BCS and IVIVC

Muluken N. 1
 Introduction
• Formulation development and optimization is an ongoing process
in the design, manufacturing and marketing of any therapeutic
agent.
• This process of formulation development and optimization may
require a significant amount of time as well as financial
investment.
• Formulation optimization may require altering:
 formulation composition,
 manufacturing process
 equipment and
 batch sizes.

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 Introduction…
• If these types of changes are applied to a formulation,
bioavailability studies may be required to prove that the new
formulation is bioequivalent with the old one.
• Certainly, implementation of these requirements not only halts the
marketing of the new formulation but also increases the cost of
the optimization processes.
• It would be, desirable, therefore, to develop in vitro tests that
reflect bioavailability data.
• Recently a regulatory guidance has been developed to minimize
the need for bioavailability studies as part of the formulation
design and optimization.
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 Biopharmaceutical Classification System
(BCS)
• The Biopharmaceutical Classification System (BCS) is a
framework for classifying drug substances based on their aqueous
solubility and intestinal permeability
• The BCS takes into account three major factors:
– solubility,
– intestinal permeability, and
– dissolution rate,

• All of which govern the rate and extent of oral drug absorption
from IR solid oral-DFs.
• Thus, it is a theoretical basis for correlating in-vitro drug
dissolution with in-vivo bioavailability
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BCS…

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 BCS…
Boundaries used in BCS
• Highly soluble: A drug substance is considered highly soluble
when the highest dose strength is soluble in 250 mL or less of
aqueous media over the pH range of 1.0–7.5
• Highly permeable: 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 the mass balance or
in comparison to intravenous dose.
• Rapidly dissolving: A drug product is considered to dissolve
rapidly 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 solution.
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 BCS…
Boundaries used in BCS

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

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 BCS…
Goals of BCS
 To identify the challenges of formulation Design.
 To guide decisions w.r.t IVIVC.
 To explain when a waiver for in vivo BA and BE may be
requested.
 To assist in QC in SUPAC.
 To recommend a class of IR solid oral DFs for which BE may be
assessed based on in vitro dissolution tests.

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 In-vitro in-vivo correlation (IVIVC)

• IVIVC is a predictive mathematical model describing the r/ship

b/n an in-vitro property of a DF and an in-vivo response.
• The main objective of an IVIVC is to enable the dissolution
test to serve as a surrogate for in vivo bioavailability studies.
• This may reduce the number of bioequivalence studies required
for approval as well as during scale-up and post-approval
changes(SUPAC).
• IVIVCs could also be employed to establish dissolution
specifications and to support and/or validate the use of dissolution
methods.

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 IVIVC…
CORRELATION LEVELS
• The concept of correlation level is based upon the ability of the
correlation to reflect the complete plasma drug level-time profile
which will result from administration of the given DF.
• Four correlation levels have been defined in the IVIVC FDA
guidance.
– Level A Correlation
– Level B Correlation
– Level C Correlation
– Multiple-level C correlation

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 IVIVC…
Level A Correlation
• Highest category of correlation
• Linear correlation
• Represents point to point correlation between in vitro dissolution
time course and in vivo response time course
• Utilizes all the dissolution and plasma level data available to
develop correlation
• Most informative and useful from a regulatory perspective

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 IVIVC…
• It is an excellent quality control procedure since it is predictive of
the dosage form’s in vivo performance.
• An in vitro dissolution curve can serve as a surrogate for in vivo
performance

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 IVIVC…
Level B Correlation
• The mean in vitro dissolution time (MDTvitro) of the product is
compared to either mean in vivo residence time (MRT) or the
mean in vivo dissolution time (MDTvivo).
• It is not a point-to-point correlation,

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 IVIVC…
Level C Correlation
• In this level of correlation, one dissolution time point (t50%, t90%,
etc.) is compared to one mean pharmacokinetic parameter such
as AUC, tmax or Cmax.
• Therefore, it represents a single point correlation and doses not
reflect the entire shape of the plasma drug concentration curve.
• This is the weakest level of correlation

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 IVIVC…
Multiple-Level C Correlation
• A multiple level C correlation relates one or several
pharmacokinetic parameters of interest (Cmax, AUC, etc) to the
amount of drug dissolved at several time points of the dissolution
profile.
• A multiple Level C correlation should be based on at least three
dissolution time points covering the early, middle, and late stages
of the dissolution profile.

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 IVIVC…
Table: IVIVC expectations based on BCS

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