透皮制剂生物等效性豁免策略的研究

Research on the Strategy for Waiving Bioequivalence of Transdermal Preparations

摘要: 透皮给药系统作为药物与医用材料的复合载体，凭借其非侵入性和控释特征，在制剂研发与仿制药注册中占据重要地位。由于皮肤屏障复杂、体内吸收差异显著，传统的人体生物等效性(BE)试验成本高且变异性大。为此，监管机构提出了基于药学一致性(Q1/Q2/Q3)与体外评价替代的“BE豁免”策略。文章系统总结了NMPA、FDA与EMA在透皮及局部制剂豁免路径上的最新监管要求及差异，重点分析了Q1/Q2/Q3一致性评估的科学方法、IVRT与IVPT技术的评价标准，以及PBPK模型在虚拟生物等效性(VBE)预测中的应用进展。研究指出，Q3微结构表征(如CRM、MDRS、流变学、SAXS、AFM等)已成为桥接体外与体内性能的关键技术，而基于机制驱动的PBPK建模则为复杂透皮仿制药提供了新的豁免思路。综合来看，透皮制剂BE豁免的发展正从实验验证向计算机模拟和系统表征相结合的科学评估体系转型，为提高仿制药研发效率与监管科学化提供了重要支撑。

Abstract: Transdermal drug delivery systems (TDDS), serving as composite carriers of drugs and medical materials, hold an important position in pharmaceutical development and generic drug registration by virtue of their non-invasive nature and controlled-release characteristics. Owing to the complexity of the skin barrier and significant variability in systemic absorption, conventional human bioequivalence (BE) studies are costly and exhibit high variability. To address this, regulatory agencies have established “BE waiver” strategies based on pharmaceutical equivalence (Q1/Q2/Q3 sameness) and advanced in vitro evaluation methods. This article systematically summarizes the latest regulatory requirements and differences among NMPA, FDA, and EMA regarding waiver pathways for transdermal and topical formulations, with emphasis on the scientific methodologies for Q1/Q2/Q3 sameness assessment, evaluation criteria for in vitro release testing (IVRT) and in vitro permeation testing (IVPT), and the advances in applying physiologically based pharmacokinetic (PBPK) models to predict virtual bioequivalence (VBE). The study indicates that Q3 microstructural characterization techniques—such as confocal Raman microscopy (CRM), MDRS, rheology, small-angle X-ray scattering (SAXS), and atomic force microscopy (AFM)—have emerged as critical technologies bridging in vitro performance with in vivo outcomes, while mechanism-driven PBPK modeling provides novel waiver strategies for complex transdermal generics. Collectively, the advancement of BE waivers for transdermal formulations is transitioning from experimental validation toward a scientific assessment framework integrating computational simulation with systematic characterization, thereby offering substantial support for enhancing the efficiency of generic drug development and advancing regulatory science.