V. A. Gray Consulting, Hockessin, DE
email correspondence to: vagray@rcn.com
The FDA and AAPS sponsored a workshop on September 25-27, 2002 on the implementation, challenges and extension opportunities for the biopharmaceutics classification system (BCS). In August 2000, the FDA published a Guidance to Industry titled; Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. The major aspects of the criteria are solubility, dissolution, and permeability.
The goals of the workshop were to discuss issues and science
related to the BCS guidance, review regulatory applications, influence
future FDA guidance direction, and debate issues related to the
BCS extension.
Gordon Amidon of the University of Michigan and Robert
Lipper of Bristol Myers Squibb began the conference by defining
the challenges ahead. Amidon reviewed the present guidance and
outlined the possible extensions that would be considered during
the workshop, especially during the breakout sessions. Lipper
reiterated the importance of the BCS as a useful tool in many
areas, but stressed the need to achieve international harmonization
and uniformity of the BCS application. He also repeated a challenge
from industry to clearly define where the extensions are headed
and when they will be accomplished.
Ajaz Hussain, Deputy Director of the Office of Pharmaceutical
Science in the Centerfor Drug Evaluation and Research at the FDA
began his message with the statement that the agency realized
that there were many biostudies that were not adding value to
the assessment of bioequivalence. This led to the development
of the biowaivers in the present guidance. He mentioned that a
more recent draft guidance justifies biowaivers of certain food-effect
studies. He focused on the need to understand the mechanisms of
drug-excipient interaction before the extensions can safely be
extended for Class III and possibly Class II drugs. Ajaz talked
about how the European and US regulatory biowaiver approaches
appear to be moving closer together. A discussion of the Process
Analytical Technology (PAT) initiative was presented.
Mehul Mehta of the FDA discussed the preliminary results
of a retrospective (spanning the years 1995 to 2001) FDA evaluation
of in-house NDA data from reviews and original submissions. The
objective was to learn about the appropriateness of the methods
and criteria recommended in the BCS guidance and to gather data
to evaluate whether the BCS guidance would need to be revised
in the future. The methodology was to identify important biopharmaceutical
variables such as the chemical properties of pKa, log P, acid
or base, the pH solubility profiles, permeability assessment,
formulation composition and dissolution profiles. The pharmacokinetic
data such as absolute bioavailability, bioavailability relative
to a solution, linearity, bioequivalence studies, metabolism,
food effects and urinary recovery were studied. The survey found
that about 20% of the compounds did not have solubility profiles
and most of those that did were performed at 25°C.
The permeability data consisted of mainly mass balance. Absolute
bioavailability data was available for 65 drugs. Intestinal permeability
data was rare. Dissolution profiles for the three media were available
for about 50% of the NDAs. There was not much information on GI
track stability. The survey found that 46 out of 100 compounds
were BCS Class 4, of these 15 showed BE failures. The definition
of a BE failure was that either AUC or Cmax failed the BE criteria
of 90% CI. He went on to say that the preliminary observations
noted that no BE failures were observed for Class 1 drugs, 6 out
of 12 BE failuresfor Class 2 drugs, and 3 out of 28 BE failures
for Class 3 drugs. Some conclusions, although he cautioned that
the database has not been audited for 100% accuracy, from the
survey are that the BCS Class 1 criteria are stringent but can
be met, there are no BE problems with Class 1 drugs, and a significant
food effect seems to be associated with only the extensively metabolized
drugs. He went on to add that the database has valuable information
that can be used to evaluate possible extensions of waivers. The
extensions being considered are: biowaivers for Class 3 drugs
with rapidly dissolving formulations, reduction of the high permeability
requirement from 90% to 85%, and defining a new intermediate permeability
class. He suggested that perhaps a new intermediate solubility
class could be defined and posed the question of biowaivers for
food effect studies on Class 1 drugs.
The next FDA speaker was Barbara Davit, who gave some of
the experiences of FDA with BCS based biowaiver applications.
She covered three applications in detail and reported on their
status. One compound met the criteria for BCS Class 1 and the
applicant has been asked to conduct a fed BE study. The second
applicant was asked to further evaluate dissolution using the
SGF and SIF without enzymes, to verify that drug loss in the GI
tract was from intestinal permeation rather that degradation,
and verify that the drug substance binds to surfaces of plates
used in the permeability studies.
The third application is still under review in the area of permeability,
especially the role of presystemic metabolism. Her analysis was
that the permeability aspects of the biowaiver are usually the
most problematic for the applicants.
Donna Volpe of the FDA further discussed the permeability
aspects. She reviewed the permeability classification in the BCS
guidance, the concept of method suitability, and FDA's evaluation
of a traditional 21-day Caco-2-cell permeability assay for 20
model drugs. She described in detail the method suitability criteria
for the cell culture models and presented the rank order correlation
between in vitro Caco-2 permeability and in vivo human extent
of absorption of the model drugs. There was a clear segregation
between high and low permeability drug substances. The study confirmed
that the concept of method suitability outlined in the BCS guidance
is a practical and feasible regulatory research tool for the evaluation
of drug substance permeability for biowaiver applications. She
went on to add that each laboratory must use method suitability
to demonstrate that its own cell culture assay is capable of classifying
drug substances as high or low permeability.
Vinod Shah of the FDA discussed the utility of BCS in establishing
dissolution specifications. He pointed out that the BCS guidance
is only for immediate release, non-narrow therapeutic index drugs.
The dissolution media and conditions were reviewed and the rapidly
dissolving criteria of 85% in less than or equal to 30 minutes
in each media (using one apparatus and speed) discussed. Vinod
examined the difference in setting specifications for new drugs
versus generic drugs, especially compendial and non-compendial
drugs. The drug product should comply with the specification throughout
its shelf life, so the final specification should be based on
experience gained during the development process and include stability
data. He emphasized that profile data is needed for tests that
have longer than 15 minute specifications (80% Q). The BE dissolution
test will include the QC test, which may be a single point specification,
and additional dissolution tests at the three pH's and profile
points. Based on BCS, dissolution specifications for Class 1 drugs
can be set at 80% Q in 30 minutes.
James Cook of Pfizer presented the industry experience
with the BCS guidance. He discussed its value and limitations.
The obvious benefits are the decreased expense of biostudies but
he showed that only 24% of drugs under the current requirements
would be candidates. He advised that there needed to be an effective
strategy to identify waiver candidates to maximize the savings.
There are some costs however in performing the initial solubility
and permeability studies. Also convincing the responsible parties
to apply for the biowaivers and deciding who will lead the initiative
is troublesome. He closed on a positive note that the implementation
has saved Pfizer one million dollars so far.
Charles DiLiberti of Barr Laboratories gave the generic
industry perspective on the BCS guidance applied to ANDAs. His
assessment of BCS biowaivers was that the current rules severely
limit the savings in cost and subject numbers. He went on to explain
that because the drugs qualifying forBCS waivers have inherently
low intrasubject variability, it is unlikely that, even with proposed
extensions, BCS waivers will ever save a large fraction of R &D
dollars or reduce subject numbers. Major concerns are the uncertainties
in acceptability of data and the potential use of data by competitors.
If the FDA permits referencing data from another firm's permeability
study, this may severely limit business opportunities for the
few firms that conduct these studies. DiLiberti did add that the
industry would gladly welcome any BCS extensions and stated that
the greatest potential benefit of BCS waivers are for the following:
drugs where human exposure is highly undesirable, to avoid the
need for bio-INDs, long half-life drugs with high inter-subject
variability, difficult to recruit subject populations, difficult
bioanalytical analysis, and endogenous compounds.
Robert Lipper from Bristol Myers Squibb reported on the
application of BCS in candidate selection and in guiding early
clinical development strategy. He examined BCS as an aspect of
determining "developability" of a compound, considering
permeability, solubility and even dose. Once a lead compound is
identified then information relevant to probable BCS classification
is critical to selection of Phase 1 dosing strategy and can significantly
influence the preclinical development timeline. He also asserted
that feedback from early clinical BA/PK evaluation of lead compounds
can assist discovery in improving biopharmaceutical characteristics
of subsequent candidates. Lipper stated there are caveats to
BCS, such as, first pass metabolism and dealing with transporters
and efflux.
William Charman of Monash University discussed the practical
approaches to delivery and assessment of BCS Class 2 drugs. With
poorly soluble drugs one must consider the formulation type and
pathway to the in vivo solubility. With conventional immediate
release formulations the in vivo dissolution can be rate limiting
to absorption therefore there is a direct effect of the formulation
and in vivo conditions on absorption. The expectation of an in
vivo/in vitro correlation with Class 2 is an area of active research.
In formulation design Charman listed the areas of improved technology
that enhance solubility: lipid-based systems, solid dispersions,
particle size manipulation, crystal engineering, and complexation
approaches. The biopharmaceutical factors of greatest concern
for Class 2 drugs are the absorption pathway, excipient effects
on GI function, and food effects. His focus shifted to the enhanced
absorption of poorly soluble drugs in the post-prandial state.
The post-prandial state, midway between fed and fasted, has yet
to be addressed. He elaborated further in describing how small
amounts of lipid can alter the luminal environment and ultimately
effect the absorption of the Class 2 drug.
Joseph Polli of GlaxoSmithKline, Inc. spoke on the usefulness
of in vitro P-glycoprotein (Pgp) assays in the context of BCS.
Pgp effects the absorption, distribution and clearance of compounds.
He emphasized that it is important in drug development to identify
the key drug transporters and their genetic variants and elucidate
their role in the disposition of a compound. This establishes
the necessity for robust transporter assays. He also highlighted
the influence of other membrane transporters. He stated that monolayer
efflux assays were his method of choice to identify Pgp substrates.
Future directions of BCS in drug discovery were examined by Vincent
Lee of the University of California. His main focus was that
a comprehensive computational framework might be developed that
incorporates the three drug properties, solubility, dissolution
rate, and intestinal permeability. Drug affinity for its receptor
would also be a component. BCS will possibly accelerate the pace
of a movement towards a cellular and subcellular focus as the
basis of optimizing drug bioavailability.
Ameeta Parekh of the FDA reviewed the evolution of the
BA/BE regulatory standards from the 1977 BA/BE regulations (Bio
Regs) to today's BCS biowaiver guidance. Some of the key questions
over the years have been- can in vitro dissolution specifications
be physiologically meaningful for immediate release products,
what types of manufacturing/formulation variables are minor, how
can in vitro testing be used to approve major formulation changes,
what mechanistic evidence could be used in lieu of in vivo BE
establishment, and can such evidence be extrapolated to the fed
condition? She reiterated the extramural regulatory research on
the effects of manufacturing variables, permeability studies,
and variables influencing in vivo BE studies. The ultimate product
of all this work has been confidence that the BCS is based on
sound scientific rationale. She suggests that it now seems reasonable
to extend the BCS to the fed state.
Gordon Amidon of the University of Michigan described in
detail the basis for extending BE dissolution standards. He stated
that there could be a new paradigm of reducing unnecessary in
vivo studies based on scientific principles, suggesting that there
could be biowaivers for over 50% of drug products. The extensions
were numerous and the topic of the breakout sessions. He reasoned
that Class 3 could have a dissolution rate specification if the
excipients would not interfere with absorption. Other extensions
were to change the solubility range from pH 1 to 7.4 to pH 1.0
to 6.8 and Class 2 drugs that were highly soluble in pH 6.8 should
be considered for biowaivers. He also commented on applicability
of BCS to the PAT initiative.
Brian Houston of the University of Manchester presented
on the role of metabolism in predicting BA/BE in the context of
BCS. His focus was that first pass metabolism is important in
dictating the systemic concentrations of a drug following oral
administration. The metabolic clearance is presently considered
an important additional drug property in BCS. The impact of intestinal
metabolism causing a marked change in therapeutic outcome is well
known. These issues are not addressed by the in vitro test but
this is the subject of recent research. Ronald Borchardt of the
University of Kansas continued on the subject of transporters,
discussing whether the cell culture models could be predictive
of transporter mediated drug permeation in the context of BCS.
The excipient effect on permeability in vivo was examined by Jim
Polli at the University of Maryland. He discussed the methodology
for permeability classification, including considerations for
excipient effects. He higlighted the excipients sodium lauryl
sulfate, Tween 80, HPMC, Vitamin E TPOS, and cremophor.
Lawrence Yu of the FDA spoke on the challenges and opportunities
for BCS-based biowaiver extensions. He observed that using literature
data was not found to provide adequate support for regulatory
requirements. Yu stated that there were many possible ways to
extend the BCS biowaiver. The first was to change the current
solubility range from pH 1.2-7.4 to pH 1.2 6.8. The second
was to look at 500 mL as the average volume for the small intestine;
therefore the 250 mL may be replaced by 500mL for solubility determinations.
The third extension may be to drop the permeability level from
90% absorbed to 85%. The fourth possibility was to use the acceptable
Class 1 dissolution rates for Class 2 with the use of surfactants
or 6.8 pH buffer. The fifth extension was to look at Class 3 and
apply the dissolution rate of 85% in 15 minutes for all three
media. With Class 3 the issue of transporters was discussed along
with excipient effects.
Hans Junginger of Leiden University spoke about the pilot
project of the FIP BCS Special Interest Group Database called
the International Biopharmaceutical Classification Data Base (IBCDAB).
This project was undertaken because there is a need for BCS data
of active substances and their finished products to be available
in the public domain.
Arthur Straughn of the University of Tennessee presented the results
of a FDA study performed to evaluate the potential for bioinequivalence
between AB rated BCS Class 1 generic formulations under fed conditions.
The conclusions were that food did not effect BE of the formulations
tested, that a biowaiver would seem rationale for Class 1 drugs,
and there was preliminary evidence for Class 3 biowaivers.
Dale Conner of the FDA reported that the draft guidance
for food effects was available for comment. The guidance allows
for BCS biowaivers for fed studies. The guidance will be official
in the near future.
The breakout sessions with the summaries can be found on the AAPS
website (www.
aaps.org) under meetings past meetings and summaries.
The key break out session on the subject of dissolution was the
session entitled Solubility Classification and Dissolution Classification.
One major issue raised in this session was that applying the F2
calculation was difficult. The suggestions were to raise or eliminate
the CV requirement, put in a two point spec-15 and 30 minutes,
or that F2 only applies if the time goes out to 45 or 60 minutes.
The extension of the time for the Class 1 requirement to 45 or
60 minutes for the pH 6.8 buffer was suggested. Another suggestion
was to raise the volume in the solubility studies from 250 mL
to 500 mL for pH 4.5 and pH 6.8. An issue with much support was
to allow the paddle speed to be increased to 75 rpm when coning
was present.
Lawrence Yu ended the meeting summarizing the proceedings
and the next steps. There were extensions to be considered for
Class 3 and Class 2, the 90 % absorption level may be lowered,
biowaivers may be in place for fed studies for Class 1, concerns
on the method suitability of the permeability classification will
be addressed, mechanistic causes for a BE failures in Class 3
will be studied, and changes to the solubility range and volumes
will be considered.
Some of the presentations of this workshop can also be found at
the AAPS website. This information will be available for only
three months. There is also another way to view the proceedings
of the workshop at the AAPS website. Go to Education, then Distance
learning and under this workshop title the presentations with
overlay of the speakers voices are available for all the talks
of the workshop. This is an excellent way to get the full information
of the meeting. You must be an AAPS member to get to this information.