Abstract
Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µg/0.5 mg/g) in order to define the acceptance range that allows concluding equivalence between these batches. Being batches of the same reference product, they are expected to be clinically equivalent and possess similar microstructure. The 90% confidence intervals for the test/reference ratio of these physical parameters were calculated with parametric and non-parametric approaches. Both methods conclude that equivalent microstructure between batches cannot be demonstrated with a reasonable sample size when the acceptance range was set at ±10%, since several physical parameters exhibit inter-batch variability >10%. An acceptance range of ±10% is therefore too strict to conclude equivalence in the microstructure of semisolid dosage forms, given the inter-batch variability observed between batches of the reference product. A wider fixed acceptance range or an acceptance range widened based on the inter-batch variability of the reference product would be advisable.
Highlights
IntroductionThe arrangement of the matter in the structure of a semisolid product, known as microstructure [1], is determined by the components employed in its formulation (e.g., polymorphism, size and shape of the dispersed particles of the active substance, grade and rheology of the excipients, interfacial tension between phases, partition coefficient of the active substance between the different phases) and the manufacturing process
The arrangement of the matter in the structure of a semisolid product, known as microstructure [1], is determined by the components employed in its formulation and the manufacturing process
The objective of the present work is to assess if the inter-batch variability of the rheological parameters in the reference product Daivobet allows concluding equivalence within a ±10% acceptance range, as defined in the European Medicines Agency (EMA) draft guideline on the quality and equivalence of topical products
Summary
The arrangement of the matter in the structure of a semisolid product, known as microstructure [1], is determined by the components employed in its formulation (e.g., polymorphism, size and shape of the dispersed particles of the active substance, grade and rheology of the excipients, interfacial tension between phases, partition coefficient of the active substance between the different phases) and the manufacturing process This microstructure and the excipient composition do affect the organoleptic properties of the product, and the drug permeation through the skin [1,2,3]. The characterization of topical semisolids includes the investigation of their physical properties, which are defined by their microstructure, influence bioavailability and usability of the product and are indicative of stability and consistency of the manufacturing process This draft guideline assumes that if the physical properties of two products with similar qualitative and quantitative composition are sufficiently similar, the microstructure of the formulation can be considered similar. This comparison should be conducted in at least three batches of the reference product and three batches of the test product with at least 12 replicates per batch
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