FDA发布新修订速释制剂BE豁免指南草案
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FDA发布新修订速释制剂BE豁免指南草案
笔记 2015-05-09 识林 生物药剂分类系统(BCS)系统豁免指南的修订自去年以来一直列在FDA的日程表上。新的指南草案《Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System》于5月5日发布。如长久以来承诺的那样，该草案涉及自2000年对BCS I类化合物豁免生物利用度/生物等效性（BA/BE）研究以外的BCS III类化合物的豁免。 基于药物BCS分类和剂型的生物利用度/生物等效性研究的豁免是多年来一直讨论的话题。BCS系统根据2个药物属性—体内溶解性和体内渗透性—将药物和药品进行分类。BCS系统4个分类如下： 处方人员很难改变药物的渗透性。渗透率是药物穿过肠黏膜被吸收的速率。一些辅料可能会影响渗透率，大多数是减缓渗透。现在我们可以影响药物的溶出速率。我们可以配制延迟释放的剂型、缓释剂型或者可以研制API复合物来增加溶出速率。然而，如果配制速释剂型，那么不会控制溶出速率，而是设计在胃中迅速崩解的剂型，以便释放药物，然后根据API的溶解性溶解。 考虑到这类情况，如果药物具有高溶解性，将迅速并完全溶解，进入体内的吸收速率将仅依赖于药物的渗透性。或者换一种说法 - “一旦药物溶解，接下来该发生什么就是什么了”。所以，从这个角度来看，如果一种药物具有高溶解性，并且剂型对溶解度没有影响，那么这些药品的效果将是一样的，即，具有相同的血药浓度曲线。这意味着如果参照药品和测试药品相比较的话，它们将具有相同的生物利用度或生物等效性。 该指南草案中“高溶解性”定义为在pH1到pH6.8范围，最高剂量速释剂型的活性成分可完全溶解在250mL水溶液中。建议使用pH1（空腹胃的最低pH），pH4.5（通过胃刚进入小肠顶端的pH），和pH6.8（小肠末端的pH）。250mL来源于单剂量生物等效性研究中与药品共服的“8盎司一杯的水”（8盎司约为240mL）。速释剂型的溶出必须满足在pH1、4.5和6.8，USP第一法装置100转/分钟或USP第二法装置50或75转/分钟的条件下，在500mL介质中30分钟取样的溶出限度Q值不少于85%。如果这些条件都满足，那么根据渗透性，产品为BCS I类或BCS III类。 该指南草案提供了4种检测渗透性的方法，最常用的方法是在体外使用上皮细胞的一个单层。如果85%的药物穿过肠壁（或模型系统）被吸收，那么被归类为高渗透性，低于85%为低渗透性。 给出的“细则”中还有很多条件需要了解，因此需要认真阅读整个指南。不过，假设你的BCS I类或BCS III类产品不是其中的众多例外情况之一，那么可以遵循BCS豁免途径。为什么这样做？因为这样更便宜（不要求禁食和进食生物等效性研究），一旦建立豁免，将来你可以变更，假设仍满足溶解性和溶出度要求，那么无需做本来可能要求的生物研究。 必须满足的条件如下：
BCS III类
对于BCS III类的处方相似性要求是为了确保是否有任何来自于辅料对渗透性的“干扰”。这在我看来是非常不可能的 ，但俗话说，FDA不会为任何碰运气买单！ 最重要的是，请记住这只是一份指南草案。如果你在考虑尝试一个BCS III类豁免，请先咨询FDA。不要在没有事先咨询FDA的情况下，冒险用BCS III类的药做任何事情（事先意味着在你开始研究之前，而不是在递交之前！） 请记住这句格言 – “如果一份指南草案意味着你可以少做工作，等它定稿后（或先询问）再做，如果一份指南草案要求你做更多的工作，那就立刻去做”。 北京大学药物信息与工程研究中心 - Garth Boehm博士 2015-05-08 English Version Revision of the BCS waivers Guidance has been on FDAs agenda since last year. A new draft guidance issued May 5th. As long promised, this draft addresses waivers for BCS Class 3 compounds in addition to BCS Class 1 compounds that have been eligible for BA/BE study waiver since 2000. Waivers of the need to perform Bioavailability/Bioequivalence studies based on a drug's BCS Classification and the dosage form has been a topic of discussion for many years. The BCS system classifies drugs and drug products according to 2 drug properties, in vivo solubility and in vivo permeability. There are 4 classes in the BCS system as follows. There is little that formulators can do to change a drug’s permeability. Permeability is the rate at which the drug is absorbed across the intestinal mucosa. Some excipients can affect the rate of permeability but mostly to slow it down. Now as formulators we can affect the rate of drug dissolution. We can formulate delayed-release dosage forms, extended-release dosage forms or we might make API complexes to increase the rate of dissolution. However, if we formulate immediate-release dosage forms, then we do not control the rate of dissolution, we design a dosage form that disintegrates quickly in the stomach so releasing the drug which then dissolves according to the API solubility properties. In considering this situation, if a drug has high solubility it will quickly and completely dissolve and the rate of absorption into the body will depend only on the drug’s permeability. Or to put it another way – “once the drug is dissolved, whatever happens next just happens”. So from this perspective, if a drug has a high solubility and the dosage form does nothing to affect solubility, then these drug products will all behave the same, that is they will all give the same blood level profiles. This means that they will all have the same bioavailability or bioequivalence if Reference and Test are being compared. The draft guidance defines “high solubility” as meaning the API of the highest strength immediate-release dosage form dissolves completely in 250 mL of aqueous solution with pHs between 1 and 6.8. It suggests using pH 1 (the lowest pH of a fasting stomach), pH 4.5 (the pH immediately after passing from the stomach into the top of the small intestine), and pH 6.8 (the pH at the distal end of the small intestine). The 250 mL comes from the “8 ounce glass of water” taken with the dose in single dose bioequivalence studies (8 oz is about 240 mL). The immediate-release dosage form dissolution must meet a Q of 85% in 30 minutes in 500 mL of medium with a pH of 1, 4.5, and 6.8 for Apparatus I at 100 rpm or Apparatus 2 at 50 rpm of 75 rpm. If these conditions are met, then you have a BCS 1 or BCS 3 product depending on permeability. The draft guidance provides 4 ways of measuring permeability, the most usual way being in vitro using a monolayer of epithelial cells. If the drug is 85% absorbed across the gut wall (or model system) it is classified as highly permeable, less than 85% is low permeability. There are many conditions given in the “fine print” which you have to be aware of. So you need to read the whole guidance thoroughly. However, assuming your BCS 1 or BCS 3 product is not one of the many exception situations, then you can follow the BCS waiver path. Why do this? Well it is cheaper (no fasting and fed studies required) and once you have established a waiver you can make changes in the future which might have required biostudies without having to do them, assuming you still meet the solubility and dissolution requirements. The conditions that must be met are as follows.
BCS 3
The formulation similarity requirement for BCS 3 is to ensure that if there is any “interference” in permeability from the excipients. This seems to me to be highly unlikely but as the saying goes, FDA is not paid to take a chance – on anything! MOST IMPORTANTLY, remember this is a draft guidance. If you are thinking of trying a BCS 3 waiver, consult FDA first. DO NOT RISK doing anything with a BCS 3 drug without consulting FDA FIRST (first means before you start, not before you file!!). Remember the adage – “if a draft guidance means you can do less work, wait until it is final (or ask first), if a draft guidance requires you to do more work, then do it immediately”. |