【干货】药品研发中可考虑豁免BE实验相关情况的总结

参考指导原则（GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCECPMP/EWP/QWP/1401/98 (生物等效性试验指导原则)），对于可以申请豁免BE的一些制剂做如下总结：

1. 口服固体制剂多规格注册申请中部分规格可豁免

BE If several strengths of a testproduct are applied for, it may be sufficient to establish bioequivalence atonly one or two strengths, depending on the proportionality in compositionbetween the different strengths and other product related issues describedbelow. The strength(s) to evaluate depends on the linearity in pharmacokineticsof the active substance.

如果同时申报该产品的多个规格，开展一个或两个规格的BE试验应该可以满足所有注册要求，主要取决于不同规格之间处方组成的比例关系和该药物的给药剂量和生物利用度是否存在正相关。

In the context of this guideline,pharmacokinetics is considered to be linear if the difference in dose-adjustedmean AUCs is no more than 25% when comparing the studied strength (or strengthin the planned bioequivalence study) and the strength(s) for which a waiver isconsidered. In order to assess linearity, the applicant should consider alldata available in the public domain with regard to the dose proportionality andreview the data critically. Assessment of linearity will consider whetherdifferences in dose-adjusted AUC meet a criterion of ± 25%.In

在本指导原则中，药代被认为符合正相关的条件为：临床规格（通常为最大规格）的单位剂量AUC值减去豁免规格的单位剂量AUC值后，除以最大规格的单位剂量AUC值应小于0.25。因此需要去检索历史文献，证明该药物的剂量与AUC值呈正相关。

   Thefollowing general requirements must be met where a waiver for additionalstrength(s) is claimed:

a)the pharmaceutical products are manufactured by the same manufacturing process,

b)the qualitative composition of the different strengths is the same,

c)the composition of the strengths are quantitatively proportional, i.e. theratio between the amount of each excipient to the amount of active substance(s)is the same for all strengths (for immediate release products coatingcomponents, capsule shell, colour agents and flavours are not required tofollow this rule),

 If there is some deviation from quantitativelyproportional composition, condition c is still considered fulfilled ifcondition i) and ii) or i) and iii) below apply to the strength used inthe bioequivalence study and the strength(s) for which a waiver is considered

i.the amount of the active substance(s) is less than 5 % of the tablet coreweight, the weight of the capsule content

ii.the amounts of the different core excipients or capsule content are the samefor the concerned strengths and only the amount of active substance is changed

iii.the amount of a filler is changed to account for the change in amount of activesubstance. The amounts of other core excipients or capsule content should bethe same for the concerned strengths

多个规格只需开展一个大剂量规格的条件，其他规格可以考虑豁免：

a）生产工艺一致；

b）处方组成一致；

c）处方中的物料比例完全一致（不包含包衣材料的比例与胶囊壳）；

如处方比例不完全一致，但处方中的活性成分小于片芯的5%或胶囊内容物的5%，处方中其他辅料一致。

如处方比例不完全一致，但处方中的活性成分小于片芯的5%或胶囊内容物的5%，填充剂用量的改变主要是因为活性成分用量的变化而引起，其他关键辅料的总量或胶囊内容物在不同规格间相同。

2. 口服速释制剂（普通片与胶囊）

Applying for a BCS-based biowaiver isrestricted to highly soluble drug substances with known human absorption andconsidered not to have a narrow therapeutic index (see section 4.1.9).

（根据BCS分类豁免BE只限于高溶解高渗透药物，其中不包括治疗指数窄的药物）。

BCS-based biowaiver are applicable foran immediate release drug product if

1)the drug substance has been proven toexhibit high solubility and complete absorption (BCSclassI; for details seesection III) and

2) either very rapid (> 85 % within15 min) or similarly rapid (85 % within 30 min ) in vitro dissolutioncharacteristics of the test and reference product has been demonstratedconsidering specific requirements (see section IV.1) and

3) excipients that might affectbioavailability are qualitatively and quantitatively the same. In general, theuse of the same excipients in similar amounts is preferred (see section IV.2).

基于BCS豁免BE的速释制剂，需满足一下几个条件：

1）该药物被证实属于高溶解和高渗透(BCSI 类，详细见section III；

2）15分钟溶出度大于85%或30分钟溶出度大于85%且与参比制剂释放曲线一致（参考段落IV.1）。

3）可能影响生物利用度的辅料需与参比制剂基本一致，通常而言尽量保持与参比制剂一致的处方组成。

3. 口服溶液剂

If the test product is an aqueous oralsolution at time of administration and contains an active substance in the sameconcentration as an approved oral solution, bioequivalence studies may bewaived.

如果药物在服用时为溶液状态且与参比制剂具有相同浓度的药效成份，可考虑豁免BE；

However if the excipients may affectgastrointestinal transit (e.g. sorbitol, mannitol, etc.), absorption (e.g.surfactants or excipients that may affect transport proteins), in vivosolubility (e.g. co-solvents) or in vivo stability of the active substance, abioequivalence study should be conducted, unless the differences in the amountsof these excipients can be adequately justified by reference to other data. Thesame requirements for similarity in excipients apply for oral solutions as forBiowaivers (see Appendix III, Section IV.2 Excipients).

但是如果存在影响肠道转运（如大豆油，甘露醇），吸收（如表明活性剂和影响转运蛋白的辅料）和影响药物体内溶解性和稳定性的辅料存在，则需开展BE，除非能证明该辅料的用量与参比制剂相似。

4.口服分散片

如可以证明该药物在口腔不吸收且该药物符合BCS分类豁免的要求，可考虑豁免BE；口崩片，口腔膜剂，咀嚼片等均属于此类；

5. 局部用药

A waiver of the need to provideequivalence data may be acceptable in the case of solutions, e.g. eye drops,nasal sprays or cutaneous solutions, if the test product is of the same type ofsolution (aqueous or oily), and contains the same concentration of the sameactive substance as the medicinal product currently approved. Minor differencesin the excipient composition may be acceptable if the relevant pharmaceuticalproperties of the test product and reference product are identical oressentially similar. Any qualitative or quantitative differences in excipientsmust be satisfactorily justified in relation to their influence on therapeuticequivalence.

局部用溶液剂可考虑豁免BE，例如滴眼液，鼻喷雾剂或皮肤用溶液剂，但需满足如下条件：与参比制剂的溶液类型相同（均为水溶液或油溶液），浓度相同，辅料组成基本相同。细微的辅料组成不同在不影响药物特性的情况下也可以接受。

6.注射给药

Bioequivalencestudies are generally not required if the test product is to be administered asan aqueous intravenous solution containing the same active substance as thecurrently approved product. However, if any excipients interact with the drugsubstance (e.g. complex formation), or otherwise affect the disposition of thedrug substance, a bioequivalence study is required unless both products containthe same excipients in very similar quantity and it can be adequately justifiedthat any difference in quantity does not affect the pharmacokinetics of theactive substance.

如果注射制剂与目前上市制剂活性成分相同，可通常可以豁免BE。但是如果辅料与药物存在相互作用或影响药物的disposition，则需开展BE研究，除非能证明该辅料的用量一致。

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