编号 | CFDA指南 | FDA指南 | 点评 |
1 | 一、药物BCS分类$ ~/ B) Z2 s# [: k4 Y. p# ^ BCS是按照药物的水溶性和肠道渗透性将药品分类的一个科学的框架系统。当涉及到常释制剂中活性药物成分(Active Pharmaceutical Ingredient，以下简称API）的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：溶解性(solubility)、胃肠道的渗透性(intestinal permeability)和溶出度(dissolution)。 | II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM' S T+ I4 j/ ^% Y2 x! k4 {$ ^4 r4 \' U The BCS is a scientific framework for classifying drug substances based 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: (1) dissolution, (2) solubility, and (3) intestinal permeability. | solubility此处翻译成溶解度更合适，毕竟溶解性在药典中另有其义。 |
2 | （一）溶解性) v* C1 a/ \: w' V1 b" L 溶解性分类是根据申请生物等效豁免制剂的最高剂量进行界定。当制剂最大规格对应的API在体积为250ml(或是更少)、pH值在1.0—6.8范围内的水溶性介质中自由溶解，则可认为该API是高溶解性的药物。250ml体积估算值是参照《化学药物制剂人体生物利用度和生物等效性研究技术指导原则》中，志愿者空腹时服药所规定用一杯水的体积。 | A. Solubility8 D, R/ }+ J' ?4 |! ` The solubility class boundary is based on the highest strength of an IR product that is the subject of a biowaiver request. A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media over the pH range of 1-6.8. 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. | |
3 | （二）渗透性2 P# U; a% N; g" _) v4 g 渗透性分类与API在人体内的吸收程度相关(指单一剂量吸收的部分，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。 | B. Permeability 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. Alternatively, other systems capable of predicting the extent of drug absorption in humans can be used (e.g., in situ animal, in vitro epithelial cell culture methods). A drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 85 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. | |
4 | （三）溶出度) O7 r5 H7 f9 d4 I7 D: l" V 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（转篮法），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。/ \ w/ V* a3 x! |3 K9 ? 口服固体常释制剂具有非常快速溶出的定义是：在上述条件下15分钟内API的溶出均能达到标示量的85%以上。 | C. Dissolution 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.+ W0 U& y& A- q2 `4 Z An IR product is considered very rapidly dissolving when 85 percent or more of the labeled amount of the drug substance dissolves within 15 minutes using the above mentioned conditions. | 中国的标准好像不包含85%。 |
5 | 根据BCS分类系统，药品被分为以下四类：+ Z$ V1 H% }* F$ e. T! _ 第一类：高溶解性、高渗透性(High Solubility- High Permeability)0 `2 s& R: u& s; }# O, Q 第二类：低溶解性、高渗透性(Low Solubility-High Permeability) 第三类：高溶解性、低渗透性(High Solubility-Low Permeability); u% s/ A' E$ ]+ h3 Q6 |# ] 第四类：低溶解性、低渗透性(Low Solubility-Low Permeability) 当口服固体常释制剂在体内的溶出相对于胃排空时间快或非常快，并且具有很高的水溶性和肠道渗透性时，药物的吸收速率和吸收程度就不会依赖于药物的溶出时间或在胃肠道的通过时间。因此，在这种情况下，对于BCS分类1类和3类的药物，只要处方中的其他辅料成分不显著影响API的吸收，则不必证明该药物在体内生物等效的可能性，即生物等效性豁免。 | According to the BCS, drug substances are classified as follows: Class 1: High Solubility – High Permeability Class 2: Low Solubility – High Permeability: p0 ]- k# n5 |4 V) u" X Class 3: High Solubility – Low Permeability! P" T4 Q% v; F1 [5 z% Y: M Class 4: Low Solubility – Low Permeability) q3 R; } O, ]# n, u In addition, some IR solid oral dosage forms are categorized as having rapid or very rapid dissolution. Within this framework, when certain criteria are met, the BCS can be used as a drug development tool to help sponsors/applicants justify requests for biowaivers. Observed 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. 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. 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. 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. | |
6 | 二、基于BCS的生物等效豁免 （一）对于BCS 1类的药物需要证明以下几点： 1.药物具有高溶解性； 2.药物具有高渗透性；1 o0 d; R' y; w. p! \+ ] 3.快速溶出和相似性的数据以及不含有影响主药成分吸收速率和吸收程度的辅料。 | IV. BIOWAIVERS BASED ON BCS3 u) E2 ]9 a8 p; g# c% G0 ^ 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. For BCS class 1 drug products, the following should be demonstrated:+ i9 S6 `" u; l2 d( k ·the drug substance is highly soluble0 L! i3 r- U, @& b6 F% D: r ·the drug substance is highly permeable; @, D6 \3 ?1 `' E5 v9 s3 I ·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.) | |
7 | （二）对于BCS 3类的药物需要证明以下几点： 1.药物具有高溶解性；0 n! f# t/ [0 G& |1 S2 o 2.制剂具有非常快速的溶出； 3.放大生产和批准后变更的制剂处方完全相同。 | For BCS class 3 drug products, the following should be demonstrated:& u+ K4 S5 w, E ·the drug substance is highly soluble0 P7 | J$ B5 ~! M+ X# C ·the drug product (test and reference) is very rapidly dissolving (see section II.C.), and ·the test product formulation is qualitatively the same and quantitatively very similar, e.g., falls within scale-up and post-approval changes (SUPAC) IR level 1 and 2 changes, in composition to the reference (see section V.A.) | 不知道是翻译的问题还是什么情况，造成第三条看不明白。其实FDA的要求很简单，与原研处方一致，或相似度符合速释制剂SUPAC中一、二类变更的比例之内即可。) c' p9 P+ W5 [4 g 中国也有《已上市化学药品变更技术指导原则》，要求与SUPAC基本上是一致的。 |
8 | （三）对于处方相同，但规格不同的同种样品，高剂量规格已做过BE试验的，低剂量规格可以免做BE试验。 | 这个好像不应该放在本指南中。 | |
9 | （四）生物等效豁免申请的其他影响因素 当一个口服固体常释制剂申请基于BCS分类的生物等效性豁免时，应注意以下因素可能影响生物等效豁免： 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。一般来说使用国家食品药品监督管理总局已经批准的常释制剂常用辅料，对于BCS1类快速溶出的常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，常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）。% H2 z$ o) f7 J) l9 W" u 当使用新的辅料，或者非常规的大量使用常释制剂常用辅料，要补充提交该辅料的使用没有影响制剂生物利用度的证明资料。该信息可以利用以单一水溶液做参比制剂的生物利用度研究来提供。大量使用特定的辅料，例如表面活性剂（例如聚山梨醇酯80）和甜味剂（例如甘露醇或山梨醇），可能会有问题。) y) W3 P5 a/ h* u4 _# ? BCS3类药物：该类药物和BCS1类药物不同，如果想要申请生物等效豁免，必须有更充分的科学依据。BCS3类药物制剂必须与参比制剂含有相同的辅料组成。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，仿制制剂与参比制剂必须有相同的辅料组成和用量。 | V. ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER2 [2 v& d/ k2 @8 s; J$ ]# q" Z, P' A 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.- U5 V6 c- N* r; x2 x4 ~ A. Excipients; Z/ x& @4 P5 P: ?' m. D" ^ (i) BCS class 1 drug products: Excipients can sometimes affect the rate and extent of drug absorption. In general, using excipients that are currently in FDA-approved IR solid oral dosage forms will not affect the rate or extent of absorption of a highly soluble and highly permeable drug substance that is formulated in a rapidly dissolving IR product. To support a biowaiver request, the quantity of excipients in the IR drug product should be consistent with the intended function (e.g., lubricant). When new excipients or atypically large amounts of commonly used excipients are included in an IR solid dosage form, additional information documenting the absence of an impact on BA of the drug may be requested by the Agency. Such information can be provided with a relative BA study using a simple aqueous solution as the reference product. Large quantities of certain excipients, such as surfactants (e.g., polysorbate 80) and sweeteners (e.g., mannitol or sorbitol) may be problematic, and sponsors are encouraged to contact the review division when this is a factor. (ii) BCS class 3 drug products: 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. | BCS3类的难点在于拆方，做分析的有前途了。% p% ?" V ^* _1 O+ I5 c. }# ]( ^ 有一点应该明确，包衣处方应该是可以不同的。 |
10 | 2.前药（Prodrugs） 制剂的渗透性取决于原料药的转化机制和（解剖学上的）转化位置。若药物前体-药物的转化主要表现在肠道膜渗透之后，则应测定该药物前体的渗透性。若转化表现在肠道膜渗透之前，则应测定该药物的渗透性。药物前体和药物的溶出、pH溶解度数据也应与之相关。 | B. Prodrugs Permeability of prodrugs will generally depend on the mechanism and (anatomical) site of conversion to the drug substance. When the prodrug-to-drug conversion is shown to occur predominantly after intestinal membrane permeation, the permeability of the prodrug should be measured. When this conversion occurs prior to intestinal permeation, the permeability of the drug should be determined. Dissolution and pH-solubility data on both prodrug and drug can be relevant. Sponsors may wish to consult with appropriate review staff before applying the BCS approach to IR products containing prodrugs. | 溶出介质中的解离速度也可以看出转化位置。 |
11 | C. Fixed Dose Combinations a. If all active components belong to BCS class 1: 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 V.A. (i). If there is a PK interaction, the excipients should fulfill the considerations outlined in section V.A. (ii). Otherwise, in vivo bioequivalence testing is required. b. If all components of the combination belong to BCS class 3 or a combination of class 1 and 3: 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. | 中国没有复方制剂吗？ | |
12 | 3.基于BCS 的生物豁免对下列情况不适用： （1）治疗范围狭窄的药品+ P, g' x4 D5 D6 r7 t' W 受治疗药物浓度或药效监控的制约，按狭窄的治疗范围设计的制剂，不适用生物等效性豁免。如:地高辛、锂制剂、苯妥英、茶碱和华法林阻凝剂。0 w, Q5 S! r5 X0 H) y7 R: Z （2）口腔吸收制剂 由于BCS分类是基于胃肠粘膜的渗透和吸收，因此不适用于口腔吸收制剂，如：类似舌下片或颊下片的制剂。对于口含片，如果该制剂从口腔吸收也不适用。 | D. Exceptions9 q' o1 [: ^ m% r4 G! n0 e BCS-based biowaivers are not applicable for the following:! j0 r. k9 q- L" j8 P 1. Narrow Therapeutic Range Drugs 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. Products Designed to be Absorbed in the Oral Cavity 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 or buccal 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. a- P, E4 d' _ This guidance uses the term narrow therapeutic range instead of narrow therapeutic index , although the latter is more commonly used. | |
13 | 三、生物等效豁免应提供的资料2 ^3 x# b! g; H. H8 j% m# b （一）高溶解性的数据支持3 g4 M7 P" O9 u' W* T5 l 1.测定方法的描述，包括分析方法和缓冲溶液的组成信息。8 b' ^, n& ~" V, p9 s3 g4 I 2.原料药的化学结构，分子量，性质（酸、碱、两性或中性）和解离常数（pKa) 3.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）以及溶解最大规格需要的介质体积。 4.pH-溶解度的曲线图 | VII. DATA TO SUPPORT A BIOWAIVER REQUEST! `, w+ T! W3 r The drug product for which a biowaiver is being requested should include a drug substance that is highly soluble (BCS class 1 and BCS class 3) and highly permeable (BCS class 1), and the drug product should be rapidly dissolving (BCS class 1) or very rapidly dissolving (BCS class 3). Sponsors/applicants requesting biowaivers based on the BCS should submit the following information to the Agency for review.6 Q% p# P# L# {" z: s A. Data Supporting High Solubility 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: • A description of test methods, including information on analytical method(s) and composition of the buffer solutions. • Information on chemical structure, molecular weight, nature of the drug substance (acid, base, amphoteric, or neutral), and dissociation constants (pKa(s)). • Test results (mean, standard deviation, and coefficient of variation) summarized in a table under solution pH, drug solubility (e.g., mg/mL), and volume of media required to dissolve the highest strength.1 A- W2 R3 X6 Y* B W • A graphic representation of mean pH-solubility profile. |
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