Current Challenges in Bioequivalence, Quality, and Novel Assessment Technologies for Topical Products

Abstract

This paper summarises the proceedings of a recent workshop which brought together pharmaceutical scientists and dermatologists from academia, industry and regulatory agencies to discuss current regulatory issues and industry practices for establishing therapeutic bioequivalence (BE) of dermatologic topical products. The methods currently available for assessment of BE were reviewed as well as alternatives and the advantages and disadvantages of each method were considered. Guidance on quality and performance of topical products was reviewed and a framework to categorise existing and alternative methods for evaluation of BE was discussed. The outcome of the workshop emphasized both a need for greater attention to quality, possibly, via a Quality-By-Design (QBD) approach and a need to develop a "whole toolkit" approach towards the problem of determination of rate and extent in the assessment of topical bioavailability. The discussion on the BE and clinical equivalence of topical products revealed considerable concerns about the variability present in the current methodologies utilized by the industry and regulatory agencies. It was proposed that academicians, researchers, the pharmaceutical industry and regulators work together to evaluate and validate alternative methods that are based on both the underlying science and are adapted to the drug product itself instead of single "universal" method.

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“…Excess product is then removed by gently washing and the degree of skin blanching or whitening of the skin is then assessed over a number of designated intervals of time. The visual assessment is based upon the utilization of an arbitrary intensity scale of 0 -4 where 0 indicates no blanching and numerical increase of numbers 1 -4 are assigned to increasing degrees of blanching observed, respectively [17]. Chromameter assessment-An instrumental method involving a tristimulus colorimeter was subsequently introduced as an objective and thus preferred method.…”

In Vitro Release Testing of Semi-Solid Dosage Forms

“…Also, IVPT typically uses skin as the membrane since it is a test designed to mimic biological conditions with a finite dose exposed to the atmosphere and a biologically relevant receptor medium, whereas IVRT typically uses synthetic membranes to detect differences in batch-batch and lot-lot comparisons (64). Various synthetic membranes have been used such as cellulose acetate/nitrate/mixed ester, polysulfone, polytetrafluoroethylene, nylon, polycarbonate, Fluoropore, and Supor (18) which separate the donor compartment containing the formulation to be tested and the receptor compartment containing the appropriate receptor medium (15,38,49,50).…”

“…The membranes may be pretreated by soaking in the receptor medium or isopropyl myristate prior to IVRT (44,65). However, synthetic membranes used for quality control tests should necessarily act as an inert support rather than a barrier and provide the least resistance to drug diffusion (36,37,50). The selection of an appropriate membrane is crucial in the design of an appropriate IVRT, and the membrane must be compatible with the formulation and not interfere with recovery of the API (11,53).…”

“…The selected receptor should permit a sufficient amount of release of API within a reasonable period (44) and sink conditions should be maintained (36). Yacobi et al (50) evaluated various parameters (viz. receptor media, membranes, and stirring speed) that could affect the in vitro release of drugs from topical dermatological products and found that the receptor medium was the most important and critical parameter that influences the drug release from the formulations.…”

“…Unlike oral drug products, there has been an absence of regulatory guidelines regarding appropriate validation procedures for the IVRT of locally acting topical products, although recently, a new FDA guideline on acyclovir cream using IVRT (48) provides some information relating to IVRT validation. Various reports have shown that alterations in IVRT method parameters can influence the results and clearly indicate that it is essential to assess the influence of each IVRT method parameter on the resulting data (49,50).…”