THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) l BIOWAIVERS

                                             

THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)

The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: (1) dissolution, (2) solubility, and (3) intestinal permeability.

 According to the BCS, drug substances are classified as follows:

                            

 Class 1: High Solubility – High Permeability    

Class 2: Low Solubility – High Permeability

Class 3: High Solubility – Low Permeability

Class 4: Low Solubility – Low Permeability

In addition, some immediate release (IR) solid oral dosage forms are categorized as having rapid or very rapid dissolution.

Within this framework, when certain criteria are met, the BCS can be used as a drug development tool to help sponsors/applicants justify requests for biowaivers.

Observed in vivo differences in the rate and extent of absorption of a drug from two pharmaceutically equivalent solid oral products may be due to differences in drug dissolution in vivo. However, when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid in relation to gastric emptying and the drug has high solubility, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or gastrointestinal (GI) transit time. Under such circumstances, demonstration of in vivo BA or BE may not be necessary for drug products containing class 1 and class 3 drug substances, as long as the inactive ingredients used in the dosage form do not significantly affect absorption of the active ingredients.

 

This BCS approach can be used to justify biowaivers for highly soluble and highly permeable drug substances (i.e., class 1) as well as highly soluble and low permeable drug substances (i.e., class 3) in IR solid oral dosage forms that exhibit rapid or very rapid in vitro dissolution using the recommended test methods.

The recommended methods for determining solubility, permeability, and in vitro dissolution are discussed below

Solubility

The solubility class boundary is based on the highest strength of an IR product that is the subject of a biowaiver request. A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media within the pH range of 1 - 6.8 at 37 ± 1°C. The volume estimate of 250 mL is derived from typical BE study protocols that prescribe administration of a drug product to fasting human volunteers with an 8 fluid ounce glass of water.

 Permeability

The permeability class boundary is based indirectly on the extent of absorption (fraction of dose absorbed, not systemic BA) of a drug substance in humans, and directly on measurements of the rate of mass transfer across human intestinal membrane. Alternatively, other systems capable of predicting the extent of drug absorption in humans can be used (e.g., in situ animal, in vitro epithelial cell culture methods). A drug substance is considered to be highly permeable when the systemic BA or the extent of absorption in humans is determined to be 85 percent or more of an administered dose based on a mass balance determination (along with evidence showing stability of the drug in the GI tract) or in comparison to an intravenous reference dose.

 Dissolution

An IR drug product is considered rapidly dissolving when a mean of 85 percent or more of the labeled amount of the drug substance dissolves within 30 minutes, using United States Pharmacopeia (USP) Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm (or at 75 rpm when appropriately justified in a volume of 500 mL or less (or 900 mL when appropriately justified) in each of the following media:

(1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes;

(2) a pH 4.5 buffer; and

(3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes.

 An IR product is considered very rapidly dissolving when a mean of 85 percent or more of the labeled amount of the drug substance dissolves within 15 minutes, using the above-mentioned conditions.

 Regulations at 21 CFR 320 address the requirements for BA and BE data for approval of NDAs, ANDAs, and supplemental applications. Provision for waivers of in vivo BA/BE studies (biowaivers) under certain conditions is provided at 21 CFR 320.22.