Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck,Pharmaceutical Research

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Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2020-10-09 , DOI: 10.1007/s11095-020-02911-y
Margarida Miranda _{1,

2} , Tânia Cova ₂ , Cátia Augusto ₃ , Alberto A C C Pais ₂ , Catarina Cardoso ₃ , Carla Vitorino _{1,

2,

4}

Affiliation

Purpose

Following the recent European Medicine Agency (EMA) draft guideline on quality and equivalence of topical products, a modular framework for bioequivalence assessment is proposed, wherein the qualitative, quantitative, microstructure and product performance sameness is demanded to support generic applications. Strict regulatory limits are now imposed, but, the suitability of these limits has been subject of intense debate. In this context, this paper aims to address these issues by characterizing a panel of 8 reference blockbuster semisolid topical products.

Methods

For each product, three batches were selected and, whenever possible, batches retrieved from different manufacturing sites were considered. Product microstructure was evaluated in terms of globule size, pH, rheological attributes and, if required, the thermal behaviour was also assessed. Performance was evaluated through in vitro release testing (IVRT). Finally, an integrated multivariate analysis was performed to highlight the features that most contribute for product variability.

Results

Marked differences were registered within reference products. Statistical analysis demonstrated that if EMA criteria are applied, none of the same product batches can be considered as equivalent. Rheological parameters as well as IVRT indicators account for the majority of batch-to-batch differences.

Conclusions

Semisolid dosage forms exhibit intrinsic variability. This calls for the attention to the need of establishing reasonable equivalence criteria applied to generic drug products.

中文翻译：

细分局部产品的批次间差异-监管瓶颈

目的

遵循最新的欧洲医学局（EMA）关于局部用产品质量和等效性的准则草案，提出了用于生物等效性评估的模块化框架，其中需要定性，定量，微观结构和产品性能的相同性以支持通用应用。现在施加了严格的监管限制，但是这些限制的适用性一直是激烈辩论的主题。在此背景下，本文旨在通过对8种参考重磅炸弹半固体外用产品进行专题讨论来解决这些问题。