BCS

1. INTRODUCTION

Scientific framework for classifying drug substances based on their aqueous solubility and
intestinal permeability. BCS was introduced in 1995. Since BCS was introduced it has been
used as regulatory tool for replacement for certain BE studies with accurate in vitro tests.

OBJECTIVES

 It allows classification according to dosage form dissolution along with the solubility–
permeability characteristics of the drug
 Allows for the prediction of in vivo pharmacokinetics of oral immediate-release (IR)
Drug products by classifying drug compounds into four classes
 Biowaiver application and hence it reduces timeline for drug development process
 Knowledge of the class of a particular drug is an important factor in influencing the
decision to continue or stop its development

1. Absorption Number (An)

MRT
An =
MAT

MRT = Mean Residence Time MAT= Mean Absorption Time

It denotes dimensionless Dose/solubility ratio for a particular formulation. The

dose/solubility ratio indicates whether the capacity of the GI fluid is sufficient to dissolve the
entire dose administered. Ideally it is greater than 1.

MRT
An =Peff ×
R

Peff is the effective permeability, and R is the radius of the intestinal segment. t res is the time
MRT.

2. Dissolution Number (Dn)

MRT
D n=
MDT

Inadequate solubility, diffusivity, excessive particle size reduce this ratio

3. Dose Number (D0)

It is defined as mass divided by the product of uptake volume (250 mL) and solubility of
drug. Ideally D0 <1 for full dissolution in principle.

M0
D 0=
CsV 0

M0 is dose,
Cs is saturation solubility and;
V0 is initial gastric volume (≈250ml)

2. CLASSIFICATION

Class I

 High Solubility and High Permeability

 High Absorption Number and High Dissolution Number

Class II

 Low Solubility and high Permeability

 High Absorption Number and Low Dissolution Number
 Dissolution-limited absorption

Class III

 High Solubility and Low Permeability

 Low Absorption Number and High Dissolution Number
 Permeation limited absorption

Class IV

 Low Solubility and Low Permeability

 Low Absorption Number and Low Dissolution Number

3. Defining BCS Boundaries

A. Solubility

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. 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.

B. Permeability
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.

C. 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.

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.

4. How are Permeability Studies performed?

1. Pharmacokinetic Studies in Humans

 Mass Balance Studies

Radiolabeled Isotopes
 Absolute Bioavailability Studies

2. Intestinal Permeability Studies

 In vivo intestinal perfusion studies in human

 In vivo intestinal perfusion studies in animals
 In vitro permeation studies using excised human or animal intestinal tissues
 In vitro permeation studies across a monolayer of cultured epithelial cells

The observed low permeability of some drug substances in humans could be caused by
efflux of drugs via membrane efflux transporters such as P-glycoprotein (P-gp), breast
cancer resistance protein (BCRP) and/or multidrug resistance associated protein 2 (MRP2).
When the efflux transporters are absent in these models, or their degree of expression is
low compared to that in humans, there may be a greater likelihood of misclassification of
permeability class for a drug subject to efflux compared to a drug transported passively.
Expression of known transporters in selected study systems should be characterized.

5. BCS based Biowaivers

For BCS Class I drug products, following should be demonstrated:

 Drug is highly soluble

 Drug is highly permeable
 Drug is rapidly dissolving
 The product does not contain any excepients that will affect rate and extent of
absorption

For BCS Class III drug products, following should be demonstrated:

  Drug is highly soluble
 Drug is rapidly dissolving

Additional Considerations

1. Excipients

 For BCS Class I: Excipients can sometimes retard the drug absorption. For BCS class I
based drug product, a biowaiver can be granted even if excipients in test product are
different from one in reference product provided that only those excipients are used
which are permitted by FDA for oral IR dosage form
 For BCS Class III: Unlike for BCS class 1 products, for a biowaiver to be scientifically
justified, BCS class 3 test drug product must contain the same excipients as the
reference product. This is due to the concern that excipients can have a greater
impact on absorption of low permeability drugs. The composition of the test product
must be qualitatively the same (except for a different color, flavor, or preservative
that could not affect the BA) and should be quantitatively very similar to the
reference product. Quantitatively very similar includes the following allowable
differences:
o Changes in the technical grade of an excipient
o Changes in excipients, expressed as percent (w/w) of the total formulation
less than or equal to the following percent ranges
 Filler (± 10%)
 Disintegrant, Starch (± 6%)
 Disintegrant, Other (± 2%)
 Binder (± 1%)
 Lubricant, Calcium or Magnesium Stearate (± 0.5%)
 Lubricant, Other (± 2%)
 Glidant, Talc (± 2%)
 Glidant, Other (± 0.2%)
 Film Coat (± 2%)

2. Prodrugs

When the prodrug-to-drug (i.e., active moiety) 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.

3. Exceptions

BCS-based biowaivers are not applicable to following:

 Narrow Therapeutic Index Drugs

 Products designed to be absorbed in Oral cavity