W H I T E P A P E R

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Challenging the drug
development blueprint:
A formulators perspective
By John G. Augustine, Ph.D.
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Introduction
There is a large, concerted, and coordinated effort that is responsible for identifying the
best active pharmaceutical ingredient (API) and drug product to be proposed for use in
Phase I clinical testing. The medicinal chemistry group optimizes API production; the
formulation group assures the appropriate solubility and stability of the active drug
product and placebo; DMPK scientists determine bioavailability, and clinical and regu-
latory teams defne the dose levels and product volumes needed for testing.
With dozens of major drugs coming off patent within the next few years, the competi-
tion to be introduced by generic versions of blockbuster drugs such as Lipitor, Plavix,
and Nexium may see pharmaceutical company revenues decrease by 30% or more.
Table 1 summarizes the top ten drugs by sales rank, revenue, and year of patent pro-
tection loss.
Table 1. Top ten drugs coming off patent in the next fve years
Sales rank and
drug name
Company
2008 annual revenue of
drug, $USD (billions)
2008 annual sales,
$USD (billions)
Patent Protection Loss
Lipitor Pfzer 13.2 48.3 2010
Plavix BMS/Sanof 7.4 20.6 2011
Nexium AstraZeneca 7.1 31.6 2014
Advair GlaxoSmithKline 6.9 14.6 2011
Risperdal Johnson & Johnson 4.7 63.8 2011
Zyprexa Eli Lilly 4.6 20.0 2011
Seroquel AstraZeneca 4.5 31.6 2011
Singulair Merck 4.4 24.2 2012
Effexor Wyeth
1
4.0 22.3 2011
Aranesp Amgen 3.9 15.0 2015
Pharmaceutical companies need to replace and supplement these revenue streams with
new products. One way in which this is done is by aquiring promising biotechnology
companies or partnering on specifc programs to complement internal discovery and
development capabilities. Amidst increasing economic pressure, internal and external
groups need to promote a greater quantity of viable programs. The substantial risk and
limited success rates associated with each stage of development demands that only the
best programs are invested in and supported (Table 2). Hence, it is crucial that better op-
tions are offered earlier in development for promotion into preclinical or clinical testing.
1
Acquired by Pzer in 2008.
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Innovation Efficiency
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Effective management throughout
Table 2. Drug development stages
Major development
stage
Discovery and early
development
Preclinical development Clinical development
Major Activities Target identifcation
Hit generation
Lead validation
Assay development
Structure-activity
relationship
Identifcation of lead(s)
In Vitro ADME
Lead optimization based on in vitro, cell-
based, and animal models of disease
Animal effcacy and dosing studies
Drug development
Establish drug characteristics including
stability, bioactivity, bioavailability
Determine both drug and drug product
processes and purity
GLP toxicology and pharmacokinetics
ADME
Phase 1: safety; <100 healthy
volunteers
Phase 2: initial effcacy and
safety; small patient popula-
tion, 100-300 patients with
condition
Phase 3: comparative effcacy
and safety; larger patient pop-
ulation, 1,000-3,000 patients
with condition
Time Range 1-2 years 3-5 years
Additional 3-6 month period to compile
IND and obtain FDA review
Phase 1: 1-2 years
Phase 2: 2-3 years
Phase 3: 3-5 years
Additional 6 month to 3 year
period to compile NDA and
obtain FDA review
Stage Success
Rate
<<1 % <10 % Phase 1: <25 %
Phase 2: <50 %
Phase 3: <75%
By increasing the number of viable programs from discovery and early development into
preclinical testing, it may be possible to increase the likelihood of success during the transi-
tion into clinical testing and through the approval process. Innovatively applying concepts
and tools from formulation development earlier can add formulation criteria to the selec-
tion process and help inform the selection of an API for continued development.

To keep intra-company operations lean, outsourcing certain activities such
as formulation development remains an option and one in-
creasingly used. In addition, contract research
organizations, CROs, that offer for-
mulation development need to offer a
comprehensive service set by which its
clients can be saved time and money. More
importantly to the prospective client, a successful CRO
will challenge the current development paradigm through
innovation, effciency, and time management (Figure 1).
Innovation
One of the key steps in drug development is identifying the
composition of formulations for use in preclinical or clinical
testing. In the current drug development paradigm, the formulation development
process begins after lead identifcation and optimization of the API or class of mol-
ecules. The main driving force in the selection process is in vitro assays which provide
key data on the API. These assays usually defne absorption, distribution, metabolism,
Figure 1. Client/CRO interface
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excretion, and toxicity (ADMET) properties. However, systemic physiological processes
are complex and can not be replicated by in vitro testing only. Thus, a chief aim of for-
mulation development is to identify the best vehicle for delivery of the API to facilitate
in vivo testing.
Formulation development often is mistakenly considered a discrete activity to be ex-
ecuted after nomination of a lead compound. By applying formulation principles in dis-
covery and early development, selection of better compounds during lead candidate(s)
identifcation and optimization may be possible. The diffculty of developing a suitable
formulation often relates to molecules that have challenging aqueous solubility and
limited stability. By considering the inherent diffculties of formulating a candidate
molecule prior to, or as part of the nomination process, formulation scientists can pro-
vide valuable insight into the likelihood of developing a successful drug product long
before considerable resources have been expended.
A molecules solubility and permeability
are two parameters that characterize
the molecule with respect to the FDAs
Biopharmaceutics Classifcation Sys-
tem; i.e. the BCS Class of the molecule.
Figure 2 represents the BCS framework
and how formulation development may
generate Class 1-like properties.
Knowledge about the molecules BCS
category will inform formulation de-
velopment efforts and correlate in vivo
performance. Furthermore, formulation
development can enhance the molecules
bioavailability by improving solubility (for Class 2 molecules) or permeability (for Class
3 molecules). Low solubility, low permeability, low dissolution rate, and susceptibility
to frst-pass metabolism in the liver comprise the primary set of reasons drugs fail on
the path from discovery to market.
By adding formulation criteria to the nomination process, more readily-soluble mol-
ecules can be selected, assuming all other required ADMET criteria are roughly equal
or comparable. Two potential strategies for obtaining solubility data are: a matrix
formulation screen or the development of a single vehicle in which numerous API are
characterized for solubility or other properties.
Figure 2. BCS framework
Class 2 Class 1
Class 4 Class 3
enhance solubility
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In a formulation screen, a series of compounds are tested against a small matrix of
vehicles, containing up to perhaps 20 different vehicle compositions. Each individual
vehicle is comprised of a blend of solubilizing agents commonly reported for use in the
FDA Inactive Ingredient Guide. In a screening mode, cost-effective LC-MS methodol-
ogy is employed to facilitate rapid testing of a large group of molecules, as in the case
of SPEED (Screen of pH and Excipients for Early Development) technology offered
by SP Formulations. Single-point calibration is employed, assuming roughly equal
response of each API from the group. With a large dynamic range, sample prepara-
tion is made easier by looking for a response consistent with standard and percentages
thereof, such as shown in Table 3 below. The selection criteria being rank order of
compounds by solubility.
Table 3. Formulation screen matrix and sample response
Molecule #
Vehicle #
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1
2
3
4
5
6
7
8
9
10
Data can be leveraged to design early formulation prototypes for ADMET and other
testing needs without the use of noxious solvents such as dimethyl sulfoxide (DMSO).
Typically, this testing can be completed within 3 business days. This can be a key selec-
tion strategy when a plethora of candidates are generated by high throughput screening
methods. Early selection of compounds more likely to be solubilized in in vivo friendly
excipients will direct the drug development program towards a more meaningful ending.
Alternatively, a single vehicle can be identifed for use initially with a single molecule,
and used without modifcation with other lead compounds as R-groups or other chem-
istry is optimized. This would be more appropriate for more serial type of development,
in which later experiments inform the necessary changes in molecule design. This
could be an a priori selection of a commonly available, commonly used vehicle, such
as saline, phosphate buffered saline or 5% dextrose. These vehicles may not offer any
particular advantage to the solubility or stability of the API in solution, but if used
uniformly, can offer comparison of solubility levels of each compound.
<10% of standard response <50% of standard response <100% of standard response
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Effciency
Following lead selection, effciency is now a key factor in the drug development process.
The data obtained to this point in the program indicate that the selected API has the
greatest chance for success and the development team eagerly awaits the frst set of
data from in vivo testing. The pre-formulation data set needs to be collected as expedi-
tiously and thoroughly as possible so a meaningful formulation can be defned. Once
collected, formulation development experiments can now be tailored to address the
intended dosage route. Formulation research and development includes the following,
with key pre-formulation experiments highlighted in bold text.
Rapid, but rigorous pre-formulation research can accelerate the time to formulation.
Choosing to work with an experienced CRO team will more effectively troubleshoot
problems and interpret data encountered during pre-formulation experiments. In addi-
tion, nuances in pre-formulation experiments will be detected and investigated. Take
for instance a solubility experiment in which the observed intrinsic solubility steadily
increased as the nominal target concentration of API was raised. Initial equilibrium
solubility experiments were conducted at much lower concentrations to conserve API.
Upon selecting a number of lead prototype formulations, successive experiments saw
progressively more API dissolve: up to 10 times the initial nominal concentration!
Later experimentation suggested the formation of micelles, with the observed increase
in solubility due to experimental conditions above the critical micelle concentration
(CMC) of the API.
Depending on resource availability, it may be desired to submit prototype formulations
for in vitro or in vivo testing, before the fnal composition of the formulation is estab-
Intrinsic solubility
Solubility and stability in key physiologic fuids
Solubility and stability with respect to pH
(for molecules with ionizable groups)
Solubility and stability in relevant
formulation matrix
Effect of buffer species, ionic strength
Hygroscopicity
pKa, partition coeffcient
Thermal properties via differential scanning
calorimetry (DSC)
Moisture content by Karl Fischer (KF), loss
on drying
Excipient selection
API stability studies and forced
degradation studies
Dissolution optimization
Compound stabilization
Design of various dosage form prototypes
Short-term accelerated stability studies on
formulation prototypes
Determination if lyophilized drug product
is required
Sterilization studies
Container-closure compatibility studies
Characterization of preclinical dosing:
dilution studies or dose recovery
Optimization studies to justify formulation
composition and process
Real-time and accelerated stability studies of
drug product and placebo
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lished. The compositions are informed by the pre-formulation data, such as whether
an organic solvent, encapsulating agent, or buffer is required to achieve a particular
solubility level. Laboratory-scale formulation prototypes can be produced for activity
assays or toxicity testing. This can include general toxicology testing (acute, sub-acute,
chronic, sub-chronic) or any special, genetic, reproductive, and developmental toxicol-
ogy required. Experience will guide the composition of the formulation vehicle, based
on knowledge of other formulations submitted for similar testing, as well as a review of
the FDA Inactive Ingredient Guide, to identify formulations that should have minimal
vehicle effects. And, again, experience can help judge how close a prototype might
be to a formulation composition suitable for either the full range of toxicology testing
or frst-in-man testing. It is important to balance the time and resources required to
develop a perfect formulation against the compelling case to start Phase I testing as
soon as possible. Since the Phase I clinical trial is oriented to establishing the safety
of the drug, an easy-to-prepare formulation that can be made in a clinical pharmacy is
likely the best approach. A simple solution or suspension formulation may be appropri-
ate to initiate clinical testing, during which development of a more optimal formulation
can occur in parallel. This may range from tablet or capsule formulations for an orally-
administered drug product, or a unit product vial for a parenteral drug product.
Conclusion
There are substantial fnancial instability and risks in the pharmaceutical industry to-
day. The path from beaker to patient is beset with far greater likelihood of failure than
success. Because of the level of investment required to see a program approved by the
FDA as well as the possibility of failure at each stage of development, it is increasingly
important to promote the best candidates for a full development program.
This article holds a broad perspective on formulation development. It is neither a
simple transactional activity nor a discrete single step, as it has substantial impact on
immediately-following and further downstream activities. By being innovative early
during discovery and effcient during later development, the formulation development
process can have a positive impact on downstream success.
Integrating concepts of formulation development throughout the discovery and devel-
opment process can help promote more viable drug candidates for testing in preclini-
cal and clinical trials. Moreover, additional data on stability and other unforeseen
drug product concerns can be collected earlier if an effort is made to defne workable
formulations as a part of the lead compound selection process. Suitable working for-
mulations may be submitted for ADMET or other testing sooner, in order to establish
important facets of the drugs safety or effcacy. Depending on the elected strategy and
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the amount of risk assumed, ongoing data collection on continued formulation develop-
ment may minimize the possibility of cross-over studies. By challenging the paradigm
that formulation development is a modular activity used only at a designated phase of
drug development, one increases the likelihood of turning an API into a successful
drug product.
References
The author wishes to thank Nicole Krilla, MS, for editorial comments to the manuscript
and graphic concepts.
For more information on drug development success, visit the following web sites:
http://www.marketwatch.com/story/is-americas-long-nightmare-of-rising-drug-prices-over
http://www.antitrustreview.com/archives/1293
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spon <http://query.nytimes.com/gst/fullpage.html?res=9D07E0DE1530F930A15751C1A9639C8B63&
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http://www.nasdaq.com/aspx/company-news-story.aspx?storyid=200908191054dowjonesdjonline000433
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