Topical bioequivalence: Experimental and regulatory considerations following formulation complexity

Area of Science:

• Pharmaceutical Sciences
• Dermatology
• Regulatory Science

Background:

• Topical bioequivalence (BE) assessment is challenging, particularly for complex semisolids.
• EMA guidelines require qualitative (Q1), quantitative (Q2), microstructure (Q3), and performance (Q4) equivalence for simple formulations.
• Complex formulations necessitate demonstrating local availability equivalence.

Purpose of the Study:

• To evaluate strategies for topical bioequivalence assessment using a simple gel and a complex emulgel.
• To investigate the feasibility of establishing wider acceptance criteria for bioequivalence testing.
• To determine the most appropriate topical bioequivalence strategy on a case-by-case basis.

Main Methods:

• Developed and validated rheology, in vitro release (IVRT), and in vitro permeation (IVPT) methods for dimetindene maleate gel and diclofenac diethylammonium emulgel.
• Assessed Q1/Q2, Q3, and Q4 equivalence between test (TP) and reference products (RP).
• Explored wider acceptance ranges for bioequivalence based on RP inter-batch variability.

Main Results:

• Dimetindene gel: Q4 equivalence met, but Q3 failed due to high RP variability. Wider acceptance criteria proposed.
• Diclofenac emulgel: Q3 and IVPT equivalence not established. Q4 equivalence achieved with wider criteria (75-133%).
• Despite formulation differences, TP showed equivalent pharmacokinetic profiles to RP, suggesting clinical insignificance.

Conclusions:

• Topical bioequivalence assessment requires a tailored, case-by-case approach.
• Wider acceptance criteria may be feasible for highly variable topical products.
• Balancing manufacturer feasibility with patient safety is key in topical bioequivalence evaluations.