Purpose of the BCS Guidance:
- Expands the regulatory application of the BCS and recommends methods for classifying drugs.
- Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS.
Goals of the BCS Guidance:
- To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical bioequivalence tests.
- To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests.
- To recommend methods for classification according to dosage form dissolution, along with the solubility and permeability characteristics of the drug substance.
According to the BCS, drug substances are classified as follows:
Class I - High Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility
- A drug substance is considered HIGHLY SOLUBLE when the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5.
- A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance or in comparison to an intravenous reference dose.
- A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions.
- pH-solubility profile of test drug in aqueous media with a pH range of 1 to 7.5.
- Shake-flask or titration method.
- Analysis by a validated stability-indicating assay.
Extent of absorption in humans:
- Mass-balance pharmacokinetic studies.
- Absolute bioavailability studies.
Intestinal permeability methods:
- In vivo intestinal perfusions studies in humans.
- In vivo or in situ intestinal perfusion studies in animals.
- In vitro permeation experiments with excised human or animal intestinal tissue.
- In vitro permeation experiments across epithelial cell monolayers.
- USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm.
- Dissolution media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and pH 6.8 buffer or simulated intestinal fluid.
- Compare dissolution profiles of test and reference products using a similarity factor (f2).
- Rapid and similar dissolution.
- High solubility.
- High permeability.
- Wide therapeutic window.
- Excipients used in dosage form used previously in FDA approved IR solid dosage forms.
REQUEST FOR BIOWAIVERS
Data Supporting Rapid and Similar Dissolution
- A brief description of the IR products used for dissolution testing.
- Dissolution data obtained with 12 individual units of the test and reference products at each specified testing interval for each individual dosage unit. A graphic representation of the mean dissolution profiles for the test and reference products in the three media.
- Data supporting similarity in dissolution profiles between the test and reference products in each of the three media, using the f2 metric.
Data supporting High Permeability:
- For human pharmacokinetic studies, information on study design and methods used along with the pharmacokinetic data.
- For direct permeability methods, information supporting method suitability with a description of the study method, criteria for selection of human subjects, animals, or epithelial cell line, drug concentrations, description of the analytical method, method to calculate extent of absorption or permeability, and information on efflux potential (if appropriate).
- A list of selected model drugs along with data on the extent of absorption in humans used to establish method suitability, permeability values and class for each model drug, and a plot of the extent of absorption as a function of permeability with identification of the low/high permeability class boundary and selected internal standard.
- Permeability data on the test drug substance, the internal standards, stability information, data supporting passive transport mechanism where appropriate, and methods used to establish high permeability of the test drug substance.
Data supporting High Solubility:
- Description of test methods (analytical method, buffer composition).
- Information on chemical structure, molecular weight, nature of drug substance, dissociation constants.
- Test results summarized in a table with solution pH, drug solubility, volume to dissolve highest dose strength.
- Graphical representation of mean pH-solubility profile.
For further information visit the BCS guidance "Waiver of In-vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System."[PDF].