INTRODUCTION:

The Biopharmaceutics Classification System (BCS) is guidance for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration ¹. The fundamental basis for the BCS was established by Dr. Gordon Amidon who was presented with a Distinguished Science Award at the August 2006 International Pharmaceutical Federation (FIP) congress in Salvador, Brazil.

In 1995 Amidon et al. devised a biopharmacetics classification system (BCS) to classify drugs based on their aqueous solubility and intestinal permeability². It was then recognized that dissolution rate has a negligible impact on bioavailability of highly soluble and highly permeable (BCS Class I) drugs when their formulation's dissolution is sufficiently rapid³. The classification is based on Fick’s first law applied to a membrane:

Jw = PwCw

Where, Jw is the drug flux through the intestinal wall at any position and time, Pw is the permeability of the membrane, and Cw is the drug concentration at the intestinal membrane surface.

International Regulatory Requirements:

1. European regulations:

According to the CPMP Guideline, bioequivalence studies should be performed for all generic immediate release products intended for systemic action. However, exceptions are possible if the following catalogues of criteria are fulfilled:

• The drug substance has certain properties, e.g. is not a drug with a narrow therapeutic index, exhibits a linear pharmacokinetics and a first pass effect less than 70%, is highly water soluble over the entire physiological pH range (1–and) at 37°C, is highly permeable in the intestine (i.e. extent of absorption is greater than and0%) and

• The drug product exhibits a particular quality pattern, e.g. excipients have no significant impact on the pharmacokinetics of the active substance(s), and release of the active substance is fast in buffers over the entire physiological pH range (pH 1–and) at 37°C.

If all these requirements are met by a certain generic medicinal product, in vitro dissolution data are considered sufficient to ensure bioequivalence. For this purpose, dissolution profiles have to be “similar” to those of the reference product. Similarity has to be assessed over the entire physiological pH range (e.g. at pH 1.3, 4.6 and 6.and) by comparing the dissolution curves by means of the f₂ equation (FDA, 1997).

2. US regulations:

Similar, although more specific requirements are given by the FDA Guidance for Industry. This document is also only relevant for oral immediate release dosage forms intended for systemic use. According to this guideline “drugs that are poorly permeable, poorly soluble and/or formulated in slowly dissolving dosage forms may be considered to be drugs with actual or potential bioequivalence problems”. As a consequence, in vivo studies are requested for such drug products.

In more specific terms, waiver of in vivo studies may be requested by the sponsor if

• The drug substance is highly soluble and highly permeable,

• The drug product dissolves rapidly, i.e. >and5%/30 min over the entire physiological pH range (e.g. at pH 1.3, 4.6 and 6.and) and

• The drug is not a drug with a narrow therapeutic index.

Moreover, stability of the active substance in the medium of the gastrointestinal tract has to be assured (>95%/3 h). This supposition is important for the appropriate interpretation of experimental findings from solubility and permeability investigations or the mass balance analysis.

Special attention should be paid to the excipients. They should be “well established” (i.e. already used in approved IR forms) and “unproblematic”. Excipients are considered critical in this respect if they significantly affect

• Dissolution of the active drug ingredient from the dosage form (e.g. surfactants),

• Permeation through the intestinal membrane (e.g. enhancers),

• Gastro-intestinal transit time or

• Drug metabolism in the mucosa.

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 (Table 1)

CLASS BOUNDARIES:

Class I - High Permeability, High Solubility:

Example: Metoprolol

Those compounds are well absorbed and their absorption rate is usually higher than excretion.

Class II - High Permeability, Low Solubility:

Example: Glibenclamide

The bioavailability of those products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.

Class III - Low Permeability, High Solubility:

Example: Cimetidine

The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro-intestinal duration time, then class I criteria can be applied.

Class IV - Low Permeability, Low Solubility:

Example: Hydrochlorothiazide

Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.

· 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 > and5% 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.

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:

1. Extent of absorption in humans:

· Mass-balance pharmacokinetic studies.

· Absolute bioavailability studies.

2. 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.and buffer or simulated intestinal fluid.

· Compare dissolution profiles of test and reference products using a similarity factor (f₂).

BCS 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:

1. 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.

2. 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.

3. 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.

BA/BE waiver for class I drugs?:

Principally, both guidelines (CPMP Note for Guidance in Europe and FDA Guidance for Industry in the USA) consider a waiver of BA or BE studies for rapidly dissolving drug products containing compounds of high solubility and high permeability (Class I). The motivation for such a regulation is the assumption that such products may behave in vivo like an oral solution for which bioavailability is considered self-evident. As a consequence, since dissolution of Class I drugs is expected to be very fast, BA/BE studies seem unnecessary for such products.

This general concept sounds conclusive. If the Class I drug substance is released from the dosage form very rapidly in vivo, gastric emptying will become the rate limiting process for drug absorption. In such cases, physiology, rather than the biopharmaceutical properties of the medicinal product, will be the decisive factor for bioavailability. Thus, bioavailability is not dependent on the product performance and consequently in vivo investigations may be waived.

Bioavailability of class III drugs:

Compounds classified as Class III drugs are also characterized by high solubility. For immediately release (IR) products manufactured with these substances, a similar assumption should be acceptable as with Class I dosage forms: If their dissolution is rapid under all physiologic pH conditions, it can be expected that they will also behave like an oral solution in vivo.

Consequently, it seems appropriate to consider a waiver of BA/BE studies also for this type of IR products. Moreover, there are additional arguments which may underscore Class III drugs as even better candidates in this respect. For these compounds, permeation through the intestinal membrane will be the rate limiting process for drug absorption. Under such circumstances, rate and extent of bioavailability is not so much dependent on the release properties of the formulation but on the in vivo permeability pattern ⁹.

CONCLUSION:

The BCS was primarily developed for a better understanding of the relationship of drug release (in vivo) from the product and the absorption process. In this respect, the question of the rate-limiting step is of primary relevance. According to current thinking in science and technology, bioavailability will be affected only by the in vivo performance of the dosage form if dissolution is rate-limiting for drug absorption. In contrast, as long as the permeation through the intestinal membrane is the slowest (and thus rate-limiting) process, bioavailability and consequently also bioequivalence are not so much dependent on the release properties of the dosage form.

As a consequence, solid oral medicinal products with very rapid dissolution in all physiological media (entire pH range) may be considered as minor problematic regarding bioavailability. For such preparations, it is reasonable to expect that they would behave in vivo like oral solutions and thus, that their bioavailability would be dependent more on gastric emptying than on the drug product properties. However, this general consideration does not necessarily imply that such (generic) products are per se bioequivalent to a given reference product (as this may exhibit different dissolution properties). Nevertheless, bioequivalence can be assessed in such cases by comparing in vitro dissolution profiles of test and reference under all physiological pH conditions and prove their sufficient similarity.

This concept is relevant not only for Class I drugs as mentioned by the current Guidelines, but principally also for Class III compounds. Moreover, the latter seem to be even better candidates for a waiver of BA/BE studies as their bioavailability are primarily dependent on permeability properties of the drug substance. As a consequence, also in cases of certain differences in dissolution between generic products of Class III compounds, their bioavailability should be similar due to the fact that drug absorption is not so much affected by the (in vivo) release from the dosage form but “controlled” by the (permeability) properties of the active drug ingredient.

On the other hand special attention should be paid to excipients which are known to modify GI transit (e.g. certain sugar alcohols) or drug absorption (e.g. enhancers). As some Class III drugs exhibit site dependent (low) permeabilities their absorption may be affected by such excipients. Consequently, for the decision process regarding bio-waivers a further specification of the BCS is suggested by inclusion of dissolution properties and introduction of sub-classes for the Class III compounds depending on certain excipients used in their formulations.

REFERENCES:

1. H. Waterbeemd, H. Lennernäs, P. Artursson (editors), Drug bioavailability: estimation of solubility, permeability, absorption and bioavailability, Wiley-VCH, Weinheim, Germany, 2003.

2. Amidon, G.L., H. Lennernäs, V.P. Shah, and J. R. Crison, "A theoretical basis for a biopharmaceutics Drug Classification: The correlation of in vitro drug product dissolution and in vivo bioavailability." Pharmaceutical Research 12 (3, March), 413-420, 1995.

3. United States Food and Drug Administration. Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. August 2000. http://www.fda.gov/cder/guidance/361andfnl.htm.

4. Kaus, L.C., W.R. Gillespie, A.S. Hussain, and G.L. Amidon, "The effect of in vivo dissolution, gastric emptying rate, and intestinal transit time on the peak concentration and area-under-the-curve of drugs with different gastrointestinal permeabilities." Pharmaceutical Research 16 (2, February), 272-2and0, 1999.

5. United States Food and Drug Administration. Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. August 2000. http://www.fda.gov/cder/ guidance/361andfnl.htm

6. European Agency for the Evaluation of Medicinal Products. Note for guidance on the investigation of bioavailability and bioequivalence, (CPMP/EWP/QWP/1401/9and), Committee for proprietary medicinal products, July 26 2001. http://www.emea.eu.int/pdfs/human/ewp/14019anden.pdf

7. United States Food and Drug Administration. CDER New and Generic Drug Approvals: 199and-2002. http://www.fda.gov/cder/ approval/index.htm

8. United States Food and Drug Administration, Division of Product Quality Research. Biopharmaceutics Research. January 16, 199and. http://www.fda.gov/cder/ dpqr/dpqr_pgm.htm

9. Henning H. Blume^,and Barbara S. Schug. The biopharmaceutics classification system (BCS): Class III drugs — better candidates for BA/BE waiver?

10. Leon shargel, Susanna wu-pong, Andrew B.C. Yu; Applied biopharmaceutics and pharmacokinetics. 5th edition. McGraw Hill Publication. 2005 P. 4and3

Received on 27.09.2008 Modified on 04.11.2008

Research J. Pharm. and Tech. 2(1): Jan.-Mar. 2009; Page 8-11

Class	Solubility	Permeability	Comments
Class 1	High	High	Drug dissolves rapidly and is well absorbed. Bioavailability problem is not expected for immediate release drug products.
Class 2	Low	High	Drug is dissolution limited and well absorbed. Bioavailability is controlled by the dosage form and rate of release of the drug substance.
Class 3	High	Low	Drug is permeability limited. Bioavailability may be incomplete if drug is not released and dissolved within absorption window.
Class 4	Low	Low	Difficulty in formulating a drug product that will deliver consistent drug bioavailability. An alternate route of administration may be needed.