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The Authority on Drug Development & Manufacturing
PharmTech.com
January 2012
Volume 36
Number 1
FDA’s Perspective
on Starting Materials
The Drug Development
and Analytical Toolbox
Jim Miller’s Outsourcing Outlook: Contract Services in 2012
PEER-REVIEWED
Assessing Tablet-Sticking Propensity

Antibody–Drug
Conjugates
Looking ahead
to an emerging class
of biotherapeutic
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phar mt ech. com
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January 2012 Volume 36 Number 1


On PharmTech.com
Cover Story:
Antibody–Drug Conjugates
42 Looking Ahead to
an Emerging Class of
Biotherapeutic by Amy Ritter
A successful antibody–drug conjugate requires
careful selection of the drug, antibody, and linker.
Compositing by Dan Ward.
Images: Nick Koudis/Ingram Publishing/Getty Images
Pharmaceutical Technology is the authoritative source of peer-reviewed research and
expert analyses for scientists, engineers, and managers engaged in process devel-
opment, manufacturing, formulation and drug delivery, API synthesis, analytical
technology and testing, packaging, IT, outsourcing, and regulatory compliance in the
pharmaceutical and biotechnology industries.
Features
Technical Forum
48 Multilayer-
Tablet Technology
Moderated by Rich Whitworth
and Stephanie Sutton
Industry experts discuss formulation
and technical challenges in multilayer
tablet manufacture.
Pharma ingredienTs
52 Broadening the
Drug Development and
Analytical Toolbox
Patricia Van Arnum
A look at recent advances in
accelerating reaction discovery,
inducing chirality and stereochemical
analysis, and nanotech applications
for protein elucidation.
Plus: Formulation Development Forum.
Fda PersPecTives
63 Designation of
Regulatory Starting
Materials in the Manufacturing
of Drug Substances:
Impact on ANDA Review Time
Barbara Scott, FDA
The author describes how provid-
ing appropriate information about
the API in the Common Technical
Document can aid FDA’s review of an
abbreviated new drug application.
Peer-reviewed research
FormulaTion develoPmenT
57 Assessing Tablet-
Sticking Propensity
Matthew P. Mullarney,
Bruce C. MacDonald, and Allan Hutchins
The authors designed an upper
punch with a removable punch tip to
determine a tablet formulation’s pro-
pensity to stick by weighing the mass
of powder adhered to the punch tip.
Continued on page 10
Issue extras

Find additional interviews
from this month’s technical forum
on multilayer tablet technology
on PharmTech.com/multilayer.

Reader comment
“Scientific facts should play a leading
role, but not an exclusive role, in de-
termining what drugs are available to
whom,” in response to a blog post on
“Is HHS Using Scientific Standards?”
Read more conversations on our blog
at blog.PharmTech.com
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Continued from page 8
Columns
From The ediTor
12 Here’s to a
year of Compromise
Angie Drakulich
The benefits of harmonization
may be on the industry’s wish list, but
buying into change is another story.
PharmTech Talk
14 Cutting Prices
to Save Sales
Erik greb
Copay coupons may help patients
and drugmakers, but who ends up
holding the bag?
agenTinPlace
16 All Systems Slow
Control, a Senior Compliance officer
Technology may expedite
operations, but the absence of the
human element could cost dearly.
washingTon rePorT
28 Budget Crunch, Politics
Shape Policy Agenda
Jill Wechsler
Pressure to approve new user fees
opens the door to action on drug
shortages, prices, and regulation.
bio Forum
36 Venture-Capital
Funding Falls
Tracey T. Lefteroff
Challenges remain, particularly for
early-stage biopharm companies.
Packaging Forum
38 Innovations for 2012
Hallie Forcinio
Packaging innovations boost
productivity, meet regulatory
requirements, and protect products.
inside usP
67 global Harmonization
opportunities and Challenges
Anthony DeStefano and Kevin Moore
To keep moving forward, the
Pharmacopoeial Discussion Group
needs industry participation.
ouTsourcing ouTlook
68 Contract Services for 2012
Jim Miller
Recent private-equity buyouts
of CROs show the up- and
down-side for investors.
viewPoinT
88 Innovator Liability Still Not
Viable after Pliva v. Mensing
Zach Hughes
Recent legal decisions have
further divided generic and
brand manufacturer cases.
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FROM THE EDITOR
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PharmTech.com/forum
I
t is in the New Year that we often set
goals to im prove ourselves, whether
it’s trying to get fit, move up the career
ladder, spend more time helping others
in need, or any other number of personal
quests. But individuals aren’t the only
ones who make long-term goals—so do
governments, organizations, and for our
purposes, this industry. Harmonization
of drug development and manufacturing
approaches comes to mind.
I’m a big supporter and follower of har-
monization initiatives, but I get the feeling
that not everyone in industry is as gung-
ho about the idea. At several industry
meetings during the past year, I’ve asked
people what they think of harmonization
and whether they believe certain aspects of
pharma manufacturing will ever be har-
monized (e.g., elemental impurity limits).
I’ve asked conference participants, for
example, about why it’s necessary for each
nation or region to have its own pharmaco-
peial guide and for an international phar-
macopeial guide to exist. And, for drug-
applicants working to bring a product to
the global market, is there a way to avoid
filling out the same information on 20 dif-
ferent forms? Inspections are another area
lacking harmonization. We all know how
many audit or inspection teams companies
must accommodate in a given year.
Most of the answers I’ve gotten are along
the lines of, “ I don’t know,” or “They would
never agree to compromise on that,” or,
“There’s too much national pride for one
country to change its standards to match
another’s.”
I get that compromise is difficult. In fact,
before coming to Pharmaceutical Technol-
ogy, I spent several years working for a non-
profit focused on the work of the United
Nations. So I understand how much effort
is required to engage productive dialogue
and garner compromise among a diverse
and global audience. I also get that the bio/
pharmaceutical industry is highly protec-
tive of its information and practices—it is
a competitive, patent-based, trillion-dollar
industry after all. But I also think that
some of the key elements of harmonization
are getting lost in translation.
Industry seems to want globally stan-
dardized approaches to their processes
and quality systems as well as minimal
routes for filing marketing applications
and other required documents. Reaching
these goals would make life easier for all
parties involved. Having an agreed-upon,
worldwide approach to quality and supply-
management, for example, could literally
solve many of the drug-product contami-
nation and adulteration issues that have
plagued the industry in recent years. And
yet, many companies and national regula-
tory or standard-setting bodies seem un-
willing to give up their current practices or
accept that another company, organization,
or nation for that matter, may have a better
way of doing things.
Perhaps my vision of global harmoniza-
tion is too lofty or naïve. But there is reason
to hope. The International Conference on
Harmonization was established in 1990
with the aim of increasing “international
harmonization of technical requirements
to ensure that safe, effective, and high qual-
ity medicines are developed and registered
in the most efficient and cost-effective
manner.” In its 20-plus years, ICH has
managed to gain consensus across North
America, the European Union, and Japan,
on 16 Efficacy guidelines, 10 Quality
guidelines, nine Safety guidelines, and has
several multidisciplinary guidelines in the
pipeline. The members of ICH’s Global Co-
operation Group extend the reach of these
guidelines to eight additional countries,
including the leading markets in Asia.
Other global standard-setting bodies,
such as the International Pharmaceutical
Excipients Council and the International
Society for Pharmaceutical Engineering,
are working to shape global industry prac-
tice. And new industry groups working to
share best practices throughout the world
seem to be popping up every month (e.g.,
the Rx–360 and IQ consortiums).
I hope you will take time to learn more
about global harmonization efforts and
talk with your colleagues about how your
organization might become involved,
whether that means providing feedback,
working to implement harmonized guide-
lines, or sharing them with your global
partners. In the meantime, Pharmaceuti-
cal Technology will do its best to keep you
apprised of happenings tied to harmoniza-
tion and what it means for your day-to-day
operations—and that’s just one of many
resolutions we intend to keep this year. PT
Here’s to a Year of Compromise
The benefits of harmonization may be on industry’s
wish list, but buying into change is another story.
Angie Drakulich
Angie Drakulich
is editorial director of
Pharmaceutical Technology.
Send your thoughts
and story ideas to
adrakulich@advanstar.com.
PharmTech.com/forum
Michelle Hoffman, our editorial director from
2007 to 2011, has moved on to pursue new scientific
opportunities. We have the highest regard for her
and the contributions she made to Pharmaceutical
Technology over the past few years, and we wish
her all the best. As the new Editorial Director, I
have many hopes and goals for Pharmaceutical
Technology in the year ahead. Our team will
be working to improve the types of articles and
resources we bring to you in print and online. I am
also happy to announce that 2012 is Pharmaceutical
Technology ‘s 35th anniversary. We will be
celebrating the occasion with retrospective and
forward-looking articles in the coming months. We
welcome your ideas and feedback.
14 Pharmaceutical Technology January 2012 Phar mTech. com
PharmTech Talk
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cutting Prices to Save Sales
Erik Greb
Erik Greb is an associate
editor of Pharmaceutical
Technology.
»
Read Erik’s blogs at
blog.PharmTech.com.
a
s patent protection expires for
top-selling drugs, some firms are
scrambling to stay one step ahead
of generic-drug competitors. Pfizer and
others are wooing insured consumers
by offering copay coupons, which re-
duce the cost of a branded drug. These
coupons are intended to discourage
a patient from switching to a generic
therapy. To redeem the coupons, con-
sumers often must submit personal
information that allows the firms to
promote products to individual patients.
The coupons may help consumers,
but they oblige plan sponsors, such as
employers or state governments, to pay
high prices for branded drugs when
generic alternatives are available. Drug
companies can prevent plan sponsors
from knowing when enrollees have re-
deemed the coupons by processing them
through a “shadow claims system,” ac-
cording to a Nov. 3, 2011 statement
from the Pharmaceutical Care Manage-
ment Association. Copay coupons will
increase costs for these sponsors by
$32 billion over the next decade, accord-
ing to research from Visante.
At a time when state governments and
private companies are pinching pennies,
it’s hard to believe that they will allow
drug companies to use these tactics for
long. Arrangements such as Pfizer’s
agreement to manufacture generic Lipi-
tor for Watson, in exchange for a share
of net sales, seem comparatively more
benign. They don’t appear to constrain
patients’ choice or force payors to spend
more than necessary. In fact, these ar-
rangements might be the “least bad” op-
tion for drugmakers without new block-
busters on the horizon. PT
Copay coupons may help patients and
drugmakers, but who ends up holding the bag?
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16 Pharmaceutical Technology January 2012 Phar mTech. com
Agent-in-PlAce
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Cautionary Tales from the Files of “Control,”
a Senior Compliance Officer
Drained
“We have a complicated computer-
controlled manufacturing system for
our product,” explained our GMP
Agent-In-Place. “It includes several ves-
sels, computer-controlled valves, and
computer-controlled clean-in-place
(CIP) systems. With low production lev-
els at startup, everything ran fine—there
was only one batch in process at a time.
But when product demand increased,
we began to process two batches at once.
We didn’t think it would be a problem
because they would be in separate ves-
sels. However, when the first batch was
done, we needed to clean the last vessel
prior to processing the second batch.
Apparently, during validation we never
checked the upstream valve status dur-
ing the last vessel’s CIP procedure, be-
cause the computer opened the bottom
valve to drain on the penultimate vessel.
The entire second batch was drained be-
fore we realized there was a problem—a
$200,000 problem.”
Double-duty filter
“Sometimes processing aides do more
than we think,” began our GMP Agent-
In-Place. “For instance, we used a depth
filter in our production to help separate
the proteins. We changed to a different
manufacturer and the first lots produced
all met the release criteria. The test re-
sults looked normal. It was only when the
stability data showed faster degradation
that we saw a problem. The degradation
was clearly associated with the change
of filter, and caused a recall of several
batches. The customer was not pleased.
“After an enormous amount of inves-
tigation and testing, it turned out that
the original filter had also removed pro-
tease from the resultant filtrate that be-
comes our product. The protease would
proteolyse our protein product over
time, showing up as degradation in our
stability studies,” sighed our Agent.
Hazy days
“A lot can happen with filtration,” our
GMP Agent-In-Place said. “We use a
filter-aid during the production process
of our sterile-liquid product. Filter-aid is
also known as diatomaceous earth and
is mined from the ground—its chemical
composition can vary.
“During a stability study, when the
samples were initially retrieved, we’d
sometimes see a slight haze wafting
from the bottom of the vial. We would
only see it upon first movement; the
haze would dissipate into the air.
Exploratory testing was conducted to
identify the haze. The haze could not
be collected, so we tested the liquid for
a variety of compounds. We identi-
fied some cadmium in our products.
It turned out that cadmium was in the
filter-aid we had used. Because filter-
aid is mined, it is variable, and at least
one locat ion had some cadmium
contamination.
“The identification of cadmium in
our product resulted in a long medi-
cal assessment, including testing every
batch that’s still in-date. We found de-
tectable levels in hundreds of batches.
The release of filter-aid now includes
a test for heavy metals. The search for
the source of the haze is still ongoing.”
Unseen
“Sometimes it’s the simple stuff that
gets you,” grumped our GMP Agent-
In-Place. “Someone forgot to place
the temperature probe in a vessel. The
computer-controlled heating step con-
tinued to pump heat into the vessel’s
jacket and thereby into the product
waiting for the probe to report the
proper temperature. Because the probe
wasn’t in the vessel, it never sensed the
correct temperature. When this was
discovered hours later, the product was
overcooked and had to be rejected.” PT
Technology may expedite operations, but the
absence of the human element could cost dearly.
All Systems Slow
Pharmaceutical Technology’s
monthly “Agent-in-Place” column
distills true industry tales from the
files of Control, a senior compli-
ance officer. If you have a story to
share, please email it to Control at
AgentinPlace@advanstar.com. We
won’t use any names, but if we do
use your experience in the column,
you’ll receive a Pharmaceutical
Technology T-shirt.
The entire second
batch was drained
before we realized
there was a problem.
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18 Pharmaceutical Technology MONTH 2012 Phar mTech. com
In the Field
18 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
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18 .....Market Report from Europe
22 .....Brazil’s Pharma Market Expectations
20 .....Corporate Social Responsibility
24 .....FDA–EMA Inspections
Sean Milmo
The European Union
market takes steps toward
continuous processing
and modular facilities.
Continuous processing in pharmaceutical production has been mak-
ing only small inroads into Europe’s drug sector, which continues to be
dominated by batch-manufacturing systems. However, the introduction
of continuous technologies is gaining momentum in the region primar-
ily due to R&D schemes backed by public-sector funds. Attention is
shifting from relatively small-scale continuous processes, particularly
in areas such as tableting and coatings, to concepts in which the pro-
duction of intermediates or even of the whole drug is transferred from
batch to continuous manufacturing. contin. on page 20
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20 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
IN THE FIELD
contin. from page 18
“The uptake of continuous technologies has been rela-
tively slow because it requires a complete rethink of the
whole production process,” says Paul Hodges, chairman of
NiTech, an Edinburgh-based startup in continuous-f low
technology, who also runs the chemicals consultancy In-
ternational eChem, London.
“To gain the full benefits of continuous processing, plants
and their adjacent facilities need to be redesigned, other-
wise the big advantages of lower capital costs will not be
realized,” he explains. “In comparison to batch production
equipment, the continuous-manufacturing unit is much
smaller but also much less space is needed for storage and
logistics.”
The largest European R&D scheme in continuous pro-
cessing in pharmaceuticals and chemicals is a four-year
€30 million (approximately US$39 million) public–private
project in Leverkusen, Germany, called the Flexible, Fast
and Future (F3) Factory. The project is backed by the EU
and 25 other partners, including Bayer, AstraZeneca, and
Proctor & Gamble.
Among other smaller, mostly national R&D projects cov-
ering continuous processing is La Maison Europeenne des
Procedes Innovants (MEPI) in Toulouse, France.
The F3 Factory scheme is developing “smart-scale” plants
consisting of individual modules that can be assembled in
container frames in central workshops. They will then be
transported to production sites to be connected together to
form a single plant.
The partners in the project believe that the modular sys-
tem eliminates many scale-up problems because the design
of the equipment in each module for commercial production
will be similar to that used during the laboratory develop-
ment stages.
“The F3 project is so important because it provides an
opportunity for a complete redesign of the process engi-
neering in plants so that they can be switched to a total con-
tinuous system for the production of pharmaceuticals and
certain chemicals,” says Hodges. “Instead of adopting the
traditional evolutionary strategy of incremental improve-
ments to processes, this is taking a revolutionary approach.”
AstraZeneca is using the F3 scheme to develop a contin-
uous-manufacturing system for making a range of pharma-
ceutical intermediates through to the final synthesis stage
of active ingredient production.
The company believes that a continuous processing ca-
pability in the production of new materials in the 10- to
100-L scale for toxicological studies will result in the quicker
assessment of new compounds, more flexibility, and lower
costs than traditional batch-processing equipment.
A case study, headed by Bayer Technology Service, the en-
gineering arm of the Bayer group, which is coordinating the
F3 project, found considerable cost reductions in the modu-
lar approach to pharmaceutical intermediates production.
Transforming a batch to a continuous process could
achieve 10 to 25% cuts in operating costs and around 20%
in investment costs, according to the study. But if the shift to
continuous production also involves fewer processing steps,
the total reduction in costs could be as high as 60%.
In a partnership with Technische Universitat (TU) Dort-
mund, which has one of the biggest chemical engineering
departments in Europe, Bayer has just opened with the help
of German government funds, a research center in Leverku-
sen called INVITE for the testing of modular processes.
“In the initial stages of development the modular meth-
odology has shown itself to have clear chemical as well as
cost advantages because it provides more efficient reactions
with more effective heat exchange and better control,” says
Wolfgang Plischke, management board member at Bayer
responsible for innovation, technology, and environment.
“Now we need to standardize the equipment and its com-
ponents so that the system can be used widely.”
Standardization could be a complex, lengthy procedure
because of the necessity to involve both drug and other
manufacturing companies and equipment makers. Con-
tinuous processing may take several more years to become
firmly established in Europe’s pharmaceuticals sector but
at least it now has a technological platform for its advance-
ment in the region.
Sean Milmo is a freelance writer based in Essex, UK
Ü CSR and sustainability forum
Pharmaceutical Technology’s Sourcing and Management eNewsletter
provides specialized coverage of the bio/pharmaceutical industry’s
activities in corporate social responsibility (CSR) and sustainability
as well as developments from other business sectors, government
organizations, professional, trade, and scientific associations, and
NGOs. In the January 2012 issue (available at www.PharmTech.com/
PTSM):
•   Big Pharma companies’ partnerships for vaccines in the developing world.
• A roundup of CSR and sustainability news.
We welcome your ideas to learn about the work of your company or
organization in CSR and sustainability. Contact Patricia Van Arnum,
executive editor, at pvanarnum@advanstar.com.
Ü Join the PharmTech dialogue on LinkedIn:
The PharmTech Group
Ü Follow us on Twitter @PharmTechGroup
Ü Read commentary on blog.PharmTech.com
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22 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
IN THE FIELD
As part of the BRIC bloc with Russia,
India, and China, Brazil is one of the
world’s leading emerging economies and
is also considered by IMS Health to be
one of seven pharmerging nations, which
also include Mexico, Turkey, and South
Korea. With expectations to achieve sig-
nificant pharmaceutical market gains in
the coming years, Pharmaceutical Tech-
nology spoke with Pedro Palmeira, head
of the Pharmaceutical Department at the
Brazilian Development Bank (BNDES) in
Rio de Janiero. The bank is the country’s
primary financing agent for development.
PharmTech: It has been noted that Bra-
zil’s northern region is growing at the
same pace as most of China and that
Brazil expects to continue to grow its
economy. Are there key goals for the
bio/pharmaceutical sector in particular?
Palmeria: Brazil should continue grow-
ing at a rate of 5% per year in the next
few years, largely driven by its internal
market. In the case of the pharmaceuti-
cal market, the past few years have been
prosperous, due to the increased income
in the lowest levels of the population that
began to acquire more health products,
and to the increased public spending to
attend the new public health needs of
the population.
This positive environment of the past
10 years has allowed for the modern-
ization of the Brazilian pharmaceutical
industry and its increased production
capacity. The main challenge in the next
few years will be to uphold the supply of
health products for the increasing de-
mand, while at the same time consolidat-
ing research, development, and innova-
tion efforts within the country, especially
in the area of biotechnology products.
PharmTech: The Brazilian government
plans to move 16 million people out of
poverty and into the healthcare system
during the next 10 years. Is this part of a
larger government initiative? What prog-
ress been made to date?
Palmeria: The recent economic boom
Global Healthcare on the Ground
Brazil’s Development Bank Leader
Discusses the Country’s Pharma Future
Angie Drakulich
Heads for Science.
Hearts for Service.
Aptuit People.
Pharmaceutical Technology JANUARY 2012 23
IN THE FIELD
in Brazil…, together with the government
policies for income transfer, have taken
more than 36 million Brazilians out of
poverty, which increased the middle class
by more than 50% of population. This
result is extremely relevant for a country
that still has a very high rate of income
inequality. Even so, it is estimated that
there are around 16 million Brazilians
with a family income of less than US$45
per month, which are families that are dif-
ficult to reach by the traditional measures
of the state.
It was for these reasons that the Brazil-
ian government created the Programa Bra-
sil Sem Miséria (Brazil without Poverty) in
2011 to take this underprivileged group of
Brazilians out of poverty and give them ac-
cess to the country’s main social services.
Within the scope of the program, health-
care is included as a fundamental right and
an important pillar in the public policy to
include this part of the population.
PharmTech: Moving so many people into
the healthcare system will provide great
business opportunity—as well as chal-
lenges—for the healthcare and drug sec-
tors. What steps is the government taking
to address these? What advantages may
exist for bio/pharmaceutical companies
outside of Brazil?
Palmeria: The key word to healthcare
in Brazil is access. The government has
been working hard to increase the supply
of medicines to the populace. On the side
of development and production in the
country, this effort involves several fronts:
technology transfer agreements via pub-
lic-private partnerships; finance for the
development and production of strategic
products for the Brazilian health system;
continued improvement of the regulatory
regime; and centralized purveying and
negotiating directly with producers.
The opportunities for companies arise
inasmuch as the government is able to
acquire more products and sustain the
adoption of new protocols in the Brazil-
ian Universal Health System.
PharmTech: What is your country’s short-
and long-term perspective on the manu-
facture of biopharmaceuticals, including
biosimilars?
Palmeria: The Brazilian government
is working to construct an industrial
platform for biotechnology within the
country that, in the short-term, produces
biological products that are not new
(biosimilars). This industrial structure
should, however, include the possibility
to innovate and develop new biotech-
nolgy products in the longterm.
PharmTech: GE Healthcare and Amgen
have recently made bold moves to ac-
quire facilities and companies in São
Paulo. Have you seen increased action
along these lines from multinational
bio/pharmaceutical firms? Do you ex-
pect more?
Palmeria: In the past two years, BNDES
has received a growing number of consul-
tations, both formal and prospective, from
foreign companies in the health industry
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24 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
IN THE FIELD
that are interested in the Brazilian market.
Yes, we do expect more—and that these
activities come to be real investments in
the Brazilian health industry. Investments
that contribute to the established indus-
trial technology and that contribute to the
challenge of increasing the access of the
Brazilian public to health products and
services will be very welcome.
PharmTech: Brazil’s regulatory sys-
tem and healthcare policies seem to be
stable and well-respected on a global
scale, which have contributed to its role
as a pharmerging nation. What compo-
nents of this governance structure hold
advantages for outside bio/pharmaceu-
tical companies wanting to do business
in Brazil (e.g., IP rights, taxes, regulatory
approvals, market access)?
Palmeria: Companies that wish to in-
vest in the Brazilian health industry will
encounter an extremely favorable envi-
ronment, especially for projects regard-
ing the abovementioned question. Brazil
has a regulatory regime and intellectual
property environment that are in com-
pliance with global standards, as well as
a scientific and technological base that
is consolidated and expanding. Finally,
regarding long-term credit, BNDES and
other government agencies offer favor-
able conditions to support industrial
investments in production facilities as
well in research, development, and in-
novation activities.
PharmTech: Brazil is known as a “phar-
merging” market by the bio/pharmaceu-
tical industries in North America and
Europe. How do you view this label? How
do you see your country in the global mar-
ketplace in terms of the bio/pharmaceuti-
cal space?
Palmeria: Today, Brazil is among the
10 largest economies in the world. With
a population of 180 million, a vast terri-
tory, and immense mineral wealth, the
country is positioned as a promising
economy. With a robust middle class, a
diversified industrial base, a sustainable
energy matrix, and a stable democracy
that is anchored in solid institutions, the
country is clearly on a path for growth—
led not only by internal consumption, but
also by a significant volume of exports.
In this scenario, Brazil can legitimately
aspire to be one of the world’s five fore-
most economies.
As far as the health industry is con-
cerned, the scenario is even more promis-
ing as it is challenging. As mentioned, the
income-transfer programs, together with
economic growth, have brought 36 mil-
lion Brazilian out of poverty to become
real citizens able to consume goods and
services. The improvements in quality of
life of Brazilians have made demographic
changes that will give Brazil, in just a few
decades, a demographic pyramid simi-
lar to that of Europe. Life expectancy
in Brazil is currently 73 years old. The
change in the epidemiological profile of
the populace is also impressive: today,
the average Brazilian has more chronic-
degenerative diseases than infecto-con-
tagious illnesses. At the same time, it is
important to point out the ambitious
public health system which covers more
than 100 million people. According to
the Constitution of Brazil, health is the
right of everyone and it is an obligation
of the State to provide it.
Our pharmaceutical industry, which
today holds the 7th rank in the world,
grows by double digits, without indi-
cations of slowing down. Projections
indicate that Brazil will occupy the 6th
position by 2015. The Brazilian govern-
ment has been stimulating the industry
by supporting and financing projects
that contribute to reducing the vulner-
abilities of our health system—a fact
that together with a continually improv-
ing regulatory regime have shown signs
of the strategic nature of our health in-
dustry. Therefore, in this promising sce-
nario it is indeed possible to affirm that,
more than having a label of ‘pharmerg-
ing market,’ Brazil is has all the condi-
tions to become a solid and developed
pharmaceutical market in the short run,
and it has huge opportunities for those
that wish to take part.
PharmTech: The growing occurrence of
South–South trade is leading to some mul-
tinational companies (as well as nations)
to question their current market-growth
strategies. How does your organization
view South–South trade in terms of ben-
efits, and perhaps disadvantages?
Palmeria: From our viewpoint, the in-
creased volume of South–South trade
reflects the search for opportunities and
exchange among commercial partners
with complementary interests. Regard-
ing Brazilian interest in developing a
strong biotechnology industry in line
with national interests, our country is
obviously seeking partnerships with
enterprises and governments where
this technological wave has been con-
solidated, regardless of the regions or
geographic location.
FDA–EMA Joint Manufacturing Inspections to Begin in 2012
FDA and EMA are moving from “confidence-building to reliance upon”each other in a step-up in coop-
eration on GMP inspections; the latest move following successful completion of pilot projects last sum-
mer. The initiative will begin this month, January 2012, and will enable the two authorities to rely on
each other’s inspections outcomes instead of conducting inspections in duplicate. The objectives are
to: enable better use of inspection resources; reduce inspection burden of medicines manufactured;
and liberate inspection capacity for other regions. “Both sides see this progression as an important
next step, and FDA believes that using EMA as a central contact point in relation to GMP inspections
for both centrally and nationally authorized products is critical,”said a press statement. The initiative
will apply to inspections within the European Economic Area and US, and will focus on sites with his-
tories of GMP compliance that are well known to both authorities. For three years, both authorities will
track deferred or waived inspections at which point the approach will be reviewed for the potential
of extension. In the interim, the joint inspection pilot project for dosage forms will continue with the
objective of maintaining confidence and building mutual understanding of inspection approaches.
—Rich Whitworth
OPTIMA Machinery Corporation · 1330 Contract Drive · Green Bay, WI, 54304 · USA · www.optima-usa.com
Germany (Headquarters), Mexico, Brazil, France, Great Britain, Italy, Japan, Korea and China
Filling x Freeze Drying x Loading/Unloading
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26 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
New Product Announcements
may be sent to New Products Editor,
Pharmaceutical Technology,
485 Route One South, Building F,
First Floor, Iselin, NJ 08830,
fax 732.596.0005,
ptpress@advanstar.com.
IN THE SPOTLIGHT: MANUFACTURING
Rotary airlock valves for
regulatory compliance
ACS Valves’s Quick-Clean series of
rotary airlock valves is designed to
aid users in achieving compliance
with regulatory standards. The
valves feature the ACS RotorRail
design that enables full validation
access to the rotor and all internal
surfaces of the housing without
requiring disassembly of the end-
plate. The stainless-steel housings
are machined to precise tolerances.
Internal surfaces are polished to a
No. 4 finish, and the ACS Valves’s
clean-in-place-ready design elimi-
nates internal crevices and joints,
where contaminants can accumulate.
The valves’ inlet–outlet seal is
produced with an eight-vane rotor
design, which eliminates excess
pressure loss through the system,
ensures cost-efficient upstream-
and downstream-material manage-
ment, and reduces process energy
consumption. The valves are avail-
able in 304 or 316 stainless steel,
and in sizes from 6 to 16 in. with
pressure differentials as high as 15
psig and temperature tolerance as
high as 500 °F.
Thermoformer offers deep-draw capabilities
MG America’s Farmo Res Prima K7 ther-
moformer is designed for the deep-draw
thermoforming of syringes, ampuls, vials,
and medical devices. The Prima K7 can run
as many as 35 cycles/min, and is operated
by a programmable logic controller with
transfer on one lane for the production of
trays in polystyrene.
The Prima K7’s deep-draw capabilities
include the ability to form blisters with
depths as great as 40 mm. Other features in-
clude a syringe buffer system with a capac-
ity of more than 2000 syringes, a loading
station for vials and ampuls, and forming
and loading capabilities from the operator
side that results in a compact forming mod-
ule and easier changeover procedures.
Quick-Clean series valve
ACS Valves
www.acsvalves.com
Farmo Res Prima K7 thermoformer
MG America
www.mgamerica.com
Manufacturing efficiency is essential to drugmakers who can’t afford to waste
expensive ingredients. Flexible and easy-to-use equipment also can help
reduce the costs of production, which can be a boon to small and mid-sized
firms. This month’s products are meant to enable companies to optimize vari-
ous parts of their manufacturing lines. Rotary airlock valves from ACS Valves
help achieve regulatory compliance. MG America’s thermoformer facilitates
product changeovers. A bioreactor from EMD Millipore lets users configure
process monitoring at the point of use.
Single-use bioreactors for
mammalian cell-culture applications
EMD Millipore’s Mobius CellReady 200-L
bioreactor is designed to expedite the
process of bringing biological drugs to
market. The machine integrates several
features that are intended for ease of use,
reliability, and operational flexibility. The
bioreactor’s hardware includes on-board
automation, which provides an ergo-
nomic operator interface.
The Mobius SensorReady technology offers the flexibility to configure process
monitoring at the point of use, thus reducing the need to customize bioreactor
process containers and enabling easy integration of new sensor technologies. The
rigid base and top panel feature of the bioreactor process container are designed
to facilitate installation. The system is available as a complete, turn-key system or
as a modular system to integrate with the platform of choice.
Mobius CellReady 200-L bioreactor
EMD Millipore
www.millipore.com
Editors’ Picks of Pharmaceutical
Science & Technology Innovations
Maximizing
API Integrity
Super Refined
®
Castor Oil
Croda’s Super Refining process removes polar impurities from excipients
without altering their fundamental structure in any way.
Using this proprietary technique, Croda has created a highly purified castor
oil that is ideal for use with sensitive APIs. Super Refined Castor Oil is an
ideal solvent for multiple dosage forms, as well as an excellent lipid vehicle
for injectable formulations.

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28 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
N
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PharmTech.com/washrep
E
lection-year politics will play a
role in a range of legislative and
policy developments affecting drug
development, manufacturing, and reim-
bursement in the coming year. Efforts to
reduce government spending on health-
care are prompting all parties to search
for opportunities to do more with less.
Although FDA received a slight increase
in its 2012 budget, limited resources
throughout the public and private sec-
tors are likely to undercut efforts to
advance biomedical research and ex-
pand public health programs. These
developments will drive manufacturers
to look overseas for less costly and more
efficient opportunities to expand R&D,
production, and sales. As the campaign
for the White House and control of
Congress heats up, pharmaceutical and
biotech companies will need to keep a
sharp eye on how new policy proposals
may affect product development, drug
regulation, and the debate over reautho-
rization of the Prescription Drug User
Fee Act (PDUFA).
Whither reform?
Manufacturers backed Obamacare two
years ago as a way to expand the mar-
ket for prescription drugs, including a
growing number of pricey biotech ther-
apies. In return, industry agreed to pay
hefty new fees as well as higher rebates
on Medicaid drugs, and to subsidize the
cost of drugs sold to seniors caught in the
“doughnut hole” of the Medicare pre-
scription drug program. The worst-case
scenario for manufacturers now would
be to eliminate the market reforms and
insurance exchanges designed to expand
enrollment in health plans, while retain-
ing provisions that cut revenues and raise
costs for industry.
The 800-pound gorilla in the room
is the looming Supreme Court decision
on the constitutionality of the Obama
healthcare reform legislation. While
the Justices ponder the weighty legal is-
sues, the US Department of Health and
Human Services (HHS) will continue to
implement the multitude of policies and
programs established by that law. The
administration’s working assumption is
that the Affordable Care Act (ACA)—or
much of it—will remain in place. Many
states are moving ahead with efforts to
expand health IT systems and to estab-
lish processes for determining insurance
eligibility and coverage. But a Republi-
can takeover of the White House in No-
vember 2012 would bring considerable
changes in health-related programs.
Whatever the legal and political out-
come, policymakers on all sides will be
looking to cut payments to providers, to
increase cost-sharing by patients, and to
reduce benefits and services. Increased
reliance on managed care plans and co-
ordinated care programs, initiatives to
reduce fraud and abuse, perennial pro-
posals to reform the nation’s medical li-
ability system, and efforts to curb phar-
macy expenditures will emerge as ways to
save money without compromising care.
Pricing pressures
The drive for healthcare savings will
continue to shine the spotlight on phar-
maceutical pricing, reimbursement, and
access. Policymakers increasingly will be
looking for more convincing evidence of
the value of new medicines and for new
ways to reduce risk in determining cov-
erage of new therapies. The Centers for
WASHINGTON REPORT
Jill Wechsler
is Pharmaceutical
Technology’s Washington
editor, 7715 Rocton Ave.,
Chevy Chase, MD 20815,
tel. 301.656.4634,
jwechsler@advanstar.com.
Pressure to approve new user fees opens the door to
action on drug shortages, prices, and regulation.
Jill Wechsler
Budget Crunch, Political Battles
Shape Policy Agenda for Year
The focus on
ensuring reliable
drug supplies
will intensify
efforts to promote
continuous quality
improvement
strategies.
In Washington this month
• Congress considers adding
pet programs to the PDUFA
reauthorization bill.
• Industry seeks new ways
to fill pipeline as blockbuster
patents expire.
• FDA initiatives aim
to boost R&D process.
www. cei a-usa. com
Call Toll-Free 888-532-CeIa
Phone: 330) 405 3190 - Fax 330) 405 3196 - e-mail: pharma@ceia-usa.com
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30 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
Washington Report
Medicare and Medicaid Services (CMS),
pharmacy benefits managers (PBMs),
and other payers and insurers will ques-
tion the value of high-cost therapies that
appear to offer limited benefit. Payers and
policymakers will face difficult questions
about cost versus safety and efficacy, as
seen in the debate over treatment of age-
related macular degeneration with off-
label use of the cancer drug Avastin (bev-
acizumab), instead of with its more costly
formulation Lucentis (ranibizumab).
Similarly, the controversy over the sharp
price hike for preterm-birth treatment
Makena (caproate) after it gained market
control under FDA’s policy for halting
sales of unapproved drugs, indicates that
prices perceived as excessive can override
some drug safety issues.
Payers will continue to look for more
drug discounts and rebates, threatening
to relegate pricey products to unfavorable
positions on health plan formularies. Al-
though the Medicare Part D drug benefit
has provided seniors with access to af-
fordable medicines, benefits may suffer
as many plans boost co-pays and limit
coverage for costly therapies. In Europe,
government agencies such as the United
Kingdom’s National Institute for Health
and Clinical Excellence (NICE) are op-
posing coverage of expensive products
that lack sufficient added benefits.
Manufacturers are responding with
risk-sharing programs that skew prices
based on patient response to a new ther-
apy. The claim by biopharmaceutical
companies that effective treatment with
expensive therapies can reduce overall
healthcare costs will remain a hard-sell
to the number-crunchers that regard
pharmacy outlays as a discrete expendi-
ture, rather than as a way to save money.
Pressure to cut costs will drive support
for the ACA provision that establishes
a pathway for bringing biosimilars to
market. FDA guidance on the scope of
preclinical and clinical testing needed to
document product comparability, if not
interchangeability, will spur manufactur-
ers of all stripes to move aggressively into
the follow-on biologics field. For the pro-
gram to be effective, policymakers will
have to decide a number of thorny issues,
including policies for names to identify
these products, coding requirements for
reimbursement, and rules governing pat-
ent challenges and protection.
Biosimilars are a big issue because
payers anticipate hefty savings from
these look-alike therapies, as has been
the case with small molecules during
the past 25 years. Generic drugs now ac-
count for about 80% of prescriptions in
the US, and the proportion will rise fur-
ther as more blockbuster brands such as
Pfizer’s Lipitor (atorvastatin) go off pat-
ent. The wave of new generic drugs puts
more pressure on FDA to speed up its
process for approving new generic drugs
for market. New user fees paid by generic
drugmakers will help fund such efforts.
Efforts by Pfizer to retain a good por-
tion of the Lipitor market by cutting its
price and negotiating long-term deals
with payers and PBMs have roiled the
drug industry and pharmacy programs.
These actions further spur industry
critics to harp about brand-generic pat-
ent settlements that can delay when a
generic comes to market and propose
policies to curb those practices.
Securing supplies
The search by pharmaceutical compa-
nies for new products and new markets
will further expand global pharmaceu-
tical production, with the relevant op-
portunities and perils. Rising interna-
tional sourcing of APIs and excipients
will put more pressure on industry to
manage production processes to ensure
the quality and safety of their products.
A sharp rise in supply problems for
vital drugs has led to a focus on drug
quality and supply chain problems. The
White House unveiled a drug short-
ages initiative in October 2011, which
supports proposals before Congress to
broaden requirements for manufactur-
ers to report to FDA production issues
that could lead to supply problems. Poli-
cymakers also seek tighter controls on
drug imports, better track-and-trace
systems, and stiffer penalties for coun-
terfeiting and drug adulteration. FDA of-
ficials are instructing pharma companies
to police suppliers and distributors more
effectively for early detection of quality
problems. The regulators also want man-
ufacturers to establish backup plans for
dealing with supplier and production
snafus that could halt production.
This increased focus on systems for en-
suring reliable drug supplies will further
intensify efforts by industry, FDA, and
other regulatory bodies to promote con-
tinuous quality improvement strategies,
including adoption of quality standards
established by the International Confer-
ence on Harmonization (ICH). Regulators
are looking to extend these quality assur-
ance policies to include generic drugs and
ingredients from other regions.
Efforts to manage manufacturing
changes more efficiently will continue,
as FDA officials promote more effective
product testing and monitoring to re-
duce variability in drugs and biologics
and to prevent “process drift” in manu-
facturing operations. FDA has proposed
modified reporting requirements for
certain postapproval manufacturing
changes, with an eye to curbing un-
necessary oversight. So far, however,
manufacturers are disappointed by the
limited scope of the regulatory changes.
Drug quality issues will keep up the
pressure on FDA to conduct more fre-
quent inspections of manufacturing
facilities and to crack down on non-
compliant firms, particularly foreign
operators exporting products to the US.
FDA is looking to expand partnerships
and cooperative programs with regula-
tory counterparts in Europe and other
regions as a way to combine inspection
resources and avoid redundant over-
sight. The regulators also are looking to
tap into manufacturing data compiled
by third parties to free up resources and
focus on the most critical compliance is-
sues. Agency officials hope to finalize a
number of manufacturing and produc-
tion policies in the coming year, but rec-
ognize that such efforts can be sidelined
by new crises and changing priorities.
Manufacturers who experience se-
rious quality control problems face
increased attention from federal and
state prosecutors, who are looking more
at violations of GMPs—in addition to
off-label marketing and illegal pricing—
as evidence of corporate malfeasance.
Pharmaceutical companies have been
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Washington Report
hit with huge fines and onerous consent
decrees for violation of GMPs and other
regulations, but the situation may get
worse. Government officials are rais-
ing the stakes by threatening to impose
penalties on individual corporate execu-
tives who fail to take action to prevent
such violations, and some of the saber-
rattling could escalate into real blows.
Filling the pipeline
The loss of patent protection for a wave
of blockbuster medicines is driving
pharmaceutial companies to search for
new models for drug development to fill
an admittedly dry drug pipeline. Public
and private backers of biomedical re-
search talk more about “game-chang-
ing, transformational leaps” in discov-
ery, as opposed to the incremental gains
that traditionally lead to important sci-
entific advances. There is growing en-
thusiasm for developing personalized
medicines that provide more effective
treatment based on individual genomic
and metabolic characteristics. This will
require the development of more diag-
nostics to identify key response factors.
Expanded international research
efforts are tapping into public-private
partnerships for developing important
therapies for malaria, tuberculosis, and
other diseases most prevalent in tropical
climates. Health authorities are pressing
for more research on new antibiotics,
along with treatments for rare condi-
tions and killer diseases, such as cancer
and AIDS. There is growing excitement
about new vaccines, which are attract-
ing more industry investment as mar-
kets mature around the world.
FDA can help the process, according
to Commissioner Margaret Hamburg,
who has been promoting the campaign
to bolster FDA involvement in regula-
tory science initiatives to provide new
tools and methods to accelerate the R&D
process. Several programs are underway
to validate biomarkers that can identify
potential safety problems early on and
improve the efficiency of clinical studies.
Other coalitions are looking to stream-
The Prescription Drug User Fee Act (PDUFA),
must be reauthorized and enacted by Sept. 30,
2012, in order for FDA to continue to collect the
funds needed to support its regulatory program.
FDA and manufacturers have agreed on new user
fees for generic drugmakers and for applications
for biosimilars.
The PDUFA bill could include these initiatives,
as well as renew the program that extends
incentives for manufacturers to develop labeling
and dosage forms for pediatric therapies. PDUFA
renewal has strong support on Capitol Hill, but
individual legislators could hold up action on the
bill to add pet programs to the package.
With Republicans and Democrats finding it
difficult to compromise on important policies,
it will take considerable political skill for a
balanced PDUFA bill to make it through the
legislative process in time to prevent an FDA
collapse.
Finalizing user fees
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34 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
Washington Report
line the long and costly R&D process by
developing research protocols for “adap-
tive” clinical trials and promoting elec-
tronic methods for recruiting patients
and collecting research data.
Yet, manufacturers complain that
a risk-averse tendency at FDA and de-
mands for more, larger studies keep
many promising medicines off the mar-
ket and raise R&D costs. The recent FDA
decision to revoke the metastatic breast
cancer indication for Avastin has gener-
ated questions about the future of FDA’s
accelerated approval process and the
threshold for bringing new cancer thera-
pies to market.
FDA officials point to last year’s jump
in approvals for new molecular entities
(NMEs) as evidence that the agency is
not keeping important new medicines
from patients. A number of the approv-
als involve treatments for rare condi-
tions and serious cancers that carry less
risk for patients and lend themselves to
speedy FDA evaluation. But it remains
to be seen if the spike in approvals is a
fluke, or a signal of real progress on the
innovation front.
The rise in overseas clinical research
activity, as pharmaceutical companies
seek more efficient drug development
operations and data to support global
marketing efforts, continues to focus at-
tention on research ethics and policies
to ensure compliance with good clinical
practices (GCPs). Several federal agencies
are examining past unsafe research prac-
tices and weighing changes in policies and
standards for clinical studies sponsored
by the federal government or regulated
by FDA.
Clinical research activities also face
more scrutiny at home under transpar-
ency requirements that expand disclo-
sure of active clinical trials and study
results on the clinicaltrials.gov website.
Health reform “sunshine” provisions
require pharma companies to disclose
payments to physicians and other health
professionals, a process that involves
major revisions in corporate policies
and information systems. The transpar-
ency campaign, moreover, may result in
broader FDA disclosure of information
on drug safety and effectiveness, possibly
even proprietary data that manufactur-
ers might prefer to keep confidential. The
assurance that US-supported investiga-
tors fully protect research participants
and ensure the validity of clinical data is
critical to improving public confidence
in the pharmaceutical R&D process.
“Patient centeredness” will continue to
shape a range of regulatory and research
initiatives. FDA is encouraging sponsors
to incorporate patient needs and opin-
ions into clinical-trial protocol design,
patient recruitment, drug delivery, and
safety evaluation. This approach will be
supported by research sponsored by the
Patient-Centered Outcomes Research In-
stitute (PCORI), which is slated to have
a $500 million annual budget by 2014 to
study effective treatments for important
conditions. PCORI plans to finalize pri-
orities for its research agenda by March
2012, and its Methodologies Committee
aims to report in May on research meth-
ods and standards for this field. PT
400 Iroquois Shore Rd, Oakville, Ontario L6H 1M5
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36 Pharmaceutical Technology January 2012 Phar mTech. com
Bio Forum
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E
choing last year’s performance
trend, biotechnology venture-
capital funding dipped during the
third quarter of 2011, but it remained on
track to outpace 2010 in total dollars in-
vested. US venture capitalists funneled
$1.1 billion into 96 deals during the
third quarter, a drop of 18% in dollars
and 20% in the number of deals from
the second quarter of 2011, according to
the MoneyTree Report from Pricewater-
houseCoopers and the National Venture
Capital Association (NVCA) based on
data provided by Thomson Reuters.
Despite this loss of momentum dur-
ing the third quarter, dollars invested
in biotechnology companies grew 26%
compared with the same quarter of 2010.
The number of deals declined 14%, but
average deal values continued to trend up-
ward. The third quarter’s largest funding,
$300 million, went to the biotechnology
firm Reata Pharmaceuticals, which is de-
veloping oral anti-inflammatory drugs.
Among all industries, biotechnology
continued to rank behind software in
dollars invested. The software sector
captured first place during the third
quarter of 2011, attracting $4.8 bil-
lion in 742 deals. Software investment,
which holds the potential for a much
quicker return, appeared to be making
a sharper recovery from the economic
recession than the biotechnology sector.
In keeping with this trend, one
venture-capital firm, Scale Venture
Partners, recently announced it was
shifting its full focus to technology and
will not make additional healthcare in-
vestments. Scale mentioned the uncer-
tainty of the regulatory environment
and capital requirements as reasons for
its move away from healthcare.
This shift comes as no surprise to those
who follow investment trends. A recent
survey by NVCA’s Medical Innovation and
Competitiveness Coalition, a partnership
of NVCA member venture-capital firms
and their early-stage companies, found
that US venture capitalists are decreasing
their investments in biopharmaceutical
companies. Firms cited the cost, time, and
unpredictability of the US approval process
as reasons for the funding slowdown.
FDA has countered reports critical
of its approval process by pointing to its
recently launched innovation initiatives
and an uptick in the number of drug ap-
provals for fiscal year 2011. Drugs tar-
geting cancer or paired with a diagnostic
are gaining quicker review and approval
from FDA. Despite these positive signs,
until investors see concrete evidence of a
more consistent, predictable, and trans-
parent approval process across a broader
spectrum of products, they will remain
cautious about funding early-stage bio-
technology companies.
For the third quarter of 2011, early-
stage funding for the biotechnology sec-
tor did manage a small gain of 7% year
over year to a total of $481 million. Late-
stage funding fared better, jumping 48%
to $598 million. Both categories dropped
from the second quarter of 2011, echoing
a similar fall from the second to the third
quarter of 2010.
Biotechnology funding by stage
Early-stage funding will remain tough in
the current regulatory and economic en-
vironment. Venture capitalists, however,
will continue to seek out companies with
experienced talent and breakthrough
products that have the potential to mea-
surably improve health outcomes.
As in years past, follow-on funding
outpaced first-time funding during
2011. Those companies with enough
cash on hand to carry them through a
milestone, such as proof of concept or
FDA approval, stand a better chance of
attracting follow-on funding.
One factor holding investment lev-
els down is that venture capitalists are
hard-pressed to find an exit in the mar-
ket for initial public offerings (IPOs).
Venture-backed IPOs during the third
quarter of 2011 had their weakest
showing since the fourth quarter of
2009. Only one venture-backed IPO
during the period represented biotech-
nology. Low venture-backed merger
and acquisition activity for the third
quarter also contributed to investors’
lack of confidence.
One bright spot for biotechnology
financing that bodes well for 2012 is
a growing willingness on the part of
Big Pharma’s venture arms to invest
in early-stage companies. Corporate
venture funds were involved in 25% of
early-stage US biotechnology financing
deals during the first half of 2011, com-
pared with 15% for all of 2010.
In the near and long term, innovative
companies developing game-changing
products that target cancer and rare
diseases or that significantly improve
outcomes and lengthen patient life-
spans will continue to attract private
and corporate investors. PT
Tracy T. Lefteroff is a partner in the life
sciences practice of PwC US, tracy.t.lefteroff@
us.pwc.com.
Challenges remain, particularly for
early-stage biopharmaceutical companies.
Tracy T. Lefteroff
Venture-Capital Funding Falls
but Shows Some momentum
Our Multi Media Platform
provides you with countless
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technology and manufacturing.
VIDEOCAST • PODCAST • PRINT • E-NEWSLETTERS • WEBCAST • WWW.PHARMTECH.COM
www.pharmtech.com
38 Pharmaceutical Technology January 2012 Phar mTech. com
PACKAGING FORUM
PharmTech.com/pack
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A
new year is a good time to look
forward as well as backward. New
developments in 2012 will support
the 10 major trends of 2011, which in-
clude increased automation, particularly
for quality-control functions; implemen-
tation of serialization and traceability
technology; adoption of anticounter-
feiting measures; new choices in blister
material; braille on labels; improvements
in cold-chain practices; greater use of
prefilled syringes and single-use product-
contact parts; rising interest in stick
packs; and stronger emphasis on sustain-
able processes, packaging, and logistics
(see “Sustainability Outside the Box” in
the October 2011 issue of Pharmaceutical
Technology).
Automation
Servo technology and software are bring-
ing a new level of automation to pharma-
ceutical packaging. Software not only au-
tomates functions, but also simplifies the
work of packaging line operators as well
as the collection and analysis of produc-
tivity data. One new software product
oversees multiple quality-control systems
on a single packaging line or multiple
lines in one or more facilities. A dash-
board system and color-coded machine
icons on the operator interface quickly
alert operators and management to qual-
ity problems in real time so remedial ac-
tion can be taken and downtime can be
minimized or eliminated. Remote setup
prevents unauthorized changes to set-
tings and errors and supports consistent
operation across lines and facilities. The
program currently oversees checkweigh-
ers, metal detectors, and X-ray inspec-
tors and will accommodate machine-
vision systems in 2012 (ProdX software,
Mettler-Toledo).
Software’s potential to simplify oper-
ation is particularly evident in machine
vision, a technology with a reputation
for being difficult to set up, operate, and
change over. In one system, Windows-
based software oversees as many as four
color or monochrome cameras and
performs tasks, including inspecting
labels, caps, containers, and fill levels,
confirming the presence and condition
of a tamper ring, and verifying date and
lot codes and one- and two-dimensional
barcodes. Capable of checking 2000
metal, glass, or plastic containers each
minute, the system includes an inte-
grated reject system (TotalVu Sensor
vision system with Teledyne Dalsa cam-
eras, Teledyne TapTone).
Serialization and traceability
With pedigree regulations looming or
already in place in some countries, in-
terest is high in implementing serializa-
tion systems that generate the supporting
data. One serialization-ready printer–ap-
plicator prints a two-dimensional Data-
Matrix code and human-readable data
on a label before applying it. A built-in
camera verifies print quality (BL400V-
TEXL label printer and application,
Marchesini Group). Data transmission,
aggregation, and storage is provided by
integrated hardware and software (Sys-
tech Serialized Product Tracking, Sys-
tech International).
Anticounterfeiting measures
Although the pharmaceutical industry
has had some success in countering coun-
terfeiters with multilevel overt and covert
security features, fake or diverted prod-
ucts continue to endanger consumers
worldwide. Because counterfeiters can’t
duplicate what they can’t see or readily
detect, covert features, such as tiny tag-
gants, rank as an essential anticounter-
feiting tool.
One taggant-based technology enables
smooth adoption by blending the tag-
gants in ink, varnish, thermal-transfer
ribbon, resin, or film. In its latest itera-
tion, taggants are combined with inkjet
ink that’s invisible under visible or ul-
traviolet light. Detection of the alphanu-
meric characters or barcode printed with
the taggant-equipped ink is only possible
with a programmable handheld reader,
which provides authentication in sec-
onds. Tight oversight of the supply chain
ensures secure handling of taggant car-
Hallie Forcinio
is Pharmaceutical
Technology’s
packaging forum
editor, 4708
morningside drive,
cleveland, oh 44109,
tel. 216.351.5824,
fax 216.351.5684,
editorhal@cs.com.
Innovations for 2012
Hallie Forcinio
Packaging innovations boost productivity, meet
regulatory requirements, and protect products.
We’ll be seeing more ...
• Automation
• Serialization and traceability
• Anticounterfeiting measures
• Blister innovations
• Braille on labels
• Improvements in
cold-chain practices
• Prefilled syringes
• Single-use product-
contact parts
• Emphasis on sustainable pro-
cesses, packaging, and logistics
• Stick packs
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BLOW-FI LL-SEAL TECHNOLOGY
40 Pharmaceutical Technology January 2012 Phar mTech. com
Packaging Forum
rier materials (Traceless AD inkjet ink
and reader, Eastman Kodak).
Blister innovations
A thick polychlorotrif luoroethylene
(PCTFE) film provides ultrahigh bar-
rier properties for blister packaging and
runs on existing thermoforming equip-
ment with only minor adjustments. At
152.4 µm, the film measures 50% thicker
and improves water-vapor-transmission
barrier properties 50% compared with
previous offerings. The enhanced bar-
rier properties allow moisture-sensitive
medicines to withstand the hottest and
most humid environments, including
Climatic Zones IVA and IVB as defined
by the World Health Organization. With
this material, pharmaceutical companies
can standardize packaging worldwide.
The clear film provides product visibility
and reduces package size as much as 55%
versus cold-formed foil, the traditional
barrier material for ultrasensitive prod-
ucts (Aclar UltRx 6000 film, Honeywell
Specialty Materials).
At least two blister-material converters
produce laminations with one layer of the
ultrahigh-barrier PCTFE. One is a two-
layer PCTFE–polyvinyl chloride (PVC)
lamination (Pentapharm Aclar PA600/02
barrier film, Klöckner Pentaplast Group).
For a stronger moisture barrier, the
PCTFE can be laminated to polypropyl-
ene, cyclic olefin copolymer (COC), poly-
ethylene terephthalate glycol, polyethyl-
ene, or ethylene vinyl alcohol. In fact, one
structure, consisting of PCTFE laminated
to a ply of coextruded COC is claimed to
boost barrier properties as much as 80%
compared with current high-barrier
PCTFE–PVC laminations (Aclar UltRx
6000 laminations, Tekni-Plex). A foil-free
PVC with barrier properties and a foil-
like, light-blocking appearance is another
alternative to cold-formed foil and alumi-
num strip packaging (Alu-Look blister
films, Tekni-Plex).
Braille on labels
When European 2004/27/CE directive
took effect on Jan. 1, 2006, it made braille
labeling mandatory on all new pharma-
ceutical packaging. Since then, a growing
number of options have been introduced
to help pharmaceutical packagers comply.
To overcome a lack of harmonization
in the configuration of braille messages,
one producer of shrink-sleeve labels has
standardized character string alignment
on the left and reading from left to right.
It also specified the distance between
dots, their width, their height, the dis-
tance between each group of six dots
(which corresponds to a letter) and in-
terlines. A proprietary marking method
and morphing tool ensure characters are
formed in compliance with parameters
and do not become distorted during the
heat-shrinking process (Sleever Braille,
Sleever International).
Better cold-chain practices
The expanding number of temperature-
sensitive biologic products and increased
regulatory insistence on proper han-
dling across the supply chain is keeping
the spotlight on packaging components
that protect products from temperature
excursions. A flat, USB-equipped wa-
terproof label about the size of a sugar
packet monitors temperature conditions
at the pallet, carton, or item level. Sur-
face readings provide a more accurate
time or temperature record than the
ambient readings taken by conventional
time and temperature loggers. When
the product reaches its destination,
light-emitting diodes on the label flash
if temperatures exceeded parameters.
Plugging the label’s USB connection into
a computer uploads the trip’s time and
temperature history (XpressPDF Label,
PakSense).
Prefilled syringes
Prefilled syringes are gaining market
share over traditional vials because
they offer great dose accuracy, simplify
administration, and eliminate overfill,
among other reasons (1). As a result, this
packaging format, particularly autoinjec-
tor versions, often is selected for products
destined for self-injection. One off-the-
shelf, disposable autoinjector shown at
INTERPHEX 2011 hides the needle be-
fore, during, and after the injection and
is designed to be handled by people with
limited dexterity. The initial offering, a
1-mL long syringe with a 0.5-in. staked
needle, is available in push-to-activate
and press-button–push-to-activate con-
figurations. Both designs provide visual
and audible feedback of activation and
automatically retract the needle (OTS
Autoinjector, bespak injectables, filled
by Catalent).
Foil-free Alu-Look blister films run on
standard thermoforming equipment.
The Pentapharm Aclar PA600/02
barrier lamination seals to any vinyl-
compatible lidstock.
Meda uses Sleever International’s
braille labels for its Betadine
disinfectant sold in Italy.
t
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Pharmaceutical Technology January 2012 41
Packaging Forum
Single-use product-contact parts
Attendees at INTERPHEX 2011 also
had a chance to explore the possibility
of converting to single-use product-
contact parts. A single-use fluid path
ensures purity, simplifies validation,
and expedites changeover on high-
throughput peristaltic filling and cap-
ping systems (AsepticSU single-use
fluid path technology, Flexicon Liquid
Filling).
Pharmaceutical packagers switch-
ing to disposable product paths have a
growing number of pump choices, in-
cluding 6- and 50-cm
3
peristaltic pumps
as well as a rolling diaphragm pump
(PreVAS Single-use Dosing System,
Robert Bosch Packaging Technology).
Stick packs
The appeal of skinny stick packs in-
cludes ease of opening, ease of dis-
pensing, and portability, plus the con-
venience and accuracy of single-dose
dispensing. In response to rising inter-
est in this flexible packaging format,
Pharma Tech Industries, a contract
manufacturer and packager of powder
products, installed a machine that forms,
crimps, fills, and seals the slender, cylin-
drical packs (Stik Pak S/N 307 machine,
Ropak Manufacturing).
Set up to handle 10 lanes simultane-
ously, the machine produces 600 stick
packs/min and features in-line collation
and cartoning, as well as a color touch-
screen operator interface. Servo-driven
continuous motion corrects deviations.
An adjustable dosing system allows tool-
less changeover of dosing-specific com-
ponents.
Reference
1 K. Abdelkader, R.M. Akers, and M.J. Akers,
“Sterile Prefilled Syringes: Market Dynam-
ics & Current Issues in Manufacturing &
Control,” in Prefilled Syringes, Innovations
that Meet Growing Demand (ONdrugDe-
livery, Newtimber, UK, 2005), p. 4. PT
The XpressPDF Label uploads time and
temperature data directly to a personal
computer through its USB port.
Pharma Tech Industries has installed a
Stik Pak S/N 307 form–crimp–fill–seal
machine from Ropak.
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42 Pharmaceutical Technology January 2012 Phar mTech. com
I
n the quest for more targeted thera-
pies and potentially more clinically
efficacious drugs, bio/pharmaceutical
companies are increasing their research
and product development in biologics.
Although the majority of this work is fo-
cused on monoclonal antibodies (mAbs)
and recombinant proteins, progress is
being made in specialized drug types.
Antibody–drug conjugates (ADCs), which
consist of a mAb chemically linked to a
small-molecule therapeutic, are a niche
class of drugs that offer promise, particu-
larly as oncology drugs. In August 2011,
FDA approved Adcetris (brentuximab
vedotin), codeveloped by Seattle Genetics
and Millennium Pharmaceuticals (now
part of Takeda Pharmaceutical), mak-
ing it only the second ADC approved by
FDA. With the approval of Adcetris, a
drug for treating Hodgkins lymphoma
and systemic anaplastic large-cell lym-
phoma and with a number of ADCs in
clinical development, the key question is
whether ADCs will be able to fill a role in
biopharmaceutical development.
ADCs at work
Adcetris consists of three parts: the chi-
meric IgG1 antibody cAC10, specific for
human CD30, the microtubule-disrupting
agent monomethyl auristatin E (MMAE),
and a protease-cleavable linker that co-
valently attaches MMAE to cAC10 (1).
Before the approval of Adcetris this
year, the only other ADC approved by
FDA was Mylotarg (gemtuzumab ozo-
gamicin), approved more than 10 years
ago in 2000. The drug, an anti-CD33
mAb conjugated to the cytotoxin ca-
licheamicin, was developed by Wyeth
(now part of Pfizer) and was granted
accelerated approval in 2000 but was
voluntarily withdrawn by Pfizer in 2010
because a required Phase III trial failed
to demonstrate a survival advantage for
Mylotarg plus chemotherapy compared
with chemotherapy alone. Despite this
setback, there are several ADCs cur-
rently in development, with more than
15 in Phase I development and several
compounds from Roche and Pfizer in
late-stage clinical trials. In the decade
that has elapsed between the first ADC
approval and the second, advances in
the understanding of cancer biology,
lessons learned from the development
of mAbs as therapeutics, and better
methods for linking small molecules to
mAbs have coalesced to advance ADCs
into the forefront of new therapies.
The most active area of development
for this class of therapeutics has been
oncology, where a mAb serves to target
the therapy to cancer cells while a po-
tent small-molecule chemotherapeutic
provides the cell-killing efficacy. Both
mAbs and small-molecule chemothera-
peutics are used individually as cancer
therapies, but an ADC is designed to
overcome the limitations of each. MAbs
are highly specific, but as therapeutics
have demonstrated only modest ef-
ficacy and often are used in combina-
tion with a conventional chemotherapy.
Chemotherapeutics are highly toxic, but
nonspecific, and so suffer from poor
side-effect profiles and dose-limiting
toxicities. In combination, the ADC
serves to keep the chemotherapuetic
bound until it reaches the cancer cell,
thereby limiting its ability to interact
with nontargeted tissues and therefore
limiting nonspecific toxicity (2).
The concept of an ADC is not a new
one, but creating a clinically success-
ful one has been challenging. For the
therapeutic to work well, each of the
parts—the antibody, the toxin, and the
linker that holds them together—must
be carefully considered.
Choosing the right antibody
In general, mAbs as therapeutics are
selected to have high affinity for the
targeted antigen and high selectivity.
Other desirable properties in an anti-
Antibody-Drug
Conjugates
Looking Ahead to an Emerging
Class of Biotherapeutic
Amy Ritter
C
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Cover Story: Antibody-drug conjugates
The cell-killing ability of a cytotoxin is joined
with the specificity of a monoclonal antibody
to produce the next generation of anticancer
therapeutics. Creating a successful antibody-
drug conjugate requires careful selection of the
drug, antibody, and linker.
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The result: maximum process reliability,
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turning science into solutions
44 Pharmaceutical Technology January 2012 Phar mTech. com
Cover Story: Antibody-drug conjugates
body include long circulation times,
immune-effector functions, and tumor-
suppressing activity (2). When choos-
ing the antigen, it is important that it
be expressed at high levels in the tissue
of interest to maximize the amount of
ADC bound by the tumor, but at low
levels elsewhere in the body to mini-
mize off-target toxicity. Moreover, it is
thought that internalization of the ADC
is important for its effectiveness. Many
of the chemical-linking strategies used
to construct ADCs rely on conditions
found inside a cell, either in the cyto-
plasm or in the lysosome, to release the
active agent (3).
In some instances, developers have
been able to leverage experience gained
through the development of mAb ther-
apies to create their ADC. Trastuzumab
emtansine (T-DM1) is an ADC in Phase
III, which combines trastuzumab, (Her-
ceptin), which targets human epidermal
growth factor receptor 2 (HER2) receptors
in breast and stomach cancer, with a may-
tansine derivative DM1, a small-molecule
cytotoxin that binds to tubulin to prevent
microtubule formation, through a nonre-
ducible bis-maleimido-trixyethylene gly-
col linker (4). Trastuzumab was developed
by Genentech (now part of Roche) and
was approved by FDA in 1998 for use in
women with metastatic breast cancer who
have tumors that overexpress the HER2
protein. The maytansine derivative DM1
and linking technology were developed
by ImmunoGen. In the case of the ADC
trastuzumab emtansine, developers were
able to use a target that had already been
validated and a well-characterized anti-
body with a known safety and efficacy
profile as the starting point for an ADC.
Choosing the right
cytotoxic small molecule
The earliest versions of ADCs used stand-
alone chemotherapeutics such as doxo-
rubicin, methotrexate, or vinca alkyloids
as the cytotoxic arm of the conjugate.
Clinical-trial results using these ADCs
were disappointing, and it is thought that
part of the problem was the relatively low
potency of the toxins used (2). The newer
classes of cytotoxins are at least 100-fold
more potent than the older molecules,
with in vitro potency against tumor cell
lines of 10
−9
to 10
−11
M (5).
There are only a few major chemical
classes of toxins being explored. They
can be divided into two types, those that
cause damage to DNA and those that in-
terfere with tubulin polymerization. Ca-
licheamicin, used in Mylotarg and in Pfiz-
er’s inotuzumab ozogamicin, an ADC in
Phase III trials, binds to the minor groove
of DNA and induces double-strand DNA
breaks that result in cell death. Duocar-
mycins, isolated originally from Strepto-
myces bacteria, are DNA minor-groove
binding alkylating agents (2). Fully syn-
thetic duocarmycin derivatives are being
used by the biopharmaceutical company
Syntarga (acquired by the pharmaceutical
company Synthon in June 2011) for ADC
constructs (see sidebar).
Microtubule disruptors are repre-
sented by two major classes: maytans-
inoids and auristatins. Maytansinoids
are deriviatives of maytansine, a natu-
ral product originally isolated from the
shrub Maytenus serrata. ImmunoGen
has focused on development of this class
of cytotoxic small molecules and associ-
ated linker technologies and has been dev-
loping maytansinoid ADC compounds
singularly and in partnership with other
companies. In addition to trastuzumab
emtansine, which is being codeveloped
by Roche and ImmunoGen, another ex-
ample of a maytansinoid ADC being de-
veloped by ImmunoGen is the company’s
IMGN901, which uses the maytansinoid
DM4. Auristatins are synthetic analogs of
dolostatin 10, a natural product derived
from a marine mollusk, Dolabela auricu-
laria. Like the maytansinoids, auristatins
are microtubule disruptors. Millennium
and Seattle Genetics’ ADC Adcetris is a
conjugate of an anti-CD30 mAb to mono-
methyl auristatin E (MMAE). Seattle
Genetics focuses on the development of
auristatin-conjugated ADCs, using the
auristatins MMAE and monomethyl au-
ristatin F (MMAF) and proprietary linkers.
Choosing the right linker
Developing the right linker and method
of attachment is a crucial part ADC
development. “Many areas around the
process have improved, however, the
linker strategy for ADC manufactur-
ing and their application has certainly
contributed perhaps the most in mov-
ing the field forward,” says Grant Boldt,
director of business development at the
CMO SAFC. The creation of linkers that
are stable in circulation but labile upon
binding of the ADC to its target has re-
sulted in the current generation of ADCs
having better stability and lower systemic
toxicity than earlier ADCs, according to
Boldt. Early versions of ADCs, including
Mylotarg, suffered from instability while
in circulation. The linkage between the
mAb and the cytotoxic small molecule
were destroyed by endogenous proteases
in the blood, and the premature release of
the cytotoxin resulted in side-effect pro-
files similar to that of an unconjugated
chemotherapeutic. The current genera-
tion of linkers is more resistant to deg-
radation in the blood while still allowing
release of the payload at the target. Choice
of a linker is influenced by which toxin is
used, as each toxin has different chemical
constraints (6).
Linkers can be divided into two broad
categories: cleavable and noncleavable.
Cleavable linkers rely on processes in-
side the cell to liberate the toxin, such
as reduction in the cytoplasm, exposure
to acidic conditions in the lysosome, or
cleavage by specific proteases within the
cell. Noncleavable linkages require cata-
bolic degradation of the conjugate for
release of the cytotoxic small molecule.
The released cytotoxic small molecule
will retain the linker and the amino acid
by which it attached to the mAb. Impor-
tantly, both classes are designed to release
the cytotoxic small molecule only after
the ADC has reached the interior of the
cancer cell (2).
There are a l imited number of
chemical moities on proteins, includ-
ing mAbs, that are available for chemi-
cal modification. Linkers can attach to
the mAb through the amino groups of
lysine residues, or by the thiol groups
on cysteine residues. Attachment is a
pseudorandom process: in theory, any
of the targeted amino acids within the
mAb, either cysteine or lysine, can be
modified (3). According to Boldt, the
conjugation reaction results in a het-
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46 Pharmaceutical Technology January 2012 Phar mTech. com
erogeneous mixture of conjugated spe-
cies, but the proportion of each species
in the mixture is reproducible from
batch-to-batch and quantifiable.
Putting it all together
Producing the ADC requires both
biologic-based and small-molecule
manufacturing. “One of the biggest
challenges in manufacturing ADCs is
controlling all the components that go
into the final conjugation step,” says
Boldt. “Namely, the three main com-
ponents that make up an ADC (e.g.,
antibody, linker, and payload) are all
manufactured in very different ways.
For example, it is not uncommon for
these components to be manufactured
by synthetic chemistry and mamma-
lian cell culture. Thus, there presents a
challenge in ensuring all these compo-
nents have been manufactured under
cGMP, and subsequently bringing
them all together to generate the final
ADC under cGMP, as well.”
The biologics portion of the ADC
and the high-potency API require very
different handling methods, and man-
ufacturers must make sure that han-
dling requirements for both are met.
“It is imperative that manufacturers
emphasize the protection of the prod-
uct from workers as well as the protec-
tion of workers from the product,” says
Jason Brady, head of business develop-
ment, conjugates and cytotoxics at the
CMO Lonza. Clinical ADC manufac-
turing is executed in an aseptic bio-
logical manufacturing environment to
protect the product from contamina-
tion, explains Brady. Once conjugated
with the high-potency API (which is
manufactured in a high-containment
environment), the resulting ADC also
is handled under high-containment
conditions. The level of containment is
determined by occupational exposure
limits for the high-potency API and
resulting ADC. The environment must
provide manufacturing personnel with
isolation from cytotoxic chemicals in the
occupational exposure range of 5 ng/m
of air. Also important is that facility de-
sign includes design of equipment and
process contact surfaces that permit
Although antibody-drug conjugates (ADCs)
offer promise for delivering a drug payload—
often a cytotoxic small molecule—with
greater specificity through its attachment to a
monoclonal antibody, one challenge is to create
the link between the antibody and the drug
molecule that remains stable until reaching
the target cell but that does not affect the
mechanism of action of the cytotoxic agent.
Meeting both needs has presented a stumbling
block for several ADCs in development. In these
cases, inappropriate drug choice or unstable
linking technologies have resulted in clinical-trial
failures (1).
One company active in ADC linker technology
is Synthon through its acquisition in June 2011
of Syntarga, a company specializing in antibody
payload chemistries. “We have a new family
of duocarmycin derivatives—our warhead
molecules—that we link to antibodies,” says
Vincent de Groot, former CEO of Syntarga and
vice-president of ADCs at Synthon. Duocarmycins
are small-molecule DNA minor groove
binding alkylating agents with potency in the
subnanomolar to picomolar range, according to
the company.
While this class of drug has been around for
some time, says de Groot, Phase II clinical trials
using the unconjugated compound proved to be
too potent to offer a therapeutic window with
adequate safety. However, given its mechanism
of action—interacting with DNA—duocarmycin
can kill tumor cells in all phases of the cell cycle,
not just in the mitosis phase. Therefore, it offers
great potential in treating solid tumors, where
cells are dividing slowly or not at all, providing
its cytotoxicity en route to the target cell can be
limited, according to de Groot.
There are two important requirements for ADC
linkers: stability in the blood and ADC lability
inside the target cell for release of the active
species (2). Synthon has three linker chemistries;
its SpaceLink technology reversibly links the
drug by means of a linear releasable linker,
and the MultiLink technology allows linkage of
multiple drugs to the antibody. The company’s
AbLoad technology offers a synthetic approach
to introduce the chemical group that reacts with
the antibody (i.e., Ab-reactive group) in the final
step of the linker-drug construct synthesis. The
key to Synthon’s SpaceLink technology is that
the linker molecule can reversibly bind to a drug
molecule’s hydroxyl group, which is particularly
complementary to the duocarmycin class of
drugs because the hydroxyl group is an essential
part of a precursor molecule that rearranges into
the active species spontaneously.
Synthon’s chief scientific officer Ian Anderson
provides the following example. “The antibody
directs the ADC to the cell of interest, for
example an anti-HER2 would go to HER2 on
the breast-cancer cell, where it would then
be internalized as the ADC. There is then a
lysosomal protease cleavage within the cell to
liberate the duocarmycin moiety. The drug, once
cleaved, spontaneously turns into the active
species.” Essentially, the linker–drug undergoes
spontaneous electronic cascade self-elimination
followed by spontaneous cyclization elimination
and finally spontaneous rearrangement into the
active species, at which point duocarmycin is free
to bind to and alkylate DNA and thus exerting its
cytotoxic effect.
The next part of the conjugation involves
attaching the linker–drug molecule to the
antibody, and there are two main methods,
according to de Groot. The first method is
to attach the linker–drug molecule to free
cysteine residues after antibody reduction,
and the second method is to attach the linker–
drug molecule to lysine residues. Lysines are
positioned throughout the antibody molecule,
so there is little control over where the linker–
drug positions itself, but if cysteine attachment
distribution can be narrowed, the number of
species variants produced can be controlled.
Both approaches are being pursued by the
industry according to de Groot.
Looking ahead, the next generation of ADCs
will likely use site-directed coupling of the
linker–drug to the antibody, which is an area of
active ADC research, says Anderson. Having more
control over the conjugation process, through
the use of nonnatural amino acids, for example,
will enable pharmaceutical companies to
develop better-characterized, more homogenous
ADCs, and the potential for increased efficacy
and safety.
References
1. S. Webb, “Pharma Interest Surges in Anti-
body Drug Conjugates,” Nat. Biotechnol. online,
DOI:10.1038/nbt0411-297, Apr. 8, 2011.
2. V. de Groot, “Novel ADC Linker–Drug Tech-
nology for Next Generation ADC Products,” pre-
sented at Peptalk–Protein Science Week (Cam-
bridge Health Institute, San Diego, Jan. 10–14,
2011).
The importance of linker technology by Rich Whitworth
Cvert Syvtn: ibyduvgn-gtcj avbscjiyr
Pharmaceutical Technology January 2012 47
clean-in-place and steam-in-place to
remove minute traces of residual drug
contamination during both interbatch
and product changeover cleaning, ac-
cording to Brady.
Room for improvement
As ADCs advance in the cl inical
pipeline so does the technology to
manufacture ADCs to control certain
product and process conditions. “New
technology that can limit the hetero-
geneity of ADC products is something
that will be important in the future,”
says Brady. “ADCs made via current
technologies are heterogenous mix-
tures. Heterogeneity can be controlled
and measured by robust and repro-
ducible manufacturing processes and
proper analytics, but new technolo-
gies will likely emerge to inf luence
and improve ADC manufacturing,” he
explains. Some fraction of the finished
drug product consists of unconjugated
antibody. The remaining portion of the
finished drug product contains conju-
gated antibody with a variable number
of the cytotoxic small molecules conju-
gated at different sites on the antibody.
Controlling the number and location of
cytotoxic molecules conjugated to the
antibody is being pursued as a means to
create a more uniform product and as a
way of being able to explore structure–
function relationships by varying the
site of attachment of the cyotoxin.
One strategy for controlling the site
of attachment has been developed by
researchers from Genentech, a member
of the Roche Group. They describe pre-
cise site-specific conjugation of human
IgG1 to MMAE by replacing Ala
114
at
the junction of the CH1 and the vari-
able heavy-chain domain with cysteine
to create an engineered antibody called
a THIOMAB. This site was chosen be-
cause it does not participate in antigen
binding or effector functions. Accord-
ing to Jagath Reddy Junutula, senior
scientist at Genentech, the process
for creating a THIOMAB differs only
slightly from that of a conventional
mAb. The THIOMAB is subjected to
partial reduction to remove cysteine
and glutathione adducts. The partial
reduction also breaks interchain disul-
fide bonds, which must be reformed by
a reoxidation step. After reoxidation,
the engineered cysteine residues are
available for conjugation.
Genentech researchers used this
process to conjugate MMAE to a THI-
OMAB version of an antibody against
MU16, a cell-surface protein expressed
in ovarian cancer cells. The THIOMAB
conjugate was shown to be homogenous
and to contain a single drug molecule
attached to each heavy chain, for a total
of two MMAE molecules per ADC. The
THIOMAB–MUC16 was found to have
comparable efficacy to a conventionally
produced ADC and to be better tolerated
in two preclinical species (7). In a subse-
quent study, a different cytotoxin, DM1,
was conjugated to a THIOMAB version
of trastuzumab. Results were similar,
with the THIOMAB T–DM1 displaying
comparable efficacy and better tolerabil-
ity in preclinical species than its conven-
tionally produced counterpart (8).
According to Junutula, the reoxidation
step is the only thing that distinguishes
manufacture of a THIOMAB drug con-
jugate from that of a conventional ADC.
“We can make up to grams scale without
any difficulty. And the results are huge—
you have a homogenously conjugated cy-
totoxic drug to the antibody,” he says.
Whi le t he THIOMAB uses t he
substitution of one amino acid for
another to control the site of conjuga-
tion, several groups are working to-
ward incorporating nonnatural amino
acids into the mAb for to control the
site of conjugation and also to provide
an expanded repertoire of functional
groups that could be used for linker
chemistry. The biopharmaceutical
company Ambrx has developed ex-
pression systems in E. coli, yeast, and
Chinese hamster ovary (CHO) cells
that can be used for such substitu-
tions and which can be scaled up to
volumes required for commercial
manufacturing. Ambrx’s expression
systems contain engineered transfer
RNAs that will read through a stop
codon called amber, as well as engi-
neered tRNA synthetases that will
aminoacylate the orthoganal tRNA
with an Ambrx nonnatural amino
acid. The expression system will insert
a nonnatural amino acid whenever the
amber stop codon is encountered (9).
Sutro Biopharma, a provider of
protein-synthesis technology, also is
developing a platform for introducing
nonnatural amino acids, but in a cell-
free translation system that is reported
to be scalable to commercial production
volumes (10). The system is based on an
extract of E. coli, and because it is an
open system, the tRNA charged with
a nonnatural amino acid can be added
directly to the reaction mix as a reagent.
Looking ahead
The future of ADCs in the biophar-
maceutical market will ultimately de-
pend on their clinical success. Com-
panies and researchers are seeking
to meet that challenge by optimizing
the selection of all the components in
the ADC—the antibody, linker, and
cytotoxin—and successfully combin-
ing manufacturing techniques for
both high- potency APIs and biolog-
ics. ADCs are sometimes described as
armed antibodies, and their cytotoxic
components as warheads. Whether
ADCs will prove to be an effective
weapon against cancer or other dis-
eases has yet to be seen as more are
tested in the clinic.
References
1. FDA, “Label for Adcetris, BLA 125338,”
FDA Approved Drug Products: Drugs@
FDA, accessed Dec. 20, 2011.
2. V.S. Goldmacher and Y.V. Kovtun, Ther.
Deliv. 2 (3), 397–416 (2011).
3. F. Dosio, P. Brusa and L. Cattel, Toxins 3,
848–883 (2011).
4. H.A. Burris, Expert Opin. Biol. Ther. 11
(6), 807–819 (2011).
5. A. Beck et al., Discov. Med. 10 (53), 329–
359 (2010).
6. S.V. Govindan and DM Goldenberg,
Scientific World Journal 10, 2070–2089
(2010).
7. Junutula et al., Nat. Biotechnol. 26 (8),
925-932 (2008).
8. Junutula et al., Clin. Canc. Res. 16, 4769–
4778 (2010).
9. A. Ritter Pharm. Tech. 35 (6), 36–39
(2011).
10. Zawada et al., Biotech. Bioeng. 108 (7),
1570–1578 (2011). PT
48 Pharmaceutical Technology January 2012 Phar mTech. com
Technical Forum: Solid-Dosage
PharmTech: What formulation considerations
are required for multilayer tablet manufacturing
(e.g., levels of fines, bulk densities and
granulation properties)?
Behrens (IMA): For efficient tableting, gran-
ule flow is crucial and a certain amount of
fines is needed to guarantee proper filling
and binding of the tablet. It is also impor-
tant that the tableting machine is designed
so that the filling range can cope with bulk
density. In addition, the system should
avoid the carry-over of particles or fines.
Calvin (Elizabeth): When utilizing a tablet
press with the proper powder-feed system,
there is usually no need for any special con-
siderations or factors, such as levels of fines
or granulation properties to be determined.
The only consideration would be the bulk
density of the granulation. Depending
upon which layer is the lighter density
granulation, it would normally be used
on the first layer if the tableting press has a
limitation of the upper-punch penetration
of the layer tamping stations that regulate
the depth of fill of the consecutive layers.
Kirsch (Natoli): The level of fines must al-
ways be considered, even for nonlayered
tablets. Excessive fines will result in poor
tablet quality, as well as tool binding and
tablet press overheating, which exacerbates
sticking and picking issues. Although fines
are a necessary evil for proper tablet com-
pressibility, it is critical that these are kept
to a minimum when compressing layered
tablets; otherwise cross-contamination
from one layer to the next will be increased
because fines will pass under feeders and
scraper blades. Bulk densities are also a
consideration because light or airy granu-
lations require increased depth of fill and
precompression. Precompression of the
first layer is required for clear demarcation
lines between the layers. If the press does
not have sufficient upper-punch penetra-
tion to precompress the first layer, the de-
sired weight may not be achieved and there
will be insufficient volume in the die bore
for the next layer. Some modern presses
are only capable of 4-mm upper-punch
penetration, whereas many older presses
were capable of almost 10-mm penetra-
tion, which, in many cases, made them
better suited for layered tablets. Granula-
tion properties would be much the same as
with non-layered tablets with the exception
of reduced fines; good flow and compress-
ibility are always desired.
Ethirajan (Tedor): It is beneficial if both layers
have relatively equal physical properties,
such as the amount of fines, bulk den-
sity, and granulation properties. It is also
ideal to maintain granule size less than
one half of the layer thickness to achieve
a clear scrape-off. Specifically, fines below
200 meshes can smear or coat the turn-
table surface and it may not be possible to
achieve a clean scrape-off, which can lead
to layer cross-contamination.
PharmTech: How can common formulation chal-
lenges (e.g., combining incompatible products),
be overcome?
Kirsch (Natoli): Incompatible APIs are the
main driver for layered tablets. They enable
incompatible ingredients to be adminis-
tered in the same tablet without degrading
the actives. As for excipient choice, this is
why we have R&D; use what works.
Ethirajan (Tedor): Incompatibility between
the tablet components can be overcome
by having the incompatible ingredients in
different layers. It is critical to understand
the physicochemical properties of the drug
substance, and preformulation compatibil-
ity studies will help identify such incom-
patibilities so that certain excipients can be
avoided or be separated into different layers
for better drug product stability. Multilay-
ered technology is used in many instances
to overcome incompatibilities between
drug substances that need to be admin-
istered in a single dosage. Occasionally, in
the case of three-layer tablets, a thin pla-
cebo layer may be used between the outer
active layers to avoid incompatibilities.
Another vital part in developing mul-
tilayered tablets is excipient selection. It is
preferable to use excipients that are com-
patible with the drug substances in both
the layers to maximize drug-product sta-
bility. Generally, scrapers present in the
multilayered machines are non-metallic
in nature; hence, it is imperative that the
use of abrasive excipients that may ruin
these scrapers is avoided. Using exces-
sive amounts of lubricants should also
be avoided because these may interfere
with adhesion between layers. Excipient
choices should be based on the function-
ality of a particular layer (e.g., immediate
release).
PharmTech: How can the weight of individual
layers be monitored and controlled accurately?
Behrens (IMA): When producing bilayer
tablets, the in-line control of production,
combining compression force measure-
ment and statistical weight check are chal-
lenging for several reasons. If the compac-
tion force for layer one is extremely low, it
could be difficult to obtain a clear signal
from the strain gauges. Low-force com-
pression rollers are available to help deal
with this. The reduced mass ensures more
accurate and reliable measurements. An-
other critical point is statistical sampling
of the layers for weight checking. For sam-
pling, the first layer has to be compressed
at a higher force to achieve enough hard-
ness to make sampling and weighing pos-
sible. Some systems can achieve this by
using specialized systems. For example, to
avoid the production of second-layer-only
tablets during layer one sampling, lower
punches can remain in the up position
while the fill-shoe for layer two is stopped.
Calvin (Elizabeth): Usually, two different
process-control methods are employed to
Multilayer-Tablet Technology
Moderated by Rich Whitworth and Stephanie Sutton
To gain insight into current trends in multilayer-tablet technology, PharmTech
spoke to Marcus Behrens, sales director at IMA Kilian; James Calvin, technical
service manager at The Elizabeth Companies; Doug Kirsch, technical service
manager at Natoli Engineering Company; and LakshmiDevi Ethirajan,
manager, formulation development at Tedor Pharma.
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50 Pharmaceutical Technology January 2012 Phar mTech. com
achieve this. The first standard method
is to utilize force control, which monitors
the layer tamping pressure by means of a
strain gauge transducer that, in turn, pro-
vides feedback to the press controller. This
information is used to automatically adjust
the metering cam to keep the set pressure
constant to maintain the correct weight
and tamping pressure. The strain gauge
should be sized so that it will be sensitive
enough to “sense” the lighter tamping pres-
sures required for producing a tablet layer
compared to the strain gauge that would
be required for final tablet compression.
The secondary method is to select a multi-
layer tablet press that automatically collects
sample tablets from each layer at regular
intervals and sends them to a weight test-
ing unit, which would be included in the
press control feedback loop, to provide in-
process checks and weight control.
Kirsch (Natoli): Tablet press manufactures will
be responsible for this through improved
technology and engineering. By utilizing
quality by design, the science of the formu-
lation is understood and the design space
can be exploited to deliver a controllable
process. Controlled processes deliver a
product with the required critical quality
attributes that define what is to be delivered
to the patient.
PharmTech: How can layer cross-contamination
be avoided?
Behrens (IMA): Product losses can be very
high when making layered tablets. Usu-
ally strong vacuum aspiration is used
to clean the residual product on the die
table after the dosage of each layer, thus
preventing cross contamination. Over
the years, vendors have developed several
technical solutions that minimize the
quantity of powder remaining on the die
plate that needs to be removed by suction.
Calvin (Elizabeth): This can be avoided in a
few ways. Ensuring the feed frame is cor-
rectly adjusted and not leaking powder,
properly adjusting the vacuum being ap-
plied to the front of the feedframe to keep
the die table clean, and installing dies that
are manufac-
tured to the high
limit on over-
all die height.
Whenever the
g r a nu l a t i o n
characteristics
and tablet size
deem it neces-
sary, a “Tail Over
Die Scraper” (a
delrin cover that
is held in place
against the die
table with spring
steel to keep any
granulation form
slinging out of
the die through
centrifugal force)
may be needed if
any powder loss
is incurred due to
centrifugal force.
Ki rsch (Natol i):
Proper press
setup is essential.
Turret die tables
have a certain
amount of verti-
cal run out. Often overlooked is the simple
task of indicating a die table to locate the
high point. Feeder clearance must be set at
this point to achieve a minimal amount of
clearance between the feeder and die table
to reduce granulation loss. Scraper blades
must be in good condition and free floating
on the die table to reduce cross contami-
nation. Die tables must also be in excel-
lent condition as any wear or damage will
contribute to granulation crossover. Proper
dust extraction is also needed as presses
suited for layered tablets generally have
more and/or specifically designed vacuum
nozzles. Skilled press setup technicians and
operators are a must.
Ethirajan (Tedor): Scraper and seal condi-
tions of the feed frames are very important.
It is also essential that excess granulation
passing the scrape-off be vacuum cleaned
so that fines from one layer don’t cross con-
taminate the other. Reduced fill cams may
be used to reduce the amount of granula-
tion that needs to be scraped off from over-
fill of the die.
PharmTech: What are the unique challenges of
applying in-process controls and process analyti-
cal technologies (PAT) to multilayer tablets?
Behrens (IMA): PAT systems based on trans-
mission or reflection are seldom used on
monolayer tablets. The amount of valida-
tion is high, and even more complex for
bilayer or multilayers. It is also difficult to
repeat the measuring results on each layer.
The industry has to put more efforts into
this issue.
Kirsch (Natoli): PAT is best used during de-
velopment to understand the variables
involved in achieving the formulation
design for a quality tablet.... However, PAT
measurements can provide information
for feedback control, which can offer the
manufacturer an opportunity to move
toward real-time release of a product. If
traditional tablet press variables are prop-
erly controlled and a quality granulation is
delivered to the tablet press, then the due
diligence time spent in process develop-
ment pays off with a robust manufactur-
ing process that does not require process
analytical instrumentation. PT
Read the full version of this article and other related
content online at PharmTech.com/multilayer.
Technical Forum: Solid-Dosage
52 Pharmaceutical Technology January 2012 Phar mTech. com
Producing pharmaceutical compounds
in a cost-effective and operationally
efficient way is an ongoing challenge
for process R&D chemists. Improving
product yield, purity, and enantioselec-
tivity requires a myriad of approaches
and tools to enhance process under-
standing and analysis. Some recent ad-
vances involve strategies for accelerat-
ing reaction discovery, approaches for
inducing chirality and stereochemical
analysis, and applications in nanotech-
nology for protein elucidation.
Accelerated serendipity
Researchers at Princeton University re-
cently reported on the use of “accelerated
serendipity,” a process involving robotics
and high-throughput and automated
workflow as a tool in process R&D. The
researchers wanted to see whether ser-
endipity could be forced or simulated
to occur on a predictable basis in the
realm of reaction discovery to provide
a reliable platform to access valuable
transformations or unexpected reaction
pathways (1). The researchers used a
high-throughput, automated workflow
and evaluated a large number of random
reactions and discovered a photoredox-
catalyzed carbon–hydrogen arylation re-
action for constructing benzylic amines,
an important structural component
within pharmaceutical compounds that
is not readily accessed by means of sim-
ple substrates. The mechanism directly
coupled tertiary amines with cyanoaro-
matics by using mild and operationally
manageable reaction conditions. The
researchers asserted that this carbon–
carbon bond-forming protocol can be
widely used in the synthesis of benzylic
and heterobenzylic amines (1).
“This is a very different way of ap-
proaching how we come up with valu- I
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Some recent advances involve strategies for
accelerating reaction discovery, approaches
for inducing chirality and stereochemical
analysis, and applications in nanotechnology
for protein elucidation.
Broadening the Toolbox in
Drug Development and Analysis
Patricia Van Arnum
Pharma Ingredients: APIs & Excipients
Patricia Van Arnum
is a executive editor at
Pharmaceutical Technology,
485 Route One South,
Bldg F, First Floor,
Iselin, NJ 08830
tel. 732.346.3072,
pvanarnum@advanstar.com.
able chemical reactions,” said David
MacMillan, professor of chemistry at
Princeton University and co-author
of the recent study, in a Nov. 28, 2011,
Princeton University release. “Our
process is designed specifically for
serendipity to occur. The molecules
that should be combined are those for
which the result is unknown,” he said.
“In our lab, we used this technique to
make new findings in a much more
routine and rapid fashion, and we
show that if you have enough events
involved, serendipity won’t be rare. In
fact, you can enable it to happen on al-
most a daily basis.”
MacMillan conceived of accelerated
serendipity following his doctoral work
at the University of California–Irvine
during the 1990s, according to the
Princeton University release. When en-
visioning his team’s recently reported
project, MacMillan calculated that if,
in a single day, he ran the equivalent of
one reaction per day for three years—
nearly 1100 reactions—the odds fa-
vored a new discovery, according to
the release. The Princeton University
researchers began running reactions
once a day using a high-throughput,
automated reaction accelerator in
Princeton’s Merck Center for Catalysis.
A key part of the process was apply-
ing photoredox catalysis, an approach
to synthesize chemical reactions using
a low-power light source, according to
the university release. MacMillan had
earlier reported on the use of photore-
dox catalysis with organocatalysis in
the direct asymmetric alkylation of
aldehydes (2). The use of photoredox
catalysts in organic-compound syn-
thesis is relatively new comparative
to other chemocatalytic approaches
and broadened the compounds and
reactions under study. For their latest
work, MacMillan and his team carried
out this process on the molecules be-
fore each reaction cycle. In the case of
the researchers’ recent work, the focus
was on benzylic amines, important in
many pharmaceutical compounds.
“We quickly realized that any phar-
maceutical research chemist could
immediately take these very simple
components and, via a reaction no one
had known about, start assembling
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molecules with an adjacent aromatic
ring rapidly,” MacMillan said in the
university release. “Instead of having
to construct these important molecules
circuitously using lots of different
chemistry over a period of days if not
weeks, we can now do it immediately
in the space of one chemical reaction
in one day,” he said.
Chiral chemistry
Inducing chirality. Researchers at Case
Western Reserve University developed
a “top-down” approach to introduce
chirality into a nonchiral molecule
by using a macroscopic blunt force to
impose and induce chirality. “The key
is that we used a macroscopic force to
create chirality down to the molecular
level,” said Charles Rosenblatt, professor
of physics at Case Western Reserve Uni-
versity in Cleveland, Ohio, in a Decem-
ber 2011, press release and senior author
of a recent paper on the research (3).
Specifically, the researchers im-
posed a macroscopic helical twist on
an achiral nematic liquid crystal by
controlling the azimuthal alignment
directions at the two substrates (3).
On application of an electric field, the
director rotates in the substrate plane.
This electroclinic effect, which requires
the presence of chirality, is strongest at
the two substrates and increases with
increasing imposed twist distortion (3).
The researchers treated two glass
slides so that cigar-shaped liquid crys-
tal molecules would align along a par-
ticular direction. They then created a
thin cell with the slides, but rotated the
two alignment directions by approxi-
mately a 20-degree angle, according to
the university release. The 20-degree
difference caused the molecules’ orien-
tation to undergo a right-handed he-
lical rotation, or a so-called imposed
“chiral twist.” Because of the higher en-
ergy needed to maintain the naturally
left-handed molecules in the crystal,
some of the left-handed molecules in
the crystal became right-handed, with
this shift being the induced chirality.
To test for chirality, the researchers
applied an electrical field perpendicu-
lar to the molecules. If there were no
chirality, there would be nothing to
see. If there were chirality, the helical
twist would rotate in proportion to the
amount of right-handed excess. The
result was a model involving a trade-
off among bulk elastic energy, surface
anchoring energy, and deracemization
entropy that suggested the large equi-
librium director rotation induced a de-
racemization of chiral conformations
in the molecules or “top-down” chiral
induction (3).
Stereochemical analysis. Researchers at
Carnegie Mellon University success-
fully used nuclear magnetic resonance
(NMR) to analyze the stereochemical
structure of gold nanoparticles, a po-
tentially important advance in drug
development. Determining a nanopar-
ticle’s chirality is a key step toward de-
veloping them as chiral catalysts.
The researchers reported on the
chiral it y in gold nanoclusters by
NMR spectroscopic probing of the
surface ligands. The Au
38
(SR)
24
and
Au
25
(SR)
18
(where, R = CH
2
CH
2
Ph)
Formulation development forum: nanosized dendrimers
Nanosized systems are important in drug delivery. Such nanosized
systems include liposomes, nanocrystals, micelles, colloidal particles,
quantum dots, and dendrimers. Dendrimers are class of synthetic
macromolecules with highly branched, monodispersed, circular, and
symmetrical architecture that are used as carrier molecules in drug
delivery (1). Researchers at the Mayo Clinic in Rochester, Minnesota,
Wayne State University in Detroit, Michigan, and John Hopkins Medicine
in Baltimore, Maryland, recently reported on using hydroxyl-terminated
polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices to
treat age-related macular degeneration and retinitis pigmentosa (2).
Dry age-related macular degeneration and retinitis pigmentosa are caused
by neuroinflammation, which progressively damages the retina and can
lead to blindness. The research tested the dendrimer delivery system in rats
that develop neuroinflammation. The researchers showed that steroids
attached to the dendrimers targeted the damage-causing cells associated
with neuroinflammation but left the rest of the eye unaffected and preserved
vision, according to a Dec. 13, 2011, Wayne State University press release.
The principal authors of the study, Raymond Iezzi, MD, an
ophthalmologist at the Mayo Clinic, and Rangaramanujam Kannan, PhD, a
professor of ophthalmology at The Wilmer Eye Institute of Johns Hopkins,
developed a clinically relevant, targeted, sustained-release drug delivery
system using a simple nanodevice construct (2). The experimental work in
rat models showed that one intravitreal administration of the nanodevice
in microgram quantities could offer neuroprotection at least for a month,
according to the press release.
Because steroids have neuroprotective and anti-inflammatory properties,
the researchers tried to deliver them precisely to the right target. The
PAMAM dendrimers were used as drug delivery vehicles. “Dendrimers are
tree-like, noncytotoxic polymeric drug delivery vehicles (approximately
4 nm),” explained Kannan in the press release. “Surprisingly, the activated
microglia in the degenerating retina appeared to eat the dendrimer
selectively and retain them for at least a month. The drug is released from
the dendrimer in a sustained fashion inside these cells, offering targeted
neuroprotection to the retina,” said Kannan.
Upon intravitreal administration, the PAMAM dendrimers selectively
localized within the activated outer retinal microglia in two rat models
of retinal degeneration, but not in the retina of healthy controls. This
biodistribution covalently conjugated fluocinolone acetonide to the dendrimer.
The conjugate released the drug in a sustained manner over 90 days.
According to the researchers, these studies suggest that PAMAM dendrimers
(with no targeting ligands) have an intrinsic ability to selectively localize in
activated microglia and to deliver drugs. Although the steroid offers only
temporary protection, the treatment as a whole provided sustained relief from
neuroinflammation. The patent-pending technology will be advanced further
through a multi-university collaboration among Johns Hopkins, the Mayo
Clinic, and Wayne State University, according to the release.
Sources
1. G. T. Tolia and H.H. Choi, Pharm. Technol. 32 (11), 88–98 (2008).
2. R. Iezzi et al., “Dendrimer-Based Targeted Intravitreal Therapy for Sustained
Attenuation of Neuroinflammation in Retinal Degeneration,” Biomaterials
online, DOI 0.1016/j.biomaterials.2011.10.010, Nov. 1, 2011.
Pharma Ingredients: APIs & Excipients
56 Pharmaceutical Technology January 2012 Phar mTech. com
were used as representative models
for chiral and nonchiral nanoclusters,
respectively (4). The researchers com-
pared the NMR signal from the hy-
drogen atoms in the nonchiral gold
nanoparticle with the NMR signal
from the hydrogen atoms in the chiral
gold nanoparticle. The NMR method
overcame the limitations of circular
dichoism spectroscopy in determin-
ing the chirality of gold nanoparticles
in a racemic mixture. The nanoparti-
cles’ chiral core induced the methylene
group’s two hydrogen atoms to give off
different frequencies, a phenomenon
known as diastereotopicity.
The researchers compared the NMR
signal from the hydrogen atoms in the
nonchiral gold nanoparticle with the
NMR signal from the hydrogen atoms
in the chiral gold nanoparticle. The
nonchiral nanoparticle’s NMR spec-
trum did not reveal any differences,
but the chiral nanoparticle’s NMR
spectrum revealed two different hy-
drogen signals, providing a simple and
efficient way of telling whether the par-
ticle is chiral or not, even for a 50/50
mixture of isomers, according to a
Dec. 7, 2011, Carnegie Mellon Univer-
sity release. The researchers concluded
that NMR spectroscopy can be a useful
tool for investigating chirality in gold
nanoclusters. Since the diastereotopic-
ity induced on the methylene protons
by chiral nanoclusters is independent
of the enantiomeric composition of
the chiral particles, NMR can probe
the chirality of the nanoclusters even
in the case of a racemic mixture while
circular dichroism spectroscopy is not
useful for racemic mixtures (4).
Applications in nanotechnology
Interdisciplinary approaches in chem-
istry, biology, polymer science, and the
new sciences, such as nanotechnology,
are important in advancing drug devel-
opment and drug delivery. Researchers
at the University at Buffalo have synthe-
sized tiny, molecular cages that can be
used to capture and purify nanomateri-
als. The traps are derived from a special
kind of molecule, so-called a “bottle-
brush molecule,” which consists of small
organic tubes whose interior walls carry
a negative charge. This feature enables
the tubes to selectively encapsulate only
positively charged particles, according
to a Dec. 5, 2011, University of Buffalo
press release. The researchers reported
on the new method for fabricating am-
phiphilic organic nanotubes from mul-
ticomponent bottlebrush copolymers
with triblock terpolymer side chains.
The obtained nanotubes were highly
selective carriers for positively charged
molecules and nanometer-size macro-
molecules by means of liquid–liquid ex-
tractions. The researchers were able to
discriminate between dendrimers with
about 2 nm size differentials (5). These
kinds of cages could be used, in the
future, to expedite tasks, such as segre-
gating large quantum dots from small
quantum dots or separating proteins by
size and charge.
“The shapes and sizes of molecules
and nanomaterials dictate their utility
for desired applications,” said Javid Rza-
yev, assistant professor of chemistry at
the University of Buffalo and co-author
of the study, in the university release.
“Our molecular cages will allow one to
separate particles and molecules with
predetermined dimensions, thus cre-
ating uniform building blocks for the
fabrication of advanced materials.”
To create the traps, Rzayev and his
team first constructed a special kind
of molecule called a bottle-brush mol-
ecule. These resemble a round hair
brush, with molecular “bristles” pro-
truding all the way around a molecular
backbone, according to the university
release. After stitching the bristles to-
gether, the researchers hollowed out the
center of each bottle-brush molecule,
leaving behind a tube-like structure.
When building the bottlebrush mol-
ecules, the scientists constructed each
molecule using molecular structures
that disintegrate upon coming into
contact with water and around this core,
attached a layer of negatively charged
carboxylic acid groups. To design the
molecule, the scientists immersed it
water, in effect hollowing the core. The
resulting structure was the trap, a nano-
tube whose inner walls were negatively
charged due to the presence of the newly
exposed carboxylic acid groups, accord-
ing to the university release.
To test the tubes’ effectiveness as traps,
the researchers designed a series of ex-
periments involving a two-layered chem-
ical cocktail, according to the university
release. The bottom layers consisted of
a chloroform solution containing the
nanotubes, and the top layer consisted
of a water-based solution containing
positively charged dyes. After shaking,
the nanotubes collided with and trapped
the dyes, bringing the dyes into the chlo-
roform solution. In similar experiments,
the researchers used the nanotubes to
extract dendrimers from an aqueous
solution. The nanotubes were designed
so that dendrimers with a diameter of
2.8 nm were trapped, and dendrimers
that were 4.3 nm across were left in solu-
tion. To remove the captured dendrimers
from the nanotubes, the researchers low-
ered the pH of the chloroform solution,
which shut down the negative charge
inside the traps and allows the captured
particles to be released from their cages,
according to the university release.
References
1. A. McNally, C.K. Prier, and D.W.C. Mac-
Millan Science 334 (6059), 1114–1117
(2011).
2. D.A. Nicewicz and D.W.C. MacMillan,
Science 322 (5898) 77–80 (2008).
3. C. Rosenblatt et al., Phys. Rev. Lett. 107
(23), 237804–7808 (2011).
4. R.R. Gil et al., ACS Nano 5 (11), 8935–
8942 (2011).
5. J. Rzayev and K. Huang, J. Am. Chem.
Soc. 133 (42), 16726–16729 (2011). PT
Pharma Ingredients: APIs & Excipients
Researchers introduced chirality into a
nonchiral molecule by
using a macroscopic blunt force to
impose and induce chirality.
Pharmaceutical Technology JANUARY 2012 57
The authors designed an upper punch with
a removable punch tip to determine a tablet
formulation’s propensity to stick by weighing the
mass of powder adhered to the punch tip. About
1000 tablets were compressed to a solid fraction
of 0.85 on a single-station tablet press, and
the punch tip was periodically weighed using a
microbalance. Sticking profiles were generated
for tablet formulations containing various levels
of sticky tableting components (i.e., ibuprofen
and mannitol) and tableting lubricant (i.e.,
magnesium stearate).
Matthew P. Mullarney* is a principal scientist, Bruce
C. MacDonald is a scientist, and Allan Hutchins is a
laboratory technician, all at Pfizer, Eastern Point Road,
Groton, CT 06340, tel. 860.715.4139, fax 860.441.3972,
matthew.p.mullarney@pfizer.com.
*To whom all correspondence should be addressed.
Submitted: Oct. 31, 2011. Accepted: Dec. 1, 2011.
Formulation Development
T
he adherence or sticking of compressed powder to the
surfaces of tablet tooling can cause significant drug-prod-
uct manufacturing problems and quality defects, such
as surface picking, surface dulling, and illegible tablet
debossing. The literature contains several methods for assess-
ing the degree of punch sticking, including chemical analysis of
dissolved material adhered to the punch tip, visual inspection
of punch tips, measurement of tablet take-off forces, powder-
impingement testing, and measurement of punch pull-off force
using an instrumented punch (1–6). Although these methods
are useful, simple and quantitative punch-sticking-assessment
tools are lacking, and many tablet-formulation scientists have
continued to assess the severity of sticking by visually inspecting
the tooling surface or the tablet. A reliance on visual inspection
represents a significant gap in a formulator’s toolbox because
the technique is based on subjective opinion, and it is nearly
impossible to systematically benchmark sticking behavior with
different active ingredients, formulation components, operators,
processing conditions, and manufacturing dates.
The authors aimed to design and test a custom tableting punch
with a removable tip that would allow users to quantitatively as-
sess material sticking to tooling surfaces by weighing the adhered
powder. This approach for measuring the adhered powder has
not been put into practice because of the practical difficulties
inherent in accurately measuring an extremely small quantity of
adhered powder (i.e., micrograms) on a punch that weighs ∼100
g. Therefore, a removable punch tip with a low mass (i.e., < 5 g)
that can be weighed on a microbalance solves this problem. A
simple calculation of the weight of powder adhered to a 12.7-mm
diameter flat-faced punch tip suggests that a uniform film thick-
ness as thin as 0.1 µm can be detected using a microbalance, as-
suming a sample true density of 1.5 g/cc (see Figure 1). This limit
of detection is reasonable because the particle diameters of most
pharmaceutical powders are greater than 1 µm. In this study, a
custom-designed punch with a removable tip was assessed as a
method for quantitatively evaluating punch-sticking behavior of
Assessing Tablet-
Sticking Propensity
By Weighing Accumulated
Powder on a Removable Punch Tip
Matthew P. Mullarney, Bruce C. MacDonald, and Allan Hutchins
58 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
Formulation Development
formulations containing various concentrations of sticky powders
in tablet formulations.
Materials
Ibuprofen (50 grade, BASF) and mannitol (spray dried, granular,
and powder grades, SPI Pharma) were chosen as sticky powders
and mixed in glass bottles using a Turbula blender (Quadro Engi-
neering) for 5 min with microcrystalline cellulose (Avicel PH102,
FMC Biopolymer) as a common, nonsticky tableting diluent and
magnesium stearate (HyQual, Mallinckrodt Baker) as a tableting
lubricant. In addition, a prototype formulation containing 50%
w/w ibuprofen, 5% w/w talc (IMI Fabi), and other proprietary
components was tested alongside commercial ibuprofen blends,
including Advil tableting blend (Pfizer), Albermarle ibuprofen 85
(Albe-tab DC85), and BASF ibuprofen (DC85 grade).
Methods
A custom F-type upper punch with a removable tip was de-
signed to be fitted on a single-station laboratory eccentric
tablet press (Manesty F3, see Figure 2). The 0.5-in. diameter,
round, flat-faced tip was attached to the punch barrel using
two set screws in series that seated against the stem of the
removable tip. The tip had a mass of approximately 3 g so that
it and any accumulated powder could be weighed periodically
using a high-precision balance after compressing tablets. The
custom upper punch, a standard lower punch, and standard
die were installed on the tablet press. The press was oper-
ated under power at a rate of 3000 compressions/h to produce
2–3-mm thick tablets with weights of 250 mg and diameter
of 12.7 mm at a solid fraction of 0.85. The punch tip was re-
moved, weighed using a microbalance (MT5, Mettler-Toledo),
and reinstalled periodically during the compression run.
Results
Effect of ibuprofen loading on sticking. To investigate the sensitivity
of the method to various concentrations of a sticky component,
different levels of ibuprofen were mixed into a blend containing
microcrystalline cellulose and 0.25% magnesium stearate. Figure 3
shows that the sticking propensity and the powder accumulated on
the punch tips during the first 100 compressions tested increased
with increasing ibuprofen concentrations. The quantitative mea-
surements of accumulated powder were supported by visual in-
spection of punch tips, which showed high degrees of surface cov-
erage at high ibuprofen concentrations. After approximately 100
compressions, the weight of adhered powder sometimes decreased
suddenly or gradually. The sudden decreases in weight were attrib-
uted to the detachment of large domains of adhered powder from
the punch tip after further compressions. The gradual decreases
were attributed to a steady wearing of the film from the punch
tip. These results highlight the unpredictable sticking behavior of
suboptimal formulations containing high levels of sticky compo-
nents and emphasize the potential for challenging manufacturing
performance.
Effect of lubricant level on sticking. The effect of tableting lubri-
cant was studied for blends containing either ibuprofen or spray-
dried mannitol with various levels of magnesium stearate. As
expected from tableting experience, the spray-dried mannitol
had a lower absolute sticking propensity relative to ibuprofen.
But, interestingly, opposite trends were observed for the man-
nitol versus the ibuprofen formulations with various lubricant
levels. For the mannitol formulations, increasing proportions
Figure 1: Theoretical calculation of the mass of powder
adhered to a punch tip as a function of powder-layer thickness,
assuming a 0.5-in., round, flat-faced punch is used and the true
density of the adhered layer is 1.5 g/cc.
0.1 1 10 100 1000
1
10
100
1000
10,000
100,000
Thickness of powder lm on punch tip
(μm)
P
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a
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(
μ
g
)
Figure 2: Custom F-type punch with removable tip for tablet
punch-sticking assessments, including (left) setscrew, (middle)
removable tip, and (right) fully assembled punch.
A
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60 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
of lubricant decreased sticking (see Figure 4). This result sug-
gests that the mannitol had a relatively high affinity for the metal
punch surface, which is reduced by lubricant. Conversely, and
perhaps counterintuitively, sticking increased for
ibuprofen formulations containing high levels of
lubricant (see Figure 5). This observation was pre-
viously reported using a different sticking assess-
ment method and attributed to the reduction in
the interparticle bond strength of ibuprofen and
to a eutectic formation between the ibuprofen
and magnesium stearate (1). Given these results,
this method was able to indicate sticking behav-
ior of sticky formulations as a function of small
changes in the level of tableting lubricant.
Effect of mannitol grade on sticking. The sticking
assessment method was also tested to determine
whether sticking propensity could be detected
using various grades of a single component. Fig-
ure 6 shows that after ∼10 compressions, the
powdered mannitol was about twice as sticky
as granular mannitol. As expected, the micro-
crystalline cellulose did not stick to the punch
surface. The higher sticking propensity of the
powdered mannitol was hypothesized to result
from its higher specific surface area, which in-
creased its bonding potential to itself and the
punch surface. A high number of compressions
was not investigated with this method because
of severe die-wall friction with the unlubricated
powders. Mixing the granular mannitol at 75%
w/w with microcrystalline cellulose, then fur-
ther decreasing its concentration to 50% w/w
and adding 1% w/w magnesium stearate signifi-
cantly decreased the sticking propensity of the
blend. This result demonstrates that the punch-
sticking detection method can guide formulators when they
optimize tableting-blend compositions and before progressing
to large-scale manufacturing.
Formulation Development
Figure 3: Sticking profiles and representative punch-tip images for blends
containing various levels of ibuprofen.
P
o
w
d
e
r

a
d
h
e
r
e
d

(
μ
g
)
Number of compressions
0
500
1000
1500
2000
0 250 500 750 1000
50%
40%
30%
20%
10%
0%
Figure 4: Tablet-sticking profile for 50% w/w spray-dried
mannitol blends with various levels of magnesium stearate.
Number of compressions
0 250 500 750 1000
P
o
w
d
e
r

a
d
h
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r
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d

(
μ
g
)
0
50
100
150
0.25% lubricant
1.5% lubricant
0.75% lubricant
200
250
Figure 5: Tablet-sticking profile for 20% wt ibuprofen blends
with various levels of magnesium stearate.
0.25% lubricant
1.5% lubricant
0.75% lubricant
10
100
1000
10,000
100,000
P
o
w
d
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a
d
h
e
r
e
d

(
μ
g
)
0 250 500 750 1000
Number of compressions
62 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
Formulation Development
Benchmarking sticking of a new ibuprofen formu-
lation. A prototype ibuprofen formulation was
tested alongside three commercially available
ibuprofen formulations to quantify sticking
risk before scale-up. The prototype formulation
contained a 50% w/w level of ibuprofen and 5%
w/w talc as the tableting lubricant. After 100
compressions, the prototype formulation had
about 1500 µg of powder adhered to the punch
tip. The commercial ibuprofen formulations
had lower sticking: Albemarle had the most,
followed by BASF and Advil (See Figure 7).
Using Advil as the gold-standard benchmark,
the prototype formulation was deemed to be
unsuitable for product scale-up without refor-
mulation. The high level of sticking for the pro-
totype ibuprofen formulation was attributed to
literature reports of talc as a suboptimal tablet-
ing lubricant for sticky formulations (7, 8), in
addition to ibuprofen’s notorious propensity to
stick. This quantitative assessment shows the
benefit of testing prototype formulations and
benchmarking alongside formulations known
to (or not to) exhibit sticking behavior. Thus,
unsuitable formulations can be flagged quickly
during drug product design.
Conclusion
The simple method of using a removable
punch tip is capable of quantitatively mea-
suring sticking for formulations containing various levels of
tableting lubricant and various grades and concentrations
of sticky ingredients. This tool can be used to screen tablet-
ing formulations during drug-product design to optimize
formulation composition, and potentially to study the effect
of sticking on tableting process parameters (e.g., tableting
speed and compression force) and tooling design features
(e.g., metal composition, surface roughness, shape, curva-
ture, and embossing).
Acknowledgments
The authors thank MDC Associates for assisting with the design
and fabrication of the custom punch. They thank Gregory (Scott)
Goeken, scientist, and John Kresevic, senior principal scientist,
both at Pfizer, for providing the prototype and commercial ibu-
profen formulation samples.
References
1. M. Roberts et al., J. Pharm. Pharmacol. 56 (3), 299–305 (2004).
2. T.S. McDermott et al., Powder Technol. 212 (1), 240–252 (2011).
3. D. Simmons, poster at the 12th Annual American Association of Phar-
maceutical ScientistsNortheast Regional Discussion Group (Rocky
Hill, CT, 2009).
4. J.J. Wang et al., J. Pharm. Sci. 93 (2), 407–417 (2004).
5. Y. Cheng et al., Proceedings of AICHE Annual Conference (Orlando,
FL, 2006), pp. 1–13.
6. F. Waimer et al., Pharm. Dev. Technol. 4 (3), 359–367 (1999).
7. M. Bose, A. Sakr, and A. Warner, Pharm. Industrie 55 (5), 519–522 (1993).
8. A. Delacourte et al., Drug Dev. Ind. Pharm. 19 (9), 1047–1060 (1993). PT
What would you do differently? Email your thoughts about this paper to ptweb@
advanstar.com and we may post them on PharmTech.com.
Figure 6: Sticking profiles and representative punch-tip images for blends
containing various grades of mannitol and various mannitol formulations.
0 50 100 150 200 250
Number of compressions
P
o
w
d
e
r

a
d
h
e
r
e
d

(
μ
g
)
0
500
1000
1500
2000
3000
Mannitol powder
Mannitol granular
75% mannitol granular, 25% Avicel PH102
50% mannitol granular, 49% diluents, 1% Mg stearate
Avicel PH102
2500
Figure 7: Sticking profiles for prototype and commercially
available ibuprofen formulations.
0 50 100 150 200
Number of compressions
P
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r

a
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1000
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Prototype
Albemarle DC 85
BASF DC85
Advil
Pharmaceutical Technology JANUARY 2012 63
The author describes how providing appropriate
information about the API in the Common
Technical Document can aid FDA’s review of an
abbreviated new drug application.
Barbara Scott is a chemistry and manufacturing
reviewer (CMC) at the Office of Generic Drugs within the
Office of Pharmaceutical Science, under the US Food
and Drug Administration’s Center for Drug Evaluation
and Research, Barbara.Scott@fda.hhs.gov.
FDA Perspectives
T
he generic drug market has become increasingly com-
petitive. The need for cheaper drugs in the American
marketplace has driven the abbreviated new drug ap-
plication (ANDA) submissions to staggering numbers,
which in turn has lead to increasingly longer US Food and
Drug Administration review and approval times. Section
3.2.S.2 of the Common Technical Document (CTD) is re-
viewed as part of the ANDA application and is intended
to convey to the reviewer and field investigators all manu-
facturing process information, critical controls, and risk
management related to the active pharmaceutical ingredient
(API). In many instances, the ANDA applicant references a
drug master file (DMF) that contains the API information.
It is important to identify a high-quality API supplier, espe-
cially with regard to understanding the impact of starting
material designation on the ANDA review time.
Presently, API starting material designation continues to
be a troublesome issue. Historically, API suppliers (DMF
holders) have relied on the 1987 Guideline for Submitting
Supporting Documentation in Drug Applications for the
Manufacturers of Drug Substances, International Conference
on Harmonisation (ICH) Q7A (good manufacturing prac-
tice starting material), and recommendations from 2004 and
2006 working groups for help in defining a starting material
for the API manufacturing process (1). The draft ICH Q11:
Development and Manufacture of Drug Substances provides
recommendations with respect to API process controls and
starting material considerations (2). The API supplier’s deci-
sion of how far back in the synthesis to go before designating
the regulatory starting material is impacted by the cost of
current good manufacturing practice (CGMP) compliance,
publishing proprietary information, and the necessity of re-
porting any future changes to the process that might involve
outsourcing. FDA uses a risk-based approach to determine
Designation of Regulatory
Starting Materials in the
Manufacturing of Drug
Substances: Impact on
ANDA Review Time
Barbara Scott
64 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
FDA Perspectives
where CGMPs should commence and defines the regulatory
starting material accordingly (3). Increasingly, DMF holders
define a key intermediate as the starting material and out-
source the synthesis without due consideration to quality.
In some cases, multiple suppliers of the outsourced starting
material are provided, each with either a DMF or technical
dossier requiring review. Inspections of these facilities or
problems with the synthetic route for outsourced materials
may significantly delay the ANDA review.
Furthermore, FDA does not formally approve DMFs. Tech-
nically only recommendations are made to the DMF holder.
In the meantime, the ANDA applicant is notified that the
DMF is currently under review. It follows that the lack of a
timely response by the DMF holder or poor quality of the
response increases the overall ANDA review time. Therefore,
it is strongly recommended that the ANDA applicant make
a judicious choice of the API supplier. High quality suppliers
should be identified prior to commencing drug product de-
velopment. Critical material attributes of the API need to be
considered as part of the overall quality
target product profile (QTPP) of the in-
tended drug product.
The Office of Generic Drugs’ cur-
rent thinking on the appropriate desig-
nation of API starting materials incor-
porate the recommendations described
in detail in the following sections.
Chemical synthesis
The starting material should be re-
moved from the finished product by
multiple synthetic steps with interme-
diates isolated and in-process controls
specified. Salt interconversions, sapon-
ifications, esterifications, recrystalliza-
tion steps, resolution of racemates, and
in-situ reactions with no intermedi-
ate isolated do not count as synthetic
steps. In Case I (Figure 1), the starting
material selection is considered inap-
propriate because the synthesis is only
one step removed from the finished
product (salt interconversion is not a
valid synthetic step). Furthermore, all
of the key structural elements found
in the API are already included in the
proposed starting material.
For chiral molecules, how each ste-
reocenter is introduced should be dis-
cussed in detail; proof of characteriza-
tion using chiral methodologies should
be provided; and appropriate in-pro-
cess controls should be highlighted. In
Case II (Figure 2), the starting material
is inappropriate because all chiral cen-
ters A, B, and C are set in the proposed starting material
with no indication of how they were put in place or resolved.
In Case III (Figure 3), the racemate is purchased, resolved,
and purified. There are no reaction steps or isolated inter-
mediates, and therefore, the racemate is not an acceptable
starting material.
This also applies even in cases where the racemate is a
drug substance in and of itself. For example, consider the
case of the API dexmethylphenidate. The racemate, methyl-
phenidate, which is also an API, cannot be declared a start-
ing material, as there is only a resolution step involved in
transforming it to dexmethylphenidate.
Molecules that contain potential genotoxic (4, 5) struc-
tural elements in intermediates anywhere along the syn-
thetic route require extra care in managing impurity profiles
and the corresponding risk associated with them. Desig-
nating a starting material too late in a synthetic route with
no information regarding impurity carryover and purifica-
tion methods is not acceptable. In Case IV (Figure 4), the
Figure 1: Case I—unacceptable.
Figure 2: Case II—unacceptable.
Pharmaceutical Technology JANUARY 2012 65
DMF holder proposes the bis-anilino moiety as the starting
material. A cyclization step and further purification leads
to the finished product. Aryl aniline functionalities are
known carcinogens and are quite frequently derived from
aryl nitro groups, a well-known genotoxic functional group
(4). From a risk-based point of view, controls of the impuri-
ties at the nitration step are critical in this manufacturing
scheme. The proposed bis-anilino starting material gives
no indication on how the nitration step was controlled or
how subsequent impurities were removed. Furthermore,
the proposed starting material is only one step from the
finished product with no intermediate isolated in between.
If a molecule is “well defined” in the literature, then the lit-
erature should be cited along with appro-
priate detailed comparative structural
analysis from the DMF holder against
the literature values (e.g., published pa-
pers and patents). It is recommended that
data from multiple lots using the com-
mercial process to demonstrate sameness
be provided for review.
Commercially available starting
materials need not be justified. In
this context and per the draft ICH
Q11, commercially available means “a
chemical that is sold as a commodity
in a pre-existing, non-pharmaceutical
market” (2). In contrast, chemicals for
which a contract manufacturer cus-
tom synthesizes a predefined amount
of material specifically for the DMF
holder are not considered “commer-
cially available.” Primary DMF hold-
ers submitting syntheses defining
non-commercially available starting
materials will be asked a number of
questions including the following:
The starting material for the manu-
facturing process does not comply with
Figure 4: Case IV—unacceptable.
Figure 3: Case III—unacceptable.
66 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
FDA Perspectives
the Agency’s current definition of an appropriate regulatory
starting material for an active pharmaceutical ingredient.
Please declare appropriate starting material(s) from an earlier
point in the process and provide complete information on
the entire process in this Drug Master File. Alternatively you
can provide the information shown below for the designated
supplier:
A) The detailed synthetic route (including in-process con-
trols, isolated intermediates, reagents/solvents, etc.) for the
outsourced starting material OR a DMF # from the out-
sourced vendor should be provided.
NOTE: If a secondary DMF is referenced within a pri-
mary DMF, the ANDA review time will be impacted.
B) The full name and address of the manufacturing site,
related phone/FAX, contact person, and email address
should be provided.
NOTE: It is possible that the Office of Compliance will
inspect the site. If issues are found then neither DMF will be
in good standing with the FDA.
C) Extensive starting material specification requirements
especially with regard to impurity carryover for both resid-
ual solvents and related compounds may be requested.
D) Updated Certificate of Analysis (COA) from the ven-
dor and in-house COA for the starting material will be
requested.
E) A commitment to notify the FDA if the starting mate-
rial vendor changes or the process is modified in any way,
and to provide again all the relevant information for any
new vendor.
Fermentation-derived starting materials
For those manufacturers using starting materials result-
ing from a fermentation process, it is necessary to pay close
attention to the specifications for the well-characterized
organic materials used in the fermentation (i.e., starch,
glucose, lactose, corn steep liquor, and soybean meal) (6).
Inorganic starting materials should meet the same require-
ments as for chemical synthesis. The microorganism cul-
tured should be properly identified including morphologi-
cal, cultural, and biochemical characteristics. More details
regarding fermentation processes can be found in the draft
guidance on fermentation (6).
Plant- or animal-based starting materials
Starting materials from plant (e.g., thebaine) or animal (e.g.,
low molecular weight heparins [7]) sources should provide
source and location of plant or animal (i.e., species and
organ tissue used), storage and transportation conditions,
drying conditions, and grinding conditions. Full disclosure
of how the starting material is isolated, purified, and char-
acterized will be required. Pre-approval inspections of the
source locations may be required on a case-by-case basis.
When choosing an API supplier, ANDA applicants must
weigh the quality and commercial aspects judiciously. The
choice will have a direct impact on the review and approval
times of submitted ANDAs. The choice of a high quality
API is also integral to building quality into a proposed drug
product as part of a quality-by-design approach. API quality
is essential to development of a quality drug product, and
API attributes should be considered as part of the QTPP (8).
While the author has highlighted a number of points with
respect to API starting material designation and process
controls, this is by no means an exhaustive list of consider-
ations when selecting a potential API supplier.
References
1. R. Giralt, “A New Definition for API Starting Materials,” Phar-
maceutical Technology Europe 16 (6), 2004.
2. ICH, Q11: Development and Manufacture of Drug Substances
(ICH, May 2011).
3. ICH Q9, Quality Risk Management (ICH, June 2006). This is di-
rectly applicable to the drug product manufacture but also applies
the risk-based thinking with regard to the drug substance.
4. Muller et al., “A Rationale for Determining, Testing, and Control-
ling Specific Impurities in Pharmaceuticals that Possess Potential
for Genotoxicity,” Regulatory Toxicology and Pharmacology 44,
198–211, (2006).
5. A. Thayer, “Genotoxic Impurities,” C&E News Sept. 2010, 88 (39),
pp. 16–26.
6. FDA, Draft Guidance for Industry: Fermentation Derived Intermedi-
ates, Drug Substances, and Related Drug Products (FDA, Dec. 2002)
7. S. Schaeffer, “Equivalence Test Case,” Biocentury 18 (34), A1–A7
(2010).
8. ICH, Q8(R2) “Quality Target Product Profile” definition; see also
Spring 2011 GPHA Meeting Slides by R. Lionberger; Yu, Pharm.
Res. 25 781–791, 2008. PT
Disclaimer
The views and opinions in this article are only those of the
author and do not necessarily reflect the views or policies
of the US Food and Drug Administration.
Acknowledgments
The author thanks Naiqi Ya, Dave Skanchy, Bob Iser, and
Aloka Srinivasan for their scientific input.
Pharmaceutical Technology JANUARY 2012 67
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PharmTech.com/usp
Global Harmonization Presents
Opportunities and Challenges
Anthony DeStefano and Kevin Moore
To keep moving forward, the Pharmacopoeial
Discussion Group needs industry participation.
M
ore than 20 years after three of
the world’s largest pharmacopeias
joined forces to work on harmoniz-
ing standards, this effort has yielded prog-
ress but has also faced numerous challenges
as inherent limitations became clear. An
activity of the Pharmacopoeial Discus-
sion Group (PDG)—which consists of the
organizations responsible for the European
Pharmacopoeia (EP), Japanese Pharmaco-
poeia (JP) and US Pharmacopeia–National
Formulary (USP–NF)—harmonization of-
fers benefits to industry, pharmacopeias,
and patients worldwide. It is a pursuit that
USP has remained steadfastly committed
to since 1990, when it was first adopted
in a resolution guiding the organization
through its five-year cycle. At the time,
USP’s then-CEO Jerome Halperin cited
“disappearing borders,” a trend that has
only intensified in the decades following.
Since that time, harmonization has been
deemed a priority for USP in all subsequent
governing cycles, but it requires increased
engagement from industry. While har-
monization occurs through a variety of
avenues, this article focuses on the formal
harmonization activities of PDG.
History and goals
PDG was formed in 1989 with the three
participating pharmacopeias as part of a
request from the pharmaceutical industry,
which was grappling with redundant test-
ing as companies were becoming increas-
ingly multinational. (The World Health
Organization was added as an observer
to PDG in 2001.) The goal was—and re-
mains—to eliminate or minimize indus-
try’s need to perform multiple tests and
procedures and to comply with different
countries’ acceptance criteria for the same
pharmaceutical article. PDG works on
harmonizing specific excipients and gen-
eral chapters contained within the three
pharmacopeias adopted under the group’s
workplan. APIs are not within the scope
of PDG, although USP has been involved
separately in a bilateral pilot program with
the European Directorate for the Quality
of Medicines & Healthcare (EDQM) for
prospectively harmonizing four drug sub-
stance monographs.
Excipients and pharmacopeial general
chapters were targeted for harmonization
because they affect a broad range of prod-
ucts, thus such efforts would be the most
far-reaching and have the greatest impact.
Today, PDG’s workplan encompasses 63
excipients and 34 chapters. Of these, 41
excipients and 27 chapters have been har-
monized to date.
Benefits
The primary benefit of harmonization
for industry is the elimination of redun-
dant testing that is inherent as manufac-
turers comply with multiple compendia.
For pharmacopeias, the benefits include
stronger monographs with an interna-
tional set of experts reviewing standards,
and specifications that are representative of
the global supply chain. Such harmoniza-
tion benefits patients as well, who should
expect a drug supply that is of high qual-
ity, consistent, and safe regardless of where
a medication is purchased. Overall, it is a
win–win situation for all parties, and offers
potential for greater cooperation between
regulatory bodies.
The benefit to manufacturers is best
illustrated by example. For carboxy-
methylcellulose calcium, a suspending
agent, harmonized in 2001, the total test
requirements in the three pharmacopeias
amounted to 37 tests: 13 in the USP mono-
graph, 13 in the JP monograph, and 11 in
the EP monograph. Following adoption of
the harmonized requirements by the three
participating pharmacopeias this fell from
37 tests to 10 total tests. This is the type of
impact such cooperation can yield.
Harmonizing process
Harmonization is a seven-stage process,
with final sign-offs at the twice yearly
PDG meetings. PDG items are published
at two stages, Stage 4 for Official Inquiry
and Stage 6 for Adoption. Each article
undergoing harmonization has a coordi-
nating pharmacopeia that takes the lead in
drafting the proposal and moving the item
through each stage of the PDG process.
Proposals for harmonization go through
a similar public process by which USP
sets all standards, with Expert Commit-
tee review and an open comment process.
However, additional steps are required to
achieve consensus among the three phar-
macopeias, because each pharmacopeia
must ultimately receive approval from its
respective Expert Committee based on the
public comments from that region.
An item is considered harmonized
when a pharmaceutical substance or prod-
uct tested by the document’s harmonized
procedure as published in EP, JP, and USP
yields the same results, and the same ac-
cept or reject decision is reached. The har-
monized text does not have to be identical;
each pharmacopeia can adapt the text to
contin. on p. 70
Anthony DeStefano, PhD, is vice-
president of general chapters, and Kevin
Moore, PhD, is scientific liaison, both with
the US Pharmacopeial Convention (USP).
68 Pharmaceutical Technology January 2012 Phar mTech. com
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PharmTech.com/outsource
t
he year 2011 ended with the buyout
of the CRO Pharmaceutical Product
Development (PPD) by two private-
equity firms, the Carlyle Group and Hell-
man & Friedman. They paid $3.9 billion,
a 30% premium over the company’s value
shortly before the deal was announced,
making it the largest private-equity deal
for a publicly traded CRO.
Clinical CROs such as PPD have proven
to be popular takeover targets for private-
equity firms: PharmSource counts at least
eight publicly owned CROs that have been
taken private by private-equity firms since
2003 (see Table I). One CRO, PRA Inter-
national, had a roundtrip. It was founded
as a private company, taken public by its
private-equity investor, Genstar Capital, in
an initial public offering in 2005, and then
taken private again by Genstar in 2007.
Management incentives
Private-equity buyouts are usually quite at-
tractive to the current shareholders of the
company because they offer a significant
premium over what the company’s stock
was selling for shortly before the deal was
announced. These deals are usually even
more enticing to the senior executives who
run the acquired company for two big rea-
sons. Going private allows executives to
pursue long-term growth strategies away
from the oversight of public shareholders
and Wall Street analysts, both of which
may be more interested in short-term re-
sults than initiatives that promise longer-
term, but more uncertain, payoffs. As im-
portantly, the private-equity buyers usually
offer the senior executives increased equity
stakes in the company that can deliver
great riches if those executives are success-
ful in substantially increasing the value of
the company through the successful imple-
mentation of those long-term strategies.
The PPD deal illustrates how senior
management’s frustrations with the pub-
lic market can drive a company’s board to
pursue a private-equity buyout. In the past
decade, the company had pursued a strat-
egy it called “compound partnering” under
which it would acquire or invest in prom-
ising early-stage drug candidates. PPD
would undertake the early-development
efforts to establish proof-of-concept, then
out-license or sell the candidate to a drug
company for late development and com-
mercialization. Despite some early suc-
cesses, the stock market and analysts fol-
lowing the company were uncomfortable
with this strategy because it introduced a
level of risk and uncertainty into a valua-
tion model that expected steady financial
performance that was easy to forecast. As
a result of the uncertainty, the market dis-
counted the value of the company’s stock.
A similar problem had been a major reason
for another CRO, Quintiles, to undertake a
management-led buyout in 2003.
PPD’s board tried to improve its stock’s
performance by making its compound-
partnering business into a separate com-
pany, which it spun off to shareholders in
2010. That move, however, did not help
the stock’s valuation as much as had been
hoped. Part of the problem had been the
underperformance of PPD’s laboratory ser-
vices business, whose disappointing profit-
ability in recent years has been blamed for
depressing the company’s stock price.
Private ownership may enable PPD
management to address the laboratory
businesses’ problems with a long-term view
while shielding it from second-guessing
by public investors. That was the story at
PharmaNet Development, which was
bought by a private-equity firm after it
was cited for noncompliant behavior in
running some of its clinical trials.
How private equity wins
The aim of private-equity investors is sim-
ple: make a large cash return on the cash
invested. This goal is accomplished in two
ways: by taking advantage of the acquired
company’s cash-generating capability and
by making the company worth more when
it is sold than when it was bought.
Most private-equity deals take advan-
tage of the acquired company’s ability to
support a significant debt burden. By using
the target’s debt capacity, the private firm is
able to borrow much of the purchase price
and limit the amount of cash it must put up
to make the acquisition in the first place.
Current interest rates make borrowing es-
pecially attractive.
Clinical CROs are an attractive ve-
hicle for leveraged buyouts. Their capital-
investment requirements are usually small
in comparison with manufacturing busi-
nesses, so they can throw off a lot of cash.
Further, those cashflows are highly pre-
dictable because clinical CROs tend to have
highly diversified multiyear project back-
logs. A growing CRO is likely to be able to
pay out substantial dividends to its owners
as well as carry a substantial debt burden.
Enhancing the value of the acquired
company may just be a matter of timing,
such as by buying the company at a low
point in the market cycle and going public
when market multiples are high again. The
private-equity firm also can improve the
value of its target through further acquisi-
tions, expansions of offerings, or restruc-
turing to improve profits. Stock analysts
who were following PPD before the ac-
quisition speculated that PPD’s laboratory
businesses might be in for restructuring.
contract services in 2012
Some recent private-equity buyouts of CROs
show both the upside and downside for investors.
Jim Miller
Jim Miller is president
of PharmSource
Information Services,
Inc., and publisher of
Bio/Pharmaceutical
Outsourcing report,
tel. 703.383.4903,
fax 703.383.4905,
info@pharmsource.com,
www.pharmsource.com.
SOURCE WI TH CONFI DENCE
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© Copyright 2010 DPT Laboratories, Ltd. All rights reserved.
DPT is the contract development and manufacturing organization (CDMO) that specializes in sterile
and non-sterile semi-solid and liquid dosage forms. With unmatched technical expertise and fully
integrated drug development and manufacturing services, we can help you successfully develop
and commercialize your next product. Partnering with DPT gives you a seamless transition
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development and manufacturing
piece together seamlessly.
70 Pharmaceutical Technology January 2012 Phar mTech. com
outsourcing outlook
risky propositions
Buyouts by private-equity companies are
not without risk as such moves are subject
to not fully understanding the prospects
of the business or changing market con-
ditions. Both of these things appeared
to happen to the buyers of the European
CMO Nextpharma, whose Belgian inject-
ables manufacturing business was recently
forced to file for bankruptcy protection, as
well as to the French CMO Osny Pharma,
which filed for bankruptcy protection in
early 2011 and was absorbed by another
CMO, Cenexi.
While PPD’s track record of profitabil-
ity and market position (it is thought to
be the second largest for Phase I–IV clini-
cal research after Quintiles) would seem
to guarantee a strong performance over
the typical private-equity holding period
of five years, the changing CRO and bio/
pharmaceutical research environment
could present challenges. As global bio/
pharmaceutical companies reduce their
CRO relationships to a few preferred pro-
viders, competition for those relationships
has become intense. There reportedly has
been aggressive price cutting in the indus-
try to get those deals, thereby leaving “win-
ners” saddled with lower profit margins but
losers shut out altogether.
Investors have been attracted to the
CRO industry because the ongoing re-
invention of the bio/pharma business
model has outsourcing as a core strategy.
The ultimate form of that business model
is still being evolved and tested, and there
is no guarantee that it will ultimately look
like what it looks like today. Buyers of
PPD bought one of the crown jewels of
the industry. The greater risk is probably
faced not by them, but the private-equity
firms that bought PPD’s small and mid-
size competitors. PT
table i: Publicly traded cros acquired in private-equity deals.
Company Year acquired Acquirer
PPD 2011 Carlyle Group; Hellman & Friedman
Kendle 2011 INC Research *
Theorem Clinical (former
Omnicare CRO)
2011 Nautic
inVentiv Clinical 2010 Thomas H. Lee Partners
Averion 2009 Comvest
PharmaNet Development 2009 JLL Partners
PRA International 2007 Genstar Capital
Quintiles 2003 Senior management
* CRO owned by private-equity firm Avista Capital Partners.
inVentiv was sold as part of a larger entity. Theorem was a unit of Omnicare.
Source: Company information and publicly available information.
inside usP
contin. from p. 67
local style. Individual pharmacopeias can
also take into consideration local reference
standards and reagents.
challenges and industry participation
While the vision of harmonization is sim-
ple and straightforward, execution presents
an array of challenges—some more easily
addressed than others. Chief among these
is differences in the regulatory and legal
requirements of each country—which
can make full harmonization difficult, or
even impossible. Both JP and EP fall under
ministerial bodies with a direct link to their
respective regulatory agencies, while USP
is an independent group separate from the
FDA. To the degree possible with these
constraints, PDG has managed to pro-
duce encouraging results. One approach is
harmonization by attribute, which moves
items forward where there is significant
agreement on the main attributes (e.g.,
definition, assay, and identification testing),
even if other portions of a standard are in
dispute. This also allows PDG to avoid
spending resources on topics where there
are insurmountable differences, and focus
on items where there is progress. Another
challenge is the time required to bring har-
monized monographs and chapters to pub-
lic status. Although the seven-stage process
will likely never be considered speedy, PDG
is taking strides to move more efficiently.
Other challenges could be more easily
addressed, such as by earlier and increased
industry participation. Frequently, the po-
tential for harmonization has not been re-
alized by manufacturers and other stake-
holders until late in the process. Moreover,
comments to proposals published in Phar-
macopeial Forum (PF), the online vehicle
through which USP accepts feedback on
standards, has often been received too
late to be considered. Unlike the inherent
challenges identified above, these are con-
querable. USP has intensified educational
and outreach activities to industry through
free webinars, a dedicated webpage that
centralizes and simplifies information
(www.usp.org/USPNF/pharmacopeial-
Harmonization/) and activities. Moreover,
USP began to offer PF free to all in January
2011, eliminating any barriers to accessing
the journal (www.usp.org/USPNF/pf/).
Industry participation is crucial for har-
monization to achieve its ultimate poten-
tial. Most vital is for manufacturers to take
notice of harmonization proposals in PF at
Stage 4 and submit comments to USP. If
there are implementation problems with
the methods proposed by PDG, USP must
hear from industry at this stage. Given that
manufacturers and users will be required
to comply with the eventual standard, ac-
tive engagement benefits all parties.
Hot topics and future work
PDG’s workplan includes a variety of hot
topics. Examples include the development
of general chapters on elemental impuri-
ties, viscosity determination for excipients,
and the strengthening of selected high-risk
monographs to control for economically
motivated adulteration. Also, PDG is look-
ing at process and other potential improve-
ments (e.g., accelerating harmonization).
Harmonization is frequently cited as an es-
sential activity but it desperately needs the
full commitment of all parties if its prom-
ises and potential are to be realized. PT
Bilcare Research
1389 School House Rd.
Delaware City, DE 19706
tel. 302.838.4000
fax 302.838.3222
www.bilcaresolutions.com
Description
Bilcare Research is an innovation-
led solutions provider that partners
with the global pharmaceutical and
healthcare industries to improve pa-
tient outcomes. The company is one
of the world’s leading manufacturers
of pharmaceutical and medical blister
films and foils, supplying a full range
of thermoforming films, Alu-lid foils,
and cold form foils.
Products and services
• Packaging films including
PVC Mono, PVC/PVDC,
PVC/Aclar®, PVC/AquaBa®
and Cold Form Foil
• Lidding foil-standard push
through aluminum foils,
paperback child-resistant foils
and eco-friendly lid foil Nova
• Anti-counterfeiting and brand-
ing solutions such as Bilcare
Protect, a blister film using
embedded images nearly
impossible to duplicate
• Formulation analysis for
optimal packaging solutions
Aptuit Inc.
Two Greenwich Office Park
Greenwich, CT 06831
Stuart Needleman, President
tel. +39 045 821 9333
info@aptuit.com
www.aptuit.com
Description
Aptuit is a global pharmaceutical ser-
vices company focusing on delivering
contract development and manufac-
turing services and streamlining the
drug development process for bio-
technology and pharmaceutical in-
novators. With heads for science and
hearts for service, Aptuit’s employees
deliver an integrated suite of product
development services to more than
800 companies worldwide.
Active Pharmaceutical
Ingredient (API) Capabilities
Aptuit offers a wide range of API
services on a global scale, ranging
from medicinal chemistry to in-silico
synthesis design, commercial produc-
tion of API post-NDA approval, and
the ability to manufacture highly
potent APIs. Aptuit provides lasting
solutions to its clients’ API needs.
A culture of quality combined with
speed and flexibility ensures a timely
and consistent supply of API.
BASF Corporation
100 Campus Drive
Florham Park, NJ 07932
tel. 800.443.0627
fax 914.785.2193
pharma-ingredients@basf.com
www.pharma-ingredients.basf.com
Description
BASF produces and markets a broad
range of active ingredients and ex-
cipients, as well as exclusive synthe-
sis services for the pharmaceutical
industry.
Within the excipients business,
BASF offers a wide variety of prod-
ucts and customized solutions for
specific customer needs:
• Experienced technical support
• Formulation and pro-
cess development
• Troubleshooting formulation
• Scale up from R&D to pilot plant
• Life cycle management
Our latest product innovations:
Kollicoat® Smartseal – taste masking
and moisture barrier coating
Soluplus® – solubility enhancer, ideal
for hot melt extrusion
Kollicoat® IR Coating Systems – dis-
tinctive coloring, robust and rapidly
soluble
Pharmaceutical Technology January 2012 71
Advertiser profiles
Cambridge Major
Laboratories
W130 N10497 Washington Drive
Germantown, WI 53022
tel. 262.251.5044
info@c-mlabs.com
www.c-mlabs.com
Description
Cambridge Major Laboratories, Inc.
(CML) is a global chemistry outsourc-
ing partner to the pharmaceutical
and biotechnology industries. The
company produces pharmaceutical
intermediates and Active Pharma-
ceutical Ingredients (API), from early
preclinical development to commer-
cial manufacture. CML operates from
FDA-inspected facilities in the U.S.
and Europe.
Services
CML offers a full suite of services
which are organized along five key
Centers of Excellence including; Pro-
cess Chemistry, Solid State Chemis-
try, API Manufacturing, Analytical
Services, and Quality/Regulatory
Compliance.
For more information, visit our
website at www.c-mlabs.com or
contact a member of our team at
info@c-mlabs.com.
CEIA USA
9155 Dutton Dr.
Twinsburg, OH 44087
tel. 888.532.CEIA (2342)
fax 330.405.3196
pharma@ceia-usa.com
www.ceia-usa.com
Description
CEIA USA is a market leader that
has been designing, engineering and
manufacturing metal detectors for
many industries worldwide for over
45 years. The Pharmaceutical divi-
sion includes state-of-the-art Quality
Control Metal Detectors that offer
full compliance with FDA require-
ments Part 210 and Part 211. CEIA
THS/PH21N Metal Detection Sys-
tems feature extremely high detection
sensitivity towards contaminating
metals, whether ferrous, non-ferrous
or stainless steel, even when these
are present in very small quantities.
Once a contamination is detected, the
system rejects the identified mate-
rial. The system’s fail safe operation
monitors the opening and closing of
the ejection flap through a redundant
conformation sensor.
Catalent
Pharma Solutions
14 Schoolhouse Rd.
Somerset, NJ 08873
tel. 866.720.3148
info@catalent.com
www.catalent.com
Catalyst + Talent. Our name com-
bines these ideas. From drug and bio-
logic development services to delivery
technologies to supply solutions, we
are the catalyst for your success. With
over 75 years of experience, we have
the deepest expertise, the broad-
est offerings, and the most unique
technologies to help you get more
molecules to market faster, enhance
product performance and provide
global reliable supply.
Catalent develops. As the #1 global
development and formulation partner
we drive faster, more efficient devel-
opment timelines to help you take
more products to market.
Catalent delivers. We are a world
leader in drug delivery technology
with a proven record of enhancing
bioavailability, improving therapeutic
profiles and optimizing patient com-
pliance for better treatments.
Catalent supplies. With 20+ sites
across 100+ markets, our global
manufacturing network provides reli-
able, integrated supply solutions for
faster, more efficient commercializa-
tion pathways.
Catalent. More products. Better
treatments. Reliably supplied.™
72 Pharmaceutical Technology January 2012 Phar mTech. com
Advertiser profiles
Croda Inc
300-A Columbus Circle
Edison, NJ 08837
tel. 732.417.0800
fax 732.417.0804
marketing-usa@croda.com
www.croda.com/healthcare
Description
Croda is a manufacturer of a com-
plete range of high purity excipients
and delivery aids, offering superior
quality for the global pharmaceutical
market. Croda excipients are ideal for
multiple dosage forms: topical, par-
enteral, oral and ophthalmic formu-
lations as well as advanced delivery
systems.
Featured products include ingredients
which have been Super Refined® via
a proprietary process which removes
polar and oxidative impurities.
• SUPER REFINED®

Oils

Arlasolve™ DMI

PEGs

Polysorbates

Propylene Glycol

Castor Oil
• CRODASOLS: High
Purity solubilizers
• CRODAMOLS: A wide range
of ester solvents and vehicles
• POLAWAX: Compendial,
self-emulsifying wax
DPT Laboratories
318 McCullough
San Antonio, TX 78215
tel. 210.476.8100
fax 210.227.5279
www.DPTLabs.com
Description
DPT is a contract development and
manufacturing organization (CDMO)
specializing in sterile and non-sterile
semi-solid and liquid dosage forms.
DPT provides fully integrated devel-
opment, manufacturing and packag-
ing solutions for biopharmaceutical
and pharmaceutical products. DPT is
the source for semi-solid and liquids
— from concept to commercializa-
tion and beyond.
Drug development services range
from pre-formulation, formulation
and biopharmaceutical development,
analytical development and valida-
tion, through process development.
Production capabilities include
five cGMP facilities, clinical trial ma-
terials, full scale commercial produc-
tion, controlled substance registration
Class II – IV and complete supply
chain management.
Packaging services encompass en-
gineering and procurement resources
necessary for conventional and spe-
cialized packaging.
Dr. Reddy’s
Laboratories Inc.
200 Somerset Corporate Blvd.
Bridgewater, NJ 08807
tel. 908.203.4932
fax 908.203.4914
cps@drreddys.com
www.drreddys-cps.com
Description
Dr. Reddy’s Custom Pharmaceuti-
cal Services (CPS) offers a variety of
programs specifically geared to solve
your development or commercial
needs. We can help you extend your
product life cycle by leveraging gener-
ic assets, by utilizing effective chiral
chemistry solutions for asymmetric
problems, by providing the right
facilities and technologies for high
potent, steroidal or prostaglandin
products, or by utilizing the variety
of formulation technology platforms
that we have at our disposal for dif-
ficult and sophisticated formulation
needs. With our vast experience in
custom solutions, we have the techni-
cal and industry experiences required
to provide the right solution services
for you.
Pharmaceutical Technology January 2012 73
Advertiser profiles
Fette Compacting
America, Inc.
400 Forge Way
Rockaway, NJ 07866
tel. 973.586.8722
fax 973.586.0450
sales@fetteamerica.com
www.fette-compacting-america.com
Description
Fette Compacting America, Inc. is
a leader in tablet press technology
servicing clients in the United States,
Canada, and Puerto Rico with new
and used machine sales, technical
assistance, machine installations,
training and seminars, validation,
maintenance, spare parts, and tool-
ing. Its latest machine, the FE55, is
considered the next generation of
tablet presses.
Major Products
Fette Compacting America’s tablet
press line includes:
• Fully automated presses with
hands-off, lights-out production
• Full-containment wash-in-place
• High-containment, for strin-
gent exposure standards
• Reconditioned/pre-owned
with warranty
• Patented die table segments to
increase output up to 25%
• FS12 turret, producing small
tablets (up to 11mm) and of-
fering a 40% yield increase
EtQ, Inc.
399 Conklin St. Ste 208
Farmingdale, NY 11735
tel. 516.293.0949
fax 516.293.0784
info@etq.com
www.etq.com
Description
EtQ for Life Sciences offers a Change
Management module that manages
all aspects of the Change Manage-
ment process. It allows the user to
provide a change summary that de-
scribes the change to be implemented
and identifies the affected docu-
ments, planned projects, and action
plans. A request can then be submit-
ted to the appropriate individuals for
approval. If the request is approved, it
then allows them to monitor all asso-
ciated activities such as implementing
the planned projects and action plans,
and updating the associated docu-
mentation. Additional best-in-class
solutions include Risk Assessment,
Corrective and Preventive Action,
Complaint Handling, and more.
Federal Equipment
8200 Bessemer Ave.
Cleveland, OH 44127
216.271.3500
216.271.5210
www.fedequip.com
Description
Federal Equipment Company has
more than 50-years experience in
the processing equipment industry,
providing quality used equipment,
outstanding service, and competitive
prices to the solid dose, sterile, API,
and related pharmaceutical process
industries. Major markets include
pharmaceutical, biopharmaceutical
and API manufacturers, including
solid dose, liquids, powders, aseptic
filling, and packaging.
Products and services
In addition to thousands of pieces of
equipment in stock and ready to ship,
Federal Equipment offers special-
ized services including the liquida-
tion and auction of process lines and
manufacturing facilities, equipment
appraisals, rigging, testing, and auc-
tion services, as well as managing
the negotiated liquidation of surplus
equipment.
74 Pharmaceutical Technology January 2012 Phar mTech. com
Advertiser profiles
Jubilant HollisterStier
Contract Manufacturing
& Services Division
U.S.A. – Canada – India
3525 N. Regal St.
Spokane, WA, U.S.A. 99207
tel. 800.655.5329
info@jublHS.com
jublHS.com
Description
Jubilant HollisterStier Contract Man-
ufacturing is an integrated contract
manufacturer, able to manufacture
sterile injectable, solid and semi solid
dosage forms. Our facilities across
North America and India provide
specialized manufacturing services
for the pharmaceutical and biophar-
maceutical industries. We provide
a full-range of support and services
to streamline the manufacturing
process.
• Sterile Injectable Fill/Finish
(clinical to commercial)
• Lyophilization (clinical
to commercial)
• Sterile Ophthalmics & Otics
• Non-Sterile Topicals & Liquids
• Solid Dosage
• Multiple Formats (vials,
ampoules, tablets, capsules,
bottles, tubes, jars, applicators)
Jubilant HollisterStier is registered
with such Regulatory authorities as the
FDA (CDER, CBER) EMA, ANVISA,
PMDA, and Health Canada.
ISOCHEM
32 rue Lavoisier
91710 Vert Le Petit, France
tel. +33 (0)1 64 99 03 00
fax +33 (0)1 64 99 03 99
www.isochem.eu
Description
ISOCHEM, one of the leading sup-
pliers of fine chemistry, is a 40 years
old company with about 500 employ-
ees world wide. The Head office is
located near Paris, in Vert-Le-Petit,
France, on one of its 5 industrial sites.
Fine chemicals company reliable,
flexible and competitive, Isochem
serves a broad range of customers in
many application fields, from lead-
ing global companies to virtual and
emerging organizations.
Products & services
ISOCHEM implements almost all the
chemical reactions classically used in
multi-step synthesis and offers you
renowned differentiating know-how:
• Safe implementation of hazard-
ous reaction such as phosgena-
tion, nitration, cryogenic reaction
and high pressure hydrogenation
• Attractive synthetic tools such
as activated aminoacids build-
ing blocks (N-CarboxyAnhy-
dride) in peptide chemistry.
GlobePharma, Inc
2B & C Janine Place
New Brunswick, NJ 08901
tel. 732.296.9700
fax 732.296.9898
Sanni@globepharma.com
www.globepharma.com
Description
GlobePharma’s vision is to provide so-
lutions for some of the problems in the
pharmaceutical industry and excellent
customer support. GlobePharma was
established in 1993 with the introduc-
tion of unit-dose powder samplers.
Our Products:
GlobePharma has introduced & pat-
ented several products. Our products
are used by pharmaceutical compa-
nies worldwide. These include a vari-
ety of unit-dose and bulk samplers for
powders, liquids and and semi-solids,
remote swabbing and microbiological
sampling tools, cleaning validation
coupons, POWDEREX™ apparatus,
accelerated powder segregation tester,
R&D and pilot scale blenders with
interchangeable V-shells, Bins and
Double-cones with high-speed
intensifier-bars, SimpleBlend™—
new stand-alone blenders, new
patent-pending attachment, SIFT-
N-BLEND™, cGMP butterfly
valves, manual tablet compaction
machine, table-top rotary tablet
presses, tablet press instrumenta-
tion, high shear granulator, tablet
de-duster, capsule polisher, empty
capsule eliminator, cone-mill, and a
line of refurbished equipment.Visit
our FaceBook page and website!
Pharmaceutical Technology January 2012 75
Advertiser profiles
Kemwell Biopharma
11 Tumkur Rd.
Bangalore, India 560 022
tel. USA – 919.397.3000
info.usa@kemwellpharma.com
info.india@kemwellpharma.com
www.kemwellbiopharma.com
Description
Kemwell Biopharma is contract pro-
vider of Pharmaceutical CMC services.
With manufacturing locations in India
and Sweden, Kemwell offers services:
• Formulation Development
• Analytical Services
• Clinical (CTM) Manufacturing
• Commercial Manufacturing
• Packaging/Storage/Distribution
• Biopharmaceutical Manufacturing
Voted as the “Best Contract Manufac-
turer in India” by OPPI in 2010, Kemwell
has been serving multinational pharma
since 1980 & offers CMC services from
Phase 1 to Commercial, for Solids, Liq-
uids, Semi-Solids, Biologics, & Injectables.
Services
Kemwell provides formulation, analyti-
cal, and manufacturing services for con-
ventional & specialized dosage forms.
• Solids (Capsules, Tablets (coated
& uncoated), Effervescent)
• Liquids (Solutions, Sus-
pensions, Syrups)
• Parenteral (Lyophilized, Sus-
pensions, Emulsions)
• Biologics (Mammalian cell culture)
• Semi-solids (Ointments, Gels,
Creams, Suppositories)
• First-in-human formulations
(API in Capsule, API/powder in
Bottle, Formulated Product)
Lonza
Muenchensteinerstrasse 38
CH-4002 Basel, Switzerland
tel. +41 61 316 81 11
fax +41 61 316 91 11
contact@lonza.com
www.lonza.com
Description
Lonza is a leading partner to the
pharmaceutical, healthcare, and life
science industries. For over 30 years,
Lonza Custom Manufacturing helped
emerging and large biotech and phar-
maceutical companies to improve and
advance their products. Whether for
clinical or commercial supply, Lonza’s
full set of development services and
industry-leading manufacturing pro-
cesses enable your products to reach
their full potential.
Services
Our extensive experience allows us
to offer a variety of services includ-
ing chemical synthesis, advanced
intermediates, APIs, HAPIs, antibody
drug conjugates, microbial fermenta-
tion, peptides, oligonucleotides and
vaccines. Lonza has the know-how
and experience to handle almost any
pharmaceutical or biotechnological
challenge in the world.
Meissner
Filtration Products
4181 Calle Tesoro
Camarillo, CA 93012
tel. 800.391.9458
tel. int’l. +1.805.388.9911
info@meissner.com
www.meissner.com
Description
Meissner is your source for advanced
microfiltration and single-use systems.
Focused on f luid technology
innovation, we leverage our R&D
efforts to offer our clients products
that deliver advanced processing and
f luid handling solutions for
pharmaceutical and biopharmaceutical
manufacturing.
Our One-Touch® single-use product
portfolio demonstrates our commitment
to manufacture innovative products.
We introduced the industry’s first slip
agent-free PE biocontainers, TepoFlex®,
thus reducing its extractables profile,
and giving the biocontainer its remark-
able visual clarity. We also delivered
the industry’s only multilayer PVDF
biocontainer, FluoroFlex®, thus
expanding the application of single-
use systems beyond the limits of
existing PE biocontainers, and into
areas such as API storage.
www.meissner.com
76 Pharmaceutical Technology January 2012 Phar mTech. com
Advertiser profiles
Micron Technologies
333 Phoenixville Pike
Malvern, PA 19355
tel. 610.251.7400
fax 610.251.7499
info@microntech.com
www.microntech.com
Description
Micron Technologies provides con-
tract particle size reduction and ana-
lytical services for the pharmaceutical
industry. We offer micronization,
mechanical milling and classification,
for enhancing bioavailability, improv-
ing content uniformity, and refining
the delivery of inhalation pharmaceu-
tical products.
Products and services
Micron is capable of micronizing
R&D to bulk production scale quanti-
ties, as well as highly potent com-
pounds and controlled substances.
Our contract analytical laboratory
provides material characterization,
release testing, stability testing,
method development and method
validation. Our facilites in the US and
UK are FDA inspected, we operate
according to cGMP regulations, and
we are committed to being the indus-
try’s “Provider of Choice.”
Informex booth 516
OPTIMA GROUP
pharma GmbH
Otto-Hahn Strasse 1
74523 Schwaebisch Hall
Germany
tel. +49 791 9495-0
fax +49 791 9495-2610
info@optima-pharma.com
Optima Machinery
Corporation
P.O. Box 28173
1330 Contract Drive
Green Bay, WI 54304
Telephone: +1.920.339.2222
Telefax: +1.920.339.2233
E-Mail: info@optima-usa.com
Website: www.optima-pharma.com
Number of employees: 1400 Worldwide
Date founded: 1922
Description
The headquarters of Optima Pharma
are located in Schwaebisch Hall,
Germany with additional facilities
in Mornshausen and Randolfzell,
Germany. The U.S. operations are
based out of Green Bay, Wisconsin.
Optima Machinery Corporation
provides direct machine sales, spare
parts inventory and after-sales service
to the North American customer base
of Optima Pharma.
Optima Pharma is known for
their diversified and innovative range
of filling and packaging machines
for pharmaceutical products, both
sterile and non-sterile liquid and
powder applications. Pharmaceutical
freeze-drying as well as isolation and
containment technology secures our
position as a single source supplier for
turnkey projects in the industry.
Patheon Inc.
4721 Emperor Blvd, Suite 200
Durham, NC 27703-8580
tel. 866.Patheon (866.728.4366) or
919.226.3200
fax 919.474.2269
DoingBusiness@Patheon.com
www.patheon.com
Description
Patheon Inc. (TSX: PTI) is a leading
global provider of contract development
and manufacturing services to the global
pharmaceutical industry. The company
provides the highest quality products
and services to approximately 300 of
the world’s leading pharmaceutical and
biotechnology companies.
Products and services
Patheon’s services range from preclini-
cal development through commercial
manufacturing of a full array of dosage
forms. Its comprehensive range of fully
integrated Pharmaceutical Develop-
ment Services includes pre-formulation,
formulation, analytical development,
clinical manufacturing, scale-up and
commercialization. The company’s
integrated network includes 10 commer-
cial facilities, nine development centers
and one clinical trial packaging facility
across North America and Europe.
Pharmaceutical Technology January 2012 77
Advertiser profiles
Powdersize, Inc.
20 Pacific Dr.
Quakertown, PA 18951
tel. 215.536.5605
fax 215.536.6630
thigley@powdersize.com
www.powdersize.com
Description
As a leader in custom powder sizing,
Powdersize has optimized its tolling
services for improved yield, grinding
performance and process robustness.
By combining expertise in both equip-
ment design and nearly two decades of
toll manufacturing, Powdersize deliv-
ers unique solutions to the challenges
of poor precision during feeding,
product “blowback” and system loss
associated with large surface areas, es-
pecially for small batch sizes necessary
for early stage R&D studies or clinical
evaluation. Capabilities of reducing
product exposure down to 10 ng/m
3

via containment approaches has also
been added to address the challenges
associated with handling cytotoxic
and/or highly sensitizing APIs.
PYRAMID
Laboratories, Inc.
3598 Cadillac Ave.
Costa Mesa, CA 92626
tel. 714.435.9800
fax 714.435.9585
info@pyramidlabs.com
pyramidlabs.com
Description
PYRAMID Laboratories, Inc. is
located in Southern California, United
States. Our facilities are housed in
three buildings covering more than
50,000 ft
2
. The combination of our
manufacturing facilities and state-of-
the-art laboratory allows PYRAMID to
offer the pharmaceutical and biotech
industry both analytical and manufac-
turing support capabilities.
Products and services
PYRAMID provides contract Aseptic
Manufacturing and Analytical
Services for Sterile Injectable Drugs.
PYRAMID provides expertise in
formulation and process develop-
ment and aseptic filling for vials and
syringes, as well as lyophilization ap-
plications for clinical and commercial
products. PYRAMID has established
a reputation of exceptional perfor-
mance, integrity, and quality.
Pfizer CentreSource
7000 Portage Rd.
Kalamazoo, MI 49001
North America/South America:
Kalamazoo, MI (World Headquarters)
tel. 269.833.5844; fax 269.833.3604
Europe/Middle East/Africa:
Brussels, Belgium
tel. +32.2.714.6502; fax +32.2.407.3007
Asia/Pacific: Singapore
tel. +65.6419.0248; fax +65.6419-0022
centresource.info@pfizer.com
www.pfizercentresource.com
Description
Pfizer CentreSource (PCS) is a recog-
nized industry leader in steroid APIs
and antibiotics; supplies GMP custom
fermentation services; manufactures
and packages finished dosage forms;
provides product development,
process development, and advanced
manufacturing for high potency oral
solid drug product; and offers thera-
peutic bioprocessing development
and manufacturing across microbial
and fermentation platforms.
Products and services
PCS supplies high quality and
high value services, including:
• High Containment Services–
Solid Dosage Form
• Steroid APIs–Corticosteroids, Hor-
monal Steroids, and Select Antibiotics
• Bioprocessing Services–Microbial
Fermentation Expression Systems
• Cytosafe®–Oncology Product
Packaging
• Blow/Fi l l /Seal –Steri le Liquid
Injectables
Questions?
Contact one of the regional offices of
Pfizer CentreSource for specific informa-
tion on your requirements.
78 Pharmaceutical Technology January 2012 Phar mTech. com
Advertiser profiles
Sartorius Stedim
North America, Inc.
5 Orville Dr.
Bohemia, NY 11716
tel. 800.368.7178
fax 631.254.4253
patricia.stancati@
sartorius-stedim.com
www.sartorius-stedim.com
Description
Sartorius Stedim Biotech is a leading
provider of cutting-edge equipment
and services for the development,
quality assurance, and production
processes of the biopharmaceutical
industry. The company’s integrated
solutions covering fermentation,
filtration, purification, fluid man-
agement, and laboratory technolo-
gies enable the biopharmaceutical
industry around the world to develop
and produce drugs safely, timely, and
economically.
Sartorius Stedim Biotech, a leading
supplier of equipment and services
for the biopharmaceutical indus-
try, offers bioreactors, fermenters,
crossflow, integrity-test equipment,
housings, single-use fluid handing,
and mixing technology. Consum-
ables include crossflow cassettes,
membrane adsorbers, depth filters,
sterilizing and prefilter cartridges
and capsules, mycoplasma, and viral
filtration. Comprehensive validation
and training services support the
company’s products.
Rommelag USA, Inc.
27905 Meadow Dr. Suite 9
PO Box 2530
Evergreen, CO 80437-2530
tel. 303.674.8333
303.670.2666
mail@rommelag.com
www.rommelag.com
Description
In aseptic packaging the most sig-
nificant source for contamination
is operator presence in the filling
environment. Operators supply
microorganisms by touch or by air.
Inherently systems requiring a higher
operator presence have increased
microbiological challenges to the
system.
Traditional aseptic packaging
utilizes preformed containers and
closures that require manual han-
dling. These systems rely heavily
on cleanroom effectiveness to keep
airborne particles (viable and non-
viable) at acceptable levels.
Rommelag® bottelpack® Blow/Fill/
Seal advanced aseptic technology is
highly automated and under normal
operations requires no operators
within the cleanroom during aseptic
filling. This effectively eliminates the
primary contamination source from
the process.
Ross, Charles &
Son Company
710 Old Willets Path
Hauppauge, NY 11788
tel. 800.243.ROSS
fax 631.234.0691
mail@mixers.com
www.powderinjection.com
Improve Dispersion with
High-Speed Powder Injection
In many plants, production can be
improved significantly by accelerat-
ing the dispersion of lightweight
powders in a liquid vehicle. Using
traditional batch mixing techniques,
in which powders such as fumed
silica are poured onto the surface of
a liquid vehicle, the powder tends to
float on the surface and resist wetting
out – even in the presence of a strong
vortex.
SLIM technology employs a spe-
cially modified rotor/stator mixer to
draw powders directly into the high-
shear zone of the mixer, where they
are wetted, subjected to intense shear,
and dispersed instantly.
Learn more:
www.PowderInjection.com
Pharmaceutical Technology January 2012 79
Advertiser profiles
Veltek Associates, Inc.
15 Lee Blvd.
Malvern, PA 19355
tel. 888.478.3745
fax 610.644.8335
vai@sterile.com
www.sterile.com
Description
Veltek Associates Inc. plays an in-
novative role to the pharmaceutical,
biotechnology and medical device
industries by developing products
and services to improve operations
and reduced costs associated with
contamination.
We focus on identification and
control of contamination in classified
areas. We produce a complete range
of sterile pharmaceutical grade dis-
infectants, sporicides, lubricants, and
buffer solutions; hand sanitizer and
hands-free dispensers; Environmen-
tal Monitoring Systems; In-line and
Cage cleaners; and Core2Clean Spray/
Mop/Fog Systems.
VAI Labs provides microbiological
testing ranging from the identifica-
tion of microorganisms to antimicro-
bial effectiveness studies to prove the
effectiveness of selected disinfectants.
Aseptic Processing Inc. provides
detailed consulting services.
Sparta Systems, Inc.
Holmdel Corporate Plaza
2137 Highway 35
Holmdel, NJ 07733
tel. 888.261.5948, 732.203.0400
fax 732.203.0375
info@spartasystems.com
www.spartasystems.com
Description
Founded in 1994, Sparta Systems, Inc.
is the industry leader for Enterprise
Quality Management Solutions. Its
TrackWise® product is a web-based
software application that enables
high-value organizations to safely and
efficiently deliver products and ser-
vices to market by providing the tools
to manage, track and report quality,
compliance and regulatory issues.
Major products
TrackWise enables corporations to
identify, define, manage, track and
report on critical business processes
such as deviations, audits, CAPA,
change control, complaint track-
ing and supply chain management.
TrackWise holistic EQMS has been
successfully enabling companies,
both big and small, to streamline
quality processes, consolidate redun-
dant systems and reduce manual
operations to generate business results.
Suheung Capsule
16610 Marquardt Ave.
Cerritos, CA 90703
tel. 562.926.5685
fax 562.926.4272
sales@suheung-america.com
www.suheung.com
Description
Suheung Capsule’s founding in 1973
has solely focused on manufacturing
the highest quality capsules. Through
our research and development, and
technical investments Suheung is
the world’s leading manufacturer of
hard capsules. Suheung’s dedication
to quality is seen in each and every
element, and every process of capsule
production.
Products
Suheung’s EMBO CAPS® Capsules
come in the following size’s #00EL,
#00, #0EL, #0, #1, #2EL, #2, #3, #4. The
capsules are made of gelatin (bovine,
porcine & fish) or Hypromellose mate-
rial. Patented Locking Mechanism/
variety of colors, print options/Kosher
and Halal certified/DMF No. 1521.
80 Pharmaceutical Technology January 2012 Phar mTech. com
Advertiser profiles
Pharmaceutical Technology JANUARY 2012 81
Q&Awith
PHARMA CAPSULES
Catalent to
Increase Biologic
Development and
Manufacturing
Capabilities
Catalent Pharma Solutions
plans to expand its biologics
facility by relocating to a new
plant in Madison, Wisconsin,
in late 2012. The move will
provide increased capacity for
the company’s cell-line and
biomanufacturing portfolio.
Catalent’s current facility is
located in Middleton, Wis-
consin.
The new facility will qua-
druple the capacity of Catal-
ent’s current facility, thus
allowing the company to
enhance its offerings in the
development and manufac-
turing of biologic products. In
addition, the expansion will
enhance the efficiency and
output of Catalent’s GPEx cell-
line engineering technology
and process-development
capabilities, as well as that of
other mammalian cell lines.
ImmunoGen, Lilly
Form Antibody–
Drug Conjugate
Collaboration
ImmunoGen has entered into
an antibody–drug conjugate
(ADC) collaboration with Eli
Lilly. Under this agreement,
Lilly will pay an up front fee
of $20 million for rights to
take a limited number of
exclusive licenses to use
ImmunoGen’s maytansinoid
targeted antibody payload
technology with Lilly mono-
clonal antibodies to develop
ADC anticancer therapeutics.
Each license entitles Immu-
noGen to receive milestone
payments that could total
approximately $200 million.
The licenses also entitle Im-
munoGen to royalties on the
sales of resulting products.
ImmunoGen also is entitled to
receive financial compensa-
tion for any research or manu-
facturing done on behalf of
Lilly. Lilly is responsible for the
development, manufacturing,
and marketing of products re-
sulting from this agreement.
Merck Establishes
New R&D Asia
Headquarters
Merck & Co. has established
an Asia R&D headquarters for
drug discovery and develop-
ment in Beijing. The new
facility is part of a $1.5-billion
commitment the company
has made to invest in R&D in
China during the next five
years. The facility will consist
of 47,000 m
2
(505,904 ft
2
) of
office and laboratory space.
The first phase of construc-
tion, scheduled to be com-
pleted by 2014, will provide
capacity for approximately
600 employees working in
the areas of drug discovery,
translational research, clini-
cal development, regulatory
affairs, and external scientific
research programs.
Eisai Commences
Operations at New
Research Facility
Eisai’s research subsidiary,
H3 Biomedicine, has opened
its new 24,000-ft
2
research
facility in Cambridge, Mas-
sachusetts. The company
plans to expand its laboratory
space and workforce to ap-
proximately 70 people. Eisai
has pledged to provide H3
Biomedicine with as much
as $200 million in research
funding.
Gilles Cottier, president of SAFC
PharmTech:
What is the biggest industry
challenge you’re now facing?
Cottier:
While companies always feel
pressure to compete on pric-
ing, the real pressure in the
market comes as a result of
the drive to provide and guar-
antee quality through process
improvements and robust
supply-chain security. Over the past few years, the market
has seen a paradigm shift toward quality and supply-chain
integrity. Demand to increase GMP compliance originated
with regulatory bodies, but has been further emphasized
by requests for compliance from customers and the in-
dustry as a whole. This shift in focus highlighted many
issues, such as contamination, counterfeiting, and falsified
documentation of pharmaceuticals and ingredients. The
industry responded with a focus on accountability and a
commitment to rectifying these matters and ensuring that
offenders were held liable for their actions. It was encour-
aging to see the industry come together as a community
to demand better quality for customers and, subsequently,
the end-patient population. However, with these demands
come pressures on suppliers and CMOs to meet these in-
creasing quality requirements while keeping costs reason-
able for customers.
PharmTech:
Do you see a new industry trend emerging?
Cottier:
As we continue to emerge from the economic downturn
of the past couple of years, our industry as a whole has
been forced to re-examine the way it does business. We
have seen an increased focus on supply-chain transparency
and quality. This problem has yet to be solved entirely,
and the industry as a whole needs to continue to address
it. Some companies offer increased transparency, but are
still searching for cost–effective solutions. Transparency
remains one of the major hurdles that the industry has yet
to overcome.
Beyond that, the industry has been looking toward
emerging markets and developing strategies to maximize
market potential and positioning. SAFC has maintained a
focus on identifying and participating in emerging markets
to ensure that we are well-positioned to serve them.
INDUSTRY PIPELINE
82 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
MANUFACTURING EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
INDUSTRY PIPELINE IN U T Y P E Y INDUSTRY PIPELINE
Visual-observation tool
The APK visual-observation tool is suitable for
random-sampling manual inspection. Users
can program spin speed according to liquid
viscosity or container diameter, thus provid-
ing repeatable rotation speed and duration
for inspected containers. The APK allows the
human eye to detect foreign particles easily.
Eisai Machinery USA, Allendale, NJ •
www.eisaiusa.com • tel. 201.746.2111
Aseptic disconnector
Sartorius offers a single-use device that al-
lows the aseptic disconnection of silicone
tubing in biopharmaceutical manufacturing
processes. Qualified by extensive validation
work, the device offers a rapid and secured
disconnection of single-use transfer lines and
bag assemblies in classified and nonclassified
environments, while maintaining product
sterility. Sartorius Stedim Biotech, Bohemia, NY •
tel. 800.368.7178 • www.sartorius-stedim.com
Capsule
filters
Meissner’s CS/
CL capsule fil-
ters for process-
ing applications
are available
with membrane media in polyvinylidene fluo-
ride. The filters also are available in microfiber
media of glass fiber and pure polypropylene,
and pure polypropylene depth-filter media.
Connection options include sanitary flange,
hosebarb, and male and female national pipe
thread fittings. The capsules can be used inde-
pendently or integrated into single-use biocon-
tainer and tubing assemblies. Meissner Filtration
Products, Camarillo, CA • www.meissner.com •
tel. 805.388.9911
Double planetary
mixers
Ross’s double planetary
mixers perform heavy-
duty mixing applica-
tions and can accom-
modate viscosities of
approximately 6 million
cP. Their vertical mixing design enables op-
erators to bypass shaft seals, bearings, pack-
ing glands, or stuffing boxes in the product
zone. In addition, the agitators are raised and
lowered into and out of the mix vessel by a
hydraulic lift, thus enabling easy access for
cleaning between batches. Ross, Charles & Son
Company, Hauppauge, NY • www.mixers.com •
tel. 800.243.ROSS
Industrial
vacuum
The Model 860/02
industrial vacuum
is designed to help
eliminate drum
handling and col-
lect and discharge
powders in a safe,
dust-free way. The
vacuum uses VAC-U-
MAX’s Air-Powered
Vacuum cover with
manual pulse-jet filter cleaning and nonstick
filtration that captures 99.9% of particles as
small as 0.5 µm. VAC-U-MAX, Belleville, NJ •
www.vac-u-max.com • tel. 973.759.4600
Powder-flow tester
Brookfield’s powder-
flow tester provides
efficient analysis of
powder-flow behavior.
The unit is suitable for
manufacturers who
process powders daily
and want to minimize
or eliminate the down-
time and expense that
occurs when hoppers
and silos fail to discharge. Customers can
perform quality-control checks on materials,
characterize new formulations, and match
established products. Brookfield Engineering
Laboratories, Middleboro, MA • www.brookfield-
engineering.com • tel. 800.628.8139
Tablet-
coating
platform
The Accela-
Cota FLEX 500
tablet-coating
platform fea-
tures seven
exchangeable
drums and
provides a batch-size range of 50–920 L.
Innovative gun positioning, a segmented
exhaust plenum, and interchangeable mix-
ing baffles configure the coater according
to the requirements of the batch size and
coating processes. Thomas Engineering,
Hoffman Estates, IL • www.thomaseng.com •
tel. 800.634.9910
Fluid-bed
dryer bags
Kavon pro-
vides custom
replacement
fluid-bed dryer
bags for US and
European equipment models. The bags are
appropriate for wet granulation, dry filtration,
and wet and dry coating applications. The
company offers flexible 1–4-bag systems in
various fabrics and also repairs bags.
Kavon Filter Products, Wall Township, NJ •
www.kavonfilter.com • tel. 732.938.3135
Turnkey vial line
Optima Group Pharma offers a turnkey
processing line for vials that comprises an
integrated freeze-drying system. Designed
to be flexible and operator-friendly, the
line processes liquids, freeze-dried phar-
maceuticals, and biopharmaceuticals.
Optima Group Pharma, Green Bay, WI •
www.optima-pharma.com •
tel. 920.339.2222
INDUSTRY PIPELINE
Pharmaceutical Technology JANUARY 2012 83
MANUFACTURING
EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
INDUSTRY PIPELINE IN D U ST R Y P I PELIN E Y INDUSTRY PIPELINE
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
Peristaltic
filling system
Flexicon’s high-
throughput
peristaltic filling
system operates
at a pace of 120
vials/min. The
system uses precision peristaltic technology
and Flexicon’s AsepticSU single-use fluid
path, thus ensuring purity and simplifying
validation. Its performance validation is
designed with a user-friendly computer inter-
face and integrated with 100% check weigh-
ing, reject stations, and automatic batch
reporting. Watson-Marlow Tubing, Wilmington,
MA • www.wmtubing.com • tel. 800.282.8823
Fluid-bed dryer
Federal Equipment offers
a Vector fluid-bed dryer–
granulator with a multipur-
pose Flo-Coater system. The
unit has 316 L stainless steel
product-contact surfaces, 20-
and 60-L spray-granulation
bowls with expansion chambers and guns, a
two-bar internal shock rating, a top blow-out
feature, an air-handling unit with filter, and a
15-hp blower. Other features include a dehu-
midification package, a dew-point monitor,
and programmable logic controls. Federal
Equipment, Cleveland, OH • www.fedequip.
com • tel. 216.271.3500
Tablet press
Fette Compact-
ing America’s
FE55 tablet press
is equipped to
handle 90%
of common
tablet formats.
The FE55 can
produce single-
and double-layer tablets and perform direct
pressing. The unit features punch stations
that allow for a 50% output increase. Fette
Compacting America, Rockaway, NJ • www.
fetteamerica.com • tel. 973.586.8722
Diaphragm
valves
Top Line’s Top-Flo
diaphragm valves
are designed to
provide efficiency
and reduce main-
tenance time
in high-purity
process-piping
applications. The diaphragms and tops fea-
ture an interchangeable functionality and are
compatible with related equipment made
by most manufacturers. Top Line Process Equip-
ment, Lewis Run, PA • www.toplineonline.com
• tel. 800.458.6095
Contract manufacturing services
Corden Pharma is a specialized contract
manufacturer that provides services, such
as custom API manufacturing, generic API
manufacturing, drug-product development
and manufacturing, generic dossier develop-
ment, formulation, packaging, and clinical-
supply services. Specialized technologies
include high-potency APIs and peptides, and
the company provides excipients, building
blocks, and generic-bulk APIs. Corden Pharma,
Cambridge, MA • www.cordenpharma.com •
tel. 617.401.2824
Cytotoxic contract
manufacturing
An eight-page brochure
describes Baxter’s cy-
totoxic manufacturing
facility in Halle, Germany.
It includes information
about cytotoxic contract
manufacturing using barrier-isolator technol-
ogy and services such as lyophilization,
liquid-vial filling, dry-powder filling, and
sterile crystallization. The facility manu-
factures for distribution markets, includ-
ing the United States, Europe, and Japan.
Baxter BioPharma Solutions, Round Lake, IL •
www.baxterbiopharmasolutions.com • tel.
800.422.9837
Contract
services
Patheon is a lead-
ing provider of
contract develop-
ment and manu-
facturing services
to the global
pharmaceutical industry. The company sup-
plies products and services to approximately
300 of the world’s leading pharmaceutical
and biotechnical companies. Patheon’s fully
integrated worldwide network helps ensure
that customer products can be launched
anywhere in the world. Patheon, Research
Triangle Park, NC • www.patheon.com •
tel. 905.821.4001
Contract services
Kemwell Biopharma
is a contract develop-
ment and manufactur-
ing organization with
locations in India and
Sweden and has a
portfolio of services that
includes formulation
development; analytical
services; and biopharmaceutical, clinical, and
commercial manufacturing. Kemwell’s chem-
istry, manufacturing, and controls services
range from Phase I to commercial manufac-
turing and include solids, liquids, semisolids,
biologics, and injectables. Kemwell Biopharma,
Bangalore, India • www.kemwellbiopharma.com
• tel. 919.397.3000
Pharmaceutical services
WellSpring Pharmaceutical is a full-service
provider of clinical and commercial manu-
facturing and packaging, blinding, method
development, analytical testing, and distribu-
tion services. Highly qualified managers and
technical professionals work at the compa-
ny’s 100,000-ft
2
facility to ensure that clients’
clinical and commercial products meet high
standards. WellSpring Pharmaceutical Canada,
Oakville, Canada • www.wpcoutsourcing.com •
tel. 866.337.4500
INDUSTRY PIPELINE
84 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
IN U T Y P E Y INDUSTRY PIPELINE
CLEANROOM EQUIPMENT & SUPPLIES
Outsourced
services
Pfizer CentreSource
provides solutions
for sterile manufac-
turing, high-con-
tainment manufac-
turing, and oral and
solid dosage forms.
Its capabilities draw
upon Pfizer’s global
network of facilities,
technologies, and expertise to fulfill a broad
range of sourcing and outsourcing require-
ments, regardless of dosage form, batch size,
or the complexity of the process. Pfizer
CentreSource (PCS), Kalamazoo, MI • www.
pfizercentresource.com • tel. 269.833.5844
Size reduction
Micron Technologies provides contract
particle-size reduction and analytical services
for the pharmaceutical industry. The company
offers micronization and mechanical milling
in isolated processing suites. Its analytical
laboratory provides material-characterization
testing, including particle size and Karl Fischer
moisture analysis. Additional services include
method development and validation and re-
lease and stability testing. Micron Technologies,
Exton, PA • www.microntech.com •
tel. 610.425.5100
Job-focused
training
PDA’s Training
and Research
Institute pro-
vides intensive,
job-focused
training that clients can apply immediately.
The curriculum is designed to foster profes-
sional development in areas such as aseptic
processing, biotechnology, environmental
monitoring, filtration, microbiology, quality,
regulatory affairs, training, and validation.
Courses can be customized and provided at
the client’s location. Parenteral Drug
Association, Bethesda, MD • www.pda.org •
tel. 301.656.5900
High-potency
micronization
Powdersize has
added the capabil-
ity to micronize
high-potency ac-
tive pharmaceutical
ingredients to con-
tainment levels of 10 ng/m
3
. The company’s
2- and 4-in. jet mills can scale to a 10-in. jet
mill. Gram and kilogram quantities as high
as 100 kg thus can be micronized. Powdersize,
Quakertown, PA • www.powdersize.com •
tel. 215.536.5605
Chemistry outsourcing
Cambridge Major Laboratories is a global,
service-based chemistry-outsourcing partner
to the pharmaceutical and biotechnology
industries. The company provides develop-
ment and large-scale manufacturing services
for active ingredients. A facility in the US
complies with good manufacturing practice,
and the company also maintains facilities
in Europe. Cambridge Major Laboratories,
Germantown, WI • www.c-mlabs.com • tel.
262.251.5044
Contract services
Metrics is a respected contract pharmaceuti-
cal research, formulation, development, and
manufacturing company. Offering first-in-
man (FTIM) development and Phase I–III
clinical-trial materials (CTM), Metrics has
conducted more than 120 FTIM studies for
various chemical entities in the past five years
while producing more than 700 batches of
CTM. Metrics, Greenville, NC • www.metricsinc.
com • tel. 252.752.3800
Contract
services
Lonza provides
services to the
pharmaceutical,
healthcare, and
life-sciences
industries. Lonza Custom Manufacturing’s
development and manufacturing services
portfolio is designed to assist large and
emerging biotechnology and pharmaceutical
companies in improving and advancing their
products. Lonza, Basel • www.lonza.com • tel.
+41 61 316 81 11
Sterile wipes
Veltek offers sodium-hypochlorite and
hydrogen-peroxide wipes that are Class 10
laundered, filtered at 0.2 µm, and formulated
with US Pharmacopeia water for injection.
The products have laser-cut edges and are
guaranteed to be sterile with lot-specific
documentation. Veltek, Malvern, PA •
www.sterile.com • tel. 610.644.8335
Packaging
films and anti-
counterfeiting
services
Bilcare Research
offers packaging
films such as poly-
vinyl chloride (PVC)–Mono, –PVDC, –Aclar, –
AquaBa, and cold-form foil, as well as lidding
foil-standard push-through aluminum foils,
paperback child-resistant foils, and environ-
mentally friendly lid foil Nova. Bilcare also
offers formulation analysis, anticounterfeit-
ing, and branding services, including Bilcare
Protect. Bilcare Research, Delaware City, DE •
www.bilcaresolutions.com • tel. 302.838.4000
INDUSTRY PIPELINE
Pharmaceutical Technology JANUARY 2012 85
IN D U ST R Y P I PELIN E Y INDUSTRY PIPELINE
PACKAGING EQUIPMENT & SUPPLIES
LABORATORY EQUIPMENT & SUPPLIES
LABORATORY EQUIPMENT & SUPPLIES
LABORATORY EQUIPMENT & SUPPLIES
CHEMICALS, RAW MATERIALS,
INTERMEDIATES, & EXCIPIENTS
INFORMATION TECHNOLOGY
Transfer
packaging for
prefillable syringes
BD TSCF packaging
ensures the secure
transfer of sterile prefill-
able syringe components into the pharma-
ceutical filling environment. The packaging
is compatible with IDC Biosafe doors for
aseptic filling machines within isolator or bar-
rier systems. This packaging is part of the BD
SCF global offer, which features expertise in
sterile processing of preservative-free drugs;
secure, reliable, easy-to-use systems; and
drug master files and technical dossiers.
BD Medical–Pharmaceutical Systems,
Franklin Lakes, NJ • www.bdpharma.com •
tel. 800.225.3310
Packaging
solution
The NextBottle
package from
Catalent and
One World De-
sign and Manu-
facturing Group
is designed to
improve patient compliance. The product’s
dial mechanism dispenses one pill at a time
and automatically reminds patients of the
last day that a pill was taken. Catalent Pharma
Solutions, Somerset, NJ • www.catalent.com •
tel. 866.720.3148
Laboratory blenders
MaxiBlend and MiniBlend laboratory blend-
ers are available in sizes from 0.5 to 16 qt. The
units are made of 316-L stainless steel and
supplied with V-shells, bins, or double cones.
The units feature a tabletop design and
include programmable logic controls and
safety-interlocked guards. GlobePharma, New
Brunswick, NJ • www.globepharma.com •
tel. 732.819.0381
Analytical
technologies
Waters Regulated
Bioanalysis
System Solution
is intended to
offer the best-
in-class analytical technologies that enable
robust assays with high sensitivity. The
solution addresses regulatory compliance,
helps maintain high productivity, and helps
reduce costs per sample. Waters Regulated
Bioanalysis System Solution is intended to
assist clients during the drug-development
process. Waters, Milford, MA • www.waters.
com • tel. 508.478.2000
Bioprocessing
analyzer
Sartorius Stedium
Biotech’s BioPAT-
Trace is a dual-
channel analyzer
for the measurement of glucose and lactate
designed for cell culture and disposable
bioprocessing. The device’s sterile sampling
systems are based on filtration, dialysis, or
ContiTRACE, and disposable probes facilitate
online sampling in bioreactors and biodis-
posables that are applied in industrial and
laboratory facilities. Sartorius Stedim Biotech,
Bohemia, NY • www.sartorius-stedim.com •
tel. 800.368.7178
On-line TOC analysis
To help pharmaceutical companies improve
quality and reduce costs, GE Analytical In-
struments offers a science- and risk-based
program for achieving real-time release of
pharmaceutical water. The program stream-
lines a complex process and helps companies
move total organic carbon testing from the
laboratory to the production floor in approxi-
mately six months. GE Analytical Instruments,
Boulder, CO • www.geinstruments.com •
tel. 800.255.6964
Metal-detection systems
CEIA’s THS/PH21N metal-detection systems
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Zach Hughes
t
he United States Supreme Court’s re-
cent decision in Pliva v. Mensing was
a watershed moment in the world
of pharmaceutical products liability (1).
In short, the majority in Mensing held
that state tort law claims for inadequate
warnings against manufacturers of ge-
neric prescription drugs are preempted
by the provisions of the Food, Drug,
and Cosmetic Act (FD&C Act), which
require the product safety informa-
tion for generic drugs to be identical to
their branded equivalents. The primary
distinction between Mensing and the
Court’s prior opinion in Wyeth v. Levine,
which came to the opposite conclusion
on the preemption question for branded
drugs, is the branded manufacturers’
ability to change the safety information
for its products through the changes
being effected (CBE) provisions of the
Act (2).
The significance of this decision for
drug manufacturers and potential plain-
tiffs is difficult to overemphasize because
of the ever-expanding use of generic
drugs in the United States. As the dissent
in Mensing noted, generic drugs consti-
tuted 75% of all dispensed prescription
drugs in the US in 2009. That number
is expected to grow as the cost savings
provided by generic drugs continue to
mount.
the history of generic-drug benefits
Congress essential ly created t he
mode r n ge ne r i c- dr ug i ndus -
try in 1984 with the passage of the
Hatch–Waxman Amendments to
the FD&C Act. The goals of Hatch–
Waxman were to make drugs less expen-
sive, while maintaining safety standards
and incentives for new drug innovation.
They achieved those goals by provid-
ing extended patent protection for new
drugs hitting the market, while at the
same time reducing the regulatory bur-
dens on generic-drug manufacturers,
thereby allowing them to provide com-
parable drugs at greatly reduced costs to
consumers once a branded drug’s patent
protection expired.
In 1984, supporters of Hatch–Waxman
predicted that the new amendments
“would save American consumers $920
million over the next 12 years” (3). But
recent studies have shown that Hatch–
Waxman saved the American healthcare
system more than $824 billion during
the decade 2000–2009, including $139.6
billion in 2009 alone, meaning that the
originally projected 12-year savings of
$920 million are now being achieved
every three days (4).
Although these cost savings are un-
questionably beneficial for everyone
paying for prescription drugs—most no-
tably the US government, which spends
hundreds of millions of dollars each
year on prescription drugs for Medicare
and Medicaid patients—the majority in
Mensing took note of the now recognized
tradeoff for consumers in the Hatch–
Waxman regulatory scheme. That is to
say that, post-Mensing, an allegedly in-
jured plaintiff’s ability to bring state law
tort claims is based solely on whether the
drug taken was a generic or its branded
equivalent.
“We recognize that from the per-
spective of Mensing and Demahy,
finding pre-emption here but
not in Wyeth makes little sense.
Had Mensing and Demahy taken
Reglan, the brand-name drug pre-
scribed by their doctors, Wyeth
would control and their lawsuits
would not be pre-empted. But be-
cause pharmacists, acting in full
accord with state law, substituted
generic metoclopramide instead,
federal law pre-empts these law-
suits. We acknowledge the unfortu-
nate hand that federal drug regula-
tion has dealt Mensing, Demahy,
and others similarly situated” (5).
The dissent put it even more starkly:
“Today’s decision introduces a
critical distinction between brand-
name drugs and generic drugs. Con-
sumers of brand-name drugs can
sue manufacturers for inadequate
warnings; consumers of generic
drugs cannot” (6).
Although plaintiffs are attempting
to assert novel and/or nuanced theories
against generic-drug manufacturers to
side-step Mensing, it is difficult to imag-
ine many, if any, of these cases surviving
summary judgment, much less appellate
scrutiny. Thus, while some plaintiffs are
attempting to plead their way around
Recent legal decisions have further divided
generic and brand manufacturer cases.
innovator Liability Still not
Viable After Pliva v. Mensing
Zach Hughes is a partner at Baker Botts,
zach.hughes@bakerbotts.com
Your opinion matters.
To contribute to this column,
send your proposal to
adrakulich@advanstar.com.
Viewpoint
Pharmaceutical Technology JANUARY 2012 89
Mensing’s pre-emption of claims against
generic-drug manufacturers, others are
refocusing on the branded manufactur-
ers by attempting to establish liability
for inadequate warnings against the
branded manufacturers, even when the
plaintiff ingested only the generic drug.
Current innovator liability
This so-called “innovator liability”
theory is not new. In fact, it pre-dates
Mensing by at least 17 years, with the
most often cited case being a decision
from the US Court of Appeals for the
Fourth Circuit in Foster v. American
Home Products Corporation (7). In-
terpreting Maryland law, the Fourth
Circuit rejected the idea of liability for
the branded drug manufacturers when
the plaintiff ingested only the generic
equivalent, regardless of whether the
cause of action asserted was a traditional
products liability claim (i.e., strict liabil-
ity, breach of warranty, negligence) or a
claim for negligent misrepresentation.
The Court first noted that traditional
products liability claims are not viable
against defendants who did not manu-
facture the product in question. The
Court then questioned whether the cause
of action for negligent misrepresentation
was simply “an effort to recover for inju-
ries caused by a product without meet-
ing the requirements the law imposes in
products liability actions, which limits li-
ability to defendants who manufactured
the product at issue” (8).
Nonetheless, the Fourth Circuit as-
sumed the theoretical viability of a neg-
ligent misrepresentation cause of action
in a products liability case and went
on to analyze the existence of a duty of
branded manufacturers to consumers
who ingest only the generic equivalents
of their drugs. The question turned to
whether it was foreseeable to the branded
manufacturer that alleged misrepresen-
tations regarding its drug would result in
injury to users of the generic equivalent.
In the most often quoted line of the case,
the Foster Court held, “We think to im-
pose a duty in the circumstances of this
case would be to stretch the concept of
foreseeability too far” (9).
During the next 14 years, courts inter-
preting the laws of at least 10 other states,
approved of Foster’s reasoning and re-
jected the innovator liability theory. But
in 2008, a California intermediate state
appellate court case called Conte v. Wyeth
went against the grain (10). In Conte, the
Court acknowledged Foster but reached
the opposite conclusion when it held that
under California law, the branded manu-
facturer of Reglan owed a common law
duty to consumers who never ingested
their product, but rather ingested only
the generic equivalent, because it was
foreseeable that doctors and patients
would rely on the safety information
provided by the branded manufacturer.
In the past three years, a single fed-
eral court interpreting Vermont law is
the only court outside of California that
has followed Conte and disagreed with
Foster. During this same period of time,
numerous courts interpreting the laws of
at least 20 states have continued to follow
the majority rule by explicitly approving
Foster and/or rejecting Conte.
Despite this overwhelming majority
rule, plaintiffs will undoubtedly argue
that Mensing changes the analysis and
requires that someone (i.e., the branded
manufacturers) must be held accountable
for injuries to a consumer injured by a
generic drug with allegedly inadequate
warnings. Indeed, several of the cases fol-
lowing the majority rule, including Fos-
ter, state the (now known to be mistaken)
belief that the generic-drug manufactur-
ers are liable for such injuries. But while
that belief may have given some courts
comfort in the equities of dismissing
the claims against the branded manu-
facturers, courts following the majority
rule before and after Mensing have recog-
nized that generic manufacturer liability
is not a prerequisite for rejecting innova-
tor liability. In fact, in 2004, seven years
before Mensing, the Eastern District of
Pennsylvania correctly predicted the out-
come of Mensing’s pre-emption conclu-
sion, yet still followed the majority rule
rejecting innovator liability.
“Accordingly, we f ind that
state tort law which would hold a
generic drug manufacturer liable
for failing to modify a label when,
pursuant to the Hatch–Waxman
Amendments to the FDCA [FD&C
Act], the ANDA approval process re-
quired that the labeling be the same
as that approved for the innovator
drug, and when the FDA would
have deemed any post-approval
enhancements ‘ false and mislead-
ing,’ would actually conflict with the
FDCA. For these reasons, as well as
our conclusion that we must af-
ford deference to the FDA’s position
that the claims are pre-empted, we
find that Plaintiff ’s failure-to-warn
claims are impliedly preempted.
“Thus, this Court holds that
under Pennsylvania law, there is no
duty of care owed by a brand-name
prescription drug manufacturer to
a plaintiff allegedly injured by a
generic equivalent drug manufac-
tured by another company. Thus,
even if this Court’s conclusion re-
garding pre-emption were found to
be improper, the claims against [the
branded manufacturer] Defendant
GSK must still be dismissed” (11).
Moreover, post-Mensing, there are no
published cases questioning the validity
of the majority rule rejecting innovator
liability, and at least three courts have
continued to follow the majority rule
despite arguments from plaintiffs that
Mensing should change the analysis.
In Smith v. Wyeth, the Sixth Circuit
affirmed the dismissal of claims against
both the generic-drug manufacturer
(based on Mensing) and the branded
manufacturer (based on the majority rule
from Foster and its progeny) by plaintiffs
who alleged injuries as a result of taking
generic metoclopramide, thereby leaving
the plaintiffs with no remedy (12). The
federal District Courts of Maryland and
the Western District of Louisiana have
reached the same conclusion.
“[T]he Supreme Court’s opin-
ion in Mensing in fact gave this
Court no reason to reconsider its
entry of final judgment in favor of
[the branded manufacturer] De-
fendants.... The Supreme Court’s
holding in Mensing neither cre-
ated nor abrogated any duty under
Maryland law with regard to brand
name manufacturers like Defen-
dants” (13).
90 Pharmaceutical Technology JANUARY 2012 Phar mTech. com
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end result for the market
Mensing’s pre-emption conclusion is
completely irrelevant to the legal ten-
ability of the innovator liability theory.
The fact that one group of potential de-
fendants is absolved of liability based on
pre-emption does not mean that liabil-
ity necessarily falls to another group. In
fact, as stated above, both the majority
and dissenting opinions in Mensing rec-
ognized that the net result of the deci-
sion on consumers of generic drugs was
that they were now without a remedy for
any claim of inadequate warnings, not
that the improper defendants had been
identified.
While this result may be unsatisfying
to some, that is the legally correct by-
product of Mensing. Compared to judi-
cially created innovator liability, the case
also makes sound policy. Altering the
long-held majority rule would be a knee-
jerk reaction to a perceived unfairness
without any basis in the law. As those
types of decisions often do, it would
likely result in a variety of unintended
and harmful consequences that would
throw off the balance created by Hatch–
Waxman and threaten the objectives that
underlie it. Branded companies would
likely pull their drugs from the market
once the patent had expired to reduce
potential liability. This would result in
less choice, less competition, and higher
prices. Alternatively, branded companies
could keep their products on the market,
but at even higher prices for both their
patented drugs and their drugs with ge-
neric competitors to compensate for the
potential liability.
If Congress decides that Hatch–
Waxman’s tradeoff of drug access and af-
fordability in exchange for the generic-
drug manufacturers’ immunity from
state law failure to warn claims is unten-
able, then Congress can act to redress the
situation. “But it is not Court’s task to
decide whether the statutory scheme es-
tablished by Congress is unusual or even
bizarre” (14). It is also not the job of the
state or federal courts interpreting state
tort law to torture the well-established
statutory and common law schemes to
rectify any perceived inequitable result.
References
1. 131 S.Ct. 2567 (2011).
2. 129 S.Ct. 1187 (2009).
3. Statement of Rep. Douglas Walgren, 130
Cong. Rec. H24456 (Sept. 6, 1984).
4. IMS Health, “Generic Medicines Saved US
Health Care System $139.6 Billion in 2009;
$824 Billion Saved over the Last Decade”
(July 2010).
5. Mensing, 131 S.Ct. at 2581.
6. Id. at 2593. (J. Sotomayor, dissenting).
7. 29 F.3d 165 (4th Cir., 1994)
8. Id.
9. Id. at 171.
10. 168 Cal.App.4th 89 (Cal. Ct. App., 2008).
11. Colacicco v. Apotex, 432 F.Supp.2d. 514,
537–538, 543 (E.D. Pa. 2006).
12. F. 3d, 2011 WL 4389211 (C.A.6 (Ky.), Sept.
22, 2011.
13. Gross v. Pfizer, Civ. A. No. 10-cv-00110-AW,
2011 WL 4005266, *2 (D.Md.), Sept. 7, 2011;
see also Morris v. Wyeth, Civ. A. No. 3:09-
CV-854, 2011 WL 4975317, *2 (W.D. La.),
Oct. 19, 2011.
14. Mensing, 131 S.Ct. at 2582. PT
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