How to assess the quality of complex drug products and their copies: the case study of semisolid preparations

Nonbiological complex drugs (NBCDs) are medicinal products that exhibit intrinsic complexity in terms of their active substance, formulation, or route of delivery, and that cannot be fully characterized using conventional physicochemical analytical methods. An example of NBCDs is topically applied drug products (e.g., semisolid preparations for cutaneous application), where even slight changes in formulation components can significantly impact the quality target profiles of the drug product. Recognizing this complexity, both the FDA and the EMA have recently updated their guidelines for assessing the equivalence of topically applied drug products. According to the FDA, copies of these products must demonstrate both qualitative (Q1) and quantitative (Q2) equivalence to the reference product [1]. In addition, similar semisolid preparations must prove their structural and functional similarity (Q3). This involves comparing their in vitro release and rheological patterns. In 2018, the EMA introduced a draft guideline proposing the concept of “extended pharmaceutical equivalence” as an alternative to traditional bioequivalence studies [2]. This extended approach requires demonstrating the sameness of two formulation in terms of the pharmaceutical form, the qualitative and quantitative composition, the equivalence of the microstructure/physical properties, and in vitro release profile (IVRT). However, if dealing with complex formulations (e.g., creams), equivalence can be established through permeation kinetic studies [e.g., in vitro permeation studies (IVPT)], pharmacodynamic equivalence tests or clinical trials. This work contributes to the existing knowledge on how to assess the Q3 similarity of not Q1/Q2 equivalent semisolid preparations, in terms of in vitro release studies (IVRT), in vitro permeation (IVPT) and rheological behaviour [3]. In this light, Ibuprofen (IB) creams at two different strengths (i.e., 1% and 10%) were used as a model formulation. Starting from reference formulations two changes were made simulating: a minor variation (addition of the humectant), and a major variation (modification of the surfactant). The experimental results highlighted that these variations impacted only in 1% IB formulations where both the equivalences of rheological data and J-values failed. At the highest concentration, the presence of IB crystals broke down the differences in rheological patterns and lead the IB thermodynamic activity at the maximum figuring out an overlapping of the J-values. Such data suggest the combination of these studies, which are thought for the development of copies, could be also applied to the management of post-marketing variations that involve product composition.