The measurement of drug release from a given dosage form is essential to drug product development. Dissolution testing for solid drug products is a method that has been accepted for decades to establish a biopharmaceutical characterization and ensure consistent quality within a defined set of criteria. By contrast, in vitro techniques have been used for semi-solid drug products but only to get FDA approval for scale-up or for other post-approval changes in the existing formulation.

Now all that is changing, and the impact on the generic topical drug products market is sure to be significant.

In December 2016, the FDA released a new draft guidance on acyclovir cream in which, for the first time, the agency proposed a surrogate methodology that combines in vitro release testing (IVRT) and in vitro permeation testing (IVPT) using an ex vivo human skin model. By releasing this guidance, the FDA has given detailed insight into the design and application of an in vitro model to compare the bioequivalence of generics and reference listed drugs (RLDs).

Dealing With Product Diversity

Topical drug products present special challenges in release measurement, because significant differences in formulation design exist for non-oral dosage forms. So far, no single test system has been devised that can be used to study the drug release properties of all products. Because of that, different apparatus, procedures and techniques must be employed for the dosage form category, the formulation type and even the particular product.

IVRT typically employs an open chamber design like the Franz diffusion cell system. This system can be used with a synthetic membrane, a tissue construct or biological sample such as ex vivo human skin. It works by separating the donor compartment (containing the test product) from the receptor compartment (filled with collection medium) with a membrane. Diffusion of the drug from the semi-solid product across the membrane is monitored by assaying sequentially collected samples of the receptor medium. At predetermined time points, an aliquot of medium is removed from the receptor compartment for drug content analysis, usually by liquid chromatography (HPLC/UPLC) linked with different kind of detectors.

Beyond Bioequivalence

Ultimately, the goal of these tests is to determine product performance and ensure its equivalence to existing products entirely in the laboratory. However, there are a wide range of other applications for IVRT already used in drug development programs. Among them:

·       Set product regulatory specification quality to ensure in vivo product performance

·       Substantiate label claim and evaluate potential dosage variations

·       Monitor product lot-to-lot consistency to ensure product uniformity for scale-up procedures or to observe changes made during the manufacturing process

·       Assess product stability programs

·       Establish possible in vitro–in vivo correlations

Skin absorption measurement studies in vivo are relatively rare because of ethical, economical and analytical concerns. As a result, significant attention has been given to developing and validating alternative in vitro test methods using human cadaver skin. However, until recently, there was no standard test protocol that could be applied to formulations.

The ex vivo human skin model is a sensitive tool that accurately measures a drug absorption rate and distribution profile,  and it has applications within multiple areas of the drug development process. These include:

·       Screen and select the optimum formulations for further development, reformulation or scale-up

·       Evaluate formulation differences between the test generic product and the RLD

·       Ensure batch-to-batch product consistency through commercial production

·       Generate shelf‐life stability data, essential for regulatory filing

·       Make predictions for pharmacokinetics and in vivo bioequivalence studies

The Future of Topical Bioequivalence Studies

The new FDA guidance is great news for any company marketing generic topical pharmaceuticals, and many are saying in vitro release rate and skin permeation testing will be the future for qualifying bioequivalence in all topical generic drugs. In addition to the time and cost savings, one major advantage of in vitro studies is the ability to control the conditions of the experiment in ways that aren’t possible using human subjects. By standardizing procedures in the lab, we may be able to ultimately create better products than with human subjects.

Is IVRT and IVPT the future for topical products on their way to regulatory approval? It appears that the FDA is signaling that this will be the case. By using validated IVRT and IVPT methodologies — while strictly following all FDA guidelines — sponsors may be able to obtain biowaivers for many generic topical formulations, waiving the expensive and time-consuming in vivo bioequivalence studies.

 

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Theo is the co-founder of Diteba, with more than 30 years of analytical R&D Chemist and pharmaceutical industry experience. With the emergence of newer, alternative dosage forms over the past 10 years, he has surfaced as a well-recognized global leader in the development of topical drug products, providing expertise in the development and validation of performance tests used to evaluate the absorption of drugs across skin and other membranes. Theo has more than 40 scientific publications covering topics in Analytical Chemistry of drug candidates, Synthesis, Characterization, chiral separations, drug-protein binding, and pharmacokinetics. Theo possesses superior knowledge and experience in analysis, identification of organic/inorganic compounds and drugs and has worked extensively in areas such as pharmaceutical research and development for solid and semisolid topical formulations, bioavailability/bioequivalence and drug interaction studies. Theo leads numerous technical projects relating to the development of Topical pharmaceutical products.