Lin Zhongqiang, Zhou Deliang, Hoag Stephen, Qiu Yihong
Oral Drug Products, Manufacturing Science and Technology, AbbVie, Inc., Dept -045M, Bldg A4-2, 1401 Sheridan Road, North Chicago, Illinois, 60064-6235, USA.
School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
AAPS J. 2016 Mar;18(2):333-45. doi: 10.1208/s12248-015-9861-2. Epub 2016 Jan 14.
Bioequivalence (BE) studies are often required to ensure therapeutic equivalence for major product and manufacturing changes. Waiver of a BE study (biowaiver) is highly desired for such changes. Current regulatory guidelines allow for biowaiver of proportionally similar lower strengths of an extended release (ER) product provided it exhibits similar dissolution to the higher strength in multimedia. The objective of this study is to demonstrate that (1) proportionally similar strengths of ER tablets exhibiting similar in vitro dissolution profiles do not always assure BE and (2) different strengths that do not meet the criteria for dissolution profile similarity may still be bioequivalent. Four marketed ER tablets were used as model drug products. Higher and lower (half) strength tablets were prepared or obtained from commercial source. In vitro drug release was compared using multi-pH media (pH 1.2, 4.5, 6.8) per regulatory guidance. In vivo performance was assessed based on the available in vivo BE data or established in vitro-in vivo relationships. This study demonstrated that the relationship between in vitro dissolution and in vivo performance is complex and dependent on the characteristics of specific drug molecules, product design, and in vitro test conditions. As a result, proportionally similar strengths of ER dosage forms that meet biowaiver requirements per current regulatory guidelines cannot ensure bioequivalence in all cases. Thus, without an established relationship between in vitro and in vivo performance, granting biowaiver based on passing in vitro tests may result in the approval of certain bioinequivalent products, presenting risks to patients. To justify any biowaiver using in vitro test, it is essential to understand the effects of drug properties, formulation design, product characteristics, test method, and its in vivo relevance. Therefore, biowaiver requirements of different strengths of ER dosage forms specified in the current regulatory guidance should be reevaluated to assure consistent safety and efficacy among different strengths.
生物等效性（BE）研究通常是确保主要产品和生产变更具有治疗等效性所必需的。对于此类变更，人们非常希望能够豁免生物等效性研究（生物豁免）。现行监管指南允许对缓释（ER）产品按比例相似的较低规格进行生物豁免，前提是该规格在多种介质中的溶出度与较高规格相似。本研究的目的是证明：（1）体外溶出曲线相似的ER片剂按比例相似的规格并不总能保证生物等效性；（2）不符合溶出曲线相似性标准的不同规格仍可能具有生物等效性。使用四种市售的ER片剂作为模型药品。通过商业渠道制备或获取了较高规格和较低（一半）规格的片剂。按照监管指南，使用多pH介质（pH 1.2、4.5、6.8）比较体外药物释放情况。根据现有的体内生物等效性数据或已建立的体外-体内关系评估体内性能。本研究表明，体外溶出与体内性能之间的关系很复杂，并且取决于特定药物分子的特性、产品设计和体外测试条件。因此，按照现行监管指南符合生物豁免要求的ER剂型按比例相似的规格并不能在所有情况下确保生物等效性。因此，如果体外和体内性能之间没有建立关系，基于体外测试通过给予生物豁免可能会导致某些生物不等效产品获得批准，给患者带来风险。为了通过体外测试证明任何生物豁免的合理性，必须了解药物性质、制剂设计、产品特性、测试方法及其体内相关性的影响。因此，应重新评估现行监管指南中规定的不同规格ER剂型的生物豁免要求，以确保不同规格之间具有一致的安全性和有效性。
