Introduction:
The Biopharmaceutics Classification System (BCS)
is not only a useful tool for obtaining waivers for in vivo bioequivalence studies but
also for decision making in the discovery and early development of new drugs.
It is because BCS is based on a scientific framework describing the three rate
limiting steps in oral absorption. The three necessary steps for a drug to be
absorbed are release of drug from dosage forms, maintenance of dissolved state
throughout gastrointestinal (GI) track, and permeation of drug molecules
through GI membrane into hepatic circulation. There is a fourth step, i.e.
enterohepatic metabolism that influences the systemic availability as well as
release of metabolites into the systemic circulation. The Biopharmaceutical
Drug Disposition Classification System (BDDCS) proposed by Y. Wu and L. Z.
Benet completes the absorption process by including the fourth rate-limiting
step of first pass effect.
The evaluation of these four
steps of oral absorption is critical to the discovery of orally efficacious
drugs. Consequently the determination of solubility, permeability, and
metabolic stability have been fully integrated by most pharmaceutical companies
as an integral part of high throughput screening (HTS) and lead optimization.
These oral absorption screening tests are often referred as pharmaceutical
profiling and automated 96 well systems are available from commercial sources.
It is argue-able that application of BCS in lead compound selection for optimal
chemistry may be more important than using BCS in biostudy waiver at a later
development stage. After all, the aim of pharmaceutical industry is to discover
better compounds not in doing less biostudies.
The pharmaceutical scientist
in early development routinely utilizes pharmaceutical profiling data to
establish the preliminary BCS classification for the lead compound. Because BCS
has ramification in drug approval process from FDA and other regulatory
agencies, it carries some weight when used as a tool of communication. During
the discovery of new drugs, classification of a compound to BCS 2, BCS 3 or BCS
4 communicates to Discovery the need to improve solubility and/or permeability
for subsequent compounds. In the same vein, a BCS classification other than 1
communicates to Manufacturing that may lead to higher formulation risks during
drug development. Most importantly, it warns the clinician of the potential for
a large variability in exposure and a significant food effect.
With the advent of high
throughput screening around 1990, a shift of lead compound biopharmaceutical
characteristics into less drug-like has propelled discovery departments in
pharmaceutical companies to utilize computational chemistry to optimize
solubility and permeability such as Lipinski’s “rule of 5”. This shift is
recently reflected in the different distributions among the four BCS classes
between the marketed and the new pipeline compounds. The new drug pipeline
tends to have lower solubility resulting in an increase of BCS 2 compounds from
~30% to 50–60% and the corresponding decrease of BCS 1 compounds from ~40% to
10–20%. It is critical for the industry to continuously integrate the BCS
principles into new drug discovery. Moreover, BCS classification may be
utilized as the basis for polymorph/salt and formulation selections in early
drug development as discussed in this paper.
The BCS based drug discovery
strategy imparts quality by designing the lead compound with a set of
solubility, permeability and metabolic properties. The BCS based polymorph/salt
form and formulation strategies can often lead into a minimum design for higher
efficiency and lower cost. It is in line with FDA’s year 2000 risk management
and 2004 critical path initiatives to streamline new drug development.
Purpose of the
BCS Guidance:
- Expands
the regulatory application of the BCS and recommends methods for
classifying drugs.
- Explains
when a waiver for in vivo bioavailability and bioequivalence studies may
be requested based on the approach of BCS.
Goals of the
BCS Guidance:
- To improve
the efficiency of drug development and the review process by recommending
a strategy for identifying expendable clinical bioequivalence tests.
- To
recommend a class of immediate-release (IR) solid oral dosage forms for
which bioequivalence may be assessed based on in vitro dissolution tests.
- To
recommend methods for classification according to dosage form dissolution,
along with the solubility and permeability characteristics of the drug
substance.
According to
the BCS, drug substances are classified as follows:
Class I - High
Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility
CLASS
BOUNDARIES
- A drug
substance is considered HIGHLY SOLUBLE when the highest dose strength is
soluble in < 250 ml water over a pH range of 1 to 7.5.
- 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
mass-balance or in comparison to an intravenous reference dose.
- A drug
product is considered to be RAPIDLY DISSOLVING 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 solutions.
SOLUBILITY
DETERMINATION
- pH-solubility
profile of test drug in aqueous media with a pH range of 1 to 7.5.
- Shake-flask
or titration method.
- Analysis
by a validated stability-indicating assay.
PERMEABILITY
DETERMINATION
Extent of
absorption in humans:
- Mass-balance
pharmacokinetic studies.
- Absolute
bioavailability studies.
Intestinal
permeability methods:
- In vivo intestinal perfusions studies in humans.
- In vivo or in situ intestinal perfusion studies
in animals.
- In vitro permeation experiments with excised human or
animal intestinal tissue.
- In vitro permeation experiments across epithelial cell
monolayers.
DISSOLUTION
DETERMINATION
- USP
apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm.
- Dissolution
media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and
pH 6.8 buffer or simulated intestinal fluid.
- Compare
dissolution profiles of test and reference products using a similarity
factor (f2).
BCS BIOWAIVER
- Rapid and
similar dissolution.
- High solubility.
- High
permeability.
- Wide
therapeutic window.
- Excipients
used in dosage form used previously in FDA approved IR solid dosage forms.
REQUEST FOR
BIOWAIVERS
Data Supporting
Rapid and Similar Dissolution
- A brief
description of the IR products used for dissolution testing.
- Dissolution
data obtained with 12 individual units of the test and reference products
at each specified testing interval for each individual dosage unit. A
graphic representation of the mean dissolution profiles for the test and
reference products in the three media.
- Data
supporting similarity in dissolution profiles between the test and
reference products in each of the three media, using the f2
metric.
Data supporting
High Permeability:
- For human
pharmacokinetic studies, information on study design and methods used
along with the pharmacokinetic data.
- For direct
permeability methods, information supporting method suitability with a
description of the study method, criteria for selection of human subjects,
animals, or epithelial cell line, drug concentrations, description of the
analytical method, method to calculate extent of absorption or
permeability, and information on efflux potential (if appropriate).
- A list of
selected model drugs along with data on the extent of absorption in humans
used to establish method suitability, permeability values and class for
each model drug, and a plot of the extent of absorption as a function of
permeability with identification of the low/high permeability class boundary
and selected internal standard.
- Permeability
data on the test drug substance, the internal standards, stability
information, data supporting passive transport mechanism where
appropriate, and methods used to establish high permeability of the test
drug substance.
Data supporting
High Solubility:
- Description
of test methods (analytical method, buffer composition).
- Information
on chemical structure, molecular weight, nature of drug substance,
dissociation constants.
- Test
results summarized in a table with solution pH, drug solubility, volume to
dissolve highest dose strength.
- Graphical
representation of mean pH-solubility profile.
BCS Class in Pharmaceutical Industry:
The Biopharmaceutical
Classification System (BCS) is an experimental model that measures
permeability and solubility under prescribed conditions. The original purpose
of the system was to aid in the regulation of post-approval changes and
generics, providing approvals based solely on in vitro data when
appropriate. Importantly, the system was designed around oral drug delivery
since the majority of drugs are and remain orally dosed. Waivers, permission to
skip in vivo bioequivalence studies, are reserved for drug products
that meet certain requirements around solubility and permeability and that
are also rapidly dissolving.
More and more however,
the industry is using the BCS as a tool in drug product development. As a
simple example, BCS can be used to flag drugs that should not be tested clinically
unless appropriate formulation strategies are employed. As an example, a BCS
Class II compound, permeable but relatively insoluble, would likely not be a
good clinical candidate without the use of enhanced formulation techniques
aimed at increasing solubility or rate of dissolution. Various schemes exist
that attempt to funnel a given API towards particular drug delivery techniques
depending on the API’s BCS category. Still, most approaches remain fragmented
in their methodology, ignoring commercially and biologically important factors.
The BCS can however, when integrated with other information provide a
tremendous tool for efficient drug development. One school of thought, very
much endorsed by the authors, is that first in human (FIH) drug dosage forms
should be designed to maximize bioavailability and that the FIH dosage form
should be a logical step towards commercialization and not simply a stop gap to facilitate data acquisition. This makes
sense both economically and ethically.
For BCS Class I
molecules, FIH formulations are straight forward and may consist of essentially
the neat API. For other compounds, effective dosage forms present greater
challenges. Although designed originally to classify APIs as to their oral
bioavailability, properly augmented, the BCS can be used as a key component of
an algorithm to guide drug delivery system design for any route of
administration. This notion has been elaborated on by a number of authors.
Briefly, the BCS places
a given API in one of four categories depending on its solubility and
permeability as they pertain to oral dosing. A drug substance is considered
“highly soluble” when the highest clinical dose strength is soluble in 250 mL
or less of aqueous media over a pH range of 1–7.5 at 37 °C. A drug substance is
considered to be “highly permeable” when the extent of the absorption (parent
drug plus metabolites) in humans is determined to be ≥90% of an administered
dose based on a mass balance determination or in
comparison to an intravenous reference dose2. Permeability can be determined a
number of ways but is most often done using Caco-2 cell lines an assay that
lends itself to high throughput automation. In this system, a monolayer of
cells is grown and drug permeation from the drug donor (apical side) to the
acceptor (basolateral side) compartments is assessed, usually by using a
direct UV or LC-MS assay. Potential issues with Caco-2 based systems range from
variation (from in vivo) in transport mechanisms to drug interactions
with the apparatus itself. Commercial companies focused on this assay have
developed multiple approaches to alleviate these issues but a review is beyond
the scope of this paper and the reader is encouraged to contact the various
suppliers. As a drug candidate moves up the development ladder, developers
will often confirm and refine their BCS assessments with increasingly complex in
vivo models.
An important subtlety
here is that the BCS accounts for potency in that solubility and permeability
are relative to clinical dose. Again, oral dosing is assumed in the testing
design. So, for example, a compound that has poor absolute solubility might
paradoxically be classified as “highly soluble” if it were a highly potent
compound and the whole clinical dose was soluble in 250 mL.
BCS and Dosage Form Trends:
It is commonly recognized that most new drugs present formulation
challenges. In fact, older drugs as compared to newer ones have higher
solubilities in general. One reference noted that BCS Class II compounds as a
percentage of compounds under development had increased from 30% to 60%. BCS
Class I compounds have fallen correspondingly from 40% to 20% over that same period3.
In practice, low solubility is the
most common theme encountered. In our own experience the majority of compounds
formulated at Particle Sciences on the behalf of our clients have low to no
aqueous solubility.
It should be noted that not every drug is classified the same by each
investigator. The variability can be due to a number of things including the
way permeability is measured. As above, in vivo permeability is
impacted by, among other things, drug transporters. Both uptake and efflux
transporters exist and can contribute to the differences seen by the various
techniques.
For the majority of
APIs a solid oral dosage form (SOD) is the preferred option. Sometimes the
physicochemical and physiologic mechanisms do not allow this and alternatives
are pursued such as suspensions or oral solutions. Other times, the target and
other factors dictate that a non-oral dosage form is most sensible. Examples
include the local delivery of female hormones, nasal allergy preparations,
ocular therapeutics and combination products aimed at prolonged drug release.
In all these cases, even though not orally dosed, the concepts inherent in the
BCS can be important tools in dosage form design.
Formulation Approach:
Having a pre-defined system in which one can make decisions based
on data is necessary for efficient drug development. Inputs into such a system
include, in addition to BCS class, a detailed solubility profile, polymorph status,
desired dosage form, target dose and dosing regimen, drug stability, excipient
compatibility and knowledge of transporter and metabolic pathways. Non-technical
factors that, as a practical matter, need to be considered are such things as
cost, intellectual property and distribution chain limitations. Integration of
these into a methodical systematic approach will maximize the chances of a
successful outcome. As R&D dollars become ever more scarce, it becomes
increasingly evident that
early consideration of as many factors as possible is the most efficient way
to proceed. This is true independent of the route of administration. In
practice, this leads to the strategy of getting to FIH as quickly as possible
with a formulation strategy that accounts for both physicochemical properties
and physiologic influences.
A complete set of
algorithms covering the four classes and all possible dosage forms is well beyond
the scope of this article. However, a few fundamental principles can be
covered. First, it is critical to characterize your compound. Understanding
the basic behavior of a given compound in various solvents and across a range
of pHs is fundamental to designing a dosage form. For instance, a compound
soluble only at lower pHs will require a different formulation than one freely
soluble at, for example, pH 7. Likewise, a soluble yet impermeable compound
will require yet another strategy. Very importantly, this is true whether one
is administering the drug, for example, IV or orally. The implications to formulation
are different for the different routes of administration but the fact that
these properties need to be accounted for is universal. It is important that
the drug developer or the CRO be equipped with a range of technologies to
address the various patterns that emerge. Nothing wastes more time and money
than trying to fit a drug to a specific preordained delivery technology.
Armed with the
proper set of tools one can rapidly narrow down the potential approaches. For
the most part, all drug delivery strategies are trying to control drug
exposure. Most often, one is trying to maximize it over time and/or
concentration but frequently goals also include extended release and/or site specific
delivery. In addition to the delivery goals, other functions are often required
such as API stabilization or taste masking as two examples. In short, no one
formulation approach will ever satisfy all or even a substantial portion of
drug delivery demands.
For oral drug
delivery, a simplified summary of approaches based on properties. Each approach
must then be tailored to meet the other demands of that particular API and
desired product profile.
If formulation
conditions dictate that a non-oral dosage form be used, similar charts exist
for virtually all routes of administration. Each route of administration will
of course have different options but they are all ruled by the interplay of the
drug’s physicochemical properties and the local and systemic physiology they
encounter.
Independent of the
final dosage form, ideal drug
development involves an iterative process of setting goals, performing
formulation work and developmental stage appropriate testing. Early on, for
example, after physicochemical evaluations are complete, screening BCS testing
and early polymorph screens might be performed. After thorough preformulation
including solubility and stability testing, early formulations might again be screened
for their impact on dissolution or bioavailability. This approach is repeated
such that at each inflection point data is gathered to support the development
plan. In this way, FIH is achieved most efficiently and in such a way as to
insure clinically relevant data is obtained.
References
1.
Chi-Yuan Wu and Leslie Z. Benet, Predicting Drug Disposition via
Application of BCS: Transport/Absorption/Elimination Interplay and Development
of a Biopharmaceutics Drug Disposition Classification System, Pharmaceutical
Research, January 2005, 22(1), 11-23.
4.
M. Sherry Ku, Use of the Biopharmaceutical Classification System
in Early Drug Development, AAPS J., March 2008, 10(1), 208–212.
