首页 > 资讯 > FDA发布指南草案关注仿制药产品物理等效

出自识林

2013-12-11 识林

分析点评 — 中文翻译

FDA日前通过联邦公报发布《仿制药片剂、胶囊大小、形状和其它物理属性的指南草案》，征询各界意见和建议。
这一指南草案涉及与仿制药产品与相应的橙皮书收录参照药品的物理等效性有关的因素。
这一备受期望的指南草案强调与相应的口服片剂和胶囊参照产品相关的仿制药的大小、形状、其它物理属性和生物等效性豁免。指南草案归纳如下。

大小
如果橙皮书收录的参照药品最大大小小于或等于17 mm,与参照药品相比，仿制药品在任一维度上不应大于20%（由此产生的大小不应超过17 mm），体积上超出参照药品不应大于40%。
如果橙皮书收录的参照药品最大尺寸大于17 mm，仿制药在任一维度和体积方面，不应大于参照药品。
片剂或胶囊的最大大小不应超过22 mm，胶囊最大不应超过00号胶囊（胶囊闭合时，长23.3 mm，直径8.53 mm）。
注意，在橙皮书收录的参照药品胶囊壳为3号或更低的情况下，上述建议允许仿制药胶囊壳大小增加1号，但在参照药品胶囊壳为2号或更大的情况下，如果没有其它理由，不应增加仿制药胶囊壳大小。

形状
总体上，与橙皮书收录的参照药品相比，仿制药应具有类似的形状或者经证明更易于吞咽的形状。通常认为横截面积较大的片剂更难以吞咽。
指南推荐使用“空间成像或计算机模型” 测量橙皮书手里参照药品体局和横截面积。
应在通用技术文件第3.2.P.1节中提供片剂和胶囊的大小和大致形状。

其它物理属性
该背景下的其它物理属性包括诸如片剂包衣、片重、表面积、崩解时间和溶胀势等因素。这些因素应包括在目标产品质量特征之中，并在通用技术文件第3.2.P.1节中予以说明。尽管并未声明将这些因素作为推荐，但这一部分内容可能是考虑到包衣对易于吞咽和防止过早溶胀和崩解的作用。

生物等效性豁免
指南的这一部分讨论了生物等效性豁免背景下的相似性比例，并提出相似性比例的其它方法可能对维持适当的片剂大小更适用。这一部分也涉及到刚被新版的“药代动力学终点生物等效性研究”指南草案取代的（目前在用）的旧版总体考虑指南。这份新的指南草案在相似性与生物等效性豁免部分略有差异。这是否属于一时兴起，或者真正意味着为总体考虑指南提供参考，还有待观察。

北京大学药物信息与工程研究中心 Garth Boehm 博士 2013-12-10
翻译：识林-Kapok 2013-12-10

分析点评 — 英文原文

FDA today issued a draft guidance on factors relating to physical equivalence of generic products to the corresponding RLD (see here).

This promised draft guidance addresses Size, Shape, Other Physical Attributes, and Biowaivers for generics relative to the corresponding Reference product (the RLD) for orally administered Tablets and Capsules. A summary of the guidance recommendations follows.

Size

Where the RLD is less than of equal to 17 mm in the largest dimension, the generic should be no more than 20% larger than the RLD in any dimension and no larger than 17 mm in any dimension, and no greater than 40% in volume compared to the RLD.

Where the RLD is greater than 17 mm in its largest dimension, the generic should be no larger than the RLD in any single dimension or in volume.

The largest dimension of a tablet should not exceed 22 mm and the largest capsule should not exceed a standard 00 (indicated to be 23.3 mm long and 8.53 mm in diameter when locked).

Note that the above recommendations allow an increase in capsule shell size of one when the RLD is size 3 or less, and no increase without additional justification when the RLD is size 2 or greater.

Shape

In general, generics should be a similar shape or a shape that has been found easier to swallow when compared to the RLD shape. Tablets with larger cross sectional area are generally considered harder to swallow.

In making measurements to determine RLD volume and cross sectional areas, the guidance recommends using "spatial imaging or .. computer models".

The size and presumably the shape of a tablet or capsule should be provided at section 3.2.P.1 of the Common Technical Document.

Other Physical Attributes

Other physical attributes in this context includes things like tablet coatings, weight, surface area, disintegration time and propensity for swelling. These should be included in the QTPP and described in section 3.2.P.2 of the CTD. Although not stated as a recommendation, the effect of coating on ease of swallowing and preventing premature swelling and disintegration would presumably be considerations in this section.

Biowaivers

This part discusses proportional similarity in the context of biowaivers and "suggests" that "other" methods of proportional similarity may be more amenable to maintaining appropriate tablet sizes. This part also refers to the (now) old General Considerations Guidance which has just been superseded (for ANDAs at least) by the new "Bioequivalence Studies with Pharmacokinetic Endpoints" draft guidance. This new draft guidance has a slightly different section on similarity and biowaivers. We will have to wait to see if this is a case of "ships passing in the night" or whether they really mean to reference the General Considerations guidance.

In summary, the message here is clear - copy the brand!

北京大学药物信息与工程研究中心 Garth Boehm 博士 2013-12-10