1.
Biowaiver Based on BCS Classification System: Criteria and Requirements
According to FDA Guidance.
1. Abbreviations:
BA: Bioavailability
BE: Bioequivalence
BCS: Biopharmaceutics Classification System
IR: Immediate release
FIP: International Pharmaceutical federation
2. Introduction:
Bioavailability (BA)/bioequivalence (BE) parameters are generally required for approval of new and
generic drugs. Bioequivalence based on plasma drug concentration has become the most frequently
used and successful biomarker of safety and efficacy of a drug. According to the FDA’s regulations BA
is defined as the rate and extent to which the active ingredient is absorbed from a drug product and
becomes available at the site of action and BE can be defined as the absence of a significant difference
in the rate and extent to which the active ingredient in pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug action when administrated at the same molar dose
under similar conditions in a properly designed study. Two oral dosage forms are considered to be
bioequivalent if both rate and extent of absorption are the same.
A Biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (not
considered necessary for product approval). Instead of conducting expensive and time consuming in
vivo studies, a dissolution test could be adopted as the surrogate basis for the decision as to whether
the two pharmaceutical products are equivalent.
3. Biopharmaceutics Classification System
The Biopharmaceutics Classification System or BCS was proposed in 1995 by Amidon et al. (Pharm.
Res. 1995 March; 12(3):413-20). It is a scientific framework which divides APIs into four groups,
according to their solubility and permeability properties.
The four different categories possible for an API according to the BCS are:
• BCS class I: “high” solubility – “high” permeability
• BCS class II: “low” solubility” – “high” permeability
• BCS class III: “high” solubility – “low” permeability
• BCS class IV: “low” solubility – “low” permeability
BCS has been developed to provide a scientific approach to allow for the prediction of in vivo
pharmacokinetics of oral IR drug products by classifying drug compounds based on their solubility
related to dose and intestinal permeability in combination with the dissolution properties of the dosage
form. BCS forms a general approach which is based on the fact that in vivo dissolution differences in
the gastrointestinal tract are a primary reason for observed differences in bioavailability of two IR solid
oral dosage forms containing the same drug substance.
The classification framework of the BCS is believed to be useful in the earliest stages of drug discovery
research. Its applications improve the prediction of oral absorption and disposition of new molecular
entities. In addition, the BCS has proven to be an asset to the FDA by creating a framework for which
to allow a waiver of in vivo bioequivalence studies.
So the intend of the BCS is to provide a regulatory tool for the replacement of certain BE studies by
conducting precise in vitro dissolution tests.

2.
4. Definitions of Solubility, permeability and Dissolution according to FDA:
i. Solubility:
A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or
less of aqueous media over the pH range of 1-6.8. 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 a glass (about 8 ounces) of water.
ii. Permeability:
A drug substance is considered to be highly permeable when 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.
iii. Dissolution:
An IR drug product is considered rapidly dissolving when 85 percent or more of the labeled
amount of the drug substance dissolves within 30 minutes, using the conditions mentioned in
United States Pharmacopeia (USP).
5. Scope:
According to FDA This guidance is applicable for BA/BE waivers (biowaivers) based on BCS, for BCS
class 1 and class 3 immediate-release solid oral dosage forms.
i. For BCS class 1 drug products, the following should be demonstrated:
a. The drug substance is highly soluble
b. The drug substance is highly permeable
c. The drug product (test and reference) is rapidly dissolving, and
d. The product does not contain any excipients that will affect the rate or extent of absorption
of the drug
ii. For BCS class 3 drug products, the following should be demonstrated:
a. The drug substance is highly soluble
b. The drug product (test and reference) is very rapidly dissolving, and
c. The test product formulation is qualitatively the same and quantitatively very similar
6. Additional Considerations for Requesting a Biowaiver:
a. Excipients
i. BCS class 1 drug products:
Although the impact of excipients in IR dosage forms on bioavailability of highly soluble
and completely absorbable drug substances (i.e., BCS-Class I) is considered rather unlikely
but it cannot be completely excluded. Therefore, even in the case of Class I drugs it is
advisable to use similar amounts of the same excipients in the composition of test like in
the reference product. To support a biowaiver request, the quantity of excipients in the IR
drug product should be consistent with the intended function. 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.
ii. BCS class 3 drug products:
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 and should be
quantitatively very similar to the reference product.

3.
b. Prodrugs
Conversion site of prodrug to drug must be considered, if it occurs before intestinal
absorption then permeability study of drug must be done otherwise permeability study of
prodrug must be done.
c. Fixed Dose Combinations
i. If all active components belong to BCS class 1: BCS-based biowaivers are applicable for IR
fixed dose combination products if all the drugs in the combination belong to BCS class 1;
provided there is no PK interaction between the components, and the excipients fulfill the
considerations outlined in section Excipients (i). If there is a PK interaction, the excipients
should fulfill the considerations outlined in section Excipients (ii). Otherwise, in vivo
bioequivalence testing is required.
ii. If all components of the combination belong to BCS class 3 or a combination of class 1 and
3: BCS-based biowaivers are applicable for IR fixed dose combination products in this
situation provided the excipients fulfill the considerations outlined in section Excipients (ii).
Otherwise, in vivo bioequivalence testing is required.
d. Exceptions:
BCS-based biowaivers are not applicable for the following:
i. Narrow Therapeutic Range Drugs
ii. Products Designed to be Absorbed in the Oral Cavity
7. Data to Support a Biowaiver Request:
i. Data Supporting High Solubility
ii. Data Supporting High Permeability
iii. Data Supporting Rapid, Very Rapid, and Similar Dissolution
iv. Additional Information:
a. The manufacturing process used to make the test product should be described briefly to
provide information on the method of manufacture.
b. A list of excipients used, the amount used, and their intended functions should be provided.
Excipients used in the test product should have been used previously in FDA-approved IR
solid oral dosage forms.
c. In addition, it is important to provide quantitative comparison of excipients between the
test and reference product, for BCS class 3 drug products.
8. Biowaiver Monographs FIP
Biowaiver monographs are literature reviews, in which publicly available data are gathered and
organized to address the question of whether a biowaiver can be recommended for a new formulation
of that API. Parameters and points discussed are: solubility and permeability, dissolution of dosage
forms, pharmacokinetics, the therapeutic use and therapeutic window of the API, data on excipient
interactions and problems with bioavailability and/or bioequivalence.
9. References:
i. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral
Dosage Forms Based on a Biopharmaceutics Classification System: Guidance for Industry
(https://www.fda.gov/downloads/Drugs/Guidances/ucm070246.pdf)
ii. Proposal to Waive In Vivo Bioequivalence Requirements for the Who Model List of Essential
Medicines Immediate Release, Solid Oral Dosage Forms
(www.who.int/medicines/services/expertcommittees/pharmprep/QAS04_109Rev1_Waive_invivo_
bioequiv.pdf)
iii. Biowaiver: An alternative to in vivo pharmacokinetic bioequivalence studies
(https://www.ncbi.nlm.nih.gov/pubmed/20383933)
iv. Biowaiver Monographs FIP (http://www.fip.org/bcs_monographs)