challenging the drug development blueprint a formulators perspective

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Challenging the drug development blueprint: A formulator’s perspectiveBy John G. Augustine, Ph.D.


IntroductionThere 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 define 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 five yearsSales rank and

drug name Company 2008 annual revenue of drug, $USD (billions)

2008 annual sales, $USD (billions) Patent Protection Loss

Lipitor Pfizer 13.2 48.3 2010

Plavix BMS/Sanofi 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 Wyeth1 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 specific 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.

1Acquired by Pfizer in 2008.

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Innovation Efficiency

SPFCLIENT

LEADIDENTIFICATION

IDENTIFICATION

SYNTHESIS ANDSELECTION,

CHARACTERIZATIONPRODUCT

DRUG

DEVELOPMENT

SUPPLIESTOXICOLOGY

PRODUCTDRUG

CHARACTERIZATIONLEADDEVELOPMENT

METHOD

ANALYTICAL

FOR IND

SUPPORTCMC

STA

RT

Effective management throughout

Table 2. Drug development stagesMajor development

stageDiscovery and early

development Preclinical development Clinical development

Major Activities • Target identification• Hit generation• Lead validation • Assay development • Structure-activity

relationship• Identification of lead(s)• In Vitro ADME

• Lead optimization based on in vitro, cell-based, and animal models of disease

• Animal efficacy 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 efficacy and safety; small patient popula-tion, 100-300 patients with condition

• Phase 3: comparative efficacy 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, efficiency, and time management (Figure 1).

InnovationOne 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 identification 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 define 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)

identification and optimization may be possible. The difficulty of developing a suitable

formulation often relates to molecules that have challenging aqueous solubility and

limited stability. By considering the inherent difficulties 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 molecule’s solubility and permeability

are two parameters that characterize

the molecule with respect to the FDA’s

Biopharmaceutics Classification 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 molecule’s BCS

category will inform formulation de-

velopment efforts and correlate in vivo

performance. Furthermore, formulation

development can enhance the molecule’s

bioavailability by improving solubility (for Class 2 molecules) or permeability (for Class

3 molecules). Low solubility, low permeability, low dissolution rate, and susceptibility

to first-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

enha

nce

perm

eabi

lity

LOW HIGHS O L U B I L I T Y

LOW

HIGH

PE

RM

EA

BIL

ITY

4


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 identified for use initially with a single molecule,

and used without modification 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

5


EfficiencyFollowing lead selection, efficiency 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 first 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 defined. 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 final composition of the formulation is estab-

• Intrinsicsolubility

• Solubilityandstabilityinkeyphysiologicfluids

• SolubilityandstabilitywithrespecttopH(for molecules with ionizable groups)

• Solubilityandstabilityinrelevant formulation matrix

• Effectofbufferspecies,ionicstrength

• Hygroscopicity

• pKa,partitioncoefficient

• Thermalpropertiesviadifferentialscanningcalorimetry (DSC)

• MoisturecontentbyKarlFischer(KF),losson drying

• Excipientselection

• APIstabilitystudiesandforced 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

6


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 first-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.

ConclusionThere are substantial financial 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 efficient 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 define 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 drug’s safety or efficacy. Depending on the elected strategy and 7


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

http://query.nytimes.com/gst/fullpage.html?res=9D07E0DE1530F930A15751C1A9639C8B63&sec=&

spon <http://query.nytimes.com/gst/fullpage.html?res=9D07E0DE1530F930A15751C1A9639C8B63&

sec=&spon> =

http://www.nasdaq.com/aspx/company-news-story.aspx?storyid=200908191054dowjonesdjonline000433

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challenging the drug development blueprint a formulators perspective

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