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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–DrugConjugates
Looking ahead to an emerging class
of biotherapeutic
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pharmtech .com
On
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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?
agenT-in-Place
16 All Systems SlowControl, 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 2012Hallie ForcinioPackaging 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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12 Pharmaceutical Technology JANUARY 2012 PharmTech .com
FROM THE EDITOR
JO
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PharmTech.com/forum
It 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
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 PharmTech .com
PharmTech Talk
AU
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cutting Prices to Save SalesErik Greb
Erik Greb is an associate
editor of Pharmaceutical
Technology.
»Read Erik’s blogs at
blog.PharmTech.com.
as 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 PharmTech .com
Agent-in-PlAce
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Agent-in-PlAce
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PharmTech.com/aipCautionary 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 location 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
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
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18 Pharmaceutical Technology MONTH 2012 PharmTech .com
In the Field
18 Pharmaceutical Technology JANUARY 2012 PharmTech .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 PharmTech .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-flow 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 [email protected].
Ü Join the PharmTech dialogue on LinkedIn:
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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 GroundBrazil’s Development Bank Leader
Discusses the Country’s Pharma FutureAngie Drakulich
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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 PharmTech .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 2012FDA 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
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26 Pharmaceutical Technology JANUARY 2012 PharmTech .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,
IN THE SPOTLIGHT: MANUFACTURING
Rotary airlock valves for regulatory complianceACS 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 capabilitiesMG 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 applicationsEMD 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 PharmaceuticalScience & 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.
North America email:[email protected] www.croda.com/healthcare
Europe, Middle East & Africa email:[email protected] www.croda.com/healthcare
Latin America email:[email protected] www.croda.com/healthcare
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n Optimizes API Stability
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Election-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,
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
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continuous quality
improvement
strategies.
In Washington this month
• Congress considers adding
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• Industry seeks new ways
to fill pipeline as blockbuster
patents expire.
• FDA initiatives aim
to boost R&D process.
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30 Pharmaceutical Technology JANUARY 2012 PharmTech .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 suppliesThe 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 pipelineThe 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 PharmTech .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
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36 Pharmaceutical Technology January 2012 PharmTech .com
Bio Forum
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Echoing 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 stageEarly-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
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38 Pharmaceutical Technology January 2012 PharmTech .com
PACKAGING FORUM
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Anew 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).
AutomationServo 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 traceabilityWith 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 measuresAlthough 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
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Innovations for 2012Hallie Forcinio
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mple to use
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rommelag Kunststoff-MaschinenVertriebsgesellschaft mbHP.O. Box 1611 · D-71306 Waiblingen, Germany
Phone: +49 7151 95811-0 · Fax: +49 7151 15526
E-mail: [email protected]
rommelag USA, Inc.27903 Meadow Drive, Suite 9
P.O. Box 2530 · Evergreen, CO 80437, USA
Phone: +1.303.674.8333 · Fax: +1.303.670.2666
E-mail: [email protected]
rommelag Trading (Shanghai) Co., Ltd. Room 1501 Xinyin Building
No. 888 Yishan Road · 200233 Shanghai, P.R.China
Phone: +86 21 6432 0166 · Fax: +86 21 6432 0266
E-mail: [email protected]
rommelag agP.O. Box · CH-5033 Buchs, Switzerland
Phone: +41 62 834 55 55 · Fax: +41 62 834 55 00
E-mail: [email protected]
www.rommelag .com
BLOW-FILL-SEAL TECHNOLOGY
40 Pharmaceutical Technology January 2012 PharmTech .com
Packaging Forum
rier materials (Traceless AD inkjet ink and reader, Eastman Kodak).
Blister innovationsA 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 labelsWhen 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 practicesThe 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 syringesPrefilled 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.
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Pharmaceutical Technology January 2012 41
Packaging Forum
Single-use product-contact partsAttendees 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-cm3 peristaltic pumps as well as a rolling diaphragm pump (PreVAS Single-use Dosing System, Robert Bosch Packaging Technology).
Stick packsThe 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 f lexible 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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In 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 workAdcetris 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 antibodyIn 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 ConjugatesLooking Ahead to an Emerging Class of Biotherapeutic
Amy Ritter
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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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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 moleculeThe 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 linkerDeveloping 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 limited 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 PharmTech .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 togetherProducing 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/m3 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.
References1. 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
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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 improvementAs ADCs advance in the clinical 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 Ala114 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.
While the THIOMAB uses the 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 aheadThe 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 PharmTech .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 TechnologyModerated 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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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 n u 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.Kir sc h (Natoli):
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 PharmTech .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 serendipityResearchers 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- IM
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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,
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 chemistryInducing 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 chirality in gold nanoclusters by NMR spectroscopic probing of the surface ligands. The Au
38(SR)
24 and
Au25
(SR)18
(where, R = CH2CH
2Ph)
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 PharmTech .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 nanotechnologyInterdisciplinary 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,
*To whom all correspondence should be addressed.
Submitted: Oct. 31, 2011. Accepted: Dec. 1, 2011.
Formulation Development
The 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 PharmTech .com
Formulation Development
formulations containing various concentrations of sticky powders in tablet formulations.
MaterialsIbuprofen (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).
MethodsA 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.
ResultsEffect 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)
Po
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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.
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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.
Po
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(μ
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Number of compressions
0
500
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1500
2000
0 250 500 750 1000
50%
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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
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(μ
g)
0
50
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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
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62 Pharmaceutical Technology JANUARY 2012 PharmTech .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.
ConclusionThe 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).
AcknowledgmentsThe 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 Scientists—Northeast 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 [email protected] 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
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(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
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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, [email protected].
FDA Perspectives
The 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 TimeBarbara Scott
64 Pharmaceutical Technology JANUARY 2012 PharmTech .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 synthesisThe 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 PharmTech .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 materialsFor 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 materialsStarting 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
DisclaimerThe 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.
AcknowledgmentsThe author thanks Naiqi Ya, Dave Skanchy, Bob Iser, and Aloka Srinivasan for their scientific input.
Pharmaceutical Technology JANUARY 2012 67
PharmTech.com/usp
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Global Harmonization Presents Opportunities and ChallengesAnthony DeStefano and Kevin Moore
To keep moving forward, the Pharmacopoeial
Discussion Group needs industry participation.
More 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 goalsPDG 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.
BenefitsThe 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 processHarmonization 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 PharmTech .com
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the 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 incentivesPrivate-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 winsThe 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,
www.pharmsource.com.
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outsourcing outlook
risky propositionsBuyouts 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. 67local style. Individual pharmacopeias can also take into consideration local reference standards and reagents.
challenges and industry participationWhile 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 workPDG’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
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
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
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 [email protected].
CEIA USA
9155 Dutton Dr.
Twinsburg, OH 44087
tel. 888.532.CEIA (2342)
fax 330.405.3196
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
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 PharmTech .com
Advertiser profiles
Croda Inc
300-A Columbus Circle
Edison, NJ 08837
tel. 732.417.0800
fax 732.417.0804
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
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
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
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 PharmTech .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
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
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
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
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
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 PharmTech .com
Advertiser profiles
Micron Technologies333 Phoenixville Pike
Malvern, PA 19355
tel. 610.251.7400
fax 610.251.7499
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 GmbHOtto-Hahn Strasse 1
74523 Schwaebisch Hall
Germany
tel. +49 791 9495-0
fax +49 791 9495-2610
Optima Machinery CorporationP.O. Box 28173
1330 Contract Drive
Green Bay, WI 54304
Telephone: +1.920.339.2222
Telefax: +1.920.339.2233
E-Mail: [email protected]
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
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
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/m3 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
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 ft2. 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
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/Fil 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 PharmTech .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
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
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
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
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
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 PharmTech .com
Advertiser profiles
Pharmaceutical Technology JANUARY 2012 81
Q&A with
PHARMA CAPSULES
Catalent to Increase Biologic Development and Manufacturing CapabilitiesCatalent 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 CollaborationImmunoGen 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 HeadquartersMerck & 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 m2 (505,904 ft2) 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 FacilityEisai’s research subsidiary,
H3 Biomedicine, has opened
its new 24,000-ft2 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
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MANUFACTURING EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
INDUSTRY PIPELINEIN U T Y P EY INDUSTRY PIPELINE
Visual-observation toolThe 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 disconnectorSartorius 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
filtersMeissner’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
mixersRoss’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
vacuumThe 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 testerBrookfield’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
platformThe 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 PIPELINEINDU STR Y PIPELIN EY INDUSTRY PIPELINE
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
Peristaltic
filling systemFlexicon’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 dryerFederal 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 pressFette 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
valvesTop 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 servicesCorden 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
manufacturingAn 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
servicesPatheon 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 servicesKemwell 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 servicesWellSpring 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-ft2 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 PharmTech .com
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
IN U T Y P EY INDUSTRY PIPELINE
CLEANROOM EQUIPMENT & SUPPLIES
Outsourced
servicesPfizer 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 reductionMicron 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
trainingPDA’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
micronizationPowdersize has
added the capabil-
ity to micronize
high-potency ac-
tive pharmaceutical
ingredients to con-
tainment levels of 10 ng/m3. 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 outsourcingCambridge 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 servicesMetrics 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
servicesLonza 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 wipesVeltek 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
servicesBilcare 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
INDU STR Y PIPELIN EY 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 syringesBD 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
technologiesWaters 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
analyzerSartorius 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 analysisTo 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 systemsCEIA’s THS/PH21N metal-detection systems
feature high detection sensitivity for con-
taminating ferrous, nonferrous, and stainless-
steel metals, even when the metals are pres-
ent in small quantities. When contamination
is detected, the system rejects the identified
material. The system’s failsafe operation
monitors the opening and closing of the ejec-
tion flap through a redundant conformation
sensor. CEIA USA, Twinsburg, OH • www.
ceia-usa.com • tel. 888.532.CEIA
High-purity
inorganic
saltsJost Chemical
has manufac-
tured high-
purity inorganic
salts for 25 years.
Jost’s FDA-registered site in St. Louis, Mis-
souri, includes 190,000 ft2 and operates under
current good manufacturing practice for bulk
pharmaceuticals. Jost is a global supplier of
chemical salts that meet compendial require-
ments, and the company tests its products in
house. Jost Chemical, St. Louis, MO • www.
jostchemical.com • tel. 314.428.4300
Compliance
softwareEtQ’s FDA Compli-
ance Management
software is an
integrated quality-
and compliance-
management
system designed to
maintain compli-
ance to various regulatory requirements and
adapt to business processes. EtQ’s modules
are tightly integrated to deliver a high-quality
FDA-compliance solution and include Med-
Watch Plus, Complaint Handling, Corrective
And Preventive Action, Document Control,
and Change Management. EtQ, Farmingdale,
NY • www.etq.com • tel. 800.354.4476
PharmTech .com
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86 Pharmaceutical Technology JANUARY 2012 PharmTech .com
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Viewpoint
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Zach Hughes
the 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 benefitsCongress essentia l ly created the m o d e r n g e n e r i c - d r u g i n d u s -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,
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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 liabilityThis 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 find 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 PharmTech .com
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end result for the marketMensing’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
Aptuit ................................................... 22-23
BASF Corporation ....................................... 53
Bilcare Research ........................................ 31
Cambridge Major Labs ............................... 10
Catalent pharma Solutions ........................92
CeiA ...........................................................29
Croda inc ...................................................27
DCAt .......................................................... 61
Dpt Laboratories .......................................69
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etQ inc ....................................................... 19
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Jubilant Hollister Stier ...............................9
Kemwell Biopharm .................................... 51
Lonza inc ................................................... 21
Meissner Filtration products ........................2
Metrics inc ................................................. 15
Micron technologies inc .............................65
optiMA Machinery Corporation .................25
patheon inc ................................................3
pDA ........................................................7, 91
pfizer Centresource ................................... 17
pharmaceutical technology ..................37, 45
powdersize inc ...........................................50
pyramid Laboratories ................................ 33
rommelag USA inc......................................39
Ross, Charles & Son Company ..................... 11
Sartorius Stedim north America inc ...........43
Sparta Systems inc ..................................... 14
Spectrum Chemical Mfg Corp ..................... 41
Suheung Capsule .........................................6
Vac U Max ..................................................34
Veltek Associates .........................................5
watson-Marlow tubing ................................6
wellspring pharmaceutical ........................ 35
April 16-18, 2012JW MARRIOTT DESERT RIDGE RESORT • PHOENIX, ARIZONA
The 2012 PDA Annual Meeting is the meeting place this April. The distinguished Program Planning Committee,
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• Post-Conference Workshop: PDA Single Use Systems Workshop on April 18-19
• PDA’s Training and Research Institute (PDA TRI)
will be offering eight courses on April 19-20
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