Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck
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RESEARCH PAPER
Diving into Batch-to-Batch Variability of Topical Products-a Regulatory Bottleneck Margarida Miranda 1,2 & Tânia Cova 2 & Cátia Augusto 3 & Alberto A. C. C. Pais 2 & Catarina Cardoso 3 & Carla Vitorino 1,2,4
Received: 22 January 2020 / Accepted: 17 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT 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.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02911-y) contains supplementary material, which is available to authorized users. * Carla Vitorino [email protected] 1
Faculty of Pharmacy, University of Coimbra, Portugal, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
2
Coimbra Chemistry Center, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal
3
Laboratórios Basi, Mortágua, Parque Industrial Manuel Lourenço Ferreira, Portugal, lote 15 3450-232, Mortágua, Portugal
4
Centre for Neurosciences and Cell Biology (CNC), Faculty of Medicine, University of Coimbra, Rua Larga, Pólo I, 1st floor, 3004-504 Coimbra, Portugal
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.
KEYWORDS batch variability . EMA . IVRT . Rheology . topical products
ABBREVIATIONS ACV API BCS BFZ C CES CI CLB CLT CQA CV DF EMA ETF G´ G´´ HC HCA HPLC
Acyclovir Active pharmaceutical ingredient Biopharmaceutical classification system Bifonazole Compliant Clinical endpoint studies Confidence intervals Clobetasol Clotrimazole Critical quality attributes Coefficient of variation Diclo
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