Permeability and Biowaivers | A Key Factor in Regulatory Justification

For obtaining a biowaiver based on permeability, regulatory authorities like USFDA, EMA, and WHO require a justification report that classifies the drug according to the Biopharmaceutics Classification System (BCS). This classification determines whether a drug is eligible for a biowaiver based on high solubility and high permeability (BCS Class I) or high solubility and low permeability (BCS Class III).

Structure of the Justification Report for BCS-Based Biowaiver

Executive Summary

Overview of the drug substance and product.
Purpose of requesting a biowaiver.
Summary of classification (e.g., “Drug X is classified as BCS Class I based on solubility and permeability studies”).

Drug Substance Information

Chemical Name & Structure
Molecular Weight & pKa
BCS Classification: Mention if the drug is a WHO-listed BCS drug or if new data is presented.

Solubility Justification

To classify the drug as highly soluble, provide:

A. Solubility Data Across pH Range

Experimental solubility data in pH 1.2, 4.5, and 6.8 (as per regulatory guidelines).
The drug is considered highly soluble if the highest strength dissolves in ≤ 250 mL of aqueous media across this pH range.

B. Experimental Methodology for Solubility

Description of methods used (shake-flask method, pH solubility profile, etc.).
Analytical methods used (e.g., HPLC, UV-Vis).

Permeability Justification

To classify the drug as highly permeable, provide:

A. In Vivo Human Data (Preferred by Regulatory Authorities)

Evidence from absolute bioavailability studies (F% > 85% considered highly permeable).
Mass balance studies (if ≥85% of drug is absorbed, it’s considered highly permeable).
If human data is unavailable, in vitro and animal data can be used.

B. In Vitro Permeability Studies

Caco-2 Cell Monolayer Studies
P_app ≥ 1 × 10⁻⁶ cm/s suggests high permeability.
Comparison with known high-permeability reference drugs e.g., Metoprolol.
Parallel Artificial Membrane Permeability Assay (PAMPA) (if used).

C. Animal Data (If Human Data Unavailable)

Permeability studies using rat/mouse intestinal perfusion models.

D. BCS Classification Reference

Comparison with already classified BCS drugs with similar structures.

Dissolution Justification

In vitro dissolution studies in pH 1.2, 4.5, and 6.8.
If drug dissolves ≥85% in 15–30 minutes, it supports the biowaiver request.

Table Example:

Dissolution profile comparison using f₂ similarity factor (f₂ > 50).

Conclusion & Regulatory Justification

Summary of solubility, permeability, and dissolution results.
Statement confirming that the drug meets BCS Class I or Class III criteria.
Reference to ICH M9 guidelines, WHO guidelines, or USFDA guidance on BCS-based biowaivers.

References & Supporting Data