Biopharmaceutics Classification System (BCS)

Introduction

The Food and Drug Administration (FDA) and the European Medicine Agency (EMEA) have issued guidelines under which pharmaceutical companies can request a waiver from in vivo bioequivalence studies based on the Biopharmaceutics Classification Systems (BCS). The theoretical basis of the BCS system was first described in 1995. BCS is a scientific framework for classifying substances according to their aqueous solubility and their 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 (e.g. tablets, capsules): dissolution, solubility and intestinal permeability.
The 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 in relation to gastric emptying and the drug has high permeability, the rate and extent of drug absorption is unlikely to be dependent on drug dissolution and/or gastrointestinal transit time. Under such circumstances, demonstration of in vivo BA or BE may not be necessary for drug products containing Class 1 drug substances, as long as the inactive ingredients used in the dosage form do not significantly affect absorption of the active ingredients.

Purpose of the Biopharmaceutics Classification System 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 Biopharmaceutics Classification System 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.

The Biopharmaceutics Classification System Classes

According to the BCS, drug substances can be classified as belonging to one of four classes:

Class I: high solubility and high permeability e.g. propranolol, verapamil, metoprolol
Class II: low solubility and high permeability e.g. ketoprofen, naproxen, carbamazepine
Class III: high solubility and low permeability e.g. ranitidine, cimetidine, atenolol, vancomycin
Class IV: low solubility and low permeability e.g. furosemide, hydrochlorothiazide

BCS Classes in a tabular form (Table 1)

	High solubility	Low solubility
High permeability	*Class I* Dissolution rate limits absorption	*Class II* Solubility limits absorption
Low permeability	*Class III* Permeability limits absorption	*Class IV* Significant problems for oral delivery expected

Class Boundaries

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. The volume estimate of 250 ml is derived from typical bioequivalent study protocols that prescribe administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water.

Permeability

In the absence of evidence suggesting instability in the gastrointestinal tract, 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. 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, nonhuman systems capable of predicting the extent of drug absorption in humans can be used (e.g., in vitro epithelial cell culture methods).

Dissolution

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 (at 100 rpm) or II (at 50 rpm) in a volume of ≤ 900 ml in each of the following media: 0.1 N HCl or SGF USP without enzymes; a pH 4.5 buffer; and a pH 6.8 buffer or SIF USP without enzymes or any other biorelevant media.
As the pH solubility profile of the test compound during passage through the gastrointestinal tract may influence drug dissolution rate and permeability, the solubility profile should be determined in the pH range of 1 – 7.5 at 37 ± 1 °C. In addition, the stability of the drug compound at different concentrations of physiological fluids that mimic gastrointestinal fluid and gastric juice must be taken in account.

Solubility determination

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.

Permeability determination

Extent of absorption in humans:

Mass-balance pharmacokinetic studies using unlabeled stable isotopes or a radiolabeled drug substance to document the extent of absorption of a drug.
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.

Dissolution determination

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).

The BCS suggests that for high solubility, high permeability (case 1) drugs and in some instances for high solubility, low permeability (case 3) drugs, 85% dissolution in 0.1N HCl in 15 min can ensure that the bioavailability of the drug is not limited by dissolution. In these cases, the rate limiting step for drug absorption is gastric emptying.
In the case of low solubility/high permeability drugs (case 2), drug dissolution may be the rate limiting step for drug absorption and an IVIVC may be expected. A dissolution profile in multiple media is recommended for drug products in this category. In the case of high solubility/low permeability drugs (case 3), permeability is the rate controlling step and a limited IVIVC may be possible, depending on the relative rates of dissolution and intestinal transit. Drugs in case 4 (i.e., low solubility/low permeability drugs) present significant problems for oral drug delivery.

Biopharmaceutics Classification System Biowaiver

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.

Summary for biowaiver (Table 2)

		*CLASS II* Poorly soluble Highly permeable Eligible for biowaiver only if weak acids, highly soluble at pH 6.8, + Dissolution
	*CLASS I* Highly soluble Highly permeable Eligible for biowaiver
*CLASS III* Highly soluble Poorly permeable Eligible for biowaiver if very rapidly dissolving		*CLASS IV* Poorly soluble Poorly permeable Not eligible for biowaiver

Additional Considerations for Requesting a Biowaiver

The following factors can affect request for biowaiver:

A. Excipients

Excipients can sometimes affect the rate and extent of drug absorption. In general, using excipients that are currently in FDA-approved IR solid oral dosage forms will not affect the rate or extent of absorption of a highly soluble and highly permeable drug substance that is formulated in a rapidly dissolving IR product. To support a biowaiver request, the quantity of excipients in the IR drug product should be consistent with the intended function (e.g., lubricant). When new excipients or atypically large amounts of commonly used excipients are included in an IR solid dosage form, additional information documenting the absence of an impact on BA of the drug may be requested by the Agency.

B. Prodrugs

Permeability of prodrugs will depend on the mechanism and (anatomical) site of conversion to the drug substance. When the prodrug-to-drug conversion is shown to occur predominantly after intestinal membrane permeation, the permeability of the prodrug should be measured. When this conversion occurs prior to intestinal permeation, the permeability of the drug should be determined. Dissolution and pH-solubility data on both prodrug and drug can be relevant.

C. Exceptions

BCS-based biowaivers are not applicable for the following:

Narrow therapeutic range drugs: This guidance defines narrow therapeutic range drug products as those containing certain drug substances that are subject to therapeutic drug concentration or pharmacodynamic monitoring, and/or where product labeling indicates a narrow therapeutic range designation. Examples include digoxin, lithium, phenytoin, theophylline, and warfarin.
Products designed to be absorbed in the oral cavity: A request for a waiver of in vivo BA/BE studies based on the BCS is not appropriate for dosage forms intended for absorption in the oral cavity (e.g. sublingual or buccal tablets).

Biopharmaceutics Classification System and Controlled Delivery Technology (CDT)

Without controlled release technologies people need to take numerous doses of drugs, OTC products and nutritional supplements to realize the benefits. At times this results in undesirable spikes in serum levels, malabsorption and dumping of excessive ingredients and compromised bioavailability. Controlled Delivery Technology addresses these concerns by optimizing bioavailability of active ingredients while diminishing adverse side effects, improving dosing compliance and maximizing overall product effectiveness. CD technologies enable precise control over the timing and amount of active ingredients released. Unique to CD technologies are the capability to provide near zero order kinetics over 24 hours; a feature which is difficult, if not impossible, to attain with first generation technologies.
In the delivery of non-BCS Class I compounds, (i.e. those compounds with low solubility or permeability), it is often advantageous to alter the physiochemical characteristics of the drug through improvements in solubility or permeability. Many delivery technologies employ techniques such as the selection of a more soluble salt or reduced particle size of the active, or use surfactants or self-emulsifying processes to improve solubility; permeability enhancers such as co-solvents, lipid-filled capsules and liposomes may also be employed (Tables 3 and 4). The incorporation of such techniques into controlled release delivery systems presents many obstacles however, since increasing the solubility of the active creates the need for more effective controlling methods – greater gel viscosity, controlling polymer volume, reduction in hydration rate – and may even be incompatible with the mechanism of control itself or impart undue complexity unto the process of manufacture.
Table 3:

		Solubility
		High	Low
P e r m e a b i l i t y	High	*CLASS I* Highly suitable for Sustained Release/Controlled Release Examples: Propranolol; Metoprolol; Diltiazem, Verapamil, Theophylline, Pseudoephedrine sulfate, Metformin hydrochloride	*CLASS II* Suitable for Sustained Release/Controlled Release Examples: Danazol; Ketoconazole; Mefenamic acid; Nisoldipine; Nifedipine; Nicardipine; Felodipine, Atovaquone, Griseofulvin, Troglitazone Glibenclamide, Carbamazepine
P e r m e a b i l i t y	Low	*CLASS III*Problematic for Sustained Release/Controlled Release Examples: Acyclovir; Neomycin B; Captopril; Enalaprilate; Alendronate, Atenolol, Cimetidine, Ranitidine	*CLASS IV*Unsuitable for Sustained Release/Controlled Release Examples: Chlorothiazide; Furosemide; Tobramycin, Cefuroxime, Itraconazole, Cyclosporin

Table 4:

Dose: solubility ratio (ml) 250 500 1000 10,000 100,000
	I	II *Solubility enhancement* Particle size reduction, soluble salts, solid dispersions, self-emulsifying systems, addition of surfactants, nanoparticles, cyclodextrin complexes, pH adjustment, salting-in, etc.
	III *Permeation enhancement* Absorption enhancing excipients, efflux inhibitors, lipid filled capsules, GI motility consideration, etc.	*Solubility enhancement* IV *Permeation enhancement* Prodrugs, salt forms, cosolvents, solubilisation by surfactants, lipid filled capsules, nanoparticles, liposomes, lyophilisation, etc.