法是每个pH点的溶解度至少重复测定三次！由于研究的变异性，为了保证溶出度数据的可靠性可能还需要更屡次的重复测定。USP中规定的标准缓冲溶液用来测定溶解度被认为是恰当的。如果上述规定的缓冲介质对药物的理化性质有影响，其他的缓冲介质也可以使用。当原料药参加到介质中，介质的pH需要进展验证。除了传统的摇瓶法，酸碱滴定法也可以被用来说明预测药物平衡溶解度的方法是合理的。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的浓度下，应该使用经验证的含量测定方法以区分API和其降解产物。如果API的降解产物影响缓冲介质的组成，如pH，需要报告。If degradation of the drug substance is observed as a function of buffer position 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、确定药物的渗透性分类API的渗透性分类可以通过受试者体内试验确定，比如质量平衡Mass Balance Studies或是全身的体内生物利用度Absolute Bioavailability Studies，这通常被认为是比拟好的方法，也可以通过肠灌注的方法。推荐的不涉与人体受试者的方法包括在动物模型上的体内或原位肠灌注或是使用切下肠组织的体外渗透的方法。在很多情况下单一的方法可能是足够的，如果单一方法无法确认渗透性分类，建议使用两种方法。如果采用不同的方法获得了互相矛盾的信息，更应该关注人体数据。（1） 人体的药代动力学研究：包括Mass Balance Studies和Absolute Bioavailability Studies，详细略。（2） 胃肠道渗透性方法：略。（3） 胃肠道不稳定Instability in the Gastrointestinal Tract：略3、测定制剂的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的片剂，也可以使用USP中规定的模拟胃液或是模拟肠液。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的要求。在药品开发过程中溶出装置的选择USP 1法和2法应该依据产品体外溶出和体内药代动力学数据的比照。USP Apparatus I篮法通常适用于胶囊剂和易于漂浮的产品，USP Apparatus II桨法通常适用于片剂。对于某些片剂，在体外不是在体内的溶出可能因为片剂崩解后沉在溶出杯底部而造成溶出很慢。在这种情况下USP的1法可能要优于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响产品在体内的快速溶出而需要调整比如使用不同的搅拌转速，这样的调整需要使用体外溶出和体内吸收数据进展比照，证明其合理性。比如使用单一水溶液作为对照品的相对生物利用度研究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 paring in vitro dissolution with in vivo absorption data (e.g., a relative BA study using a simple aqueous solution as the reference product).生物等效豁免试验需要至少12个单剂量产品进展支持评估。溶出曲线测定过程需要取足够多的时间点进展溶出曲线的绘制。比如：5min、10min、15min、20min和30min当进展供试品和参比制剂的溶出曲线比照时应使用相似因子的方法f2。当f2 value is 50可判断两条溶出曲线相似。为了确保可以使用平均数据，在初始取样点如10min溶出数据的变异系数不能超过20%，其他取样点的变异系数不能超过10%。需要注意的是当供试品和参比制剂在推荐的三种溶出介质中15min内的溶出均达到标示量的85%以上，就不需要进展f2因子比照。4、 基于BCS的生物等效豁免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类的药物需要证明以下几点：（1） the drug substance is highly soluble （2） the drug substance is highly permeable（3） the drug product (test and reference) israpidly 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类药物需要证明以下几点：（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 similare.g., falls within scale-up and post-approval changes (SUPAC-SUPAC-IR指导原如此：速释口服固体制剂：放大生产和批准后变更) IR level 1 and 2 changes, inposition to the reference (see section V.A.) 5、 生物等效豁免申请的其他考虑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 thedocumentation of their request。（1） 辅料BCS1类药物：辅料有时候可能会影响药物的吸收速率和吸收程度。一般来说使用FDA已经批准的速释制剂中使用的辅料，对于BCS1类速释制剂的药物吸收速率和吸收程度不会有影响。为了支持生物等效豁免的申请，速释制剂中辅料的用量应该和辅料在处方中对应的功能保持一致比如说润滑剂。但是处方中使用新的辅料或是辅料的用量超过常规的用量X围，申请人必须提供文件证明该行为对生物利用度没有影响。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可能是个问题，比如说外表活性剂吐温80和甜味剂如甘露醇和山梨醇，当遇到这种情况鼓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类药物必须与参比制剂含有一样的辅料组成。这主要是考虑辅料可能对低渗透性药物的吸收影响更显著。因此，供试样品与参比制剂必须有一样的辅料组成，辅料用料也应该与参比制剂相似。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 position of the test product must be qualitatively the same and should be quantitatively very similar to the reference product.（2） 前药Prodrugs前体药物的渗透性通常取决于前提药物转化为活性成分的机制和转化部位。当前药转化为活性成分prodrug-to-drug主要是发生在胃肠道膜转运之后，那么应该测定前药的渗透性。When the prodrug-to-drug conversion is shown to occur predominantly after intestinal membrane permeation, the permeability of the prodrug should be measured.相反的，如果转化发生在药物的跨膜转运之前，如此应该测定活性成分的渗透性。溶出度和pH-溶解性数据对于前药和活性成分可以是相关联的。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咨询相应的审评人员。（3） 复方药物Fixed Dose binations如果所有活性成分均为BCS1类：BCS-based biowaivers are applicable for IR fixed dose bination products if all the drugs in the bination belong to BCS class 1; provided there is no PK interaction between the ponents, 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如果所有的活性成分均属于BCS3类或是一个是BCS1类另外一个是3类：BCS-based biowaivers are applicable for IR fixed dose bination products in this situation provided the excipients fulfill the considerations outlined in section V.A. (ii). Otherwise, in vivo bioequivalence testing is required6、 其他情况BCS-based biowaivers are not applicable for the following：（1） 窄治疗窗的药物：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） 口腔吸收的药物：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 out7、 BCS监管的应用A. INDs/NDAsB. ANDAsC. Supplemental NDAs/ANDAs (Postapproval Changes)8、 支持生物等效豁免需要提供的数据（1） 高溶解性的数据支持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: 测定方法的描述，包括分析方法和缓冲溶液的组成 化学结构式、分子量、药物属性酸性、碱性、两性、中性和解离常数pKas 测试结果平均值、标准偏差、变异系数以表格的形式汇总，不同pH溶液、药物溶解度如mg/ml以与溶解最大规格需要的介质体积 pH-溶解度的曲线图（2） 高渗透性的数据支持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: 测定方法的描述，包括分析方法和缓冲溶液的组成 人体药物代谢动力学研究PK，包括设计方案和PK数据对应的方法 对于直接渗透性的测定： （3） 对于快速溶出、非常快速溶出和相似溶出的数据要求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: 测定方法的描述，包括分析方法和缓冲溶液的组成 详细描述溶出测定使用样品的信息，包括批号、有效期、规格、重量、直径 溶出数据必须是使用12个单位计量的样品测定的结果，且必须按照上述推荐的测试方法。每个单位计量在不同取样点的溶出数据均需要提供。对于平均溶出度、溶出X围上下限以与变异系数应该汇总成表格。三种介质中供试品和对照品的溶出曲线均需要提供 还需要提供供试品和参比制剂在三种介质中溶出曲线具有相似性的数据（4） 其它信息自制样品的制备工艺也需要详细描述如湿法制粒or直接压片包括辅料的列表、用量、功能；辅料的种类必须是FDA已批准的口服速释固体制剂中使用过的辅料。对于BCS3类药物还需要提供自制样品和参比制剂辅料用量的比照。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 identifiedGroup 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 13 / 13