Assessment of “Sameness” and/or Differences between Marketed Creams Containing Miconazole Nitrate Using a Discriminatory in vitro Release Testing (IVRT) Method

Abstract

In vitro release testing (IVRT) provides an efficient method for the evaluation of drug release from semi-solid formulations. The aim of this research was to develop and validate a discriminatory IVRT system using vertical diffusion cells (VDCs) to assess generic topical products containing miconazole nitrate (MCZ). A comprehensive approach addressing all essential suitability criteria supporting the reliability of IVRT results was applied. These include mechanical validation of the VDCs, a performance verification test (PVT), validation of the analytical method (HPLC) used to quantify the drug release and validation of the IVRT method to confirm its precision, reproducibility, discriminatory ability, and robustness. Two marketed generic products were tested and assessed in accordance with the acceptance criteria for “sameness” in the FDA’s SUPAC-SS guidance which requires that the 90% confidence interval (CI) should fall within the limits of 75%–133.33%. One product was found to be in vitro equivalent to the reference product whereas the other was not. The results confirmed the suitability of the IVRT method to accurately measure the release of MCZ from topical cream products and, importantly, demonstrated the necessary discriminatory ability to assess “sameness”/differences of dermatological creams containing MCZ. Furthermore, the developed IVRT method was able to detect differences between formulations, which may be attributed to qualitative (Q1) and quantitative (Q2) properties and the microstructure and arrangement of matter (Q3).

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

“…The basic concepts for validation of the IVRT method are presented in Table 2 . Since 2018, an increasing number of studies deals with validation of IVRT method for different semisolid drug products (e.g., acyclovir cream [ 35 ], diclofenac emulgel [ 36 ], miconazole nitrate cream [ 45 ], hydrocortisone acetate cream [ 46 ], metronidazole cream [ 47 ]). The first comprehensive report in scientific literature on the successful qualification/validation of IVRT was published by Tiffner and coworkers in 2018 [ 35 ].…”

“…Table 2. IVRT method validation and acceptance criteria according to FDA Draft Guidance on Acyclovir [44], EMA Draft guideline on quality and equivalence of topical products [14] and recent literature reports [35,36,[45][46][47].…”

“…The dose depletion ≤30% has no influence on the steady-state conditions for drug release [35,36,[45][46][47] Finally, for the demonstration of extended pharmaceutical equivalence, EMA set the following requirement: "the 90% confidence interval for the ratio of means of the test and comparator products for the parameters (R), (A) should be contained within the acceptance interval of 90-111%" [14]. However, it is important to emphasize that FDA sameness criterion is not too strict, i.e., 90% CIs of in vitro release rate should be within 75-133.33% [38,44].…”