The Implications of Regulatory Framework for Topical Semisolid Drug Products: From Critical Quality and Performance Attributes towards Establishing Bioequivalence

Abstract

Due to complex interdependent relationships affecting their microstructure, topical semisolid drug formulations face unique obstacles to the development of generics compared to other drug products. Traditionally, establishing bioequivalence is based on comparative clinical trials, which are expensive and often associated with high degrees of variability and low sensitivity in detecting formulation differences. To address this issue, leading regulatory agencies have aimed to advance guidelines relevant to topical generics, ultimately accepting different non-clinical, in vitro/in vivo surrogate methods for topical bioequivalence assessment. Unfortunately, according to both industry and academia stakeholders, these efforts are far from flawless, and often upsurge the potential for result variability and a number of other failure modes. This paper offers a comprehensive review of the literature focused on amending regulatory positions concerning the demonstration of (i) extended pharmaceutical equivalence and (ii) equivalence with respect to the efficacy of topical semisolids. The proposed corrective measures are disclosed and critically discussed, as they span from mere demands to widen the acceptance range (e.g., from ±10% to ±20%/±25% for rheology and in vitro release parameters highly prone to batch-to-batch variability) or reassess the optimal number of samples required to reach the desired statistical power, but also rely on specific data modeling or novel statistical approaches.

Does the Freeze–Thaw Technique Affect the Properties of the Alginate/Chitosan Glutamate Gels with Posaconazole as a Model Antifungal Drug?

“…Cohesiveness determines the effect of repeated shearing stress on the structural properties of the analyzed gels. The high value of cohesiveness enables full structural recovery during gel application [ 31 , 32 , 33 ]. Finally, adhesiveness, which is closely related to bioadhesion, represents the work required to remove the sample, which is connected with the breaking of cohesive bonds.…”

Novel Hydrogels for Topical Applications: An Updated Comprehensive Review Based on Source

“…A challenge in SSDFs is the need to deliver the API across the skin or other physical membranes of the patient to reach the desired system [ 6 ]. Since ancient times, there have been several kinds of topical semi-solid dosage forms widely used in human society for treating various skin diseases [ 7 ]. The semi-solid dosage forms used topically usually come in creams, gels, ointments, or pastes [ 8 ].…”

“…In TDDS, skin is one of the primary and accessible organs [ 9 ]. Most topical semi-solid formulations are designed to target the skin or underlying tissues [ 7 ]. Among the three layers (stratum corneum (SC), epidermis, and dermis) of skin, the SC is primarily responsible for protecting the tissues underneath the skin.…”

Advanced harmonization techniques result in accurate establishment of in vitro–in vivo correlations for oxybenzone from four complex dermal formulations with reapplication

“…The application of IVIVC to dermal products is currently being investigated and shows promising results for transdermal delivery systems under both baseline and elevated skin temperature conditions with in vitro permeation testing (IVPT) proving to be predictive of in vivo pharmacokinetic (PK) pro les [2][3][4][5][6][7][8][9][10][11][12]. Unfortunately, their use for predicting drug absorption from semisolid and liquid dermal formulations has proven challenging [13][14][15][16].…”