01-05-2013, 03:15 PM
Summary Workshop Report: Bioequivalence, Biopharmaceutics Classification System, and Beyond
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Abstract.
The workshop “Bioequivalence, Biopharmaceutics Classification System, and Beyond” was
held May 21–23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for
pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System
(BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path
Initiative. The objective of this Summary Workshop Report is to document the main points from this
workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based
biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued
scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid
dissolution, © scientific support for a number of permeability methodologies to assess BCS permeability
class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in
vitro dissolution methods to predict dosage form performance.
REGULATORY SIGNIFICANCE OF BCS
A preceding AAPS/FDA workshop was held in September
2002, shortly after the introduction of the BCS guidance.
The workshop was entitled “Biopharmaceutics Classification
System—Implementation Challenges and Extension Opportunities”(
2). At that time, there was consensus that “The
regulatory impact of the guidance has not been substantial, in
part since the guidance was issued less than two years before
the workshop. Additionally, with the need among sponsors
for certainty of regulatory outcome, the BCS approach at this
time was viewed as less familiar and thus less desirable,
relative to in vivo bioequivalence studies.”
IMPLEMENTATION OF BCS AND BIOWAIVER
FOR CLASS III DRUGS
In this workshop session, current BCS case studies, Class
III biowaivers, and permeability methodologies were discussed.
Case Studies. Several case studies of BCS-based biowaivers
for both new drugs and generics were presented. In a
case study of pregabalin, bioequivalence needed to be studied
near the time of submission. Three different formulation series
comprised 11 different strengths. A strategy was devised to
compare dissolution profiles of the highest and lowest strengths
of each series. An in-house educational effort, along with
interactions with FDA scientists, allayed in-house concerns
about BCS as less familiar compared to the traditional in vivo
BE approach. The subsequent BCS Class I biowaiver resulted
in filing over one month earlier, with a savings of more than
one million dollars compared to a more traditional approach
that would have utilized four separate bioequivalence studies
BIORELEVANT DISSOLUTION AND BCS FUTURE
DEVELOPMENT
In this workshop session, the topics of Biorelevant
Dissolution and BCS Future Development were discussed.
A key highlight of the workshop was broad support for
further scientific progress in in vitro dissolution methods to
predict dosage form performance. The FDA guidance on in
vitro–in vivo correlations is well in place (8). The majority of
lectures and discussions concerned strategies and computational
approaches to better employ dissolution data to
understand product performance, including during product
development, where drug biopharmaceutic characteristics are
also considered.
BIOEQUIVALENCE FOR HIGHLY VARIABLE DRUGS
Currently, the bioequivalence statistical analysis involves
the following metrics and criteria: AUC and Cmax; logtransformed
data; ANOVA model with period, sequence,
subject (sequence), and treatment; and 90% confidence
intervals must fit between 80–125%. This analysis is applied
to highly variable drugs (HVD), as well as non-HVD. HVDs
are drugs with high within-subject variabilities (ANOVA-CV
≥30%) in Cmax and/or AUC. It is well appreciated that
HVDs often require a greater numbers of subjects than non-
HVD. This added complexity in study design has motivated
the development of several novel methods and possible
alternative acceptance criteria for HVDs.
FDA AND INTERNATIONAL INITIATIVES
In addition to the above discussions, the workshop
featured several other initiatives at FDA and at international
agencies that impacts on pharmaceutical product quality,
including oral biopharmaceutics and bioequivalence.
FDA Initiatives. FDA initiatives include the Critical Path
Initiative, the Drug Safety Initiative, and the Quality by
Design (QbD) Initiative. The Critical Path Initiative aims to
stimulate and facilitate a national effort to modernize the
scientific process through which a potential human drug,
biological product, or medical device is transformed from a
discovery or “proof of concept” into a medical product (3). A
Critical Path Opportunities for Generic Drugs document was
recently released (14, 15). Bioequivalence plays an important
role in this process of developing medications. It is recognized
that products change over their lifetime (e.g. clinical formulations
evolve on the way to market, major changes to
formulation or manufacturing after approval, generic drugs).
Bioequivalence studies are conducted to fill gaps in knowledge
about product performance. Success along the critical
path will reduce knowledge gaps.