Topical products are exemplified by medicines for cutaneous use, but in broadest scope, they are locally applied and locally acting products.
They can be applied to any of the diverse external surfaces of the body that may present a physiological barrier to drug absorption such as the skin, eyes and ear.
In assessing generic formulations, regulatory agencies require the demonstration of bioequivalence (BE) to a reference drug product. For the majority of topical drug products, comparative clinical endpoint studies are used to demonstrate BE to the reference listed drug (RLD). The use of clinical endpoints to determine the BE of topical products, although providing a direct assessment of patients that is reassuring to clinicians, is associated with a number of challenges such as:
- Formulation differences might not be detected efficiently
- High-variability and low-sensitivity that make such studies less reliable and less efficient
- The number of patients enrolled can be quite large
- The high cost
- Their invasive nature
It is evident from the above that there is a clear need for BE studies using alternate approaches that are faster, less expensive, more reproducible and sensitive to differences in locally applied products. This need for suitable surrogates seems to be “embraced”, as reflected by the recent guidance documents European Medicine Agency (EMA) Concept Paper on the development of a guideline on quality and equivalence of topical products.
Qualimetrix performs in-vitro release (IVR) testing for semisolid preparations according to the provisions of the United States Pharmacopoeia (USP) General Chapter <1724> Semisolid Drug Products – Performance Tests. The Diffusion cell is a reliable and reproducible means of measuring drug release from semisolid dosage forms.
Method development (receptor medium selection, synthetic membrane selection, number of samples, temperature and sampling) and method validation (apparatus qualification, membrane qualification, receptor medium qualification and analytical method validation according to ICH Q2, including mass balance and dose depletion, discrimination sensitivity and selectivity) are part of the IVR package of studies.
In-vitro permeation IVR studies
Tissues from human or animal sources can be used. Although viable tissue is preferred, non-viable tissue can also be used provided that its integrity can be demonstrated. Either epidermal membranes or split-thickness skin prepared with a dermatome, are acceptable. Other tissue models, based in artificial membranes, provided by MatTek Corporation, can also be employed, including EpiDermTM, EpiOcularTM, EpiIntestinalTM and EpiOralTM.
The first and most critical step is the development of an analytical method that will be suitable for its intended purpose.
The in-vitro permeation method should be suitably discriminating while the analytical methods for determining the content of the test substance in the receptor fluid should be validated according to ICH Q2(R1).
The solubility of the target analyte is experimentally substantiated by the demonstration that the analyte’s solubility in the receptor medium is at least an order of magnitude higher than the maximum concentration expected during the in-vitro permeation experiment.
In cases where the purpose of the in-vitro permeation study is the pharmacokinetic comparison between a test and a reference product, a pilot study should preferably be performed in order to estimate the number of donors required for the pivotal study and optimise the sampling scheme.
Following the pilot study, the pivotal study intends to compare the rate and extent of in-vitro permeation between a reference and a test formulation in order to support submissions claiming equivalence. Its design (such as sampling times, number of time points, number of donors and lots) highly depends on the outcome of the pilot study.